U.S. patent application number 12/288993 was filed with the patent office on 2009-05-28 for novel phosphonic acid compounds as inhibitors of serine proteases.
Invention is credited to Harold R. Almond, JR., Sergio Cesco-Cancian, Lawrence de Garavilla, Michael N. Greco, Michael J. Hawkins, Michael J. Humora, Christopher Norman Nilsen, Mitul N. Patel, Eugene Powell, Yun Qian, Kirk Leonard Sorgi, Donald Gilmore Walker.
Application Number | 20090137528 12/288993 |
Document ID | / |
Family ID | 33309497 |
Filed Date | 2009-05-28 |
United States Patent
Application |
20090137528 |
Kind Code |
A1 |
Greco; Michael N. ; et
al. |
May 28, 2009 |
Novel phosphonic acid compounds as inhibitors of serine
proteases
Abstract
The present invention is directed to phosphonic acid compounds
useful as serine protease inhibitors, compositions thereof and
methods for treating inflammatory and serine protease mediated
disorders.
Inventors: |
Greco; Michael N.;
(Lansdale, PA) ; Almond, JR.; Harold R.; (Maple
Glen, PA) ; de Garavilla; Lawrence; (Downingtown,
PA) ; Hawkins; Michael J.; (Ambler, PA) ;
Humora; Michael J.; (Cranbury, NJ) ; Qian; Yun;
(Doylestown, PA) ; Walker; Donald Gilmore;
(Pipersville, PA) ; Cesco-Cancian; Sergio;
(Bethlehem, PA) ; Nilsen; Christopher Norman;
(Branchburg, NJ) ; Patel; Mitul N.; (Newark,
NJ) ; Sorgi; Kirk Leonard; (Buckingham, PA) ;
Powell; Eugene; (Pipersville, PA) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
33309497 |
Appl. No.: |
12/288993 |
Filed: |
October 24, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10414782 |
Apr 16, 2003 |
7459461 |
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12288993 |
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10273208 |
Oct 17, 2002 |
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10414782 |
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60330343 |
Oct 19, 2001 |
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Current U.S.
Class: |
514/85 ; 514/89;
544/232; 546/22 |
Current CPC
Class: |
A61P 13/12 20180101;
A61P 31/12 20180101; C07F 9/3882 20130101; A61P 9/10 20180101; A61P
9/12 20180101; A61P 11/08 20180101; C07F 9/6561 20130101; C07F
9/65583 20130101; C07F 9/59 20130101; A61P 27/16 20180101; A61P
11/06 20180101; A61P 29/00 20180101; C07F 9/65586 20130101; C07F
9/65517 20130101; A61P 17/06 20180101; A61P 37/08 20180101; C07F
9/572 20130101; A61P 27/02 20180101; A61P 11/00 20180101; A61P
19/02 20180101; C07F 9/650952 20130101 |
Class at
Publication: |
514/85 ; 544/232;
546/22; 514/89 |
International
Class: |
A61K 31/675 20060101
A61K031/675; C07F 9/547 20060101 C07F009/547 |
Claims
1. A process for preparing a compound of Formula (I): ##STR00033##
wherein R.sub.1 is selected from the group consisting of a
heterocyclyl ring (wherein the point of attachment for the
heterocyclyl ring at R.sub.1 is a nitrogen ring atom) and
--N(R.sub.7R.sub.8); wherein the heterocyclyl ring is optionally
substituted with one to two substituents independently selected
from the group consisting of: a) C.sub.1-8 alkyl optionally
substituted on a terminal carbon atom with a substituent selected
from the group consisting of aryl, heteroaryl, (halo).sub.1-3 and
hydroxy; b) C.sub.1-8 alkoxy optionally substituted on a terminal
carbon atom with a substituent selected from the group consisting
of carboxyl, (halo).sub.1-3 and hydroxy; c) aryl; d) heteroaryl; e)
cyano; f) halogen; g) hydroxy; h) nitro; and i) heterocyclyl
optionally substituted with one to two substituents independently
selected from the group consisting of oxo and aryl; and, optionally
fused with the carbon of attachment to form a spiro heterocyclyl
moiety; and, wherein the aryl portion of the a) and i) substituent,
the heteroaryl portion of the a) substituent and the c) aryl and d)
heteroaryl substituents are optionally substituted with one to four
substituents independently selected from the group consisting of
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.1-4 alkoxy, cycloalkyl,
heterocyclyl, aryl, aryl(C.sub.1-4)alkyl, aryloxy, heteroaryl,
heteroaryl(C.sub.1-4)alkyl, halogen, hydroxy, nitro,
(halo).sub.1-3(C.sub.1-4)alkyl and (halo).sub.1-3(C.sub.1-4)alkoxy;
R.sub.7 is selected from the group consisting of hydrogen,
C.sub.1-8 alkyl and C.sub.2-8 alkenyl; R.sub.8 is selected from the
group consisting of: aa) C.sub.1-8 alkyl optionally substituted on
a terminal carbon atom with a substituent selected from the group
consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, amino
(substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-8 alkyl), (halo).sub.1-3
and hydroxy; ab) cycloalkyl; ac) cycloalkenyl; and ad) heterocyclyl
(wherein the point of attachment at R.sub.8 is a carbon ring atom);
wherein the ab) cycloalkyl, ac) cycloalkenyl and ad) heterocyclyl
(wherein the ad) heterocyclyl contains at least one nitrogen ring
atom) substituents and the cycloalkyl, heterocyclyl, aryl and
heteroaryl portions of the aa) substituent are optionally
substituted with one to four substituents independently selected
from the group consisting of: ba) C.sub.1-8 alkyl optionally
substituted on a terminal carbon atom with a substituent selected
from the group consisting of amino (with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-8 alkyl), (halo).sub.1-3 and hydroxy; bb) C.sub.1-8 alkoxy
optionally substituted on a terminal carbon atom with a substituent
selected from the group consisting of carboxyl, (halo).sub.1-3 and
hydroxy; bc) carbonyl substituted with a substituent selected from
the group consisting of C.sub.1-8 alkyl, aryl,
aryl(C.sub.1-8)alkyl, aryl(C.sub.2-8)alkenyl, heteroaryl,
heteroaryl(C.sub.1-8)alkyl and heteroaryl(C.sub.2-8)alkenyl; bd)
aryl; be) heteroaryl; bf) amino substituted with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-8 alkyl; bg) cyano; bh) halogen; bi) hydroxy; bj) nitro;
bk) heterocyclyl optionally substituted with one to two oxo
substituents; and, bl) sulfonyl substituted with a substituent
selected from the group consisting of C.sub.1-8 alkyl, aryl,
aryl(C.sub.1-8)alkyl, aryl(C.sub.2-8)alkenyl, heteroaryl,
heteroaryl(C.sub.1-8)alkyl and heteroaryl(C.sub.2-8)alkenyl;
wherein the bd) aryl, be) heteroaryl and bk) heterocyclyl
substituents and the aryl and heteroaryl portions of the bc)
substituent are optionally substituted with one to four
substituents independently selected from the group consisting of
C.sub.1-4 alkyl (optionally substituted on a terminal carbon atom
with a substituent selected from the group consisting of amino
(substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-8 alkyl), (halo).sub.1-3
and hydroxy), C.sub.1-4 alkoxy (optionally substituted on a
terminal carbon atom with a substituent selected from the group
consisting of (halo).sub.1-3), amino (substituted with two
substituents independently selected from the group consisting of
hydrogen and C.sub.1-4 alkyl), halogen, hydroxy and nitro; and,
provided that the optional substituent attached to the ad)
heterocyclyl nitrogen ring atom is not selected from the group
consisting of bf) amino (substituted with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-8 alkyl), bh) halogen, bi) hydroxy and bj) nitro; R.sub.4
is selected from the group consisting of C.sub.1-4 alkyl
(optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of aryl and
heteroaryl), aryl and heteroaryl; wherein aryl and heteroaryl and
the aryl and heteroaryl portions of the substituted alkyl are
optionally substituted with one to four substituents independently
selected from the group consisting of C.sub.1-4 alkyl, amino
(substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-4 alkyl), cyano, halogen,
hydroxy and (halo).sub.1-3(C.sub.1-8)alkyl; R.sub.2 and R.sub.3 are
attached to a benzene ring and independently selected from the
group consisting of ca) hydrogen; cb) C.sub.1-4 alkyl optionally
substituted on a terminal carbon atom with a substituent selected
from the group consisting of amino (substituted with two
substituents independently selected from the group consisting of
hydrogen and C.sub.1-4 alkyl), (halo).sub.1-3 and hydroxy; cc)
C.sub.1-4 alkoxy optionally substituted on a terminal carbon atom
with a substituent selected from the group consisting of
(halo).sub.1-3 and hydroxy; cd) C.sub.2-4 alkenyl; ce) amino
substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-4 alkyl; cf) halogen; and
cg) hydroxy; optionally, R.sub.2 and R.sub.3 together form at least
one ring fused to the benzene ring; thereby providing a multiple
ring system wherein the multiple ring system is selected from the
group consisting of C.sub.9-C.sub.14 benzo fused cycloalkyl,
C.sub.9-C.sub.14 benzo fused cycloalkenyl, C.sub.9-C.sub.14 benzo
fused aryl, benzo fused heterocyclyl and benzo fused heteroaryl;
and, wherein the multiple ring system can optionally be substituted
with one to four substituents independently selected from the group
consisting of: da) C.sub.1-4 alkyl optionally substituted on a
terminal carbon atom with a substituent selected from the group
consisting of amino (substituted with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-4 alkyl), (halo).sub.1-3 and hydroxy; db) C.sub.1-4 alkoxy
optionally substituted on a terminal carbon atom with a substituent
selected from the group consisting of (halo).sub.1-3 and hydroxy;
dc) amino substituted with two substituents independently selected
from the group consisting of hydrogen and C.sub.1-4 alkyl; dd)
halogen; de) hydroxy; and df) nitro; R.sub.5 is selected from the
group consisting of hydrogen and C.sub.1-8 alkyl (optionally
substituted on a terminal carbon atom with a substituent selected
from the group consisting of amino (substituted with two
substituents independently selected from the group consisting of
hydrogen and C.sub.1-4 alkyl), (halo).sub.1-3 and hydroxy) and aryl
(optionally substituted with one to four substituents independently
selected from the group consisting of C.sub.1-8 alkyl and halogen);
R.sub.6 is selected from the group consisting of C.sub.1-8 alkyl,
aryl(C.sub.1-8)alkyl, C.sub.1-8 alkoxy, aryl(C.sub.1-8)alkoxy,
C.sub.2-8 alkenyl, C.sub.2-8 alkenyloxy, aryl(C.sub.2-8)alkenyl,
aryl(C.sub.2-8)alkenyloxy, aryl, aryloxy and hydroxy; X and Y are
independently selected from the group consisting of hydrogen,
C.sub.1-8 alkyl (optionally substituted on a terminal carbon atom
with a substituent selected from the group consisting of
cycloalkyl, heterocyclyl, aryl, heteroaryl, amino (substituted with
two substituents independently selected from the group consisting
of hydrogen and C.sub.1-8 alkyl), (halo).sub.1-3 and hydroxy),
C.sub.1-8 alkoxy (optionally substituted on a terminal carbon atom
with a substituent selected from the group consisting of aryl,
(halo).sub.1-3 and hydroxy), C.sub.2-8 alkenyloxy, cycloalkyl,
heterocyclyl, aryl, aryloxy, heteroaryl and hydroxy; optionally, X
and Y are fused together with the carbon of attachment to form a
spiro cycloalkyl or heterocyclyl moiety; and, optionally, Y is not
present; wherein X is one substituent attached by a double-bond
selected from the group consisting of O, S, imino,
(C.sub.1-4)alkylimino and hydroxyimino; and Z is selected from the
group consisting of a bond, hydrogen and C.sub.1-8 alkyl; if Z is a
bond (wherein Z forms a double bond with the carbon of attachment
for X), then Y is not present and X is one substituent attached by
a single-bond selected from the group consisting of hydrogen,
C.sub.1-8 alkoxy, C.sub.2-8 alkenyloxy, aryloxy,
aryl(C.sub.1-4)alkoxy and hydroxy, and isomers, racemates,
enantiomers, diastereomers and salts thereof; comprising coupling
under suitable conditions a first compound of Formula (A):
##STR00034## with a second compound selected from the group
consisting of Formula (B) and Formula (C): ##STR00035## to produce
a third compound selected from the group consisting of Formula (D)
and Formula (E): ##STR00036## Wherein R.sub.7 is selected from the
group consisting of hydrogen, C.sub.1-8 alkyl and C.sub.2-8
alkenyl; R.sub.8 is selected from the group consisting of: aa)
C.sub.1-8 alkyl optionally substituted on a terminal carbon atom
with a substituent selected from the group consisting of
cycloalkyl, heterocyclyl, aryl, heteroaryl, amino (substituted with
two substituents independently selected from the group consisting
of hydrogen and C.sub.1-8 alkyl), (halo).sub.1-3 and hydroxy; ab)
cycloalkyl; ac) cycloalkenyl; and, ad) heterocyclyl (wherein the
point of attachment at R.sub.8 is a carbon ring atom); wherein the
ab) cycloalkyl, ac) cycloalkenyl and ad) heterocyclyl (wherein the
ad) heterocyclyl contains at least one nitrogen ring atom)
substituents and the cycloalkyl, heterocyclyl, aryl and heteroaryl
portions of the aa) substituent are optionally substituted with one
to four substituents independently selected from the group
consisting of: ba) C.sub.1-8 alkyl optionally substituted on a
terminal carbon atom with a substituent selected from the group
consisting of amino (with two substituents independently selected
from the group consisting of hydrogen and C.sub.1-8 alkyl),
(halo).sub.1-3 and hydroxy; bb) C.sub.1-8 alkoxy optionally
substituted on a terminal carbon atom with a substituent selected
from the group consisting of carboxyl, (halo).sub.1-3 and hydroxy;
bc) carbonyl substituted with a substituent selected from the group
consisting of C.sub.1-8 alkyl, aryl, aryl(C.sub.1-8)alkyl,
aryl(C.sub.2-8)alkenyl, heteroaryl, heteroaryl(C.sub.1-8)alkyl and
heteroaryl(C.sub.2-8)alkenyl; bd) aryl; be) heteroaryl; bf) amino
substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-8 alkyl; bg) cyano; bh)
halogen; bi) hydroxy; bj) nitro; bk) heterocyclyl optionally
substituted with one to two oxo substituents; and bl) sulfonyl
substituted with a substituent selected from the group consisting
of C.sub.1-8 alkyl, aryl, aryl(C.sub.1-8)alkyl,
aryl(C.sub.2-8)alkenyl, heteroaryl, heteroaryl(C.sub.1-8)alkyl and
heteroaryl(C.sub.2-8)alkenyl; wherein the bd) aryl, be) heteroaryl
and bk) heterocyclyl substituents and the aryl and heteroaryl
portions of the bc) substituent are optionally substituted with one
to four substituents independently selected from the group
consisting of C.sub.1-4 alkyl (optionally substituted on a terminal
carbon atom with a substituent selected from the group consisting
of amino (substituted with two substituents independently selected
from the group consisting of hydrogen and C.sub.1-8 alkyl),
(halo).sub.1-3 and hydroxy), C.sub.1-4 alkoxy (optionally
substituted on a terminal carbon atom with a substituent selected
from the group consisting of (halo).sub.1-3), amino (substituted
with two substituents independently selected from the group
consisting of hydrogen and C.sub.1-4 alkyl), halogen, hydroxy and
nitro; and, provided that the optional substituent attached to the
ad) heterocyclyl nitrogen ring atom is not selected from the group
consisting of bf) amino (substituted with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-8 alkyl), bh) halogen, bi) hydroxy and bj) nitro; R.sub.4
is selected from the group consisting of C.sub.1-4 alkyl
(optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of aryl and
heteroaryl), aryl and heteroaryl; wherein aryl and heteroaryl and
the aryl and heteroaryl portions of the substituted alkyl are
optionally substituted with one to four substituents independently
selected from the group consisting of C.sub.1-4 alkyl, amino
(substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-4 alkyl), cyano, halogen,
hydroxy and (halo).sub.1-3(C.sub.1-8)alkyl; R.sub.2 and R.sub.3 are
attached to a benzene ring and independently selected from the
group consisting of ca) hydrogen; cb) C.sub.1-4 alkyl optionally
substituted on a terminal carbon atom with a substituent selected
from the group consisting of amino (substituted with two
substituents independently selected from the group consisting of
hydrogen and C.sub.1-4 alkyl), (halo).sub.1-3 and hydroxy; cc)
C.sub.1-4 alkoxy optionally substituted on a terminal carbon atom
with a substituent selected from the group consisting of
(halo).sub.1-3 and hydroxy; cd) C.sub.2-4 alkenyl; ce) amino
substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-4 alkyl; cf) halogen; and
cg) hydroxy; optionally, R.sub.2 and R.sub.3 together form at least
one ring fused to the benzene ring; thereby providing a multiple
ring system; wherein the multiple ring system is selected from the
group consisting of C.sub.9-C.sub.14 benzo fused cycloalkyl,
C.sub.9-C.sub.14 benzo fused cycloalkenyl, C.sub.9-C.sub.14 benzo
fused aryl, benzo fused heterocyclyl and benzo fused heteroaryl;
and, wherein the multiple ring system can optionally be substituted
with one to four substituents independently selected from the group
consisting of: da) C.sub.1-4 alkyl optionally substituted on a
terminal carbon atom with a substituent selected from the group
consisting of amino (substituted with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-4
alkyl), (halo).sub.1-3 and hydroxy; db) C.sub.1-4 alkoxy optionally
substituted on a terminal carbon atom with a substituent selected
from the group consisting of (halo).sub.1-3 and hydroxy; dc) amino
substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-4 alkyl; dd) halogen; de)
hydroxy; and, df) nitro; R.sub.5 is selected from the group
consisting of hydrogen and C.sub.1-8 alkyl (optionally substituted
on a terminal carbon atom with a substituent selected from the
group consisting of amino (substituted with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-4 alkyl), (halo).sub.1-3 and hydroxy) and aryl (optionally
substituted with one to four substituents independently selected
from the group consisting of C.sub.1-8 alkyl and halogen); R.sub.6
is selected from the group consisting of C.sub.1-8 alkyl,
aryl(C.sub.1-8)alkyl, C.sub.1-8 alkoxy, aryl(C.sub.1-8)alkoxy,
C.sub.2-8 alkenyl, C.sub.2-8 alkenyloxy, aryl(C.sub.2-8)alkenyl,
aryl(C.sub.2-8)alkenyloxy, aryl, aryloxy and hydroxy; X is selected
from the group consisting of O, S, imino, (C.sub.1-4)alkylimino and
hydroxyimino; and Z is selected from the group consisting of a
bond, hydrogen and C.sub.1-8 alkyl; if Z is a bond (wherein Z forms
a double bond with the carbon of attachment for X), then X is
selected from the group consisting of hydrogen, C.sub.1-8 alkoxy,
C.sub.2-8 alkenyloxy, aryloxy, aryl(C.sub.1-4)alkoxy and hydroxy,
and isomers, racemates, enantiomers, diastereomers and salts
thereof.
2. The process of claim 1 wherein the first compound of Formula (A)
is selected from a compound of Formula (A'): ##STR00037## wherein
R.sub.8b is selected from the group consisting of C.sub.1-8 alkyl,
aryl, aryl(C.sub.1-8)alkyl, aryl(C.sub.2-8)alkenyl, heteroaryl,
heteroaryl(C.sub.1-8)alkyl and heteroaryl(C.sub.2-8)alkenyl.
3. The process of claim 1 wherein the second compound of Formula
(B) is selected from a compound of Formula (B'): ##STR00038##
4. The process of claim 1 wherein the coupling is conducted in the
presence of a solvent selected from the group consisting of acetone
and methylethyl ketone.
5. The process of claim 1 wherein the coupling is performed at a
temperature of about 56 to 65.degree. C.
6. The process of claim 5 wherein the coupling is performed at a
temperature of about 56 to 65.degree. C. for a period of from about
6 to about 7 hours.
7. The process of claim 1 wherein the third compound is
purified.
8. The process of claim 7 wherein the purification is by
crystallization.
