U.S. patent application number 10/514625 was filed with the patent office on 2006-03-09 for amino-functional chalcones.
Invention is credited to Thomas Boesen, Majbritt Hansen, Hasse Kromann, Mogens Larsen, Simone Feldbaek Nielsen.
Application Number | 20060052600 10/514625 |
Document ID | / |
Family ID | 29553776 |
Filed Date | 2006-03-09 |
United States Patent
Application |
20060052600 |
Kind Code |
A1 |
Nielsen; Simone Feldbaek ;
et al. |
March 9, 2006 |
Amino-functional chalcones
Abstract
The invention provides novel amino-functionalised chalcone
derivatives and analogues thereof. Use of the compounds, or
compositions comprising them, as pharmaceutically active agents, in
particular against bacterial and parasitic infections, is also
disclosed. The invention further relates to a method for detecting
inhibitory effects against e.g., bacteria, parasites, fungi, and
helminths. The chalcones of the invention carry amino substituents
and exhibit enhanced biological effects combined with improved
metabolic and physicochemical properties, making the compounds
useful as drug substances, in particular as antiparasitic, and
bacteriocidal agents.
Inventors: |
Nielsen; Simone Feldbaek;
(Herlev, DK) ; Kromann; Hasse; (Copenhagen,
DK) ; Larsen; Mogens; (Smorum, DK) ; Hansen;
Majbritt; (Frederiksberg, DK) ; Boesen; Thomas;
(Copenhagen, DK) |
Correspondence
Address: |
HUNTON & WILLIAMS LLP;INTELLECTUAL PROPERTY DEPARTMENT
1900 K STREET, N.W.
SUITE 1200
WASHINGTON
DC
20006-1109
US
|
Family ID: |
29553776 |
Appl. No.: |
10/514625 |
Filed: |
May 19, 2003 |
PCT Filed: |
May 19, 2003 |
PCT NO: |
PCT/DK03/00331 |
371 Date: |
June 27, 2005 |
Current U.S.
Class: |
544/238 ;
544/333; 544/405; 546/148; 546/176; 548/200; 548/312.7; 548/365.1;
548/465; 548/518 |
Current CPC
Class: |
C07C 217/22 20130101;
C07C 233/33 20130101; C07C 49/813 20130101; C07C 255/56 20130101;
C07D 295/088 20130101; C07D 317/66 20130101; C07C 47/277 20130101;
C07C 225/22 20130101; C07C 323/32 20130101; C07D 295/185 20130101;
C07C 47/575 20130101; C07C 47/277 20130101; C07D 213/65 20130101;
C07D 309/12 20130101; C07C 225/16 20130101; C07C 311/21 20130101;
C07C 45/00 20130101; C07C 233/36 20130101; C07C 45/44 20130101;
C07C 45/00 20130101; A61P 31/04 20180101; C07D 295/112 20130101;
C07C 47/575 20130101; C07C 237/04 20130101; C07C 47/55 20130101;
C07D 307/79 20130101; C07C 45/44 20130101 |
Class at
Publication: |
544/238 ;
544/405; 544/333; 546/176; 546/148; 548/200; 548/518; 548/465;
548/312.7; 548/365.1 |
International
Class: |
C07D 417/02 20060101
C07D417/02; C07D 403/02 20060101 C07D403/02; C07D 401/02 20060101
C07D401/02 |
Foreign Application Data
Date |
Code |
Application Number |
May 17, 2002 |
DK |
PA 2002 00762 |
May 17, 2002 |
DK |
PA 2002 00763 |
Jul 18, 2002 |
DK |
PA 2002 01114 |
Claims
1. A compound of the formula
(Y.sup.1).sub.m--Ar.sup.1(X.sup.1)--C(.dbd.O)VAr.sup.2(X.sup.2)--(Y.sup.2-
).sub.p and salts thereof; wherein Ar.sup.1 and Ar.sup.2
independently are selected from aryl and heteroaryl; V designates
--CH.sub.2--CH.sub.2--, --CH.dbd.CH-- or --C.ident.C--; m is a
whole number selected from the group consisting of 0, 1, and 2, p
is a whole number selected from the group consisting of 0, 1, and
2, wherein the sum of m and p is at least 1; each Y.sup.1 is
independently selected from an amino-functional substituent of the
formula -Z-N(R.sup.1)R.sup.2, each Y.sup.2 is independently
selected from an amino-functional substituent of the formula
-Z-N(R.sup.1)R.sup.2, wherein Z is a biradical
--(C(R.sup.H).sub.2).sub.n--, wherein n is an integer in the range
of 1-6, and each R.sup.H is independently selected from hydrogen
and C.sub.1-6-alkyl, or wherein (R.sup.H).sub.2 is .dbd.O; R.sup.1
and R.sup.2 independently are selected from hydrogen, optionally
substituted C.sub.1-12-alkyl, optionally substituted
C.sub.2-12-alkenyl, optionally substituted C.sub.4-12-alkadienyl,
optionally substituted C.sub.6-12-alkatrienyl, optionally
substituted C.sub.2-12-alkynyl, optionally substituted
C.sub.1-12-alkoxycarbonyl, optionally substituted
C.sub.1-12-alkylcarbonyl, optionally substituted aryl, optionally
substituted aryloxycarbonyl, optionally substituted arylcarbonyl,
optionally substituted heteroaryl, optionally substituted
heteroaryloxycarbonyl, optionally substituted heteroarylcarbonyl,
aminocarbonyl, mono- and di(C.sub.1-6-alkyl)aminocarbonyl,
amino-C.sub.1-6-alkyl-aminocarbonyl, mono- and
di(C.sub.1-6-alkyl)amino-C.sub.1-6-alkyl-aminocarbon-yl; or wherein
N(R.sup.1)R.sup.2) forms an optionally substituted
nitrogen-containing heterocyclic ring; X.sup.1 and X.sup.2
independently designates a substituent present 0-5 times, on
Ar.sup.1 and Ar.sup.2, respectively, wherein each X.sup.1 and
X.sup.2 is independently selected from the group consisting of
optionally substituted C.sub.1-12-alkyl, optionally substituted
C.sub.2-12-alkenyl, optionally substituted C.sub.4-12-alkadienyl,
optionally substituted C.sub.6-12-alkatrienyl, optionally
substituted C.sub.2-12-alkynyl, hydroxy, optionally substituted
C.sub.1-12-alkoxy, optionally substituted C.sub.2-12-alkenyloxy,
carboxy, optionally substituted C.sub.1-12-alkoxycarbonyl,
optionally substituted C.sub.1-12-alkylcarbonyl, formyl,
C.sub.1-6-alkylsulphonylamino, optionally substituted aryl,
optionally substituted aryloxycarbonyl, optionally substituted
aryloxy, optionally substituted arylcarbonyl, optionally
substituted arylamino, arylsulphonylamino, optionally substituted
heteroaryl, optionally substituted heteroaryloxycarbonyl,
optionally substituted heteroaryloxy, optionally substituted
heteroarylcarbonyl, optionally substituted heteroarylamino,
optionally substituted (heteroarylalkyl)amino, optionally
substituted (heteroarylalkyl)alkylamino, heteroarylsulphonylamino,
optionally substituted heterocyclyloxycarbonyl, optionally
substituted heterocyclyloxy, optionally substituted
heterocyclylcarbonyl, optionally substituted heterocyclylamino,
heterocyclylsulphonylamino, amino, mono- and
di(C.sub.1-6-alkyl)amino, carbamoyl, mono- and
di(C.sub.1-6-alkyl)aminocarbonyl,
amino-C.sub.1-6-alkyl-aminocarbonyl, mono- and
di(C.sub.1-6-alkyl)amino-C.sub.1-6-alkyl-aminocarbonyl,
C.sub.1-6-alkylcarbonylamino, cyano, guanidino, carbamido,
C.sub.1-6-alkanoyloxy, C.sub.1-6-alkylsulphonyl,
C.sub.1-6-alkylsulphinyl, C.sub.1-6-alkylsulphonyl-oxy,
aminosulfonyl, mono- and di(C.sub.1-6-alkyl)aminosulfonyl, nitro,
optionally substituted C.sub.1-6-alkylthio, and halogen, where any
nitrogen-bound C.sub.1-6-alkyl is optionally substituted with
hydroxy, C.sub.1-6-alkoxy, C.sub.2-6-alkenyloxy, carboxy, halogen,
C.sub.1-6-alkylthio, C.sub.1-6-alkyl-sulphonyl-amino, or
guanidine.
2-50. (canceled)
51. A compound of the formula
(Y.sup.1).sub.m--Ar.sup.1(X.sup.1)--C(.dbd.O)VAr.sup.2(X.sup.2)--(Y.sup.2-
).sub.p and salts thereof; wherein Ar.sup.1 and Ar.sup.2
independently are selected from aryl and heteroaryl; V designates
--CH.sub.2--CH.sub.2--, --CH.dbd.CH-- or --C.ident.C--; m is a
whole number selected from the group consisting of 0, 1, and 2, p
is a whole number selected from the group consisting of 0, 1, and
2, wherein the sum of m and p is at least 1; each Y.sup.1 is
independently selected from an amino-functional substituent of the
formula -Z-N(R.sup.1)R.sup.2, each Y.sup.2 is independently
selected from an amino-functional substituent of the formula
-Z-N(R.sup.1)R.sup.2, wherein Z is a biradical
--(C(R.sup.H).sub.2).sub.n--, wherein n is an integer in the range
of 1-6, and each R.sup.H is independently selected from hydrogen
and C.sub.1-6-alkyl, or wherein (R.sup.H).sub.2 is .dbd.O; R.sup.1
and R.sup.2 independently are selected from the group consisting of
hydrogen, optionally substituted C.sub.1-12-alkyl, optionally
substituted C.sub.2-12-alkenyl, optionally substituted
C.sub.4-12-alkadienyl, optionally substituted
C.sub.6-12-alkatrienyl, optionally substituted C.sub.2-12-alkynyl,
optionally substituted C.sub.1-12-alkoxycarbonyl, optionally
substituted C.sub.1-12-alkylcarbonyl, optionally substituted aryl,
optionally substituted aryloxycarbonyl, optionally substituted
arylcarbonyl, optionally substituted heteroaryl, optionally
substituted heteroaryloxy-carbonyl, optionally substituted
heteroarylcarbonyl, aminocarbonyl, mono- and
di(C.sub.1-6-alkyl)aminocarbonyl,
amino-C.sub.1-6-alkyl-aminocarbonyl, mono- and
di(C.sub.1-6-alkyl)amino-C.sub.1-6-alkyl-aminocarbonyl; or wherein
N(R.sup.1)R.sup.2) forms an optionally substituted
nitrogen-containing heterocyclic ring; X.sup.1 and X.sup.2
independently designates a substituent present 0-5 times, on
Ar.sup.1 and Ar.sup.2, respectively, wherein each X.sup.1 and
X.sup.2 is independently selected from the group consisting of
optionally substituted C.sub.1-12-alkyl, optionally substituted
C.sub.2-12-alkenyl, optionally substituted C.sub.4-12-alkadienyl,
optionally substituted C.sub.6-12-alkatrienyl, optionally
substituted C.sub.2-12-alkynyl, hydroxy, optionally substituted
C.sub.1-12-alkoxy, optionally substituted C.sub.2-12-alkenyloxy,
carboxy, optionally substituted C.sub.1-12-alkoxycarbonyl,
optionally substituted C.sub.1-12-alkylcarbonyl, formyl,
C.sub.1-6-alkylsulphonylamino, optionally substituted aryl,
optionally substituted aryloxycarbonyl, optionally substituted
aryloxy, optionally substituted arylcarbonyl, optionally
substituted arylamino, arylsulphonylamino, optionally substituted
heteroaryl, optionally substituted heteroaryloxycarbonyl,
optionally substituted heteroaryloxy, optionally substituted
heteroarylcarbonyl, optionally substituted heteroarylamino,
optionally substituted (heteroarylalkyl)amino, optionally
substituted (heteroarylalkyl)alkylamino, heteroarylsulphonylamino,
optionally substituted heterocyclyloxycarbonyl, optionally
substituted heterocyclyloxy, optionally substituted
heterocyclylcarbonyl, optionally substituted heterocyclylamino,
heterocyclylsulphonylamino, amino, mono- and
di(C.sub.1-6-alkyl)amino, carbamoyl, mono- and and
di(C.sub.1-6-alkyl)aminocarbonyl,
amino-C.sub.1-6-alkyl-aminocarbonyl, mono- and
di(C.sub.1-6-alkyl)amino-C.sub.1-6-alkyl-aminocarbonyl,
C.sub.1-6-alkylcarbonylamino, cyano, guanidino, carbamido,
C.sub.1-6-alkanoyloxy, C.sub.1-6-alkylsulphonyl,
C.sub.1-6-alkylsulphinyl, C.sub.1-6-alkylsulphonyl-oxy,
aminosulfonyl, mono- and di(C.sub.1-6-alkyl)aminosulfonyl, nitro,
optionally substituted C.sub.1-6-alkylthio, and halogen, where any
nitrogen-bound C.sub.1-6-alkyl is optionally substituted with
hydroxy, C.sub.1-6-alkoxy, C.sub.2-6-alkenyloxy, carboxy, halogen,
C.sub.1-6-alkylthio, C.sub.1-6-alkyl-sulphonyl-amino, or
guanidine.
52. The compound of claim 51, wherein, when Ar.sup.1 and Ar.sup.2
are both phenyl, V is --CH.dbd.CH--, Z is CH.sub.2, R.sup.1 and
R.sup.2 are methyl or together form a morpholino group, and one of
m and p is 2 while the other of m and p is 0, then X.sup.1 and
X.sup.2 independently designates 0-5 substituents, where such
optional substituents independently are selected from the group
consisting of optionally substituted C.sub.1-12-alkyl, optionally
substituted C.sub.2-12-alkenyl, optionally substituted
C.sub.4-12-alkadienyl, optionally substituted
C.sub.6-12-alkatrienyl, optionally substituted C.sub.2-12-alkynyl,
2-, 3-, 5-, or 6-hydroxy, optionally substituted C.sub.1-12-alkoxy,
optionally substituted C.sub.2-12-alkenyloxy, carboxy, optionally
substituted C.sub.1-12-alkoxycarbonyl, optionally substituted
C.sub.1-12-alkylcarbonyl, formyl, C.sub.1-6-alkylsulphonylamino,
optionally substituted aryl, optionally substituted
aryloxycarbonyl, optionally substituted aryloxy, optionally
substituted arylcarbonyl, optionally substituted arylamino,
arylsulphonylamino, optionally substituted heteroaryl, optionally
substituted heteroaryloxycarbonyl, optionally substituted
heteroaryloxy, optionally substituted heteroarylcarbonyl,
optionally substituted heteroarylamino, optionally substituted
(heteroarylalkyl)amino, optionally substituted
(heteroarylalkyl)alkylamino, heteroarylsulphonylamino, optionally
substituted heterocyclyloxycarbonyl, optionally substituted
heterocyclyloxy, optionally substituted heterocyclylcarbonyl,
optionally substituted heterocyclylamino,
heterocyclylsulphonylamino, amino, mono- and
di(C.sub.1-6-alkyl)amino, carbamoyl, mono- and
di(C.sub.1-6-alkyl)aminocarbonyl,
amino-C.sub.1-6-alkyl-aminocarbonyl, mono- and
di(C.sub.1-6-alkyl)amino-C.sub.1-6-alkyl-aminocarbonyl,
C.sub.1-6-alkylcarbonylamino, cyano, guanidino, carbamido,
C.sub.1-6-alkanoyloxy, C.sub.1-6-alkylsulphonyl,
C.sub.1-6-alkylsulphinyl, C.sub.1-6-alkylsulphonyl-oxy,
aminosulfonyl, mono- and di(C.sub.1-6-alkyl)aminosulfonyl, nitro,
optionally substituted C.sub.1-6-alkylthio, and halogen, where any
nitrogen-bound C.sub.1-6-alkyl may be substituted with hydroxy,
C.sub.1-6-alkoxy, C.sub.2-6-alkenyloxy, carboxy, halogen,
C.sub.1-6-alkylthio, C.sub.1-6-alkyl-sulphonyl-amino, or guanidine;
provided that when Ar.sup.1 and Ar.sup.2 are both phenyl, V is
--CH.dbd.CH--, m is 1, p is 0, Y.sup.1 is 2--CH.sub.2NMe.sub.2,
X.sup.2 is absent, and X.sup.1 is present 1 time, then X.sup.1 is
not 4-methoxy, when Ar.sup.1 and Ar.sup.2 are both phenyl, V is
--CH.dbd.CH--, m is 1, p is 0, Y.sup.1 is 3- or 4-CH.sub.2NR.sup.1
R.sup.2, wherein R.sup.1 and R.sup.2 are selected from hydrogen,
methyl, and ethyl, and X.sup.2 is present 0 or 1 time and is
selected from 4-hydroxy or 4-alkoxy, and X.sup.2 is present 0 or 1
time, then X.sup.2 is not selected from the group consisting of
nitro, dichloro, carboxymethoxy, methoxycarbonylmethoxy,
ethoxycarbonylmethoxy, 2-carboxyethyl, when Ar.sup.1 and Ar.sup.2
are both phenyl, V is --CH.dbd.CH--, m is 0, p is 1, Y.sup.2
present 1 time and is 2- or 3CH.sub.2NR.sup.1R.sup.2, wherein
R.sup.1 and R.sup.2 are selected from hydrogen, methyl, and ethyl,
X.sup.2 is present 0 or 1 time and is 4-OH, and X.sup.1 is present
0 or 1 time, then X.sup.1 is not ethoxycarbonylmethoxy or
dichloro.
53. The compound of claim 51, wherein R.sup.1 and R.sup.2
independently are selected from the group consisting of hydrogen,
optionally substituted C.sub.1-12-alkyl, optionally substituted
C.sub.2-12-alkenyl, optionally substituted C.sub.2-12-alkynyl,
optionally substituted C.sub.1-12-alkylcarbonyl, arylcarbonyl,
heteroarylcarbonyl, aminocarbonyl, mono- and
di(C.sub.1-6-alkyl)-aminocarbonyl,
amino-C.sub.1-6-alkyl-aminocarbonyl, and mono- and
di(C.sub.1-6-alkyl)amino-C.sub.1-6-alkyl-aminocarbonyl.
54. The compound of claim 51, wherein X.sup.1 and X.sup.2
independently designates 0-4 substituents, where such optional
substituents independently are selected from the group consisting
of optionally substituted C.sub.1-12-alkyl, hydroxy, optionally
substituted C.sub.1-12-alkoxy, optionally substituted
C.sub.2-12-alkenyloxy, carboxy, optionally substituted
C.sub.1-12-alkylcarbonyl, formyl, C.sub.1-6-alkylsulphonylamino,
optionally substituted aryl, optionally substituted
aryloxycarbonyl, optionally substituted aryloxy, optionally
substituted arylcarbonyl, optionally substituted arylamino,
arylsulphonylamino, optionally substituted heteroaryl, optionally
substituted heteroarylamino, optionally substituted
(heteroarylalkyl)amino, optionally substituted
(heteroarylalkyl)alkylamino, amino, mono- and
di(C.sub.1-6-alkyl)amino, optionally substituted
heteroarylcarbonyl, optionally substituted heteroaryloxy,
heteroarylsulphonylamino, optionally substituted heterocyclyloxy,
optionally substituted heterocyclylamino, carbamoyl, mono- and
di(C.sub.1-6-alkyl)amino-carbonyl,
amino-C.sub.1-6-alkyl-aminocarbonyl, mono- and
di(C.sub.1-6-alkyl)amino-C.sub.1-6-alkyl-aminocarbonyl, guanidino,
carbamido, C.sub.1-6-alkylsulphonyl, C.sub.1-6-alkylsulphinyl,
C.sub.1-6-alkylsulphonyloxy, optionally substituted
C.sub.1-6-alkylthio, aminosulfonyl, mono- and
di(C.sub.1-6-alkyl)aminosulfonyl, and halogen, where any
nitrogen-bound C.sub.1-6-alkyl may be substituted with at least one
substituent selected from the group consisting of hydroxy,
C.sub.1-6-alkoxy, and halogen.
55. The compound of claim 51, wherein R.sup.1 and R.sup.2
independently are selected from the group consisting of hydrogen,
optionally substituted C.sub.1-6-alkyl, optionally substituted
C.sub.1-6-alkylcarbonyl, heteroarylcarbonyl, aminocarbonyl, mono-
and di(C.sub.1-6-alkyl)aminocarbonyl,
amino-C.sub.1-6-alkyl-aminocarbonyl, mono- and
di(C.sub.1-6-alkyl)amino-C.sub.1-6-alkyl-aminocarbonyl.
56. The compound of claim 51, wherein X.sup.1 and X.sup.2
independently designates 0-3 substituents, where such optional
substituents independently are selected from the group consisting
of optionally substituted C.sub.1-6-alkyl, hydroxy, optionally
substituted C.sub.1-6-alkoxy, carboxy, optionally substituted
C.sub.1-6-alkylcarbonyl, C.sub.1-6-alkylsulphonylamino, optionally
substituted aryl, optionally substituted aryloxy, optionally
substituted arylamino, amino, mono- and di(C.sub.1-6-alkyl)amino,
arylsulphonylamino, optionally substituted heteroaryl, optionally
substituted heteroarylamino, optionally substituted
(heteroarylalkyl)amino, optionally substituted
(heteroarylalkyl)alkylamino, heteroarylsulphonylamino, carbamoyl,
C.sub.1-6-alkylcarbonylamino, guanidino, carbamido, optionally
substituted C.sub.1-6-alkylthio, optionally substituted
heterocyclyloxy, optionally substituted heterocyclylamino and
halogen, where any nitrogen-bound C.sub.1-6-alkyl may be
substituted with at least one substituent selected from the group
consisting of hydroxy, C.sub.1-6-alkoxy, and halogen.
57. The compound of claim 51, wherein V designates
--CH.dbd.CH--.
58. The compound of claim 51, wherein at least one of Ar.sup.1 and
Ar.sup.2 are aryl.
59. The compound of claim 58, wherein both of Ar.sup.1 and Ar.sup.2
are phenyl rings, m is 1 or 2, and p is 0.
60. The compound of claim 51, wherein X.sup.2 represents at least
one substituent selected from the group consisting of
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6-alkylcarbonyl,
optionally substituted aryl, optionally substituted aryloxy,
optionally substituted arylamino, amino, mono- and
di(C.sub.1-6-alkyl)amino, optionally substituted heteroaryl,
optionally substituted heteroarylamino, optionally substituted
(heteroarylalkyl)amino, optionally substituted
(heteroarylalkyl)alkylamino, optionally substituted
C.sub.1-6-alkylthio, optionally substituted heterocyclyloxy,
optionally substituted heterocyclylamino and halogen.
61. The compound of claim 51, wherein at least one of Ar.sup.1 and
Ar.sup.2 is selected from the group consisting of thiazolyl,
pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,
pyridazinyl, thienyl, quinolyl, isoquinolyl, and indolyl.
62. The compound of claim 51, wherein Z is --(CH.sub.2).sub.n--
wherein n is 1-4.
63. The compound of claim 51, wherein one of Y.sup.1 and Y.sup.2
represents a substituent of the formula
--CH.sub.2--N(R.sup.1)R.sup.2 wherein R.sup.1 and R.sup.2 are
selected from hydrogen and C.sub.1-6-alkyl.
64. The compound of claim 63, wherein V is --CH.dbd.CH--, and
Ar.sup.1 and Ar.sup.2 both are phenyl rings.
65. The compound of claim 63, wherein Y.sup.1 represents the
substituent of the formula --CH.sub.2--N(R.sup.1)R.sup.2.
66. The compound of claim 51, selected from the group consisting
of:
1-(4-Methoxy-phenyl)-3-(4-morpholin-4-ylmethyl-phenyl)-propenone,
3-(4-Diethylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone,
1-(4-Methoxy-phenyl)-3-(4-propylaminomethyl-phenyl)-propenone,
3-(4-Dimethylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone,
3-{4-[(2-Dimethylamino-ethylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-p-
ropenone,
1-(4-Methoxy-phenyl)-3-(4-piperidin-1-ylmethyl-phenyl)-propenon- e,
3-{4-[(3-Dimethylamino-propylamino)-methyl]-phenyl}-1-(4-methoxy-pheny-
l)-propenone,
3-(4-Dibutylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone,
3-{4-[(4-Diethylamino-1-methyl-butylamino)-methyl]-phenyl}-1-(4-methoxy-p-
henyl)-propenone,
3-{3-[(2-Dimethylamino-ethylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-p-
ropenone,
3-(2,4-Dichloro-phenyl)-1-(4-dimethylaminomethyl-phenyl)-propen-
one, 1-(4-Methoxy-phenyl)-3-(3-propylaminomethyl-phenyl)-propenone,
1-(4-Methoxy-phenyl)-3-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propeno-
ne,
1-(4-Methoxy-phenyl)-3-[3-(4-methyl-[1,4]diazepan-1-ylmethyl)-phenyl]-
-propenone,
3-(3-Dimethylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone,
1-(2-Bromo-phenyl)-3-(2-dimethylaminomethyl-phenyl)-propenone,
3-{3-[(3-Dimethylamino-propylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)--
propenone,
3-(2,5-Dimethoxy-phenyl)-1-(4-dimethylaminomethyl-phenyl)-propenone,
3-(4-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-phenyl)-propenone,
3-(2,4-Dichloro-phenyl)-1-(3-dimethylaminomethyl-phenyl)-propenone,
3-(2,4-Dichloro-phenyl)-1-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-prop-
enone,
3-(2,4-Dichloro-phenyl)-1-{3-[(3-dimethylamino-propylamino)-methyl-
]-phenyl}-propenone,
3-(2,5-Dimethoxy-phenyl)-1-{4-[(3-dimethylamino-propylamino)-methyl]-phen-
yl}-propenone,
3-(3-Dimethylaminomethyl-phenyl)-1-(2-fluoro-4-methoxy-phenyl)-propenone,
3-(4-Dibutylamino-phenyl)-1-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-p-
ropenone,
3-(2,4-Dichloro-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-ph-
enyl]-propenone,
3-(2,4-Dichloro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,
3-(2,5-Dimethoxy-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-pro-
penone,
3-(2,5-Dimethoxy-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propeno-
ne,
3-(4-Dibutylamino-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,
3-(4-Dibutylamino-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-p-
ropenone,
3-(3-Dimethylaminomethyl-phenyl)-1-pyridin-2-yl-propenone,
3-(4-Dibutylamino-phenyl)-1-(4-dimethylaminomethyl-phenyl)-propenone,
3-[5-(1,1-Dimethyl-allyl)-2-methoxy-phenyl]-1-(2-dimethylaminomethyl-phen-
yl)-propenone,
1-{2-[(tert-Butyl-methyl-amino)-methyl]-phenyl}-3-(2,4-dichloro-phenyl)-p-
ropenone, Acetic acid
1-{2-[3-(2,4-dichloro-phenyl)-acryloyl]-benzyl}-piperidin-4-yl
ester,
3-(2,4-Dichloro-phenyl)-1-(2-morpholin-4-ylmethyl-phenyl)-propenone,
3-(2,4-Dichloro-phenyl)-1-(2-{[(2-dimethylamino-ethyl)-methyl-amino]-meth-
yl}-phenyl)-propenone,
3-(4-Diethylaminomethyl-phenyl)-1-o-tolyl-propenone,
3-(3-Dimethylaminomethyl-phenyl)-1-(2-methoxy-phenyl)-propenone,
3-(4-Chloro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,
3-(2,4-Difluoro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,
3-(3-Butylamino-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,
3-(4-Diethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenon-
e,
3-(2,4-Dichloro-phenyl)-1-(2-diethylaminomethyl-phenyl)-propenone,
3-(2,5-Dimethoxy-phenyl)-1-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-pro-
penone,
1-(2-Dimethylaminomethyl-phenyl)-3-(4-hydroxy-2-methoxy-5-propyl--
phenyl)-propenone,
3-(2,4-Dichloro-phenyl)-1-(2-piperazin-1-ylmethyl-phenyl)-propenone,
3-(2,5-Dimethoxy-phenyl)-1-(2-piperazin-1-yl
methyl-phenyl)-propenone,
1-(2-Dimethylaminomethyl-phenyl)-3-(4-dipropylamino-2-fluoro-phenyl)-prop-
enone,
3-(2,4-Dichloro-phenyl)-1-[2-(4-hydroxy-piperidin-1-ylmethyl)-phen-
yl]-propenone,
1-(3-Diethylaminomethyl-phenyl)-3-(2,5-dimethoxy-phenyl)-propenone,
3-(2-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-1-[2-(4-meth-
yl-piperazin-1-ylmethyl)-phenyl]-propenone,
3-(2,4-Dimethoxy-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-pro-
penone, 3-(4-l
midazol-1-yl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propeno-
ne,
1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-pyridin-2-yl-propenone-
,
1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-pyridin-3-yl-propenone,
1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-pyridin-4-yl-propenone,
1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-(1-methyl-1H-pyrrol-2-yl)--
propenone,
1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-(1H-pyrrol-2-yl)-propenone-
,
1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-thiophen-2-yl-propenone,
1,3-Bis-(2-diethylaminomethyl-phenyl)-propenone,
3-(2,4-Dichloro-phenyl)-1-(3-diethylaminomethyl-phenyl)-propenone,
3-(4-Dimethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phe-
nyl]-propenone,
3-(3-Dimethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phe-
nyl]-propenone,
3-(3-Dimethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propeno-
ne,
3-(2-Diethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl)-prop-
enone,
3-[3-(Butyl-ethyl-amino)-phenyl]-1-(2-dimethylaminomethyl-phenyl)--
propenone,
3-(3-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-1-(4-methoxy-
-phenyl)-propenone,
3-(2-Dimethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phe-
nyl]-propenone,
3-(2-Diethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phen-
yl]-propenone, 1,3-Bis-(2-dimethylaminomethyl-phenyl)-propenone,
3-(4-Dimethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propeno-
ne,
3-(1H-Indol-5-yl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propen-
one,
3-(2,4-Dimethoxy-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,
1-(2-Dimethylaminomethyl-phenyl)-3-(4-imidazol-1-yl-phenyl)-propenone,
1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-[3-(pyridin-3-ylamino)-phe-
nyl]-propenone,
3-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-1-(2,3,4-trimethoxy-phenyl)--
propenone,
3-{3-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-oxo-propenyl}-benzoic
acid,
1-(2-Dimethylaminomethyl-phenyl)-3-(2,4-dimethyl-phenyl)-propenone-
,
3-(2,4-Dimethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-pr-
openone,
1-(2-Dimethylaminomethyl-phenyl)-3-(1-methyl-1H-pyrrol-2-yl)-pro-
penone,
3-[4-Chloro-5-(1,1-dimethyl-allyl)-2-methoxy-phenyl]-1-[2-(4-meth-
yl-piperazin-1-ylmethyl)-phenyl]-propenone,
1-(2-Dimethylaminomethyl-phenyl)-3-(4-dipropylamino-2-ethoxy-phenyl)-prop-
enone,
1-(2-Dimethylaminomethyl-phenyl)-3-[2-(4-methyl-piperazin-1-ylmeth-
yl)-phenyl]-propenone,
3-(3-Dimethylaminomethyl-4-methoxy-phenyl)-1-(4-methoxy-phenyl)-propenone-
,
1-(2-Methoxy-phenyl)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-prope-
none,
1-(2-Fluoro-4-methoxy-phenyl)-3-[2-(4-methyl-piperazin-1-ylmethyl)--
phenyl]-propenone,
3-(2-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-1-(2-dimethy-
laminomethyl-phenyl)-propenone,
1-(2-Dimethylaminomethyl-phenyl)-3-[3-(pyridin-3-ylamino)-phenyl]-propeno-
ne,
3-(2-Dimethylaminomethyl-phenyl)-1-(3-dimethylaminomethyl-phenyl)-pro-
penone,
1-(3-Dimethylaminomethyl-phenyl)-3-(3-morpholin-4-ylmethyl-phenyl-
)-propenone,
1-(3-Dimethylaminomethyl-phenyl)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phe-
nyl]-propenone,
1-(3-Dimethylaminomethyl-phenyl)-3-(4-pyridin-2-yl-phenyl)-propenone,
1-(4-Methoxy-phenyl)-3-(3-{[methyl-(2-methylamino-ethyl)-amino]-methyl-ph-
enyl)-propenone,
3-(2-Dimethylaminomethyl-phenyl)-1-(2-fluoro-4-methoxy-phenyl)-propenone,
3-(2-Dimethylaminomethyl-phenyl)-1-(2,3,4-trimethoxy-phenyl)-propenone,
3-(3-{[(2-Hydroxy-ethyl)-methyl-amino]-methyl}-phenyl)-1-(4-methoxy-pheny-
l)-propenone,
1-(4-Methoxy-phenyl)-3-(3-methylaminomethyl-phenyl)-propenone,
1-(3-Dimethylaminomethyl-phenyl)-3-(4-methoxy-biphenyl-3-yl)-propenone,
3-{3-[(2-Methoxy-ethylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-propeno-
ne,
1-(2-Dimethylaminomethyl-phenyl)-3-[2-methoxy-5-(pyridin-3-ylamino)-p-
henyl]-propenone,
3-(2,4-Dichloro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propanone,
3-[4-(2-Dimethylamino-ethyl)-phenyl]-1-(2-fluoro-4-methoxy-phenyl)-propen-
one,
1-(4-Methoxy-phenyl)-3-(3-piperazin-1-ylmethyl-phenyl)-propenone,
3-(3-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-phenyl)-1-(4-methoxy-pheny-
l)-propenone,
3-(3-{[(2-3-{3-[(2-Hydroxy-ethylamino)-methyl]-phenyl}-1-(4-methoxy-pheny-
l)-propenone,
3-(4-Dimethylaminomethyl-biphenyl-3-yl)-1-(2-fluoro-4-methoxy-phenyl)-pro-
penone,
3-(4-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-4-methoxy-phen-
yl)-propenone,
3-[2-(2-Dimethylamino-ethyl)-phenyl]-1-(4-methoxy-phenyl)-propenone,
3-[2-(2-Dimethylamino-ethyl)-phenyl]-1-(2-fluoro-4-methoxy-phenyl)-propen-
one,
3-[2-(2-Dimethylamino-ethyl)-phenyl]-1-(2,3,4-trimethoxy-phenyl)-pro-
penone,
3-[4-(2-Dimethylamino-ethyl)-phenyl]-1-(4-methoxy-phenyl)-propeno-
ne,
3-[4-(2-Dimethylamino-ethyl)-phenyl]-1-(2,3,4-trimethoxy-phenyl)-prop-
enone,
3-(2,5-Dimethoxy-phenyl)-1-[4-(2-dimethylamino-ethyl)-phenyl]-prop-
enone,
1-[4-(2-Dimethylamino-ethyl)-phenyl]-3-(4-methoxy-biphenyl-3-yl)-p-
ropenone,
3-(4,2'-Dimethoxy-biphenyl-3-yl)-1-[4-(2-dimethylamino-ethyl)-p-
henyl]-propenone,
3-(4-Dimethylaminomethyl-biphenyl-3-yl)-1-(2,3,4-trimethoxy-phenyl)-prope-
none,
3-(2,5-Dimethoxy-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-
-propenone,
3-[4-Chloro-5-(1,1-dimethyl-allyl)-2-methoxy-phenyl]-1-(3-dimethylaminome-
thyl-4-hydroxy-phenyl)-propenone,
3-(2,4-Dichloro-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propen-
one,
3-(2,4-Dichloro-phenyl)-1-(3-dimethylaminomethyl-4-methoxy-phenyl)-p-
ropenone,
3-[4-Chloro-5-(1,1-dimethyl-allyl)-2-methoxy-phenyl]-1-(3-dimet-
hylaminomethyl-4-methoxy-phenyl)-propenone,
3-(3',5'-Dichloro-4,6-dimethoxy-biphenyl-3-yl)-1-(3-dimethylaminomethyl-4-
-methoxy-phenyl)-propenone,
1-(3-Dimethylaminomethyl-4-methoxy-phenyl)-3-(4-methoxy-biphenyl-3-yl)-pr-
openone,
3-(2,4-Dichloro-phenyl)-1-(2-dimethylaminomethyl-4-methoxy-pheny-
l)-propenone,
3-(3-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-prop-
enone,
3-(3-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-4-methoxy-pheny-
l)-propenone,
1-(2-Dimethylaminomethyl-4-methoxy-phenyl)-3-{3-[(pyridin-3-ylmethyl)-ami-
no]-phenyl}-propenone,
1-(2-Dimethylaminomethyl-phenyl)-3-{3-[(pyridin-3-ylmethyl)-amino]-phenyl-
}-propenone,
1-(2-Dimethylaminomethyl-phenyl)-3-[3-(pyridin-4-ylamino)-phenyl]-propeno-
ne,
1-(2-Dimethylaminomethyl-4-methoxy-phenyl)-3-[3-(pyridin-4-ylamino)-p-
henyl]-propenone,
3-(3,5-Di-tert-butyl-2-methoxy-phenyl)-1-[4-hydroxy-3-(4-methyl-piperazin-
-1-ylmethyl)-phenyl]-propenone,
3-(5-tert-Butyl-2-methoxy-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phen-
yl)-propenone,
3-(3,5-Di-tert-butyl-2-methoxy-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-
-phenyl)-propenone,
3-[5-(1,1-Dimethyl-allyl)-4-hydroxy-2-methoxy-phenyl]-1-(2-dimethylaminom-
ethyl-phenyl)-propenone,
3-[5-(1,1-Dimethyl-allyl)-4-hydroxy-2-methoxy-phenyl]-1-(3-dimethylaminom-
ethyl-phenyl)-propenone, and salts thereof.
