Note: Descriptions are shown in the official language in which they were submitted.
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1
METHOD FOR THE TREATMENT OF CYSTIC FIBROSIS
FIELD OF THE INVENTION
The present invention is directed to a method for
treating cystic fibrosis. More specifically, the present
invention is directed to a method for treating the symptoms
of cystic fibrosis by administering a therapeutically
effective amount of an sPLA2 inhibitor.
BACKGROUND OF THE INVENTION
Cystic fibrosis is a hereditary disorder of the lungs,
digestive, and reproductive systems. One in 2500 people in
the general population in America are born with cystic
fibrosis. It typically appears in early childhood and is a
lifelong illness that generally gets more severe with age.
Average life expectancy and quality of life are
significantly reduced. There is no cure for cystic fibrosis
at this time.
In cystic fibrosis the glands which produce mucus,
saliva, and intestinal fluids do not work properly. Thick
mucus in the lungs interferes with removal of pollutants and
can cause breathing problems, infections, and lung damage.
Thick secretions also may clog the pancreatic duct and block
transfer of enzymes from the pancreas to the intestine.
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2
These enzymes help break down food so the body has proper
growth and weight gain.
Males with cystic fibrosis are usually infertile and
females may have reduced fertility due to thick secretions
in the reproductive tract.
Major therapies for cystic fibrosis include the
following:
1, gene therapy
2. breathing exercises
3. agents that degrade the high concentration of DNA
in cystic fibrosis, e.g., human recombinant DNAse
4. drugs to restore salt and water balance, e.g.,
amiloride, triphosphite nucleotides
5. antibiotics for lung infection
6. inhaled beta-adrenergic agonists
7. pancreatic enzymes are taken with meals
U.S. Patent No. 5,453,443 describes bis(aryloxy)alkanes
as inhibitors of phopholipase A2 enzymes useful for a list
of many disease states, inclusive of cystic fibrosis.
The mechanism of action for airway inflammation in
cystic fibrosis remains poorly understood, but arachidonic
acid may have a role (see, "Cystic Fibrosis Gene Mutation
(dF508) is Associated with Intrinsic Abnormality in Ca2+ _
Induced Arachiodonic Acid Release by Epithelial Cells" by
Miele, L.; Cordella-Miele, Eleonora; Xing, Mingzhao;
Frizzell, R.; Mukherjee, Anil., DNA and Cell Biology, Vol
16, No. 6, 1997, Many Ann Liebert, Inc., pp. 749-759).
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U.S. Patent No. 5,654,326 describes the use of
1H-indole-3-glyoxylamide-sPLA2 inhibitors to inhibit the
sPLA2 mediated release of fatty acid.
Accordingly, there is a substantial need for a novel
effective, and easy to administer treatment for the many
symptoms of cystic fibrosis. It is therefore an object of
the present invention to provide a methodology for
effectively treating cystic fibrosis.
SUMMARY OF THE INVENTION
This invention is a method of alleviating the symptoms
of a human afflicted with cystic fibrosis by administering a
therapeutically effective amount of a selected sPLA2
inhibitor.
This invention is also a method of facilitating the
clearance of retained pulmonary secretions in a human
afflicted with cystic fibrosis.
This invention is also a method of facilitating lung
mucus clearance in a human afflicted with cystic fibrosis.
This invention is also a method of inhibiting
inflammation in the lungs in a human afflicted with cystic
fibrosis.
This invention is also the use of sPLA2 inhibitors to
reduce the complications of acute or chronic infections of
the respiratory tree in a human afflicted with cystic
fibrosis.
This invention is also the use of sPLA2 inhibitors for
the manufacture of a medicament for the prophylactic or
therapeutic treatment of a human afflicted with cystic
fibrosis.
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DETAILED DESCRIPTION OF THE INVENTION
Definitions:
General Definitions:
The term, "therapeutically effective amount" is a
quantity of sPLA2 inhibitor sufficient to significantly
alleviate symptoms of cystic fibrosis in a human. .
The term, "parenteral" means not through the alimentary
canal but by some other route such as subcutaneous,
intramuscular, intraorbital, intracapsular, intraspinal,
intrasternal, or intravenous.
The term, "active compound" means one or more sPLA2
inhibitors used in the method of the invention.
I. sPLA2 INHIBITORS USEFUL IN THE METHOD OF THE INVENTION:
Selected classes of secretary phopholipase A2 (sPLA2)
inhibitors are useful in the practice of the method of this
invention.
Exemplary of classes of suitable sPLA2 useful in the
the method of the invention for treatment of cystic fibrosis
are the following:
1H-indole-3-glyoxylamides
1H-indole-3-hydrazides
1H-indole-3-acetamides
1H-indole-1-glyoxylamides
1H-indole-1-hydrazides
1H-indole-1-acetamides
indolizine-1-acetamides
indolizine-1-acetic acid hydrazides
indolizine-1-glyoxylamides
indene-1-acetamides
indene-1-acetic acid hydrazides
indene-1-glyoxylamides
carbazoles & tetrahydrocarbazoles
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pyrazoles
phenyl glyoxamides
pyrroles
naphthyl glyoxamides
5 phenyl acetamides
naphthyl acetamides
Each of the above sPLA2 inhibitor types is discussed in the
following sections (a) through (m) wherein details of their
molecular configuration are given along with methods for
their preparation.
a) The 1H-indole-3-glyoxylamide sPLA2 inhibitors and
method of making them are described in U.S. Patent
5,654,326, the entire disclosure of which is incorporated
herein by reference. Another method of making 1H-indole-
3-glyoxylamide sPLA2 inhibitors is described in United
States Patent Application Serial No. 09/105381, filed June
26, 1998 and titled, "Process for Preparing 4-substituted
1-H-Indole-3-glyoxyamides" the entire disclosure of which
is incorporated herein by reference. United States Patent
Application Serial No. 09/105381 discloses the following
process having steps (a) thru (i):
Preparing a compound of the formula I or a pharmaceutically
acceptable salt or prodrug derivative thereof
R4 CH20
R5 \ \ 'NHZ
s ~ / ~Rz
R ~ ~r11 (I)
R~ R
wherein:
R1 is selected from the group consisting of
-C~-C20 alkyl,
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6
( Rio ) t
- ( CHa ) 1-a
- CHs ~ -
' ( CH )
a o-2 ~ ~ , and
\ \
- CHa
Rio
where
R10 is selected from the group consisting of halo,
C1-C10 alkyl, C1-C10 alkoxy, -S-(C1-C10 alkyl) and
halo(C1-C10)alkyl, and t is an integer from 0 to 5 both
inclusive;
R2 is selected from the group consisting of hydrogen,
halo, C1-C3 alkyl, C3-Cq cycloalkyl, C3-C4 cycloalkenyl,
-O-(C1-C2 alkyl), -S-(C1-C2 alkyl), aryl, aryloxy and HET;
R4 is selected from the group consisting of -C02H,
-S03H and -P(O)(OH)2 or salt and prodrug derivatives
thereof; and
R5, R6 and R~ are each independently selected from the
group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy,
halo(C1-Cg)alkoxy, halo(C2-C6)alkyl, bromo, chloro, fluoro,
iodo and aryl;
which process comprises the steps of:
a) halogenating a compound of formula X
O O
R\O~~R2
X
where R8 is (C1-C6)alkyl, aryl or HET;
with SOZC12 to form a compound of formula IX
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O O
R~0 RZ
C1 IX
b) hydrolyzing and decarboxylating a compound of
formula IX
0 O
RIO R2
C1 IX
to form a compound of formula VIII
O
C1~
R VIII
c) alkylating a compound of formula VII
O
R5
R6 O
R7 VII
with a compound of formula VIII
O
C1..~
R VIII
to form a compound of formula VI
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O
Rs Rz
O
R6 O
R7 VI ;
d) aminating and dehydrating a compound of
formula VI
0
Rs Rz
O
R6 O
R~ VI
with an amine of the formula R1NH2 in the presence
of a solvent that forms and azeotrope with water
to form a compound of formula V;
e) oxidizing a compound of formula V
O
Rs
R6 ~ ~N Rz
R' R1
V
by refluxing in a polar hydrocarbon solvent having
a boiling point of at least 150 °C and a
dielectric constant of at least 10 in the presence
of a catalyst to form a compound of formula IV
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OH
Rs
R6 ~ N/'~RZ
R' R1
IV;
f) alkylating a compound of the formula IV
OH
Rs
Rs ~,. N~R2
R' R1
IV
with an alkylating agent of the formula XCH2R4a
where X is a leaving group and R4a is -C02R4b~
-S03R4b, -P(0)(OR4b)2, or -P(0)(OR4b)H, where R4b
is an acid protecting group to form a compound of
formula III
OCHZR4a
Rs
R6 ~Ni ~RZ
R' R1
III ;
g) reacting a compound of formula III
OCHZR4a
Rs
Rs wNi ~.R2
R' R1
III
*rB
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with oxalyl chloride and ammonia to form a
compound of formula II
O
R
RE
~z
5 R~ Ry II; and
h) optionally hydrolyzing a compound of
formula II
O
R
Rf
~z
10 R~ R1 II
to form a compound of formula I; and
i) optionally salifying a compound of formula I.
The synthesis methodology for making the 1H-indole-3-
glyoxylamide sPLA2 inhibitor starting material may be by
any suitable means available to one skilled in the
chemical arts. However, such methodology is not part of
the present invention which is a method of use,
specifically, a method of treating mammal afflicted or
susceptible to cystic fibrosis.
The method of the invention is for treatment of a
mammal, including a human, afflicted with cystic fibrosis,
said method comprising administering to said human a
therapeutically effective amount of the compound
represented by formula (Ia), or a pharmaceutically
acceptable salt or prodrug derivative thereof;
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X
(Ia)
wherein ;
both X are oxygen;
R1 is selected from the group consisting of
(Rio) t
~CH2) i 2
and
(CH2)\~
CH2) 0 2
where R10 is a radical independently selected from halo,
C1-C10 alkyl, C1-Clp alkoxy, -S-(C1-Clp alkyl), and C1-C10
haloalkyl and t is a number from 0 to 5;
R2 is selected from the group; halo, cyclopropyl,
methyl, ethyl, and propyl;
R4 and R5 are independently selected from hydrogen, a
non-interfering substituent, or the group, -(La)-(acidic
group) wherein -(La)- is an acid linker; provided, the
acid linker group, -(La)-, for Rq is selected from the
group consisting of;
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p Cg2
CHZ .
CH2
CH2 CHZ and
CH3
~O
-O
and provided, the acid linker, -(La)-, for R5 is selected
from group consisting of;
13
Image
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14
Re4
0 C (CH2) 1_s
Res ,
R84
S C (CH2) i-3
Ra5
Re~
1
N C (CHZ) 1_3
Re s and
R84
H2 C~-- C (CH2) i-3
Res
wherein Rg4 and Rg5 are each independently selected from
hydrogen, C1-C10 alkyl, aryl, C1-C10 alkaryl, C1-C10
aralkyl, carboxy, carbalkoxy, and halo; and
provided, that at least one of R4 and R5 must be the
group, -(La)-(acidic group) and wherein the (acidic group)
on the group -(La)-(acidic group) of R4 or R5 is selected
from -C02H, -S03H, or -P(0)(OH)2;
R6 and R~ are each independently selected form
hydrogen and non-interfering substituents, with the non-
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interfering substituents being selected from the group
consisting of the following: C1-C6 alkyl, C2-C6 alkenyl,
C2-C6 alkynyl, C~-C12 aralkyl, C~-C12 alkaryl, C3-Cg
cycloalkyl, C3-Cg cycloalkenyl, phenyl, tolulyl, xylenyl,
5 biphenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6
alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, .
C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12
alkoxyamino, C2-C12 alkoxyaminocarbonyl, C2-C12
alkylamino, C1-C6 alkylthio, C2-C12 alkylthiocarbonyl,
10 C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C6
haloalkoxy, C1-C6 haloalkylsulfonyl, C2-C6 haloalkyl,
C1-C6 hydroxyalkyl, -C(O)0(C1-C6 alkyl), -(CH2)n-0-(C1-C6
alkyl), benzyloxy, phenoxy, phenylthio, -(CONHS02R), -CHO,
amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy,
15 -(CH2)n-C02H, chloro, cyano, cyanoguanidinyl, fluoro,
guanidino, hydrazide, hydrazino, hydrazido, hydroxy,
hydroxyamino, iodo, nitro, phosphono, -S03H, thioacetal,
thiocarbonyl, and C1-C6 carbonyl; where n is from 1 to 8.
Preferred for practicing the method of the invention
are 1H-indole-3-glyoxylamide compounds and all corresponding
pharmaceutically acceptable salts, solvates and prodrug
derivatives thereof which are useful in the method of the
invention include the following:
(A) [[3-(2-Amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-
1H-indol-4-yl]oxy]acetic acid,
(B) dl-2-[[3-(2-Amino-1,2-dioxoethyl)-2-methyl-1-
(phenylmethyl)-1H-indol-4-yl]oxy]propanoic acid,
(C) [[3-(2-Amino-1,2-dioxoethyl)-1-([1,1'-biphenyl]-2-
ylmethyl)-2-methyl-1H-indol-4-yl]oxy]acetic acid,
(D) [[3-(2-Amino-1,2-dioxoethyl)-1-([1,1'-biphenyl]-3-
ylmethyl)-2-methyl-1H-indol-4-yl]oxy]acetic acid,
(E) [[3-(2-Amino-1,2-dioxoethyl)-1-([1,1'-biphenyl]-4-
ylmethyl)-2-methyl-1H-indol-4-yl]oxy]acetic acid,
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(F) [[3-(2-Amino-1,2-dioxoethyl)-1-[{2,&-
dichlorophenyl)methyl]-2-methyl-1H-indol-4-
yl]oxy]acetic acid
(G) [[3-(2-Amino-1,2-dioxoethyl)-1-[4(-
fluorophenyl)methyl]-2-methyl-1H-indol-4-yl]oxy]acetic
acid,
(H) [[3-(2-Amino-1,2-dioxoethyl)-2-methyl-1-[(1-
naphthalenyl)methyl]-1H-indol-4-yl]oxy]acetic acid,
(I) [[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-
1H-indol-4-yl]oxy]acetic acid,
(J) [[3-(2-Amino-1,2-dioxoethyl)-1-[(3-
chlorophenyl)methyl]-2-ethyl-1H-indol-4-yl]oxy]acetic
acid,
(K) [[3-(2-Amino-1,2-dioxoethyl)-1-([1,1'-biphenyl]-2-
ylmethyl)-2-ethyl-1H-indol-4-yl]oxy]acetic acid,
(L) [[3-(2-amino-1,2-dioxoethyl)-1-([1,1'-biphenyl]-2-
ylmethyl)-2-propyl-1H-indol-4-yl]oxy]acetic acid,
(M) [[3-(2-Amino-1,2-dioxoethyl)-2-cyclopropyl-1-
(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid,
(N) [[3-(2-Amino-1,2-dioxoethyl)-1-([1,1'-biphenyl]-2-
ylmethyl)-2-cyclopropyl-1H-indol-4-yl]oxy]acetic acid,
(O) 4-[[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-
(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid,
(P) mixtures of (A) through (P) in any combination.
Particularly useful prodrugs of the compounds of
formula (I) and named compounds (A) thru (0) are the simple
aromatic and aliphatic esters, such as the methyl ester,
ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester,
sec-butyl, tert-butyl ester, N,N-diethylglycolamido ester,
and morpholino-N-ethyl ester. Methods of making ester
prodrugs are disclosed in U.S. Patent No. 5,654,326.
Additional methods of prodrug synthesis are disclosed in
U.S. Provisional Patent Application Serial No. 60/063280
filed October 27, 1997 (titled, N,N-diethylglycolamido ester
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Prodrugs of Indole sPLA2 Inhibitors), the entire disclosure
of which is incorporated herein by reference: U.S.
Provisional Patent Application Serial No. 60/063646 filed
October 27, 1997 (titled, Morpholino-N-ethyl Ester Prodrugs
of Indole sPLA2 Inhibitors), the entire disclosure of which
is incorporated herein by reference; and U.S. Provisional,
Patent Application Serial No. 60/063284 filed October 27,
1997 (titled, Isopropyl Ester Prodrugs of Indole sPLA2
Inhibitors), the entire disclosure of which is incorporated
herein by reference.
Most preferred in the practice of the method of the
invention are the acid, sodium salt, methyl ester, and
morpholino-N-ethyl ester forms of [[3-(2-Amino-1,2-
dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-
yl]oxy]acetic acid as represented by the following formulae:
HO
O
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NHZ
Na*-O O
~O
\O
O
N
NH2
CH30 O
~O \
\O
O
N
and
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O
'N
O O
Another highly preferred compound is the indole-3-
glyoxylamide morpholino ethyl ester of represented by the
formula:
NH2
O O
~N 'O
\0
O O
N
the preparation of which is further described in United
States provisional patent application SN 60/063,646 filed
October 27, 1997.
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Synthesis methods for 1H-indole-3-glyoxylamide sPLA2
inhibitors are additionally depicted in the following
reaction scheme:
1H-indole-3-glyoxylamide Reaction Scheme
OCH3 OCH3
CH3 ~ CH3
/ ~1 ~~, NH
R4 N02 R4 2
1 2
OCH3 OCH3
CH3 R2
~ ' ~ ~ 'O
/ NHC02t -Bu R4 NHC02t -Bu
3 4
OCH3 OCH3
R2 -~ ~ / N R2 R -'>-
R 3
R4 H 4 \ /
5 6
R5
OH CH3~ O
O
I / N R2 -,' I~~ R2 R
R4 .I R3 R4 I 3
\ / 8 \ /
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R
CH30 R5 O O CH30 5 O O O
O Cl ]r.. O ~z
~-Rz ~/~ ~-Rz
R4 N -~ R3 R4 N i R3
g ~"~/~ 10
R5
HO~
O
O ' NHz
~i- Rz
R4 i N y Rs
11
Explanation of Reaction Scheme:
To obtain the glyoxylamides substituted in the
4-position with an acidic function through an oxygen atom,
the reactions outlined in scheme 1 are used (for conversions
1 through 5, see ref. Robin D. Clark, Joseph M. Muchowski,
Lawrence E. Fisher, Lee A. Flippin, David B. Repke, Michel
Souchet, Synthesis, 1991, 871-878, the disclosures of which
are incorporated herein by reference). The ortho-
nitrotoluene, 1, is readily reduced to the 2-methylaniline,
2, using Pd/C as catalyst. The reduction can be carried out
in ethanol or tetrahydrofuran (THF) or a combination of
both, using a low pressure of hydrogen. The aniline, 2, on
heating with di-tert-butyl dicarbonate in THF at reflux
temperature is converted to the N-tert-butylcarbonyl
derivative, 3, in good yield. The dilithium salt of the
dianion of 3 is generated at -40 to -20 °C in THF using sec-
butyl lithium and reacted with the appropriately substituted
N-methoxy-N-methylalkanamide. This product, 4, may be
purified by crystallization from hexane, or reacted directly
with trifluoroacetic acid in methylene chloride to give the
1,3-unsubstituted indole 5. The 1,3-unsubstituted indole 5
is reacted with sodium hydride in dimethylformamide at room
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temperature (20-25 °C) for 0.5-1.0 hour. The resulting
sodium salt of 5 is treated with an equivalent of arylmethyl
halide and the mixture stirred at a temperature range of
0-100 °C, usually at ambient room temperature, for a period
of 4 to 36 hours to give the 1-arylmethylindole, 6. This
indole, 6, is 0-demethylated by stirring with boron
tribromide in methylene chloride for approximately 5 hours
(see ref. Tsung-Ying Shem and Charles A Winter, Adv. Drug
Res., 1977, 12, 176, the disclosure of which is incorporated
herein by reference). The 4-hydroxyindole, 7, is alkylated
with an alpha bromoalkanoic acid ester in dimethylformamide
(DMF) using sodium hydride as a base, with reactions
conditions similar to that described for the conversion of 5
to 6. The a-[(indol-4-yl)oxy]alkanoic acid ester, 8, is
reacted with oxalyl chloride in methylene chloride to give
9, which is not purified but reacted directly with ammonia
to give the glyoxamide 10. This product is hydrolyzed using
1N sodium hydroxide in MeOH. The final glyoxylamide, 11, is
isolated either as the free carboxylic acid or as its sodium
salt or in both forms.
The most preferred compound, [[3-(2-Amino-1,2-
dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-
yl]oxy]acetic acid (as well as its sodium salt and methyl
ester) useful in the practice of the method of the
invention, may be prepared by the following procedure:
Preparation of [[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-
(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid, a compound
represented by the formula:
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HO O ~2
O
O ~ n
f2 CH3
Part A. Preparation of 2-Ethyl-4-methoxy-1H-indole.
A solution of 140 mL (0.18 mol) of 1.3M sec-butyl
lithium in cyclohexane is added slowly to N-tert-
butoxycarbonyl-3-methoxy-2-methylaniline (21.3g, 0.09 mol)
in 250 mL of THF keeping the temperature below -40 °C with a
dry ice-ethanol bath. The bath is removed and the
temperature allowed to rise to 0 °C and then the bath
replaced. After the temperature has cooled to -60 °C,
18.5 g (0.18 mmol) of N-methoxy-N-methylpropanamide in an
equal volume of THF iss added dropwise. The reaction
mixture is stirred 5 minutes, the cooling bath removed and
stirred an additional 18 hours. It is then poured into a
mixture of 300 mL of ether and 400 mL of 0.5N HCl. The
organic layer is separated, washing with water, brine,
dried over MgS04, and concentrated at reduced pressure to
give 25.58 of a crude of 1-[2-(tert-butoxycarbonylamino)-6-
methoxyphenyl]-2-butanone. This material is dissolved in
250 mL of methylene chloride and 50 mL of trifluoroacetic
acid and stirred for a total of 17 hours. The mixture is
concentrated at reduced pressure and ethyl acetate and water
added to the remaining oil. The ethyl acetate is separated,
washed with brine, dried (MgS04) and concentrated. The
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residue is chromatographed three times on silica eluting
with 20% EtOAc/hexane to give 13.98 of 2-ethyl-4-methoxy-1H-
indole.
Analysis for C11H13N0:
Calculated: C, 75.90; H, 7.48; N, 7.99;
Found: C, 74.41; H, 7.64; N, 7.97.
Part B. Preparation of 2-Ethyl-4-methoxy-1-(phenylmethyl)-
1H-indole.
2-Ethyl-4-methoxy-1H-indole (9.2g, 24 mmol) is
dissolved in 30 mL of DMF and 960mg (24 mmol) of 60%
NaH/mineral oil is added. After 1.5 hours, 2.9 mL(24 mmol)
of benzyl bromide is added. After 4 hours, the mixture is
diluted with water extracting twice with ethyl acetate. The
combined ethyl acetate is washed with brine, dried (MgS04)
and concentrated at reduced pressure. The residue is
chromatographed on silica gel and eluted with 20%
EtOAc/hexane to give 3.1g (49% yield) of 2-ethyl-4-methoxy-
1-(phenylmethyl)-1H-indole.
Part C. Preparation of 2-Ethyl-4-hydroxy-1-(phenylmethyl)-
1H-indole.
A solution of 3.1g (11.7 mmol) of 2-ethyl-4-methoxy-1-
(phenylmethyl)-1H-indole and 48.6 mL of 1M BBr3/CH2C12 in
50 mL of methylene chloride is stirred at room temperature
for 5 hours and concentrated at reduced pressure. The
residue is dissolved in ethyl acetate, washed with brine and
dried (MgS04). After concentrating at reduced pressure, the
residue is chromatographed on silica gel eluting with 20%
EtOAc/hexane to give 1.588 (54% yield) of 2-ethyl-4-hydroxy-
1-(phenylmethyl)-1H-indole, mp, 86-90 °C.
Analysis for C17H17N0:
Calculated: C, 81.24; H, 6.82; N, 5.57;
Found: C, 81.08; H, 6.92; N, 5.41.
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Part D. Preparation of [[2-Ethyl-1-(phenylmethyl)-1H-indol-
4-yl]oxy]acetic acid tert-butyl ester.
2-Ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole (5.82 g,
5 20 mmol) is added to 7.828 (24 mmol) cesium carbonate in
25 mL DMF and the mixture is stirred at 35 °C for .
minutes. After cooling to 20 °C, a solution of tert-
butyl bromoacetate (4.65 g, 23.8 mmol) in 5 mL DMF is added
and stirring maintained until the reaction is judged
10 complete by TLC analysis (several hours). The mixture is
diluted with water and extracted with ethyl acetate. The
ethyl acetate solution is washed with brine, dried (MgS04)
and concentrated at reduced pressure to give 6.8g of solid.
Mass spectrum: 365
15 Analyses for C23H27NO3:
Calculated: C, 75.59; H, 7.75: N, 3.83;
Found: C, 75.87; H, 7.48; N, 3.94.
Part E. Preparation of [[2-Ethyl-1-(phenylmethyl)-3-ureido-
20 1H-indol-4-yl]oxy]acetic acid tert-butyl ester.
A solution of 2.3g (6.3 mmol) [[2-ethyl-1-
(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid tert-butyl
ester and 4.8g (12.6 mmol) bis(2,2,2-trichloroethyl)-
azodicarboxylate in diethyl ether is stirred for 24 hours at
25 room temperature. The resulting solid is filtered and
vacuum dried. This adduct (lg, 1.3 mmol) is dissolved in
10 mL of THF and treated with zinc (1 g) and glacial acetic
acid (0.5 mL). After stirring for 30 minutes at room
temperature an excess of trimethylsilylisocyanate in 1 mL of
30 THF is added and stirring is continued at room temperature
for 18 hours. The mixture is diluted with water and
extracted with ethyl acetate. The organic layer is washed
with brine, dried over MgS04 and concentrated to dryness to
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26
give 0.3858 (69$ yield) of the subtitled material. Mass
spectrum: 423.
Analyses for C24H2gN304:
Calculated: C, 68.07; H, 6.90; N, 9.92;
Found: C, 67.92; H, 6.84; N, 9.70.
Part F. Preparation of [[3-(2-Amino-1,2-dioxoethyl)-2-
ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid.
