U.S. patent application number 10/386083 was filed with the patent office on 2003-11-13 for morpholinone and morpholine derivatives and uses thereof.
This patent application is currently assigned to Synaptic Pharmaceutical Corporation. Invention is credited to Gluchowski, Charles, Lagu, Bharat, Nagarathnam, Dhanapalan, Tian, Dake.
Application Number | 20030212062 10/386083 |
Document ID | / |
Family ID | 22795490 |
Filed Date | 2003-11-13 |
United States Patent
Application |
20030212062 |
Kind Code |
A1 |
Lagu, Bharat ; et
al. |
November 13, 2003 |
Morpholinone and morpholine derivatives and uses thereof
Abstract
This invention is directed to morpholinone and morpholine
derivatives which are selective antagonists for human
.alpha..sub.1a receptors. This invention is also related to uses of
these compounds for lowering intraocular pressure, inhibiting
cholesterol synthesis, relaxing lower urinary tract tissue, the
treatment of benign prostatic hyperplasia, impotency, cardiac
arrhythmia, sympathetic mediated pain, migraine, and for the
treatment of any disease where the antagonism of the .alpha..sub.1a
receptor may be useful. The invention further provides a
pharmaceutical composition comprising a therapeutically effective
amount of the above-defined compounds and a pharmaceutically
acceptable carrier.
Inventors: |
Lagu, Bharat; (Belle Meade,
NJ) ; Nagarathnam, Dhanapalan; (Bethany, CT) ;
Tian, Dake; (Belle Mead, NJ) ; Gluchowski,
Charles; (Danville, CA) |
Correspondence
Address: |
John P. White
Cooper & Dunham LLP
1185 Avenue of the Americas
New York
NY
10036
US
|
Assignee: |
Synaptic Pharmaceutical
Corporation
|
Family ID: |
22795490 |
Appl. No.: |
10/386083 |
Filed: |
March 11, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10386083 |
Mar 11, 2003 |
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10017263 |
Dec 14, 2001 |
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6531471 |
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10017263 |
Dec 14, 2001 |
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09702015 |
Oct 30, 2000 |
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6362182 |
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09702015 |
Oct 30, 2000 |
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09213539 |
Dec 17, 1998 |
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6218390 |
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Current U.S.
Class: |
514/227.5 ;
514/230.5; 514/231.2; 514/249; 514/255.02; 544/170; 544/231;
544/384; 544/59; 544/71 |
Current CPC
Class: |
A61K 31/5375 20130101;
A61P 15/10 20180101; C07D 413/14 20130101; A61P 3/06 20180101; A61P
13/02 20180101; C07D 265/32 20130101; A61P 13/08 20180101; A61P
9/06 20180101; A61K 31/5377 20130101; A61P 25/02 20180101; A61P
27/02 20180101; A61P 25/06 20180101; C07D 413/12 20130101; A61P
43/00 20180101 |
Class at
Publication: |
514/227.5 ;
514/230.5; 514/231.2; 514/249; 514/255.02; 544/59; 544/71; 544/170;
544/231; 544/384 |
International
Class: |
A61K 031/54; A61K
031/58; A61K 031/537; A61K 031/495; A61K 031/498; C07D 279/12 |
Claims
What is claimed is:
1. A compound having the structure 42where W is O, S, or NR.sub.8;
wherein R.sub.8 is independently H, straight chained or branched
C.sub.1-C.sub.7 alkyl, straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl, C.sub.3-C.sub.7 cycloalkyl, or C.sub.5-C.sub.7
cycloalkenyl; where Y is independently O or S; where R.sub.2 is
aryl or heteroaryl; wherein the aryl or heteroaryl may be
substituted with one or more of F; Cl; Br; I; --CN; --NO.sub.2;
--N(R.sub.8).sub.2; --SO.sub.2R.sub.8;
--(CH.sub.2).sub.nC(Y)R.sub.8; --(CH.sub.2).sub.nYR.su- b.8;
--(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.s- ub.8; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl; or
C.sub.5-C.sub.7 cycloalkenyl; and wherein n independently is an
integer from 0 to 7 inclusive; where R.sub.3 is independently H;
straight chained or branched C.sub.1-C.sub.7 alkyl,
monofluoroalkyl, or polyfluoroalkyl; where R.sub.4 is H,
--(CH.sub.2).sub.tYR.sub.8, --(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2,
--(CH.sub.2).sub.tC(Y)R.sub.8, --(CH.sub.2).sub.tCO.sub.2R.sub.8,
--(CH.sub.2).sub.tN(R.sub.8).sub.2, --(CH.sub.2).sub.tCN,
--C(Y)R.sub.8, --C(Y)N(R.sub.8).sub.2, --CO.sub.2R.sub.8, straight
chained or branched C.sub.1-C.sub.7 alkyl, straight chained or
branched C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7
cycloalkyl, C.sub.5-C.sub.7 cycloalkenyl, or phenyl or benzyl;
wherein the phenyl or benzyl may be substituted with one or more of
F; Cl; Br; I; --CN; --NO.sub.2; --N(R.sub.8).sub.2;
--SO.sub.2R.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8- ; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl; or
C.sub.5-C.sub.7 cycloalkenyl; and wherein t independently is an
integer from 1 to 4 inclusive; where R.sub.5 is H,
--(CH.sub.2).sub.tYR.sub.8, --(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2,
--(CH.sub.2).sub.tC(Y)R.sub.8, --(CH.sub.2).sub.tCO.sub.2R.sub.8,
--(CH.sub.2).sub.tN(R.sub.8).sub.2, --(CH.sub.2).sub.tCN, straight
chained or branched C.sub.1-C.sub.7 alkyl, straight chained or
branched C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7
cycloalkyl, C.sub.5-C.sub.7 cycloalkenyl, or phenyl or benzyl;
wherein the phenyl or benzyl may be substituted with one or more of
F; Cl; Br; I; --CN; --NO.sub.2; --N(R.sub.8).sub.2;
--SO.sub.2R.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8- ; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl; or
C.sub.2-C.sub.7 cycloalkenyl; where R.sub.6 is H,
--(CH.sub.2).sub.tYR.sub.8, --(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2,
--(CH.sub.2).sub.tC(Y)R.sub.8, --(CH.sub.2).sub.tCO.sub.2R.sub.8,
--(CH.sub.2).sub.tN(R.sub.8).sub.2, --(CH.sub.2).sub.tCN,
--C(Y)R.sub.8, --C(Y)N(R).sub.2, --CO.sub.2R.sub.8, straight
chained or branched C.sub.1-C.sub.7 alkyl, straight chained or
branched C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7
cycloalkyl, C.sub.5-C.sub.7 cycloalkenyl, or phenyl or benzyl;
wherein the phenyl or benzyl may be substituted with one or more of
F; Cl; Br; I; --CN; --NO.sub.2; --N(R.sub.8).sub.2;
--SO.sub.2R.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl; or
C.sub.5-C.sub.7 cycloalkenyl; where R.sub.7 is H,
--(CH.sub.2).sub.tYR.sub.8, --(CH.sub.2).sub.tC(Y)N(R-
.sub.8).sub.2, --(CH.sub.2).sub.tC(Y)R.sub.8,
--(CH.sub.2).sub.tCO.sub.2R.- sub.8,
--(CH.sub.2).sub.tN(R.sub.8).sub.2, --(CH.sub.2).sub.tCN, straight
chained or branched C.sub.1-C.sub.7 alkyl, straight chained or
branched C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7
cycloalkyl, C.sub.5-C.sub.7 cycloalkenyl, or phenyl or benzyl;
wherein the phenyl or benzyl may be substituted with one or more of
F; Cl; Br; I; --CN; --NO.sub.2; --N(R.sub.8).sub.2;
--SO.sub.2R.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8- ; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl; or
C.sub.5-C.sub.7 cycloalkenyl; where q is an integer from 0 to 4
inclusive; where each R.sub.8, n, and t independently is as defined
above; where R.sub.1 is 43wherein each R.sub.9 is H; straight
chained or branched C.sub.1-C.sub.7 alkyl, hydroxyalkyl,
aminoalkyl, alkoxyalkyl, monofluoroalkyl, or polyfluoroalkyl;
straight chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl, or
polyfluorocycloalkyl; C.sub.5-C.sub.7 cycloalkenyl; or aryl or
heteroaryl, wherein the aryl or heteroaryl may be substituted with
one or more of F; Cl; Br; I; --(CH.sub.2).sub.nYR.sub- .8;
--(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8; --CN; --NO.sub.2;
--N(R.sub.8).sub.2; --SO.sub.2R.sub.8; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, or polyfluoroalkyl;
straight chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl, or
polyfluorocycloalkyl; or C.sub.5-C.sub.7 cycloalkenyl; wherein each
R.sub.10 is H; F; --OH; --(CH.sub.2).sub.nC(Y)R.sub.8,
--(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8- ; --CN; --NO.sub.2;
--N(R.sub.8).sub.2; aryl or heteroaryl; straight chained or
branched C.sub.1-C.sub.7 alkyl, hydroxyalkyl, aminoalkyl,
carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl, or polyfluoroalkyl;
straight chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl, or
polyfluorocycloalkyl; or C.sub.5-C.sub.7 cycloalkenyl; wherein the
alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxamidoalkyl,
alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted
with one or more aryl or heteroaryl; wherein the aryl or heteroaryl
may be substituted with one or more of F; Cl; Br; I;
--(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8; --CN; --NO.sub.2;
--N(R.sub.8).sub.2; --SO.sub.2R.sub.8; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, or polyfluoroalkyl;
straight chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl, or
polyfluorocycloalkyl; or C.sub.5-C.sub.7 cycloalkenyl; wherein each
R.sub.11 is independently H, --(CH.sub.2).sub.tYR.sub.8,
--(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2,
--(CH.sub.2).sub.tC(Y)R.sub.8, --(CH.sub.2).sub.tCO.sub.2R.sub.8,
--(CH.sub.2)N(R.sub.8).sub.2, --(CH.sub.2).sub.tCN, --C(Y)R.sub.8,
--C(Y)N(R.sub.8).sub.2, --CO.sub.2R.sub.8, straight chained or
branched C.sub.1-C.sub.7 alkyl, straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7 cycloalkyl, or
C.sub.5-C.sub.7 cycloalkenyl; wherein each R.sub.12 is
independently H, --(CH.sub.2).sub.tYR.sub.8,
--(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2,
--(CH.sub.2).sub.tC(Y)R.sub.8, --(CH.sub.2).sub.tCO.sub.2R.sub.8,
--(CH.sub.2)N(R.sub.8).sub.2, --(CH.sub.2).sub.tCN, straight
chained or branched C.sub.1-C.sub.7 alkyl, straight chained or
branched C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7
cycloalkyl, or C.sub.5-C.sub.7 cycloalkenyl; wherein R.sub.13 is H,
C.sub.1-C.sub.7 alkyl, --C(O)R.sub.2, aryl, heteroaryl,
C.sub.1-C.sub.7 alkyl substituted with one or two aryl, or
C.sub.1-C.sub.7 alkyl substituted with one or two heteroaryl;
wherein the aryl or heteroaryl may be substituted with one or more
of F; Cl; Br; I; --CN; --NO.sub.2; --N(R.sub.8).sub.2;
--SO.sub.2R.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nYR.su- b.8;
--(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2)CO.sub.2R.sub.8; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl, or
carboxamidoalkyl; straight chained or branched C.sub.2-C.sub.7
aminoalkyl, alkenyl, choralkynyl; C.sub.3-C.sub.7 cycloalkyl; or
C.sub.5-C.sub.7 cycloalkenyl; wherein R.sub.14 is H, straight
chained or branched C.sub.1-C.sub.7 akyl; wherein Z is O, S,
NR.sub.14, CO, CH.sub.2, 44wherein Y.sub.1, Y.sub.2, and Y.sub.3
independently are H; F; Cl; Br; I; --CN; --NO.sub.2;
--N(R.sub.8).sub.2; --SO.sub.2R.sub.8;
--(CH.sub.2).sub.nC(Y)R.sub.8; --(CH.sub.2).sub.nYR.su- b.8;
--(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.s- ub.8; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl; or
C.sub.5-C.sub.7 cycloalkenyl; wherein each m is independently 1 or
2; whereineach p is independently an integer from 0 to 2 inclusive;
wherein J is 45or C.sub.2-C.sub.7 alkenyl; wherein each R.sub.15 is
independently H, --(CH.sub.2).sub.tYR.sub.8,
--(CH.sub.2).sub.tC(Y)N(R.su- b.8).sub.2,
--(CH.sub.2).sub.tC(Y)R.sub.8, --(CH.sub.2).sub.tCO.sub.2R.sub- .8,
--(CH.sub.2).sub.tN(R.sub.8).sub.2, --(CH.sub.2).sub.tCN,
--C(Y)R.sub.8, --C(Y)N(R.sub.8).sub.2, --CO.sub.2R.sub.8, straight
chained or branched C.sub.1-C.sub.7 alkyl, straight chained or
branched C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7
cycloalkyl, or C.sub.5-C.sub.7 cycloalkenyl; wherein each R.sub.16
is independently H, --(CH.sub.2).sub.tYR.sub.8,
--(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2,
--(CH.sub.2).sub.tC(Y)R.sub.8, --(CH.sub.2).sub.tCO.sub.2R.sub.8,
--(CH.sub.2).sub.tN(R.sub.8).sub.2, --(CH.sub.2).sub.tCN, straight
chained or branched C.sub.1-C.sub.7 alkyl, straight chained or
branched C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7
cycloalkyl, or C.sub.5-C.sub.7 cycloalkenyl; wherein each R.sub.17
is independently H; F; --(CH.sub.2).sub.tYR.sub.8;
--(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.tC(Y)R.sub.8; --(CH.sub.2).sub.tCO.sub.2R.sub.8;
--(CH.sub.2).sub.tN(R.sub.8).sub.2; --(CH.sub.2).sub.tCN;
--C(Y)R.sub.8; --C(Y)N(R.sub.8).sub.2; --CO.sub.2R.sub.8; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7
cycloalkyl; or C.sub.5-C.sub.7 cycloalkenyl; wherein each R.sub.18
is independently H; F; --(CH.sub.2).sub.tYR.sub.8;
--(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.tC(Y)R.sub.8; --(CH.sub.2).sub.tCO.sub.2R.sub.8;
--(CH.sub.2).sub.tN(R.sub.8).sub.2; --(CH.sub.2).sub.tCN; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7
cycloalkyl; or C.sub.5-C.sub.7 cycloalkenyl; wherein L is S, O, or
N(R.sub.8); wherein u is an integer from 0 to 1 inclusive; or a
pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein the compound comprises the (+)
enantiomer.
3. The compound of claim 1, wherein the compound comprises the (-)
enantiomer.
4. The compound of claim 1, wherein W is O.
5. The compound of claim 1, wherein J is 46
6. The compound of claim 5, wherein R.sub.1 is 47
7. The compound of claim 6, wherein R.sub.9 is aryl or heteroaryl,
wherein the aryl or heteroaryl may be substituted with one or more
of F; Cl; Br; I; --(CH.sub.2).sub.nYR.sub.8;
--(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8- ; --CN; --NO.sub.2;
--N(R.sub.8).sub.2; --SO.sub.2R.sub.8; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, or polyfluoroalkyl; and
wherein R.sub.10 is H; --CN; --OH; --CO.sub.2R.sub.8; aryl or
heteroaryl; wherein the aryl or heteroaryl may be substituted with
one or more of F; Cl; Br; I; --(CH.sub.2).sub.nYR.sub- .8;
--(CH.sub.2).sub.nC(Y)R.sub.8;
(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8; --CN; --NO.sub.2;
--N(R.sub.8).sub.2; --SO.sub.2R.sub.8; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, or polyfluoroalkyl.
8. The compound of claim 7 having the structure: 48wherein R.sub.2
is phenyl; wherein the phenyl may be substituted with one or more
of F; Cl; Br; I; --CN; --NO.sub.2; --N(R.sub.8).sub.2;
--SO.sub.2R.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8- ; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, or polyfluoroalkyl.
9. The compound of claim 8 wherein J is 49
10. The compound of claim 9 wherein R.sub.1 is 50
11. The compound of claim 10, wherein R.sub.9 is phenyl or pyridyl,
wherein the phenyl or pyridyl may be substituted with one or more
of F; Cl; Br; I; --(CH.sub.2).sub.nYR.sub.8;
--(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8- ; --CN; --NO.sub.2;
--N(R.sub.8).sub.2; --SO.sub.2R.sub.8; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, or polyfluoroalkyl; wherein
R.sub.10 is H, --CN, --OH, --CO.sub.2R.sub.8, or phenyl; wherein
the phenyl may be substituted with one or more of F; Cl; Br; I;
--(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8- , --CN; --NO.sub.2;
--N(R.sub.8).sub.2; --SO.sub.2R.sub.8; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, or polyfluoroalkyl; and
wherein R.sub.13 is phenyl; wherein the phenyl may be substituted
with one or more of F; Cl; Br; I; --CN; --NO.sub.2;
--N(R.sub.8).sub.2; --SO.sub.2R.sub.8;
--(CH.sub.2).sub.nC(Y)R.sub.8; --(CH.sub.2).sub.nYR.sub.8;
--(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl, or
carboxamidoalkyl; straight chained or branched C.sub.2-C.sub.7
aminoalkyl, alkenyl, or alkynyl; C.sub.3-C.sub.7 cycloalkyl; or
C.sub.5-C.sub.7 cycloalkenyl.
12. A pharmaceutical composition comprising a therapeutically
effective amount of the compound of claim 1 and a pharmaceutically
acceptable carrier.
13. The pharmaceutical composition of claim 12, wherein the amount
of the compound is an amount from about 0.01 mg to about 800
mg.
14. The pharmaceutical composition of claim 13, wherein the amount
of the compound is from about 0.01 mg to about 500 mg.
15. The pharmaceutical composition of claim 14, wherein the amount
of the compound is from about 0.01 mg to about 250 mg.
16. The pharmaceutical composition of claim 15, wherein the amount
of the compound is from about 0.1 mg to about 60 mg.
17. The pharmaceutical composition of claim 16, wherein the amount
of the compound is from about 1 mg to about 20 mg.
18. The pharmaceutical composition of claim 12, wherein the carrier
is a liquid and the composition is a solution.
19. The pharmaceutical composition of claim 12, wherein the carrier
is a solid and the composition is a tablet.
20. The pharmaceutical composition of claim 12, wherein the carrier
is a gel and the composition is a suppository.
21. The pharmaceutical composition of claim 12, wherein the
compound additionally does not cause a fall in blood pressure at
dosages effective to alleviate benign prostatic hyperplasia.
22. A method of treating a subject suffering from benign prostatic
hyperplasia which comprises administering to the subject an amount
of the compound of claim 1 effective to treat benign prostatic
hyperplasia.
23. A method of claim 22, wherein the compound additionally does
not cause a fall in blood pressure at dosages effective to
alleviate benign prostatic hyperplasia.
24. The method of claim 23, wherein the compound effects treatment
of benign prostatic hyperplasia by relaxing lower urinary tract
tissue.
25. The method of claim 24, wherein lower urinary tract tissue is
prostatic smooth muscle.
26. A method of treating a subject suffering from high intraocular
pressure which comprises administering to the subject an amount of
the compound of claim 1 effective to lower intraocular
pressure.
27. A method of treating a subject suffering from a disorder
associated with high cholesterol which comprises administering to
the subject an amount of the compound of claim 1 effective to
inhibit cholesterol synthesis.
28. A method of treating a subject suffering from cardiac
arrhythmia which comprises administering to the subject an amount
of the compound of claim 1 effective to treat cardiac
arrhythmia.
29. A method of treating a subject suffering from impotency which
comprises administering to the subject an amount of the compound of
claim 1 effective to treat impotency.
30. A method of treating a subject suffering from sympathetically
mediated pain which comprises administering to the subject an
amount of the compound of claim 1 effective to treat
sympathetically mediated pain.
31. A method of treating a subject suffering from migraine which
comprises administering to the subject an amount of the compound of
claim 1 effective to treat migraine.
32. A method of treating a disease which is susceptible to
treatment by antagonism of the .alpha..sub.1a receptor which
comprises administering to the subject an amount of the compound of
claim 1 effective to treat the disease.
33. A method of treating a subject suffering from benign prostatic
hyperplasia which comprises administering to the subject an amount
of the compound of claim 1 in combination with a 5-alpha reductase
inhibitor effective to treat benign prostatic hyperplasia.
34. The method of claim 33, wherein the 5-alpha reductase inhibitor
is finasteride.
35. A pharmaceutical composition comprising a therapeutically
effective amount of the compound of claim 1 in combination with a
therapeutically effective amount of finasteride and a
pharmaceutically acceptable carrier.
36. The pharmaceutical composition of claim 35, wherein the
compound is present in an amount from about 0.01 mg to about 800 mg
and the therapeutically effective amount of the finasteride is
about 5 mg.
37. The pharmaceutical composition of claim 36, wherein the
compound is present in an amount from about 0.1 mg to about 60 mg
and the therapeutically effective amount of finasteride is about 5
mg.
38. The pharmaceutical composition of claim 37, wherein the
compound is present in an amount from about 1 mg to about 20 mg and
the therapeutically effective amount of finasteride is about 5
mg.
39. A method of relaxing lower urinary tract tissue which comprises
contacting the lower urinary tract tissue with an amount of the
compound of claim 1 effective to relax lower urinary tract
tissue.
40. The method of claim 39, wherein the lower urinary tract tissue
is prostatic smooth muscle.
41. A method of relaxing lower urinary tract tissue in a subject
which comprises administering to the subject an amount of the
compound of claim 1 effective to relax lower urinary tract
tissue.
