U.S. patent application number 15/589303 was filed with the patent office on 2017-10-26 for tri-aryl compounds and compositions comprising the same.
The applicant listed for this patent is BEN-GURION UNIVERSITY OF THE NEGEV RESEARCH AND DEVELOPMENT AUTHORITY. Invention is credited to Aviv GAZIT, Esther PRIEL, Shimon SLAVIN, Sara YITZCHAK.
Application Number | 20170305836 15/589303 |
Document ID | / |
Family ID | 40094272 |
Filed Date | 2017-10-26 |
United States Patent
Application |
20170305836 |
Kind Code |
A1 |
PRIEL; Esther ; et
al. |
October 26, 2017 |
TRI-ARYL COMPOUNDS AND COMPOSITIONS COMPRISING THE SAME
Abstract
The present invention relates to a novel class of tri-aryl
compounds, compositions comprising the same and processes for the
preparation thereof.
Inventors: |
PRIEL; Esther; (Beer Sheva,
IL) ; GAZIT; Aviv; (Jerusalem, IL) ; SLAVIN;
Shimon; (Jerusalem, IL) ; YITZCHAK; Sara;
(Tiberias, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BEN-GURION UNIVERSITY OF THE NEGEV RESEARCH AND DEVELOPMENT
AUTHORITY |
BEER SHEVA |
|
IL |
|
|
Family ID: |
40094272 |
Appl. No.: |
15/589303 |
Filed: |
May 8, 2017 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14070073 |
Nov 1, 2013 |
9663448 |
|
|
15589303 |
|
|
|
|
12602632 |
Jun 17, 2010 |
8604245 |
|
|
PCT/IL2008/000747 |
Jun 3, 2008 |
|
|
|
14070073 |
|
|
|
|
60924875 |
Jun 4, 2007 |
|
|
|
60929524 |
Jul 2, 2007 |
|
|
|
60929525 |
Jul 2, 2007 |
|
|
|
61006924 |
Feb 6, 2008 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/136 20130101;
A61P 7/06 20180101; C07D 213/30 20130101; C07C 215/50 20130101;
A61P 25/00 20180101; A61P 21/00 20180101; A61P 31/00 20180101; A61K
31/03 20130101; A61P 37/00 20180101; A61K 31/695 20130101; A61K
31/05 20130101; A61P 35/00 20180101; A61P 3/10 20180101; A61P 37/02
20180101; A61P 19/10 20180101; A61P 27/02 20180101; C07D 213/16
20130101; C07C 39/367 20130101; A61K 31/66 20130101; A61P 9/00
20180101; C07C 215/80 20130101; A61P 17/14 20180101; A61P 25/28
20180101; C07D 295/135 20130101; A61P 19/08 20180101; C07C 43/225
20130101; A61P 39/00 20180101; A61P 19/02 20180101; A61P 9/14
20180101; A61P 43/00 20180101; A61P 17/02 20180101; A61P 19/00
20180101; C07D 295/096 20130101; C07C 43/23 20130101; A61K 31/055
20130101; A61P 15/08 20180101; A61P 15/00 20180101; C07F 9/5022
20130101; A61P 17/00 20180101; A61P 29/00 20180101 |
International
Class: |
C07C 215/80 20060101
C07C215/80; A61K 31/03 20060101 A61K031/03; C07D 295/096 20060101
C07D295/096; C07D 213/30 20060101 C07D213/30; C07D 213/16 20060101
C07D213/16; C07C 215/50 20060101 C07C215/50; C07C 43/23 20060101
C07C043/23; C07C 43/225 20060101 C07C043/225; C07C 39/367 20060101
C07C039/367; A61K 31/695 20060101 A61K031/695; A61K 31/66 20060101
A61K031/66; A61K 31/136 20060101 A61K031/136; A61K 31/055 20060101
A61K031/055; A61K 31/05 20060101 A61K031/05; C07D 295/135 20060101
C07D295/135; C07F 9/50 20060101 C07F009/50 |
Claims
1.-50. (canceled)
51. A compound represented by the structure of Formula XIIIA or its
isomer, salt, hydrate, N-oxide, crystal or any combination thereof:
##STR00036## wherein X is carbon or nitrogen; R.sub.1 is nothing,
C.sub.1-6alkoxy, OCH2COOAlkyl, or halogen; R.sub.2 and R.sub.3 are
independently hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy, hydroxyl,
or OCH2COOAlkyl; R.sub.4 and R.sub.5 are hydrogen or form together
a saturated or unsaturated 5-7 carbocyclic ring; and R.sub.6 is
C.sub.1-6alkyl, hydroxyl, or halogen.
52. The compound of claim 51, wherein X is carbon, R.sub.1 is
halogen, R.sub.2 and R.sub.3 are independently hydrogen, methyl,
C.sub.1-6alkyl, C.sub.1-6alkoxy or hydroxyl, R.sub.4 and R.sub.5
are hydrogen or form together a saturated or unsaturated 5-7
carbocyclic ring, and R.sub.6 is methyl, hydroxyl or halogen.
53. The compound of claim 51, wherein X is nitrogen, R.sub.1 is
nothing, R.sub.2 and R.sub.3 are independently hydrogen, methyl,
C.sub.1-6alkyl, C.sub.1-6alkoxy or hydroxyl, R.sub.4 and R.sub.5
are hydrogen, and R.sub.6 is methyl, hydroxyl or halogen.
54. The compound of claim 51, wherein the compound is selected from
the group consisting of: ##STR00037## ##STR00038##
55. The compound of claim 52, wherein the compound is
##STR00039##
56. The compound of claim 52, wherein the compound is
##STR00040##
57. The compound of claim 52, wherein the compound is
##STR00041##
58. The compound of claim 52, wherein the compound is
##STR00042##
59. The compound of claim 52, wherein the compound is
##STR00043##
60. The compound of claim 53, wherein the compound is
##STR00044##
62. The compound of claim 53, wherein the compound is
##STR00045##
62. The compound of claim 53, wherein the compound is
##STR00046##
63. The compound of claim 51, wherein the compound is
##STR00047##
64. A pharmaceutical composition comprising the compound of claim
51 and a carrier.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a novel class of tri-aryl
compounds, pharmaceutical compositions comprising the same and
methods of preparation thereof.
BACKGROUND OF THE INVENTION
[0002] Nucleic acid polymerases are enzymes, whose primary function
is to polymerize new nucleic acids such as deoxyribonucleic acid
(DNA) or ribonucleic acid (RNA) using an existing DNA or RNA
template. Polymerases typically are involved in the processes of
replication and transcription.
[0003] The primary sequences of nucleic acids are crucial for
understanding the function and control of genes and for applying
many of the basic techniques of molecular biology. The ability to
do rapid and reliable DNA sequencing is, therefore, a very
important technology. The DNA sequence is an important tool in
genomic analysis as well as other applications, such as genetic
identification, forensic analysis, genetic counseling, medical
diagnostics, etc. With respect to the area of medical diagnostic
sequencing, disorders, susceptibilities to disorders, and prognoses
of disease conditions, can be correlated with the presence of
particular DNA sequences or the degree of variation (or mutation)
in DNA sequences, at one or more genetic loci.
[0004] Polymerases are thus useful in genetic engineering,
nucleotide sequencing, DNA labeling, site-directed mutagenesis, and
the like. Thermostable DNA polymerases have found application in
polymerase chain reactions (PCR), and various DNA polymerases
suitable for the PCR method have been developed and
commercialized.
[0005] Polymerase activity can be modulated, in part, by other
molecules which bind to the polymerase. Such modulation may
comprise enhancing polymerase activity or diminishing such
activity, which in turn modulates multiple cellular processes, and
other applications. Compounds which bind to polymerases and thereby
modulate its activity thus will have a wide array of important
applications.
SUMMARY OF THE INVENTION
[0006] In one embodiment, this invention provides a compound
represented by the structure represented by formula I:
##STR00001## [0007] wherein [0008] Z is carbon, nitrogen, phosphor,
arsenic, silicon or germanium; [0009] R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5 and R.sub.6 are independently the same or
different comprising alkyl (C.sub.2-C.sub.6), alkenyl
(C.sub.2-C.sub.6), alkynyl (C.sub.2-C.sub.6), alkoxy
(C.sub.2-C.sub.6), alkylalkoxy, haloalkyl, alkylhaloalkyl, aryl,
alkylaryl, haloaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl,
alkylheterocycloalkyl, heteroaryl, alkylheteroaryl, amino,
monoalkylamino, dialkylamino or arylamino; and [0010] R.sub.7 is
nothing, oxo, hydrogen, hydroxy, halogen, CN, NO.sub.2, alkyl
(C.sub.1-C.sub.6), alkenyl (C.sub.1-C.sub.6), alkynyl
(C.sub.1-C.sub.6), alkoxy (C.sub.1-C.sub.6), haloalkyl, aryl,
alkylaryl, haloaryl, heterocycloalkyl, alkylheterocycloalkyl,
heteroaryl or alkylheteroaryl; or its isomer, salt, hydrate,
N-oxide, crystal or any combination thereof.