9. The process of claim 1 wherein the third compound selected from
the group consisting of Formula (D) and Formula (E); wherein,
R.sub.5 is selected from the group consisting of C.sub.1-8 alkyl
(optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of amino
(substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-4 alkyl), (halo).sub.1-3
and hydroxy) and aryl (optionally substituted with one to four
substituents independently selected from the group consisting of
C.sub.1-8 alkyl and halogen); and R.sub.6 is selected from the
group consisting of C.sub.1-8 alkyl, aryl(C.sub.1-8)alkyl,
C.sub.1-8 alkoxy, aryl(C.sub.1-8)alkoxy, C.sub.2-8 alkenyl,
C.sub.2-8 alkenyloxy, aryl(C.sub.2-8)alkenyl,
aryl(C.sub.2-8)alkenyloxy, aryl and aryloxy; is hydrolyzed under
suitable conditions to convert R.sub.5 to H and R.sub.6 to OH.
10. The process of claim 1 wherein the compound of Formula (D) or
Formula (E) is contacted with a cation to form a salt.
11. The process of claim 10 wherein the cation is selected from the
group consisting of cation is selected from benzathine,
t-butylamine, calcium gluconate, calcium hydroxide, choline
bicarbonate, choline chloride, cyclohexylamine, diethanolamine,
ethylenediamine, LiOMe, L-lysine, NH.sub.3, NH.sub.4OH,
N-methyl-D-glucamine, piperidine, potassium-t-butoxide, potassium
hydroxide (aqueous), procaine, quinine, sodium carbonate,
sodium-2-ethylhexanoate, sodium hydroxide, triethanolamine and
tromethane.
12. The process of claim 10 wherein the cation is provided in an
amount sufficient to produce predominately a dibasic salt.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. Ser. No.
10/414,782, filed Apr. 16, 2003, which is a continuation-in-part of
U.S. Ser. No. 10/273,208, filed Oct. 17, 2002, now abandoned, which
claims benefit of provisional application Ser. No. 60/330,343,
filed Oct. 19, 2001, which are incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The present invention relates to certain novel compounds,
methods for preparing the compounds, compositions, intermediates
and derivatives thereof and for treating inflammatory and serine
protease mediated disorders. More particularly, the phosphonic acid
compounds of the present invention are serine protease inhibitors
useful for treating inflammatory and serine protease mediated
disorders.
BACKGROUND OF THE INVENTION
[0003] Serine proteases represent a broad class of endopeptidases
that are involved in physiological processes such as blood
coagulation, complement activation, phagocytosis and turnover of
damaged cell tissue. For example, cathepsin G (cat G) is a
chymotrypsin-like serine protease found in the azurophilic granules
of polymorphonuclear leukocytes. Along with other serine proteases
such as human neutrophil elastase and protease 3, cat G functions
to degrade proteins during inflammatory responses. Cat G is thought
to degrade human elastin during chronic lung inflammation, a
process which may in part be responsible for asthma, pulmonary
emphysema, chronic obstructive pulmonary diseases (COPD) as well as
other pulmonary inflammatory conditions. Similarly, human chymase
(HC) is a chymotrypsin-like serine protease synthesized in mast
cells. HC has a variety of functions, including degradation of
extracellular matrix proteins, cleavage of angiotensin I to
angiotensin II and activation of matrix proteases and cytokines.
Inadequate control by their natural inhibitors can cause these
enzymes to degrade healthy constituents of the extracellular
matrix, and thereby contribute to inflammatory disorders such as
asthma, emphysema, bronchitis, psoriasis, allergic rhinitis, viral
rhinitis, ischemia, arthritis and reperfusion injury. Thus, small
molecule inhibitors of cat G and HC are likely to represent useful
therapeutic agents.
[0004] U.S. Pat. No. 5,508,273 to Beers, et al. and Bioorganic
& Med. Chem. Lett., 1995, 5, (16), 1801-1806 describe
phosphonic acid compounds useful in treating bone wasting diseases.
In particular, 1-napthylmethylphosphonic acid derivatives have been
described as osteoclastic acid phosphatase inhibitors of the
formula:
##STR00001##
[0005] Accordingly, it is an object of the present invention to
provide phosphonic acid compounds that are serine protease
inhibitors (in particular, inhibitors of cathepsin G and chymase)
useful for treating inflammatory and serine protease mediated
disorders. It is another object of the invention to provide a
process for preparing phosphonic or phosphinic acid compounds,
compositions, intermediates and derivatives thereof. It is a
further object of the invention to provide methods for treating
inflammatory and serine protease mediated disorders.
SUMMARY OF THE INVENTION
[0006] This invention is directed to compounds of Formula (I):
##STR00002##
wherein [0007] R.sub.1 is selected from the group consisting of a
heterocyclyl ring (wherein the point of attachment for the
heterocyclyl ring at R.sub.1 is a nitrogen ring atom) and
--N(R.sub.7R.sub.8); wherein the heterocyclyl ring is optionally
substituted with one to two substituents independently selected
from the group consisting of: [0008] a). C.sub.1-8 alkyl optionally
substituted on a terminal carbon atom with a substituent selected
from the group consisting of aryl, heteroaryl, (halo).sub.1-3 and
hydroxy; [0009] b). C.sub.1-8 alkoxy optionally substituted on a
terminal carbon atom with a substituent selected from the group
consisting of carboxyl, (halo).sub.1-3 and hydroxy; [0010] c).
aryl; [0011] d). heteroaryl; [0012] e). cyano; [0013] f). halogen;
[0014] g). hydroxy; [0015] h). nitro; and, [0016] i). heterocyclyl
optionally substituted with one to two substituents independently
selected from the group consisting of oxo and aryl; and, optionally
fused with the carbon of attachment to form a spiro heterocyclyl
moiety; [0017] and, wherein the aryl portion of the a). and i).
substituent, the heteroaryl portion of the a). substituent and the
c). aryl and d). heteroaryl substituents are optionally substituted
with one to four substituents independently selected from the group
consisting of C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.1-4 alkoxy,
cycloalkyl, heterocyclyl, aryl, aryl(C.sub.1-4)alkyl, aryloxy,
heteroaryl, heteroaryl(C.sub.1-4)alkyl, halogen, hydroxy, nitro,
(halo).sub.1-3(C.sub.1-4)alkyl and (halo).sub.1-3(C.sub.1-4)alkoxy;
[0018] R.sub.7 is selected from the group consisting of hydrogen,
C.sub.1-8 alkyl and C.sub.2-8 alkenyl; [0019] R.sub.8 is selected
from the group consisting of: [0020] aa). C.sub.1-8 alkyl
optionally substituted on a terminal carbon atom with a substituent
selected from the group consisting of cycloalkyl, heterocyclyl,
aryl, heteroaryl, amino (with two substituents independently
selected from the group consisting of hydrogen and C.sub.1-8
alkyl), (halo).sub.1-3 and hydroxy; [0021] ab). cycloalkyl; [0022]
ac). cycloalkenyl; and, [0023] ad). heterocyclyl (wherein the point
of attachment at R.sub.8 is a carbon ring atom); [0024] wherein the
ab). cycloalkyl, ac). cycloalkenyl and ad). heterocyclyl (wherein
the ad). heterocyclyl contains at least one nitrogen ring atom)
substituents and the cycloalkyl, heterocyclyl, aryl and heteroaryl
portions of the aa). substituent are optionally substituted with
one to four substituents independently selected from the group
consisting of: [0025] ba). C.sub.1-8 alkyl optionally substituted
on a terminal carbon atom with a substituent selected from the
group consisting of amino (with two substituents independently
selected from the group consisting of hydrogen and C.sub.1-8
alkyl), (halo).sub.1-3 and hydroxy; [0026] bb). C.sub.1-8 alkoxy
optionally substituted on a terminal carbon atom with a substituent
selected from the group consisting of carboxyl, (halo).sub.1-3 and
hydroxy; [0027] bc). carbonyl substituted with a substituent
selected from the group consisting of C.sub.1-8 alkyl, aryl,
aryl(C.sub.1-8)alkyl, aryl(C.sub.2-8)alkenyl, heteroaryl,
heteroaryl(C.sub.1-8)alkyl and heteroaryl(C.sub.2-8)alkenyl; [0028]
bd). aryl; [0029] be). heteroaryl; [0030] bf). amino substituted
with two substituents independently selected from the group
consisting of hydrogen and C.sub.1-8 alkyl; [0031] bg). cyano;
[0032] bh). halogen; [0033] bi). hydroxy; [0034] bj). nitro; [0035]
bk). heterocyclyl optionally substituted with one to two oxo
substituents; and, [0036] bl). sulfonyl substituted with a
substituent selected from the group consisting of C.sub.1-8 alkyl,
aryl, aryl(C.sub.1-8)alkyl, aryl(C.sub.2-8)alkenyl, heteroaryl,
heteroaryl(C.sub.1-8)alkyl and heteroaryl(C.sub.2-8)alkenyl; [0037]
wherein the bd). aryl, be). heteroaryl and bk). heterocyclyl
substituents and the aryl and heteroaryl portions of the bc).
substituent are optionally substituted with one to four
substituents independently selected from the group consisting of
C.sub.1-4 alkyl (optionally substituted on a terminal carbon atom
with a substituent selected from the group consisting of amino
(substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-8 alkyl), (halo).sub.1-3
and hydroxy), C.sub.1-4 alkoxy (optionally substituted on a
terminal carbon atom with a substituent selected from the group
consisting of (halo).sub.1-3), amino (substituted with two
substituents independently selected from the group consisting of
hydrogen and C.sub.1-4 alkyl), halogen, hydroxy and nitro; [0038]
and, provided that the optional substituent attached to the ad).
heterocyclyl nitrogen ring atom is not selected from the group
consisting of bf). amino (substituted with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-8 alkyl), bh). halogen, bi). hydroxy and bj). nitro; [0039]
R.sub.4 is selected from the group consisting of C.sub.1-4 alkyl
(optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of aryl and
heteroaryl), aryl and heteroaryl; wherein aryl and heteroaryl and
the aryl and heteroaryl portions of the substituted alkyl are
optionally substituted with one to four substituents independently
selected from the group consisting of C.sub.1-4 alkyl, amino
(substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-4 alkyl), cyano, halogen,
hydroxy and (halo).sub.1-3(C.sub.1-8)alkyl; [0040] R.sub.2 and
R.sub.3 are attached to a benzene ring and independently selected
from the group consisting of [0041] ca). hydrogen; [0042] cb).
C.sub.1-4 alkyl optionally substituted on a terminal carbon atom
with a substituent selected from the group consisting of amino
(substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-4 alkyl), (halo).sub.1-3
and hydroxy; [0043] cc). C.sub.1-4 alkoxy optionally substituted on
a terminal carbon atom with a substituent selected from the group
consisting of (halo).sub.1-3 and hydroxy; [0044] cd). C.sub.2-4
alkenyl; [0045] ce). amino substituted with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-4 alkyl; [0046] cf. halogen; and, [0047] cg). hydroxy;
optionally, R.sub.2 and R.sub.3 together form at least one ring
fused to the benzene ring; thereby providing a multiple ring
system; wherein the multiple ring system is selected from the group
consisting of C.sub.9-C.sub.14 benzo fused cycloalkyl,
C.sub.9-C.sub.14 benzo fused cycloalkenyl, C.sub.9-C.sub.14 benzo
fused aryl, benzo fused heterocyclyl and benzo fused heteroaryl;
and, wherein the multiple ring system can optionally be substituted
with one to four substituents independently selected from the group
consisting of [0048] da). C.sub.1-4 alkyl optionally substituted on
a terminal carbon atom with a substituent selected from the group
consisting of amino (substituted with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-4 alkyl), (halo).sub.1-3 and hydroxy; [0049] db). C.sub.1-4
alkoxy optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of (halo).sub.1-3
and hydroxy; [0050] dc). amino substituted with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-4 alkyl; [0051] dd). halogen; [0052] de). hydroxy; and,
[0053] df). nitro; [0054] R.sub.5 is selected from the group
consisting of hydrogen and C.sub.1-8 alkyl (optionally substituted
on a terminal carbon atom with a substituent selected from the
group consisting of amino (substituted with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-4 alkyl), (halo).sub.1-3 and hydroxy) and aryl (optionally
substituted with one to four substituents independently selected
from the group consisting of C.sub.1-8 alkyl and halogen); [0055]
R.sub.6 is selected from the group consisting of C.sub.1-8 alkyl,
aryl(C.sub.1-8)alkyl, C.sub.1-8 alkoxy, aryl(C.sub.1-8)alkoxy,
C.sub.2-8 alkenyl, C.sub.2-8 alkenyloxy, aryl(C.sub.2-8)alkenyl,
aryl(C.sub.2-8)alkenyloxy, aryl, aryloxy and hydroxy; [0056] X and
Y are independently selected from the group consisting of hydrogen,
C.sub.1-8 alkyl (optionally substituted on a terminal carbon atom
with a substituent selected from the group consisting of
cycloalkyl, heterocyclyl, aryl, heteroaryl, amino (substituted with
two substituents independently selected from the group consisting
of hydrogen and C.sub.1-8 alkyl), (halo).sub.1-3 and hydroxy),
C.sub.1-8 alkoxy (optionally substituted on a terminal carbon atom
with a substituent selected from the group consisting of aryl,
(halo).sub.1-3 and hydroxy), C.sub.2-8 alkenyloxy, cycloalkyl,
heterocyclyl, aryl, aryloxy, heteroaryl and hydroxy; optionally, X
and Y are fused together with the carbon of attachment to form a
spiro cycloalkyl or heterocyclyl moiety; and, optionally, Y is not
present; wherein X is one substituent attached by a double-bond
selected from the group consisting of O, S, imino,
(C.sub.1-4)alkylimino and hydroxyimino; and, [0057] Z is selected
from the group consisting of a bond, hydrogen and C.sub.1-8 alkyl;
if Z is a bond (wherein Z forms a double bond with the carbon of
attachment for X), then Y is not present and X is one substituent
attached by a single-bond selected from the group consisting of
hydrogen, C.sub.1-8 alkoxy, C.sub.2-8 alkenyloxy, aryloxy,
aryl(C.sub.1-4)alkoxy and hydroxy, and isomers, racemates,
enantiomers, diastereomers and salts thereof.
[0058] Embodiments of the present invention include a process for
preparing a compound of Formula (I) comprising coupling under
suitable conditions a first compound of Formula (A):
##STR00003## [0059] with a second compound selected from the group
consisting of Formula (B) and Formula (C):
[0059] ##STR00004## [0060] to produce a third compound selected
from the group consisting of Formula (D) and Formula (E):
##STR00005##
[0060] wherein [0061] R.sub.7 is selected from the group consisting
of hydrogen, C.sub.1-8 alkyl and C.sub.2-8 alkenyl; [0062] R.sub.8
is selected from the group consisting of: [0063] aa). C.sub.1-8
alkyl optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of cycloalkyl,
heterocyclyl, aryl, heteroaryl, amino (substituted with two
substituents independently selected from the group consisting of
hydrogen and C.sub.1-8 alkyl), (halo).sub.1-3 and hydroxy; [0064]
ab). cycloalkyl; [0065] ac). cycloalkenyl; and, [0066] ad).
heterocyclyl (wherein the point of attachment at R.sub.8 is a
carbon ring atom); [0067] wherein the ab). cycloalkyl, ac).
cycloalkenyl and ad). heterocyclyl (wherein the ad). heterocyclyl
contains at least one nitrogen ring atom) substituents and the
cycloalkyl, heterocyclyl, aryl and heteroaryl portions of the aa).
substituent are optionally substituted with one to four
substituents independently selected from the group consisting of:
[0068] ba). C.sub.1-8 alkyl optionally substituted on a terminal
carbon atom with a substituent selected from the group consisting
of amino (with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-8 alkyl), (halo).sub.1-3
and hydroxy; [0069] bb). C.sub.1-8 alkoxy optionally substituted on
a terminal carbon atom with a substituent selected from the group
consisting of carboxyl, (halo).sub.1-3 and hydroxy; [0070] bc).
carbonyl substituted with a substituent selected from the group
consisting of C.sub.1-8 alkyl, aryl, aryl(C.sub.1-8)alkyl,
aryl(C.sub.2-8)alkenyl, heteroaryl, heteroaryl(C.sub.1-8)alkyl and
heteroaryl(C.sub.2-8)alkenyl; [0071] bd). aryl; [0072] be).
heteroaryl; [0073] bf). amino substituted with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-8 alkyl; [0074] bg). cyano; [0075] bh). halogen; [0076]
bi). hydroxy; [0077] bj). nitro; [0078] bk). heterocyclyl
optionally substituted with one to two oxo substituents; and,
[0079] bl). sulfonyl substituted with a substituent selected from
the group consisting of C.sub.1-8 alkyl, aryl,
aryl(C.sub.1-8)alkyl, aryl(C.sub.2-8)alkenyl, heteroaryl,
heteroaryl(C.sub.1-8)alkyl and heteroaryl(C.sub.2-8)alkenyl; [0080]
wherein the bd). aryl, be). heteroaryl and bk). heterocyclyl
substituents and the aryl and heteroaryl portions of the bc).
substituent are optionally substituted with one to four
substituents independently selected from the group consisting of
C.sub.1-4 alkyl (optionally substituted on a terminal carbon atom
with a substituent selected from the group consisting of amino
(substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-8 alkyl), (halo).sub.1-3
and hydroxy), C.sub.1-4 alkoxy (optionally substituted on a
terminal carbon atom with a substituent selected from the group
consisting of (halo).sub.1-3), amino (substituted with two
substituents independently selected from the group consisting of
hydrogen and C.sub.1-4 alkyl), halogen, hydroxy and nitro; [0081]
and, provided that the optional substituent attached to the ad).
heterocyclyl nitrogen ring atom is not selected from the group
consisting of bf). amino (substituted with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-8 alkyl), bh). halogen, bi). hydroxy and bj). nitro; [0082]
R.sub.4 is selected from the group consisting of C.sub.1-4 alkyl
(optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of aryl and
heteroaryl), aryl and heteroaryl; wherein aryl and heteroaryl and
the aryl and heteroaryl portions of the substituted alkyl are
optionally substituted with one to four substituents independently
selected from the group consisting of C.sub.1-4 alkyl, amino
(substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-4 alkyl), cyano, halogen,
hydroxy and (halo).sub.1-3(C.sub.1-8)alkyl; [0083] R.sub.2 and
R.sub.3 are attached to a benzene ring and independently selected
from the group consisting of [0084] ca). hydrogen; [0085] cb).
C.sub.1-4 alkyl optionally substituted on a terminal carbon atom
with a substituent selected from the group consisting of amino
(substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-4 alkyl), (halo).sub.1-3
and hydroxy; [0086] cc). C.sub.1-4 alkoxy optionally substituted on
a terminal carbon atom with a substituent selected from the group
consisting of (halo).sub.1-3 and hydroxy; [0087] cd). C.sub.2-4
alkenyl; [0088] ce). amino substituted with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-4 alkyl; [0089] cf). halogen; and, [0090] cg). hydroxy;
[0091] optionally, R.sub.2 and R.sub.3 together form at least one
ring fused to the benzene ring; thereby providing a multiple ring
system; wherein the multiple ring system is selected from the group
consisting of C.sub.9-C.sub.14 benzo fused cycloalkyl,
C.sub.9-C.sub.14 benzo fused cycloalkenyl, C.sub.9-C.sub.14 benzo
fused aryl, benzo fused heterocyclyl and benzo fused heteroaryl;
and, wherein the multiple ring system can optionally be substituted
with one to four substituents independently selected from the group
consisting of: [0092] da). C.sub.1-4 alkyl optionally substituted
on a terminal carbon atom with a substituent selected from the
group consisting of amino (substituted with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-4 alkyl), (halo).sub.1-3 and hydroxy; [0093] db). C.sub.1-4
alkoxy optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of (halo).sub.1-3
and hydroxy; [0094] dc). amino substituted with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-4 alkyl; [0095] dd). halogen; [0096] de). hydroxy; and,
[0097] df). nitro; [0098] R.sub.5 is selected from the group
consisting of hydrogen and C.sub.1-8 alkyl (optionally substituted
on a terminal carbon atom with a substituent selected from the
group consisting of amino (substituted with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-4 alkyl), (halo).sub.1-3 and hydroxy) and aryl (optionally
substituted with one to four substituents independently selected
from the group consisting of C.sub.1-8 alkyl and halogen); [0099]
R.sub.6 is selected from the group consisting of C.sub.1-8 alkyl,
aryl(C.sub.1-8)alkyl, C.sub.1-8 alkoxy, aryl(C.sub.1-8)alkoxy,
C.sub.2-8 alkenyl, C.sub.2-8 alkenyloxy, aryl(C.sub.2-8)alkenyl,
aryl(C.sub.2-8)alkenyloxy, aryl, aryloxy and hydroxy; [0100] X is
selected from the group consisting of O, S, imino,
(C.sub.1-4)alkylimino and hydroxyimino; and, [0101] Z is selected
from the group consisting of a bond, hydrogen and C.sub.1-8 alkyl;
if Z is a bond (wherein Z forms a double bond with the carbon of
attachment for X), then X is selected from the group consisting of
hydrogen, C.sub.1-8 alkoxy, C.sub.2-8 alkenyloxy, aryloxy,
aryl(C.sub.1-4)alkoxy and hydroxy, and isomers, racemates,
enantiomers, diastereomers and salts thereof.
