U.S. patent application number 11/152753 was filed with the patent office on 2005-11-03 for 4-carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines.
Invention is credited to DeNinno, Michael P., Magnus-Aryitey, George T., Ruggeri, Roger B., Wester, Ronald T..
Application Number | 20050245570 11/152753 |
Document ID | / |
Family ID | 22281914 |
Filed Date | 2005-11-03 |
United States Patent
Application |
20050245570 |
Kind Code |
A1 |
DeNinno, Michael P. ; et
al. |
November 3, 2005 |
4-carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines
Abstract
Cholesteryl ester transfer protein inhibitors, pharmaceutical
compositions containing such inhibitors and the use of such
inhibitors to elevate certain plasma lipid levels, including high
density lipoprotein-cholesterol and to lower certain other plasma
lipid levels, such as LDL-cholesterol and triglycerides and
accordingly to treat diseases which are exacerbated by low levels
of HDL cholesterol and/or high levels of LDL-cholesterol and
triglycerides, such as atherosclerosis and cardiovascular diseases
in some mammals, including humans.
Inventors: |
DeNinno, Michael P.; (Gales
Ferry, CT) ; Magnus-Aryitey, George T.; (Ledyard,
CT) ; Ruggeri, Roger B.; (Waterford, CT) ;
Wester, Ronald T.; (Ledyard, CT) |
Correspondence
Address: |
PFIZER INC.
PATENT DEPARTMENT, MS8260-1611
EASTERN POINT ROAD
GROTON
CT
06340
US
|
Family ID: |
22281914 |
Appl. No.: |
11/152753 |
Filed: |
June 13, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11152753 |
Jun 13, 2005 |
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10607640 |
Jun 27, 2003 |
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6906082 |
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10607640 |
Jun 27, 2003 |
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09685380 |
Oct 10, 2000 |
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6586448 |
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09685380 |
Oct 10, 2000 |
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09391152 |
Sep 7, 1999 |
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6197786 |
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60100860 |
Sep 17, 1998 |
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Current U.S.
Class: |
514/313 ;
546/159 |
Current CPC
Class: |
C07D 409/04 20130101;
A61K 31/47 20130101; C07D 409/12 20130101; A61P 3/06 20180101; C07D
215/48 20130101; A61P 35/00 20180101; C07D 221/16 20130101; A61P
9/00 20180101; A61P 9/08 20180101; A61P 43/00 20180101; C07D 215/42
20130101; A61P 3/10 20180101; A61P 39/02 20180101; A61P 9/12
20180101; A61P 9/10 20180101; A61P 3/04 20180101 |
Class at
Publication: |
514/313 ;
546/159 |
International
Class: |
A61K 031/47; C07D
215/38 |
Claims
1. A compound of the Formula I 10a prodrug thereof, or a
pharmaceutically acceptable salt of said compound or of said
prodrug; wherein R.sup.1 is hydrogen, Y, W--X or W--Y; wherein W is
a carbonyl, thiocarbonyl, sulfinyl or sulfonyl; X is --O--Y,
--S--Y, --N(H)--Y or --N--(Y).sub.2; wherein Y for each occurrence
is independently Z or a fully saturated, partially unsaturated or
fully unsaturated one to ten membered straight or branched carbon
chain wherein the carbons, other than the connecting carbon, may
optionally be replaced with one or two heteroatoms selected
independently from oxygen, sulfur and nitrogen and said carbon is
optionally mono-, di- or tri-substituted independently with halo,
said carbon is optionally mono-substituted with hydroxy, said
carbon is optionally mono-substituted with oxo, said sulfur is
optionally mono- or di-substituted with oxo, said nitrogen is
optionally mono-, or di-substituted with oxo, and said carbon chain
is optionally mono-substituted with Z; wherein Z is a partially
saturated, fully saturated or fully unsaturated three to eight
membered ring optionally having one to four heteroatoms selected
independently from oxygen, sulfur and nitrogen, or a bicyclic ring
consisting of two fused partially saturated, fully saturated or
fully unsaturated three to six membered rings, taken independently,
optionally having one to four heteroatoms selected independently
from nitrogen, sulfur and oxygen; wherein said Z substituent is
optionally mono-, di- or tri-substituted independently with halo,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkyl, hydroxy,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.4)alkylthio, amino, nitro,
cyano, oxo, carboxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.6)alkylamino wherein said
(C.sub.1-C.sub.6)alkyl substituent is optionally mono-, di- or
tri-substituted independently with halo, hydroxy,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.4)alkylthio, amino, nitro,
cyano, oxo, carboxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.6)alkylamino, said (C.sub.1-C.sub.6)alkyl
substituent is also optionally substituted with from one to nine
fluorines; R.sup.2 is a partially saturated, fully saturated or
fully unsaturated one to six membered straight or branched carbon
chain wherein the carbons, other than the connecting carbon, may
optionally be replaced with one or two heteroatoms selected
independently from oxygen, sulfur and nitrogen wherein said carbon
atoms are optionally mono-, di- or tri-substituted independently
with halo, said carbon is optionally mono-substituted with oxo,
said carbon is optionally mono-substituted with hydroxy, said
sulfur is optionally mono- or di-substituted with oxo, said
nitrogen is optionally mono- or di-substituted with oxo; or said
R.sup.2 is a partially saturated, fully saturated or fully
unsaturated three to seven membered ring optionally having one to
two heteroatoms selected independently from oxygen, sulfur and
nitrogen, wherein said R.sup.2 ring is optionally attached through
(C.sub.1-C.sub.4)alkyl; wherein said R.sup.2 ring is optionally
mono-, di- or tri-substituted independently with halo,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkyl, hydroxy,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.4)alkylthio, amino, nitro,
cyano, oxo, carboxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.6)alk- ylamino wherein said
(C.sub.1-C.sub.6)alkyl substituent is optionally mono-, di- or
tri-substituted independently with halo, hydroxy,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.4)alkylthio, oxo or
(C.sub.1-C.sub.6)alkyloxycarbonyl; with the proviso that R.sup.2 is
not methyl; R.sup.3 is hydrogen or Q; wherein Q is a fully
saturated, partially unsaturated or fully unsaturated one to six
membered straight or branched carbon chain wherein the carbons
other than the connecting carbon, may optionally be replaced with
one heteroatom selected from oxygen, sulfur and nitrogen and said
carbon is optionally mono-, di- or tri-substituted independently
with halo, said carbon is optionally mono-substituted with hydroxy,
said carbon is optionally mono-substituted with oxo, said sulfur is
optionally mono- or di-substituted with oxo, said nitrogen is
optionally mono- or di-substituted with oxo, and said carbon chain
is optionally mono-substituted with V; wherein V is a partially
saturated, fully saturated or fully unsaturated three to eight
membered ring optionally having one to four heteroatoms selected
independently from oxygen, sulfur and nitrogen, or a bicyclic ring
consisting of two fused partially saturated, fully saturated or
fully unsaturated three to six membered rings, taken independently,
optionally having one to four heteroatoms selected independently
from nitrogen, sulfur and oxygen; wherein said V substituent is
optionally mono-, di-, tri-, or tetra-substituted independently
with halo, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
hydroxy, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.4)alkylthio,
amino, nitro, cyano, oxo, carboxamoyl, mono-N- or
di-N,N-(C.sub.1-C.sub.6)alkylcarboxamoyl, carboxy,
(C.sub.1-C.sub.6)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.6)alkylamino wherein said
(C.sub.1-C.sub.6)alkyl or (C.sub.2-C.sub.6)alkenyl substituent is
optionally mono-, di- or tri-substituted independently with
hydroxy, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.4)alkylthio,
amino, nitro, cyano, oxo, carboxy,
(C.sub.1-C.sub.6)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.6)alk- ylamino, said (C.sub.1-C.sub.6)alkyl
or (C.sub.2-C.sub.6)alkenyl substituents are also optionally
substituted with from one to nine fluorines; R.sup.4 is Q.sup.1 or
V.sup.1; wherein Q.sup.1 a fully saturated, partially unsaturated
or fully unsaturated one to six membered straight or branched
carbon chain wherein the carbons, other than the connecting carbon,
may optionally be replaced with one heteroatom selected from
oxygen, sulfur and nitrogen and said carbon is optionally mono-,
di- or tri-substituted independently with halo, said carbon is
optionally mono-substituted with hydroxy, said carbon is optionally
mono-substituted with oxo, said sulfur is optionally mono- or
di-substituted with oxo, said nitrogen is optionally mono- or
di-substituted with oxo, and said carbon chain is optionally
mono-substituted with V.sup.1; wherein V.sup.1 is is a partially
saturated, fully saturated or fully unsaturated three to six
membered ring optionally having one to two heteroatoms selected
independently from oxygen, sulfur and nitrogen; wherein said
V.sup.1 substituent is optionally mono-, di-, tri-, or
tetra-substituted independently with halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, amino, nitro, cyano,
(C.sub.1-C.sub.6)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.6)alkylamino wherein said
(C.sub.1-C.sub.6)alkyl substituent is optionally mono-substituted
with oxo, said (C.sub.1-C.sub.6)alkyl substituent is also
optionally substituted with from one to nine fluorines; wherein
either R.sup.3 must contain V or R.sup.4 must contain V.sup.1;
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen, a bond, nitro or halo wherein said bond is substituted
with T or a partially saturated, fully saturated or fully
unsaturated (C.sub.1-C.sub.12) straight or branched carbon chain
wherein carbon, may optionally be replaced with one or two
heteroatoms selected independently from oxygen, sulfur and nitrogen
wherein said carbon atoms are optionally mono-, di- or
tri-substituted independently with halo, said carbon is optionally
mono-substituted with hydroxy, said carbon is optionally
mono-substituted with oxo, said sulfur is optionally mono- or
di-substituted with oxo, said nitrogen is optionally mono- or
di-substituted with oxo, and said carbon is optionally
mono-substituted with T; wherein T is a partially saturated, fully
saturated or fully unsaturated three to eight membered ring
optionally having one to four heteroatoms selected independently
from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of
two fused partially saturated, fully saturated or fully unsaturated
three to six membered rings, taken independently, optionally having
one to four heteroatoms selected independently from nitrogen,
sulfur and oxygen; wherein said T substituent is optionally mono-,
di- or tri-substituted independently with halo,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, hydroxy,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.4)alkylthio, amino, nitro,
cyano, oxo, carboxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.6)alkylamino wherein said
(C.sub.1-C.sub.6)alkyl substituent is optionally mono-, di- or
tri-substituted independently with hydroxy,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.4)alkylthio, amino, nitro,
cyano, oxo, carboxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.6)alkylamino, said (C.sub.1-C.sub.6)alkyl
substituent is also optionally substituted with from one to nine
fluorines; and wherein R.sup.5 and R.sup.6, or R.sup.5 and R.sup.7,
and/or R.sup.7 and R.sup.5 may also be taken together and can form
at least one four to eight membered ring that is partially
saturated or fully unsaturated optionally having one to three
heteroatoms independently selected from nitrogen, sulfur and
oxygen; wherein said ring or rings formed by R.sup.5 and R.sup.6,
or R.sup.5 and R.sup.7, and/or R.sup.7 and R.sup.8 are optionally
mono-, di- or tri-substituted independently with halo,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.4)alkylsu- lfonyl,
(C.sub.2-C.sub.6)alkenyl, hydroxy, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.4)alkylthio, amino, nitro, cyano, oxo, carboxy,
(C.sub.1-C.sub.6)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.6)alk- ylamino wherein said
(C.sub.1-C.sub.6)alkyl substituent is optionally mono-, di- or
tri-substituted independently with hydroxy,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.4)alkylthio, amino, nitro,
cyano, oxo, carboxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.6)alkylamino, said (C.sub.1-C.sub.6)alkyl
substituent is also optionally substituted with from one to nine
fluorines; with the proviso that when R.sup.2 is carboxyl or
(C.sub.1-C.sub.4)alkylcarboxyl, then R.sup.1 is not hydrogen.
2-47. (canceled)
48.
cis-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydroquinolin-4-yl)carbami-
c acid methyl ester.
Description
[0001] This application claims priority from provisional
application U.S. Ser. No. 60/100,860 filed Sep. 17, 1998, the
benefit of which is hereby claimed under 37 C.F.R.
.sctn.1.78(a)(3).
BACKGROUND OF INVENTION
[0002] This invention relates to cholesteryl ester transfer protein
(CETP) inhibitors, pharmaceutical compositions containing such
inhibitors and the use of such inhibitors to elevate certain plasma
lipid levels, including high density lipoprotein (HDL)-cholesterol
and to lower certain other plasma lipid levels, such as low density
lipoprotein (LDL)-cholesterol and triglycerides and accordingly to
treat diseases which are affected by low levels of HDL cholesterol
and/or high levels of LDL-cholesterol and triglycerides, such as
atherosclerosis and cardiovascular diseases in certain mammals
(i.e., those which have CETP in their plasma), including
humans.
[0003] Atherosclerosis and its associated coronary artery disease
(CAD) is the leading cause of mortality in the industrialized
world. Despite attempts to modify secondary risk factors (smoking,
obesity, lack of exercise) and treatment of dyslipidemia with
dietary modification and drug therapy, coronary heart disease (CHD)
remains the most common cause of death in the U.S., where
cardiovascular disease accounts for 44% of all deaths, with 53% of
these associated with atherosclerotic coronary heart disease.
[0004] Risk for development of this condition has been shown to be
strongly correlated with certain plasma lipid levels. While
elevated LDL-C may be the most recognized form of dyslipidemia, it
is by no means the only significant lipid associated contributor to
CHD. Low HDL-C is also a known risk factor for CHD (Gordon, D. J.,
et al.,: "High-density Lipoprotein Cholesterol and Cardiovascular
Disease", Circulation, (1989), 79: 8-15).
[0005] High LDL-cholesterol and triglyceride levels are positively
correlated, while high levels of HDL-cholesterol are negatively
correlated with the risk for developing cardiovascular diseases.
Thus, dyslipidemia is not a unitary risk profile for CHD but may be
comprised of one or more lipid aberrations.
[0006] Among the many factors controlling plasma levels of these
disease dependent principles, cholesteryl ester transfer protein
(CETP) activity affects all three. The role of this 70,000 dalton
plasma glycoprotein found in a number of animal species, including
humans, is to transfer cholesteryl ester and triglyceride between
lipoprotein particles, including high density lipoproteins (HDL),
low density lipoproteins (LDL), very low density lipoproteins
(VLDL), and chylomicrons. The net result of CETP activity is a
lowering of HDL cholesterol and an increase in LDL cholesterol.
This effect on lipoprotein profile is believed to be
pro-atherogenic, especially in subjects whose lipid profile
constitutes an increased risk for CHD.
[0007] No wholly satisfactory HDL-elevating therapies exist. Niacin
can significantly increase HDL, but has serious toleration issues
which reduce compliance. Fibrates and the HMG CoA reductase
inhibitors raise HDL-C only modestly (.about.10-12%). As a result,
there is a significant unmet medical need for a well-tolerated
agent which can significantly elevate plasma HDL levels, thereby
reversing or slowing the progression of atherosclerosis.
[0008] Thus, although there are a variety of anti-atherosclerosis
therapies, there is a continuing need and a continuing search in
this field of art for alternative therapies.
[0009] EP.sup.0818448 (970624) discloses the preparation of certain
5,6,7,8 substituted tetrahydroquinolines and analogs as cholesteryl
ester transfer protein inhibitors.
[0010] U.S. Pat. No. 5,231,102 discloses a class of 4-substituted
1,2,3,4-tetrahydroquinolines that possess an acidic group (or group
convertible thereto in vivo) at the 2-position that are specific
antagonists of N-methyl-D-aspartate (NMDA) receptors and are
therefore useful in the treatment and/or prevention of
neurodegenerative disorders.
[0011] U.S. Pat. No. 5,288,725 discloses pyrroloquinoline
bradykinin antagonists.
SUMMARY OF THE INVENTION
[0012] This invention is directed to compounds of Formula I 1
[0013] prodrugs thereof, and pharmaceutically acceptable salts of
said compounds and said prodrugs;
[0014] wherein R.sup.1 is hydrogen, Y, W--X or W--Y;
[0015] wherein W is a carbonyl, thiocarbonyl, sulfinyl or
sulfonyl;
[0016] X is --O--Y, --S--Y, --N(H)--Y or --N--(Y).sub.2;
[0017] wherein Y for each occurrence is independently Z or a fully
saturated, partially unsaturated or fully unsaturated one to ten
membered straight or branched carbon chain wherein the carbons,
other than the connecting carbon, may optionally be replaced with
one or two heteroatoms selected independently from oxygen, sulfur
and nitrogen and said carbon is optionally mono-, di- or
tri-substituted independently with halo, said carbon is optionally
mono-substituted with hydroxy, said carbon is optionally
mono-substituted with oxo, said sulfur is optionally mono- or
di-substituted with oxo, said nitrogen is optionally mono-, or
di-substituted with oxo, and said carbon chain is optionally
mono-substituted with Z;
[0018] wherein Z is a partially saturated, fully saturated or fully
unsaturated three to eight membered ring optionally having one to
four heteroatoms selected independently from oxygen, sulfur and
nitrogen, or a bicyclic ring consisting of two fused partially
saturated, fully saturated or fully unsaturated three to six
membered rings, taken independently, optionally having one to four
heteroatoms selected independently from nitrogen, sulfur and
oxygen;
[0019] wherein said Z substituent is optionally mono-, di- or
tri-substituted independently with halo, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkyl, hydroxy, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.4)alkylthio, amino, nitro, cyano, oxo, carboxy,
(C.sub.1-C.sub.6)alkyloxycarbonyl, mono-N- or
di-N,N-C.sub.1-C.sub.6)alky- lamino wherein said
(C.sub.1-C.sub.6)alkyl substituent is optionally mono-, di- or
tri-substituted independently with halo, hydroxy,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.4)alkylthio, amino, nitro,
cyano, oxo, carboxy, (C.sub.1-C.sub.0)alkyloxycarbonyl, mono-N- or
di-N,N(C.sub.1-C.sub.6)alkylamino, said (C.sub.1-C.sub.6)alkyl
substituent is also optionally substituted with from one to nine
fluorines;
[0020] R.sup.2 is a partially saturated, fully saturated or fully
unsaturated one to six membered straight or branched carbon chain
wherein the carbons, other than the connecting carbon, may
optionally be replaced with one or two heteroatoms selected
independently from oxygen, sulfur and nitrogen wherein said carbon
atoms are optionally mono-, di- or tri-substituted independently
with halo, said carbon is optionally mono-substituted with oxo,
said carbon is optionally mono-substituted with hydroxy, said
sulfur is optionally mono- or di-substituted with oxo, said
nitrogen is optionally mono- or di-substituted with oxo; or said
R.sup.2 is a partially saturated, fully saturated or fully
unsaturated three to seven membered ring optionally having one to
two heteroatoms selected independently from oxygen, sulfur and
nitrogen, wherein said R.sup.2 ring is optionally attached through
(C.sub.1-C.sub.4)alkyl;
[0021] wherein said R.sup.2 ring is optionally mono-, di- or
tri-substituted independently with halo, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkyl, hydroxy, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.4)alkylthio, amino, nitro, cyano, oxo, carboxy,
(C.sub.1-C.sub.6)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.6)alk- ylamino wherein said
(C.sub.1-C.sub.6)alkyl substituent is optionally mono-, di- or
tri-substituted independently with halo, hydroxy,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.4)alkylthio, oxo or
(C.sub.1-C.sub.6)alkyloxycarbonyl;
[0022] with the proviso that R.sup.2 is not methyl;
[0023] R.sup.3 is hydrogen or Q;
[0024] wherein Q is a fully saturated, partially unsaturated or
fully unsaturated one to six membered straight or branched carbon
chain wherein the carbons other than the connecting carbon, may
optionally be replaced with one heteroatom selected from oxygen,
sulfur and nitrogen and said carbon is optionally mono-, di- or
tri-substituted independently with halo, said carbon is optionally
mono-substituted with hydroxy, said carbon is optionally
mono-substituted with oxo, said sulfur is optionally mono- or
di-substituted with oxo, said nitrogen is optionally mono- or
di-substituted with oxo, and said carbon chain is optionally
mono-substituted with V;
[0025] wherein V is a partially saturated, fully saturated or fully
unsaturated three to eight membered ring optionally having one to
four heteroatoms selected independently from oxygen, sulfur and
nitrogen, or a bicyclic ring consisting of two fused partially
saturated, fully saturated or fully unsaturated three to six
membered rings, taken independently, optionally having one to four
heteroatoms selected independently from nitrogen, sulfur and
oxygen;
[0026] wherein said V substituent is optionally mono-, di-, tri-,
or tetra-substituted independently with halo,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl, hydroxy,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.4)alkylthio, amino, nitro,
cyano, oxo, carboxamoyl, mono-N- or di-N,N-(C.sub.1-C.sub.6)
alkylcarboxamoyl, carboxy, (C.sub.1-C.sub.6)alkyloxycarbonyl,
mono-N- or di-N,N-(C.sub.1-C.sub.6)alk- ylamino wherein said
(C.sub.1-C.sub.6)alkyl or (C.sub.2-C.sub.6)alkenyl substituent is
optionally mono-, di- or tri-substituted independently with
hydroxy, (C.sub.1)alkoxy, (C.sub.1-C.sub.4)alkylthio, amino, nitro,
cyano, oxo, carboxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, mono-N- or
di-N,N-C.sub.1-C.sub.6)alkylamino, said (C.sub.1-C.sub.6)allyl or
(C.sub.2-C.sub.6)alkenyl substituents are also optionally
substituted with from one to nine fluorines;
[0027] R.sup.4 is Q.sup.1 or V.sup.1;
[0028] wherein Q.sup.1 a fully saturated, partially unsaturated or
fully unsaturated one to six membered straight or branched carbon
chain wherein the carbons, other than the connecting carbon, may
optionally be replaced with one heteroatom selected from oxygen,
sulfur and nitrogen and said carbon is optionally mono-, di- or
tri-substituted independently with halo, said carbon is optionally
mono-substituted with hydroxy, said carbon is optionally
mono-substituted with oxo, said sulfur is optionally mono- or
di-substituted with oxo, said nitrogen is optionally mono- or
di-substituted with oxo, and said carbon chain is optionally
mono-substituted with V.sup.1;
[0029] wherein V.sup.1 is is a partially saturated, fully saturated
or fully unsaturated three to six membered ring optionally having
one to two heteroatoms selected independently from oxygen, sulfur
and nitrogen;
[0030] wherein said V.sup.1 substituent is optionally mono-, di-,
tri-, or tetra-substituted independently with halo,
(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.6)alkoxy, amino, nitro,
cyano, (C.sub.1-C.sub.6)alkyloxyca- rbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.6)alkylamino wherein said
(C.sub.1-C.sub.6)alkyl substituent is optionally mono-substituted
with oxo, said (C.sub.1-C.sub.6)alkyl substituent is also
optionally substituted with from one to nine fluorines;
[0031] wherein either R.sup.3 must contain V or R.sup.4 must
contain V.sup.1; R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each
independently hydrogen, a bond, nitro or halo wherein said bond is
substituted with T or a partially saturated, fully saturated or
fully unsaturated (C.sub.1-C.sub.12) straight or branched carbon
chain wherein carbon may optionally be replaced with one or two
heteroatoms selected independently from oxygen, sulfur and nitrogen
wherein said carbon atoms are optionally mono-, di- or
tri-substituted independently with halo, said carbon is optionally
mono-substituted with hydroxy, said carbon is optionally
mono-substituted with oxo, said sulfur is optionally mono- or
di-substituted with oxo, said nitrogen is optionally mono- or
di-substituted with oxo, and said carbon is optionally
mono-substituted with T;
[0032] wherein T is a partially saturated, fully saturated or fully
unsaturated three to eight membered ring optionally having one to
four heteroatoms selected independently from oxygen, sulfur and
nitrogen, or a bicyclic ring consisting of two fused partially
saturated, fully saturated or fully unsaturated three to six
membered rings, taken independently, optionally having one to four
heteroatoms selected independently from nitrogen, sulfur and
oxygen;
[0033] wherein said T substituent is optionally mono-, di- or
tri-substituted independently with halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, hydroxy, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.4)alkylthio, amino, nitro, cyano, oxo, carboxy,
(C.sub.1-C.sub.6)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.6)alk- ylamino wherein said
(C.sub.1-C.sub.6)alkyl substituent is optionally mono-, di- or
tri-substituted independently with hydroxy,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.4)alkylthio, amino, nitro,
cyano, oxo, carboxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.6)alkylamino, said (C.sub.1-C.sub.6)alkyl
substituent is also optionally substituted with from one to nine
fluorines; and
[0034] wherein R.sup.5 and R.sup.6, or Re and R.sup.7, and/or
R.sup.7 and R.sup.8 may also be taken together and can form at
least one four to eight membered ring that is partially saturated
or fully unsaturated optionally having one to three heteroatoms
independently selected from nitrogen, sulfur and oxygen;
[0035] wherein said ring or rings formed by R.sup.5 and R.sup.6, or
R.sup.6 and R.sup.7, and/or R.sup.7 and R.sup.8 are optionally
mono-, di- or tri-substituted independently with halo,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.4)alkylsulfonyl,
(ce)alkenyl, hydroxy, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.4)alkylthio, amino, nitro, cyano, oxo, carboxy,
(C.sub.1-C.sub.6)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.6)alkylamino wherein said
(C.sub.1-C.sub.6)alkyl substituent is optionally mono-, di- or
tri-substituted independently with hydroxy,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.4)alkylthio, amino, nitro,
cyano, oxo, carboxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.6)alkylamino, said (C.sub.1-C.sub.6)alkyl
substituent is also optionally substituted with from one to nine
fluorines;
[0036] with the proviso that when R.sup.2 is carboxyl or
(C.sub.1-C.sub.4)alkylcarboxyl, then R.sup.1 is not hydrogen.
[0037] A preferred group of compounds, designated the A Group,
contains those compounds having the Formula I as shown above
wherein
[0038] R.sup.2 is beta;
[0039] the C.sup.4 nitrogen is beta:
[0040] R.sup.1 is W--X;
[0041] W is carbonyl, thiocarbonyl or --SO.sub.2--;
[0042] X is --O--Y--, S--Y--, --N(H)Y-- or --N--(Y)--;
[0043] Y for each occurrence is independently Z or
(C.sub.1-C.sub.4)alkyl, said (C.sub.1-C.sub.4)alkyl optionally
substituted with from one to nine fluorines or hydroxy, or said
(C.sub.1-C.sub.4)alkyl optionally mono-substituted with Z;
[0044] wherein Z is a partially saturated, fully saturated or fully
unsaturated three to six membered ring optionally having one to two
heteroatoms selected independently from oxygen, sulfur and
nitrogen;
[0045] wherein said Z substituent is optionally mono-, di- or
tri-substituted independently with halo, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.4)alkylthio, nitro, cyano,
oxo, or (C.sub.1-C.sub.6)alkyloxycarbonyl, said
(C.sub.1-C.sub.4)alkyl is optionally substituted with from one to
nine fluorines;
[0046] R.sup.2 is a partially saturated, fully saturated or fully
unsaturated one to four membered straight or branched carbon chain
wherein the carbons, other than the connecting carbon, may
optionally be replaced with one heteroatom selected independently
from oxygen, sulfur and nitrogen wherein said carbon atoms are
optionally mono-, di- or tri-substituted independently with halo,
said carbon is optionally mono-substituted with oxo, said carbon is
optionally mono-substituted with hydroxy, said sulfur is optionally
mono- or di-substituted with oxo, said nitrogen is optionally mono-
or di-substituted with oxo; or said R.sup.2 is a partially
saturated, fully saturated or fully unsaturated three to five
membered ring optionally having one heteroatom selected
independently from oxygen, sulfur and nitrogen;
[0047] wherein said R.sup.2 ring is optionally mono-, di- or
tri-substituted independently with halo, hydroxy,
(C.sub.1-C.sub.6)alkoxy or (C.sub.1-C.sub.6)alkoxycarbonyl; R.sup.3
is Q-V wherein Q is (C.sub.1-C.sub.4)alkyl and V is a five or six
membered partially saturated, fully saturated or fully unsaturated
ring optionally having one to three heteroatoms selected
independently from oxygen, sulfur and nitrogen;
[0048] wherein said V ring is optionally mono-, di-, tri- or
tetra-substituted independently with halo, (C.sub.1-C.sub.6)alkyl,
hydroxy, (C.sub.1-C.sub.6)alkoxy, nitro, cyano or oxo wherein said
(C.sub.1-C.sub.6)alkyl substituent optionally has from one to nine
fluorines;
[0049] R.sup.4 is (C.sub.1-C.sub.4)alkyl;
[0050] R.sup.6 and R.sup.7 are each independently H, halo, T or
(C.sub.1-C.sub.6)alkyl, said (C.sub.1-C.sub.6)alkyl optionally
having from one to nine fluorines or said (C.sub.1-C.sub.6)alkyl is
optionally mono-substituted with T;
[0051] wherein T is a partially saturated, fully saturated or fully
unsaturated five to six membered ring optionally having one to two
heteroatoms selected independently from oxygen, sulfur and
nitrogen;
[0052] wherein said T substituent is optionally mono-, di- or
tri-substituted independently with halo, (C.sub.1-C.sub.6)alkyl,
hydroxy, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.4)alkylthio,
amino, oxo, carboxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.6)alk- ylamino wherein said
(C.sub.1-C.sub.6)alkyl substituent optionally has from one to nine
fluorines; and
[0053] R.sup.1 and R.sup.8 are H,
[0054] and pharmaceutically acceptable salts thereof.