67. A composition comprising the compound of claim 51 and a
pharmaceutically acceptable carrier.
68. A method for treating bacterial infections in a mammal
comprising administering to the mammal of a compound of claim 51
and a pharmaceutically acceptable carrier.
69. A method for treatment of infections associated with protozoa
in a mammal comprising administering to the mammal a compound of
claim 51.
Description
FIELD OF THE INVENTION
[0001] The present Invention relates to a novel class of chalcone
derivatives and analogues thereto as well as to use of a class of
chalcone derivatives as pharmaceutically active agents, In
particular against bacterial and parasitic infections.
[0002] Furthermore, the Invention relates to a method of predicting
whether a chemical compound has a potential inhibitory effect
against an organism such as Helicobacter pylori and Plasmodium
falciparum. The prediction is based on the ability of the chemical
compound to act as an inhibitior of the enzyme dihydroorotate
dehydrogenase which is involved in the synthesis of pyrimidine in
prokaryotic as well as eukaryotic cells such as bacteria,
parasites, fungi, helminths and any type of mammalian cells such as
human cells.
BACKGROUND OF THE INVENTION
[0003] Chalcones, e.g., for use against parasitic infections are
known from earlier patent applications assigned to the applicant,
e.g. WO 93/17671 and WO 99/00114. Moderate antibacterial activity
has been reported for a limited number of chalcones in earlier
publications e.g. Haraguchi, H. et al Phytochemistry 1998, 48,
125-129 and Hatano, T. et al Chem. Pharm. Bull (Tokyo) 2000, 48,
1286-92.
[0004] The bioavailability of several of the known chalcones is low
due to the low solubility of the compounds. The compounds do not
typically dissolve in the intestine and are therefore not available
for absorption.
[0005] The spread of antimicrobial resistance determinants
particular among nosocomial bacterial pathogens is an increasing
problem. Such resistant pathogens Include Staphylococcus aureus
resistant to methicillin and thus to all .beta.-lactam-antibiotics
and Enterococci resistant to vancomycin (VRE). Such resistant
bacteria pose a significant therapeutic challenge and bacterial
strains resistant to all currently available antimicrobials are
emerging. Furthermore, bacterial species intrinsically resistant to
commonly employed antimicrobials are being recognized as important
opportunistic pathogens in the setting of long-term
immunocompromized patients. An example of this is Stenotrophomonas
maltophilia which possesses a .beta.-lactamase rendering the
bacteria intrinsically resistant to carbapenems. As
cross-resistance within a given class of antibiotics often occurs
the development of new classes of antibiotics is a neccisity to
counter the emerging threat of bacterial resistance.
[0006] The resistance of Plasmodium falciparum to chloroquine and
other antimalarial drugs have created an urgent need for new drugs
that are safe and effffective for the prophylaxis and treatment of
malaria.
[0007] Furthermore, the Increasing appearance of resistance to
first line antileishmanial drugs, e.g. Pentostam or Glucantime,
emphasizes the need for new drugs for the treatment of Leishmania
infections.
[0008] Thus, there is a need for chalcone derivatives with Improved
therapeutic or prophylactic activity against parasites and
bacteria.
[0009] Chalcones carrying certain amino substituents are known from
Dimmock et al (I. Med. Chem. 1998, 41, 1014-26) and Cain et al
(U.S. Pat. No. 5,523,302).
BRIEF DESCRIPTION OF THE FIGURES
[0010] FIG. 1 Illustrates the general synthetic scheme for the
preparation of amino-functional chalcones where the aromatic rings
are phenyl rings. R.sup.1, R.sup.2, and Z are as defined
herein.
[0011] FIG. 2 illustrates the synthesis of amino-dihydrochalcones.
R.sup.1, R.sup.2, and Z are as defined herein.
[0012] FIG. 3 illustrates a time-kill curve of A031 against S.
aureus ATCC29213. Bacterial growth is inhibited at concentrations
at or above the MIC (MIC=9.4 .mu.M). As CFU counts per ml decreases
at concentrations of compound above the MIC, the compound is
bactericidal. The reduction in CFU/ml is faster as the
concentration of test compound increases above the MIC. This
indicates that the bactericidal action of the compound is primarily
dependent on the concentration of the test compound.
[0013] FIG. 4 Illustrates a time-kill curve of A019 against S.
aureus ATCC29213. Bacterial growth is inhibited at concentrations
of test compound at or above the MIC (MIC=9.4 .mu.M). As CFU counts
per ml decreases at concentrations of compound above the MIC, the
compound is bactericidal. The rate of reduction of CFU/ml is not
significantly affected by increasing concentrations of test
compound. Thus, the bactericidal action of the compound is
primarily dependent on incubation time.
[0014] FIG. 5 illustrates a dose-response curve of Licochalcone A
(LicA) and one of the novel amino-chalcones (A139) at Plasmodium
falciparum. As shown at the figure, A139 is 18 times more potent
than LicA.
[0015] FIG. 6 illustrates a dose-response curve of LicA and one of
the novel amino-chalcones A037 at Leishmania Major. As shown at the
figure, A037 is 46 times more potent than LicA.
[0016] FIG. 7 illustrates an effect curve of A027 in Plasmodium
berghei K173 infected NMRI female mice following multiple intra
venous administrations. As shown at the figure, treatment with A027
causes a significant decrease in the parasitaemia.
[0017] FIG. 8 illustrates an effect curve of A027 in Plasmodium
berghei K173 infected NMRI female mice following multiple oral
administrations. As shown at the figure, treatment with 027 causes
a significant decrease in the parasitaemia.
DESCRIPTION OF THE INVENTION
[0018] The present inventors have found that the amino-functional
chalcones defined herein exhibit interesting biological properties
combined with improved metabolic and physicochemical properties
which make the compound useful as drug substances, in particular as
antiparasitic agents, bacterlostatic agents, and bacterlocidal
agents.
[0019] It is believed that the amino group or groups of the
amino-functional chalcone will be charged according to pH of the
medium and the pKa of the compound. The solubility of the charged
compounds is significantly higher than the solubility of the
neutral compounds. As the amino-functional chalcones will be
partially charged and thus soluble in aqueous solutions at
physiological pH values in the intestine or stomach, they will
dissolve in the gastric juices and then be available for
absorption. The bioavailability of the amino-functional chalcones
will therefore be improved compared to the known neutral chalcones,
thus making the compounds generally useful as drug candidates.
Also, the present amino-functional chalcones possess different pKa
values which allows the selection of a chalcone derivative with
optimal charged/non-charged ratio at a given pH value.
[0020] Furthermore, the application of the known chalcones as drug
candidates have been limited due to extensive metabolism of the
compounds, which results in short half-lives in vivo. The present
inventors have now found that introduction of an amino group in the
chalcone molecule affects the metabolic properties so as to achieve
improved metabolic stability.
[0021] The introduction of an alifatic amino-group and hence a
positive charge (at the pH value of the target site) affects the
mode of interaction with the biological target. It is anticipated
that the compounds interact with the target in a different way than
neutral chalcones, due to the possibility of strong electrostatic
interactions (attraction as well as repulsion). This is indeed
reflected in the activity of the compounds, being more potent than
the previously described neutral chalcones.
[0022] Of particular interest, the present inventors have found
that the amino-functional chalcones defined herein are far more
potent against malaria and leishmania parasites than the earlier
described neutral chalcone compounds, and that they exhibit
excellent bacteriocidal and bacteriostatic properties, even against
multi-resistant bacteria strains.
[0023] Thus, in a first aspect, the present invention provides
chalcone derivatives and analogues of the general formula:
(Y.sup.1).sub.m--Ar.sup.1(X.sup.1)--C(.dbd.O)VAr.sup.2(X.sup.2)--(Y.sup.2-
).sub.p
[0024] wherein Ar.sup.1 and Ar2 independently may be selected from
aryl or heteroaryl;
[0025] V designates --CH.sub.2--CH.sub.2--, --CH.dbd.CH-- or
--C.ident.C--, preferably --CH.dbd.CH--;
[0026] m is 0, 1, or 2,
[0027] p is 0, 1, or 2,
[0028] wherein the sum of m and p is at least 1;
[0029] each Y.sup.1 is independently selected from an
amino-functional substituent of the formula
-Z-N(R.sup.1)R.sup.2,
[0030] each Y.sup.2 is independently selected from an
amino-functional substituent of the formula
-Z-N(R.sup.1)R.sup.2,
[0031] wherein Z is a biradical --(C(R.sup.H).sub.2).sub.n--,
wherein n is an integer in the range of 1-6, preferably 1-4, such
as 1-3, and each R.sup.H is independently selected from hydrogen or
C.sub.1-6-alkyl, or two R.sup.H on the same carbon atom may
designate .dbd.O;
[0032] R.sup.1 and R.sup.2 independently may be selected from
hydrogen, optionally substituted C.sub.1-12-alkyl, optionally
substituted C.sub.2-12-alkenyl, optionally substituted
C.sub.4-12-alkadienyl, optionally substituted
C.sub.6-12-alkatrienyl, optionally substituted C.sub.2-12-alkynyl,
optionally substituted C.sub.1-12-alkoxycarbonyl, optionally
substituted C.sub.1-12-alkylcarbonyl, optionally substituted aryl,
optionally substituted aryloxycarbonyl, optionally substituted
arylcarbonyl, optionally substituted heteroaryl, optionally
substituted heteroaryloxycarbonyl, optionally substituted
heteroarylcarbonyl, aminocarbonyl, mono- and
di(C.sub.1-6-alkyl)aminocarbonyl,
amino-C.sub.1-6-alkyl-aminocarbonyl, or mono- and
di(C.sub.1-6-alkyl)amino-C.sub.1-6-alkyl-aminocarbonyl,
[0033] or R.sup.1 and R.sup.2 together with the nitrogen atom to
which they are attached (--N(R.sup.1)R.sup.2) form an optionally
substituted nitrogen-containing heterocyclic ring; X.sup.1 and
X.sup.2 independently may designate 0-5, preferably 0-4, such as
0-3, e.g. 0-2, substituents, where such optional substituents
independently may be selected from optionally substituted
C.sub.1-12-alkyl, optionally substituted C.sub.2-12-alkenyl,
optionally substituted C.sub.4-12-alkadienyl, optionally
substituted C.sub.6-12-alkatrienyl, optionally substituted
C.sub.2-12-alkynyl, hydroxy, optionally substituted
C.sub.1-12-alkoxy, optionally substituted C.sub.2-12-alkenyloxy,
carboxy, optionally substituted C.sub.1-12-alkoxycarbonyl,
optionally substituted C.sub.1-12-alkylcarbonyl, formyl,
C.sub.1-6-alkylsulphonylamino, optionally substituted aryl,
optionally substituted aryloxycarbonyl, optionally substituted
aryloxy, optionally substituted arylcarbonyl, optionally
substituted arylamino, arylsulphonylamino, optionally substituted
heteroaryl, optionally substituted heteroaryloxycarbonyl,
optionally substituted heteroaryloxy, optionally substituted
heteroarylcarbonyl, optionally substituted heteroarylamino,
optionally substituted (heteroarylalkyl)amino, optionally
substituted (heteroarylalkyl)alkylamino, heteroarylsulphonylamino,
optionally substituted heterocyclyl, optionally substituted
heterocyclyloxycarbonyl, optionally substituted heterocyclyloxy,
optionally substituted heterocyclylcarbonyl, optionally substituted
heterocyclylamino, heterocyclylsulphonylamino, amino, mono- and
di(C.sub.1-6-alkyl)amino, carbatnoyl, mono- and
di(C.sub.1-6-alkyl)aminocarbonyl,
amino-C.sub.1-6-alkyl-aminocarbonyl, mono- and
di(C.sub.1-6-alkyl)amino-C.sub.1-6-alkyl-aminocarbonyl,
C.sub.1-6-alkylcarbonylamino, amino-C.sub.1-6-alkyl-carbonylamino,
mono- and di(C.sub.1-6-alkyl)amino-C.sub.1-6-alkyl-carbonylamino,
cyano, guanidino, carbamido, C.sub.1-6-alkanoyloxy,
C.sub.1-6-alkylsulphonyl, C.sub.1-6-alkylsulphinyl,
C.sub.1-6-alkylsulphonyl-oxy, aminosulfonyl, mono- and
di(C.sub.1-6-alkyl)aminosulfonyl, nitro, optionally substituted
C.sub.1-6-alkylthio, or halogen, where any nitrogen-bound
C.sub.1-6-alkyl may be substituted with hydroxy, C.sub.1-6-alkoxy,
C.sub.2-6-alkenyloxy, amino, mono- and di(C.sub.1-6-alkyl)amino,
carboxy, C.sub.1-6-alkylcarbonylamino, halogen,
C.sub.1-6-alkylthio, C.sub.1-6-alkyl-sulphonyl-amino, or
guanidine;
[0034] and salts thereof.
[0035] The substituents R.sup.1 and R.sup.2 carried by the nitrogen
atom of the amino substituent are believed to slightly alter the
pKa value of the chalcone derivative. Thus, the particular
selection of the groups R.sup.1 and R.sup.2 may be used to
"fine-tune" the pKa value in view of the particular condition or
disease and the intended route of administration.
[0036] In one embodiment, R.sup.1 and R.sup.2 may be independently
selected from hydrogen, optionally substituted C.sub.1-12-alkyl,
optionally substituted C.sub.2-12-alkenyl, optionally substituted
C.sub.2-12-alkynyl, optionally substituted
C.sub.1-12-alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,
amino-carbonyl, mono- and di(C.sub.1-6-alkyl)aminocarbonyl,
amino-C.sub.1-6-alkyl-aminocarbonyl, and mono- and
di(C.sub.1-6-alkyl)amino-C.sub.1-6-alkyl-aminocarbonyl. In
particular R.sup.1 and R.sup.2 are independently selected from
hydrogen, optionally substituted C.sub.1-6-alkyl, optionally
substituted C.sub.1-6-alkylcarbonyl, heteroarylcarbonyl,
aminocarbonyl, mono- and di(C.sub.1-6-alkyl)aminocarbonyl,
amino-C.sub.1-6-alkyl-aminocarbonyl, or mono- and
di(C.sub.1-6-alkyl)amino-C.sub.1-6-alkyl-aminocarbonyl.
[0037] In another embodiment, R.sup.1 and R.sup.2 together with the
nitrogen atom to which they are attached (--N(R.sup.1)R.sup.2) form
an optionally substituted nitrogen-containing heterocyclic
ring.
[0038] In still a further embodiment, X.sup.1 and X.sup.2
independently may designate 0-4, such as 0-3, e.g. 0-2,
substituents, where such optional substituents independently may be
selected from optionally substituted C.sub.1-12-alkyl, hydroxy,
optionally substituted C.sub.1-12-alkoxy, optionally substituted
C.sub.2-12-alkenyloxy, carboxy, optionally substituted
C.sub.1-12-alkylcarbonyl, formyl, C.sub.1-6-alkylsulphonylamino,
optionally substituted aryl, optionally substituted
aryloxycarbonyl, optionally substituted aryloxy, optionally
substituted arylcarbonyl, optionally substituted arylamino,
arylsulphonylamino, optionally substituted heteroaryl, optionally
substituted heteroarylamino, optionally substituted
(heteroarylalkyl)amino, optionally substituted
(heteroarylalkyl)alkylamino, optionally substituted
heteroarylcarbonyl, optionally substituted heteroaryloxy,
heteroarylsulphonylamino, optionally substituted heterocyclyl,
optionally substituted heterocyclyloxy, optionally substituted
heterocyclylamino, amino, mono- and di(C.sub.1-6-alkyl)amino,
carbamoyl, mono- and di(C.sub.1-6-alkyl)aminocarbonyl,
amino-C.sub.1-6-alkyl-aminocarbonyl, mono- and
di(C.sub.1-6-alkyl)amino-C.sub.1-6-alkyl-aminocarbonyl,
C.sub.1-6-alkylcarbonylamino, amino-C.sub.1-6-alkyl-carbonylamino,
mono- and di(C.sub.1-6-alkyl)amino-C.sub.1-6-alkyl-carbonylamino,
guanidino, carbamido, C.sub.1-6-alkylsulphonyl,
C.sub.1-6-alkylsulphinyl, C.sub.1-6-alkylsulphonyloxy, optionally
substituted C.sub.1-6-alkylthio, aminosulfonyl, mono- and
di(C.sub.1-6-alkyl)aminosulfonyl, and halogen, where any
nitrogen-bound C.sub.1-6-alkyl may be substituted with hydroxy,
C.sub.1-6-alkoxy, and/or halogen, in particular X.sup.1 and X.sup.2
independently designates 0-3, e.g. 0-2, substituents, where such
optional substituents independently are selected from optionally
substituted C.sub.1-6-alkyl, hydroxy, optionally substituted
C.sub.1-6-alkoxy, carboxy, optionally substituted
C.sub.1-6-alkylcarbonyl, C.sub.1-6-alkylsulphonylamino, optionally
substituted aryl, optionally substituted aryloxy, optionally
substituted arylamino, arylsulphonylamino, optionally substituted
heteroaryl, optionally substituted heteroarylamino, optionally
substituted (heteroarylalkyl)amino, optionally substituted
(heteroarylalkyl)alkylamino, heteroarylsulphonylamino, amino, mono-
and di(C.sub.1-6-alkyl)amino, carbamoyl,
C.sub.1-6-alkyl-carbonylamino, guanidino, carbamido, optionally
substituted C.sub.1-6-alkylthio, optionally substituted
heterocyclyl, optionally substituted heterocyclyloxy, optionally
substituted heterocyclylamino and halogen, where any nitrogen-bound
C.sub.1-6-alkyl may be substituted with hydroxy, C.sub.1-6-alkoxy,
and/or halogen.
[0039] In a suitable embodiment, X.sup.1 and X.sup.2 independently
designates 0-5, preferably 0-4, such as 0-3, e.g. 0-2,
substituents, where such optional substituents independently are
selected from optionally substituted C.sub.1-12-alkyl, optionally
substituted C.sub.2-12-alkenyl, optionally substituted
C.sub.4-12-alkadienyl, optionally substituted
C.sub.6-12-alkatrienyl, optionally substituted C.sub.2-12-alkynyl,
hydroxy, optionally substituted C.sub.1-12-alkoxy, optionally
substituted C.sub.2-12-alkenyloxy, carboxy, optionally substituted
C.sub.1-12-alkoxycarbonyl, optionally substituted
C.sub.1-12alkylcarbonyl, formyl, C.sub.1-6-alkylsulphonylamino,
optionally substituted aryl, optionally substituted
aryloxycarbonyl, optionally substituted aryloxy, optionally
substituted arylcarbonyl, optionally substituted arylamino,
arylsulphonylamino, optionally substituted heteroaryl, optionally
substituted heteroaryloxycarbonyl, optionally substituted
heteroaryloxy, optionally substituted heteroarylcarbonyl,
optionally substituted heteroarylamino, optionally substituted
(heteroarylalkyl)amino, optionally substituted
(heteroarylalkyl)alkylamino, heteroarylsulphonylamino, optionally
substituted heterocyclyloxycarbonyl, optionally substituted
heterocyclyloxy, optionally substituted heterocyclylcarbonyl,
optionally substituted heterocyclylamino,
heterocyclylsulphonylamino, amino, mono- and
di(C.sub.1-6-alkyl)amino, carbamoyl, mono- and
di(C.sub.1-6-alkyl)aminocarbonyl,
amino-C.sub.1-6-alkyl-aminocarbonyl, mono- and
di(C.sub.1-6-alkyl)amino-C.sub.1-6-alkyl-aminocarbonyl,
C.sub.1-6-alkylcarbonylamino , cyano, guanidino, carbamido,
C.sub.1-6-alkanoyloxy, C.sub.1-6-alkylsulphonyl,
C.sub.1-6-alkylsulphinyl, C.sub.1 6-alkylsulphonyl-oxy,
aminosulfonyl, mono- and di(C.sub.1-6-alkyl)aminosulfonyl, nitro,
optionally substituted C.sub.1-6-alkylthio, and halogen, where any
nitrogen-bound C.sub.1-6-alkyl may be substituted with hydroxy,
C.sub.1-6-alkoxy, C.sub.2-6-alkenyloxy, carboxy, halogen,
C.sub.1-6-alkylthio, C.sub.1-6-alkyl-sulphonyl-amino, or
guanidine.
[0040] In a particular embodiment, X.sup.1 and X.sup.2
independently may designate 0-3, e.g. 0-2, substituents, where such
optional substituents may independently be selected from optionally
substituted C.sub.1-6-alkyl, hydroxy, optionally substituted
C.sub.1-6-alkoxy, carboxy, optionally substituted
C.sub.1-6-alkylcarbonyl, C.sub.1-6-alkylsulphonylamino, optionally
substituted aryl, optionally substituted aryloxy, optionally
substituted arylamino, amino, mono- and di(C.sub.1-6-alkyl)amino,
arylsulphonylamino, optionally substituted heteroaryl, optionally
substituted heteroarylamino, optionally substituted
(heteroarylalkyl)amino, optionally substituted
(heteroarylalkyl)alkylamino, heteroarylsulphonylamino, carbamoyl,
C.sub.1-6-alkyl-carbonylamino, guanidino, carbamido, optionally
substituted C.sub.1-6-alkylthio, optionally substituted
heterocyclyloxy, optionally substituted heterocyclylamino and
halogen, where any nitrogen-bound C.sub.1-6-alkyl may be
substituted with at least one substituent selected from the group
consisting of hydroxy, C.sub.1-6-alkoxy, or halogen.
[0041] The group V is relevant with respect to the spatial
orientation of the rings Ar.sup.1 and Ar.sup.2. Thus, the group V
may be --CH.sub.2--CH.sub.2--, --CH.dbd.CH-- or --C.ident.C-- in a
currently interesting embodiment thereof, V designates
--CH.dbd.CH--.
[0042] In the context of the present invention, the expression
"chalcone derivative" is to be assigned to the compounds of the
above formula in that the overall structure namely
Ar.sup.1--C(.dbd.O)--C--C--Ar.sup.2 resembles that of the chalcone
structure. This being said, Ar.sup.1 and Ar.sup.2 are selected from
aromatic rings and heteroaromatic rings. It is currently believed
that particularly interesting compounds are those where at least
one of Ar.sup.1 and Ar.sup.2, preferably both, are aryl, in
particular phenyl. This being said, the inventors envisage that the
functionality of the compounds may be substantially preserved (or
even improved) when one or both of Ar.sup.1 and Ar.sup.2 are
heteroaromatic rings.
[0043] In one embodiment, at least one of Ar.sup.1 and Ar.sup.2 is
selected from thiazolyl, pyrrolyl, imidazolyl, pyrazolyl,
pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, quinolyl,
isoquinolyl, and indolyl.
[0044] In another embodiment, both of Ar.sup.1 and Ar.sup.2 are
phenyl rings and Y.sup.1 represent at least one amino-functional
substituent, i. e. m is 1 or 2, and p is 0.
[0045] In a further embodiment, X.sup.2 represents at least one
substituent selected from C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
C.sub.1-6-alkylcarbonyl, optionally substituted aryl, optionally
substituted aryloxy, optionally substituted arylamino, optionally
substituted heteroaryl, optionally substituted heteroarylamino,
optionally substituted (heteroarylalkyl)amino, optionally
substituted (heteroarylalkyl)alkylamino, mono- and
di(C.sub.1-6-alkyl)amino, C.sub.1-6-alkylcarbonylamino, optionally
substituted C.sub.1-6-alkylthio, optionally substituted
heterocyclyl, optionally substituted heterocyclyloxy, optionally
substituted heterocyclylamino and halogen.
[0046] In a yet further embodiment, X.sup.2 represents at least one
substituent selected from C.sub.1-alkyl, C.sub.1-6-alkoxy,
optionally substituted aryl, optionally substituted aryloxy,
optionally substituted arylamino, optionally substituted
heteroaryl, optionally substituted heteroarylamino, optionally
substituted (heteroarylalkyl)amino, optionally substituted
(heteroarylalkyl)alkylamino, mono- and di(C.sub.1-6-alkyl)amino,
optionally substituted heterocyclyl and halogen.
[0047] The Z group represents the biradical between the ring and
the amino functionality. This group Z is typically a biradical
--(C(R.sup.H).sub.2).sub.n--, wherein n is an integer in the range
of 1-6, preferably 1-4, such as 1-3, where each R.sup.H is
independently selected from hydrogen and C.sub.1-6-alkyl, or two
R.sup.H on the same carbon atom may designate .dbd.O. A particular
example of Z is --(CH.sub.2).sub.n-- wherein n is 1-4, such as
1-3.
[0048] Thus, in a particular embodiment, one of Y.sup.1 and Y.sup.2
represent a substituent of the formula
--CH.sub.2--N(R.sup.1)R.sup.2
[0049] wherein R.sup.1 and R.sup.2 is selected from hydrogen and
C.sub.1-6-alkyl. Furthermore, V is preferably --CH.dbd.CH--, and
Ar.sup.1 and Ar.sup.2 both are phenyl rings. In a particular
embodiment, Y.sup.1 represents the substituent for the formula
--CH.sub.2--N(R.sup.1)R.sup.2.
[0050] In one preferred embodiment, m is 1 and p is 0. in another
preferred embodiment m is 0 and p is 1. in a further interesting
embodiment, m and p are both 1.
[0051] In a further typical embodiment, where Ar.sup.1 and Ar.sup.2
are both phenyl, V is --CH.dbd.CH--, Z is CH.sub.2, R.sup.1 and
R.sup.2 are methyl or together form a morpholino group, and one of
m and p is 2 while the other of m and p is 0,
[0052] X.sup.1 and X.sup.2 independently may designate 0-5,
preferably 0-4, such as 0-3, e.g. 0-2, substituents, where such
optional substituents may independently be selected from optionally
substituted C.sub.1-12-alkyl, optionally substituted
C.sub.2-12-alkenyl, optionally substituted C.sub.4-12-alkadienyl,
optionally substituted C.sub.6-12-alkatrienyl, optionally
substituted C.sub.2-12-alkynyl, 2-, 3-, 5-, or 6-hydroxy,
optionally substituted C.sub.1-12-alkoxy, optionally substituted
C.sub.2-12-alkenyloxy, carboxy, optionally substituted
C.sub.1-12-alkoxycarbonyl, optionally substituted
C.sub.1-12-alkylcarbonyl, formyl, C.sub.1-6-alkylsulphonylamino,
optionally substituted aryl, optionally substituted
aryloxycarbonyl, optionally substituted aryloxy, optionally
substituted arylcarbonyl, optionally substituted arylamino,
arylsulphonylamino, optionally substituted heteroaryl, optionally
substituted heteroaryloxycarbonyl, optionally substituted
heteroaryloxy, optionally substituted heteroarylcarbonyl,
optionally substituted heteroarylamino, optionally substituted
(heteroarylalkyl)amino, optionally substituted
(heteroarylalkyl)alkylamino, heteroarylsulphonylamino, optionally
substituted heterocyclyloxycarbonyl, optionally substituted
heterocyclyloxy, optionally substituted heterocyclylcarbonyl,
optionally substituted heterocyclylamino,
heterocyclylsulphonylamino, amino, mono- and
di(C.sub.1-6-alkyl)amino, carbamoyl, mono- and
di(C.sub.1-6-alkyl)aminocarbonyl,
amino-C.sub.1-6-alkyl-aminocarbonyl, mono- and
di(C.sub.1-6-alkyl)amino-C.sub.1-6-alkyl-aminocarbonyl,
C.sub.1-6-alkylcarbonylamino , cyano, guanidino, carbamido,
C.sub.1-6-alkanoyloxy, C.sub.1-6-alkylsulphonyl,
C.sub.1-6-alkylsulphinyl, C.sub.1-6-alkylsulphonyl-oxy,
aminosulfonyl, mono- and di(C.sub.1-6-alkyl)aminosulfonyl, nitro,
optionally substituted C.sub.1-6-alkylthio, or halogen, where any
nitrogen-bound C.sub.1-6-alkyl may be substituted with hydroxy,
C.sub.1-6-alkoxy, C.sub.2-6-alkenyloxy, carboxy, halogen,
C.sub.1-6-alkylthio, C.sub.1-6-alkyl-sulphonyl-amino, or
guanidine;
[0053] provided that
[0054] when Ar.sup.1 and Ar.sup.2 are both phenyl, V is
--CH.dbd.CH--, m is 1, p is 0, Y1 is 2--CH.sub.2NMe2, and X2 is
absent, then X1 is not solely 4-methoxy;
[0055] when Ar.sup.1 and Ar.sup.2 are both phenyl, V is
--CH.dbd.CH--, m is 1, p is 0, Y1 is 3- or 4--CH2NR1R2, wherein R1
and R2 are selected from hydrogen, methyl, and ethyl, and X1 is
solely 4-hydroxy or 4-alkoxy, or absent, then X2 is not solely
nitro, dichloro, carboxymethoxy, methoxycarbonylmethoxy,
ethoxycarbonylmethoxy, 2-carboxyethyl, or absent;
[0056] when Ar.sup.1 and Ar.sup.2 are both phenyl, V is
--CH.dbd.CH--, m is 0, p is 1, Y.sup.2 is solely 2- or
3-CH.sub.2NR.sup.1R.sup.2, wherein R.sup.1 and R.sup.2 are selected
from hydrogen, methyl, and ethyl, and X.sup.2 is solely 4-OH, or
absent, then X.sup.1 is not solely ethoxycarbonylmethoxy, dichloro,
or absent.