A mixture of 788mg (2 mmol) of [3-(2-amino-1,2-
dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-
acetic acid methyl ester, 10 mL of 1n NaOH and 30 mL of MeOH
is heated to maintain reflux for 0.5 hour, stirred at room
temperature for 0.5 hour and concentrated at reduced
pressure. The residue is taken up in ethyl acetate and
water, the aqueous layer separated and made acidic to pH 2-3
with 1N HC1. The precipitate is filtered and washed with
ethyl acetate to give 559 mg (74~ yield) of [[3-(2-amino-
1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-
yl]oxy]acetic acid, mp, 230-234 °C.
Analyses for C21H20N205~
Calculated: C, 65.96; H, 5.80; N, 7.33;
Found: C, 66.95: H, 5.55: N, 6.99.
b) 1H-indole-3-hydrazide sPLA2 inhibitors useful in
practicing the method of the invention are described in U.S.
Patent No. 5,578,634; the entire disclosure of which is
incorporated herein by reference. The method of the
invention is for treatment of a mammal, including a human,
afflicted with cystic fibrosis, said method comprising
administering to said human a therapeutically effective
amount of the described as 1H-indole-3-acetic acid
hydrazides represented by the formula (Ib), and
pharmaceutically acceptable salts, and prodrugs thereof;
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27
R3. NHNH2
R3 ~ X
R2 (Ib)
AI/
R6
1
wherein;
X is oxygen or sulfur;
R1 is selected from groups (i), (ii) and (iii) where;
(i) is Cq-C2p alkyl, Cq-C20 alkenyl, Cq-C20
alkynyl, Cq-C20 haloalkyl, Cq-C12 cycloalkyl, or
(ii) is aryl or aryl substituted by halo, -CN,
-CHO, -OH, -SH, C1-C10 alkylthio, C1-C10 alkoxy, C1-C10
alkyl, carboxyl, amino, or hydroxyamino;
(iii) is
74
C R75
R74 Y
where y is from 1 to 8, R7q is, independently, hydrogen or
C1-C10 alkyl, and R75 is aryl or aryl substituted by halo,
-CN, -CHO, -OH, nitro, phenyl, -SH, C1-C1p alkylthio, C1-C10
alkoxy, C1-C10 alkyl, amino, hydroxyamino or a substituted
or unsubstituted 5- to 8-membered heterocyclic ring;
R2 is halo, C1-C3 alkyl, ethenyl, C1-C2 alkylthio,
C1-C2 alkoxy, -CHO, -CN;
each R3 is independently hydrogen, C1-C3 alkyl, or
halo;
Rq~ R5, R6, and R7 are each independently hydrogen,
C1-C10 alkyl, C1-C10 alkenyl, C1-C1p alkynyl, C3-Cg
cycloalkyl, aryl, aralkyl, or any two adjacent hydrocarbyl
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28
groups in t-he set Rq~ R5, R6, and R~ combined with the ring
carbon atoms to which they are attached to form a 5- or 6-
membered substituted or unsubstituted carbocyclic ring: or
C1-C1p haloalkyl, C1-C10 alkoxy, C1-C10 haloalkoxy, C4-Cg
cycloalkoxy, phenoxy, halo, hydroxy, carboxyl, -SH, -CN,
-S(C1-C10 alkyl), arylthio, thioacetal, -C(O)0(C1-C10
alkyl), hydrazino, hydrazido, -NH2, -N02, -NRg2Rg3, and
-C(0)NRg2Rg3, where, Rg2 and R83 are independently hydrogen,
C1-C10 alkyl, C1-C10 hydroxyalkyl, or taken together with N,
Rg2 and Rg3 form a 5- to 8-membered heterocyclic ring; or a
group having the formula;
R~
Z C Q
R~ p
where,
each R~6 is independently selected from
hydrogen, C1-C10 alkyl, hydroxy, or both R~6 taken
together are =0;
p is 1 to 8,
Z is a bond, -O-, -N(C1-C10 alkyl)-, -NH, or -S-; and
Q is -CON(Rg2Rg3), -5-tetrazolyl, -S03H,
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29
0
- OR86 ,
OR86
O
0 I - OR86
~R86
186
O (CH2)~.- ~-Re6
ORg6 R86
186
O P O (CH2)n N-Rgs
1 I
ORg6 Rg6 '
O
C- OR86 ,
N
S
RasO ~N~
where Rg6 is independently selected from hydrogen, a metal,
or C1-Clp alkyl.
The synthesis of the 1H-indole-3-acetic acid hydrazides
of structure (I) can be accomplished by known methods such
as outlined in the following reaction schemes:
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Scheme 1
R2 O R2 O
~ OR5 _ OR5
Rl r/ \ R3 ' R1 / ~ \ R3
meth a ~ N~ meth b
R
g 4
R2 0
2
Rl..-/ ' ~ R3
N
R4
The 1H-indole-3-acetic acid ester can be readily alkylated
by an alkyl halide or arylalkyl halide in a solvent such as
N,N-dimethylformamide(DMF) in the presence of a base(meth a)
5 to give the intermediate 1-alkyl-1H-indole-3-acetic acid
esters, III. Bases such as potassium t-butoxide and sodium
hydride were particularily useful. It is advantageous to
react the indole, II, with the base to first form the salt
of II and then add the alkylating agent. Most alkylations
10 can be carried out at room temperature. Treatment of the
1-alkyl-1H-indole-3-acetic acid esters, III, with hydrazine
or hydrazine hydrate in ethanol(meth b) gives the desired
1-alkyl-1H-indole-3-acetic acid hydrazides, I. This
condensation to form I is usually carried out at the reflux
15 temperature of the solvent for a period of 1 to 24 hours.
c) 1H-indole-3-acetamide sPLA2 inhibitors and methods of
making these inhibitors are set out in U.S. Patent No.
5,684,034, the entire disclosure of which is incorporated
20 herein by reference. The method of the invention is for
treatment of a mammal, including a human, afflicted with
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31
cystic fibrosis, said method comprising administering to
said human a therapeutically effective amount of the
compound represented by (IIb), and pharmaceutically
acceptable salts and prodrug derivatives thereof,
R1
14
R15 R13'X
J---R12 ( I I b )
R16
R17 R11
wherein ;
X is oxygen or sulfur;
R11 is selected from groups (i), (ii) (iii) and (iv)
where:
(i) is C6-C20 alkyl, C6-C20 alkenyl, C6-C20
alkynyl, C6-C20 haloalkyl, Cq-C12 cycloalkyl, or
(ii) is aryl or aryl substituted by halo, nitro,
-CN, -CHO, -OH, -SH, C1-C10 alkyl, C1-C10 alkylthio, C1-C10
alkoxyl, carboxyl, amino, or hydroxyamino; or
(iii) is -(CH2)n-(Rg0), or -(NH)-(Rgl), where n is
1 to 8, and Rg0 is a group recited in (i), and Rgl is
selected from a group recited in (i) or (ii);
(iv) is
I
Raa
Rep
where Rg~ is hydrogen or C1-C10 alkyl, and Rgg is selected
from the group; phenyl, naphthyl, indenyl, and biphenyl,
unsubstituted or substituted by halo, -CN, -CHO, -OH, -SH,
C1-C10 alkylthio, C1-C10 alkoxyl, phenyl, nitro, C1-C10
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32
alkyl, C1-C10 haloalkyl, carboxyl, amino, hydroxyamino; or a
substituted or unsubstituted 5 to 8 membered heterocyclic
ring;
R12 is halo, C1-C2 alkylthio, or C1-C2 alkoxy;
each R13 is independently hydrogen, halo, or methyl;
R14, R15~ R16~ and R1~ are each independently hydrogen,
C1-C10 alkyl, C1-C10 alkenyl, C1-C10 alkynyl, C3-Cg
cycloalkyl, aryl, aralkyl, or any two adjacent hydrocarbyl
groups in the set R14, R15~ R16~ and R1~, combine with the
ring carbon atoms to which they are attached to form a 5 or
6 membered substituted or unsubstituted carbocyclic ring; or
C1-C10 haloalkyl, C1-Clp alkoxy, C1-C10 haloalkoxy, C4-Cg
cycloalkoxy, phenoxy, halo, hydroxy, carboxyl, -SH, -CN,
C1-C1p alkylthio, arylthio, thioacetal, -C(O)O(C1-C10
alkyl), hydrazide, hydrazino, hydrazido, -NH2, -N02,
-NRg2Rg3, and -C(0)NRg2Rg3, where, Rg2 and Rg3 are
independently hydrogen, C1-C10 alkyl, C1-C10 hydroxyalkyl,
or taken together with N, Rg2 and Rg3 form a 5- to 8-
membered heterocyclic ring; or
a group having the formula;
84
Z C Q
Re P
where,
Rg4 and Rg5 are each independently selected from
hydrogen, C1-C10 alkyl, hydroxy, or Rg4 and Rg5
taken together are =0;
p is 1 to 5,
Z is a bond, -0-, -N(C1-C10 alkyl)-, -NH-, or -S-; and
Q is -CON(Rg2Rg3), -5-tetrazolyl, -S03H,
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33
O
- ORg s ,
ORg s
O
O ~ - OR86 '
ORg s
9
O ~CH2)~-- ~-R99 '
ORg s R9 9
0
~99
O ~ O (CH2)n ~ - R99
~Rg6 R99
O
\I
/C- ORgs
O
C ORgs
N
HO ~ /S '
N
where n is 1 to 8, Rg6 is independently selected from
hydrogen, a metal, or C1-Clp alkyl, and Rg9 is selected from
hydrogen or C1-Clp alkyl.
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34
The synthesis of the 1H-indole-3-acetamides of
structure (IIb) useful in the method of the invention can be
accomplished by known methods. A procedure useful for the
syntheses of these compounds is shown in the following
reaction scheme:
R3 O
ORB
R5 '-~'~ ~I ' R2
~N
g II
meth a
R3 O Rs O
ORa NHNH2
RS ~'' JI ~ R~- -~.Rm't~~.~ ~I ~ R2
v 1N meth b ~~N
R1 R1
Iv
rII
meth c
meth d
R3 O Rs O
OH NH2
R5 _'~ I ~ R2- ~5 ~ I ~ Rz
~~N meth a ~N
Ri R1
V
The 1H-indole-3-acetamide II may be alkylated by an alkyl
halide or arylalkyl halide in a solvent such as N,N-
dimethylformamide (DMF) in the presence of a base (method a)
to give intermediate 1-alkyl-1H-indole-3-acetic acid esters,
III. Bases such as potassium t-butoxide and sodium hydride
are useful. It is advantageous to react the indole, II, with
the base to first form the salt of II and then add alkylating
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agent. Treatment of the 1-alkyl-1H-indole-3-acetic acid
esters, III, with hydrazine or hydrazine hydrate in ethanol
(method b) gives the desired 1-alkyl-1H-indole-3-acetic acid
hydrazides, IV. This condensation to form IV may be carried
5 out at the reflux temperature of the solvent for a period of
1 to 24 hours. The acetic acid hydrazides, IV, are
hydrogenated to give the acetamides, I, by heating with Raney
nickel in ethanol (method c). The intermediate acetic acid
esters, III, can be first hydrolyzed to the acetic acid
10 derivatives, V (method d), which on treatment with an alkyl
chloroformate followed by anhydrous ammonia, also give
amides, I (method e).
d) 1H-indole-1-functional sPLA2 inhibitors of the
15 hydrazide, amide, or glyoxylamide types as described in
United States Patent No. 5,641,800, the entire disclosure of
which is incorporated herein by reference. The method of
the invention is for treatment of a mammal, including a
human, afflicted with cystic fibrosis, said method
20 comprising administering to said human a therapeutically
effective amount of a 1H-indole-1-acetamide or a
pharmaceutically acceptable salt, solvate or prodrug
derivative thereof; wherein said compound is represented by
the formula (Ic)
12
K
(Ic)
wherein for Formula (Ic):
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36
X is oxygen or sulfur;
each R1 is independently hydrogen, or C1-C3 alkyl;
R3 is selected from groups (a), (b) and (c) where;
(a) is C~-C20 alkyl, C-7-C2p alkenyl, C~-C20
alkynyl, carbocyclic radical, or heterocyclic radical, or
(b) is a member of (a) substituted with one or
more independently selected non-interfering substituents; or
(c) is the group -(L)-RgO; where, -(L)- is a
divalent linking group of 1 to 12 atoms and where Rgp is a
group selected from (a) or (b)
R2 is hydrogen, halo, C1-C3 alkyl, C3-C4
cycloalkyl, C3-C4 cycloalkenyl, -0-(C1-C2 alkyl), -S-(C1-C2
alkyl), or a non-interfering substituent having a total of
1 to 3 atoms other than hydrogen;
R6 and R~ are independently selected from
hydrogen, a non-interfering substituent, or the group,
-(La)-(acidic group) wherein -(La)-, is an acid linker
having an acid linker length of 1 to 10; provided, that at
least one of R6 and R~ must be the group, -(La)-(acidic
group);
R4 and R5 are each independently selected from
hydrogen, non-interfering substituent, carbocyclic radical,
carbocyclic radical substituted with non-interfering
substituents, heterocyclic radical, and heterocyclic radical
substituted with non-interfering substituents.
1H-indole-1-hydrazide compounds useful as sPLA2 inhibitors
in the practice of the method of the invention are as
follows:
A 1H-indole-1-hydrazide compound or a pharmaceutically
acceptable salt, solvate or prodrug derivative thereof;
wherein said compound is represented by the formula (IIc);
CA 02304482 2000-03-24
WO 99116453 PCT/US98/19906
37
R4
R5
(IIc)
~R12
Rfi \ N~ R1
R1
HNH2
wherein for formula (IIc);
X is oxygen or sulfur;
each R1 is independently hydrogen, or C1-C3 alkyl;
R3 is selected from groups (a), (b) and (c) where;
(a) is C7-C2p alkyl, C7-C2p alkenyl, C7-C20
alkynyl, carbocyclic radical, or heterocyclic radical, or
(b) is a member of (a) substituted with one or
more independently selected non-interfering substituent; or
(c) is the group -(L)-RgO; where, -(L)- is a
divalent linking group of 1 to 12 atoms and where Rg0 is a
group selected from (a) or (b);
R2 is hydrogen, halo, C1-C3 alkyl, C3-C4
cycloalkyl, C3-Cq cycloalkenyl, -O-(C1-C2 alkyl), -S-(C1-C2
alkyl), or a non-interfering substituent having a total of
ltto 3 atoms other than hydrogen;
R6 and R7 are independently selected from
hydrogen, a non-interfering substituent, or the group,
-(La)-(acidic group) wherein -(La)-, is an acid linker
having an acid linker length of 1 to 10; provided, that at
least one of R6 and R7 must be the group, -(La)-(acidic
group);
Rq and R5 are each independently selected from
hydrogen, non-interfering substituent, carbocyclic radical,
carbocyclic radical substituted with non-interfering
substituents, heterocyclic radical, and heterocyclic radical
substituted with non-interfering substituents.
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38
e) Indolizine sPLA2 inhibitors and their method of
preparation are described in US Patent Application Serial
No. 08/765566, filed July 20, 1995 (titled, "Synovial
Phospholipase A2 Inhibitor Compounds Having an Indolizine
Type Nucleus, Parmaceutical Formulations Containing Said
compounds, and Therapeutic Methods of Using said .
Compounds"), the entire disclosure of which is incorporated
herein by reference; and also in European Patent
Publication No. 0772596, published May 14, 1997. The method
of the invention is for treatment of a mammal, including a
human, afflicted with cystic fibrosis, said method
comprising administering to said human a therapeutically
effective amount of 1H-indole-1-functional compound or a
pharmaceutically acceptable salt, solvate or prodrug
derivative thereof; wherein said compound is represented by
the formula (Id) ;
R11
18
R17 R11- X
R12 (I
N
R16
R15 R13
wherein;
X is oxygen or sulfur;
each R11 is independently hydrogen, C1-C3 alkyl, or
halo;
R13 is selected from groups (a), (b) and (c) where;
(a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20
alkynyl, carbocyclic radical, or heterocyclic radical, or
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39
(b) is a member of (a) substituted with one or
more independently selected non-interfering substituents; or
(c) is the group -(L)-RgO; where, -(L)- is a
divalent linking group of 1 to 12 atoms and where Rgp is a
group selected from (a) or (b) ;
R12 is hydrogen, halo, C1-C3 alkyl, C3-Cq cycloalkyl,_
C3-Cq cycloalkenyl, -O-(C1-C2 alkyl), -S-(C1-C2 alkyl), or a
non-interfering substituent having a total of 1 to 3 atoms
other than hydrogen;
R1~ and R1g are independently selected from hydrogen, a
non-interfering substituent, or the group, -(La)-(acidic
group) wherein -(La)-, is an acid linker having an acid
linker length of 1 to 10; provided, that at least one of R1~
and R1g must be the group, -(La)-(acidic group); and
R15 and R16 are each independently selected from
hydrogen, non-interfering substituent, carbocyclic radical,
carbocyclic radical substituted with non-interfering
substituents, heterocyclic radical, and heterocyclic radical
substituted with non-interfering substituents.
Particularly preferred 1H-indole-1-functional compounds
useful as sPLA2 inhibitors in the practice of the method of
the invention are as follows:
An indolizine-1-acetic acid hydrazide compound or a
pharmaceutically acceptable salt, solvate or prodrug
derivative thereof where said compound is represented by the
formula (IId);
NHNHZ
R1 g R11 \
R17 R11~ X
R12 (IId)
R16
15 R13
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Particularly preferred 1H-indole-1-functional compounds
useful as sPLA2 inhibitors in the practice of the method of
the invention are as follows:
5 An indolizine-1-glyoxylamide compound or a pharmaceutically
acceptable salt, solvate or prodrug derivative thereof;
wherein said compound is represented by the formula (IIId);
X
R18
R17 ~ X
R12 (IIId)
N.", /
R16
R15 R13
10 Another preferred 1H-indole-1-functional compounds
useful as sPLA2 inhibitors in the practice of the method of
the invention are as follows:
An indolizine-3-acetamide compound or a pharmaceutically
acceptable salt, solvate or prodrug derivative thereof;
15 wherein said compound is represented by the formula (IVd),
as set out below:
Dsl
R7
R6
(IVd)
wherein;
20 X is selected from oxygen or sulfur;
each R3 is independently hydrogen, C1-C3 alkyl, or
halo;
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41
R1 is selected from groups (a), (b) and (c) where;
(a) is C~-C20 alkyl, C~-C2p alkenyl, C~-C20
alkynyl, carbocyclic radical, or heterocyclic radical, or
(b) is a member of (a) substituted with one or
more independently selected non-interfering substituents; or
(c) is the group - (L) -RgO; where, - (L) - is a
divalent linking group of 1 to 12 atoms and where Rg0 is a
group selected from (a) or (b);
R2 is hydrogen, halo, C1-C3 alkyl, C3-Cq cycloalkyl,
C3-Cq cycloalkenyl, -0-(C1-C2 alkyl), -S-(C1-C2 alkyl), or a
non-interfering substituent having a total of 1 to 3 atoms
other than hydrogen;
R5 and R6 are independently selected from hydrogen, a
non-interfering substituent, or the group, -(La)-(acidic
group) wherein -(La)-, is an acid linker having an acid
linker length of 1 to 10; provided, that at least one of R5
and R6 must be the group, -(La)-(acidic group);
R~ and Rg are each independently selected from
hydrogen, non-interfering substituent, carbocyclic radical,
carbocyclic radical substituted with non-interfering
substituents, heterocyclic radical, and heterocyclic radical
substituted with non-interfering substituents.
Particularly preferred 1H-indole-1-functional compounds
useful as sPLA2 inhibitors in the practice of the method of
the invention are as follows:
An indolizine-3-hydrazide compound or a pharmaceutically
acceptable salt, solvate or prodrug derivative thereof;
wherein said compound is represented by the formula (Vd), as
set out below:
CA 02304482 2000-03-24
WO 99/16453 PCT/L1S98/19906
42
R1
R7
R2 (Vd)
N
R6 \ _R3~X
HNHZ
Particularly preferred 1H-indole-1-functional compounds
useful as sPLA2 inhibitors in the practice of the method of
the invention are as follows:
An indolizine-3-glyoxylamide compound or a pharmaceutically
acceptable salt, solvate or prodrug derivative thereof;
wherein said compound is represented by the formula (VId),
as set out below:
R7
R6
(VId)
Particularly preferred 1H-indole-1-functional compounds
useful as sPLA2 inhibitors in the practice of the method of
the invention are as follows:
An indolizine-1-acetamide functional compound or a
pharmaceutically acceptable salt, solvate or prodrug
derivative thereof; wherein said compound is selected from
the group represented by the following formulae:
43
Image
44
Image
45
Image
CA 02304482 2000-03-24
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46
HOOC
and mixtures of the above compounds.
Other particularly preferred 1H-indole-1-functional
compounds useful as sPLA2 inhibitors in the practice of the
method of the invention are as follows:
An indolizine-1-glyoxylamide functional compound and a
pharmaceutically acceptable salt, solvate or prodrug
derivative thereof; wherein said compound is selected from
the group represented by the following formulae:
HOOC~ O __ ~__-_
CH~ CONH
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47
HOOC~ O ~,"",T,TTT
HOOC~ O .""",TTTT
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WO 99/16453 PCT/US98/19906
48
HOOC
C1
HOOC/ \ O
,.
CF3
CA 02304482 2000-03-24
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49
HOOC~ O ........_...
HOOC~ O ,~~~,~"T,t
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WO 99/16453 PCT/US98/19906
HOOC~ O ........_,..
H
~N ~ O /'1/'1/~IITTTT
N- N
C1
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51
HOOC
HOOC~ O ""n""T,.
HOOC
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52
HOOC/ \ O r~nnn~.~rv_
HOOC~ O rnr,,.~NH2
C2 H5
~ n- C4Hg
HOOC
CA 02304482 2000-03-24
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53
HOOC~ O ",""""TT
HOOC~ O /~I~(~t,,TTV
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54
HOOC~ O r,",-~r,rru
HOOC/ \ O /Y !1 /Y!1'ATTT
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HOOC
HOOC~ O /-./,/~/~T,TTT
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HOOC/ \ O nnnn,.m
OMe
HOOC/
02 N
HOOC~ O r.,r,~.",nT_
(n-CsHli
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HOOC~ O r''nr''r~NH2
CH3
~1-adamantyl
HOOC/ \ O rt"~~1/~T,TTT
HOOC~ O r~nrTnrTU_
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HOOC
(n-C4H9
HOOC~ 0 r~nr~n~.TU_
Hood
59
Image
60
Image
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61
HOOC~ O nnnnTTV
HOOC~ O "~"~,,TTT
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HOOC~ ~
HOOC~ O
2
C2H5
CH=CH
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HOOC~ O
C2 H5
~H2 - CH2
HOOC~ O ~~~~___t
HOOC
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64
HOOC ~ 0 ~~~~a,tr
HOOC
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HOOC
HOOC O ~~ ~~,.'._
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66
HOOC
rnc~nNU.,
HOOC
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67
HOOC
HOOC
~,/ O ......~_w.
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68
COCONH~
HOOC
CD CONH.,
HOOC
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HOOC/ \ ~ COCONH~
HOOC
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HOOC/ \ O ~~~~~r.r
HOOC ( CH2 ) 30
COCONH2
5
and mixtures of the above compounds.
The indolizine compounds may be made by one of more of the
following reaction schemes:
The following abbreviations are used throughout the
synthesis Schemes:
Bn benzyl
THF tetrahydrofuran
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71
LAH lithium aluminum hydride
LDA lithium diiopropyl amine
DBU 1,8-diazabicyclo 5.4.0]undec-7-une
Scheme le - Part 1
CH3 ~ CN ~ Bra
~i .. O
CH O~ LD I ~ NaHC03~
3 CH30~ N O
1 2
O
LiAIH ~~ CICOCOOEt
~ A
CH O~N~rEt > ~ ~~ Et
s 3 CH3 ~ N
4
1 ) (COCI)2
2) NH40H
1) CICOOEt
i ~. ~_ l LiOf~ i ~ ' l Z) NH40H
-Et ~ N ~ Et ~ w NJ Et
CH30 COCOOEt CH3 COCOOR CH30 'COCONH2
6: R=Li, 7:R=H 8
BBr ~ ~ Br(CH2)3COO~t
HO ~ N ~ Et ROOC ( CHz ) 30 1 N COCONH
COCONH2 2
10: R=Et, 11: R=H
The anion of 2-methyl-5-methoxypyridine is formed in
THF using lithium diisopropyl amide and reacted with
benzonitrile to produce 2. Alkylation of the nitrogen of
2tby 1-bromo-2-butanone followed by base catalyzed
cyclization forms 3 which is reduced by LAH to 4. Sequential
treatment of 4 with oxalyl chloride and ammonia gives 8.
Alternatively, 4 is acylated with ethyl oxalyl chloride to
give 5 which is converted to 6 with lithium hydroxide and
then to 8 by sequential treatment with ethyl chloroformate
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72
and ammonium hydroxide. Demethylation of 8 by BBr3 yields 9
which is 0-alkylated using base and ethyl 4-bromobutyrate to
form 10. Hydrolysis of 10 by aqueous base produces 11.
Scheme 2e - Part 1
Bn0 Bn0 HO
w COOEt Hz. Pd- ~ COOEt COOEt
.N ~ .N ~' ~ .N
12 13 14
HO Bn0 ~R
NH40H ~CONHz CONHz X II z
> ~I BnCI ~' O
N KzC03 > ~ N NaHCO >
3
16 13~
Rs0 CORD
Rs0 CORD
R4COCI ~ ~ Rz
Rz >
Ra
17a-d O 18a-g
17 R~ R~ 18 R~ Rz R3 R4
R,
a: Et Bn a: OEt Et Bn o-Ph-Ph
OEt
b: Et Bn b: NHz Et Bn o-Ph-Ph
NHz
c: Et CH2COEt c: NHz Et Bn m-CI-Ph
NHz
d: cyclo-PrBn d: NHz Et CH2COEtm-CI-Ph
NHz
e: NHz cyclo-PrBn o-Ph-Ph
f: NHz Et Bn Ph
g: NHz Et Bn 1-Naphthyl
Compound 12 (N. Desidiri, A. Galli, I. Sestili, and M.