[0055] A group of compounds which is preferred among the A Group of
compounds, designated the B Group, contains those compounds
wherein
[0056] W is carbonyl;
[0057] X is O--Y wherein Y is (C.sub.1-C.sub.4)alkyl, said
(C.sub.1-C.sub.4)alkyl substituent optionally substituted with from
one to nine fluorines or hydroxy;
[0058] Q is (C.sub.1-C.sub.4)alkyl and V is phenyl, pyridinyl, or
pyrimidinyl;
[0059] wherein said V ring is optionally mono-, di- or
tri-substituted independently with halo, (C.sub.1-C.sub.6)alkyl,
hydroxy, (C.sub.1-C.sub.6)alkoxy, nitro, cyano or oxo wherein said
(C.sub.1-C.sub.6)alkyl substituent optionally has from one to nine
fluorines;
[0060] R.sup.2 is a fully saturated (C.sub.1-C.sub.4) straight or
branched carbon chain; or said R.sup.2 is a fully saturated three
to five membered ring; wherein said R.sup.2 chain or ring is
optionally mono-, di- or tri-substituted independently with
halo;
[0061] R.sup.6 and R.sup.7 are each independently hydrogen, halo or
(C.sub.1-C.sub.6)alkyl, said (C.sub.1-C.sub.6)alkyl optionally
having from one to nine fluorines; and pharmaceutically acceptable
salts thereof.
[0062] A group of compounds which is preferred among the B Group of
compounds designated the C Group, contains those compounds wherein
Q is methyl and V is phenyl or pyridinyl;
[0063] wherein said V ring is optionally mono-, di- or
tri-substituted independently with halo, (C.sub.1-C.sub.2)alkyl, or
nitro wherein said (C.sub.1-C.sub.2)alkyl optionally has from one
to five fluorines, and pharmaceutically acceptable salts
thereof.
[0064] Especially preferred compounds of Formula I are the
compounds
[0065]
[2S,4S]4[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2--
isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-arboxylic
acid isopropyl ester,
[0066]
[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]ch-
loro-2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
isopropyl ester;
[0067]
[2S,4S]2-cyclopropyl-4-[(3,5-dichloro-benzyl)-methoxycarbonyl-amino-
]+trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
isopropyl ester;
[0068]
[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-
-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid tert-butyl ester,
[0069]
[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-
-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester,
[0070]
[2S,4S]4-[((3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]--
2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester,
[0071] and pharmaceutically acceptable salts of said compounds.
[0072] Especially preferred compounds of Formula I are the
compounds
[0073]
[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]2--
ethyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1 carboxylic acid
isopropyl ester,
[0074]
[2S,4S]4[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2
methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-rboxylic
acid isopropyl ester;
[0075]
[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-
-ethyl trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
2-hydroxy-ethyl ester,
[0076]
[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]2--
cyclopropyl trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid ethyl ester,
[0077]
[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-
-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
ethyl ester,
[0078]
[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-
-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-carboxylic
acid propyl ester,
[0079]
[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-
-ethyl trifluoromethyl-3,4-dihydro-2H-quinoline-1 arboxylic acid
propyl ester,
[0080] and pharmaceutically acceptable salt thereof.
[0081] Especially preferred compounds within the C Group of
compounds are compounds wherein
[0082] a. Y is isopropyl;
[0083] R.sup.2 is isopropyl;
[0084] R.sup.3 is 3,5-bis-trifluoromethylphenylmethyl;
[0085] R.sup.4 is methyl;
[0086] R.sup.6 is trifluoromethyl; and
[0087] R.sup.7 is H;
[0088] b. Y is isopropyl;
[0089] R.sup.2 is cyclopropyl;
[0090] R.sup.3 is 3,5-bis-trifluoromethylphenylmethyl;
[0091] R.sup.4 is methyl;
[0092] R.sup.6 is chloro; and
[0093] R.sup.7 is H;
[0094] c. Y is isopropyl;
[0095] R.sup.2 is cyclopropyl;
[0096] R.sup.3 is 3,5-dichlorophenylmethyl;
[0097] R.sup.4 is methyl;
[0098] R.sup.6 is trifluoromethyl; and R.sup.7 is H;
[0099] d. Y is tert-butyl;
[0100] R.sup.2 is cyclopropyl;
[0101] R.sup.3 is 3,5-bis-trifluoromethylphenylmethyl;
[0102] R.sup.4 is methyl;
[0103] R.sup.6 trifluoromethyl; and
[0104] R.sup.7 is H;
[0105] e. Y is isopropyl;
[0106] R.sup.2 is cyclopropyl;
[0107] R.sup.3 is 3,5-bis-trifluoromethylphenylmethyl;
[0108] R.sup.4 is methyl;
[0109] R.sup.6 trifluoromethyl; and
[0110] R.sup.7 is H;
[0111] f. Y is isopropyl;
[0112] R.sup.2 is cyclobutyl;
[0113] R.sup.3 is 3,5-bis-trifluoromethylphenylmethyl;
[0114] R.sup.4 is methyl;
[0115] R.sup.6 trifluoromethyl; and
[0116] R.sup.7 is H;
[0117] g. Y is isopropyl;
[0118] R.sup.2 is ethyl;
[0119] R.sup.3 is 3,5-bis-trifluoromethylphenylmethyl;
[0120] R.sup.4 is methyl;
[0121] R.sup.6 is trifluoromethyl; and
[0122] R.sup.7 is H;
[0123] h. Y is isopropyl;
[0124] R.sup.2 is methoxymethyl;
[0125] R.sup.3 is 3,5-bis-trifluoromethylphenylmethyl;
[0126] R.sup.4 is methyl;
[0127] R.sup.6 is trifluoromethyl; and
[0128] R.sup.7 is H;
[0129] I. Y is 2-hydroxyethyl;
[0130] R.sup.2 is ethyl;
[0131] R.sup.3 is 3,5-bis-trifluoromethylphenylmethyl;
[0132] R.sup.4 is methyl;
[0133] R.sup.6 is trifluoromethyl; and
[0134] R.sup.7 is H;
[0135] j. Y is ethyl;
[0136] R.sup.2 is cyclopropyl;
[0137] R.sup.3 is 3,5-bis-trifluoromethylphenylmethyl;
[0138] R.sup.4 is methyl;
[0139] R.sup.6 is trifluoromethyl; and
[0140] R.sup.7 is H;
[0141] k. Y is ethyl;
[0142] R.sup.2 is ethyl;
[0143] R.sup.3 is 3,5-bis-trifluoromethylphenylmethyl;
[0144] R.sup.4 is methyl;
[0145] R.sup.6 is trifluoromethyl; and
[0146] R.sup.7 is H;
[0147] I. Y is n-propyl;
[0148] R.sup.2 is cyclopropyl;
[0149] R.sup.3 is 3,5-bis-trifluoromethylphenylmethyl;
[0150] R.sup.4 is methyl;
[0151] R.sup.6 is trifluoromethyl; and
[0152] R.sup.7 is H; and
[0153] m. Y is n-propyl;
[0154] R.sup.2 is ethyl;
[0155] R.sup.3 is 3,5-bis-trifluoromethylphenylmethyl;
[0156] R.sup.4 is methyl;
[0157] R.sup.6 is trifluoromethyl; and R.sup.7 is H; and
pharmaceutically acceptable salts of said compounds.
[0158] Other preferred compounds are the compounds
[0159]
[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-
-isopropyl trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester;
[0160]
[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-
-chloro-2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
isopropyl ester;
[0161]
[2S,4S]2-cyclopropyl-4-[(3,5-dichloro-benzyl)-methoxycarbonyl-amino-
]-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
isopropyl ester
[0162]
[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]2--
cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid tert-butyl ester,
[0163]
[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-
-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester;
[0164]
[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-
-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester;
[0165]
[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]2--
h trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
isopropyl ester,
[0166]
[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonylamino]-2--
methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester;
[0167]
[2R,4S]4-(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino-2-h
trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
2-hydroxy-ethyl ester,
[0168]
[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-
-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid ethyl ester;
[0169]
[2R,4S]4[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]2-h
trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic add ethyl
ester;
[0170]
[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]2--
cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid propyl ester;
[0171]
[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-
-ethyl trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
propyl ester, pharmaceutically acceptable salts of said
compounds.
[0172] A preferred group of compounds, designated the E Group,
contains those compounds having the Formula I as shown above
wherein
[0173] R.sup.2 is beta;
[0174] the C.sup.4 nitrogen is beta;
[0175] R.sup.1 is W--X;
[0176] W is carbonyl, thiocarbonyl or sulfonyl;
[0177] X is --O--Y--, S--Y--, N(H)--Y-- or --N--(Y).sub.2--;
[0178] Y for each occurrence is independently Z or
(C.sub.1-C.sub.4)alkyl, said (C.sub.1-C.sub.4)alkyl optionally
having from one to nine fluorines or said (C.sub.1-C.sub.4)alkyl
optionally mono-substituted with Z;
[0179] wherein Z is a partially saturated, fully saturated or fully
unsaturated three to six membered ring optionally having one to two
heteroatoms selected independently from oxygen, sulfur and
nitrogen;
[0180] wherein said Z substituent is optionally mono-, di- or
tri-substituted independently with halo, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.4)alkylthio, nitro, cyano,
oxo, or (C.sub.1-C.sub.6)alkyloxycarbonyl, said
(C.sub.1-C.sub.4)alkyl substituent optionally substituted with from
one to nine fluorines;
[0181] R.sup.2 is a partially saturated, fully saturated or fully
unsaturated one to four membered straight or branched carbon chain
wherein the carbons, other than the connecting carbon, may
optionally be replaced with one heteroatom selected independently
from oxygen, sulfur and nitrogen wherein said carbon atoms are
optionally mono-, di- or tri-substituted independently with halo,
said carbon is optionally mono-substituted with oxo, said carbon is
optionally mono-substituted with hydroxy, said sulfur is optionally
mono- or di-substituted with oxo, said nitrogen is optionally mono-
or di-substituted with oxo; or said R.sup.2 is a partially
saturated, fully saturated or fully unsaturated three to five
membered ring optionally having one heteroatom selected
independently from oxygen, sulfur and nitrogen;
[0182] wherein said R.sup.2 ring is optionally mono-, di- or
tri-substituted independently with halo, hydroxy,
(C.sub.1-C.sub.6)alkoxy or (C.sub.1-C.sub.6)alkoxycarbonyl;
[0183] R.sup.3 is Q-V wherein Q is (C.sub.1-C.sub.4)alkyl and V is
a five or six membered partially saturated, fully saturated or
fully unsaturated ring optionally having one to three heteroatoms
selected independently from oxygen, sulfur and nitrogen;
[0184] wherein said V ring is optionally mono-, di-, tri- or
tetra-substituted independently with halo, (C.sub.1-C.sub.6)alkyl,
hydroxy, (C.sub.1-C.sub.6)alkoxy, nitro, cyano or oxo wherein said
(C.sub.1-C.sub.6)alkyl substituent optionally has from one to nine
fluorines;
[0185] R.sup.4 is (C.sub.1-C.sub.4)alkyl; and
[0186] R.sup.5 and R.sup.6, or R.sup.6 and R.sup.7, or R.sup.7 and
R.sup.8 are taken together and form one ring that is a partially
saturated or fully unsaturated five or six membered ring optionally
having one to two heteroatoms independently selected from nitrogen,
sulfur and oxygen;
[0187] wherein said ring formed by R.sup.5 and R.sup.6, or R.sup.6
and R.sup.7, or R.sup.7 and R.sup.8 are optionally mono-, di- or
tri-substituted independently with halo, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkylsulfonyl, (C.sub.1-C.sub.4)alkenyl, hydroxy,
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.4)alkylthio, amino, nitro,
cyano, oxo, carboxy, (C.sub.1-C.sub.4)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.4)alkylamino wherein said
(C.sub.1-C.sub.4)alkyl substituent is optionally mono-, di- or
tri-substituted independently with hydroxy,
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.4)alkylthio, amino, nitro,
cyano, oxo, carboxy, (C.sub.1-C.sub.4)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.4)alkylamino or said (C.sub.1-C.sub.4)alkyl
substituent optionally has from one to nine fluorines;
[0188] provided that the R.sup.5, R.sup.6, R.sup.7 and/or R.sup.8,
as the case may be, that do not form the ring are hydrogen;
[0189] and pharmaceutically acceptable salts thereof.
[0190] A preferred group of compounds, designated the F Group,
contains those compounds having the Formula I as shown above
wherein
[0191] R.sup.2 is beta;
[0192] the C.sup.4 nitrogen is beta;
[0193] R.sup.1 is W--Y;
[0194] W is carbonyl, thiocarbonyl or sulfonyl;
[0195] Y is (C.sub.1-C.sub.6)alkyl, said (C.sub.1-C.sub.6)alkyl
optionally having from one to nine fluorines or said
(C.sub.1-C.sub.6)alkyl optionally mono-substituted with Z;
[0196] wherein Z is a partially saturated, fully saturated or fully
unsaturated three to six membered ring optionally having one to two
heteroatoms selected independently from oxygen, sulfur and
nitrogen;
[0197] wherein said Z substituent is optionally mono-, di- or
trisubstituted independently with halo, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.4)alkylthio, nitro, cyano,
oxo, or (C.sub.1-C.sub.6)alkyloxycarbonyl, said
(C.sub.1-C.sub.4)alkyl optionally substituted with from one to nine
fluorines; R.sup.2 is a partially saturated, fully saturated or
fully unsaturated one to four membered straight or branched carbon
chain wherein the carbons, other than the connecting carbon, may
optionally be replaced with one heteroatom selected independently
from oxygen, sulfur and nitrogen wherein said carbon atoms are
optionally mono-, di- or tri-substituted independently with halo,
said carbon is optionally mono-substituted with oxo, said carbon is
optionally mono-substituted with hydroxy, said sulfur is optionally
mono- or di-substituted with oxo, said nitrogen is optionally mono-
or di-substituted with oxo; or said R.sup.2 is a partially
saturated, fully saturated or fully unsaturated three to five
membered ring optionally having one heteroatom selected
independently from oxygen, sulfur and nitrogen;
[0198] wherein said R.sup.2 ring is optionally mono-, di- or
tri-substituted independently with halo, hydroxy,
(C.sub.1-C.sub.6)alkoxy or (C.sub.1-C.sub.6)alkoxycarbonyl; R.sup.3
is Q-V wherein Q is (C.sub.1-C.sub.4)alkyl and V is a five or six
membered partially saturated, fully saturated or fully unsaturated
ring optionally having one to three heteroatoms selected
independently from oxygen, sulfur and nitrogen;
[0199] wherein said V ring is optionally mono-, di-, tri- or
tetra-substituted independently with halo, (C.sub.1-C.sub.6)alkyl,
hydroxy, (C.sub.1-C.sub.6)alkoxy, nitro, cyano or oxo wherein said
(C.sub.1-C.sub.6)alkyl substituent optionally has from one to nine
fluorines;
[0200] R.sup.4 is (C.sub.1-C.sub.4)alkyl;
[0201] R.sup.6 and R.sup.7 are each independently
(C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)alkoxy, said
(C.sub.1-C.sub.4)alkyl or (C.sub.1-C.sub.6)alkoxy substituents
optionally having from one to nine fluorines or said
(C.sub.1-C.sub.6)alkoxy or (C.sub.1-C.sub.6)alkyl substituents
optionally mono-substituted with T;
[0202] wherein T is a partially saturated, fully saturated or fully
unsaturated five to six membered ring optionally having one to two
heteroatoms selected independently from oxygen, sulfur and
nitrogen;
[0203] wherein said T substituent is optionally mono-, di- or
tri-substituted independently with halo, (C.sub.1-C.sub.6)alkyl,
hydroxy, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.4)alkylthio,
amino, oxo, carboxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.6)alk- ylamino wherein said
(C.sub.1-C.sub.6)alkyl substituent optionally has from one to nine
fluorines; or R.sup.6 and R.sup.7 are taken together and form one
ring that is a partially saturated or fully unsaturated five or six
membered ring optionally having one to two heteroatoms
independently selected from nitrogen, sulfur and oxygen;
[0204] wherein said ring formed by R.sup.6 and R.sup.7 is
optionally mono-, di- or tri-substituted independently with halo,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkylsulfonyl,
(C.sub.2-C.sub.4)alkenyl, hydroxy, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkylthio, amino, nitro, cyano, oxo, carboxy,
(C.sub.1-C.sub.4)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.4)alk- ylamino wherein said
(C.sub.1-C.sub.4)alkyl substituent optionally has from one to nine
fluorines;
[0205] R.sup.5 and R.sup.8 are H; and pharmaceutically acceptable
salts thereof.
[0206] A preferred group of compounds, designated the G Group,
contains those compounds having the Formula I as shown above
wherein
[0207] R.sup.2 is beta;
[0208] the C.sup.4 nitrogen is beta;
[0209] R.sup.1 is Y;
[0210] Y is (C.sub.2-C.sub.6)alkenyl or (C.sub.1-C.sub.6)alkyl,
said (C.sub.2-C.sub.6)alkenyl or (C.sub.1-C.sub.6)alkyl optionally
having from one to nine fluorines or said (C.sub.2-C.sub.6)alkenyl
or (C.sub.1-C.sub.6)alkyl optionally mono-substituted with Z;
[0211] wherein Z is a partially saturated, fully saturated or fully
unsaturated three to six membered ring optionally having one to two
heteroatoms selected independently from oxygen, sulfur and
nitrogen;
[0212] wherein said Z substituent is optionally mono-, di- or
tri-substituted independently with halo, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.4)alkylthio, nitro, cyano,
oxo, or (C.sub.1-C.sub.6)alkyloxycarbonyl, said
(C.sub.1-C.sub.4)alkyl substituent optionally substituted with from
one to nine fluorines;
[0213] R.sup.2 is a partially saturated, fully saturated or fully
unsaturated one to four membered straight or branched carbon chain
wherein the carbons, other than the connecting carbon, may
optionally be replaced with one heteroatom selected independently
from oxygen, sulfur and nitrogen wherein said carbon atoms are
optionally mono-, di- or tri-substituted independently with halo,
said carbon is optionally mono-substituted with oxo, said carbon is
optionally mono-substituted with hydroxy, said sulfur is optionally
mono- or di-substituted with oxo, said nitrogen is optionally mono-
or di-substituted with oxo; or said R.sup.2 is a partially
saturated, fully saturated or fully unsaturated three to five
membered ring optionally having one heteroatom selected
independently from oxygen, sulfur and nitrogen;
[0214] wherein said R.sup.2 ring is optionally mono-, di- or
tri-substituted independently with halo, hydroxy,
(C.sub.1-C.sub.6)alkoxy or (C.sub.1-C.sub.6)alkoxycarbonyl;
[0215] R.sup.3 is Q-V wherein Q is (C.sub.1-C.sub.4)alkyl and V is
a five or six membered partially saturated, fully saturated or
fully unsaturated ring optionally having one to three heteroatoms
selected independently from oxygen, sulfur and nitrogen;
[0216] wherein said V ring is optionally mono-, di-, tri- or
tetra-substituted independently with halo, (C.sub.1-C.sub.6)alkyl,
hydroxy, (C.sub.1-C.sub.6)alkoxy, nitro, cyano or oxo wherein said
(C.sub.1-C.sub.6)alkyl substituent optionally has from one to nine
fluorines;
[0217] R.sup.4 is (C.sub.1-C.sub.4)alkyl;
[0218] R.sup.6 and R.sup.7 are each independently
(C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)alkoxy, said
(C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)alkoxy substituents
optionally having from one to nine fluorines or said
(C.sub.1-C.sub.6)alkoxy or (C.sub.1-C.sub.6)alkyl substituents
optionally mono-substituted with T,
[0219] wherein T is a partially saturated, fully saturated or fully
unsaturated five to six membered ring optionally having one to two
heteroatoms selected independently from oxygen, sulfur and
nitrogen;
[0220] wherein said T substituent is optionally mono-, di- or
tri-substituted independently with halo, (C.sub.1-C.sub.6)alkyl,
hydroxy, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.4)alkylthio,
amino, oxo, carboxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.6)alk- ylamino wherein said
(C.sub.1-C.sub.6)alkyl substituent optionally has from one to nine
fluorines; or R.sup.6 and R.sup.7 are taken together and form one
ring that is a partially saturated or fully unsaturated five or six
membered ring optionally having one to two heteroatoms
independently selected from nitrogen, sulfur and oxygen;
[0221] wherein said ring formed by R.sup.6 and R.sup.7 is
optionally mono-, di- or tri-substituted independently with halo,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkylsulfonyl,
(C.sub.1-C.sub.4)alkenyl, hydroxy, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkylthio, amino, nitro, cyano, oxo, carboxy,
(C.sub.1-C.sub.4)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.4)alk- ylamino wherein said
(C.sub.1-C.sub.4)alkyl substituent optionally has from one to nine
fluorines;
[0222] R.sup.5 and R.sup.8 are H; and pharmaceutically acceptable
salts thereof.
[0223] A preferred group of compounds, designated the H Group,
contains those compounds having the Formula I as shown above
wherein
[0224] R.sup.2 is beta;
[0225] the C.sup.4 nitrogen is beta;
[0226] R.sup.1 is Z;
[0227] Z is a partially saturated, fully saturated or fully
unsaturated three to six membered ring optionally having one to two
heteroatoms selected independently from oxygen, sulfur and
nitrogen;
[0228] wherein said Z substituent is optionally mono-, di- or
tri-substituted independently with halo, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.4)alkylthio, nitro, cyano,
oxo, or (C.sub.1-C.sub.6)alkyloxycarbonyl, said
(C.sub.1-C.sub.4)alkyl substituent optionally having one to nine
fluorines;
[0229] R.sup.2 is a partially saturated, fully saturated or fully
unsaturated one to four membered straight or branched carbon chain
wherein the carbons, other than the connecting carbon, may
optionally be replaced with one heteroatom selected independently
from oxygen, sulfur and nitrogen wherein said carbon atoms are
optionally mono-, di- or tri-substituted independently with halo,
said carbon is optionally mono-substituted with oxo, said carbon is
optionally mono-substituted with hydroxy, said sulfur is optionally
mono- or di-substituted with oxo, said nitrogen is optionally mono-
or di-substituted with oxo; or said R.sup.2 is a partially
saturated, fully saturated or fully unsaturated three to five
membered ring optionally having one heteroatom selected
independently from oxygen, sulfur and nitrogen;
[0230] wherein said R.sup.2 ring is optionally mono-, di- or
tri-substituted independently with halo, hydroxy,
(C.sub.1-C.sub.6)alkoxy or (C.sub.1-C.sub.6)alkoxycarbonyl; R.sup.3
is Q-V wherein Q is (C.sub.1-C.sub.4)alkyl and V is a five or six
membered partially saturated, fully saturated or fully unsaturated
ring optionally having one to three heteroatoms selected
independently from oxygen, sulfur and nitrogen;
[0231] wherein said V ring is optionally mono-, di-, tri- or
tetra-substituted independently with halo, (C.sub.1-C.sub.6)alkyl,
hydroxy, (C.sub.1-C.sub.6)alkoxy, nitro, cyano or oxo wherein said
(C.sub.1-C.sub.6)alkyl substituent optionally has from one to nine
fluorines;
[0232] R.sup.4 is (C.sub.1-C.sub.4)alkyl;
[0233] R.sup.6 and R.sup.7 are each independently
(C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)alkoxy, said
(C.sub.1-C.sub.4)alkyl or (C.sub.1-C.sub.6)alkoxy substituents
optionally having from one to nine fluorines or said
(C.sub.1-C.sub.6)alkoxy or (C.sub.1-C.sub.6)alkyl substituents
optionally mono-substituted with T;
[0234] wherein T is a partially saturated, fully saturated or fully
unsaturated five to six membered ring optionally having one to two
heteroatoms selected independently from oxygen, sulfur and
nitrogen;
[0235] wherein said T substituent is optionally mono-, di- or
trisubstituted independently with halo, (C.sub.1-C.sub.6)alkyl,
hydroxy, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.4)alkylthio,
amino, oxo, carboxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.6)alk- ylamino wherein said
(C.sub.1-C.sub.6)alkyl substituent optionally has from one to nine
fluorines; or R.sup.6 and R.sup.7 are taken together and form one
ring that is a partially saturated or fully unsaturated five or six
membered ring optionally having one to two heteroatoms
independently selected from nitrogen, sulfur and oxygen;
[0236] wherein said ring formed by R.sup.6 and R.sup.7 is
optionally mono-, di- or tri-substituted independently with halo,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkylsulfonyl,
(C.sub.2-C.sub.4)alkenyl, hydroxy, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkylthio, amino, nitro, cyano, oxo, carboxy,
(C.sub.1-C.sub.4)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.4)alk- ylamino wherein said
(C.sub.1-C.sub.4)alkyl substituent optionally has from one to nine
fluorines;
[0237] R.sup.5 and R.sup.8 are H; and pharmaceutically acceptable
salts thereof.
[0238] A preferred group of compounds, designated the I Group,
contains those compounds having the Formula I as shown above
wherein
[0239] R.sup.2 is beta;
[0240] the C.sup.4 nitrogen is beta;
[0241] R.sup.1 is W-Z;
[0242] W is carbonyl, thiocarbonyl or sulfonyl;
[0243] Z is a partially saturated, fully saturated or fully
unsaturated three to six membered ring optionally having one to two
heteroatoms selected independently from oxygen, sulfur and
nitrogen;
[0244] wherein said Z substituent is optionally mono-, di- or
tri-substituted independently with halo, (C.sub.1-C.sub.4)alkyl,
(C, C.sub.4)alkoxy, (C.sub.1-C.sub.4)alkylthio, nitro, cyano, oxo,
or (C.sub.1-C.sub.6)alkyloxycarbonyl, said (C.sub.1-C.sub.4)alkyl
substituent optionally having from one to nine fluorines;
[0245] R.sup.2 is a partially saturated, fully saturated or fully
unsaturated one to four membered straight or branched carbon chain
wherein the carbons, other than the connecting carbon, may
optionally be replaced with one heteroatom selected independently
from oxygen, sulfur and nitrogen wherein said carbon atoms are
optionally mono-, di- or tri-substituted independently with, halo,
said carbon is optionally mono-substituted with oxo, said carbon is
optionally mono-substituted with hydroxy, said sulfur is optionally
mono- or di-substituted with oxo, said nitrogen is optionally mono-
or di-substituted with oxo; or said R.sup.2 is a partially
saturated, fully saturated or fully unsaturated three to five
membered ring optionally having one heteroatom selected
independently from oxygen, sulfur and nitrogen;
[0246] wherein said R.sup.2 ring is optionally mono-, di- or
tri-substituted independently with halo, hydroxy,
(C.sub.1-C.sub.5)alkoxy or (C.sub.1-C.sub.6)alkoxycarbonyl; R.sup.3
is Q-V wherein Q is (C.sub.1-C.sub.4)alkyl and V is a five or six
membered partially saturated, fully saturated or fully unsaturated
ring optionally having one to three heteroatoms selected
independently from oxygen, sulfur and nitrogen;
[0247] wherein said V ring is optionally mono-, di-, tri- or
tetra-substituted independently with halo, (C.sub.1-C.sub.6)alkyl,
hydroxy, (C.sub.1-C.sub.6)alkoxy, nitro, cyano or oxo wherein said
(C.sub.1-C.sub.6)alkyl substituent optionally has from one to nine
fluorines;
[0248] R.sup.4 is (C.sub.1-C.sub.4)alkyl;
[0249] R.sup.6 and R.sup.7 are each independently
(C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)alkoxy, said
(C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)alkoxy substituents
optionally having from one to nine fluorines or said
(C.sub.1-C.sub.6)alkoxy or (C.sub.1-C.sub.6)alkyl substituents
optionally mono-substituted with T;
[0250] wherein T is a partially saturated, fully saturated or fully
unsaturated five to six membered ring optionally having one to two
heteroatoms selected independently from oxygen, sulfur and
nitrogen;
[0251] wherein said T substituent is optionally mono-, di- or
tri-substituted independently with halo, (C.sub.1-C.sub.6)alkyl,
hydroxy, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.4)alkylthio,
amino, oxo, carboxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.6)alk- ylamino wherein said
(C.sub.1-C.sub.6)alkyl substituent optionally has from one to nine
fluorines; or R.sup.6 and R.sup.7 are taken together and form one
ring that is a partially saturated or fully unsaturated five or six
membered ring optionally having one to two heteroatoms
independently selected from nitrogen, sulfur and oxygen;
[0252] wherein said ring formed by R.sup.6 and R.sup.7 is
optionally mono-, di- or tri-substituted independently with halo,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkylsulfonyl,
(C.sub.4)alkenyl, hydroxy, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkylthio, amino, nitro, cyano, oxo, carboxy,
(C.sub.1-C.sub.4)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.4)alkylamino wherein said
(C.sub.1-C.sub.4)alkyl substituent optionally has from one to nine
fluorines; R.sup.5 and R.sup.8 are H; or a pharmaceutically
acceptable salts thereof
[0253] A preferred group of compounds, designated the J Group,
contains those compounds having the Formula I as shown above
wherein
[0254] R.sup.2 is beta;
[0255] the C.sup.4 nitrogen is beta;
[0256] R.sup.1 is W--X;
[0257] W is carbonyl, thiocarbonyl or sulfonyl;
[0258] X is --O--Y--, S--Y--, N(H)--Y-- or --N--(Y).sub.z--;
[0259] Y for each occurrence is independently Z or
(C.sub.1-C.sub.4)alkyl, said (C.sub.1-C.sub.4)alkyl substituent
optionally having from one to nine fluorines or said
(C.sub.1-C.sub.4)alkyl optionally mono-substituted with Z;
[0260] wherein Z is a partially saturated, fully saturated or fully
unsaturated three to six membered ring optionally having one to two
heteroatoms selected independently from oxygen, sulfur and
nitrogen;
[0261] wherein said Z substituent is optionally mono-, di- or
tri-substituted independently with halo, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.4)alkylthio, nitro, cyano,
oxo, or (C.sub.1-C.sub.6)alkyloxycarbonyl, said
(C.sub.1-C.sub.4)alkyl substituent optionally substituted with from
one to nine fluorines;
[0262] R.sup.2 is a partially saturated, fully saturated or fully
unsaturated one to four membered straight or branched carbon chain
wherein the carbons, other than the connecting carbon, may
optionally be replaced with one heteroatom selected independently
from oxygen, sulfur and nitrogen wherein said carbon atoms are
optionally mono-, di- or tri-substituted independently with halo,
said carbon is optionally mono-substituted with oxo, said carbon is
optionally mono-substituted with hydroxy, said sulfur is optionally
mono- or di-substituted with oxo, said nitrogen is optionally mono-
or di-substituted with oxo; or said R.sup.2 is a partially
saturated, fully saturated or fully unsaturated three to five
membered ring optionally having one heteroatom selected
independently from oxygen, sulfur and nitrogen;
[0263] wherein said R.sup.2 ring is optionally mono-, di- or
tri-substituted independently with halo, hydroxy,
(C.sub.1-C.sub.6)alkoxy or (C.sub.1-C.sub.6)alkoxycarbonyl;
[0264] R.sup.3 is Q-V wherein Q is (C.sub.1-C.sub.4)alkyl and V is
a five or six membered partially saturated, fully saturated or
fully unsaturated ring optionally having one to three heteroatoms
selected independently from oxygen, sulfur and nitrogen;
[0265] wherein said V ring is optionally mono-, di-, tri- or
tetra-substituted independently with halo, (C.sub.1-C.sub.6)alkyl,
hydroxy, (C.sub.1-C.sub.6)alkoxy, nitro, cyano or oxo wherein said
(C.sub.1-C.sub.6)alkyl substituent optionally has from one to nine
fluorines;
[0266] R.sup.4 is (C.sub.1-C.sub.4)alkyl;
[0267] at least one of R.sup.6 and R.sup.7 is
(C.sub.1-C.sub.4)alkoxy and at least one of R.sup.6 and R.sup.7 is
(C.sub.1-C.sub.6)alkyl, said (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.4)alkoxy substituents optionally having from one to
nine fluorines or said (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.4)alkoxy substituents optionally mono-substituted
win T;
[0268] wherein T is a partially saturated, fully saturated or fully
unsaturated five to six membered ring optionally having one to two
heteroatoms selected independently from oxygen, sulfur and
nitrogen;
[0269] wherein said T substituent is optionally mono-, di- or
tri-substituted independently with halo, (C.sub.1-C.sub.6)alkyl,
hydroxy, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.4)alkylthio,
amino, oxo, carboxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.6)alk- ylamino wherein said
(C.sub.1-C.sub.6)alkyl substituent optionally has from one to nine
fluorines; --R.sup.5 and R.sup.8 are H; and pharmaceutically
acceptable salts thereof.