[0011] In one embodiment, this invention provides a compound
represented by the structure represented by formula II:
##STR00002## [0012] wherein [0013] Z is carbon, nitrogen, phosphor,
arsenic, silicon or germanium; [0014] R', R'' and R''' are
independently the same or different comprising hydrogen, alkyl,
haloalkyl, alkylamino, alkylester, phenyl, benzyl, alkanyloyl,
acetyl or benzoyl;
[0015] R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are
independently the same or different comprising alkyl
(C.sub.2-C.sub.6), alkenyl (C.sub.2-C.sub.6), alkynyl
(C.sub.2-C.sub.6), alkoxy (C.sub.2-C.sub.6), alkylalkoxy,
haloalkyl, alkylhaloalkyl, aryl, alkylaryl, haloaryl, cycloalkyl,
heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl,
heteroaryl, alkylheteroaryl, amino, monoalkylamino, dialkylamino or
arylamino; and [0016] R.sub.7 is nothing, oxo, hydrogen, hydroxy,
halogen, CN, NO.sub.2, alkyl (C.sub.1-C.sub.6), alkenyl
(C.sub.1-C.sub.6), alkynyl (C.sub.1-C.sub.6), alkoxy
(C.sub.1-C.sub.6), haloalkyl, aryl, alkylaryl, haloaryl,
heterocycloalkyl, alkylheterocycloalkyl, heteroaryl or
alkylheteroaryl; or its isomer, salt, hydrate, N-oxide, crystal or
any combination thereof.
[0017] In one embodiment, this invention provides a compound
represented by the structure of formula XIII:
##STR00003## [0018] wherein [0019] X is carbon or nitrogen; [0020]
R.sub.1 is nothing, alkoxy, OCH.sub.2COOEt or halogen [0021]
R.sub.2 and R.sub.3 are independently hydrogen, alkyl, alkoxy,
hydroxyl, or OCH.sub.2COOAlk; and [0022] R.sub.4 and R.sub.5 are
hydrogens or form together a saturated or unsaturated of 5-7
carbocyclic ring; or its isomer, salt, hydrate, N-oxide, crystal or
any combination thereof; and a carrier, diluents, or any
combination thereof
[0023] In one embodiment, this invention provides a pharmaceutical
composition comprising a compound of formula I:
##STR00004## [0024] wherein [0025] Z is carbon, nitrogen, phosphor,
arsenic, silicon or germanium; [0026] R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5 and R.sub.6 are independently the same or
different comprising alkyl (C.sub.2-C.sub.6), alkenyl
(C.sub.2-C.sub.6), alkynyl (C.sub.2-C.sub.6), alkoxy
(C.sub.2-C.sub.6), alkylalkoxy, haloalkyl, alkylhaloalkyl, aryl,
alkylaryl, haloaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl,
alkylheterocycloalkyl, heteroaryl, alkylheteroaryl, amino,
monoalkylamino, dialkylamino or arylamino; and [0027] R.sub.7 is
nothing, oxo, hydrogen, hydroxy, halogen, CN, NO.sub.2, alkyl
(C.sub.1-C.sub.6), alkenyl (C.sub.1-C.sub.6), alkynyl
(C.sub.1-C.sub.6), alkoxy (C.sub.1-C.sub.6), haloalkyl, aryl,
alkylaryl, haloaryl, heterocycloalkyl, alkylheterocycloalkyl,
heteroaryl or alkylheteroaryl; or its isomer, salt, hydrate,
N-oxide, crystal or any combination thereof; and [0028] a carrier,
diluents, or any combination thereof.
[0029] In one embodiment, this invention provides a pharmaceutical
composition comprising a compound of formula II:
##STR00005## [0030] wherein [0031] Z is carbon, nitrogen, phosphor,
arsenic, silicon or germanium; [0032] R', R'' and R''' are
independently the same or different comprising hydrogen, alkyl,
haloalkyl, alkylamino, alkylester, phenyl, benzyl, alkanyloyl,
acetyl or benzoyl; [0033] R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5 and R.sub.6 are independently the same or different
comprising alkyl (C.sub.2-C.sub.6), alkenyl (C.sub.2-C.sub.6),
alkynyl (C.sub.2-C.sub.6), alkoxy (C.sub.2-C.sub.6), alkylalkoxy,
haloalkyl, alkylhaloalkyl, aryl, alkylaryl, haloaryl, cycloalkyl,
heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl,
heteroaryl, alkylheteroaryl, amino, monoalkylamino, dialkylamino or
arylamino; and [0034] R.sub.7 is nothing, oxo, hydrogen, hydroxy,
halogen, CN, NO.sub.2, alkyl (C.sub.1-C.sub.6), alkenyl
(C.sub.1-C.sub.6), alkynyl (C.sub.1-C.sub.6), alkoxy
(C.sub.1-C.sub.6), haloalkyl, aryl, alkylaryl, haloaryl,
heterocycloalkyl, alkylheterocycloalkyl, heteroaryl or
alkylheteroaryl; or its isomer, salt, hydrate, N-oxide, crystal or
any combination thereof; and [0035] a carrier, diluents, or any
combination thereof
[0036] In one embodiment, this invention provides a pharmaceutical
composition comprising a compound of formula XIII:
##STR00006## [0037] wherein [0038] X is carbon or nitrogen; [0039]
R.sub.1 is nothing, alkoxy, OCH.sub.2COOEt or halogen [0040]
R.sub.2 and R.sub.3 are independently hydrogen, alkyl, alkoxy,
hydroxyl, or OCH.sub.2COOAlk; and [0041] R.sub.4 and R.sub.5 are
hydrogens or form together a saturated or unsaturated of 5-7
carbocyclic ring; or its isomer, salt, hydrate, N-oxide, crystal or
any combination thereof; and a carrier, diluents, or any
combination thereof
DETAILED DESCRIPTION OF THE PRESENT INVENTION
[0042] In the following detailed description, numerous specific
details are set forth in order to provide a thorough understanding
of the invention. However, it will be understood by those skilled
in the art that the present invention may be practiced without
these specific details. In other instances, well-known methods,
procedures, and components have not been described in detail so as
not to obscure the present invention.
[0043] In one embodiment, this invention provides a compound
represented by the structure represented by formula I:
##STR00007## [0044] wherein [0045] Z is carbon, nitrogen, phosphor,
arsenic, silicon or germanium; [0046] R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5 and R.sub.6 are independently the same or
different comprising alkyl (C.sub.2-C.sub.6), alkenyl
(C.sub.2-C.sub.6), alkynyl (C.sub.2-C.sub.6), alkoxy
(C.sub.2-C.sub.6), alkylalkoxy, haloalkyl, alkylhaloalkyl, aryl,
alkylaryl, haloaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl,
alkylheterocycloalkyl, heteroaryl, alkylheteroaryl, amino,
monoalkylamino, dialkylamino or arylamino; and [0047] R.sub.7 is
nothing, oxo, hydrogen, hydroxy, halogen, CN, NO.sub.2, alkyl
(C.sub.1-C.sub.6), alkenyl (C.sub.1-C.sub.6), alkynyl
(C.sub.1-C.sub.6), alkoxy (C.sub.1-C.sub.6), haloalkyl, aryl,
alkylaryl, haloaryl, heterocycloalkyl, alkylheterocycloalkyl,
heteroaryl or alkylheteroaryl; or its isomer, salt, hydrate,
N-oxide, crystal or any combination thereof.
[0048] In another embodiment Z is carbon. In another embodiment
R.sub.7 is a methyl group. In another embodiment R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are
--(CH.sub.2).sub.n-heterocycloalkyl group, wherein n is between
1-6. In another embodiment R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5, and R.sub.6 are --(CH.sub.2).sub.n-aminoalkyl group,
wherein n is between 1-6. In another embodiment R.sub.1, R.sub.2,
R.sub.3, R.sub.4 R.sub.5, and R.sub.6 are
--(CH.sub.2).sub.n-dialkylamino group, wherein n is between 1-6 In
another embodiment R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and
R.sub.6 are --(CH.sub.2).sub.n--N(CH.sub.3).sub.2 group, wherein n
is between 1-6. In another embodiment R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, and R.sub.6 are --(CH.sub.2).sub.nN(Et).sub.2
group, wherein n is between 1-6. In another embodiment R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are
--(CH.sub.2).sub.n-aryl group, wherein n is between 1-6. In another
embodiment R.sub.1, R.sub.2, R.sub.3, R.sub.4 R.sub.5, and R.sub.6
are --(CH.sub.2).sub.n-heteroaryl group, wherein n is between 1-6.
In another embodiment R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
and R.sub.6 are --(CH.sub.2).sub.n-haloalkyl group, wherein n is
between 1-6. In another embodiment R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, and R.sub.6 are --(CH.sub.2).sub.n-alkoxy group,
wherein n is between 1-6. In another embodiment R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are
--(CH.sub.2).sub.n-ethoxy group, wherein n is between 1-6. In
another embodiment R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and
R.sub.6 are --(CH.sub.2).sub.n-cycloalkyl group, wherein n is
between 1-6.