L. Stein, Arch. Pharm. (Weinheim) 325, 29, (1992)) is
10 reduced by hydrogen in the presence of Pd/C to 14 which
gives 15 on ammonolysis using ammonium hydroxide.
O-alkylation of 15 using benzyl chloride and base affords
16. Alkylation of the nitrogen atom of 13 or 16 by 1-bromo-
2-ketones followed by base catalyzed cyclization yields
15 indolizines 17 which are acylated by aroyl halides to form
18.
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Scheme 2e - Part 2
R30 R~ HO CONHz
tBuNHz BH ~ w ~Rz Hz, Pd- ~ ~ ~R2 Bra COORS
AICI3 ~' R4 '- R4
19a-g 20v-z
R300C~ HOOC~ O CONHz
O CONHz
'Rz H2, Pd-C
~ ~ Rz
'
s
or LiOH
R
21
v-z 22v-z
19 RL R2 R3 R9.
a: CH20HEt Bn o-Ph-Ph
b: CONHzEt Bn o-Ph-Ph
c: CONHzEt CH2CH(OH)Et m-CI-Ph
d: CONHzEt Bn m-CI-Ph
e: CONHzcyclo-PrBn o-Ph-Ph
f: CONHzEt Bn Ph
g: CONHzEt Bn 1-Naphthyl
20-22Rz R3 R4
v: Et Et Ph
w: Et Me 1-Naphthyl
x: Et Bn o-Ph-Ph
y: Et Bn m-CI-Ph
z: cyclo-Pr Me o-Ph-Ph
Reduction of 18 by tert-butylamine-borohydride and
aluminum chloride yields 19 which is reduced by hydrogen in
the presence of Pd/C to give 20. 0-alkylation of 20 by
benzyl bromoacetate and base forms 21 which is converted to
the acid 22 by debenzylation using hydrogen in the presence
of Pd/C.
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Scheme 3e - Part 1
~, Ri
OH BnCI Bn0 O
NaHC03
( ~I~ COOEt '~'>~ ~I~ COOEt ~>
~N ~N
23 24
Bn0 ~ OOEt
Bn0 COOEt ~ N / Ri 1) 1N KOH1DMS0
R2COC1 ~- 2) 1 N HCI
N~-Rl Et3N > ~ R2 3 ) heat >
25a: R~=Et 26a-f
b: R~=cyclo-Pr
Bn0 Bn0
~,~Rl w N~Ri
~ LiAIH4
O?' R2 > ~ R2
27a-f 28a-f
26-28R~ R2
a: Et Ph
b: Et o-Ph-Ph
c: Et m-CI-Ph
d: Et m-CF3-Ph
e: Et 1-Naphthyl
f: cyclo-Pro-Ph-Ph
Compound 23 (N. Desideri F. Manna, M. L. Stein, G.
Bile, W. Filippeelli, and E. Marmo, Eur. J. Med. Chem. Chim.
Ther., 18, 295, (1983)) is 0-alkylated using sodium hydride
and benzyl chloride to give 24. N-alkylation of 24 by
1-bromo-2-butanone or chloromethylcyclopropyl ketone and
subsequent base catalyzed cyclization gives 25 which is
acylated by aroyl halide to give 26. Hydrolysis of the ester
function of 26 followed by acidification forms an acid which
is thermally decarboxylated to give 27. Reduction of the
ketone function of 27 by LAH yields indolizines 28.
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Scheme 3e - Part 2
R1 COOEt
0 Rl i
+ a w N ~ Me KOH
R2~ ~ ~ COOEt ~ ~ DMS(
Br N R
2
29a: RrPh 24a: R~=OBn 31a: R~=H, Rz=Ph
b: Rrcyclo-Hex. b: R~=OMe b: R1=OBn, R2=Ph
30a: R~=H c: R~=OMe, R2=Ph
d R~=OBn, RZ=cyclo-Hex
Rl COOH Ri
w N ~ Me o w N ~ Me
Rz R2
32a: R~=H, R2=Ph 33a: R~=H, R2=Ph
b: R~=OBn, RZ=Ph b: R~=OBn, R2=Ph
c: R~=OMe, R2=Ph c: R~=OBn, R2=cyclo-Hex
d: R~=OBn, R2=cyclo-Hex
Heating a mixture of 3-bromo-4-phenyl-butan-2-one or
5 3-bromo-4-cyclohexyl-butan-2-one and ethyl pyridine-2-
acetate, or a substituted derivative, in the presence of
base yields indolizine 31. Treatment of 31 with aqueous base
in DMSO at elevated temperature followed by acidification
gives 32 which is thermally decarboxylated to 33.
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Scheme 4e - Part 1
COCONHz Bn0 COCONR1R2
1 ) (COCIy~ ~ ~.
28a-f 2) HNR~ RZ ~ N ~ Me ~ N ~ R3 H2, Pd-C
or > or -y>
33a-c R
4
34 35a-I
HO COCONR1R2 grCH2COOR5 R500C,,~0 COCONR1R2
I NaH ~ .-
~ N / R3 > ~N~ R3
R4 ~ R4
36a-I 37a-d,f-k: R5=Et
38a: RS=tBu
39d,i,k, I: RS=Me
HOOC,~O COCONRIRz
35-40R~ R2 R3 R4
KOHaq ~ .--
~ R3 a: H H Et Ph
N b: H Me Et Ph
MeOH
~ c: Me Me Et Ph
R4
d: H H Et o-Ph-Ph
40a-d,f-1 e: H Me Et o-Ph-Ph
f: Me Me Et o-Ph-Ph
g: H H Me Ph
h: H H Et m-CI-Ph
i: H H Et m-CF3-Ph
j: H H Et 1-Naphthyl
k: H H cyclo-Pr
o-Ph-Ph
I: H H Me cyclo-Hex
Sequential treatment of 28 or 33 with oxalyl chloride
and ammonium hydroxide forms 35 which is debenzylated by
hydrogen in the presence of Pd/C to give 36. Indolizines 36
are O-alkylated using sodium hydride and bromoacetic acid
esters to form 37, 38, or 39 which are converted to
indolizines 40 by hydrolysis with aqueous base followed by
acidification.
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Scheme 4e - Part 2
N~
NG 1) M SnN ~~~0 COCONHZ
Na iH2CN 2) HC gas3 ~ ,'
36h s --~ ~ N / ~Et
CJ C1
41 42
The O-alkylation of 36h produces nitrile 41 which is
converted to 42 on reaction with trialkyltin azide.
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78
Scheme 5e
OH OR ~ R2
Me BnBr ~, Me O
-> ~1 >
~
N or N RZ=Me,
Et,
Mel cycto-Pro
43 44a: R=Bn
Br
X=CI
~ R=Me ,
ORl
MeD DBU ORl RCOCI
w N*~ ~ l / R2 -.>
R ~N~
2
Br
45a-e 46a-e
ORl
LiAIH4 or
~N~R2 >
NaBH4
O R3 AIC13
47a-m,o-w
45, R~ R2 47-52R~ R2 R3
46
a: Bn Et a-o Bn Et a-o (see
below)
b: Me Et p Bn Me 1-adamantyl
c: Bn Me q Bn Me o-biphenyl
d: Me cyclo-Pror Bn cycloProphenyl
e: Bn cyclo-Pro$ Me Et p-n-C4ti9-Ph
t Bn Me cyclo-Hex
a Me cycloProcyclo-Hex
v Bn cycloProcyclopentyl
w Bn Me cyclolpentyl
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79
OR1 1) (COCI 2 OR1 COCONH2
) I H2, Pd-C
i ~ _ i _
w N~ R2 > w N~ R2
2) NH40H or BBr3
R3 R3
48a-t, v, w 49a-t, v, w
OH COCONH2 Me00C~ O COCONH2 HOOC~ O COCONHz
Br's COOMe ~~ ~ OH-
.\ N / -R2 s w N / Rz > w N~R2
R KZC03' KI ~ Rs ~ Ra
3
50a-t, v, w 51a-t, v, w 52a-t, v, w
ORS 1) (COCI)2 ORl COCONH2 H , Pd-C
2
w N / R2 ~ ~ N / R2
2) NH40H or BBr3
R3 R3
48a-t 49a-t
OH COCONH2 Me00C~0 COCONH2 HOOC~O COCONH2
Br's COOMe ~ ~ OH'
w N R2 s .. N / R2 > N / R2
R K2C03, KI R3 R3
3
50a-t 51 a-t 52a-t
*rB
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47-52 R3=
a: ~ b: c: d:
i
e: n-C4HS f: g: ~ ~ ~ h: ~ ,
i: J~ k' / S i' ~ \~S
i S
N02
m: \ ~ n: \ ~ o: traps
OMe
nCSHlz
The hydroxypyridine is 0-alkylated to give 44 which is
heated with 2-haloketones to produce 45. Treatment of 45
5 with base causes cyclization to 46 which on heating with
acid chlorides yields acylindolizines 47 which are reduced
by aluminum hydride to the corresponding alkylindolizines
48. Sequential treatment of 48 with oxalyl chloride and then
ammonia gives 49. Cleavage of the ether functionality of 49
10 yields 50. The oxyacetic ester derivatives 51 are formed by
0-alkylation of 50 and then hydrolyzed to the oxyacetic
acids 52.
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Scheme 5e - Part 1
R
OH gr~COOMe Me00C~0 X~l'f
Me Me O DBU
II s ~ ~ > --s
R =Me, Et, iPr,
tBu, cyclo-Pro,
43 53 cyclo-pentyl
COC1
O~ COOMe ' ~ O~ COOMe Me00C" O
NaBH4
_AIC13 i
w NJ R1 ~ ~ N ~ R ~ ~, N~R7.
54a-e O' R' ~ R2
55a, b, d
56a-k
RzCH2X
54,55 R~ RZ
a: Me o-biphenyl
b: Et o-biphenyl
c: iPro o-biphenyl
ct cyclo-Pro cyclohexyl
e: tBu o-biphenyl
f: cyclopentyo-biphenyll
1) (COCI)Me00C~0 COCONH2 HOOC H
COCONH2
2 OH-
~ ~-R~ -s ~
N
/
R~
2) NH40H
R2 R2
57a,c,e-k 58a,c,e-k
56-58 RZ R~ RZ
R~
a Me o-biphenyl f cyclopentyl o-biphenyl
b Et o-biphenyl g Et m-biphenyl
c iPr o-biphenyl h Et cinnamyl
d cycloP ro o-biphenyl i Et phenethyl
a tBu o-biphenyl j cyclopropyl 1-naphthyl
k cyclopropyl cyclohexyl
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ROC~O i OCONHZ
r-
\ N ~-Et
I
58a-k
59a-k R=
a: -ONa b: -OCH(Me)OCOOMe c: -OCH(Me)OCOOiPr d: -OCH20COtBu
e:-OCH (Me) OCOO--( ) f;-OCH (Me) OCOO--O g; -OCH (Me) OCO-
b:-OCH (Me) OCO~~ i:-O (CH2) 2N~0 J: -(CH2)ZO- (dimer) k: COEt
HCI
Pyridine 43 is O-alkylated to produce 53. Heating 53
with 2-haloketones gives intermediate N -alkylated pyridinium
compounds which are cyclized to 54 on treatment with base.
Heating 54 with acyl chlorides gives the acylindolizines 55
which are reduced to the alkylindolizines 56 by sodium
borohydride-aluminum chloride. Alternatively, 56 are
produced by C-alkylation of 54 using alkyl halides.
Sequential treatment of 56 with oxalyl chloride and then
ammonia gives 57 which are hydrolyzed to produce 58.
Compound 58b is converted to its sodium salt 59a which
yields 59b-k on reaction with the appropriate alkyl halide.
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83
Scheme 6e - Part 2
OH COCONH2 R~ 0 COCONH2
~ N / -Et ~ N / Et
I
~i ~i
36d 591-p
591-p R=
H
N' NTr N-N
I: -(~, N m: -(N.N n: I
o: ~ p: \'N I
Compound 36b is 0-alkylated to give 591-p.
Scheme 7e
R1
Me ~Me X ~ CB~ MeO~~ RZCOCI
~~ ~N --s > ~ N~Ri >
R~= Et,
60 cyclo-Pro
61 a: R ~=Et
X=CI, Br b: R~=cycloPro
MeO~ ~ tBuNH2 BH3 MeO
N / Ri > ~ N / Ri
0 R AICI3 R
2 2
82a-d 63a-d
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84
COCONH
1) (COCI)2 COCONHz 2
Me0 \~~ BBr3 H01'
/ R1 > N..J Ri
2) NH40H
R2 ~ Rz
64a-d 65a-d
COOEt COOH
Br(CH2)3COOEt ~ COCONHz LiOH ~ COCONHz
0
_---.~ ~-Rl -> ~N / ~Rl
NaH
Rz Rz
66a-d 67a-d
62-67 R1 R2
a: Et Ph
b: cyclo Pro o-Ph-Ph
c: Et o-Ph-Ph
d: Et cyclohexyl
Pyridine 60 is N-alkylated by 2-haloketones to produce
intermediate pyridinium compounds which are cyclized by base
to give 61. Reaction of 61 with acyl chlorides produces 62
which are reduced to 63 by tert butylamine-borane and
aluminum chloride. Sequential treatment of 63 with oxalyl
chloride and then ammonia yields 64 which are 0-demethylated
by BBr3 to give 65. The sodium salt of 65 is reacted with
ethyl 9-bromobutyrate to give 66 which is hydrolyzed to the
acid 67.
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Scheme 8e
(CH2)nCOOR (CH2)nCOOH
Br(CHZj"COOEt I COCONHZ OH-
~~-Et
I~
~ i
36d, 65c ~ O ~ i '
O g~-c 69a-c
tBuOK 68-89 n position
(CH2)2COOR
I COCONHa
a: 3 8
N -Et b: 1 7
c: a 7
I~
i 70a: 8-, R=H
b: 7-, R=H
c: 8-, R=Me
Compounds 36d and 65c are 0-alkylated by omega
bromocarboxylic esters to give 68 which are hydrolyzed to
5 the acids 69. Compounds 36d and 65c produce 70 on treatment
with propiolactone and base.
Scheme 9e
(CH2)3COOEt (CH2)3COOR
COCONH2 ~ CH2 CONH2
tBuNHz BH3
AICI3
66c 71a: R=Et
b: R=H
Compounds 66 are reduced to 71 by tert-butylamine-
borane and aluminum chloride.
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86
Scheme 10e
OBn OBn
Br'~COOEt ~ 1)CSz
n
~N ~' ~ N*~ COOEt
2) ~ COOEt
Br
72
OBn Br COOEt OBn COOEt KOtBu
ii S s
~, N+ i COOEt '' ~. COOEt s-
5'~ DBU
COOEt 73
COOEt
74a+b a; g-substituted
b: 6-substituted
OBn COOEt NaH OBnCOOEt KOH OBnCOOH
N / SH ~ ~N~SMe -'' ~ N % SMe ~s
CH31 'r DMSO 1
COOEt COOEt COOH
75a,b 76 77
a: 8-substituted
b: 6-substituted
I ~ OBn
OBn ~ II i ~- _gMe 1) (COCI)2
i ~ ~ w N ~
~N~ SMe
2) NH40H
78
79
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87
OBnCOCONH2 OH COCONH2
1 N ~ -SMe BBr3 \ N ~ -SMe BrCH2COOMe
-v s
w I i w I i
I '' g0 I ~ 81
Me00C~ O HOOC'~ O COCONH2
COCONH2
i~
LiOH ' N j -SMe
\ N~SMe
I~
I
i
82 83
Pyridine 44b reacts with ethyl bromoacetate to produce
72 which is treated with CS2 and base and then with ethyl
acrylate to form 73. Reaction of 73 with base and ethyl
bromoacetate yields a mixture of regioisomers 74a+b, 6- and
8-benzyloxy compounds. Base treatment of 74a+b eliminates
ethyl acrylate to form 75 which is separated from the isomer
of 6-benzyloxy derivative and S-alkylated to give 76.
Hydrolysis of 76 forms 77 which is thermally decarboxylated
to yield 78. Compound 78 is C-alkylated to form 79 which on
sequential treatment with oxalyl chloride and then ammonia
forms 80. Ether cleavage of 80 gives 81 whose sodium salt is
alkylated by methyl bromoacetate to form 82 which are
hydrolyzed to acids 83.
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88
Scheme 11e - Part 1
0
Z-0-N ~Z Me00C~ NZ
Me
Me 0 ~ Me BrCHzCOOMe
II s - II s w N
~. N ~ N
84 85 86
Br
Me00C~ NZ Me00C'~ NZ COCONH2
~) ~COCIy
I _ ~
~ Me 2) NH40H
~ -Me
> ~
NaHC03 N N
l
87a: R=Ph
b: R=cyclo-Hexyl~ 88a-b
Me00C'~ HOOC~ NH COCONH2
NH COCONH2 LiOH I~ Me
H2, Pd-C ~
~ ~
M
> \ N
- >
e
lR lR
89a-b 90a-b
Aminopicoline 84 is converted to its N-CBZ derivative
85 whose anion is alkylated by methyl bromoacetate to
produce 86. Reaction of 86 with methyl alpha-bromoalkyl
ketones in the presence of base yields 87. Sequential
treatment of 87 with oxalyl chloride and then ammonia gives
88 which is converted to 89 by hydrogenolysis of the N-CBZ
20 function. Hydrolysis of 89 yields acids 90.
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89
Scheme lle - Part 2
Me00C~ NZ COCONHz 1) tBuNHz~BH3
~I ,.. AICI3
Me >
2) H2,Pd-C
I
88a
Me00C~ NH CONHZ HOOCH NH CONHz
i ..- LiOH
Me > ~ ~ Me
I
91 92
Compounds 88 are reduced by tert-butylamine-borane and
aluminum chloride to 91 which are hydrolyzed to acids 92.
Scheme 12e
OBn excess
OBn
Bra COOMe
/ I COOEt > / ~ COOEt KzC's
w N y COOMe
24
93
OBn COOEt Me O OBn COOEt NaOH
25 4 _
w N ~ OH KzCO 3 w N / OMe pMSO >
94
~~ I
I
OBn
1 ) (COCI) z
/)- OMe
2) NH40H
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OBn COCONH2 OH COCONH2
- OMe / ~-
OMe Br~ COOMe
--s
Pd-C
K2C0 3 , KI
,J
Me00C~ O ~ncp~2 HOOC~ 0 COCONH
2
' Na0' ~ N~- OMe
L ~J 97
Pyridine 24 is N-alkylated by methyl bromoacetate,
cyclized with base, and o-methylated using dimethysulfate to
5 give 94. Hydrolysis of the ester function of 94 followed by
thermal decarboxylation yields 2-methoxy-8-
benzyloxyindolizine which is C-alkylated at position 3 and
then reacted sequentially with oxalyl chloride and ammonia
to produce 95. Hydrogenolysis of the 8-benzyloxy group
10 followed by 0-alkylation gives 96 which is hydrolyzed to 97.
f) Indene sPLA2 inhibitors as described in US Patent
Application 08/776618 filed July 20 1995, (titled, Synovial
Phospholipase A2 Inhibitor Compounds having an Indene Type
15 Nucleus, Pharmaceutical Formulations Containing said
Compounds, and Therapeutic Methods of Using Said
Compounds"), the entire disclosure of which is incorporated
herein by reference, are useful in practicing the method of
the invention.
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The method of the invention is for treatment of a
mammal, including a human, afflicted with cystic fibrosis,
said method comprising administering to said human a
therapeutically effective amount of an indene-1-acetamide
compound or a pharmaceutically acceptable salt, solvate or
prodrug derivative thereof; wherein said compound is
represented by the formula (If);
N
(If)
wherein;
X is oxygen or sulfur;
each R1 is independently hydrogen, C1-C3 alkyl, or
halo;
R3 is selected from groups (a), (b) and (c) where;
(a) is C~-C20 alkyl, C~-C20 alkenyl, C~-C20
alkynyl, carbocyclic radical, or heterocyclic radical, or
(b) is a member of (a) substituted with one or
more independently selected non-interfering substituents; or
(c) is the group -(L)-RgO; where, -(L)- is a
divalent linking group of 1 to 12 atoms and where Rg0 is a
group selected from (a) or (b);
R2 is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl,
C3-C4 cycloalkenyl, -0-(C1-C2 alkyl), -S-(C1-C2 alkyl), or a
non-interfering substituent having a total of 1 to 3 atoms
other than hydrogen:
R6 and R~ are independently selected from hydrogen, a
non-interfering substituent, or the group, -(La)-(acidic
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group) wherein -(La)-, is an acid linker having an acid
linker length of 1 to 10; provided, that at least one of R6
and R~ must be the group, -(La)-(acidic group): and
Rq and R5 are each independently selected from
hydrogen, non-interfering substituent, carbocyclic radical,
carbocyclic radical substituted with non-interfering
substituents, heterocyclic radical, and heterocyclic radical
substituted with non-interfering substituents.
Suitable indene compounds also include the following:
An indene-1-acetic acid hydrazide compound or a
pharmaceutically acceptable salt, solvate or prodrug
derivative thereof; wherein said compound is represented by
the formula (IIf);
R1
R7
R1 'NHNHZ
R6
R2
R5
R4 R3
(IIf)
wherein:
X is oxygen or sulfur;
each R1 is independently hydrogen, C1-C3 alkyl, or
halo;
R3 is selected from groups (a), (b) and (c) where;
(a) is C~-C20 alkyl, C~-C20 alkenyl, C~-C20
alkynyl, carbocyclic radical, or heterocyclic radical, or
(b) is a member of (a) substituted with one or
more independently selected non-interfering substituents; or
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(c) is the group -(L)-RgO; where, -(L)- is a
divalent linking group of 1 to 12 atoms and where Rg0 is a
group selected from (a) or (b);
R2 is hydrogen, halo, C1-C3 alkyl, C3-Cq cycloalkyl,
C3-Cq cycloalkenyl, -0-(C1-C2 alkyl), -S-(C1-C2 alkyl), or a
non-interfering substituent having a total of 1 to 3 atoms
other than hydrogen;
R6 and R~ are independently selected from hydrogen, a
non-interfering substituent, or the group, -(La)-(acidic
group); wherein -(La)-, is an acid linker having an acid
linker length of 1 to 10; provided, that at least one of R6
and R~ must be the group, -(La)-(acidic group); and
Rq and R5 are each independently selected from
hydrogen, non-interfering substituent, carbocyclic radical,
carbocyclic radical substituted with non-interfering
substituents, heterocyclic radical, and heterocyclic radical
substituted with non-interfering substituents.
Suitable indene compounds for use in the method of the
invention also include the following:
An indene-1-glyoxylamide compound or a pharmaceutically
acceptable salt, solvate or prodrug derivative thereof;
wherein said compound is represented by the formula (IIIf);
R6
R5
(IIIf)
X is oxygen or sulfur;
R3 is selected from groups (a), (b) and (c) where;
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(a) is C~-C20 alkyl, C~-C20 alkenyl, C~-C20
alkynyl, carbocyclic radical, or heterocyclic radical, or
(b) is a member of (a) substituted with one or
more independently selected non-interfering substituents; or
(c) is the group -(L)-RgO; where, -(L)- is a
divalent linking group of 1 to 12 atoms and where Rg0 is a
group selected from (a) or (b);
R2 is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl,
C3-C4 cycloalkenyl, -O-(C1-C2 alkyl), -S-(C1-C2 alkyl), or a
non-interfering substituent having a total of 1 to 3 atoms
other than hydrogen;
R6 and R~ are independently selected from hydrogen, a
non-interfering substituent, or the group, -(La)-(acidic
group) wherein -(La)-, is an acid linker having an acid
linker length of 1 to 10; provided, that at least one of R6
and R~ must be the group, -(La)-(acidic group);
R4 and R5 are each independently selected from
hydrogen, non-interfering substituent, carbocyclic radical,
carbocyclic radical substituted with non-interfering
substituents, heterocyclic radical, and heterocyclic radical
substituted with non-interfering substituents.
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The method of making the indene compounds is as follows:
Scheme-if
OMe
OMe (RaCO)z0 OMe Ra cat.Pd-C/H2 _ Ra Brz
RaCOONa ~ i ~ COOH MeOH ~ ~ COOH AcOH
cxo
2a:4-OMe, Ra=Me 3a-c -
1 a:4-OMe PPA
1b:3-OMe 2b:3-OMe, R~Me
2c:3-OMe, Ra=Et TFA
r
OMe OMe O Me0 O O
Et PPA~ I i _Et ''at.Pd_C/H2' I / Ra (Et0)2NaH 2COOEt~
NaOAc
COOH
Br gr AcOH toluene
4 5 6a:6-OMe, Ra=Me
6b:7-OMe, R~Me
fic:7-OMe, Ra=Et
5
COOEt Me0 ~ COOEt
MeO~ ~ ~~ Ra
Me Of
7a 8b,c
8b:7-OMe, R"=Me
8c:7-OMe, Ra=Et
OMe COOEt OMe COOEt OMe COOEt
NBS, cat.(CeHSCOO)z ~ ~ ~ Ra H2 cat.P~ ~ ~ ~ Ra
CCI4 ~~ gr AcOH
8b,c 9b,c 7b,c
cat.H ZS04
CHC13
A mixture of an anisaldehyde 1, propionic anhydride,
10 and sodium propionate is heated to produce 2 which is
reduced by hydrogen in the presence of Pd/C to give 3. Acid
cyclization of 3 yields 6. Alternatively, the aromatic
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position para to the methoxy group of 3 is blocked by
bromination to give 4 which is cyclized to 5 by acid and
then debrominated using hydrogen and Pd/C to give 6.
Reaction of 6 with the anion of triethyl phosphonoacetate
produces 7 and/or 8. Radical bromination of 8 gives 9,
which on reduction with hydrogen in the presence of Pt02 .
yields 7. Alternatively, treatment of 8 with acid gives 7.