[0270] Yet another aspect of this invention is directed to methods
for treating atherosclerosis, peripheral vascular disease,
dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia,
hypercholesterolemia, hypertriglyceridemia,
familial-hypercholesterolemia, cardiovascular disorders, angina,
ischemia, cardiac ischemia, stroke, myocardial infarction,
reperfusion injury, angioplastic restenosis, hypertension, vascular
complications, of diabetes, obesity or endotoxemia in a mammal
(including a human being either male or female) by administering to
a mammal in need of such treatment an atherosclerosis, peripheral
vascular disease, dyslipidemia, hyperbetalipoproteinemia,
hypoalphalipoproteinemia- , hypercholesterolemia,
hypertriglyceridemia, familial-hypercholesterolemi- a,
cardiovascular disorders, angina, ischemia, cardiac ischemia,
stroke, myocardial infarction, reperfusion injury, angioplastic
restenosis, hypertension, vascular complications of diabetes,
obesity or endotoxemia treating amount of a Formula I compound, a
prodrug thereof, or a pharmaceutically acceptable salt of said
compound or of said prodrug.
[0271] Yet another aspect of this invention is directed to a method
for treating atherosclerosis in a mammal (including a human being)
by administering to a mammal in need of such treatment an
atherosclerotic treating amount of a Formula I compound, a prodrug
thereof, or a pharmaceutically acceptable salt of said compound or
of said prodrug.
[0272] Yet another aspect of this invention is directed to a method
for treating peripheral vascular disease in a mammal (including a
human being) by administering to a mammal in need of such treatment
a peripheral vascular disease treating amount of a Formula I
compound, a prodrug thereof, or a pharmaceutically acceptable salt
of said compound or of said prodrug.
[0273] Yet another aspect of this invention is directed to a method
for treating dyslipidemia in a mammal (including a human being) by
administering to a mammal in need of such treatment a dyslipidemia
treating amount of a Formula I compound, a prodrug thereof, or a
pharmaceutically acceptable salt of said compound or of said
prodrug.
[0274] Yet another aspect of this invention is directed to a method
for treating hyperbetalipoproteinemia in a mammal (including a
human being) by administering to a mammal in need of such treatment
a hyperbetalipoproteinemia treating amount of a Formula I compound,
a prodrug thereof, or a pharmaceutically acceptable sat of said
compound or of said prodrug.
[0275] Yet another aspect of this invention is directed to a method
for treating hypoalphalipoproteinemia in a mammal (including a
human being) by administering to a mammal in need of such treatment
a hypoalphalipoproteinemia treating amount of a Formula I compound,
a prodrug thereof, or a pharmaceutically acceptable salt of said
compound or of said prodrug.
[0276] Yet another aspect of this invention is directed to a method
for treating hypercholesterolemia in a mammal (including a human
being) by administering to a mammal in need of such treatment a
hypercholesterolemia treating amount of a Formula I compound, a
prodrug thereof, or a pharmaceutically acceptable salt of said
compound or of said prodrug.
[0277] Yet another aspect of this invention is directed to a method
for treating hypertriglyceridemia in a mammal (including a human
being) by administering to a mammal in need of such treatment a
hypertriglyceridemia treating amount of a Formula I compound, a
prodrug thereof, or a pharmaceutically acceptable salt of said
compound or of said prodrug.
[0278] Yet another aspect of this invention is directed to a method
for treating familial-hypercholesterolemia in a mammal (including a
human being) by administering to a mammal in need of such treatment
a familial-hypercholesterolemia treating amount of a Formula I
compound, a prodrug thereof, or a pharmaceutically acceptable salt
of said compound or of said prodrug.
[0279] Yet another aspect of this invention is directed to a method
for treating cardiovascular disorders in a mammal (including a
human being) by administering to a mammal in need of such treatment
a cardiovascular disorder treating amount of a Formula I compound,
a prodrug thereof, or a pharmaceutically acceptable salt of said
compound or of said prodrug.
[0280] Yet another aspect of this invention is directed to a method
for treating angina in a mammal (including a human being) by
administering to a mammal in need of such treatment an angina
treating amount of a Formula I compound, a prodrug thereof, or a
pharmaceutically acceptable salt of said compound or of said
prodrug.
[0281] Yet another aspect of this invention is directed to a method
for treating ischemia in a mammal (including a human being) by
administering to a mammal in need of such treatment an ischemic
disease treating amount of a Formula I compound, a prodrug thereof,
or a pharmaceutically acceptable salt of said compound or of said
prodrug.
[0282] Yet another aspect of this invention is directed to a method
for treating cardiac ischemia in a mammal (including a human being)
by administering to a mammal in need of such treatment a cardiac
ischemic treating amount of a Formula I compound, a prodrug
thereof, or a pharmaceutically acceptable salt of said compound or
of said prodrug.
[0283] Yet another aspect of this invention is directed to a method
for treating stroke in a mammal (including a human being) by
administering to a mammal in need of such treatment a stroke
treating amount of a Formula I compound, a prodrug thereof, or a
pharmaceutically acceptable salt of said compound or of said
prodrug.
[0284] Yet another aspect of this invention is directed to a method
for treating a myocardial infarction in a mammal (including a human
being) by administering to a mammal in need of such treatment a
myocardial infarction treating amount of a Formula I compound, a
prodrug thereof, or a pharmaceutically acceptable salt of said
compound or of said prodrug.
[0285] Yet another aspect of this invention is directed to a method
for treating: reperfusion injury in a mammal (including a human
being) by administering to a mammal in need of such treatment a
reperfusion injury treating amount of a Formula I compound, a
prodrug thereof, or a pharmaceutically acceptable salt of said
compound or of said prodrug.
[0286] Yet another aspect of this invention is directed to a method
for treating angioplastic restenosis in a mammal (including a human
being) by administering to a mammal in need of such treatment an
angioplastic restenosis treating amount of a Formula I compound, a
prodrug thereof, or a pharmaceutically acceptable salt of said
compound or of said prodrug.
[0287] Yet another aspect of this invention is directed to a method
for treating hypertension in a mammal (including a human being) by
administering to a mammal in need of such treatment a hypertension
treating amount of a Formula I compound, a prodrug thereof, or a
pharmaceutically acceptable salt of said compound or of said
prodrug.
[0288] Yet another aspect of this invention is directed to a method
for treating the vascular complications of diabetes in a mammal
(including a human being) by administering to a mammal in need of
such treatment a vascular complications of diabetes treating amount
of a Formula I compound, a prodrug thereof, or a pharmaceutically
acceptable salt of said compound or of said prodrug.
[0289] Yet another aspect of this invention is directed to a method
for treating obesity in a mammal (including a human being) by
administering to a mammal in need of such treatment an obesity
treating amount of a Formula I compound, a prodrug thereof, or a
pharmaceutically acceptable salt of said compound or of said
prodrug.
[0290] Yet another aspect of this inventions directed to a method
for treating endotoxemia in a mammal (including a human being) by
administering to a mammal in need of such treatment an endotoxemia
treating amount of a Formula I compound, a prodrug thereof, or a
pharmaceutically acceptable salt of said compound or of said
prodrug.
[0291] A preferred dosage is about 0.001 to 100 mg/kg/day of a
Formula I compound, a prodrug thereof, or a pharmaceutically
acceptable salt of said compound or of said prodrug. An especially
preferred dosage is about 0.01 to 10 mg/kg/day of a Formula I
compound, a prodrug thereof, or a pharmaceutically acceptable salt
of said compound or of said prodrug.
[0292] This invention is also directed to pharmaceutical
compositions which comprise a therapeutically effective amount of a
compound of Formula I, a prodrug thereof, or a pharmaceutically
acceptable salt of said compound or of said prodrug and a
pharmaceutically acceptable carrier.
[0293] This invention is also directed to pharmaceutical
compositions for the treatment of atherosclerosis, peripheral
vascular disease, dyslipidemia, hyperbetalipoproteinemia,
hypoalphalipoproteinemia, hypercholesterolemia,
hypertriglyceridemia, familial-hypercholesterolemia- ,
cardiovascular disorders, angina, ischemia, cardiac ischemia,
stroke, myocardial infarction, reperfusion injury, angioplastic
restenosis, hypertension, vascular complications of diabetes,
obesity or endotoxemia in a mammal (including a human being) which
comprise a therapeutically effective amount of a compound of
Formula I, a prodrug thereof, or a pharmaceutically acceptable salt
of said compound or of said prodrug and a pharmaceutically
acceptable carrier.
[0294] This invention is also directed to pharmaceutical
compositions for the treatment of atherosclerosis in a mammal
(including a human being) which comprise an atherosclerosis
treating amount of a compound of Formula I, a prodrug thereof, or a
pharmaceutically acceptable salt of said compound or of said
prodrug and a pharmaceutically acceptable carrier.
[0295] This invention is also directed to pharmaceutical
compositions for the treatment of peripheral vascular disease in a
mammal (including a human being) which comprise a peripheral
vascular disease treating amount of a compound of Formula I, a
prodrug thereof, or a pharmaceutically acceptable salt of said
compound or of said prodrug and a pharmaceutically acceptable
carrier.
[0296] This invention is also directed to pharmaceutical
compositions for the treatment of dyslipidemia in a mammal
(including a human being) which comprise a dyslipidemia treating
amount of a compound of Formula I, a prodrug thereof, or a
pharmaceutically acceptable salt of said compound or of said
prodrug and a pharmaceutically acceptable carrier.
[0297] This invention is also directed to pharmaceutical
compositions for the treatment of hyperbetalipoproteinemia in a
mammal (including a human being) which comprise a
hyperbetalipoproteinemia treating amount of a compound of Formula
I, a prodrug thereof, or a pharmaceutically acceptable salt of said
compound or of said prodrug and a pharmaceutically acceptable
carrier.
[0298] This invention is also directed to pharmaceutical
compositions for the treatment of hypoalphalipoproteinemia in a
mammal (including a human being) which comprise a
hypoalphalipoproteinemia treating amount of a compound of Formula
I, a prodrug thereof, or a pharmaceutically acceptable salt of said
compound or of said prodrug and a pharmaceutically acceptable
carrier.
[0299] This invention is also directed to pharmaceutical
compositions for the treatment of hypercholesterolemia in a mammal
(including a human being) which comprise a hypercholesterolemia
treating amount of a compound of Formula 1, a prodrug thereof, or a
pharmaceutically acceptable salt of said compound or of said
prodrug and a pharmaceutically acceptable carrier.
[0300] This invention is also directed to pharmaceutical
compositions for the treatment of hypertriglyceridemia in a mammal
(including a human being) which comprise a hypertriglyceridemia
treating amount of a compound of Formula I, a prodrug thereof, or a
pharmaceutically acceptable salt of said compound or of said
prodrug and a pharmaceutically acceptable carrier.
[0301] This invention is also directed to pharmaceutical
compositions for the treatment of familial-hypercholesterolemia in
a mammal (including a human being) which-comprise a
familial-hypercholesterolemia treating amount of a compound of
Formula I, a prodrug thereof, or a pharmaceutically acceptable salt
of said compound or of said prodrug and a pharmaceutically
acceptable carrier.
[0302] This invention is also directed to pharmaceutical
compositions for the treatment of angina in a mammal (including a
human being) which comprise an angina treating amount of a compound
of Formula I, a prodrug thereof, or a pharmaceutically acceptable
salt of said compound or of said prodrug and a pharmaceutically
acceptable carrier.
[0303] This invention is also directed to pharmaceutical
compositions for the treatment of ischemia in a mammal (including a
human being) which comprise an ischemic treating amount of a
compound of Formula I, a prodrug thereof, or a pharmaceutically
acceptable salt of said compound or of said prodrug and a
pharmaceutically acceptable carrier.
[0304] This invention is also directed to pharmaceutical
compositions for the treatment of cardiac ischemia in a mammal
(including a human being) which comprise a cardiac ischemic
treating amount of a compound of Formula I, a prodrug thereof, or a
pharmaceutically acceptable salt of said compound or of said
prodrug and a pharmaceutically acceptable carrier.
[0305] This invention is also directed to pharmaceutical
compositions for the treatment of stroke in a mammal (including a
human being) which comprise a stroke treating amount of a compound
of Formula I, a prodrug thereof, or a pharmaceutically acceptable
salt of said compound or of said prodrug and a pharmaceutically
acceptable carrier.
[0306] This invention is also directed to pharmaceutical
compositions for the treatment of a myocardial infarction in a
mammal (including a human being) which comprise a myocardial
infarction treating amount of a compound of Formula I, a prodrug
thereof, or a pharmaceutically acceptable salt of said compound or
of said prodrug and a pharmaceutically acceptable carrier.
[0307] This invention is also directed to pharmaceutical
compositions for the treatment of reperfusion injury in a mammal
(including a human being) which comprise a reperfusion injury
treating amount of a compound of Formula I, a prodrug thereof, or a
pharmaceutically acceptable salt of said compound or of said
prodrug and a pharmaceutically acceptable carrier.
[0308] This invention is also directed to pharmaceutical
compositions for the treatment of angioplastic restenosis in a
mammal (including a human being) which comprise an angioplastic
restenosis treating amount of a compound of Formula I, a prodrug
thereof, or a pharmaceutically acceptable salt of said compound or
of said prodrug and a pharmaceutically acceptable carrier.
[0309] This invention is also directed to pharmaceutical
compositions for the treatment of hypertension in a mammal
(including a human being) which-comprise a hypertension treating
amount of a compound of Formula I, a prodrug thereof, or a
pharmaceutically acceptable salt of said compound or of said
prodrug and a pharmaceutically acceptable carrier.
[0310] This invention is also directed to pharmaceutical
compositions for the treatment of the vascular complications of
diabetes in a mammal (including a human being) which comprise a
vascular complications of diabetes treating amount of a compound of
Formula I, a prodrug thereof, or a pharmaceutically acceptable salt
of said compound or of said prodrug and a pharmaceutically
acceptable carrier.
[0311] This invention is also directed to pharmaceutical
compositions for the treatment of obesity in a mammal (including a
human being) which comprise an obesity treating amount of a
compound of Formula I, a prodrug thereof, or a pharmaceutically
acceptable salt of said compound or of said prodrug and a
pharmaceutically acceptable carrier.
[0312] This invention is also directed to pharmaceutical
compositions for the treatment of endotoxemia in a mammal
(including a human being) which comprise an endotoxemia treating
amount of a compound of Formula I, a prodrug thereof, or a
pharmaceutically acceptable salt of said compound or of said
prodrug and a pharmaceutically acceptable carrier.
[0313] This invention is also directed to a pharmaceutical
combination composition comprising: a therapeutically effective
amount of a composition comprising
[0314] a first compound, said first compound being a Formula I
compound, a prodrug thereof, or a pharmaceutically acceptable salt
of said compound or of said prodrug;
[0315] a second compound, said second compound being an HMG-CoA
reductase inhibitor, an microsomal triglyceride transfer protein
(MTP)/Apo B secretion inhibitor, a PPAR activator, a bile acid
reuptake inhibitor, a cholesterol absorption inhibitor, a
cholesterol synthesis inhibitor, a fibrate, niacin, an ion-exchange
resin, an antioxidant, an ACAT inhibitor or a bile acid
sequestrant; and/or optionally
[0316] a pharmaceutical carrier.
[0317] Preferred among the second compounds are an HMG-CoA
reductase inhibitor and a MTP/Apo B secretion inhibitor.
[0318] A particularly preferred HMG-CoA reductase inhibitor is
lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or
rivastatin.
[0319] Another aspect of this invention is a method for treating
atherosclerosis in a mammal comprising administering to a mammal
suffering from atherosclerosis;
[0320] a first compound, said first compound being a Formula I
compound a prodrug thereof, or a pharmaceutically acceptable salt
of said compound or of said prodrug; and
[0321] a second compound, said second compound being an HMG-CoA
reductase inhibitor, an MTP/Apo B secretion inhibitor, a
cholesterol absorption inhibitor, a cholesterol synthesis
inhibitor, a fibrate, niacin, an ion-exchange resin, an
antioxidant, an ACAT inhibitor or a bile acid sequestrant wherein
the amounts of the first and second compounds result in a
therapeutic effect.
[0322] A preferred aspect of the above method is wherein the second
compound is an HMG-CoA reductase inhibitor or an MTP/Apo B
secretion inhibitor.
[0323] A particularly preferred aspect of the above method is
wherein the HMG-CoA reductase inhibitor is lovastatin, simvastatin,
pravastatin, fluvastatin, atorvastatin or rivastatin.
[0324] Yet another aspect of this invention is a kit
comprising:
[0325] a. a first compound, said first compound being a Formula I
compound, a prodrug thereof, or a pharmaceutically acceptable salt
of said compound or of said prodrug and a pharmaceutically
acceptable carrier in a first unit dosage form;
[0326] b. of a second compound, said second compound being an HMG
CoA reductase inhibitor, an MTP/Apo B secretion inhibitor, a
cholesterol absorption inhibitor, a cholesterol synthesis
inhibitor, a fibrate, niacin, an ion-exchange resin, an
antioxidant, an ACAT inhibitor or a bile acid sequestrant and a
pharmaceutically acceptable carrier in a second unit dosage form;
and
[0327] c. means for containing said first and second dosage forms
wherein the amounts of the first and second compounds result in a
therapeutic effect.
[0328] A preferred second compound is an HMG-CoA reductase
inhibitor or an MTP/Apo B secretion inhibitor.
[0329] A particularly preferred HMG-CoA reductase inhibitor is
lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or
rivastatin.
[0330] As used herein the term mammals is meant to refer to all
mammals which contain CETP in their plasma, for example, rabbits
and primates such as monkeys and humans. Certain other mammals
e.g., dogs, cats, cattle, goats, sheep and horses do not contain
CETP in their plasma and so are not included herein.
[0331] The term "treating", "treat" or "treatment" as used herein
includes preventative (e.g., prophylactic) and palliative
treatment.
[0332] By "pharmaceutically acceptable" is meant the carrier,
diluent, excipients, and/or salt must be compatible with the other
ingredients of the formulation, and not deleterious to the
recipient thereof.
[0333] The expression "prodrug" refers to compounds that are drug
precursors which following administration, release the drug in vivo
via some chemical or physiological process (e.g., a prodrug on
being brought to the physiological pH or through enzyme action is
converted to the desired drug form). Exemplary prodrugs upon
cleavage release the corresponding free acid, and such hydrolyzable
ester-forming residues of the Formula I compounds include but are
not limited to those having a carboxyl moiety wherein the free
hydrogen is replaced by (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.7)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having
from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having
from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to
6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7
carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to
8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9
carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10
carbon atoms, 3-phthalidyl, 4-crotonolactonyl,
gamma-butyrolacton-4-yl,
di-N,N-(C.sub.1-C.sub.2)alkylamino(C.sub.2-C.sub.3)alkyl (such as
b-dimethylaminoethyl), carbamoyl-(C.sub.1-C.sub.2)alkyl,
N,N-di(C.sub.1-C.sub.2)alkylcarbamoyl(C.sub.1-C.sub.2)alkyl and
piperidino-, pyrrolidino- or morpholino(C.sub.2-C.sub.3)alkyl.
[0334] The following paragraphs describe exemplary ring(s) for the
generic ring descriptions contained herein.
[0335] Exemplary five to six membered aromatic rings optionally
having one or two heteroatoms selected independently from oxygen,
nitrogen and sulfur include phenyl, furyl, thienyl, pyrrolyl,
oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,
isothiazolyl, pyridinyl, pyridiazinyl, pyrimidinyl and
pyrazinyl.
[0336] Exemplary partially saturated, fully saturated or fully
unsaturated five to eight membered rings optionally having one to
four heteroatoms selected independently from oxygen, sulfur and
nitrogen include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl
and phenyl. Further exemplary five membered rings include
2H-pyrrolyl, 3H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl,
1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H-imidazolyl,
2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl,
pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2-dithiolyl,
1,3-dithiolyl, 3H-1,2-oxathiolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl,
1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 3H-1,2,3-dioxazolyl,
1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl,
5H-1,2,5-oxathiazolyl and 1,3-oxathiolyl.
[0337] Further exemplary six membered rings include 2H-pyranyl,
4H-pyranyl, pyridinyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl,
1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl,
pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl,
1,2,4 triazinyl, 1,2,3-triazinyl, 1,3,5-trithianyl,
4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 6H-1,3-oxazinyl, 6H-1,2-oxazinyl,
1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl, 1,2,5 oxathiazinyl,
1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6
oxathiazinyl, 1,4,2-oxadiazinyl and 1,3,5,2-oxadiazinyl.
[0338] Further exemplary seven membered rings include azepinyl,
oxepinyl, and thiepinyl.
[0339] Further exemplary eight membered rings include cyclooctyl,
cyclooctenyl and cyclooctadienyl.
[0340] Exemplary bicyclic rings consisting of two fused partially
saturated, fully saturated or fully unsaturated five or six
membered rings, taken independently, optionally having one to four
heteroatoms selected independently from nitrogen, sulfur and oxygen
include indolizinyl, indolyl, isoindolyl, 3H-indolyl,
1H-isoindolyl, indolinyl, cyclopenta(b)pyridinyl,
pyrano(3,4-b)pyrrolyl, benzofuryl, isobenzofuryl, benzo(b)thienyl,
benzo(c)thienyl, 1H-indazolyl, indoxazinyl, benzoxazolyl,
benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl,
quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,
quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, isoindenyl,
naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl,
pyrido(3,4-b)-pyridinyl, pyrido(3,2-b)-pyridinyl,
pyrido(4,3-b)-pyridinyl- , 2H-1,3-benzoxazinyl,
2H-1,4-benzoxazinyl, 1H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl,
2H-1,2-benzoxazinyl and 4H-1,4-benzoxazinyl.
[0341] By alkylene is meant saturated hydrocarbon (straight chain
or branched) wherein a hydrogen atom, is removed from each of the
terminal carbons. Exemplary of such groups (assuming the designated
length encompasses the particular example) are methylene, ethylene,
propylene, butylene, pentylene, hexylene, heptylene).
[0342] By halo is meant chloro, bromo, iodo, or fluoro.
[0343] By alkyl is meant straight chain saturated hydrocarbon or
branched chain saturated hydrocarbon. Exemplary of such alkyl
groups (assuming the designated length encompasses the particular
example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,
tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl,
1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl,
heptyl and octyl.
[0344] By alkoxy is meant straight chain saturated alkyl or
branched chain saturated alkyl bonded through an oxy. Exemplary of
such alkoxy groups (assuming the designated length encompasses the
particular example) are methoxy, ethoxy, propoxy, isopropoxy,
butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy,
neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and
octoxy.
[0345] As used herein the term mono-N- or
di-N,N-(C.sub.1-C.sub.x)alkyl . . . refers to the
(C.sub.1-C.sub.x)alkyl moiety taken independently when it is
di-N,N-(C.sub.1-C.sub.x)alkyl . . . (x refers to integers).
[0346] It is to be understood that if a carbocyclic or heterocyclic
moiety may be bonded or otherwise attached to a designated
substrate through differing ring atoms without denoting a specific
point of attachment, then all possible points are intended, whether
through a carbon atom or, for example, a trivalent nitrogen atom.
For example, the term "pyridyl" means 2-, 3-, or 4-pyridyl, the
term "thienyl" means 2-, or 3-thienyl, and so forth.
[0347] References (e.g., claim 1) to "said carbon" in the phrase
"said carbon is optionally mono-, di- or tri-substituted
independently with halo, said carbon is optionally mono-substituted
with hydroxy, said carbon is optionally mono-substituted with oxo"
refers to each of the carbons in the carbon chain including the
connecting carbon.
[0348] References to "nitrogen . . . di-substituted with oxo"
herein (e.g., claim 1) refer to a terminal nitrogen which
constitutes a nitro functionality.
[0349] The expression "pharmaceutically-acceptable salt" refers to
nontoxic anionic salts containing anions such as (but not limited
to) chloride, bromide, iodide, sulfate, bisulfate, phosphate,
acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate,
gluconate, methanesulfonate and 4-toluene-sulfonate. The expression
also refers to nontoxic cationic salts such as (but not limited to)
sodium, potassium, calcium, magnesium, ammonium or protonated
benzathine (N,N'-dibenzylethylenediamine), choline, ethanolamine,
diethanolamine, ethylenediamine, meglamine (N-methyl-glucamine),
benethamine (N-benzylphenethylamine), piperazine or tromethamine
(2-amino-2-hydroxymethyl-1,3-propanediol).
[0350] As used herein, the expressions "reaction-inert solvent" and
"inert solvent" refers to a solvent or a mixture thereof which does
not interact with starting materials, reagents, intermediates or
products in a manner which adversely affects the yield of the
desired product.
[0351] The term "cis" refers to the orientation of two substituents
with reference to each other and the plane of the ring (either both
"up" or both "down"). Analogously, the term "trans" refers to the
orientation of two substituents with reference to each other and
the plane of the ring (the substituents being on opposite sides of
the ring).
[0352] Alpha and Beta refer to the orientation of a substituent
with reference to the plane of the ring (i.e., page). Beta is above
the plane of the ring (i.e., page) and Alpha is below the plane of
the ring (i.e., page).
[0353] The chemist of ordinary skill will recognize that certain
compounds of this invention will contain one or more atoms which
may be in a particular stereochemical or geometric configuration,
giving rise to stereoisomers and configurational isomers. All such
isomers and mixtures thereof are included in this invention.
Hydrates and solvates of the compounds of this invention are also
included.
[0354] It will be recognized that the compounds of this invention
can exist in radiolabelled form, i.e., said compounds may contain
one or more atoms containing an atomic mass or mass number
different from the atomic mass or mass number usually found in
nature. Radioisotopes of hydrogen, carbon, phosphorous, fluorine
and chlorine include .sup.3H, .sup.14C, .sup.32P, .sup.35S,
.sup.18F and .sup.36Cl, respectively. Compounds of this invention,
a prodrug thereof, or a pharmaceutically acceptable salt of said
compound or of said prodrug which contain those radioisotopes
and/or other radioisotopes of other atoms are within the scope of
this invention. Tritiated, i.e., .sup.3H, and carbon-14, i.e.,
.sup.14C, radioisotopes are particularly preferred for their ease
of preparation and detectability. Radiolabelled compounds of
Formula I of this invention and prodrugs thereof can generally be
prepared by methods well known to those skilled in the art.