[0049] In one embodiment, this invention provides a compound
represented by the structure represented by formula II:
##STR00008## [0050] wherein [0051] Z is carbon, nitrogen, phosphor,
arsenic, silicon or germanium; [0052] R', R'' and R''' are
independently the same or different comprising hydrogen, alkyl,
haloalkyl, alkylamino, alkylester, phenyl, benzyl, alkanyloyl,
acetyl or benzoyl; [0053] R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5 and R.sub.6 are independently the same or different
comprising alkyl (C.sub.2-C.sub.6), alkenyl (C.sub.2-C.sub.6),
alkynyl (C.sub.2-C.sub.6), alkoxy (C.sub.2-C.sub.6), alkylalkoxy,
haloalkyl, alkylhaloalkyl, aryl, alkylaryl, haloaryl, cycloalkyl,
heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl,
heteroaryl, alkylheteroaryl, amino, monoalkylamino, dialkylamino or
arylamino; and [0054] R.sub.7 is nothing, oxo, hydrogen, hydroxy,
halogen, CN, NO.sub.2, alkyl (C.sub.1-C.sub.6), alkenyl alkynyl
(C.sub.1-C.sub.6), alkoxy (C.sub.1-C.sub.6), haloalkyl, aryl,
alkylaryl, haloaryl, heterocycloalkyl, alkylheterocycloalkyl,
heteroaryl or alkylheteroaryl; or its isomer, salt, hydrate,
N-oxide, crystal or any combination thereof.
[0055] In one embodiment, this invention provides a compound
represented by the structure of formula III:
##STR00009## [0056] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5 , and R.sub.6 areas defined above and R.sub.7 is oxo,
hydrogen, hydroxy, halogen, CN, NO.sub.2, alkyl (C.sub.1-C.sub.6),
alkenyl (C.sub.1-C.sub.6), alkynyl (C.sub.1-C.sub.6), alkoxy
(C.sub.1-C.sub.6), haloalkyl, aryl, alkylaryl, haloaryl,
heterocycloalkyl, alkylheterocycloalkyl, heteroaryl or
alkylheteroaryl; or its isomer, salt, hydrate, N-oxide, crystal or
any combination thereof.
[0057] In one embodiment, this invention provides a compound
represented by the structure of formula IV:
##STR00010## [0058] wherein [0059] R', R'', R''' are independently
the same or different comprising hydrogen, alkyl, haloalkyl,
phenyl, alkylester, benzyl, alkanyloyl, acetyl or benzoyl; [0060]
R.sub.1', R.sub.2', R.sub.3', R.sub.4' R.sub.5', and R.sub.6' are
the same or different comprising halogen, aryl, alkyl, cycloalkyl,
heterocycloalkyl, alkoxy (C.sub.2-C.sub.6), amino, monoalkylamino,
dialkylamino or arylamino group; and R.sub.7 is oxo, hydrogen,
hydroxy, halogen, CN, NO.sub.2, alkyl (C.sub.1-C.sub.6), alkenyl
(C.sub.1-C.sub.6), alkynyl (C.sub.1-C.sub.6), alkoxy
(C.sub.1-C.sub.6), haloalkyl, aryl, alkylaryl, haloaryl,
heterocycloalkyl, alkylheterocycloalkyl, heteroaryl or
alkylheteroaryl; or its isomer, salt, hydrate, N-oxide, crystal or
any combination thereof.
[0061] In another embodiment, R.sub.1', R.sub.2', R.sub.3',
R.sub.4' R.sub.5', and R.sub.6' are dialkylamino group. In another
embodiment, R.sub.1', R.sub.2', R.sub.3', R.sub.4' R.sub.5', and
R.sub.6' are dimethylamino group. In another embodiment, R.sub.1',
R.sub.2', R.sub.3', R.sub.4' R.sub.5', and R.sub.6' are
diethylamino group. In another embodiment, R.sub.1', R.sub.2',
R.sub.3', R.sub.4' R.sub.5', and R.sub.6' are N-piperidine group.
In another embodiment, R.sub.1', R.sub.2', R.sub.3', R.sub.4'
R.sub.5', and R.sub.6' are N-pyrolidine group. In another
embodiment, R.sub.1', R.sub.2', R.sub.3', R.sub.4' R.sub.5', and
R.sub.6' are N-piperazine group. In another embodiment, R.sub.1',
R.sub.2', R.sub.3', R.sub.4' R.sub.5', and R.sub.6' are
N-piperazine-4-methyl group. In another embodiment, R.sub.1',
R.sub.2', R.sub.3', R.sub.4' R.sub.5', and R.sub.6' are
N-morpholine group. In another embodiment, R.sub.1', R.sub.2',
R.sub.3', R.sub.4' R.sub.5', and R.sub.6' are ethoxy group.
[0062] In one embodiment, this invention provides a compound
represented by the structure of formula V:
##STR00011## [0063] wherein R.sub.1', R.sub.2', R.sub.3', R.sub.4'
R.sub.5', and R.sub.6' are the same or different comprising
halogen, aryl, alkyl, cycloalkyl, heterocycloalkyl, alkoxy
(C.sub.2-C.sub.6), amino, monoalkylamino, dialkylamino or arylamino
group; and R.sub.7 is and R.sub.7 is oxo, hydrogen, hydroxy,
halogen, CN, NO.sub.2, alkyl (C.sub.1-C.sub.6), alkenyl
(C.sub.1-C.sub.6), alkynyl (C.sub.1-C.sub.6), alkoxy
(C.sub.1-C.sub.6), haloalkyl, aryl, alkylaryl, haloaryl,
heterocycloalkyl, alkylheterocycloalkyl, heteroaryl or
alkylheteroaryl.
[0064] In another embodiment, R.sub.1.sup.', R.sub.2.sup.',
R.sub.3.sup.', R.sub.4' R.sub.5', and R.sub.6' are dialkylamino
group. In another embodiment, R.sub.1', R.sub.2', R.sub.3',
R.sub.4' R.sub.5', and R.sub.6' are dimethylamino group. In another
embodiment, R.sub.1', R.sub.2', R.sub.3', R.sub.4' R.sub.5', and
R.sub.6' are diethylamino group. In another embodiment, R.sub.1',
R.sub.2', R.sub.3', R.sub.4' R.sub.5', and R.sub.6' are
N-piperidine group. In another embodiment, R.sub.1', R.sub.2',
R.sub.3', R.sub.4' R.sub.5', and R.sub.6' are N-pyrolidine group.
In another embodiment, R.sub.1', R.sub.2', R.sub.3', R.sub.4'
R.sub.5', and R.sub.6' are N-piperazine group. In another
embodiment, R.sub.1', R.sub.2', R.sub.3', R.sub.4' R.sub.5', and
R.sub.6' are N-piperazine-4-methyl group. In another embodiment,
R.sub.1', R.sub.2', R.sub.3', R.sub.4' R.sub.5', and R.sub.6' are
N-morpholine group. In another embodiment, R.sub.1', R.sub.2',
R.sub.3', R.sub.4' R.sub.5', and R.sub.6' are ethoxy group.
[0065] In one embodiment, this invention provides a compound
represented by the structure of formula VI:
##STR00012## [0066] and its pharmaceutical composition comprising
the same.
[0067] In one embodiment, this invention provides a compound
represented by the structure of formula VII:
##STR00013## [0068] and its pharmaceutical composition comprising
the same.
[0069] In one embodiment, this invention provides a compound
represented by the structure of formula VIII:
##STR00014## [0070] and its pharmaceutical composition comprising
the same.
[0071] In one embodiment, this invention provides a compound
represented by the structure of formula IX:
##STR00015## [0072] and its pharmaceutical composition comprising
the same.
[0073] In one embodiment, this invention provides a compound
represented by the structure of formula X:
##STR00016## [0074] and its pharmaceutical composition comprising
the same.
[0075] In one embodiment, this invention provides a compound
represented by the structure of formula XI:
##STR00017## [0076] and its pharmaceutical composition comprising
the same.
[0077] In one embodiment, this invention provides a compound
represented by the structure represented by formula XII:
##STR00018## [0078] wherein [0079] Z is carbon, nitrogen, phosphor,
arsenic, silicon or germanium; [0080] R.sub.8 to R.sub.16 are the
same or different, H, D, OH, halogen, nitro, CN, nitrileamido,
amidosulfide, amino, aldehyde, substituted ketone, --COOH, ester,
trifluoromethyl, amide, substituted or unsubstituted alkyl,
alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, arylsulfonyl,
arylalkylenesulfonyl, alkoxy, haloalkyl, haloaryl, aryloxy, amino,
monoalkylamino, dialkylamino, alkylamido, arylamino, arylamido,
alkylthio, arylthio, heterocycloalkyl, alkylheterocycloalkyl,
heterocycloalkylalkyl, heteroaryl, hetroarylalkyl, alkylheteroaryl;
or R.sub.10, R.sub.11, or R.sub.14, forms a fused cycloalkyl,
heterocycloalkyl, aromatic or heteroaromatic ring with the main
aromatic ring; and [0081] R.sub.17 is H, D, OH, halogen, oxo,
nitro, CN, nitrileamido, amidosulfide, amino, aldehyde, substituted
ketone, --COOH, ester, trifluoromethyl, amide, substituted or
unsubstituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl,
arylsulfonyl, arylalkylenesulfonyl, alkoxy, haloalkyl, haloaryl,
aryloxy, monoalkylamino, dialkylamino, alkylamido, arylamino,
arylamido, alkylthio, arylthio, heterocycloalkyl,
alkylheterocycloalkyl, heterocycloalkylalkyl, heteroaryl,
hetroarylalkyl, alkylheteroaryl; or its isomer, salt, hydrate,
N-oxide, crystal or any combination thereof; and its pharmaceutical
composition comprising the same and [0082] a carrier, diluents, or
any combination thereof
[0083] In one embodiment, this invention provides a compound
represented by the structure represented by formula XIII:
##STR00019## [0084] wherein [0085] X is carbon or nitrogen; [0086]
R.sub.1 is nothing, alkoxy, OCH.sub.2COOEt or halogen [0087]
R.sub.2 and R.sub.3 are independently hydrogen, alkyl, alkoxy,
hydroxyl, or OCH.sub.2COOAlk; and [0088] R.sub.4 and R.sub.5 are
hydrogens or form together a saturated or unsaturated of 5-7
carbocyclic ring; or its isomer, salt, hydrate, N-oxide, crystal or
any combination thereof; and its pharmaceutical composition
comprising the same and [0089] a carrier, diluents, or any
combination thereof.