Scheme-2f
COOEt COON CONH2
PhCHO > I ' \ _Ra 1)BOP, NEt3 \ - a
\ _Ra MeONa ~i 2)NH3aq. > ~i R
MeOH Me0
Me0/ Me0 R~ CH3CN R,
Ta-c 10a-j 11 a j
CONH2 CONH2
BBr3 ~ ~\)-Ra 1)NaH > I ' \ _Ra
CH2Ch> Hp ~ 2)Br(CH2)~COOEt
R~ DMF EtOOC(CH2)n0 R\
12a-j 13a j
CONH2
1N NaOH~ ( ' \ _Ra
DMSO HOOC ( CH2 ) n~
R
14a j
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CONH2
\ Ra
Rb0
R
a : R=Ph Ra=Me6-Rd0n=3
b : R=Ph Ra=Me7-Rb0n=1 _
c : R=Ph Ra=Et7-Re0n=1
d : R=o-Ph-PhRa=Et7-Re0n=1
a : R=o-Bn-PhRa=Et7-Rb0n=1
f : R=m-CI-PhRa=Et7-Rb0n=1
g ; R=o,m-di-CI-Ph 7-Rb0n=1
Ra=Et
h : R=m-CF3-PhR~=Et7-Rb0n=1
I ; R=1-NaphthylRa=Et7-Rb0n=1
J : R=2-NaphthylRe=Et7-Re0n=1
where Rb i s - ( CHZ ) nCOOH
Compound 7 is condensed with benzaldehyde and its
derivatives in the presence of base to give 10. Indenes 10
are converted to an active ester using benzotriazo-1-
yloxytris(dimethylamino) hexafluorophosphonate and then
reacted with ammonium hydroxide to form 11. Demethylation of
11 with BBr3 forms 12 which is 0-alkylated using sodium
hydride and an omega-bromoalkanoic acid ester to produce 13.
Aqueous base hydrolysis of 13 yields 14.
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Scheme-3f
OH CONH2 Me00C~ CONH2
~ Et 1)NaH ,~ I ~ ~ Et
2)BrCHZCOOMe
DMF
I~ I~
12c 15
Me00C~ CONHz HOOCH CONH2
I ' "Et 1 N NaOH~ I ~ ~ Et
MeOH
I
cat. Pd/C 16a 17a
Hz
Me00C~ CONHZ HOOCH CONH2
Et 1 N NaOH' I ~ / Et
MeOH
I
16b 17b
Compound 12c is 0-alkylated using sodium hydride and
methylbromoacetate to product 15 which is reduced by
hydrogen in the presence of Pd/C to give a mixture of
isomers 16a and 16b. Aqueous base hydrolysis of 16a and 16b
gives I7a and 17b respectively.
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OMe H
COOH OMe ~ COOH
~ -Et ~~. I ~>-Et )BOP, NEt3 ~
2) Air ~ ' 2)NH3aq.
THF ~ CH3CN
I i I ~ I i
10d 18
H
OMe ~ CONHZ cat.TPAP OMe CONHZ
~~_Et NMO ~ ~ ~ ~ -Et
CHZCIZ
19 20
Compound lOd is treated with lithium diisopropylamine,
then air is bubbled into the solution to give 18. The
indene 18 is converted to an active ester using benzotriazo-
1-yloxytris(dimethylamino)hexafluorophosphonate and then
reacted with ammonium hydroxide to form the hydroxy
acetamide 19. Compound 19 is oxidized to 20 using
N-methylmorpholine N-oxide in the presence of
tetrapropylammonium perruthenate.
g) Carbazole and tetrahydrocarbazole sPLA2 inhibitors and
methods of making these compounds are set out in United
States Patent Application SN 09/063066 filed April 21, 1998
(titled, "Substituted Carbazoles and 1,2,3,4-
Tetrahydrocarbazoles"), the entire disclosure of which is
incorporated herein by reference. The method of the
invention includes treatment of a mammal with these
compounds.
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The method of the invention is for treatment of a
mammal, including a human, afflicted with cystic fibrosis,
said method comprising administering to said human a
therapeutically effective amount carbazole or
tetrahydrocarbazole represented by the following:
A compound of the formula (Ie)
COR1
Rz,
sue, , D a
6 A s Z 3 Rzi
7 8~ 9.. 1 2
R3, B
Rzo
(Ie)
wherein;
R is phenyl or pyridyl wherein the nitrogen is at the 5-,
6-, 7- or 8-position;
one of B or D is nitrogen and the other is carbon;
Z is cyclohexenyl, phenyl, pyridyl, wherein the nitrogen
is at the 1-, 2-, or 3-position, or a 6-membered
heterocyclic ring having one heteroatom selected from
the group consisting of sulfur or oxygen at the 1-,
2- or 3-position, and nitrogen at the 1-, 2-, 3- or
4-position;
is a double or single bond;
R20 is selected from groups (a), (b) and (c) where;
(a) is -(C5-C20)alkyl, -(C5-C20)alkenyl,
(C5-C20)alkynyl, carbocyclic radicals, or
heterocyclic radicals, or
(b) is a member of (a) substituted with one or more
independently selected non-interfering
substituents; or
(c) is the group -(L)-R80; where, -(L)- is a divalent
linking group of 1 to 12 atoms selected from
carbon, hydrogen, oxygen, nitrogen, and sulfur;
wherein the combination of atoms in -(L)- are
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selected from the group consisting of (i) carbon
and hydrogen only, (ii) one sulfur only, (iii)
one oxygen only, (iv) one or two nitrogen and
hydrogen only, (v) carbon, hydrogen, and one
sulfur only, and (vi) and carbon, hydrogen, and
oxygen only; and where R$0 is a group selected
from (a) or (b) ;
R21 is a non-interfering substituent;
R1' is -NHNH2, -NH2 or -CONH2;
R2' is selected from the group consisting of -OH, and
-O(CH2)tR5' where
R5~ is H, -CN, -NH2, -CONH2~ -CONR9R10 -NHS02R15~
-CONHS02R15, where R15 is -(C1-C6)alkyl or -CF3;
phenyl or phenyl substituted with -C02H or
-C02(C1-Cq)alkyl; and -(La)-(acidic group), wherein
-(La)- is an acid linker having an acid linker length
of 1 to 7 and t is 1-5;
R3~ is selected from non-interfering substituent,
carbocyclic radicals, carbocyclic radicals
substituted with non-interfering substituents,
heterocyclic radicals, and heterocyclic radicals
substituted with non-interfering substituents; or a
pharmaceutically acceptable racemate, solvate,
tautomer, optical isomer, prodrug derivative or salt
thereof;
provided that; when R3~ is H, R20 is benzyl and m is 1 or
2; R2~ cannot be -0(CH2)mH; and
provided that when D is nitrogen, the heteroatom of Z is
selected from the group consisting of sulfur or oxygen at
the 1-, 2- or 3-position and nitrogen at the 1-, 2-, 3- or
4-position.
Preferred in the practice of the method of the invention
are compounds represented by the formula (IIe):
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R2i
R_ _.
CHZR4 (IIe)
wherein;
Z is cyclohexenyl, or phenyl;
R21 is a non-interfering substituent;
R1 is -NHNH2 or -NH2;
R2 is selected from the group consisting of -OH and
-O(CH2)mR5 where
O
R5 is H, -C02H, -CONH2, -C02(Cl-Cq alkyl); P(R6R~),where
R6 and R~ are each independently -OH or
-0(C1-Cq)alkyl; -SO~H, -S03(C1-Cq alkyl), tetrazolyl,
-CN, -NH2, -NHS02R15; -CONHS02R15, where R15 is
-(C1-C6)alkyl or -CF3, phenyl or phenyl substituted
with -C02H or -C02(C1-Cq)alkyl where m is 1-3;
R3 is H, -O(C1-Cq)alkyl, halo, -(C1-C6)alkyl, phenyl,
-(Cl-Cq)alkylphenyl; phenyl substituted with
-(C1-C6)alkyl, halo, or -CF3; -CH20Si(C1-C6)alkyl,
furyl, thiophenyl, -(C1-C6)hydroxyalkyl; or -(CH2)nR8
where R8 is H, -CONH2, -NR9R10, -CN or phenyl where R9
and R10 are independently -(C1-Cq)alkyl or
-phenyl(Cl-Cq)alkyi and n is 1 to 8;
Rq is H, -(C5-Clq)alkyl, -(C3-Clq)cycloalkyl, pyridyl,
phenyl or phenyl substituted with -(Cl-C6)alkyl, halo,
-CF3, -OCF3, -(C1-Cq)alkoxy, -CN, -(C1-Cq)alkylthio,
phenyl(C1-Cq)alkyl, -(C1-Cq)alkylphenyl, phenyl,
phenoxy or naphthyl;
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or a pharmaceutically acceptable racemate, solvate,
tautomer, optical isomer, prodrug derivative or salt,
thereof.
Preferred specific compounds including all salts and
prodrug derivatives thereof, for practicing the method of
the invention are as follows:
9-benzyl-5,7-dimethoxy-1,2,3,4-tetrahydrocarbazole-4-
carboxylic acid hydrazide;
9-benzyl-5,7-dimethoxy-1,2,3,4-tetrahydrocarbazole-4-
carboxamide;
[9-benzyl-4-carbamoyl-7-methoxy-1,2,3,4-tetrahydrocarbazol-
5-yl]oxyacetic acid sodium salt;
[9-benzyl-4-carbamoyl-7-methoxycarbazol-5-yl]oxyacetic acid;
methyl [9-benzyl-4-carbamoyl-7-methoxycarbazol-5-
yl]oxyacetic acid;
9-benzyl-7-methoxy-5-cyanomethyloxy-1,2,3,4
tetrahydrocarbazole-4-carboxamide;
9-benzyl-7-methoxy-5-(1H-tetrazol-5-yl-methyl)oxy)-1,2,3,4-
tetrahydrocarbazole-4-carboxamide;
{9-[(phenyl)methyl]-5-carbamoyl-2-methyl-carbazol-4-
yl}oxyacetic acid;
{9-[(3-fluorophenyl)methyl]-5-carbamoyl-2-methyl-carbazol-4-
yl}oxyacetic acid;
{9-[(3-methylphenyl)methyl]-5-carbamoyl-2-methyl-carbazol-4-
yl}oxyacetic acid;
{9-[(phenyl)methyl]-5-carbamoyl-2-(4-trifluoromethylphenyl)-
carbazol-4-yl}oxyacetic acid;
9-benzyl-5-(2-methanesulfonamido)ethyloxy-7-methoxy-1,2,3,4-
tetrahydrocarbazole-4-carboxamide;
9-benzyl-4-(2-methanesulfonamido)ethyloxy-2-
methoxycarbazole-5-carboxamide;
9-benzyl-4-(2-trifluoromethanesulfonamido)ethylaxy-2-
methoxycarbazole-5-carboxamide;
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9-benzyl-5-methanesulfonamidoylmethyloxy-7-methoxy-1,2,3,4-
tetrahydrocarbazole-9-carboxamide;
9-benzyl-4-methanesulfonamidoylmethyloxy-carbazole-5-
carboxamide;
[5-carbamoyl-2-pentyl-9-(phenylmethyl)carbazol-4-
yl]oxyacetic acid;
[5-carbamoyl-2-(1-methylethyl)-9-(phenylmethyl)carbazol-4-
yl]oxyacetic acid;
[5-carbamoyl-9-(phenylmethyl)-2-[(tri(-1-
methylethyl)silyl)oxymethyl]carbazol-4-yl]oxyacetic
acid;
[5-carbamoyl-2-phenyl-9-(phenylmethyl)carbazol-4-
yl]oxyacetic acid[5-carbamoyl-2-(4-chlorophenyl)-9-
(phenylmethyl)carbazol-4-yl]oxyacetic acid;
[5-carbamoyl-2-(2-furyl)-9-(phenylmethyl)carbazol-9-
yl]oxyacetic acid;
[5-carbamoyl-9-(phenylmethyl)-2-[(tri(-1-
methylethyl)silyl)oxymethyl]carbazol-4-yl]oxyacetic
acid, lithium salt;
{9-[(phenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
{9-[(3-fluorophenyl)methyl]-5-carbamoylcarbazol-9-
yl}oxyacetic acid;
{9-[(3-phenoxyphenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid;
{9-[(2-Fluorophenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid;
{9-[(2-trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic aci d
{9-[(2-benzylphenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid;
{9-[(3-trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid;
{9-[(1-naphthyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic
acid;
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{9-[(2-cyanophenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid;
{9-[(3-cyanophenyl)methyl)-5-carbamoylcarbazol-4-
yl}oxyacetic acid;
{9-[(2-methylphenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid;
{9-[(3-methylphenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid;
{9-[(3,5-dimethylphenyl)methyl)-5-carbamoylcarbazol-4-
yl}oxyacetic acid;
{9-[(3-iodophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic
acid;
{9-((2-Chlorophenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid;
{9-[(2,3-difluorophenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid;
{9-[(2,6-difluorophenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid;
{9-[(2,6-dichlorophenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid;
{9-[(3-trifluoromethoxyphenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid;
{9-[(2-biphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic
acid;
{9-[(2-Biphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic
acid;
the {9-[(2-Biphenyl)methyl)-5-carbamoylcarbazol-4-
yl}oxyacetic acid;
[9-Benzyl-9-carbamoyl-1,2,3,4-tetrahydrocarbaole-5-
yl]oxyacetic acid;
{9-[(2-Pyridyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic
acid;
{9-[(3-Pyridyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic
acid;
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[9-benzyl-4-carbamoyl-8-methyl-1,2,3,4-tetrahydrocarbazol-5-
yl]oxyacetic acid;
[9-benzyl-5-carbamoyl-1-methylcarbazol-4-yl]oxyacetic acid;
[9-benzyl-4-carbamoyl-8-fluoro-1,2,3,4-tetrahydrocarbazol-5-
yl]oxyacetic acid;
[9-benzyl-5-carbamoyl-1-fluorocarbazol-4-yl]oxyacetic acid;
[9-benzyl-4-carbamoyl-8-chloro-1,2,3,4-tetrahydrocarbazol-5-
yl]oxyacetic acid;
[9-benzyl-5-carbamoyl-1-chlorocarbazol-4-yl]oxyacetic acid;
[9-[(Cyclohexyl)methyl]-5-carbamoylcarbazol-4-yl]oxyacetic
acid;
[9-[(Cyclopentyl)methyl]-5-carbamoylcarbazol-4-yl]oxyacetic
acid;
5-carbamoyl-9-(phenylmethyl)-2-[[(propen-3-
yl)oxy]methyl]carbazol-4-yl]oxyacetic acid;
[5-carbamoyl-9-(phenylmethyl)-2-[(propyloxy)methyl]carbazol-
4-yl]oxyacetic acid;
9-benzyl-7-methoxy-5-((carboxamidomethyl)oxy)-1,2,3,4-
tetrahydrocarbazole-4-carboxamide;
9-benzyl-7-methoxy-5-cyanomethyloxy-carbazole-4-carboxamide;
9-benzyl-7-methoxy-5-((1H-tetrazol-5-yl-methyl)oxy)-
carbazole-4-carboxamide;
9-benzyl-7-methoxy-5-((carboxamidomethyl)oxy)-carbazole-4-
carboxamide; and
[9-Benzyl-4-carbamoyl-1,2,3,4-tetrahydrocarbaole-5-
yl]oxyacetic acid
or a pharmaceutically acceptable racemate, solvate,
tautomer, optical isomer, prodrug derivative or salt,
thereof .
Other desireable carbazole compounds suitable for
practicing the method of the m invention are selected from
those represented by the formula (XXX):
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i
R?
5\ 4
6 3
Z
z
B~ 9 1
R3
CHzR9
(XXX)
wherein:
R1 is -NHNH2, or -NH2;
R2 is selected from the group consisting of -OH and -
O (CH2 ) mR5 where
O
R5 is H, -C02H, -C02(C1-C4 alkyl); P(R6R7),where R6 and
R7 are each independently -OH or -O(C1-C4)alkyl;
-S03H, -S03(C1-Cq alkyl), tetrazolyl, -CN, -NH2
-NHS02R15; -CONHS02R15, where R15 is -(C1-C6)alkyl or
-CF3, phenyl or phenyl substituted with -C02H or
-C02(C1-Cq)alkyl where m is 1-3;
R3 is H, -O(C1-C4)alkyl, halo, -(C1-C6)alkyl, phenyl,
-(C1-Cq)alkylphenyl; phenyl substituted with
-(C1_C6)alkyl, halo, or -CF3; -CH20Si(C1-C6)alkyl,
furyl, thiophenyl, -(C1-C6)hydroxyalkyl; or -(CH2)nR8
where R8 is H, -CONH2, -NR9R10, -CN or phenyl where Rg
and R10 are independently -(C1-C4)alkyl or
-phenyl(C1-C4)alkyl and n is 1 to 8;
R4 is H, -(C5-C14)alkyl, -(C3-C14)cycloalkyl, pyridyl,
phenyl or phenyl substituted with -(C1-C6)alkyl, halo,
-CF3, -OCFg , -(C1-C4)alkoxy, -CN, -(C1-CQ)alkylthio,
phenyl(C1-Cq)alkyl, -(C1-C4)alkylphenyl, phenyl,
phenoxy or naphthyl;
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A is phenyl or pyridyl wherein the nitrogen is at the 5-,
6-, 7- or 8-position;
Z is cyclohexenyl, phenyl, pyridyl wherein the nitrogen is
at the 1-, 2- or 3-position or a 6-membered
heterocyclic ring having one heteroatom selected from
the group consisting of sulfur or oxygen at the 1-,
2- or 3-position and nitrogen at the 1-, 2-, 3- or 4-
position, or
wherein one carbon on the heterocyclic ring is optionally
substituted with =0;
or a pharmaceutically acceptable racemate, solvate,
tautomer, optical isomer, prodrug derivative or salt
thereof;
provided that one of A or Z is a heterocyclic ring.
Further desirable specific compounds suitable for the
method of the invention are selected from the following:
(R,S)-(9-benzyl-4-carbamoyl-1-oxo-3-thia-1,2,3,4-
tetrahydrocarbazol-5-yl)oxyacetic acid; (R,S)-(9-benzyl-4-
carbamoyl-1-oxo-3-thia-1,2,3,4-tetrahydrocarbazol-5-
yl)oxyacetic acid; [N-benzyl-1-carbamoyl-1-aza-1,2,3,4-
tetrahydrocarbazol-8-yl]oxyacetic acid; 4-methoxy-6-
methoxycarbonyl-10-phenylmethyl-6,7,8,9-
tetrahydropyrido[1,2-a]indole; (4-carboxamido-9-
phenylmethyl-4,5-dihydrothiopyrano[3,4-b]indol-5-
yl)oxyacetic acid; 3,4-dihydro-4-carboxamidol-5-methoxy-9-
phenylmethylpyrano[3,4-b]indole; 2-[(2,9 bis-benzyl-4-
carbamoyl-1,2,3,4-tetrahydro-beta-carbolin-5-yl)oxy]acetic
acid or a pharmaceutically acceptable racemate, solvate,
tautomer, optical isomer, prodrug derivative or salt
thereof .
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Particularly preferred compounds for the treatment of
cystic fibrosis are represented by the formulae (Xe) and
(XIe) below:
O
(Xe)
and
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110
(Xle)
For all of the above compounds of the carbazole or
tetrahydrocarbazole type it is advantageous to use them in
their (i)acid form, or (ii) pharmaceutically acceptable
(e. g., Na, K) form, or (iii) and prodrugs derivatives (e. g.,
methyl ester, ethyl ester, n-butyl ester, morpholino ethyl
ester) .
Prodrugs are derivatives of sPLA2 inhibitors used in
the method of the invention which have chemically or
metabolically cleavable groups and become by solvolysis or
under physiological conditions the compounds of the
invention which are pharmaceutically active in vivo.
Derivatives of the compounds of this invention have activity
in both their acid and base derivative forms, but the acid
derivative form often offers advantages of solubility,
tissue compatibility, or delayed release in a mammalian
organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9,
21-24, Elsevier, Amsterdam 1985). Prodrugs include acid
derivatives well known to practitioners of the art, such as,
for example, esters prepared by reaction of the parent
O
~"'OH
NH.,
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111
acidic compound with a suitable alcohol, or amides prepared
by reaction of the parent acid compound with a suitable
amine. Simple aliphatic or aromatic esters derived from
acidic groups pendent on the compounds of this invention are
preferred prodrugs. In some cases it is desirable to
prepare double ester type prodrugs such as (acyloxy) alkyl.
esters or ((alkoxycarbonyl)oxy)alkyl esters. Specific
preferred prodrugs are ester prodrugs inclusive of methyl
ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl
ester, sec-butyl, tert-butyl ester, N,N-diethylglycolamido
ester, and morpholino-N-ethyl ester. Methods of making
ester prodrugs are disclosed in U.S. Patent No. 5,654,326.
Additional methods of prodrug synthesis are disclosed in
U.S. Provisional Patent Application Serial No. 60/063280
filed October 27, 1997 (titled, N,N-diethylglycolamido ester
Prodrugs of Indole sPLA2 Inhibitors), the entire disclosure
of which is incorporated herein by reference; U.S.
Provisional Patent Application Serial No. 60/063646 filed
October 27, 1997 (titled, Morpholino-N-ethyl Ester Prodrugs
of Indole sPLA2 Inhibitors), the entire disclosure of which
is incorporated herein by reference; and US Provisional
Patent Application Serial No. 60/063284 filed October 27,
1997 (titled, Isopropyl Ester Prodrugs of Indole sPLA2
Inhibitors), the entire disclosure of which is incorporated
herein by reference.
Carbazole and tetrahydrocarbazole sPLA2 inhibitor compounds
useful for practicing the method of the invention may be
made by the following general methods:
The compounds of formula Ie where Z is
cyclohexene are prepared according to the following
reaction Schemes Ig(a)and (c).
Scheme Ig (a)
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112
CH30 CH30 CH30
\ (a) ~ \ (b) ~ \
R3 (a) / NOz R3 (a) / NHz R3 ca) / i H
(1) (2) (3) CHzRa
(c)
COZEt COzEt
CH30 \ ~ d) - CH30 \ O
3 (a) N 3la) N
R CH2R9 R CHzR4
(5) (f ) (4)
(e)
z (a) CONHz CONHNHz
R CH30
I\
R3 / N R3 (a> / N
CHZR4 CHzR4
(7) (6)
(h) (i)
Rz CONHz z CONHNHz
R
\ ~ ~ ,
3 / N R3 (a) N
R i I
CHZR9 CH2R9
(9) (8)
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113
wherein;
R1 is -NH2~ R3(a) is H, -0(C1-Cq)alkyl, halo, -(C1-C6)alkyl,
phenyl, -(C1-Cq)alkylphenyl; phenyl substituted with
-(C1-Cg)alkyl, halo, or -CF3; -CH20Si(C1-C6)alkyl,
furyl, thiophenyl, -(C1-C6)hydroxyalkyl,
-(C1_C6)alkoxy(C1-C6)alkyl, -(C1-C6)alkoxy(C1_ .
C6)alkenyl; or -(CH2)nR8 where R8 is H, -CONH2,
-NRgRlO, -CN or phenyl where R9 and R10 are
independently hydrogen, -CF3, phenyl, -(Cl-Cq)alkyl,
-(C1-Cq)alkylphenyl or -phenyl(C1-Cq)alkyl and n is 1
to 8;
when R1 is -NHNH2~ R3(a) is H, -0(C1-Cq)alkyl, halo,
-(C1-C6)alkyl, phenyl, -(C1-Cq)alkylphenyl; phenyl
substituted with -(Cl-C6)alkyl, halo or -CF3;
-CH20Si(Cl-C6)alkyl, furyl, thiophenyl,
-(Cl-C6)hydroxyalkyl,-(C1-C6)alkoxy(C1-C6)alkyl,
-(Cl-C6)alkoxy(C1-C6)alkenyl; or -(CH2)nR8 where R8 is
H, -NR9R10, -CN or phenyl where R9 and R10 are
independently hydrogen, -CF3, phenyl, -(Cl-Cq)alkyl,
-(Cl-Cq)alkylphenyl or -phenyl(Cl-Cq)alkyl and n is 1
to 8;
R2(a) is -OCH3 or -OH.
An appropriately substituted nitrobenzene (1)
can be reduced to the aniline (2) by treatment with a
reducing agent, such as hydrogen in the presence of Pd/C,
preferably at room temperature,
Compound (2) is N-alkylated at temperatures of
from about 0 to 20 °C using an alkylating agent such as an
appropriately substituted aldehyde and sodium
cyanoborohydride to form (3). Alternately, an
appropriately substituted benzyl halide may be used for
the first alkylation step. The resulting intermediate is
further N-alkylated by treatment with 2-carbethoxy-6-
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114
bromocyclohexanone, preferably at temperatures of about
80 °C to yield (4) or by treatment with potassium
hexamethyldisilazide and the bromoketoester.
The product (4) is cyclized to the
tetrahydrocarbazole (5) by refluxing with ZnCl2 in benzene
for from about 1 to 2 days, preferably at 80 °C. (Ref 1).
Compound (5) is converted to the hydrazide (6) by
treatment with hydrazine at temperatures of about 100 °C,
or to the amide (7) by reacting with methylchloroaluminum
amide in benzene. (Ref 2) Alternatively, (7) may be
produced by treatment of (6) with Raney nickel active
catalyst.
It will be readily appreciated that when R3(a) is;
0
II
- ( CHZ ) nC0 ( C1-C9 al kyl ) ,
conversion to the amide will also be achieved in this
procedure.
Compounds (6) and (7) may be dealkylated,
preferably at 0 °C to room temperature, with a
dealkylating agent, such as boron tribromide or sodium
thioethoxide, to give compound (7) where R2(a) is -OH,
which may then be further converted to compound (9), by
realkylating with a base, such as sodium hydride, and an
alkylating agent, such as Br(CH2)mRS, where R5 is the
carboxylate or phosphonic diester or nitrile as defined
above. Conversion of R2 to the carboxylic acid may be
accomplished by treatment with an aqueous base. When R2
is nitrile, conversion to the tetrazole may be achieved by
reacting with tri-butyl tin azide or conversion to the
carboxamide may be achieved by reacting with basic
hydrogen peroxide. When R2 is the phosphonic diester,
conversion to the acid may be achieved by reacting with a
dealkylating agent such as trimethylsilyl bromide. The
*rB
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115
monoester may be accomplished by reacting the diester with
an aqueous base.
When R2 and R3 are both methoxy, selective
demethylation can be achieved by treating with sodium
ethanethiolate in dimethylformamide at 100 °C.
