U.S. patent application number 09/915047 was filed with the patent office on 2002-03-07 for phenylpyridine derivatives useful as phosphodiesterase inhibitors.
Invention is credited to Manley, Paul W..
Application Number | 20020028831 09/915047 |
Document ID | / |
Family ID | 10790065 |
Filed Date | 2002-03-07 |
United States Patent
Application |
20020028831 |
Kind Code |
A1 |
Manley, Paul W. |
March 7, 2002 |
Phenylpyridine derivatives useful as phosphodiesterase
inhibitors
Abstract
(4-oxy-3-(aryl)phenyl)pyridine compounds, in free or acid
addition salt form, are useful as pharmaceuticals for treatment and
prophylaxis of inflammation, particularly inflammatory or
obstructive diseases of the airways, e.g. for asthma therapy.
Preferred compounds are novel biphenyl pyridines, biphenyl
benzamides and biphenyl phenylcarboxy compounds. The compounds are
selective inhibitors of PDE 4 isoenzyme activity and also act to
down regulate or inhibit TNF-.alpha. release.
Inventors: |
Manley, Paul W.; (Arlesheim,
CH) |
Correspondence
Address: |
THOMAS HOXIE
NOVARTIS CORPORATION
PATENT AND TRADEMARK DEPT
564 MORRIS AVENUE
SUMMIT
NJ
079011027
|
Family ID: |
10790065 |
Appl. No.: |
09/915047 |
Filed: |
July 25, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09915047 |
Jul 25, 2001 |
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09655668 |
Sep 6, 2000 |
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6288092 |
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09655668 |
Sep 6, 2000 |
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09559520 |
Apr 27, 2000 |
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6258843 |
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09559520 |
Apr 27, 2000 |
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09142099 |
Sep 1, 1998 |
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6090817 |
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Current U.S.
Class: |
514/311 ;
514/314; 514/365; 546/152; 548/202 |
Current CPC
Class: |
C07C 65/24 20130101;
C07D 271/08 20130101; A61P 29/00 20180101; A61P 43/00 20180101;
C07C 255/57 20130101; C07D 405/10 20130101; C07C 235/42 20130101;
C07D 471/04 20130101; C07D 213/30 20130101; C07C 205/59 20130101;
C07D 213/57 20130101; A61P 11/06 20180101; C07C 69/94 20130101 |
Class at
Publication: |
514/311 ;
514/314; 514/365; 546/152; 548/202 |
International
Class: |
A61K 031/47; A61K
031/426; C07D 215/00; C07D 277/20 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 8, 1996 |
GB |
9604926.7 |
Claims
1. A (4-oxy-3-(aryl)phenyl)-azaryl or -arylcarbonyloxy compound, in
free or pharmaceutically acceptable acid addition salt form, for
use as a pharmaceutical
2. A pharmaceutical composition comprising a
(4-oxy-3-(aryl)phenyl)-azaryl or -arylcarbonyloxy compound, in free
or pharmaceutically acceptable acid addition salt form.
3. The use of a (4-oxy-3-(aryl)phenyl)-azaryl or -arylcarbonyloxy
compound, in free or pharmaceutically acceptable acid addition salt
form, for the preparation of a medicament for treatment or
prophylaxis of inflammation.
4. A method for the treatment or prophylaxis of inflammation
comprising administering an effective amount of a
(4-oxy-3-(aryl)phenyl)-azaryl or -arylcarbonyloxy compound, in free
or pharmaceutically acceptable acid addition salt form, to a
subject in need of such therapy.
5. A (4-oxy-3-(aryl)phenyl)-azaryl or -arylcarbonyloxy compound, in
free or pharmaceutically acceptable acid addition salt form,
provided: that the 3-aryl moiety is not unsubstituted phenyl when,
the arylcarbonyloxy moiety is phenyl-4-carboxylic acid or
phenyl-4-methylcarboxylate, or the azaryl moiety is
5-methylthiazol-2-yl, or that the 3-aryl moiety is not
unsubstituted phenyl or 2-methoxyphen.-1-yl when, the azaryl moiety
is unsubstituted 2-quinoline or 2-quinoline substituted by methyl
or phenyl at position 3 and/or by carboxy at position 4.
6. A (4-oxy-3-(aryl)phenyl)-azaryl compound according to claim 1 or
5.
7. A (4-oxy-3-(aryl)phenyl)-arylcarbonyloxy compound according to
claim 1 or 5.