[0057] Generally preferred compounds may, e.g., be selected from
the group comprising: [0058]
1-(4-Methoxy-phenyl)-3-(4-morpholin-4-ylmethyl-phenyl)-propenone,
[0059]
3-(4-Diethylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone,
[0060]
1-(4-Methoxy-phenyl)-3-(4-propylaminomethyl-phenyl)-propenone,
[0061]
3-(4-Dimethylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone,
[0062]
3-{4-[(2-Dimethylamino-ethylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-p-
ropenone, [0063]
1-(4-Methoxy-phenyl)-3-(4-piperidin-1-ylmethyl-phenyl)-propenone,
[0064]
3-{4-[(3-Dimethylamino-propylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-
-propenone, [0065]
3-(4-Dibutylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone,
[0066]
3-{4-[(4-Diethylamino-1-methyl-butylamino)-methyl]-phenyl}-1-(4-methoxy-p-
henyl)-propenone, [0067]
3-{3-[(2-Dimethylamino-ethylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-p-
ropenone, [0068]
3-(2,4-Dichloro-phenyl)-1-(4-dimethylaminomethyl-phenyl)-propenone,
[0069]
1-(4-Methoxy-phenyl)-3-(3-propylaminomethyl-phenyl)-propenone,
[0070]
1-(4-Methoxy-phenyl)-3-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-
-propenone, [0071]
1-(4-Methoxy-phenyl)-3-[3-(4-methyl-[1,4]diazepan-1-ylmethyl)-phenyl]-pro-
penone, [0072]
3-(3-Dimethylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone,
[0073]
1-(2-Bromo-phenyl)-3-(2-dimethylaminomethyl-phenyl)-propenone,
[0074]
3-{3-[(3-Dimethylamino-propylamino)-methyl]-phenyl{-1-(4-methoxy-phenyl)--
propenone [0075]
3-(2,5-Dimethoxy-phenyl)-1-(4-dimethylaminomethyl-phenyl)-propenone,
[0076]
3-(4-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-phenyl)-propen-
one, [0077]
3-(2,4-Dichloro-phenyl)-1-(3-dimethylaminomethyl-phenyl)-propenone,
[0078]
3-(2,4-Dichloro-phenyl)-1-[3-(4-methyl-piperazin-1-ylmethyl)-phen-
yl]-propenone, [0079]
3-(2,4-Dichloro-phenyl)-1-{3-[(3-dimethylamino-propylamino)-methyl]-pheny-
l}-propenone, [0080]
3-(2,5-Dimethoxy-phenyl)-1-{4-[(3-dimethylamino-propylamino)-methyl]-phen-
yl}-propenone, [0081]
3-(3-Dimethylaminomethyl-phenyl)-1-(2-fluoro-4-methoxy-phenyl)-propenone,
[0082]
3-(4-Dibutylamino-phenyl)-1-[4-(4-methyl-piperazin-1-ylmethyl)-p-
henyl]-propenone, [0083]
3-(2,4-Dichloro-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-prop-
enone, [0084]
3-(2,4-Dichloro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,
[0085]
3-(2,5-Dimethoxy-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phe-
nyl]-propenone, [0086]
3-(2,5-Dimethoxy-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,
[0087]
3-(4-Dibutylamino-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propen-
one, [0088]
3-(4-Dibutylamino-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-pr-
openone, [0089]
3-(3-Dimethylaminomethyl-phenyl)-1-pyridin-2-yl-propenone, [0090]
3-(4-Dibutylamino-phenyl)-1-(4-dimethylaminomethyl-phenyl)-propenone,
[0091]
3-[5-(1,1-Dimethyl-allyl)-2-methoxy-phenyl]-1-(2-dimethylaminomet-
hyl-phenyl)-propenone, [0092]
1-{2-[(tert-Butyl-methyl-amino)-methyl]-phenyl]-3-(2,4-dichloro-phenyl)-p-
ropenone, [0093] Acetic acid
1-{2-[3-(2,4-dichloro-phenyl)-acryloyl]-benzyl}-piperidin-4-yl
ester, [0094]
3-(2,4-Dichloro-phenyl)-1-(2-morpholin-4-ylmethyl-phenyl)-propeno-
ne, [0095]
3-(2,4-Dichloro-phenyl)-1-(2-{[(2-dimethylamino-ethyl)-methyl-amino]-meth-
yl}-phenyl)-propenone, [0096]
3-(4-Diethylaminomethyl-phenyl)-1-o-tolyl-propenone, [0097]
3-(3-Dimethylaminomethyl-phenyl)-1-(2-methoxy-phenyl)-propenone,
[0098]
3-(4-Chloro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,
[0099]
3-(2,4-Difluoro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,
[0100]
3-(3-Butylamino-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenon-
e, [0101]
3-(4-Diethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenon-
e, [0102]
3-(2,4-Dichloro-phenyl)-1-(2-diethylaminomethyl-phenyl)-propenone,
[0103]
3-(2,5-Dimethoxy-phenyl)-1-[4-(4-methyl-piperazin-1-ylmethyl)-phe-
nyl]-propenone, [0104]
1-(2-Dimethylaminomethyl-phenyl)-3-(4-hydroxy-2-methoxy-5-propyl-phenyl)--
propenone, [0105]
3-(2,4-Dichloro-phenyl)-1-(2-piperazin-1-ylmethyl-phenyl)-propenone,
[0106]
3-(2,5-Dimethoxy-phenyl)-1-(2-piperazin-1-ylmethyl-phenyl)-propen-
one, [0107]
1-(2-Dimethylaminomethyl-phenyl)-3-(4-dipropylamino-2-fluoro-phenyl)-prop-
enone, [0108]
3-(2,4-Dichloro-phenyl)-1-[2-(4-hydroxy-piperidin-1-ylmethyl)-phenyl]-pro-
penone, [0109]
1-(3-Diethylaminomethyl-phenyl)-3-(2,5-dimethoxy-phenyl)-propenone,
[0110]
3-(2-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-1-[2-
-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone, [0111]
3-(2,4-Dimethoxy-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-pro-
penone, [0112]
3-(4-Imidazol-1-yl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-p-
ropenone, [0113]
1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-pyridin-2-yl-propenone,
[0114]
1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-pyridin-3-yl-prope-
none, [0115]
1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-pyridin-4-yl-propenone,
[0116]
1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-(1-methyl-1H-pyrro-
l-2-yl)-propenone, [0117]
1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-(1H-pyrrol-2-yl)-propenone-
, [0118]
1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-thiophen-2-yl-pr-
openone, [0119] 1,3-Bis-(2-diethylaminomethyl-phenyl)-propenone,
[0120]
3-(2,4-Dichloro-phenyl)-1-(3-diethylaminomethyl-phenyl)-propenone,
[0121]
3-(4-Dimethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmet-
hyl)-phenyl]-propenone, [0122]
3-(3-Dimethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phe-
nyl]-propenone, [0123]
3-(3-Dimethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propeno-
ne, [0124]
3-(2-Diethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenon-
e, [0125]
3-[3-(Butyl-ethyl-amino)-phenyl]-1-(2-dimethylaminomethyl-phenyl)-propeno-
ne, [0126]
3-(3-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-1-(4-methoxy-
-phenyl)-propenone, [0127]
3-(2-Dimethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phe-
nyl]-propenone, [0128]
3-(2-Diethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phen-
yl]-propenone, [0129]
1,3-Bis-(2-dimethylaminomethyl-phenyl)-propenone, [0130]
3-(4-Dimethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl)-
-propenone, [0131]
3-(1H-Indol-5-yl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone,
[0132]
3-(2,4-Dimethoxy-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propen-
one, [0133]
1-(2-Dimethylaminomethyl-phenyl)-3-(4-imidazol-1-yl-phenyl)-propenone,
[0134]
1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-[3-(pyridin-3-ylam-
ino)-phenyl]-propenone, [0135]
3-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-1-(2,3,4-trimethoxy-phenyl)--
propenone, [0136]
3-{3-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-oxo-propenyl}-benzoic
acid, [0137]
1-(2-Dimethylaminomethyl-phenyl)-3-(2,4-dimethyl-phenyl)-propenone,
[0138]
3-(2,4-Dimethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phen-
yl]-propenone, [0139]
1-(2-Dimethylaminomethyl-phenyl)-3-(1-methyl-1H-pyrrol-2-yl)-propenone,
[0140]
3-[4-Chloro-5-(1,1-dimethyl-allyl)-2-methoxy-phenyl]-1-[2-(4-meth-
yl-piperazin-1-ylmethyl)-phenyl]-propenone, [0141]
1-(2-Dimethylaminomethyl-phenyl)-3-(4-dipropylamino-2-ethoxy-phenyl)-prop-
enone, [0142]
1-(2-Dimethylaminomethyl-phenyl)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phe-
nyl]-propenone, [0143]
3-(3-Dimethylaminomethyl-4-methoxy-phenyl)-1-(4-methoxy-phenyl)-propenone-
, [0144]
1-(2-Methoxy-phenyl)-3-[2-(4-methyl-piperazin-1-ylmethyl)-pheny-
l]-propenone, [0145]
1-(2-Fluoro-4-methoxy-phenyl)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl-
]-propenone, [0146]
3-(2-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-1-(2-dimethy-
laminomethyl-phenyl)-propenone, [0147]
1-(2-Dimethylaminomethyl-phenyl)-3-[3-(pyridin-3-ylamino)-phenyl]-propeno-
ne, [0148]
3-(2-Dimethylaminomethyl-phenyl)-1-(3-dimethylaminomethyl-phenyl)-propeno-
ne, [0149]
1-(3-Dimethylaminomethyl-phenyl)-3-(3-morpholin-4-ylmethyl-phenyl)-propen-
one, [0150]
1-(3-Dimethylaminomethyl-phenyl)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phe-
nyl]-propenone, [0151]
1-(3-Dimethylaminomethyl-phenyl)-3-(4-pyridin-2-yl-phenyl)-propenone,
[0152]
1-(4-Methoxy-phenyl)-3-(3-{[methyl-(2-methylamino-ethyl)-amino]-m-
ethyl}-phenyl)-propenone, [0153]
3-(2-Dimethylaminomethyl-phenyl)-1-(2-fluoro-4-methoxy-phenyl)-propenone,
[0154]
3-(2-Dimethylaminomethyl-phenyl)-1-(2,3,4-trimethoxy-phenyl)-pro-
penone, [0155]
3-(3-{[(2-Hydroxy-ethyl)-methyl-amino]-methyl}-phenyl)-1-(4-methoxy-pheny-
l)-propenone, [0156]
1-(4-Methoxy-phenyl)-3-(3-methylaminomethyl-phenyl)-propenone,
[0157]
1-(3-Dimethylaminomethyl-phenyl)-3-(4-methoxy-biphenyl-3-yl)-propenone,
[0158]
3-{3-[(2-Methoxy-ethylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl)-
-propenone, [0159]
1-(2-Dimethylaminomethyl-phenyl)-3-[2-methoxy-5-(pyridin-3-ylamino)-pheny-
l]-propenone, [0160]
3-(2,4-Dichloro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone,
[0161]
3-[4-(2-Dimethylamino-ethyl)-phenyl]-1-(2-fluoro-4-methoxy-phenyl-
)-propenone, [0162]
1-(4-Methoxy-phenyl)-3-(3-piperazin-1-ylmethyl-phenyl)-propenone,
[0163]
3-(3-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-phenyl)-1-(4-methoxy-phen-
yl)-propenone, [0164]
3-(3-{[(2-3-{3-[(2-Hydroxy-ethylamino)-methyl]-phenyl}-1-(4-methoxy-pheny-
l)-propenone, [0165]
3-(4-Dimethylaminomethyl-biphenyl-3-yl)-1-(2-fluoro-4-methoxy-phenyl)-pro-
penone, [0166]
3-(4-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-4-methoxy-phenyl)-prop-
enone, [0167]
3-[2-(2-Dimethylamino-ethyl)-phenyl]-1-(4-methoxy-phenyl)-propenone,
[0168]
3-[2-(2-Dimethylamino-ethyl)-phenyl]-1-(2-fluoro-4-methoxy-phenyl-
)-propenone, [0169]
3-[2-(2-Dimethylamino-ethyl)-phenyl]-1-(2,3,4-trimethoxy-phenyl)-propenon-
e, [0170]
3-[4-(2-Dimethylamino-ethyl)-phenyl]-1-(4-methoxy-phenyl)-propenone,
[0171]
3-[4-(2-Dimethylamino-ethyl)-phenyl]-1-(2,3,4-trimethoxy-phenyl)--
propenone, [0172]
3-(2,5-Dimethoxy-phenyl)-1-[4-(2-dimethylamino-ethyl)-phenyl]-propenone,
[0173]
1-[4-(2-Dimethylamino-ethyl)-phenyl]-3-(4-methoxy-biphenyl-3-yl)--
propenone, [0174]
3-(4,2'-Dimethoxy-biphenyl-3-yl)-1-[4-(2-dimethylamino-ethyl)-phenyl]-pro-
penone, [0175]
3-(4-Dimethylaminomethyl-biphenyl-3-yl)-1-(2,3,4-trimethoxy-phenyl)-prope-
none, [0176]
3-(2,5-Dimethoxy-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-prope-
none, [0177]
3-[4-Chloro-5-(1,1-dimethyl-allyl)-2-methoxy-phenyl]-1-(3-dimethylaminome-
thyl-4-hydroxy-phenyl)-propenone, [0178]
3-(2,4-Dichloro-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-propen-
one, [0179]
3-(2,4-Dichloro-phenyl)-1-(3-dimethylaminomethyl-4-methoxy-phenyl)-propen-
one, [0180]
3-[4-Chloro-5-(1,1-dimethyl-allyl)-2-methoxy-phenyl]-1-(3-dimethylaminome-
thyl-4-methoxy-phenyl)-propenone, [0181]
3-(3',5'-Dichloro-4,6-dimethoxy-biphenyl-3-yl)-1-(3-dimethylaminomethyl-4-
-methoxy-phenyl)-propenone, [0182]
1-(3-Dimethylaminomethyl-4-methoxy-phenyl)-3-(4-methoxy-biphenyl-3-yl)-pr-
openone, [0183]
3-(2,4-Dichloro-phenyl)-1-(2-dimethylaminomethyl-4-methoxy-phenyl)-propen-
one, [0184]
3-(3-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phenyl)-prop-
enone, [0185]
3-(3-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-4-methoxy-phenyl)-prop-
enone, [0186]
1-(2-Dimethylaminomethyl-4-methoxy-phenyl)-3-{3-[(pyridin-3-ylmethyl)-ami-
nol-phenyl}-propenone, [0187]
1-(2-Dimethylaminomethyl-phenyl)-3-{3-[(pyridin-3-ylmethyl)-amino]-phenyl-
}-propenone, [0188]
1-(2-Dimethylaminomethyl-phenyl)-3-[3-(pyridin-4-ylamino)-phenyl]-propeno-
ne, [0189]
1-(2-Dimethylaminomethyl-4-methoxy-phenyl)-3-[3-(pyridin-4-ylamino)-pheny-
l]-propenone, [0190]
3-(3,5-Di-tert-butyl-2-methoxy-phenyl)-1-[4-hydroxy-3-(4-methyl-piperazin-
-1-ylmethyl)-phenyl]-propenone, [0191]
3-(5-tert-Butyl-2-methoxy-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phen-
yl)-propenone, [0192]
3-(3,5-Di-tert-butyl-2-methoxy-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-
-phenyl)-propenone, [0193]
3-[5-(1,1-Dimethyl-allyl)-4-hydroxy-2-methoxy-phenyl]-1-(2-dimethylaminom-
ethyl-phenyl)-propenone, or [0194]
3-[5-(1,1-Dimethyl-ally)-4-hydroxy-2-methoxy-phenyl]-1-(3-dimethylaminome-
thyl-phenyl)-propenone.
[0195] While the above-mentioned group of compounds is intended to
include all stereoisomers, including optical isomers, and mixtures
thereof, as well as pure, partially enriched, or, where relevant,
racemic forms, a generally preferred embodiment of the
above-mentioned compounds has the E-configuration at the enone
functionality.
[0196] In a further aspect, the invention further provides
combinatorial libraries, mixtures and kits for screening compounds
as defined above.
[0197] In one embodiment, a combinatorial library comprising at
least two compounds of the general formula is provided. Such
library may be in the form of an equimolar mixture, or in a mixture
of any stoichiometry. Typical embodiments comprise at least two,
such as at least 10, such as at least 100, such as at least 1000,
such as at least 10000, such as at least 100000 compounds as
defined above.
[0198] In another embodiment, combinatorial compound collections in
the form of kits for screening for biologically or
pharmacologically active compounds are provided. Such kits comprise
at least two topologically distinct singular compounds of the
general formula defined above. Typical kits comprise at least 10,
such as at least 100, such as at least 1000, such as at least
10000, such as at least 100000 compounds as defined above. Kits are
preferably provided in the form of solutions of the compounds in
appropriate solvents.
[0199] Further provided are methods for screening for
pharmacologically active compounds, especially bacteriostatic,
bacteriocidal and antiparasitic agents, consisting of the steps of
preparing a kit or library comprising at least two compounds of the
general formula defined above, contacting said kit or library with
a target molecule, such as a protein or nucleic acid, a target
tissue, or a target organism, such as a bacterium or parasite, and
detecting a biological or pharmacological response caused by at
least one compound. Optionally, the steps may be repeated as
appropriate to achieve deconvolution.
DEFINITIONS
[0200] In the present context, the term "bacteriostatic" is
intended to describe an antimicrobial activity of a test compound,
characterized by an inhibition of bacterial growth in the absence
of a reduction of viable bacteria (bacterial kill) during
incubation with the test compound, as evidenced in the killing
curve determination by a stationary number of colony forming units
(CFU) during incubation time.
[0201] In the present context, the term "bacteriocidal" is intended
to describe an antimicrobial activity of a test compound,
characterized by the reduction of viable bacteria (bacterial kill)
during incubation with the test compound, as evidenced in the
killing curve determination by a reduction of colony forming units
(CFU) during incubation time.
[0202] In the present contest, the term "antiparasitic" is intended
to describe the ability of a test compound to upon incubation in
vitro with a culture of parasites, e.g. Leishmania major or
Plasmodium falciparum, to inhibit metabolic labelling of the
parasites by at least 50% compared to mock treated control
cultures.
[0203] In the present context, the term "C.sub.1-12-alkyl" is
intended to mean a linear, cyclic or branched hydrocarbon group
having 1 to 12 carbon atoms, such as methyl, ethyl, propyl,
iso-propyl, cyclopropyl, butyl, tert-butyl, iso-butyl, cyclobutyl,
pentyl, cyclopentyl, hexyl, cyclohexyl, etc. Analogously, the term
"C.sub.1-6-alkyl" is intended to mean a linear, cyclic or branched
hydrocarbon group having 1 to 6 carbon atoms, such as methyl,
ethyl, propyl, iso-propyl, pentyl, cyclopentyl, hexyl, cyclohexyl,
and the term "C.sub.1-4-alkyl" is intended to cover linear, cyclic
or branched hydrocarbon groups having 1 to 4 carbon atoms, e.g.
methyl, ethyl, propyl, iso-propyl, cyclopropyl, butyl, iso-butyl,
tert-butyl, cyclobutyl.
[0204] Whenever the term "C.sub.1-12-alkyl is used herein, it
should be understood that a particularly interesting embodiment
thereof is "C.sub.1-6-alkyl".
[0205] Similarly, the terms "C.sub.2-12-alkenyl",
"C.sub.4-12-alkadienyl", and "C.sub.6-12-alkatrienyl" are intended
to cover linear, cyclic or branched hydrocarbon groups having 2 to
12, 4 to 12, and 6 to 12, carbon atoms, respectively, and
comprising one, two, and three unsaturated bonds, respectively.
Examples of alkenyl groups are vinyl, allyl, butenyl, pentenyl,
hexenyl, heptenyl, octenyl, heptadecaenyl. Examples of alkadienyl
groups are butadienyl, pentadienyl, hexadienyl, heptadienyl,
heptadecadienyl. Examples of alkatrienyl groups are hexatrienyl,
heptatrienyl, octatrienyl, and heptadecatrienyl. Preferred examples
of alkenyl are vinyl, allyl, butenyl, especially allyl.
[0206] Similarly, the term "C.sub.2-12-alkynyl" is intended to mean
a linear or branched hydrocarbon group having 2 to 12 carbon atoms
and comprising a triple bond. Examples hereof are ethynyl,
propynyl, butynyl, octynyl, and dodecaynyl.
[0207] Whenever the terms "C.sub.2-12-alkenyl",
"C.sub.4-12-alkadienyl", "C.sub.6-12-alkatrienyl", and
"C.sub.2-12-alkynyl" are used herein, It should be understood that
a particularly interesting embodiment thereof are the variants
having up to six carbon atoms.
[0208] In the present context, i.e. in connection with the terms
"alkyl", "alkenyl", "alkadienyl", "alkatrienyl", and "alkynyl", the
term "optionally substituted" is intended to mean that the group in
question may be substituted one or several times, preferably 1-3
times, with group(s) selected from hydroxy (which when bound to an
unsaturated carbon atom may be present in the tautomeric keto
form), C.sub.1-6-alkoxy (i.e. C.sub.1-6-alkyl-oxy),
C.sub.2-6-alkenyloxy, carboxy, oxo (forming a keto or aldehyde
functionality), C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkylcarbonyl,
formyl, aryl, aryloxycarbonyl, aryloxy, arylamino, arylcarbonyl,
heteroaryl, heteroarylamino, heteroaryloxycarbonyl, heteroaryloxy,
heteroarylcarbonyl, amino, mono- and di(C.sub.1-6-alkyl)amino,
carbamoyl, mono- and di(C.sub.1-6-alkyl)aminocarbonyl,
amino-C.sub.1-6-alkyl-aminocarbonyl, mono- and
di(C.sub.1-6-alkyl)amino-C.sub.1-6-alkyl-aminocarbonyl,
C.sub.1-6-alkyl-carbonylamino, cyano, guanidino, carbamido,
C.sub.1-6-alkyl-sulphonyl-amino, aryl-sulphonyl-amino,
heteroaryl-sulphonyl-amino, C.sub.1-6-alkanoyloxy,
C.sub.1-6-alkyl-sulphonyl, C.sub.1-6-alkyl-sulphinyl,
C.sub.1-6-alkylsulphonyloxy, nitro, C.sub.1-6-alkylthio, halogen,
where any aryl and heteroaryl may be substituted as specifically
describe below for "optionally substituted aryl and heteroaryl",
and any alkyl, alkoxy, and the like representing substituents may
be substituted with hydroxy, C.sub.1-6-alkoxy,
C.sub.2-6-alkenyloxy, amino, mono- and di(C.sub.1-6-alkyl)amino,
carboxy, C.sub.1-6-alkylcarbonylamino, halogen,
C.sub.1-6-alkylthio, C.sub.1-6-alkyl-sulphonyl-amino, or
guanidine.
[0209] Preferably, the substituents are selected from hydroxy
(which when bound to an unsaturated carbon atom may be present in
the tautomeric keto form), C.sub.1-6-alkoxy (i.e.
C.sub.1-6-alkyl-oxy), C.sub.2-6-alkenyloxy, carboxy, oxo (forming a
keto or aldehyde functionality), C.sub.1-6-alkylcarbonyl, formyl,
aryl, aryloxy, arylamino, arylcarbonyl, heteroaryl,
heteroarylamino, heteroaryloxy, heteroarylcarbonyl, amino, mono-
and di(C.sub.1-6-alkyl)amino; carbamoyl, mono- and
di(C.sub.1-6-alkyl)aminocarbonyl,
amino-C.sub.1-6-alkyl-aminocarbonyl, mono- and
di(C.sub.1-6-alkyl)amino-C.sub.1-6-alkyl-aminocarbonyl,
C.sub.1-6-alkylcarbonylamino, guanidino, carbamido,
C.sub.1-6-alkyl-sulphonyl-amino, C.sub.1-6-alkyl-sulphonyl,
C.sub.1-6-alkylsulphinyl, C.sub.1-6-alkylthio, halogen, where any
aryl and heteroaryl may be substituted as specifically describe
below for "optionally substituted aryl and heteroaryl".
[0210] Especially preferred examples are hydroxy, C.sub.1-6-alkoxy,
C.sub.2-6-alkenyloxy, amino, mono- and di(C.sub.1-6-alkyl)amino,
carboxy, C.sub.1-6-alkylcarbonylamino, halogen,
C.sub.1-6-alkylthio, C.sub.1-6-alkyl-sulphonyl-amino, and
guanidine.
[0211] The terms "optionally substituted C.sub.1-12-alkoxy" and
"optionally substituted C.sub.1-6-alkoxy" are intended to mean that
the alkoxy groups may be substituted one or several times,
preferably 1-3 times, with group(s) selected from hydroxy (which
when bound to an unsaturated carbon atom may be present in the
tautomeric keto form), C.sub.1-6-alkoxy (i.e. C.sub.1-6-alkyl-oxy),
C.sub.2-6-alkenyloxy, carboxy, oxo (forming a keto or aldehyde
functionality), C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkylcarbonyl,
formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl,
heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl,
carbamoyl, mono- and di(C.sub.1-6-alkyl)aminocarbonyl,
amino-C.sub.1-6-alkyl-aminocarbonyl, mono- and
di(C.sub.1-6-alkyl)amino-C.sub.1-6-alkyl-aminocarbonyl, cyano,
guanidino, carbamido, C.sub.1-6-alkyl-sulphonyl-amino,
aryl-sulphonyl-amino, heteroaryl-sulphonyl-amino,
C.sub.1-6-alkanoyloxy, C.sub.1-6-alkyl-sulphonyl,
C.sub.1-6-alkyl-sulphinyl, C.sub.1-6-alkylsulphonyloxy, nitro,
C.sub.1-6-alkylthio, halogen, where any aryl and heteroaryl may be
substituted as specifically describe below for "optionally
substituted aryl and heteroaryl.
[0212] Especially preferred examples of "optionally substituted
C.sub.1-12-alkoxy" and "optionally substituted C.sub.1-6-alkoxy"
groups are unsubstituted such groups as well as those carrying one
or two substituents selected from hydroxy, C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, C.sub.2-6-alkenyloxy, carboxy, halogen, or
C.sub.1-6-alkylthio.
[0213] "Halogen" includes fluoro, chloro, bromo, and iodo.
[0214] In the present context the term "aryl" is intended to mean a
fully or partially aromatic carbocyclic ring or ring system, such
as phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracyl,
phenanthracyl, pyrenyl, benzopyrenyl, fluorenyl and xanthenyl,
among which phenyl is a preferred example.
[0215] The term "heteroaryl" is intended to mean a fully or
partially aromatic carbocyclic ring or ring system where one or
more of the carbon atoms have been replaced with heteroatoms, e.g.
nitrogen (.dbd.N-- or --NH--), sulphur, and/or oxygen atoms.
Examples of such heteroaryl groups are oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl,
pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,
coumaryl, furyl, thienyl, quinolyl, benzothiazolyl, benzotriazolyl,
benzodiazolyl, benzooxozolyl, phthalazinyl, phthalanyl, triazolyl,
tetrazolyl, isoquinolyl, acridinyl, carbazolyl, dibenzazepinyl,
indolyl, benzopyrazolyl, phenoxazonyl. Particularly interesting
heteroaryl groups are oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl,
pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, quinolyl,
triazolyl, tetrazolyl, isoquinolyl, indolyl in particular pyrrolyl,
imidazolyl, pyridinyl, pyrimidinyl, thienyl, quinolyl, tetrazolyl,
and isoquinolyl.
[0216] The term "heterocyclyl" is intended to mean a non-aromatic
carbocyclic ring or ring system where one or more of the carbon
atoms have been replaced with heteroatoms, e.g. nitrogen (.dbd.N--
or --NH--), sulphur, and/or oxygen atoms. Examples of such
heterocyclyl groups are imidazolidine, piperazine,
hexahydropyridazine, hexahydropyrimidine, diazepane, diazocane,
pyrrolidine, piperidine, azepane, azocane, aziridine, azirine,
azetidine, pyroline, tropane, oxazinane (morpholine), azepine,
dihydroazepine, tetrahydroazepine, and hexahydroazepine, oxazolane,
oxazepane, oxazocane, thiazolane, thiazinane, thiazepane,
thiazocane, oxazetane, diazetane, thiazetane, tetrahydrofuran,
tetrahydropyran, oxepane, tetrahydrothlophene,
tetrahydrothiopyrane, thiepane, dithiane, dithiepane, dioxane,
dioxepane, oxathiane, oxathiepane. The most interesting examples
are imidazolidine, piperazine, hexahydropyridazine,
hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine,
azepane, azocane, azetidine, tropane, oxazinane (morpholine),
oxazolane, oxazepane, thiazolane, thiazinane, and thiazepane, in
particular imidazolidine, piperazine, hexahydropyridazine,
hexahydropyrimidine, diazepane, pyrrolidine, piperldine, azepane,
oxazinane (morpholine), and thiazinane.
[0217] In the present context, when applied to groups of aromatic
character, i.e. in connection with the terms "aryl", "heteroaryl",
"heterocyclyl", "heteroarylamino", "(heteroarylalkyl)amino",
"(heteroarylalkyl)alkylamino", etc, the term "optionally
substituted" is intended to mean that the group in question may be
substituted one or several times, preferably 1-5 times, in
particular 1-3 times) with group(s) selected from hydroxy (which
when present in an enol system may be represented in the tautomeric
keto form), C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
C.sub.2-6-alkenyloxy, oxo (which may be represented in the
tautomeric enol form), carboxy, C.sub.1-6-alkoxycarbonyl,
C.sub.1-6-alkylcarbonyl, formyl, aryl, aryl-oxy, arylamino,
aryloxycarbonyl, arylcarbonyl, heteroaryl, heteroarylamino, amino,
mono- and di(C.sub.1-6-alkyl)amino; carbamoyl, mono- and
di(C.sub.1-6-alkyl)aminocarbonyl,
amino-C.sub.1-6-alkyl-aminocarbonyl, mono- and
di(C.sub.1-6-alkyl)amino-C.sub.1-6-alkyl-aminocarbonyl,
C.sub.1-6-alkylcarbonylamino, cyano, guanidino, carbamido,
C.sub.1-6-alkanoyloxy, C.sub.1-6-alkyl-sulphonyl-amino,
aryl-sulphonyl-amino, heteroaryl-sulphonyl-amino,
C.sub.1-6-alkyl-sulphonyl, C.sub.1-6-alkyl-sulphinyl,
C.sub.1-6-alkylsulphonyloxy, nitro, sulphanyl, amino,
amino-sulfonyl, mono- and di(C.sub.1-6-alkyl)amino-sulfonyl,
dihalogen-C.sub.1-4-alkyl, trihalogen-C.sub.1-4-alkyl, halogen,
where aryl and heteroaryl representing substituents may be
substituted 1-3 times with C.sub.1-4-alkyl, C.sub.1-4-alkoxy,
nitro, cyano, amino or halogen, and any alkyl, alkoxy, and the like
representing substituents may be substituted with hydroxy,
C.sub.1-6-alkoxy, C.sub.2-6-alkenyloxy, amino, mono- and
di(C.sub.1-6-alkyl)amino, carboxy, C.sub.1-6-alkylcarbonylamino,
halogen, C.sub.1-6-alkylthio, C.sub.1-6-alkyl-sulphonyl-amino, or
guanidine.
[0218] Preferably, the substituents are selected from hydroxy,
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, oxo (which may be represented in
the tautomeric enol form), carboxy, C.sub.1-6-alkylcarbonyl,
formyl, amino, mono- and di(C.sub.1-6-alkyl)amino; carbamoyl, mono-
and di(C.sub.1-6-alkyl)aminocarbonyl,
amino-C.sub.1-6-alkyl-aminocarbonyl, C.sub.1-6-alkylcarbonylamino,
guanidino, carbamido, C.sub.1-6-alkyl-sulphonyl-amino,
aryl-sulphonyl-amino, heteroaryl-sulphonyl-amino,
C.sub.1-6-alkyl-suphonyl, C.sub.1-6-alkyl-sulphinyl,
C.sub.1-6-alkylsulphonyloxy, sulphanyl, amino, amino-sulfonyl,
mono- and di(C.sub.1-6-alkyl)amino-sulfonyl or halogen, where any
alkyl, alkoxy and the like representing substituents may be
substituted with hydroxy, C.sub.1-6-alkoxy, C.sub.2-6-alkenyloxy,
amino, mono- and di(C.sub.1-6-alkyl)amino, carboxy,
C.sub.1-6-alkylcarbonylamino, halogen, C.sub.1-6-alkylthio,
C.sub.1-6-alkyl-sulphonyl-amino, or guanidine. Especially preferred
examples are C.sub.1-6-alkyl, C.sub.1-6-alkoxy, amino, mono- and
di(C.sub.1-6-alkyl)amino, sulphanyl, carboxy or halogen, where any
alkyl, alkoxy and the like representing substituents may be
substituted with hydroxy, C.sub.1-6-alkoxy, C.sub.2-6-alkenyloxy,
amino, mono- and di(C.sub.1-6-alkyl)amino, carboxy,
C.sub.1-6-alkylcarbony-lamino, halogen, C.sub.1-6-alkylthio,
C.sub.1-6-alkyl-sulphonyl-amino, or guanidine. lamino, in the
present context the term "nitrogen-containing heterocyclic ring" is
intended to mean heterocyclic ring or ring system in which at least
one nitrogen atom is present. Such a nitrogen is, with reference to
the formula, carrying the substituents R.sub.1 and R.sub.2. The
"nitrogen-containing heterocyclic ring" may further comprise
additional heteroatoms, e.g. nitrogen (.dbd.N-- or --N--), sulphur,
and/or oxygen atoms. Examples of such rings are aromatic rings such
as pyridine, pyridazine, pyrimidine, pyrazine, triazine, thiophene,
oxazole, isoxazole, thiazole, isothlazole, pyrrole, imidazole,
pyrazole, tetrazole, quinoline, benzothiazole, benzotriazole,
benzodiazole, benzoxozole, triazole, isoquinoline, indole,
benzopyrazole, thiadiazole, and oxadiazole. The most interesting
examples of aromatic rings are pyridine, pyridazine, pyrimidine,
pyrazine, thiophene, tetrazole, oxazole, isoxazole, thiazole,
isothiazole, pyrrole, imidazole, pyrazole, quinoline, triazole,
isoquinoline, and indole, in particular pyridine, thiophene,
imidazole, quinoline, isoqutnoline, indole, and tetrazole.
[0219] Other examples of such rings are non-aromatic rings such as
imidazolidine, piperazine, hexahydropyridazine,
hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine,
azepane, azocane, aziridine, azirine, azetidine, pyroline, tropane,
oxazinane (morpholine), azepine, dihydroazepine, tetrahydroazepine,
and hexahydroazepine, oxazolane, oxazepane, oxazocane, thiazolane,
thiazinane, thiazepane, thiazocane, oxazetane, diazetane, and
thiazetane. The most interesting examples of non-aromatic rings are
imidazolidine, piperazine, hexahydropyridazine,
hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine,
azepane, azocane, azetidine, tropane, oxazinane (morpholine),
oxazolane, oxazepane, thiazolane, thiazinane, and thiazepane, in
particular imidazolidine, piperazine, hexahydropyridazine,
hexahydropyrimidine, diazepane, pyrrolidine, piperidine, azepane,
oxazinane (morpholine), and thiazinane.