[0090] In one embodiment, this invention provides a compound
represented by the structure of formula XIV:
##STR00020## [0091] and its pharmaceutical composition comprising
the same and [0092] a carrier, diluents, or any combination
thereof.
[0093] In one embodiment, this invention provides a compound
represented by the structure of formula XV:
##STR00021## [0094] and its pharmaceutical composition comprising
the same and [0095] a carrier, diluents, or any combination
thereof.
[0096] In one embodiment, this invention provides a compound
represented by the structure of formula XVI:
##STR00022## [0097] and its pharmaceutical composition comprising
the same and [0098] a carrier, diluents, or any combination
thereof.
[0099] In one embodiment, this invention provides a compound
represented by the structure of formula XVII:
##STR00023## [0100] and its pharmaceutical composition comprising
the same; and [0101] a carrier, diluents, or any combination
thereof.
[0102] In one embodiment, this invention provides a compound
represented by the structure of formula XVIII:
##STR00024## [0103] and its pharmaceutical composition comprising
the same; and [0104] a carrier, diluents, or any combination
thereof.
[0105] In one embodiment, this invention provides a compound
represented by the structure of formula XIX:
##STR00025## [0106] and its pharmaceutical composition comprising
the same; and [0107] a carrier, diluents, or any combination
thereof.
[0108] In one embodiment, this invention provides a compound is
represented by the structure of formula XX:
##STR00026## [0109] and its pharmaceutical composition comprising
the same; and [0110] a carrier, diluents, or any combination
thereof.
[0111] In one embodiment, this invention provides a compound is
represented by the structure of formula XXI:
##STR00027## [0112] and its pharmaceutical composition comprising
the same; and [0113] a carrier, diluents, or any combination
thereof.
[0114] In one embodiment, this invention provides a compound is
represented by the structure of formula XXII:
##STR00028## [0115] and its pharmaceutical composition comprising
the same; and [0116] a carrier, diluents, or any combination
thereof.
[0117] In one embodiment, this invention provides a compound
represented by the structure of formula XXIII:
##STR00029## [0118] and its pharmaceutical composition comprising
the same; and [0119] a carrier, diluents, or any combination
thereof.
[0120] In one embodiment, this invention provides a compound
represented by the structure of formula XXIV:
##STR00030## [0121] its pharmaceutical composition comprising the
same; and [0122] a carrier, diluents, or any combination
thereof.
[0123] In another embodiment, the fused heterocycloalkyl, with the
main aromatic ring forms a phenylpyrrolidone group. In another
embodiment, the fused aryl, with the main aromatic ring forms a
naphtalene group. In another embodiment, the fused heteroaryl, with
the main aromatic ring forms a quinoline or isoquinoline group.
[0124] In one embodiment, the heteroaryl is pyrrolyl, thienyl,
thiazolyl, benzothienyl, naphthothienyl, purinyl, isothiazolyl,
furyl, furazanyl, isobenznzofuranyl, pyranyl, chromenyl, xanthenyl,
phenoxyxanthiinyl, indolyl, isoindolyl, indolizinyl,
isoindolyzinyl, benzothienyl, oxazolyl, isoxazolyl, pyrazolyl,
pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, or any combination
thereof.
[0125] In one embodiment said heterocycloalkyl is a cyclic urea,
imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, oxazolinyl,
isoxazolinyl, oxazolidinyl, oxazolidonyl, isoxazolidonyl,
pyrazolinyl, pyrazolidinyl, piperidyl, piperazine, morpholinyl.
[0126] The term "alkyl" refers, in one embodiment, to a saturated
aliphatic hydrocarbon, including straight-chain, branched-chain and
cyclic alkyl groups. In one embodiment, the alkyl group has 1-12
carbons. In another embodiment, the alkyl group has 1-7 carbons. In
another embodiment, the alkyl group has 1-6 carbons. In another
embodiment, the alkyl group has 1-7 carbons. In another embodiment,
the alkyl group has 2-6 carbons. In another embodiment, the alkyl
group has 1-7 carbons. In another embodiment, the alkyl group has
2-8 carbons. In another embodiment, the alkyl group has 3-6
carbons. In another embodiment, the alkyl group has 3-7 carbons. In
another embodiment, the alkyl group has 1-4 carbons. In another
embodiment, the branched alkyl is an alkyl substituted by alkyl
side chains of 1 to 5 carbons. In another embodiment, the branched
alkyl is an alkyl substituted by haloalkyl side chains of 1 to 5
carbons. The alkyl group may be unsubstituted or substituted by a
halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amino, alkylamido,
dialkylamido, nitro, cyano, amino, monoalkylamino, carboxyl, thio
and/or thioalkyl.
[0127] An "alkenyl" group refers, in one embodiment, to an
unsaturated hydrocarbon, including straight chain, branched chain
and cyclic groups having one or more double bonds. The alkenyl
group may have one double bond, two double bonds, three double
bonds, etc. In another embodiment, the alkenyl group has 2-12
carbons. In another embodiment, the alkenyl group has 2-6 carbons.
In another embodiment, the alkenyl group has 2-4 carbons. In
another embodiment the alkenyl group is ethenyl (--CH.dbd.CH.sub.2)
Examples of alkenyl groups are ethenyl, propenyl, butenyl,
cyclohexenyl, etc. The alkenyl group may be unsubstituted or
substituted by a halogen, hydroxy, alkoxy, carbonyl, amido,
alkylamido, dialkylamido, nitro, cyano, amino, monoalkylamino,
dialkylamino, carboxyl, thio and/or thioalkyl.
[0128] An alkynyl" group refers, in one embodiment, to an
unsaturated hydrocarbon, including straight chain, branched chain
and cyclic groups having one or more triple bonds. The alkynyl
group may have one triple bond, two triple bonds, triple double
bonds, etc. In another embodiment, the alkynyl group has 2-12
carbons. In another embodiment, the alkynyl group has 2-6 carbons.
In another embodiment, the alkenyl group has 2-4 carbons. In
another embodiment the alkynyl group is ethynyl
(--CH.ident.CH.sub.2). Examples of alkynyl groups are ethynyl,
propynyl, butynyl, cyclohexynyl, etc. The alkynyl group may be
unsubstituted or substituted by a halogen, hydroxy, alkoxy,
carbonyl, amido, alkylamido, dialkylamido, nitro, cyano, amino,
monoalkylamino, dialkylamido, carboxyl, thio and/or thioalkyl.
[0129] An "alkoxy" group refers, in another embodiment is an alkyl
group as defined above, which is linked to an oxygen. Examples of
alkoxy groups are ethoxy, propoxy, tert-butoxy etc.
[0130] A "haloalkyl" group refers, in one embodiment, to an alkyl
group as defined above, which is substituted by one or more halogen
atoms, e.g. by F, Cl, Br or I.
[0131] An "aryl" group refers, in another embodiment, to an
aromatic group having at least one carbocyclic aromatic group or
heterocyclic aromatic group, which may be unsubstituted or
substituted by one or more groups selected from halogen, haloalkyl,
hydroxy, alkoxy, carbonyl, amido, alkylamido, dialkylamido, nitro,
cyano, amino, monoalkylamino, dialkylamido, carboxy or thio or
thioalkyl. In another embodiment, the aryl group is between 4-12
membered ring(s). In another embodiment, the aryl group is between
6-18 membered ring(s). In another embodiment, the aryl group is
between 4-8 membered ring(s). In another embodiment, the aryl group
is a 6 membered ring. In another embodiment, the aryl group is a
fused ring system comprising of between 2-3 rings. Nonlimiting
examples of aryl rings are phenyl, naphthyl, pyranyl, pyrrolyl,
pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl, furanyl, thiophenyl,
thiazolyl, imidazolyl, isoxazolyl, and the like.
[0132] A "hydroxyl" group refers, in one embodiment, to an OH
group. In some embodiments, when R.sub.1, R.sub.2 or R.sub.3 of the
compounds of the present invention is OR, then R is not OH.
[0133] In one embodiment, the term "halo" refers to a halogen, such
as F, Cl, Br or I.
[0134] In another embodiment, the phrase "phenol" refers to an
alcohol (OH) derivative of benzene.