Conveniently, such radiolabelled compounds can be prepared by
carrying out the procedures disclosed in the Schemes and/or in the
Examples and Preparations below by substituting a readily available
radiolabelled reagent for a non-radiolabelled reagent.
[0355] DTT means dithiothreitol. DMSO means dimethyl sulfoxide.
EDTA means ethylenediamine tetraacetic acid.
[0356] Other features and advantages of this invention will be
apparent from this specification and the appendant claims which
describe the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0357] In general the compounds of this invention can be made by
processes which include processes analogous to those known in the
chemical arts, particularly in light of the description contained
herein. Certain processes for the manufacture of the compounds of
this invention are provided as further features of the invention
and are illustrated by the following reaction schemes. Other
processes may be described in the experimental section. 2 3 4 5 6 7
8 9
[0358] As an initial note, in the preparation of the Formula I
compounds it is noted that some of the preparation methods useful
for the preparation of the compounds described herein may require
protection of remote functionality (e.g., primary amine, secondary
amine, carboxyl in Formula I precursors). The need for such
protection will vary depending on the nature of the remote
functionality and the conditions of the preparation methods. The
need for such protection is readily determined by one skilled in
the art. The use of such protection/deprotection methods is also
within the skill in the art. For a general description of
protecting groups and their use, see T. W. Greene, Protective
Groups in Organic Synthesis, John Wiley & Sons, New York,
1991.
[0359] For example, in Reaction Schemes I and II certain Formula I
compounds contain primary amines or carboxylic acid functionalities
which may interfere with reactions at other sites of the molecule
if left unprotected. Accordingly, such functionalities may be
protected by an appropriate protecting group which may be removed
in a subsequent step. Suitable protecting groups for amine and
carboxylic acid protection include those protecting groups commonly
used in peptide synthesis (such as N-t-butoxycarbonyl,
benzyloxycarbonyl, and 9-fluorenylmethylenoxycarbo- nyl for amines
and lower alkyl or benzyl esters for carboxylic acids) which are
generally not chemically reactive under the reaction conditions
described and can typically be removed without chemically altering
other functionality in the Formula I compound.
[0360] According to Reaction Scheme I, the Formula III compounds
wherein R.sup.2, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are as
described above and P is an appropriate protecting group may be
prepared from the appropriate Formula II aromatic amine wherein
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as described above.
[0361] The Formula III tetrahydroquinoline is prepared by treating
the appropriate Formula II aromatic amine with the requisite
carboxaldehyde in an inert solvent such as a hydrocarbon (e.g.,
hexanes, pentanes or cyclohexane), an aromatic hydrocarbon (e.g.,
benzene, toluene or xylene), a halocarbon (e.g., dichloromethane,
chloroform, carbon tetrachloride or dichloroethane), an ether
(e.g., diethyl ether, diisopropyl ether, tetrahydrofuran,
tetrahydropyran, dioxane, dimethoxyethane, methyl tert-butyl ether,
etc.), a nitrile (e.g., acetonitrile or propionitrile), a
nitroalkane (e.g., nitromethane or nitrobenzene), preferably
dichloromethane with a dehydrating agent (e.g., sodium sulfate or
magnesium sulfate) at a temperature of about 0.degree. C. to about
100.degree. C. (preferably ambient temperature) for 1-24 hours
(preferably 1 hour). The resulting solution is treated with a
suitably substituted (e.g., benzyloxycarbonyl, t-butoxycarbonyl,
methoxycarbonyl, formyl-, acetyl-, diallyl- or dibenzyl-),
preferably carboxybenzyloxy-, N-vinyl species and with a Lewis acid
(e.g., boron trifluoride, boron trifluoride etherate, zinc
chloride, titanium tetrachloride, iron trichloride, aluminum
trichloride, alkyl aluminum dichloride, dialkyl aluminum chloride
or ytterbium (III) triflate; preferably boron trifluoride etherate)
or a protic acid such as a hydrohalogenic acid (e.g., fluoro,
chloro, bromo or iodo), an alkyl sulfonic acid (e.g., p-toluene,
methane or trifloromethane) or carboxylic acid (e.g., formic,
acetic, trifluoroacetic or benzoic) at a temperature of from about
-78.degree. C. to about 50.degree. C. (preferably ambient
temperature) for 0.1 to 24 hours (preferably 1 hour).
[0362] Alternatively, the Formula II amine and appropriate
carboxaldehyde may be condensed by treating a solution of the amine
and an alkyl amine base (preferably triethylamine) in a polar
aprotic solvent (preferably dichloromethane) with titanium
tetrachloride in a polar aprotic solvent (preferably in
dichloromethane) at a temperature between about -78.degree. C. to
about 40.degree. C. (preferably 0.degree. C.) followed by treatment
with the carboxaldehyde at a temperature between about -78.degree.
C. to about 40.degree. C. (preferably 0.degree. C.). The reaction
is allowed to proceed for about 0.1 to about 10 hours (preferably 1
hour) at a temperature between about 0.degree. C. to about
40.degree. C. (preferably room temperature) yielding the imine
which is reacted with the N-vinyl species as above.
[0363] The compounds of Formula IV wherein R.sup.1, R.sup.2,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as described above and
P.sup.1 and P.sup.2 are protecting groups may be prepared from the
corresponding Formula III amine by various amine reaction routes
known to those skilled in the art.
[0364] Thus, the Formula IV compounds wherein R.sup.1, R.sup.2,
R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are as described above and
P.sup.1 and P.sup.2 are appropriately differentiated protecting
groups for the amine moieties are prepared from the corresponding
Formula III tetrahydroquinoline employing standard methods for
derivatizing amines into the functional groups described for
R.sup.1 above, see Richard Larock, Comprehensive Organic
Transformations, VCH Publishers Inc., New York, 1989 and Jerry
March, Advanced Organic Chemistry, John. Wiley & Sons, New
York, 1985. For example, a Formula III compound is treated with the
appropriate carbonyl chloride, sulfonyl chloride, or sulfinyl
chloride, isocyanate or thioisocyanate in a polar aprotic solvent
(preferably dichloromethane) in the presence of a base (preferably
pyridine) at a temperature of from about -78.degree. C. to about
100.degree. C. (preferably starting at 0.degree. C. and letting
warm to room temperature) for a period of 1 to 24 hours (preferably
12 hours).
[0365] Formula IV carbamate and urea compounds (wherein R.sup.1 is
W.dbd.C(O), X.dbd.O--Y, S--Y, N(H)--Y, or NY.sub.2) may be prepared
from the Formula III amines via the corresponding carbamoyl
chlorides by treating the Formula III amine with a phosgene
solution in a hydrocarbon solvent (preferably toluene) at a
temperature between about 0.degree. C. and about 200.degree. C.
(preferably at reflux) for between 0.1 and 24 hours (preferably 2
hours).
[0366] The corresponding ureas may be prepared by treating a
solution of the carbamoyl chlorides (prepared as described above)
with the appropriate amine in a polar solvent (preferably
dichloromethane) at a temperature between about -78.degree. C. and
about 100.degree. C. (preferably ambient temperature) for between 1
and 24 hours (preferably 12 hours).
[0367] The corresponding carbamate may be prepared by treating a
solution of the carbamoyl chlorides (prepared as described above)
with the appropriate alcohol and a suitable base (preferably sodium
hydride) in a polar solvent (preferably dioxane) at a temperature
between about -78.degree. C. and about 100.degree. C. (preferably
ambient temperature) for between 1 and 24 hours (preferably 12
hours).
[0368] Alternatively, the corresponding carbamate may be prepared
by treating a solution of the carbamoyl chlorides at a temperature
between about 0.degree. C. and about 200.degree. C. in the
appropriate alcohol for between 1 and 240 hours (preferably 24
hours).
[0369] The Formula IV compound wherein R.sup.1 is Y may be prepared
using methods known to those skilled in the art to introduce Y
substituents such as an alkyl or alkyl linked substituent. Methods
include, for example, formation of the amide from the Formula III
amine and an activated carboxylic acid followed by reduction of the
amide with borane in an etheral solvent such as tetrahydrofuran.
Alternatively, the alkyl or alkyl linked substituent may be
appended by reduction after condensing the Formula III amine with
the required carbonyl containing reactant. Also, the amine may be
reacted with the appropriate alkyl or aryl halide according to
methods known to those skilled in the art.
[0370] Thus, the Formula III amine and an acid (e.g., halogenic,
sulfuric, sulfonic or carboxylic, preferably acetic) are treated
with the appropriate carbonyl containing reactant in a polar
solvent (preferably ethanol) at a temperature of about 0.degree. C.
to about 100.degree. C. (preferably room temperature) for about 0.1
to 24 hours (preferably 1 hour) followed by treatment with a
hydride source (e.g., sodium borohydride, sodium cyanoborohydride,
preferably sodium triacetoxyborohydride) at a temperature of about
0.degree. C. to about 100.degree. C. (preferably ambient
temperature) for 0.1 to 100 hours (preferably 6 hours).
[0371] The Formula V amine wherein R.sup.1, R.sup.2, R.sup.5,
R.sup.6, R.sup.7, and R.sup.8 are as described above and P.sup.1 is
a protecting group may be prepared from the corresponding Formula
IV compound by deprotection (P.sup.2) using methods known to those
skilled in the art, including hydrogenolysis, treatment with an
acid (e.g., trifluoroacetic acid, hydrobromic), a base (sodium
hydroxide), or reaction with a nucleophile (e.g. sodium
methylthiolate, sodium cyanide, etc.) and for the
trialkylsilylethoxy carbonyl group a fluoride is used (e.g.,
tetrabutyl ammonium fluoride). For removal of a benzyloxycarbonyl
group, hydrogenolysis is performed by treating the Formula IV
compound with a hydride source (e.g., 1 to 10 atmospheres of
hydrogen gas, cyclohexene or ammonium formate) in the presence of a
suitable catalyst (e.g., 5-20% palladium on carbon, palladium
hydroxide; preferably 10% palladium on carbon) in a polar solvent
(e.g., methanol, ethanol or ethyl acetate; preferably ethanol) at a
temperature between about -78.degree. C. and about 100.degree. C.,
preferably ambient temperature, for 0.1 to 24 hours, preferably 1
hour.
[0372] The compounds of Formula VI wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.5, R.sup.6, R.sup.7 and Re are as described above
and P.sup.1 is a protecting group as described above may be
prepared from the corresponding Formula V amine by various amine
reaction routes known to those skilled in the art.
[0373] The Formula VI secondary amine wherein R.sup.3 is as
described above may be prepared using methods known to those
skilled in the art to introduce R.sup.3 substituents such as an
alkyl or alkyl linked substituent. Methods include, for example,
formation of an amide from the Formula V amine and an activated
carboxylic acid followed by reduction of the amide with borane in
an etheral solvent such as tetrahydrofuran.
[0374] Alternatively, an alkyl or alkyl linked substituent may be
appended by reduction of the appropriate imine, the imine being
formed by condensing the Formula V amine with the required carbonyl
containing reactant. Also, the Formula V amine may be reacted with
the appropriate alkyl halide according to methods known to those
skilled in the art.
[0375] Thus, the Formula V amine and an acid (e.g., halogenic,
sulfuric, sulfonic or carboxylic, preferably hydrochloric) are
treated with the appropriate carbonyl containing reactant in a
polar solvent (preferably dichloromethane) at a temperature of
about 0.degree. to about 100.degree. C. (preferably room
temperature) for about 0.1 to 24 hours (preferably 1 hour) followed
by treatment with a hydride source (e.g., sodium borohydride or
sodium cyanoborohydride; preferably sodium triacetoxyborohydride)
at a temperature of about 0.degree. C. to about 100.degree. C.
(preferably ambient temperature) for 0.1 to 100 hours (preferably 5
hours).
[0376] The Formula VII compound wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as described above and
P.sup.1 and P.sup.2 are protecting groups may be prepared from the
corresponding Formula IV compound by methods known to those skilled
in the art; for example, the methods described for the introduction
of the R.sup.3 substituent above in the transformation of the
Formula V compound to the Formula VI compound. Following this, the
corresponding Formula VI compound may be prepared from the Formula
VII compound by appropriate deprotection such as the methods
described above for the transformation of the Formula IV compound
to the Formula V compound.
[0377] When R.sup.3 is H and R.sup.4 is as described above R.sup.4
may be represented by R.sup.3 in the Formulas VI and VII in Scheme
I, thus providing a synthetic scheme for such compounds.
[0378] According to Scheme II, the Formula XI dihydroquinolone
compounds wherein R.sup.2, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and Y
are as described above, and P.sup.1 is a protecting group, may be
prepared from the corresponding Formula X quinolines by treatment
with an organometallic species and a chloroformate followed by
hydrolysis.
[0379] Thus, a mixture of the Formula X quinoline and an excess
(preferably 1.5 equivalents) of an organomagnesium species
(Grignard reagent) in a polar aprotic solvent (e.g., diethyl ether
or dichloromethane; preferably tetrahydrofuran) is treated with an
excess (preferably 1.5 equivalents) of a Y- or
P.sup.1-chloroformate at a temperature between about -100.degree.
C. and about 70.degree. C. (preferably -78.degree. C.) followed by
warming to a temperature between about 0.degree. C. and about
70.degree. C. (preferably ambient temperature) for between 0.1 and
24 hours (preferably 1 hour). The resulting mixture is combined
with an excess (preferably 2 equivalents) of an aqueous acid
(preferably 1 molar hydrochloric acid) and mixed vigorously for
between 0.1 and 24 hours (preferably 1 hour, or until hydrolysis of
the intermediate enol ether is determined to be complete).
[0380] Of course, the Formula XI compounds are the Formula XVI
compounds wherein R.sup.1 is --C(O)OY or P.sup.1 is --C(O)OP.sup.1
without further transformation.
[0381] The Formula XV compounds wherein R.sup.2, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are as described above may be prepared from the
corresponding Formula XI dihydroquinolone (wherein compound XI
contains P.sup.1) by appropriate deprotection (including
spontaneous decarboxylation) as described for the transformation of
the Formula IV compound to the Formula V compound.
[0382] The Formula XVI compounds wherein R.sup.1, R.sup.2, R.sup.5,
R.sup.8, R.sup.7 and R.sup.8 are as described above and P.sup.1 is
a protecting group may be prepared from the corresponding Formula
XV dihydroquinolone as described for the transformation of the
Formula III compound to the Formula IV compound. In certain cases
where the reagent has also reacted on the 4-position carbonyl
oxygen, the substituent may be conveniently removed by treatment
with acid (e.g., aqueous HCl) or base (e.g., aqueous sodium
hydroxide).
[0383] Again, for those Formula XVI compounds wherein R.sup.1 or
P.sup.1 is the same as for the Formula XI compound such
transformation as described above is not needed.
[0384] The Formula VI amine compounds wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are as described
above and P.sup.1 is a protecting group may be prepared from the
corresponding Formula XVI dihydroquinolone by a reductive amination
sequence. The Formula XVI dihydroquinolone, an excess (preferably
1.1 equivalents) of an R.sup.3-amine and an excess (preferably 7
equivalents) of an amine base (preferably triethylamine) in a polar
solvent (preferably dichloromethane) are treated with 0.5 to 1.0
equivalents (preferably 0.55 equivalents) of titanium tetrachloride
as a solution in a suitable polar solvent (preferably
dichloromethane) at a temperature between about 0.degree. C. and
about 40.degree. C. (preferably ambient temperature) for between 1
to 24 hours (preferably 12 hours). The resulting Formula XII imine
is reduced by treatment with a reducing agent (preferably sodium
borohydride) in an appropriate polar solvent (preferably ethanol)
at a temperature between about 0.degree. C. and about 80.degree. C.
(preferably room temperature) for between 1 and 24 hours
(preferably 12 hours) resulting in a mixture of diastereomeric
Formula VI amines, generally favoring the trans isomer.
Alternatively, the reduction may be performed by treating the
Formula XII imine directly with an excess (preferably 5
equivalents) of zinc borohydride as a solution in ether (preferably
0.2 molar) at a temperature between about 0.degree. C. and about
40.degree. C. (preferably ambient temperature) for between 1 and 24
hours (preferably 12 hours) resulting in a mixture of
diastereomeric Formula VI, amines, generally favoring the cis
isomer.
[0385] Alternatively, the Formula VI amine wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.5, R.sup.7 and R.sup.8 are as described
above and P.sup.1 is a protecting group may be prepared from the
corresponding Formula XVI dihydroquinolones by formation of an
oxime, reduction and substitution of the amine. Thus, the Formula
XVI dihydroquinolone, excess (preferably 3 equivalents)
hydroxylamine hydrochloride and an excess (preferably 2.5
equivalents) of base (preferably sodium acetate) are reacted at a
temperature between about 0.degree. C. and about 100.degree. C.
(preferably at reflux) for between 1 and 24 hours (preferably 2
hours) in a polar solvent (preferably ethanol). The resulting
Formula XIII oxime is treated with excess (preferably 6
equivalents) aqueous base (preferably 2N potassium hydroxide) in a
polar solvent (preferably ethanol) and an excess (preferably 4
equivalents) of a nickel-aluminum alloy (preferably 1:1 by weight)
at a temperature between about 0.degree. C. and about 100.degree.
C. (preferably ambient temperature) for between 0.25 and 24 hours
(preferably 1 hour). The resulting Formula V amine is obtained as a
diastereomeric mixture (generally favoring the cis isomer).
[0386] The Formula VI secondary amine wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as described
above and P.sup.1 is a protecting group may be prepared from the
appropriate Formula V amine as described in Scheme I for the
transformation of the Formula V compound to the Formula VI
compound.
[0387] According to Scheme III the Formula I compounds as described
above may be prepared from the appropriate Formula VI compounds by
conversion to the desired carbamate. Thus, the Formula VI amine is
treated with the appropriate activated carbonate (e.g.,
chloroformate, dicarbonate or carbonyl diimidazole followed by the
appropriate alcohol) in a polar solvent (preferably
dichloromethane) in the presence of an excess of amine base
(preferably pyridine) at a temperature between about -20.degree. C.
and about 40.degree. C. (preferably ambient temperature) for
between 1 and 24 hours (preferably 12 hours) to yield the Formula I
compound.
[0388] Alternatively, according to Scheme III, where appropriate,
if the functionality at R.sup.1 is incompatible with the reaction
to form the Formula I compound, then the P.sup.1 protected Formula
VI compound may be transformed to the Formula I compound through
protection/deprotection sequences and introduction of the desired
substituents. Thus, the Formula VI amine is treated with the
appropriate reagent (e.g., protecting group precursor, activated
carbonate (e.g., chloroformate, dicarbonate or carbonyl imidazole))
in a polar solvent (preferably dichloromethane) in the presence of
an excess of amine base (preferably pyridine) at a temperature
between about -20.degree. C. and about 40.degree. C. (preferably
ambient temperature) for between 1 and 24 hours (preferably 12
hours) to yield the Formula XX compound.
[0389] Also, the Formula XX compounds, wherein P.sup.2 is present
may be obtained as shown in Scheme I for the Formula VII compounds
(having P.sup.1).
[0390] The Formula XXI amines wherein R.sup.2, R.sup.3, R.sup.5,
R.sup.6, R.sup.7, R.sup.8 and R.sup.4 are as described above and
P.sup.2 is a protecting group may be prepared from the Formula XX
compound by selective deprotection of P.sup.1.
[0391] When P.sup.1 is, for example, t-butoxycarbonyl, the Formula
XXI compound is conveniently prepared by treatment with an acid
(preferably trifluoroacetic acid)) at a temperature between about
0.degree. C. and about 100.degree. C. (preferably room temperature)
for 0.1 to 24 hours (preferably 1 hour).
[0392] The compounds of Formula I or compounds of Formula XXII
(wherein R.sup.1 is as described above) may be prepared from the
corresponding Formula XXI amine (wherein R.sup.4 or P.sup.2 is
present respectively) by various amine reaction routes known to
those skilled in the art; for example, those described in Scheme I
for the transformation of the Formula III compound to the Formula
IV compound.
[0393] The Formula XXIII amines may be prepared from the Formula
XXII compounds by suitable deprotection. When P.sup.2 is, for
example, benzyloxycarbonyl, the Formula XXII compound is prepared
by treatment with an excess of a hydride source (e.g., cyclohexene,
hydrogen gas or preferably ammonium formate) in the presence of
0.01 to 2 equivalents (preferably 0.1 equivalent) of a suitable
catalyst (preferably 10% palladium on carbon) in a polar solvent
(preferably ethanol) at a temperature between about 0.degree. C.
and about 100.degree. C. (preferably room temperature) for 0.1 to
24 hours (preferably 1 hour).
[0394] The Formula I compound wherein R.sup.4 is as described above
may be prepared using the methods described for the conversion of
the Formula VI compound to the Formula I compound in Scheme III
above.
[0395] According to Scheme IV the Formula V compounds wherein
R.sup.1, R.sup.2, R.sup.5, R.sup.7 and R.sup.8 are as described
above, and R.sup.6 is an ether linked moiety can be obtained from
the Formula XXX quinolones having a OP.sup.3 moiety, wherein
P.sup.3 is a protecting group, at the R.sup.6 position employing
the following methods. In addition, in an analogous manner such
processes may be used to prepare the corresponding compounds
wherein R.sup.5, R.sup.7, or R.sup.8 are an ether linked moiety
starting from the corresponding Formula XXX compound having an
OP.sup.3 moiety at either the R.sup.5, R.sup.7, or R.sup.8
positions.
[0396] Thus, the Formula XXX quinolone is combined with
hydroxylamine hydrochloride and a mineral base (preferably sodium
acetate) in a polar solvent (preferably ethanol) at a temperature
between about 0.degree. C. and about 100.degree. C. (preferably at
reflux) for between 1 and 24 hours (preferably 2 hours) to yield
the Formula XXXI oxime.
[0397] The Formula XXXI oxime is treated with an excess (preferably
six equivalents) of an aqueous base (preferably 2N potassium
hydroxide) and an excess (preferably four equivalents) of a
nickel-aluminum alloy (preferably 1:1 by weight) in a polar solvent
(preferably ethanol) at a temperature between about 0.degree. C.
and about 100.degree. C. (preferably ambient temperature) for
between 0.25 and 24 hours (preferably 2 hours) to prepare the
corresponding Formula XXXII amine. If necessary, the P.sup.3
protecting group may be removed using standard methods if the oxime
transformations does not result in such cleavage.
[0398] Alternatively, the Formula XXX compound may be deprotected
(removal of the P.sup.3) by methods known to those skilled in the
art prior to formation of the Formula XXXI oxime (wherein P.sup.3
is H) which can then be reduced to form the Formula XXXII
amine.
[0399] The Formula V compound wherein R.sup.6 is an oxy-linked
moiety may be prepared by treating the Formula XXXII alcohol under,
for example, Mitsunobu conditions. Thus, the Formula XXXII phenol
is treated with a phosphine (preferably triphenylphosphine) and an
azodicarboxylate (preferably
bis-(N-methylpiperazinyl)-azodicarboxamide) and the required
alcohol in a polar solvent (preferably benzene).
[0400] Of course, via Schemes I and II the resulting Formula V
compound may be transformed into the Formula VI precursors for the
Formula I compounds of this invention.
[0401] Alternatively, the Formula XX compound wherein R.sup.6 is an
ether linked moiety and wherein R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are as described above and P.sup.1 and P.sup.2 are
protecting groups may be prepared from the Formula XXXII alcohols
as described below. In addition, in an analogous manner such
processes may be used to prepare the corresponding compounds
wherein R.sup.5, R.sup.7, or R.sup.8 are an ether linked moiety
starting from the corresponding Formula XXXII compound and thus
ultimately the Formula XXX compound (i.e., the Formula XXX compound
having a P.sup.3O-- at either the R.sup.5, R.sup.7, or R.sup.8
positions).
[0402] The Formula XXXIII secondary amine wherein R.sup.3 is as
described above may be prepared from the corresponding Formula
XXXII compound according to methods in Scheme I described above for
the conversion of the Formula V compound to the Formula VI
compound.
[0403] The Formula XXXIV compounds wherein R.sup.4 is as described
above may be prepared from Formula XXXIII amines by methods
analogous to that described in Scheme III for the transformation of
the Formula VI compound to the Formula I compound.
[0404] The Formula XXXV phenol may be selectively deprotected for
example when R.sup.4O.sub.2CO-- is present by treating the Formula
XXXIV carbonate with potassium carbonate in a polar solvent
(preferably methanol) at a temperature between about 0.degree. C.
and about 100.degree. C. (preferably ambient temperature) for
between 1 and 24 hours (preferably 12 hours).
[0405] The corresponding XX ethers may be prepared from the Formula
XXXV phenol using, for example, the Mitsunobu conditions described
above for the conversion of the Formula XXXII compounds to the
Formula V compounds.
[0406] Of course one skilled in the art will appreciate that the
phenol may be derivatized to a variety of functional groups using
standard methods, for example, as described in March or Larock, or
by conversion to the corresponding triflate for use in a variety of
reactions involving transition metal catalysis.
[0407] Although the following description of Scheme V is directed
to modifications of the R.sup.6 position (the R.sup.6 position
described in Formula I above) those skilled in the art will
appreciate that analogous methods may be applied to the R.sup.5,
R.sup.7 and Re positions. According to Scheme V the Formula Li
alcohol wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 are as described above, P.sup.1 and P.sup.2 are
protecting groups, and X.sup.1 is a linking group wherein a carbon
(e.g., methylene) is directly linked to the carbonyl moiety may be
prepared from the corresponding ester (wherein R.sup.12 is a
convenient alkyl moiety) by reduction.
[0408] Thus, the Formula L ester is treated with sodium
borohydride/methanol or a borane-dimethylsulfide complex in a polar
solvent (preferably tetrahydrofuran) at a temperature between about
0.degree. C. and about 100.degree. C. (preferably at reflux) for
between 1 and 24 hours (preferably 3 hours).
[0409] The Formula LII compounds wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are as described above,
P.sup.1 and P.sup.2 are protecting groups and wherein the R.sup.6
position includes an alkyl halide functionality may be prepared
from the corresponding Formula LI alcohol by treatment with a
trialkylphosphine (preferably triphenylphosphine) and a dihalogen
(e.g., bromine) in a polar solvent (preferably dichloromethane) at
a temperature between about -78.degree. C. and about 100.degree. C.
(preferably 0.degree. C.) for between 0.1 and 10 hours (preferably
0.5 hours) followed by warming to room temperature for between 0.1
and 10 hours (preferably 3 hours).
[0410] The Formula LIII compounds wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.7 and R are as described above,
P.sup.1 and P.sup.2 are protecting groups, the R.sup.6 position
includes ether or thioether moieties (i.e., Y.sup.1 is S or O) and
R.sup.13 is a carbon linked substituent may be prepared by treating
the Formula LII alkyl halide in a polar solvent (preferably
N,N-dimethylformamide) with the requisite alkoxide or thioalkoxide
at a temperature between about 0.degree. C. and about 100.degree.
C. (preferably at room temperature) for between 1 and 24 hours
(preferably 6 hours).
[0411] Alternatively, the Formula LIII ethers and thioethers may be
prepared by treating the corresponding Formula LIV alcohols and
thiols (i.e., Y.sup.1 is S or O), wherein X.sup.1 is a substituent
linked directly through carbon to the methylene moiety, with a base
(preferably sodium hydride) and the requisite alkylating agent in a
polar solvent (preferably N,N-dimethylformamide) at a temperature
between about 0.degree. C. and about 100.degree. C. (preferably at
room temperature) for between 1 and 50 hours (preferably 18
hours).
[0412] The Formula LV compounds wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are as described above,
P.sup.1 and P.sup.2 are protecting groups, the R.sup.6 position
includes alkyl halides (e.g., fluorides) and X.sup.1 is a
substituent that is carbon linked directly to the methylene moiety
may be prepared by treating the corresponding Formula LI alcohol
with a halogenating agent. For example, the alcohol is treated with
a fluorinating agent (preferably diethylaminosulfur trifluoride) in
a polar solvent (preferably 1,2-dichloroethane) at a temperature
between about 0.degree. C. and about 100.degree. C. (preferably
80.degree. C.) for between 0.1 and 10 hours (preferably 0.75
hours).
[0413] The Formula LVII amide compounds wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are as described
above, P.sup.1 and P.sup.2 are protecting groups and wherein
R.sup.6 includes an amide functionality (such that X is a
substituent that is carbon linked directly to the carbonyl moiety
and R.sup.10 and R.sup.11 are substituents selected to yield the
desired R.sup.6 substituent defined above) may be prepared from the
corresponding Formula LVI carboxylic acid which may in turn be
prepared from the corresponding Formula L carboxylic ester.
[0414] Thus, the Formula L ester is treated with an aqueous
hydroxide (preferably lithium, sodium or potassium) in a polar
solvent (preferably tetrahydrofuran and/or methanol) at a
temperature between about 0.degree. C. and about 100.degree. C.
(preferably room temperature) for between 0.1 and 100 hours
(preferably 1 hour).
[0415] The Formula LVII amide may be prepared from the
corresponding Formula LVI acid by standard methods. Preferred is
conversion of the carboxylic acid to the acid chloride by
dissolving the acid in thionyl chloride and maintaining the
solution at a temperature between about 0.degree. C. and about
80.degree. C. (preferably at reflux) for between 0.1 and 24 hours
(preferably 1 hour) before evaporation of the excess thionyl
chloride. This step is followed by treating the resulting acid
chloride residue in a polar solvent (preferably dichloromethane)
with the appropriate amine, selected to yield the amide
functionality, and optionally an amine base (preferably
triethylamine) at a temperature between about -78.degree. C. and
about 100.degree. C. (preferably room temperature) for between 0.1
and 100 hours (preferably 1 hour).