[0220] In the present context, i.e. in connection with the term
"nitrogen-containing heterocyclic ring", the term "optionally
substituted" is intended to mean that the group in question may be
substituted one or several times, preferably 1-5 times, in
particular 1-3 times) with group(s) selected from the same
substituents as defined above for "optionally substituted
aryl".
[0221] As is evident from the formulae defined herein and the
definitions associated therewith, certain compounds of the present
invention are chiral. Moreover, the presence of certain cyclic
fragments or multiple stereogenic atoms provides for the existence
of diastereomeric forms of some of the compounds. The invention is
intended to include all stereoisomers, including optical isomers,
and mixtures thereof, as well as pure, partially enriched, or,
where relevant, racemic forms.
[0222] Embodiments where V is --CH.dbd.CH-- may comprise E- and
Z-stereoisomers, or mixtures of such isomers, which may exist in a
dynamic equilibrium is solution. The E-isomers are generally
preferred.
[0223] It should furthermore be understood that the compounds
defined herein include possible salts thereof, of which
pharmaceutically acceptable salts are of course especially relevant
for the therapeutic applications. Salts include acid addition salts
and basic salts. Examples of acid addition salts are hydrochloride
salts, fumarate, oxalate, etc. Examples of basic salts are salts
where the (remaining) counter ion is selected from alkali metals,
such as sodium and potassium, alkaline earth metals, such as
calcium salts, potassium salts, and ammonium ions
(.sup.+N(R').sub.4), where the R's independently designate
optionally substituted C.sub.1-6-alkyl, optionally substituted
C.sub.2-6-alkenyl, optionally substituted aryl, or optionally
substituted heteroaryl). Pharmaceutically acceptable salts are,
e.g., those described in Remington's --The Science and Practice of
Pharmacy, 20th Ed. Alfonso R. Gennaro (Ed.), Lippincott, Williams
& Wilkins; ISBN: 0683306472, 2000, and in Encyclopedia of
Pharmaceutical Technology. However, generally preferred salt
forming agents for application in the present invention are organic
dicarboxylic acids such as oxalic, fumaric, and maleic acid, and
the like.
[0224] Thus, chalcones with amino groups can be prepared in their
salt-forms thereby making the compounds particularly useful for
pharmaceutical formulations. The use of appropriate selected salt
form can be used to control the dissolution rate in vivo.
Furthermore, the different salt forms have different
bulk-properties which is of importance for the manufacturing
process.
[0225] Preparation of Compounds
[0226] The amino-functional chalcones defined herein may be
produced by methods known per se for the preparation of chalcones
or methods which are analogous to such methods. Examples of
excellent methods for preparing compounds of the
1,3-bis-aromatic-prop-2-enone or the 1,3-bis-aromatic-prop-2-ynone
types are given in the following. Further examples of methods for
the preparation of the compound used according to the present
invention are described in WO 95/06628 and WO 93/17671 and in the
references cited therein.
[0227] Compounds of the general formula I in which V is
--CH.dbd.CH-- can be prepared by reacting a ketone (an acetophenone
in the case where Ar.sup.1 is phenyl)
(Y.sup.1).sub.m--Ar.sup.1(X.sup.1)--C(.dbd.O)--CH.sub.3
[0228] with an aldehyde (a benzaldehyde in the case where Ar.sup.2
is phenyl) HCO--Ar.sup.2(X.sup.2)--(Y.sup.2).sub.p
[0229] wherein Ar.sup.1, Ar.sup.2, X.sup.1, X.sup.2, Y.sup.1,
Y.sup.2, m, and p refer to the definitions given elsewhere
herein.
[0230] This reaction, which is a condensation reaction, is suitably
carried out under acid or base catalysed conditions. A review of
such processes may be found in Nielsen, A. T., Houlihahn, W. J.,
Org. React. 16, 1968, p 1-444. in particular the method described
by Wattanasin, S. and Murphy, S., Synthesis (1980) 647 has been
found quite successful. The reaction may suitably be carried out in
protic organic solvents, such as lower alcohols (e.g. methanol,
ethanol, or tert-butanol), or lower carboxylic acids (formic,
glacial acetic, or propionic acid), or in aprotic organic solvents
such as ethers (e.g. tetrahydrofuran, dioxane, or diethyl ether),
liquid amides (e.g. dimethylformamide or
hexamethylphosphordiamide), dimethylsulfoxide, or hydrocarbons
(e.g. toluene or benzene), or mixtures of such solvents. When
carrying out the reaction under base catalysed conditions, the
catalyst may be selected from sodium, lithium, potassium, barium,
calcium, magnesium, aluminum, ammonium, or quaternary ammonium
hydroxides, lower alkoxides (e.g. methoxides, ethoxides,
tert-butoxides), carbonates, borates, oxides, hydrides, or amides
of lower secondary amines (e.g. diisopropyl amides or methylphenyl
amides). Primary aromatic amines such as aniline, free secondary
amines such as dimethyl amine, diethyl amine, piperidine, or
pyrrolidine as well as basic ion exchange resins may also be
used.
[0231] Acid catalysts may be selected from hydrogen chloride,
hydrogen bromide, hydrogen iodide, sulfuric acid, sulfonic acids
(such as paratoluenesulfonic or methanesulfonic acid), lower
carboxylic acids (such as formic, acetic or propionic acid), lower
halogenated carboxylic acids (such as trifluoroacetic acid), Lewis
acids (such as BF.sub.3, POCl.sub.3, PCl.sub.5, or FeCl.sub.3), or
acid ion exchange resins.
[0232] A drawback of the base catalysed condensation is the poor
yield obtained if the aromatic ring in which the ketone or the
aldehyde or both is substituted with one or more hydroxy groups.
This drawback can be overcome by masking the phenolic group as
described by T. Hidetsugu et al. in EP 0 370 461. Deprotection is
easily performed by mineral acids such as hydrochloric acid.
[0233] The reaction is typically carried out at temperatures in the
range of 0-100.degree. C., e.g. at room temperature. Reaction times
are typically from 30 min to 24 hours.
[0234] The alkyl- or dialkyl aminomethyl-acetophenones and
-benzaldehydes were prepared by reductive amination using
substituted benzaldehyde, amine and sodium triacetoxyborohydride.
The alkyl- or dialkyl aminoalkyl-acetophenones and -benzaldehydes
were prepared from the corresponding bromo-compounds using
halogen/metal exchange (n-BuLi) and quenching with
N,N-dimethylacetamide and dimethylformamide, respectively.
[0235] Compounds of the general formula I in which V is
--C.ident.C-- may be prepared by reacting an activated derivative
of a carboxylic acid of the general formula
(Y.sup.1).sub.m--(X.sup.1)Ar.sup.1--COOH
[0236] with an ethyne derivative
H--C.ident.C--Ar.sup.2(X.sup.2)--(Y.sup.2).sub.p wherein Ar.sup.1,
Ar.sup.2, X.sup.1, X.sup.2, Y.sup.1, Y.sup.2, m, and p refer to the
definitions given elsewhere herein.
[0237] Reactions of this type are described by Tohda, Y.,
Sonogashihara, K., Haghara, N., Synthesis 1977, p 777-778. It is
contemplated that the activated derivative of the carboxylic acid
may be an activated ester, an anhydride or, preferably, an acid
halogenide, in particular the acid chloride. The reaction is
normally carried out using the catalysts described by Tohda, Y. et
al. cited above, namely
copper(I)iodide/triphenylphosphine-palladium dichloride. The
reaction is suitably carried out in triethylamine, a mixture of
triethylamine and pyridine or triethylamine and toluene under a dry
inert atmosphere such as nitrogen or argon. The reaction is
generally carried out at reduced temperature such as in the range
from -80.degree. C. to room temperature, the reaction time
typically being from 30 minutes to 6 hours.
[0238] In the above reactions, it may be preferred or necessary to
protect various sensitive or reactive groups present in the
starting materials to prevent said groups from interfering with the
reactions. Such protection may be carried out in a well-known
manner, e.g. as described in "Protective Groups in Organic
Chemistry" by Wuts and Greene, Wiley-Interscience; ISBN:
0471160199; 3nd edition (May 15, 1999). For example, in the
reaction between the activated acid derivative and the acetylene
derivative, a hydroxy group on Ar.sup.1 and/or Ar.sup.2 may be
protected in the form of the methoxymethyl ether,
N,N-dimethylcarbamoyl ester, or allyl ether. The protecting group
may be removed after the reaction in a manner known per se.
[0239] The ethyne derivative may be prepared by standard methods,
e.g. as described by Nielsen, S. F. Et al., Bioorg. Med. Chem. 6,
pp 937-945 (1998). The carboxylic acids may likewise be prepared by
standard procedures or by reductive amination as described in the
examples.
[0240] Compounds of the general formula I in which V is
--CH.sub.2--CH.sub.2-- can be prepared by ionic hydrogenation of
the corresponding .alpha.,.beta.-unsaturated compound where V is
--CH.dbd.CH-- as it has been described by the inventors in Nielsen,
S. F. et al. Tetrahedron, 53, pp 5573-5580 (1997) and in the
examples (see FIG. 2).
[0241] Further possible synthetic routes for the preparation of the
saturated variants are described in "Advanced Organic Chemistry" by
Jerry March, 3.sup.rd ed. (especially chapter 15, pages 691-700)
and references cited therein. Thus, it is possible to obtain a
large variety of compounds of the 1,3-bis-aromatic-propan-1-one
type from the corresponding prop-2-en-1-ones.
[0242] Therapeutic Uses
[0243] The present inventors have found that that the novel
compound have interesting properties as bacteriostatic,
bacteriocidal and antiparasitic agents (see the Examples section).
It is of course possible that the compounds also have other
interesting properties to be utilised in the medical field.
[0244] Thus, the present invention provides, in a further aspect, a
compound (chalcone derivative) as defined herein for use as a drug
substance, i. e. a medicament.
[0245] Moreover, in further aspects the invention relates to the
use of the compounds as defined herein for the preparation of a
medicament for the treatment of infections, such as infections
associated with bacteria, protozoas or Leishmania spp.
[0246] The invention also provides in still further aspects a
method for the treatment of infections such as bacteria, protozoas
or Leishmania spp in a mammal comprising the administration of the
compounds as defined herein to said mammal.
[0247] In one aspect, the chalcone derivatives may be used for the
treatment of bacterial infections in a mammal in need thereof. Such
bacterial infection may be associated with common Gram-positive
and/or Gram-negative pathogenes or with microaerophilic or
anaerobic bacteria. As a particularly relevant example of bacteria
against which chalcone derivatives demonstrates an effect can be
mentioned antibiotic-sensitive or -resistant strains of S. aureus
and/or E. faecium. Other examples include community acquired and
nosocomial respiratory infections, including S. pneumoniae, S.
pyogenes and members of Enterobacteriaceae (e.g. E. coli),
microaerophilic bacteria associated with gastric disease (e.g.
Helicobacter pylori) or pathogenic anaerobic bacteria (e.g.
Bacteroides fragilis and Clostridium species).
[0248] In still another aspect, the chalcone derivatives as
provided herein can be used for the treatment of infections
associated with protozoa in a mammal. Examples of infections are
those caused by a protozoa selected from Plasmodium falciparum,
Plasmodlum vivax, Plasmodium ovale and Plasmodium malariae.
[0249] In a still further aspect, the chalcone derivatives as
defined herein can be used for the treatment of infections in a
mammal associated with Leishmania spp. Such infections may be
cutaneous and/or visceral.
[0250] Preliminary results have shown that compounds wherein the
Y.sup.1 is the amino-substituent, i. e. m is one and p is 0, in
particular positioned the 2-, 3- or 4-position, and preferably
positioned in the 2-position, where Ar.sup.1 is phenyl, are
particularly promising for the treatment of infections associated
with Leishmania spp. Those in which X.sup.2 represents at least one
substituent selected from C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
C.sub.1-6-alkylcarbonyl, optionally substituted aryl, optionally
substituted aryloxy, optionally substituted arylamino, optionally
substituted heteroaryl, optionally substituted heteroarylamino,
mono- and di(C.sub.1-6-alkyl)amino, C.sub.1-6-alkylcarbonylamino,
optionally substituted C.sub.1-6-alkylthio, optionally substituted
heterocyclyl, optionally substituted heterocyclyloxy, optionally
substituted heterocyclylamino and halogen, such as where X.sup.2
represent the 2,4 or 2,5 substituents of a phenyl group as
Ar.sup.2, appear to be particularly promising. Further, embodiments
wherein X.sup.2 represents one or more halogens located in the 2-,
3- and/or 4-position, especially in the 2- and/or 4-position,
optionally in conjunction with an optionally substituted aryl or
optionally substituted heteroaryl group in the 3- or 5-position are
suitable in this aspect.
[0251] Other preliminary results indicate that compounds wherein
the Y.sup.1 is the amino-substituent, in particular positioned in
the 2-, 3-, or 4-position, preferably in the 2- and/or 4-position,
where Ar.sup.1 is phenyl, are particularly promising for the
treatment of infections caused by malaria. Those in which X.sup.2
represents at least one substituent selected from C.sub.1-6-alkyl,
C.sub.1-6-alkoxy, C.sub.1-6-alkylcarbonyl, optionally substituted
aryl, optionally substituted aryloxy, optionally substituted
arylamino, optionally substituted heteroaryl, optionally
substituted heteroarylamino, optionally substituted
(heteroarylalkyl)amino, optionally substituted
(heteroarylalkyl)alkylamino, mono- and di(C.sub.1-6-alkyl)amino,
C.sub.1-6-alkylcarbonylamino, optionally substituted
C.sub.1-6-alkylthio, optionally substituted heterocyclyl,
optionally substituted heterocyclyloxy, optionally substituted
heterocyclylamino and halogen, such as where X.sup.2 represent the
2,5 substituents of a phenyl group as Ar.sup.2, appear to be
particularly promising. Further, suitable embodiments are those in
which X.sup.1 is hydrogen, methoxy or hydroxy. Yet further
particularly useful embodiments are those wherein X.sup.2
represents one or two halogen atoms, such as chloro, located in the
2- and/or 4-positions. Another interesting embodiment is the one
wherein X.sup.2 represents two substituents, located in the 2- and
5-positions, independently selected from alkoxy, alkyl, aryl,
dialkylamino and pyridinylamino, with methoxy being a preferred
alkoxy group. When X.sup.2 represents one substituent, especially
interesting compounds have X.sup.2 located in the 3- or 4-position,
and selected from mono- or di-alkylamino, pyridinylamino,
imidazolyl and halogen, the latter being particularly suitable in
the 4-position. Typical embodiments wherein X.sup.2 represents
three substituents are those wherein these substituents are located
in the 2-, 4-, and 5-positions, such as 2-alkoxy, 4-alkoxy, hydroxy
or halo, and 5-alkyl or aryl, as well as those wherein the three
substituents are located in the 2-, 3-, and 5-positions, such as
2-alkoxy or alkyl, 3-alkoxy or alkyl, and 5-alkoxy or alkyl. In the
context of treating infections associated with malaria, further,
preferred meanings of R are alkyl, especially methyl.
[0252] Additionally, embodiments wherein both m and p are 1 are
suitable for treatment of infections associated with malaria. Such
embodiments typically have Y.sup.2 in the 2-, 3-, or
5-position.
[0253] Embodiments in which m is 0 and p is 1 are currently
interesting for the treatment of infections associated with
malaria. Those typically have Y.sup.2 in the 2-, 3-, or 4-position
when Ar.sup.2 is phenyl. Preferred such compounds are those where
Y.sup.2 is located at the 2-position, with further optional
presence (X.sup.2) of a 5-aryl substituent. Additionally, typical
meanings of X.sup.1 in this context are 2- and/or 4-halo and 2-
and/or 4-alkoxy, with 4-methoxy and 2-fluoro being preferred.
[0254] Still other preliminary results indicate that compounds
wherein the Y.sup.1 is the amino-substituent, in particular
positioned in the 2, 3 or 4 position where Ar.sup.1 is phenyl, are
particularly promising for the treatment of infections caused by S.
aureus. Those in which X.sup.2 represents at least one substituent
selected from C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
C.sub.1-6-alkylcarbonyl, optionally substituted aryl, optionally
substituted aryloxy, optionally substituted arylamino, optionally
substituted heteroaryl, optionally substituted heteroarylamino,
mono- and di(C.sub.1-6-alkyl)amino, C.sub.1-6-alkylcarbonylamino,
optionally substituted C.sub.1-6-alkylthio, optionally substituted
heterocyclyl, optionally substituted heterocyclyloxy, optionally
substituted heterocyclylamino and halogen appear to be particularly
promising.
[0255] Formulation of Pharmaceutical Compositions
[0256] The chalcone derivatives are typically formulated in a
pharmaceutical composition prior to use as a drug substance.
[0257] The administration route of the compounds as defined herein
may be any suitable route which leads to a concentration in the
blood or tissue corresponding to a therapeutic effective
concentration. Thus, e.g., the following administration routes may
be applicable although the invention is not limited thereto: the
oral route, the parenteral route, the cutaneous route, the nasal
route, the rectal route, the vaginal route and the ocular route. It
should be clear to a person skilled in the art that the
administration route is dependent on the particular compound in
question, particularly, the choice of administration route depends
on the physico-chemical properties of the compound together with
the age and weight of the patient and on the particular disease or
condition and the severity of the same.
[0258] The compounds as defined herein may be contained in any
appropriate amount in a pharmaceutical composition, and are
generally contained in an amount of about 1-95% by weight of the
total weight of the composition. The composition may be presented
in a dosage form which is suitable for the oral, parenteral,
rectal, cutaneous, nasal, vaginal and/or ocular administration
route. Thus, the composition may be in form of, e.g., tablets,
capsules, pills, powders, granulates, suspensions, emulsions,
solutions, gels including hydrogels, pastes, ointments, creams,
plasters, drenches, delivery devices, suppositories, enemas,
injectables, implants, sprays, aerosols and in other suitable
form.
[0259] The pharmaceutical compositions may be formulated according
to conventional pharmaceutical practice, see, e.g., "Remington's
Pharmaceutical Sciences" and "Encyclopedia of Pharmaceutical
Technology", edited by Swarbrick, J. & J. C. Boylan, Marcel
Dekker, inc., New York, 1988. Typically, the compounds defined
herein are formulated with (at least) a pharmaceutically acceptable
carrier or exipient. Pharmaceutically acceptable carriers or
exipients are those known by the person skilled in the art.
[0260] Thus, the present invention provides in a further aspect a
pharmaceutical composition comprising a compound as defined herein
in combination with a pharmaceutically acceptable carrier.
[0261] Pharmaceutical compositions according to the present
invention may be formulated to release the active compound
substantially immediately upon administration or at any
substantially predetermined time or time period after
administration. The latter type of compositions are generally known
as controlled release formulations.
[0262] In the present context, the term "controlled release
formulation" embraces i) formulations which create a substantially
constant concentration of the drug within the body over an extended
period of time, ii) formulations which after a predetermined lag
time create a substantially constant concentration of the drug
within the body over an extended period of time, iii) formulations
which sustain drug action during a predetermined time period by
maintaining a relatively, constant, effective drug level in the
body with concomitant minimization of undesirable side effects
associated with fluctuations in the plasma level of the active drug
substance (sawtooth kinetic pattern), iv) formulations which
attempt to localize drug action by, e.g., spatial placement of a
controlled release composition adjacent to or in the diseased
tissue or organ, v) formulations which attempt to target drug
action by using carriers or chemical derivatives to deliver the
drug to a particular target cell type.
[0263] Controlled release formulations may also be denoted
"sustained release", "prolonged release", "programmed release",
"time release", "rate-controlled" and/or "targeted release"
formulations.
[0264] Controlled release pharmaceutical compositions may be
presented in any suitable dosage forms, especially in dosage forms
intended for oral, parenteral, cutaneous nasal, rectal, vaginal
and/or ocular administration. Examples include single or multiple
unit tablet or capsule compositions, oil solutions, suspensions,
emulsions, microcapsules, microspheres, nanoparticles, liposomes,
delivery devices such as those intended for oral, parenteral,
cutaneous, nasal, vaginal or ocular use.
[0265] Preparation of solid dosage forms for oral use, controlled
release oral dosage forms, fluid liquid compositions, parenteral
compositions, controlled release parenteral compositions, rectal
compositions, nasal compositions, percutaneous and topical
compositions, controlled release percutaneous and topical
compositions, and compositions for administration to the eye can be
performed essentially as described in the applicant's earlier
International application No. WO 99/00114, page 29, line 9, to page
40, line 3. Also, and more generally, the formulation and
preparation of the above-mentioned compositions are well-known to
those skilled in the art of pharmaceutical formulation. Specific
formulations can be found in "Remington's Pharmaceutical
Sciences".
[0266] Dosages
[0267] The compound are preferably administered in an amount of
about 0.1-50 mg per kg body weight per day, such as about 0.5-25 mg
per kg body weight per day.
[0268] For compositions adapted for oral administration for
systemic use, the dosage is normally 2 mg to 1 g per dose
administered 1-4 times daily for 1 week to 12 months depending on
the disease to be treated.
[0269] The dosage for oral administration for the treatment of
parasitic diseases is normally 1 mg to 1 g per dose administered
1-2 times daily for 1-4 weeks, in particular the treatment of
malaria is to be continued for 1-2 weeks whereas the treatment of
leishmaniasis will normally be carried out for 3-4 weeks.
[0270] The dosage for oral administration for the treatment of
bacterial diseases is normally 1 mg to 1 g per dose administered
1-4 times daily for 1 week to 12 months; in particular, the
treatment of tuberculosis will normally be carried out for 6-12
months.
[0271] The dosage for oral administration of the composition in
order to prevent diseases is normally 1 mg to 75 mg per kg body
weight per day. The dosage may be administered once or twice daily
for a period starting 1 week before the exposure to the disease
until 4 weeks after the exposure.
[0272] For compositions adapted for rectal use for preventing
diseases, a somewhat higher amount of the compound is usually
preferred, i.e. from approximately 1 mg to 100 mg per kg body
weight per day.
[0273] For parenteral administration, a dose of about 0.1 mg to
about 50 mg per kg body weight per day is convenient. For
intravenous administration a dose of about 0.1 mg to about 20 mg
per kg body weight per day administered for 1 day to 3 months is
convenient. For intraarticular administration a dose of about 0.1
mg to about 20 mg per kg body weight per day is usually preferable.
For parenteral administration in general, a solution in an aqueous
medium of 0.5-2% or more of the active ingredients may be
employed.
[0274] For topical administration on the skin, a dose of about 1 mg
to about 5 g administered 1-times daily for 1 week to 12 months is
usually preferable.
[0275] In many cases, it will be preferred to administer the
compound defined herein together with another antiparasitic,
antimycotic or antibiotic drug, thereby reducing the risk of
development of resistance against the conventional drugs, and
reducing the amount of each of the drugs to be administered, thus
reducing the risk of side effects caused by the conventional drugs.
Important aspects of this is the use of the compound against
Leishmania, where the compound I is combined with another
antileishmanial drug, or the antimalarial use of the compound I
where the compound I is used together with another antimalarial
drug.
[0276] Method of Prediction
[0277] In a separate aspect, the present invention also provides a
method of predicting whether a chemical compound has a potential
inhibitory effect against a microorganism selected from
Helicobacter pylori and Plasmodium falciparum, said method
comprising preparing a mixture of a dihydroorotate dehydrogenase, a
substrate for dihydroorotate dehydrogenase and the chemical
compound, measuring the enzymatic activity of dihydroorotate
dehydrogenase (A), comparing the enzymatic activity of
dihydroorotate dehydrogenase (A) with the standard activity of
dihydroorotate dehydrogenase (B) corresponding to the activity of a
dihydroorotate dehydrogenase in a similar sample, but without the
chemical compound, predicting that the chemical compound has a
potential inhibitory effect against Helicobacter pylon and
Plasmodium falciparum if A is significantly lower than B.
[0278] The method can be performed as described under DHODH Assay
in the Examples section. It should be noted that the method is not
only applicable for the chalcone derivatives defined herein, but
can be generally applied to predict the potential inhibitory effect
of any compound. Preferably, however, the chemical compound is a
chalcone derivative, e.g. a chalcone derivative as defined
herein.
EXAMPLES
[0279] Preparation of Compounds
[0280] Chemical names presented below were generated using the
software ChemDraw Ultra, version 6.0.1, from CambridgeSoft.com.
[0281] The general method for the preparation of the A ring or B
ring having the amino-functional group is illustrated in FIG.
1.
[0282] General Procedure A
Preparation of alkyl- or dialkyl aminomethyl acetophenones
[0283] To a solution of 2-methyl-[1,3]dioxan-2-yl benzaldehyde (165
mmol) and amine (247 mmol) in dry THF (1.5 L) was added sodium
triacetoxyborohydride (257 mmol) under argon. The resulting
suspension was stirred at room temperature for 18 hr. A solution of
sodium hydroxide (2M) was added and stirring was continued for
approximately 30 min, before the mixture was acidified using HCl
(6M). The mixture was stirred for 1 hr. and extracted with diethyl
ether, which was discarded. The pH of the aqueous phase was
adjusted to 11-14 using sodium hydroxide and extracted again with
diethyl ether. The latter organic phase, was dried over sodium
sulphate, filtered and evaporated to give the title products, which
were used without further purification. General Procedure B
Preparation of alkyl- or dialkyl aminomethyl benzaldehydes
[0284] To a solution of diethoxymethyl benzaldehyde (16.5 mmol) and
amine (24.7 mmol) in dry THF (150 mL) was added sodium
triacetoxyborohydride (25.7 mmol) under argon. The resulting
suspension was stirred at room temperature for 6-18 hr. A solution
of sodium hydroxide (2M) was added and stirring was continued for
approximately 30 min, before the mixture was acidified using HCl
(6M). The mixture was stirred for 1 hr. and extracted with diethyl
ether, which was discarded. The pH of the aqueous phase was
adjusted to 11-14 using sodium hydroxide and extracted again with
diethyl ether. The latter organic phase, was dried over sodium
sulphate, filtered and evaporated to give the title products, which
were used without further purification.
[0285] General Procedure C
Preparation of biaryl carbaldehydes
[0286] A solution of Na.sub.2CO.sub.3 (44 mmol) in water (20 mL)
was added to a solution of bromobenzaldehyde (14.7 mmol) and
arylboronic acid (17.6 mmol) in DME (40 mL). The mixture was
flushed with argon for 2 minutes followed by addition of
Pd(PPh.sub.3).sub.2Cl.sub.2 (310 mg, 3 mol %). The reaction was
heated at reflux and left overnight under an atmosphere of argon.
The reaction was cooled, 2M Na.sub.2CO.sub.3 was added, and the
mixture was extracted with EtOAc (3.times.20 mL). The title
products were purified by flash chromatography.
[0287] General Procedure D
Preparation of amino benzaldehydes
[0288] Bromobenzaldehyde diethyl acetal (40 mmol), amine (48 mmol),
Pd.sub.2(dba).sub.3 (0.2 mmol, 1 mol % Pd), rac-BINAP (0.6 mmol)
and t-BuONa (68 mmol) was stirred in degassed toluene (60 mL) at
80.degree. C. for 18 h. The darkbrown mixture was poured into
icecold hydrochloric acid (1 M, 200 mL) and stirred vigorously for
2 hours at 25.degree. C. The solution was cooled to 0.degree. C.
and pH was adjusted to 10 using 6M NaOH(aq) and extracted with
Et.sub.2O (4.times.100 mL). The organic phase was dried
(K.sub.2CO.sub.3) and the solvent was removed under reduced
pressure. The resulting crude oil purified by flash chromatography
using 5% Et.sub.3N in EtOAc
[0289] General Procedure E
Preparation of aminochalcones with phenolic substituents
[0290] To a solution of an acetophenone (2 mmol) and a
tetrahydro-pyran-2-yloxy benzaldehyde (2 mmol) in 96% EtOH (10 mL)
was added 8M NaOH (0.3 mL), and the mixture was stirred for 3-18
hours at 25.degree. C. The mixture was evaporated on Celite.RTM.
and the product was isolated by flash chromatography. The
aminochalcone was dissolved in MeOH:Et.sub.2O (1:9 v/v, 10 mL) and
a solution of fumaric acid or oxalic acid in MeOH:Et.sub.2O (1:9
v/v) was added. The salt was filtered off. Hydrolysis of the
tetrahydropyran ether was carried out by adding H.sub.2O and MeOH
and stirring at reflux for 72 hr. The salts of the phenolic
aminochalcones were isolated by evaporation. Some aminochalcones
did not undergo salt formation, and was isolated as the free base,
by extraction from aqueous NaHCO.sub.3. The purity was >95%
determined by HPLC and the molecular weight was determined by
LC-MS.
[0291] General Procedure F
Preparation of aminochalcones from acetophenones and aldehydes
[0292] To a solution of an acetophenone (2 mmol) and a benzaldehyde
(2 mmol) in 96% EtOH (10 mL) was added NaOH (0.2 mmol), and the
mixture was stirred for 3-18 hours at 25.degree. C. The mixture was
evaporated on Celite.RTM. and the product was isolated by flash
chromatography. The aminochalcone was dissolved in MeOH:Et.sub.2O
(1:9 v/v, 10 mL) and a solution of fumaric acid or oxalic acid in
MeOH:Et.sub.2O (1:9 v/v) was added. The salt was filtered off and
recrystallised from MeOH or MeCN. Some aminocalcones did not
undergo salt formation, and was isolated as the free base. The
purity was >95% determined by HPLC.
[0293] General Procedure G
Preparation of formylchalcones, substituted in the A-ring
[0294] A solution of 1-(diethoxymethyl-phenyl)-ethanone (29 mmol),
an benzaldehyde (29 mmol), and NaOH (2.9 mmol) in 96% EtOH (100 mL)
was stirred for 18 hours at 25.degree. C. 6M HCl (10 mL) and
Et.sub.2O (50 mL) was added and the solution was stirred for 5
hours at 25.degree. C. H.sub.2O (50 mL) and the mixture was
extracted with Et.sub.2O. The organic phases were pooled, dried
over Na.sub.2SO.sub.4, and filtered. Evaporation gave the crude
title product, which was purified by flash chromatography or
crystallization.
[0295] General Procedure H
Preparation of formylchalcones, substituted in the B-ring
[0296] A solution of diethoxymethyl-benzaldehyde (42 mmol), an
acetophenone (42 mmol), and sodium hydroxide (8 mmol) in 96% EtOH
(100 mL) was stirred for 18 hours at 25.degree. C. 6M HCl (10 mL)
and Et.sub.2O (50 mL) was added and the solution was stirred for 5
hours at 25.degree. C. H.sub.2O (50 mL) and the mixture was
extracted with Et.sub.2O. The organic phases were pooled, dried
over Na.sub.2SO.sub.4, and filtered. Evaporation gave the crude
title product, which was purified by flash chromatography or
crystallization.
[0297] General Procedure I
Preparation of aminochalcones from formylchalcones
[0298] To a solution of an formylchalcone (3.8 mmol) and amine (5.6
mmol) in dry THF (40 mL) was added sodium triacetoxyborohydride
(5.6 mmol) under argon. The resulting suspension was stirred at
room temperature for 6-18 hr. A solution of sodium hydroxide (2M)
was added and stirring was continued for approximately 30 min,
before the mixture extracted with ethyl acetate. The organic phase,
was dried over sodium sulphate, filtered, and evaporated on
Celite.RTM.. The product was isolated by flash chromatography. The
purity was >95% determined by HPLC.
[0299] Characterisation of the Compounds
[0300] The compounds were characterised by NMR (300 MHz) and
GC-MS/LC-MS.
[0301] Acetophenones
1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-ethanone
[0302] General procedure A gave the title product as brown oil in
78% yield. .sup.1H-NMR (CDCl.sub.3,): .delta. 7.42-7.29 (m, 4H),
3.65 (s, 2H), 2.54 (s, 3H), 2.43 (b, 8H), 2.27 (s, 3H).
1-{4-[(3-Dimethylamino-propylamino)-methyl]-phenyl}-ethanone
[0303] General procedure A gave the title product as yellow oil in
18% yield. .sup.1H-NMR (CDCl.sub.3): .delta. 7.91 (d, 2H), 7.42 (d,
2H), 3.85 (s, 2H), 2.68 (t, 2H), 2.60 (s, 3H), 2.36 (t, 2H), 2.22
(s, 6H), 1.73-1.62 (m, 2H).
1-(3-Diethylaminomethyl-phenyl)-ethanone
[0304] General procedure A gave the title product as yellow oil in
80% yield. .sup.1H-NMR (CDCl.sub.3): .delta. 7.91 (s, 1H), 7.82 (d,
1H), 7.57 (d, 1H), 7.40 (t, 1H), 3.61 (s, 2H), 2.61 (s, 3H), 2.52
(t, 4H), 1.04 (t, 6H).
1-(3-Dimethylaminomethyl-phenyl)-ethanone
[0305] General procedure A gave the title product as yellow oil in
89% yield. .sup.1H-NMR (CDCl.sub.3): .delta. 7.89 (s, 1H), 7.85 (d,
1H), 7.52 (d, 1H), 7.42 (t, 1H), 3.47 (s, 2H), 2.61 (s, 3H), 2.25
(s, 6H).
1-(2-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-ethanone
[0306] General procedure A gave the title product as brown oil in
88% yield. .sup.1H-NMR (DMSO) .delta. 7.51 (d, 1H), 7.40-7.30 (m,
3H), 3.57 (s, 2H), 2.56 (s, 3H), 2.39-2.32 (m, 2H), 2.99-2.23 (m,
2H), 2.07 (s, 6H), 2.03 (s, 3H).
1-{2-[(tert-Butyl-methyl-amino)-methyl]-phenyl}-ethanone
[0307] General procedure A gave the title product as brown oil in
44% yield. .sup.1H-NMR (DMSO) .delta. 7.52 (dd, 1H), 7.51 (dd, 1H),
7.40 (td, 1H), 7.30 (td, 1H), 3.63 (s, 2H), 2.48 (s, 3H), 1.91 (s,
3H), 1.03 (s, 9H).