[0102] Embodiments of the present invention include a compound of
Formula (C):
##STR00006##
wherein [0103] R.sub.2 and R.sub.3 are attached to a benzene ring
and independently selected from the group consisting of [0104] ca).
hydrogen; [0105] cb). C.sub.1-4 alkyl optionally substituted on a
terminal carbon atom with a substituent selected from the group
consisting of amino (substituted with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-4 alkyl), (halo).sub.1-3 and hydroxy; [0106] cc). C.sub.1-4
alkoxy optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of (halo).sub.1-3
and hydroxy; [0107] cd). C.sub.2-4 alkenyl; [0108] ce). amino
substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-4 alkyl; [0109] cf).
halogen; and, [0110] cg). hydroxy; [0111] optionally, R.sub.2 and
R.sub.3 together form at least one ring fused to the benzene ring;
thereby providing a multiple ring system; wherein the multiple ring
system is selected from the group consisting of C.sub.9-C.sub.14
benzo fused cycloalkyl, C.sub.9-C.sub.14 benzo fused cycloalkenyl,
C.sub.9-C.sub.14 benzo fused aryl, benzo fused heterocyclyl and
benzo fused heteroaryl; and, wherein the multiple ring system can
optionally be substituted with one to four substituents
independently selected from the group consisting of [0112] da).
C.sub.1-4 alkyl optionally substituted on a terminal carbon atom
with a substituent selected from the group consisting of amino
(substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-4 alkyl), (halo).sub.1-3
and hydroxy; [0113] db). C.sub.1-4 alkoxy optionally substituted on
a terminal carbon atom with a substituent selected from the group
consisting of (halo).sub.1-3 and hydroxy; [0114] dc). amino
substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-4 alkyl; [0115] dd).
halogen; [0116] de). hydroxy; and, [0117] df. nitro; [0118] R.sub.4
is selected from the group consisting of C.sub.1-4 alkyl
(optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of aryl and
heteroaryl), aryl and heteroaryl; wherein aryl and heteroaryl and
the aryl and heteroaryl portions of the substituted alkyl are
optionally substituted with one to four substituents independently
selected from the group consisting of C.sub.1-4 alkyl, amino
(substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-4 alkyl), cyano, halogen,
hydroxy and (halo).sub.1-3(C.sub.1-8)alkyl; [0119] R.sub.5 is
selected from the group consisting of hydrogen and C.sub.1-8 alkyl
(optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of amino
(substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-4 alkyl), (halo).sub.1-3
and hydroxy) and aryl (optionally substituted with one to four
substituents independently selected from the group consisting of
C.sub.1-8 alkyl and halogen); and, [0120] R.sub.6 is selected from
the group consisting of C.sub.1-8 alkyl, aryl(C.sub.1-8)alkyl,
C.sub.1-8 alkoxy, aryl(C.sub.1-8)alkoxy, C.sub.2-8 alkenyl,
C.sub.2-8 alkenyloxy, aryl(C.sub.2-8)alkenyl,
aryl(C.sub.2-8)alkenyloxy, aryl, aryloxy and hydroxy.
[0121] Embodiments of the present invention include a process for
making a benzolactone of Formula (C) comprising [0122] a) reacting
an anhydride of Formula (F):
##STR00007##
[0122] with a compound of Formula (G):
##STR00008##
under suitable conditions in the presence of an alkali metal (M) to
provide a compound of Formula (H):
##STR00009## [0123] b) and, reacting the compound of Formula (H)
under conditions suitable to form the benzolactone of Formula
(C):
##STR00010##
[0123] wherein [0124] R.sub.2 and R.sub.3 are attached to a benzene
ring and independently selected from the group consisting of [0125]
ca). hydrogen; [0126] cb). C.sub.1-4 alkyl optionally substituted
on a terminal carbon atom with a substituent selected from the
group consisting of amino (substituted with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-4 alkyl), (halo).sub.1-3 and hydroxy; [0127] cc). C.sub.1-4
alkoxy optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of (halo).sub.1-3
and hydroxy; [0128] cd). C.sub.2-4 alkenyl; [0129] ce). amino
substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-4 alkyl; [0130] cf).
halogen; and, [0131] cg). hydroxy; [0132] optionally, R.sub.2 and
R.sub.3 together form at least one ring fused to the benzene ring;
thereby providing a multiple ring system; wherein the multiple ring
system is selected from the group consisting of C.sub.9-C.sub.14
benzo fused cycloalkyl, C.sub.9-C.sub.14 benzo fused cycloalkenyl,
C.sub.9-C.sub.14 benzo fused aryl, benzo fused heterocyclyl and
benzo fused heteroaryl; and, wherein the multiple ring system can
optionally be substituted with one to four substituents
independently selected from the group consisting of [0133] da).
C.sub.1-4 alkyl optionally substituted on a terminal carbon atom
with a substituent selected from the group consisting of amino
(substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-4 alkyl), (halo).sub.1-3
and hydroxy; [0134] db). C.sub.1-4 alkoxy optionally substituted on
a terminal carbon atom with a substituent selected from the group
consisting of (halo).sub.1-3 and hydroxy; [0135] dc). amino
substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-4 alkyl; [0136] dd).
halogen; [0137] de). hydroxy; and, [0138] df). nitro; [0139]
R.sub.4 is selected from the group consisting of C.sub.1-4 alkyl
(optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of aryl and
heteroaryl), aryl and heteroaryl; wherein aryl and heteroaryl and
the aryl and heteroaryl portions of the substituted alkyl are
optionally substituted with one to four substituents independently
selected from the group consisting of C.sub.1-4 alkyl, amino
(substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-4 alkyl), cyano, halogen,
hydroxy and (halo).sub.1-3(C.sub.1-8)alkyl; [0140] R.sub.5 is
selected from the group consisting of hydrogen and C.sub.1-8 alkyl
(optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of amino
(substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-4 alkyl), (halo).sub.1-3
and hydroxy) and aryl (optionally substituted with one to four
substituents independently selected from the group consisting of
C.sub.1-8 alkyl and halogen); and [0141] R.sub.6 is selected from
the group consisting of C.sub.1-8 alkyl, aryl(C.sub.1-8)alkyl,
C.sub.1-8 alkoxy, aryl(C.sub.1-8)alkoxy, C.sub.2-8 alkenyl,
C.sub.2-8 alkenyloxy, aryl(C.sub.2-8)alkenyl,
aryl(C.sub.2-8)alkenyloxy, aryl, aryloxy and hydroxy.
[0142] Embodiments of the present invention include compounds of
Formula (II):
##STR00011##
wherein [0143] R.sub.10 is selected from the group consisting of:
[0144] a). sulfonyl substituted with a substituent selected from
the group consisting of C.sub.1-8 alkyl, aryl,
aryl(C.sub.1-8)alkyl, aryl(C.sub.2-8)alkenyl, cycloalkyl,
cycloalkenyl, heterocycl, heteroaryl, heteroaryl(C.sub.1-8)alkyl
and heteroaryl(C.sub.2-8)alkenyl; [0145] b). carbonyl substituted
with a substituent selected from the group consisting of C.sub.1-8
alkyl, aryl, aryl(C.sub.1-8)alkyl, aryl(C.sub.2-8)alkenyl,
cycloalkyl, cycloalkenyl, heterocycl heteroaryl,
heteroaryl(C.sub.1-8)alkyl, heteroaryl(C.sub.2-8)alkenyl,
--OR.sub.11 and amino (with two substituents independently selected
from the group consisting of hydrogen, C.sub.1-8 alkyl, aryl,
arylC.sub.1-8 alkyl, arylcarbonyl, arylC.sub.1-8 alkyl carbonyl and
heteroaryl C.sub.1-8 alkyl); [0146] c). C.sub.1-8 alkyl optionally
substituted on a terminal carbon atom with a substituent selected
from the group consisting of aryl, cycloalkyl, cycloalkenyl,
heterocycl, heteroaryl, (halo).sub.1-3, hydroxy, --C(O)R.sub.12 and
amino (with two substituents independently selected from the group
consisting of hydrogen, C.sub.1-8 alkyl, arylC.sub.1-8 alkyl,
arylcarbonyl, arylC.sub.1-8 alkyl carbonyl and heteroaryl C.sub.1-8
alkyl); [0147] d). aryl; [0148] e). heteroaryl; [0149] f).
cycloalkyl [0150] g). cycloalkenyl; and, [0151] h). heterocyclyl
[0152] wherein the heterocycl, cycloalkyl, cycloalkenyl portion of
a)., b)., and c)., the cylcoalkyl f)., cylcoalkenyl g)., and
heterocyclyl h). are optionally substituted with one to two
substituents independently selected from the group consisting of:
[0153] ea). oxo [0154] eb). carbonyl substituted with a substituent
selected from the group consisting of C.sub.1-8 alkyl, aryl,
aryl(C.sub.1-8)alkyl, aryl(C.sub.2-8)alkenyl, cycloalkyl,
cycloalkenyl, heterocycl heteroaryl, heteroaryl(C.sub.1-8)alkyl,
heteroaryl(C.sub.2-8)alkenyl and amino (with two substituents
independently selected from the group consisting of hydrogen,
C.sub.1-8 alkyl, arylC.sub.1-8 alkyl, arylcarbonyl, arylC.sub.1-8
alkyl carbonyl and heteroaryl C.sub.1-8 alkyl); [0155] ec).
C.sub.1-8 alkyl optionally substituted with a substituent selected
from the group consisting of amino (with two substituents
independently selected from the group consisting of hydrogen,
C.sub.1-8 alkyl, arylC.sub.1-8 alkyl, arylcarbonyl, arylC.sub.1-8
alkyl carbonyl and heteroaryl C.sub.1-8 alkyl), aryl, cycloalkyl,
cycloalkenyl, heterocycl, heteroaryl, (halo).sub.1-3, and hydroxy;
[0156] ed). aryl; and [0157] ef. (halo).sub.1-3 [0158] wherein the
aryl portion of the a)., b)., c)., ec). and ed). substituents, the
heteroaryl portion of the a)., b)., c). and ec). substituents and
the d). aryl and e). heteroaryl substituents are optionally
substituted with one to four substituents independently selected
from the group consisting of [0159] fa). C.sub.1-4 alkyl optionally
substituted on a terminal carbon atom with a substituent selected
from the group consisting of aryl, cycloalkyl, cycloalkenyl,
heterocycl, heteroaryl, (halo).sub.1-3, hydroxy, --C(O)R.sub.12 and
amino (with two substituents independently selected from the group
consisting of hydrogen, C.sub.1-8 alkyl, arylC.sub.1-8 alkyl,
arylcarbonyl, arylC.sub.1-8 alkyl carbonyl and heteroaryl C.sub.1-8
alkyl); [0160] fb). C.sub.2-4 alkenyl optionally substituted on a
terminal carbon atom with a substituent selected from the group
consisting of amino (with two substituents independently selected
from the group consisting of hydrogen and C.sub.1-8 alkyl),
(halo).sub.1-3 and hydroxy; [0161] fc). C.sub.1-4 alkoxy optionally
substituted on a terminal carbon atom with a substituent selected
from the group consisting of (halo).sub.1-3 and hydroxy; [0162]
fd). cycloalkyl, [0163] fe). heterocyclyl, [0164] ff). aryl
optionally substituted with one to four substituents independently
selected from the group consisting of C.sub.1-8 alkyl and halogen;
[0165] fg). heteroaryl, [0166] fh). hydroxy; [0167] fi). hydroxy;
[0168] fj). nitro; and [0169] fk). (halo).sub.1-3; [0170] wherein
the aryl portion of the arylC.sub.1-8 alkyl, arylcarbonyl,
arylC.sub.1-8 alkyl carbonyl of fa). are optionally substituted
with one to four substituents independently selected from the group
consisting of C.sub.1-4 alkyl (optionally substituted on a terminal
carbon atom with a substituent selected from the group consisting
of amino (substituted with two substituents independently selected
from the group consisting of hydrogen and C.sub.1-8 alkyl),
(halo).sub.1-3 and hydroxy), C.sub.1-4 alkoxy (optionally
substituted on a terminal carbon atom with a substituent selected
from the group consisting of (halo).sub.1-3), amino (substituted
with two substituents independently selected from the group
consisting of hydrogen and C.sub.1-4 alkyl), halogen, hydroxy and
nitro.
BRIEF DESCRIPTION OF THE DRAWINGS
[0171] FIG. 1 shows the percent change in specific lung resistance
(SR.sub.L) from baseline for Compound 2 compared to control in a
spontaneous ascaris suum antigen-induced model of asthma in sheep
over an 8 hour period.
[0172] FIG. 2 shows the change in the cumulative carbachol dose
required to increase SR.sub.L 400% (PC 400) from a baseline value
(BSL) measured at 24 hours post-dosing of Compound 2 in the
spontaneous ascaris suum antigen-induced model of asthma in sheep
compared to a 24 hour post-dosing challenge with carbachol (Post
Antigen).
DETAILED DESCRIPTION OF THE INVENTION
[0173] Embodiments of the present invention include those compounds
wherein R.sub.1 is selected from the group consisting of a
heterocyclyl ring (wherein the point of attachment for the
heterocyclyl ring at R.sub.1 is a nitrogen ring atom) and
--N(R.sub.7R.sub.8); wherein the heterocyclyl ring is optionally
substituted with a substituent selected from the group consisting
of a). aryl(C.sub.1-4)alkyl, c). aryl, d). heteroaryl and i).
heterocyclyl (optionally substituted with one to two substituents
independently selected from the group consisting of oxo and aryl;
and, optionally fused with the carbon of attachment to form a spiro
heterocyclyl moiety); and, wherein the aryl portion of the a). and
i). substituent and the c). aryl substituent are optionally
substituted with one to two substituents independently selected
from the group consisting of C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
aryl, heteroaryl, halogen, hydroxy, (halo).sub.1-3(C.sub.1-4)alkyl
and (halo).sub.1-3(C.sub.1-4)alkoxy; and, all other variables are
as previously defined.
[0174] Preferably, R.sub.1 is selected from the group consisting of
a heterocyclyl ring (wherein the point of attachment for the
heterocyclyl ring at R.sub.1 is a nitrogen ring atom) and
--N(R.sub.7R.sub.8); wherein the heterocyclyl ring is optionally
substituted with a substituent selected from the group consisting
of a). aryl(C.sub.1-4)alkyl, c). aryl, d). heteroaryl and i).
heterocyclyl (optionally substituted with two substituents
independently selected from the group consisting of oxo and aryl;
and, optionally fused with the carbon of attachment to form a spiro
heterocyclyl moiety); and, wherein the aryl portion of the a). and
i). substituent and the c). aryl substituent are optionally
substituted with one to two substituents independently selected
from the group consisting of C.sub.1-4 alkoxy and aryl; and, all
other variables are as previously defined.
[0175] More preferably, R.sub.1 is selected from the group
consisting of pyrrolidinyl, piperidinyl and --N(R.sub.7R.sub.8);
wherein the point of attachment for pyrrolidinyl and piperidinyl is
a nitrogen ring atom; and, wherein pyrrolidinyl and piperidinyl are
optionally substituted with a substituent selected from the group
consisting of a). phenylethyl, c). phenyl (optionally substituted
with methoxy), d). benzothiazolyl and i). imidazolidinyl
(optionally substituted with two substituents independently
selected from the group consisting of oxo and phenyl; and,
optionally fused with the carbon of attachment to form a spiro
moiety); and, all other variables are as previously defined.
[0176] Most preferably, R.sub.1 is selected from the group
consisting of pyrrolidinyl, piperidinyl and --N(R.sub.7R.sub.8);
wherein the point of attachment for pyrrolidinyl and piperidinyl is
a nitrogen ring atom in the one position; and, wherein pyrrolidinyl
and piperidinyl are optionally substituted with a substituent
selected from the group consisting of a). phenylethyl, c). phenyl
(optionally substituted with methoxy), d). benzothiazolyl and i).
imidazolidinyl (optionally substituted with two substituents
independently selected from the group consisting of oxo and phenyl;
and, optionally fused with the carbon of attachment to form a spiro
moiety); and, all other variables are as previously defined.
[0177] Preferred embodiments of the present invention include those
compounds wherein R.sub.7 is selected from the group consisting of
hydrogen, C.sub.1-4 alkyl and C.sub.2-4 alkenyl.
[0178] More preferably, R.sub.7 is selected from the group
consisting of hydrogen and C.sub.1-4 alkyl.
[0179] Most preferably, R.sub.7 is selected from the group
consisting of hydrogen and methyl.
[0180] Embodiments of the present invention include those compounds
wherein R.sub.8 is selected from the group consisting of: [0181]
aa). C.sub.1-8 alkyl optionally substituted on a terminal carbon
atom with a substituent selected from the group consisting of
cycloalkyl, heterocyclyl, (halo).sub.1-3 and hydroxy; [0182] ab).
cycloalkyl; [0183] ac). cycloalkenyl; and, [0184] ad). heterocyclyl
(wherein the point of attachment at R.sub.8 is a carbon ring atom);
[0185] wherein the ab). cycloalkyl, ac). cycloalkenyl and ad).
heterocyclyl substituents (wherein the ad). heterocyclyl contains
at least one nitrogen ring atom) and the cycloalkyl portion of the
aa). substituent are optionally substituted with one to four
substituents independently selected from the group consisting of:
[0186] ba). C.sub.1-8 alkyl optionally substituted on a terminal
carbon atom with a substituent selected from the group consisting
of amino (with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-8 alkyl), (halo).sub.1-3
and hydroxy; [0187] bb). C.sub.1-8 alkoxy; [0188] bc). carbonyl
substituted with a substituent selected from the group consisting
of C.sub.1-8 alkyl, aryl, aryl(C.sub.1-8)alkyl,
aryl(C.sub.2-8)alkenyl, heteroaryl, heteroaryl(C.sub.1-8)alkyl and
heteroaryl(C.sub.2-8)alkenyl; [0189] bd). aryl; [0190] be).
heteroaryl; [0191] bf. amino substituted with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-8 alkyl; [0192] bh). halogen; [0193] bi). hydroxy; [0194]
bk). heterocyclyl; and, [0195] bl). sulfonyl substituted with a
substituent selected from the group consisting of C.sub.1-8 alkyl,
aryl, aryl(C.sub.1-8)alkyl, aryl(C.sub.2-8)alkenyl, heteroaryl,
heteroaryl(C.sub.1-8)alkyl and heteroaryl(C.sub.2-8)alkenyl; [0196]
wherein the bd). aryl, be). heteroaryl and bk). heterocyclyl
substituents and the aryl and heteroaryl portions of the bc).
substituent are optionally substituted with one to four
substituents independently selected from the group consisting of
C.sub.1-4 alkyl (optionally substituted on a terminal carbon atom
with a substituent selected from the group consisting of
(halo).sub.1-3), C.sub.1-4 alkoxy, amino (substituted with two
substituents independently selected from the group consisting of
hydrogen and C.sub.1-4 alkyl), halogen and hydroxy; [0197] and,
provided that the optional substituent attached to the ad).
heterocyclyl nitrogen ring atom is not selected from the group
consisting of bf). amino (substituted with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-8 alkyl), bh). halogen, bi). hydroxy and bj). nitro.
[0198] Preferably, R.sub.8 is selected from the group consisting of
aa). cycloalkyl(C.sub.1-4)alkyl, ab). cycloalkyl, ac). cycloalkenyl
and ad). heterocyclyl (wherein the point of attachment for the ad).
heterocyclyl at R.sub.8 is a carbon ring atom; and, the ad).
heterocyclyl contains a single nitrogen ring atom); wherein the
ab). cycloalkyl, ac). cycloalkenyl and ad). heterocyclyl
substituents and the cycloalkyl portion of the aa). substituent are
optionally substituted with one to two substituents independently
selected from the group consisting of ba). C.sub.1-4 alkyl, bc).
carbonyl (substituted with a substituent selected from the group
consisting of C.sub.1-4 alkyl, aryl, aryl(C.sub.1-4)alkyl and
aryl(C.sub.2-4)alkenyl) and bd). aryl; wherein the bd). aryl
substituent and the aryl portions of the bc). substituent are
optionally substituted with one to two substituents independently
selected from the group consisting of C.sub.1-4 alkyl, C.sub.1-4
alkoxy, di(C.sub.1-4 alkyl)amino, halogen, hydroxy and
(halo).sub.1-3(C.sub.1-4)alkyl.