8. A compound according to claim 1, 5, 6 or 7 of formula Ia or
formula Ib: 6wherein in formula Ia W is N or C--CO--R, wherein R is
OH, O--(C.sub.1-6)alkyl or NR.sub.3R.sub.4 wherein R.sub.3 and
R.sub.4 which may be the same or different are H or
(C.sub.1-6)alkyl, or in formula Ib Az is an azaryl group containing
one or more nitrogen atoms, such as quinoline, isoquiniline,
indole, imidazopyridine, e g. imidazo[1,2-a]pyridine, and in both
formula Ia and Ib R.sub.1 is C.sub.1-4alkyl, preferably methyl; and
R.sub.2 is a phenyl moiety, e.g., of formula II 7wherein R.sub.5
and R.sub.6 are, independently, H, nitro, halo (e.g., chloro),
trifluoromethyl, C.sub.1-4alkoxy, cyano, or phenoxy; or R.sub.5 and
R.sub.6 together form a bridge of 3-5 atoms in length wherein the
bridge atoms are selected from S, O, N, and C, e.g. --OCH.sub.2O--,
or propylene; or R.sub.2 is a 2,5-cyclohexadien-3,4-ylidi- ne-1-yl
moiety, e.g., of formula III 8wherein R.sub.7 and R.sub.8 together
form an aromatic bridge of 3-5 atoms in length wherein the bridge
atoms are selected from S, O, N, and C, e.g., .dbd.N--O--N.dbd.; in
free or pharmaceutically acceptable acid addition salt form.
9. A compound selected from the group consisting of
4-[2-(methoxy)-biphenyl-5-yl]pyridine,
4-[2-(methoxy)-3'-(nitro)biphenyl-- 5-yl]pyridine,
4-[2-(methoxy)-3'-(trifluoromethyl)biphenyl-5-yl]pyridine,
4-[2-(methoxy)-3',4'-(propylene)biphenyl]pyridine,
4-[4-(methoxy)-3-(benzofurazan-5-yl)phenyl]pyridine,
4-[2-(methoxy)-3'-(cyano)biphenyl-5-yl]pyridine,
4-[2-(methoxy)-3'-(chlor- o)biphenyl-5-yl]pyridine,
4-[2-(methoxy)-3',4'-(methylenedioxy)biphenyl-5-- yl]pyridine,
4-[2-(methoxy)-3'-(phenoxy)biphenyl-5-yl]pyridine,
4-[2-(methoxy)-4'-(phenoxy)biphenyl-5-yl]pyridine,
4-[2-(Methoxy)-3'-(chloro)-4'-(fluoro)biphenyl-5-yl]pyridine,
4'-Methoxy-3 -(benzofurazan-5-yl )-[1,1'-biphenyl]4-carboxamide,
4'-Methoxy-3'-(3-nitrophenyl)-[1,1'-biphenyl]-4-carboxylic acid,
ethyl ester,
4'-Methoxy-3'-(3-nitrophenyl)-[1,1'-biphenyl]-3-carboxylic acid,
ethyl ester,
4'-Methoxy-3-methyl-3-(3-nitrophenyl)-[1,1'-biphenyl]-4-carb-
oxylic acid ethyl ester,
3'-(5-Benzofurazanyl)-4'-methoxy-[1,1'-biphenyl]4- -carboxylic acid
ethyl ester, 3'-(5-Benzofurazanyl)4'-methoxy-[1,1'-biphen-
yl]4-carboxylic acid, 2,2-dimethylpropyl ester,
3'-(5-Benzofurazanyl)-4'-m- ethoxy-[1,1'-biphenyl]4-carboxylic
acid, 4'-Methoxy-3'-(3-nitrophenyl)-[1,- 1'-biphenyl]-3-carboxylic
acid, 4'-Methoxy-3-methyl-3'-(3-nitrophenyl)-[1,-
1'-biphenyl]4-carboxylic acid,
3-(5-Benzofurazanyl)-4'-methoxy-[1,1'-biphe- nyl]4-carboxylic acid,
4-Methoxy-3'-(3-chlorophenyl)-[1,1'-biphenyl]-4-car- boxylic acid,
and 4'-Methoxy-3'-(3-cyanophenyl)-[1,1'-biphenyl]4-carboxyli- c
acid, 4'-Methoxy-3'-(3-nitrophenyl)-[1,1'-biphenyl]4-carboxamide,
4'-Methoxy-3'-(3-nitrophenyl)-[1,1'-biphenyl]-3-carboxamide,
4'-Methoxy-3-methyl-3'-(3-nitrophenyl)-[1,1'-biphenyl]-4-carboxamide,
N-Methyl-4'-methoxy-3'-(3-nitrophenyl
)-[1,1'-biphenyl]-4-carboxamide,
6-[4-Methoxy-3-(5-benzofurazanyl)phenyl]imidazo[1,2-a]pyridine in
free or pharmaceutically acceptable acid addition salt form.