1-[2-(4-Hydroxy-piperidin-1-ylmethyl)-phenyl]-ethanone
[0308] General procedure A gave the title product as brown oil in
82% yield. .sup.1H-NMR (CDCl.sub.3) .delta. 7.32 (dt, 1H),
7.28-7.19 (m, 3H), 3.65-3.56 (m, 1H), 3.54 (s, 2H), 2.63-2.55 (m,
2H), 2.45 (s, 3H), 2.10-2.01 (m, 2H), 1.79-1.70 (m, 2H), 1.49-1.36
(m, 2H).
1-(2-Morpholin-4-ylmethyl-phenyl)-ethanone
[0309] General procedure A gave the title product as yellow oil in
89% yield. Pure according to GCMS m/z: 219.
1-[4-Hydroxy-3-(4-methyl-piperazin-1-yl
methyl)-phenyl]-ethanone
[0310] A solution of formaldehyde (37% w/w, 8.2 mL) was added to a
solution of 4'-Hydroxy acetophenone (100 mmol), and
N-methylpiperazine (110 mmol) in EtOH. Heated at reflux overnight.
The solvent was evaporated on celite and the residue was purified
by flash chromatography and crystallized from heptane to give the
title product as white needles in 55% yield. .sup.1H-NMR (DMSO)
.delta. 7.76 (dd, 1H), 7.74 (s, 1H), 6.81 (d, 1H), 3.69 (s, 2H),
2.47 (br, 4H), 2.46 ((s, 3H), 2.35 (br, 4H), 2.17 (s, 3H).
1-(3-Dimethylaminomethyl-4-methoxy-phenyl)-ethanone
[0311] (5-Bromo-2-methoxy-benzyl)-dimethyl-amine (29 mmol),
Butoxy-ethene (100 mmol), Palladium acetate (0.9 mmol),
1,3-Bis(diphenylphosphino) propane (1.8 mmol), and potassium
carbonate were suspended in DMF (50 ml) and H.sub.2O under argon.
Heated at 80.degree. C. overnight. Poured into hydrochloric acid (2
M) and stirred for 1 hour. The mixture was adjusted to basic pH and
extracted with CH.sub.2Cl.sub.2. The organic phase was evaporated
on celite and the residue was purified by flash chromatography to
give the title product as orange oil in 42% yield. .sup.1H-NMR
(CDCl.sub.3) .delta. 7.90 (s, 1H), 7.88 (dd, 1H), 6.89 (d, 1H),
3.88 (s, 3H), 3.44 (s, 2H), 2.55 (s, 3H), 2.25 (s, 6H).
[0312] Benzaldehydes
2-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-benzaldehyde
[0313] General procedure B gave the title product as brown oil in
82% yield. .sup.1H-NMR (CDCl.sub.3): .delta. 10.48 (s, 1H), 7,89
(dd, 1H), 7.53-7.24 (m, 3H), 3.87 (s, 2H), 2.55 (t, 2H), 2.44 (t,
2H), 2.23-2.18 (m, 9H).
2-(4-Methyl-piperazin-1-ylmethyl)-benzaldehyde
[0314] General procedure B gave the title product as brown oil in
80% yield. .sup.1H-NMR (CDCl.sub.3): .delta. 10.41 (s, 1H), 7.87
(d, 1H), 7.51 (dt, 1H)7.41 (t, 1H), 7.38 (d, 1H), 3.81 (s, 2H),
2.6-2.3 (m, 8H), 2.27 (s, 3H).
3-Dimethylaminomethyl-4-methoxy-benzaldehyde
[0315] To a solution of 4-bromo-2-(dimethylaminomethyl)anisole
(12.2 g, 50 mmol) in dry THF (150 mL) at -78.degree. C. was added
n-BuLi (2.5 M, 20 mL, 50 mmol) keeping the temperature below
-70.degree. C. The orange mixture was stirred for 15 min and dry
DMF (4.7 mL, 60 mmol) was added in one portion. The cooling bath
was removed and the light yellow mixture was allowed to warm to
20.degree. C. After 30 min the mixture was hydrolysed with 5%
Na.sub.2CO.sub.3 (100 mL), and extracted with Et.sub.2O
(3.times.100 mL). The organic phase was dried (K.sub.2CO.sub.3) and
the solvent was removed under reduced pressure leaving yellow oil
(79%) that was pure enough for further reaction.
.sup.1H-NMR(DMSO-d.sub.6): .delta. 9.87 (s, 1H), 7.88-7.40 (m, 1H),
7.81 (d, 1H), 7.19 (d, 1H), 3.88 (s, 3H), 3.42 (s, 2H), 2.17 (s,
6H).
3-(Pyridin-3-ylamino)-benzaldehyde
[0316] General procedure D gave the title compound as white
crystals in 69% yield..sup.1H-NMR(DMSO-d.sub.6): .delta. 9.94 (s,
1H), 8.67 (s, 1H), 8.40 (d, 1H), 8.11 (dd, 1H), 7.58-7.50 (m, 2H),
7.47 (d, 1H), 7.43-7.35 (m, 2H), 7.29 (dd, 1H).
3-{[(2-Hydroxy-ethyl)-methyl-amino]-methyl}-benzaldehyde
[0317] General procedure B gave the title product as yellow oil in
84% yield. .sup.1H-NMR (CDCl.sub.3): .delta. 10.04 (s, 1H), 7.82
(m, 2H), 7.62 (dt, 1H), 7.52 (t, 1H), 3.67 (m, 4H), 2.64 (t, 2H),
2.26 (s, 2H).
3-[(2-Methoxy-ethylamino)-methyl]-benzaldehyde
[0318] General procedure B gave the title product as yellow oil in
24% yield. .sup.1H-NMR (CDCl.sub.3): .delta. 10.04, (s, 1H), 7.89
(t, 1H), 7.79 (dt, 1H), 7.65 (dt, 1H), 7.51 (t, 1H), 3.92 (s, 2H),
3.55 (t, 2H), 3.39 (s, 3H), 2.84 (t, 2H), 1.79 (s, 1H).
4-Diethylaminomethyl-benzaldehyde
[0319] General procedure B gave the title product as brown oil in
74% yield. .sup.1H-NMR (CDCl.sub.3): .delta. 10.02 (s, 1H), 7.85
(d, 2H), 7.55 (d, 2H), 3.66 (s, 2H), 2.56 (k, 4H), 1.07 (t,
6H).
3-Butylamino-benzaldehyde
[0320] General procedure D gave the title compound as yellow oil in
78 % yield. .sup.1H-NMR(DMSO-d.sub.6): .delta. 9.90 (s, 1H), 7.34
(t, 1H), 7.21 (s, 1H), 7.15-7.05 (m, 2H), 6.96 (dd, 1H), 3.30 (t,
2H), 1.57-1.42 (m, 2H), 1.40-1.25 (m, 2H), 0.92 (t, 3H).
4-Dibutylamino-2-fluoro-benzaldehyde
[0321] General procedure B gave the title product as yellow oil in
56% yield. .sup.1H-NMR (CDCl.sub.3): .delta. 10.02 (s, 1H), 7.68
(t, 1H), 6.23 (d, 1H), 6.18 (d, 1H), 3.29 (t, 4H), 1.71-1.57 (m,
4H), 0.96 (t, 6H).
4-Methoxy-3',5'-dimethyl-biphenyl-3-carbaldehyde
[0322] General procedure C gave the title compound as white
crystals in 81% yield. .sup.1H-NMR(CDCl.sub.3): .delta. 10.41 (s,
1H), 8.00 (d, 1H), 7.68 (dd, 1H), 7.31 (s, 2H), 7.19 (d, 1H), 6.93
(s, 1H), ), 4.25 (t, 2H), 2.81 (t, 2H), 2.38 (s, 6H), 2.26 (s,
6H).
3-(Butyl-ethyl-amino)-benzaldehyde
[0323] General procedure D gave the title compound as yellow oil in
40% yield. .sup.1H-NMR(DMSO-D.sub.6): .delta. 9.90 (s, 1H), 7.35
(t, 1H), 7.12-7.05 (m, 2H), 6.96 (dd, 1H), 3.39 (q, 2H), 3.30 (t,
2H), 1.57-1.42 (m, 2H), 1.40-1.25 (m, 2H), 1.08 (t, 3H), 0.92 (t,
3H).
4-Chloro-5-(1,1-dimethyl-allyl)-2-methoxy-benzaldehyde
2-(2-Chloro-4-methoxy-phenyl)propionitrile
[0324] A solution of 2'-chloro-4'-methoxyacetophenone (18.5 g, 0.10
mol) and tosylmethylisocyanide (TOSMIC, 21.5 g, 0.11 mol) in dry
1,2-dimethoxyethane (100 mL) was cooled to -10.degree. C. A
solution of t-BuOK (22.4 g, 0.20 mol) in dry t-BuOH (250 mL) was
added slowly keeping the temperature below 5.degree. C. The
homogeneous orange solution was stirred for 2 h/0.degree. C. and 1
h/25.degree. C. The resulting suspension was evaporated to a
slurry. Water (200 mL) was added and extracted with Et.sub.2O
(3.times.150 mL). The organic phase was dried (Na.sub.2SO.sub.4)
and the solvent was removed under reduced pressure leaving an
orange oil. Yield: 19 g (97%). GCMS: >98%;
.sup.1H-NMR(DMSO-d.sub.6): .delta. 7.49 (d, 1H), 7.12 (d, 1H), 7.02
(dd, 1H), 4.42 (q, 1H), 3.80 (s, 3H), 1.55 (d, 3H).
2-(2-Chloro-4-methoxy-phenyl)-2-methyl-propionitrile
[0325] A solution of 2-(2-chloro-4-methoxy-phenyl)propionitrile (19
g, 0.097 mol) and methyliodide (7 mL, 0.11 mol) in dry DMF (100 mL)
was flushed with argon for 2 min and cooled to 0.degree. C. Sodium
hydride (60% oil susp., 4.4 g, 0.11 mol) was added in small
portions. The thick suspension was stirred for another 18 h at
25.degree. C. and then poured into water (300 mL) and extracted
with Et.sub.2O (3.times.100 mL). The organic phase was dried
(Na.sub.2SO.sub.4) and the solvent was removed under reduced
pressure leaving a yellow oil which was distilled. Bp:
103-106.degree. C./0.06 mbar, clear oil that solidifies on
standing. Yield: 17.5 g (83%). GCMS: >99%;
.sup.1H-NMR(DMSO-d.sub.6): .delta. 7.43 (d, 1H), 7.13 (d, 1H), 6.98
(dd, 1H), 3.80 (s, 3H), 1.77 (s, 6H).
2-(5-Bromo-2-chloro-4-methoxy-phenyl)-2-methyl-propionitrile
[0326] A solution of
2-(2-chloro-4-methoxy-phenyl)-2-methyl-propionitrile (17.5 g,
0.0835 mol) in TFA (100 mL) was cooled to 0.degree. C.
N-bromosuccinimide (14.9 g, 0.0835 mol) was added in small portions
keeping the temperature below 5.degree. C. The orange solution was
stirred for 2 h/25.degree. C. and evaporated to dryness. Water (200
mL) was added and the mixture was stirred vigorously for 1 h. The
crude product was filtered off and recrystallized from boiling
MeOH. The pure product was isolated as white needles. Yield: 13 g
(54%). GCMS: >99% .sup.1H-NMR(DMSO-d.sub.6): .delta. 7.56 (s,
1H), 7.23 (s, 1H), 3.84 (s, 3H), 1.70 (s, 6H).
2-(5-Bromo-2-chloro-4-methoxy-phenyl)-2-methyl-propionaldehyde
[0327] A solution of
2-(5-bromo-2-chloro-4-methoxy-phenyl)-2-methyl-propionitrile (13 g,
0.045 mol) in dry THF (80 mL) was cooled to -10.degree. C. under
argon. DIBALH (1M in THF, 100 mL, 0.10 mol) was added keeping the
temperature below 0.degree. C. The mixture was stirred for 30
min/0.degree. C. and then 2 h/25.degree. C. The clear solution was
carefully poured into icecold hydrochloric acid (2M, 100 mL). The
THF was removed under reduced pressure. The aqueous phase was
cooled and the crude product was filtered off and recrystallized
from boiling MeOH. Yield: 7.8 g (59%). GCMS: >99%;
.sup.1H-NMR(DMSO-d.sub.6): .delta. 9.61 (s, 1H), 7.68 (s, 1H), 7.27
(s, 1H), 3.89 (s, 3H), 1.40 (s, 6H).
1-Bromo-4-chloro-5-(1,1-dimethyl-allyl)-2-methoxy-benzene
[0328] A suspension of methyltriphenylphosphonium bromide (11.4 g,
0.032 mol) in dry THF (100 mL) was cooled to 0.degree. C. under
argon. n-BuLi (2.5M, 12 mL, 0.030 mol) was added slowly. The
suspension became more homogenous. The resulting clear orange
solution of the ylide was stirred for another 15 min at 0.degree.
C. 2-(5-Bromo-2-chloro-4-methoxy-phenyl)-2-methyl-propionaldehyde
(7.8 g, 0.027 mol) was dissolved in dry THF (50 mL) and added to
ylide-solution. The mixture was stirred for 3 h/25.degree. C. and
the resulting suspension was quenched with MeOH (10 mL). The
solvent was removed under reduced pressure and the crude product
was purified by flash chromatography using n-heptane as eluent.
Yield: 3.92 g (50%). GCMS: >99%; .sup.1H-NMR(DMSO-d.sub.6):
.delta. 7.55 (s, 1H), 7.14 (s, 1H), 6.05 (dd, 1H), 5.04 (dd, 1H),
4.92 (dd, 1H), 3.87 (s, 3H), 1.45 (s, 6H).
4-Chloro-5-(1,1-dimethyl-allyl)-2-methoxy-benzaldehyde
[0329] To a solution of
1-bromo-4-chloro-5-(1,1-dimethyl-allyl)-2-methoxy-benzene (3.92 g,
0.0135 mol) in dry THF (30 mL) was cooled to -78.degree. C. under
argon. n-BuLi (2.5M, 6 mL, 0.0145 mol) was added keeping the
temperature below -70.degree. C. The yellow mixture was stirred for
another 15 min and quenched with dry DMF (1.2 mL, 0.015 mol). The
cooling bath was removed and the mixture was allowed to warm to
25.degree. C. A saturated solution of NaHCO.sub.3 (30 mL) was added
and then extracted with EtOAc (3.times.50 mL). The organic phase
was dried (Na.sub.2SO.sub.4) and evaporated to dryness. The crude
product was recrystallized from MeOH. Yield: 3.00 g (93%). GCMS:
>99%; .sup.1H-NMR(DMSO-d.sub.6): .delta. 10.30 (s, 1H), 7.80 (s,
1H), 7.30 (s, 1H), 6.08 (dd, 1H), 5.06 (dd, 1H), 4.91 (dd, 1H),
3.93 (s, 3H), 1.49 (s, 6H).
5-(1,1-Dimethyl-allyl)-2-methoxy-benzaldehyde
2-(3-Bromo-4-methoxy-phenyl)-2-methyl-propionitrile
[0330] A solution of 2-(4-methoxy-phenyl)-2-methyl-propionitrile
(17.5 g, 0.10 mol) in TFA (80 mL) was cooled to 0.degree. C.
N-bromosuccinimide (17.8 g, 0.10 mol) was added in small portions
keeping the temperature below 5.degree. C. The orange solution was
stirred for 2 h/25.degree. C. and evaporated to dryness. Water (200
mL) was added and the mixture was stirred vigorously for 1 h. The
crude product was filtered off and recrystallized from boiling
MeOH. The pure product was isolated as white needles. Yield: 19.3 g
(76%). GCMS: >99%; .sup.1H-NMR(DMSO-d.sub.6): .delta. 7.68 (d,
1H), 7.50 (dd, 1H), 7.16 (d, 1H), 3.86 (s, 3H), 1.70 (s, 6H).
2-(3-Bromo-4-methoxy-phenyl)-2-methyl-propionaldehyde
[0331] A solution of
2-(3-bromo-4-methoxy-phenyl)-2-methyl-propionitrile (12.71 g, 0.050
mol) in dry THF (100 mL) was cooled to -10.degree. C. under argon.
DIBALH (1M in THF, 100 mL, 0.10 mol) was added keeping the
temperature below 0.degree. C. The mixture was stirred for 30
min/0.degree. C. and then 2 h/25.degree. C. The clear solution was
carefully poured into icecold hydrochloric acid (2M, 100 mL). The
THF was removed under reduced pressure to give clear oil. The oil
was destilled (b.p. 114-130.degree. C./4.3.times.10.sup.-3 mbar)
Yield: 7.40 g (58%). GCMS: >99%; .sup.1H-NMR(CDCl.sub.3):
.delta. 9.44 (s, 1H), 7.45 (d, 1H), 7.15 (dd, 1H), 6.90 (d, 1H),
3.89 (s, 3H), 1.43 (s, 6H).
2-Bromo-4-(1,1-dimethyl-allyl)-1-methoxy-benzene
[0332] A suspension of methyltriphenylphosphonium bromide (7.71 g,
0.0215 mol) in dry THF (100 mL) was cooled to 0.degree. C. under
argon. n-BuLi (2.5M, 8 mL, 0.020 mol) was added slowly. The
resulting clear orange solution of the ylide was stirred for
another 15 min at 0.degree. C.
2-(3-Bromo-4-methoxy-phenyl)-2-methyl-propionaidehyde (3.7 g, 0.014
mol) was dissolved in dry THF (50 mL) and added to ylide-solution.
The mixture was stirred for 3 h/25.degree. C. and the resulting
suspension was quenched with MeOH (10 mL). The solvent was removed
under reduced pressure and the crude product was purified by flash
chromatography using n-heptane as eluent. Yield: 3.1 g (84%). GCMS:
>99%; .sup.1H-NMR(CDCl.sub.3): .delta. 7.50 (d, 1H), 7.23 (dd,
1H), 6.83 (d, 1H), 5.97 (dd, 1H), 5.06 (dd, 1H), 5.02 (dd, 1H),
3.87 (s, 3H), 1.44 (s, 6H).
5-(1,1-Dimethyl-allyl)-2-methoxy-benzaldehyde
[0333] To a solution of
2-Bromo-4-(1,1-dimethyl-allyl)-1-methoxy-benzene (3.1 g, 0.012 mol)
in dry THF (50 mL) was cooled to -78.degree. C. under argon. n-BuLi
(2.5M, 5.1 mL, 0.0128 mol) was added keeping the temperature below
-70.degree. C. The yellow mixture was stirred for another min and
quenched with dry DMF (1.4 mL, 0.018 mol). The cooling bath was
removed and the mixture was allowed to warm to 25.degree. C. A
saturated solution of NaHCO.sub.3 (30 mL) was added and then
extracted with EtOAc (3.times.50 mL). The organic phase was dried
(Na.sub.2SO.sub.4) and evaporated to yellow oil. Yield: 2.31 g
(94%). .sup.1H-NMR(CDCl.sub.3): .delta. 10.48 (s, 1H), 7.84 (d,
1H), 7.55 (dd, 1H), 6.94 (d, 1H), 6.00 (dd, 1H), 5.05 (dd, 1H),
5.01 (dd, 1H), 3.93 (s, 3H), 1.41 (s, 6H).
3-Morpholin-4-ylmethyl-benzaldehyde
[0334] General procedure B gave the title product as yellow oil in
71% yield. .sup.1H-NMR (CDCl.sub.3): .delta. 10.05 (s, 1H), 7.88
(s, 1H), 7.81 (d, 1H), 7.64 (d, 1H), 7.51 (t, 1H), 3.74 (t, 4H),
3.58 (s, 2H), 2.48 (t, 4H).
2-Methoxy-5-(pyridin-3-ylamino)-benzaldehyde
[0335] General procedure D gave the title product as yellow oil
that precipitated on standing in 39% yield. .sup.1H-NMR
(CDCl.sub.3): .delta. 10.42 (s, 1H), 8.27 (d, 1H), 8.08 (dd, 1H),
7.55 (d, 1H), 7.33 (dd, 1H), 7.26 (ddd, 1H), 7.11 (dd, 1H), 6.95
(d, 1H), 6.34 (bs, 1H), 3.90 (s, 3H).
4-Dimethylaminomethyl-biphenyl-3-carbaldehyde
[0336] Biphenyl-4-ylmethyl-dimethyl-amine (55 mmol) was dissolved
in diethyl ether and a solution of n-BuLi (65 mmol) was added.
Heated at reflux for 6 hours under argon. The solution was cooled
on ice-bath, before DMF (60 mmol) was added. Stirred overnight.
Aqueous work-up and vacuum destillation (b.p. 130-145.degree.
C./0.015 mbar) gave the title product as yellow oil in 40% yield.
.sup.1H-NMR (DMSO) .delta. 10.38 (s, 1H), 8.03 (d, 1H), 7.89 (dd,
1H), 7.73-7.69 (m, 2H), 7.53-7.39 (m, 4H), 3.76 (s, 2H), 2.17 (s,
6H).
3',5'-Dichloro-4,6-dimethoxy-biphenyl-3-carbaldehyde
[0337] General procedure C gave the title product as beige powder
in 54% yield. .sup.1H-NMR (DMSO) .delta. 10.22 (s, 1H), 7.62 (s,
1H), 7.55 (t, 1H), 7.48 (d, 2H), 6.87 (s, 1H), 4.02 (s, 3H), 3.96
(s, 3H).
3-(Pyridin-4-ylamino)-benzaldehyde
[0338] General procedure D gave the title product as brown crystals
in 11% yield. .sup.1H-NMR (d.sub.6-DMSO): .delta. 9.99 (s, 1H),
9.07 (s, 1H), 8.25 (d, 2H), 7.78 (s, 1H), 7.57-7.51 (m, 3H), 6.97
(d, 2H).
3-[(Pyridin-3-ylmethyl)-amino]-benzaldehyde
[0339] General procedure D gave the title product as brown crystals
in 87% yield. .sup.1H-NMR (d.sub.6-DMSO): 9.85 (s, 1H), 8.61 (d,
1H), 8.45 (dd, 1H), 7.76 (dt, 1H), 7.35 (dd, 1H), 7.29 (t, 1H),
7.11-7.08 (m, 2H), 6.95 (dd, 1H), 6.71 (t, 1H), 4.37 (d, 2H).
[0340] Formylchalcones
(E)-2-[3-(2-Bromo-phenyl)-3-oxo-propenyl]-benzaldehyde
[0341] General procedure H gave the title product as yellow
crystals in 47% yield. .sup.1H-NMR (CDCl.sub.3): .delta. 10.21 (s,
1H), 8.24 (d, 1H), 7.86 (dd, 1H), 7.73 (dd, 1H), 7.67-7.57 (m, 3H),
7.50 (dd, 1H); 7.45 (td, 1H), 7.35 (td, 1H), 7.00 (d, 1H).
(E)-3-[3-(4-Methoxy-phenyl)-3-oxo-propenyl]-benzaldehyde
[0342] General procedure H gave the title compound as white
crystals in 53% yield. .sup.1H NMR (CDCl.sub.3): .delta. 10.08 (s,
1H), 8.42 (bs, 1H), 8.2 (m, 3H), 8.07 (d, 1H), 7.88 (dt, 1H), 7.78
(d, 1H), 7.69 (t, 1H), 7.11 (d, 2H), 3.88 (s, 3H).
(E)-4-[3-(2,4-Dichloro-phenyl)-acryloyl]-benzaldehyde
[0343] General procedure G gave the title compound as white
crystals in 7% yield. .sup.1H NMR (CDCl.sub.3): .delta. 10.13 (s,
1H), 8.15 (m, 3H), 8.02 (d, 2H), 7.70 (d, 1H), 7.49 (d, 1H), 7.46
(d, 1H), 7.33 (dd, 1H).
(E)-3-[3-(2,4-Dichloro-phenyl)-acryloyl]-benzaldehyde
[0344] General procedure G gave the title products as a white solid
in 7% yield. .sup.1H-NMR(CDCl.sub.3): .delta. 10.12 (s, 1H), 8.5
(t, 1H), 8.32-8.26 (m, 1H), 8.18 (d, 1H), 8.15-8.10 (m, 1H), 7.72
(d, 1H), 7.72 (s, 1H), 7.54-7.48 (m, 2H), 7.36-7.30 (m, 1H).
[0345] Aminochalcones
A001:
(E)-1-(4-Methoxy-phenyl)-3-(4-morpholin-4-ylmethyl-phenyl)-propenone
[0346] General procedure I gave the fumaric acid salt of the title
compound as slightly yellow crystals in 16% yield.
.sup.1H-NMR(DMSO-d.sub.6): .delta. 8.15 (d, 2H), 7.91 (d, 1H), 7.83
(d, 2H), 7.69 (d, 1H), 7.39 (d, 2H), 7.08 (d, 2H), 6.63 (s, 2H),
3.86 (s, 3H), 3.59 (t, 4H), 3.52 (s, 2H), 2.40 (t, 4H).
A002:
(E)-3-(4-Diethylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone
[0347] General procedure I gave fumaric acid salt of the title
compound as slightly yellow crystals in 25% yield.
.sup.1H-NMR(DMSO-d.sub.6): .delta. 8.16 (d, 2H), 7.92 (d, 1H), 7.84
(d, 2H), 7.69 (d, 1H), 7.43 (d, 2H), 7.09 (d, 2H), 6.59 (s, 2H),
3.88 (s, 3H), 3.75 (s, 2H), 2.61 (q, 4H), 1.05 (t, 6H).
A003:
(E)-1-(4-Methoxy-phenyl)-3-(4-propylaminomethyl-phenyl)-propenone
[0348] General procedure I gave fumaric acid salt of the title
compound as white crystals in 59% yield. .sup.1H-NMR(DMSO-d.sub.6):
.delta. 8.17 (d, 2H), 7.95 (d, 1H), 7.88 (d, 2H), 7.70 (d, 1H),
7.51 (d, 2H), 7.09 (d, 2H), 6.51 (s, 2H), 3.96 (s, 2H), 3.87 (s,
3H), 2.70-2.61 (m, 2H), 1.60-1.49 (m, 2H), 0.88 (s, 3H).
A004:
(E)-3-(4-Dimethylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone
[0349] General procedure I gave fumaric acid salt of the title
compound as off-white crystals in 60% yield.
.sup.1H-NMR(DMSO-d.sub.6): .delta. 8.16 (d, 2H), 7.93 (d, 1H), 7.83
(d, 2H), 7.70 (d, 1H), 7.41 (d, 2H), 7.09 (d, 2H), 6.59 (s, 2H),
3.88 (s, 3H), 3.60 (s, 2H), 2.28 (s, 6H).
A005:
(E)-3-{4-[(2-Dimethylamino-ethylamino)-methyl]-phenyl}-1-(4-methoxy--
phenyl)-propenone
[0350] General procedure I gave the fumaric acid salt of the title
compound as white crystals in 27% yield. .sup.1H-NMR(DMSO-d.sub.6):
.delta. 8.17 (d, 2H), 7.94 (d, 1H), 7.86 (d, 2H), 7.70 (d, 1H),
7.48 (d, 2H), 7.09 (d, 2H), 6.53 (s, 2H), 3.90 (s, 2H), 3.88 (s,
3H), 2.79 (t, 2H), 2.63 (t, 2H), 2.31 (s, 6H).
A006:
(E)-1-(4-Methoxy-phenyl)-3-(4-piperidin-1-ylmethyl-phenyl)-propenone
[0351] General procedure I gave the title compound as yellow
crystals in 79% yield. .sup.1H-NMR(CDCl.sub.3): .delta. 8.04 (d,
2H), 7.90 (d, 1H), 7.58 (d, 2H), 7.52 (d, 1H), 7.37 (d, 2H), 6.98
(d, 2H), 3.87 (s, 3H), 3.50 (s, 2H), 2.39 (br, 4H), 1.62-1.52 (m,
4H), 1.49-1.40 (m, 2H).
A007:
(E)-3-{4-[(3-Dimethylamino-propylamino)-methyl]-phenyl}-1-(4-methoxy-
-phenyl)-propenone
[0352] General procedure I gave the fumaric acid salt of the title
compound as off-white crystals in 23% yield.
.sup.1H-NMR(DMSO-d.sub.6): .delta. 8.17 (d, 2H), 7.94 (d, 1H), 7.87
(d, 2H), 7.70 (d, 1H), 7.49 (d, 2H), 7.09 (d, 2H), 6.49 (s, 2H),
3.92 (s, 2H), 3.88 (s, 3H), 2.71 (t, 2H), 2.46 (t, 2H), 2.23 (s,
6H), 1.88-1.65 (m, 2H).
A008:
(E)-3-(4-Dibutylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone
[0353] General procedure I gave the title compound as yellow
crystals in 62% yield. 1H-NMR(CDCl.sub.3): .delta. 8.04 (d, 2H),
7.80 (d, 1H), 7.58 (d, 2H), 7.52 (d, 1H), 7.38 (d, 2H), 6.98 (d,
2H), 3.90 (s, 3H), 3.57 (s, 2H), 2.40 (t, 4H), 1.49-1.40 (m, 4H),
1.36-1.20 (m, 4H), 0.88 (t, 6H).
A009:
(E)-3-{4-[(4-Diethylamino-1-methyl-butylamino)-methyl]-phenyl}-1-(4--
methoxy-phenyl)-propenone
[0354] General procedure I gave the title compound as brown oil in
24% yield. .sup.1H-NMR(CDCl.sub.3): .delta. 8.04 (d, 2H), 7.80 (d,
1H), 7.59 (d, 2H), 7.52 (d, 1H), 7.38 (d, 2H), 6.98 (d, 2H), 3.90
(s, 3H), 3.57 (s, 2H), 2.79-2.61 (m, 1H), 2.60-2.50 (q, 4H),
2.49-2.40 (t, 2H), 1.52-1.48 (m, 2H), 1.38-1.23(m, 2H), 1.06 (d,
3H), 1.01 (t, 6H).
A010:
(E)-3-{3-[(2-Dimethylamino-ethylamino)-methyl]-phenyl}-1-(4-methoxy--
phenyl)-propenone
[0355] General procedure I gave the fumaric acid salt of the title
compound as white crystals in 43% yield. .sup.1H-NMR(DMSO-d.sub.6):
.delta. 8.16 (d, 2H), 7.95 (s, 1H), 7.93 (d, 1H), 7.81 (d, 1H),
7.70 (d, 1H), 7.52-7.43 (m, 2H), 7.10 (d, 2H), 6.58 (s, 2H), 3.95
(s, 2H), 3.88 (s, 3H), 2.85 (t, 2H), 2.70 (t, 2H), 2.35 (s,
6H).
A011:
(E)-3-(2,4-Dichloro-phenyl)-1-(4-dimethylaminomethyl-phenyl)-propeno-
ne
[0356] General procedure I gave the fumaric acid salt of the title
compound as off-white crystals in 72% yield.
.sup.1H-NMR(DMSO-d.sub.6): .delta. 8.26 (d, 1H), 8.15 (d, 2H), 8.04
(d, 1H), 7.96 (d, 1H), 7.78 (d, 1H), 7.56 (dd, 1H), 7.52 (d, 2H),
6.60 (s, 2H), 3.60 (s, 2H), 2.22 (s, 6H).
A012:
(E)-1-(4-Methoxy-phenyl)-3-(3-propylaminomethyl-phenyl)-propenone
[0357] General procedure I gave the fumaric acid salt of the title
compound as white crystals in 28% yield. .sup.1H-NMR(DMSO-d.sub.6):
.delta. 8.15 (d, 2H), 7.98 (s, 1H), 7.94 (d, 1H), 7.80 (d, 1H),
7.69 (d, 1H), 7.52-7.43 (m, 2H), 7.10 (d, 2H), 6.52 (s, 2H), 3.99
(s, 2H), 3.86 (s, 3H), 2.69 (t, 2H), 1.62-1.50 (m, 2H), 0.89 (t,
3H).
A013:
(E)-1-(4-Methoxy-phenyl)-3-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl-
]-propenone
[0358] General procedure I gave the fumaric acid salt of the title
compound as off-white crystals in 43% yield.
.sup.1H-NMR(DMSO-d.sub.6): .delta. 8.16 (d, 2H), 7.92 (d, 1H),
7.80-7.75 (m, 2H), 7.69 (d, 1H), 7.45-7.37 (m, 2H), 6.99 (d, 2H),
6.59 (s, 2H), 3.87 (s, 3H), 3.55 (s, 2H), 2.70-2.55 (br, 4H),
2.54-2.45 (br, 4H), 2.35 (s, 3H).
A014:
(E)-1-(4-Methoxy-phenyl)-3-[3-(4-methyl-[1,4]diazepan-1-ylmethyl)-ph-
enyl]-propenone
[0359] General procedure I gave the fumaric acid salt of the title
compound as off-white crystals in 70% yield.
.sup.1H-NMR(DMSO-d.sub.6): .delta. 8.16 (d, 2H), 7.92 (d, 1H),
7.80-7.75 (m, 2H), 7.70 (d, 1H), 7.45-7.40 (m, 2H), 7.09 (d, 2H),
6.57 (s, 2H), 3.87 (s, 3H), 3.69 (s, 2H), 3.08-3.00 (m, 2H),
2.99-2.97 (m, 2H), 2.80-2.75 (m, 2H), 2.72-2.65 (m, 2H), 2.58 (s,
190-1.81 (m, 2H).
A015:
(E)-3-(3-Dimethylaminomethyl-phenyl)-1-(4-methoxy-phenyl)-propenone
[0360] General procedure I gave the fumaric acid salt of the title
compound as white crystals in 23% yield. .sup.1H-NMR(DMSO-d.sub.6):
.delta. 8.16 (d, 2H), 7.92 (d, 1H), 7.80-7.75 (m, 2H), 7.69 (d,
1H), 7.45-7.37 (m, 2H), 7.09 (d, 2H), 6.60 (s, 2H), 3.87 (s, 3H),
3.51 (s, 2H), 2.21 (s, 6H).