42. The method of claim 41, wherein the lower urinary tract tissue
is prostatic smooth muscle.
43. A pharmaceutical composition made by combining a
therapeutically effective amount of the compound of claim 1 and a
pharmaceutically acceptable carrier.
44. A pharmaceutical composition made by combining a
therapeutically effective amount of the compound of claim 1 with a
therapeutically effective amount of finasteride and a
pharmaceutically acceptable carrier.
45. A process for making a pharmaceutical composition comprising
combining a therapeutically effective amount of the compound of
claim 1 and a pharmaceutically acceptable carrier.
46. A process for making a pharmaceutical composition comprising
combining a therapeutically effective amount of the compound of
claim 1 with a therapeutically effective amount of finasteride and
a pharmaceutically acceptable carrier.
Description
[0001] Throughout this application, various references are referred
to within parentheses. Disclosures of these publications in their
entireties are hereby incorporated by reference into this
application to more fully describe the state of the art to which
this invention pertains.
BACKGROUND OF THE INVENTION
[0002] The designation ".alpha..sub.1a" is the appellation recently
approved by the IUPHAR Nomenclature Committee for the previously
designated ".alpha..sub.1c" cloned subtype as outlined in the
Pharmacological Reviews (Hieble, et al. (1995) Pharmacological
Reviews 47: 267-270). The designation .alpha..sub.1a is used
throughout this application and the supporting tables and figures
to refer to this receptor subtype. At the same time, the receptor
formerly designated .alpha..sub.1a was renamed .alpha..sub.1d. The
new nomenclature is used throughout this application. Stable cell
lines expressing these receptors are described herein; however,
these cell lines were deposited with the American Type Culture
Collection (ATCC) under the old nomenclature (infra).
[0003] Benign Prostatic Hyperplasia (BPH), also called Benign
Prostatic Hypertrophy, is a progressive condition which is
characterized by a nodular enlargement of prostatic tissue
resulting in obstruction of the urethra. This results in increased
frequency of urination, nocturia, a poor urine stream, and
hesitancy or delay in starting the urine flow. Chronic consequences
of BPH can include hypertrophy of bladder smooth muscle, a
decompensated bladder, and an increased incidence of urinary tract
infection. The specific biochemical, histological, and
pharmacological properties of the prostate adenoma leading to the
bladder outlet obstruction are not yet known. However, the
development of BPH is considered to be an inescapable phenomenon
for the aging male population. BPH is observed in approximately 70%
of males over the age of 70. Currently, in the United States, the
method of choice for treating BPH is surgery (Lepor, H., Urol.
Clinics North Amer:, 17: 651, 1990). Over 400,000 prostatectomies
are performed annually (data from 1986). The limitations of surgery
for treating BPH include the morbidity rate of an operative
procedure in elderly men, persistence or recurrence of obstructive
and irritative symptoms, as well as the significant cost of
surgery. A medicinal alternative to surgery is clearly very
desirable.
[0004] .alpha.-Adrenergic receptors (McGrath et al., Med. Res. Rev.
9: 407-533, 1989) are specific neuroreceptor proteins located in
the peripheral and central nervous systems on tissues and organs
throughout the body. These receptors are important switches for
controlling many physiological functions and, thus, represent
important targets for drug development. In fact, many
.alpha.-adrenergic drugs have been developed over the past 40
years. Examples include clonidine, phenoxybenzamine and prazosin
(for treatment of hypertension), naphazoline (a nasal
decongestant), and apraclonidine (for treatment of glaucoma).
.alpha.-adrenergic drugs can be broken down into two distinct
classes: agonists (e.g., clonidine and naphazoline), which mimic
the receptor activation properties of the endogenous
neurotransmitter norepinephrine, and antagonists (e.g.,
phenoxybenzamine and prazosin), which act to block the effects of
norepinephrine. Many of these drugs are effective, but also produce
unwanted side effects (e.g., clonidine produces dry mouth and
sedation in addition to its antihypertensive effects).
[0005] During the past 15 years, a more precise understanding of
.alpha.-adrenergic receptors and their drugs has evolved through
increased scientific scrutiny. Prior to 1977, only one
.alpha.-adrenergic receptor was known to exist. Between 1977 and
1988, it was accepted by the scientific community that at least two
.alpha.-adrenergic receptors, .alpha..sub.1 and .alpha..sub.2,
existed in the central and peripheral nervous systems. Since 1988,
new techniques in molecular biology have led to the identification
of at least six .alpha.-adrenergic receptors which exist throughout
the central and peripheral nervous systems: .alpha..sub.1a (new
nomenclature), .alpha..sub.1b, .alpha..sub.1d (new nomenclature),
.alpha..sub.2a, .alpha..sub.2b and .alpha..sub.2c (Bylund, D. B.,
FASEB J. 6: 832, 1992). In many cases, it is not known precisely
which physiological responses in the body are controlled by each of
these receptors. In addition, current .alpha.-adrenergic drugs are
not selective for any particular .alpha.-adrenergic receptor. Many
of these drugs produce untoward side effects that may be attributed
to their poor .alpha.-adrenergic receptor selectivity.
[0006] Since the mid 1970's, nonselective .alpha.-antagonists have
been prescribed to treat BPH. In 1976, M. Caine et al. (Brit. J.
Urol. 48: 255, 1976) reported that the nonselective
.alpha.-antagonist phenoxybenzamine was useful in relieving the
symptoms of BPH. This drug may produce its effects by interacting
with .alpha.-receptors located on the prostate. However, this drug
also produces significant side effects such as dizziness and
asthenia, which severely limit its use in treating patients on a
chronic basis. More recently, the .alpha.-adrenergic antagonists
prazosin and terazosin have also been found to be useful for
treating BPH. However, these drugs also produce untoward side
effects. It has recently been discovered that the .alpha..sub.1a
receptor is responsible for mediating the contraction of human
prostate smooth muscle (Gluchowski, C. et al., WO 94/10989, 1994;
Forray, C. et al., Mol. Pharmacol. 45: 703, 1994). This discovery
indicates that the .alpha..sub.1a antagonists may be effective
agents for the treatment of BPH with decreased side effects.
Further studies have indicated that the .alpha..sub.1a receptor may
also be present in other lower urinary tract tissues, such as
urethral smooth muscle (Ford et al., Br. J. Pharmacol. 114: 24P,
1995).
[0007] This invention is directed to morpholinone and morpholine
derivatives which are selective antagonists for cloned human
.alpha..sub.1a receptors. This invention is also related to uses of
these compounds for lowering intraocular pressure (Zhan, et al.,
Ophthalmol. Vis. Sci. 34: Abst. #1133, 928, 1993), inhibiting
cholesterol synthesis (D'Eletto and Javitt, J. Cardiovascular
Pharmacol. 13: (Suppl. 2) S1-S4, 1989), benign prostatic
hyperplasia, impotency (Milne and Wyllie, EP 0 459 666 A2, 1991),
sympathetically mediated pain (Campbell, WO 92/14453, 1992),
cardiac arrhythmia (Spiers, et al., J. Cardiovascular Pharmacol.
16: 824-830, 1990), migraine (K. A. Vatz, Headache 37: 107-108,
1997) and for the treatment of any disease where antagonism of the
.alpha..sub.1a receptor may be useful.
SUMMARY OF THE INVENTION
[0008] This invention is directed to a compound having the
structure: 1
[0009] where W is O, S, or NR.sub.8; wherein R.sub.8 is
independently H, straight chained or branched C.sub.1-C.sub.7
alkyl, straight chained or branched C.sub.2-C.sub.7 alkenyl or
alkynyl, C.sub.3-C.sub.7 cycloalkyl, or C.sub.5-C.sub.7
cycloalkenyl;
[0010] where Y is independently O or S;
[0011] where R.sub.2 is aryl or heteroaryl; wherein the aryl or
heteroaryl may be substituted with one or more of F; Cl; Br; I;
--CN; --NO.sub.2; --N(R.sub.8).sub.2; --SO.sub.2R.sub.8;
--(CH.sub.2).sub.nC(Y)R.sub.8; --(CH.sub.2).sub.nYR.sub.8;
--(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl; or
C.sub.5-C.sub.7 cycloalkenyl; and wherein n independently is an
integer from 0 to 7 inclusive;
[0012] where R.sub.3 is independently H; straight chained or
branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl, or
polyfluoroalkyl;
[0013] where R.sub.4 is H, --(CH.sub.2).sub.tYR.sub.8,
--(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2,
--(CH.sub.2).sub.tC(Y)R.sub.8, --(CH.sub.2).sub.tCO.sub.2R.sub.8,
--(CH.sub.2).sub.tN(R.sub.8).sub.2, --(CH.sub.2).sub.tCN,
--C(Y)R.sub.8, --C(Y)N(R.sub.8).sub.2, --CO.sub.2R.sub.8, straight
chained or branched C.sub.1-C.sub.7 alkyl, straight chained or
branched C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7
cycloalkyl, C.sub.5-C.sub.7 cycloalkenyl, or phenyl or benzyl;
wherein the phenyl or benzyl may be substituted with one or more of
F; Cl; Br; I; --CN; --NO.sub.2; --N(R.sub.8).sub.2;
--SO.sub.2R.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8- ; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl; or
C.sub.5-C.sub.7 cycloalkenyl; and wherein t independently is an
integer from 1 to 4 inclusive;
[0014] where R.sub.5 is H, --(CH.sub.2).sub.tYR.sub.8,
--(CH.sub.2)C(Y)N(R.sub.8).sub.2, --(CH.sub.2).sub.tC(Y)R.sub.8,
--(CH.sub.2).sub.tCO.sub.2R.sub.8,
--(CH.sub.2).sub.tN(R.sub.8).sub.2, --(CH.sub.2).sub.tCN, straight
chained or branched C.sub.1-C.sub.7 alkyl, straight chained or
branched C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7
cycloalkyl, C.sub.5-C.sub.7 cycloalkenyl, or phenyl or benzyl;
wherein the phenyl or benzyl may be substituted with one or more of
F; Cl; Br; I; --CN; --NO.sub.2; --N(R.sub.8).sub.2;
--SO.sub.2R.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8S;
--(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8- ; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl; or
C.sub.5-C.sub.7 cycloalkenyl;
[0015] where R.sub.6 is H, --(CH.sub.2).sub.tYR.sub.8,
--(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2,
--(CH.sub.2).sub.tC(Y)R.sub.8, --(CH.sub.2).sub.tCO.sub.2R.sub.8,
--(CH.sub.2).sub.tN(R.sub.8).sub.2, --(CH.sub.2).sub.tCN,
--C(Y)R.sub.8, --C(Y)N(R.sub.8).sub.2, --CO.sub.2R.sub.8, straight
chained or branched C.sub.1-C.sub.7 alkyl, straight chained or
branched C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7
cycloalkyl, C.sub.5-C.sub.7 cycloalkenyl, or phenyl or benzyl;
wherein the phenyl or benzyl may be substituted with one or more of
F; Cl; Br; I; --CN; --NO.sub.2; --N(R.sub.8).sub.2;
--SO.sub.2R.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8- ; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl; or
C.sub.5-C.sub.7 cycloalkenyl;
[0016] where R.sub.7 is H, --(CH.sub.2).sub.tYR.sub.8,
--(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2,
--(CH.sub.2).sub.tC(Y)R.sub.8, --(CH.sub.2).sub.tCO.sub.2R.sub.8,
--(CH.sub.2)N(R.sub.8).sub.2, --(CH.sub.2).sub.tCN, straight
chained or branched C.sub.1-C.sub.7 alkyl, straight chained or
branched C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7
cycloalkyl, C.sub.5-C.sub.7 cycloalkenyl, or phenyl or benzyl;
wherein the phenyl orbenzyl may be substituted with one or more of
F; Cl; Br; I; --CN; --NO.sub.2; --N(R.sub.8).sub.2;
--SO.sub.2R.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8- ; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl; or
C.sub.5-C.sub.7 cycloalkenyl;
[0017] where q is an integer from 0 to 4 inclusive;
[0018] where each R.sub.8, n, and t independently is as defined
above;
[0019] where R.sub.1 is 2
[0020] wherein each R.sub.9 is H; straight chained or branched
C.sub.1-C.sub.7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl,
monofluoroalkyl, or polyfluoroalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, or polyfluorocycloalkyl; C.sub.5-C.sub.7
cycloalkenyl; or aryl or heteroaryl, wherein the aryl or heteroaryl
may be substituted with one or more of F; Cl; Br; I;
--(CH.sub.2).sub.nYR.sub- .8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8; --CN; --NO.sub.2;
--N(R.sub.8).sub.2; --SO.sub.2R.sub.8; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, or polyfluoroalkyl;
straight chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl, or
polyfluorocycloalkyl; or C.sub.5-C.sub.7 cycloalkenyl;
[0021] wherein each R.sub.10 is H; F; --OH;
--(CH.sub.2).sub.nC(Y)R.sub.8; --(CH.sub.2).sub.nYR.sub.8;
--(CH.sub.2).sub.nC((Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8; --CN; --NO.sub.2;
--N(R.sub.8).sub.2; aryl or heteroaryl; straight chained or
branched C.sub.1-C.sub.7 alkyl, hydroxyalkyl, aminoalkyl,
carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl, or polyfluoroalkyl;
straight chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl, or
polyfluorocycloalkyl; or C.sub.5-C.sub.7 cycloalkenyl; wherein the
alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxamidoalkyl,
alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted
with one or more aryl or heteroaryl; wherein the aryl or heteroaryl
may be substituted with one or more of F; Cl; Br; I;
--(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8; --CN; --NO.sub.2;
--N(R.sub.8).sub.2; --SO.sub.2R.sub.8; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, or polyfluoroalkyl;
straight chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl, or
polyfluorocycloalkyl; or C.sub.5-C.sub.7 cycloalkenyl;
[0022] wherein each R.sub.11 is independently H,
--(CH.sub.2).sub.tYR.sub.- 8,
--(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2,
--(CH.sub.2).sub.tC(Y)R.sub.8, --(CH.sub.2).sub.tCO.sub.2R.sub.8,
--(CH.sub.2).sub.tN(R).sub.2, --(CH.sub.2).sub.tCN, --C(Y)R.sub.8,
--C(Y)N(R.sub.8).sub.2, --CO.sub.2R.sub.8, straight chained or
branched C.sub.1-C.sub.7 alkyl, straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7 cycloalkyl, or
C.sub.5-C.sub.7 cycloalkenyl;
[0023] wherein each R.sub.12 is independently H,
--(CH.sub.2).sub.tYR.sub.- 8,
--(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2,
--(CH.sub.2).sub.tC(Y)R.sub.8, --(CH.sub.2).sub.tCO.sub.2R.sub.8,
--(CH.sub.2).sub.tN(R.sub.8).sub.2, --(CH.sub.2).sub.tCN, straight
chained or branched C.sub.1-C.sub.7 alkyl, straight chained or
branched C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7
cycloalkyl or C.sub.5-C.sub.7 cycloalkenyl;
[0024] wherein R.sub.13 is H, C.sub.1-C.sub.7 alkyl, --C(O)R.sub.2,
aryl, heteroaryl, C.sub.1-C.sub.7 alkyl substituted with one or two
aryl, or C.sub.1-C.sub.7 alkyl substituted with one or two
heteroaryl; wherein the aryl or heteroaryl may be substituted with
one or more of F; Cl; Br; .I; --CN; --NO.sub.2; --N(R.sub.8).sub.2;
--SO.sub.2R.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8- ; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl, or
carboxamidoalkyl; straight chained or branched C.sub.2-C.sub.7
aminoalkyl, alkenyl, or alkynyl; C.sub.3-C.sub.7 cycloalkyl; or
C.sub.5-C.sub.7 cycloalkenyl;
[0025] wherein R.sub.14 is H, straight chained or branched
C.sub.1-C.sub.7 akyl;
[0026] wherein Z is O, S, NR.sub.14, CO, CH.sub.2, 3
[0027] wherein Y.sub.1, Y.sub.2, and Y.sub.3 independently are H;
F; Cl; Br; I; --CN; --NO.sub.2; --N(R.sub.8).sub.2;
--SO.sub.2R.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8- ; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl; or
C.sub.5-C.sub.7 cycloalkenyl;
[0028] wherein each m is independently 1 or 2;
[0029] wherein each p is independently an integer from 0 to 2
inclusive;
[0030] wherein J is 4
[0031] or C.sub.2-C.sub.7 alkenyl;
[0032] wherein each R.sub.15 is independently H,
--(CH.sub.2).sub.tYR.sub.- 8,
--(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2,
--(CH.sub.2).sub.tC(Y)R.sub.8, --(CH.sub.2).sub.tCO.sub.2R.sub.8,
--(CH.sub.2).sub.tN(R.sub.8).sub.2, --(CH.sub.2).sub.tCN,
--C(Y)R.sub.8, --C(Y)N(R.sub.8).sub.2, --CO.sub.2R.sub.8, straight
chained or branched C.sub.1-C.sub.7 alkyl, straight chained or
branched C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7
cycloalkyl, or C.sub.1-C.sub.7 cycloalkenyl;
[0033] wherein each R.sub.16 is independently H,
--(CH.sub.2).sub.tYR.sub.- 8,
--(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2,
--(CH.sub.2).sub.tC(Y)R.sub.8, --(CH.sub.2).sub.tCO.sub.2R.sub.8,
--(CH.sub.2).sub.tN(R.sub.8).sub.2, --(CH.sub.2).sub.tCN, straight
chained or branched C.sub.1-C.sub.7 alkyl, straight chained or
branched C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7
cycloalkyl, or C.sub.5-C.sub.7 cycloalkenyl;
[0034] wherein each R.sub.17 is independently H; F;
--(CH.sub.2).sub.tYR.sub.8; --(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.tC(Y)R.sub.8; --(CH.sub.2).sub.tCO.sub.2R.sub.8;
--(CH.sub.2).sub.tN(R.sub.8).sub.2; --(CH.sub.2).sub.tCN;
--C(Y)R.sub.8; --C(Y)N(R.sub.8).sub.2; --CO.sub.2R.sub.8; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7
cycloalkyl; or C.sub.5-C.sub.7 cycloalkenyl;
[0035] wherein each R.sub.18 is independently H; F;
--(CH.sub.2).sub.tYR.sub.8; --(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.tC(Y)R.sub.8; --(CH.sub.2).sub.tCO.sub.2R.sub.8;
--(CH.sub.2).sub.tN(R.sub.8).sub.2; --(CH.sub.2).sub.tCN; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7
cycloalkyl; or C.sub.5-C.sub.7 cycloalkenyl;
[0036] wherein L is S, O, or N(R.sub.8);
[0037] wherein u is an integer from 0 to 1 inclusive;
[0038] or a pharmaceutically acceptable salt thereof.
[0039] This invention provides for a pharmaceutical composition
comprising a therapeutically effective amount of any one of the
compounds described herein and a pharmaceutically acceptable
carrier.
[0040] This invention provides for a method of treating a subject
suffering from benign prostatic hyperplasia which comprises
administering to the subject an amount of any one of the compounds
described herein effective to treat benign prostatic
hyperplasia.
[0041] This invention provides for a method of treating a subject
suffering from high intraocular pressure which comprises
administering to the subject an amount of any one of the compounds
described herein effective to lower intraocular pressure.
[0042] This invention provides for a method of treating a subject
suffering from a disorder associated with high cholesterol which
comprises administering to the subject an amount of any one of the
compounds described herein effective to inhibit cholesterol
synthesis.
[0043] This invention provides for a method of treating a subject
suffering from cardiac arrhythmia which comprises administering to
the subject an amount of any one of the compounds described herein
effective to treat cardiac arrhythmia.
[0044] This invention provides for a method of treating a subject
suffering from impotency which comprises administering to the
subject an amount of any one of the compounds described herein
effective to treat impotency.
[0045] This invention provides for a method of treating a subject
suffering from sympathetically mediated pain which comprises
administering to the subject an amount of any one of the compounds
described herein effective to treat sympathetically mediated
pain.
[0046] This invention provides for a method of treating a subject
suffering from migraine which comprises administering to the
subject an amount of any one of the compounds described herein
effective to treat migraine.
[0047] This invention provides for a method of treating a disease
which is susceptible to treatment by antagonism of the
.alpha..sub.1a receptor which comprises administering to the
subject an amount of any one of the compounds described herein
effective to treat the disease.
[0048] This invention provides for a method of treating a subject
suffering from benign prostatic hyperplasia which comprises
administering to the subject an amount of any one of the compounds
described herein in combination with a 5-alpha reductase inhibitor
effective to treat benign prostatic hyperplasia.
[0049] This invention provides for a pharmaceutical composition
comprising a therapeutically effective amount of any one of the
compounds described herein in combination with a therapeutically
effective amount of finasteride and a pharmaceutically acceptable
carrier.
[0050] This invention provides for a method of relaxing lower
urinary tract tissue which comprises contacting the lower urinary
tract tissue with an amount of any one of the compounds described
herein effective to relax lower urinary tract tissue.
[0051] This invention provides for a method of relaxing lower
urinary tract tissue in a subject which comprises administering to
the subject an amount of any one of the compounds described herein
effective to relax lower urinary tract tissue.
[0052] This invention provides for a pharmaceutical composition
made by combining a therapeutically effective amount of any one of
the compounds described herein and a pharmaceutically acceptable
carrier.
[0053] This invention provides for a pharmaceutical composition
made by combining a therapeutically effective amount of any one of
the compounds described herein with a therapeutically effective
amount of finasteride and a pharmaceutically acceptable
carrier.