[0416] Although the following description of Scheme VI is directed
to modifications of the R.sup.8 position those skilled in the art
will appreciate that analogous methods may be applied to the
R.sup.5, R.sup.6 and R.sup.7 positions.
[0417] According to Scheme VI the Formula LXI compound wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7
are as described above and P.sup.1 and p are protecting groups may
be prepared from the corresponding Formula LX compound by
nitration. The Formula LX compound is treated with nitrosyltriflate
in a halogenated solvent, such as dichloromethane at a temperature
of about -78.degree. C. to about 0.degree. C. for about 0.5 hour to
about 3 hours followed by warming to ambient temperature.
[0418] The Formula LXII amine wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sub.5, R.sup.6, and R.sup.7 are as described above and
P.sup.1 and P.sup.2 are protecting groups may be prepared from the
corresponding Formula LXI compound by reduction. The Formula LXI
compound is hydrogenated by treatment with hydrogen gas in the
presence of a noble metal catalyst (e.g., palladium on carbon) in a
polar solvent such as ethanol at a temperature of about 0.degree.
C. to about 100.degree. C. for about 1 to 24 hours at elevated
pressure (e.g., 1 to 3 atmospheres).
[0419] The Formula LXIII compound wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 are as described
above, P.sup.1 and P.sup.2 are protecting groups and R.sup.8 is an
amine linked functionality may be prepared from the corresponding
Formula LXII.
[0420] Briefly, the Formula LXII amine is derivatized following
procedures analogous to those described in Scheme I for the
conversion of the Formula III compound to the Formula IV
compound.
[0421] The Formula LXIV compound wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, and R.sup.7 are as described above and
P.sup.1 and P.sup.2 are protecting groups may be prepared from the
corresponding Formula LXII compound. The Formula LXII amine is
treated with t-butyl nitrate and anhydrous cupric halide in a polar
solvent at a temperature of about 30.degree. C. to about
100.degree. C. for about 1 hour to about 24 hours.
[0422] Of course, one skilled in the art will understand that the
halide may be derivatized to a variety of functional groups using
standard methods, for example, as described in Larock or March.
[0423] According to Scheme VII the Formula LXXI heterocycles
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.8 are
as described above, P.sup.1 and P.sup.2 are protecting groups and
R.sup.20 is a nitrogen containing heterocycle fused to the
quinoline ring structure, may be prepared from the Formula LXX
compound, wherein P.sup.3 is a protecting group, by selective
deprotection.
[0424] When P.sup.3 is for example, benzyloxycarbonyl, the Formula
LXX compound is conveniently cleaved to yield the Formula LXXI
compound by treatment with a hydrogen source (preferably 3
atmospheres of hydrogen gas) in the presence of a suitable catalyst
(preferably 10% palladium on carbon) in a polar solvent (preferably
ethanol) at a temperature between about 0.degree. C. and about
100.degree. C. (preferably room temperature) for 0.1 to 24 hours
(preferably 1 hour).
[0425] The compounds of Formula LXXII, wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5 and R.sup.8 are as described above,
P.sup.1 and P.sup.2 are protecting groups, R.sup.20 is a nitrogen
containing heterocycle fused to the quinoline ring structure, and
the "Substituent" is selected to afford the desired compounds
described above, may be prepared from the corresponding Formula
LXXI amine by various amine reaction routes known to those skilled
in the art; for example, those described in Scheme I for the
transformation of the Formula III compounds to the Formula IV
compounds.
[0426] The compounds of Formula LXX may be prepared according to
the methods described in Schemes I, II and III. For example, in
Scheme II the quinolines of Formula X are formed by methods known
to those skilled in the art from the arylamines of Formula II
wherein R.sup.5 and R.sup.6, R.sup.6 and R.sup.7, or R.sup.7 and
R.sup.8 comprise a ring as described above. These bicyclic
arylamines are also synthesized by a variety of methods known to
those skilled in the art. Such bicyclic arylamines are used in the
sequence of transformations as illustrated in Schemes I and III to
prepare the desired compounds.
[0427] The compounds of Formula LXX may also be obtained from
compounds of Formula I, wherein R.sup.5 and R.sup.6, R.sup.6 and
R.sup.7, or R.sup.7 and R.sup.8 contain functionality amenable to
cyclization, for example according to Scheme VIII, thus forming the
desired ring, employing methods known to those skilled in the art
to cyclize such substituents.
[0428] For example, the Formula LXXXII compound of Scheme VIII is
reacted with P.sup.3NH.sub.2 to give the P.sup.3 protected
isoindoline.
[0429] According to Scheme VIII the Formula LXXX diesters are
reduced affording the corresponding Formula LXXXI dialcohols
according to methods analogous to those described in Scheme V for
the transformation of the Formula L compounds to the Formula LI
compounds. Activation of these alcohols for electrophillic attack
may be achieved by a number of standard methods, such as conversion
to a halide or sulfonate (preferably conversion to the Formula
LXXXII bis-bromide by treatment with two equivalents of
dibromotriphenylphosphorane). Formation of the Formula LXXXIII
thiacycle may be achieved by treatment of the bis-bromide with a
sulfide (preferably sodium sulfide) in an aqueous/organic
immiscible solvent system (preferably a water and toluene mixture)
containing a suitable phase transfer catalyst (preferably
triethylhexylammonium bromide) at a temperature between about
0.degree. C. and about 100.degree. C. (preferably room temperature)
for between 1 and 100 hours (preferably 12 hours).
[0430] The Formula LXXXIV oxygen heterocycles may be formed using
standard etherification methods including a nucleophillic
displacement reaction with an appropriate bis-electrophile from the
corresponding Formula LXXXII compound. For example, formation of
the oxacycle may be achieved by treatment of a bis-bromide in an
aqueous immiscible solvent (preferably benzene) with an aqueous
hydroxide solution (preferably 30% sodium hydroxide) containing a
suitable phase transfer catalyst (preferably benzyl
tri-n-butylammonium chloride) at a temperature between about
0.degree. C. and about 100.degree. C. (preferably 80.degree. C.)
for between 1 and 100 hours (preferably 4 hours).
[0431] The Formula LXXXV and LXXXVI lactones, wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.8 are as described
above and P.sup.1 and P.sup.2 are protecting groups, may be formed
using standard lactonization methods including an oxidative
cyclization of the corresponding Formula LXXXI dialcohol. Thus, a
suitable bis-alcohol is treated with an oxidizing agent (preferably
pyridinium chlorochromate) in a polar aprotic solvent (preferably
dichloromethane) at a temperature between about 0.degree. C. and
about 100.degree. C. (conveniently room temperature) for between 1
and 100 hours (preferably 24 hours) to prepare a mixture of the
Formula LXXXV and Formula LXXXVI lactones which may be separated by
standard methods.
[0432] Prodrugs of the compounds of Formula I may be prepared
according to methods known to those skilled in the art. Exemplary
processes are described below.
[0433] Prodrugs of this invention where a carboxyl group in a
carboxylic acid of Formula I is replaced by an ester may be
prepared by combining the carboxylic acid with the appropriate
alkyl halide in the presence of a base such as potassium carbonate
in an inert solvent such as dimethylformamide at a temperature of
about 0 to 100.degree. C. for about 1 to about 24 hours.
[0434] Alternatively the acid is combined with appropriate alcohol
as solvent in the presence of a catalytic amount of acid such as
concentrated sulfuric acid at a temperature of about 20 to
100.degree. C., preferably at a reflux, for about 1 hour to about
24 hours. Another method is the reaction of the acid with a
stoichiometric amount of the alcohol in the presence of a catalytic
amount of acid in an inert solvent such as toluene or
tetrahydrofuran, with concomitant removal of the water being
produced by physical (e.g., Dean-Stark trap) or chemical (e.g.,
molecular sieves) means.
[0435] Prodrugs of this invention where an alcohol function has
been derivatized as an ether may be prepared by combining the
alcohol with the appropriate alkyl bromide or iodide in the
presence of a base such as potassium carbonate in an inert solvent
such as dimethylformamide at a temperature of about 0 to
100.degree. C. for about 1 to about 24 hours. Alkanoylaminomethyl
ethers may be obtained by reaction of the alcohol with a
bis-(alkanoylamino)methane in the presence of a catalytic amount of
acid in an inert solvent such as tetrahydrofuran, according to a
method described in U.S. Pat. No. 4,997,984. Alternatively, these
compounds may be prepared by the methods described by Hoffman et
al. in J. Org. Chem. 1994, 59, 3530: Glycosides are prepared by
reaction of the alcohol and a carbohydrate in an inert solvent such
as toluene in the presence of acid. Typically the water formed in
the reaction is removed as it is being formed as described
above.
[0436] An alternate procedure is the reaction of the alcohol with a
suitably protected glycosyl halide in the presence of base followed
by deprotection. N-(1-hydroxyalkyl) amides,
N-(1-hydroxy-1-(alkoxycarbonyl)m- ethyl) amides may be prepared by
the reaction of the parent amide with the appropriate aldehyde
under neutral or basic conditions (e.g., sodium ethoxide in
ethanol) at temperatures between 25 and 70.degree. C.
N-alkoxymethyl or N-1-(alkoxy)alkyl derivatives can be obtained by
reaction of the N-unsubstituted compound with the necessary alkyl
halide in the presence of a base in an inert solvent.
[0437] The compounds of this invention may also be used in
conjunction with other pharmaceutical agents (e.g., LDL-cholesterol
lowering agents, triglyceride lowering agents) for the treatment of
the disease/conditions described herein. For example, they may be
used in combination with cholesterol synthesis inhibitors,
cholesterol absorption inhibitors, MTP/Apo B secretion inhibitors,
and other cholesterol lowering agents such as fibrates, niacin,
ion-exchange resins, antioxidants, ACAT inhibitors and bile acid
sequestrants. In combination therapy treatment, both the compounds
of this invention and the other drug therapies are administered to
mammals (e.g., humans, male or female) by conventional methods.
[0438] Any HMG-CoA reductase inhibitor may be used as the second
compound in the combination aspect of this invention. The term
HMG-CoA reductase inhibitor refers to compounds which inhibit the
bioconversion of hydroxymethylglutaryl-coenzyme A to mevalonic acid
catalyzed by the enzyme HMG-CoA reductase. Such inhibition is
readily determined by those skilled in the art according to
standard assays (e.g., Meth. Enzymol. 1981; 71:455-509 and
references cited therein). A variety of these compounds are
described and referenced below however other HMG-CoA reductase
inhibitors will be known to those skilled in the art. U.S. Pat. No.
4,231,938 (the disclosure of which is hereby incorporated by
reference) discloses certain compounds isolated after cultivation
of a microorganism belonging to the genus Aspergillus, such as
lovastatin. Also, U.S. Pat. No. 4,444,784 (the disclosure of which
is hereby incorporated by reference) discloses synthetic
derivatives of the aforementioned compounds, such as simvastatin.
Also, U.S. Pat. No. 4,739,073 (the disclosure of which is
incorporated by reference) discloses certain substituted indoles,
such as fluvastatin. Also, U.S. Pat. No. 4,346,227 (the disclosure
of which is incorporated by reference) discloses ML-236B
derivatives, such as pravastatin. Also, EP-491226A (the disclosure
of which is incorporated by reference) discloses certain
pyridyldihydroxyheptenoic acids, such as rivastatin. In addition,
U.S. Pat. No. 5,273,995 (the disclosure of which is incorporated by
reference) discloses certain
6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones such as
atorvastatin.
[0439] Any MTP/Apo B secretion (microsomal triglyceride transfer
protein and or apolipoprotein B) inhibitor may be used as the
second compound in the combination aspect of this invention. The
term MTP/Apo B secretion inhibitor refers to compounds which
inhibit the secretion of triglycerides, cholesteryl ester, and
phospholipids. Such inhibition is readily determined by those
skilled in the art according to standard assays (e.g., Wetterau, J.
R. 1992; Science 258:999). A variety of these compounds are
described and referenced below however other MTP/Apo B secretion
inhibitors will be known to those skilled in the art.
[0440] WO 96/40640 and WO 98/23593 are two exemplary
publications.
[0441] For example, the following MTP/Apo B secretion inhibitors
are particularly useful: 4'-trifluoromethyl-biphenyl-2-carboxylic
acid
[2-(1H-[1,2,4,]triazo-3-ylmethyl)-1,2,3,4-tetrahydro-isoquinolin-yl]-amid-
e;
[0442] 4'-trifluoromethyl-biphenyl-2-carboxylic
acid[2-(2-acetylamino-ethy-
l)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide;
[0443]
(2-{6-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro--
1H-isoquinolin-2-yl}-ethyl)-carbamic acid methyl ester;
[0444] 4'-trifluoromethyl-biphenyl-2-carboxylic
acid[2-(1H-imidazol-2-ylme-
thyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide;
[0445] 4'-trifluoromethyl-biphenyl-2-carboxylic
acid[2-(2,2-diphenyl-ethyl-
)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide; and
[0446] 4'-trifluoromethyl-biphenyl-2-carboxylic
acid[2-(2-ethoxy-ethyl)-1,-
2,3,4-tetrahydro-isoquinolin-6-yl]-amide.
[0447] Any HMG-CoA synthase inhibitor may be used as the second
compound in the combination aspect of this invention. The term
HMG-CoA synthase inhibitor refers to compounds which inhibit the
biosynthesis of hydroxymethylglutaryl-coenzyme A from
acetyl-coenzyme A and acetoacetyl-coenzyme A, catalyzed by the
enzyme HMG-CoA synthase. Such inhibition is readily determined by
those skilled in the art according to standard assays (Meth
Enzymol. 1975; 35:155-160: Meth. Enzymol. 1985; 110:19-26 and
references cited therein). A variety of these compounds are
described and referenced below, however other HMG-CoA synthase
inhibitors will be known to those skilled in the art. U.S. Pat. No.
5,120,729 (the disclosure of which is hereby incorporated by
reference) discloses certain beta-lactam derivatives. U.S. Pat. No.
5,064,856 (the disclosure of which is hereby incorporated by
reference) discloses certain spiro-lactone derivatives prepared by
culturing a microorganism (MF5253). U.S. Pat. No. 4,847,271 (the
disclosure of which is hereby incorporated by reference) discloses
certain oxetane compounds such as
1-(3-hydroxymethyl-4-oxo-2-oxetayl)-3,5,7-trimethyl-2,4-undeca-dienoic
acid derivatives.
[0448] Any compound that decreases HMG-CoA reductase gene
expression may be used as the second compound in the combination
aspect of this invention. These agents may be HMG-CoA reductase
transcription inhibitors that block the transcription of DNA or
translation inhibitors that prevent translation of mRNA coding for
HMG-CoA reductase into protein. Such compounds may either affect
transcription or translation directly, or may be biotransformed to
compounds that have the aforementioned activities by one or more
enzymes in the cholesterol biosynthetic cascade or may lead to the
accumulation of an isoprene metabolite that has the aforementioned
activities. Such regulation is readily determined by those skilled
in the art according to standard assays (Meth. Enzymol. 1985;
110:9-19). Several compounds are described and referenced below,
however other inhibitors of HMG-CoA reductase gene expression will
be known to those skilled in the art. U.S. Pat. No. 5,041,432 (the
disclosure of which is incorporated by reference) discloses certain
15 substituted lanosterol derivatives. Other oxygenated sterols
that suppress synthesis of HMG-CoA reductase are discussed by E. I.
Mercer (Prog. Lip. Res. 1993;32:357-416).
[0449] Any squalene synthetase inhibitor may be used as the second
compound of this invention. The term squalene synthetase inhibitor
refers to compounds which inhibit the condensation of 2 molecules
of farnesylpyrophosphate to form squalene, catalyzed by the
enzyme-squalene synthetase. Such inhibition is readily determined
by those skilled in the art according to standard assays (Meth.
Enzymol. 1969; 15: 393-454 and Meth. Enzymol. 1985; 110:359-373 and
references contained therein). A variety of these compounds are
described in and referenced below however other squalene synthetase
inhibitors will be known to those skilled in the art. U.S. Pat. No.
5,026,554 (the disclosure of which is incorporated by reference)
discloses fermentation products of the microorganism MF5465 (ATCC
74011) including zaragozic acid. A summary of other patented
squalene synthetase inhibitors has been compiled (Curr. Op. Ther.
Patents (1993) 861-4).
[0450] Any squalene epoxidase inhibitor may be used as the second
compound in the combination aspect of this invention. The term
squalene epoxidase inhibitor refers to compounds which inhibit the
bioconversion of squalene and molecular oxygen into
squalene-2,3-epoxide, catalyzed by the enzyme squalene epoxidase.
Such inhibition is readily-determined by those skilled in the art
according to standard assays (Biochim. Biophys. Acta 1984;
794:466471). A variety of these compounds are described and
referenced below, however other squalene epoxidase inhibitors will
be known to those skilled in the art. U.S. Pat. Nos. 5,011,859 and
5,064,864 (the disclosures of which are incorporated by reference)
disclose certain fluoro analogs of squalene. EP publication 395,768
A (the disclosure of which is incorporated by reference) discloses
certain substituted allylamine derivatives. PCT publication WO
9312069 A (the disclosure of which is hereby incorporated by
reference) discloses certain amino alcohol derivatives. U.S. Pat.
No. 5,051,534 (the disclosure of which is hereby incorporated by
reference) discloses certain cyclopropyloxy-squalene
derivatives.
[0451] Any squalene cyclase inhibitor may be used as the second
component in the combination aspect of this invention. The term
squalene cyclase inhibitor-refers to compounds which inhibit the
bioconversion of squalene-2,3-epoxide to lanosterol, catalyzed by
the enzyme squalene cyclase. Such inhibition is readily determined
by those skilled in the art according to standard assays (FEBS
Lett. 1989;244:347-350.). In addition, the compounds described and
referenced below are squalene cyclase inhibitors, however other
squalene cyclase inhibitors will also be known to those skilled in
the art. PCT publication WO9410150 (the disclosure of which is
hereby incorporated by reference) discloses certain
1,2,3,5,6,7,8,8.alpha.-octahydro-5,5,8.alpha.(beta)-trimethyl-6-i-
soquinolineamine derivatives, such as
N-trifluoroacetyl-1,2,3,5,6,7,8,8.al-
pha.-octahydro-2-allyl-5,5,8.alpha.(beta)-trimethyl-6(beta)-isoquinolineam-
ine. French patent publication 2697250 (the disclosure of which is
hereby incorporated by reference) discloses certain beta,
beta-dimethyl-4-piperidine ethanol derivatives such as
1-(1,5,9-trimethyldecyl)-beta,beta-dimethyl-4-piperidineethanol.
[0452] Any combined squalene epoxidase/squalene cyclase inhibitor
may be used as the second component in the combination aspect of
this invention. The term combined squalene epoxidase/squalene
cyclase inhibitor refers to compounds that inhibit the
bioconversion of squalene to lanosterol via a squalene-2,3-epoxide
intermediate. In some assays it is not possible to distinguish
between squalene epoxidase inhibitors and squalene cyclase
inhibitors, however, these assays are recognized by those skilled
in the art. Thus, inhibition by combined squalene
epoxidase/squalene cyclase inhibitors is readily determined by
those skilled in art according to the aforementioned standard
assays for squalene cyclase or squalene epoxidase inhibitors. A
variety of these compounds are described and referenced below,
however other squalene epoxidase/squalene cyclase inhibitors will
be known to those skilled in the art. U.S. Pat. Nos. 5,084,461 and
5,278,171 (the disclosures of which are incorporated by reference)
disclose certain azadecalin derivatives. EP publication 468,434
(the disclosure of which is incorporated by reference) discloses
certain piperidyl ether and thio-ether derivatives such as
2-(1-piperidyl)pentyl isopentyl sulfoxide and 2-(1-piperidyl)ethyl
ethyl sulfide. PCT publication WO 9401404 (the disclosure of which
is hereby incorporated by reference) discloses certain
acyl-piperidines such as
1-(1-oxopentyl-5-phenylthio)-4-(2-hydroxy-1-methyl)-ethyl)piperidine.
U.S. Pat. No. 5,102,915 (the disclosure of which is hereby
incorporated by reference) discloses certain
cyclopropyloxy-squalene derivatives.
[0453] The starting materials and reagents for the above described
Formula I compounds, are also readily available or can be easily
synthesized by those skilled in the art using conventional methods
of organic synthesis. For example, many of the compounds used
herein, are related to, or are derived from compounds in which
there is a large scientific interest and commercial need, and
accordingly many such compounds are commercially available or are
reported in the literature or are easily prepared from other
commonly available substances by methods which are reported in the
literature.
[0454] Some of the Formula I compounds of this invention or
intermediates in their synthesis have asymmetric carbon atoms and
therefore are enantiomers or diastereomers. Diasteromeric mixtures
can be separated into their individual diastereomers on the basis
of their physical chemical differences by methods known per se.,
for example, by chromatography and/or fractional crystallization.
Enantiomers can be separated by, for example, chiral HPLC methods
or converting the enantiomeric mixture into a diasteromeric mixture
by reaction with an appropriate optically active compound (e.g.,
alcohol), separating the diastereomers and converting (e.g.,
hydrolyzing) the individual diastereomers to the corresponding pure
enantiomers. Also, an enantiomeric mixture of the Formula I
compounds or an intermediate in their synthesis which contain an
acidic or basic moiety may be separated into their compounding pure
enantiomers by forming a diastereomeric salt with an optically pure
chiral base or acid (e.g., 1-phenylethyl amine or tahtaric acid)
and separating the diasteromers by fractional crystallization
followed by neutralization to break the salt, thus providing the
corresponding pure enantiomers. All such isomers, including
diastereomers, enantiomers and mixtures thereof are considered as
part of this invention. Also, some of the compounds of this
invention are atropisomers (e.g., substituted biaryls) and are
considered as part of this invention.
[0455] More specifically, the Formula I compounds of this invention
may be obtained in enantiomerically enriched form by resolving the
racemate of the final compound or an intermediate in its synthesis
(preferably the final compound) employing chromatography
(preferably high pressure liquid chromatography [HPLC]) on an
asymmetric resin (preferably Chiralcel.TM. AD or OD [obtained from
Chiral Technologies, Exton, Pa.]) with a mobile phase consisting of
a hydrocarbon (preferably heptane or hexane) containing between 0
and 50% isopropanol (preferably between 2 and 20%) and between 0
and 5% of an alkyl amine (preferably 0.1% of diethylamine).
Concentration of the product containing fractions affords the
desired materials.
[0456] Some of the Formula I compounds of this invention are acidic
and they form a salt with a pharmaceutically acceptable cation.
Some of the Formula I compounds of this invention are basic and
they form a salt with a pharmaceutically acceptable anion. All such
salts are within the scope of this invention and they can be
prepared by conventional methods such as combining the acidic and
basic entities, usually in a stoichiometric ratio, in either an
aqueous, non-aqueous or partially aqueous medium, as appropriate.
The salts are recovered either by filtration, by precipitation with
a non-solvent followed by filtration, by evaporation of the
solvent, or, in the case of aqueous solutions, by lyophilization,
as appropriate. The compounds can be obtained in crystalline form
by dissolution in an appropriate solvent(s) such as ethanol,
hexanes or water/ethanol mixtures.
[0457] In addition, when the Formula I compounds of this invention
form hydrates or solvates they are also within the scope of the
invention.
[0458] The Formula I compounds of this invention, their prodrugs
and the salts of such compounds and prodrugs are all adapted to
therapeutic use as agents that inhibit cholesterol ester transfer
protein activity in mammals, particularly humans. Thus, the
compounds of this invention elevate plasma HDL cholesterol, its
associated components, and the functions performed by them in
mammals, particularly humans. By virtue of their activity, these
agents also reduce plasma levels of triglycerides, VLDL cholesterol
LDL cholesterol and their associated components in mammals,
particularly humans. Hence, these compounds are useful for the
treatment and correction of the various dyslipidemias observed to
be associated with the development and incidence of atherosclerosis
and cardiovascular disease, including hypoalphalipoproteinemia,
hyperbetalipoproteinemia, hypertriglyceridemia, and
familial-hypercholesterolemia.
[0459] Further, introduction of a functional CETP gene into an
animal lacking CETP (mouse) results in reduced HDL levels (Agellon,
L. B., et al: J. Biol. Chem. (1991) 266: 10796-10801.) and
increased susceptibility to atherosclerosis. (Marotti, K. R., et
al: Nature (1993) 364: 73-75.). Also, inhibition of CETP activity
with an inhibitory antibody raises HDL-cholesterol in hamster
(Evans, G. F., et al: J. of Lipid Research (1994) 35: 1634-1645.)
and rabbit (Whitlock, M. E., et al: J. Clin. Invest. (1989) 84:
129-137). Suppression of increased plasma CETP by intravenous
injection with antisense oligodeoxynucleotides against CETP mRNA
reduced atherosclerosis in cholesterol-fed rabbits (Sugano, M., et
al: J. of Biol. Chem. (1998) 273: 5033-5036.) Importantly, human
subjects deficient in plasma CETP, due to a genetic mutation
possess markedly elevated plasma HDL-cholesterol levels and
apolipoprotein A-1, the major apoprotein component of HDL. In
addition, most demonstrate markedly decreased plasma LDL
cholesterol and apolipoprotein B (the major apolipoprotein
component of LDL. (Inazu, A., Brown, M. L., Hesler, C. B., et al.:
N. Engl. J. Med. (1990) 323: 1234-1238.)
[0460] Given the negative correlation between the levels of HDL
cholesterol and HDL associated lipoproteins, and the positive
correlation between triglycerides, LDL cholesterol, and their
associated apolipoproteins in blood with the development of
cardiovascular, cerebral vascular and peripheral vascular diseases,
the Formula I compounds of this invention, their prodrugs and the
salts of such compounds and prodrugs, by virtue of their
pharmacologic action, are useful for the prevention, arrestment
and/or regression of atherosclerosis and its associated disease
states. These include cardiovascular disorders (e.g., angina,
cardiac ischemia and myocardial infarction), complications due to
cardiovascular disease therapies (e.g., reperfusion injury and
angioplastic restenosis), hypertension, stroke, and atherosclerosis
associated with organ transplantation.
[0461] Because of the beneficial effects widely associated with
elevated HDL levels, an agent which inhibits CETP activity in
humans, by virtue of its HDL increasing ability, also provides
valuable avenues for therapy in a number of other disease areas as
well.
[0462] Thus, given the ability of the Formula I compounds of this
invention, their prodrugs and the salts of such compounds and
prodrugs to alter lipoprotein composition via inhibition of
cholesterol ester transfer, they are of use in the treatment of
vascular complications associated with diabetes. Hyperlipidemia is
present in most subjects with diabetes mellitus (Howard, B. V.
1987. J. Lipid Res. 28, 613). Even in the presence of normal lipid
levels, diabetic subjects experience a greater risk of
cardiovascular disease (Kannel, W. B. and McGee, D. L. 1979.
Diabetes Care 2, 120). CETP-mediated cholesteryl ester transfer is
known to be abnormally increased in both insulin-dependent
(Bagdade, J. D., Subbaiah, P. V. and Ritter, M. C. 1991. Eur. J.
Clin. Invest. 21, 161) and non-insulin dependent diabetes (Bagdade.
J. D., Ritter, M. C., Lane, J. and Subbaiah. 1993. Atherosclerosis
104, 69). It has been suggested that the abnormal increase in
cholesterol transfer results in changes in lipoprotein composition,
particularly for VLDL and LDL, that are more atherogenic (Bagdade,
J. D., Wagner, J. D., Rudel, L. L., and Clarkson, T. B. 1995. J.
Lipid Res. 36, 759). These changes would not necessarily be
observed during routine lipid screening. Thus the present invention
will be useful in reducing the risk of vascular complications as a
result of the diabetic condition.
[0463] The described agents are useful in the treatment of obesity.
In both humans (Radeau, T., Lau, P., Robb, M., McDonnell, M.,
Ailhaud, G. and McPherson, R., 1995. Journal of Lipid Research. 36
(12):2552-61) and nonhuman primates (Quinet, E., Tall, A.,
Ramakrishnan, R. and Rudel, L., 1991. Journal of Clinical
Investigation. 87 (5):1559-66) mRNA for CETP is expressed at high
levels in adipose tissue. The adipose message increases with fat
feeding (Martin, L. J., Connelly, P. W., Nancoo, D., Wood, N.,
Zhang, Z. J., Maguire, G., Quinet, E., Tall, A. R., Marcel, Y. L.
and McPherson, R., 1993. Journal of Lipid Research; 34 (3):437-46),
and is translated into functional transfer protein and through
secretion contributes significantly to plasma CETP levels. In human
adipocytes the bulk of cholesterol is provided by plasma LDL and
HDL (Fong, B. S., and Angel, A., 1989. Biochimica et Biophysica
Acta. 1004 (1):53-60). The uptake of HDL cholesteryl ester is
dependent in large part on CETP (Benoist, F., Lau, P., McDonnell,
M., Doelle, H., Milne, R. and McPherson, R., 1997. Journal of
Biological Chemistry. 272 (38):23572-7). This ability of CETP to
stimulate HDL cholesteryl uptake, coupled with the enhanced binding
of HDL to adipocytes in obese subjects (Jimenez, J. G., Fong, B.,
Julien, P., Despres, J. P., Rotstein, L., and Angel, A., 1989.
International Journal of Obesity. 13 (5):699-709), suggests a role
for CETP, not only in generating the low HDL phenotype for these
subjects, but in the development of obesity itself by promoting
cholesterol accumulation. Inhibitors of CETP activity that block
this process therefore serve as useful adjuvants to dietary therapy
in causing weight reduction.