A016:
(E)-1-(2-Bromo-phenyl)-3-(2-dimethylaminomethyl-phenyl)-propenone
[0361] General procedure I gave the title compound as slightly
green crystals in 17% yield. .sup.1H-NMR(CDCl.sub.3): .delta. 7.96
(d, 1H), 7.72-7.67 (m, 1H), 7.64 (dd, 1H), 7.44-7.37 (m, 2H),
7.36-7.29 (m, 3H), 7.25-7.21 (m, 1H), 6.95 (d, 1H), 3.35 (s, 2H),
2.07 (s, 6H).
A017:
(E)-3-{3-[(3-Dimethylamino-propylamino)-methyl]-phenyl}-1-(4-methoxy-
-phenyl)-propenone
[0362] General procedure I gave the title compound as yellow oil in
27% yield. .sup.1H-NMR(CDCl.sub.3): .delta. 8.06 (d, 2H), 7.80 (d,
1H), 7.65-7.50 (m, 3H), 7.40-7.37 (m, 2H), 6.99 (d, 2H), 3.90 (s,
3H), 3.84 (s, 2H), 2.70 (t, 2H), 2.35 (t, 2H), 2.20 (s, 6H),
1.70-1.60 (m, 2H).
A018:
(E)-3-(2,5-Dimethoxy-phenyl)-1-(4-dimethylaminomethyl-phenyl)-propen-
one
[0363] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 64% yield.
.sup.1H-NMR(DMSO-d.sub.6): .delta. 7.99 (d, 2H), 7.90 (d, 1H), 7.78
(d, 1H), 7.45-7.30 (m, 3H), 6.90 (s, 2H), 6.45 (s, 2H), 3.70 (s,
2H), 3.65 (s, 3H), 3.45 (s, 3H), 2.21 (s, 6H).
A019:
(E)-3-(4-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-phenyl)-prope-
none
[0364] General procedure F gave the title compound as orange oil in
24% yield. .sup.1H-NMR(CDCl.sub.3): .delta. 7.91 (d, 2H), 7.84 (d,
1H), 7.75-7.41 (m, 4H), 7.32 (d, 1H), 6.62 (d, 2H), 3.58 (s, 2H),
3.32 (t, 4H), 2.26 (s, 6H), 1.64-1.54 (m, 4H), 1.46-29 (m, 4H),
0.97 (t, 6H).
A020:
(E)-3-(2,4-Dichloro-phenyl)-1-(3-dimethylaminomethyl-phenyl)-propeno-
ne
[0365] General procedure I gave the fumaric acid salt of the title
compound as white powder in 29% yield. .sup.1H-NMR(DMSO-d.sub.6):
.delta. 8.27 (d, 1H), 8.15-8.07 (m, 2H), 8.02 (d, 1H), 7.95 (d,
1H), 7.77 (d, 1H), 7.65 (d, 1H), 7.60-7.52 (m, 2H), 6.60 (s, 2H),
3.65 (s, 2H), 2.28 (s, 6H).
A021:
(E)-3-(2,4-Dichloro-phenyl)-1-[3-(4-methyl-piperazin-1-ylmethyl)-phe-
nyl]-propenone
[0366] General procedure I gave the fumaric acid salt of the title
compound as white powder in 33% yield. .sup.1H-NMR(DMSO-d.sub.6):
.delta. 8.04 (d, 1H), 7.87 (d, 1H), 7.84-7.69 (m, 3H), 7.55 (d,
1H), 7.43-7.29 (m, 3H), 6.60 (s, 4H), 3.61 (s, 2H), 2.70-2.55 (br,
4H), 2.50-2.40 (br, 4H), 2.35 (s, 3H).
A022:
(E)-3-(2,4-Dichloro-phenyl)-1-{3-[(3-dimethylamino-propylamino)-meth-
yl]-phenyl}-propenone
[0367] General procedure I gave the fumaric acid salt of the title
compound as white powder in 8% yield. .sup.1H-NMR(DMSO-d.sub.6):
.delta. 8.26-8.23 (m, 2H), 8.13 (br d, 1H), 8.03 (d, 1H), 7.96 (d,
1H), 7.77 (d, 1H), 7.74 (br d, 1H), 7.62-7.55 (m, 2H), 6.53 (s,
4H), 4.05 (s, 2H), 2.78 (t, 2H), 2.59 (t, 2H), 2.34 (s, 6H), 1.78
(p, 2H).
A023:
(E)-3-(2,5-Dimethoxy-phenyl)-1-{4-[(3-dimethylamino-propylamino)-met-
hyl]-phenyl}-propenone
[0368] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 9% yield. .sup.1H-NMR(DMSO-d.sub.6):
.delta. 8.15 (d, 2H), 8.04 (d, 1H), 7.90 (d, 1H), 7.64 (d, 2H),
7.56 (t, 1H), 7.04 (d, 2H), 6.53 (s, 4H), 4.07 (s, 2H), 3.84 (s,
3H), 3.80 (s, 3H), 2.81 (t, 2H), 2.74 (t, 2H), 2.45 (s, 6H), 1.86
(p, 2H).
A024:
(E)-3-(3-Dimethylaminomethyl-phenyl)-1-(2-fluoro-4-methoxy-phenyl)-p-
ropenone
[0369] General procedure F gave the fumaric acid salt of the title
compound as slightly yellow crystals in 60% yield.
.sup.1H-NMR(DMSO-d.sub.6): .delta. 7.84 (t, 1H), 7.69 (br, 2 H),
7.65 (d, 1H), 7.49 (dd, 1H), 7.43-7.40 (m, 2H), 6.97 (dd, 1H), 6.96
(t, 1H), 6.60 (s, 2H), 3.88 (s, 3H), 3.52 (s, 2H), 2.21 (s,
6H).
A025:
(E)-3-(4Dibutylamino-phenyl)-1-[4-(4-methyl-piperazin-1-ylmethyl)-ph-
enyl]-propenone
[0370] General procedure F gave the fumaric acid salt of the title
compound as orange crystals in 2% yield. .sup.1H-NMR(DMSO-d.sub.6):
.delta. 8.05 (d, 2H), 7.67-7.54 (m, 4H), 7.46 (d, 2H), 6.68 (d,
2H), 6.59 (s, 4H), 3.59 (s, 2H), 3.34 (t, 4H), 2.71 (br, 4H), 2.41
(s, 3H,), 1.52-1.47 (m, 4H), 1.39-1.27 (m, 4H), 0.92 (t, 6H).
A026:
(E)-3-(2,4-Dichloro-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phe-
nyl]-propenone
[0371] General procedure F gave the fumaric acid salt of the title
compound as white crystals in 50% yield. .sup.1H-NMR(DMSO-d.sub.6):
.delta. 8.06 (d, 1H), 7.71-7.70 (m, 1H), 7.52-7.39 (m, 6H), 7.30
(d, 1H), 6.56 (s, 4H), 3.61 (s, 2H), 2.49 (br, under DMSO, 4H),
2.35 (br, 4H), 2.27 (s, 3H).
A027:
(E)-3-(2,4-Dichloro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propeno-
ne
[0372] General procedure F gave the fumaric acid salt of the title
compound as white crystals in 31% yield. .sup.1H-NMR(DMSO-d.sub.6):
.delta. 8.10 (d, 1H), 7.71 (d, 1H), 7.62-7.59 (m, 2H), 7.55-7.39
(m, 6H), 6.59 (s, 2H), 3.73 (s, 2H), 2.19 (s, 6H).
A028:
(E)-3-(2,5-Dimethoxy-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-ph-
enyl]-propenone
[0373] General procedure F gave the title compound as brown oil in
69% yield. .sup.1H-NMR(CDCl.sub.3): .delta. 7.51 (d, 2H), 7.41-7.27
(m, 3H), 7.08-7.03 (m, 2H), 6.93-6.82 (m, 2H), 3.79 (s, 3H), 3.78
(s, 3H), 3.75 (s, 2H), 2.38-2.19 (br, 8H), 2.19 (s, 3H).
A029:
(E)-3-(2,5-Dimethoxy-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propen-
one
[0374] General procedure F gave the title compound as brown oil in
82% yield. .sup.1H-NMR(CDCl.sub.3): .delta. 7.58 (d, 1H), 7.43-7.32
(m, 4H), 7.13-7.07 (m, 2H), 6.95-6.83 (m, 2H), 3.81 (s, 3H), 3.80
(s, 3H), 3.56 (s, 2H), 2.19 (s, 6H).
A030:
(E)-3-(4-Dibutylamino-phenyl)-1-(2-dimethylaminomethyl-phenyl)-prope-
none
[0375] General procedure F gave the title compound as brown oil in
49% yield. .sup.1H-NMR(CDCl.sub.3): .delta. 7.46 (d, 1H), 7.42-7.28
(m, 5H), 7.21 (d, 1H), 6.85 (d, 1H), 6.59 (d, 2H), 3.53 (s, 2 H),
3.30 (t, 4H), 2.16 (s, 6H), 1.61-1.53 (m, 4H), 1.40-1.35 (m, 4H),
0.96 (t, 6H).
A031:
(E)-3-(4-Dibutylamino-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-p-
henyl]-propenone
[0376] General procedure F gave the title compound as orange oil in
71% yield. .sup.1H-NMR(CDCl.sub.3): .delta. 7.38-7.28 (m, 6H), 7.18
(d, 1H), 6.82 (d, 1H), 6.59 (d, 2H), 3.60 (s, 2H), 3.30 (t, 4H),
2.39-2.26 (br, 8H), 2.19 (s, 3H), 1.63-1.53 (m, 4H), 1.40-1.30 (m,
4H).
A032:
(E)-3-(3-Dimethylaminomethyl-phenyl)-1-pyridin-2-yl-propenone
[0377] General procedure I gave the fumaric acid salt of the title
compound as white crystals in 30% yield. .sup.1H-NMR(DMSO-d.sub.6):
.delta. 8.82 (d, 1H), 8.28 (d, 1H), 8.14-8.03 (m, 2H), 7.87 (d,
1H), 7.79-7.69 (m, 2H), 7.56-7.43 (m, 2H), 7.11-7.04 (m 1H), 6.60
(s, 2H), 3.58 (s, 2H), 2.25 (s, 6H).
A033:
(E)-3-(4-Dibutylamino-phenyl)-1-(4-dimethylaminomethyl-phenyl)-prope-
none
[0378] General procedure F gave the title compound as orange oil in
28% yield. .sup.1H-NMR(CDCl.sub.3): .delta. 7.98 (d, 2H), 7.79 (d,
1H), 7.53 (d, 2H), 7.44 (d, 2H), 7.33 (d, 1H), 6.64 (d, 2H), 6.63
(s, 2H), 4.14 (q, 4H), 2.28 (s, 6H), 1.66-1.57 (m, 4H), 1.45-1.38
(m, 4H), 0.99 (t, 6H).
A034:
(E)-3-[5-(1,1-Dimethyl-allyl)-2-methoxy-phenyl]-1-(2-dimethylaminome-
thyl-phenyl)-propenone
[0379] General procedure F gave the title compound as yellow oil in
26% yield. .sup.1H-NMR(CDCl.sub.3): .delta. 7.58 (d, 1H), 7.53 (d,
1H), 7.44-7.33 (m, 5H), 7.15 8d, 1H), 6.86 (d, 1H), 6.01 (dd, 1H),
5.10-5.04 (m, 2H), 3.83 (s, 3H), 3.57 (s, 2H), 2.16 (s, 6H), 1.41
(s, 6H).
A035:
(E)-1-{2-[(tert-Butyl-methyl-amino)-methyl]-phenyl}-3-(2,4-dichloro--
phenyl)-propenone
[0380] General procedure F gave the title compound as orange oil in
33% yield. .sup.1H-NMR(CDCl.sub.3): .delta. 7.48-7.12 (m 8H), 6.82
(d, 1H), 3.57 (s, 2H), 1.81 (s, 3H), 0.90 (s, 9H).
A036: (E)-Acetic acid
1-{2-[3-(2,4-dichloro-phenyl)-acryloyl]-benzyl}-piperidin-4-yl
ester
[0381] General procedure F gave the title compound as orange oil in
45% yield. .sup.1H-NMR(CDCl.sub.3): .delta. 7.60 (d, 1H), 7.48 (d,
1H), 7.45-7.29 (m, 6H), 6.97 (d, 1H), 4.74-4.68 (m, 1H), 3.61 (s,
2H), 2.61-2.54 (m, 2H), 2.25-2.17 (m, 2H), 2.02 (s. 3H), 1.77-1.71
(m, 2H), 1.62-1,49 (m, 2H).
A037:
(E)-3-(2,4-Dichloro-phenyl)-1-(2-morpholin-4-ylmethyl-phenyl)-propen-
one
[0382] General procedure F gave the title compound as yellow oil in
38% yield. .sup.1H-NMR(CDCl.sub.3): .delta. 7.62 (d, 1H, 7.565 (d,
1H), 7.54-7.30 (m, 6H), 6.99 (d, 1H), 3.62 (s, 2H), 3.55 (t, 4H),
2.37 (t, 4H).
A038:
(E)-3-(2,4-Dichloro-phenyl)-1-(2-{[(2-dimethylamino-ethyl)-methyl-am-
ino]-methyl}-phenyl)-propenone
[0383] General procedure F gave the title compound as orange oil in
10% yield. .sup.1H-NMR(CDCl.sub.3): .delta. 7.63 (d, 1H), 7.58 (d,
1H), 7.45-7.29 (m, 6H), 6.99 (d, 1H), 3.67 (s, 2H), 2.49-2.44 (m,
2H), 2.35-2.30 (m, 2H), 2.16 (s, 6H), 2.11 (s, 3H).
A039: (E)-3-(4-Diethylaminomethyl-phenyl)-1-o-tolyl-propenone
[0384] General procedure F gave the fumaric acid salt of the title
compound as slightly yellow crystals in 32% yield.
.sup.1H-NMR(DMSO): .delta. 7.77 (d, 2H), 7.62 (dd, 1H), 7.49-7.32
(m, 7H), 6.60 (s, 3H), 3.79 (s, 2H), 2.64 (q, 4H), 2.38 (s, 3H),
1.05 (t, 6H).
A040:
(E)-3-(3-Dimethylaminomethyl-phenyl)-1-(2-methoxy-phenyl)-propenone
[0385] General procedure F gave the title compound as orange oil in
22% yield. .sup.1H-NMR(CDCl.sub.3): .delta. 7.52 (d, 1H), 7.51 (dd,
1H), 7.44-7.37 (m, 3H), 7.28-7.26 (m 2H), 7.27 (d, 1H), 6.99-6.91
(m, 2H), 3,82 (s, 3H), 3.37 (s, 2H), 2.18 (s, 6H).
A041:
(E)-3-(4-Chloro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone
[0386] General procedure F gave the fumaric acid salt of the title
compound as white crystals in 22% yield. .sup.1H-NMR(DMSO): .delta.
7.80 (d, 2H), 7.59 (d, 1H), 7.55-7.41 (m, 5H), 7.37 (s, 2H), 6.60
(s, 2H), 3.71 (s, 2H), 2.19 (s, 6H).
A042:
(E)-3-(2,4-Difluoro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propeno-
ne
[0387] General procedure F gave the fumaric acid salt of the title
compound as white crystals in 46% yield. .sup.1H-NMR(DMSO): .delta.
8.09-8.02 (m, 1H), 7.55-7.19 (m, 7H), 7.17-7.16 (m, 1H), 6.60 (s,
2H), 3.66 (s, 2H), 2.15 (s, 6H).
A043:
(E)-3-(3-Butylamino-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propeno-
ne
[0388] General procedure F gave the title compound as brown oil in
34% yield. .sup.1H-NMR (CDCl.sub.3): .delta. 7.45-7.32 (m, 4H),
7.21-7.16 (m, 1H), 7.17 (d, 1H), 7.01 (d, 1H), 6.87 (d, 1H), 6.74
(t, 1H), 6.64 (dd, 1H), 3.69 (br, 1H), 3.60 (s, 2H), 3.14 (t, 2H),
2.15 (s, 6H), 1.68-1.61 (m, 2H), 1.49-1.39 (m, 2H), 0.98 (t,
3H).
A044:
(E)-3-(4-Diethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl)-
-propenone
[0389] General procedure F gave the title compound as brown oil in
20% yield. .sup.1H-NMR(CDCl.sub.3): .delta. 7.46 (d, 2H), 7.41-7.20
(m, 7H), 7.03 (d, 1H), 3.57 (s, 2H), 3.53 (s, 2H), 2.52 (q, 4H),
2.13 (s, 6H), 1.04 (t, 6H).
A045:
(E)-3-(2,4-Dichloro-phenyl)-1-(2-diethylaminomethyl-phenyl)-propenon-
e
[0390] General procedure F gave the fumaric acid salt of the title
compound as white powder in 28% yield. .sup.1H-NMR (DMSO): .delta.
13.07 (br, 1H), 8.08 (d, 1H), 7.72 (d, 1H), 7.54-7.37 (m, 6H), 7.32
(d, 1H), 6.61 (s, 2H), 3.72 (s, 2H), 2.40 (q, 4H), 0.85 (t,
6H).
A046:
(E)-3-(2,5-Dimethoxy-phenyl)-1-[4-(4-methyl-piperazin-1-ylmethyl)-ph-
enyl]-propenone
[0391] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 5% yield. .sup.1H-NMR (DMSO) .delta.
8.11 (d, 2H), 8.03 (d, 1H), 7.96 (d, 1H), 7.55-7.54 (m, 1H), 7.50
(d, 2H), 7.06-7.05 (m, 2H), 6.59 (s, 4H), 3.85 (s, 3H), 3.80 (s,
3H), 3.60 (s, 2H), 2.65 (br, 4H), 2.56-2.49 (under DMSO, 2H), 2.37
(s, 3H).
A047:
(E)-1-(2-Dimethylaminomethyl-phenyl)-3-(4-hydroxy-2-methoxy-5-propyl-
-phenyl)-propenone
[0392] General procedure F, using acidic work-up, gave the title
compound as red oil in 20% yield. .sup.1H-NMR (DMSO) .delta. 10.23
(br, 1H), 7.65 (d, 1H), 7.60-7.47 (m, 5H), 7.17 (d, 1H), 6.62 (s,
1H), 3.88 (s, 3H), 3.61 (s, 2H), 2.59 (t, 2H), 2.18 (s, 6H),
1.73-1.63 (m, 2H), 1.01 (t, 3H).
A048:
(E)-3-(2,4-Dichloro-phenyl)-1-(2-piperazin-1-ylmethyl-phenyl)-propen-
one
[0393] General procedure F gave the fumaric acid salt of the title
compound as white powder in 27% yield. .sup.1H-NMR (DMSO) .delta.
8.08 (d, 1H), 7.72 (d, 1H), 7.53-7.40 (m, 6H), 7.40 (d, 1H), 6.45
(s, 2H), 3.64 (s, 2H), 2.8 (br, 4H), 2.4 (br, 4H).
A049:
(E)-3-(2,5-Dimethoxy-phenyl)-1-(2-piperazin-1-ylmethyl-phenyl)-prope-
none
[0394] General procedure F gave the fumaric acid salt of the title
compound as white powder in 30% yield. .sup.1H-NMR (DMSO) .delta.
10.37 (br, 2H), 7.53 (d, 1H), 7.44-7.33 (m, 5H), 7.25 (d, 1H), 7.00
(d, 2H), 6.44 (s, 2H), 3.75 (s, 3H), 3.75 (s, 3H), 3.59 (s, 2H),
2.78 (br, 4H), 2.37 (br, 4H).
A050:
(E)-1-(2-Dimethylaminomethyl-phenyl)-3-(4-dipropylamino-2-fluoro-phe-
nyl)-propenone
[0395] General procedure F gave the title compound as brown oil in
39% yield. .sup.1H-NMR(CDCl.sub.3): .delta. 7.54-7.27 (m, 6H), 6.85
(d, 1H), 6.32 (dd, 1H), 6.18 (dd, 1H), 3.47 (s, 2H), 3.18 (t, 4H),
2.08 (s, 6H), 1.61-1.49 (m, 4 H), 0.87 (t, 6H).
A051:
(E)-3-(2,4-Dichloro-phenyl)-1-[2-(4-hydroxy-piperidin-1-ylmethyl)-ph-
enyl]-propenone
[0396] General procedure F gave the title compound as brown
semi-solid in 39% yield. .sup.1H-NMR (DMSO) .delta. 8.05 (d, 1H),
7.70 (d, 1H), 7.50-7.25 (m, 7H), 4.46 (br, 1H), 3.55 (s, 2H),
3.35-3.32 (m, 2H), 2.47-2.44 (m, 2H (under DMSO)), 2.00-1.93 (m,
2H), 1.53-1.49 (m, 2H), 1.24-1.21 (m, 2H).
A052:
(E)-1-(3-Diethylaminomethyl-phenyl)-3-(2,5-dimethoxy-phenyl)-propeno-
ne
[0397] General procedure F gave the title compound as yellow oil in
41% yield. .sup.1H-NMR (DMSO) .delta. 8.07 (d, 1H), 7.95 (s, 1H),
7.87 (d, 1H), 7.59 (d, 1H), 7.58 (d, 1H), 7.44 (t, 1H), 7.18 (d,
1H), 6.94 (dd, 1H), 6.88 (d, 1H), 3.87 (s, 3H), 2.82 (s, 3H), 3.60
(s, 2H), 2.55 (q, 4H), 1.06 (t, 6H).
A053:
(E)-3-(2-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-1-[-
2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-propenone
[0398] General procedure F gave the fumaric acid salt of the title
compound as white crystals in 39% yield. .sup.1H-NMR (DMSO) .delta.
7.71-7.68 (m, 1H), 7.50 (d, 1H), 7.27-7.11 (m, 7H), 6.86 (d, 1H),
6.34 (s, 4H), 3.38 (s, 2H), 3.27 (s, 2H), 2.40 (t, 2H), 2.24 (t,
2H), 2.15 (s, 6H), 2.11 (br, 4H), 1.94 (s, 3H), 1.79 (s, 3H).
A054:
(E)-3-(2,4-Dimethoxy-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-ph-
enyl]-propenone
[0399] General procedure F gave the fumaric acid salt of the title
compound as white crystals in 48% yield. .sup.1H-NMR (DMSO) .delta.
7.46 (d, 1H), 7.25 (d, 1H9, 7.19-7.12 (m, 5H), 6.82 (d, 1H),
6.38-6.33 (m, 2H), 6.36 (s, 4H), 3.58 (s, 3H), 3.58 (s, 3H), 3.30
(s, 2H), 2.25 (br, 4H), 1.94 (s, 3H).
A055:
(E)-3-(4-imidazol-1-yl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmethyl)--
phenyl]-propenone
[0400] General procedure F gave the fumaric acid salt of the title
compound as white crystals in 46% yield..sup.1H-NMR (DMSO) .delta.
8.38 (t, 1H), 7.91 (d, 2H), 7.85 (t, 1H), 7.74 (d, 2H), 7.44-7.31
(m, 6H), 7.14 (t, 1H), 6.60 (s, 4H), 3.60 (s, 2H), 2.34 (br, 8H),
2.19 (s, 3H).
A056:
(E)-1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-pyridin-2-yl-prop-
enone
[0401] General procedure F gave the fumaric acid salt of the title
compound as white crystals in 58% yield. .sup.1H-NMR (DMSO) .delta.
8.64 (d, 1H), 8.85 (td, 1H), 7.76 (d, 1H), 7.48-7.37 (m, 6H), 7.19
(d, 1H), 6.68 (s, 2H), 3.55 (s, 2H), 2.29 (br, 8H), 2.13 (s,
3H).
A057:
(E)-1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-pyridin-3-yl-prop-
enone
[0402] General procedure F gave the fumaric acid salt of the title
compound as white crystals in 19% yield. .sup.1H-NMR (DMSO) .delta.
8.88 (d, 1H), 8.58 (dd, 1H), 8.21 (d, 1H), 7.48-7.39 (m, 5H), 7.37
(d, 1H), 7.29 (d, 1H), 6.59 (s, 4H), 3.60 (s, 2H), 2.41 (br, 4H),
2.33 (br, 4H), 2.21 (s, 3H).
A058:
(E)-1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-pyridin-4-yl-prop-
enone
[0403] General procedure F gave the fumaric acid salt of the title
compound as off-white crystals in 6% yield. .sup.1H-NMR (DMSO)
.delta. 8.61 (d, 2H), 7.70 (d, 2H), 7.47-7.40 (m, 5H), 7.20 (d,
1H), 6.60 (s, 4H), 3.60 (s, 2H), 2.40-2.32 (br 8H), 2.21 (s,
3H).
A059:
(E)-1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-(1-methyl-1H-pyrr-
ol-2-yl)-propenone
[0404] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 44% yield. .sup.1H-NMR (DMSO)
.delta. 7.44-7.36 (m, 4H), 7.27 (d, 1H), 7.05 (t, 1H), 6.87 (d,
1H), 6.86 (dd, 1H), 6.60 (s, 4H), 6.14 (dd, 1H), 3.65 (s, 3H), 3.57
(s, 2H), 2.42-3.30 (br, 8H), 2.20 (s, 3H).
A060:
(E)-1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-(1H-pyrrol-2-yl)--
propenone
[0405] General procedure F gave the fumaric acid salt of the title
compound as orange crystals in 24% yield. .sup.1H-NMR (DMSO)
.delta. 11.58 (1H), 7.44-7.35 (m, 4H), 7.10 (d, 1H), 7.08-7.06 (m,
1H), 6.83 (d, 1H), 6.61-6.60 8m, 1H), 6.59 (s, 4H), 6.19-6.17 (m,
1H), 3.55 (s, 2H), 2.47 (br, 4H), 2.35 (br, 4H), 2.24 (s, 3H).
A061:
(E)-1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-thiophen-2-yl-pro-
penone
[0406] General procedure F gave the oxalate salt of the title
compound as slightly yellow crystals in 96% yield. .sup.1H-NMR
(DMSO) .delta. 7.76 (d, 1H), 7.58 (d, 1H), 7.53-7.41 (m, 6H), 7.16
(dd, 1H), 6.93 (d, 1H), 3.65 (s, 2H), 3.05 (br, 4H), 2.66 (s, 3H),
2.55 (br, 4H).
A062: (E)-1,3-Bis-(2-diethylaminomethyl-phenyl)-propenone
[0407] General procedure F gave the fumaric acid salt of the title
compound as white powder in 15% yield. .sup.1H-NMR (DMSO) .delta.
13.04 (br, 2H), 7.90-7.85 (m, 1H), 7.84 (d, 1H) 7.46-7.28 (m, 7H),
7.03 (d, 1H), 6.62 (s, 4H), 3.69 (s, 2H), 3.47 (s, 2H), 2.43 (q,
4H), 2.29 (q, 4H), 0.87 (t, 6H), 0.76 (t, 6H).
A063:
(E)-3-(2,4-Dichloro-phenyl)-1-(3-diethylaminomethyl-phenyl)-propenon-
e
[0408] General procedure F gave the title compound as orange oil in
15% yield. .sup.1H-NMR(CDCl.sub.3): .delta. 8.09 (d, 1H), 7.96 (s,
1H), 7.87 (d, 1H), 7.69 (d, 1H), 7.61 (d, 1H), 7.50-7.32 (m, 3H),
7.30 (dd, 1H), 3.65 (s, 2H), 2.55 (q, 4H), 1.05 (t, 6H).
A064:
(E)-3-(4-Dimethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylme-
thyl)-phenyl]-propenone
[0409] General procedure F gave the fumaric acid salt of the title
compound as white crystals in 23% yield. .sup.1H-NMR (DMSO) .delta.
7.72 (d, 2H), 7.43-7.38 (m, 6H), 7.27 (d, 1H), 7.24 (d, 1H), 6.57
(s, 6H), 3.70 (s, 2H), 3.59 (s, 2H), 2.36 (br, 4H), 2.32 (s, 6H),
2.26 (s, 3H).
A065:
(E)-3-(3-Dimethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylme-
thyl)-phenyl]-propenone
[0410] General procedure F gave the fumaric acid salt of the title
compound as off-white crystals in 33% yield. .sup.1H-NMR (DMSO)
.delta. 7.70-7.67 (m, 2H), 7.50-7.40 (m, 6H), 7.25 (d, 1H), 7.21
(d, 1H), 6.56 (s, 4H), 3.67 (s, 2H), 3.57 (s, 2H), 2.34 (br, 4H),
2.32 (br, 4H), 2.30 (s, 6H), 2.20 (s, 3H).
A066:
(E)-3-(3-Dimethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl-
)-propenone
[0411] General procedure F gave the fumaric acid salt of the title
compound as white crystals in 32% yield. .sup.1H-NMR (DMSO) .delta.
7.78 (s, 1H), 7.72 (br, 1H), 7.73-7.34 (m, 8H), 6.57 (s, 4H), 3.82
(s, 2H), 3.72 (s, 2H), 2.40 (s, 6H), 2.21 (s, 6H).
A067:
(E)-3-(2-Diethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl)-
-propenone
[0412] General procedure F gave the fumaric acid salt of the title
compound as white crystals in 54% yield. .sup.1H-NMR (DMSO) .delta.
7.91-7.87 (m, 1H), 7.87 (d, 1H), 7.53-7.32 (m, 7H), 7.09 (d, 1H),
6.61 (s, 4H), 3.67 (s, 2H), 3.50 (s, 2H), 2.31 (q, 4H), 2.19 (s,
6H), 0.78 (t, 6H).
A068:
(E)-3-[3-(Butyl-ethyl-amino)-phenyl]-1-(2-dimethylaminomethyl-phenyl-
)-propenone
[0413] General procedure F gave the title compound as yellow oil in
3% yield. .sup.1H-NMR (DMSO) .delta. 7.61-7.29 (m, 4H), 7.23-7.15
(m, 2H), 6.99 (d, 1H), 6.91-6.76 (m, 2H), 6.68 (dd, 1H), 3.53 (s,
2H), 3.37 (q, 2H), 3.37 (q, 2H), 2.14 (s, 6H), 1.60-1.52 (m, 2H),
1.43-1.26 (m, 2H), 1.15 (t, 3H), 0.96 (t, 3H).
A069:
(E)-3-(3-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-1-(-
4-methoxy-phenyl)-propenone
[0414] General procedure I gave the fumaric acid salt of the title
compound as yellow crystals in 45% yield. .sup.1H-NMR (DMSO)
.delta. 8.12 (d, 2H), 7.90 (d, 1H), 7.77 (s, 1H), 7.74-7.72 (m,
1H), 7.64 (d, 1H), 7.37 (d, 2H), 7.04 (d, 2H), 6.51 (s, 4H), 3.82
(s, 3H), 3.55 (s, 2H), 3.01 (t, 2H), 2.62 (t, 2H), 2.57 (s, 6H),
2.13 (s, 3H).
A070:
(E)-3-(2-Dimethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylme-
thyl)-phenyl]-propenone
[0415] General procedure F gave the fumaric acid salt of the title
compound as pale brown crystals in 44% yield. .sup.1H-NMR (DMSO)
.delta. 7.90-7.87 (m, 1H), 7.61 (d, 1H), 7.44-7.36 (m, 6H),
7.26-7.24 (m, 1H), 7.00 (d, 1H), 6.57 (s, 3H), 3.58 (s, 2H), 3.28
(s, 2H), 2.40 (br, 4H), 2.32 (br, 4H), 2.20 (s, 3H), 1.95 (s,
6H).
A071:
(E)-3-(2-Diethylaminomethyl-phenyl)-1-[2-(4-methyl-piperazin-1-ylmet-
hyl)-phenyl]-propenone
[0416] General procedure F gave the fumaric acid salt of the title
compound as white crystals in 44% yield. .sup.1H-NMR (DMSO) .delta.
7.90 (dd, 1H), 7.77 (d, 1H), 7.43-7.27 (m, 7H), 7.00 (d, 1H), 6.59
(s, 3H), 3.55 (s, 2H), 3.37 (s, 2H), 2.30 (br, 8H), 2.27 (q, 4H),
2.19 (s, 3H), 1.09 (t, 6H).
A072: (E)-1,3-Bis-(2-dimethylaminomethyl-phenyl)-propenone
[0417] General procedure F gave the title compound as brown oil in
37% yield. 1H-NMR(CDCl.sub.3): .delta. 7.71-7.68 (m, 1H), 7.67 (d,
1H), 7.41-7.20 (m, 7H), 6.93 (d, 1H), 3.57 (s, 2H), 3.29 (s, 2H),
2.11 (s, 6H), 2.03 (s, 6H).
A073:
(E)-3-(4-Dimethylaminomethyl-phenyl)-1-(2-dimethylaminomethyl-phenyl-
)-propenone
[0418] General procedure F gave the fumaric acid salt of the title
compound as white crystals in 39% yield. .sup.1H-NMR (DMSO) .delta.
7.73 (d, 2H), 7.55-7.42 (m, 4H), 7.39 (d, 2H), 7.32 (s, 2H), 6.59
(s, 4H), 3.65 (s, 4H), 2.29 (s, 6H), 2.14 (s, 6H).
A074:
(E)-3-(1H-Indol-5-yl)-1-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-p-
ropenone
[0419] General procedure F gave the title compound as yellow
crystals in 13% yield. .sup.1H-NMR (DMSO) .delta. 11.33 (s, 1H),
7.85 (s, 1H), 7.50 (dd, 1H), 7.47-7.35 (m, 7H), 7.09 (d, 1H), 6.47
(t, 1H), 3.54 (s, 2H), 2.26 (br, 4H), 2.15 (br, 4H), 2.00 (s,
3H).
A075:
(E)-3-(2,4-Dimethoxy-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propen-
one
[0420] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 32% yield. .sup.1H-NMR (DMSO)
.delta. 7.75 (d, 1H), 7.63 (d, 1H), 7.57-7.42 (m, 4H), 7.21 (d,
1H), 6.63-6.58 (m, 3H), 6.60 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H),
3.69 (s, 2H), 2.22 (s, 6H).