[0199] More preferably, R.sub.8 is selected from the group
consisting of aa). adamant-1-yl methyl, ab). cyclopentyl, ab).
cyclohexyl, ac). cyclohexenyl, ad). pyrrolidinyl and ad).
piperidinyl (wherein the point of attachment for pyrrolidinyl and
piperidinyl at R.sub.8 is a carbon ring atom); wherein ab).
cyclohexyl, ac). cyclohexenyl, ad). pyrrolidinyl and ad).
piperidinyl are optionally substituted with one to two substituents
independently selected from the group consisting of ba). C.sub.1-4
alkyl, bc). carbonyl (substituted with a substituent selected from
the group consisting of C.sub.1-4 alkyl, aryl, aryl(C.sub.1-4)alkyl
and aryl(C.sub.2-4)alkenyl) and bd). aryl; wherein the bd). aryl
substituent and the aryl portions of the bc). substituent are
optionally substituted with one to two substituents independently
selected from the group consisting of C.sub.1-4 alkyl, C.sub.1-4
alkoxy, di(C.sub.1-4 alkyl)amino, halogen, hydroxy and
(halo).sub.1-3(C.sub.1-4)alkyl.
[0200] Most preferably, R.sub.8 is selected from the group
consisting of aa). adamant-1-ylmethyl, ab). cyclopentyl, ab).
cyclohexyl, ac). cyclohexenyl, ad). pyrrolidinyl and ad).
piperidinyl (wherein the point of attachment for pyrrolidinyl and
piperidinyl at R.sub.8 is a carbon ring atom); wherein ab).
cyclohexyl, ac). cyclohexenyl, ad). pyrrolidinyl and ad).
piperidinyl are optionally substituted with one to two substituents
independently selected from the group consisting of ba). methyl,
ba). t-butyl, bc). methylcarbonyl, bc). i-propylcarbonyl, bc).
phenylcarbonyl, bc). naphthalenylcarbonyl, bc). phenethylcarbonyl,
bc). phenethenylcarbonyl and bd). phenyl; and, wherein the bd).
phenyl substituent and the phenyl and naphthalenyl portions of the
bc). substituent are optionally substituted with one to two
substituents independently selected from the group consisting of
methyl, methoxy, N,N-dimethylamino, fluorine, bromine, hydroxy and
trifluoromethyl.
[0201] Embodiments of the present invention include those compounds
wherein R.sub.2 and R.sub.3 are attached to the benzene ring (shown
in Formula I) on adjacent carbon atoms. Preferred embodiments of
the present invention include those compounds wherein R.sub.2 and
R.sub.3 are independently selected from the group consisting of
ca). hydrogen, cb). C.sub.1-4 alkyl, cc). C.sub.1-4 alkoxy, cd).
C.sub.2-4 alkenyl, ce). amino (substituted with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-4 alkyl), cf). halogen and cg). hydroxy; optionally R.sub.2
and R.sub.3 together form at least one ring fused to the benzene
ring; thereby providing a multiple ring system; wherein the
multiple ring system is selected from the group consisting of
naphthalene and anthracene; and, wherein the multiple ring system
can optionally be substituted with one to four substituents
independently selected from the group consisting of da). C.sub.1-4
alkyl, db). C.sub.1-4 alkoxy, dc). amino (substituted with two
substituents independently selected from the group consisting of
hydrogen and C.sub.1-4 alkyl), dd). halogen and de). hydroxy.
[0202] More preferably, R.sub.2 and R.sub.3 are attached to the
benzene ring on adjacent carbon atoms and independently selected
from the group consisting of ca). hydrogen, cb). C.sub.1-4 alkyl,
cd). C.sub.2-4 alkenyl, cf). halogen and cg). hydroxy; optionally,
R.sub.2 and R.sub.3 together form at least one ring fused to the
benzene ring; thereby providing a multiple ring system; wherein the
multiple ring system is naphthalene; and, wherein the multiple ring
system can optionally be substituted with one to four substituents
independently selected from the group consisting of da). C.sub.1-4
alkyl, db). C.sub.1-4 alkoxy, dc). amino (substituted with two
substituents independently selected from the group consisting of
hydrogen and C.sub.1-4 alkyl), dd). halogen and de). hydroxy.
[0203] Most preferably, the multiple ring system is a
non-substituted naphthalene.
[0204] Embodiments of the present invention include those compounds
wherein R.sub.4 is selected from the group consisting of aryl and
heteroaryl optionally substituted with one to two substituents
independently selected from the group consisting of C.sub.1-4
alkyl, amino (substituted with two substituents independently
selected from the group consisting of hydrogen and C.sub.1-4
alkyl), cyano, halogen, hydroxy and
(halo).sub.1-3(C.sub.1-8)alkyl.
[0205] Preferably, R.sub.4 is selected from the group consisting of
aryl and heteroaryl (wherein heteroaryl is optionally substituted
with one to two substituents independently selected from the group
consisting of C.sub.1-4 alkyl, amino (substituted with two
substituents independently selected from the group consisting of
hydrogen and C.sub.1-4 alkyl), cyano, halogen, hydroxy and
(halo).sub.1-3(C.sub.1-8)alkyl).
[0206] More preferably, R.sub.4 is selected from the group
consisting of phenyl, naphthalenyl and benzothienyl (wherein
benzothienyl is optionally substituted with one to two halogen
substituents).
[0207] Most preferably, R.sub.4 is selected from the group
consisting of phenyl, naphthalenyl and benzothienyl (wherein
benzothienyl is optionally substituted with a chloro
substituent).
[0208] Embodiments of the present invention include those compounds
wherein R.sub.5 is selected from the group consisting of hydrogen
and C.sub.1-4 alkyl (optionally substituted on a terminal carbon
atom with a substituent selected from the group consisting of amino
(substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-4 alkyl), (halo).sub.1-3
and hydroxy).
[0209] Preferably, R.sub.5 is selected from the group consisting of
hydrogen and C.sub.1-4 alkyl.
[0210] More preferably, R.sub.5 is selected from the group
consisting of hydrogen and methyl.
[0211] Most preferably, R.sub.5 is hydrogen.
[0212] Preferred embodiments of the present invention include those
compounds wherein R.sub.6 is selected from the group consisting of
C.sub.1-4 alkyl, aryl(C.sub.1-4)alkyl, C.sub.1-4 alkoxy,
aryl(C.sub.1-4)alkoxy, C.sub.2-4 alkenyl, C.sub.2-4 alkenyloxy,
aryl(C.sub.2-4)alkenyl, aryl(C.sub.2-4)alkenyloxy, aryl, aryloxy
and hydroxy.
[0213] More preferably, R.sub.6 is selected from the group
consisting of methyl, methoxy, phenyloxy and hydroxy.
[0214] Most preferably, R.sub.6 is selected from the group
consisting of methyl and hydroxy.
[0215] Preferred embodiments of the present invention include those
compounds wherein Y is not present and X is one substituent
attached by a double-bond selected from the group consisting of O,
S, imino, (C.sub.1-4)alkylimino and hydroxyimino.
[0216] More preferably, Y is not present and X is one substituent
attached by a double-bond selected from the group consisting of O,
imino and hydroxyimino.
[0217] Most preferably, Y is not present and X is O attached by a
double-bond.
[0218] Preferred embodiments of the present invention include those
compounds wherein Z is selected from the group consisting of
hydrogen and C.sub.1-4 alkyl.
[0219] More preferably, Z is hydrogen.
[0220] Embodiments of the present invention include those compounds
of Formula (Ia) shown in Table 1.
TABLE-US-00001 TABLE 1 Formula (Ia) ##STR00012## wherein R.sub.5,
R.sub.7 and R.sub.8 are dependently selected from the group
consisting of: Cpd R.sub.7 R.sub.8 1 CH.sub.3 4-phenylcyclohexyl 2
CH.sub.3 1-(2-naphthalenylcarbonyl)-4-piperidinyl 3 CH.sub.3
1-[(6-methoxy-2-naphthalenyl)carbonyl]-3-pyrrolidinyl 4 CH.sub.3
1-[(6-bromo-2-naphthalenyl)carbonyl]-4-piperidinyl 5 CH.sub.3
1-[3-(4-fluorophenyl)-1-oxo-2-propenyl]-3-pyrrolidinyl 6 CH.sub.3
1-[1-oxo-3-phenyl-2-propenyl]-4-piperidinyl 9 CH.sub.3
1-[3-(4-methylphenyl)-1-oxo-2-propenyl]-4-piperidinyl 10 CH.sub.3
1-[1-oxo-3-[4-(trifluoromethyl)phenyl]-2-propenyl]-4- piperidinyl
13 CH.sub.3 1-[3-[4-(dimethylamino)phenyl]-1-oxo-2-propenyl]-4-
piperidinyl 15 CH.sub.3 1-benzoyl-4-piperidinyl 17 CH.sub.3
Cyclohexyl 18 CH.sub.3
1-[1-oxo-3-[4-(trifluoromethyl)phenyl]propyl]-4-piperidinyl 20
CH.sub.3 1-(2-methyl-1-oxopropyl)-4-piperidinyl 21 CH.sub.3
Cyclopentyl 22 CH.sub.3 4-(1,1-dimethylethyl)cyclohexyl 24 CH.sub.3
1-[(6-hydroxy-2-naphthalenyl)carbonyl]-4-piperidinyl 26 CH.sub.3
1-acetyl-4-piperidinyl 27 CH.sub.3 4-methylcyclohexyl 28 CH.sub.3
adamant-1-ylmethyl 29 CH.sub.3 4-phenyl-3-cyclohexen-1-yl And, 30 H
1-(2-naphthalenylcarbonyl)-4-piperidinyl
and racemates, enantiomers, diastereomers and salts thereof.
[0221] Embodiments of the present invention include those compounds
of Formula (Ib) shown in Table 2.
TABLE-US-00002 TABLE 2 Formula (Ib) ##STR00013## wherein R.sub.1 is
selected from the group consisting of: Cpd R.sub.1 7
4-phenyl-1-piperidinyl 8
4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl 12
4-(4-methoxyphenyl)-1-piperidinyl 14
4-(3-methoxyphenyl)-1-piperidinyl 16
4-(2-benzothiazolyl)-1-piperidinyl 19 3-phenyl-1-pyrrolidinyl and,
25 3-(2-phenylethyl)-1-pyrrolidinyl
and racemates, enantiomers, diastereomers and salts thereof.
[0222] Embodiments of the present invention include those compounds
of Formula (Ic) shown in Table 3.
TABLE-US-00003 TABLE 3 Formula (Ic) ##STR00014## wherein R.sub.2,
R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are dependently selected from
the group consisting of: Cpd R.sub.2 R.sub.3 R.sub.4 R.sub.5
R.sub.6 11 taken together to form phenyl H OH phenyl 23 taken
together to form 1-naphthalenyl CH.sub.3 OH phenyl 31 H H
1-naphthalenyl H OH 32 taken together to form 1-naphthalenyl H
CH.sub.3 phenyl And, 33 taken together to form
5-chloro-benzo[b]thien-3-yl H OH phenyl
and racemates, enantiomers, diastereomers and salts thereof.
[0223] In embodiments for Formula (II) the preferred embodiments of
R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as previously
described.
[0224] Preferably, R.sub.10 is selected from the group consisting
of [0225] a). sulfonyl substituted with a substituent selected from
the group consisting of C.sub.1-8 alkyl, aryl,
aryl(C.sub.1-8)alkyl, aryl(C.sub.2-8)alkenyl, cycloalkyl,
cycloalkenyl, heterocycl, heteroaryl, heteroaryl(C.sub.1-8)alkyl
and heteroaryl(C.sub.2-8)alkenyl; [0226] b). carbonyl substituted
with a substituent selected from the group consisting of C.sub.1-8
alkyl, aryl, aryl(C.sub.1-8)alkyl, aryl(C.sub.2-8)alkenyl,
cycloalkyl, cycloalkenyl, heterocycl heteroaryl,
heteroaryl(C.sub.1-8)alkyl, heteroaryl(C.sub.2-8)alkenyl,
--OR.sub.11 and amino (with two substituents independently selected
from the group consisting of hydrogen, C.sub.1-8 alkyl, aryl,
arylC.sub.1-8 alkyl, arylcarbonyl, arylC.sub.1-8 alkyl carbonyl and
heteroaryl C.sub.1-8 alkyl); [0227] c). C.sub.1-8 alkyl optionally
substituted on a terminal carbon atom with a substituent selected
from the group consisting of aryl, cycloalkyl, cycloalkenyl,
heterocycl, heteroaryl, (halo).sub.1-3, hydroxy, --C(O)R.sub.12 and
amino (with two substituents independently selected from the group
consisting of hydrogen, C.sub.1-8 alkyl, arylC.sub.1-8 alkyl,
arylcarbonyl, arylC.sub.1-8 alkyl carbonyl and heteroaryl C.sub.1-8
alkyl); [0228] d). aryl; and [0229] e). heteroaryl; [0230] wherein
the heterocycl, cycloalkyl, cycloalkenyl portion of a)., b)., and
c). are optionally substituted with one to two substituents
independently selected from the group consisting of: [0231] ea).
oxo [0232] eb). carbonyl substituted with a substituent selected
from the group consisting of C.sub.1-8 alkyl, aryl,
aryl(C.sub.1-8)alkyl, aryl(C.sub.2-8)alkenyl, cycloalkyl,
cycloalkenyl, heterocycl heteroaryl, heteroaryl(C.sub.1-8)alkyl,
heteroaryl(C.sub.2-8)alkenyl and amino (with two substituents
independently selected from the group consisting of hydrogen,
C.sub.1-8 alkyl, arylC.sub.1-8 alkyl, arylcarbonyl, arylC.sub.1-8
alkyl carbonyl and heteroaryl C.sub.1-8 alkyl); [0233] ec).
C.sub.1-8 alkyl optionally substituted with a substituent selected
from the group consisting of amino (with two substituents
independently selected from the group consisting of hydrogen,
C.sub.1-8 alkyl, arylC.sub.1-8 alkyl, arylcarbonyl, arylC.sub.1-8
alkyl carbonyl and heteroaryl C.sub.1-8 alkyl), aryl, cycloalkyl,
cycloalkenyl, heterocycl, heteroaryl, (halo).sub.1-3, and hydroxy;
[0234] ed). aryl; and [0235] ef). (halo).sub.1-3 [0236] wherein the
aryl portion of the a)., b)., c)., ec). and ed). substituents, the
heteroaryl portion of the a)., b)., c). and ec). substituents and
the d). aryl and e). heteroaryl substituents are optionally
substituted with one to four substituents independently selected
from the group consisting of [0237] fa). C.sub.1-4 alkyl optionally
substituted on a terminal carbon atom with a substituent selected
from the group consisting of aryl, cycloalkyl, cycloalkenyl,
heterocycl, heteroaryl, (halo).sub.1-3, hydroxy, --C(O)R.sub.12 and
amino (with two substituents independently selected from the group
consisting of hydrogen, C.sub.1-8 alkyl, arylC.sub.1-8 alkyl,
arylcarbonyl, arylC.sub.1-8 alkyl carbonyl and heteroaryl C.sub.1-8
alkyl); [0238] fb). C.sub.2-4 alkenyl optionally substituted on a
terminal carbon atom with a substituent selected from the group
consisting of amino (with two substituents independently selected
from the group consisting of hydrogen and C.sub.1-8 alkyl),
(halo).sub.1-3 and hydroxy; [0239] fc). C.sub.1-4 alkoxy optionally
substituted on a terminal carbon atom with a substituent selected
from the group consisting of (halo).sub.1-3 and hydroxy; [0240]
fd). cycloalkyl, [0241] fe). heterocyclyl, [0242] ff). aryl
optionally substituted with one to four substituents independently
selected from the group consisting of C.sub.1-8 alkyl and halogen;
[0243] fg). heteroaryl, [0244] fh). hydroxy; [0245] fi). hydroxy;
[0246] fj). nitro; and [0247] fk). (halo).sub.1-3; [0248] wherein
the aryl portion of the arylC.sub.1-8 alkyl, arylcarbonyl,
arylC.sub.1-8 alkyl carbonyl of fa). are optionally substituted
with one to four substituents independently selected from the group
consisting of C.sub.1-4 alkyl (optionally substituted on a terminal
carbon atom with a substituent selected from the group consisting
of amino (substituted with two substituents independently selected
from the group consisting of hydrogen and C.sub.1-8 alkyl),
(halo).sub.1-3 and hydroxy), C.sub.1-4 alkoxy (optionally
substituted on a terminal carbon atom with a substituent selected
from the group consisting of (halo).sub.1-3), amino (substituted
with two substituents independently selected from the group
consisting of hydrogen and C.sub.1-4 alkyl), halogen, hydroxy and
nitro.
[0249] Preferably, R.sub.11 is selected from the group consisting
of: [0250] aa). C.sub.1-4 alkyl optionally substituted on a
terminal carbon atom with a substituent selected from the group
consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, amino
(with two substituents independently selected from the group
consisting of hydrogen and C.sub.1-4 alkyl), (halo).sub.1-3 and
hydroxy; [0251] wherein the cycloalkyl, heterocyclyl, aryl and
heteroaryl portions of the aa). substituent are optionally
substituted with one to four substituents independently selected
from the group consisting of: [0252] ba). C.sub.1-4 alkyl
optionally substituted on a terminal carbon atom with a substituent
selected from the group consisting of amino (with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-4 alkyl), (halo).sub.1-3 and hydroxy; [0253] bb). C.sub.1-4
alkoxy optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of carboxyl,
(halo).sub.1-3 and hydroxy; [0254] bc). carbonyl substituted with a
substituent selected from the group consisting of C.sub.1-4 alkyl,
aryl, aryl(C.sub.1-4)alkyl, aryl(C.sub.2-4)alkenyl, heteroaryl,
heteroaryl(C.sub.1-4)alkyl and heteroaryl(C.sub.2-4)alkenyl; [0255]
bd). aryl; [0256] be). heteroaryl; [0257] bf). amino substituted
with two substituents independently selected from the group
consisting of hydrogen and C.sub.1-4 alkyl; [0258] bh).
(halo).sub.1-3; [0259] bi). hydroxy; and [0260] bk). heterocyclyl
optionally substituted with one to two oxo substituents; and,
[0261] wherein the bd). aryl, be). heteroaryl and bk). heterocyclyl
substituents and the aryl and heteroaryl portions of the bc).
substituent are optionally substituted with one to four
substituents independently selected from the group consisting of
C.sub.1-4 alkyl (optionally substituted on a terminal carbon atom
with a substituent selected from the group consisting of amino
(substituted with two substituents independently selected from the
group consisting of hydrogen and C.sub.1-4 alkyl), (halo).sub.1-3
and hydroxy), C.sub.1-4 alkoxy (optionally substituted on a
terminal carbon atom with a substituent selected from the group
consisting of (halo).sub.1-3), amino (substituted with two
substituents independently selected from the group consisting of
hydrogen and C.sub.1-4 alkyl), halogen, hydroxy and nitro;
[0262] Preferably, R.sub.12 is selected from the group consisting
of C.sub.1-4 alkyl, aryl, aryl(C.sub.1-4)alkyl,
aryl(C.sub.2-4)alkenyl, cycloalkyl, cycloalkenyl, heterocycl
heteroaryl, heteroaryl(C.sub.1-4)alkyl,
heteroaryl(C.sub.2-4)alkenyl, --OR.sub.11 and amino (with two
substituents independently selected from the group consisting of
hydrogen, C.sub.1-4 alkyl, arylC.sub.1-4 alkyl, arylcarbonyl,
arylC.sub.1-4 alkyl carbonyl and heteroaryl C.sub.1-4 alkyl);
wherein the aryl, the heteroaryl portion of R.sub.12 are optionally
substituted with one to four substituents independently selected
from the group consisting of: [0263] fa). C.sub.1-4 alkyl
optionally substituted on a terminal carbon atom with a substituent
selected from the group consisting of aryl, cycloalkyl,
cycloalkenyl, heterocycl, heteroaryl, (halo).sub.1-3, hydroxy,
--C(O)R.sub.11 and amino (with two substituents independently
selected from the group consisting of hydrogen, C.sub.1-8 alkyl,
arylC.sub.1-4 alkyl, arylcarbonyl, arylC.sub.1-4 alkyl carbonyl and
heteroaryl C.sub.1-4 alkyl); [0264] fb). C.sub.2-4 alkenyl
optionally substituted on a terminal carbon atom with a substituent
selected from the group consisting of amino (with two substituents
independently selected from the group consisting of hydrogen and
C.sub.1-4 alkyl), (halo).sub.1-3 and hydroxy; [0265] fc). C.sub.1-4
alkoxy optionally substituted on a terminal carbon atom with a
substituent selected from the group consisting of (halo).sub.1-3
and hydroxy; [0266] fd). cycloalkyl, [0267] fe). heterocyclyl,
[0268] ff). aryl optionally substituted with one to four
substituents independently selected from the group consisting of
C.sub.1-4 alkyl and halogen; [0269] fg). heteroaryl, [0270] fh).