[0135] An "amino" group refers to, in one embodiment, to a nitrogen
atom attached by single bonds to hydrogen atoms, alkyl groups,
alkenyl groups or aryl groups as described above, as described
above, or a combination thereof. Nonlimiting examples of amino
groups are NH.sub.2, N(Me).sub.2, N(Et).sub.2, N(Ph).sub.2 and the
like.
[0136] A "cycloalkyl" group refers, in one embodiment, to a
non-aromatic, monocyclic or polycyclic ring comprising carbon and
hydrogen atoms. A cycloalkyl group can have one or more
carbon-carbon double bonds in the ring so long as the ring is not
rendered aromatic by their presence. Examples of cycloalkyl groups
include, but are not limited to, (C.sub.3-C.sub.7)cycloalkyl
groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
and cycloheptyl, and saturated cyclic and bicyclic terpenes and
(C.sub.3-C.sub.7)cycloalkenyl groups, such as cyclopropenyl,
cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl, and
unsaturated cyclic and bicyclic terpenes. Preferably, the
cycloalkyl group is a monocyclic ring or bicyclic to a ring
structure comprising in addition to carbon atoms, sulfur, oxygen,
nitrogen or any combination thereof, as part of the ring. In
another embodiment the cycloalkyl is a 3-12 membered ring. In
another embodiment the cycloalkyl is a 6 membered ring. In another
embodiment the cycloalkyl is a 5-7 membered ring. In another
embodiment the cycloalkyl is a 4-8 membered ring. In another
embodiment, the cycloalkyl group may be unsubstituted or
substituted by a halogen, haloalkyl, hydroxyl, alkoxy, carbonyl,
amido, alkylamido, dialkylamido, cyano, nitro, CO.sub.2H, amino,
monoalkylamino, dialkylamino, carboxyl, thio and/or thioalkyl.
[0137] A "heterocycloalkyl" group refers, in one embodiment, to a
non-aromatic, monocyclic or polycyclic ring comprising carbon and
in addition to carbon, sulfur, phosphor, oxygen or nitrogen, as
part of the ring. A heterocycloalkyl group can have one or more
double bonds in the ring so long as the ring is not rendered
aromatic by their presence. Examples of heterocycloalkyl groups
include, but are not limited to, piperidine, piperazine, pyrane,
morpholine. Preferably, the heterocycloalkyl group is a monocyclic
ring or bicyclic to a ring structure comprising in addition to
carbon atoms, sulfur, oxygen, nitrogen or any combination thereof,
as part of the ring. In another embodiment the heterocycloalkyl is
a 3-12 membered ring. In another embodiment the heterocycloalkyl is
a 6 membered ring. In another embodiment the heterocycloalkyl is a
5-7 membered ring. In another embodiment the heterocycloalkyl is a
4-8 membered ring. In another embodiment, the heterocycloalkyl
group may be unsubstituted or substituted by a halogen, haloalkyl,
hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano,
nitro, CO.sub.2H, amino, monoalkylamino, dialkylamino, carboxyl,
thio and/or thioalkyl.
[0138] The terms "alkylalkoxy", "alkylhaloalkyl", "alkylaryl",
"alkylcycloalkyl", "alkylheterocycloalkyl", "alkylheteroaryl" and
"alkylamino" refer, in one embodiment, to an alkyl group, as
defined above, linked to alkoxy, haloalkyl, aryl, cycloalkyl,
heterocycloalkyl, heteroaryl or amino group, respectively. The
alkoxy, haloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl
or amino groups are as defined hereinabove. Examples include, but
are not limited to, CH.sub.2--OEt, CH.sub.2--N-piperidine,
CH.sub.2--N-piperazine, CH.sub.2--N(Me).sub.2 etc.
[0139] Some embodiments of a synthetic procedure for some of the
tri-aryl compounds are provided in scheme 1:
##STR00031##
[0140] In another embodiment compounds IV-IX are prepared using the
Mannich reaction as described in scheme 1 and in Example 1-7 using
1,1,1 tris(4-hydroxyphenyl)ethane as the starting material.
[0141] Some embodiments of a synthetic procedure for some of the
tri-aryl compounds are provided in scheme 2:
##STR00032##
[0142] In another embodiment bromination or nitration of the
commercial 1,1,1 tris(4-hydroxyphenyl)ethane provides the tris
phenol substituted ortho positions. In another embodiment,
exhaustive reaction conditions give the hexa substituted tris
phenol. Methylation or alkylation lead to the tris-methoxy or
tris-alkyl analogs.
[0143] Some embodiments of a synthetic procedure for some of the
tri-aryl compounds are provided in scheme 3:
##STR00033##
[0144] In one embodiment, a Grignard reaction of aryl magnesium
bromide with aryl ester or diarylketone provides the triarylmethyl
alcohol, as described in scheme 3. Chlorination of the
triarylmethyl alcohol followed by its reaction with methylmagnesium
iodide yields the compound as shown, with R.sub.10 being a methyl
group.
[0145] In one embodiment, this invention provides a pharmaceutical
composition comprising the compounds of this invention and a
carrier, dilluent, or any combination thereof.
[0146] In one embodiment, this invention provides a pharmaceutical
composition comprising a compound of formula I:
##STR00034## [0147] wherein [0148] Z is carbon, nitrogen, phosphor,
arsenic, silicon or germanium; [0149] R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5 and R.sub.6 are independently the same or
different comprising alkyl (C.sub.2-C.sub.6), alkenyl
(C.sub.1-C.sub.6), alkynyl (C.sub.1-C.sub.6), alkoxy
(C.sub.2-C.sub.6), alkylalkoxy, haloalkyl, alkylhaloalkyl, aryl,
alkylaryl, haloaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl,
alkylheterocycloalkyl, heteroaryl, alkylheteroaryl, amino,
monoalkylamino, dialkylamino, or arylamino; and [0150] R.sub.7 is
nothing, oxo, hydrogen, hydroxy, halogen, CN, NO.sub.2, alkyl
(C.sub.1-C.sub.6), alkenyl (C.sub.1-C.sub.6), alkynyl
(C.sub.1-C.sub.6), alkoxy (C.sub.1-C.sub.6), haloalkyl, aryl,
alkylaryl, haloaryl, heterocycloalkyl, alkylheterocycloalkyl,
heteroaryl or alkylheteroaryl; and [0151] a carrier, diluents, or
any combination thereof.
[0152] In another embodiment, the composition of formula I, further
comprises an excipient, an additive or any combination thereof.
[0153] In one embodiment, this invention provides a pharmaceutical
composition comprising a compound of formula II:
##STR00035## [0154] wherein [0155] Z is carbon, nitrogen, phosphor,
arsenic, silicon or germanium; [0156] R', R'' and R''' are
independently the same or different comprising hydrogen, alkyl,
haloalkyl, alkylamino, alkylester, phenyl, benzyl, alkanyloyl,
acetyl or benzoyl; [0157] R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5 and R.sub.6 are independently the same or different
comprising alkyl (C.sub.2-C.sub.6), alkenyl (C.sub.2-C.sub.6),
alkynyl (C.sub.2-C.sub.6), alkoxy (C.sub.2-C.sub.6), alkylalkoxy,
haloalkyl, alkylhaloalkyl, aryl, alkylaryl, haloaryl, cycloalkyl,
heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl,
heteroaryl, alkylheteroaryl, amino, monoalkylamino, dialkylamino or
arylamino; and [0158] R.sub.7 is nothing, oxo, hydrogen, hydroxy,
halogen, CN, NO.sub.2, alkyl (C.sub.1-C.sub.6), alkenyl
(C.sub.1-C.sub.6), alkynyl (C.sub.1-C.sub.6), alkoxy
(C.sub.1-C.sub.6), haloalkyl, aryl, alkylaryl, haloaryl,
heterocycloalkyl, alkylheterocycloalkyl, heteroaryl or
alkylheteroaryl; and [0159] a carrier, diluents, or any combination
thereof.
[0160] In another embodiment, the composition of formula II,
further comprises an excipient, an additive or any combination
thereof.
[0161] In some embodiments, this invention provides compositions
which may comprise at least one compound of this invention, in any
form or embodiment as described herein. In some embodiments, the
term "a" is to be understood to encompass a single or multiple of
the indicated material. In some embodiments, the term "a" or "an"
refers to at least one.
[0162] In some embodiments, any of the compositions of this
invention will consist of a compound of this invention, in any form
or embodiment as described herein. In some embodiments, of the
compositions of this invention will consist essentially of a
compound of this invention, in any form or embodiment as described
herein.
[0163] In some embodiments, the term "comprise" refers to the
inclusion of the indicated active agent, such as the compounds of
this invention, as well as inclusion of other active agents, and
pharmaceutically acceptable carriers, excipients, emollients,
stabilizers, etc., as are known in the pharmaceutical industry. In
some embodiments, the term "consisting essentially of" refers to a
composition, whose only active ingredient is the indicated active
ingredient, however, other compounds may be included which are for
stabilizing, preserving, etc. the formulation, but are not involved
directly in the therapeutic effect of the indicated active
ingredient. In some embodiments, the term "consisting essentially
of" may refer to components which facilitate the release of the
active ingredient, or other active ingredients, however the primary
compound mediating a therapeutic effect is the indicated active
ingredient. In some embodiments, the term "consisting" refers to a
composition, which contains the active ingredient and a
pharmaceutically acceptable carrier or excipient.