Ref 1 Julia, M.; Lenzi, J. Preparation d'acides
tetrahydro-1,2,3,4-carbazole-1 ou -4.
Bull.Soc.Chim.France, 1962, 2262-2263.
Ref 2 Levin, J.I.; Turos, E.; Weinreb, S.M. An
alternative procedure for the aluminum-mediated conversion
of esters to amides. Syn.Comm., 1982, 12, 989-993.
An alternative synthesis of intermediate (5) is
shown in Scheme I(b), as follows.
Scheme Ig (b)
COzEt
PGO \ PGO
O
31a) ~ / 3 (a) ~ / N
R NHZ R I
H
(2) (4')
COZEt COZEt
PGO PGO
'.E.-
3la) N 31a) -N-
R I 4 R I
CHZR H (5')
(5)
where PG is a protecting group;
R3a is as defined in Scheme 1, above.
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The aniline (2) is N-alkylated with 2-carbethoxy-
6-bromocyclohexanone in dimethyl formamide in the presence
of sodium bicarbonate for 8-24 hours at 50 °C. Preferred
protecting groups include methyl, carbonate, and silyl
groups, such as t-butyldimethylsilyl. The reaction product
(4') is cyclized to (5') using the ZnCl2 in benzene _
conditions described in Scheme I(a), above. N-alkylation of
(5') to yield (5) is accomplished by treatment with sodium
hydride and the appropriate alkyl halide in
dimethylformamide at room temperature for 4-8 hours.
Scheme IIg
COzEt C02H
CH30 CH30
R3caJ / N R3 (a)
CHZR9 CHZR
(5) (10)
0
"' 0
)CHZPh 0 N'
~\
CH30 CH30 H
R3~a) R3 (a) / N
CHZR'(12a) (R) CH2R9 (11a) (R, S)
(12b) (S) (11b) (S, S)
0~ NHz IHZ
CH30 CH30
R3(a1 / N R3Ia)
CHzR9 (~a) (R) CHzRy
(9a) (R)
(7b) (S) (9b) (S)
R3(a) is as defined in Scheme Ig.
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117
As discussed in Scheme I above, carbazole (5) is
hydrolyzed to the carboxylic acid (10) by treatment with
an aqueous base, preferably at room temperature to about
100 °C. The intermediate is then converted to an acid
chloride utilizing, for example, oxalyl chloride and
dimethylformamide, and then further reacted with a lithium.
salt of (S) or (R)-4-alkyl-2-oxazolidine at a temperature
of about -75 °C, to give (lla) and (llb), which are
separable by chromatography.
The diastereomers are converted to the
corresponding enantiomeric benzyl esters (12) by brief
treatment at temperatures of about 0 °C to room
temperature with lithium benzyl oxide. (Ref 3) The esters
(12) are then converted to (7) preferably by treatment
with methylchloroaluminum amide (Ref 2, above) or,
alternately, by hydrogenation using, for example, hydrogen
and palladium on carbon, as described above, to make the
acid and then reacting with an acyl azide, such as
diphenylphosphoryl azide followed by treatment with
ammonia. Using the procedure described above in Scheme I,
compound (9a) or (9b) may be accomplished.
Ref 3 Evans, D.A.; Ennis, M.D.; Mathre, D.J. Asymmetric
alkylation reactions of chiral imide enolates. A practical
approach to the enantioselective synthesis of alpha-
substituted carboxylic acid derivatives. J.Am.Chem.Soc.,
1982, 104, 1737-1738.
Compounds of formula Ie where Z is phenyl can be
prepared as follows in Schemes III(a)-(f), below.
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118
Scheme III (a
COR1 COR1
R2 RZ
s ~ N 3 N
R CHZR9 R CHZR4
(13) (14)
A 1,2,3,4-tetrahydrocarbazole-4-carboxamide or
~4-carboxhydrazide (13) is dehydrogenated by refluxing in a
solvent such as carbitol in the presence of Pd/C to
produce the carbazole-4-carboxamide. Alternately,
treatment of (13) with DDQ in an appropriate solvent such
as dioxane yields carbozole (14).
Depending on the substituent pattern oxidation
as described above may result in de-alkylation of the
nitrogen. For example when R3 is substituted at the 8-
position with methyl, oxidation results in dealkylation of
the nitrogen which may be realkylated by treatment with
sodium hydride and the appropriate alkyl halide as
described in Scheme I(a) above to prepare the deired
product ( 14 ) .
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119
0
Scheme III(b)
O OH 0 OPG O OPG 0 Rg~a)
Hz, sulfided Pt/C. or
\ X X SnClz, HC1, or \ X (15)
\ NazSzO<
0
I / N+ / ~ / NO Rzi / NHz
Rz~ I Rzi z
0
(15) (16) (25)
0 OPG O OPG
O O cszc0" xzco3
or Triton B,
Pd(OAc)z, Ar3P, XCHZR4
Et~N, CH3CN I \ I
I / I _~..
NH N
Rzl R3(a) Rzl H 3laJ
(26) (19)
0 OPG 0 OPG
0 methylbenzene OH
sulfinate
NH90H
\ I DDQ I \ I \ _
/ N / N
Rzl I 9 R3(a) R ~ 9 Rica)
CHzR CHZR
(20) (21)
0 NHz 0 NHz z
OH R
XR, KzC03
I ~ I ~ I ~ I \ I ~ ) NdOH
-a
/ / 2.) Salification
Rzl N N
4 R3 (al R21 I 3fa)
CHZR CHzR4 R
(22) (23)
0 NHz z
R
R'~a~ is as defined in Scheme I(a)above
PG is an acid protecting group
N ~%'~ X is halo
R21 I 3(a)
CHzR9 R
(24)
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120
Benzoic acid derivative(16) where X is preferably
chlorine, bromine or iodine and the protecting group is
preferably -CH3, are reduced to the corresponding aniline
(25) with a reducing agent, such as stannous chloride in the
presence of acid under the general conditions of Sakamoto et
al, Chem Pharm. Bull. 35 (5), 1823-1828 (1987).
Alternatively, reduction with sodium dithionite in
the presence of a base, such as sodium carbonate in a
noninterferring solvent, such as water, ethanol, and/or
tetrahydrofuran affords starting material (16).
Alternatively, reduction by hydrogenation over a
sulfided platinum catalyst supported on carbon with hydrogen
at 1 to 60 atmospheres in a noninterfering solvent,
preferably ethyl acetate, to form a starting material (16).
The reactions are conducted at temperatures from
about 0 to 100 °C. preferably at ambient temperature, and
are substantially complete in about 1 to 48 hours depending
on conditions.
The aniline (25) and dione (15) are condensed
under dehydrating conditions, for example, using the general
procedure of Iida, et al., (Ref 5), with or without a
noninterfering solvent, such as toluene, benzene, or
methylene chloride, under dehydrating conditions at a
temperature about 10 to 150 °C. The water formed in the
process can be removed by distillation, azetropic removal
via a Dean-Stark apparatus, or the addition of a drying
agent, such as molecular sieves, magnesium sulfate, calcium
carbonate, sodium sulfate, and the like.
The process can be performed with or without a
catalytic amount of an acid, such a p-toluenesulfonic acid
or methanesulfonic acid. Other examples of suitable
catalysts include hydrochloric acid, phenylsulfonic acid,
.calcium chloride, and acetic acid.
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121
Examples of other suitable solvents include
tetrahydrofuran, ethyl acetate, methanol, ethanol, 1,1,2,2-
tetrachloroethane, chlorobenzene, bromobenzene, xylenes, and
carbotetrachloride.
The condensation of the instant process is
preferably carried out neat, at a temperature about 100 to
150 °C with the resultant water removed by distillation via
a stream of inert gas, such as, nitrogen or argon.
The reaction is substantially complete in about 30
minutes to 24 hours.
Intermediate (26) may then be readily cyclized in
the presence of a palladium catalyst, such as Pd(OAc)2 or
Pd(PPh3)4 and the like, a phosphine, preferably a trialkyl-
or triarylphosphine, such as triphenylphosphine, tri-o-
tolylphosphine , or tricyclohexylphosphine, and the like, a
base, such as, sodium bicarbonate, triethylamine, or
diisopropylethylamine, in a noninterfering solvent, such as,
acetonitrile, triethylamine, or toluene at a temperature
about 25 to 200°C to form (19) .
Examples of other suitable solvents include
tetrahydrofuran, benzene, dimethylsulfoxide, or
dimethylformamide.
Examples of other suitable palladium catalysts
include Pd(PPh3)C12, Pd(OCOCF3)2, [(CH3C6H4)3P]2PdCl2,
[(CH3CH2)3P]2PdC12, [(C6H11)3P]2PdC12, and [(C6H5)3P]2PdBr2.
Examples of other suitable phosphines include
triisopropylphosphine, triethylphosphine,
tricyclopentylphosphine, 1,2-bis(diphenylphosphino)ethane,
1,3-bis(diphenylphosphino)propane, and 1,4-
bis(diphenylphosphino)butane.
Examples of other suitable bases include tripropyl
amine, 2,2,6,6-tetramethylpiperidine, 1,5-
diazabicyclo[2.2.2]octane (DABCO), 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-
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diazabicyclo[4.3.0]non-5-ene, (DBN) sodium carbonate,
potassium carbonate, and potassium bicarbonate.
The cyclization of the instant process is
preferably carried out with palladium(II)acetate as catalyst
in the presence of either triphenylphosphine, tri-o-
tolylphosphine, 1,3-bis(diphenylphosphino)propane, or .
tricyclohexylphosphine in acetonitrile as solvent and
triethylamine as base at a temperature about 50 to 150 °C.
The reaction is substantially complete in about 1 hour to 14
days.
Alternatively, a preferred process for cyclization
consists of the reaction of intermediate (26) with a
palladacycle catalyst such as trans-di(~-acetato)-bis[o-(di-
o-tolylphosphino)benzyl]dipalladium (II) in a solvent such
as dimethylacetamide (DMAC) at 120-140 °C in the presence of
a base such as sodium acetate.
Intermediate (19) may be alkylated with an
alkylating agent XCH2R4, where X is halo in the presence of
a base to form (20). Suitable bases include potassium
carbonate, sodium carbonate, lithium carbonate, cesium
carbonate, sodium bicarbonate, potassium bicarbonate,
potassium hydroxide, sodium hydroxide, sodium hydride,
potassium hydride, lithium hydride, and Triton B
(N-benzyltrimethylammonium hydroxide).
The reaction may or may not be carried out in the
presence of a crown ether. Potassium carbonate and Triton B
are preferred. The amount of alkylating agent is not
critical, however, the reaction is best accomplished using
an excess of alkyl halide relative to the starting material.
A catalytic amount of an iodide, such as sodium
iodide or lithium iodide may or may not be added to the
reaction mixture. The reaction is preferably carried out in
an organic solvent, such as, acetone, dimethylformamide,
dimethylsulfoxide, or acetonitrile. Other suitable solvents
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123
include tetrahydrofuran, methyl ethyl ketone, and t-butyl
methyl ether.
The reaction is conducted at temperatures from
about -10 to 100 °C. preferably at ambient temperature, and
is substantially complete in about 1 to 48 hours depending
on conditions. Optionally, a phase transfer reagent such as
tetrabutylammonium bromide or tetrabutylammonium chloride
may be employed.
Intermediate (20) May by dehydrogenated by
oxidation with 2,3-dichloro-5,6-dicyano-1,9-benzoquinone in
a noninterfering solvent to form (21).
Suitable solvents include methylene chloride,
chloroform, carbon tetrachloride, diethyl ether, methyl
ethyl ketone, and t-butyl methyl ether. Toluene, benzene,
dioxane, and tetrahydrofuran are preferred solvents. The
reaction is carried out at a temperature about 0 to 120 °C.
Temperatures from 50 to 120 °C are preferred. The reaction
is substantially complete in about 1 to 48 hours depending
on conditions.
Intermediate (21) may be aminated with ammonia in
the presence of a noninterfering solvent to form a(22).
Ammonia may be in the form of ammonia gas or an ammonium
salt, such as ammonium hydroxide, ammonium acetate, ammonium
trifluoroacetate, ammonium chloride, and the like. Suitable
solvents include ethanol, methanol, propanol, butanol,
tetrahydrofuran, dioxane, and water. A mixture of
concentrated aqueous ammonium hydroxide and tetrahydrofuran
or methanol is preferred for the instant process. The
reaction is carried out at a temperature about 20 to 100 °C.
Temperatures from 50 to 60 °C are preferred. The reaction is
substantially complete in about 1 to 48 hours depending on
conditions.
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124
Alkylation of (22) is achieved by treatment with
an alkylating agent of the formula XCH2R9 where X is halo
and R~0 is -C02R~1, -S03R~1,-P(O)(OR~1)2, or -P(O)(OR~1)H,
where R~1 is an acid protecting group or a prodrug function,
in the presence of a base in a noninterfering solvent to
form (23). Methyl bromoacetate and t-butyl bromoacetate are
the preferred alkylating agents.
Suitable bases include potassium carbonate, sodium
carbonate, lithium carbonate, cesium carbonate, sodium
bicarbonate, potassium bicarbonate, potassium hydroxide,
sodium hydroxide, sodium hydride, potassium hydride, lithium
hydride, and Triton B (N-benzyltrimethylammonium hydroxide).
The reaction may or may not be carried out in the presence
of a crown ether. Cesium carbonate and Triton B are
25 preferred.
The amount of alkylating agent is not critical,
however, the reaction is best accomplished using an excess
of alkyl halide relative to the starting material. The
reaction is preferably carried out in an organic solvent,
such as, acetone, dimethylformamide, dimethylsulfoxide, or
acetonitrile. Other suitable solvents include
tetrahydrofuran, methyl ethyl ketone, and t-butyl methyl
ether.
The reaction is conducted at temperatures from
about -10 to 100 °C. preferably at ambient temperature, and
is substantially complete in about 1 to 48 hours depending
on conditions. Optionally, a phase transfer reagent such as
tetrabutylammonium bromide or tetrabutylammonium chloride
may be employed.
Intermediate (23) may be optionally hydrolyzed
with a base or acid to form desired product (24) and
optionally 'salified.
Hydrolysis of (23) is achieved using a base such
as sodium hydroxide, potassium hydroxide, lithium hydroxide,
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125
aqueous potassium carbonate, aqueous sodium carbonate,
aqueous lithium carbonate, aqueous potassium bicarbonate,
aqueous sodium bicarbonate, aqueous lithium bicarbonate,
preferably sodium hydroxide and a lower alcohol solvent,
such as, methanol, ethanol, isopropanol, and the like. Other
suitable solvents include acetone, tetrahydrofuran, and
dioxane.
Alternatively, the acid protecting group may be
removed by organic and inorganic acids, such as
trifluoroacetic acid and hydrochloric acid with or without a
noninterferring solvent. Suitable solvents include methylene
chloride, tetrahydrofuran, dioxane, and acetone. The t-butyl
esters are preferably removed by neat trifluoroacetic acid.
The reaction is conducted at temperatures from
about -10 to 100°C. preferably at ambient temperature, and
is substantially complete in about 1 to 48 hours depending
on conditions.
The starting material (16) is prepared by
esterifying compound (15) with a alkyl halide = XPG; where X
is halo and PG is an acid protecting group, in the presence
of a base, preferably potassium carbonate or sodium
cabonate, in a noninterferring solvent, preferably
dimethylformamide or dimethylsulfoxide. The preferred alkyl
halide is methyl iodide. The reaction is conducted at
temperatures from about 0 to 100°C. preferably at ambient
temperature, and is substantially complete in about 1 to 48
hours depending on conditions.
Alternatively the starting material (16) may be
prepared by condensation with an alcohol HOPG, where PG is
an acid protecting group, in the presence of a dehydrating
catalyst such as, dicyclohexylcarbodiimide (DCC) or carbonyl
diimidazole.
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In addition, U.S. Patent No. 4,885,338 and Jpn.
Kokai Tokkyo Koho 05286912, Nov 1993 Hesei teach a method
for preparing 2-fluoro-5-methoxyaniline derivatives.
Scheme IIIg(c)
Me0 \
Me0 /
0 OH 0 OPG (Hp)zg COzP
3(a1
Where PG = CH3, R \ \
\ X CH3I, K2C03 \ X (2~) v ~R3(a1
.. / + .. 0
N*~'0 ~ / +'.0 PdIAr~P)9. R21 N
Rzi ~ Rzi N- KZCO3 O
O
(15) (16) 0 (28)
0 OPG O OPG
(A1ky10)3P or OMe OMe
(ArylO) 3P \ ,~ NaH, XCHzR9 ~ ~ 1 . BBr3
/ zi ~ / N ~ 2.
21 N R , 4 Rica)
R H R3 (al CHzR
(29) (30)
0 NHz O NHz Rz
OH
KZC03 or Triton B
XR ~ \ ~ \ NaOH
R21 / Ij 9 'R3 (al R21 N - \ 3(a>
CHZR CH2R
(22) (23)
O NHz Z
R
RZ1 / N 31a~
CHZR° R
(29)
R is as defined in Scheme IIIg(b),
R3(a) is as defined in Scheme Ig(a), above; and
X is halo.
Benzoic acid derivatives (16) (X= Cl, Br, or I)
and boronic acid derivative (27) (either commercially
available or readily prepared by known techniques from
commercially available starting materials) are condensed
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under the general procedure of Miyaura, et al., (Ref 8a)
or Trecourt, et al., (Ref 8b) in the presence of a
palladium catalyst, such as Pd(Ph3P)q, a base, such as
sodium bicarbonate, in an inert solvent, such as THF,
toluene or ethanol, to afford compound (28).
Compound (28) is converted to the carbazole .
product (29) by treatment with a trialkyl or triaryl
phosphite or phosphine, such as, triethylphosphite or
triphenyl phosphine, according to the general procedure of
Cadogan, et al. (Ref &).
Compound (29) is N-alkylated with an
appropriately substituted alkyl or aryl halide XCH2Rq in
the presence of a base, such as sodium hydride or
potassium carbonate, in a noninterfering solvent, such as
toluene, dimethylformamide, or dimethylsulfoxide to afford
carbazole ( 30 ) .
Compound (30) is converted to the corresponding
amide (22) by treatment with boron tribromide or sodium
thioethoxide, followed by ammonia or an ammonium salt,
such as ammonium acetate, in an inert solvent, such as
water or alcohol, or with methylchloroaluminum amide in an
inert solvent, such as toluene, at a temperature between 0
to 110 °C.
When R3(a) is substituted at the 8-position with
chloro, de-alkylation of (30) with boron tribromide
results in de-benzylation of the nitrogen as described
above. Alkylation may be readily accomplished in a two
step process. First, an O-alkylation by treatment with a
haloalkyl acetate such as methyl bromo acetate using
sodium hydride in tetrahydrofuran, followed by
N-alkylation using for example a base such as sodium
hydride and an appropriately substituted alkyl or aryl
halide in dimethoxy formamide. Compound (22) can be
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converted to product carbazole product (24) as described
previously in Scheme IIIg(b) above.
Conversion to the desired prodrug may be
accomplished by techniques known to the skilled artisan,
such as for example, by treatment with a primary or
secondary halide to make an ester prodrug.
Scheme IIIg(d)
COZPG OCH3 COZPG OCH3
Ref: 8b
Hz/Pd(C) ~ ~ ~ 1)HzS09
2 ) NaNOz
21 / NO ~\\~ 3 ( a ~ 21 / NH ~\~ 3 a
R R z R ( > 3 ) NaN3
(28) (32) 4) 0
COzPG OCH3
R21 ~ H R3 (a)
(29)
Alternatively, reduction of the nitro group of
compound (28) with a reducing agent, such as hydrogen in
the presence of palladium on carbon, in a noninterfering
solvent, such as ethanol, at 1 to 60 atmospheres, at a
temperature of 0 to 60°C affords the corresponding aniline
(32). Compound (32) is converted to the carbazole (29)
according to the general procedure described by Trecourt,
et al. (Ref 8b). The aniline is treated with sulfuric
acid and sodium nitrite, followed by sodium azide to form
an intermediate azide which is cyclized to carbazole (29)
by heating in an inert sovent, such as toluene. Compound
(29) is converted to carbazole product (24) as described
previously in Schemes IIIg(b) and IIIg(c).
References:
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129
8) a. N. Miyaura, et al., Synth. Commun. 11, 513 (1981)
b. F. Trecourt, et al., Tetrahedron, 51, 11743 6)
6) J. Cadogan et al., J. Chem. Soc., 4831 (1965)
Scheme IIIg(e)
OCH2C CONHz OCH2CH2NH2 CONH2
Z Rzi --~ ~ z R21 -.~
Rs ~ R3
CH2R CH2R
(40) (91)
( CHz ) ~NHSO2R15 CONHz
-~--R21
R3
CH2R9
In an aprotic solvent, preferably
tetrahydrofuran, reduction of (40) is achieved using a
reducing agent such as aluminum trihydride. Preferably,
the reaction is conducted under inert atmosphere such as
nitrogen, at room temperature.
Sulfonylation may be achieved with an
appropriate acylating agent in the presence of an acid
scavenger such as triethyl amine.
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Scheme IIIg(f)
OCHzCOzH CONHz activating
agent H2NSOZR1
Z R z i --.-
R3 N
i
CHzR4
i50)
OCHzCONHSOzR~s CONHz
Rzi
R
CHzR4
(51)
In a two-step, one-pot process, intermediate
(50), prepared as described in Scheme I(a) above, is first
activated with an activating agent such as carbonyl
diimidazole. The reaction is preferably run in an aprotic
polar or non-polar solvent such as tetrahydrofuran.
Acylation with the activated intermediate is accomplished
by reacting with H2NSOR15 in the presence of a base,
preferably diazabicycloundecene.
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Scheme IIIg(g)
0 OPG 0 OPG
0 O
\ \ 1. NaH PhSO2Me
NaH I 1,4-dioxane
-"~''" / z z
Rzl N RX Rzl N R 2. HOAc, 100°C
OH
R4 R4
(20) (60)
0 OPG OH 0 NHz OH
\ NH3 ~ \ ~ \ CszC03
N~Rzz THF " / N~Rzz Br~ a
Rzi ~ Rzi
RQ RQ
(61) (62)
~Urle 0 NHz
l~~f ~I'(0
0 LiOH ~ \ ~ \ O
-' /
Rzz N Rz2
R21
Rq
(63) (64)
PG is an acid protecting group;
R22 is (C1-C6)alkoxy (C1-C6)alkyl is (Cl-C6)alkoxy
(C1-C6)alkenyl
Starting material (20) is O-alkylated with an
alkyl halide or alkenyl halide, using a base such as NaH,
in an aprotic polar solvent preferably anhydrous DMF, at
ambient temperature under a nitrogen atmosphere. The
process of aromatization from a cyclohexenone
functionality to a phenol functionality can be performed
by treating the tetrahydrocabazole intermediate (60) with
a base such as NaH in the presence of methyl
benzenesulfinate in an anhydrous solvent, such as
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132
1,4-dioxane or DMF, to form the ketosulfoxide derivative.
Upon heating at about 100 °C for 1-2 hours, the
ketosulfoxide derivative (60) is converted to the phenol
derivative (61). Conversion of the ester (61) to the
amide (62) can be achieved by treating a solution of (61)
in an aprotic polar solvent such as tetrahydrofuran with .
ammonia gas. Phenolic O-alkylation of (62) with, for
example, methyl bromoacetate can be carried out in
anhydrous DMF at ambient temperature using Cs2C03 or K2C03
as a base to form (63). Desired product (64) can be
derived from the basic hydrolysis of ester (63) using LiOH
or NaOH as a base in an H20/CH30H/THF solution at 50 °C
for 1-2 hours.
When R22 is -(C1-C6)alkoxy(C1-C6)alkenyl,
hydrogenation of the double bond can be performed by
treating (63) in THF using Pt02 as a catalysis under a
hydrogen atmosphere. Desired product can then be derived as
described above in Scheme III(g) from the basic hydrolysis
of ester (63) using LiOH or NaOH as a base in an
H20/CH30H/THF solution at 50°C for 1-2 hours.
Compounds of formula Ie where the A ring is
phenyl and the heteroatom in Z is sulfur, oxygen or
nitrogen can be prepared as described in
Schemes IV(a)-(f), below.
*rB
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Scheme Ivg(a)
PGOZ PG02
Me0 Me0
KNR2
_ . J
R3 la) N JzRq BnOCH2C1 3!a) ~ q O
R 'NC R
(101) (102)
H2
Pd/C
PGOZ PGOZ
Me0 Me0
_ ~ KNRZ _
OH ICHZOMe 3 ~ q OCHZOMe
R3 la) ~ 'NCHZR R ca) NCH2R
(103) (104)
BF3
OZPG 2
Me0 MeC
MeCIAINH2
~4 ~0
R3 la) NCH2Rv R3la)
(105) ggr3 (106)
Hz
0 O ( CHZ ) nR5
Na
X(CHZ)nRs
R3la Rsca> NCHZF
(107) (108)
1. NaOH
2. HC1
...2
O ( CH2 ) ~R5
i
R3
(109)
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PG is an acid protecting group.
X is halo.
R3(a) is H, -O(C1-C4)alkyl, halo, -(C1-C6)alkyl, phenyl, -
(C1-C4)alkylphenyl; phenyl substituted with -(C1-
C6)alkyl, halo or -CF3; -CH20Si(C1-C6)alkyl, furyl,
thiophenyl, -(C1-C6)hydroxyalkyl; or -(CH2)nR8 where-
R8 is H, -NR9R10, -CN or phenyl where R9 and R10 are
independently -(C1-C4)alkyl or -phenyl(C1-C4)alkyl
and n is 1 to 8;
An indole-3-acetic ester (101), Ref 10, is
alkylated by treatment with alkalai metal amide and
benzyloxymethyl chloride to give (102) which is converted
to the alcohol (103) by catalytic hydrogenation. The
alcohol is alkylated to provide the formaldehyde acetal
(104) which is cyclized by Lewis acid to produce the
pyrano[3,4-b]indole (105). The ester is converted to the
amide (106) by methylchloroaluminum amide, and then to the
phenol (107) with boron tribromide. The phenol is
O-alkylated to give (108) which is hydrolyzed to the acid
(109) .
10) Dillard; R. et al., J, Med Chem. Vol 39, No. 26,
5119-5136.