(halo).sub.1-3; [0271] fi). hydroxy; and [0272] fj). nitro; [0273]
wherein the aryl portion of the arylC.sub.1-8 alkyl, arylcarbonyl,
arylC.sub.1-8 alkyl carbonyl of fa). are optionally substituted
with one to four substituents independently selected from the group
consisting of C.sub.1-4 alkyl (optionally substituted on a terminal
carbon atom with a substituent selected from the group consisting
of amino (substituted with two substituents independently selected
from the group consisting of hydrogen and C.sub.1-8 alkyl),
(halo).sub.1-3 and hydroxy), C.sub.1-4 alkoxy (optionally
substituted on a terminal carbon atom with a substituent selected
from the group consisting of (halo).sub.1-3), amino (substituted
with two substituents independently selected from the group
consisting of hydrogen and C.sub.1-4 alkyl), halogen, hydroxy and
nitro;
[0274] Embodiments of the present invention include those compounds
of Formula (IIa) shown in Table 4.
TABLE-US-00004 TABLE 4 ##STR00015## Cpd R.sub.10 37
naphthalene-2-yl-acetyl 38 2-naphthoyl 39 1-(4-hydroxyphenyl) 40
1-(4-methoxyphenyl) 41
N-[5-(sulfonyl)-thiophene-2-ylmethyl]-benzamide 42
6-chloro-5-sulfonyl-imidazo[2,1-b]thiazole 43
Naphthyl-2-aminocarbonyl 44 1-(4-fluorophenyl)
and racemates, enantiomers, diastereomers and salts thereof.
[0275] The compounds of the present invention may also be present
in the form of pharmaceutically acceptable salts. For use in
medicine, the salts of the compounds of this invention refer to
non-toxic "pharmaceutically acceptable salts." FDA approved
pharmaceutically acceptable salt forms (Ref. International J.
Pharm. 1986, 33, 201-217; J. Pharm. Sci., 1977, January, 66(1), p
1) include pharmaceutically acceptable acidic/anionic or
basic/cationic salts.
[0276] Pharmaceutically acceptable acidic/anionic salts include,
and are not limited to acetate, benzenesulfonate, benzoate,
bicarbonate, bitartrate, bromide, calcium edetate, camsylate,
carbonate, chloride, citrate, dihydrochloride, edetate, edisylate,
estolate, esylate, fumarate, glyceptate, gluconate, glutamate,
glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,
hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,
lactobionate, malate, maleate, mandelate, mesylate, methylbromide,
methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate,
pantothenate, phosphate/diphospate, polygalacturonate, salicylate,
stearate, subacetate, succinate, sulfate, tannate, tartrate,
teoclate, tosylate and triethiodide. Organic or inorganic acids
also include, and are not limited to, hydriodic, perchloric,
sulfuric, phosphoric, propionic, glycolic, methanesulfonic,
hydroxyethanesulfonic, oxalic, 2-naphthalenesulfonic,
p-toluenesulfonic, cyclohexanesulfamic, saccharinic or
trifluoroacetic acid.
[0277] Pharmaceutically acceptable basic/cationic salts include,
and are not limited to aluminum,
2-amino-2-hydroxymethyl-propane-1,3-diol (also known as
tris(hydroxymethyl)aminomethane, tromethane or "TRIS"), ammonia,
benzathine, t-butylamine, calcium, calcium gluconate, calcium
hydroxide, chloroprocaine, choline, choline bicarbonate, choline
chloride, cyclohexylamine, diethanolamine, ethylenediamine,
lithium, LiOMe, L-lysine, magnesium, meglumine, NH.sub.3,
NH.sub.4OH, N-methyl-D-glucamine, piperidine, potassium,
potassium-t-butoxide, potassium hydroxide (aqueous), procaine,
quinine, SEH, sodium, sodium carbonate, sodium-2-ethylhexanoate,
sodium hydroxide, triethanolamine (TEA) or zinc.
[0278] Compounds of the present invention may be contacted with a
pharmaceutically acceptable cation selected from the group
consisting of aluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol
(also known as tris(hydroxymethyl)aminomethane, tromethane or
"TRIS"), ammonia, benzathine, t-butylamine, calcium, calcium
gluconate, calcium hydroxide, chloroprocaine, choline, choline
bicarbonate, choline chloride, cyclohexylamine, diethanolamine,
ethylenediamine, lithium, LiOMe, L-lysine, magnesium, meglumine,
NH.sub.3, NH.sub.4OH, N-methyl-D-glucamine, piperidine, potassium,
potassium-t-butoxide, potassium hydroxide (aqueous), procaine,
quinine, SEH, sodium, sodium carbonate, sodium-2-ethylhexanoate,
sodium hydroxide, triethanolamine (TEA) and zinc to form a
salt.
[0279] Preferred cations for use with the instant compounds are
selected from the group consisting of benzathine, t-butylamine,
calcium gluconate, calcium hydroxide, choline bicarbonate, choline
chloride, cyclohexylamine, diethanolamine, ethylenediamine, LiOMe,
L-lysine, NH.sub.3, NH.sub.4OH, N-methyl-D-glucamine, piperidine,
potassium-t-butoxide, potassium hydroxide (aqueous), procaine,
quinine, sodium carbonate, sodium-2-ethylhexanoate, sodium
hydroxide, triethanolamine and tromethane.
[0280] More preferably, cations for use with the instant compounds
are selected from the group consisting of t-butylamine, NH.sub.4OH
and tromethane.
[0281] Most preferably, the cation for use with the instant
compounds is tromethane.
[0282] The present invention includes within its scope prodrugs of
the compounds of this invention. In general, such prodrugs will be
functional derivatives of the compounds, which are readily
convertible in vivo into an active compound. Thus, in the methods
of treatment of the present invention, the term "administering"
shall encompass the treatment of the various disorders described
with the compound specifically disclosed or a prodrug compound
which would be obviously included within the scope of the invention
although not specifically disclosed including, but not limited to
diphenylphosphonate or diphenylphosphinate esters of certain of the
instant compounds. Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for
example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
Phosphonic acid prodrugs (as described in De Lombaert S., et al,
Non-Peptidic Inhibitors of Neutral Endopeptidase 24.11; Design and
Pharmacology of Orally Active Phosphonate Prodrugs, Bioorganic and
Medicinal Chemistry Letters, 1995, 5(2), 151-154; and, De Lombaert
S., et al, N-Phosphonomethyl Dipeptides and Their Phosphonate
Prodrugs, a New Generatrion Neutral Endopeptidase (NEP, EC
3.424.11) Inhibitors, J. Med. Chem., 1994, 37, 498-511) and
phosphinic acid prodrugs are intended to be included within the
scope of the present invention.
[0283] The compounds according to this invention may have at least
one chiral center and thus may exist as enantiomers. In addition,
the compounds of the present invention may also possess two or more
chiral centers and thus may also exist as diastereomers. Where the
processes for the preparation of the present compounds give rise to
a mixture of stereoisomers, these isomers may be separated by
conventional techniques such as preparative chromatography.
Accordingly, the compounds may be prepared as a racemic mixture or,
by either enantiospecific synthesis or resolution, as individual
enantiomers. The compounds may, for example, be resolved from a
racemic mixture into their component racemates by standard
techniques, such as the formation of diastereomeric pairs by salt
formation with an optically active base, followed by fractional
crystallization and regeneration of the compounds of this
invention. The racemic mixture may also be resolved by formation of
diastereomeric esters or amides, followed by chromatographic
separation and removal of the chiral auxiliary. Alternatively, the
compounds may be resolved using a chiral HPLC column. It is to be
understood that all such isomers and mixtures thereof are
encompassed within the scope of the present invention.
[0284] The compounds according to this invention wherein Z forms a
double bond with the carbon of attachment for X, Y is not present
and X is hydroxy may have at least one keto-enol tautomeric form
and thus may exist in equilibrium as geometric isomers. It is to be
understood that all such isomers and mixtures thereof are
encompassed within the scope of the present invention.
[0285] During any of the processes for preparation of the compounds
of the present invention, it may be necessary and/or desirable to
protect sensitive or reactive groups on any of the molecules
concerned. This may be achieved by means of conventional protecting
groups, such as those described in Protective Groups in Organic
Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.
Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis,
John Wiley & Sons, 1991. The protecting groups may be removed
at a convenient subsequent stage using methods known in the
art.
[0286] Furthermore, some of the crystalline forms for the compounds
may exist as polymorphs and as such are intended to be included in
the present invention. In addition, some of the compounds may form
solvates with water (i.e., hydrates) or common organic solvents,
and such solvates are also intended to be encompassed within the
scope of this invention.
[0287] As used herein, unless otherwise noted, "alkyl" whether used
alone or as part of a substituent group refers to straight and
branched carbon chains having 1 to 8 carbon atoms or any number
within this range. The term "alkoxy" refers to an --O-alkyl
substituent group, wherein alkyl is as defined supra. Similarly,
the terms "alkenyl" and "alkynyl" refer to straight and branched
carbon chains having 2 to 8 carbon atoms or any number within this
range, wherein an alkenyl chain has at least one double bond in the
chain and an alkynyl chain has at least one triple bond in the
chain. An alkyl and alkoxy chain may be substituted on a terminal
carbon atom or, when acting as a linking group, within the carbon
chain.
[0288] The term "cycloalkyl" refers to saturated, moncyclic or
polycyclic hydrocarbon rings of from 3 to 20 carbon atom members
(preferably from 3 to 12 carbon atom members). Further, a
cycloalkyl ring may optionally be fused to one or more cycloalkyl
rings. Examples of such rings include, and are not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or
adamantyl.
[0289] The term "cycloalkenyl" refers to partially unsaturated,
nonaromatic moncyclic or polycyclic hydrocarbon rings of 3 to 20
carbon atom members (preferably from 3 to 12 carbon atom members).
Typically, a 3 to 5 member ring contains one double bond and a 6 to
9 member ring contains multiple double bonds. Further, a
cycloalkenyl ring may optionally be fused to one or more cycloalkyl
rings or cycloalkenyl rings. Examples of such rings include, and
are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl,
cyclohexenyl, or cycloheptenyl.
[0290] The term "heterocyclyl" refers to a nonaromatic cyclic ring
of 5 to 8 members in which 1 to 4 members are nitrogen or a
nonaromatic cyclic ring of 5 to 8 members in which zero, one or two
members are nitrogen and one member is oxygen or sulfur; wherein,
optionally, the ring contains zero, one or two unsaturated bonds.
Alternatively, the heterocyclyl ring may be fused to a benzene ring
(benzo fused heterocyclyl), a 5 or 6 membered heteroaryl ring
(containing one of O, S or N and, optionally, one additional
nitrogen), a 5 to 7 membered cycloalkyl or cycloalkenyl ring, a 5
to 7 membered heterocyclyl ring (of the same definition as above
but absent the option of a further fused ring) or fused with the
carbon of attachment of a cycloalkyl, cycloalkenyl or heterocyclyl
ring to form a spiro moiety. For instant compounds of the
invention, the carbon atom ring members that form the heterocyclyl
ring are fully saturated. Other compounds of the invention may have
a partially saturated heterocyclyl ring. Additionally, the
heterocyclyl can be bridged to form bicyclic rings. Preferred
partially saturated heterocyclyl rings may have from one to two
double bonds. Such compounds are not considered to be fully
aromatic and are not referred to as heteroaryl compounds. Examples
of heterocyclyl groups include, and are not limited to, pyrrolinyl
(including 2H-pyrrole, 2-pyrrolinyl or 3-pyrrolinyl), pyrrolidinyl,
2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl,
piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl. In the
present invention, when R.sub.1 is selected from heterocyclyl, the
term "heterocyclyl" refers to a nonaromatic cyclic ring of 5 to 8
members in which 1 to 4 members are nitrogen; wherein, the point of
attachment for the heterocyclyl ring at R.sub.1 is a nitrogen ring
member; and, wherein optionally the ring contains zero, one (for 5
and 6 member rings) or two (for 6, 7 and 8 member rings)
unsaturated bonds.
[0291] The term "aryl" refers to an unsaturated, aromatic
monocyclic ring of 6 carbon members or to an unsaturated, aromatic
polycyclic ring of from 10 to 20 carbon members. Further, an aryl
ring may optionally be fused to one or more benzene rings (benzo
fused aryl), cycloalkyl rings (e.g. benzo fused cycloalkyl) or
cycloalkenyl rings (e.g. benzo fused cycloalkenyl) wherein, for the
purpose of these definitions, the cycloalkyl rings and cycloalkenyl
rings may be fused to an additional benzene ring (to provide fused
multiple ring systems such as fluorene). Examples of such aryl
rings include, and are not limited to, phenyl, naphthalenyl,
fluorenyl, indenyl or anthracenyl.
[0292] The term "heteroaryl" refers to an aromatic ring of 5 or 6
members wherein the ring consists of carbon atoms and has at least
one heteroatom member. Suitable heteroatoms include nitrogen,
oxygen or sulfur. In the case of 5 membered rings, the heteroaryl
ring contains one member of nitrogen, oxygen or sulfur and, in
addition, may contain up to two additional nitrogens. In the case
of 6 membered rings, the heteroaryl ring may contain from one to
three nitrogen atoms. For the case wherein the 6 member ring has
three nitrogens, at most two nitrogen atoms are adjacent.
Optionally, the heteroaryl ring is fused to a benzene ring (benzo
fused heteroaryl), a 5 or 6 membered heteroaryl ring (containing
one of O, S or N and, optionally, one additional nitrogen), a 5 to
7 membered alicyclic ring or a 5 to 7 membered heterocyclo ring (as
defined supra but absent the option of a further fused ring).
Examples of heteroaryl groups include, and are not limited to,
furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,
thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl;
fused heteroaryl groups include indolyl, isoindolyl, indolinyl,
benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl,
benzoxazolyl, benzisoxazolyl, benzothiadiazolyl, benzotriazolyl,
quinolizinyl, quinolinyl, isoquinolinyl or quinazolinyl.
[0293] The term "arylalkyl" means an alkyl group substituted with
an aryl group (e.g., benzyl, phenethyl). Similarly, the term
"arylalkoxy" indicates an alkoxy group substituted with an aryl
group (e.g., benzyloxy).
[0294] As used herein, the term "carboxyl" refers to the linking
group --C(O)O-- or (when used accordingly) to the substituent
--COOH; the term "imino" refers to the substituent HN.dbd..
[0295] Whenever the term "alkyl" or "aryl" or either of their
prefix roots appear in a name of a substituent (e.g., arylalkyl,
alkylamino) it shall be interpreted as including those limitations
given above for "alkyl" and "aryl." Designated numbers of carbon
atoms (e.g., C.sub.1-C.sub.6) shall refer independently to the
number of carbon atoms in an alkyl moiety or to the alkyl portion
of a larger substituent in which alkyl appears as its prefix root.
However, for clarity in the terms "C.sub.9-C.sub.14 benzo fused
cycloalkyl", "C.sub.9-C.sub.14 benzo fused cycloalkenyl",
"C.sub.9-C.sub.14 benzo fused aryl"; C.sub.9-C.sub.14 refers to the
number of carbon atoms both in the benzene ring (6) and the number
of atoms in the ring fused to the benzene ring, but does not
include carbon atoms that may be pendent from these multiple ring
systems. The amount of substituents attached to a moiety
"optionally substituted with one to five substituents" is limited
to that amount of open valences on the moiety available for
substitution.
[0296] In general, under standard nomenclature rules used
throughout this disclosure, the terminal portion of the designated
side chain is described first followed by the adjacent
functionality toward the point of attachment. Thus, for example, a
"phenylC.sub.1-C.sub.6 alkylamidoC.sub.1-C.sub.6alkyl" substituent
refers to a group of the formula:
##STR00016##
[0297] It is intended that the definition of any substituent or
variable at a particular location in a molecule be independent of
its definitions elsewhere in that molecule. It is understood that
substituents and substitution patterns on the compounds of this
invention can be selected by one of ordinary skill in the art to
provide compounds that are chemically stable and that can be
readily synthesized by techniques known in the art as well as those
methods set forth herein.
[0298] Illustrative of the invention is a composition comprising a
pharmaceutically acceptable carrier and any of the compounds
described above. Also illustrative of the invention is a
composition made by mixing any of the compounds described above and
a pharmaceutically acceptable carrier. A further illustration of
the invention is a process for making a composition comprising
mixing any of the compounds described above and a pharmaceutically
acceptable carrier. The present invention also provides
compositions comprising one or more compounds of this invention in
association with a pharmaceutically acceptable carrier.
[0299] The compounds of the present invention are useful serine
protease inhibitors (in particular, inhibitors of cathepsin G and
chymase) useful for treating inflammatory and serine protease
mediated disorders. Some of these disorders include, inflammatory
and serine protease mediated disorders include, and are not limited
to, pulmonary inflammatory conditions, chronic obstructive
pulmonary diseases, asthma, pulmonary emphysema, bronchitis,
psoriasis, allergic rhinitis, viral rhinitis, ischemia, arthritis,
glomerulonephritis, postoperative adhesion formation and
reperfusion injury. These compounds would be useful in treating
disease states caused by angiotensin II including but not limited
to hypertension, hypercardia myocardial infarction,
arteriosclerosis, diabetic and non-diabetic retinopathy, vascular
restenosis and the like. Additionally, these compounds can be used
for immune modulation. The utility of the compounds to treat
inflammatory and serine protease mediated disorders can be
determined according to the procedures described herein.
[0300] An embodiment of the invention is a method for treating
inflammatory and serine protease mediated disorders in a subject in
need thereof which comprises administering to the subject a
therapeutically effective amount of any of the compounds or
compositions described above. Also included in the invention is the
use of a compound of Formula (I) for the preparation of a
medicament for treating an inflammatory or serine protease mediated
disorder in a subject in need thereof. The term "treating" as used
herein refers to a method for improving, halting, retarding or
palliating an inflammatory or serine protease mediated disorder in
the subject in need thereof. All such methods of treatment are
intended to be within the scope of the present invention.
[0301] In accordance with the methods of the present invention, the
individual components of the compositions described herein can also
be administered separately at different times during the course of
therapy or concurrently in divided or single combination forms. The
instant invention is therefore to be understood as embracing all
such regimes of simultaneous or alternating treatment and the term
"administering" is to be interpreted accordingly.
[0302] The term "subject" as used herein, refers to an animal
(preferably, a mammal; most preferably, a human) who has been the
object of treatment, observation or experiment.
[0303] The term "therapeutically effective amount" as used herein,
means that amount of active compound or pharmaceutical agent that
elicits the biological or medicinal response in a tissue system,
animal or human, that is being sought by a researcher,
veterinarian, medical doctor, or other clinician, which includes
alleviation of the symptoms of the disease or disorder being
treated.
[0304] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combinations of the specified ingredients in
the specified amounts.
[0305] To prepare the compositions of this invention, one or more
compounds of Formula (I) or salt thereof as the active ingredient,
is intimately admixed with a pharmaceutical carrier according to
conventional pharmaceutical compounding techniques, which carrier
may take a wide variety of forms depending of the form of
preparation desired for administration (e.g. oral or parenteral).
Suitable pharmaceutically acceptable carriers are well known in the
art. Descriptions of some of these pharmaceutically acceptable
carriers may be found in The Handbook of Pharmaceutical Excipients,
published by the American Pharmaceutical Association and the
Pharmaceutical Society of Great Britain.
[0306] Methods of formulating compositions have been described in
numerous publications such as Pharmaceutical Dosage Forms: Tablets,
Second Edition, Revised and Expanded, Volumes 1-3, edited by
Lieberman et al; Pharmaceutical Dosage Forms: Parenteral
Medications, Volumes 1-2, edited by Avis et al; and Pharmaceutical
Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et
al; published by Marcel Dekker, Inc.
[0307] In preparing a composition of the present invention in
liquid dosage form for oral, topical, inhalation/insufflation and
parenteral administration, any of the usual pharmaceutical media or
excipients may be employed. Thus, for liquid dosage forms, such as
suspensions (i.e. colloids, emulsions and dispersions) and
solutions, suitable carriers and additives include but are not
limited to pharmaceutically acceptable wetting agents, dispersants,
flocculation agents, thickeners, pH control agents (i.e. buffers),
osmotic agents, coloring agents, flavors, fragrances, preservatives
(i.e. to control microbial growth, etc.) and a liquid vehicle may
be employed. Not all of the components listed above will be
required for each liquid dosage form.