[0464] CETP inhibitors are useful in the treatment of inflammation
due to Gram-negative sepsis and septic shock. For example, the
systemic toxicity of Gram-negative sepsis is in large part due to
endotoxin, a lipopolysaccharide (LPS) released from the outer
surface of the bacteria, which causes an extensive inflammatory
response. Lipopolysaccharide can form complexes with lipoproteins
(Ulevitch, R. J., Johhston, A. R., and Weinstein, D. B., 1981. J.
Clin. Invest. 67, 827-37). In vitro studies have demonstrated that
binding of LPS to HDL substantially reduces the production and
release of mediators of inflammation (Ulevitch, R. J., Johhston, A.
R., 1978. J. Clin. Invest. 62, 1313-24). In vivo studies show that
transgenic mice expressing human apo-AI and elevated HDL levels are
protected from septic shock (Levine, D. M., Parker, T. S.,
Donnelly, T. M., Walsh, A. M., and Rubin, A. L. 1993. Proc. Natl.
Acad. Sci. 90, 12040-44). Importantly, administration of
reconstituted HDL to humans challenged with endotoxin resulted in a
decreased inflammatory response (Pajkrt, D., Doran, J. E., Koster,
F., Lerch, P. G., Amet, B., van der Poll, T., ten. Cate, J. W., and
van Deventer, S. J. H. 1996. J. Exp. Med. 184, 1601-08). The CETP
inhibitors, by virtue of the fact that they raise HDL levels,
attenuate the development of inflammation and septic shock.
[0465] The utility of the Formula I compounds of the invention,
their prodrugs and the salts of such compounds and prodrugs as
medical agents in the treatment of the above described
disease/conditions in mammals (e.g. humans, male or female) is
demonstrated by the activity of the compounds of this invention in
conventional assays and the in vivo assay described below. The in
vivo assay (with appropriate modifications within the skill in the
art) may be used to determine the activity of other lipid or
triglyceride controlling agents as well as the compounds of this
invention. The combination protocol described below is useful for
demonstrating the utility of the combinations of the lipid and
triglyceride agents (e.g., the compounds of this invention)
described herein. Such assays also provide a means whereby the
activities of the Formula I compounds of this invention, their
prodrugs and the salts of such compounds and prodrugs (or the other
agents described herein) can be compared to each other and with the
activities of other known compounds. The results of these
comparisons are useful for determining dosage levels in mammals,
including humans, for the treatment of such diseases.
[0466] The following protocols can of course be varied by those
skilled in the art.
[0467] The hyperalphacholesterolemic activity of the Formula I
compounds can be determined by assessing the effect of these
compounds on the action of cholesteryl ester transfer protein by
measuring the relative transfer ratio of radiolabeled lipids
between lipoprotein fractions, essentially as previously described
by Morton in J. Biol. Chem. 256, 11992, 1981 and by Dias in Clin.
Chem. 34, 2322, 1988.
CETP In Vitro Asssay
[0468] The following is a brief description of the assay of
cholesteryl ester transfer in human plasma (in vitro) and animal
plasma (ex vivo): CETP activity in the presence absence of drug is
assayed by determining the transfer of .sup.3H-labeled cholesteryl
oleate (CO) from exogenous tracer HDL to the nonHDL lipoprotein
fraction in human plasma, or from .sup.3H-labeled LDL to the HDL
fraction in transgenic mouse plasma. Labeled human lipoprotein
substrates are prepared similarly to the method described by Morton
in which the endogenous CETP activity in plasma is employed to
transfer .sup.3H--CO from phospholipid liposomes to all the
lipoprotein fractions in plasma. .sup.3H-labeled LDL and HDL are
subsequently isolated by sequential ultracentrifugation at the
density cuts of 1.019-1.063 and 1.10-1.21 g/ml, respectively. For
the activity assay, .sup.3H-labeled lipoprotein is added to plasma
at 10-25 nmoles CO/ml and the samples incubated at 37.degree. C.
for 2.5-3 hrs. Non-HDL lipoproteins are then precipitated by the
addition of an equal volume of 20% (wt/vol) polyethylene glycol
8000 (Dias). The samples are centrifuged 750 g.times.20 minutes and
the radioactivity contained in the HDL containing supernatant
determined by liquid scintillation. Introducing varying quantities
of the compounds of this invention as a solution in
dimethylsulfoxide to human plasma, before addition of the
radiolabeled cholesteryl oleate, and comparing the relative amounts
of radiolabel transferred allows relative cholesteryl ester
transfer inhibitory activities to be determined.
CETP In Vivo Asssay
[0469] Activity of these compounds in vivo can be determined by the
amount of agent required to be administered, relative to control,
to inhibit cholesteryl ester transfer activity by 50% at various
time points ex vivo or to elevate HDL cholesterol by a given
percentage in a CETP-containing animal species. Transgenic mice
expressing both human CETP and human apolipoprotein Al (Charles
River, Boston, Mass.) may be used to assess compounds in vivo. The
compounds to be examined are administered by oral gavage in an
emulsion vehicle containing olive oil and sodium taurocholate.
Blood is taken from mice retroorbitally before dosing. At various
times after dosing, ranging from 4 h to 24 h, the animals are
sacrificed, blood obtained by heart puncture, and lipid parameters
measured, including total cholesterol, HDL and LDL cholesterol, and
triglycerides. CETP activity is determined by a method similar to
that described above except that .sup.3H-cholesteryl oleate
containing LDL is used as the donor source as opposed to HDL. The
values obtained for lipids and transfer activity are compared to
those obtained prior to dosing and/or to those from mice receiving
vehicle alone.
Plasma Lipids Assay
[0470] The activity of these compounds may also be demonstrated by
determining the amount of agent required to alter plasma lipid
levels, for example HDL cholesterol levels, LDL cholesterol levels,
VLDL cholesterol levels or triglycerides, in the plasma of certain
mammals, for example marmosets that possess CETP activity and a
plasma lipoprotein profile similar to that of humans (Crook et al.
Arteriosclerosis 10, 625, 1990). Adult marmosets are assigned to
treatment groups so that each group has a similar mean .+-.D for
total, HDL, and/or LDL plasma cholesterol concentrations. After
group assignment, marmosets are dosed daily with compound as a
dietary admix or by intragastric intubation for from one to eight
days. Control marmosets receive only the dosing vehicle. Plasma
total, LDL, VLDL and HDL cholesterol values can be determined at
any point during the study by obtaining blood from an antecubital
vein and separating plasma lipoproteins into their individual
subclasses by density gradient centrifugation, and by measuring
cholesterol concentration as previously described (Crook et al.
Arteriosclerosis 10, 625, 1990).
In Vivo Atherosclerosis Assay
[0471] Anti-atherosclerotic effects of the compounds can be
determined by the amount of compound required to reduce the lipid
deposition in rabbit aorta. Male New Zealand White rabbits are fed
a diet containing 0.2% cholesterol and 10% coconut oil for 4 days
(meal-fed once per day). Rabbits are bled from the marginal ear
vein and total plasma cholesterol values are determined from these
samples. The rabbits are then assigned to treatment groups so that
each group has a similar mean.+-.SD for total plasma cholesterol
concentration, HDL cholesterol concentration, triglyceride
concentration and/or cholesteryl ester transfer protein activity.
After group assignment, rabbits are dosed daily with compound given
as a dietary admix or on a small piece of gelatin based confection.
Control rabbits receive only the dosing vehicle, be it the food or
the gelatin confection. The cholesterol/coconut oil diet is
continued along with the compound administration throughout the
study. Plasma cholesterol values and cholesteryl ester transfer
protein activity can be determined at any point during the study by
obtaining blood from the marginal ear vein. After 3-5 months, the
rabbits are sacrificed and the aortae are removed from the thoracic
arch to the branch of the iliac arteries. The aortae are cleaned of
adventitia, opened longitudinally and then stained with Sudan IV as
described by Holman et. al. (Lab. Invest. 1958, 7, 4247). The
percent of the surface area stained is quantitated by densitometry
using an Optimas Image Analyzing System (Image Processing Systems).
Reduced lipid deposition is indicated by a reduction in the percent
surface area stained in the compound-receiving group in comparison
with the control rabbits.
Antiobesity Protocol
[0472] The ability of CETP inhibitors to cause weight loss can be
assessed in obese human subjects with body mass index
(BMI).gtoreq.30 kg/m.sup.2. Doses of inhibitor are administered
sufficient to result in an increase of .gtoreq.25% in HDL
cholesterol levels. BMI and body fat distribution, defined as waist
(W) to hip (H) ratio (WHR), are monitored during the course of the
36 month studies, and the results for treatment groups compared to
those receiving placebo.
In Vivo Sepsis Assay
[0473] In vivo studies show that transgenic mice expressing human
apo-AI and elevated HDL levels are protected from septic shock.
Thus the ability of CETP inhibitors to protect from septic shock
can be demonstrated in transgenic mice expressing both human apo-AI
and human CETP transgenes (Levine, D. M., Parker, T. S., Donnelly,
T. M., Walsh, A. M. and Rubin, A. L., 1993. Proc. Natl. Acad. Sci.
90, 12040-44). LPS derived from E. coli is administered at 30 mg/kg
by i.p. injection to animals which have been administered a CETP
inhibitor at an appropriate dose to result in elevation of HDL. The
number of surviving mice is determined at times up to 48 h after
LPS injection and compared to those mice administered vehicle
(minus CETP inhibitor) only.
[0474] Administration of the compounds of this invention can be via
any method which delivers a compound of this invention systemically
and/or locally. These methods include oral routes, parenteral,
intraduodenal routes, etc. Generally, the compounds of this
invention are administered orally, but parenteral administration
(e.g., intravenous, intramuscular, subcutaneous or intramedullary)
may be utilized, for example, where oral administration is
inappropriate for the target or where the patient is unable to
ingest the drug.
[0475] In general an amount of a compound of this invention is used
that is sufficient to achieve the therapeutic effect desired (e.g.,
HDL elevation).
[0476] In general an effective dosage for the Formula I compounds
of this invention, their prodrugs and the salts of such compounds
and prodrugs is in the range of 0.01 to 10 mg/kg/day, preferably
0.1 to 5 mg/kg/day.
[0477] A dosage of the combination pharmaceutical agents to be used
in conjunction ith the CETP inhibitors is used that is effective
for the indication being treated.
[0478] For example, typically an effective dosage for HMG-CoA
reductase inhibitors is in the range of 0.01 to 100 mg/kg/day. In
general an effect dosage for the MTP/Apo B secretion inhibitors is
in the range of 0.01 to 100 mg/kg/day.
[0479] The compounds of the present invention are generally
administered in the form of a pharmaceutical composition comprising
at least one of the compounds of this invention together with a
pharmaceutically acceptable vehicle, diluent or carrier. Thus, the
compounds of this invention can be administered individually or
together in any conventional oral, parenteral, rectal or
transdermal dosage form.
[0480] For oral administration a pharmaceutical composition can
take the form of solutions, suspensions, tablets, pills, capsules,
powders, and the like. Tablets containing various excipients such
as sodium citrate, calcium carbonate and calcium phosphate are
employed along with various disintegrants such as starch and
preferably potato or tapioca starch and certain complex silicates,
together with binding agents such as polyvinylpyrrolidone, sucrose,
gelatin and acacia. Additionally, lubricating agents such as
magnesium stearate, sodium lauryl sulfate and talc are often very
useful for tabletting purposes. Solid compositions of a similar
type are also employed as fillers in soft and hard-filled gelatin
capsules; preferred materials in this connection also include
lactose or milk sugar as well as high molecular weight polyethylene
glycols. A preferred formulation is a solution or suspension in an
oil, for example olive oil, Miglyol.TM. or Capmul.TM., in a soft
gelatin capsule. Antioxidants may be added to prevent long term
degradation as appropriate. When aqueous suspensions and/or elixirs
are desired for oral administration, the compounds of this
invention can be combined with various sweetening agents, flavoring
agents, coloring agents, emulsifying agents and/or suspending
agents, as well as such diluents as water, ethanol, propylene
glycol, glycerin and various like combinations thereof.
[0481] For purposes of parenteral administration, solutions in
sesame or peanut oil or in aqueous propylene glycol can be
employed, as well as sterile aqueous solutions of the corresponding
water-soluble salts. Such aqueous solutions may be suitably
buffered, if necessary, and the liquid diluent first rendered
isotonic with sufficient saline or glucose. These aqueous solutions
are especially suitable for intravenous, intramuscular,
subcutaneous and intraperitoneal injection purposes. In this
connection, the sterile aqueous media employed are all readily
obtainable by standard techniques well-known to those skilled in
the art.
[0482] For purposes of transdermal (e.g., topical) administration,
dilute sterile, aqueous or partially aqueous solutions (usually in
about 0.1% to 5% concentration), otherwise similar to the above
parenteral solutions, are prepared.
[0483] Methods of preparing various pharmaceutical compositions
with a certain amount of active ingredient are known, or will be
apparent in light of this disclosure, to those skilled in this art.
For examples of methods of preparing pharmaceutical compositions,
see Remington's Pharmaceutical Sciences, Mack Publishing Company,
Easter, Pa., 15th Edition (1975). Pharmaceutical compositions
according to the invention may contain 0.1%-95% of the compound(s)
of this invention, preferably 1%-70%. In any event, the composition
or formulation to be administered will contain a quantity of a
compound(s) according to the invention in an amount effective to
treat the disease/condition of the subject being treated, e.g.,
atherosclerosis.
[0484] Since the present invention has an aspect that relates to
the treatment of the disease/conditions described herein with a
combination of active ingredients which may be administered
separately, the invention also relates to combining separate
pharmaceutical compositions in kit form. The kit comprises two
separate pharmaceutical compositions: a compound of Formula I, a
prodrug thereof or a salt of such compound or prodrugs and a second
compound as described above. The kit comprises means for containing
the separate compositions such as a container, a divided bottle or
a divided foil packet. Typically the kit comprises directions for
the administration of the separate components. The kit form is
particularly advantageous when the separate components are
preferably administered in different dosage forms (e.g., oral and
parenteral), are administered at different dosage intervals, or
when titration of the individual components of the combination is
desired by the prescribing physician.
[0485] An example of such a kit is a so-called blister-pack.
Blister packs are well known in the packaging industry and are
being widely used for the packaging of pharmaceutical unit dosage
forms (tablets, capsules, and the like). Blister packs generally
consist of a sheet of relatively stiff material covered with a foil
of a preferably transparent plastic material. During the packaging
process recesses are formed in the plastic foil. The recesses have
the size and shape of the tablets or capsules to be packed. Next,
the tablets or capsules are placed in the recesses and the sheet of
relatively stiff material is sealed against the plastic foil at the
face of the foil which is opposite from the direction in which the
recesses were formed. As a result, the tablets or capsules are
sealed in the recesses between the plastic foil and the sheet.
Preferably the strength of the sheet is such that the tablets or
capsules can be removed from the blister pack by manually applying
pressure on the recesses whereby an opening is formed in the sheet
at the place of the recess. The tablet or capsule can then be
removed via said opening.
[0486] It may be desirable to provide a memory aid on the kit,
e.g., in the form of numbers next to the tablets or capsules
whereby the numbers correspond with the days of the regimen which
the tablets or capsules so specified should be ingested. Another
example of such a memory aid is a calendar printed on the card,
e.g., as follows "First Week, Monday, Tuesday, . . . etc. . . .
Second Week, Monday, Tuesday, . . . " etc. Other variations of
memory aids will be readily apparent. A "daily dose" can be a
single tablet or capsule or several pills or capsules to be taken
on a given day. Also, a daily dose of Formula I compound can
consist of one tablet or capsule while a daily dose of the second
compound can consist of several tablets or capsules and vice versa.
The memory aid should reflect this.
[0487] In another specific embodiment of the invention, a dispenser
designed to dispense the daily doses one at a time in the order of
their intended use is provided. Preferably, the dispenser is
equipped with a memory-aid, so as to further facilitate compliance
with the regimen. An example of such a memory-aid is a mechanical
counter which indicates the number of daily doses that has been
dispensed. Another example of such a memory-aid is a
battery-powered micro-chip memory coupled with a liquid crystal
readout, or audible reminder signal which, for example, reads out
the date that the last daily dose has been taken and/or reminds one
when the next dose is to be taken.
[0488] The compounds of this invention either alone or in
combination with each other or other compounds generally will be
administered in a convenient formulation. The following formulation
examples only are illustrative and are not intended to limit the
scope of the present invention.
[0489] In the formulations which follow, "active ingredient" means
a compound of this invention.
1 Formulation 1: Gelatin Capsules Hard gelatin capsules are
prepared using the following: Ingredient Quantity (mg/capsule)
Active ingredient 0.25-100 Starch, NF 0-650 Starch flowable powder
0-50 Silicone fluid 350 centistokes 0-15
[0490] A tablet formulation is prepared using the ingredients
below:
2 Formulation 2: Tablets Ingredient Quantity (mg/tablet) Active
ingredient 0.25-100 Cellulose, microcrystalline 200-650 Silicon
dioxide, fumed 10-650 Stearate acid 5-15
[0491] The components are blended and compressed to form
tablets.
[0492] Alternatively, tablets each containing 0.25-100 mg of active
ingredients are made up as follows:
3 Formulation 3: Tablets Ingredient Quantity (mg/tablet) Active
ingredient 0.25-100 Starch 45 Cellulose, microcrystalline 35
Polyvinylpyrrolidone (as 10% solution in water) 4 Sodium
carboxymethyl cellulose 4.5 Magnesium stearate 0.5 Talc 1
[0493] The active ingredients, starch, and cellulose are passed
through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution
of polyvinylpyrrolidone is mixed with the resultant powders which
are then passed through a No. 14 mesh U.S. sieve. The granules so
produced are dried at 50.degree.-60.degree. C. and passed through a
No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium
stearate, and talc, previously passed through a No. 60 U.S. sieve,
are then added to the granules which, after mixing, are compressed
on a tablet machine to yield tablets.
[0494] Suspensions each containing 0.25-100 mg of active ingredient
per 5 ml dose are made as follows:
4 Formulation 4: Suspensions Ingredient Quantity (mg/5 ml) Active
ingredient 0.25-100 mg Sodium carboxymethyl cellulose 50 mg Syrup
1.25 mg Benzoic acid solution 0.10 mL Flavor q.v. Color q.v.
Purified Water to 5 mL
[0495] The active ingredient is passed through a No. 45 mesh U.S.
sieve and mixed with the sodium carboxymethyl cellulose and syrup
to form smooth paste. The benzoic acid solution, flavor, and color
are diluted with some of the water and added, with stirring.
Sufficient water is then added to produce the required volume.
[0496] An aerosol solution is prepared containing the following
ingredients:
5 Formulation 5: Aerosol Ingredient Quantity (% by weight) Active
ingredient 0.25 Ethanol 25.75 Propellant 22 (Chlorodifluoromethane)
70.00
[0497] The active ingredient is mixed with ethanol and the mixture
added to a portion of the propellant 22, cooled to 30.degree. C.,
and transferred to a filling device. The required amount is then
fed to a stainless steel container and diluted with the remaining
propellant. The valve units are then fitted to the container.
[0498] Suppositories are prepared as follows:
6 Formulation 6: Suppositories Ingredient Quantity (mg/suppository)
Active ingredient 250 Saturated fatty acid glycerides 2,000
[0499] The active ingredient is passed through a No. 60 mesh U.S.
sieve and suspended in the saturated fatty acid glycerides
previously melted using the minimal necessary heat. The mixture is
then poured into a suppository mold of nominal 2 g capacity and
allowed to cool.
[0500] An intravenous formulation is prepared as follows:
7 Formulation 7: Intravenous Solution Ingredient Quantity Active
ingredient dissolved in ethanol 1% 20 mg Intralipid .TM. emulsion
1,000 mL
[0501] The solution of the above ingredients is intravenously
administered to a patient at a rate of about 1 mL per minute.
[0502] Soft gelatin capsules are prepared using the following:
8 Formulation 8: Soft Gelatin Capsule with Oil Formulation
Ingredient Quantity (mg/capsule) Active ingredient 10-500 Olive Oil
or Miglyol .TM. Oil 500-1000
[0503] The active ingredient above may also be a combination of
agents.
General Experimental Procedures
[0504] NMR spectra were recorded on a Varian XL-300 (Varian Co.,
Palo Alto, Calif.), a Bruker AM-300 spectrometer (Bruker Co.,
Billerica, Mass.) or a Varian Unity 400 at about 23.degree. C. at
300 MHz for proton and 75.4 mHz for carbon nuclei. Chemical shifts
are expressed in parts per million downfield from
tetramethylsilane. The peak shapes are denoted as follows: s,
singlet; d, doublet; t, triplet, q, quartet; m, multiplet; bs=broad
singlet. Resonances designated as exchangeable did not appear in a
separate NMR experiment where the sample was shaken with several
drops of D.sub.2O in the same solvent. Atmospheric pressure
chemical ionization (APCI) mass spectra were obtained on a Fisons
Platform II Spectrometer. Chemical ionization mass spectra were
obtained on a Hewlett-Packard 5989 instrument (Hewlett-Packard Co.,
Palo Alto, Calif.) (ammonia ionization, PBMS). Where the intensity
of chlorine or bromine-containing ions are described, the expected
intensity ratio was observed (approximately 3:1 for
.sup.35Cl/.sup.37Cl-containing ions) and 1:1 for
.sup.79Br/.sup.81Br-containing ions) and the intensity of only the
lower mass ion is given.
[0505] Column chromatography was performed with either Baker Silica
Gel (40 .mu.m) (J. T. Baker, Phillipsburg, N.J.) or Silica Gel 60
(EM Sciences, Gibbstown, N.J.) in glass columns under low nitrogen
pressure. Radial Chromatography was performed using a Chromatron
(model 7924T, Harrison Research). Unless otherwise specified,
reagents were used as obtained from commercial sources.
Dimethylformamide, 2-propanol, tetrahydrofuran, and dichloromethane
used as reaction solvents were the anhydrous grade supplied by
Aldrich Chemical Company (Milwaukee, Wis.). Microanalyses were
performed by Schwarzkopf Microanalytical Laboratory, Woodside, N.Y.
The terms "concentrated" and "evaporated" refer to removal of
solvent at water aspirator pressure on a rotary evaporator with a
bath temperature of less than 45.degree. C. Reactions conducted at
"0-20.degree. C." or "0-25.degree. C." were conducted with initial
cooling of the vessel in an insulated ice bath which was allowed to
warm to room temperature over several hours. The abbreviation "min"
and "h" stand for "minutes" and "hours" respectively.
EXAMPLES
Example 1
[0506]
cis-4-Benzyloxycarbonylamino-6,7-dimethoxy-1,2,3,4-tetrahydro-quino-
line-2-carboxylic acid butyl ester: 3,4-Dimethoxyaniline (7.5 g,
49.0 mmol), n-butyl glyoxylate (6.5 g, 49.0 mmol) and anhydrous
sodium sulfate (20 g) were stirred in anhydrous dichloromethane
(100 mL) at room temperature. After 90 min. the sodium sulfate was
then filtered off, and to the filtrate was added O-benzyl-N-vinyl
carbamate (5.0 g, 28.2 mmol), followed by boron trifluoride diethyl
etherate (1.0 ml). After stirring at room temperature for 18 h, the
reaction mixture was concentrated and the crude product was
purified by silica gel chromatography using 25% ethyl
acetate/hexanes as eluent to afford 7.0 g of the title product.
.sup.1H NMR (CDCl.sub.3) .delta. 0.95 (t, 3H), 1.4 (m, 2H), 1.6 (m,
2H), 2.3 (m, 1H), 2.5 (m, 1H), 3.8 (s, 3H), 3.9 (s, 3H), 5.2 (q,
2H), 6.2 (s, 1H), 6.6 (s, 1H), 7.4 (m, 5H).
Example 2
[0507]
cis-4-Benzyloxycarbonylamino-6,7-dimethoxy-3,4-dihydro-2H-quinoline-
-1,2-dicarboxylic acid 2-butyl ester 1-ethyl ester: To a solution
of
cis-4-benzyloxycarbonylamino-6,7-dimethoxy-1,2,3,4-tetrahydroquinoline-2--
carboxylic acid butyl ester (Example 1) (3.0 g, 6.8 mmol) in
anhydrous dichloromethane (100 mL) was added pyridine (1.34 g,
16.9). The mixture was cooled to 0.degree. C., and ethyl
chloroformate (1.47 g, 13.6 mmol) was slowly added. The reaction
was stirred at 0.degree. C. or 30 min, then at room temperature for
18 h. The reaction mixture was washed twice with 2N HCl and the
organic layer was dried over magnesium sulfate, filtered nd
concentrated in vacuo. Purification by silica gel chromatography
using 20% ethyl acetate/hexanes as eluent afforded the title
compound (3.1 g). .sup.1H NMR (CDCl.sub.3) s 0.85 (t, 3H), 1.3 (m,
5H), 1.5 (m, 2H), 3.7 (s, 3H), 3.8 (s, 3H), 6.65 (s, 1H), 7.4 (m,
6H).
Example 3
[0508]
cis-4-Amino-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylic
acid 2-butyl ester 1-ethyl ester:
cis-4-Benzyloxycarbonylamino-6,7-dimeth-
oxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylic acid 2-butyl ester
1-ethyl ester (Example 2) (800 mg), 10% palladium on carbon (800
mg), and a mixture of ethanol-cyclohexene (2:1, 60 mL) was heated
to 70.degree. C. for 2 h. The reaction mixture was cooled to room
temperature, filtered through Celite.RTM., and concentrated in
vacuo. Purification by silica gel chromatography using to 5%
methanol ethyl acetate-afforded the title compound (500 mg).
.sup.1H NMR (CDCl.sub.3) .delta. 0.9 (t, 3H), 1.4 (m, 5H), 2.5 (m,
1H), 3.9 (d, 6H), 6.9 (s, 1H), 7.2 (s, 1H).
Example 4
[0509]
cis-4-(3,5-Bis-trifluoromethyl-benzylamino)-6,7-dimethoxy-3,4-dihyd-
ro-2H-quinoline-1,2-dicarboxylic acid 2-butyl ester 1-ethyl ester:
To a solution of
4-amino-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxyl- ic
acid 2-butyl ester 1-ethyl ester (Example 3) (500 mg, 1.30 mmol) in
anhydrous dichloroethane (30 mL) was added acetic acid (79 mg, 1.30
mmol), followed by 3,5-bis(trifluoromethyl)benzaldehyde (318 mg,
1.30 mmol) and sodium triacetoxyborohydride (418 mg, 1.97 mmol).
The reaction was stirred at room temperature for 30 min. The
reaction mixture was then diluted with chloroform and washed with 1
N NaOH. The organic layer was separated, dried over magnesium
sulfate, filtered and concentrated in vacuo to afford the crude
title compound (approximately 500 mg) which was used directly in
Example 5.
Example 5
[0510]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7--
dimethoxy-3,4 dihydro-2H-quinoline-1,2-dicarboxylic acid 2-butyl
ester 1-ethyl ester.
cis-4-(3,5-Bis-trifluoromethyl-benzylamino)-6,7-dimethoxy--
3,4-dihydro-2H-quinoline-1,2-dicarboxylic acid 2-butyl ester
1-ethyl ester (Example 4) (approximately 500 mg, 0.83 mmol) and
pyridine (195 mg, 2.5 mmol) were dissolved in anhydrous
dichloromethane (100 mL) cooled to 0.degree. C. Methyl
chloroformate (195 mg, 2.1 mmol) was added slowly. The reaction was
stirred at 0.degree. C. for 1 h, then at room temperature for 18 h.
The reaction mixture was then diluted with chloroform, and washed
with 1N HCl. The organic layer was dried over magnesium sulfate,
filtered and concentrated in vacuo. Purification by silica gel
chromatography using 15% ethyl acetate/hexanes as eluent afforded
the title product (400 mg). MS m/z 664.2 (M.sup.+); .sup.1H NMR
(CDCl.sub.3) .delta. 0.9 (t, 3H), 1.3 (t, 3H), 1.5 (m, 2H), 3.85
(s, 3H), 4.0 (t, 2H) 6.3 (s, 1H), 7.8 (s, 1H).
Example 6
[0511]
trans-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,-
7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylic acid 2-butyl
ester 1-ethyl ester.
trans-4-Amino-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-d-
icarboxylic-acid 2-butyl ester 1-ethyl ester was isolated as a
minor component during the preparation of Example 3, and was
carried through to desired product as described for Examples 4 and
5. .sup.1H NMR (CDCl.sub.3) .delta. 0.9 (t, 3H), 1.3 (t, 3H), 3.9
(s, 3H), 4.1 (t, 2H), 6.3 (s, 1H), 7.8 (s, 1H).
Example 7A
[0512] Propylidene-(4-trifluoromethyl-phenyl)-amine: To a solution
of 4-trifluoromethylaniline (3.3 g, 20.5 mmol) and triethylamine
(8.3 g, 83 mmol) in 100 mL of dichloromethane, cooled in an
ice/water bath, was added slowly titanium tetrachloride (11.4 mL of
a 1.0M solution in dichloromethane, 11.4 mmol). After 25 min,
propionaldehyde (1.8 g, 25.6 mmol) was added slowly as a solution
in dichloromethane. After an additional hour of stirring in the
ice/water bath, an aqueous potassium carbonate solution was added
(.about.100 mL of a 1 M solution). The organic phase was separated,
dried over magnesium sulfate, filtered and concentrated in vacuo to
afford the crude title product which was used without further
purification. .sup.1H NMR (CDCl.sub.3) .delta. 1.2 (t, 3H), 2.5
(dq, 2H), 7.05 (d, 2H), 7.56 (d, 2H), 7.84 (t, 1H, J=4.4 Hz).