A076:
(E)-1-(2-Dimethylaminomethyl-phenyl)-3-(4-imidazol-1-yl-phenyl)-prop-
enone
[0421] General procedure F gave the fumaric acid salt of the title
compound as pale yellow powder in 17% yield. .sup.1H-NMR (DMSO)
.delta. 8.38 (t, 1H), 7.92 (d, 2H), 7.85 (t, 1H), 7.74 (d, 2H),
7.56-7.43 (m, 4H), 7.38 (s, 2H), 7.13 (t, 1H), 6.61 (s, 2H), 3.65
(s, 2H), 2.14 (s, 6H).
A077:
(E)-1-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-13-(pyridin-3-yla-
mino)-phenyl]-propenone
[0422] General procedure F gave the oxalate salt of the title
compound as yellow crystals in 38% yield. .sup.1H-NMR (DMSO)
.delta. 8.55 (br, 1H), 8.38 (d, 1H), 8.06 (t, 1H), 7.54-7.13 (m,
12H), 3.67 (2H), 2.90 (br, 8H), 2.66 (s, 3H).
A078:
(E)-3-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-i-(2,3,4-trimethoxy-
-phenyl)-propenone
[0423] General procedure F gave the fumaric acid salt of the title
compound as off-white crystals in 14% yield. .sup.1H-NMR (DMSO)
.delta. 8.00 (d, 1H), 7.83 (dd, 1H), 7.44-7.31 (m, 4H), 7.24 (d,
1H), 6.93 (d, 1H), 6.59 (s, 4H), 3.87 (s, 3H), 3.82 (s, 3H), 3.79
(s, 3H), 3.53 (s, 2H), 2.5 (br, under DMSO, 4H), 2.39 (br, 4H),
2.32 (s, 3H).
A079:
(E)-3-{3-[2-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-3-oxo-propenyl}--
benzoic acid
[0424] General procedure F gave the title compound as brown
crystals in 57% yield. .sup.1H-NMR (DMSO) .delta. 8.15 (s, 1H),
7.93 (t, 2H), 7.49 (t, 1H), 7.52-7.37 (m, 4H), 7.30 (d, 1H), 7.21
(d, 1H), 3.55 (s, 2H), 2.26 (br, 4H), 2.20 (br, 4H), 2.05 (s,
3H).
A080:
(E)-1-(2-Dimethylaminomethyl-phenyl)-3-(2,4-dimethyl-phenyl)-propeno-
ne
[0425] General procedure F gave the fumaric acid salt of the title
compound as white crystals in 50% yield. .sup.1H-NMR (DMSO) .delta.
7.75 (d, 1H), 7.61-7.56 (m, 2H), 7.50-7.45 (m, 3H), 7.19 (d, 1H),
7.22-7.07 (m, 2H), 6.59 (s, 2H), 3.70 (s, 2H), 2.29 (s, 3H), 2.28
(s, 3H), 2.20 (s, 6H).
A081:
(E)-3-(2,4-Dimethyl-phenyl)-1-12-(4-methyl-piperazin-1-ylmethyl)-phe-
nyl]-propenone
[0426] General procedure F gave the fumaric acid salt of the title
compound as off-white crystals in 32% yield. .sup.1H-NMR (DMSO)
.delta. 7.72 (d, 1H), 7.50 (d, 1H), 7.46-7.39 (m, 4H), 7.11-7.06
(m, 3H), 6.59 (s, 4H), 3.60 (s, 2H), 2.5 (under DMSO, 4H), 2.37
(br, 4H), 2.29 8s, 6H), 2.26 (s, 3H).
A082:
(E)-1-(2-Dimethylaminomethyl-phenyl)-3-(1-methyl-1H-pyrrol-2-yl)-pro-
penone
[0427] General procedure F gave the fumaric acid salt of the title
compound as brown crystals in 22% yield. .sup.1H-NMR (DMSO) .delta.
7.57-7.40 (m, 4H), 7.39 (d, 1H), 7.07 (t, 1H), 6.99 (d, 1H), 6.92
(dd, 1H), 6.59 (s, 2H), 6.16 (dd, 1H), 3.68 (br, 6H), 2.21 (s,
6H).
A083:
(E)-3-[4-Chloro-5-(1,1-dimethyl-allyl)-2-methoxy-phenyl]-1-[2-(4-met-
hyl-piperazin-1-ylmethyl)-phenyl]-propenone
[0428] General procedure F gave the fumaric acid salt of the title
compound as orange crystals in 25% yield.
.sup.1H-NMR(DMSO-d.sub.6): .delta.: 7.68 (s, 1H), 7.46-7.37 (m,
5H), 7.18 (d, 1H), 7.11 (s, 1H), 6.59 (s, 4H), 6.13-6.04 (dd, 1H),
5.04-5.00 (dd, 1H), 4.94-4.88 (dd, 1H), 3.83 (s, 3H), 3.56 (s, 2H),
2.60-2.25 (m, 8H), 2.23 (s, 3H), 1.49 (s, 6H).
A084:
(E)-1-(2-Dimethylaminomethyl-phenyl)-3-(4-dipropylamino-2-ethoxy-phe-
nyl)-propenone
[0429]
(E)-3-(4-Dibutylamino-2-fluoro-phenyl)-1-(2-dimethylaminomethyl-ph-
enyl)-propenone (4 mmol), was stirred in 0.1 M sodium ethanolate in
EtOH (50 mL) at 25.degree. C. overnight. The solution was
evaporated on Celite.RTM. and purified by flash chromatography to
give the title compound as brown oil in 0.9% yield.
.sup.1H-NMR(CDCl.sub.3): .delta.: 7.59 (d, 1H), 7.49 (d, 1H),
7.40-7.34 (m, 3H), 7.29 (dd, 1H), 6.96 (d, 1H), 6.23 (dd, 1H), 6.05
(d, 1H), 4.00 (q, 2H), 3.56 (s, 2H), 3.27 (t, 4H), 2.17 (s, 6H),
1.68-1.57 (m, 4H), 1.36 (t, 3H), 0.94 (t, 6H).
A085:
(E)-1-(2-Dimethylaminomethyl-phenyl)-3-[2-(4-methyl-piperazin-1-ylme-
thyl)-phenyl]-propenone
[0430] General procedure F gave the fumaric acid salt of the title
compound as brown crystals in 1% yield. .sup.1H-NMR(DMSO-d.sub.6):
.delta. 7.89-7.86 (m, 1H), 7.70 (d, 1H), 7.46-7.34 (m, 6H),
7.27-7.24 (m, 1H), 7.00 (d, 1H), 6.60 (s, 4H), 3.53 (s, 2H), 3.35
(s, 2H), 2.5 (under DMSO, 4H), 2.20 (br, 4H), 2.20 (s, 3H), 2.08
(s, 6H).
A086:
(E)-3-(3-Dimethylaminomethyl-4-methoxy-phenyl)-1-(4-methoxy-phenyl)--
propenone
[0431] General procedure F gave the fumaric acid salt of the title
compound as slightly yellow crystals in 38% yield.
.sup.1H-NMR(DMSO-d.sub.6): .delta. 8.13 (d, 2H), 7.90 (d, 1H), 7.83
(dd, 1H), 7.78 (d, 1H), 7.67 (d, 1H), 7.10 (t, 3H), 6.58 (s, 2H),
3.87 (s, 6H), 3.74 (s, 2H), 2.38 (s, 6H).
A087:
(E)-1-(2-Methoxy-phenyl)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl-
]-propenone
[0432] General procedure F gave the fumaric acid salt of the title
compound as slightly yellow crystals in 3% yield.
.sup.1H-NMR(DMSO-d.sub.6): .delta. 7.92 (d, 1H), 7.84-7.81 (m, 1H),
7.55-7.49 (m, 1H), 7.43 (dd, 1H), 7.38-7.28 (m, 3H), 7.19 (d, 1H),
7.15 (d, 1H), 7.06 (td, 1H), 6.60 (s, 4H), 3.84 (s, 3H), 3.45 (s,
2H), 2.5 (under DMSO, 4H), 2.30 (br, 4H), 2.24 (s, 3H).
A088:
(E)-1-(2-Fluoro-4-methoxy-phenyl)-3-[2-(4-methyl-piperazin-1-ylmethy-
l)-phenyl]-propenone
[0433] General procedure F gave the fumaric acid salt of the title
compound as slightly yellow crystals in 15% yield.
.sup.1H-NMR(DMSO-d.sub.6): .delta. 8.12 (d, 1H), 7.87-7.77 (m, 2H),
7.40-7.29 (m, 4H), 7.01-6.91 (m, 2H), 6.60 (s, 3H), 3.87 (s, 3H),
3.56 (s, 2H), 2.5 (under DMSO, 4H), 2.41 (br, 4H), 2.28 (s,
3H).
A089:
(E)-3-(2-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-phenyl)-1-(-
2-dimethylaminomethyl-phenyl)-propenone
[0434] General procedure F gave the fumaric acid salt of the title
compound as pale brown crystals in 4% yield.
.sup.1H-NMR(DMSO-d.sub.6): .delta. 7.91-7.88 (m, 1H), 7.75 (d, 1H),
7.50-7.33 (m, 7H), 7.13 (d, 1H), 6.57 (s, 6H), 3.62 (s, 2H), 3.48
(s, 2H), 2.79 (t, 2H), 2.5 (under DMSO, 2H), 2.46 (s, 6H), 2.12 s,
6H), 2.00 (s, 3H).
A090:
(E)-1-(2-Dimethylaminomethyl-phenyl)-3-[3-(pyridin-3-ylamino)-phenyl-
]-propenone
[0435] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 7% yield. .sup.1H-NMR(DMSO-d.sub.6):
.delta. 8.46 (s, 1H), 8.36 (d, 1H), 8.06 (dd, 1H), 7.64-7.13 (m,
11H), 6.60 (s, 3H), 3.65 (s, 2H), 2.16 (s, 6H).
A091:
(E)-3-(2-Dimethylaminomethyl-phenyl)-1-(3-dimethylaminomethyl-phenyl-
)-propenone
[0436] General procedure F gave the title compound as brown oil in
48% yield. 1H NMR (CDCl.sub.3) .delta. 8.30 (d, 1H), 7.97-7.94 (m,
2H), 7.79-7.76 (m, 1H), 7.58 (d, 1H), 7.50-7.45 (m, 2H, 7.38-7.35
(m, 3H), 3.55 (s, 2H), 3.53 (s, 2H), 2.29 (s, 6H), 2.26 (s,
6H).
A092:
(E)-1-(3-Dimethylaminomethyl-phenyl)-3-(3-morpholin-4-ylmethyl-pheny-
l)-propenone
[0437] General procedure F gave the title compound as yellow oil in
26% yield. .sup.1H NMR (CDCl.sub.3) .delta. 7.98-7.94 (m, 2H), 7.84
(d, 1H), 7.64-7.28 (m, 7H), 3.75 (t, 4H), 3.56 (s, 2H), 3.55 (s,
2H), 2.49 (t, 4H), 2.30 (s, 6H).
A093:
(E)-1-(3-Dimethylaminomethyl-phenyl)-3-[2-(4-methyl-piperazin-1-ylme-
thyl)-phenyl]-propenone
[0438] General procedure F gave the title compound as brown oil in
18% yield. .sup.1H NMR (DMSO) .delta. 8.31 (d, 1H), 7.94-7.91 (m,
2H), 7.75-7.72 (m, 1H), 7.55 (d, 1H), 7.48-7.39 (m, 2H), 7.33 (dd,
3H), 7.26 (s, 2H), 3.60 (s, 2H), 3.51 (s, 2H), 2.52-2.33 (bs, 4H),
2.26 (s, 6H), 2.25 (s, 3H).
A094:
(E)-1-(3-Dimethylaminomethyl-phenyl)-3-(4-pyridin-2-yl-phenyl)-prope-
none
[0439] General procedure F gave the fumaric acid salt of the title
compound as slightly yellow crystals in 3% yield. .sup.1H NMR
(DMSO) .delta. 8.70 (d, 1H), 8.21-7.98 (m, 8H), 7.92 (d, 1H), 7.81
(d, 1H), 7.66 (d, 1H), 7.57 (t, 1H), 3.39 (dd, 1H), 6.60 (s, 2H),
3.74 (s, 2H), 2.32 (s, 6H).
A095:
(E)-1-(4-Methoxy-phenyl)-3-(3-{[methyl-(2-methylamino-ethyl)-amino]--
methyl}-phenyl)-propenone.
[0440] General procedure I gave the title compound as slightly
yellow crystals in 34% yield. .sup.1H-NMR (CDCl.sub.3) .delta. 8.05
(d, 2H), 7.80 (d, 1H), 7.75 (s, 1H), 7.61-7.57 (m, 1H), 7.56 (d,
1H), 7.48-7.37 (m, 2H), 6.98 (d, 2H), 3.89 (s, 3H), 3.56-3.40 (m,
2H), 3.31 (s, 2H), 2.62-2.56 (m, 2H), 2.20 (s, 9H).
A096:
(E)-3-(2-Dimethylaminomethyl-phenyl)-1-(2-fluoro-4-methoxy-phenyl)-p-
ropenone
[0441] General procedure F gave the fumaric acid salt of the title
compound as slightly yellow crystals in 12% yield. .sup.1H NMR
(DMSO) .delta. 8.10 (d, 1H), 7.98-7.80 (m, 2H), 7.40-7.31 (m, 4H),
7.01-6.92 (m, 2H), 6.59 (s, 3H), 3.87 (s, 3H), 3.50 (s, 2H), 2.14
(s, 6H).
A097:
(E)-3-(2-Dimethylaminomethyl-phenyl)-1-(2,3,4-trimethoxy-phenyl)-pro-
penone
[0442] General procedure F gave the fumaric acid salt of the title
compound as white crystals in 17% yield. .sup.1H NMR (DMSO) .delta.
7.99 (d, 1H), 7.85-7.82 (m, 1H), 7.49-7.28 (m, 5H), 6.94 (d, 1H),
6.59 (s, 4H), 3.87 (s, 3H), 3.83 (s, 3H), 3.78 (s, 3H), 3.46 (s,
2H), 2.11 (s, 3H).
A098:
(E)-3-(3-{[(2-Hydroxy-ethyl)-methyl-amino]-methyl}-phenyl)-1-(4-meth-
oxy-phenyl)-propenone
[0443] General procedure F gave the fumaric acid salt of the title
compound as pale yellow crystals in 16% yield. .sup.1H NMR (DMSO)
.delta. 8.17 (d, 2H), 7.93 (d, 1H), 7.84 (s, 1H), 7.78-7.76 (m,
1H), 7.70 (d, 1H), 7.42 (d, 2H), 7.09 (d, 2H), 6.59 (s, 2H), 3.87
(s, 3H), 3.66 (s, 2H), 3.56 (t, 2H), 2.54 (t, 2H), 2.26 (s,
3H).
A099:
(E)-1-(4-Methoxy-phenyl)-3-(3-methylaminomethyl-phenyl)-propenone
[0444] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 18% yield. 1H NMR (DMSO) .delta.
8.15 (d, 2H), 8.04 (s, 1H), 7.95 (d, 1H), 7.80 (d, 1H), 7.69 (d,
1H), 7.52-7.47 (m, 2H), 7.09 (d, 2H), 6.51 (s, 2H), 4.04 (s, 2H),
3.87 (s, 3H), 2.48 (s, 3H).
A100:
(E)-1-(3-Dimethylaminomethyl-phenyl)-3-(4-methoxy-biphenyl-3-yl)-pro-
penone
[0445] General procedure F gave the title compound as yellow
crystals in 37% yield. .sup.1H-NMR (CDCl.sub.3) .delta. 8.17 (d,
1H), 7.94-7.91 (m, 2H), 7.86 (d, 1H), 7.67 (d, 1H), 7.63-7.57 (m,
4H), 7.55-7.43 (m, 3H), 7.35 (t, 1H), 7.03 (d, 1H), 3.96 (s, 3H),
3.51 (s, 2H), 2.27 (s, 6H).
A101:
(E)-3-{3-[(2-Methoxy-ethylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl-
)-propenone
[0446] General procedure F gave the fumaric acid salt of the title
compound as white crystals in 63% yield. .sup.1H NMR (DMSO) .delta.
8.15 (d, 2H), 7.97 (s, 1H), 7.94 (d, 1H), 7.80 (d, 1H), 7.70 (d,
1H), 7.49-7.45 (m, 2H), 7.10 (d, 2H), 6.55 (s, 2H), 3.99 (s, 2H),
3.87 (s, 3H), 3.52 (t, 2H), 3.26 (s, 3H), 2.88 (t, 2H).
A102:
(E)-1-(2-Dimethylaminomethyl-phenyl)-3-[2-methoxy-5-(pyridin-3-ylami-
no)-phenyl]-propenone
[0447] General procedure F gave the title compound as yellow
crystals in 35% yield. .sup.1H NMR (CDCl.sub.3) .delta. 8.29 (dd,
1H), 8.13 (dd, 1H), 7.56 (d, 1H), 7.43-7.33 (m, 5H), 7.28-7.22 (m,
1H), 7.18-7.14 (m, 2H), 7.10 (d, 1H), 6.90 (d, 1H), 5.60 (s, 1H),
3.85 (s, 3H), 3.57 (s, 2H), 2.16 (s, 6H).
A103:
(E)-3-(2,4-Dichloro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propano-
ne
[0448] Triethylsilane (0.150 mol) was added to a solution of
3-(2,4-Dichloro-phenyl)-1-(2-dimethylaminomethyl-phenyl)-propenone
(0.0075 mol) in trifluoro acetic acid stirred at 25.degree. C. for
30 hours, before the solution was poured into ice-cold NaOH (2M,
150 mL). Extracted with EtOAc, dried over Na.sub.2SO.sub.4,
filtered and evaporated on Celite.RTM.. Purified by flash
chromatography (EtOAc/heptane, 3% Et.sub.3N). The resulting oil was
dissolved in MeOH:Et.sub.2O (1:9 v/v, 10 mL) and a solution of
fumaric acid in MeOH:Et.sub.2O (1:9 v/v) was added. The fumaric
acid salt of title compound was isolated as white crystals in 24%
yield (614 mg).The purity was >95% determined by HPLC.
.sup.1H-NMR (DMSO) .delta. 12.96 (br, 1H), 7.58-7.35 (m, 7H), 6.60
(s, 2H), 3.57 (s, 2H), 3.16 (t, 2H), 3.00 (t, 2H), 2.14 (s,
6H).
A104:
(E)-3-[4-(2-Dimethylamino-ethyl)-phenyl]-1-(2-fluoro-4-methoxy-pheny-
l)-propenone
[0449] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 61% yield. .sup.1H-NMR(DMSO-d.sub.6)
.delta. 7.83 (t, 1H), 7.62 (d, 2H), 7.63 (d, 1H), 7.47 (dd, 1H),
7.32 (d, 2H), 7.05-6.90 (m, 2H), 6.56 (s, H, fumarat), 3.87 (s,
3H), 2.90-2.68 (m, 4H), 2.39 (s, 6H).
A105:
(E)-1-(4-Methoxy-phenyl)-3-(3-piperazin-1-ylmethyl-phenyl)-propenone
[0450] Prepared by general procedure I using
piperazine-1-carboxylic acid tert-butyl ester followed by
deprotecton using trifluoroacetic acid in methylene chloride. The
title compound was isolated as trifluoroacetate salt 43% yield
(yellow crystals). .sup.1H-NMR (DMSO-d.sub.6) .delta. 8.16 (d, 2H),
7.95 (m, 3H), 7.71 (d, 1H), 7.53 (m, 2H), 7.1 0 (d, 2H), 3.88 (s,
3H), 3.33 (bs, 4H), 3.16 (bs, 4H).
A106:
(E)-3-(3-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-phenyl)-1-(4-meth-
oxy-phenyl)-propenone
[0451] Prepared by refuxing A101, formic acid (20 eqv) and
formaldehyde (20 eqv) in water for 18 hours. The fumaric acid salt
of the title compound was isolated in 70% yield (yellow crystals).
.sup.1H-NMR (DMSO d.sub.6) .delta. 8.16 (d, 2H), 7.89 (d, 1H), 7.79
(m, 2H), 7.69 (d, 1H), 7.42 (m, 2H), 7.09 (d, 2H), 6.61 (s, 2H),
3.87 (s, 3H), 3.63 (s, 2H), 3.49 (t, 2H), 3.24 (s, 3H), 2.61 (s,
3H), 2.24 (s, 3H).
A107:
(E)-3-(3-{[(2-Amino-ethyl)-methyl-amino]-methyl}-phenyl)-1-(4-methox-
y-phenyl)-propenone
[0452] General procedure I using (2-Methylamino-ethyl)-carbamic
acid tert-butyl ester followed by deprotection using
Trifluoroacetic acid in CH.sub.2Cl.sub.2. The fumaric acid salt of
the title compound was isolated in 10% yield (yellow crystals).
.sup.1H-NMR (DMSO-d.sub.6) .delta. 8.17 (d, 2H), 7.95 (d, 1H),
7.86-7.77 (m, 2H), 7.72 (d, 1H), 7.43-7.41 (m, 2H), 7.09 (d, 2H),
6.41 (s, 2H), 3.87 (s, 3H), 3.57 (s, 2H), 2.94 (t, 2H), 2.59 (t,
2H), 2.14 (s, 3H).
A108:
(E)-3-{3-[(2-Hydroxy-ethylamino)-methyl]-phenyl}-1-(4-methoxy-phenyl-
)-propenone
[0453] General procedure I gave the fumaric acid salt of the title
compound as yellow crystals in 26% yield. .sup.1H-NMR
(DMSO-d.sub.6) .delta. 8.16 (d, 2H), 7.96-7.91 (m, 2H), 7.76 (dt,
1H), 7.69 (d, 1H), 7.46-7.43 (m, 2H), 7.10 (d, 2H), 6.49 (s, 1H),
3.91 (s, 2H), 3.87 (s, 3H), 3.55 (t, 2H), 2.72 (t, 2H).
A109:
(E)-3-(4-Dimethylaminomethyl-biphenyl-3-yl)-1-(2-fluoro-4-methoxy-ph-
enyl)-propenone
[0454] General procedure F gave the title compound as yellow
crystals in 18% yield. .sup.1H-NMR (DMSO-d.sub.6): .delta. 8.15 (d,
2H), 7.86 (t, 1H), 7.78 (d, 2H), 7.68 (dd,1H), 7.60-7.45 (m, 3H),
7.43-7.35 (m, 2H), 7.02-6.90 (m, 2H), 3.86 (s, 3H), 3.50 (s, 2H),
2.15 (s, 6H).
A110:
(E)-3-(4-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-4-methoxy-phe-
nyl)-propenone
[0455] General procedure F gave the fumaric acid salt of the title
compound as orange crystals in 14% yield. .sup.1H-NMR
(d.sub.6-DMSO): .delta. 8.14-8.11 (m, 2H), 7.65 (d, 2H), 7.64 (d,
1H), 7.56 (d, 1H), 7.15 (d, 1H), 6.68 (d, 2H), 6.58 (d, 2H), 3.90
(s, 3H), 3.71 (s, 2H), 3.34 (t, 4H), 2.35 (s, 6H), 1.58-1.47 (m,
4H), 1.36 (sixtet, 4H), 0.93 (s, 6H).
A1111:
(E)-3-[2-(2-Dimethylamino-ethyl)-phenyl]-1-(4-methoxy-phenyl)-prope-
none
[0456] General procedure F gave the fumaric acid salt of the title
compound as white powder in 49% yield. .sup.1H-NMR (d.sub.6-DMSO):
.delta. 8.18 (d, 2H), 8.04-7.97 (m, 2H), 7.85 (d, 1H), 7.42-7.31
(m, 3H), 7.09 d, 2H), 6.56 (s, 2H), 3.87 (s, 3H), 3.00 (dd, 2H)
2.64 (dd, 2H), 2.39 (s, 6H).
A112:
(E)-3-[2-(2-Dimethylamino-ethyl)-phenyl]-1-(2-fluoro-4-methoxy-pheny-
l)-propenone
[0457] General procedure F gave the fumaric acid salt of the title
compound as beighe crystals in 34% yield. .sup.1H-NMR
(d.sub.6-DMSO): .delta. 7.67-7.82 (m, 3H), 7.46-7.29 (m, 4H),
7.01-6.92 (m, 2H), 6.56 (s, 2H), 3.87 (s, 3H), 2.97 (dd, 2H), 2.64
(dd, 2H), 2.39 (s, 6H).
A113:
(E)-3-[2-(2-Dimethylamino-ethyl)-phenyl]-1-(2,3,4-trimethoxy-phenyl)-
-propenone
[0458] General procedure F gave the fumaric acid salt of the title
compound as white crystals in 35% yield. .sup.1H-NMR
(d.sub.6-DMSO): .delta. 7.84-7.79 (m, 2H), 7.42-7.38 (m, 2H),
7.37-7.29 (m, 3H), 6.95 (d, 1H), 6.58 (s, 3H), 3.88 (s, 3H), 3.85
(s, 3H), 3.79 (s, 3H), 2.97 (dd, 2H), 2.70 (dd, 2H), 2.42 (s,
6H).
A114:
(E)-3-[4-(2-Dimethylamino-ethyl)-phenyl]-1-(4-methoxy-phenyl)-propen-
one
[0459] General procedure F gave the fumaric acid salt of the title
compound as beighe crystals in 43% yield. .sup.1H-NMR
(d.sub.6-DMSO): .delta. 8.18 (d, 2H), 7.93 (d, 1H), 7.83 (d, 2H),
7.70 (d, 1H), 7.36 (d, 2H), 7.10 (d, 2H), 6.57 (s, 2H), 3.88 (s,
3H), 2.92 (bs, 4H), 2.5 (s, 6H).
A115:
(E)-3-[4-(2-Dimethylamino-ethyl)-phenyl]-1-(2,3,4-trimethoxy-phenyl)-
-propenone
[0460] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 44% yield. .sup.1H-NMR
(d.sub.6-DMSO): .delta. 7.68 (d, 2H), 7.54 (d, 1H), 7.42 (d, 1H),
7.37 (d, 1H), 7.33 (d, 2H), 6.94 (d, 1H), 6.55 (s, 2H), 3.88 (s,
3H), 3.84(s, 3H), 3.79 (s, 3H), 2.86 (br, 4H), 2.47 (s, 6H).
A116:
(E)-3-(2,5-Dimethoxy-phenyl)-1-[4-(2-dimethylamino-ethyl)-phenyl]-pr-
openone
[0461] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 32% yield. .sup.1H-NMR
(d.sub.6-DMSO): .delta. 8.09 (d, 2H), 8.02 (d, 1H), 7.89 (d, 1H),
7.55 (bs, 1H), 7.40 (d, 2H), 7.04 (bs, 2H), 6.56 (s, 2H), 3.84 (s,
3H), 3.80 (s, 3H), 2.98-2.93 (m, 2H), 2.90-2.85 (m, 2H), 2.47 (s,
6H).
A117:
(E)-1-[4-(2-Dimethylamino-ethyl)-phenyl]-3-(4-methoxy-biphenyl-3-yl)-
-propenone
[0462] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 95% yield. .sup.1H-NMR
(d.sub.6-DMSO): .delta. 8.27 (d, 1H), 8.14-8.01 (m, 4H), 7.78-7.75
(m, 3H), 7.51-7.44 (m, 4H), 7.36 (tt, 1H), 7.22 (d, 1H), 6.57 (s,
2H), 3.95 (s, 3H), 2.96-2.90 (m, 2H), 2.85-2.79 (m, 2H), 2.43 (s,
6H).
A118:
(E)-3-(4,2'-Dimethoxy-biphenyl-3-yl)-1-[4-(2-dimethylamino-ethyl)-ph-
enyl]-propenone
[0463] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 27% yield. .sup.1H-NMR
(d.sub.6-DMSO): .delta. 8.12-8.06 (m, 3H), 8.02 (d, 1H), 7.91 (d,
1H), 7.56 (dd, 1H), 7.43 (d, 2H), 7.36 (d, 2H), 7.14 (bt, 2H), 7.07
(td, 1H), 6.56 (s, 2H), 3.94 (s, 3H), 3.78 (s, 3H), 2.97-2.92 (m,
2H), 2.89-2.84 (m, 2H), 2.47 (s, 6H).
A119:
(E)-3-(4-Dimethylaminomethyl-biphenyl-3-yl)-1-(2,3,4-trimethoxy-phen-
yl)-propenone
[0464] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 50% yield. .sup.1H-NMR
(d.sub.6-DMSO): .delta. 8.07 (d, 1H), 8.02 (d, 1H), 7.77-7.74 (m,
2H), 7.67 (dd, 1H), 7.51-7.36 (m, 6H), 6.95 (d, 1H), 3.87 (s, 3H),
3.84 (s, 3H), 3.79 (s, 3H), 3.46 (s, 2H), 2.12 (s, 6H).
A120:
(E)-3-(2,5-Dimethoxy-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phen-
yl)-propenone
[0465] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 18% yield. .sup.1H-NMR
(d.sub.6-DMSO): .delta. 8.08-8.05 (m, 2H), 7.98 (d, 1H), 7.85 (d,
1H), 7.51 (bs, 1H), 7.03 (d, 2H), 6.96 (d, 1H), 6.59 (s, 3H), 3.94
(bs, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 2.47 (s, 6H).
A121:
(E)-3-[4-Chloro-5-(1,1-dimethyl-allyl)-2-methoxy-phenyl]-1-(3-dimeth-
ylaminomethyl-4-hydroxy-phenyl)-propenone
[0466] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 4% yield. .sup.1H-NMR
(d.sub.6-DMSO): .delta. 8.01 (dd, 1H), 7.95 (d, 1H), 7.90 (d, 1H),
7.85 (d, 1H), 7.82 (d, 1H), 7.14 (bs, 1H), 6.92 (d, 1H), 6.59 (s,
2H), 6.11 (dd, 1H), 5.03 (dd, 1H), 4.93 (dd, 1H), 3.92 (s, 3H),
3.84 (s, 2H), 2.39 (s, 6H), 2.08 (s, 6H).
A122:
(E)-3-(2,4-Dichloro-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-pheny-
l)-propenone
[0467] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 41% yield. .sup.1H-NMR
(d.sub.6-DMSO): .delta. 8.22 (d, 1H), 8.08-8.04 (m, 2H), 7.99 (d,
1H), 7.900 (d, 1H), 7.75 (d, 1H), 7.55 (dd, 1H), 6.92 (d, 1H), 6.60
(s, 2H), 3.85 (s, 2H), 2.40 (s, 6H).
A123:
(E)-3-(2,4-Dichloro-phenyl)-1-(3-dimethylaminomethyl-4-methoxy-pheny-
l)-propenone
[0468] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 12% yield. .sup.1H-NMR
(d.sub.6-DMSO): .delta. 8.24 (d, 1H), 8.22 (dd, 1H), 8.14 (d, 1H),
8.01 (d, 1H), 7.93 (d, 1H), 7.76 (d, 1H), 7.56 (dd, 1H), 7.18 (d,
1H), 6.58 (s, 2H), 3.92 (s, 3H), 3.64 (s, 2H), 2.3 (s, 6H).
A124:
(E)-3-[4-Chloro-5-(1,1-dimethyl-allyl)-2-methoxy-phenyl]-1-(3-dimeth-
ylaminomethyl-4-methoxy-phenyl)-propenone
[0469] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 40% yield. .sup.1H-NMR
(d.sub.6-DMSO): .delta. 8.14 (dd, 1H), 8.08 (d, 1H), 7.90 (d, 1H),
7.85 (d, 1H), 7.83 (s, 1H), 7.18 (d, 1H), 7.15 (s, 1H), 6.58 (s,
2H), 6.11 (dd, 1H), 5.04 (dd, 1H), 4.93 (dd, 1H), 3.93 (s, 3H),
3.91 (s, 3H), 3.69 (bs, 2H), 2.34 (s, 6H), 1.54 (s, 5 6H).
A125:
(E)-3-(3',5'-Dichloro-4,6-dimethoxy-biphenyl-3-yl)-1-(3-dimethylamin-
omethyl-4-methoxy-phenyl)-propenone
[0470] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 45% yield. .sup.1H-NMR
(d.sub.6-DMSO): .delta. 8.18 (dd, 1H), 8.08 (d, 1H), 8.01 (d, 1H),
7.97 (s, 1H), 7.85 (d, 1H), 7.57 (bs, 3H), 7.15 (d, 1H), 6.84 (s,
1H), 6.58 (s, 2H), 401 (s, 3H), 3.92 (s, 3H), 3.91 (s, 3H), 3.65
(s, 2H), 2.31 (s, 6H).
A126:
(E)-1-(3-Dimethylaminomethyl-4-methoxy-phenyl)-3-(4-methoxy-biphenyl-
-3-yl)-propenone
[0471] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 39% yield. .sup.1H-NMR
(d.sub.6-DMSO): .delta. 8.24-8.20 (m, 2H), 8.09 (d, 1H), 8.06 (d,
1H), 8.00 (d, 1H), 7.77-7.75 (m, 3H), 7.48 (t, 2H), 7.36 (tt, 1H),
7.22 (d, 1H), 7.15 (d, 1H), 6.57 (s, 1H), 3.93 (s, 3H), 3.90 (s,
3H), 3.58 (s, 2H), 2.27 (s, 6H).
A127:
(E)-3-(2,4-Dichloro-phenyl)-1-(2-dimethylaminomethyl-4-methoxy-pheny-
l)-propenone
[0472] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 34% yield. .sup.1H-NMR
(d.sub.6-DMSO): .delta. 8.10 (d, 1H), 7.73 (d, 1H), 7.68 (d, 1H),
7.62 (d, 1H), 7.51 (dd, 1H), 7.48 (d, 1H), 7.07 (d, 1H), 6.97 (d,
2H), 6.59 (s, 2H), 3.84 (s, 3H), 3.69 (s, 2H), 2.16 (s, 6H).
A128:
(E)-3-(3-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-4-hydroxy-phe-
nyl)-propenone
[0473] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 29% yield. .sup.1H-NMR
(d.sub.6-DMSO): .delta. 8.02-7.98 (m, 1H), 7.95 (d, 1H), 7.76 (d,
1H), 7.62 (d, 1H), 7.21 (t, 1H), 7.09 (d, 1H), 6.97 (bs, 1H), 6.88
(d, 1H), 6.69 (dd, 1H), 6.58 (s, 1H), 3.77 (s, 2H), 3.31 (t, 4H),
2.34 (s, 6H), 1.56-1.46 (m, 4H), 1.32 (sixtet, 4H), 0.93 (t,
6H).