10. A process for the preparation of a compound according to any
one of claims 1 or 5-9 comprising reacting a compound of formula
I'a or I'b: 9wherein X is, halogen or a leaving group and R.sub.1,
W and Az are as defined in claim 8, with an activated aryl compound
of formula IIa or IIIa: 10wherein Y is halogen (preferably bromine)
or a leaving group, such as a tin or boron containing group
(preferably --B(OH).sub.2), and the R groups are as defined in
claim 8; and recovering the resulting compound, in free or
pharmaceutically acceptable acid addition salt form.
11. A compound of formula I'a or formula I'b: 11wherein X is
halogen (preferably bromine) or a leaving group, such as a tin or
boron containing group (preferably --B(OH).sub.2), and R.sub.1, W
and Az are as defined in claim 8, with the provisos that when X is
bromine and R.sub.1 is methyl, W is other than C--COOCH.sub.3 when
X is chlorine or bromine, and R.sub.1 is methyl, ethyl, propyl or
butyl, W is other than C--COOH when X is chlorine and R.sub.1 is
methyl, W is other than C--COOCH.sub.2CH.sub.3 or
C--COOCH.sub.2CH.sub.2CH.sub.3 and when R.sup.1 is methyl and Az is
a substituted quinoline or an unsubstituted or substituted indole
group, X is other than fluorine.
12. A method a) for the down-regulation or inhibition of
TNF-.alpha. release, b) for the inhibition of PDE 4 isoenzyme
activity, c) of effecting immunosuppression, d) for the treatment
of inflammatory disease, or e) for the treatment of any particular
condition or disease as hereinabove set forth, in a subject in need
thereof, which method comprises administering to said subject an
effective amount of an AGENT OF THE INVENTION.
Description
[0001] The present invention relates to triaryl compounds,
particularly biphenyl pyridines, biphenyl benzamides and biphenyl
phenylcarboxy compounds, processes for their production, their use
as pharmaceuticals and pharmaceutical compositions comprising
them.
[0002] Specifically, the invention provides a
(4-oxy-3-(aryl)phenyl)-azary- l or -arylcarbonyloxy compound, in
free or pharmaceutically acceptable acid addition salt form, for
use as a pharmaceutical, e.g. for use in the treatment or
prophylaxis of inflammation, particularly inflammatory or
obstructive diseases of the airways, e.g. asthma.
[0003] In a further embodiment the invention provides a
pharmaceutical composition comprising a
(4-oxy-3-(aryl)phenyl)-azaryl or -arylcarbonyloxy compound, in free
or pharmaceutically acceptable acid addition salt form, e.g. in
combination with a pharmaceutically acceptable diluent or
carrier.
[0004] In a yet further embodiment the invention includes the use
of a (4-oxy-3-(aryl)phenyl)-azaryl or -arylcarbonyloxy compound, in
free or pharmaceutically acceptable acid addition salt form, for
the preparation of a medicament for treatment or prophylaxis of
inflammation, particularly inflammatory or obstructive diseases of
the airways, e.g. asthma.
[0005] In a still yet further embodiment the invention provides a
method for treatment or prophylaxis of inflammation, particularly
inflammatory or obstructive diseases of the airways, e.g. asthma,
comprising administering an effective amount of a
(4-oxy-3-(aryl)phenyl) -azaryl or -arylcarbonyloxy compound, in
free or pharmaceutically acceptable acid addition salt form, to a
subject in need of such therapy.
[0006] The (4-oxy-3-(aryl)phenyl)-azaryl or -arylcarbonyloxy
compounds of the invention and their pharmaceutically acceptable
acid addition salt forms are hereinafter referred to as AGENTS OF
THE INVENTION. In these compounds, the 4-oxy moiety is suitably
(optionally fluoro-substituted)alkoxy, e.g.,
(fluoro.sub.0-3-)C.sub.1-4alkoxy, e.g. methyl, ethyl,
difluoromethyl, or trifluoromethyl. The 3-aryl moiety is suitably a
mono- or bicyclic moiety having at least one aromatic ring, e.g.,
azaryl, for example pyridyl, C.sub.1-4alkylpyridyl, or quinolinyl;
aromatic 2,5-cyclohexadien-3,4-ylidine-1-yl, e.g., benzofurazanyl
or benzofuranyl; or phenyl, preferably suitably substituted, e.g.,
meta- and/or para-substituted, with (i) one or two substitutents
selected from nitro, carbamoyl, halo (e.g., chloro),
trifluoromethyl, alkoxy (e.g. C.sub.1-4alkoxy), thioalkoxy (e.g.
thio(C.sub.1-4)alkoxy), alkylsulphoxy (e.g.