Example 7B
[0513]
cis-(2-Ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-ca-
rbamic acid, benzyl ester: The crude
propylidene-(4-trifluoromethyl-phenyl- )-amine from Example 7A and
O-benzyl-N-vinyl carbamate (3.1 g, 17.4 mmol) were combined in 200
mL of dichloromethane, and the mixture was cooled in an ice/water
bath as boron trifluoride diethyl etherate (0.25 g, 1.7 mmol) was
added. After stirring at room temperature for 1 h, the reaction
mixture was concentrated to .about.50 mL and directly purified by
silica gel chromatography using 50% dichloromethane/hexanes as
eluent to afford 2.5 g of the title product. .sup.1H NMR
(CDCl.sub.3) .delta. 0.96 (t, 3H), 1.42 (q, 1H), 1.53 (m, 2H), 2.29
(m, 1H), 3.37 (m, 1H), 4.05 (s, 1H), 4.88 (d, 1H), 5.00, (m, 1H),
5.16 (s, 2H), 6.44 (d, 1H), 7.20 (dd, .sub.1H), 7.38 (m, 6H).
Example 7C
[0514]
cis-4-Benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro--
2H-quinoline-1-carboxylic acid ethyl ester: A solution of
cis-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic
acid benzyl ester (Example 7B) (37.0 g, 97.9 mmol) and pyridine
(23.2 g, 293.7 mmol) in dichloromethane (1 L) was cooled in an
ice/water bath as ethyl chloroformate (37.2 g, 342.6 mmol) was
added slowly. After stirring at room temperature overnight, the
mixture was cooled with an ice/water bath as a 1 M potassium
hydroxide solution was added to quench the reaction. The organic
phase was washed twice with a 2M hydrochloric acid solution, dried
over magnesium sulfate, filtered and concentrated in vacuo to
afford the crude product which was purified by silica gel
chromatography using 10-15% ethyl acetate/hexanes as eluent to
afford 40 g of the title product. .sup.1H NMR (CDCl.sub.3) .delta.
0.83 (t, 3H), 1.28 (t, 3H).sub., 1.4-1.6 (m, 3H), 2.53 (m, 1H),
4.23 (m, 2H), 4.47 (m, 1H), 4.80 (m, 1H), 4.94 (m, 1H), 5.18 (s,
2H), 7.3-7.6 (m, 8H).
Example 7D
[0515]
cis-4-Amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1
arboxylic acid ethyl ester: A solution of
cis-4-benzyloxycarbonylamino-2--
ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
ethyl ester (Example 7C) (18.0 g, 40 mmol) in 150 mL each of
cyclohexene and ethanol was treated with 10% palladium on carbon
(10.0 g, 50% water by weight). After heating at reflux for 1 h, the
cooled mixture was filtered through Celite.RTM. and concentrated in
vacuo to afford the crude product, which was purified by silica gel
chromatography using 25-50% ethyl acetate/hexanes as eluent to
afford 8.8 g of the title product. .sup.1H NMR (CDCl.sub.3) .delta.
0.83 (t, 3H), 1.25 (m, 4H), 1.45 (m, 1H), 1.6 (m, 1H), 2.49 (m,
1H), 3.81 (m, 1H), 4.2 (m, 2H), 4.4 (m, 1H), 7.47 (m, 2H), 7.69 (s,
1H).
Example 7E
[0516]
cis-4-(3,5-Bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluorometh-
yl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester: A
solution of cis-4-amino-2-ethyl-4
trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxyl- ic acid ethyl
ester (Example 7D) (8.8 g, 27.8 mmol) was treated sequentially with
acetic acid (5.0 g, 83.5 mmol), 3,5
bis-trifluoromethyl-benzaldehyde (6.74 g, 27.8 mmol), followed by
sodium triacetoxyborohydride (29.5 g, 139.2 mmol). After stirring
at room temperature for 24 h, the mixture was combined with 500 mL
of 1M potassium hydroxide, and the aqueous layer was extracted with
dichloromethane (2.times.200 mL). The combined organic phases were
dried over magnesium sulfate, filtered and concentrated in vacuo to
afford the crude product, which was purified by silica gel
chromatography using 5-10% ethyl acetate/hexanes as eluent to
afford 13.8 g of the title product. 1H NMR (CDCl.sub.3) .delta.
0.85 (t, 3H), 1.27 (m, 4H), 1.45 (m, 2H), 1.67 (m, 1H), 2.66 (m,
1H), 3.56 (m, 1H), 4.14.3 (m, 4H), 4.42 (m, 1H), 7.49 (d, 1H, J=8.5
Hz), 7.52 (d, 1H, J=8.5 Hz), 7.76 (s, 1H), 7.79 (s, 1H), 7.91 (s,
2H).
Example 7F
[0517]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-et-
hyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
ethyl ester: A solution of
cis-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl--
trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl
ester (Example 7E) (2.0 g, 3.7 mmol) and pyridine (0.58 g, 7.4
mmol) in 100 mL of dichloromethane was cooled in an ice/water bath
as methyl chloroformate (0.87 g, 9.2 mmol) was added slowly. After
stirring overnight at room temperature, the reaction mixture was
washed twice with a 2N hydrochloric acid solution, dried over
magnesium sulfate, filtered and concentrated in vacuo to afford the
crude product, which was purified by silica gel chromatography
using 5-10% ethyl acetate/hexanes as eluent to afford 1.8 g of the
title product. MS m/z 601 (M.sup.++1); .sup.1H NMR (coalescing
mixture of conformers, CDCl.sub.3) .delta. 0.6-0.8 (bm, 3H),
1.2-1.3 (bm, 3H), 1.3-1.5 (bm, 2H), 1.6-1.75 (bm, 1H), 2.1-2.3 (bm,
1H), 3.7-3.9 (bs, 3H). 4.0-4.4 (bm, 4H), 5.0-5.6 (bm, 2H), 7.1 (s,
1H), 7.4-7.6 (bm, 2H), 7.6-7.8 (bm, 3H).
[0518] Using the appropriate starting materials, Examples 8-91 were
prepared in an analogous manner to the sequence of reactions
described for Examples 1-5 or 7A-7F as appropriate.
Example 8
[0519]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl trifluoromethoxy-3,4-dihydro-2H-quinoline-1-carboxylic
acid ethyl ester. MS m/z 628.3 (M.sup.+); .sup.1H NMR (CDCl.sub.3)
.delta. 6.85 (s, 1H).
Example 9
[0520]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-6,7 difluoro-3,4-dihydro-2H-quinoline-1-carboxylic acid
ethyl ester. MS m/z 580.2 (M.sup.+); .sup.1H NMR (CDCl.sub.3)
.delta. 3.8 (s, 3H), 6.8 (t, 1H).
Example 10
[0521]
cis-4-[(3,5-Bis-trifuoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyc-
lopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. MS m/z 626.5 (M.sup.+); .sup.1H NMR
(CDCl.sub.3) .delta. 3.75 (s, 3H), 7.1 (s, 1H).
Example 11
[0522]
cis-4--[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-c-
yclopropyl-6,7-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
isopropyl ester. MS m/z 586.3 (M.sup.+); .sup.1H NMR (CDCl.sub.3),
.delta. 3.8 (s, 3H), 6.7 (s, 1H).
Example 12
[0523]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-6-pentafluoroethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid ethyl ester. MS m/z 662.4 (M.sup.+); .sup.1H NMR (CDCl.sub.3)
.delta. 3.7 (s, 3H), 7.1 (s, 1H).
Example 13
[0524]
cis-4[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyc-
lopropyl-6-trifluoromethoxy-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. MS m/z 642.3 (M.sup.+); .sup.1H NMR
(CDCl.sub.3) .delta. 3.8 (s, 3H), 6.75 (s, 1H).
Example 14
[0525]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-7-trifluoromethoxy-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. MS m/z 642.3 (M.sup.+); .sup.1H NMR
(CDCl.sub.3) .delta. 3.8 (s, 3H), 7.0 (m, 1H).
Example 15
[0526]
cis-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethy-
l trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
isopropyl ester. MS m/z 614.5 (M.sup.+); .sup.1H NMR (CDCl.sub.3)
.delta. 3.8 (s, 3H), 7.1 (s, 1H).
Example 16
[0527]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-pr-
opyl trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
isopropyl ester. MS m/z 328 (M.sup.+-300); .sup.1H NMR (CDCl.sub.3)
.delta. 3.8 (s, 3H), 7.1 (s, 1H).
Example 17
[0528]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-se-
c-butyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. MS m/z 642.5 (M.sup.+); .sup.1H NMR
(CDCl.sub.3) .delta. 3.8 (s, 3H), 7.0 (s, 1H).
Example 18
[0529]
cis-4[(3,5-Bis-trifluoromethyl-benzyl)-isopropoxycarbonyl-amino]-2--
cyclopropyl trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. MS m/z 655 (M.sup.++1); .sup.1H NMR
(CDCl.sub.3) .delta. 0.8 (br, 1H), 2.4 (br, 1H), 7.1 (s, 1H), 7.1
(s, 1H), 7.7 (s, 1H), 7.8 (s, 1H).
Example 19
[0530]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-is-
obutyl trifluoromethyl-3,4-dihydro-2H-quinoline-carboxylic acid
isopropyl ester. MS m/z 342 (M.sup.+-300); .sup.1H NMR (CDCl.sub.3)
.delta. 0.9 (m, 6H), 1.1 (br, 1H), 2.2 (br, 1H), 3.8 (a, 3H), 7.1
(s, 1H), 7.5-7.9 (m, 5H).
Example 20
[0531]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-is-
opropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. MS m/z 629.2 (M.sup.++1); .sup.1H NMR
(CDCl.sub.3) .delta. 0.7 (d, 3H), 3.8 (s, 3H), 7.1 (s, 1H), 7.6
(br, 2H), 7.8 (m, 3H).
Example 21
[0532]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-is-
obutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
ethyl ester. MS m/z 328 (M.sup.+-300); .sup.1H NMR (CDCl.sub.3)
.delta. 1.1 (br, 1H), 2.1 (br, 1H), 3.8 (s, 3H), 7.1 (s, 1H), 7.6
(br, 2H).
Example 22
[0533]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-is-
opropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 arboxylic acid
isopropyl ester. MS m/z 643.3 (M.sup.+); .sup.1H NMR (CDCl.sub.3)
.delta. 0.7 (d, 3H), 0.8 (d, 3H), 2.1 (br, 2H), 7.1 (s, 1H), 7.5
(br, 2H).
Example 23
[0534]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-isopropoxycarbonyl-amino]-2-
-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. MS m/z 656.3 (M.sup.+); .sup.1H NMR
(CDCl.sub.3) .delta. 0.7 (d, 3H), 0.8 (d, 3H), 1.2 (d, 3H), 1.3 (d,
3H), 7.1 (s, 1H), 7.6 (br, 2H), 7.8 (s, 2H).
Example 24
[0535]
cis-4-Acetyl-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-am-
ino]-2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylic acid-ethyl
ester. MS m/z 586.4 (M.sup.+); .sup.1H NMR (CDCl.sub.3) .delta. 2.6
(s, 3H), 3.8 (s, 3H), 7.5-8.0 (m, 6H).
Example 25
[0536]
cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl
methoxy-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid ethyl ester. MS m/z 642.5 (M.sup.+); .sup.1H NMR (CDCl.sub.3)
.delta. 1.3 (t, 3H), 3.8 (s, 6H), 6.5 (s, 1H), 7.7 (s, 1H), 7.8 (s,
2H), 7.85 (s, 1H).
Example 26
[0537]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl)-5,6-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
ethyl ester. MS m/z 572.7 (M.sup.+); .sup.1H NMR (CDCl.sub.3)
.delta. 1.3 (t, 3H), 1.7 (d, 3H), 1.8 (d, 3H), 3.9 (d, 3H), 4.3 (m,
2H), 6.9 (d, 1H), 7.1 (d. 1H), 7.2 (s, 1H), 7.3 (s, 1H), 7.5 (s,
1H).
Example 27
[0538]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-6,7-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
ethyl ester. MS m/z 272.7 (M.sup.+-300); .sup.1H NMR (CDCl.sub.3)
.delta. 1.3 (t, 3H), 2.3 (d, 6H), 3.8 (s, 3H), 6.6 (s, 1H), 7.2 (s,
1H), 7.7 (m, 3H).
Example 28
[0539]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-7-7-trifluoromethoxy-3,4-dihydro-2H-quinoline-1-carboxylic
acid ethyl ester. MS m/z 642.2 (M.sup.+); .sup.1H NMR (CDCl.sub.3)
.delta. 3.8 (s, 3H), 7.4 (s, 1H), 7.8 (s, 1H).
Example 29
[0540]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid 2,2,2-trichloro-1,1-dimethyl-ethyl ester. MS m& 743.2
(M.sup.+); .sup.1H NMR (CDCl.sub.3) .delta. 1.9 (s; 3H), 2.0 (s,
3H), 3.8 (s, 3H), 7.1 (s, 1H), 7.8 (s, 1H).
Example 30
[0541]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-6-methylsulfanyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. MS m/z 604.5 (M.sup.+); .sup.1H NMR
(CDCl.sub.3) .delta. 2.2 (s, 3H), 3.8 (s, 3H), 6.8 (s, 1H), 7.1 (d,
1H), 7.4 (s, 1H), 7.7 (m, 3H).
Example 31
[0542]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-6-methanesulfonyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. MS m/z 637.5 (M.sup.++1); .sup.1H NMR
(CDCl.sub.3) .delta. 1.2 (m, 6H), 3.1 (s, 3H), 3.8 (s, 3H), 7.5 (s,
1H).
Example 32
[0543]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-ethoxycarbonyl-amino]-2-iso-
butyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
isopropyl ester. MS m/z 642.6 (M.sup.+1); .sup.1H NMR (CDCl.sub.3)
.delta. 0.9 (d, 6H), 1.1 (br, 1H), 7.1 (s, 1H), 7.6 (m, 2H), 7.8
(m, 3H).
Example 33
[0544]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-ch-
loro-2-cyclopropyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. MS m/z 662 (M.sup.++2), 679 (M.sup.++19);
.sup.1H NMR (CDCl.sub.3) .delta. 7.03 (s, 1H), 3.81 (s, 3H).
Example 34
[0545]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7--
dichloro-2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
isopropyl ester. MS m/z 627 (M.sup.+), 644 (M.sup.+17); .sup.1H NMR
(CDCl.sub.3) .delta. 7.00 (s, 1H), 3.81 (s, 3H).
Example 35
[0546]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. MS m/z 627 (M.sup.++1), 644 (M.sup.+18);
.sup.1H NMR (CDCl.sub.3) .delta. 7.40 (d, 1H), 7.06 (d, 1H), 3.81
(p, 3H).
Example 36
[0547]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-ch-
loro-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. .sup.1H NMR (CDCl.sub.3).delta. 7.18 (s, 1H),
3.81 (s, 3H).
Example 37
[0548]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-7-fluoro-6-trifuoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. MS m/z 695 (M.sup.++1), 712 (M.sup.+18);
.sup.1H NMR (CDCl.sub.3) .delta. 8.01 (s, 1H), 3.83 (s, 1H).
Example 38
[0549]
cis-4[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyc-
lopropyl-7-fluoro
6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
isopropyl ester. MS m/z 645 (M.sup.+0.1), 662 (M.sup.++18); .sup.1H
NMR (CDCl.sub.3) .delta. 7.81 (s, 1H), 3.81 (s, 3H).
Example 39
[0550]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-ethoxycarbonyl-amino]-7-dim-
ethoxy-2-phenyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl
ester. MS m/z 654.6 (M.sup.+); .sup.1H NMR (CDCl.sub.3) .delta. 1.1
(t, 3H), 2.4 (m, 1H), 3.8 (s, 3H), 3.9 (s, 3H), 6.5 (s, 1H), 7.6
(br, 2H), 7.7 (br, 1H)
Example 40
[0551]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-ethoxycarbonyl-amino]6,7-di-
methoxy-2-(4-trifluoromethyl-phenyl)-3,4-dihydro-2H-quinoline-1-carboxylic
acid ethyl ester. MS m/z 722.6 (M.sup.+); .sup.1H NMR (CDCl.sub.3)
.delta. 1.2 (t, 3H), 3.8 (s, 3H), 3.9 (s, 3H), 6.5 (s, 1H), 7.3 (d,
2H), 7.5 (d, 2H), 7.7 (br, 2H), 7.8 (br, 1H)
Example 41
[0552]
cis-4-[(3-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-di-
methoxy-2-thiophen-2-yl-3,4-dihydro-2H-quinoline-1-carboxylic acid
ethyl ester. MS m/z 646 (M+); .sup.1H NMR (CDCl.sub.3) 6.1.2 (t,
3H), 3.8 (s, 3H), 6.4 (s, 1H), 6.9 (m, 2H), 7.1 (m, 2H), 7.5 (br,
.sub.1H), 7.6 (br, 1H), 7.8 (br, 1H)
Example 42
[0553]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-ch-
loro-2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
isopropyl ester. MS m/z 0.594 (M.sup.++1), 611 (M.sup.++18);
.sup.1H NMR (CDCl.sub.3) 6.91 (C.sub.5, s, 1H).
Example 43
[0554]
cis-4-[(4-Bromo-thiophen-2-ylmethyl)-methoxycarbonyl-amino]-2-cyclo-
propyl; trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
isopropyl ester. MS m/z 576 (M.sup.++1), 593 (M.sup.+18); .sup.1H
NMR (CDCl.sub.3) .delta. 2.45-2.50 (m, 1H), 3.86 (s, 3H).
Example 44
[0555]
cis-2-Cyclopropyl-4-(methoxycarbonyl-thiophen-2-ylmethyl-6-amino)-6-
-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
isopropyl ester. MS m/z 496 (M.sup.+), 514 (M.sup.++18); .sup.1H
NMR (CDCl.sub.3) .delta. 3.86 (s, 3H), 7.26 (s, 1H).
Example 45
[0556]
cis-2-Cyclopropyl-4-[(3,5-dichloro-benzyl)-methoxycarbonyl-amino]-6-
-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
isopropyl ester. MS m/z 559 (M.sup.+), .sup.1H NMR (CDCl.sub.3)
.delta. 2.40-2.34 (m, 1H), 3.80 (s, 3H).
Example 46
[0557]
cis-4-(Benzyl-methoxycarbonyl-amino)-2-cyclopropyl-6-trifluoromethy-
l-3,4-dihydro 2H-quinolin-1-carboxylic acid isopropyl ester. MS m/z
492 (M.sup.++2), 509 (M.sup.++19); .sup.1H NMR (CDCl.sub.3) .delta.
2.30-2.35 (m, 1H), 3.79 (s, 3H).
Example 47
[0558]
cis-(3,5-Bis-trifluoromethyl-benzyl)-(2-cyclopropyl-1-trifluoroacet-
yl-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid
methyl ester. MS m/z 655 (M.sup.++19); .sup.1H NMR (CDCl.sub.3)
.delta. 7.25 (C5, s, 1H).
Example 48
[0559]
cis-2-cyclopropyl-4-[(4-isopropenyl-cyclohex-1-enylmethyl)-methoxyc-
arbonyl-amino]-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. MS m/z 536 (M.sup.++2), 553 (M.sup.++19);
.sup.1H NMR (CDCl.sub.3) .delta. 3.74 (s, 3H), 7.18 (s, 1H).
Example 49
[0560]
cis-4-(Cyclohex-3-enylmethyl-methoxycarbonyl-amino)-2-cyclopropyl-6-
-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
isopropyl ester. MS m/z 496 (M.sup.++2), 513 (M.sup.++19); .sup.1H
NMR (CDCl.sub.3) .delta. 3.73 (s, 3H), 5.68 (bs, 2H).
Example 50
[0561]
cis-2-cyclopropyl-4-[(6,6-dimethyl-bicyclo[3,1,1]hept-2-en-2-ylmeth-
yl)-methoxycarbonyl-amino]-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carb-
oxylic add isopropyl ester. MS m/z 536 (M.sup.++2), 553
(M.sup.++19); .sup.1H NMR (CDCl.sub.3) .delta. 3.74 (s, 3H), 7.16
(s, 1H).
Example 51
[0562]
cis-4-(Bicyclo[2.2.1]hept-5-en-2-ylmethyl-methoxycarbonyl-amino)-2--
cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. MS m/z 508 (M.sup.++2), 525 (M.sup.++19);
.sup.1H NMR (CDCl.sub.3) .delta. 1.30-1.42 (m, 6H), 3.73 (s,
3H).
Example 52
[0563]
cis-4-[(2-Bromo-3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-ami-
no]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid is isopropyl ester. MS m/z 706 (M.sup.+), 724 (M.sup.+19);
.sup.1H NMR (CDCl.sub.3) .delta. 3.78 (s, 3H), 7.22 (s, 1H).
Example 53
[0564]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-(2-
-ethoxycarbonyl-cyclopropyl)-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1--
carboxylic acid isopropyl ester. MS m/z 698.6 (M.sup.+); .sup.1H
NMR (CDCl.sub.3) .delta. 1.2 (t, 3H), 2.3 (br, 1H), 3.8 (s, 3H),
4.1 (q, 4H), 7.1 (s, 1H), 7.5 (s, 2H), 7.8 (s, 1H).
Example 54
[0565]
cis-4-[(2,4-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-carboxylic
acid isopropyl ester. MS m/z 628 (M.sup.++2), 645 (M.sup.++19);
.sup.1H NMR (CDCl.sub.3) .delta. 3.78 (s, 3H), 7.20 (s, 1H).
Example 55
[0566]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-7-methyl-4-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. MS m/z 642 (M.sup.++2), 659 (M.sup.++19);
.sup.1H NMR (CDCl.sub.3) .delta. 2.46 (s, 3H), 3.80 (3H).
Example 56
[0567]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-te-
rt-butyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. MS m/z 643 (M.sup.+); .sup.1H NMR
(CDCl.sub.3) .delta. 0.6 (s, 9H), 1.1 (br, 6H), 3.8 (s, 3H), 7.1
(s, 1H), 7.5 (br, 1H), 7.7 (s, 1H), 7.8 (s, 2H).
Example 57
[0568]
cis-4-[(6-Chloro-4-trifluoro-ethyl-pyridin-2-ylmethyl)-methoxycarbo-
nyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carb-
oxylic acid isopropyl ester. MS m/z 595 (M.sup.++2), 612
(M.sup.++19); .sup.1H NMR (CDCl.sub.3) .delta. 3.78 (s, 3H), 7.15
(s, 1H).
Example 58
[0569]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clohexyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. MS m/z 669.1 (M.sup.++1); .sup.1H NMR
(CDCl.sub.3) .delta. 3.8 (s, 3H), 7.1 (s, 1H), 7.5 (br, 1H), 7.7
(s, 1H), 7.8 (s, 2H).
Example 59
[0570]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-6-ethylsulfanyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. MS m/z 318 (M.sup.+-300); .sup.1H NMR
(CDCl.sub.3) .delta. 1.3 (t, 3H), 2.9 (q, 2H), 3.8 (s, 3H), 6.9 (s,
1H), 7.4 (s, 1H), 7.6 (s, 1H), 7.7 (s, 1H), 7.8 (s, 1H).
Example 60
[0571]
cis-2-Cyclopropyl-4-[(4-mercapto-3,5-bis-trifluoromethyl-benzyl)-me-
thoxycarbonyl-amino]-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxyl-
ic acid isopropyl ester. MS m/z 657 (M.sup.+-1), 658 (M.sup.+);
.sup.1H NMR (CDCl.sub.3) .delta. 3.80 (s, 3H), 7.15 (s, 1H).
Example 61
[0572]
cis-4,4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2--
cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
and isopropenyl ester. MS m/z 625.5 (M.sup.+); .sup.1H NMR
(CDCl.sub.3) .delta. 2.0 (s, 3H), 3.8 (s, 3H), 7.1 (s, 1H).
Example 62
[0573]
cis-4-{[2-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-methoxycarbonyl-a-
mino}-2-cyclopropyl-6-trifluoromethyl-3.4-dihydro-2H-quinoline-1
arboxylic acid isopropyl ester. MS m/z 657 (M+NH3).sup.+; .sup.1H
NMR (CDCl.sub.3) .delta. 1.26 (d, 3H), 1.31 (d, 3H), 7.12 (s, 1H),
7.50 (d, 1H), 7.59 (d, 1H), 7.65 (s, 2H), 7.76 (s, 1H).
Example 63
[0574]
cis-4-[(3,5-Bis-trifuoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyc-
lopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid propyl ester. MS m/z 627 (M.sup.++1); .sup.1H NMR (CDCl.sub.3)
.delta. 3.8 (s, 3H), 7.1 (s, 1H), 7.5-7.8 (m, 5H).
Example 64
[0575]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-6-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylic
acid ethyl ester. MS m/z 584 (M.sup.+); .sup.1H NMR (CDCl.sub.3)
.delta. 3.8 (s, 3H), 6.8 (s; 1H), 7.3 (s, 1H).
Example 65
[0576]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-6-ethanesulfinyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. .sup.1H NMR (CDCl.sub.3) .delta. 2.8 (m, 3H),
4.1 (2H), 3.8 (s, 3H), 7.8 (s, 1H).
Example 66
[0577]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-6-ethanesulfonyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. MS m/z 651.1 (M.sup.+); .sup.1H NMR
(CDCl.sub.3) .delta. 3.7 (s, H), 7.5 (s, 1H).
Example 67
[0578]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-6-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylic
acid isopropyl ester. MS m/z 298.3 (M.sup.+-300); .sup.1H NMR
(CDCl.sub.3) .delta. 2.9 (t, 4H), 3.8 (s, 3H), 6.8, (s, 1H), 7.6
(s, 1H), 7.7 (s, 1H), 7.8 (s, 1H).
Example 68
[0579]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. MS m/z 655.2 (M.sup.+); .sup.1H NMR
(CDCl.sub.3) .delta. 3.8 (s, 3H), 7.1 (s, 1H), 7.5 (br, 2H).
Example 69
[0580]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clobutyl-6 trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. MS m/z 640.1 (M.sup.+); .sup.1H NMR
(CDCl.sub.3) .delta. 3.8 (s, 3H), 7.1 (s, 1H), 7.5 (br, 2H).
Example 70
[0581]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-7-methoxy-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxyli-
c acid isopropyl ester. MS m/z 658 (M.sup.+2), 675 (M.sup.++19);
.sup.1H NMR (CDCl.sub.3) .delta. 3.88 (s, 3H), 3.79 (s, 3H).
Example 71
[0582]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl 2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylic
acid 1-ethyl-propyl ester. MS m/z 326.6 (M.sup.+-300); .sup.1H NMR
(CDCl.sub.3) .delta. 3.8 (s, 3H), 6.8 (s, 1H), 7.3 (s, 1H).
Example 72
[0583]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-6-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1
carboxylic acid 2,2,2-trifluoro-ethyl ester. MS m/z 338.1
(M.sup.+-300); .sup.1H NMR (CDCl.sub.3) .delta. 2.9 (m, 4H), 3.8
(s, 3H), 6.8 (s, 1H).
Example 73
[0584]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-6-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylic
acid dicyclopropylmethyl ester. MS m/z 350.2 (M.sup.+-300); .sup.1H
NMR (CDCl.sub.3) .delta. 3.8 (s, 3H), 6.8 (s, 1H).
Example 74
[0585]
cis-(3,5-Bis-trifluoromethyl-benzyl)-(2-cyclopropyl-1-trifluoroacet-
yl-2,3,4,6,7,8-hexahydro-1H-cyclopenta[g]quinolin-4-yl)-carbamic
acid methyl ester .sup.1H NMR (CDCl.sub.3) .delta. 3.8 (s, 3H), 6.9
(br, 1H), 7.8 (br, 2H).
Example 75
[0586]
cis-4-[(4-Chloro-3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-am-
ino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. MS m/z 660 (M.sup.+); .sup.1H NMR
(CDCl.sub.3) .delta. 3.81 (s, 3H), 7.12 (s, 1H).
Example 76
[0587]
cis-4-[(3,5-Bis-trifuoromethyl-benzyl)-methoxycarbonyl-amino]-2-iso-
propyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
ethyl ester .sup.1H NMR (CDCl.sub.3) .delta. 3.8 (s, 3H), 7.1 (s,
1H), 7.5 (br, 2H).
Example 77
[0588]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-is-
opropyl trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
propyl ester .sup.1H NMR (CDCl.sub.3) .delta. 3.8 (s, 3H), 7.1 (s,
1H), 7.5 (br, 2H).
Example 78
[0589]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl) trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid ethyl ester. MS m/z 613.1 (M.sup.+); .sup.1H NMR (CDCl.sub.3)
.delta. 3.8 (s, 3H), 7.1 (s, 1H).
Example 79
[0590]
cis-4[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-eth-
yl trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
propyl ester. MS m/z 314.1 (M.sup.+-300); .sup.1H NMR (CDCl.sub.3)
.delta. 3.8 (s, 3H), 7.1 (s, 1H).
Example 80
[0591]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-is-
opropyl trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
2-hydroxy-ethyl ester 1H NMR (CDCl.sub.3) .delta. 2.0 (br, 3H), 3.8
(s, 5H), 7.1 (s, 1H), 7.5 (br, 2H).