[0308] In solid oral preparations such as, for example, powders,
granules, capsules, caplets, gelcaps, pills and tablets (each
including immediate release, timed release and sustained release
formulations), suitable carriers and additives include but are not
limited to diluents, granulating agents, lubricants, binders,
glidants, disintegrating agents and the like. Because of their ease
of administration, tablets and capsules represent the most
advantageous oral dosage unit form, in which case solid
pharmaceutical carriers are obviously employed. If desired, tablets
may be sugar coated, gelatin coated, film coated or enteric coated
by standard techniques.
[0309] Preferably these compositions are in unit dosage forms from
such as tablets, pills, capsules, powders, granules, lozenges,
sterile parenteral solutions or suspensions, metered aerosol or
liquid sprays, drops, ampoules, autoinjector devices or
suppositories for administration by oral, intranasal, sublingual,
intraocular, transdermal, parenteral, rectal, vaginal, inhalation
or insufflation means. Alternatively, the composition may be
presented in a form suitable for once-weekly or once-monthly
administration; for example, an insoluble salt of the active
compound, such as the decanoate salt, may be adapted to provide a
depot preparation for intramuscular injection.
[0310] For preparing solid compositions such as tablets, the
principal active ingredient is mixed with a pharmaceutical carrier,
e.g. conventional tabletting ingredients such as diluents, binders,
adhesives, disintegrants, lubricants, antiadherents and glidants.
Suitable diluents include, but are not limited to, starch (i.e.
corn, wheat, or potato starch, which may be hydrolized), lactose
(granulated, spray dried or anhydrous), sucrose, sucrose-based
diluents (confectioner's sugar; sucrose plus about 7 to 10 weight
percent invert sugar; sucrose plus about 3 weight percent modified
dextrins; sucrose plus invert sugar, about 4 weight percent invert
sugar, about 0.1 to 0.2 weight percent cornstarch and magnesium
stearate), dextrose, inositol, mannitol, sorbitol, microcrystalline
cellulose (i.e. AVICEL.TM. microcrystalline cellulose available
from FMC Corp.), dicalcium phosphate, calcium sulfate dihydrate,
calcium lactate trihydrate and the like. Suitable binders and
adhesives include, but are not limited to accacia gum, guar gum,
tragacanth gum, sucrose, gelatin, glucose, starch, and cellulosics
(i.e. methylcellulose, sodium carboxymethycellulose,
ethylcellulose, hydroxypropylmethylcellulose,
hydroxypropylcellulose, and the like), water soluble or dispersible
binders (i.e. alginic acid and salts thereof, magnesium aluminum
silicate, hydroxyethylcellulose [i.e. TYLOSE.TM. available from
Hoechst Celanese], polyethylene glycol, polysaccharide acids,
bentonites, polyvinylpyrrolidone, polymethacrylates and
pregelatinized starch) and the like. Suitable disintegrants
include, but are not limited to, starches (corn, potato, etc.),
sodium starch glycolates, pregelatinized starches, clays (magnesium
aluminum silicate), celluloses (such as crosslinked sodium
carboxymethylcellulose and microcrystalline cellulose), alginates,
pregelatinized starches (i.e. corn starch, etc.), gums (i.e. agar,
guar, locust bean, karaya, pectin, and tragacanth gum),
cross-linked polyvinylpyrrolidone and the like. Suitable lubricants
and antiadherents include, but are not limited to, stearates
(magnesium, calcium and sodium), stearic acid, talc waxes,
stearowet, boric acid, sodium chloride, DL-leucine, carbowax 4000,
carbowax 6000, sodium oleate, sodium benzoate, sodium acetate,
sodium lauryl sulfate, magnesium lauryl sulfate and the like.
Suitable gildants include, but are not limited to, talc,
cornstarch, silica (i.e. CAB-O-SIL.TM. silica available from Cabot,
SYLOID.TM. silica available from W. R. Grace/Davison, and
AEROSIL.TM. silica available from Degussa) and the like. Sweeteners
and flavorants may be added to chewable solid dosage forms to
improve the palatability of the oral dosage form. Additionally,
colorants and coatings may be added or applied to the solid dosage
form for ease of identification of the drug or for aesthetic
purposes. These carriers are formulated with the pharmaceutical
active to provide an accurate, appropriate dose of the
pharmaceutical active with a therapeutic release profile.
[0311] Generally these carriers are mixed with the pharmaceutical
active to form a solid preformulation composition containing a
homogeneous mixture of the pharmaceutical active of the present
invention, or a pharmaceutically acceptable salt thereof. Generally
the preformulation will be formed by one of three common methods:
(a) wet granulation, (b) dry granulation and (c) dry blending. When
referring to these preformulation compositions as homogeneous, it
is meant that the active ingredient is dispersed evenly throughout
the composition so that the composition may be readily subdivided
into equally effective dosage forms such as tablets, pills and
capsules. This solid preformulation composition is then subdivided
into unit dosage forms of the type described above containing from
about 0.01 mg to about 500 mg of the active ingredient of the
present invention. The tablets or pills containing the novel
compositions may also be formulated in multilayer tablets or pills
to provide a sustained or provide dual-release products. For
example, a dual release tablet or pill can comprise an inner dosage
and an outer dosage component, the latter being in the form of an
envelope over the former. The two components can be separated by an
enteric layer, which serves to resist disintegration in the stomach
and permits the inner component to pass intact into the duodenum or
to be delayed in release. A variety of materials can be used for
such enteric layers or coatings, such materials including a number
of polymeric materials such as shellac, cellulose acetate,
cellulose acetate phthalate, polyvinyl acetate phthalate,
hydroxypropyl methylcellulose phthalate, hydroxypropyl
methylcellulose acetate succinate, methacrylate and ethylacrylate
copolymers and the like. Sustained release tablets may also be made
by film coating or wet granulation using slightly soluble or
insoluble substances in solution (which for a wet granulation acts
as the binding agents) or low melting solids a molten form (which
in a wet granulation may incorporate the active ingredient). These
materials include natural and synthetic polymers waxes,
hydrogenated oils, fatty acids and alcohols (i.e. beeswax, carnauba
wax, cetyl alcohol, cetylstearyl alcohol, and the like), esters of
fatty acids metallic soaps, and other acceptable materials that can
be used to granulate, coat, entrap or otherwise limit the
solubility of an active ingredient to achieve a prolonged or
sustained release product.
[0312] The liquid forms in which the novel compositions of the
present invention may be incorporated for administration orally or
by injection include, but are not limited to aqueous solutions,
suitably flavored syrups, aqueous or oil suspensions, and flavored
emulsions with edible oils such as cottonseed oil, sesame oil,
coconut oil or peanut oil, as well as elixirs and similar
pharmaceutical vehicles. Suitable suspending agents for aqueous
suspensions, include synthetic and natural gums such as, acacia,
agar, alginate (i.e. propylene alginate, sodium alginate and the
like), guar, karaya, locust bean, pectin, tragacanth, and xanthan
gum, cellulosics such as sodium carboxymethylcellulose,
methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropyl cellulose and hydroxypropyl methylcellulose, and
combinations thereof, synthetic polymers such as polyvinyl
pyrrolidone, carbomer (i.e. carboxypolymethylene), and polyethylene
glycol; clays such as bentonite, hectorite, attapulgite or
sepiolite; and other pharmaceutically acceptable suspending agents
such as lecithin, gelatin or the like. Suitable surfactants include
but are not limited to sodium docusate, sodium lauryl sulfate,
polysorbate, octoxynol-9, nonoxynol-10, polysorbate 20, polysorbate
40, polysorbate 60, polysorbate 80, polyoxamer 188, polyoxamer 235
and combinations thereof. Suitable deflocculating or dispersing
agent include pharmaceutical grade lecithins. Suitable flocculating
agent include but are not limited to simple neutral electrolytes
(i.e. sodium chloride, potassium, chloride, and the like), highly
charged insoluble polymers and polyelectrolyte species, water
soluble divalent or trivalent ions (i.e. calcium salts, alums or
sulfates, citrates and phosphates (which can be used jointly in
formulations as pH buffers and flocculating agents). Suitable
preservatives include but are not limited to parabens (i.e. methyl,
ethyl, n-propyl and n-butyl), sorbic acid, thimerosal, quaternary
ammonium salts, benzyl alcohol, benzoic acid, chlorhexidine
gluconate, phenylethanol and the like. There are many liquid
vehicles that may be used in liquid pharmaceutical dosage forms,
however, the liquid vehicle that is used in a particular dosage
form must be compatible with the suspending agent(s). For example,
nonpolar liquid vehicles such as fatty esters and oils liquid
vehicles are best used with suspending agents such as low HLB
(Hydrophile-Lipophile Balance) surfactants, stearalkonium
hectorite, water insoluble resins, water insoluble film forming
polymers and the like. Conversely, polar liquids such as water,
alcohols, polyols and glycols are best used with suspending agents
such as higher HLB surfactants, clays silicates, gums, water
soluble cellulosics, water soluble polymers and the like. For
parenteral administration, sterile suspensions and solutions are
desired. Liquid forms useful for parenteral administration include
sterile solutions, emulsions and suspensions. Isotonic preparations
which generally contain suitable preservatives are employed when
intravenous administration is desired.
[0313] Furthermore, compounds of the present invention can be
administered in an intranasal dosage form via topical use of
suitable intranasal vehicles or via transdermal skin patches, the
composition of which are well known to those of ordinary skill in
that art. To be administered in the form of a transdermal delivery
system, the administration of a therapeutic dose will, of course,
be continuous rather than intermittent throughout the dosage
regimen.
[0314] Compounds of the present invention can also be administered
in a form suitable for intranasal or inhalation therapy. For such
therapy, compounds of the present invention are conveniently
delivered in the form of a solution or suspension from a pump spray
container that is squeezed or pumped or as an aerosol spray from a
pressurized container or a nebulizer (such as, a metered dose
inhaler, a dry powder inhaler or other conventional or
non-conventional modes or devices for inhalation delivery) using a
suitable propellant (such as, dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide
or other suitable gas). In the case of a pressurized aerosol, the
dosage unit may be determined by providing a valve to deliver a
metered amount. The pressurized container or nebulizer may contain
a solution or suspension of the active compound. Capsules and
cartridges (such as, those made from gelatin) for use in an inhaler
or insufflator may be formulated containing a powder mix of a
compound of the invention and a suitable powder base such as
lactose or starch.
[0315] Compounds of the present invention can also be administered
in the form of liposome delivery systems, such as small unilamellar
vesicles, large unilamellar vesicles, multilamellar vesicles and
the like. Liposomes can be formed from a variety of phospholipids,
such as cholesterol, stearylamine, phosphatidylcholines and the
like.
[0316] Compounds of the present invention may also be delivered by
the use of monoclonal antibodies as individual carriers to which
the compound molecules are coupled. The compounds of the present
invention may also be coupled with soluble polymers as targetable
drug carriers. Such polymers can include, but are not limited to
polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropylmethacrylamidephenol,
polyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysine
substituted with palmitoyl residue. Furthermore, the compounds of
the present invention may be coupled to a class of biodegradable
polymers useful in achieving controlled release of a drug, for
example, to homopolymers and copolymers (which means polymers
containing two or more chemically distinguishable repeating units)
of lactide (which includes lactic acid d-, l- and meso lactide),
glycolide (including glycolic acid), .epsilon.-caprolactone,
p-dioxanone (1,4-dioxan-2-one), trimethylene carbonate
(1,3-dioxan-2-one), alkyl derivatives of trimethylene carbonate,
.delta.-valerolactone, .beta.-butyrolactone, .gamma.-butyrolactone,
.epsilon.-decalactone, hydroxybutyrate, hydroxyvalerate,
1,4-dioxepan-2-one (including its dimer
1,5,8,12-tetraoxacyclotetradecane-7,14-dione), 1,5-dioxepan-2-one,
6,6-dimethyl-1,4-dioxan-2-one, polyorthoesters, polyacetals,
polydihydropyrans, polycyanoacrylates and cross-linked or
amphipathic block copolymers of hydrogels and blends thereof.
[0317] The therapeutically effective amount of a compound or
composition thereof may be from about 0.001 mg/Kg/dose to about 300
mg/Kg/dose. Preferably, the therapeutically effective amount may be
from about 0.001 mg/Kg/dose to about 100 mg/Kg/dose. More
preferably, the therapeutically effective amount may be from about
0.001 mg/Kg/dose to about 50 mg/Kg/dose. Most preferably, the
therapeutically effective amount may be from about 0.001 mg/Kg/dose
to about 30 mg/Kg/dose. Therefore, the therapeutically effective
amount of the active ingredient contained per dosage unit (e.g.,
tablet, capsule, powder, injection, suppository, teaspoonful and
the like) as described herein will be in the range of from about 1
mg/day to about 21,000 mg/day for a subject, for example, having an
average weight of 70 Kg. For oral administration, the compositions
are preferably provided in the form of tablets containing, 0.01,
0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,
200, 250 and 500 milligrams of the active ingredient for the
symptomatic adjustment of the dosage to the subject to be
treated.
[0318] Optimal dosages to be administered may be readily determined
by those skilled in the art, and will vary with the particular
compound used, the mode of administration, the strength of the
preparation, and the advancement of the disease condition. In
addition, factors associated with the particular subject being
treated, including subject age, weight, diet and time of
administration, will result in the need to adjust the dose to an
appropriate therapeutic level. Advantageously, compounds of the
present invention may be administered in a single daily dose or the
total daily dosage may be administered in divided doses of two,
three or four times daily.
[0319] Representative IUPAC names for the compounds of the present
invention were derived using the ACD/LABS SOFTWARE.TM. Index Name
Pro Version 4.5 nomenclature software program provided by Advanced
Chemistry Development, Inc., Toronto, Ontario, Canada.
[0320] Abbreviations used in the instant specification,
particularly the Schemes and Examples, are as follows:
Boc=tert-butoxycarbonyl BuLi=n-butyllithium Cpd=compound
DCC=dicyclohexylcarbodiimide h=hour/hours HOBT=hydroxybenzotriazole
KH=potassium hydride Mel=methyliodide NT=not tested rt/RT=room
temperature TFA=trifluoroacetic acid TMSBr=bromotrimethylsilane
General Synthetic Methods
[0321] Representative compounds of the present invention can be
synthesized in accordance with the general synthetic methods
described below and are illustrated more particularly in the scheme
that follows. Since the scheme is an illustration, the invention
should not be construed as being limited by the chemical reactions
and conditions expressed. The preparation of the various starting
materials used in the schemes is well within the skill of persons
versed in the art.
Scheme A
[0322] Scheme A is illustrative of a general method for the
preparation of compounds of the invention by addition of a
phosphonate or phosphinate anion, prepared from a phosphonate or
phosphinate Compound A2, and an organometallic base such as
n-butyllithium, to an anhydride Compound A1 in a solvent such as
THF to afford a ketophosphonate or ketophosphinate Compound A3,
wherein Z is hydrogen, Y is not present and X is one oxygen
substituent attached by a double-bond to the carbon in the position
.beta. to R.sub.4.
[0323] Other compounds of the present invention may be obtained
from Compound A3 using standard ketone manipulations wherein the
.beta. position carbon may be reduced from the ketone to a compound
of Formula (I) wherein X and Y are both present or wherein Z is a
bond. Examples of ketone manipulations include, but are not limited
to, the use of 1) organometallic reagents to form alkoxy groups; 2)
hydroxylamines to form imino groups; and, 3) Lawesson's reagent to
substitute a thio group in place of the ketone (with appropriate
protecting groups added to the COOH group shown).
[0324] Compound A2, wherein R.sub.6 is as previously defined, can
be made according to known methods, such as those described in
Katritsky, et. al., Org. Prep. Proced. Int., 1990, 22(2), 209-213;
J. Am. Chem. Soc., 2002, 124, 9386-9387; and, Chem. Ber., 1963, 96,
3184-3194. In an embodiment of a general synthetic method, the
R.sub.5 substitutent of Compound A4 is hydrogen and the R.sub.6
substitutent is ethoxy.
[0325] Compound A2, wherein R.sub.4 is heteroaryl, can be prepared
from commercially available or known haloalkyl substituted
heteroaryl starting materials (such as
3-bromomethyl-5-Cl-benzothiophene used to prepare Cpd 33) using
techniques known to those skilled in the art.
[0326] Compound A3 may be coupled to the R.sub.1 portion of Formula
(I) using standard coupling reactions. For example, when R.sub.1 is
a secondary amine in a heterocyclyl ring, the nitrogen on the ring
may be coupled to Compound A3 (similar to the reaction shown in
Scheme A, e.g. the ring nitrogen in Compound A4 would be coupled
with Compound A8). Appropriate blocking groups can be employed to
minimize undesirable side reactions. Analogous coupling reactions
with Compound A3 can be performed when R.sub.1 is N(R.sub.7R.sub.8)
to couple the substituted amine to the carboxylic acid of Compound
A3. In one embodiment of the present invention the coupling
reaction of Compound A3 with R.sub.1 when R.sub.1 is
N(R.sub.7R.sub.8) and R.sub.8 is a heterocycle is provided to
further illustrate the present invention.
[0327] In Scheme A, the reaction of a suitably protected amino
substituted heterocycle Compound A4 (wherein the protected amino is
substituted with a hydrogen atom for R.sub.7 and an unsubstituted
ad). heterocycle for R.sub.8) with a Q-substituted R.sub.8a
Compound A5 (wherein Q is a suitable leaving group (such as, but
not limited to, a halogen atom) and R.sub.8a is a substituent as
previously defined in the R.sub.8 ba).-bl) list) in a solvent such
as DMF containing a base (such as, but not limited to,
triethylamine) provided an R.sub.8b substituted Compound A6.
[0328] In an embodiment of a general synthetic method, the
heterocyclyl portion of Compound A4 was further substituted on a
nitrogen ring atom by reaction with an acid chloride Compound A5,
wherein the Q portion was chlorine and wherein the R.sub.8a portion
was bc). carbonyl substituted with an R.sub.8b substituent selected
from C.sub.1-8alkyl, aryl, aryl(C.sub.1-8)alkyl,
aryl(C.sub.2-8)alkenyl, heteroaryl, heteroaryl(C.sub.1-8)alkyl or
heteroaryl(C.sub.2-8)alkenyl. In an alternate embodiment, the
reaction may performed by reaction with an acid chloride Compound
A5, wherein the Q portion is chlorine and wherein the R.sub.8a
portion is bl). sulfonyl substituted with an R.sub.8b substituent;
wherein R.sub.8b is as previously defined.
[0329] Treatment of Compound A6 with a base such as potassium
hydride followed by treatment with an R.sub.7X alkylating agent
such as iodomethane in a solvent such as THF yielded Compound A7.
The amine Compound A8 can be obtained from Compound A7 by removal
of the Boc protecting group upon treatment with an acid such as TFA
in a solvent such as CH.sub.2Cl.sub.2. The free base of Compound A8
is obtained upon treatment with a base such as aqueous
Na.sub.2CO.sub.3.
[0330] Compound A9 can be prepared by a standard coupling procedure
between Compound A3 and Compound A8 using routine reagents such as
DCC and HOBT in a solvent such as CH.sub.3CN. Dealkylation of
Compound A9 with reagent such as bromotrimethylsilane in a solvent
such as pyridine, followed by treatment with dilute HCl afforded
Compound A10 (wherein, in an embodiment of a general synthetic
method, the R.sub.5 ethyl group and the R.sub.6 ethoxy group were
replaced with hydrogen). A salt of Compound A10 such as target
Compound A11 can be prepared by treating Compound A10 with a
monobasic or dibasic amine such as tris(hydroxymethyl)aminomethane
in a solvent system such as i-PrOH and water.
##STR00017## ##STR00018##
Scheme B
[0331] Scheme B is illustrative of an alternative general synthetic
method for the preparation of compounds of the invention by
addition of a Compound A2 (in an embodiment of an alternative
general method, the R.sub.5 substitutent of Compound A2 is ethyl
and the R.sub.6 substitutent is ethoxy) and R''M (wherein R''M
represents an organometallic reagent such as LiHMDS (lithium
hexamethyldisilylazide), lithium tetramethylpiperidide or NaHMDS
(sodium hexamethyldisilazide)) to an anhydride Compound A1.