C.sub.1-4alkylsulphoxy), alkylsulphonyl (e.g.
C.sub.1-4alkylsulphonyl), cyano, or phenoxy, or (ii) a bridging
substituent of 3-5 atoms in length wherein the bridge atoms are
selected from C, O, S, and N, e.g. indanyl, benzopyrolidonyl,
indanonyl, or benzodioxolanyl. By "azaryl" is meant a
nitrogen-containing aromatic group, for example, pyridine, e.g.,
3-pyridine or 4-pyridine, quinoline, isoquinoline, imidazopyridine
(e.g. imidazo[1,2-a]pyridine or benzamide, e.g., 3- or 4-
benzamide. By "arylcarbonyloxy" is meant an aryl moiety, e.g. as
defined above for the 3-aryl moiety, bearing at least one
carbonyloxy substituent, e.g. in free acid, ester, amide or salt
form, preferably a phenylcarboxy moiety, e.g. a phenyl-3- or
phenyl-4-carboxy moiety, such as a phenyl carboxylic acid or phenyl
carboxylate ester (e.g. lower alkyl phenyl carboxylate ester) or
phenylcarboxamido moiety. Halo or halogen as used herein refers to
F, Cl, Br or I unless otherwise indicated.
[0007] AGENTS OF THE INVENTION include compounds which are known
per se but for which no pharmaceutical activity has been described
or suggested. Thus Jin et al. (Macromol. Symp. ( 1995), 96
[International Conference on Liquid Crystal Polymers 1994],
125-134) describe methyl-4-methoxy-3-pheny- lbiphenyl-4-carboxylate
and 4'-acetoxy-3'-phenylbiphenyl-4-carboxylic acid as intermediates
in the preparation of copolyester liquid crystal materials. Buu-Hoi
et al. (J. Org. Chem. 21, [1956], 136-138) describe the preparation
of 2-(6-methoxy-biphenyl-3-yl)-quinoline and anolgues thereof
further substituted in the quinoline ring by methyl or phenyl at
position 3 and/or by carboxy at position 4, and (J. Org. Chem. 29,
[1964], 762-763) also describe the preparation of
2-(6,2'-dimethoxy-biphe- nyl-3-yl)-quinoline and analogues thereof
further substituted in the quinoline ring by methyl at position 3
and/or by carboxy at position 4. Buu-Hoi et al. do not identify any
utility or activity for these quinoline compounds. Du Pont Belgian
patent 652,320 describes the preparation of
5-(6-methoxy-biphenyl-3-yl)-2-methyl thiazole as an intermediate in
the preparation 5,5'-diphenylthiazolecarbocyanine sensitisers of
silver halide emulsions for photographic use.
[0008] Accordingly the present invention provides a
(4-oxy-3-(aryl)phenyl)-azaryl or -arylcarbonyloxy compound, e.g.
wherein the 4-oxy, 3-aryl, azaryl and arylcarbonyloxy moieties are
as defined above, provided
[0009] that the 3-aryl moiety is not unsubstituted phenyl when
[0010] the arylcarbonyloxy moiety is phenyl-4-carboxylic acid or
phenyl-4-methylcarboxylate, or
[0011] the azaryl moiety is 5-methylthiazol-2-yl, or
[0012] that the 3-aryl moiety is not unsubstituted phenyl or
2-methoxyphen-1-yl when
[0013] the azaryl moiety is unsubstituted 2-quinoline or
2-quinoline substituted by methyl or phenyl at position 3 and/or by
carboxy at position 4,
[0014] or a pharmaceutically acceptable acid addition salts
thereof.
[0015] The novel compounds of this aspect of the invention are
encompassed by the AGENTS OF THE INVENTION.
[0016] The AGENTS OF THE INVENTION may exist in free form or in the
form of pharmaceutically acceptable acid addition salts.
Pharmaceutically active acid addition salts for use in the present
invention include for example chlorhydrates, oxalates and
fumarates.
[0017] In particular, the invention provides an AGENT OF THE
INVENTION which is a 4-(oxy)-3-[phenyl or
(2,5-cyclohexadien-3,4-ylidine-1-yl)]-phe- nyl-azaryl or
-arylcarbonyloxy, in free or pharmaceutically acceptable acid
addition salt form. Optionally, the 3-phenyl moiety is substituted,
e.g. 3- and/or 4-substituted. The
2,5-cyclohexadien-3,4-ylidine-1-yl moiety is preferably a
2,5-cyclohexadien-3,4-N-ylidine-1-yl moiety, preferably aromatic.