Example 81
[0592]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clobutyl-6-trifuoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid propyl ester .sup.1HNMR (CDCl.sub.3) .delta. 3.8 (s, 3H), 7.1
(s, 1H), 7.5 (s, 2H).
Example 82
[0593]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-is-
opropyl trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
2-methoxy-ethyl ester .sup.1H NMR (CDCl.sub.3) .delta. 3.3 (m, 4H),
3.6 (m, 4H), 3.8 (s, 3H), 7.1 (s, 1H).
Example 83
[0594]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clobutyl-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
ethyl ester MS m/z 326 (M.sup.+-300); .sup.1H NMR (CDCl.sub.3)
.delta. 3.8 (s, 3H), 7.1 (s, 1H), 7.5 (br, 2H).
Example 84
[0595]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-et-
hyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
2-hydroxy-ethyl ester. MS m/z 316.1 (M.sup.+-300); .sup.1H NMR
(CDCl.sub.3) .delta. 3.8 (s, 3H), 7.1 (s, 1H).
Example 85
[0596]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid 2-hydroxy-ethyl ester, MS m/z 643.1 (M.sup.++2); .sup.1H NMR
(CDCl.sub.3) .delta. 3.8 (m, 5H), 7.1 (s, 1H), 7.5-7.8 (m, 5H).
Example 86
[0597]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-me-
thoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester .sup.1H NMR (CDCl.sub.3) .delta. 3.2 (s, 3H),
3.8 (s, 3H), 7.1 (s, 1H).
Example 87
[0598]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-me-
thoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-arboxylic
acid ethyl ester .sup.1H NMR (CDCl.sub.3) .delta. 3.1 (s, 3H), 3.8
(s, 3H), 7.1 (s, 1H).
Example 88
[0599]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-me-
thoxymethyl trifluoromethyl-3,4-dihydro-2H-quinoline-1 carboxylic
acid propyl ester. MS m/z 630.9 (M.sup.+); .sup.1H NMR (CDCl.sub.3)
.delta. 3.2 (s, 3H), 3.8 (s, 3H), 7.1 (s, 1H).
Example 89
[0600]
cis-2-Cyclopropyl-4-[methoxycarbonyl-(4-methyl-3,5-bis-trifluoromet-
hyl-benzyl)-amino]-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. MS m/z 640.8 (M.sup.+); .sup.1H NMR
(CDCl.sub.3) .delta. 2.55 (s, 3H), 3.79 (s, 3H).
Example 90
[0601] cis
4[(2,6-Bis-trifluoromethyl-biphenyl-4-ylmethyl)-methoxycarbonyl-
-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxy-
lic acid isopropyl ester. MS m/z 703 (M.sup.++1), 705 (M.sup.++3);
.sup.1H NMR (CDCl.sub.3) .delta. 2.15-2.39 (m, 1H), 3.83 (bs,
3H).
Example 91
[0602]
cis-4-[(3,5-Bis-trifluoromethyl-cyclohexylmethyl)-methoxycarbonyl-a-
mino]2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-carboxylic
acid isopropyl ester. MS m/z 633 (M.sup.++1); .sup.1H NMR
(CDCl.sub.3) .delta. 3.74 (s, 3H), 7.18 (s, 1H).
Example 92
[0603]
6,7-Dimethoxy-2-isopropyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxyl-
ic add ethyl ester. 4,6,7-Trimethoxyquinoline (0.3 g, 1.4 mmol) was
dissolved in anhydrous tetrahydrofuran (6 mL). The mixture was
cooled to -78.degree. C., and isopropyl magnesium chloride (0.8 mL
of a 2M solution in tetrahydrofuran, 1.6 mmol) was added. The
mixture was stirred at -78.degree. C. for 10 min, then ethyl
chloroformate (0.16 mL, 1.6 mmol) was added. The reaction was
warmed to room temperature and stirred overnight, then 1N HCl (6
mL) was added. After stirring for 1 h, the tetrahydrofuran was
removed in vacuo, and the remaining aqueous phase was extracted
with ethyl acetate (3.times.50 mL). The organic phases were
combined and washed with water (15 mL), dried over sodium sulfate,
filtered, and concentrated in vacuo to give 0.26 g crude product.
Purification by silica gel chromatography using 0-40% ethyl
acetate/hexanes as eluent afforded the title product (0.23 g, 51%).
.sup.1H NMR (CDCl.sub.3) .delta. 0.85 (d, 3H), 0.9 (d, 3H), 1.33
(t, 3H), 1.8 (m, 1H), 2.8 (dd, 1H), 2.93 (dd, 1H), 3.9 (s, 3H),
3.95 (s, 3H), 4.3 (m, 2H), 4.5 (m, 1H), 7.3 (bs, 1H), 7.37 (s,
1H).
Examples 93 and 94
[0604]
cis-4-Benzylamino-6,7-dimethoxy-2-isopropyl-3,4-dihydro-2H-quinolin-
e-1-carboxylic acid ethyl ester and
trans-4-Benzylamino-6,7-dimethoxy-2-is- opropyl-3,4-dihydro-2H
quinoline-1-carboxylic acid ethyl ester,
6,7-Dimethoxy-2-isopropyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic
acid ethyl ester (Example 92) (0.254 g, 0.79 mmol) was combined
with triethylamine (0.75 mL, 5.4 mmol) and benzylamine (0.17 mL,
1.6 mmol) in anhydrous dichloromethane (4 mL). This solution was
immersed in a room temperature water bath, and titanium
tetrachloride (0.8 mL of a 1M solution in dichloromethane, 0.8
mmol) was slowly added. After stirring overnight, a solution of
sodium borohydride (0.27 g, 7.2 mmol) in methanol (6 mL) was
carefully added to the mixture. After 3 days, the mixture was made
basic with 2N KOH and extracted with ethyl acetate (3.times.50 mL),
the combined organic phases were dried over sodium sulfate,
filtered, and concentrated in vacuo to afford 0.315 g of material.
This material was purified by silica gel chromatography eluting
with 0-30% ethyl acetate in hexanes to afford 35 mg of the title
cis product of Example 93. .sup.1H NMR (CDCl.sub.3) .delta. 0.78
(d, 3H), 0.88 (d, 3H), 1.26 (t, 3H), 1.35 (m, 1H), 1.9 (m, 1H),
2.43 (ddd, 1H), 3.57 (dd, 1H), 3.85 (s, 3H), 3.87 (s, 3H), 3.95 (d,
1H), 4.07 (d, 1H), 4.15 (m, 1H), 4.25 (m, 2H), 6.95 (s, 1H), 7.03
(s, 1H), 7.25-7.45 (m, 5H). Further elution of the silica gel with
40% ethyl acetate in hexanes afforded 130 mg of the tide trans
product of Example 94. .sup.1H NMR (CDCl.sub.3) .delta. 0.78 (d,
3H), 0.88 (d, 3H), 1.28 (t, 3H), 1.8 (m, 1H), 2.08 (t, 2H),
3.70-3.85 (m, 3H), 3.87 (s, 6H), 4.10-4.35 (m, 3H), 6.80 (s, 1H),
7.10 (s, 1H), 7.25-7.45 (m, 5H).
Example 95
[0605]
cis-4-(Benzyl-methoxycarbonyl-amino)-2-isopropyl-6,7-dimethoxy-3,4--
dihydro-2H-quinoline-1-carboxylic acid ethyl ester To a solution of
cis-4-benzylamino-6,7-dimethoxy-2-isopropyl-3,4-dihydro-2H-quinoline-1-ca-
rboxylic acid ethyl ester (Example 93) (22 mg, 0.05 mmol) and
pyridine (0.50 mL, 6.2 mmol) in anhydrous dichloromethane (1 mL)
was added methyl chloroformate (0.10 mL, 1,3-mmol) while cooled in
an ice bath. After stirring at room temperature overnight water (10
mL), and aqueous 2N KOH (10 mL) were added to the reaction mixture.
The solution was stirred for 30 min, then the mixture was extracted
with ethyl acetate (2.times.10 mL). The organic phases were
combined and washed with 1N HCl (2.times.10 mL), a saturated odium
bicarbonate solution (10 mL), and brine (10 mL). The organic layer
was dried over sodium sulfate, filtered and concentrated in vacuo
to give 88 mg crude product. Purification by silica gel
chromatography using 040% ethyl acetate/hexanes as eluent afforded
the title product (12 mg, 50%). MS m/z 471 (M.sup.++1), 488
(M.sup.++18); .sup.1H NMR (CDCl.sub.3) .delta. 0.6-0.8 (m, 6H),
1.25 (t, 3H), 1.4 (m, 1H), 1.8-2.3 (m, 3H), 3.8 (s, 6H), 3.85 (s,
3H), 4.04.3 (m, 5H), 5.1 (m, 1H), 6.96 (C.sub.8, bs, 1H), 6.42
(C.sub.5, bs, 1H), 7.2-7.4 (m, 5H).
[0606] Example 96 was prepared from Example 94 in an analogous
manner to Example 95.
Example 96
[0607]
trans-4-(Benzyl-methoxycarbonyl-amino)-2-isopropyl-6,7-dimethoxy-3,-
4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester. MS m/z 471
(M.sup.++1), 488 (M.sup.++18). .sup.1H NMR (CDCl.sub.3) .delta.
3.86 (C.sub.6-OMe, s, 3H), 3.77 (C.sub.7-OMe, s, 3H).
[0608] Examples 97-99 were prepared in an analogous manner to the
sequence of reactions described for Examples 92-95.
Example 97
[0609]
cis-4-(Benzyl-ethoxycarbonyl-amino)-2-ethyl-6,7-dimethoxy-3,4-dihyd-
ro-2H-quinoline-1-carboxylic acid ethyl ester. MS m/z 471
(M.sup.+1), 488 (M.sup.++18); .sup.1H NMR (CDCl.sub.3) .delta. 7.00
(C.sub.8, s, 1H), 6.42 (C5, s, 1H), 0.71 (C.sub.2-Et, m, 3H).
Example 98
[0610]
trans-4-(Benzyl-ethoxycarbonyl-amino)-2-ethyl-6,7-dimethoxy-3,4-dih-
ydro-2H-quinoline-carboxylic acid ethyl ester. MS m/z 471
(M.sup.+1), 488 (M.sup.++18); .sup.1H NMR (CDCl.sub.3) .delta. 6.47
(C5, s, 1H), 0.86 (C.sub.2-Et, t, 3H).
Example 99
[0611]
cis-2-Allyl-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-ami-
no]-6,7-dimethoxy 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl
ester. MS m/z 605 (M.sup.++H); .sup.1H NMR (CDCl.sub.3) .delta. 7.7
(bs, 1H), 7.5 (bs, 2H), 7.2 (bs, 1H), 6.3 (bs, 1H), 3.6 (s, 3H),
1.35 (t, 3H, J=7 Hz).
Example 100A
[0612]
cis-4-Amino-8-bromo-2-cyclopropyl-6-trifluoromethyl-1,2,3,4-tetrahy-
dro-quinoline To a solution of
cis-4-benzyloxycarbonylamino-8-bromo-2-cycl-
opropyl-6-trifluoromethyl 1,2,3,4-tetrahydro-quinoline (1.0 g)
(prepared from 2-bromo-4-trifluoromethylaniline and
cyclopanecarboxaldehyde as in Example 1) in 20 ml dichloromethane
was added 30% HBr in HOAc (10 ml) over 5 min, and the resulting
mixture was stirred for 18 h. The reaction was quenched with 1M
K.sub.2CO.sub.3 solution, the layers were separated and the aqueous
layer was extracted with 50 mL dichloromethane. The combined
extracts were dried (MgSO.sub.4), filtered and concentrated, and
the residue was chromatographed (70% EtOAc/hexane) to afford the
title product (500 mg). MS-m& 335.9 (M.sup.++1); .sup.1H NMR
(CDCl.sub.3) .delta. 0.3 (m, 2H), 0.6 (m, 2H), 1.0 (m, 1H), 4.0 (m,
1H), 7.5 (s, 1H), 7.6 (s, 1H),
Example 100B
[0613]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-amino]-8-bromo-2-cyclopropy-
l-6-trifluoromethyl-3,4-dihydro-2-quinoline To a solution of
cis-4-amino-8-bromo-2-cyclopropyl-6-trifluoromethyl-1,2,3,4-tetrahydro-qu-
inoline (Example 100A) (250 mg, 0.75 mmol) in anhydrous
dichloromethane (10 mL) was added acetic acid (112 mg, 1.90 mmol),
followed by 3,5-bis(trifluoromethyl)benzaldehyde (180 mg, 0.75
mmol) and sodium triacetoxyborohydride (791 mg, 3.73 mmol). The
reaction was stirred at room temperature for 5 h. The reaction
mixture was then diluted with dichloromethane and washed with 1N
NaOH. The organic layer was separated, dried over magnesium
sulfate, filtered and concentrated in vacuo to afford the title
crude product (420 mg) which was used without further purification.
.sup.1H NMR (CDCl.sub.3) .delta. 0.3 (m, 2H), 0.6 (m, 2H), 1.0 (m,
1H), 7.5 (s, 1H), 7.8 (s, 2H), 7.9 (s, 2H).
Example 100C
[0614]
cis-4[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-8-bro-
mo-2 cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline
cis-4-[(3,5-bis-trifluoromethyl-benzyl)-amino]-8-bromo-2-cyclopropyl-6-tr-
ifluoromethyl-3,4-dihydro-2H-quinoline (Example 100B) (420 mg, 0.75
mmol) and pyridine (148 mg, 1.88 mmol) were dissolved in anhydrous
dichloromethane (15 mL) and cooled to 0.degree. C. Methyl
chloroformate (142 mg, 1.5 mmol) was added over 1 min. The reaction
was stirred at 0.degree. C. for 1 h, then at room temperature for
24 h. The reaction mixture was then diluted with 50 mL of
dichloromethane, and washed twice with 1N HCl. The organic layer
was dried over magnesium sulfate, filtered and concentrated in
vacuo to afford the title product (400 mg) which was used without
further purification. MS m/z 618.8 (M.sup.+).
Example 100D
[0615]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-8-br-
omo-2-cyclopropyl
trifuoromethyl-3,4-dihydro-2H-quinoline-1-carbonyl chloride A
solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycar-
bonyl-amino]-8-2
-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (Example
100C) (1.0 g) in 50 mL of a 20% phosgene in toluene solution was
heated to reflux for 24 h. Additional phosgene/toluene (50 ml) was
added and heating was continued for an additional 24 h. Excess
phosgene was removed by purging with nitrogen. The resulting
solution was concentrated to afford the crude title product which
was used without further purification. MS 681.5 (M.sup.+).
Example 101
[0616]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-8-br-
omo-2
cyclopropyl-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester A solution of
cis-4-[(3,5-bis-trifluoromethyl-benzyl-
)-methoxycarbonyl-amino]-8-bromo-2-cyclopropyl-6-trifluoromethyl-3,4-dihyd-
ro-2H-quinoline-1-carbonyl chloride (Example 100D) (1.5 g) in
isopropanol was heated to reflux for 48 h. The reaction was cooled
and concentrated, and the residue was chromatographed (5-10%
EtOAc/hexane) to afford the title product (1.0 g). MS m/z 705.4
(M.sup.+); .sup.1H NMR (CDCl.sub.3) .delta. 3.8 (s, 3H), 7.1 (s,
1H), 7.8 (s, 2H).
Example 102A
[0617]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline
cis-(3,5-Bis-trifluoromethyl-benzyl)-2-cyclopropyl-1-trifluoroacetyl-trif-
luoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl) carbamic acid methyl
ester (Example 47) (900 mg, 1.41 mmol) was dissolved in 20 mL of
methanol and 60 mL of tetrahydrofuran before adding lithium
hydroxide (1.6 mL of 1.0M aqueous solution, 1.6 mmol) to the
solution. After 2 h at room temperature, 100 mL of water was added
and the mixture extracted with ethyl acetate (3.times.100 mL). The
combined organic extracts were washed with 50 mL of brine, dried
over sodium sulfate, filtered and concentrated in vacuo to afford
the title product (740 mg) as a colorless solid which was used
without further purification. MS m/z 542 (M+2).sup.+; .sup.1H NMR
(CDCl.sub.3) .delta. 0.2 (m, 2H), 0.55 (m, 2H), 0.0.8 (m, 1H).
Example 102B
[0618]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-lcarbonyl
chloride A solution of cis-4-[(3,5
bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino-
]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (Example
102A) (180 mg, 0.33 mmol) in 2 mL of a 1.93M solution of phosgene
in toluene was heated to reflux for 1 h. Excess phosgene was
removed by purging with nitrogen, and the resulting solution was
concentrated to afford the crude title product (208 mg) which was
used without further purification. MS m/z 621 (M+19.sup.+); .sup.1
H NMR (CDCl.sub.3) .delta. 0.2 (m, 1H), 0.45 (m, 2H), 0.55 (1H),
0.75 (m, 1H).
Example 102C
[0619]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid 2,2,2-trifluoro-ethyl ester. A solution of
cis-4[(3,5-bis-trifluoromethyl- -benzyl)-methoxycarbonyl-amino]-2
cyclopropyl-6-trifluoromethyl-3,4-dihydr- o-2H-quinoline-1-arbonyl
chloride (Example 102B) (20 mg) in 2,2,2-trifluoroethanol (5 mL)
was heated to reflux. After 1 h, the reaction was cooled and
concentrated, and the residue was chromatographed (5-10%
EtOAc/hexane) to afford the title product (22 mg, 77%). MS m/z 685
(M.sup.++19); .sup.1H NMR (CDCl.sub.3) .delta. 3.82 (s, 3H), 7.17
(C.sub.5 s, s1H).
[0620] Examples 103-106 were prepared using the appropriate alcohol
in an analogous manner to the sequence of reactions used in
Examples 102A-102C.
Example 103
[0621]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic add
cyclopropylmethyl ester. MS m/z 640 (M.sup.++2), 657 (M.sup.++19);
.sup.1H NMR (CDCl.sub.3) .delta. 3.81 (s, 3H), 7.14 (C.sub.5, s,
1H).
Example 104
[0622]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid butyl ester. MS m/z 642 (M.sup.++2), 659 (M.sup.+19); .sup.1H
NMR (CDCl.sub.3) 3.81 (s, 3H), 7.14 (C.sub.5, s, 1H).
Example 105
[0623]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
add 2,2-dimethyl-propyl ester. MS m/z 656 (M.sup.++2), 673
(M.sup.++19); .sup.1H NMR (CDCl.sub.3) .delta. 3.81 (s, 3H), 7.14
(C.sub.5, s, 1H).
Example 106
[0624]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid pentyl ester. MS m/z 656 (M.sup.++2), 673 (M.sup.++19);
.sup.1H NMR (CDCl.sub.3) .delta. 3.81 (s, 3H), 7.14 (C5, s,
1H).
Example 107A
[0625]
cis-4-(N-Benzyloxycarbonyl-N-tert-butoxycarbonyl)amino-2-cyclopropy-
l-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
tert-butyl ester. To a solution of
cis-(2-cyclopropyl-6-trifluoromethyl-1,2,3,4-tetr-
ahydro-quinolin-4-yl)-carbamic acid benzyl ester (4.0 g, 10.3 mmol)
(prepared from 4-trifluoromethylaniline and
cyclopropanecarboxaldehyde as in Example 1) in 150 ml anhydrous
tetrahydrofuran was added 4-dimethylaminopyridine (5.0 g) and
di-tert-butyl dicarbonate (8.96 g, 41 mmol) and the resulting
solution was stirred for 24 h. The reaction mixture was poured into
100 ml 2N HCl and was extracted 2.times.200 ml EtOAc. The combined
extracts were dried (MgSO.sub.4), filtered and concentrated to
afford the title product (6.5 g) which was used without further
purification. .sup.1H NMR (CDCl.sub.3) .delta. 1.4 (s, 9H), 1.5 (s,
9H), 2.35 (m, 1H), 2.55 (m, 1H), 4.0 (q, 1H), 7.3 (s, 5H), 7.5 (m,
3H).
Example 107B
[0626]
cis-4-tert-Butoxycarbonylamino-2-cyclopropyl-6-trifluoromethyl-3,4--
dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester. A mixture
of
cis(N-benzyloxycarbonyl-N-tert-butoxycarbonyl)amino-2-cyclopropyl-6-trifl-
uoromethyl-3,4-dihydro-2H-quinoline 1-carboxylic acid tert-butyl
ester (Example 107A) (6.5 g) and 10% Pd/C in 50 mL EtOH and 50 ml
cyclohexene was refluxed for 1 h. The cooled reaction mixture was
filtered through Celite.RTM. and concentrated to afford the title
product (3.4 g) which was used without further purification.
.sup.1H NMR (CDCl.sub.3) .delta. 1.5 (d, 18H), 1.7 (m, 1H), 2.5 (m,
1H), 4.0 (q, .sub.1H), 7.6 (m, 3H).
Example 107C
[0627]
cis-4-Amino-2-cyclopropyl-4-trifluoromethyl-3,4-dihydro-2H-quinolin-
e-1-carboxylic acid tert-butyl ester. Trifluoroacetic acid (3.4 g)
was added in portions to a solution of
cis-4-tert-butoxycarbonylamino-2-cyclo-
propyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
tert-butyl ester (Example 107B) (3.4 g; 7.4 mmol) in 150 ml
dichloromethane, and the reaction was stirred until no starting
material was observed by thin-layer chromatography. A small amount
of 1 N NaOH was added and the reaction mixture was dried
(MgSO.sub.4), filtered and concentrated. Chromatography on silica
gel (50% ethyl acetate:hexane through 5% MeOH:dichloromethane)
afforded the title product (1.0 g). .sup.1H NMR (CDCl.sub.3)
.delta. 1.5 (s, 9H), 1.7 (m, 1H), 2.5 (m, 1H), 4.1 (q, 1H), 7.6 (m,
3H).
Example 107D
[0628]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl-methoxycarbonyl-amino]-2-cyc-
lopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid tert-butyl ester.
cis-4-Amino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-
-2H-quinoline-1-carboxylic acid tert-butyl ester (Example 107C)
(1.0 g) was subjected to reductive amination (with 3,5,
bis(trifluoromethyl)benza- ldehyde as in Example 4 and acylation
with methyl chloroformate as in Example 5) to, afford 2.4 g of the
title compound. MS m/z 640 (M.sup.+); .sup.1H NMR (CDCl.sub.3)
.delta. 1.5 (s, 9H), 3.8 (s, 3H), 7.1 (s, 1H), 7.5-8.0 (m, 4H).
[0629] Examples 108-111 were prepared for the appropriate starting
materials in an analogous manner to the sequence of reactions
described for Examples 107A-107D.
Example 108
[0630]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-6-trifluoromethoxy-3,4-dihydro-2H-quinoline-1-carboxylic
acid tert-butyl ester. MS m/z 657.3 (M.sup.+); .sup.1H NMR
(CDCl.sub.3) 553.8 (s, 3H), 6.8 (t, 1H).
Example 109
[0631]
cis-4-1-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2--
ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
tert-butyl ester MS m/z 529.1 (M.sup.+-CO.sub.2-tBu); 1H NMR
(CDCl.sub.3) .delta. 0.9 (t, 3H), 1.4 (s, 9H), 8 (s, 3H), 7.4 (s,
1H).
Example 110
[0632]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-is-
opropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid tert-butyl ester .sup.1H NMR (CDCl.sub.3) .delta. 1.4 (s, 9H),
3.8 (s, 3H), 7.1 (s, 1H), 7.8 (br, 2H).
Example 111
[0633]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy-
clopropyl-6-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylic
acid tert-butyl ester MS m/z 513.2 (M.sup.+-CO.sub.2-tBu); .sup.1H
NMR (CDCl.sub.3) .delta. 2.1 (t, 2H), 2.9 (m, 4H), 3.8 (s, 3H), 6.8
(s, 1H).
Example 112A
[0634] (3,5-Bis-trifluoromethyl-benzyl)-(7,8-dimethoxy-1-oxo-3,3a,
4,5-tetrahydro-2-oxa-9b-aza-cyclopenta[a]naphthalen-5-yl)-carbamic
acid methyl ester To a solution of as
4-[(3,5-bis-trifluoromethyl-benzyl)-meth-
oxycarbonyl-amino]-6,7-dimethoxy-3,4-dihydro
2H-quinoline-1,2-dicarboxylic add 2-butyl ester 1-ethyl ester
(Example 5) (100 mg, 0.15 mmol) in 8.5 mL methanol at 0.degree. C.
was added sodium borohydride (57 mg, 1.5 mmol) and the resulting
mixture was stirred at room temperature for 1 h. The reaction
mixture was poured into water and extracted twice with ethyl
acetate. The combined extracts were dried over magnesium sulfate,
filtered and concentrated. The residue was chromatographed using
80% ethyl acetate/hexanes to afford the title product (70 mg).
.sup.1H NMR (CDCl.sub.3) .delta. 1.8 (br, 1H), 2.4 (br, 1H), 3.6
(s, 3H), 6.5 (br, 1H), 7.6 (br, 2H), 7.9 (s, 1H).
Example 112B
[0635]
cis-(3,5-Bis-trifluoromethyl-benzyl)-(6,7-dimethoxy-2-methylsulfany-
lmethyl-1,2,3,4 tetrahydro-quinolin-4-yl)-amine: To a solution of
(3,5-bis-trifluoromethyl-benzyl)-(7,8
dimethoxy-1-oxo-3,3a,4,5-tetrahydro-
-2-oxa-9-aza-cyclopenta[a]naphthalen-5-yl)-carbamic acid methyl
ester (Example 112A) (700 mg) in dimethyl formamide (15 ml) was
added sodium methylthiolate (105 mg, 1.5 mmol) and the resulting
solution was heated to 90.degree. C. for 15 h. The reaction was
cooled, water was added and the mixture was extracted twice with
ethyl acetate. The extracts were dried (MgSO.sub.4), filtered and
concentrated. The residue was chromatographed using 25% ethyl
acetate/hexanes to afford the title product (120 mg).
Example 112C
[0636]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-ethoxycarbonyl-amino]-6,7-d-
imethoxy-2-methylsulfanylmethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid ethyl ester. To an ice-cold solution of
cis-(3,5-bis-trifluoromethyl-benz-
yl)-(6,7-dimethoxy-2-methylsulfanylmethyl-1,2,3,4-tetrahydro-quinolin-4-yl-
)-amine (Example 112B) (120 mg) and pyridine (0.50 ml) in
dichloromethane (30 ml) was added ethyl chloroformate (0.5 ml). The
solution was stirred at 0.degree. C. for 30 min and then at room
temperature for 18 h. The reaction was quenched with water and the
mixture was extracted twice with ethyl acetate. The combined
extracts were dried over magnesium sulfate, filtered and
concentrated. The residue was chromatographed with 25% ethyl
acetate/hexanes to afford the title product (100 mg). MS m/z 638.3
(M.sup.+); .sup.1H NMR (CDCl.sub.3) .delta. 2.1 (s, 3H), 3.8 (s,
3H), 3.9 (s, 3H), 6.4 (s, 1H), 7.0 (s, 1H).
Example 113
[0637]
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-(2-
-hydroxymethyl-cyclopropyl)-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1
arboxylic add isopropyl ester. To a solution of
cis-4[(3,5-bis-trifluorom-
ethyl-benzyl)-methoxycarbonyl-amino]-2-(2-ethoxycarbonyl-cyclopropyl)+trif-
luoromethyl-3,4-dihydro-2H-quinolin-carboxylic acid isopropyl ester
(Example 53) (100 mg, 0.14 mmol) in refluxing methanol (40 ml) was
added sodium borohydride (1.0 g) in portions, and the resulting
mixture was heated to reflux for an additional 30 min. The cooled
reaction was concentrated and the residue was partitioned between
ethyl acetate and 2N HCl. The aqueous layer was extracted again
with ethyl acetate and the combined extracts were dried
(MgSO.sub.4), filtered and concentrated. The residue was
chromatographed with 15-20% ethyl acetate/hexane to afford the
title product (55 mg). MS m/z 657.2 (M.sup.+); .sup.1H NMR
(CDCl.sub.3) .delta. 3.8 (s, 3H), 3.9 (q, 1H), 7.1 (s, 1H), 7.5 (s,
2H), 7.7 (s, 1H).
[0638] Examples 114-122 were prepared in optically enriched form by
resolution of the corresponding racemate indicated, or an
intermediate in its synthesis, using the methods described in the
specification.
Example 114
[0639]
4(S)-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2(S)--
isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. Enantiomer of the title product of Example
20.
Example 115
[0640]
4(S)[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2(S)-c-
yclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid isopropyl ester. Enantiomer of the title product of Example
10.
Example 116
[0641]
4(S)-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2(S)--
cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid tert-butyl ester. Enantiomer of the title product of Example
107D.
Example 117
[0642]
4(S)-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2(S)--
cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid propyl ester. Enantiomer of the title product of Example
63.
Example 118
[0643]
4(S)-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2(R)--
ethyl trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
isopropyl ester. Enantiomer of the title product of Example 15.
Example 119
[0644]
4(S)-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2(S)--
cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic
acid ethyl ester. Enantiomer of the title product of Example
78.
Example 120
[0645]
4(S)-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2(R)--
ethyl trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
ethyl ester. Enantiomer of the title product of Example 7F.
Example 121
[0646]
4(S)-[(3,5-Bis-trifuoromethyl-benzyl)-methoxycarbonyl-amino]-2(R)-e-
thyl-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
propyl ester. Enantiomer of the title product of Example 79.
Example 122
[0647]
4(S)-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2(R)--
ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
2-hydroxy-ethyl ester, Enantiomer of Example 84.
* * * * *