A129:
(E)-3-(3-Dibutylamino-phenyl)-1-(3-dimethylaminomethyl-4-methoxy-phe-
nyl)-propenone
[0474] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 66% yield. .sup.1H-NMR
(d.sub.6-DMSO): .delta. 8.16 (dd, 1H), 8.12 (d, 1H), 7.76 (d, 1H),
7.66 (d, 1H), 7.22 (t, 1H), 7.17 (d, 1H), 7.10 (d, 1H), 6.98 (bs,
1H), 6.71 (dd, 1H), 6.59 (s, 2H), 3.91 (s, 3H), 3.69 (s, 2H), 3.31
(t, 4H), 2.34 (s, 6H), 1.56-1.47 (m, 4H), 1.33 (sixtet, 4H), 0.93
(t, 6H).
A130:
(E)-1-(2-Dimethylaminomethyl-4-methoxy-phenyl)-3-{3-[(pyridin-3-ylme-
thyl)-amino]-phenyl}-propenone
[0475] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 28% yield. .sup.1H-NMR
(DMSO-d.sub.6): .delta. 8.60 (d, 1H), 8.44 (dd, 1H), 7.76 (dt, 1H),
7.64 (d, 1H), 7.34 (dd, 1H), 7.24 (s, 2H), 7.14-7.07 (m, 2H), 6.98
(dd, 1H), 6.93-6.91 (m, 2H), 6.68 (dd, 1H), 6.60 (s, 3H), 6.41 (bs,
1H), 4.36 (s, 2H), 3.84 (s, 3H), 3.69 (s, 2H), 2.19 (s, 6H).
A131:
(E)-1-(2-Dimethylaminomethyl-phenyl)-3-[3-(pyridin-4-ylamino)-phenyl-
]-propenone
[0476] General procedure F gave the fumaric acid salt of the title
compound as yellow crystals in 86% yield. .sup.1H-NMR
(DMSO-d.sub.6): .delta. 9.06 (s, 1H), 8.21 (d, 2H), 7.53-7.35 (m,
7H), 7.30-7.23 (m, 3H), 6.94 (d, 2H), 6.60 (s, 3H), 3.62 (s, 2H),
2.12 (s, 6H).
A132:
(E)-1-(2-Dimethylaminomethyl-4-methoxy-phenyl)-3-[3-(pyridin-4-ylami-
no)-phenyl]-propenone
[0477] General procedure F gave the fumaric acid salt of the title
compound as yellow-brown crystals in 29% yield. .sup.1H-NMR
(DMSO-d.sub.6): .delta. 8.85 (s, 1H), 8.20 (d, 2H), 7.55 (d, 1H),
7.51 (bs, 1H), 7.44-7.36 (m, 2H), 7.31 (d, 2H), 7.23 (dt, 1H), 7.04
(d, 1H), 6.94-6.91 (m, 3H), 3.82 (s, 3H), 3.56 (s, 2H), 2.07 (s,
6H).
A133:
(E)-3-(3,5-Di-tert-butyl-2-methoxy-phenyl)-1-[4-hydroxy-3-(4-methyl--
piperazin-1-ylmethyl)-phenyl]-propenone
[0478] General procedure F gave the title compound as yellow-white
crystals in 25% yield. 1H NMR (CDCl.sub.3) .delta. 8.05 (d, 1H),
7.92 (dd, 1H), 7.78 (d, 1H), 7.48 (d, 1H), 7.47 (d, 1H), 7.41 (d,
1H), 6.89 (d, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 2.67 (bs, 8H), 2.33
(s, 3H), 1.41 (s, 9H), 1.35 (s, 9H).
A134:
(E)-3-(5-tert-Butyl-2-methoxy-phenyl)-1-(3-dimethylaminomethyl-4-hyd-
roxy-phenyl)-propenone
[0479] General procedure F gave the title compound as orange
crystals in 23% yield. .sup.1H NMR (CDCl.sub.3) .delta. 8.04 (d,
1H), 7.92 (dd, 1H), 7.77 (d, 1H), 7.63 (d, 1H), 7.61 (d, 1H), 7.39
(dd, 1H), 6.89 (dd, 1H), 3.90 (s, 3H), 3.76 (s, 2H), 2.37 (s, 6H),
1.34 (s, 9H).
A135:
(E)-3-(3,5-Di-tert-butyl-2-methoxy-phenyl)-1-(3-dimethylaminomethyl--
4-hydroxy-phenyl)-propenone
[0480] General procedure F gave the title compound as orange
crystals in 21% yield. .sup.1H NMR (CDCl.sub.3) .delta. 8.05 (d,
1H), 7.93 (dd, 1H), 7.78 (d, 1H), 7.49 (d, 1H), 7.49 (d, 1H), 7.41
(d, 1H), 6.91 (d, 1H), 3.78 (s, 3H), 3.77 (s, 2H), 2.39 (s, 6H),
1.42 (s, 9H), 1.35 (s, 9H).
A136:
(E)-3-[5-(1,1-Dimethyl-allyl)-4-hydroxy-2-methoxy-phenyl]-1-(2-dimet-
hylaminomethyl-phenyl)-propenone
[0481] General procedure E gave the title product as a red oil in
9% yield. .sup.1H-NMR (DMSO-d.sub.6): .delta. 7.48 (d, 1H),
7.46.7.42 (m, 2H), 7.38 (s, 1H), 7.37-7.24 (m, 2H), 6.96 (d, 1H),
6.48 (s, 1H), 6.21 (dd, 1H), 4.95 (s, 1H), 4.90 (dd, 1H), 3.73 (s,
3H), 3.45 (s, 2H), 2.04 (s, 6H).
A137:
(E)-3-[5-(1,1-Dimethyl-allyl)-4-hydroxy-2-methoxy-phenyl]-1-(3-dimet-
hylaminomethyl-phenyl)-propenone
[0482] General procedure E gave the title product as orange oil in
41% yield. .sup.1H-NMR (DMSO-d.sub.6): .delta. 7.93 (dt, 1H), 7.93
(d, 1H), 7.88 (br, 1H), 7.56 (d, 1H), 7.54-7.47 (m, 3H), 6.53 (s,
1H), 6.24 (dd, 1H), 4.96 (dd, 1H), 4.91 (dd, 1H), 3.82 (s, 3H),
3.48 (s, 2H), 2.17 (s, 6H), 1.45 (s, 6H).
A138:
(E)-3-(4-Dimethylaminomethyl-biphenyl-3-yl)-1-(2-dimethylaminomethyl-
-phenyl)-propenone
[0483] General procedure F gave the title compound as beighe
crystals in 57% yield. .sup.1H-NMR (DMSO): .delta. 8.12 (d, 1H),
7.80-7.77 (m, 2H), 7.69 (d, 1H), 7.63 (d, 1H), 7.50-7.36 (m, 7H),
7.34 (d, 1H), 7.23 (d, 1H), 3.52 (s, 2H), 3.31 (s, 2H), 2.02 (s,
6H), 1.98 (s, 6H).
A139:
(E)-1-(2-Dimethylaminomethyl-phenyl)-3-{3-[(pyridin-3-ylmethyl)-amin-
o]-phenyl}-propenone
[0484] General procedure F gave the title compound as yellow oil in
30% yield. .sup.1H-NMR (DMSO-d.sub.6): .delta. 8.58 (d, 1H), 8.43
(dd, 1H), 7.75 (dt, 1H), 7.47-7.31 (m, 5H), 7.12-7.00 (m, 3H),
6.87-6.85 (m, 2H), 6.68 (bd, 1H), 6.39 (t, 1H), 4.35 (d, 2H), 3.46
(s, 2H), 2.00 (s, 6H.
[0485] Determination of Metabolic Stability
[0486] Incubations were performed with Wistar rat liver microsomes
(0.25 mg/ml) in 2% sodium bicarbonate solution. NADP (0.13 mg/ml),
glucose-6-phosphate (0.63 mg/ml) and glucose-6-phosophate
dehydrogenase (0.38 units/ml) were used as NADPH generation system
and UDPGA (0.48 mg/ml) was added to include the phase II reaction,
glucuronic acid conjugation, in the assay. After 5 minutes of
pre-incubation the reaction was started by addition of the test
article to give a final concentration of 20 .mu.M. Samples were
incubated for 15 min at 37.degree. C. and the reactions were
terminated by addition of equal volumes of acetonitrile. Blank
incubations were performed at the same concentration but without
addition of microsomes. Both blank and microsome-containing samples
were made in replicats of three. Prior to analysis samples were
centrifuged for 10 min. at 3500 rpm, HPLC system:
[0487] The fraction of compound metabolised during the 15 min of
incubation was determined by comparison of blank and
microsome-containing samples using a Waters Alliance 2690
separation module and Waters 996 PDA-detector (Waters. Milford,
Mass., USA.) Separation was performed on a XTerra MS C.sub.18
column (150*2.1 mm I.D., 3.5 .mu.m particle size) (Waters Milford,
Mass., USA) by. initial conditions were 40% mobile phase A
(acetonitrile) and 60% mobile phase B (10 mM ammonium acetate pH
9.5). During the first 20 minutes, the mobile phase was changed via
a linear gradient to 90% A and 10% B. This was followed by a 5
minutes linear gradient to initial conditions, which were
maintained for 5 min. The flow rate was 0.20 ml/min and injection
volume 10 .mu.l.
[0488] Determination of Solubility
[0489] Solubility of the compounds was determined by preparing a
saturated solution of compound in 0.3 M phosphate buffer (pH
7.4.+-.0.3) in a brown glass tube. The suspensions were rotated
slowly for 24 hours. Aliquots were centrifuged for 10 minutes at
14.000 rpm and supernatants were diluted in 40% (v/v) acetonitrile
in water prior to HPLC analysis. Concentrations of analytes were
quantified against a standard curve and used as term of
solubility.
[0490] The HPLC-UV method used for the assessment of solubility is
the same as used in the in vitro metabolism assay.
[0491] Pharmacokinetic Studies
[0492] Evaluation of the pharmacokinetic properties of the
compounds was done using female NMRI mice (weighing app. 30 g).
Test articles were administrated intravenously and orally as a
cassette dose formulations containing three compounds or as
individual compounds. Samples of serum were taken at defined
timepoints.
[0493] Standards and QC-samples in plasma were prepared and the
serum concentrations of the test compounds quantified by
HPLC-MS.
[0494] Prior to analysis, proteins were precipitated by deluding
the samples (1:1) (v/v) with 100% acetonitrile followed by
centrifugation at 14.000 rpm in 10 min. The supernatant was used
for the analysis.
[0495] HPLC-MS System:
[0496] A Waters Alliance HPLC-system (Milford, Mass., USA) was
coupled to a Quatro Micro triple quadropl mass spectrometer
(Micromass, Manchester, UK) operating in positive (ESI) mode.
Separation was performed on a XTerra MS C.sub.18 column (150*2.1 mm
I.D., 3.5 .mu.m particle size) (Waters Milford, Mass., USA).
[0497] Mobile phase A: 0.1% (v/v) formic acid or 10 mM ammonium
acetate pH-adjusted to 9.5 in MilIQ-water, mobile phase B: 100%
methanol. The gradient was as follows: 0 min=70% A-30% B, 0-10 min.
a linear gradient to 10% A and 90% B this was maintained till 11
min, 11-13 linear gradient to 70% A and 30% B this was maintained
till 18 min. The flow rate was 0.20 ml/min, injection volume 10
.mu.l.
[0498] Biological Testing
[0499] General Methods
[0500] In vitro Microbiological Testing
[0501] MIC Determination in Broth Microdilution Assay
[0502] Compounds were screened for activity against a panel of 10
different non-fastidious bacteria growing aerobically
(Staphylococcus aureus ATCC29213; Staphylococcus aureus ATCC33591;
Staphylococcus intermedius #2357(clinical isolate from the
Copenhagen area); Enterococcus faecalis ATCC29212;Enterococcus
faeclum #17501 (vancomycin-resistant clinical isolate);
Streptococcus pneumoniae #998 (clinical isolate); Streptococcus
pyogenes #14813 (clinical isolate); Streptococcus agalactiae #19855
(clinical isolate); Eschericia coli ATCC25922 and Escherdcia coli
ESS). The screening assay was done in 200 .mu.l MH-broth cultures
in microtitre plates. For compounds exhibiting activity in the
initial screen MIC was determined in a microdilution assay using
MH-broth as described by NCLLS (National Committee for Clinical
Laboratory Standards. Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically; Approved
Standard--Fifth Edition. M7-A5 NCCLS 2000) modified to include
uninoculated dilution series of test compounds to facilitate MIC
determination if the test compound should precipitate. MIC was
determined as the lowest concentration of test compound able to
inhibit visible growth of bacteria. MICs for ATCC type strains fell
within the limits posted by the NCCLS (National Committee for
Clinical Laboratory Standards. Performance Standards for
Antimicrobial Susceptibility Testing; Eleventh informational
Supplement. M100-S11 NCCLS 2001) when tested against vancomycin,
tetracycline, gentamycin.
[0503] MIC and MBC Determination in Broth Macrodilution Assay
[0504] MIC and MBC of test compounds were determined in a broth
macrodilution assay using 2 ml MH-broth cultures and an inoculum of
approximately 5.times.10E5 CFU/ml as described by Amsterdam
(Amsterdam, D. Susceptibility testing of antimicrobials in liquid
media. In V. Lorian (ed.): Antibiotics in Laboratory Medicin 4.
edition. Williams & Wilkins 1996). MIC was determined as the
minimal concentration of test compound able to inhibit visible
growth of bacteria. Samples from cultures inhibited by test
compound were plated onto unselective blood agar plates. MBC was
determined as the minimal concentration of test compound able to
decrease colony count on these plates below 0.1% compared to the
original inoculum.
[0505] Killing Curve Determination
[0506] For the determination of the killing curve of a test
compound a dilution series of test compound was made and inoculated
with approximately 5.times.10E5 CFU/ml as described for the MIC
macrodilution assay above. At the timepoints indicated 100 .mu.l
samples was withdrawn from the test tubes, serially diluted and
spotted in duplicate on unselective agar plates to determine CFU.
Test compounds with bactericidal activity is capable of decreasing
surviving colony counts (CFU/ml) when incubated with bacteria.
Bactericidal activity may be either primarily dependent on
concentration of test compound or on incubation time with test
compound. An example of a bactericidal compound (A031), which is
primarily dependent on the concentration of the test compound is
shown in FIG. 3. An example of a bactericidal compound (A019) which
is primarily dependent on the incubation time with the compound is
shown in FIG. 4.
[0507] MIC Determination Against Helicobacter pylon
[0508] Six strains of Helicobacter pylon were used in an agar
dilution assay according to the standards of NCCLS (National
Committee for Clinical Laboratory Standards. Methods for Dilution
Antimicrobial Susceptibility Tests for Bacteria That Grow
Aerobically; Approved Standard--Fifth Edition. M7-A5 NCCLS 2000).
MH-agar plates supplemented with 5% horse blood and containing a
dilution series of the test compound were inoculated in duplicate
with 10 .mu.l spots of a 2 McF suspension of the different strains
of H. pylori. This inoculum corresponds to approximately 10E6
CFU/spot. Plates were then incubated in a microaerophilic
atmosphere at 35.degree. C. for 72 hours. The MIC endpoint was
determined as the lowest concentration of test compound able to
completely inhibit or most significantly reduce growth compared to
growth control plates not containing test compounds.
[0509] Activity Determination Against Anaerobic Bacteria
[0510] Screening for activity against anaerobic bacteria was done
against two isolates of Bacteroides fragilis, an isolate of
Clostridium difficile and an isolate of Clostridium perfringens in
an agar dilution assay as described by NCCLS (National Committee
for Clinical Laboratory Standards. Methods for Antimicrobial
Susceptibility Testing of Anaerobic Bacteria; Approved
Standard--Fifth Edition. M11-A5 NCCLS 2000) with the exception that
Mueller-Hinton agar was used in place of supplemented Brucella
broth. Plates containing test compound at a single concentration
(either 100 or 150 .mu.M) were prepared in duplicate along with
appropriate control plates. Activity was present if growth in the
presence of test substance was absent or most significantly reduced
compared to growth control plates not containing test compound.
[0511] Leishmania promastigote Assay
[0512] A WHO reference vaccine strain of L. major originally
isolated from a patient in Iran were cultured in Medium 199 with
Hanks' Salts containing 0.02 mg/ml gentamycin, 25 mM HEPES, 4 mM
L-glutamine, and 10% heat inactivated fetal calf serum (FCS).
incubation was carried out at 27.degree. C. Promastigotes were
harvested at day 3 of culture and used for the assay of inhibition
of parasite growth.
[0513] The effect of test compounds on promastigotes was assessed
by a method modified from Pearson et al. Briefly, promastigotes
(0.8.times.10.sup.6/well) were incubated in 200 .mu.l duplicate
cultures either with a dilution series of test compound or medium
alone in 96 wells flat buttom microtiter plates. After 2 h of
incubation, 1.5 .mu.Ci of 3H-thymidine was added to each well and
further incubated for 18 hours. The cultures were then harvested on
Unifilter-GF/C microtiter filter plates (Packard instruments),
washed extensively and counted in a TopCount-NXT microplate
scintillation counter (Packard instruments).
[0514] Plasmodium falciparum Assay
[0515] Plasmodium falciparum 3D7 was maintained in culture by a
modification of the method originally described by Trager and
Jensen. In brief, the parasites were grown in suspensions of human
blood group 0 erythrocytes (RBC) maintained in RPMI1640 medium
supplemented with 4.5 g/l Albumax II (invitrogen), 10 mM
hypoxantine, 1.4 mM L-glutamine and 0.05 mg/ml gentamicin. Cultures
were incubated at 37.degree. C. in atmosphere of 92.5% nitrogen,
5.5% carbon dioxide, and 2% oxygen. To obtain synchronized cultures
og parasites erythrocytes infected with late trophozoite and
schizont stages were separated from ring stages and uninfected RBC
by magnet-activated cell sorting (MACS; Miltenyi BioTec) (Staalsoe,
T., H. A. Giha, D. Dodoo, T. G. Theander, and L. Hvild. 1999.
Detection of antibodies to variant antigens on Plasmodium
falciparum-infected erythrocytes by flow cytometry. Cytometry
35:329-336). Because of their high content of paramagnetic
haemozoin, erythrocytes infected with late developmental stages of
malaria parasites are specifically retained within the column. The
column was washed with PBS supplemented with 2% foetal calf serum
and then the column was removed from the magnet and the retained
late developmental stages of parasites were eluted and cultured for
an additional 18 hours. At this time the culture is highly
synchronous containing more than 90% ring stages.
[0516] These synchronized cultures of ring stage parasites were
used to assay for antimalarial parasites. Briefly, cultures of ring
stage parasites were adjusted to 1% parasitemia by addition of
uninfected RBC. Then, these were incubated in 125 .mu.l duplicate
cultures containing 2.5.times.10.sup.7 RBC/well with either a
dilution series of test compound or with medium alone. Plates were
then incubated at 37.degree. C. for 24 hours when cultures were
labelled by the addition 1.1 .mu.Ci 3H-phenyalanine and incubated
overnight. Then, the cultures were harvested on Unifilter-GF/C
microfilter plates (Packard instruments) and washed extensively
with water followed by a wash with 10% H.sub.2O.sub.2 to bleach
hemoglobin. Filter plates were counted in a TopCount-NXT microplate
scintillation counter (Packard instruments).
[0517] DHODH Assay
[0518] 100 .mu.l chalcone or 0.1 M Tris-HCl pH 8.0 is added to a
well in a 96-wells microtiter plate. Then 50 .mu.l enzyme dilution
is added. The microtiter plate is placed in the Powerwave.sub.x340
and the enzymatic reactions starts when adding 100 .mu.l assay
mixture. The reaction are measured every 20 sec. for 10 min. The
samples with chalcones are compared with the samples with 0.1 M
Tris-HCl pH 8.0 and the percent inhibition is calculated. Enzyme
dilution: The solution of recombinant purified enzyme is dissolved
in 0.1 M Tris-HCl pH 8 to give an initial velocity of 0.04-0.05
.DELTA.A/min.
[0519] 2,6-dichlorophenolindophenol (DClP)-stock solution: 40 mg
DClP and 10 ml 99% Ethanol are mixed for min at RT. Then 100 .mu.l
1.0 M Tris-HCl pH 8 and miliQ H.sub.2O are added to a final volume
of 100 ml. The A.sub.600 of the DClP-stock solution are measured in
a microtiter plate on the Powerwave.sub.x340 (Bio-Tek instruments,
Inc.)
[0520] Dihydroorotate dehydrogenase (DHODH)-stock solution: 25 mM
dihydroorotate stock-solution is prepared by first dissolving in
the same amount of mol NaOH and then miliQ H.sub.2O is added to the
final volume.
[0521] Assay mix (10 ml solution): 600 .mu.l of DHODH-stock
solution and X ml (depending on the A.sub.600 value of
stock-solution) DClP to a final A.sub.600=2.5 are mixed. Then 0.1 M
Tris-HCl pH 8.0 are added to a final volume of 10 ml.
[0522] Preparation of compound solution: A 10 mM stock-solution of
compound (e.g. a chalcone derivative) is made in dimethylsulfoxid
(DMSO). The compound is then diluted in 0.1 M Tris-HCl pH 8 to the
test concentrations. The final DMSO concentration in the sample is
10%
[0523] In vivo Models
[0524] Effect of Chalcones Following Multiple intra venous
Administration in Plasmodium berghei K173 infected NMRI Female
Mice.
[0525] Animals in groups of 6 were inoculated intra peritoneally
with 1.times.10.sup.6 infected red blood cells (RBC). On day 4
after infection, when the parsitaemia was 2-5%, treatment was
initiated and the animals were dosed, according to the body weight
recorded, once daily for 3 consecutive days (day 4-7). The doses
stated were administered intra venously as solutions in a suitable
vehicle. Parasitaemia, as percentage infected blood cells, was
determined by counting 500 RBCs in stained (Giemsa) blood smears,
prepared from blood samples from the tail vein taken on day 4 to 9
after infection.
[0526] Effect of Chalcones Following Multiple Oral Administrations
in Plasmodium berghei K173 infected NMRI Female Mice.
[0527] Animals in groups of 4 were inoculated intra peritoneally
with 1.times.10.sup.6 infected red blood cells (RBC). 2 hours after
infection, treatment was initiated and the animals were dosed,
according to the body weight recorded, twice daily for 3
consecutive days (day 0-3). The doses stated were administered
orally as solutions in a suitable vehicle. Parasitaemia, as
percentage infected blood cells, was determined by counting 500
RBCs in stained (Giemsa) blood smears, prepared from blood samples
from the tail vein taken on day 6 after infection.
[0528] Biological Results
[0529] Licochalcone A (LicA) and 4'methoxy chalcone (4'MC)
described in WO 93/17671 are used as reference compounds in the
following discussion.
[0530] Activity Against Non-fastidious Bacteria:
[0531] Licochalcone A exhibit moderate bactericidal activity
against common pathogenic Gram-positive non-fastidious bacteria
including Staphylococcus aureus, Enterococcus faecalis,
Enterococcus faecium, Streptococcus pneumoniae, Streptococcus
pyogenes, and Streptococcus agalactiae. Licochalcone A maintains
its activity also against antibiotic resistant bacteria, e.g.
Staphylococcus aureus ATCC33591 (resistant to methicillin) and
Enterococcus faecium #17051 (resistant to vancomycin). In contrast,
Licochalcone A have only modest or no activity against the
prototype pathogenic Gram-negative bacterium, Eschericia coli. 4'MC
as a representative of non-hydroxyl chalcones exhibit no
antibacterial effect at all.
[0532] In comparison with Licochalcone A, aminochalcones retain the
activity of Licochalcone A against pathogenic Gram-positive
bacteria including antibiotic-resistant strains (cf. Table 1).
Several aminochalcones exhibit increased potency against
Gram-positive pathogens (e.g. A025, A030, A019, A033, A083). in
contrast to Licochalcone A, aminochalcones exhibit activity against
Eschericia coli. Thus, several aminochalcones (e.g. A030, A031,
A019, A083, A084) exhibit considerable activity against the ESS
strain of E. coli, which generally is more susceptible to
antibiotics than the type strain E. coli ATCC25922. However,
several aminochalcones (e.g. A022) exhibit similar high activity
against both Gram-positive bacteria and E. coli ESS and ATTC 25922
strains. Thus, aminochalcones can be modified to permeate and
inhibit Gram-negative bacteria. This indicates the potential use of
aminochalcones in the treatment of infections with Gram-negative
bacteria.
[0533] In the treatment of severe infections in immunocompromised
patients bactericidal action of a antibiotic is a necessity. As
exemplified in FIGS. 3 and 4, aminochalcones retain the
bactericidal action of Licochalcone A. For some aminochalcones the
bactericidal action is predominantly dependent on the concentration
of the compound (e.g. A031; cf. FIG. 3); for others the
bactericidal action is predominantly dependent on the time of
incubation with the compound (e.g. A019; cf. FIG. 4). This
knowledge is helpful when designing dosing regimens for in vivo
efficacy trials. TABLE-US-00001 TABEL 1 Comparasion of the effect
of amino-chalcones and Licochalcone/4'MC on bacteria; MIC values in
.mu.M. A B C D E F G H LICA 37.5 37.5 37.5 37.5 37.5 75.0 300.0
4'-MC NA NA NA NA NA NA NA NA A025 9.4 9.4 9.4 9.4 9.4 37.5 75.0
A030 9.4 9.4 9.4 18.8 18.8 18.8 18.8 A019 9.4 9.4 9.4 9.4 9.4 18.8
18.8 A033 4.7 9.4 4.7 9.4 9.4 75.0 150.0 A083 9.4 9.4 18.8 18.8 9.4
18.8 9.4 A022 37.5 37.5 37.5 18.8 18.8 18.8 18.8 18.8 A117 9.4 9.4
9.4 37.5 37.5 37.5 150 9.4 A137 4.7 9.4 9.4 9.4 9.4 37.5 A129 4.7
9.4 9.4 9.4 9.4 37.5 9.4 A: Staphylococcus aureusATCC29213; B:
Staphylococcus aureus ATCC33591 (resistant to methicillin); C:
Staphylococcus intermedius #2357 (clinical isolate from the
Copenhagen area); D: Enterococcus faecalisATCC29212; E:
Enterococcus faecium #17501 (vancomycin-resistant clinical
isolate); F: Streptococcus pneumoniae#998 (clinical isolate); G:
Eschericia coliATCC25922 and H: Eschericia coli ESS. NA: no
activity.
[0534] Activity against Helicobacter pylori:
[0535] Colonization of the gastric mucosa with Helicobacter pylori
is an important pathogenic determinant for the development of
gastritis and peptic ulcer. Aminochalcones exhibit activity against
Helicobacter pylori. Several aminochalcones (e.g. A026, A035, A037,
A038, A045, A051, A063, A118, A124) exhibit MICs in the range
between 12.5 .mu.M and 100 .mu.M when tested against a panel of six
strains Helicobacter pylori, that includes strains resistant to
metronidazole. Metronidazol is an antibiotic commonly included in
treatment regimens designed to eradicate Helicobacter colonization
for the treatment of peptic ulcer. The activity of aminochalcones
against both metronidazole-resistant and sensitive Helicobacter
pylori clearly indicates the potential use of these compounds in
the treatment of Helicobacter infections.
[0536] Activity Against Anaerobic Bacteria:
[0537] Aminochalcones have been assayed in a single concentration
of compound (100 .mu.M) for activity against a panel of anaerobic
bacteria containing common human pathogenic bacteria (Bacteroides
fragilis, Clostridium perfringens, Clostridium difficele). Several
aminochalcones (e.g. A011, A026, A034, A037, A038, A063, A090)
exhibit activity against all microorganisms within the test panel.
This clearly indicates the potential use of aminochalcones in
treatment of infection caused by anaerobic bacteria.
[0538] Activity Against Protozoa:
[0539] Activity against Plasmodium falciparum:
[0540] Plasmodium falciparum is a protozoan parasite transmitted by
the mosquito, Anopheles, and causing malignant or severe malaria in
humans. Licochalcone A exhibit activity against Plasmodium
falciparum in vitro and protects mice from infection with P. yoelii
and P. berghei (Chen et al., 1994). Aminochalcones exhibit activity
in vitro against Plasmodium falciparum and several aminochalcones
exhibit improved potency compared to Licochalcone A (cf. Table 2
and FIG. 5). Futhermore the compounds are potent against
chloroquine resistant parasites as shown in Table 3. The results
clearly indicate the potential use of aminochalcones in the
treatment of malaria. TABLE-US-00002 TABLE 2 Activity against
Plasmodium falciparum 3D7. Comp. LicA 4'MC A027 A035 A038 A043 A066
A090 A102 IC.sub.50 (.mu.M) 6.4 40.0 0.7 0.9 1.2 1.3 0.9 1.0 0.5
Comp. A127 A130 A131 A132 A139 A141 IC.sub.50 (.mu.M) 0.6 0.5 0.5
0.6 0.4 0.7
[0541] TABLE-US-00003 TABLE 3 Activity against resistant strains of
Plasmodium falciparum Plasmodium falciparum IC.sub.50 (.mu.M)
3D7(Cq-sen) DD2 (Cq-res) 7G8(Cq-res) K1(Cq-res) A027 0.7 1.1 1.1
1.1 A102 0.5 1.2 1.1 1.1 Chloroquine 0.13 1.0 1.09 >1.56
[0542] Activity Against Leishamania major:
[0543] Leishamania major is a protozoan parasite transmitted by the
sandfly, Phlebotomus, and causing cutaneous leishmaniasis or
kala-azar in humans. Licochalcone A exhibit activity against
Leishmania parasites and has shown efficacy in experimental animal
models of cutaneous and visceral Leishmania infection (Chen et al.,
1994). Aminochalcones exhibit activity in vitro against Leishamania
major with significantly improved potency compared to Licochalcone
A and 4'MC (cf. Table 4 and FIG. 6). The results clearly indicate
the potential use of aminochalcones in the treatment of Leishamania
infection. TABLE-US-00004 TABLE 4 Effect of amino-chalcones on L.
major. Comp. LicA 4'MC A027 A034 A035 A037 A038 A051 A063 A083 A100
IC.sub.50 (.mu.M) 4.6 5.6 0.2 0.9 0.3 0.1 0.8 0.5 0.9 1.0 0.2
[0544] Inhibition of DHODH.
[0545] Several of the amino-chalcones prepared are potent
inhibitors of DHODH. The compounds are as potent as LicA and by far
more potent than ordinary chalcones exemplified by 4'MC.
TABLE-US-00005 TABLE 5 Inhibition of DHODH. Comp. LicA 4'MC A020
A021 A022 A025 A035 A038 A045 Inhibition 25% 7% 23% 27% 28% 26% 26%
22% 20%
[0546] Metabolism
[0547] The usefulness of chalcones as drug candidates have been
limited by the metabolism of the compounds resulting in short
half-lives in vivo (Lica: 100% turn-over in vitro and t1/2=10 min
in vivo).
[0548] The introduction of an amino group in the chalcone changes
the metabolic properties; this is clear from Table 6 where the
metabolic turn-over of a number of amino-chalcones are compared to
LicA. The amino-chalcones prepared are expected to show low or no
metabolism in vivo as the metabolic turn-over are between 0-10%
(compared to 100% turn-over for Lica). Consequently, the half-life
of an amino-chalcone will be longer, reducing the dose needed for
treatment. TABLE-US-00006 TABLE 6 Metabolic turn-over (rat) in
vitro (%). Comp. LicA A010 A019 A029 A049 A099 A102 A110 Turn-over
100% 1% 5% 3% 0% 7% 2% 6%
[0549] Solubility
[0550] The aqueous solubility of the neutral chalcones described in
WO 93/17671 is very low. A representative chalcone
4'-methoxy-chalcone has a solubility of <<0.05 mg/ml. A few
chalcones have a higher solubility due to (metabolically unstable)
hydroxyl groups in the molecule. LicA has a solubility of
approximately 0.01 mg/ml.
[0551] The amino-chalcones described in this application are by far
superior having solubility numbers in mg/ml (cf. Table 7).
TABLE-US-00007 TABLE 7 Solubility in aqueous buffer at pH 7.4.
Comp. A005 A010 A013 A049 A066 A069 A086 Solubility >6 33.4 31.2
6.3 7.4 >10 8.9 (mg/ml)
[0552] The high solubility means that dissolution and hence
absorption will be no problem. This will inevitably cause a
dramatic reducing of the dose needed making the amino-chalcones
very usable as drug candidates.
[0553] Bioavailabiblity
[0554] The bioavailability of the amino chalcones in mice is in
general very high (e.g. 34% for A048). As the mouse is a very fast
metabolizer of the amino chalcones compared to rat and human (e.g.
A102 mice: 28%; rat: 2%; human: in general lower than rat) the
bloavailability in rat and man is expected to be even higher due to
limited first pass metabolism.
[0555] In vivo Results
[0556] A number of amino-chalcones have significant effect in the
in vivo models. As illiustrated on FIG. 7 and 8 the compounds cause
a significant reduction of parasitaemia in plasmodium infedted
mice, showing the potential of the compounds as drug
candidates.
[0557] Conclusion: The use of chalcones as drug candidates for the
treatment of parasitic or bacterial infections have been limited by
the low in vivo potency of the compounds and a narrow spectrum of
activity.
[0558] Several factors contribute to the low in vivo potency: Fast
metabolism resulting in short half-lives in vivo; Low/no solubility
in the intestine and consequently low/no absorption; Medium potency
of the compounds against parasites and no activity against bacteria
(except for LicA).
[0559] The amino-chalcones in this application are expected to
fulfill the criteria for a drug candidate. The metabolism is low,
the solubility is high and the compounds are potent against
parasites as well as (resistant) Gram positive and Gram negative
bacteria.
* * * * *