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Scheme IVg(b)
CO2PG
CH30 OH CO2PG
! ! CH30
R3 (a) N ( NH
H
3 (a)
(103) R H R21 -
(113)
BF3
R21CH0
1. HZ
C02PG C02PG Pd/C
CH30 OCH3 W 2 . R21CH0 , BF3
! ! o ! ~
R3 (a) N ~Z1 R3(a) H NaN3 C02PG
H
R
(110) (111) CH30 ! ! Ns
NaSAc
R3 (a) NJ
H
(112)
CO2PG
CH30
~COCH3
!J
R3 (a) N (114)
H
K2C03
EtOH
CO2PG C02PG
CH30 SH CH30
!
! ! _
S
R3(a> N R2y R3(a)
H R2 i
( 115) (116)
PG is an acid protecting group
W is halo, alkyl or aryl sulfonyl
R3(a) is H, -O(C1-C4)alkyl, halo, -(C1-C~)alkyl, phenyl,
-(C1-C4)alkylphenyl; phenyl substituted with
-(C1-C6)alkyl, halo or -CF3; -CH20Si(C1-C6)alkyl,
furyl, thiophenyl, -(C1-C6)hydroxyalkyl; or -(CH2)nR8
where R8 is H, -NR9R1~, -CN or phenyl where R9 and
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136
R10 are independently -(C1-Cq)alkyl or
-phenyl(C1-Gq)alkyl and n is 1 to 8;
Reaction of this alcohol (103) with aldehyde and
acid produces the pyranoindole (110).
Conversion of the hydroxyl function of (103) to a
halide or sulfate functionality is achieved by treatment
with triphenylphosphine and CH3X (where X is a halogen) to
make compounds of formula (111) where X is a halide; or by
treatment with triethylamine and methanesulfonyl chloride to
make the sulfonate. Displacement with the sodium salt of
thiol acetic acid gives (114) which in turn is hydrolyzed by
base to the thiol (115) which is reacted with an
appropriately substituted aldehyde and acid to produce the
thiopyranoindoles (116).
Intermediate (111) may also be reacted with
sodium azide to give the azido derivative (112) which is
reduced by hydrogen catalytically to give the amine which
is converted to the carboline (123) with aldehyde and
acid.
Intermediates (113), (110) and (116) may be
N-alkylated, using sodium hydride and an appropriately
substituted alkylhalide XCH2Rq.
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Scheme Ivg(c)
0
OMe ~ OMe
COZPG COzPG
SnCl4 ~
R3 (a) / H~ R3 (a) / H
(117) (118) Ph3P
BrCIzCCCI2Br
C02 P
OMe KZC03 OMe CpzpG
CH3CN
Br
R9 (a) / N R3 (a) ~ N
(121) (119) H
BnBr .~. COZPG
OMe
OMe COZPG
Br
r R3 (a) / NJ
/ q H
R3 (a) NCHZR (122) (120)
OzPG
OMe
I Br
R3(a) / N H Rq
(123) KSAc
OzPG
~OMe
I ~ Ac
R3 (a) / NCHzRq
(124) KZC03
ROH
*rB
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OZ PG
OMe
~H
9
R3 (a) / CH R
( 12 5 ) KNRZ
ICHzOMe
OMe OZ PG
I
SCHZOMe
/ CH 4
Rica)
(126)
ZnX2
O NHz
OzPG
OMe OMe
MeCIAINH2 I \ I
I
\/ S / S
R CH2R9
R3 (a) / CH R4 3 (a)
2
(128) (127)
BBr3
2 PGCOZ ( CHZ )
NaH
-s
Br (CHZ) nC02Et
R3 (a)
R3 ~aW.aaZm
(129) (130)
1. NaOH
2. HC1
HCOZ { CHZ ) nC
PG is an acid protecting
group
R3(a) is as defined above
R3 (a> -
(131)
4-Methoxyindole (11~) is converted to the indole
acetic acid derivative (118) by alkylation with an epoxy
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139
propionate. Treatment of (118) with a brominating reagent
affords the mixture of bromo isomers (119) and (120) which
give the spiro compound (121) upon basic treatment. Heating
(121) with benzyl bromide provides a mixture of the isomeric
bromo compounds (122) and (123) which react with potassium
thioacetate to give a mixture of isomers from which (124)_
may be separated. Solvolysis of the thioester produces the
thiol (125) which is alkylated to give (126). Lewis acids
convert (126) to the thiopyrano[3,4-b]indole (127). The
ester function is converted to amide using
methylchloroaluminum amide, the methyl ether cleaved by
boron tribromide, and the product phenol O-alkylated with
bromoacetic ester to give (130) which is hydrolyzed to
( 131 ) .
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Scheme IVg(d)
TBSC1 TBSO
HO _ ~ 1) n-BuLi
I ~ I N NH 2 ) ZnClz
R3 tal ~ N J ~ R3la~ / NJ 3 ) X ~\ Cp2Et
H THF H
(CHZC12) THF
(132) (133)
TBSO RQCHZX TBSO
~CO2Et
I \ ( \CO2Et -~ K-N ( TMS ) 2
K-N (TMS) ~ 3tat /
Rata) ~ NJ THF R TMSC1~
H CHzRa
(134) (135)
COZCHzCH3
TBSO OTMS
I \ I \~ TBSO
OCHZCH3 I \ I ~ CH3C1A1NH2
R3ta1 ~ N
C1 S C1 R3tat ~ N S
a
(136) CHZR ZnBr2 (137) CHzRq
CONHZ
TBSO \ CONHZ
RO
S TBAF \ ~ 1 ) LiOH
R3lat / N
XR
3tat / S 2 ) HC1
CHZR CH3CN R I
(13$) (139) CHZRQ
CONHZ
R2
\ (
R3 (a1 / N~S
(140) CHzR4
X is halo,
R3(a) is as defined in Scheme I(a) above; and
R is - (CH2 ) mR5 .
Protection of the oxygen by treatment of (132)
with tert-butyldimethylsilyl chloride and imidazole in an
aprotic polar solvent such as tetrahydrofuran or
methylene chloride accomplishes (133).
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Alkylation at the 3-position of the indole (133)
is achieved by treatment with n-butyllithum then zinc
chloride at temperatures starting at about 10 °C and
warming to room temperature, followed by reaction with an
appropriate haloalkyl ester such as methyl or ethyl
bromoacetate. The reaction is preferably conducted at
room temperature in an appropriate aprotic polar solvent
such as tetrahydrofuran.
Alkylation of the indole-nitrogen can then be
achieved by reacting (134) with a suitable alkyl halide in
the presence of potassium bis(trimethylsilyl)amide to
prepare (135).
The ester functionality of (135) is converted to a
trimethylsilylketene acetal (136) by treatment with
potassium bis(trimethylsilyl)amide and trimethylsilyl
chloride. Treatment of the ketene acetal (136) with
bis(chloromethyl)sulfide and zinc bromide in methylene
chloride affords the cyclized product (137). Conversion to
amide (138) can be accomplished by a Weinreb reaction with
methylchloroaluminum amide. Removal of the oxygen
protecting group with a fluoride source, such as
tetrabutylammonium fluoride (TBAF), and concommitant
reaction of the resulting anion with, for example, ethyl
bromoacetate yields the ester (139). Deprotection of the
ester yields the desired acid (140).
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Scheme IVg(e)
OMTS COZEt
TBSO
TBSO \pEt
\ \ ~ \
/ ~O MeCIAlNH2
R3la) ~ N C1~ R3~a~ N ---~,
CH R9 ZnBrz CHzR9
z
(136) (141)
CONH2
CONHZ RO
TBSO ~ \ ( 1 1)LiOH
\ ~ ~ TBAF 1 0
XR 3ta> ~~,/
R3 ~a~ ~ N 0 -.~. R N 2 ) HC1
acetonitrile CHZRQ
(142) CHzR9 (143)
CONHz
R2
\
Rs(a) / N/~/0
CHZRQ
(144) R3 (a
) is as described in Scheme I(a) and
R is as described in Scheme IV(d).
Treatment of the ketene acetal (136) with
bis(chloromethyl)ether and zinc bromide in methylene
chloride affords the cyclized product (141). Conversion to
amide (142) can be accomplished by a Weinreb reaction with
methylchloroaluminum amide. Removal of the oxygen
protecting group with a fluoride source, such as
tetrabutylammonium fluoride, and concommitant reaction of
the resulting anion with ethyl bromoacetate yields the
ester (143). Deprotection of the ester yields the desired
acid (144).
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Scheme IVg(f)
i i
0 O
\ ~ ~ ~ \
BnBr
R3 tai / H R3 (a) NCHzR
(231) (232)
pyr
0'
O / 0\ / MeOCOCOCl
R3 ta)~NCHZR4
(233)
NaBH9
COZMe
0'~ O ~ S
O HO \ ~COZH
1)MsCl
\
N~H RQ 2 ) HSCHzCOzH R3 (a) / NCHZR
Rata) / 2
(234) (235)
(COC1)2
OZMe
0
S
R3 (a) / NCHZR4~0
(236)
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144
ONHz
0 / S OH S
1) LiOH ~ \ \ BBr3
2) (COC1)z'3ta1 / NCH~O R3 (a) ~ NCHZR9 0
3 ) NH3 R
(237) CszC03 (238)
BrCH2CO2Et
GOzEt
J NH2
0
S
\
R3ta1 NCHZR 0
LiOH ~OZH
(239) ONHZ
0 S
R3 (al ~ NCHZR9 O
OZEt
1 ) NaBHg ~ CONHZ OZH
p S ~ ONHZ
2) Et3SiH, TFA LiOH O S
\ \ --",
~3(a~ / NCHZR9
NCHZRg
(241) (242)
N-alkylation of commercially available 4-methoxy indole
(231) under basic conditions using an alkyl halide affords
the N-alkyl indole (232). Acylation with a suitable acid
chloride provides the glyoxalate ester product (233) which
can be reduced with a variety of hydride reducing agents to
give intermediate alcohols (234). Conversion of the alcohol
to a suitable leaving group and displacement with sulfur
nucleophiles affords the thioether product (235).
Conversion to the acid chloride and spontaneous cyclization
affords the thioketone product (236). Cleavage of the ester
can be effected under basic conditions to give the
correponding acid which upon formation of the acid chloride
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and reaction with an appropriate amine gives the amide
product (237). Cleavage of the methyl ether gives the
phenol (238) which can be alkylated under basic conditions
using alkyl halides to give the 0-alkylated product (239).
Cleavage of the ester under basic conditions gives the
desired product (240). Alternatively, reduction of the .
benzylic ketone with a hydride reducing agent and subsequent
deoxygenation of the resulting alcohol gives the
deoxygenated product (244). Cleavage of the oxyacetic ester
proceeds under basic conditions to give the desired
oxyacetic acid (242).
Compounds where Z is an aromatic or heterocyclic
ring containing nitrogen can be prepared as described in
Schemes Vg(a)-(e), below.
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Scheme Vg(a)
CH 0 CH30 X N a ) Pd ( OAc ) z
\ X ~ ~ \ ~ b)BrCN _
N
R3ta1 NH2 R3 (al H
(145) (146)
CN 0 ~ NHz
CH30 N a ) XCHZR4 CH30 N
BBr3
\ ~ NaH ~ ~ / I --
R3 (a) / H b) HzOz OH R3(a> N
CHZR
(147) (148)
O \' NHz 0 \' NHz
OH ~N R2 ~'N
R3 tai 'Ij ' 4 C ) H30+ R3 / N
CH2R CH R9
z
(149) (150)
Substituted haloaniline (145) is condensed with N-benzyl-3-
piperidone to provide enamine (146). Ring closure is
effected by treatment of (14&) with palladium (II) acetate
and the resultant product is converted to (147) by treatment
with cyanogen bromide. Alkylation of (147) is accomplished
by treatment with the appropriate alkyl bromide using sodium
hydride as base. Hydrolysis of this N-alkylated product
with basic hydrogen peroxide under standard conditions
provides (148). Demethylation of (148) is carried out by
treatment with boron tribromide in methylene chloride. The
resulting phenol (149) is converted by the standard sequence
of O-alkylation with methyl bromoacetate in the presence of
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147
a base, hydrolysis with hydroxide to provide the
intermediate salt which is then protonated in aqueous acid
to provide desired b-carboline (150}.
Scheme Vg(b)
TBSO
OTMS
0
I
R3 (a) ,~.~ ~ OCHzCH3
N
(136) CH R9
z
EtO2C
TBSO 1 ) LiOH Rz~O NHzCO
2)HC1 KHMDS
N ~ ~ ~ XR
R3(a) .i- 3 ) EDC, NH3 ~ \ N --
N
/ R3la) N
CHZR ~ q /
CHzR
(151) (152)
NHzOC
RO 1 ) LiOH ~ Hz
-~ Pd (C)
R3 (a) s ~N 2 ) HC1 V H
N R3 la)
/ ~ /
CHZRq
154 ) CHZR
(153)
NHzCO
Rz Pd (C) 1
NH Carbitol
R3fa) i" 3(a)
N HC1 R
CHzR9
( 155 ) ( 156 ) CHZRy
X is halo,
R is as defined in Scheme IV(d), and
R3 (a} is as defined in Scheme I (a) .
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148
Ketene acetal (136), prepared as described in
Scheme IV(d), is reacted with benzyl bis(methoxymethyl)amine
in the presence of zinc chloride to give the tetrahydro-
beta-carboline (151).
Treatment of (151) with lithium hydroxide, .
neutralization with hydrochloric acid and subsequent
treatment with 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride and ammonia provides the
desilyated amide (152) where R20 is hydrogen, which can be
alkylated with, for example, ethylbromoacetate to give
ester (153).
Alternatively, treatment of (115) with the
appropriate Weinreb reagent provides amide (152) (R20 is
t-butyldimethylsilyl) which is desilylated with tetra-n-
butylammonium fluoride and alkylated with, for example,
ethyl bromoacetate to give ester (153). Lithium
hydroxide-mediated hydrolysis gives acid (154), which may
be hydrogenated over an appropriate catalyst in the
presence of hydrochloride acid to give the tetrahydro-
beta-carboline as the hydrochloride salt(155). Compound
(155) may in turn be aromatized by refluxing in carbitol
with palladium on carbon to provide beta-carboline (156).
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Scheme Vg(c)
TBSO
TBSO 1)n-BuLi \
2)CO 2)LiAlH
-~- Rsca> ~ ~ N ~ ~ NOz a
R3~a~ NJ 3) t-Bull H
H
9) Me N~NOz (157)
(133)
COOEt
TBSO TBSO
0 \ NH XCHzR°
H I NaH
~OEt RslaJ ~ N
R3~a~ / H NHZ ~:- H
EtOH/Q
(158) (159)
0 NHZ
COOEt
TBSO \ N~R9 TBSO \ N~R9 1 )~
MeOH/NH3Q ~ ' / ~ 2 ) XR
R3~a~ / N N3CN R3~a> N
I 4 C H R'
CHZR (161) 2
(160)
O NHZ 0 NHz
1)HZ/Pd(C)
RI \ ~ N/\Ra 2 ) -OH R \ NH Pd
\ -~%-
3)+H ~~ J Carbitol
R3(a) ~ N R3(a) ~ N~ 0
I
CHZR9 CH2R'
0 NHZ (163)
(162)
RZ
~N
R3laJ ~ N
I
CHZR9
(164)
X is halo,
R is as defined in Scheme IV(d); and
R3(a) is as defined in Scheme I(a).
In a one-pot reaction, indole (133) is
successively treated with one equivalent n-butyllithium,
carbon dioxide gas, one equivalent of t-butyllithium, and
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1-dimethylamino-2-nitroethene to give (157). Nitroalkene
(157) is reduced with lithium aluminum hydride to amine
(158), which is cyclized with methyl glyoxylate (Ref. 9)
in refluxing ethanol to give tetrahydrocarboline (159).
Alkylation of both nitrogens of (159) leads to
intermediate (160), which is treated with the appropriate
Weinreb reagent to provide amide (161). Fluoride-assisted
desilylation and alkylation with, for example, ethyl
iodoacetate gives ester (162), which may be hydrogenated
over a suitable catalyst and base-hydrolyzed to give acid
(163). Aromatization of (163) to carboline (169) is
achieved by refluxing in carbitol in the presence of
palladium-on-carbon.
Reference 9:
Kelley, T. R.; Schmidt, T. E.; Haggerty, J. G.
A convenient preparation of methyl and ethyl glyoxylate,
Synthesis, 1972, 544-5.
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Scheme Vg(d)
COOH CHO
1)LiAlH4 TBSO NaN
HO / g 2 ) PCC _ / F s
3)TBSC1/imidazole
R3 (a) R3 (af
(17~) (171.)
OTBS OTBS
NO
CHO 1)CH3NOz/EtOH/KOH \ z
~ O
3~a) 2)Acetic anhydride/ s(a) Xylene
N3 pyridine R N3
(172) (173)
OTBS OTBS
XCHzR4 / Hz/Pd(C)
Na~
R3ca> N NOz R3 (a) N NOz
H
(174)
CHZR
(175)
OTBS
_~" OTBS
0 0
C1~C00Et ~ ~ ~ O 0 - ~ -~-
3 (a) ~ ~ ~
R N NHz R3 (a) N~N'~~COOEt
CH2R9 CH R9 H
z
(176) OTBS COOEt (177)
NaBHZS3
R3 (a) N N 0
H
CHZR9
(178)
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OTBS COOEt
R3 (a) \ \N/ \N
H
Boc O/P CH R4 Pd(C) /carbitol/~
z Y z
(179)
OTBS COOEt OTBS COOEt
R3~a) i ~ w ~ Rg~B)
N~ ~N
(180) CHzR4 Boc (183) CHZRq
MeAICINHz MeAICINHz
0 NHZ ~ MHz
OTBS
R3~a) N~N R3fa)
(181) CHZR9 Boc (184) CH2R''
1)F- 1)F-
2)RX/K2C03 2)RX/KzC03
3)-OH 3)NaOH
4)H+
O NHz
Rz
R3~a) R3la> N~,N/
CHZRy CHZRq
(182) (185)
The commercially available acid (170) is reduced
with lithium aluminum hydride, oxidized with pyridinium
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chlorochromate, and silylated with t-butyldimethylsilyl
chloride to give (171). Treatment with sodium azide
provides azide (172), which is reacted with nitromethane and
potassium hydroxide in ethanol, followed by treatment with
acetic anhydride and pyridine to give nitroolefin (173).
Heating in xylene induces cyclization to produce indole .
(174). Alkylation with, for example, benzyl iodide and
sodium hydride gives (175), which is hydrogenated in the
presence of palladium-on-carbon to give amine (176).
Acylation with the acid chloride of commercially available
oxalacetic acid monoethyl ester gives (177), which is
thermally cyclized to lactam (178). Selective reduction of
the lactam carbonyl may be accomplished by treatment with
NaBH2S3 to provide amine (179).
Protection of amine (179) with di-t-butyl
dicarbonate and pyridine produces (180), which is converted
via the appropriate Weinreb reagent to amide (181).
Fluoride-assisted desilylation, alkylation with, for
example, ethyl iodoacetate and potassium carbonate, base
hydrolysis, and acid hydrolysis produce the tetrahydro-
alpha-carboline (182).
Alternatively, amine (179) may be aromatized by
refluxing in carbitol or some other suitable high boiling
solvent to give alpha-carboline (183), which is converted
via the appropriate Weinreb reagent to amide (184).
Fluoride-assisted desilylation, alkylation with ethyl
iodoacetate and potassium carbonate, and base hydrolysis
as described above provides alpha-carboline (185).
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Scheme Vg(e)
Rz
2
R \ CszC03 I \ I LiAlH9
BnBr
R3~a) I / N I CO Me 1~~ Rata) / i COzMe EtzO
CHzR4
H
(190) (191)
Rz Rz
\ MnOz \ malonic acid
I I CHZClz I / I base
R3(a) ~ N CH OH R i CHO
2
CH R4 CHzR4
z
(192) (193)
z Rz
1 ) H" /MeOH \ CO CH
----~ ~ ~ 2 3
R3(a) ~ N ~ COzH 2)Pd/C R3la> ~ N
4
CHZR (194) (195) CHzRg
H
2
1)BTCEAD/EtzO R \ N O 1)LiAlH4/THF
2)Zn/HOAc ' I '~ ~ 2)TMSNCO
R3la) N
CHzR4
(196)
O_"NHz
0"NHz z
R N
Rz 1)BBr3/CHZC12 I ~ I
I \ I N 2)XR
R3 N
3 ca) ~ N 3 ) NaOH/MeOH-THF
R I 9 ) H30+ CHzR
CHZR9 (198)
(197)
X is halo
R3(a) is as defined above
Scheme V(e) provides b-carboline (198) by the indicated
sequence of reactions. N-alkylation of 2-carboethoxyindole
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(190) followed by a standard two carbon homologation
sequence provides 2-(3-propenoic acid)indoles (194). In
this sequence, the condensation of aldehyde (193) with
malonic acid utilized a mixture of pyridine and piperidine
as the base. After methyl ester formation and hydrogenation
(195), ring closure (196) was effected by treatment with
bis(2,2,2-trichloroethyl)azodicarboxylate (BTCEAD) followed
by zinc in acetic acid. Reduction of the cyclic amide with
lithium aluminum hydride followed by treatment with
trimethylsilylisocyanate provided the urea (197).
Conversion to the desired d-carboline (198) was accomplished
under the usual conditions of demethylation and subsequent
alkylation and ester hydrolysis steps.
Reverse indoles, i.e., compounds where B is
carbon and D is nitrogen can be prepared as described in
Scheme VIg, below.
Scheme VIg
OCHZRS O H OCHZRS
H
NH ~R~ PC13 / N
/
PhCH3 CHzClz
(200) (201) Ra
C1~COZMe NaH
Br DMF
MeO2C
OCHzRs
But3SnH
'~ O
9
(203) R
(202)
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Aryl hydrazines (200) are condensed with
substituted prpionaldehydes to form hydrazones which are
cyclized to indoles (201) by treatment with phosphorous
trichloride at room temperature (Ref 1). The indoles are
N-alkylated on reaction with a base such as sodium hydride
and an alph-bromo ester to give indoles (202) which are
cyclized to tetrahydrocarbazoles (203) by Lewis acids
(e. g., aluminum chloride) or by radical initiators (e. g.,
tributyltin hydride). Compounds (203) can be converted to
carbazoles by, for example, refluxing in a solvent such as
carbitol in the presence of Pd/C.
Compounds of formula I wherein A is pyridyl can
be prepared as described in Schemes VIIg(a)-(b), below.
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Scheme VIIg(a)
1) 3 eq - t-BuLi
C1 2) COz COOH
\ 3) 1 eq n-BuLi
I I \ CH30H/H+
4 ) MezN~NOz
H 5 ) H+/heat OzN \ N
H _
(210) (211)
COOCH3 COOCH3
I \ XCHZRQ I I ~ Hz / Pd ( C ) _
0 N \ N / 02N \ N
2 I
H CH2Rn
(212) COOCH3 (213)
O COOCH3
\ C1COC1 Pd(C)
I I ~ ~.~. HN I I \
HZN N / Carbitol/0
CH2R9 N
I
(214) CHZR' (215)
OH COOCH3 OH O NHz
1 ) XR/KZC03
N ~ \ AlMeCINHz N / \ 2 ) AqNaOH
\ I N I ~ ~ \ I I ~ --
I N
CHZR4 CH R4
z
(216) Rz O NHZ (217)
N\ I I ~
N
I
CHzR9
(218)
X is halo and
R is (CH2)mR5,
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Commercially available 4-chloroindole (210) is
treated with 3 equivalents of t-butyllithium followed by
carbon dioxide, 1 equivalent of n-butyllithium,
1-dimethylamino-2-nitroethene, and acid to provide
carboxylic acid (211), which may be esterified to give
(212). Alkylation at the 1-position followed by .
hydrogenation provides aminoethyl indole (214). Cyclization
with phosgene to (215) followed by aromatization gives
carboline (216). Treatment of (216) with the appropriate
Weinreb reagent provides amide (217), which may be alkylated
with, for example, ethyl bromoacetate and saponified with
sodium hydroxide to give the carboline (218).
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Scheme VIIg(b)
Pd(OAc)z(o-tol)3P
triethylamine or
COZCH3 COzCH3 O pd ( ph3P)
X ~ X HMPA Ref:l
O N~ ~ ~ ~ or
R3(aJ ~ / PC'Rs(al / NPG
NHz ( 8 H NaH, CuI
(221) HM PA Ref:z
(220)
COzCH3 0 COzCH3 O
1)HOAc/Pd(c)~
NaH
XCHZRQ I 1 2 ) Hz ( Pd) ( c )
/ NPG / ~NPG
R3(a) N Rica) ~ '~N
H
I
(222) CHzR'
(223)
COZCH3 OH
NH3/methano CONHz OH
CsC03
XR
R3 (a) / N ~ N R3 (a) ~ / N~N -
CHZR9 CH RQ
z
(225)
(224)
CONH Rz 1 ) LiOH CONHz Rz
z 2)HC1
/ --_,
3 (a) ~ / ~ ~ R3 (a) ~ / N
R N I
CH R9 CHzR'
z
(226) (227)
R3(a) is as defined in Scheme I(a),
X is halo, and
R is (CH2)mRS.
The 1,3-dione structures (228) are either
commercially available or readily prepared by known
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techniques from commercially available starting materials.
Preparation of the aniline derivatives (220) (X=C1, Br, or
I) are accomplished by reducing an appropriately
substituted benzoic acid derivative to the corresponding
aniline by treatment with a reducing agent such as SnCl2
in hydrochloric acid in an inert solvent such as ethanol
or by hydrogenation using hydrogen gas and sulfided
platinum or carbon or palladium on carbon. The amino
group of (228) is protected with an appropriate protecting
group, such as the, carboethoxyl, benzyl, CBZ
(benzyloxycarbonyl) or BOC (tert-butoxycarbonyl)
protecting group, and the like.
The dione (228) and aniline derivative (220) are
condensed according to the general procedure of Chen, et
al., (Ref 10) or Yang, et al., (Ref 11), with or without a
noninterfering solvent, such as methanol, toluene, or
methylene chloride, with or without an acid, such as
p-toluenesulfonic acid or trifluoroacetic acid, with or
without N-chlorosuccinimide and dimethyl sulfide, to
afford the coupled product (221).