[0054] This invention provides for a process for making a
pharmaceutical composition comprising combining a therapeutically
effective amount of any one of the compounds described herein and a
pharmaceutically acceptable carrier.
[0055] This invention provides for a process for making a
pharmaceutical composition comprising combining a therapeutically
effective amount of any one of the compounds described herein with
a therapeutically effective amount of finasteride and a
pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE FIGURES
[0056] FIGS. 1A-1F
[0057] FIGS. 1A-1F show the structures of the compounds described
herein in the Examples.
DETAILED DESCRIPTION OF THE INVENTION
[0058] This invention provides for a compound having the structure:
5
[0059] where W is O, S, or NR.sub.8; wherein R.sub.8 is
independently H, straight chained or branched C.sub.1-C.sub.7
alkyl, straight chained or branched C.sub.2-C.sub.7 alkenyl or
alkynyl, C.sub.3-C.sub.7 cycloalkyl, or C.sub.5-C.sub.7
cycloalkenyl;
[0060] where Y is independently O or S;
[0061] where R.sub.2 is aryl or heteroaryl; wherein the aryl or
heteroaryl may be substituted with one or more of F; Cl; Br; I;
--CN; --NO.sub.2; --N(R.sub.8).sub.2; --SO.sub.2R.sub.8;
--(CH.sub.2).sub.nC(Y)R.sub.8; --(CH.sub.2).sub.nYR.sub.8;
--(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl; or
C.sub.5-C.sub.7 cycloalkenyl; and wherein n independently is an
integer from 0 to 7 inclusive;
[0062] where R.sub.3 is independently H; straight chained or
branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl, or
polyfluoroalkyl;
[0063] where R.sub.4 is H, --(CH.sub.2).sub.tYR.sub.8,
--(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2,
--(CH.sub.2).sub.tC(Y)R.sub.8, --(CH.sub.2).sub.tCO.sub.2R.sub.8,
--(CH.sub.2).sub.tN(R.sub.8).sub.2, --(CH.sub.2).sub.tCN,
--C(Y)R.sub.8, --C(Y)N(R.sub.8).sub.2, --CO.sub.2R.sub.8, straight
chained or branched C.sub.1-C.sub.7 alkyl, straight chained or
branched C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7
cycloalkyl, C.sub.5-C.sub.7 cycloalkenyl, or phenyl or benzyl;
wherein the phenyl or benzyl may be substituted with one or more of
F; Cl; Br; I; --CN; --NO.sub.2; --N(R.sub.8).sub.2;
--SO.sub.2R.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8- ; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl; or
C.sub.5-C.sub.7 cycloalkenyl; and wherein t independently is an
integer from 1 to 4 inclusive;
[0064] where R.sub.5 is H, --(CH.sub.2).sub.tYR.sub.8,
--(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2,
--(CH.sub.2).sub.tC(Y)R.sub.8, --(CH.sub.2).sub.tCO.sub.2R.sub.8,
--(CH.sub.2).sub.tN(R.sub.8).sub.2, --(CH.sub.2).sub.tCN, straight
chained or branched C.sub.1-C.sub.7 alkyl, straight chained or
branched C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7
cycloalkyl, C.sub.5-C.sub.7 cycloalkenyl, or phenyl or benzyl;
wherein the phenyl or benzyl may be substituted with one or more of
F; Cl; Br; I; --CN; --NO.sub.2; --N(R.sub.8).sub.2;
--SO.sub.2R.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8- ; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl; or
C.sub.5-C.sub.7 cycloalkenyl;
[0065] where R.sub.6 is H, --(CH.sub.2).sub.tYR.sub.8,
--(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2,
--(CH.sub.2).sub.tC(Y)R.sub.8, --(CH.sub.2).sub.tCO.sub.2R.sub.8,
--(CH.sub.2).sub.tN(R.sub.8).sub.2, --(CH.sub.2).sub.tCN,
--C(Y)R.sub.8, --C(Y)N(R.sub.8).sub.2, CO.sub.2R.sub.8, straight
chained or branched C.sub.1-C.sub.7 alkyl, straight chained or
branched C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7
cycloalkyl, C.sub.5-C.sub.7 cycloalkenyl, or phenyl or benzyl;
wherein the phenyl or benzyl may be substituted with one or more of
F; Cl; Br; I; --CN; --NO.sub.2; --N(R.sub.8).sub.2;
--SO.sub.2R.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8- ; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl; or
C.sub.5-C.sub.7 cycloalkenyl;
[0066] where R.sub.7 is H, --(CH.sub.2).sub.tYR.sub.8,
(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2,
--(CH.sub.2).sub.tC(Y)R.sub.8, --(CH.sub.2).sub.tCO.sub.2R.sub.8,
--(CH.sub.2).sub.tN(R.sub.8).sub.2, --(CH.sub.2).sub.tCN, straight
chained or branched C.sub.1-C.sub.7 alkyl, straight chained or
branched C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7
cycloalkyl, C.sub.5-C.sub.7 cycloalkenyl, or phenyl or benzyl;
wherein the phenyl or benzyl may be substituted with one or more of
F; Cl; Br; I; --CN; --NO.sub.2; --N(R.sub.8).sub.2;
--SO.sub.2R.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC
(Y)N(R.sub.8).sub.2; --(CH.sub.2)CO.sub.2R.sub.8; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7
cycloalkyl; or C.sub.5-C.sub.7 cycloalkenyl;
[0067] where q is an integer from 0 to 4 inclusive;
[0068] where each R.sub.8, n, and t independently is as defined
above;
[0069] where R.sub.1 is 6
[0070] wherein each R.sub.9 is H; straight chained or branched
C.sub.1-C.sub.7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl,
monofluoroalkyl, or polyfluoroalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, or polyfluorocycloalkyl; C.sub.5-C.sub.7
cycloalkenyl; or aryl or heteroaryl, wherein the aryl or heteroaryl
may be substituted with one or more of F; Cl; Br; I;
--(CH.sub.2).sub.nYR.sub- .8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8; --CN; --NO.sub.2;
--N(R.sub.8).sub.2; --SO.sub.2R.sub.8; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, or polyfluoroalkyl;
straight chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl, or
polyfluorocycloalkyl; or C.sub.5-C.sub.7 cycloalkenyl;
[0071] wherein each R.sub.10 is H; F; --OH;
--(CH.sub.2).sub.nC(Y)R.sub.8; --(CH.sub.2).sub.nYR.sub.8;
--(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8; --CN; --NO.sub.2;
--N(R.sub.8).sub.2; aryl or heteroaryl; straight chained or
branched C.sub.1-C.sub.7 alkyl, hydroxyalkyl, aminoalkyl,
carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl, or polyfluoroalkyl;
straight chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl, or
polyfluorocycloalkyl; or C.sub.5-C.sub.7 cycloalkenyl; wherein the
alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxamidoalkyl,
alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted
with one or more aryl or heteroaryl; wherein the aryl or heteroaryl
may be substituted with one or more of F; Cl; Br; I;
--(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8; --CN; --NO.sub.2;
--N(R.sub.8).sub.2; --SO.sub.2R.sub.8; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, or polyfluoroalkyl;
straight chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl, or
polyfluorocycloalkyl; or C.sub.5-C.sub.7 cycloalkenyl;
[0072] wherein each R.sub.11 is independently H,
--(CH.sub.2).sub.tYR.sub.- 8,
--(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2,
--(CH.sub.2).sub.tC(Y)R.sub.8, --(CH.sub.2).sub.tCO.sub.2R.sub.8,
--(CH.sub.2).sub.tN(R.sub.8).sub.2, --(CH.sub.2).sub.tCN,
--C(Y)R.sub.8, --C(Y)N(R.sub.8).sub.2, --CO.sub.2R.sub.8, straight
chained or branched C.sub.1-C.sub.7 alkyl, straight chained or
branched C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7
cycloalkyl, or C.sub.5-C.sub.7 cycloalkenyl;
[0073] wherein each R.sub.12 is independently H,
--(CH.sub.2).sub.tYR.sub.- 8,
--(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2,
--(CH.sub.2).sub.tC(Y)R.sub.8, --(CH.sub.2).sub.tCO.sub.2R.sub.8,
--(CH.sub.2).sub.tN(R.sub.8).sub.2, --(CH.sub.2).sub.tCN, straight
chained or branched C.sub.1-C.sub.7 alkyl, straight chained or
branched C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7
cycloalkyl or C.sub.5-C.sub.7 cycloalkenyl;
[0074] wherein R.sub.13 is H, C.sub.1-C.sub.7 alkyl, --C(O)R.sub.2,
aryl, heteroaryl, C.sub.1-C.sub.7 alkyl substituted with one or two
aryl, or C.sub.1-C.sub.7 alkyl substituted with one or two
heteroaryl; wherein the aryl or heteroaryl may be substituted with
one or more of F; Cl; Br; I; --CN; --NO.sub.2; --N(R.sub.8).sub.2;
--SO.sub.2R.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8- ; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl, or
carboxamidoalkyl; straight chained or branched C.sub.2-C.sub.7
aminoalkyl, alkenyl, or alkynyl; C.sub.3-C.sub.7 cycloalkyl; or
C.sub.5-C.sub.7 cycloalkenyl;
[0075] wherein R.sub.14 is H, straight chained or branched
C.sub.1-C.sub.7 akyl;
[0076] wherein Z is O, S, NR.sub.14, CO, CH.sub.2, 7
[0077] wherein Y.sub.1, Y.sub.2, and Y.sub.3 independently are H;
F; Cl; Br; I; --CN; --NO.sub.2; --N(R.sub.8).sub.2;
--SO.sub.2R.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8- ; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl; or
C.sub.5-C.sub.7 cycloalkenyl;
[0078] wherein each m is independently 1 or 2;
[0079] wherein each p is independently an integer from 0 to 2
inclusive;
[0080] wherein J is 8
[0081] or C.sub.2-C.sub.7 alkenyl;
[0082] wherein each R.sub.15 is independently H,
--(CH.sub.2).sub.tYR.sub.- 8,
--(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2,
--(CH.sub.2).sub.tC(Y)R.sub.8; --(CH.sub.2).sub.tCO.sub.2R.sub.8,
--(CH.sub.2).sub.tN(R.sub.8).sub.2, --(CH.sub.2).sub.tCN,
--C(Y)R.sub.8, --C(Y)N(R.sub.8).sub.2, --CO.sub.2R.sub.8, straight
chained or branched C.sub.1-C.sub.7 alkyl, straight chained or
branched C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7
cycloalkyl, or C.sub.5-C.sub.7 cycloalkenyl;
[0083] wherein each R.sub.16 is independently H,
--(CH.sub.2).sub.tYR.sub.- 8,
--(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2,
--(CH.sub.2).sub.tC(Y)R.sub.8, --(CH.sub.2).sub.tCO.sub.2R.sub.8,
--(CH.sub.2).sub.tN(R.sub.8).sub.2, --(CH.sub.2).sub.tCN, straight
chained or branched C.sub.1-C.sub.7 alkyl, straight chained or
branched C.sub.2-C.sub.7 alkenyl or alkynyl, C.sub.3-C.sub.7
cycloalkyl, or C.sub.5-C.sub.7 cycloalkenyl;
[0084] wherein each R.sub.17 is independently H; F;
--(CH.sub.2).sub.tYR.sub.8; --(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.tC(Y)R.sub.8; --(CH.sub.2).sub.tCO.sub.2R.sub.8;
--(CH.sub.2).sub.tN(R.sub.8).sub.2; --(CH.sub.2).sub.tCN;
--C(Y)R.sub.8; --C(Y)N(R.sub.8).sub.2; --CO.sub.2R.sub.8; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7
cycloalkyl; or C.sub.5-C.sub.7 cycloalkenyl;
[0085] wherein each R.sub.18 is independently H; F;
--(CH.sub.2).sub.tYR.sub.8; --(CH.sub.2).sub.tC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.tC(Y)R.sub.8; --(CH.sub.2).sub.tCO.sub.2R.sub.8;
--(CH.sub.2).sub.tN(R.sub.8).sub.2; --(CH.sub.2).sub.tCN; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7
cycloalkyl; or C.sub.5-C.sub.7 cycloalkenyl;
[0086] wherein L is S, O, or N(R.sub.8);
[0087] wherein u is an integer from 0 to 1 inclusive;
[0088] or a pharmaceutically acceptable salt thereof.
[0089] The invention also provides for the (-) and (+) enantiomers
of all compounds of the subject application described herein.
[0090] The invention further provides for the cis and trans
enantiomers of all of the compounds of the subject application
described herein. It is noted herein that the terms "cis" and
"trans" correspond to relative stereochemistry, as determined, for
example, by NOE (Nuclear Overhauser Effect) experiments.
[0091] The compounds of the present invention are preferably at
least 80% pure, more preferably at least 90% pure, and most
preferably at least 95% pure.
[0092] In the present invention, the term "aryl" is used to include
phenyl, benzyl, benzoyl, or naphthyl; and the term "heteroaryl" is
used to include pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyridyl,
imidazolyl, indolyl, aminophenyl, benzamidyl, benzimidazolyl,
benzfurazanyl, benzfuranyl,or quinolyl.
[0093] The compounds of this invention exhibit greater affinity,
preferably at least ten-fold greater affinity, for the human
.alpha..sub.1a receptor over the human .alpha..sub.1b or human
.alpha..sub.1d receptors.
[0094] In one embodiment, W is O.
[0095] In another embodiment, J is 9
[0096] In another embodiment, R.sub.1 is 10
[0097] In another embodiment, R.sub.9 is aryl or heteroaryl,
wherein the aryl or heteroaryl may be substituted with one or more
of F; Cl; Br;. I; --(CH.sub.2).sub.nYR.sub.8;
--(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
(CH.sub.2).sub.nCO.sub.2R.sub.8; --CN; --NO.sub.2;
--N(R.sub.8).sub.2; --SO.sub.2R.sub.8; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, or polyfluoroalkyl; and
R.sub.10 is H; --CN; --OH; --CO.sub.2R.sub.8; aryl or heteroaryl;
wherein the aryl or heteroaryl may be substituted with one or more
of F; Cl; Br; I; --(CH.sub.2).sub.nYR.sub.8;
--(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8- ; --CN; --NO.sub.2;
--N(R.sub.8).sub.2; --SO.sub.2R.sub.8; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, or polyfluoroalkyl.
[0098] In another embodiment of the invention, the compound has the
structure: 11
[0099] wherein R.sub.2 is phenyl; wherein the phenyl may be
substituted with one or more of F; Cl; Br; I; --CN; --NO.sub.2;
--N(R.sub.8).sub.2; --SO.sub.2R.sub.8;
--(CH.sub.2).sub.nC(Y)R.sub.8; --(CH.sub.2).sub.nYR.su- b.8;
--(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.s- ub.8; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, or polyfluoroalkyl.
[0100] In another embodiment, J is 12
[0101] In another embodiment, R.sub.1 is 13
[0102] In another embodiment, R.sub.9 is phenyl or pyridyl, wherein
the phenyl or pyridyl may be substituted with one or more of F; Cl;
Br; I; --(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8- ; --CN; --NO.sub.2;
--N(R.sub.8).sub.2; --SO.sub.2R.sub.8; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, or polyfluoroalkyl;
[0103] R.sub.10 is H, --CN, --OH, --CO.sub.2R.sub.8, or phenyl;
wherein the phenyl may be substituted with one or more of F; Cl;
Br; I; --(CH.sub.2).sub.nYR.sub.8; --(CH.sub.2).sub.nC(Y)R.sub.8;
--(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.sub.8- , --CN; --NO.sub.2;
--N(R.sub.8).sub.2; --SO.sub.2R.sub.8; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, or polyfluoroalkyl; and
[0104] R.sub.13 is phenyl; wherein the phenyl may be substituted
with one or more of F; Cl; Br; I; --CN; --NO.sub.2;
--N(R.sub.8).sub.2; --SO.sub.2R.sub.8;
--(CH.sub.2).sub.nC(Y)R.sub.8; --(CH.sub.2).sub.nYR.su- b.8;
--(CH.sub.2).sub.nC(Y)N(R.sub.8).sub.2;
--(CH.sub.2).sub.nCO.sub.2R.s- ub.8; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl, or
carboxamidoalkyl; straight chained or branched C.sub.2-C.sub.7
aminoalkyl, alkenyl, or alkynyl; C.sub.3-C.sub.7 cycloalkyl; or
C.sub.5-C.sub.7 cycloalkenyl.
[0105] In another preferred embodiment, the R.sub.4 is H, alkyl,
cycloalkyl, --CO.sub.2R.sub.3, or --C(Y)N(R.sub.3).sub.2; and
R.sub.10 is H, F, C.sub.1-C.sub.7 alkyl, C.sub.1-C.sub.7 alkoxy, or
OH.
[0106] The invention provides for a pharmaceutical composition
comprising a therapeutically effective amount of any of the
compounds described above and a pharmaceutically acceptable
carrier. In the subject invention, a "therapeutically effective
amount" is any amount of a compound which, when administered to a
subject suffering from a disease against which the compounds are
effective, causes reduction, remission, or regression of the
disease.
[0107] In one embodiment, the therapeutically effective amount is
an amount from about 0.01 mg per subject per day to about 800 mg
per subject per day, preferably from about 0.01 mg per subject per
day to about 500 mg per subject per day, more preferably from about
0.01 mg per subject per day to about 250 mg per subject per day,
more preferably from about 0.1 mg per subject per day to about 60
mg per subject per day and most preferably from about 1 mg per
subject per day to about 20 mg per subject per day. In the practice
of this invention, the "pharmaceutically acceptable carrier" is any
physiological carrier known to those of ordinary skill in the art
useful in formulating pharmaceutical compositions.
[0108] In one embodiment the pharmaceutical carrier may be a liquid
and the pharmaceutical composition would be in the form of a
solution. In another embodiment, the pharmaceutically acceptable
carrier is a solid and the composition is in the form of a powder
or tablet. In a further embodiment, the pharmaceutical carrier is a
gel and the composition is in the form of a suppository or cream.
In a further embodiment the compound may be formulated as a part of
a pharmaceutically acceptable transdermal patch.
[0109] A solid carrier can include one or more substances which may
also act as flavoring agents, lubricants, solubilizers, suspending
agents, fillers, glidants, compression aids, binders or
tablet-disintegrating agents; it can also be an encapsulating
material. In powders, the carrier is a finely divided solid which
is in admixture with the finely divided active ingredient. In
tablets, the active ingredient is mixed with a carrier having the
necessary compression properties in suitable proportions and
compacted in the shape and size desired. The powders and tablets
preferably contain up to 99% of the active ingredient. Suitable
solid carriers include, for example, calcium phosphate, magnesium
stearate, talc, sugars, lactose, dextrin, starch, gelatin,
cellulose, polyvinylpyrrolidine, low melting waxes, and ion
exchange resins.
[0110] Liquid carriers are used in preparing solutions,
suspensions, emulsions, syrups, elixirs and pressurized
compositions. The active ingredient can be dissolved or suspended
in a pharmaceutically acceptable liquid carrier such as water, an
organic solvent, a mixture of both or pharmaceutically acceptable
oils or fats. The liquid carrier can contain other suitable
pharmaceutical additives such as solubilizers, emulsifiers,
buffers, preservatives, sweeteners, flavoring agents, suspending
agents, thickening agents, colors, viscosity regulators,
stabilizers or osmo-regulators. Suitable examples of liquid
carriers for oral and parenteral administration include water
(partially containing additives as above, e.g. cellulose
derivatives, preferably sodium carboxymethyl cellulose solution),
alcohols (including monohydric alcohols and polyhydric alcohols,
e.g. glycols) and their derivatives, and oils (e.g. fractionated
coconut oil and arachis oil). For parenteral administration, the
carrier can also be an oily ester such as ethyl oleate and
isopropyl myristate. Sterile liquid carriers are useful in sterile
liquid form compositions for parenteral administration. The liquid
carrier for pressurized compositions can be halogenated hydrocarbon
or other pharmaceutically acceptable propellent.
[0111] Liquid pharmaceutical compositions which are sterile
solutions or suspensions can be utilized by for example,
intramuscular, intrathecal, epidural, intraperitoneal or
subcutaneous injection. Sterile solutions can also be administered
intravenously. The compounds may be prepared as a sterile solid
composition which may be dissolved or suspended at the time of
administration using sterile water, saline, or other appropriate
sterile injectable medium. Carriers are intended to include
necessary and inert binders, suspending agents, lubricants,
flavorants, sweeteners, preservatives, dyes, and coatings.
[0112] The compound can be administered orally in the form of a
sterile solution or suspension containing other solutes or
suspending agents, for example, enough saline or glucose to make
the solution isotonic, bile salts, acacia, gelatin, sorbitan
monoleate, polysorbate 80 (oleate esters of sorbitol and its
anhydrides copolymerized with ethylene oxide) and the like.
[0113] The compound can also be administered orally either in
liquid or solid composition form. Compositions suitable for oral
administration include solid forms, such as pills, capsules,
granules, tablets, and powders, and liquid forms, such as
solutions, syrups, elixirs, and suspensions. Forms useful for
parenteral administration include sterile solutions, emulsions, and
suspensions.
[0114] Optimal dosages to be administered may be determined by
those skilled in the art, and will vary with the particular
compound in use, the strength of the preparation, the mode of
administration, and the advancement of the disease condition.
Additional factors depending on the particular subject being
treated will result in a need to adjust dosages, including subject
age, weight, gender, diet, and time of administration.
[0115] In another embodiment, any one of the compounds described
herein additionally does not cause a fall in blood pressure at
dosages effective to alleviate benign prostatic hyperplasia.