[0332] The reaction is subsequently quenched with 6N HCl to a pH
between 4 and 6 to afford an enol Compound B1, wherein for a
compound of Formula (I), Z is a bond, Y is not present and X is one
oxygen substituent attached by a single-bond to the carbon in the
position .beta. to R.sub.4. Other compounds of the present
invention may be obtained from Compound B1 using standard ketone
manipulation wherein the enol double bond may be reduced to the
ketone; wherein for a compound of Formula (I), Y is not present and
X is one oxygen substituent attached by a double-bond on the .beta.
position carbon. A coupling reagent (such as, but not limited to,
chloroformates (such as, but not limited to, isobutyl
chloroformate), cyanuric chloride, methanesulfonyl chloride, or
diethyl chlorophosphate) may then be employed for ring closure to
form a substituted lactone intermediate Compound B2 in the presence
of a base such as, but not limited to, Et.sub.3N.
[0333] Reaction of a dihydroxy substituted heterocycle Compound B3
(or other ketones and other protected ketones) with a Q-substituted
R.sub.8a Compound A5 in a solvent (such as, but not limited to,
CH.sub.2Cl.sub.2, THF or mixtures thereof) containing a base (such
as, but not limited to, sodium bicarbonate, potassium carbonate)
provided an R.sub.8b substituted Compound B4.
[0334] Compound B4 was treated with R.sub.7NH.sub.2 in a solvent
(such as, but not limited to, CH.sub.2Cl.sub.2, THF or mixtures
thereof) then subjected to reductive amination or hydrogenation
using a hydride reducing agent (such as, but not limited to,
NaBH(OAc).sub.3, or hydrogenation with Pd, Pt or Ni catalyst). The
free base of Compound A8 was obtained upon quenching the reaction
with a base such as aqueous Na.sub.2CO.sub.3.
[0335] Compound A9 (in tautomeric equilibrium with Compound B6) was
prepared by opening the 5-membered lactone ring intermediate
Compound B2 with Compound A8 (or Compound B5, a salt of Compound
A8) in the presence of DIEA (diisopropylethylamine) in a solvent
(such as, but not limited to, acetone or MEK (methylethyl
ketone)).
[0336] Dealkylation of the equilibrium mixture of Compound
A9-Compound B6 with a reagent (such as, but not limited to, TMSBr
(bromotrimethylsilane) or TMSl) in a solvent (such as, but not
limited to, CH.sub.3CN or pyridine), followed by recrystallization
afforded Compound A10 (wherein the R.sub.5 ethyl group is replaced
with hydrogen and the R.sub.6 ethoxy group is replaced with
hydroxy). A salt of Compound A10 such as Compound A11 (and
tautomers thereof) was prepared by treating Compound A10 with a
diamine such as tris(hydroxymethyl)aminomethane in a solvent system
such as a mixture of EtOH and water.
##STR00019##
Scheme C
[0337] Scheme C is illustrative of an alternative method for the
preparation of the intermediate Compound B2, wherein the enol
Compound B1 is protonated to the free acid ketone Compound A3 by
adjusting the pH to about pH 1, followed by intramolecular
dehydration to provide the target lactone intermediate Compound
B2.
##STR00020##
Scheme D
[0338] Scheme D is illustrative of a method for the preparation of
an acid addition compound B5, wherein Compound A8 is reacted with
an acid HA (such as, but not limited to, HCl, HBr or
p-toluenesulfonic acid) to provide the target Compound B5 which may
be carried forward in place of Compound A8 in the reaction with
Compound B2.
##STR00021##
Scheme E
[0339] Scheme E is illustrative of a method of the preparation of
compounds of Formula (II).
[0340] Compound A3 may be reacted with a compound of E1 under
appropriate conditions to couple the compounds via an amide
linkage. For example a salt can be formed from E1 and reacted with
A3 to form an ammonium salt of the carboxylic acid that can be
dehydrated to form the amide linkage.
##STR00022##
[0341] Compound E1 can be prepared from commercially available or
known starting materials using techniques known to those of skill
in the art.
SPECIFIC SYNTHETIC EXAMPLES
[0342] Specific compounds which are representative of this
invention were prepared as per the following examples and reaction
sequences; the examples and the diagrams depicting the reaction
sequences are offered by way of illustration, to aid in the
understanding of the invention and should not be construed to limit
in any way the invention set forth in the claims which follow
thereafter. The depicted intermediates may also be used in
subsequent examples to produce additional compounds of the present
invention. These reactions can be further optimized to increase the
yields. One skilled in the art would know how to increase such
yields through routine variations in reaction times, temperatures,
solvents and/or reagents.
[0343] All chemicals were obtained from commercial suppliers and
used without further purification. .sup.1H and .sup.13C NMR spectra
were recorded on a Bruker AC 300B (300 MHz proton) or a Bruker
AM-400 (400 MHz proton) spectrometer with Me.sub.4Si as an internal
standard (s=singlet, d=doublet, t=triplet, br=broad). APCI-MS and
ES-MS were recorded on a VG Platform II mass spectrometer.
Example 1
[2-[3-[[methyl[1-(2-naphthalenylcarbonyl)-4-piperidinyl]amino]carbonyl]-2--
naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic Acid
(Compound 2)
[0344] To a solution of 2.5M n-BuLi in hexanes (40 mL, 0.1 mol) in
70 mL of THF at -78.degree. C. was added dropwise a solution of
1-naphthyldiethylphosphonate (Compound 1A, 28 g, 0.1 mol) in 60 mL
THF over 30 min. After stirring for an additional 30 min,
2,3-naphthalenedicarboxylic anhydride (Compound 1B, 20 g, 0.1 mol)
was added portionwise via solid-addition funnel to the mixture over
20 min. After the addition was complete, the slurry was allowed to
reach 0.degree. C. gradually where it was held for another 1.5 h.
Excess NH.sub.4Cl (sat'd., aq.) was added, and the mixture was
filtered through a pad of Celite 545. The filtrate was extracted
with 200 mL of EtOAc and the layers were separated. The organic
phase was concentrated (without drying) under reduced pressure at
rt and the residue was triturated 4.times. with boiling ether. The
residue was treated with 200 mL of EtOAc and adjusted to pH 3 with
2N HCl (aq.) with vigorous stirring. The layers were separated, and
the organic phase was washed once with H.sub.2O, dried
(Na.sub.2SO.sub.4) and concentrated to afford 24 g of Compound 1C
as a white powder: MS (ES) MH+=477; HPLC: 3.68 min.
[0345] To a solution of Compound 1D (4 g, 20 mmol) containing 3.1
mL of triethylamine (22 mmol) in 45 mL of DMF was added Compound 1E
(3.8 g, 20 mmol). After stirring overnight, the mixture was
filtered and concentrated under reduced pressure. The residue was
taken up in CH.sub.2Cl.sub.2 and washed sequentially with H.sub.2O,
Na.sub.2CO.sub.3 (10%, aq.), H.sub.2O, KHSO.sub.4 (1N aq.) and
H.sub.2O. The organic phase was dried (Na.sub.2SO.sub.4), and
concentrated to afford 6.0 g of Compound 1F as a foam: MS (ES)
MH.sup.+=355.
[0346] Potassium hydride (2.3 g of a 35% oil dispersion; 20 mmol)
was washed with hexanes, then treated with 30 mL of THF and cooled
to 0.degree. C. To the suspension was added dropwise a solution of
Compound 1F (5.9 g, 16.8 mmol) in 15 mL of THF. The mixture was
stirred at 0.degree. C. for 0.5 h, then stirred an additional 0.5 h
at rt. The mixture was cooled to 0.degree. C. and iodomethane (15.7
g, 100 mmol) was added dropwise. The mixture was stirred at
0.degree. C. for 0.5 h then warmed to rt and stirred an additional
1.5 h. Excess 10% Na.sub.2CO.sub.3 (aq) was added slowly at
0.degree. C., and the volatiles were removed under reduced
pressure. The aqueous layer was extracted 3 times with EtOAc and
the combined extracts were dried (Na.sub.2SO.sub.4) and
concentrated to yield 6.1 g of Compound 1G as foam. HPLC
R.sub.t=3.76 min, 100%; MS (ES) MH+=369.
[0347] A solution of Compound 1G (6.1 g, 16.5 mmol) was dissolved
in 15 mL of a 1:1 solution of TFA:CH.sub.2Cl.sub.2 and stirred for
1 h at rt. Volatiles were removed under reduced pressure, and the
residue was dissolved in CH.sub.2Cl.sub.2 and treated with excess
10% Na.sub.2CO.sub.3 (aq). The layers were separated, and the
aqueous phase was extracted 3 times with CH.sub.2Cl.sub.2. The
organic extracts were combined, dried (Na.sub.2SO.sub.4) and
concentrated to afford 4.3 g of Compound 1H as a viscous oil. HPLC
R.sub.t=1.5 min, 100%; MS (ES) MH.sup.+=269.
[0348] A solution of Compound 1C (4.9 g, 10.3 mmol), Compound 1H
(3.3 g, 12.3 mmol) and HOBT (2.1 g, 15.4 mmol) in 100 mL CH.sub.3CN
was treated with a solution of DCC (2.5 g, 12.3 mmol) in 7 mL of
CH.sub.3CN. After stirring for 12 h, 5 mL of DIPEA was added and
the reaction was stirred for an additional 48 h. The mixture was
filtered and concentrated. The residue was purified by flash column
chromatography (silica: CH.sub.2Cl.sub.2:MeOH ramped from 98:1 to
95:5) to yield 6.9 g of Compound 1I. HPLC R.sub.t=4.3 min; MS (ES)
MH+=727.
[0349] To a solution of Compound 1I in 15 mL of pyridine was added
5 mL of bromotrimethylsilane. The mixture was stirred for 15 min,
then concentrated under reduced pressure. The residue was treated
with excess 3N HCl(aq), then stirred for 3 h. The white precipitate
was collected and rinsed with water, then triturated with
CH.sub.3CN to afford 5.1 g of Compound 1J. HPLC R.sub.t=3.6 min; MS
(ES) MH+=671. To a solution of Compound 1J in 50 mL of CH.sub.3CN
was added a solution of tris(hydroxymethyl)aminomethane (0.9 g, 7.7
mmol) in 7 mL of H.sub.2O. The solution was filtered and the
filtrate lyophilized after partial concentration to remove most of
the CH.sub.3CN. The resulting white solid was recrystallized from
i-PrOH to yield 5.5 g of Compound 2 as an off-white solid. HPLC:
R.sub.t=3.6 min; 100%; MS (ES) MH+=671; Anal. Calc'd for
C.sub.40H.sub.35N.sub.2O.sub.6P.1.0 C.sub.4H.sub.11NO.sub.3.1.0
i-PrOH.1.5H.sub.2O: C, 64.23; H, 6.54; N, 4.79; H.sub.2O, 3.08.
Found: C, 63.93; H, 6.40; N, 4.85; H.sub.2O, 2.74.
[0350] For Example 1, TLC was performed using Whatman 250-.mu.m
silica gel plates. Preparative TLC was performed with Analtech
1000-.mu.m silica gel GF plates. Flash column chromatography was
conducted with flash column silica gel (40-63 .mu.m) and column
chromatography was conducted with standard silica gel. HPLC
separations were carried out on three Waters PrepPak.RTM.
Cartridges (25.times.100 mm, Bondapak.RTM. C18, 15-20 .mu.m, 125
.ANG.) connected in series; detection was at 254 nm on a Waters 486
UV detector. Analytical HPLC was carried out on a Supelcosil
ABZ+PLUS column (5 cm.times.2.1 mm), with detection at 254 nm on a
Hewlett Packard 1100 UV detector. Microanalysis was performed by
Robertson Microlit Laboratories, Inc.
##STR00023## ##STR00024## ##STR00025##
[0351] Following the procedure of Example 1 and substituting the
appropriate starting materials, compounds and reagents, the
following Compounds 1 and 3-33 of the invention were also
prepared:
TABLE-US-00005 MS m/e Cpd Name (MH.sup.+). (1)
[2-[3-[[methyl(4-phenylcyclohexyl)amino]carbonyl]-2- 592
naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (3)
[2-[3-[[[1-[(6-methoxy-2-naphthalenyl)carbonyl]-3- 687
pyrrolidinyl]methylamino]carbonyl]-2-naphthalenyl]-1-(1-
naphthalenyl)-2-oxoethyl]-phosphonic acid (4)
[2-[3-[[[1-[(6-bromo-2-naphthalenyl)carbonyl]-4- 771
piperidinyl]methylamino]carbonyl]-2-naphthalenyl]-1-(1- (M.sup.+Na)
naphthalenyl)-2-oxoethyl]-phosphonic acid (5)
[2-[3-[[[1-[(2E)-3-(4-fluorophenyl)-1-oxo-2-propenyl]-3- 651
pyrrolidinyl]methylamino]carbonyl]-2-naphthalenyl]-1-(1-
naphthalenyl)-2-oxoethyl]-phosphonic acid (6)
[2-[3-[[methyl[1-[(2E)-1-oxo-3-phenyl-2-propenyl]-4- 647
piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-
naphthalenyl)-2-oxoethyl]-phosphonic acid (7)
[1-(1-naphthalenyl)-2-oxo-2-[3-[(4-phenyl-1- 564
piperidinyl)carbonyl]-2-naphthalenyl]ethyl]-phosphonic acid (8)
[1-(1-naphthalenyl)-2-oxo-2-[3-[(4-oxo-1-phenyl-1,3,8- 634
triazaspiro[4.5]dec-8-yl)carbonyl]-2-naphthalenyl]ethyl]-
phosphonic acid (9)
[2-[3-[[methyl[1-[(2E)-3-(4-methylphenyl)-1-oxo-2-propenyl]- 661
4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-
naphthalenyl)-2-oxoethyl]-phosphonic acid (10)
[2-[3-[[methyl[1-[(2E)-1-oxo-3-[4-(trifluoromethyl)phenyl]-2- 715
propenyl]-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-
naphthalenyl)-2-oxoethyl]-phosphonic acid (11)
[2-[3-[[methyl[1-(2-naphthalenylcarbonyl)-4- 621
piperidinyl]amino]carbonyl]-2-naphthalenyl]-2-oxo-1-
phenylethyl]-phosphonic acid (12)
[2-[3-[[4-(4-methoxyphenyl)-1-piperidinyl]carbonyl]-2- 594
naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (13)
[2-[3-[[[1-[(2E)-3-[4-(dimethylamino)phenyl]-1-oxo-2- 690
propenyl]-4-piperidinyl]methylamino]carbonyl]-2-
naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (14)
[2-[3-[[4-(3-methoxyphenyl)-1-piperidinyl]carbonyl]-2- 594
naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (15)
[2-[3-[[(1-benzoyl-4-piperidinyl)methylamino]carbonyl]-2- 621
naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (16)
[2-[3-[[4-(2-benzothiazolyl)-1-piperidinyl]carbonyl]-2- 621
naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (17)
[2-[3-[(cyclohexylmethylamino)carbonyl]-2-naphthalenyl]-1- 516
(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (18)
[2-[3-[[methyl[1-[1-oxo-3-[4-(trifluoromethyl)phenyl]propyl]-4- 717
piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-
naphthalenyl)-2-oxoethyl]-phosphonic acid (19)
[1-(1-naphthalenyl)-2-oxo-2-[3-[(3-phenyl-1- 550
pyrrolidinyl)carbonyl]-2-naphthalenyl]ethyl]-phosphonic acid (20)
[2-[3-[[methyl[1-(2-methyl-1-oxopropyl)-4- 587
piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-
naphthalenyl)-2-oxoethyl]-phosphonic acid (21)
[2-[3-[(cyclopentylmethylamino)carbonyl]-2-naphthalenyl]-1- 502
(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (22) [2-[3-[[[4-(1,1-
572 dimethylethyl)cyclohexyl]methylamino]carbonyl]-2-
naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (23)
[2-[3-[[methyl[1-(2-naphthalenylcarbonyl)-4- 685
piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-
naphthalenyl)-2-oxoethyl]-phosphonic acid methyl ester (24)
[2-[3-[[[1-[(6-hydroxy-2-naphthalenyl)carbonyl]-4- 687
piperidinyl]methylamino]carbonyl]-2-naphthalenyl]-1-(1-
naphthalenyl)-2-oxoethyl]-phosphonic acid (25)
[1-(1-naphthalenyl)-2-oxo-2-[3-[[3-(2-phenylethyl)-1- 578
pyrrolidinyl]carbonyl]-2-naphthalenyl]ethyl]-phosphonic acid (26)
[2-[3-[[(1-acetyl-4-piperidinyl)methylamino]carbonyl]-2- 559
naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (27)
[2-[3-[[methyl(4-methylcyclohexyl)amino]carbonyl]-2- 530
naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (28)
[2-[1-[[methyl(tricyclo[3.3.1.1.sup.3,7]dec-1- 582
ylmethyl)amino]carbonyl]-2-naphthalenyl]-1-(1-
naphthalenyl)-2-oxoethyl]-phosphonic acid (29)
[2-[3-[[methyl(4-phenyl-3-cyclohexen-1-yl)amino]carbonyl]-2- 590
naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (30)
[1-(1-naphthalenyl)-2-[3-[[[1-(2-naphthalenylcarbonyl)-4- 657
piperidinyl]amino]carbonyl]-2-naphthalenyl]-2-oxoethyl]- phosphonic
acid (31) [2-[2-[[methyl[1-(2-naphthalenylcarbonyl)-4- 621
piperidinyl]amino]carbonyl]phenyl]-1-(1-naphthalenyl)-2-
oxoethyl]-phosphonic acid (32)
methyl[2-[3-[[methyl[1-(2-naphthalenylcarbonyl)-4- 669
piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-
naphthalenyl)-2-oxoethyl]-phosphinic acid (33)
[1-(5-chlorobenzo[b]thien-3-yl)-2-[3-[[methyl[1-(2- 712
naphthalenylcarbonyl)-4-piperidinyl]amino]carbonyl]-2-
naphthalenyl]-2-oxoethyl]-phosphonic acid
Example 2
Alternative Method of Synthesis for Compound 2
[0352] THF (tetrahydrofuran) (1081.0 mL) and
1-naphthyldiethylphosphonate Compound 2B (223.0 gm, 0.7612 mol)
were combined in a flask and cooled to about -20.degree. C. using a
dry ice-methanol cooling bath. A solution of 1M LiHMDS (1597.0 mL,
1.597 mol) in THF was added to the cooled mixture while keeping the
temperature at about -20.degree. C. to form a fine slurry which was
stirred for an additional 30 minutes. A 2,3-naphthalinedicarboxylic
anhydride Compound 2A (158.80 gm, 0.7612 mol) was added portionwise
over about a 1 h period while keeping the temperature of the
mixture at about -20.degree. C. The addition funnel and flask walls
were rinsed with THF (100.0 mL), the cooling bath was removed and
the mixture temperature raised to about 5.degree. C. for about 1.5
h. Once the reaction was complete (as shown by HPLC), the final pH
of the mixture was adjusted to about pH 5 by slowly adding 6N HCl
(422 mL, 2.34 mol) while the temperature of the mixture was
maintained at about 5.degree. C. The mixture was stirred for about
30 min more at about 5.degree. C. to provide a crude product as a
fine white solid. The crude product was filtered using a porcelain
filter. The wet solid was then washed with water (1000.0 mL), left
to filter overnight, then dried at 70.degree. C. to provide a
dilithium salt Compound 2C (365.1 gms; mass yield: 100.6%).
Compound 2C was used in the next step without further
purification.
[0353] Methanol (2500.0 mL) and water (360.0 mL) were added to a
flask and stirred. Compound 2C (365.1 gm, 0.7612 mol) was added to
the stirring solution and the flask was rinsed with methanol (100.0
mL) to form a slurry. The slurry was stirred at RT for 30 minutes
and then 12 N HCl (80.0 mL, 0.960 mol) was added over a 2 min
period as the slurry turned into a hazy solution. The solution was
stirred at RT until crystallization began, then was cooled to about
5.degree. C. for 1 h to provide a crude product as a white granular
solid. The product was filtered and washed with water (500.0 mL),
then dried in vacuo overnight at a temperature of about 50.degree.