Preferably, the oxy moiety is alkoxy, e.g. C.sub.1-4alkoxy. The
azaryl moiety is preferably pyridine, e.g., 4-pyridine,
imidazopyridine, e.g. 6-imidazo[1,2-a]pyridine, or benzamide, e.g.,
3- or 4-benzamide. Preferably the arylcarbonyloxy moiety is
phenylcarboxy, e.g. phenyl-3- or -4-carboxy. For example, the
AGENTS OF THE INVENTION include a
[2-(C.sub.1-4alkoxy)-biphenyl-5-yl]pyridine,
[2-(C.sub.1-4alkoxy)-biphenyl-5-yl]benzamide or
[2-(C.sub.1-4alkoxy)-biph- enyl-5-yl]phenylcarboxy wherein the
biphenyl moiety is optionally 3'- and/or 4'-substituted or
optionally 3',4'-fused to a second aromatic ring, preferably a
compound of formula Ia or formula Ib: 1
[0018] wherein
[0019] in formula Ia W is N or C--CO--R,
[0020] wherein R is OH, O--(C.sub.1-6)alkyl or NR.sub.3R.sub.4
[0021] wherein R.sub.3 and R.sub.4 which may be the same or
different are H or (C.sub.1-6)alkyl, or
[0022] in formula Ib Az is an azaryl group containing one or more
nitrogen atoms, such as quinoline, isoquiniline, indole,
imidazopyridine, e.g. imidazo[1,2-a]pyridine,
[0023] and in both formula Ia and Ib
[0024] R.sub.1 is (C.sub.1-4)alkyl, preferably methyl; and
[0025] R.sub.2 is a phenyl moiety, e.g., of formula II 2
[0026] wherein R.sub.5 and R.sub.6 are, independently, H, nitro,
halo (e.g., chloro), trifluoromethyl, (C.sub.1-4)alkoxy, cyano, or
phenoxy; or R.sub.5 and R.sub.6 together form a bridge of 3-5 atoms
in length wherein the bridge atoms are selected from S, O, N, and
C, e.g. --OCH.sub.2O--, or propylene;
[0027] or R.sub.2 is a 2,5-cyclohexadien-3,4-ylidine-1-yl moiety,
e.g., of formula III 3
[0028] wherein R.sub.7 and R.sub.8 together form an aromatic bridge
of 3-5 atoms in length wherein the bridge atoms are selected from
S, O, N, and C, e.g., .dbd.N--O--N.dbd.;
[0029] in free or pharmaceutically acceptable acid addition salt
form.
[0030] Most preferably, R.sub.2 is selected from 3-nitrophenyl,
3-(trifluoromethyl)phenyl, 3-cyanophenyl, 3- or 3,4-halophenyl
(e.g., 3-chlorophenyl or 3-chloro-4-fluorophenyl), indan-5-yl,
benzofurazan-5-yl, and 1,3-benzo[d]dioxolan-5-yl.
[0031] Compounds of formula I thus include:
[0032] 1. 4-[2-(methoxy)-biphenyl-5-yl]pyridine
[0033] 2. 4-[2-(methoxy)-3'-(nitro)biphenyl-5-yl]pyridine
[0034] 3. 4-[2-(methoxy )-3'-(trifluoromethyl
)biphenyl-5-yl]pyridine
[0035] 4. 4-[2-(methoxy)-3',4'-(propylene)biphenyl]pyridine
[0036] 5. 4-[4-(methoxy)-3-(benzofurazan-5-yl)phenyl]pyridine
[0037] 6. 4-[2-(methoxy)-3'-(cyano)biphenyl-5-yl]pyridine
[0038] 7. 4-[2-(methoxy)-3'-(chloro)biphenyl-5-yl]pyridine
[0039] 8.
4-[2-(methoxy)-3',4'-(methylenedioxy)biphenyl-5-yl]pyridine
[0040] 9. 4-[2-(methoxy)-3'-(phenoxy)biphenyl-5-yl]pyridine
[0041] 10. 4-[2-(methoxy)-4'-(phenoxy)biphenyl-5-yl]pyridine
[0042] 11.
4-[2-(Methoxy)-3'-(chloro)-4'-(fluoro)biphenyl-5-yl]pyridine
[0043] 12.
4'-Methoxy-3'-(benzofurazan-5-yl)-[1,1'-biphenyl]4-carboxamide
[0044] 13.
4'-Methoxy-3'-(3-nitrophenyl)-[1,1'-biphenyl]-4-carboxylic acid,
ethyl ester
[0045] 14.
4'-Methoxy-3'-(3-nitrophenyl)-[1,1'-biphenyl]-3-carboxylic acid,
ethyl ester
[0046] 15.