[0116] The invention provides a method of treating a subject
suffering from benign prostatic hyperplasia, which comprises
administering to the subject any one of the compounds described
herein effective to treat benign prostatic hyperplasia. In a
preferred embodiment, the compound of the pharmaceutical
composition additionally does not cause a fall in blood pressure at
dosages effective to alleviate benign prostatic hyperplasia. In a
preferred embodiment, the compound effects treatment of benign
prostatic hyperplasia by relaxing lower urinary tract tissue and in
particular where lower urinary tract tissue is prostatic smooth
muscle.
[0117] In the practice of this invention, the term "lower urinary
tract tissue" is used to include prostatic capsule, prostate
urethra, urethral smooth muscle, prostatic smooth muscle, and
bladderneck.
[0118] The invention further provides a method of treating a
subject suffering from elevated intraocular pressure, which
comprises administering to the subject one of the compounds
described herein effective to lower intraocular pressure.
[0119] The invention further provides a method of treating a
subject suffering from a disorder associated with elevated blood
cholesterol, which comprises administering to the subject one of
the compounds described herein effective to inhibit cholesterol
synthesis.
[0120] The invention provides a method of treating a subject
suffering from cardiac arrhythmia, which comprises administering to
the subject one of the compounds described herein effective to
treat cardiac arrhythmia.
[0121] The invention further provides a method of treating a
subject suffering from impotency, which comprises administering to
the subject one of the compounds described herein effective to
treat impotency.
[0122] The invention further provides a method of treating a
subject suffering from sympathetically mediated pain, which
comprises administering to the subject one of the compounds
described herein effective to treat sympathetically mediated
pain.
[0123] This invention provides a method of treating a subject
suffering from migraine which comprises administering to the
subject one of the compounds described herein effective to treat
migraine.
[0124] The invention also provides a method of treating a disease
which is susceptible to treatment by antagonism of the
.alpha..sub.1a receptor, which comprises administering to the
subject one of the compounds described herein effective to treat
the disease.
[0125] The invention provides a method of treating a subject
suffering from benign prostatic hyperplasia, which comprises
administering to the subject one of the compounds described herein
in combination with a 5-alpha reductase inhibitor effective to
treat benign prostatic hyperplasia. In one preferred embodiment the
5-alpha reductase inhibitor is finasteride.
[0126] This invention provides for a pharmaceutical composition
comprising a therapeutically effective amount of any one of the
compound described herein in combination with a therapeutically
effective amount of finasteride and a pharmaceutically acceptable
carrier. This invention also provides for a pharmaceutical
composition comprising any one of the compounds described herein
present in an amount from about 0.01 mg to about 800 mg and the
therapeutically effective amount of the finasteride is about 5 mg.
In one embodiment, the pharmaceutical composition is any one of the
compounds described herein present in an amount from about 0.1 mg
to about 60 mg and the therapeutically effective amount of
finasteride is about 5 mg. In another embodiment, the
pharmaceutical composition is any one of the compounds described
herein present in an amount from about 1 mg to about 20 mg and the
therapeutically effective amount of finasteride is about 5 mg.
[0127] The invention further provides a method of relaxing lower
urinary tract tissue which comprises contacting the lower urinary
tract tissue with an amount of one of the compounds described
herein effective to relax lower urinary tract tissue. In one
embodiment the lower urinary tract tissue is prostatic smooth
muscle. In one preferred embodiment, the compound additionally does
not cause a fall in blood pressure when it is effective to relax
lower urinary tract tissue.
[0128] The invention provides a method of relaxing lower urinary
tract tissue in a subject which comprises administering to the
subject an amount of one of the compounds described herein
effective to relax lower urinary tract tissue. In one embodiment
the lower urinary tract tissue is prostatic smooth muscle. In one
preferred embodiment, the compound additionally does not cause a
fall in blood pressure when it is effective to relax lower urinary
tract tissue.
[0129] This invention provides for a pharmaceutical composition
made by combining a therapeutically effective amount of any one of
the compounds described herein and a pharmaceutically acceptable
carrier.
[0130] This invention provides for a pharmaceutical composition
made by combining a therapeutically effective amount of any one of
the compounds described herein with a therapeutically effective
amount of finasteride and a pharmaceutically acceptable
carrier.
[0131] This invention provides for a process for making a
pharmaceutical composition comprising combining a therapeutically
effective amount of any one of the compounds described herein and a
pharmaceutically acceptable carrier.
[0132] This invention provides for a process for making a
pharmaceutical composition comprising combining a therapeutically
effective amount of any one of the compounds described herein with
a therapeutically effective amount of finasteride and a
pharmaceutically acceptable carrier.
[0133] Included in this invention are pharmaceutically acceptable
salts and complexes of all of the compounds described herein. The
salts include but are not limited to the following acids and bases:
inorganic acids which include hydrochloric acid, hydrobromic acid,
hydroiodic acid, sulfuric acid, and boric acid; organic acids which
include acetic acid, oxalic acid, malonic acid, succinic acid,
fumaric acid, tartaric acid, maleic acid, citric acid,
methanesulfonic acid, benzoic acid, glycolic acid, lactic acid, and
mandelic acid; inorganic bases which include ammonia; and organic
bases which include methylamine, ethylamine, hydroxyethylamine,
propylamine, dimethylamine, diethylamine, trimethylamine,
triethylamine, ethylenediamine, hydroxyethylamine, morpholine,
piperazine, and guanidine. This invention further provides for the
hydrates and polymorphs of all of the compounds described
herein.
[0134] The present invention includes within its scope prodrugs of
the compounds of this inventions. In general, such prodrugs will be
functional derivatives of the compounds of the invention which are
readily convertible in vivo into the required compound. Thus, in
the methods of treatment of the present invention, the term
"administering" shall encompass the treatment of the various
conditions described with the compound specifically disclosed or
with a compound which may not be specifically disclosed, but which
converts to the specified compound in vivo after administration to
the patient. Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for
example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier,
1985.
[0135] The present invention further includes metabolites of the
compounds of the present invention. Metabolites include active
species produced upon introduction of compounds of this invention
into the biological milieu.
[0136] One skilled in the art will readily appreciate that
appropriate biological assays will be used to determine the
therapeutic potential of the claimed compounds for the treating the
above noted disorders.
[0137] This invention will be better understood from the
Experimental Details which follow. However, one skilled in the art
will readily appreciate that the specific methods and results
discussed are merely illustrative of the invention as described
more fully in the claims which follow thereafter.
EXPERIMENTAL DETAILS
I. Synthesis of Morpholinone Examples (Schemes 1 and 2)
1. Synthesis of
3-(3,4-difluorophenyl)-5-oxo-morpholine-4-carboxylic
acid-4-nitro-phenyl ester (Scheme 1)
[0138] a. 1-Hydroxy-(3,4-difluorophenyl)-acetophenone
[0139] To a solution of KOH (56 g, 1.0 mol) in MeOH (500 mL) was
added 3,4-difluoroacetophenone (15.6 g, 0.1 mol) dropwise over 15
min at 0.degree. C. Phenyliodosodiacetate (64.4 g, 0.2 mol) was
added in small portions over a 20 min period, and the resulting
yellow-orange solution was stirred overnight at room temperature.
The solvent was removed in vacuo to obtain a yellow-orange gum. The
residue was dissolved in 100 mL of water and 100 mL of brine and
was thoroughly extracted with ethyl acetate (3.times.150 mL). The
organic layer was dried over Na.sub.2SO.sub.4 and was decanted. The
solvent was removed in vacuo to obtain 31.0 g of the acetal as
thick yellow oil. It was dissolved in 200 mL of acetone and about
10 drops of concentrated sulfuric acid. The reaction mixture was
stirred at room temperature for 2 hours until TLC analysis showed
complete consumption of the starting material. The solvent was
removed in vacuo and the solid that was obtained was first basified
by adding saturated NaHCO.sub.3 solution and then it was extracted
with ethyl acetate (300 mL). The organic layer was separated and
washed with brine. The organic layer was dried over MgSO.sub.4,
filtered, and the solvent was removed in vacuo to obtain a yellow
solid. The yellow solid was washed with cold hexane (to remove
iodobenzene impurities) and dried to obtain 11.4 g (66% yield) of
1-hydroxy-(3,4-difluorophenyl)-acetophenone as pale yellow solid.
The product was shown to be >90% pure by NMR and was used in the
next step without further purification.
[0140] b. 1-Hydroxy-(3,4-difluorophenyl)-acetophenone oxime
[0141] To a solution of 1-hydroxy-(3,4-difluorophenyl)-acetophenone
(6.0 g, 34.9 mmol) in 150 mL of MeOH was added hydroxylamine
hydrochloride (3.16 g, 45.6 mmol) and sodium acetate (9.6 g, 69.6
mmol) at room temperature and the resulting solution was stirred
overnight. The solvent was removed and the residue was dissolved in
methylene chloride (150 mL) and was washed with 100 mL of saturated
NaHCO.sub.3 solution followed by brine. The organic layer was
separated and dried over MgSO.sub.4, filtered, and the solvent was
removed in vacuo to obtain
1-hydroxy-(3,4-difluorophenyl)-acetophenone-oxime as a yellow solid
(5.6 g, 86%). It was used in the next step without any
purification.
[0142] c. 2-Amino-2-(3,4-difluorophenyl)-ethanol
[0143] To a well stirred suspension of LiAlH.sub.4 (3.4 g, 89.5
mmol) in THF (120 mL) in a 3-necked round bottom flask fitted with
a condenser and a dropping funnel was added a solution of
1-hydroxy-(3,4-difluorophenyl)-- acetophenone-oxime (4.6 g, 24.6
mmol) in THF (50 mL) dropwise at 0.degree. C. The resulting greyish
yellow suspension was heated to reflux for 2 hours. The reaction
mixture was cooled to 0.degree. C. and then carefully quenched
sequentially with 3.4 mL of water, 3.4 mL of 3N NaOH, and 10 mL of
water. The resulting suspension was filtered through a fritted
glass funnel. To the residue was added 100 mL Et.sub.2O and the
suspension was heated to reflux for 20 min. The suspension was
filtered and was combined with the previous filtrate, dried over
MgSO.sub.4, filtered, and the solvent was removed in vacuo.
2-Amino-2-(3,4-difluorophenyl)-ethanol was obtained as a yellow
glassy syrup (4.1 g, 96%) which was used in the next step without
further purification.
[0144] Method A for the synthesis of
5-(3,4-difluoro-phenyl)-morpholin-3-o- ne:
[0145] d.
2-Chloro-N-[1-(3,4-difluoro-phenyl)-2-hydroxy-ethyl]-acetamide
[0146] To a solution of 2-amino-2-(3,4-difluorophenyl)-ethanol 2.6
g, 15.0 mmol) in CH.sub.2Cl.sub.2 (15 mL) and 20% (by wt.) NaOH (15
mL) was added a solution of chloroacetyl chloride (1.32 mL, 16.5
mmol) in 15 mL of CH.sub.2Cl.sub.2 at -10.degree. C. dropwise under
argon atmosphere. After the addition was complete, the reaction
mixture was stirred for 15 min and then it was transferred to a
separatory funnel. The organic layer was separated and the aqueous
layer was extracted with CH.sub.2Cl.sub.2 (2.times.20 mL). The
combined organic extracts were washed with a solution containing 10
mL of brine and 5 drops of concentrated HCl. The organic layer was
dried over MgSO.sub.4, filtered and the solvent was removed in
vacuo to give a white solid. It was further purified with flash
column chromatography on silica gel with 1:1 hexane/EtOAc followed
by EtOAc as the eluting system.
2-Chloro-N-[1-(3,4-difluoro-phenyl)-2-hyd- roxy-ethyl]-acetamide
was obtained as a white solid (2.6 g, 69.5% yield).
[0147] e. 5-(3,4-Difluoro-phenyl)-morpholin-3-one
[0148] To a suspension of sodium hydride (0.29 g, 11.39 mmol) in 48
mL THF was added a solution of
2-chloro-N-[1-(3,4-difluoro-phenyl)-2-hydroxy-eth- yl]-acetamide
(2.6 g, 10.4 mmol) in 48 mL THF dropwise via a dropping funnel at
-25.degree. C. over 20 min. After the addition was over, the
cooling bath was removed and the reaction mixture was stirred at
room temperature for 8 hours. TLC analysis indicated-a complete
disappearance of the starting material. The reaction was quenched
by adding a few crystals of ice. It was extracted thoroughly with
EtOAc (3.times.30 mL) and was washed with brine. The organic layer
was separated and dried over MgSO.sub.4. The organic layer was
filtered and the solvent was removed in vacuo. The residue was
suspended in EtOAc and the white solid was collected via filtration
which was found to be 5-(3,4-difluoro-phenyl)-mo- rpholin-3-one
(0.8 g, 38% yield).
[0149] Method B for the synthesis of
5-(3,4-difluoro-phenyl)-morpholin-3-o- ne:
[0150] f. 5-(3,4-difluoro-phenyl)-morpholin-3-one
[0151] To a suspension of NaH (8.0 mmol, 0.19 g) in 10 mL THF at
0.degree. C. was added a solution of
2-amino-2-(3,4-difluorophenyl)-ethanol (7.51 mmol, 1.3 g) in 20 mL
THF dropwise via an addition funnel and after 30 min ethyl
chloroacetate was added dropwise via syringe. The orange colored
reaction mixture was stirred for 2 hours at 0.degree. C. and then
for 2 hours at 35.degree. C. The solvent was removed and the
5-(3,4-difluoro-phenyl)-morpholin-3-one was isolated as a thick
yellow oil (0.5 g). .sup.1H NMR showed that the product was about
85% pure and any attempts to purify it further by column
chromatography were not successful. It was used in the next
reaction as described below without further purification.
[0152] g. 3-(3,4-Difluorophenyl)-5-oxo-morpholine-4-carboxylic
acid-4-nitro-phenyl ester
[0153] To a solution of 5-(3,4-difluoro-phenyl)-morpholin-3-one
(0.34 g, 1.57 mmol) in 10 mL of THF was added NaH (0.05 g, 1.9
mmol) and the resulting solution was stirred for 30 min. It was
then transferred via a syringe into a solution of 4-nitrophenyl
chloroformate in 20 mL of anhydrous THF at -78.degree. C. under
argon. The resulting solution was stirred for 2 hours after which
the solvent was removed and the residue was purified by column
chromatography on silica gel with 1:1 hexane/CH.sub.2Cl.sub.2
followed by CH.sub.2Cl.sub.2 to obtain
3-(3,4-difluorophenyl)-5-oxo-morpholine-4-carboxylic
acid-4-nitro-phenyl ester as a colorless thick oil (0.31 g,
51%).
2. Synthesis of
(+)-3-(3,4-difluorophenyl)-5-oxo-morpholine-4-carboxylic
acid-4-nitro-phenyl ester (Scheme 2)
[0154] a. [1-(3,4-Difluorophenyl)-2-hydroxy-ethyl]-carbamic
acid-tert-butyl ester
[0155] To a solution of 2-amino-2-(3,4-difluorophenyl)-ethanol (8.6
g, 49.7 mmol) in CHCl.sub.3 (150 mL) at 0.degree. C. was added a
solution of di-tert-butyl dicarbonate (11.4 g, 52.0 mmol) in
CHCl.sub.3 (50 mL) in one portion and the resulting solution was
stirred overnight at room temperature. The solvent was removed in
vacuo and the residue was subjected to column chromatography on
silica gel (2:1 hexane-EtOAc followed by EtOAc) to obtain
[1-(3,4-difluorophenyl)-2-hydroxy-ethyl]-car- bamic acid-tert-butyl
ester as white solid (10.0 g, 74%).
[0156] b. (+)-4-(3,4-Difluorophenyl)-oxazolidin-2-one
[0157] To a well stirred suspension of NaH (1.1 g, 45.8 mmol) in
THF (40 mL) at room temperature was added a solution of
[1-(3,4-difluorophenyl)-2- -hydroxy-ethyl]-carbamic acid-tert-butyl
ester (5.0 g, 18.3 mmol) in 20 mL THF via a dropping funnel at room
temperature. The resulting suspension was stirred for 3 hours and
then quenched carefully with 10 mL of water. The biphasic mixture
was extracted with 100 mL of Et.sub.2O, washed with brine,
filtered, and the solvent was removed in vacuo. The gummy residue
thus obtained was purified by column chromatography over silica gel
(R.sub.f=0.15, 3:2 hexane-EtOAc) to obtain
4-(3,4-difluorophenyl)-oxazoli- din-2-one as a white flaky solid
(2.8 g, 77%). M.P. 81-83.degree. C.; .sup.1H NMR .delta.4.13 (dd,
J=6.6 Hz, J=8.7 Hz, 1 H), 4.73 (t, J=8.7 Hz, 1 H), 4.94 (dd, J=6.6
Hz, J=8.7 Hz, 1 H), 6.08 (br, s, 1 H), 7.03-7.23 (m, 3 H). The
enantiomers were separated by using Chiralcel OD column
(4.6.times.250 mm) using 80% hexane/20% isopropyl alcohol/0.1%
diethylamine as the eluting system under isothermal conditions
(U.V. 254 nM). The retention times for the two isomers were 16.19
min and 20.08 min respectively. First isomer: [.alpha.].sub.D=+62.9
(c=0.67, acetone); Analysis calculated for
C.sub.9H.sub.7NO.sub.2F.sub.2: C, 54.28; H, 3.54; N, 7.03. Found:
C, 54.16; H, 3.44; N, 6.96. Second isomer: [.alpha.].sub.D=-56.9
(c=0.75, acetone); Analysis calculated for
C.sub.9H.sub.7NO.sub.2F.sub.2: C, 54.28; H, 3.54; N, 7.03. Found:
C, 54.31; H, 3.46; N, 6.98. The first isomer was used in the next
step.
[0158] c. (+)-2-Amino-2-(3,4-difluorophenyl)-ethanol
[0159] To a solution of (+)-4-(3,4-difluorophenyl)-oxazolidin-2-one
(1.39 mmol, 0.27 g) in 5.0 mL ethanol was added 5.0 mL of water and
pellets of potassium hydroxide (5.0 mmol, 0.28 g). The resulting
solution was then heated to reflux overnight. The solvent was
removed in vacuo and the resulting residue was extracted with EtOAc
(2.times.50 mL). The organic extracts were washed with brine and
the organic layer was dried over Na.sub.2SO.sub.4. It was filtered
and the solvent was removed in vacuo to obtain
(+)-2-amino-2-(3,4-difluorophenyl)-ethanol as a white solid (0.21
g, 87% yield).
[0160] This material was converted into
(+)-3-(3,4-difluorophenyl)-5-oxo-m- orpholine-4-carboxylic
acid-4-nitro-phenyl ester in the same manner as described in
section I part 1g.
3. Typical Reaction for the Coupling of Side Chains (RNH.sub.2)
with Activated Morpholinones (Schemes 1 and 2). Synthesis of
(+)-3-(3,4-difluorophenyl)-5-oxo-morpholine-4-carboxylic
acid-{3-[4-(5-fluoro-2-methoxyphenyl)-4-phenyl-piperidin-1-yl}-propyl}-am-
ide (Compound 1)
[0161] a. 4-(5-Fluoro-2-methoxy)-phenyl-4-phenyl-piperidine
hydrochloride
[0162] To a 100 mL round bottom flask equipped with a rubber septum
and a stirring bar was added 4-hydroxy-4-phenyl-piperidine (1.25
g., 7.0 mmol) followed by 10 mL of 4-fluoroanisole. The resulting
solution was stirred at room temperature under argon atmosphere and
AlCl.sub.3 (2.82 g, 21.0 mmol) was added in one portion. An
exotherm was observed. The reaction mixture was stirred for 8 hours
and then poured carefully over 150 ml of ice-water. The white solid
that precipitated out was filtered and washed thoroughly with water
followed by diethyl ether to obtain
4-(5-fluoro-2-methoxy)-phenyl-4-phenyl-piperidine hydrochloride
(1.59 g, 50%) as a white solid.
[0163] b.
3-[4-(2-methoxy-5-fluoro)phenyl-4-phenyl-piperidin-1-yl]propylam-
ine
[0164] To a solution of
4-(5-fluoro-2-methoxy)-phenyl-4-phenyl-piperidine (0.6 g, 2.1 mmol)
in 30 mL dioxane was added 3-bromo-N-tert-butoxycarbony-
l-propylamine (0.6 g, 2.5 mmol) and K.sub.2CO.sub.3 (0.6 g, 6.0
mmol) and the resulting suspension was heated to reflux for 10
hours. The suspension was allowed to cool, filtered, and the
solvent was evaporated to obtain yellow residue which was purified
by column chromatography (Rf=0.4, 3:1 EtOAc/MeOH) to obtain
3-[4-(5-fluoro-2-methoxy)phenyl-4-phen-
yl-piperidin-1-yl]-N-tert-butoxycarbonyl-propylamine as a yellow
oil (0.35 g). This was dissolved in 15 mL of CH.sub.2Cl.sub.2 and
3.0 mL of trifluoroacetic acid was added with stirring at room
temperature under argon atmosphere for 1 hour. The solvent was
evaporated in vacuo and the residue was basified to pH 10 by adding
minimum amount of 1 N KOH solution. The product was extracted with
CH.sub.2Cl.sub.2 (3.times.25 mL), dried over MgSO4, filtered, and
the solvent was removed in vacuo to obtain
3-[4-(5-fluoro-2-methoxy)phenyl-4-phenyl-piperidin-1-yl]propylamin-
e as a yellow oil (0.25 g, 35% for two steps). It was used in the
next step without further purification.