C. to provide Compound 2D (280 gms; mass yield: 77.3%).
[0354] Compound 2D (199.8 gm) and THF (2 L) were combined in a
flask, then agitated and cooled to a temperature of from about
0.degree. C. to about 5.degree. C. NMM (4-methylmorpholine) (51.5
mL) was added to the flask while the mixture temperature was
maintained at a temperature of from about 0.degree. C. to about
5.degree. C. The mixture was then agitated for an additional 15 min
or until a solution was obtained. IBCF (isobutylchloroformate) (56
mL) was added portionwise while the mixture temperature was
maintained at a temperature of from about 0.degree. C. to about
15.degree. C. When the addition was complete, the mixture
temperature was warmed to a temperature of from about 20.degree. C.
to about 25.degree. C., then agitated for 1 h. Once the reaction
was complete, the NMM salts were filtered, washed with THF (150 mL)
and allowed to dry. The filtrate was then combined with n-heptane
(2.5 L) over a period of about 10 min and then agitated at a
temperature of from about 20.degree. C. to about 25.degree. C. for
about 30-45 min. Additional n-heptane (1.5 L) was added over a
period of about 10 min. The mixture was then cooled to a
temperature of from about 0.degree. C. to about 5.degree. C. and
aged for about 1.5 h. The resulting suspension was filtered and
washed with n-heptane (250 mL), allowed to air dry over a period of
about 30 min and then dried in vacuo overnight at a temperature of
from about 45 to about 50.degree. C. to provide Compound 2E (165
gms; mass yield: 88.4%).
[0355] DCM (dichloromethane) (600 mL) and a 2-naphthoyl chloride
Compound 2F (189.0 gm) were combined in a flask and agitated until
solubilized. 4-Piperidone hydrate hydrochloride Compound 2G (150 g)
and NaHCO.sub.3 (sodium hydrogen carbonate) (260.0 gms) were then
added via addition funnel. DCM (300 mL) was used to rinse the
funnel and the resulting mixture was agitated for 18 h. Once the
reaction was complete (as shown by HPLC), water (2.6 L) was added
to the flask and the mixture was stirred vigorously to dissolve the
NaHCO.sub.3. After a period of about 5 to about 10 minutes, the
layers were allowed to separate over a period of about 30 minutes.
The aqueous layer was removed. Saturated aqueous NaHCO.sub.3 (300
mL) was again added and the mixture agitated for a period of about
5 to about 10 min. The layers were allowed to separate over a
period of about 30 min and the aqueous layer was removed. Water
(300 mL) was added and the mixture stirred gently for a period of
from about 5 to about 10 min. The layers were allowed to separate
over a period of about 30 min and the organic layer (.about.960 mL)
containing Compound 2H was removed (concentration of Compound 2H in
DCM: 235.98 mg/mL; calculated mass of Compound 2H in DCM: 226.54
gms; calculated mass yield: 93.46%).
[0356] Compound 2H (.about.50 gms, .about.265 mg/mL in DCM) and
acetic acid (4.9 mL) were combined in a flask and the mixture was
cooled to a temperature of from about 0.degree. C. to about
5.degree. C. 2.0M MeNH.sub.2 (methylamine) (296 mL) in THF was
added portionwise while maintaining the mixture at a temperature of
from about 0.degree. C. to about 19.degree. C. The mixture was
allowed to warm to ambient temperature and was agitated for a
period of about 30 min. NaBH(OAc).sub.3 (sodium
triacetoxyborohydride) (51.4 gms) was then added portionwise while
maintaining the solution at a temperature of from about 19.degree.
C. to about 27.degree. C. The mixture was aged for about 40 min at
a temperature of from about ambient to about 27.degree. C. Once the
reaction was complete (as shown by HPLC), water (500 mL) was added
while maintaining the solution at a temperature of below about
30.degree. C. Sodium hydroxide (115 mL; 5% w/v in water) was then
added to the mixture to raise the pH to from about pH 10 to about
pH 11. The mixture was agitated vigorously for a period of from
about 3 to about 10 min. The layers were separated and the aqueous
layer was removed. Water (143 mL) was added and the mixture
agitated for a period of from about 3 to about 10 min. The layers
were again separated and the organic layer containing Compound 2I
was removed (concentration of Compound 2I in DCM: 0.229 mg/mL;
calculated mass of Compound 2I in DCM: 45.18 gms; mass yield:
85.3%).
[0357] Compound 2I (150 mL, 0.069 mol) was placed in solution with
CH.sub.2Cl.sub.2:THF (150 mL; 1:8) and concentrated to a thick oil
in vacuo while maintaining the mixture at a temperature of about or
below 40.degree. C. using a cooling bath. 2-Butanone (320 mL) was
added portionwise to the thick oil to transfer the oil to another
flask. The mixture was agitated and EtN(i-Pr).sub.2
(diisopropylethylamine) (11.0 mL, 0.063 mol) and Compound 2E (27.3
gms, 0.057 mol) were added. The mixture was heated to a temperature
of about 65.degree. C. for a period of from about 6 to about 7 h.
Once the reaction was complete (as shown by HPLC), the mixture was
cooled to ambient temperature and crystallized over a period of
from about 72 to about 96 h (the product can take up to 48 h to
start to crystallizing, having a cloud point time around 28 h). The
product was filtered and washed with acetone (2.times.10 mL) (each
wash), then dried in vacuo overnight at a temperature of about
75.degree. C. to provide Compound 2J (31.4 gms; yield: 75.1%) as a
white powder.
[0358] Compound 2J (10.0 g) and acetonitrile (40 mL) under nitrogen
were added to a flask to form a suspension. The suspension was
agitated for a period of from about 5 to about 10 min, then
bromotrimethylsilane (10 mL) was added via additional funnel over a
period of from about 10 to about 15 min at RT. The solution was
stirred for at least a time period of about 1 h at rt. Once the
reaction was complete (as shown by HPLC), the mixture was
transferred to an addition funnel and then added to water (250 mL).
The resulting slurry was stirred vigorously during the addition and
the temperature maintained at from about 20.degree. C. to about
25.degree. C. The slurry was further agitated over a period of from
about 1 to about 1.5 h, then filtered and washed with water
(2.times.15 mL). The resulting wet cake was then dried in vacuo
overnight at a temperature of about 40.degree. C. to provide a
crude product Compound 2K (10.2 gms) as a white solid.
[0359] Compound 2K (110.0 gms, 0.127 mol) and methanol (550 mL)
were added to a flask to form a slurry. The slurry was stirred at
RT over a period of from about 55 to about 60 min (the
recrystallization mixture gave a hazy solution within about 5
minutes after adding MeOH and gradually afforded a white suspension
after about 30 minutes). An acetone:water (1100 mL; 4:1) solution
was added and the suspension was stirred at RT for a period of from
about 180 to about 190 min to afford a white solid. The solid was
filtered and washed with water (3.times.350 mL), forming a wet cake
was then dried in vacuo overnight at a temperature of from about 30
to about 35.degree. C. to provide a recrystallized Compound 2K
(82.3 gms; yield: 96.1%) as a fine white solid.
[0360] Recrystallized Compound 2K (30.0 g, 0.0431 mol) and
tris(hydroxymethyl)aminomethane (13.07 g, 0.107 mol; a clear white
crystalline solid) were combined in a flask and ethanol (300 mL)
and water (30 mL) were added. The solution was agitated to provide
a clear solution after a period of about 15 min. A thin suspension
was formed after a period of from about 2 to about 3 h and a thick
white suspension was formed after a period of from about 3 to about
5 h (the mixture may need to be seeded to enhance crystallization
if a thin suspension is not formed after a period of about 3 h).
The suspension was stirred at RT for an additional period of about
4 h. The thick suspension was thinned by adding ethanol (180 mL),
then filtered and washed with ethanol (120 mL), allowed to air dry
over a period of about 30 min and then dried in vacuo for a time
period of from about 24 to about 67 h at a temperature of about
40.degree. C. to provide Compound 2E (38.6 gms; yield: 91.8%) as a
bis-tromethane salt (ratio of
tris(hydroxymethyl)aminomethane:Compound 2E:1.99:1).
[0361] For Example 2, analytical HPLC was carried out using
Phenomenex Luna (15 cm.times.4.6 mm; 5.mu.; detection was at 220
nm), Phenomenex Luna 5.mu. C18(2) (4.6 mm.times.250; detection was
at 225 nm) and Synergi 4.mu. MAX-RP 80A (15 cm.times.4.6 mm;
detection was at 225 nm) columns. Microanalysis was performed by
Quantitative Technologies, Inc.
##STR00026## ##STR00027##
Example 3
[0362] As a specific embodiment of an oral composition, 100 mg of
the Compound 2 of Example 1 is formulated with sufficient finely
divided lactose to provide a total amount of 580 to 590 mg to fill
a size O hard gel capsule.
Example 4
##STR00028##
[0364] A solution of 4A (1.0 g, 2.1 mmol), 4-N-Boc-aminopiperidine
(0.42 g, 2.2 mmol; Astatech Inc.) and HOBt (0.28 g, 2.1 mmol) in 5
mL of DMF was treated with a solution of DCC (0.43 g, 2.1 mmol) in
1 mL of DMF dropwise. After stirring for 24 h, the mixture was
filtered through dicalite and the filtrate concentrated under
reduced pressure. The residue was purified by flash column
chromatography (silica; 5% CH.sub.3OH--CH.sub.2Cl.sub.2) to afford
1 g of 4B as a white foam, 72%. MS (ES) m/z 731 (MH.sup.+ adduct
ion with MeOH and CH.sub.3CN).
[0365] A solution of 20% TFA in CH.sub.2Cl.sub.2 and 4B (1 g, 1.5
mmol) was stirred for 45 min, then concentrated under a stream of
N.sub.2. The residue was triturated with ether to give 0.80 g of C
as a white powder (TFA salt): MS (ES) m/z=530
(M-C.sub.2H.sub.5).sup.+.
[0366] To a mixture of 0.40 g (0.59 mmol) of 4C and 0.17 mL (1.2
mmol) of Et.sub.3N in 30 mL of CH.sub.2Cl.sub.2 was added a
solution of 2-naphthoyl chloride (0.11 g, 0.60 mmol) in 1 mL of
CH.sub.2Cl.sub.2. The reaction was stirred for 2 h, then diluted
with water and the layers were separated. The organic layer was
washed sequentially with H.sub.2O, NaHCO.sub.3 (satd, aq.), 1N
KHSO.sub.4 (aq), and H.sub.2O, then dried over Na.sub.2SO.sub.4,
filtered and concentrated. The residue was purified by flash column
chromatography (silica, 5% CH.sub.3OH--CH.sub.2Cl.sub.2) to afford
0.29 g (70%) of 4D as a white powder: MS (ES) m/z 713
(MH.sup.+).
[0367] A solution of 0.29 g (0.40 mmol) of 4D in 2.5 mL of pyridine
was treated with 0.4 mL (3.3 mmol) of bromotrimethylsilane and the
mixture was stirred for 2 h. Volatiles were removed under reduced
pressure, and the white solid residue was treated with 15 mL of 1N
HCl (aq). The slurry was stirred for 2.5 h and the white solid was
collected and rinsed with H.sub.2O. The solid was triturated with
CH.sub.3CN to yield 0.12 g of the title compound (46%) as a white
powder: MS (ES) m/z 657 (MH.sup.+).
##STR00029##
##STR00030##
[0368] To a stirred solution of 5A (0.55 g, 1.16 mmol), the
trifluoroacetate salt of 5B (0.5 g, 1.16 mmol), triethylamine (1.28
mmol, 0.18 mL), and HOBt (0.24 g, 1.75 mmol) in 5 mL of
acetonitrile was added a solution of DCC in 2 mL of acetonitrile.
(0.26 g, 1.28 mmol). The reaction was stirred for 24 h, then
treated with 1 mL of DIPEA, and stirred an additional 5 h. The
mixture was filtered, and the filtrate was concentrated under
reduced pressure. The residue was purified by flash column
chromatography (silica; 100% CH.sub.2Cl.sub.2->98%
CH.sub.2Cl.sub.2-MeOH) to afford 0.66 g of 5C as a foam: MS
(ES.sup.+) MH.sup.+=735.
[0369] To a stirred solution of 5C (0.11 g, 0.75 mmol) in 1 mL of
pyridine was added 0.15 mL of bromotrimethylsilane. The reaction
was stirred for 1.5 h, then concentrated under reduced pressure.
The residue was stirred with excess 3N HCl for 1 h, and the product
collected and washed sequentially with water and ether. The product
was suspended in acetonitrile and stirred for 0.5 h at 0.degree. C.
then collected to afford 0.067 g of the title compound as a white
solid: MS (ES.sup.+) MH.sup.+=679.
##STR00031##
[0370] Following the procedure of Example 5 and substituting the
appropriate starting materials, compounds and reagents, the
following Compounds of the invention were also prepared:
TABLE-US-00006 ##STR00032## MS m/e Cpd R.sub.10 (MH.sup.+). 37
naphthalene-2-yl-acetyl 657 38 2-naphthoyl 641 (MH.sup.-) 39
1-(4-hydroxyphenyl) 581 40 1-(4-methoxyphenyl) 595 41
N-[5-(sulfonyl)-thiophene-2-ylmethyl]-benzamide 768 42
6-chloro-5-sulfonyl-imidazo[2,1-b]thiazole 709 43
Naphthyl-2-aminocarbonyl 658 44 1-(4-fluorophenyl) 583
Biological Experimental Examples
[0371] The utility of the compounds of the present invention as a
serine protease inhibitor and, particularly, as a cathepsin G or
chymase inhibitor useful for the treatment of inflammatory or
serine protease mediated disorders can be determined according to
the procedures described herein.
Example 1
Enzyme-Catalyzed Hydrolysis Assays--Cathepsin G
[0372] Enzyme-catalyzed hydrolysis rates were measured
spectrophotometrically using human neutrophil cathepsin G (Athens
Research and Technology) or human skin chymase (Cortex Biochem), a
chromogenic substrate (Suc-Ala-Ala-Pro-Phe-pNa) (Bachem) in aqueous
buffer (100 mM Hepes, 500 mM NaCl, pH 7.4 for catG; 450 mM Tris,
1800 mM NaCl, pH 8.0 for chymase), and a microplate reader
(Molecular Devices). IC.sub.50 experiments were conducted by fixing
the enzyme and substrate concentrations (70 nM enzyme, 5 mM
substrate for cat G, 10 nM enzyme, 0.7 mM substrate for chymase)
and varying the inhibitor concentration. Changes in absorbance at
405 nM were monitored using the software program Softmax (Molecular
Devices), upon addition of enzyme, with and without inhibitor
present at 37.degree. C. for 30 minutes. Percent inhibition was
calculated by comparing the initial reaction slopes of the samples
without inhibitor to those with inhibitor. IC.sub.50 values were
determined using a four parameter fit logistics model. The term
"NT" indicates a compound that was not tested.
[0373] Table 4 summarizes the assay results for cathepsin G and
chymase inhibition for compounds of the present invention:
TABLE-US-00007 TABLE 4 IC.sub.50 (.mu.M) IC.sub.50 (.mu.M) Cpd CatG
n Chymase n 1 0.083 .+-. 0.014 7 0.0053 .+-. 0.0019 8 2 0.081 .+-.
0.009 70 0.0067 .+-. 0.0018 70 3 0.068 .+-. 0.019 2 0.072 .+-.
0.008 3 4 0.090 .+-. 0.020 5 0.0039 .+-. 0.0001 4 5 0.072 .+-.
0.021 5 0.2 .+-. 0.4 6 6 0.067 .+-. 0.014 4 0.0035 .+-. 0.0015 2 7
0.210 .+-. 0.050 12 0.008 .+-. 0.022 1 8 0.130 .+-. 0.010 11 0.0074
.+-. 0.0022 8 9 0.053 .+-. 0.015 5 0.011 .+-. 0.003 2 10 0.053 .+-.
0.016 5 0.014 .+-. 0.006 5 11 4.9 .+-. 2.8 2 0.032 1 12 0.179 .+-.
0.038 10 0.0073 .+-. 0.0017 10 13 0.064 .+-. 0.008 3 0.004 1 14
0.230 .+-. 0.030 6 0.010 .+-. 0.001 9 15 0.075 .+-. 0.030 5 0.017
.+-. 0.005 3 16 0.190 .+-. 0.020 7 0.0085 .+-. 0.0023 7 17 0.098
.+-. 0.026 4 0.0072 .+-. 0.0015 6 18 0.028 .+-. 0.006 3 0.0010 1 19
0.238 .+-. 0.030 8 0.022 .+-. 0.062 9 20 0.090 .+-. 0.023 5 0.004
.+-. 0.002 2 21 0.070 .+-. 0.020 5 0.0096 .+-. 0.0034 5 22 0.140
.+-. 0.040 18 0.009 .+-. 0.023 12 23 0.670 1 0.416 1 24 0.078 .+-.
0.015 7 0.0035 .+-. 0.0013 6 25 0.156 .+-. 0.028 7 0.0097 .+-.
0.0035 7 26 0.096 .+-. 0.018 3 0.015 .+-. 0.001 3 27 0.070 .+-.
0.010 4 0.0051 .+-. 0.0022 4 28 0.400 .+-. 0.090 11 0.036 .+-.
0.011 10 29 0.150 .+-. 0.030 13 0.0082 .+-. 0.0028 10 30 0.590 .+-.
0.040 2 0.0158 .+-. 0.0008 2 31 >100.0 1 14.95 .+-. 0.67 2 32
0.86 .+-. 0.03 2 0.31 1 33 0.121 .+-. 0.007 2 0.001 .+-. 0.000 2 34
0.09 .+-. 0.04 3 0.007 .+-. 0.001 2 35 0.56 .+-. 0.18 3 37 0.74
.+-. 0.29 3 38 0.78 .+-. 0.22 2 39 0.18 .+-. 0.05 2 40 0.17 .+-.
0.05 2 41 0.31 1 42 0.14 .+-. 0.03 2 43 0.95 .+-. 0.21 5 44 0.52
.+-. 0.29 2
Example 2
Anti-Asthmatic Effects in a Sheep Model of Asthma
[0374] The efficacy of Compound 2 for the treatment of asthma was
evaluated in a validated model of Ascaris suum antigen-induced
asthmatic response in conscious sheep (Abraham, W. M., Pharmacology
of allergen-induced early and late airway responses and
antigen-induced airway hyperresponsiveness in allergic sheep,
Pulmonary Pharmacology, 1989, 2, 33-40).
Experimental Protocol
[0375] Baseline dose response curves to aerosol carbachol were
obtained 1-3 days prior to antigen challenge. Baseline values of
specific lung resistance (SR.sub.L) were obtained and the sheep
were then given a specified amount (mg) of the test compound as an
inhaled aerosol at a specified time before antigen challenge. Post
drug measurements of SR.sub.L were obtained and the sheep were then
challenged with Ascaris suum antigen. Measurements of SR.sub.L were
obtained immediately after challenge, hourly from 1-6 h after
challenge and on the half-hour from 61/2-8 h after challenge.
Measurements of SR.sub.L were obtained 24 h after challenge
followed by a 24 h post-challenge with carbachol to measure airway
hyperreactivity.
[0376] Compound 2 was administered as an aerosol at 0.1 mg/Kg/dose,
twice-a-day (BID) for three consecutive days, followed by a dose on
day 4, 0.5 h prior to antigen challenge. Ascaris suum antigen
challenge was given at the zero time point.
[0377] FIG. 1 shows that the early airway response (0-2 h after
antigen challenge) was dramatically reduced and that the late
airway response (6-8 h after antigen challenge) was completely
blocked (n=4 sheep/group).
[0378] FIG. 2 shows that the delayed airway hyperreactivity
measured at 24 h post antigen challenge as measured using carbachol
challenge was also completely blocked.
[0379] In addition to blocking the increase in airway resistance,
as shown in Table 5, Compound 2 also blocked the rise in
inflammatory cell numbers in the broncho-alveolar lavage (BAL)
fluid sampled from these sheep.
TABLE-US-00008 TABLE 5 Treatment Group/Time BAL Cell Count
(.times.1000/mL) Baseline Neutrophils Lymphocytes Eosinophils
Macrophages Baseline 22.04 .+-. 12.89 4.82 .+-. 1.74 6.29 .+-. 3.98
172.2 .+-. 20.8 8 h Post 24.55 .+-. 14.08 13.39 .+-. 5.44 61.58
.+-. 29.87 209.3 .+-. 44.7 Antigen 24 h Post 111.7 .+-. 38.9 36.30
.+-. 15.68 168.4 .+-. 95.1 245.6 .+-. 20.4 Antigen Compound 2 (1.0
mg/kg .times. 4 days) (last dose - 30 min prior to antigen
challenge) Baseline 12.66 .+-. 2.07 3.15 .+-. 0.79 0.00 69.06 .+-.
1.97 8 h Post 3.17 .+-. 0.65 4.16 .+-. 1.10 0.37 .+-. 0.32 77.85
.+-. 2.36 Antigen 24 h Post 3.86 .+-. 0.95 3.72 .+-. 0.77 0.04 .+-.
0.03 75.16 .+-. 2.71 Antigen
[0380] While the foregoing specification teaches the principles of
the present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the
invention encompasses all of the usual variations, adaptations
and/or modifications as come within the scope of the following
claims and their equivalents.
* * * * *