Compound (221) is cyclized under basic
conditions with a copper (I) salt in an inert solvent
according to the general procedure of Yang, et al.,
(Reft8). The derivative (221) is treated with a base,
such as sodium hydride, in an inert solvent, such as HMPA,
at a temperature between 0 and 25 °C. A copper (I) salt,
such as copper (I) iodide, is added and the resultant
mixture stirred at a temperature between 25 and 150 °C for
1 to 48 hours to afford compound (222).
Compound (221) may also be cyclized according to
the general procedure of Chen, et al., (Ref 10). The
derivative (221) is treated with a base, such as sodium
bicarbonate, and a palladium catalyst, such as Pd(PPh3)4,
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in an inert solvent, such as HMPA, at a temperature
between 25 and 150 °C to afford compound (222).
In a preferred method, intermediate (171) is
treated with a transition metal catalyst, such as
Pd(OAc)2(O-tol)3P in the presence of a base such as
triethylamine using a cosolvent of DMF/acetonitrile to _
prepare (222).
Compound (222) is N-alkylated with an
appropriately substituted benzyl halide in the presence of
a base, such as sodium hydride or potassium carbonate, in
a noninterfering solvent, such as dimethylformamide or
dimethylsulfoxide to afford ketone (223). In a two step,
one pot process(222) is aromatized by treatment with
acetic acid and palladium on carbon in a noninterfering
solvent, such as carbitol or cymene, followed by treatment
with hydrogen gas and palladium on carbon to cleave the
nitrogen protecting group and produce the phenolic
derivative (224).
The ester (224) is converted to the
corresponding amide (225) under standard conditions with
ammonia (preferably) or an ammonium salt, such as ammonium
acetate, in an inert solvent, such as water or alcohol,
preferably methanol, or with MeCIAINH2 in an inert
solvent, such as toluene, at a temperature between 0 to
110 °C. Alkylation of the phenolic oxygen of compound 38
with an appropriate haloester, such as methyl
bromoacetate, in the presence of a base, such as cesium
carbonate, potassium or sodium carbonate, in an inert
solvent, such as dimethylformamide or dimethylsulfoxide
affords the ester-amide (226). Other haloesters, such as
ethyl bromoacetate, propyl bromoacetate, butyl
bromoacetate, and the like can also be used to prepare the
corresponding esters.
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Saponification of compound (226), with lithium
hydroxide in an inert solvent, such as methanol-water,
affords (227). The intermediate and final products may
isolated and purified by conventional techniques such as
chromatography or recrystallization. Regioisomeric
products and intermediates can be separated by standard
methods, such as, recrystallization or chromatography.
References:
10) L.-C. Chen et al., Synthesis 385 (1995)
11) S.-C. Yang et al., Heterocycles, 32, 2399 (1991)
h) Pyrazole sPLA2 inhibitors
The method of the invention may be practiced using
pyrazole sPLA2 inhibitors, which are described (together
with the method of making) in US Patent Application
No. 08/984261, filed December 3, 1997, the entire disclosure
of which is incorporated herein by reference. Suitable
pyrazole compounds are represented by formula (Ih)
R1
S N
(R3)(~H2)/ ~ ~ \SO2R2
N N
(Ih)
wherein:
R1 is phenyl, isoquinolin-3-yl, pyrazinyl, pyridin-2-
yl, pyridin-2-yl substituted at the 4-position
with -(C1-C4)alkyl, (C1-C4)alkoxyl, -CN or
-(CH2)nCONH2 where n is 0-2;
R2 is phenyl; phenyl substituted with 1 to 3
substituents selected from the group consisting of
-(C1-C4)alkyl, -CN, halo, -N02, C02(C1-C4)alkyl
and -CF3; naphthyl; thiophene or thiophene
substituted with 1 to 3 halo groups;
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R3 is hydrogen; phenyl; phenyl(C2-C6)alkenyl; pyridyl;
naphthyl; quinolinyl; (C1-C4)alkylthiazolyl;
phenyl substituted with 1 to 2 substituents
selected from the group consisting of
-(C1-C4)alkyl, -CN, -CONH2, -N02, -CF3, halo,
(C1-C4)alkoxy, C02(C1-Cq)alkyl, phenoxy and SR4_
where R4 is -(C1-C4)alkyl or halophenyl;
phenyl substituted with one substituent selected
from the group consisting of
-O(CH2)pR5 where p is 1 to 3 and R5 is -CN,
-C02H, -CONH2, or tetrazolyl,
phenyl and
-OR6 where R~ is cyclopentyl, cyclohexenyl,
or phenyl substituted with halo or
(C1-C4)alkoxy;
or phenyl substituted with two substituents which,
when taken together with the phenyl ring to which
they are attached form a methylenedioxy ring; and
m is 1 to 5;
or a pharmaceutically acceptable salt thereof.
Particularly preferred are pyrazole type sPLA2
inhibitors as follows:
A pyrazole compound of formula (I), supra, wherein:
R1 is pyridine-2-yl or pyridine-2-yl substituted
at the 4-position with -(C1-C4)alkyl, (C1-C4)alkoxy, -CN or
-(CH2)nCONH2 where n is 0-2;
R2 is phenyl substituted with 1 to 3 substituents
selected from the group consisting of -(C1-C4)alkyl, -CN,
halo, -N02, C02(C1-Cq)alkyl and -CF3; and
R3 is phenyl; phenyl(C2-C6)alkenyl; phenyl
substituted with 1 or 2 substituents selected from the group
consisting of -(C1-C4)alkyl, -CN, -CONH2, -N02, -CF3, halo,
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(C1-C4)alkoxy, C02(C1-C4)alkyl, phenoxy and SR4 where R4 is
-(C1-C4)alkyl or halo phenyl;
phenyl substituted with one substituent selected
from the group consisting of -O(CH2)pR5 where p is 1 to 3
and R5 is -CN, -C02H, -CONH2 or tetrazolyl, phenyl and -OR6
where R6 is cyclopentyl, cyclohexenyl or phenyl substituted
with halo or (C1-C4)alkoxy;
or phenyl substituted with two substituents which
when taken together with the phenyl ring to which they are
attached form a methylenedioxy ring.
Specific suitable pyrazole type sPLA2 inhibitors useful
in the method of the invention are as follows:
Compounds selected from the group consisting of 3-(2-chloro-
6-methylphenylsulfonylamino)-4-(2-(4-acetamido)pyridyl)-5-
(3-(4-fluorophenoxy)benzylthio)-(1H)-pyrazole and 3-(2,6-
dichlorophenylsulfonylamino)-4-(2-(9-acetamido)pyridyl)-5-
(3-(4-fluorophenoxy)benzylthio)-(1H)-pyrazole.
The pyrazole compounds of formula Ih are prepared as
described in Scheme Ih below.
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Scheme Ih
R1 CN
R1 cN hydrazine
R3 ( CH2 ) mL (~ I ( b )
(1) (2) R3 (CH2)mS \S(CH2)mR3
Rl ( 3 ) Ri
R3 ( CH2 ) m ~2 R3 ( CH2 ) mS NHS02R2
+ R2SOZC1
(c) ~
N N
H
(5) H (6) N
L is a leaving group.
In an aprotic polar solvent, such as
tetrahydrofuran, an acetonitrile compound (1) is
deprotonated by treatment with an excess of a strong base,
such as sodium hydride, preferably under an inert gas, such
as nitrogen. The deprotonated intermediate is treated with
carbon disulfide and then alkylated twice with an
appropriately substituted alkyl halide (2) of the formula
R3(CH2)mL, where L is a leaving group, preferably bromine,
and R3 and m are as defined above, to prepare intermediate
compound (3). The reaction is conducted at ambient
temperatures and is substantially complete in 1 to 24 hours.
Cyclization to form the amino substituted pyrazole
(4) is achieved by reacting intermediate (3) with hydrazine
at room temperature for from about 1 to 24 hours.
Selective sulfonylation of the amino group of
intermediate (4) can be accomplished by treatment with a
sulfonyl chloride (5) of the formula R2S02C1, where R2 is as
defined above, to prepare product (6). The reaction is
preferably conducted in a solvent, such as pyridine, at
ambient temperature for a period of time of from 1 to 24
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hours. Preparation of 2,6-dimethylphenylsulfonyl chloride
can be accomplished as described in J. Org. Chem. 25, 1996
(1960). All other sulfonyl chlorides are commercially
available.
i) Phenyl glyoxamide sPLA2 inhibitors (and the method of
making them) are described in U.S. Patent Application Serial
No. 08/979446, filed November 24, 1997 (titled, Phenyl
Glyoxamides as sPLA2 Inhibitors), the entire disclosure of
which is incorporated herein by reference.
The method of the invention is for treatment of a
mammal, including a human, afflicted with cystic fibrosis,
said method comprising administering to said human a
therapeutically effective amount a phenyl glyoxamide type
sPLA2 inhibitors useful in the method of the invention are
as follows:
A compound of the formula (Ii)
R1 ~ YRP
;HZ)n
R2
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wherein:
X is -O- or -(CH2)m_, where m is 0 or 1;
Y is -C02-, -P03-, -S03-;
R is independently -H or -(C1-Cq)alkyl;
R1 and R2 are each independently -H, halo or
-(C1-Cq)alkyl;
R3 and R4 are each independently -H, -(C1-C4)alkyl,
(C1-Cq)alkoxy, (C1-Cq)alkylthio, halo, phenyl or phenyl
substituted with halo;
n is 1-8; and
p is 1 when Y is -C02- or -S03- and 1 or 2 when Y is
_P03_;
or a pharmaceutically acceptable salt thereof.
A specific suitable phenyl glyoxamide type sPLA2 inhibitors
is 2-(4-carboxybut-1-yl-oxy)-9-(3-phenylphenoxy)-
phenylglyoxamide.
These phenyl glyoxylamide compounds useful in the method of
the invention are prepared as follows:
Compounds where R1, R2, R3 and R9 are H, and X, Y
and n and p are as defined above can be prepared according
to the following Scheme Ii.
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Scheme Ii
0
\ _o
OH C ~I
> fib) > _
1 ~ ~ 2
() ()
O O
O
(c) > (d~
x
(3) (4)
O O
p N O \ NHZ
O(CHZ~,YR'P ,~ O(CH2~YHP
(e)
x~ x
~ ~ 6
() ()
R' is -(C1-Cq)alkyl
5
Reflux of (1) with oxalyl chloride in an alkyl
halide solvent, such as chloroform, using 4-N, N'
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dimethylamino pyridine as a catalyst achieves
intermediate (2).
Under Friedel-Crafts conditions, using a suitable
Lewis-acid catalyst such as aluminum chloride, compound (2)
is internally cyclized to form compound (3). The reaction
is preferably conducted at temperatures from about 0 °C to
room temperature and allowed to proceed for about 24 hours.
Aminolysis of (3) to amide (4) can be achieved by
treatment with concentrated ammonium hydroxide.
Alkylation of the hydroxyl of compound (4) can be
readily achieved by treatment with an appropriate alkylating
agent, such as Br(CH2)nY, where Y is -C02R, -P03R2 or S03R
and R is -(C1-C4)alkyl, to form intermediate (5). The
reaction is preferably conducted in an aprotic polar
solvent, such as dimethyl formamide, in the presence of
potassium carbonate and a suitable catalyst, such as
potassium iodide.
Conversion of (5) to the carboxylic or sulfonic
acid or acid salt (6) may be achieved by treatment with an
appropriate base, such as aqueous sodium hydroxide, in a
polar protic solvent, such as methanol.
When n is 2, a bromoacetal must be employed as an
alkylating agent to achieve the carboxylic acid (6). The
alkylated moiety (5) is then converted to the acid (6) by
oxidizing with sodium dichromatate in aqueous conditions.
When Y is -P03-, conversion to the acid (6), is
preferably conducted in an alkyl halide solvent, such as
methylene chloride, using a dealkylating agent, such as
trimethylsilyl bromide, and an excess of potassium
carbonate, followed by treatment with methanol.
When R1, R2, R3 or R4 are other than hydrogen, the
preparation proceeds as described in Scheme IIi on the
following page.
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Scheme IIi
1
R ~~OH OH
7
Scheme I OH
/ Steps (a-b~
R I R3 (c) s (--
3
R 3
4 w R
R
~"~ R4 ~ 4
/ R
(8)
(9)
O NHZ
OH
O
t
(°) (0
R3
3
R 1
I i1 R~ ~ R
(»>
(I0)
/(h)
r
0
NHZ NHZ
(CH2)~YR'p ~ (CH2)nYHp
(8)
Rs R3
y
/ /
(12) {13)
R' is as defined in Scheme Ii.
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An appropriately R1, R2 substituted phenol (7) is
converted to lactone (8) following the procedures described
in Scheme Ii, steps (a-b) above.
Conversion to the intermediate (9) is accomplished
by reacting (2a) with an aqueous acid, such as hydrochloric
acid which affords removal of aluminum chloride from the
reaction. Acid (9) is converted to the corresponding acid
chloride using oxalyl chloride with dimethyl formamide as a
catalyst. The acid chloride is recyclized to the lactone
(10) on removal of the solvent, preferably under vacuum.
The lactone (10) is converted to the glyoxamide (11) by
treatment with an excess of ammonia as described in
SchemetI, step (c), above.
Alkylation of (11) to prepare the ester (12),
followed by conversion to the acid is accomplished according
to the procedure outlined in Scheme I, steps (d) and (e).
Alternately, conversion of (10) to (12) can be
accomplished in a one-pot procedure by treating the lactone
(10) with sodium amide in an aprotic polar solvent, such as
dimethylformamide, preferably at temperatures of from about
0 °C to 20 °C, followed by alkylation with an appropriate
alkyl halide.
j) Pyrrole sPLA2 inhibitors and methods of making them are
disclosed in U.S. Patent Applicaton Serial No. 08/985518
filed December 5, 1997 (titled, "Pyrroles as sPLA2
Inhibitors"), the entire disclosure of which is incorporated
herein by reference.
The method of the invention is for treatment of a
mammal, including a human, afflicted with cystic fibrosis,
said method comprising administering to said human a
therapeutically effective amount a pyrrole sPLA2 inhibitors
useful in the method of the invention as follows:
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A compound of the formula (Ij)
R6
X \
R3 R5
R7
R9 R2 (Ij)
N
CHZR~
R1 is hydrogen, (C1-Cq)alkyl, phenyl or phenyl
substituted with one or two substituents selected from the
group consisting of -(C1-Cq)alkyl, (C1-Cq)alkoxy,
phenyl(C1-C4)alkyl, (C1-Cq)alkylthio, halo and phenyl;
R2 is hydrogen, -(C1-C4)alkyl, halo, (C1-C4)alkoxy or
(C1-C4)alkylthio;
R3 and R4 are each hydrogen or when taken together are
=0;
R5 is -NH2 or -NHNH2;
R6 and R7 are each hydrogen or when one of R6 and R7 is
hydrogen, the other is -(C1-C4)alkyl, -(CH2)nRlO where R10
is -C02R11, -P03(R11)2~ -p04(R11)2 or -S03R11 where R11 is
independently hydrogen or -(C1-C4)alkyl and n is 0 to 4; or
R6 and R7, taken together, are =O or =S;
X is R8(C1-C6)alkyl; R8(C2-C6)alkenyl or phenyl
substituted at the ortho position with R8 where R8 is
(CH2)nRlO where R10 is -C02R11, -P03(R11)2~ -p04(R11) or
-S03R11, R11 and n is 1 to 9 as defined above, and
additionally substituted with one or two substituents
selected from the group consisting of hydrogen,
-(C1-C4)alkyl, halo, (C1-C4)alkoxy, or two substituents
which, when taken together with the phenyl ring to which
they are attached, form a naphthyl group; and
R9 is hydrogen or methyl or ethyl;
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or a pharmaceutically acceptable salt thereof.
Preferred pyrrole sPLA2 inhibitors useful in the method of
the invention are compounds of formula Ij wherein;
R1 is phenyl;
R2 is methyl or ethyl;
R5 is -NH2;
R6 and R7 are each hydrogen;
X is R8(Cl-C6)alkyl or phenyl substituted at the ortho
position with R8 where
R8 is -C02R11; and
R9 is methyl or ethyl.
A specific suitable pyrrole sPLA2 inhibitors useful in the
method of the invention is 2-[1-benzyl-2,5-dimethyl-4-(2-
carboxyphenylmethyl)pyrrol-3-yl]glyoxamide.
The pyrrole compounds are prepared as follows:
Compounds of formula I where R5 is -NH2 can be
prepared as shown in Scheme Ij, below.
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Scheme Ij
X 6
I'R
R9 Rz (a) R7
-~ R9 ~ ~ '-R2 (b) ' 9 z
I II N R R
O O I N
CH2R1 CH R1
(1) (2) (3) z
(c)
X Rs NHz ~ Rs H 1 NHz ~ Rs v NHz
R' ~ ~ 10 ~ R~ ~ ~(d) R~ ~ ~ O
R9 - Rz R9 ~ ~ Rz R9 N~ Rz
NI N
CHzRl ~HzRl CH2R1
(6) (5) (4)
An appropriately substituted gamma-diketone (1) is
reacted with an alkylamine of the formula NHCH2R1 to give
pyrrole (2). Under Friedel-Crafts conditions, using a
suitable Lewis-acid catalyst such as stannic chloride,
aluminum chloride, or titanium tetrachloride (preferably
stannic chloride) pyrrole (2) is ring alkylated with an
alkyl or arylalkyl halide compound of the formula ZCR6R~X
where Z is a suitable halogen and R8 of X is a protected
acid or ester. The reaction is preferably conducted in a
halogenated hydrocarbon solvent, such as dichloromethane, at
ambient temperatures and allowed to proceed for from about 1
to about 24 hours.
Intermediate (3) is converted to (4) by sequential
treatment with oxalyl chloride followed by ammonia.
Selective reduction of (4) is accomplished in a two step
process. In a hydride reduction using, for example, sodium
borohydride, the hydroxy intermediate (5) is prepared which
can be further reduced using either catalytic or hydride
reduction (preferably palladium on carbon) to prepare (6).
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Deprotection of R8 to the acid may be readily achieved by
conventional techniques. For example, when an alkyl ester
is used as a protecting group, deprotection can be
accomplished by treatment with a base, such as sodium
hydroxide.
k) Naphthyl glyoxamide sPLA2 inhibitors and methods of
making them are described in U.S. Patent Application Serial
No. 09/091079, filed December 9, 1966 (titled, "Naphthyl
Glyoxamides as sPLA2 Inhibitors"), the entire disclosure of
which is incorporated herein by reference.
The method of the invention is for treatment of a
mammal, including a human, afflicted with cystic fibrosis,
said method comprising administering to said human a
therapeutically effective amount a naphthyl glyoxamide sPLA2
inhibitors useful in the method of the invention are as
follows:
A naphthyl glyoxamide compound or a pharmaceutically
acceptable salt, solvate or prodrug derivative thereof;
wherein said compound is represented by the formula Ik
(Ik)
wherein:
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R1 and R2 are each independently hydrogen or a non-
interfering substituent with the proviso that at least one
of R1 or R2 must be hydrogen;
X is -CH2- or -0-; and
Y is (CH2)nZ where n is a number from 1-3 and Z is an
acid group selected from the group consisting of C02H, -S03H
or -PO(OH)2.
A specific suitable naphthyl glyoxamide sPLA2 inhibitors
useful in the method of the invention has the following
structural formula:
O
NH2
HO
O °\
The naphthyl glyoxamide compounds are prepared as
follows:
Compounds of formula I where X is oxygen can be
prepared by the following reaction Scheme Ik.
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Scheme Ik
HO OK+ CH 3 O
2 equivalents dimethyl-
sulfate
1 ) KOHL
2) HCl
1 equivalent
OH OH OH
(1) (2) (3)
OH OCH3
appropriately
40~ HBr substituted
\ HOAC / ~ \ phenol
\ ~ / R1 \ ~ R1 K2C03/Cu0
R
R2 \ 2
(4)
oxayl
chloride O
O O A1C13
1
4-dimethylamin 1) NaN~
pyridene 2) BrC~COZCH3
I C1 KI
R1 R2
R2
(6)
Step A
r
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l'1111vTT T
0
aqueous
1) NaOH
HO ~ute CHsO
2) HC1
0 ~ R2 Step B R2
(9)
In the above depicted reaction scheme, the
1,5-dihydroxy napthalene starting material (1) is dispersed
in water and then treated with 2 equivalents of potassium
hydroxide. The resultant solution is chilled in an ice bath
and one equivalent of a strong mineral acid, such as
hydrochloric acid, is added to produce the potassium
saltt(2).
Alkylation of the radical (2) can then be
accomplished by treatment with a methylating agent such as
dimethyl sulfate to prepare the ether (3).
Preparation of (9) is achieved by reacting the
ether (3) with an appropriately substituted phenol in an
Ullman-type reaction using potassium carbonate and cupric
oxide.
De-methylation of (4) can be accomplished by
treating (4) with a 40~ HBr/HOAC solution at reflux in a
protic polar solvent such as acetic acid, to prepare (5).
Reflux of compound (5) with oxalyl chloride and
4-demethylamino pyridine, in an alkylhalide solvent such as
methylene chloride, prepares the oxalyl chloride (6).
Internal cyclization of (6) can be achieved under
Friedel-Crafts condition using aluminum chloride or other
similar metal halide as the catalyst. The reaction can be
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conveniently conducted in an alkyl halide solvent, such as
1, 2-dichloro ethane.
Alkylation and hydrolysis of the cyclized compound
(7) can be achieved by reacting (7) with an alkaliamide
base, such as sodium amide, followed by treatment with an
alkylating agent, such as methyl bromoacetate, using .
potassium iodide as a catalyst.
Finally, the acid (9) is achieved by treating the
ester (8) with an alkali base, such as aqueous sodium
hydroxide, followed by treatment with a dilute aqueous
mineral acid such as hydrochloric acid The acid compound
(9) is then extracted with an organic solvent such as ethyl
acetate.
The final product (9) can be purified using
standard recrystallization procedures in a suitable organic
solvent such as methylene chloride/hexane.
Compounds of formula I where X is methylene can be
prepared as shown in the following Scheme IIk
Scheme IIk
Br OCH
R1 1) Mg, ET20
~N
2)
R2 ~ /
R2
CH3 O
3) aqueous acid
NaBH4
CF3 CO2H
r
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H.,CO
R2
(2a)
Using an appropriately substituted phenyl bromide,
a Grignard reagent is prepared. The phenyl Grignard is then
reacted with 4-methoxy naphthylnitrile and the resultant
compound is hydrolyzed with a dilute acid such as
hydrochloric acid to form the benzoyl naphthylene compound
(la) .
Reduction of (1a) to form compound (2a) is
accomplished by treatment with a reducing agent such as
sodium borohydride. The reaction is conducted in a solvent-
catalyst such as trifluoroacetic acid and initiated in an
ice bath which is allowed to warm to room temperature as the
reaction proceeds.
The desired naphthyl glyoxamide may then be
prepared from (2a) according to the procedure in Scheme I
starting with the chloromethylation step.
It will be readily appreciated by a person skilled
in the art that the substituted benzyl bromide, substituted
phenol and substituted naphthylnitrile compounds of Schemes
I and TI are either commercially available or can be readily
prepared by known techniques from commercially available
starting materials.
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1) Phenyl acetamide sPLA2 inhibitors and methods of
making them are disclosed in US Patent Application
08/976858, filed November 24 1997 (titled, "Phenyl
Acetamides as sPLA2 Inhibitors"), the entire disclosure of
which is incorporated herein by reference.
The method of the invention is for treatment of a
mammal, including a human, afflicted with cystic fibrosis,
said method comprising administering to said human a
therapeutically effective amount of a phenyl acetamide sPLA2
inhibitor represented by formula (I1)
as follows:
N
R1
Rfi (I1)
wherein:
R1 is -H or -O(CH2)nZ;
R2 is -H or -OH;
R3 and R4 are each independently -H, halo or
-(C1-C4)alkyl;
One of R5 and R6 is -YR7 and the other is -H,
where Y is -0- or -CH2- and R7 is phenyl or phenyl
substituted with one or two substituents selected from the
group consisting of halo, -(C1-C4)alkyl, (Cl-C4)alkoxy,
phenyl or phenyl substituted with one or two halo groups;
Z is -C02R, -P03R2 or -S03R where R is -H or
-(C1-C4)alkyl~ and
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n is 1-8;
or a pharmaceutically acceptable salt, racemate or
optical isomer thereof;
provided that when R6 is YR~, R1 is hydrogen; and
when R1, R2, R3, R4 and R6 are hydrogen and R5 is YR~
where Y is -0-, R~ cannot be phenyl; and .
when R1, R2, R3, R4 and R6 are hydrogen, R5 is YR~
where Y is CH2, R~ cannot be phenyl substituted with one
methoxy or two chloro groups.
Preferred suitable phenyl acetamide sPLA2 inhibitors useful
in the method of the invention are as follows:
Compounds of formula I wherein R2, R3 and R4 is H, Y is
oxygen or CH2, R~ is phenyl or phenyl substituted at the
meta position with one or two substituents ,selected from
halo, -(C1-C4)alkyl, (C1-Cq)alkoxy, phenyl or phenyl
substituted with halo and n is 4-5.
A specific suitable phenyl acetamide sPLA2 inhibitors useful
in the method of the invention is 2-(4-carboxybutoxy)-4-(3-
phenylphenoxy)phenylacetamide.
The phenyl acetimde compounds are prepared as follows:
Compounds of formula I where R1 and R2 are H, R5 or R6 are
YR~ where R~ is phenyl or substituted phenyl and Y is oxygen
can be prepared as illustrated in Scheme Il(a), below.
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Scheme I1(a)
O
R8 R3
(b) _
R9
R4
OPG OH
J
(1) (2)
Ra
(3)
;c)
Rs Rs
X is halo:
R8 and R9 are each independently -H, halo,
-(C1-C4)alkyl, (C1-C4)alkoxy, phenyl or phenyl
substituted with one or two halo groups: and
PG is a carboxyl protecting group
An appropriately substituted carboxy-protected
halophenyl compound (1), where the halogen is preferably
bromine, is coupled with an appropriately substituted phenol
(2) under modified Ullmann conditions, by refluxing with
potassium carbonate and cupric oxide in an aprotic polar
solvent, such as pyridine, under an inert gas such as argon.