[0165] c. (+)-3-(3,4-Difluorophenyl)-5-oxo-morpholine-4-carboxylic
acid-{3-[4-(5-fluoro-2-methoxyphenyl)-4-phenyl-piperidin-1-yl}-propyl}-am-
ide (Compound 1)
[0166] To a solution of
(+)-3-(3,4-difluorophenyl)-5-oxo-morpholine-4-carb- oxylic
acid-4-nitro-phenyl ester (0.05 g, 0.13 mmol) in 5 mL THF was added
3-[4-(5-fluoro-2-methoxy)phenyl-4-phenyl-piperidin-1-yl)-propylamine(0.06
g) in one portion and the resulting mixture was stirred at room
temperature overnight. The solvent was removed in vacuo and the
residue was passed through a short silica gel column with 1:
hexane/EtOAc followed by 10% MeOH/EtOAc as the eluting system.
3-(3,4-Difluorophenyl)-- 5-oxo-morpholine-4-carboxylic
acid-{3-[4-(5-fluoro-2-methoxyphenyl)-4-phen-
yl-piperidin-1-yl}-propyl}-amide was obtained as a colorless oil
(0.05 g). It was dissolved in 4 mL of CHCl.sub.3 and then treated
with 1 mL of 1N HCl in diethyl ether to obtain its HCl salt. White
solid. M.P.=110-113.degree. C.; [.alpha.].sub.D=+25.3 (c=0.14,
MeOH) ; Analysis calculated for
C.sub.32H.sub.35N.sub.3O.sub.4F.sub.3Cl.1.1 CHCl.sub.3: C, 53.05;
H, 4.86; N, 5.61. Found: C, 53.24; H, 5.06; N, 5.44.
4. Morpholinone Example: The Synthesis of
(+)-3-(3,4-Difluoro-phenyl)-5-ox- o-morpholine-4-carboxylic
acid-{3-[4-(4-fluoro-2-methyl)phenyl piperidin-1-yl]-propyl}-amide
(Compound 2)
[0167] a. 1-Benzyl-4-(5-fluoro-2-methyl)-phenyl-4-piperidinol
[0168] To a cooled solution of n-BuLi (6.0 mL, 15.0 mmol) in 20 mL
THF was added 2-bromo-5-fluoro toluene (1.9 mL, 15.0 mmol) dropwise
at -78.degree. C. over 15 min. The reaction mixture was allowed to
warm to 0.degree. C. over 1 hour and was then cooled to -78.degree.
C. 1-Benzyl-4-piperidone (1.48 mL, 8.0 mmol) was added to the white
slurry and the reaction mixture was warmed to 0.degree. C. over 2
hours. The reaction was quenched with 10 mL of saturated NH.sub.4Cl
solution. The organic layer was extracted with diethyl ether
(2.times.50 mL) and the combined organic layers were washed with
brine (100 mL). The organic layer was separated, dried over
Na.sub.2SO.sub.4, filtered, and the solvent was removed in vacuo to
obtain a yellow oil. It was purified by column chromatography over
silica gel with 3:2 hexane-EtOAc as the eluting system to obtain
1-benzyl-4-(5-fluoro-2-methyl)-phenyl-4-piperidi- nol as a yellow
thick oil (1.1 g, 46% yield).
[0169] b.
1-Benzyl-4-(4-Fluoro-2-methyl)-phenyl-1,2,3,6-tetrahydropyridine
[0170] To a solution of
1-benzyl-4-(5-fluoro-2-methyl)-phenyl-4-piperidino- l (1.1 g, 3.68
mmol) in 100 mL toluene was added p-toluenesulfonic acid
monohydrate (1.39 g, 7.35 mmol) and the resulting solution was
heated to reflux for 8 hours. The suspension was cooled and the
basified with 10% KOH solution and extracted with EtOAc (2.times.50
mL). The organic layer was washed with brine (30 mL). The organic
layer was separated, dried over Na.sub.2SO.sub.4, filtered, and the
solvent was removed in vacuo to obtain
1-benzyl-4-(4-fluoro-2-methyl)-phenyl-1,2,3,6-tetrahydropyridine as
a pale yellow oil (0.9 g, 87% yield). It was used in the next step
without further purification.
[0171] c. 4-(4-Fluoro-2-methyl)-phenyl-piperidine
[0172] To a cooled suspension of 10% Pd-C(0.1 g) in 10 mL methanol
was added a solution of
1-benzyl-4-(4-fluoro-2-methyl)-phenyl-1,2,3,6-tetrahy- dropyridine
(0.9 g, 3.2 mmol) in 20 mL of methanol and the resulting suspension
was hydrogenated at room temperature under 1 atm of hydrogen for 10
hours. The suspension was filtered through a pad of celite and the
solvent was removed from the filtrate to obtain
4-(4-fluoro-2-methyl)-phe- nyl-piperidine which was converted into
its hydrochloride salt (0.62 g, 99% yield). It was used in the next
step without further purification.
[0173] d. (+)-3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylic
acid-{3-[4-(4-fluoro-2-methyl)phenyl piperidin-1-yl]-propyl}-amide
(Compound 2)
[0174] 4-(4-Fluoro-2-methyl)-phenyl-piperidine was converted into
3-amino-propyl-4-(4-fluoro-2-methyl)phenyl-piperidine by the same
manner as described in section I, part 3b. This was further
converted into
(+)-3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylic
acid-{3-[4-(4-fluoro-2-methyl)phenyl piperidin-1-yl]-propyl}-amide
by the same manner as described in section I part 3c. White solid.
M.P.=92-96.degree. C.; [.alpha.].sub.D=+19.1 (c=0.12, MeOH);
Analysis calculated for C.sub.26H.sub.31N.sub.3O.sub.3F.sub.3Cl.0.5
CHCl.sub.3: C, 54.35; H, 5.42; N, 7.17. Found: C, 54.20; H, 5.51;
N, 6.81.
5. Morpholinone Example: The Synthesis of
(+)-3-(3,4-difluoro-phenyl)-5-ox- o-morpholine-4-carboxylic
acid-{3-[4-(4-fluoro)phenyl-piperidin-1-yl]-prop- yl}-amide
(Compound 3)
[0175] a.
1-benzyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine
[0176] To a solution of 4-fluorophenylmagnesium bromide (110.0
mmol, 55.0 mL of 2.0 M solution) in 150.0 mL THF at 0.degree. C.
was added 1-benzyl-4-piperidone (55.0 mmol, 10.2 mL) dropwise. The
resulting solution was stirred under argon atmosphere for 1.5 hours
and then quenched with 100.0 mL of saturated NH.sub.4Cl solution.
The organic layer was separated and the aqueous layer was extracted
with 100.0 mL of Et.sub.2O. The combined organic extracts were
washed with brine, separated, and dried over Na.sub.2SO.sub.4. The
solution was filtered and the solvent was removed in vacuo to
obtain a yellow oil which was purified by passing through a silica
gel column with 4:1 hexane/EtOAc followed by 1:1 hexane/EtOAc as
the eluting system. 1-Benzyl-4-(4-fluoro-phenyl)-piperidin-4-ol was
obtained as a pale yellow oil in 89% yield (13.9 g). It was
dissolved in 150.0 mL of toluene and p-toluenesulfonic acid
monohydrate (50.0 mmol, 9.5 g) was added. The resulting suspension
was heated to reflux for 8 hours. After the suspension was cooled,
it was basified with 3 N NaOH solution and was extracted with
Et.sub.2O (2.times.50 mL). The organic extracts were combined,
washed with brine, and the organic layer was dried over
Na.sub.2SO.sub.4. The solvent was removed in vacuo to obtain
1-benzyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine as a
yellow viscous oil (12.0 g, 92% yield) which was used in the next
step without further purification.
[0177] b. 4-(4-fluoro)-phenyl-piperidine
[0178] To a solution of
1-benzyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-py- ridine (45.0
mmol, 12.0 g) in 100 mL MeOH was added 1.0 g of Pd(OH).sub.2 and
the resulting suspension was hydrogenated under 200 psi of H.sub.2
in a stainless steel bomb for two days. The suspension was passed
through a pad of celite and the filtrate was concentrated in vacuo
to obtain 4-(4-fluoro)-phenyl-piperidine (7.5 g, 94%) as a viscous
oil.
[0179] c. (+)-3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylic
acid-{3-[4-(4-fluoro)phenyl-piperidin-1-yl]-propyl}-amide (Compound
3)
[0180] 4-(4-Fluoro)-phenyl-piperidine was converted into
3-[4-(4-fluoro-phenyl)-piperidin-1-yl]-propylamine in the same
manner as described in section I part 3b. This was further
converted into
(+)-3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylic
acid-{3-[4-(4-fluoro)phenyl-piperidin-1-yl]-propyl}-amide by the
same manner described section I part 3c. White solid.
M.P.=86-90.degree. C.; [.alpha.].sub.D=+22.7 (c=0.23, MeOH);
Analysis calculated for C.sub.25H.sub.29N.sub.3O.sub.3F.sub.3Cl.0.4
CHCl.sub.3: C, 54.51; H, 5.29; N, 7.51. Found: C, 54.74; H, 5.48;
N, 7.26.
6.Morpholinone Example:
3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxy- lic
acid-{3-[4-(2-carboxamido)-phenyl-piperiazin-1-yl]-propyl}-amide
(Compound 4)
[0181] a. 1-(2-carboxamidophenyl)piperazine
[0182] Concentrated sulfuric acid (15 mL) was added to
1-(2-cyanophenyl)piperazine (1.5 g, 8.0 mmol) placed in a round
bottom flask, and the resulting slurry was stirred at room
temperature for 48 hours. The reaction mixture was poured on
crushed ice very slowly and then basified (pH 9) with 50% solution
of NaOH. The aqueous layer was extracted several times with EtOAc,
dried over K.sub.2CO.sub.3, filtered, and the solvent was
evaporated. 1-(2-carboxamidophenyl)piperazine was obtained as an
off-white solid (1.2 g, 73%).
[0183] b.3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylic
acid-{3-[4-(2-carboxamido)-phenyl-piperiazin-1-yl]-propyl}-amide
(Compound 4)
[0184] 1-(2-carboxamidophenyl)piperazine was converted into
1-(3-amino-propyl)-4-(2-carboxamido)-phenyl-piperazine in the same
manner as described in section I part 3b. This was further
converted into
3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylic
acid-{3-[4-(2-carboxamido)-phenyl-piperiazin-1-yl]-propyl}-amide in
the same manner as described in section I part 3c. Pale yellow
powder. M.P.=118-122.degree. C.; Analysis calculated for
C.sub.25H.sub.30N.sub.5O- .sub.4F.sub.2Cl.1.1 hexane: C, 59.98; H,
7.23; N, 11.07. Found: C, 60.20; H, 7.50; N, 11.32.
7. Morpholinone Example: Synthesis of
3-(3,4-Difluoro-phenyl)-5-oxo-morpho- line-4-carboxylic
acid-{3-[4-(2-nitro)-phenyl-piperazin-1-yl]-propyl}-amid- e
(Compound 5)
[0185] a. 1-(2-nitrophenyl)-piperazine
[0186] A heterogenous reaction mixture containing
2-bromo-nitrobenzene (2.02 g, 10.0 mmol) and piperazine (4.3 g,
50.0 mmol) was heated at 100.degree. C. for 10 hours. The
orange-red solid was extracted with ethyl acetate and washed
thoroughly with 3 N NaOH solution followed by brine. The organic
layer was separated and dried over Na.sub.2SO.sub.4, filtered and
the solvent was removed in vacuo. The resulting red oil was
purified by column chromatography on silica gel (1:1 hexane/EtOAc
followed by 4:1 EtOAc/MeOH) to yield 1-(2-nitrophenyl)-piperazine
as an orange-red oil (1.90 g, 92%). It was characterized as a
hydrochloride salt. Analysis calculated for
C.sub.10H.sub.14N.sub.3O.sub.2Cl.0.10 CHCl.sub.3: C, 47.46; H,
5.56; N, 16.44. Found: C, 47.63; H, 5.69; N, 16.42.
[0187] b. 3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylic
acid-{3-[4-(2-nitro)-phenyl-piperazin-1-yl]-propyl}-amide (Compound
5)
[0188] 1-(2-nitrophenyl)-piperazine was converted into
1-(3-amino-propyl)-4-(2-nitrophenyl)-phenyl-piperazine in the same
manner as described in section I part 3b. This was further
converted into
3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylic
acid-{3-[4-(2-nitro)-phenyl-piperiazin-1-yl]-propyl)-amide in the
same manner as described in section I part 3c. Pale yellow sticky
solid. M.P.=68-72.degree. C.; Mass spec. 504 (M+1, 100%); Analysis
calculated for C.sub.24H.sub.28N.sub.5O.sub.5F.sub.2Cl.1.2 hexane:
C, 58.25; H, 7.02; N, 10.89. Found: C, 58.39; H, 7.02; N,
10.13.
8. Morpholinone Example:
3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carbox- ylic
acid-{3-[4-(2-methyl)phenyl-4-(4-methyl)-phenyl-piperidin-1-yl]-propy-
l}-amide (Compound 6)
[0189] a. 4-(4-Methyl)-phenyl-4-(2-methyl)phenyl piperidine
hydrochloride
[0190] To a 100 mL round bottom flask equipped with a rubber septum
and a stirring bar was added
4-hydroxy-4-(4-methyl)phenyl-piperidine (1.25 g, 6.54 mmol)
followed by 20 mL of anhydrous toluene. The resulting solution was
stirred at room temperature under argon atmosphere and then
AlCl.sub.3 (1.4 g, 10.2 mmol) was added in one portion. An exotherm
was observed. The reaction mixture was stirred for 10 hours and
then poured carefully over 100 ml of ice-water. The white solid
that precipitated out was filtered and washed thoroughly with water
followed by diethyl ether to obtain
4-(4-methyl)-phenyl-4-(2-methyl)phenyl piperidine hydrochloride
(1.95 g, 99%) as a white solid. Mass spectrum: 266 (M+1, 100%).
Analysis calculated for C.sub.19H.sub.24NCl 0.15 CH.sub.2Cl.sub.2:
C, 73.11; H, 7.79; N, 4.45. Found: C, 73.33; H, 7.82; N, 3.92.
[0191] b. 3-[4-(4-methyl-phenyl-4-(2-methyl)phenyl
piperidin-1-yl]propylam- ine
[0192] To a solution of 4-(4-methyl)-phenyl-4-(2-methyl)phenyl
piperidine hydrochloride (2.6 g, 9.8 mmol) in 100 mL dioxane was
added 3-bromo-N-tert-butoxycarbonyl-propylamine (2.57 g, 10.8 mmol)
and K.sub.2CO.sub.3 (4.06 g, 29.4 mmol) and the resulting
suspension was heated to reflux for 10 hours. The suspension was
allowed to cool, filtered, and the solvent was evaporated to obtain
a yellow residue which was purified by column chromatography
(Rf=0.4, 3:1 EtOAc/MeOH) to obtain
3-[4-(4-methyl-phenyl-4-(2-methyl)phenyl
piperidin-1-yl]-N-tert-butoxycar- bonyl-propylamine as a yellow oil
(2.30 g). It was dissolved in 60 mL of CH.sub.2Cl.sub.2 and 10.0 mL
of trifluoroacetic acid was added with stirring at room temperature
under argon atmosphere for 1 hour. The solvent was evaporated in
vacuo and the residue was basified to pH 10 by adding minimum
amount of 1 N KOH solution. The product was extracted with
CH.sub.2Cl.sub.2 (3.times.25 mL), dried over MgSO4, filtered, and
the solvent was removed in vacuo to obtain
3-[4-(4-methyl)-phenyl-4-(2-methyl- )phenyl
piperidin-1-yl]propylamine as a yellow oil (1.39 g, 44% for two
steps).
[0193] c. 3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylic
acid-{3-[4-(2-methyl)-phenyl-4-(4-methyl)-phenyl-piperidin-1-yl]-propyl}--
amide (Compound 6)
[0194] 3-[4-(4-methyl-phenyl-4-(2-methyl)phenyl
piperidin-1-yl]propylamine was converted -into
3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylic
acid-{3-[4-(2-methyl)-phenyl-4-(4-methyl)-phenyl-piperidin-1-yl]-propyl}--
amide in the same manner as described in section I part 3c. Yellow
sticky solid.; Mass spec. 562 (M+1, 100%); Analysis calculated for
C.sub.33H.sub.38N.sub.3O.sub.3F.sub.2Cl.0.75. CH.sub.2Cl.sub.2: C,
61.25; H, 6.02; N, 6.35. Found: C, 61.07; H, 6.46; N, 5.95.
9. Morpholinone Example: The Synthesis of
3-(3,4-Difluoro-phenyl)-5-oxo-mo- rpholine-4-carboxylic
acid-{3-[4-cyano-4-(phenyl)cyclohex-1-yl]-ethyl}]-am- ide (Compound
7)
[0195] A general procedure was utilized to form
3-[4-cyano-4-(phenyl)cyclo- hex-1-yl]-ethylamine. A mixture of
4-cyano-4-aryl-cyclohexanone (48.7 mmol) and ethylenediamine (8.78
g, 146 mmol) and p-toluenesulfonic acid (92 mg) in benzene (200 mL)
was refluxed for 4 hour with Dean-Stark trap to remove the water
that formed. Solvent was evaporated and the residue was redissolved
in methanol (60 mL) and cooled to 0.degree. C. Sodium borohydride
(6.45 g) was added in portions and the mixture was stirred at room
temperature for 3 hours. Solvent was evaporated, the residue was
dissolved in dichloromethane (300 mL), washed with brine
(3.times.500 mL), dried (potassium carbonate), and the solvent
evaporated to leave the product as a pale yellow viscous oil
(90-95%). The product was found to contain the cis/trans isomers in
a ratio of about 9:1. Careful chromatography of this mixture with
chloroform/methanol/2 M ammonia in methanol (100/10/5 to 100/20/10)
yielded several earlier fractions enriched in trans isomer with
respect to the amino and cyano groups. Later fractions eluted
contained almost pure cis isomer relative to the amino and cyano
groups. 3-[4-cyano-4-(phenyl)cyclohex-1-yl]-ethylamine was
converted to 3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylic
acid-{3-[4-cyano-4-(phenyl)cyclohex-1-yl]-ethyl}]-amide in the same
manner as described in section I part 3c. Yellow powder.;
M.P.=85-89.degree. C.; Analysis calculated for
C.sub.26H.sub.29N.sub.4O.s- ub.3F.sub.2Cl.1.0 CH.sub.2Cl.sub.2: C,
53.70; H, 5.17; N, 9.28. Found: C, 53.78; H, 5.30; N, 8.87.
10. Morpholinone Example: The Synthesis of
3-(3,4-difluoro-phenyl)-5-oxo-m- orpholine-4-carboxylic
acid-{3-[4-(2-carbomethoxy-phenyl-piperazin-1-yl]-p- ropyl}-amide
(Compound 8)
[0196] a. 1-(2-carbomethoxyphenyl)-piperazine
[0197] To a solution of methyl 2-bromobenzoate (1.63 g, 17.8 mmol)
in 1,6-dioxane (100 ml) at room temperature was added piperazine
(15.3 g, 178 mmol) and K.sub.2CO.sub.3 (4.92 g, 35 mmol). The
resulting mixture was heated to reflux for 7 days after which the
reaction mixture was cooled to room temperature. The solvent and
the excess piperazine were removed in vacuo along with heating with
a hot water bath. The residue was dissolved in 1N NaOH solution,
extracted with CH.sub.2Cl.sub.2 (6.times.30 ml), and dried over
Na.sub.2SO.sub.4. The solvent was removed in vacuo to obtain
1-(2-carbomethoxyphenyl)-piperazine as a yellow oil (1.0 g,
26%).
[0198] b. 3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylic
acid-{3-[4-(2-carbomethoxy-phenyl-piperazin-1-yl]-propyl}-amide
(Compound 8)
[0199] 1-(2-Carbomethoxyphenyl)-piperazine was converted into
1-(3-amino-propyl)-4-(2-carbomethoxyphenyl)-piperazine in the same
manner as described in section I part 3b. This was further
converted into
3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylic
acid-{3-[4-(2-carbomethoxy-phenyl-piperazin-1-yl]-propyl}-amide in
the same manner as described in section I, part 3c. Yellow
hygroscopic solid; Analysis calculated for
C.sub.26H.sub.32N.sub.4O.sub.5F.sub.2Cl.sub.2.0.3 CH.sub.2Cl.sub.2:
C, 51.37; H, 5.34; N, 9.11. Found: C, 51.16; H, 5.37; N, 8.27.
11. 3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylic
acid-{2-[4-carbomethoxy-4-phenyl-piperidin-1-yl]-ethyl}-amide
(Compound 9)
[0200] a. 3-[4-Carbomethoxy-4-phenyl-piperidin-1-yl]-ethylamide
[0201] To a solution of 4-carbomethoxy-4-phenyl-piperidine (0.4 g,
2.1 mmol) in 30 mL dioxane was added
3-bromo-N-tert-butoxycarbonyl-ethylamine (0.5 g, 2.5 mmol) and
K.sub.2CO.sub.3 (0.6 g, 6.0 mmol) and the resulting suspension was
heated to reflux for 10 hours. The suspension was allowed to cool,
was filtered, and the solvent was evaporated to obtain a yellow
residue which was purified by column chromatography (Rf=0.4, 3:1
EtOAc/MeOH) to obtain
3-[4-carbomethoxy-4-phenyl-piperidin-1-yl]-N-tert-b-
utoxycarbonyl-ethylamine as a yellow oil (0.35 g). It was dissolved
in 15 mL of CH.sub.2Cl.sub.2 and 3.0 mL of trifluoroacetic acid was
added with stirring at room temperature under argon atmosphere for
1 hours. The solvent was evaporated in vacuo and the residue was
basified to pH 10 by adding minimum amount of 1 N KOH solution. The
product was extracted with CH.sub.2Cl.sub.2 (3.times.25 mL), dried
over MgSO4, filtered and the solvent was removed in vacuo to obtain
3-[4-carbomethoxy-4-phenyl-piperid- in-1-yl]ethylamine as a yellow
oil (0.25 g, 55% for two steps). Yellow solid; M.P.=113-117.degree.