[0164] In another embodiment, the invention provides a composition
comprising a compound of this invention, as herein described, or
its prodrug, analog, isomer, metabolite, derivative,
pharmaceutically acceptable salt, pharmaceutical product,
polymorph, crystal, impurity, N-oxide, ester, hydrate or any
combination thereof and a suitable carrier or diluent.
[0165] An active component can be formulated into the composition
as neutralized pharmaceutically acceptable salt forms.
Pharmaceutically acceptable salts include the acid addition salts,
which are formed with inorganic acids such as, for example,
hydrochloric or phosphoric acids, or such organic acids as acetic,
oxalic, tartaric, mandelic, and the like. Salts formed from the
free carboxyl groups can also be derived from inorganic bases such
as, for example, sodium, potassium, ammonium, calcium, or ferric
hydroxides, and such organic bases as isopropylamine,
trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the
like.
[0166] The compositions of the present invention are formulated in
one embodiment for oral delivery, wherein the active compounds may
be incorporated with excipients and used in the form of ingestible
tablets, buccal tables, troches, capsules, elixirs, suspensions,
syrups, wafers, and the like. The tablets, troches, pills, capsules
and the like may also contain the following: a binder, as gum
tragacanth, acacia, cornstarch, or gelatin; excipients, such as
dicalcium phosphate; a disintegrating agent, such as corn starch,
potato starch, alginic acid and the like; a lubricant, such as
magnesium stearate; and a sweetening agent, such as sucrose,
lactose or saccharin may be added or a flavoring agent, such as
peppermint, oil of wintergreen, or cherry flavoring. When the
dosage unit form is a capsule, it may contain, in addition to
materials of the above type, a liquid carrier. Various other
materials may be present as coatings or to otherwise modify the
physical form of the dosage unit. For instance, tablets, pills, or
capsules may be coated with shellac, sugar, or both. Syrup of
elixir may contain the active compound, sucrose as a sweetening
agent methyl, and propylparabens as preservatives, a dye and
flavoring, such as cherry or orange flavor. In addition, the active
compounds may be incorporated into sustained-release, pulsed
release, controlled release or postponed release preparations and
formulations.
[0167] In another embodiment, the compositions of this invention
comprise one or more, pharmaceutically acceptable carrier
materials.
[0168] In one embodiment, the carriers for use within such
compositions are biocompatible, and in another embodiment,
biodegradable. In other embodiments, the formulation may provide a
relatively constant level of release of one active component. In
other embodiments, however, a more rapid rate of release
immediately upon administration may be desired. In other
embodiments, release of active compounds may be event-triggered.
The events triggering the release of the active compounds may be
the same in one embodiment, or different in another embodiment.
Events triggering the release of the active components may be
exposure to moisture in one embodiment, lower pH in another
embodiment, or temperature threshold in another embodiment. The
formulation of such compositions is well within the level of
ordinary skill in the art using known techniques. Illustrative
carriers useful in this regard include microparticles of poly
(lactide-co-glycolide), polyacrylate, latex, starch, cellulose,
dextran and the like. Other illustrative postponed-release carriers
include supramolecular biovectors, which comprise a non-liquid
hydrophilic core (e.g., a cross-linked polysaccharide or
oligosaccharide) and, optionally, an external layer comprising an
amphiphilic compound, such as phospholipids. The amount of active
compound contained in one embodiment, within a sustained release
formulation depends upon the site of administration, the rate and
expected duration of release and the nature of the condition to be
treated suppressed or inhibited.
[0169] In one embodiment it will be desirable to deliver the
compositions disclosed herein parenterally, intravenously,
intramuscularly, or even intraperitoneally. Such approaches are
well known to the skilled artisan, some of which are further
described, for example, in U.S. Pat. No. 5,543,158; U.S. Pat. No.
5,641,515 and U.S. Pat. No. 5,399,363, all of which are fully
incorporated by reference. In certain embodiments, solutions of the
active compounds as free base or pharmacologically acceptable salts
may be prepared in water suitably mixed with a surfactant, such as
hydroxypropylcellulose. Dispersions may also be prepared in
glycerol, liquid polyethylene glycols, and mixtures thereof and in
oils. It must be stable under the conditions of manufacture and
storage and must be preserved against the contaminating action of
microorganisms, such as bacteria and fungi.
[0170] In another embodiment, it will be preferable to include
isotonic agents, for example, sugars or sodium chloride. In other
embodiments, prolonged absorption of the injectable compositions
will be desirable. Prolonged absorption of the injectable
compositions can be brought about by the use of agents delaying
absorption, for example, aluminum monostearate and gelatin, in the
compositions.
[0171] Parenteral vehicles include in certain embodiments sodium
chloride solution, Ringer's dextrose, dextrose and sodium chloride,
lactated Ringer's and fixed oils. Intravenous vehicles include
fluid and nutrient replenishers, electrolyte replenishers such as
those based on Ringer's dextrose, and the like. Preservatives and
other additives may also be present, such as, for example,
antimicrobials, antioxidants, collating agents, inert gases and the
like
[0172] In some embodiments, the compounds of this invention may be
administered at various dosages to a subject, which in one
embodiment, is a human subject. In one embodiment, the compounds of
this invention is administered at a dosage of 0.1-200 mg per day.
In one embodiment, the compound of this invention is administered
at a dose of 0.1-10 mg, or in another embodiment, 0.1-25 mg, or in
another embodiment, 0.1-50 mg, or in another embodiment, 0.3-15 mg,
or in another embodiment, 0.3-30 mg, or in another embodiment,
0.5-25 mg, or in another embodiment, 0.5-50 mg, or in another
embodiment, 0.75-15 mg, or in another embodiment, 0.75-60 mg, or in
another embodiment, 1-5 mg, or in another embodiment, 1-20 mg, or
in another embodiment, 3-15 mg, or in another embodiment, 1-30 mg,
or in another embodiment, 30-50 mg, or in another embodiment, 30-75
mg, or in another embodiment, 100-2000 mg. In some embodiments, the
compounds of this invention may be administered at different
dosages, as a function of time, or disease/symptom/condition
severity, or age, or other factors, as will be appreciated by one
skilled in the art.
[0173] The compounds of this invention may be administered at
various dosages. In one embodiment, the compounds of this invention
are administered at a dosage of 1 mg. In another embodiment the
compounds of this invention are administered at a dosage of 5 mg,
or in another embodiment, 3 mg, or in another embodiment 10 mg, or
in another embodiment 15 mg, or in another embodiment 20 mg, or in
another embodiment 25 mg, or in another embodiment 30 mg, or in
another embodiment 35 mg, or in another embodiment 40 mg, or in
another embodiment 45 mg, or in another embodiment 50 mg, or in
another embodiment 55 mg, or in another embodiment 60 mg, or in
another embodiment 65 mg, or in another embodiment 70 mg, or in
another embodiment 75 mg, or in another embodiment 80 mg, or in
another embodiment 85 mg, or in another embodiment 90 mg, or in
another embodiment 95 mg or in another embodiment 100 mg.
[0174] While the compounds of the invention can be administered as
the sole active pharmaceutical agent, they can also be used in
combination with one or more other compound, and/or in combination
with other agents used in the treatment and/or prevention of the
diseases, disorders and/or conditions, as will be understood by one
skilled in the art. In another embodiment, the compounds of the
present invention can be administered sequentially with one or more
such agents to provide sustained therapeutic and prophylactic
effects. In another embodiment, the compounds may be administered
via different routes, at different times, or a combination
thereof.
[0175] In addition, the compounds of the present invention can be
used, either singly or in combination, in combination with other
modalities for preventing or treating conditions, diseases or
disorders. In some embodiments, such other treatment modalities may
include without limitation, surgery, radiation, hormone
supplementation, diet regulation, wound debridement, etc., as will
be appropriate for the condition being treated. These can be
performed sequentially (e.g., treatment with a compound of the
invention following surgery or radiation) or in combination (e.g.,
in addition to a diet regimen).
[0176] The additional active agents may generally be employed in
therapeutic amounts as indicated in the PHYSICIANS' DESK REFERENCE
(PDR) 53rd Edition (1999), or such therapeutically useful amounts
as would be known to one of ordinary skill in the art. The
compounds of the invention and the other therapeutically active
agents can be administered at the recommended maximum clinical
dosage or at lower doses. Dosage levels of the active compounds in
the compositions of the invention may be varied to obtain a desired
therapeutic response depending on the route of administration,
severity of the disease and the response of the patient. The
combination can be administered as separate compositions or as a
single dosage form containing both agents. When administered as a
combination, the therapeutic agents can be formulated as separate
compositions that are given at the same time or different times, or
the therapeutic agents can be given as a single composition.
[0177] The pharmaceutical composition can comprise the compounds of
this invention alone or can further include a pharmaceutically
acceptable carrier and can be in solid or liquid form such as
tablets, powders, capsules, pellets, solutions, suspensions,
elixirs, emulsions, gels, creams, or suppositories, including
rectal and urethral suppositories. Pharmaceutically acceptable
carriers include gums, starches, sugars, cellulosic materials, and
mixtures thereof. The pharmaceutical preparation containing the
compounds of this invention can be administered to a subject by,
for example, subcutaneous implantation of a pellet; in a further
embodiment, the pellet provides for controlled release of the
compounds of this invention over a period of time. The preparation
can also be administered by intravenous, intraarterial, or
intramuscular injection of a liquid preparation, oral
administration of a liquid or solid preparation, or by topical
application. Administration can also be accomplished by use of a
rectal suppository or a urethral suppository. The pharmaceutical
composition can also be a parenteral formulation; in one
embodiment, the formulation comprises a liposome that includes a
complex of a compound of this invention.