4'-Methoxy-3-methyl-3'-(3-nitrophenyl)-[1,1'-biphenyl]-4-carbox-
ylic acid, ethyl ester
[0047] 16.
3'-(5-Benzofurazanyl)-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid,
ethyl ester
[0048] 17.
3'-(5-Benzofurazanyl)-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid,
2,2-dimethylpropyl ester
[0049] 18.
3-(5-Benzofurazanyl)-4'-methoxy-[1,1'-biphenyl]-4-carboxylic
acid
[0050] 19.
4'-Methoxy-3'-(3-nitrophenyl)-[1,1'-biphenyl]-3-carboxylic acid
[0051] 20.
4-Methoxy-3-methyl-3'-(3-nitrophenyl)-[1,1'-biphenyl]-4-carboxy-
lic acid
[0052] 21.
3'-(5-Benzofurazanyl)-4'-methoxy-[1,1'-biphenyl]-4-carboxylic
acid
[0053] 22.
4'-Methoxy-3'-(3-chlorophenyl)-[1,1'-biphenyl]-4-carboxylic
acid
[0054] 23.
4'-Methoxy-3'-(3-cyanophenyl)-[1,1'-biphenyl]-4-carboxylic acid
[0055] 24.
4'-Methoxy-3'-(3-nitrophenyl)-[1,1'-biphenyl]-4-carboxamide
[0056] 25.
4'-Methoxy-3'-(3-nitrophenyl)-[1,1'-biphenyl]-3-carboxamide
[0057] 26.
4'-Methoxy-3-methyl-3'-(3-nitrophenyl)-[1,1'-biphenyl]-4-carbox-
amide
[0058] 27.
N-Methyl-4'-methoxy-3'-(3-nitrophenyl)-[1,1'-biphenyl]-4-carbox-
amide
[0059] 28.
6-[4-Methoxy-3-(5-benzofurazanyl)phenyl]imidazo[1,2-a]pyridine
[0060] in free or pharmaceutically acceptable acid addition, e.g.,
hydrochloride, salt form.
[0061] Compounds of formula I are suitably prepared by reacting a
compound of formula I'a or formula I'b: 4
[0062] wherein X is halogen(preferably bromine) or a leaving group,
such as a tin or boron containing group (preferably --B(OH).sub.2),
and R.sub.1, W and Az are as defined above for formula Ia and Ib,
with the desired activated aryl, e.g., aryl halide or aryl boronic
acid, for example, a compound of formula IIa or IIIa: 5
[0063] wherein Y is halogen (preferably bromine) or a leaving
group, such as a tin or boron containing group (preferably
--B(OH).sub.2), and the R groups are as defined above for Formula
II and III ; and recovering the resulting compound of the
invention, e.g., of formula Ia or Ib, in free or acid addition salt
form. Preferably, one of X or Y is halogen, e.g. bromine, and the
other is a leaving group, e.g., --B(OH).sub.2. Suitable reaction
conditions may include reaction in the presence of one or more of
the following: a nucleophile such as triarylphiosphine (preferably
tri-o-tolylphosphine or tri-2-furylphosphine); a base such as
sodium carbonate, a solvent such as toluene, acetonitrile, or DMF,
and/or a suitable catalyst such as a palladium catalyst. Suitable
reaction temperatures include from ambient temperature to the
boiling point of the solvant, e.g., from 20-150.degree. C.,
preferably 70-90.degree. C.
[0064] Novel intermediates, especially of formula I'a and I'b, are
comprised within the scope of the invention. Compounds of formula
I'a and I'b can be prepared by a Suzuki- or Stille-type coupling
reaction, for example between a 4-alkoxyboronic acid derivative and
the suitably substituted haloaromatic system, or alternatively
prepared from 4-halopyridine and the corresponding Grignard reagent
e.g., by reacting 4-bromopyridine with a compound of formula
R.sub.1O--C.sub.6H.sub.4-MgBr wherein R.sub.1 is as defined above,
in the presence of a suitable catalyst, e.g., a nickel catalyst, to
obtain the 4-aryl-pyridine, which is then halogenated, e.g. by
reaction with Br.sub.2, to obtain the compound of formula I'a or
I'b where X is halogen, and optionally further reacting with one or
more alkylmetal reagents, e.g., with alkyllithium, e.g.,
butyllithium, followed by reaction with alkylborate, e.g.,
triethylborate, to obtain the compound of formula I'a or I'b where
X is --B(OH).sub.2. Compounds of formula IIa or IIIa can be
prepared analogously, by halogenation of the aryl, e.g.,
bromination, optionally followed by exchange of the halogen for a
leaving group, e.g., --B(OH).sub.2.