C.; Analysis calculated for
C.sub.26H.sub.30N.sub.3O.sub.5F.sub.2Cl.0.3 Et.sub.2O: C, 58.32; H,
6.14; N, 6.81. Found: C, 58.31; H, 5.94; N, 7.50.
[0202] b. 3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylic
acid-{2-[4-carbomethoxy-4-phenyl-piperidin-1-yl]-ethyl}-amide
(Compound 9)
[0203] 3-[4-Carbomethoxy-4-phenyl-piperidin-1-yl]-ethylamine was
converted into
3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylic
acid-{2-[4-carbomethoxy-4-phenyl-piperidin-1-yl]-ethyl}-amide in
the same manner as described in section I, part 3c. Yellow solid;
M.P.=113-117.degree. C.; Analysis calculated for
C.sub.26H.sub.30N.sub.3O- .sub.5F.sub.2Cl.0.3 Et.sub.2O: C, 58.32;
H, 6.14; N, 6.81. Found: C, 58.31; H, 5.94; N, 7.50.
12. Morpholinone Example: Synthesis of
3-(3,4-Difluoro-phenyl)-5-oxo-morph- oline-4-carboxylic
acid-{3-[4-hydroxy-4-phenyl-piperidin-1-yl]-propyl}-ami- de
(Compound 10)
[0204] a. 3-[4-Hydroxy-4-phenyl-piperidin-1-yl]-propylamine
[0205] 3-[4-Hydroxy-4-phenyl-piperidin-1-yl]-propylamine was
synthesized from commercially available 4-hydroxy-4-phenyl
piperidine using the same procedure as described in section I, part
3b.
[0206] b. 3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylic
acid-{3-[4-hydroxy-4-phenyl-piperidin-1-yl]-propyl}-amide (Compound
10)
[0207] 3-[4-Hydroxy-4-phenyl-piperidin-1-yl]-propylamine was
converted into
3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylic
acid-{3-[4-hydroxy-4-phenyl-piperidin-1-yl]-propyl}-amide in the
same manner as described in section I, part 3c. Yellow solid.;
M.P.=85-88.degree. C.; Analysis calculated for
C.sub.25H.sub.30N.sub.3O.s- ub.4F.sub.2Cl.0.2 MeOH: C, 58.61; H,
6.01; N, 8.14. Found: C, 58.29; H, 6.42; N, 7.98.
13. (-)-3-Phenyl)-5-oxo-morpholine-4-carboxylic
acid-{3-[4-(5'-fluoro-2'-m-
ethoxy)phenyl-4-phenyl-piperidin-1-yl]-propyl)-amide (Compound
11)
[0208] 3-Phenyl-5-oxo-morpholine-4-carboxylic acid-4-nitro-phenyl
ester was prepared from R-(-)-phenyl glycinol in the same manner as
described in section I, parts 1d-g. It was coupled with
3-[4-(5-fluoro-2-methoxy)ph-
enyl-4-phenyl-piperidin-1-yl)-propylamine (section I parts 3a-b) in
the same manner as described in section I, part 3c. White powder.
M.P.=105-109.degree. C.; [.alpha.].sub.D=-49.0 (c=0.12, MeOH)
Analysis calculated for C.sub.32H.sub.37N.sub.3O.sub.4F.sub.2Cl.1.0
CH.sub.2Cl.sub.2: C, 59.42; H, 5.89; N, 6.30. Found: C, 59.51; H,
6.22; N, 6.05.
II. Synthesis of Substituted Morpholinone Examples
1. Synthesis of
3-(3,4-difluorophenyl)-2-methyl-5-oxo-morpholine-4-carboxy- lic
acid-4-nitro-phenyl ester (Scheme 3)
[0209] a. 2-Hydroxy-1-pyrrolidin-1-yl-propan-1-one
[0210] The procedure has been reported (Vilarrasa et al.,
Tetrahedron Lett. 38, 1633, 1997). S-(+)-Methyl lactate (48.03
mmol, 5.0 g) and pyrrolidine (52.8 mmol, 4.4 mL) were mixed in a
round bottom flask and the reaction mixture was allowed to stir at
room temperature for four days. Methanol was distilled off using a
short path distillation apparatus to obtain
2-hydroxy-1-pyrrolidin-1-yl-propan-1-one as a yellow oil. It was
used in the next reaction without further purification.
[0211] b.
2-(tert-Butyl-dimethyl-silanyloxy)-1-pyrrolidin-1-yl-propan-1-on-
e
[0212] To a solution of 2-hydroxy-1-pyrrolidin-1-yl-propan-1-one
(47.0 mmol, 6.72 g) in DMF (25 mL) was added imidazole (70.5 mmol,
4.8 g), N,N-dimethyl-4-aminopyridine (4.7 mol, 0.57 g) at room
temperature. tert-Butyl-dimethylsilyl chloride (48.5 mmol, 7.31 g)
was then added while stirring. Some exotherm was observed. The
initial pale yellow solution turned brown-red in color and some
precipitate was observed after 30 min. The reaction mixture was
stirred overnight and was then filtered through a sintered glass
funnel. The solid was washed with Et.sub.2O. The filtrate was
diluted with water (150 mL) and it was extracted with Et.sub.2O
(2.times.100 mL). The organic extracts were combined and washed
successively with water (100 mL), saturated NH.sub.4Cl solution,
and the organic layer was separated. It was dried over
Na.sub.2SO.sub.4, filtered, and the solvent was removed in vacuo to
obtain
2-(tert-butyl-dimethyl-silanyloxy)-1-pyrrolidin-1-yl-propan-1-one
as a golden yellow oil (10.4 g, 86% yield). The product was judged
to be >95% pure by NMR and was used in next step without any
purification.
[0213] c.
2-(tert-Butyl-dimethyl-silanyloxy)-1-(3,4-difluoro-phenyl)-1-yl--
propan-1-one
[0214] To a round bottom flask containing 72.0 mL of THF at
-78.degree. C. was added a solution of n-butyllithium in hexane
(72.0 mmol, 45.0 mL) under an argon atmosphere followed by
1-bromo-3,4-difluorobenzene (72.0 mmol, 8.1 mL). A solution of
2-(tert-butyl-dimethyl-silanyloxy)-1-pyrroli- din-1-yl-propan-1-one
(60.0 mmol, 15.4 g) in 10.0 mL THF was then added in a steady
stream and the orange colored solution was stirred for 35 min at
-78.degree. C. It was quenched with 20.0 mL of saturated NH.sub.4Cl
solution and was allowed to attain room temperature. The solution
was extracted with Et.sub.2O (2.times.50 mL), washed with brine,
and the organic layer was dried over Na.sub.2SO.sub.4. The solution
was filtered, and the solvent was removed in vacuo to obtain the
product as an orange oil. The crude product was subjected to silica
gel flash column chromatography (9:1 hexane/EtOAc to 4:1
hexane/EtOAc as the eluent system).
2-(tert-Butyl-dimethyl-silanyloxy)-1-(3,4-difluoro-phenyl)-1-yl--
propan-1-one was obtained as a pale yellow oil (14.1 g, 78% yield,
96% based on the recovered starting material).
[0215] d.
2-(tert-Butyl-dimethyl-silanyloxy)-1-(3,4-difluoro-phenyl)-1-yl--
propan-1-one-oxime
[0216] To a solution of
2-(tert-butyl-dimethyl-silanyloxy)-1-(3,4-difluoro-
-phenyl)-1-yl-propan-1-one (13.7 mmol, 4.1 g) in 60.0 mL of
methanol was added sodium acetate (3.76 g) and hydroxylamine
hydrochloride(1.24 g) and the resulting solution was stirred at
room temperature overnight. Methanol was then removed in vacuo and
the resulting residue was extracted with EtOAc (2.times.50 mL) and
brine. The organic layer was separated, dried over
Na.sub.2SO.sub.4, filtered, and the solvent was removed in vacuo.
2-(tert-Butyl-dimethyl-silanyloxy)-1-(3,4-difluoro-phen-
yl)-1-yl-propan-1-one-oxime was obtained as a colorless oil (4.04
g, 94% yield) and was used in the next step without further
purification.
[0217] e. 1-Amino-1-(3,4-difluorophenyl)-propan-2-ol
[0218] To a solution of
2-(tert-butyl-dimethyl-silanyloxy)-1-(3,4-difluoro-
-phenyl)-1-yl-propan-1-one-oxime (12.2 mmol, 3.84 g) in 20.0 mL of
Et.sub.2O was added a 1.0 M solution of lithium aluminum hydride
(25.0 mmol, 25.0 mL) at 0.degree. C. under an argon atmosphere.
After 1 hour, the solution was heated to reflux for 2 hours at
which time some solid was observed. The reaction mixture was cooled
to 0.degree. C. and then quenched sequentially with water (1.0 mL),
1.0 N KOH (1.0 mL), and water (3.0 mL). The residue was filtered
and the solid was washed with warm Et.sub.2O (20.0 mL). The
filtrates were combined and dried over Na.sub.2SO.sub.4. The
solution was filtered and the solvent was removed in vacuo to
obtain 1-amino-1-(3,4-difluorophenyl)-propan-2-ol as a colorless
oil which solidified into a low melting solid (2.1 g, 92% yield).
It was used in the next step without purification.
[0219] f.
3-(3,4-Difluorophenyl)-2-methyl-5-oxo-morpholine-4-carboxylic
acid-4-nitro-phenyl ester
[0220] 1-Amino-1-(3,4-difluorophenyl)-propan-2-ol was converted to
3-(3,4-difluorophenyl)-2-methyl-5-oxo-morpholine-4-carboxylic
acid-4-nitro-phenyl ester in the same manner as described in
section I, parts 1d-g or 2.
2. Substituted Morpholinone Example:
(+)-3-(3,4-Difluoro-phenyl)-2-methyl--
5-oxo-morpholine-4-carboxylic
acid-{3-[4-(4-fluoro)phenyl-piperidin-1-yl]-- propyl}-amide
(Compound 12)
[0221]
3-(3,4-Difluorophenyl)-2-methyl-5-oxo-morpholine-4-carboxylic
acid-4-nitro-phenyl ester (section II part 1) was coupled to
3-[4-(4-fluoro)phenyl-piperidin-1-yl]-propylamine (section I part
5) in the same manner as described in section I, part 3c. Yellow
hygroscopic solid. M.P.=69-73.degree. C.; Mass spec. 490 (M+1,
100%); [.alpha.].sub.D=+20.2 (c=0.08, MeOH). Analysis calculated
for C.sub.26H.sub.31N.sub.3O.sub.3F.sub.2Cl.2.0 H.sub.2O: C, 57.51;
H, 6.50; N, 7.74. Found: C, 57.61; H, 6.15; N, 7.27.
3. Substituted Morpholinone Example:
(+)-3-(3,4-Difluoro-phenyl)-2-methyl--
5-oxo-morpholine-4-carboxylic
acid-{3-[4-(4-fluoro-2-methoxy)phenyl-4-phen-
yl-piperidin-1-yl]-propyl}-amide (Compound 13)
[0222]
3-(3,4-Difluorophenyl)-2-methyl-5-oxo-morpholine-4-carboxylic
acid-4-nitro-phenyl ester (section II part 1) was coupled to
3-[4-(4-fluoro-2-methoxy)phenyl-4-phenyl-piperidin-1-yl]-propylamine
(section I, part 3a-b) in the same manner as described in section
I, part 3c. Yellow powder. M.P.=95-99.degree. C.; Mass spec. 596
(M+1, 100%); [.alpha.].sub.D=+56.9 (c=0.13, MeOH) Analysis
calculated for C.sub.33H.sub.36N.sub.3O.sub.4F.sub.2Cl.1.5
CH.sub.2Cl.sub.2: C, 54.56; H, 5.31; N, 5.53. Found: C, 54.51; H,
5.63; N, 5.20.
4. Substituted Morpholinone Example:
(+)-3-(3,4-Difluoro-phenyl)-2-methyl--
5-oxo-morpholine-4-carboxylic
acid-{3-[4-(cyano-4-phenyl-piperidin-1-yl]-p- ropyl}-amide
(Compound 14)
[0223] a. 3-(4-Cyano-4-phenylpiperidin-1-yl)propylphthalimide
[0224] A mixture of 4-cyano-4-phenylpiperidine hydrochloride (111
g, 0.5 mol), 3-bromopropylphthalimide (135.39 g, 0.505 mol),
potassium carbonate (276.42 g, 2 mol), and potassium iodide (5.4 g)
in DMF (1 L) was stirred and heated at 100-110.degree. C. for 8
hours. About 80% of the solvent was evaporated at reduced pressure,
the residue was diluted with dichloromethane (1 L) and washed with
brine (3.times.300 mL) and dried (Na.sub.2SO.sub.4). Solvent was
evaporated from the dichloromethane solution and the residue was
treated with isopropanol (400 mL) and cooled. The pale yellow
crystalline product formed was filtered, washed with ice-cold
isopropanol and dried (168.6 g, 90%); M.p. 96-98.degree. C.
[0225] b. 3-(4-Cyano-4-phenylpiperidin-1-yl)propylamine
[0226] To a solution of
3-(4-cyano-4-phenylpiperidin-1-yl)propylphthalimid- e (112 g, 0.3
mol) in methanol (1.5 L), hydrazine (30 mL) was added and the
mixture was stirred and refluxed for 20 hours. It was cooled, the
white solid formed was filtered and washed with more methanol (200
mL). Solvent was evaporated from the filtrate and residue was dried
under vacuum for 4 hours. Chloroform (500 mL) was added to this,
stirred for 1 hour and filtered. The white solid was washed with
more chloroform (200 mL), the solvent was evaporated from the
combined filtrates to leave the product as an oil (70 g, 96%).
[0227] c.
(+)-3-(3,4-Difluoro-phenyl)-2-methyl-5-oxo-morpholine-4-carboxyl-
ic acid-{3-[4-(cyano-4-phenyl-piperidin-1-yl]-propyl}-amide
[0228]
3-(3,4-Difluorophenyl)-2-methyl-5-oxo-morpholine-4-carboxylic
acid-4-nitro-phenyl ester (section II, part 1) was coupled to
3-[4-(cyano-4-phenyl-piperidin-1-yl]-propylamine in the same manner
as described in section I, part 3c. White powder.
M.P.=191-194.degree. C.; Mass spec. 497 (M+1, 100%);
[.alpha.].sub.D=+23.1 (c=0.09, MeOH) Analysis calculated for
C.sub.33H.sub.36N.sub.3O.sub.4F.sub.2Cl.0.35 CH.sub.2Cl.sub.2: C,
58.38; H, 5.68; N, 9.96. Found: C, 58.57; H, 6.03; N, 9.72.
III. Synthesis of Substituted Morpholinone Examples (Schemes 4a and
4b)
1. Synthesis of (+)-4-nitrophenyl
2,2-dimethyl-3-(3,4-difluorophenyl)-5-ox- o-morpholinecarboxylate
(Scheme 4a)
[0229] a. Amino-(3,4,-difluorophenyl)-acetonitrile
[0230] Through a solution of 3,4-difluorobenzaldehyde (25.0 g, 0.18
mol) in MeOH (500 mL) in a round bottom flask was bubbled ammonia
gas for two hours at room temperature. The flask was then cooled to
0.degree. C. and trimethylsilyl cyanide (1.3 eq., 0.23 mmol) was
then added slowly. The reaction mixture was stirred for 2 hours
when TLC analysis indicted that the reaction was complete
(R.sub.f=0.35, 3:2 hexane/EtOAc). Solvent was removed in vacuo and
the residue was subjected to flash column chromatography on silica
gel to obtain 25.0 g (81%) of
amino-(3,4-difluorophenyl)-acetonitrile as a yellow syrup.
[0231] b. Methyl 2-amino-2-(3,4-difluorophenyl)acetate
[0232] To a well stirred solution of
amino-(3,4-difluorophenyl)-acetonitri- le (22.0 g., 0.130 mol), a
solution of HCl in MeOH (200 mL) was added at room temperature. The
resulting yellow solution was stirred at room temperature for 10
hours and then heated to reflux for 1.5 hours. After cooling, the
solvent was removed in vacuo and the resulting yellow solid was
dissolved in water (200 mL). The aqueous solution was then
carefully basified with 20% NaOH solution to pH 9. The aqueous
layer was extracted with CH.sub.2Cl.sub.2 (3.times.100 mL). The
organic layer was separated and dried over Na.sub.2SO.sub.4,
filtered and the solvent was removed in vacuo to obtain 22.2 g
(84%) of methyl 2-amino-2-(3,4-difluorophenyl)acet- ate as a
brownish yellow liquid. It was used in the next step without
purification.
[0233] c.
(+)-1-(3,4-Difluorophenyl)-2,2-dimethyl-2-hydroxypropylamine
[0234] To a well-stirred solution of methyl
2-amino-2-(3,4-difluorophenyl)- acetate (10.5 g, 52.19 mmol) in
anhydrous ether (200 mL) at 0.degree. C. was added a solution of
methylmagnesium bromide in ether (3 M, 87 mL, 261 mmol) over 10
minutes. The mixture was stirred at 0.degree. C. for 2.5 hours and
allowed to warm to room temperature. After 12 hours, the mixture
was carefully poured onto a mixture of ice (300 g) and saturated
ammonium chloride (50 g). The ether layer was separated and the
aqueous layer was extracted with more ether (4.times.200 mL). The
combined extracts were dried over magnesium sulfate and the solvent
evaporated. The crude product was purified by column chromatography
on silica gel using chloroform/methanol/2M ammonia in methanol
(1000:20:10, 1000:40:20, 1000:80:40) as eluents to give the product
as an oil (6.5 g, 62%). The .sup.1H-NMR and MS confirmed this to be
the desired product.
[0235] d.
(+)-1-(3,4-Difluorophenyl)-2,2-dimethyl-2-hydroxypropylamine
chloroacetamide
[0236] To a solution of
1-(3,4-difluorophenyl)-2,2-dimethyl-2-hydroxypropy- lamine (10.20
g, 50.70 mmol) and triethylamine (5.0 mL) in dichloromethane (100
mL) at -78.degree. C. was added chloroacetyl chloride (4.64 mL,
60.83 mmol) dropwise over 10 min. The resulting mixture was stirred
at -78.degree. C. for 2 hours and was then slowly warmed to
-40.degree. C. over one hour. The reaction was quenched by adding
H.sub.2O (20 mL) and the mixture was extracted with EtOAc
(2.times.100 mL). The ethyl acetate extracts were dried over
MgSO.sub.4 and concentrated to a residue which was purified by
column chromatography (SiO.sub.2, 30% to 50% EtOAc/Hex) to afford
the product as a colorless oil (6.50 g, 46% yield).
[0237] e.
(+)-2,2-Dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholine
[0238] Lithium bis(trimethylsilyl)amide (5.68 mL, 1.0 M in THF) was
added to a stirred solution of
1-(3,4-difluorophenyl)-2-methyl-2-hydroxypropyla- mine
2-chloroacetamide (1.21 g, 4.37 mmol) in THF at 0.degree. C. The
resulting mixture was stirred while warmed to room temperature over
30 min. It was then heated to 50.degree. C. and stirred for 60 min.
The mixture was quenched with water (2 mL) and extracted with EtOAc
(2.times.100 mL). The extracts were dried (Na.sub.2SO.sub.4) and
the solvent was evaporated. The crude product was purified by
column chromatography (SiO.sub.2, 50:50 to 90:10 EtOAc/Hexanes) to
give 0.36 g (34%) of morpholinone as a pale yellow oil.
[0239] f. (+)-4-Nitrophenyl
2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morp-
holinecarboxylate
[0240] To a solution of
(.+-.)-2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-m- orpholine (240
mg, 0.996 mmol) in THF (10 mL) at -78.degree. C. was added lithium
bis(trimethylsilyl)amide (1.10 mL, 1.0 M in THF). The mixture was
stirred for 30 min at 0.degree. C. and then cooled back to
-78.degree. C. The mixture was transferred via a cannula to a
precooled solution of 4-nitrophenyl chloroformate (605 mg, 3.0
mmol) in THF (10 mL) at -78.degree. C. The resulting mixture was
stirred while warmed to room temperature over 3 hours. The reaction
was quenched with water (2 mL) and extracted with EtOAc
(2.times.100 mL). The organic layer was dried with Na.sub.2SO.sub.4
and the solvent was evaporated. The residue was purified by column
chromatography (SiO.sub.2, 40:60 EtOAc/Hexanes) to afford 0.328 g
(81%) of the product as a pale oil.