[0178] The pharmaceutical composition of the invention can be
prepared by known dissolving, mixing, granulating, or
tablet-forming processes. For oral administration, the compounds of
this invention or their physiologically tolerated derivatives such
as salts, esters, N-oxides, and the like are mixed with additives
customary for this purpose, such as vehicles, stabilizers, or inert
diluents, and converted by customary methods into a suitable form
for administration, such as tablets, coated tablets, hard or soft
gelatin capsules, aqueous, alcoholic or oily solutions. Examples of
suitable inert vehicles are conventional tablet bases such as
lactose, sucrose, or cornstarch in combination with binders like
acacia, cornstarch, gelatin, or with disintegrating agents such as
cornstarch, potato starch, alginic acid, or with a lubricant such
as stearic acid or magnesium stearate. Examples of suitable oily
vehicles or solvents are vegetable or animal oils such as sunflower
oil or fish-liver oil. Preparations can be effected both as dry and
as wet granules. For parenteral administration (subcutaneous,
intravenous, intraarterial, or intramuscular injection), the
compounds of this invention or their physiologically tolerated
derivatives such as salts, esters, N-oxides, and the like are
converted into a solution, suspension, or emulsion, if desired with
the substances customary and suitable for this purpose, for
example, solubilizers or other auxiliaries. Examples are: sterile
liquids such as water and oils, with or without the addition of a
surfactant and other pharmaceutically acceptable adjuvants.
Illustrative oils are those of petroleum, animal, vegetable, or
synthetic origin, for example, peanut oil, soybean oil, or mineral
oil. In general, water, saline, aqueous dextrose and related sugar
solutions, and glycols such as propylene glycols or polyethylene
glycol are preferred liquid carriers, particularly for injectable
solutions.
[0179] The preparation of pharmaceutical compositions which contain
an active component is well understood in the art. Typically, such
compositions are prepared as an aerosol of the polypeptide
delivered to the nasopharynx or as injectables, either as liquid
solutions or suspensions, however, solid forms suitable for
solution in, or suspension in, liquid prior to injection can also
be prepared. The preparation can also be emulsified. The active
therapeutic ingredient is often mixed with excipients which are
pharmaceutically acceptable and compatible with the active
ingredient. Suitable excipients are, for example, water, saline,
dextrose, glycerol, ethanol, or the like and combinations thereof.
In addition, if desired, the composition can contain minor amounts
of auxiliary substances such as wetting or emulsifying agents, or
pH buffering agents which enhance the effectiveness of the active
ingredient.
[0180] For topical administration to body surfaces using, for
example, creams, gels, drops, and the like, the compounds of this
invention or their physiologically tolerated derivatives such as
salts, esters, N-oxides, and the like are prepared and applied as
solutions, suspensions, or emulsions in a physiologically
acceptable diluent with or without a pharmaceutical carrier.
[0181] In another embodiment, the active compound can be delivered
in a vesicle, in particular a liposome (see Langer, Science
249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy of
Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.),
Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp.
317-327; see generally ibid).
[0182] In some embodiments, any of the compositions of this
invention will comprise a compound of formula I-XXIV, in any form
or embodiment as described herein. In some embodiments, any of the
compositions of this invention will consist of a compound of
formula I-XXIV, in any form or embodiment as described herein. In
some embodiments, of the compositions of this invention will
consist essentially of a compound of I-XXIV in any form or
embodiment as described herein. In some embodiments, the term
"comprise" refers to the inclusion of the indicated active agent,
such as the compound of formula I-XXIV, as well as inclusion of
other active agents, and pharmaceutically acceptable carriers,
excipients, emollients, stabilizers, etc., as are known in the
pharmaceutical industry. In some embodiments, the term "consisting
essentially of" refers to a composition, whose only active
ingredient is the indicated active ingredient, however, other
compounds may be included which are for stabilizing, preserving,
etc. the formulation, but are not involved directly in the
therapeutic effect of the indicated active ingredient. In some
embodiments, the term "consisting essentially of" refers to a
composition, whose only active ingredient with a comparable mode of
action, or comparable molecular target is the indicated active
ingredient, however, other active ingredients may be incorporated,
with such secondary active ingredients acting on different targets,
or in a palliative capacity. In some embodiments, the term
"consisting essentially of" may refer to components which
facilitate the release of the active ingredient. In some
embodiments, the term "consisting" refers to a composition, which
contains the active ingredient and a pharmaceutically acceptable
carrier or excipient.
[0183] In one embodiment, the present invention provides combined
preparations. In one embodiment, the term "a combined preparation"
defines especially a "kit of parts" in the sense that the
combination partners as defined above can be dosed independently or
by use of different fixed combinations with distinguished amounts
of the combination partners i.e., simultaneously, concurrently,
separately or sequentially. In some embodiments, the parts of the
kit of parts can then, e.g., be administered simultaneously or
chronologically staggered, that is at different time points and
with equal or different time intervals for any part of the kit of
parts. The ratio of the total amounts of the combination partners,
in some embodiments, can be administered in the combined
preparation. In one embodiment, the combined preparation can be
varied, e.g., in order to cope with the needs of a patient
subpopulation to be treated or the needs of the single patient
which different needs can be due to a particular disease, severity
of a disease, age, sex, or body weight as can be readily made by a
person skilled in the art.
[0184] It is to be understood that this invention is directed to
compositions and combined therapies as described herein, for any
disease, disorder or condition, as appropriate, as will be
appreciated by one skilled in the art. Certain applications of such
compositions and combined therapies have been described
hereinabove, for specific diseases, disorders and conditions,
representing embodiments of this invention, and methods of treating
such diseases, disorders and conditions in a subject by
administering a compound as herein described, alone or as part of
the combined therapy or using the compositions of this invention
represent additional embodiments of this invention.
[0185] In some embodiments, the compounds of this invention
modulate the activity of a nucleic acid polymerase. In some
embodiments, the term "modulate" refers to the compound's
enhancement or stimulation of enzyme activity. In some embodiments,
according to this aspect of the invention, the compounds of this
invention promote greater activity of a nucleic acid polymerase. In
some embodiments, such promotion is direct, or in some embodiments,
such promotion of enhanced activity is indirect.
[0186] Such effects on polymerase activity can be readily
ascertained by standard methodology known in the art, for example,
via performance of co-immunoprecipitation assays to ascertain
binding of the compound to the polymerase, performance of
quantitative PCR to determine effects of the compound on polymerase
activity, and others. See for example, See, for example, "Molecular
Cloning: A laboratory Manual" Sambrook et al., (1989); "Current
Protocols in Molecular Biology" Volumes I-III Ausubel, R. M., ed.
(1994); Ausubel et al., "Current Protocols in Molecular Biology",
John Wiley and Sons, Baltimore, Maryland (1989); Perbal, "A
Practical Guide to Molecular Cloning", John Wiley & Sons, New
York (1988); Watson et al., "Recombinant DNA", Scientific American
Books, New York; Birren et al. (eds) "Genome Analysis: A Laboratory
Manual Series", Vols. 1-4, Cold Spring Harbor Laboratory Press, New
York (1998); methodologies as set forth in U.S. Pat. Nos.
4,666,828; 4,683,202; 4,801,531; 5,192,659 and 5,272,057; "Cell
Biology: A Laboratory Handbook", Volumes I-III Cells, J. E., ed.
(1994); "Current Protocols in Immunology" Volumes I-III Coligan J.
E., ed. (1994); Stites et al. (eds), "Basic and Clinical
Immunology" (8th Edition), Appleton & Lange, Norwalk, Conn.
(1994); Mishell and Shiigi (eds), "Selected Methods in Cellular
Immunology", W. H. Freeman and Co., New York (1980);
"Oligonucleotide Synthesis" Gait, M. J., ed. (1984); "Nucleic Acid
Hybridization" Hames, B. D., and Higgins S. J., eds. (1985);
"Transcription and Translation" Hames, B. D., and Higgins S. J.,
eds. (1984); "Animal Cell Culture" Freshney, R. I., ed. (1986);
"Immobilized Cells and Enzymes" IRL Press, (1986); "A Practical
Guide to Molecular Cloning" Perbal, B., (1984) and "Methods in
Enzymology" Vol. 1-317, Academic Press; "PCR Protocols: A Guide To
Methods And Applications", Academic Press, San Diego, Calif.
(1990); Marshak et al., "Strategies for Protein Purification and
Characterization--A Laboratory Course Manual" CSHL Press (1996);
all of which are incorporated fully by reference herein.
[0187] The following examples are presented in order to more fully
illustrate the preferred embodiments of the invention. They should
in no way be construed, however, as limiting the broad scope of the
invention.