The reaction is substantially complete in 1-24 hours.
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Intermediate (3) is deprotected by treatment with
a base such as aqueous potassium hydroxide using a solvent,
such as diethylene glycol. The reaction, preferably
conducted at about 100°-150 °C, is substantially complete in
1-24 hours.
Conversion to the amide (5) can then be readily .
achieved by treatment first with oxalyl chloride in an alkyl
halide solvent, such as methylene chloride, using
dimethylformamide as a catalyst, at temperatures of from
about 0 °C to ambient temperature, followed by treatment
with an excess of ammonia gas, again in an alkyl halide
solvent.
Alternately, compounds of formula I can be
prepared according to the procedure of Scheme I(b), below.
The substituted phenol (2) is coupled with an
appropriately substituted benzyl halide (6) as described in
Scheme I(a), step a, above, to prepare (7).
Halogenation of (7) is achieved using a
halogenating agent, such as N-bromosuccinimide and a
catalyst, such as 2,2'azobisisobutyronitrile, in an alkyl
halide solvent, such as chloroform, to prepare (8).
Treatment of (8) with sodium cyanide in an aprotic
polar solvent, such as dimethyl formamide produces the
nitrile (9) which can then be readily converted to the amide
(10) by treatment with an aqueous acid, such as hydrochloric
acid.
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185
Scheme Il(b)
OH CH3 CH3
R R
(_ a) _~ \ {b)
i + ~ . ~ J Re
Rs Ra O
X Ra
{2)
Rs
X
CN
R3
R3
O) ,.~ ~ {d) t
/ Re Re
J
4
R O / Ra
{8) ~ ~ i
Rs {9)
Rs ~."~ Rs
R8 and Rg are as shown in Scheme I(a),
X is halo.
In another procedure, compounds of formula I where
R1, R2, R3 and R4 are hydrogen, Y is -O- or -CH2- and R~ is
phenyl can be prepared as portrayed in Scheme II1.
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186
Scheme II1
~X
(a) (b)
Y\
(12) Y ~ ~
(11)
'~ CN \~ CONH2
(c)
(13) Y ~ / (14) Y
X is a halogen.
An appropriate diphenyl compound (11) is treated
with paraformaldehyde and a halogenating agent, such as 40%
hydrogen bromide in acetic acid. Two positional isomers
result with the X substituent at either the meta or para
position of the phenyl ring to which it is attached.
Displacement of the halogen to prepare the nitrile
isomers (13) can be achieved by treatment of (12) with
sodium cyanide in dimethylformamide as described in
SchemetI(b), step (c), above. The isomers can then be
readily separated by conventional chromatographic techniques
and each isomer may be converted to its respective amide
(14) by treatment with hydrogen peroxide and potassium
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carbonate in an aprotic polar solvent, such as
dimethylsulfoxide.
Compounds where R1 is -0(CH2)nZ can be prepared as
illustrated in Scheme III1, below.
Scheme III1
0
0
OH CI
(ate
X R I
(15)
R9
R°
O O O
_ NH2
R3 ~ 0 R3 / OH
Ra (c) > R4 ~./ (d~~
X Re Re
(17) ~ (18)
~ Re ~ ~ Re
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0
O '\ NH2
R O(C~~,Z(R)P Z(R)v
Ra
X Ra
iy~
R9 R9
NHZ NH2
O(CHZ~,Z(H)p O(CHz~,ZPC~,
X Ra X Ra
(21 ) ~ ~ (22)
i R9 --~ Rs
(h
;H)P
R
Re
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R is -(C1-C4)alkyl and
p = 1 or 2.
Intermediate (16) is prepared by refluxing an
appropriately substituted diphenyl compound (15) with oxalyl
chloride in an alkyl halide solvent, such as chloroform.
Preferably the reaction is catalyzed with 4,4-N-
dimethylaminopyridine.
Cyclization to the lactone (17) can be achieved
under Friedel-Crafts conditions using a suitable metal
halide, such as aluminum chloride, as the catalyst.
Conversion to the glyoxamide (18) can be achieved by
aminolysis of the lactone ring using concentrated ammonium
hydroxide.
Alkylation of the hydroxy group to prepare the
desired alkyl-linked ester (19) occurs by treatment of (18)
with an appropriate alkylating agent, such as (X)(CH2)nB
where B is C02PG, -P03PG or -S03PG, X is halo and PG is an
acid protecting group, preferably methyl.
Partial reduction of the carbonyl in the
glyoxamide (19) is achieved by treatment with a suitable
reducing agent, such as sodium borohydride in methanol,
preferably at temperatures of from 0°-20 °C, to prepare the
intermediate (20). The desired acid or acid salt (21) can
be accomplished by treatment with a suitable base, such as
sodium hydroxide.
Further reduction of intermediate (20) can be
achieved by treatment with triethylsilane in a strong acid,
such as trifluroacetic acid, under an inert gas, such as
argon, to prepare (22) followed, again, by conversion to the
acid or salt (23) with a strong base.
m) Naphthyl acetamide sPLA2 inhibitors and the method of
making them are described in U.S. Patent Application Serial
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190
No. 09/091077, filed December 9, 1996 (titled, "Benzyl
naphthalene sPLA2 Inhibitors"), the entire disclosure of
which is incorporated herein by reference.
The method of the invention is for treatment of a
mammal, including a human, afflicted with cystic fibrosis,
said method comprising administering to said human a
therapeutically effective a naphthyl acetamide sPLA2
inhibitor represented by formula (Im)as follows:
R3
(Im)
R2
wherein:
R1 and R2 are each independently hydrogen or a
non-interfering substituent with the proviso that at least
one of R1 and R2 must be hydrogen;
CH3
H Y -O~\ )n ' -O~ )nY
R is hydrogen, -0(C 2)n ,
where n is from 2 to 4 and Y is -C02H, -P03H2 or S03H; and
X is -0- or -CH2-.
Compounds where X is oxygen can be prepared by the
following Scheme Im.
*rB
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191
Scheme Im
CH3 O-H CH3
R3 Ri R3
K2C03
Copp'-
RZ Bronze ~ RI
Br RZ _
ti)
NBS
r
CN
R
Br
Na CN
R2
(3) (2)
(1) KOH
(2) HCL
oxalylchloride
DMF
!) NH3
R2 R2
m (5)
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In the first step of the above reaction scheme, an
appropriately substituted 1-bromo-4-methylnapthalene and an
appropriately substituted phenol are dissolved in an aprotic
polar solvent such as pyridine. The mixture is treated with
an excess of potassium carbonate and an excess of copper-
bronze and refluxed under a nitrogen blanket to produce (1).
Bromination of compound (1) to produce (2) is
accomplished by refluxing (1) with a brominating agent, such
as N-bromosuccinamide, in a non-polar alkyl halide solvent,
such as carbon tetrachloride, using 2,2-
azobisisobutyronitrile as a catalyst.
Treatment of (2) with sodium cyanide produces (3).
This reaction is best conducted in an aprotic polar solvent,
such as dimethyl sulfoxide (DMSO), while heating to a
temperature of about 60 °C.
Hydrolysis of the cyano compound (3) to produce
the acid (4) is accomplished in two steps. Using a polar
protic solvent, such as diethylene glycol as a cosolvent,
the cyano compound (3) is treated with an alkali metal base,
such as potassium hydroxide, and the mixture is heated to
about 90-95 °C. The resultant product is then reacted with
a strong mineral acid such as hydrochloric acid.
Conversion of (4) to the desired naphthyl
acetamide compound (5) is accomplished by another two-step
process. First, the acid (4) is dissolved in an alkyl
halide solvent such as methylene chloride. The acid/alkyl
halide solution is chilled in an ice bath then treated with
oxalyl chloride, using dimethylformamide (DMF) as a
catalyst, to produce the acid chloride. The solution is
allowed to warm to room temperature and then treated with
ammonia gas at room temperature to produce (5).
The desired product (5) can be purified using
standard recrystallization procedures in a suitable organic
solvent, preferably methylene chloride/hexane.
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Compounds where X is methylene can be prepared by
the following Scheme IIm
Scheme IIm
Br
R~ 1 ) Mg ET20
N
2)
R2
R' 2
R
3) aqueous acid
NaBH4
CF3C02H
CI
z
H2C0
HOAc
HCl(Conc.)
H3P04(85°/a 2
T
R2
(3 a) (2a)
( 1 ) KCN
(2) DMF
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ru
H202
K2C03
DMSO
R2 R2
~4a~ (Sa)
Compound (la) is prepared by a grignard reaction.
The Grignard reagent starting material is prepared by
reacting an appropriately substituted phenyl bromide with
magnesium and ether. The reagent is then reacted with an
appropriately substituted naphthyl nitrile and the resultant
compound is hydrolyzed with an aqueous acid such as
hydrochloric acid to form the benzoyl napthyl (la).
Reduction of (1a) is accomplished by treatment
with a molar excess of a reducing agent such as sodium
borohydride. The reaction is initiated in an ice bath using
a solvent-catalyst such as trifluoroacetic acid and then
allowed to warm to room temperature as the reduction
proceeds.
Chloromethylation of (2a) is achieved by treatment
with an excess of formaldehyde and concentrated hydrochloric
acid in a polar acidic solvent such as an acetic/phosphoric
acid mixture. The reaction is best conducted at a
temperature of about 90 °C.
The nitrile 4(a) is prepared by a nucleophilic
displacement of the chloride compound (3a)with cyanide. The
reaction is conducted by refluxing (3a) with a slight molar
excess in an aprotic polar solvent of sodium cyanide such as
dimethylformamide (DMF) for about five hours, then allowing
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195
the reaction to continues while it cools to room
temperature.
The desired naphthylamide (5a) is then prepared
from the nitrile (4a) in a three-step process. To a
solution of nitrile (4a), dissolved in an aprotic polar
solvent such as DMSO, potassium carbonate is added to make
the nitrite solution slightly basic. Hydrolysis of the
nitrite is then achieved by treatment with an aqueous
hydrogen peroxide solution. Crystallization of the naphthyl
acetamide may be accomplished by adding water to the
peroxide solution.
Compounds where R3 is other than hydrogen can be
readily prepared by using a 1-bromo-4-methyl-napthalene with
a protected phenol, such as a methoxy group, on the
6-position of the napthalene ring as a starting material.
The process is conducted, as described above, to prepare
compounds (1) - (3). Acid hydrolysis of the cyano group (3)
and deprotection of the protected phenol can be accomplished
by treating (3) with a 40o hydrogen bromide solution in
acetic acid. The deprotected phenol can then be reacted to
prepare the appropriate substituent at the 6-position of the
napthyl ring. For example, preparation of compounds where
R3 is -O(CH2)nC00H can be achieved by alkyalting the phenol
with an appropriate alkyl halide followed by conversion to
the acid by treatment with a base such as aqueous sodium
hydroxide followed by dilute hydrochloric acid.
It will be readily appreciated by one skilled in
the art that the substituted phenol and phenyl bromide
starting materials are either commercially available or can
be readily prepared by known techniques from commercially
available starting materials. All other reactants and
reagents used to prepare the compounds of the present
invention are commercial7.y available.
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FORMULATIONS SUITABLE FOR USE IN THE METHOD OF THE INVENTION
The sPLA2 inhibitors used in the method of the
invention may be administered to treat cystic fibrosis by
any means that produces contact of the active agent with the
agent's site of action in the human body. They can be
administered by any conventional means available for use in
conjunction with pharmaceuticals, either as individual
therapeutic agents or in a combination of therapeutic
agents. The sPLA2 inhibitors can be administered alone, but
are generally administered with a pharmaceutical carrier
selected on the basis of the chosen route of administration
and standard pharmaceutical practice.
Suitable formulations are those comprising a
therapeutically effective amount of sPLA2 inhibitor together
with a pharmaceutically acceptable diluent or carrier, the
composition being adapted for the particular route of
administration chosen. By "pharmaceutically acceptable" it
is meant the carrier, diluent or excipient must be
compatible with the sPLA2 inhibitor ("active compound") in
the formulation and not deleterious to the subject being
treated.
For the pharmaceutical formulations any suitable
carrier known in the art can be used. In such a
formulation, the carrier may be a solid, liquid, or mixture
of a solid and a liquid. A solid carrier can be one or more
substances which may also act as flavoring agents,
lubricants, solubilisers, suspending agents, binders, tablet
disintegrating agents and encapsulating material.
Tablets for oral administration may contain suitable
excipients such as calcium carbonate, sodium carbonate,
lactose, calcium phosphate, together with disintegrating
agents, such as maize, starch, or alginic acid, and/or
binding agents, for example, gelatin or acacia, and
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lubricating agents such as magnesium stearate, stearic acid,
or talc. In tablets the sPLA2 inhibitor is mixed with a
carrier having the necessary binding properties in suitable
proportions and compacted in the shape and size desired.
The powders and tablets preferably contain from about 1 to
about 99 weight percent of the sPLA2 inhibitor.
Sterile liquid form formulations include suspensions,
emulsions, syrups and elixirs. The active compound can be
dissolved or suspended in a pharmaceutically acceptable
carrier, such as sterile water, saline, dextrose solution,
sterile organic solvent or a mixture of both.
The active compound can be administered orally in solid
dosage forms, such as capsules, tablets, and powders, or in
liquid dosage forms, such as elixirs, syrups, and
suspensions. It can also be administered parenterally, in
sterile liquid dosage forms. It can also be administered by
inhalation in the form of a nasal spray or lung inhaler. It
can also be administered topically as an ointment, cream,
gel, paste, lotion, solution, spray, aerosol, liposome, or
patch. Dosage forms used to administer the active compound
usually contain suitable carriers, diluents, preservatives,
or other excipients, as described in Remington's
Pharmaceutical Sciences, Mack Publishing Company, a standard
reference text in the field.
Gelatin capsules may be prepared containing the active
compound and powdered carriers, such as lactose, sucrose,
mannitol, starch, cellulose derivatives, magnesium stearate,
stearic acid, and the like. Similar diluents can be used to
make compressed tablets and powders. Both tablets and
capsules can be manufactured as sustained release products
to provide for continuous release of medication over a
period of hours. Compressed tablets can be sugar coated or
film coated to mask any unpleasant taste and protect the
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tablet from the atmosphere, or enteric coated for selective
disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can contain
coloring and flavoring to increase patient acceptance.
For parenteral and intravenous solutions, water, a
suitable oil, saline, aqueous dextrose (glucose), and
related sugar solutions and glycols such as propylene glycol
or polyethylene glycols are suitable carriers for parenteral
solutions. Solutions for parenteral administration contain
the active compound, suitable stabilizing agents, and if
necessary, buffer substances. Anti-oxidizing agents such as
sodium bisulfate, sodium sulfite, or ascorbic acid either
alone or combined are suitable stabilizing agents. Also
used are citric acid and its salts and sodium EDTA. In
addition, parenteral solutions can contain preservatives,
such as benzalkonium chloride, methyl- or propyl-paraben,
and chlorobutanol.
Topical ointments, creams, gels, and pastes contain
with the active compound diluents such as waxes, paraffins,
starch, polyethylene glycol, silicones, bentonites, silicic
acid, animal and vegetable fats, talc and zinc oxide or
mixtures of these or other diluents.
Topical solutions and emulsions can, for example,
contain with the active compound, customary diluents (with
the exclusion of solvents having a molecular weight below
200 except in the presence of a surface-active agent), such
as solvents, dissolving agents and emulsifiers; specific
examples are water, ethanol, 2-propanol, ethyl carbonate,
benzyl alcohol, propylene glycol, oils, glycerol, and fatty
acid esters of sorbitol or mixtures thereof. Compositions
for topical dosing may also contain preservatives or anti-
oxidizing agents.
Powders and sprays can contain along with the active
compound, the usual diluents, such as lactose, talc, silicic
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acid, aluminum hydroxide, calcium silicate, and polyamide
powders or mixtures of these materials. Aerosol sprays can
contain the usual propellants. Liposomes can be made from
such materials as animal or vegetable fats which will form
lipid bilayers in which the active compound can be
incorporated.
For inhalation administration, the sPLA2 inhibitor
or formulations containing the inhibitor can be dissolved or
dispersed in liquid form, such as in water or saline,
preferably at a concentration at which the composition is
fully solubilized and at which a suitable dose can be
administered within an inhalable volume. A nebulizer (e. g.,
De Vilbiss 646) and compressed air generator (Pulmoaide,
DeVilbiss) can be used to nebulize and deliver the compound
or formulation containing the compound to the airway
surfaces once or several times a day, as required. For
infants, the dose may be adjusted proportionately for size
or body weight.
Formulations containing compounds of the invention may
be administered through the skin by an appliance such as a
transdermal patch. Patches can be made of a matrix such as
polyacrylamide and a semipermeable membrane made from a
suitable polymer to control the rate at which the material
is delivered to the skin. Other suitable transdermal patch
formulations and configurations are described in U.S. Patent
Nos. 5,296,222 and 5,271,990, the disclosures of which are
incorporated herein by reference. Lipophilic prodrug
derivatives of the sPLA2 inhibitors are particularly well
suited for transdermal absorption administration and
delivery systems.
Formulations within the scope of this invention include
the admixture of sPLA2 inhibitor with a therapeutically
effective amount of any therapeutically effective co-agents
for cystic fibrosis such as N-acetyl-cysteine, human
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recombinant DNAse, antibiotics, etc., as set out in the
section "CO-AGENT - COMBINED THERAPY", infra.
Formulations used for facilitating lung mucus clearance
in a human afflicted with cystic fibrosis may further
comprise the step of concurrently administering a sodium
channel blocker such as amiloride to the subject in an .
amount effective to inhibit the reabsorption of water from
lung mucus membranes.
For all of the above formulations the preferred active
compound are the 1H-indole-3-glyoxylamide compounds as
previously described and methods of making as described in
U.S. Patent No. 5,654,326 (the disclosure of which is
incorporated herein by reference). Most preferred compounds
within the general class of 1H-indole-3-glyoxylamides are
((3-(2-amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-
indol-4y1}oxy)acetic acid, sodium salt; and 1H-indole-3-
glyoxylamides are ((3-(2-amino-1,2-dioxoethyl)-2-ethyl-1-
(phenylmethyl)-1H-indol-4y1)oxy)acetic acid, methyl ester.
PROPORTION AND WEIGHT OF ACTIVE COMPOUNDS USED IN THE METHOD
OF THE INVENTION
The 1H-indole-3-glyoxylamide compound may be used at a
concentration of 0.1 to 99.9 weight percent of the
formulation.
Preferably the pharmaceutical formulation is in unit
dosage form. The unit dosage form can be a capsule or
tablet itself, or the appropriate number of any of these.
The quantity of active compound in a unit dose of
composition may be varied or adjusted from about 0.1 to
about 1000 milligrams or more according to the particular
treatment involved.
Compositions (dosage forms) suitable for internal
administration contain from about 1 milligram to about
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500 milligrams of active compound per unit. In these
pharmaceutical compositions the active compound will
ordinarily be present in an amount of about 0.5-95~ by
weight based on the total weight of the composition.
Examples of useful pharmaceutical compositions and
their proportions of ingredients are illustrated as follows:
Capsules: Capsules may be prepared by filling standard two-
piece hard gelatin capsules each with 50 mg of powdered
active compound, 175 mg of lactose, 24 mg of talc, and 6 mg
of magnesium stearate.
Soft Gelatin Capsules: A mixture of active compound in
soybean oil is prepared and injected by means of a positive
displacement pump into gelatin to form soft gelatin capsules
containing 50 mg of the active compound. The capsules are
washed in petroleum ether and dried.
Tablets: Tablets may be prepared by conventional procedures
so that the dosage unit is 50 mg of active compound, 6 mg of
magnesium stearate, 70 mg of microcrystalline cellulose,
11 mg of cornstarch, and 225 mg of lactose. Appropriate
coatings may be applied to increase palatability or delay
absorption.
Suspensions: An aqueous suspension is prepared for oral
administration so that each 5 ml contain 25 mg of finely
divided active compound, 200 mg of sodium carboxymethyl
cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol
solution, U.S.P., and 0.025 mg of vanillin.
Injectables: A parenteral composition suitable for
administration by injection is prepared by stirring 1.5o by
weight of active compound in 10~ by volume propylene glycol
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and water. The solution is sterilized by commonly used
techniques.
Nasal Spray: An aqueous solution is prepared such that each
1 ml contains 10 mg of active compound, 1.8 mg
methylparaben, 0.2 mg propylparaben and 10 mg .
methylcellulose. The solution is dispensed into 1 ml vials.
The active compound may be used at a concentration of 0.1 to
99.9 weight percent of the formulation.
Aerosol formulations are capable of dispersing into
particle sizes of from about 0.5 to about 10 microns and
have sufficient sPLA2 inhibitor to achieve concentrations of
the inhibitor on the airway surfaces of from about 10-10 to
10'2 moles per liter.
THE PRACTICE OF THE METHOD OF THE INVENTION
The use of sPLA2 inhibitors in the method of the
invention prevents progressive deterioration of lung tissue
and lung function by inhibiting or reducing the degree of
inflammation which may be a primary pathologic process in
cystic fibrosis. The method of the invention is preferably
used early in the life of the patient afflicted with cystic
fibrosis, most preferably in a child just after diagnosis of
cystic fibrosis.
The method of the invention can be practiced using
pharmaceutical formulations containing sPLA2 inhibitors
(preferably, sPLA2 inhibitors taught to be preferred in this
specification) or formulations containing such sPLA2
inhibitors as taught in the preceding section.
The underlying cause of cystic fibrosis will not be
prevented by the method of this invention, but symptoms will
be reduced in severity or extent ameliorated by
administration of sPLA2 inhibitors (and their formulations).
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The dosage administered will, of course, vary depending
upon known factors such as the pharmacodynamic
characteristics of the particular agent, and its mode and
route of administration; age, health, and weight of the
recipient; nature and extent of symptoms, kind of concurrent
treatment, frequency of treatment, and the effect desired..
Usually a daily dosage of active compound can be about 0.1
to 200 milligrams per kilogram of body weight. Ordinarily
0.5 to 50, and preferably 1 to 25 milligrams per kilogram
per day given in divided doses 1 to 6 times a day or in
sustained release form is effective to obtain desired
results.
In general, the sPLA2 inhibitor will be administered to
a human so that a therapeutically effective amount is
received. A therapeutically effective amount may
coventionally be determined for an individual patient by
administering the active compound in increasing doses and
observing the effect on the patient, for example, reduction
in the amount of daily sputum production, improvement in
lung function as assessed by standard pulmonary function
listing, improvement in exercise, reduction in frequency of
bacterial infections, or a reduction in other symptoms
associated with cystic fibrosis.
The exact amount of sPLA2 inhibitor required for
preventing or treating the symptoms of cystic fibrosis (or
other indications listed in the "Summary of the Invention",
supra.) will vary from person to person, depending on the
age and general condition of the subject and the severity of
the disease, mode of administration, etc. An appropriate
amount may be determined by one of ordinary skill by judging
the effective elimination, reduction, or prevention of
symptoms associated with cystic fibrosis (e. g., lung mucus
clearance).
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Generally, the compound must be administered in a
manner and a dose to achieve in the human a blood level
concentration of sPLA2 inhibitor of from 10 to 3000
nanograms/ml, and preferably a concentration of 100 to 800
nanograms/ml.
The treatment regimen for many cystic firbosis may
stretch over many days to months or to years. Oral dosing
is preferred for patient convenience and tolerance. With
oral dosing, one to four oral doses per day, each from about
0.01 to 25 mg/kg of body weight with preferred doses being
from about 0.1 mg/kg to about 2 mg/kg.
Parenteral administration (particularly, intravenous
administration) is often preferred in instances where rapid
alleviation of patient distress is required. With
parenteral administration doses of 0.01 to 100 mg/kg/day
administered continuously or intermittently throughout the
day may be used. For parenteral administation, the comound
may be administered in a physiologic saline vehicle (e. g.,
0.9% normal saline, 0.45% normal saline, etc.) a dextrose
vehicle (e.g., 5% dextrose in water), or a combination of
saline and dextrose vehicle (0.9% normal saline in 5%
dextrose).
Inhalation therapy also may be useful either alone or
as an adjunct to other routes of administration. With
inhalation therapy, doses necessary to produce a decrease in
the clinical symptoms of cystic fibrosis are readily
determined and used.
CO-AGENT - COMBINED THERAPY
The sPLA2 inhibitor (viz., active compound in a
formulation of the invention) can also be administered in
the method of the invention in combination with another
pharmacologically active agent known to have utility for
alleviating the symptoms of cystic fibrosis. For example,
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the sPLA2 inhibitors taught herein may be combined with the
following therapeutic agents:
1. Agents for increasing mucus clearance
a. N-acetyl-cysteine
2. Agents that DNA in cystic fibrosis sputum
a. human recombinant DNAse
3. Drugs for restoring water and salt content
a. amiloride
b. triphosphate nucleotides
4. Agents that control lung infection
a. antibiotics
(i) penicillins
(ii) cephalosporins, ceftazadime
(iii) aminoglycosides
5. Inhaled drugs
a. beta-adrenergic agonists
b. anticholinergics
6. Oral Steroids
7. Pancreatic enzymes
8. Gene Therapy
TESTING METHODS FOR CYSTIC FIBROSIS
The diagnostic criteria for cystic fibrosis are those
found in standard medical references (e. g., Harrison's
Principles of Internal Medicine, thirteenth ed., 1994, by
McGraw-Hill, Inc., ISBN 0-07-032370-9, pgs., 1194-1197).
These criteria may be used to determine when to begin using
the method of the invention, the frequency and degree of
treatment, and the time for cessation of treatment.
The cystic fibrosis patient having lung disease may be
evaluated with any conventional measure of lung capacity,
nature of extent of sputum, and etc.
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The cystic fibrosis patient having gastointestinal
disease may be evaluated by conventional criteria for
adaquate nutrition.
While the present invention has been illustrated above
by certain specific embodiments, these are not intended to
limit the scope of the invention as described in the
appended claims.