EXAMPLES
Example 1
[0065] 4-[2-(Methoxy)biphenyl-5-yl]pyridine
[0066] a) 4-(4-Methoxyphenyl)pyridine
[0067] A solution of 4-methoxyphenylmagnesium bromide, prepared
from 4-bromoanisole (150 g 0.80 mol) and magnesium (20 g, 0.83 mol)
in dry tetrahydrofuran (300 mL) is filtered, cooled to -10.degree.
C. and added cautiously to a stirred mixture of
bis-(triphenylphosphine)nickel (II) chloride (1.5 g, 2.25 mmol) and
4-bromopyridine hydrochloride (65 g, 0.334 mol) in dry
tetrahydrofuran (300 mL) at 10.degree. C. under an argon
atmosphere. After 50% of the Grignard reagent had been added a
vigorous, exothermic reaction sets in and the temperature of the
mixture is maintained between 50 and 60.degree. C. throughout the
rest of the addition by employing an ice-methanol cooling bath.
When the addition is complete the mixture is stirred for 60 min at
50.degree. C. The solvent is evaporated off under reduced pressure
to yield a residue which is treated with t-butylmethylether (500
mL) and extracted with hydrochloric acid (3.times.300 mL of 5M).
The combined extracts are washed (t-butylmethylether), basified
(aqueous NaOH) and extracted with
[0068] t-butylmethylether (4.times.300 mL). The combined extracts
are dried (Na.sub.2SO.sub.4) and the solvent is evaporated off
under reduced pressure to yield the crude product which is purified
by recrystallization from t-butylmethylether-cyclohexane to give
4-(4-methoxyphenyl)pyridine as a colourless crystalline solid, m.p.
94-96.degree. C.
[0069] b) 4-(3-bromo-4-methoxyphenyl)pyridine
[0070] Bromine (26.0 g. 163 mmol) is added to a stirred solution of
4-(4-methoxyphenyl)pyridine (13.6 g. 73.5 mmol) in acetic acid (500
mL) and heated at 60.degree. C. for 72 h. The mixture is then
evaporated to dryness under reduced pressure and the residue is
treated with aqueous ammonia (400 mL of 6M) and extracted with
ethyl acetate (3.times.200 mL). The combined extracts are dried
(Na.sub.2SO.sub.4), filtered and the solvent is evaporated off
under reduced pressure to yield the crude product which is purified
by chromatography (silica gel, 95% t-butylmethyl ether/4.5%,
methanol/0.5% aqueous NH.sub.3(25%)) and recrystallised from
ether-cyclohexane to give 4-(3-bromo-4-methoxyphenyl)- pyridine as
a pale-yellow crystalline solid, m.p. 82-84.degree. C.
[0071] c) 4-[2-(Methoxy)biphenyl-5-yl]pyridine
[0072] A stirred mixture of 4-(3-bromo-4-methoxyphenyl)pyridine
(1.32 g, 5 mmol), phenylboronic acid (0.67 g, 5.5 mmol),
tri-o-tolylphosphine (0.152 g, 0.50 mmol), palladium (II) acetate
(0.056 g 0.25 mmol), sodium carbonate (1.06 g, 10 mmol) and water
(10 mL) in dimethylformamide (20 mL) is heated at 80.degree. C. for
3 h. The mixture is then treated with water (100 mL) and extracted
with ethyl acetate (3.times.80 mL). The combined extracts are
washed (saturated NaCl), dried (Na.sub.2SO.sub.4), filtered and the
solvent is evaporated off under reduced pressure to yield the crude
product which is purified by chromatography (silica gel, 98% ethyl
acetate/1.8% ethanol/0.2% aqueous NH.sub.3(25%)) to give
4-[4-methoxy-3-(phenyl)phenyl]pyridine base. The base is dissolved
in diethylether (5 mL), treated with methanolic HCl (excess),
evaporated to dryness under reduced pressure and recrystallised
from isopropanol-diethylether to give
4-[2-methoxy-(1,1-biphenyl)-5-yl]pyridin- e, hydrochloride as a
pale-yellow crystalline solid, m.p. 180-200.degree. C., and having
the following physical characteristics:
[0073] .sup.1H-NMR (.delta. DMSO-d.sub.6): 3.89 (s, 3H), 7.35 (d,
J=8.7 Hz, 1H), 7.39 (d, J=7.2 Hz, 1H), 7.45 (dd, J=7.1 Hz, J=7.2
Hz, 2H), 7.58 (d, J=7.1 Hz, 2H), 7.95 (d, J=2.3 Hz, 1H), 8.08 (dd,
J=8.7 Hz, J=2.3 Hz, 1H), 8.2 (broad s, 1H), 8.36 (d, J=6.0 Hz, 2H)
and 8.83 (d, J=6.0 Hz, 2H).