2. Synthesis of Enantiomerically Pure 4-nitrophenyl
2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate
(Scheme 4b)
[0241] a. (S)-(+)-O-Acetylmandelyl
(+/-)-2,2-dimethyl-3-(3,4-difluoropheny-
l)-5-oxo-morpholine-3-amide
[0242] To a solution of (S)-(+)-O-acetylmandelic acid (408 mg, 2.10
mmol) in Et.sub.2O (50 mL) and triethylamine (212 mg) under argon
at -78.degree. C, was added 2,2,2-trimethylacetyl chloride (272 mg,
2.10 mmol). The resulting mixture was warmed to 0.degree. C. in
ice-bath for 10 min to yield the acid chloride and it was then
cooled back to -78.degree. C. At the same time,
(+/-)-2,2-dimethyl-3-(3,4-difluorophenyl- )-6-oxo-morpholine (406
mg, 1.68 mmol) was dissolved in THF (15 mL) in another dried flask
and cooled to -78.degree. C., and n-BuLi (0.75 mL, 2.5 M) was added
dropwise. The resulting solution was stirred for 10 min and was
then transferred to the acid chloride via a cannula. The reaction
mixture was stirred for 10 min at -78.degree. C. and was then
warmed to 0.degree. C. and stirred for 1 hour before quenching with
water (2 mL). The mixture was extracted with EtOAc (2.times.50 mL),
dried (Na.sub.2SO.sub.4), and the solvent was evaporated. The crude
product was purified by column chromatography (SiO.sub.2, 15:85 to
30:70 EtOAc/Hexanes) to obtain 0.476 g of the two diastereomers as
pure compounds. (combined yield: 68%) (Higher R.sub.f product: 318
mg; Lower R.sub.f product: 158 mg).
[0243] b.
(-)-2,2-Dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholine
[0244] LiOH.H.sub.2O (281 mg, 6.71 mmol) was added to a solution of
the amide from the previous step (Higher R.sub.f compound, 280 mg,
0.671 mmol) in THF (20 mL), H.sub.2O (2 mL) and H.sub.2O.sub.2 (5
mL). The resulting mixture was stirred vigorously for one hour. The
mixture was filtered and the filtrate was extracted with EtOAc
(2.times.50 mL), dried (Na.sub.2SO.sub.4), and the solvent was
evaporated. The crude product was purified by column chromatography
(SiO.sub.2, 50:50 to 90:10 EtOAc/Hexanes) (0.120 g, 74%). optical
rotation [.alpha.].sub.D=-10.0 (c=4.5, MeOH).
[0245] c.
(+)-2,2-Dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholine
[0246] Prepared in the same manner as described in section III,
part 2b from 150 mg of amide (lower R.sub.f compound). Yield: 65 mg
(75%); [.alpha.].sub.D=+9.6 (c=2.5, MeOH)
[0247] d. Enantiomerically Pure 4-nitrophenyl
2,2-dimethyl-3-(3,4-difluoro-
phenyl)-5-oxo-morpholinecarboxylate
[0248] The enantiomerically pure
4-nitrophenyl-2,2-dimethyl-3-(3,4-difluor-
ophenyl)-5-oxo-morpholinecarboxylates were prepared from
(-)-2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholine and
(+)-2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholine in a
similar manner as described in section III, part 1d.
3. Typical Reaction Sequence for the Coupling of Side Chains
(RNH.sub.2) with Activated Morpholinones (Scheme 4) Synthesis of
N-4-[3-(4-methoxycarbonyl-4phenylpiperidino)propyl]-3-(3,4-difluorophenyl-
)-2,2-dimethyl-5-oxo-4-morpholinecarboxamide hydrochloride
(Compound 15)
[0249] a. 4-Methoxycarbonyl-4-phenylpiperidine
[0250] To a stirred solution of H.sub.2SO.sub.4 (16 mL) in MeOH
(400 mL), 4-phenyl-4-piperidinecarboxylic acid 4-methyl
benzenesulfonate (37.7 g, 0.1 mole) was added and the mixture was
stirred and refluxed for 8 hours. Excess methanol was evaporated at
reduced pressure and the residue was poured into a mixture of ice
and 6 N NaOH. The pH was adjusted to 10-11 by adding more 6 N NaOH
and extracted with CH.sub.2Cl.sub.2 (3.times.150 mL). The combined
CH.sub.2Cl.sub.2 extracts were dried (MgSO.sub.4) and the solvent
evaporated to leave the desired product as a viscous oil. The
product (20.2 g, 92%) was used without further purification.
[0251] b.
3-(4-Methoxycarbonyl-4-phenylpiperidin-1-yl)propylamine
[0252] A mixture of 4-methoxycarbonyl-4-phenylpiperidine (8.5 g,
0.039 mol), 3-bromopropylamine hydrobromide (12.7 g, 0.058 mol),
potassium carbonate (13.475 g, 0.0957 mole), and KI (3.24 g, 0.0195
mol) in 1,4-dioxane (200 mL) was stirred and refluxed for 24 hours.
Dioxane was evaporated at reduced pressure, the residue was treated
with ice-cold 6 N NaOH (400 mL) and extracted with CH.sub.2Cl.sub.2
(4.times.120 mL). Solvent was evaporated from the combined dried
(K.sub.2CO.sub.3) extracts and the residue was purified by column
chromatography on silica gel using CHCl.sub.3/MeOH/2 M NH.sub.3 in
MeOH (20:2:1) as the eluent to afford the product as a viscous oil
(7.8 g, 72%).
[0253] c.
N-4-[3-(4-methoxycarbonyl-4-phenylpiperidino)propyl]-3-(3,4-difl-
uorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamide
hydrochloride
[0254] 4-Methylcarboxyl-4-phenyl-piperidinyl-N-propylamine (100 mg,
0.384 mmol) was added to a stirred solution of
(.+-.)-4-nitrophenyl-2,2-dimethy-
l-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (15 mg, 0.037
mmol) in CH.sub.2Cl.sub.2 (5 mL). The resulting mixture was stirred
at room temperature overnight and purified by prep. TLC on silica
gel using EtOAc as the eluent to give 10 mg product (50%). The HCl
salt was prepared by treatment with 1 N HCl in ether.
4. Substituted Morpholinone Example: Methyl
4-[2-([3-(3,4-difluorophenyl)--
2,2-dimethyl-5-oxomorpholino]carbonylamino)ethyl]amino-1-phenyl-1-cyclohex-
anecarboxylate hydrochloride (cis isomer) (Compound 16)
[0255] a.
2-[4-Methoxycarbonyl-4-phenyl-cyclohexylamino]ethylamine
[0256] A mixture of 2-[4-cyano-4-phenylcyclohexylamino]ethylamine
(2.34 g, 10 mmol) and concentrated sulfuric acid (20 mL) was heated
at 80-85.degree. C. for 10 hours. It was cooled to room
temperature, mixed with anhydrous methanol (200 mL), and refluxed
for 20 hours. Solvent was evaporated and the residue was poured
onto ice (200 g) and basified to pH 11 by addition of 6 N NaOH. It
was extracted with dichloromethane (4.times.125 mL), dried
(potassium carbonate) and solvent evaporated to leave the product
as an oil (2.1 g, 76%). This product was a pure mixture of cis and
trans isomers. It was used in the next step without any further
purification.
[0257] b. Methyl
4-[2-([3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxomorpholin-
o]carbonylamino)ethyl]amino-1-phenyl-1-cyclohexanecarboxylate
hydrochloride (cis isomer)
[0258] 4-Methylcarboxyl-4-phenyl-cyclohexyl-amino-ethylamine (25
mg, 0.091 mmol) was added to a stirred solution of
(.+-.)-4-nitrophenyl
2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (15
mg, 0.037 mmol) in CH.sub.2Cl.sub.2 (5 mL). The resulting mixture
was stirred at RT overnight and purified by prep. TLC on silica gel
using EtOAc as eluent to give 10 mg product (51%). MH.sup.+=544.
The HCl salt was prepared by treatment with 1 N HCl in ether.
5. Substituted Morpholinone Example:
N-4-(3-{4-(2-pyridyl}piperidino)propy-
l]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamide
hydrochloride (Compound 17)
[0259] a. 1-Benzyl-4-cyano-4-(2-pyridyl)piperidine
[0260] To a mixture of N,N-bis-(2-chloroethyl)benzylamine
(Szarvasi, E., Eur. J. Med. Chem. Chim. Ther. 11(2), 115-124, 1976)
(60 g, 22 mmol), 2-pyridylacetonitrile (2.51 mL, 22 mmol) and
tetrabutylammonium hydrogen sulfate (0.26 g, 0.7 mmol) in toluene
(10 mL), sodium hydroxide solution (2.43 g in 4.86 mL H.sub.2O) was
added over a 20 minute period. The reaction mixture was heated at
65.degree. C. for 4 hours. The reaction mixture was cooled to room
temperature, 10 mL of water was added and the solution partitioned
between ethyl acetate (45 mL) and water. The organic layer was
dried over sodium sulfate, filtered and concentrated. Purification
of the crude product by column chromatography (hexane:EtOAc, 2:3)
gave 6.2 g (87%) of the title compound as a red solid; .sup.1H-NMR
(CDCl.sub.3): .delta.2.05 (d, J=13.1 Hz, 2H), 2.30 (t, J=13.2 Hz,
2H), 2.48 (t, J=13.2 Hz, 2 H), 2.97 (d, J=12.1 Hz, 2 H), 3.57 (s, 2
H), 7.19-7.27 (m, 6 H), 7.30 (d, J=7.6 Hz, 1 H), 7.60 (t, J=7.6 Hz,
1 H ), 8.58 (d, J=4.6 Hz, 1 H).
[0261] b. 1-Benzyl-4-carboxamido-4-(2-pyridyl)piperidine
[0262] To 1-benzyl-4-cyano-4-(2-pyridyl) piperidine (4.5 g, 14.3
mmol), 10 mL of conc. H.sub.2SO.sub.4 was added and the solution
was stirred at room temperature for 24 hours. It was cooled to
0.degree. C., diluted with ice pieces and poured into crushed ice.
The mixture was then carefully neutralized with 50% NaOH solution.
The reaction mixture was repeatedly extracted with chloroform
(3.times.25 mL), dried over sodium sulfate, filtered and
concentrated to give 4.5 g (95%) of the crude product which was
used as such for the subsequent step; .sup.1H-NMR (CDCl.sub.3):
.delta.2.21-2.28 (m, 2 H), 2.47 (s, 6 H), 3.41 (s, 2 H), 5.23 (s, 1
H), 6.40 (s, 1 H), 7.12-7.29 (m, 6 H), 7.33 (d, J=7.6 Hz, 1 H),
7.63 (t, J=7.6 Hz, 1 H), 8.55 (d, J=4.6 Hz, 1 H).
[0263] c. 1-Benzyl-4-(2-pyridyl)-piperidine
[0264] To 1-benzyl-4-carboxamido-4-(2-pyridyl)piperidine (4.5 g,
13.5 mmol) in anhydrous methanol (100 mL), HCl gas was bubbled
through the solution at 0.degree. C. for 15 minutes. The reaction
mixture was then refluxed for 24 hours. It was cooled to room
temperature, concentrated, neutralized with 50% NaOH and repeatedly
extracted with chloroform (3.times.25 mL). The combined organic
layer was then dried over sodium sulfate, filtered and
concentrated. Flash chromatography (hexane:ethylacetate, 1:4) of
the crude product yielded 1.72 g (50%) of the product as a syrup;
.sup.1H-NMR (CDCl.sub.3): .delta.1.8-1.94 (m, 4 H), 2.11 (t, J=11.4
Hz, 2 H), 2.70-2.72 (m, 1 H), 3.02 (d, J=11.4 Hz, 2 H), 3.54 (s, 2
H), 7.07-7.36 (m, 7 H), 7.58 (t, J=7.6 Hz, 1 H), 8.52 (d, J=4.6 Hz,
1 H).
[0265] d. 3-[4-(2-Pyridyl)-piperidine-1-yl]propylamine
[0266] To 1-benzyl-4-(2-pyridyl)-piperidine (3.26 g, 12.9 mmol) in
dry methanol (25 mL), 10% palladium hydroxide (1.9 g) was added and
the solution was hydrogenated at 200 psi for 24 hours. The solution
was filtered over celite, concentrated to give 2.1 g (99%) of
4-(2-pyridyl)-piperidine which was used as such for the subsequent
step. A mixture of 3-bromopropylamine hydrobromide (20 g, 91.3
mmol), potassium carbonate (37.85 g, 273.9 mmol) and
di-tert-butyldicarbonate (21.90 g, 100 mmol) in methanol was
stirred at room temperature for 24 hours. The reaction mixture was
concentrated and partitioned between 250 mL EtOAc and 50 mL water,
dried over sodium sulfate, filtered and concentrated. Purification
of the crude product by column chromatography (hexane:EtOAc,
4.5:0.5) gave 17.5 g (80%) of the product as a pale yellow oil. To
a stirred solution of the 4-(2-pyridyl)-piperidine (1.86 g, 11.4
mmol) in dioxane (20 mL),
N-(tert-butoxycarbonyl)-3-bromopropylamine (2.82 g, 11.4 mmol) and
potassium carbonate (3.16 g, 22.9 mmol) were added and the solution
was refluxed for 24 hours. The reaction mixture was cooled to room
temperature, concentrated and partitioned between 40 mL chloroform
and 5 mL water. The organic layer was dried over sodium sulfate,
filtered and concentrated. The crude product was purified by column
chromatography (ethyl acetate:methanol, 4:1) to yield 1.86 g (49%)
of the required product as a colorless oil; .sup.1H-NMR
(CDCl.sub.3): .delta.1.45 (s, 9 H), 1.54-1.69 (m, 8 H), 2.21-2.68
(m, 2 H), 2.74-2.80 (m, 1 H), 3.02-3.22 (m, 4 H), 5.41 (s, 1 H),
7.13-7.17 (m, 1 H), 7.33 (d, J=7.93 Hz, 1 H), 7.63 (t, J=7.6 Hz, 1
H), 8.54 (d, J=4.6 Hz, 1 H). To
N-(tert-butoxycarbonyl)-3-[4-(2-pyridyl)-piperidin-1-yl]propylamine
(0.15 g, 0.45 mmol) in 5 mL of dichloromethane, 1 mL of
trifluoroacetic acid was added and the solution was stirred at room
temperature for 1 hour. The solution was concentrated, neutralized
with 10% KOH solution and extracted into 25 mL of dichloromethane.
The organic layer was dried over sodium sulfate, filtered, and
concentrated to give 0.098 g (100%) of
3-[4-2-pyridyl)-piperidin-1-yl]propylamine which was used as such
for the subsequent step.
[0267] e.
N-4-[3-{4-(2-pyridyl}piperidino)propyl]-3-(3,4-difluorophenyl)-2-
,2-dimethyl-5-oxo-4-morpholinecarboxamide hydrochloride
[0268] 4-(2-Pyridinyl)piperidinyl-N-propylamine (25 mg, 0.114 mmol)
was added to a stirred solution of (.+-.)-4-nitrophenyl
2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (15
mg, 0.037 mmol) in CH.sub.2Cl.sub.2 (5 mL). The resulting mixture
was stirred at RT overnight and purified by prep. TLC on silica gel
using EtOAc as eluent to give 10 mg product (52%). MH+=487. The HCl
salt was prepared by treatment with 1 N HCl in ether.
6. Substituted Morpholinone Example:
N-4-[3-(4-Cyan-4-phenylpiperidino)pro-
pyl]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamide
hydrochloride (Compound 18)
[0269] a. 3-(4-Cyano-4-phenylpiperidin-1-yl)propyl phthalimide
[0270] A mixture of 4-cyano-4-phenylpiperidine hydrochloride (111
g, 0.5 mol), 3-bromopropylphthalimide (135.39 g, 0.505 mol),
potassium carbonate (276.42 g, 2 mol), and potassium iodide (5.4 g)
in DMF (1 L) was stirred and heated at 100-110.degree. C. for 8
hours. About 80% of the solvent was evaporated at reduced pressure,
the residue was diluted with dichloromethane (1 L) and washed with
brine (3.times.300 mL) and dried (Na.sub.2SO.sub.4). Solvent was
evaporated from the dichloromethane solution and the residue was
treated with isopropanol (400 mL) and cooled. The pale yellow
crystalline product formed was filtered, washed with ice-cold
isopropanol and dried (168.6 g, 90%); M.p. 96-98.degree. C.
[0271] b. 3-(4-Cyano-4-phenylpiperidin-1-yl)propylamine
[0272] To a solution of
3-(4-cyano-4-phenylpiperidin-1-yl)propylphthalimid- e (112 g, 0.3
mol) in methanol (1.5 L), hydrazine (30 mL) was added and the
mixture was stirred and refluxed for 20 hours. It was cooled, the
white solid formed was filtered and washed with more methanol (200
mL). Solvent was evaporated from the filtrate and residue was dried
under vacuum for 4 hours. Chloroform (500 mL) was added to this,
stirred for 1 hour and filtered. The white solid was washed with
more chloroform (200 mL), the solvent was evaporated from the
combined filtrates to leave the product as an oil (70 g, 96%).
[0273] c.
N-4-[3-(4-Cyan-4-phenylpiperidino)propyl]-3-(3,4-difluorophenyl)-
-2,2-dimethyl-5-oxo-4-morpholinecarboxamide hydrochloride
[0274] 4-Cyan-4-phenyl-piperidinyl-N-propylamine (25 mg, 0.103
mmol) was added to a stirred solution of (.+-.)-4-nitrophenyl
2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (15
mg, 0.037 mmol) in CH.sub.2Cl.sub.2(5 mL). The resulting mixture
was stirred at room temperature overnight and purified by prep. TLC
on silica gel using EtOAc as eluent to give 10 mg product (51%).
MH.sup.+=511. The HCl salt was prepared by treatment with 1 N HCl
in ether.
7. Substituted Morpholinone Example:
(+)-N-4-[3-(4-Cyano-4-phenylpiperidin-
o)propyl]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamid-
e hydrochloride (Compound 18)
[0275] a. 3-(4-Cyano-4-phenylpiperidin-1-yl)propyl phthalimide
[0276] A mixture of 4-cyano-4-phenylpiperidine hydrochloride (111
g, 0.5 mol), 3-bromopropylphthalimide (135.39 g, 0.505 mol),
potassium carbonate (276.42 g, 2 mol), and potassium iodide (5.4 g)
in DMF (1 L) was stirred and heated at 100-110.degree. C. for 8
hours. About 80% of the solvent was evaporated at reduced pressure,
the residue was diluted with dichloromethane (1 L) and washed with
brine (3.times.300 mL) and dried (Na.sub.2SO.sub.4). Solvent was
evaporated from the dichloromethane solution and the residue was
treated with isopropanol (400 mL) and cooled. The pale yellow
crystalline product formed was filtered, washed with ice-cold
isopropanol and dried (168.6 g, 90%); M.p. 96-98.degree. C.
[0277] b. 3-(4-Cyano-4-phenylpiperidin-1-yl)propylamine
[0278] To a solution of
3-(4-cyano-4-phenylpiperidin-1-yl)propylphthalimid- e (112 g, 0.3
mol) in methanol (1.5 L), hydrazine (30 mL) was added and the
mixture was stirred and refluxed for 20 hours. It was cooled, the
white solid formed was filtered and washed with more methanol (200
mL). Solvent was evaporated from the filtrate and residue was dried
under vacuum for 4 hours. Chloroform (500 mL) was added to this,
stirred for 1 hour and filtered. The white solid was washed with
more chloroform (200 mL), the solvent was evaporated from the
combined filtrates to leave the product as an oil (70 g, 96%).
[0279] c.
(+)-N-4-[3-(4-Cyano-4-phenylpiperidino)propyl]-3-(3,4-difluoroph-
enyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamide hydrochloride
[0280] 4-Cyano-4-phenyl-piperidinyl-N-propylamine (40 mg, 0.165
mmol) was added to a stirred solution of (-)-4-nitrophenyl
2,2-dimethyl-3-(3,4-difl- uorophenyl)-5-oxo-morpholinecarboxylate
(15 mg, 0.037 mmol) in CH.sub.2Cl.sub.2(5 mL). The resulting
mixture was stirred at room temperature overnight and purified by
prep. TLC on silica gel using EtOAc as the eluent to give 16 mg
product (85%). [.alpha.].sub.D=+26.3 (c=0.8, CH.sub.2Cl.sub.2).
MH.sup.+=511. The HCl salt was prepared by treatment with 1 N HCl
in ether.
8. Substituted Morpholinone Example:
(-)-N4-[3-(4-Cyano-4-phenylpiperidino-
)propyl]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamide
hydrochloride (Compound 18)
[0281] a. 3-(4-Cyano-4-phenylpiperidin-1-yl)propyl phthalimide
[0282] A mixture of 4-cyano-4-phenylpiperidine hydrochloride (111
g, 0.5 mol), 3-bromopropylphthalimide (135.39 g, 0.505 mol),
potassium carbonate (276.42 g, 2 mol), and potassium iodide (5.4 g)
in DMF (1 L) was stirred and heated at 100-110.degree. C. for 8
hours. About 80% of the solvent was evaporated at reduced pressure,
the residue was diluted with dichloromethane (1 L) and washed with
brine (3.times.300 mL) and dried (Na.sub.2SO.sub.4). Solvent was
evaporated from the dichloromethane solution and the residue was
treated with isopropanol (400 mL) and cooled. The pale yellow
crystalline product formed was filtered, washed with ice-cold
isopropanol and dried (168.6 g, 90%); M.p. 96-98.degree. C.
[0283] b. 3-(4-Cyano-4-phenylpiperidin-1-yl)propylamine
[0284] To a solution of
3-(4-cyano-4-phenylpiperidin-1-yl)propylphthalimid- e (112 g, 0.3
mol) in methanol (1.5 L), hydrazine (30 mL) was added and the
mixture was stirred and refluxed for 20 hours. It was cooled, the
white solid formed was filtered and washed with more methanol (200
mL). Solvent was evaporated from the filtrate and residue was dried
under vacuum for 4 hours. Chloroform (500 mL) was added to this,
stirred for 1 hour and filtered. The white solid was washed with
more chloroform (200 mL), the solvent was evaporated from the
combined filtrates to leave the product as an oil (70 g, 96%).
[0285] c.