EXAMPLE 1
Synthesis of Compound of Formula VI
[0188] 1,1,1-tris(4-hydroxyphenyl)ethane (4 g, 13 mM), formaldehyde
(3.6 g, 120 mM) and a 40% solution of dimethylamine in water (15
ml) were added to a solution of 50 ml water and 60 ml EtOH. The
solution was refluxed for 2.5 hours. Partial evaporation of the
solvent precipitated a white solid, which was filtered, washed with
water and dried to give 7.85 g white solid of compound of formula
VI, 93% yield, mp.=169.degree..
[0189] NMR CDCl.sub.3.TM. 6.64 (6H, s, ArH), 3.40 (12H, s,
CH.sub.2), 2.22 (36H, s, N--CH.sub.3), 2.06 (3H, s,
C--CH.sub.3).
EXAMPLE 2
Synthesis of Compound of Formula VII
[0190] Compound of formula VII was synthesized by a process
comparable to that described in Example 1.
[0191] NMR CDCl.sub.3.TM. 6.71 (6H, s, ArH), 3.58 (12H, s,
CH.sub.2), 2.54 (24H, q, J=7.0 Hz), 1.04 (24H, t, J=7.0 Hz).
EXAMPLE 3
Synthesis of Compound of Formula VIII
[0192] 1,1,1-tris(4-hydroxyphenyl)ethane (1.53 gr, 5 mM),
formaldehyde (1.35 gr, 45 mM) and 1-methyl piperazine (2.5 ml, 50
mM) in 20 ml water and 25 ml EtOH were refluxed for 3 hours.
Evaporation provided a solid that by TLC and NMR contained 2
products, which was not the starting material. Formaldehyde (0.75
gr, 25 mM) and 1-methyl piperazine (1.5 ml, 30 mM) were added to 5
ml water and 10 ml EtOH and the reaction was refluxed for 4 hours.
Evaporation and workup gave 3.3 gr light yellow-white solid, 67%
yield, mp. -63.degree.. Soluble in ethanol, and very good
solubility in water.
[0193] NMR CDCl.sub.3.TM.6.67 (6H, s, ArH), 3.53 (12H, s,
CH.sub.2), 2.44 (48H, br.m, ring piperazine), 2.26 (18H, s,
N--CH.sub.3), 2.00 (3H, s, C--CH.sub.3).
EXAMPLE 4
Synthesis of Compound of Formula IX
[0194] A compound of formula IX was synthesized by a process
comparable to that described in Example 1. A white solid was
obtained. mp.=178.degree..
[0195] NMR CDCl.sub.3.TM. 6.68 (6H, s, ArH), 3.55 (12H, s,
CH.sub.2), 2.51 (24H, br.t, N--CH.sub.2 ring), 2.03 (3H, s,
C--CH.sub.3), 1.55 (24H, br.t, N--CH.sub.2 ring), 1.42 (12H,
br.s).
EXAMPLE 5
Synthesis of Compound of Formula X
[0196] A compound of formula X was synthesized by a process
comparable to that described in Example 1. A white solid was
obtained. mp.=135.degree..
[0197] NMR CDCl.sub.3.TM. 6.68 (6H, s, ArH), 3.61 (12H, s,
CH.sub.2), 2.51 (24H, br.t, N--CH.sub.2 ring), 2.03 (3H, s,
C--CH.sub.3), 1.76 (24H, br.t, N--CH.sub.2 ring).
EXAMPLE 6
Synthesis of Compound of Formula XI
[0198] A compound of formula XI was synthesized by a process
comparable to that described in Example 1. White solid was
obtained. mp.=212.degree..
[0199] NMR CDCl.sub.3.TM. 6.68 (6H, s, ArH), 3.69 (24H, t, J=4.5
Hz, N--CH.sub.2 ring), 3.52 (12H, s, CH.sub.2), 2.45 (24H, br.t,
O--CH.sub.2 ring), 2.03 (3H, s, C--CH.sub.3).
EXAMPLE 7
Synthesis of 1,1,1-tris(4-hydroxy-3,5-diethoxy-phenyl)-ethane
[0200] Step 1: Compound of formula IV (2.98 g, 4.6 mM), prepared by
a process comparable to that described in Example 1 was added to 20
ml acetic anhydride, and heated to 100.degree. for 4 hours. The
mixture was cooled and water was added. The mixture was stirred
overnight at room temperature, and then extracted with
CH.sub.2Cl.sub.2. The solvent was evaporated to give a nona-acetate
derivative as yellow oil and was further purified by chromatography
(silica gel; 1% MeOH/CH.sub.2Cl.sub.2) to give 3.2 gr of viscous
yellow oil, 80% yield.
[0201] Step 2: A KOH (4 g) solution in water was added to a
solution of the nona-acetate of step 1 (2.5 g) in 20 ml EtOH. The
mixture was stirred for 20 hours at room temperature. The mixture
was acidified with HCl, and extracted with CH.sub.2Cl.sub.2. The
solvent was evaporated and gave 2.2 g of a yellow oil that and was
further purified by column chromatography (silica gel; 2%
MeOH/CH.sub.2Cl.sub.2) and recrystallized from toluene-hexane to
give 1 gr of 1,1,1-tris(4-hydroxy-3,5-diethoxy-phenyl)-ethane, 53%
yield, white solid, mp-78.degree.. TLC-Rf=0.55 in 5%
MeOH/CH.sub.2Cl.sub.2.
[0202] NMR CDCl.sub.3.TM. 7.93 (3H, s, OH), 6.79 (6H, s, Ar--H),
4.54 (12H, s, Ar--CH.sub.2), 3.55 (12H, q, J=7.0 Hz, CH.sub.2),
2.05 (3H, s, C--CH.sub.3), 1.22 (18H, t, J=7.0 Hz, CH.sub.3).
EXAMPLE 8
Synthesis of 1,1,1-tris(4-hydroxy-3,5-dibromo-phenyl)-ethane
[0203] Step 1: A solution of NaOH (1 g, 25 mM) in 10 ml water and
dimethyl sulphate (5.1 gr, 40 mM)(1:8 molar ratio) was added during
1 hour and simultaneously in portions to a solution of
1,1,1-tris(4-hydroxyphenyl)-ethane (1.53 g, 5 mM) in 20 ml ethanol
and 10 ml water. The solution was then refluxed for 1 hour, and
stirred 70 hours at RT. The white precipitate was filtered, washed
with water and dried to give 1.74 g of
1,1,1-tris(4-methoxyphenyl)-ethane. Recrystalization twice from 50
ml ethanol gave 1.15 gr white crystals, 66% yield,
m.p.-160.degree.. TLC Rf=0.85 in CH.sub.2Cl.sub.2.
[0204] NMR CDCl.sub.3.TM. 6.99, 6.79 (12H, AB.sub.q, J.sub.AB=8.8
Hz), 3.78 (9H, s, OCH.sub.3), 2.11 (3H, s, CH.sub.3).
[0205] Step 2: To a solution of 1,1,1-tris(4-methoxyphenyl)-ethane
(0.49 gr, 1.4 mM,), from step 1, in 22 ml 1,2-dichloroethane, a
solution of bromine (1.65 gr, 10.2) (7.3:1 ratio) in 5 ml
1,2-dichloroethane was added in portions. The solution was stirred
at RT overnight and heated for 3 hours to 70.degree., and worked up
(sodium thiosulphate) to give 1.0 gr crude product. TLC shows no
starting material, but NMR showed mixtures, indicating that the
bromination was not complete (m at 6.90 ppm, and 4 methoxy). The
solid was brominated again with 1 gr bromine and refluxed 18 hours.
The mixture was worked up as above and triturated with hot ethanol
to give 0.27 gr white solid, 23% yield, mp=160.degree.. TLC Rf=0.95
in CH.sub.2Cl.sub.2.
[0206] NMR CDCl.sub.3.TM. 7.16 (6H, s, ArH), 3.92, 3.91 (6:4
ratio)(9H, 2s, OCH.sub.3), 2.04, 2.03 (4:6 ratio)(3H, s,
CH.sub.3).
EXAMPLE 9
Synthesis of 1,1,1-tris(4-hydroxy-3,5 -diiodo-phenyl)-ethane
(Compound XIV)
[0207] To 1,1,1-tris(4-hydroxyphenyl)-ethane (1.53 gr, 5 mM) in 40
ml ethanol and 40 ml water cooled in ice, KOH (2.2 gr, 39.2 mM)
followed by KI (5.8 gr, 34.8 mM) and iodine (8.8 gr, 34.7 mM) were
added. The color turns from violet to brown. The reaction was
stirred at room temperature for 3 hours. The mixture was added to
crushed ice. Concentrated HCl was added to obtain acidic pH and was
treated with thiosulphate solution and extracted with
dichloromethane. Evaporation gave 5.1 gr light brown solid, hexa
iodo product followed by trituration in ethanol gave 3 gr white
solid, 61% yield, mp=230.degree.. RF=0.8 (in 5%
MeOH--CH.sub.2Cl.sub.2).
[0208] NMR CDCl.sub.3.TM. 7.3 (6H, s), 5.77 (br.s, OH), 1.97 (3H,
s, CH.sub.3).
[0209] While certain features of the invention have been
illustrated and described herein, many modifications,
substitutions, changes, and equivalents will now occur to those of
ordinary skill in the art. It is, therefore, to be understood that
the appended claims are intended to cover all such modifications
and changes as fall within the true spirit of the invention.
* * * * *