(-)-N4-[3-(4-Cyano-4-phenylpiperidino)propyl]-3-(3,4-difluorophe-
nyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamide hydrochloride
[0286] 4-Cyano-4-phenyl-piperidinyl-N-propylamine (40 mg, 0.165
mmol) was added to a stirred solution of (+)-4-nitrophenyl
2,2-dimethyl-3-(3,4-difl- uorophenyl)-5-oxo-morpholinecarboxylate
(15 mg, 0.037 mmol) in CH.sub.2Cl.sub.2(5 mL). The resulting
mixture was stirred at room temperature overnight and purified by
prep. TLC with EtOAc as eluent to give 14 mg product (74%).
[.alpha.].sub.D=-25.7 (c=0.7, CH.sub.2Cl.sub.2). MH.sup.+=511. The
HCl salt was prepared by treatment with 1 N HCl in ether.
9. Substituted Morpholinone Example:
3-(3,4-Difluorophenyl)-2,2-dimethyl-5- -oxo-morpholine-4-carboxylic
acid-{2-[4-(2-pyridyl)piperidin-1-yl]-1-methy- l-ethyl}-amide
hydrochloride (Compound 19)
[0287] a. N-(tert-Butoxycarbonyl)-L-alanine
4-(2-pyridyl)piperidin-1-yl amide
[0288] To a solution of N-(tert-butoxycarbonyl)-L-alanine (1.485 g,
7.847 mmol) and 4-(2-pyridyl)piperidine (0.910 g, 5.60 mmol) in
dichloromethane (20 mL) at 0.degree. C., was added
N,N-dimethylaminopyridine (DMAP, 2.05 g, 16.8 mmol) and
1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride
(DMAPECD, 2.147 g, 11.2 mmol). The resulting mixture was stirred
overnight while warmed up to room temperature. The reaction mixture
was quenched with aqueous NH.sub.4Cl (30 mL) and extracted with
CH.sub.2Cl.sub.2 (30 mL.times.2). The combined extracts were dried
(K.sub.2CO.sub.3), concentrated, and purified by flash
chromatography on silica gel (100% EtOAc) to obtain 2.09 g (80%) of
N-(tert-Butoxycarbonyl)- -L-alanine 4-(2-pyridyl)piperidin-1-yl
amide.
[0289] b.
(S)-N-(tert-Butoxycarbonyl)amino-3-[4-(2-pyridyl)piperidin-1-yl]-
propane
[0290] To a solution of N-(tert-butoxycarbonyl)-L-alanine
4-(2-pyridyl)piperidin-1-yl amide (0.650 g, 1.95 mmol) in THF (20
mL) at 0.degree. C. was added LAH (4.0 mL, 1.0 M in THF) dropwise.
The resulting mixture was stirred for 3 hours before quenching with
1 mL of H.sub.2O and 5 mL of 1 N NaOH. The mixture was extracted
with CH.sub.2Cl.sub.2 (30 mL.times.2). The combined extracts were
dried (K.sub.2CO.sub.3), concentrated, and purified by flash
chromatography on silica gel (chloroform:MeOH:2.0 M NH.sub.3 in
MeOH=100:5:1) to afford the product (0.479 g, 77%) as an colorless
oil.
[0291] c. (S)-Amino-3-[4-(2-pyridyl)piperidin-1-yl]propane
[0292] A solution of
(S)-N-(tert-butoxycarbonyl)amino-3-[4-(2-pyridyl)pipe-
ridin-1-yl]propane (0.460 g, 1.44 mmol) in CH.sub.2Cl.sub.2 (10 mL)
and TFA (5 mL) was stirred for 12 hours at room temperature. The
mixture was concentrated at reduced pressure and the residue was
washed with 20% NaOH, and extracted with extracted with
CH.sub.2Cl.sub.2 (50 mL.times.2). The combined extracts were dried
(K.sub.2CO.sub.3), concentrated to yield the product (0.209 g, 66%)
without further purification.
[0293] d.
3-(3,4-Difluorophenyl)-2,2-dimethyl-5-oxo-morpholine-4-carboxyli- c
acid-{2-[4-(2-pyridyl)piperidin-1-yl]-1-methyl-ethyl}-amide
hydrochloride (Compound 19)
[0294] 4-(2-Pyridinyl)piperidinyl-N-(1-methyl)ethylamine (25 mg,
0.114 mmol) was added to a stirred solution of (.+-.)-4-nitrophenyl
2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (15
mg, 0.037 mmol) in CH.sub.2Cl.sub.2(5 mL). The resulting mixture
was stirred at room temperature overnight and purified by prep. TLC
on silica gel using EtOAc as eluent to give 10 mg product (55%).
MH.sup.+=487. The HCl salt was prepared by treatment with 1 N HCl
in ether.
10. Substituted Morpholinone Example:
N-4-(2-[1-(2,4-Difluorobenzoyl)-4-pi-
peridyl]aminoethyl)-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholine-
carboxamide hydrochloride (Compound 20) (Scheme 5)
[0295] a. 4-(2,4-Difluorobenzoyl)piperidinone
[0296] To a suspension of 4-piperidinone monohydrate hydrochloride
(2.00 g, 13.28 mmol) in CH.sub.2Cl.sub.2 (40 mL) and triethylamine
(5.0 mL) was added 2,4-difluorobenzoyl chloride (2.84 g, 15.93
mmol). The resulting mixture was stirred at room temperature for 5
hours before quenching with aqueous NaHCO.sub.3 (30 mL). Extracted
with EtOAc (3.times.50 mL), dried (MgSO.sub.4), and concentrated to
a residue which was purified by flash chromatography (EtOAc:Hexanes
9:1 to 1:1) afford product as an oil (2.25 g, 71%).
[0297] b.
2-{[4-(2,4-Difluorobenzoyl)piperidinyl]amino}-ethylamine
[0298] A solution of 4-(2,4-difluorobenzoyl)piperidinone (1.50 g,
6.27 mmol) in benzene (40 mL) and ethylenediamine (4.0 mL) was
refluxed for 6 hours. The resulting mixture was concentrated to a
residue which was dissolved in MeOH (30 mL). The mixture was cooled
(0.degree. C.) and NaBH.sub.4 (1.0 g, 26.4 mmol) was slowly added.
After stirred for an hour, the mixture was concentrated and
quenched with 1 N NaOH (50 mL). The mixture was extracted with
CH.sub.2Cl.sub.2 (5.times.20 mL), dried (K.sub.2CO.sub.3), and was
concentrated. The residue was purified by flash chromatography
(CHCl.sub.3-MeOH-2 M NH.sub.3 in MeOH 100:10:2 to 100:20:5) to
afford the product as an pale yellow solid (670 mg, 38%).
[0299] c.
3-(3,4-Difluorophenyl)-2,2-dimethyl-5-oxo-morpholine-4-carboxyli- c
acid-{2-[1-(2,4-difluoro benzoylpiperidin-4-yl]-aminoethylamide
hydrochloride
[0300] 4-N-(2,4-Difluorobenzoyl)-piperidinyl-amino-ethylamine (25
mg, 0.088 mmol) was added to a stirred solution of
(.+-.)-4-nitrophenyl
2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (15
mg, 0.037 mmol) in CH.sub.2Cl.sub.2 (5 mL). The resulting mixture
was stirred at room temperature overnight and purified by prep. TLC
on silica gel using EtOAc as eluent to give 10 mg product (49%).
MH.sup.+=551. The HCl salt was prepared by treatment with 1 N HCl
in ether.
IV. Synthesis of Morpholine Example (Scheme 6)
1. Synthesis of 3-(3,4-difluoro-phenyl)-morpholine-4-carboxylic
acid[3-(4,4-diphenyl-piperidin-1-yl)-propyl]-amide (Compound
21)
[0301] a. 3-(3,4-Difluoro-phenyl)-morpholine
[0302] To a suspension of LiAlH.sub.4 (6.0 mmol, 0.23 g) in 25.0 mL
of Et.sub.2O was added a solution of
5-(3,4-difluoro-phenyl)-morpholin-3-one (2.0 mmol, 0.42 g) in 20.0
mL Et.sub.2O and 5.0 mL THF at room temperature. The resulting
suspension was heated to reflux for 2 hours and was then quenched
with water and aq. NaOH solution. The solid was filtered off and
the filtrate was dried over Na.sub.2SO.sub.4. The filtrate was then
decanted and the solvent was removed in vacuo to obtain
5-(3,4-difluoro-phenyl)-morpholine as a viscous oil. It was
converted to its hydrochloride salt for its analysis. Yellow
powder. M.P.=171-173.degree. C.; Mass spec. 200 (M+1, 100%).
Analysis calculated for C.sub.10H.sub.12NOF.sub.2Cl.0.5 acetone: C,
51.96; H, 5.61; N, 5.41. Found: C, 51.98; H, 5.70; N, 5.34.
[0303] b. 3-(4,4-Diphenyl-piperidin-1-yl)-propyl]-carbamic
acid-4-nitro-phenyl ester
[0304] To a solution containing
3-(4,4-diphenyl-piperidin-1-yl)-propylamin- e (0.8 mmol, 0.24 g)
and triethylamine (0.96 mmol, 0.13 mL) in 10 mL of THF was added
4-nitrophenylchloroformate (0.94 mmol, 0.19 9) at 0.degree. C. The
solution was allowed to reach room temperature over 1 hour. The
solvent was removed and the product was passed through a short
silica gel column with EtOAc as an eluent (Rf=0.25).
3-(4,4-Diphenyl-piperidin-1-yl)- -propyl]-carbamic
acid-4-nitro-phenyl ester was obtained as a yellow oil which was
immediately used in the next step.
[0305] c. 3-(3,4-Difluoro-phenyl)-morpholine-4-carboxylic
acid[3-(4,4-diphenyl-piperidin-1-yl)-propyl]-amide
[0306] To a solution of
3-(4,4-diphenyl-piperidin-1-yl)-propyl]-carbamic
acid-4-nitro-phenyl ester (0.35 mmol, 150 mg) in 10.0 mL THF was
added 3-(3,4-difluoro-phenyl)-morpholine (0.4 mmol, 50 mg) at room
temperature. The solvent was removed in vacuo and the residue was
subjected to silica gel column chromatography (8:1 EtOAc/MeOH as
the eluting system).
3-(3,4-Difluoro-phenyl)-morpholine-4-carboxylic
acid[3-(4,4-diphenyl-pipe- ridin-1-yl)-propyl]-amide was obtained
as a pale yellow oil which was converted into its hydrochloride
salt by treatment with 1 N HCl in ether (34 mg, 61%) Yellow sticky
solid. M.P.=71-74.degree. C.; Mass spec. 520 (M+1, 100%); Analysis
calculated for C.sub.31H.sub.36N.sub.3O.sub.2F.sub.- 2Cl.0.8
CH.sub.2Cl.sub.2: C, 61.21; H, 6.07; N, 6.73. Found: C, 61.45; H,
6.35; N, 6.27.
V. General Syntheses of Morpholinones and Morpholines
[0307] The examples described in Sections I-IV are merely
illustrative of the methods used to synthesize morpholine and
morpholinone derivatives. Further derivatives may be obtained
utilizing the methods shown in Schemes 7-22. The substituents in
Schemes 7-22 are described in the Detailed Description.
[0308] It may be necessary to incorporate protection and
deprotection strategies for substituents such as amino, amido,
carboxylic acid, and hydroxyl groups in the synthetic methods
described above to form morpholine and morpholinone derivatives.
Methods for protection/deprotection of such groups are well-known
in the art, and may be found, for example in Greene, T. W. and
Wuts, P. G. M. (1991) Protective Groups in Organic Synthesis. 2nd
Edition John Wiley & Sons, New York.
VI. Oral Composition
[0309] As a specific embodiment of an oral composition of a
compound of this invention, 100 mg of one of the compounds
described herein is formulated with sufficient finely divided
lactose to provide a total amount of 580 to 590 mg to fill a size O
hard gel capsule.
VII. Pharmacological Profiles of the Compounds in Cloned Human
Adrenergic Receptors
[0310] Binding affinities were measured for selected compounds of
the invention at six cloned human .alpha..sub.1 and .alpha..sub.2
receptor subtypes, as well as at the L-type calcium channel. The
protocols for these experiments are given below.
[0311] 1. Protocol for the Determination of the Potency of
.alpha..sub.1 Antagonists
[0312] The activity of compounds at the different human receptors
was determined in vitro using cultured cell lines that selectively
express the receptor of interest. These cell lines were prepared by
transfecting the cloned cDNA or cloned genomic DNA or constructs
containing both genomic DNA and cDNA encoding the human
.alpha.-adrenergic receptors as follows:
[0313] .alpha..sub.1d Human Adrenergic Receptor: The entire coding
region of .alpha..sub.1d (1719 bp), including 150 base pairs of 5'
untranslated sequence (5' UT) and 300 bp of 3' untranslated
sequence (3' UT), was cloned into the BamHI and ClaI sites of the
polylinker-modified eukaryotic expression vector pCEXV-3, called
EXJ.HR. The construct involved the ligation of partial overlapping
human lymphocyte genomic and hippocampal cDNA clones: 5' sequence
were contained on a 1.2 kb SmaI-XhoI genomic fragment (the
vector-derived BamHI site was used for subcloning instead of the
internal insert-derived SmaI site) and 3' sequences were contained
on an 1.3 kb XhoI-ClaI cDNA fragment (the ClaI site was from the
vector polylinker). Stable cell lines were obtained by
cotransfection with the plasmid .alpha.1A/EXJ (expression vector
containing the .alpha..sub.1a receptor gene (old nomenclature)) and
the plasmid pGCcos3neo (plasmid containing the aminoglycoside
transferase gene) into LM(tk-) cells using calcium phosphate
technique. The cells were grown, in a controlled environment
(37.degree. C., 5% CO.sub.2), as monolayers in Dulbecco's modified
Eagle's Medium (GIBCO, Grand Island, N.Y.) containing 25 mM glucose
and supplemented with 10% bovine calf serum, 100 units/ml
penicillin g, and 100 .mu.g/ml streptomycin sulfate. Stable clones
were then selected for resistance to the antibiotic G-418 (1
mg/ml), and membranes were harvested and assayed for their ability
to bind [.sup.3H]prazosin as described below (see "Radioligand
Binding assays").
[0314] The cell line expressing the human .alpha..sub.1d receptor
used herein was designated L-.alpha..sub.1A (old nomenclature) and
was deposited with the American Type Culture Collection, 12301
Parklawn Drive, Rockville, Md. 20852, U.S.A. under the provisions
of the Budapest Treaty for the International Recognition of the
Deposit of Microorganisms for the Purposes of Patent Procedure. The
cell line expressing the human .alpha..sub.1d receptor, was
accorded ATCC Accession No. CRL 11138, and was deposited on Sep.
25, 1992.
[0315] .alpha..sub.1b Human Adrenergic Receptor: The entire coding
region of .alpha..sub.1b (1563 bp), including 200 base pairs and 5'
huntranslated sequence (5' UT) and 600 bp of 3' untranslated
sequence (3' UT), was cloned into the EcoRI site of pCEXV-3
eukaryotic expression vector. The construct involved ligating the
full-length containing EcoRI brainstem cDNA fragment from .lambda.
ZapII into the expression vector. Stable cell lines were selected
as described above. The cell line used herein was designated
L-.alpha..sub.1B and was deposited with the American Type Culture
Collection, 12301 Parklawn Drive, Rockville, Md. 20852, U.S.A.
under the provisions of the Budapest Treaty for the International
Recognition of the Deposit of Microorganisms for the Purposes of
Patent Procedure. The cell line L-.alpha..sub.1B was accorded ATCC
Accession No. CR 11139, on Sep. 29, 1992.
[0316] .alpha..sub.1a Human Adrenergic Receptor: The entire coding
region of .alpha..sub.1a (1401 bp), including 400 base pairs of 5'
untranslated sequence (5' UT) and 200 bp of 3' untranslated
sequence (3' UT), was cloned into the KpnI site of the
polylinker-modified pCEXV-3-derived eukaryotic expression vector,
EXJ.RH. The construct involved ligating three partial overlapping
fragments: a 5' 0.6 kb HincII genomic clone, a central 1.8 EcoRI
hippocampal cDNA clone, and a 3' 0.6 Kb PstI genomic clone. The
hippocampal cDNA fragment overlaps with the 5' and 3' genomic
clones so that the HincII and PstI sites at the 5' and 3' ends of
the cDNA clone, respectively, were utilized for ligation. This
full-length clone was cloned into the KpnI site of the expression
vector, using the 5' and 3' KpnI sites of the fragment, derived
from vector (i.e., pBluescript) and 3'-untranslated sequences,
respectively. Stable cell lines were selected as described above.
The stable cell line expressing the human .alpha..sub.1a receptor
used herein was designated L-.alpha..sub.1C (old nomenclature) and
was deposited with the American Type Culture Collection, 12301
Parklawn Drive, Rockville, Md. 20852, U.S.A. under the provisions
of the Budapest Treaty for the International Recognition of the
Deposit of Microorganisms for the Purposes of Patent Procedure. The
cell line expressing the human .alpha..sub.1a receptor was accorded
Accession No. CR 11140, on Sep. 25, 1992.
[0317] Radioligand Binding Assays for .alpha..sub.1 receptors:
Transfected cells from culture flasks were scraped into 5 ml of 5
mM Tris-HCl, 5 mM EDTA, pH 7.5, and lysed by sonication. The cell
lysates were centrifuged at 1000 rpm for 5 min at 4.degree. C., and
the supernatant was centrifuged at 30,000.times.g for 20 min at
4.degree. C. The pellet was suspended in 50 mM Tris-HCl, 1 mM
MgCl.sub.2, and 0.1% ascorbic acid at pH 7.5. Binding of the
.alpha..sub.1 antagonist [.sup.3H]prazosin (0.5 nM, specific
activity 76.2 Ci/mmol) to membrane preparations of LM(tk-) cells
was done in a final volume of 0.25 ml and incubated at 37.degree.
C. for 20 min. Nonspecific binding was determined in the presence
of 10 .mu.g phentolamine. The reaction was stopped by filtration
through GF/B filters using a cell harvester. Inhibition
experiments, routinely consisting of 7 concentrations of the tested
compounds, were analyzed using a non-linear regression
curve-fitting computer program to obtain Ki values.
[0318] .alpha..sub.2 Human Adrenergic Receptors: To determine the
potency of .alpha..sub.1 antagonists at the .alpha..sub.2
receptors, LM(tk-) cell lines stably transfected with the genes
encoding the .alpha..sub.2a, .alpha..sub.2b, and .alpha..sub.2c
receptors were used. The cell line expressing the .alpha..sub.2a
receptor is designated L-.alpha..sub.2A, and was deposited on Nov.
6, 1992 under ATCC Accession No. CRL 11180. The cell line
expressing the .alpha..sub.2b receptor is designated
L-NGC-.alpha..sub.2B, and was deposited on Oct. 25, 1989 under ATCC
Accession No. CRL10275. The cell line expressing the .alpha..sub.2c
receptor is designated L-.alpha..sub.2C, and was deposited on Nov.
6, 1992 under ATCC Accession No. CRL-11181. All the cell lines were
deposited with the American Type Culture Collection, 12301 Parklawn
Drive, Rockville, Md. 20852, U.S.A. under the provisions of the
Budapest Treaty for the International Recognition of the Deposit of
Microorganisms for the Purposes of Patent Procedure. Cell lysates
were prepared as described above (see Radioligand Binding Assays),
and suspended in 25 mM glycylglycine buffer (pH 7.6 at room
temperature). Equilibrium competition binding assay were performed
using [3H]rauwolscine (0.5 nM), and nonspecific binding was
determined by incubation with 10 .mu.M phentolamine. The bound
radioligand was separated by filtration through GF/B filters using
a cell harvester.
[0319] Determination of the Activity of .alpha..sub.1 Antagonists
at Calcium Channels:
[0320] The potency of .alpha..sub.1 antagonists at calcium channels
may be determined in competition binding assays of [3H]nitrendipine
to membrane fragments of rat cardiac muscle, essentially as
described by Glossman and Ferry (Methods in Enzymology 109:513-550,
1985). Briefly, the tissue is minced and homogenized in 50 mM
Tris-HCl (pH 7.4) containing 0.1 mM phenylmethylsulfonyl fluoride.
The homogenates are centrifuged at 1000 g for 15 minutes, and the
resulting supernatant centrifuged at 45,000 g for 15 minutes. The
45,000 g pellet is suspended in buffer and centrifuged a second
time. Aliquots of membrane protein are then incubated for 30
minutes at 37.degree. C. in the presence of [3H]nitrendipine (1
nM), and nonspecific binding determined in the presence of 10 .mu.g
nifedipine. The bound radioligand is separated by filtration
through GF/B filters using a cell harvester.
[0321] The compounds described above were assayed using cloned
human alpha adrenergic receptors. The preferred compounds were
found to be selective .alpha..sub.1a antagonists. The binding
affinities of several compounds are illustrated in the following
table.
[0322] Binding affinities of selected compounds of the present
invention at cloned human .alpha..sub.1d, .alpha..sub.1b and
.alpha..sub.1a receptors. (h=human)
1 h.alpha..sub.1d h.alpha..sub.1b h.alpha..sub.1a Compound K.sub.i
(nM) K.sub.i (nM) K.sub.i (nM) 1 306.7 243.6 1.6 4 3162.3 3630.8
32.0 7 204.2 245.5 12.6 14 4200.8 1456.6 2.6 17 579.9 464.2 3.8
[0323] 1415 1617 18 19 20 21 22 23 2425 26 2728 29 30 3132 33 34 35
36 37 38 39 40 41
* * * * *