Example 2
[0074] 4-[2-(methoxy)-3'-(nitro)biphenyl-5-yl]pyridine
[0075] This compound is prepared analogously to example 1 using
3-(nitro)phenylboronic acid in place of phenylboronic acid to yield
the title compound, m.p. 145-150.degree. C.
Example 3
[0076] 4-[2-(methoxy
)-3'-(trifluoromethyl)biphenyl-5-yl]pyridine
[0077] This compound is prepared analogously to example 1 using
3-(trifluoromethyl)phenylboronic acid in place of phenylboronic
acid to obtain the title compound as the hydrochloride. m.p.
103-106.degree. C.
Example 4
[0078] 4-[2-(Methoxy)-3',4'-(propylene)biphenyl]pyridine
[0079] a) Indan-5-boronic acid
[0080] A solution of n-butyllithium in hexane (13.2 mL of 1.6 M, 21
mmol) is added to a stirred solution of 5-bromo-indane (1.06 g, 4
mmol) in dry tetrahydrofuran (30 mL) at -75.degree. C. under an
argon atmosphere. The mixture is stirred for 30 min at -65.degree.
C., then treated with triethylborate (3.07 g, 21 mmol) and stirred
for 60 min at -50.degree. C. The resulting mixture is allowed to
warm to 0.degree. C. and then treated with a saturated aqueous
solution of ammonium chloride (60 mL) and extracted with ethyl
acetate (2.times.80 mL). The combined extracts are dried
(Na.sub.2SO.sub.4). filtered and the solvent is evaporated off
under reduced pressure to yield the crude product which is purified
by chromatography (silica gel, 50% ethyl acetate in hexaen) and
recrystallised from ethyl acetate-hexane to give indan-5-boronic
acid as a colourless crystalline solid.
[0081] b) 4-[2-(Methoxy)-3',4'-(propylene)biphenyl]pyridine
[0082] Utilising the procedure described in Example 1c), but
employing indan-5-boronic acid in lieu of phenylboronic acid
yielded a crude product which is purified by chromatography (silica
gel, 98% ethyl acetate/1.8% ethanol/0.2% aqueous NH.sub.3(25%)) to
give 4-[2-(methoxy)-3',4'-(propylene)biphenyl]pyridine base. The
base is dissolved in acetone (5 mL), treated with methanolic HCl
(excess), evaporated to dryness under reduced pressure and
recrystallised from isopropanol-ether to give
4-[2-(methoxy)-3',4'-(propylene)biphenyl]pyridi- ne, hydrochloride
as a pale-yellow crystalline solid, m.p. 185-205.degree. C., and
having the following physical characteristics:
[0083] .sup.1H-NMR (.delta. DMSO-d.sub.6): 2.06 (m, 2H), 2.91 (m,
4H), 3.07 (s, 3H), 7.27-7.32 (m, 2H), 7.33 (d, J=8.7 Hz, 1H), 7.41
(s, 1H), 7.93 (d, J=2.5 Hz, 1H), 8.07 (dd, J=8.7 Hz, J=2.5 Hz, 1H),
8.42 (d, J=6.0 Hz, 2H) and 8.86 (d, J=6.0 Hz, 2H).
Example 5
[0084] 4-[4-Methoxy-3-(5-benzofurazanyl)phenyl]pyridine
[0085] a) 4-(5-benzofurazanyl)phenylboronic acid
[0086] Utilising the procedure described in Example 1c), but
employing 5-bromobenzofuran in lieu of
4-(3-bromo-4-methoxyphenyl)pyridine yielded a crude product which
is purified by recrystallisation from ethyl acetate-hexane to give
4-(5-benzofurazanyl)phenylboronic acid as a beige crystalline
solid, m.p. >300.degree. C., and having the following physical
characteristics:
[0087] .sup.1H-NMR (.delta. DMSO-d.sub.6, +D.sub.2O): 3.66 (s, 3H),
7.84 (d, J=9.1 Hz, 1H), 7.95 (d, J=9.1 Hz, 1H), and 8.37 (s,
1H).
[0088] b) 4-[4-Methoxy-3-(5-benzofurazanyl)phenyl]pyridine
[0089] Utilising the procedure described in Example 1c), but
employing 4-(5-benzofurazanyl)phenylboronic acid in lieu of
phenylboronic acid yielded a crude product which is purified by
chromatography (silica gel, 98% ethyl acetate/1.8% ethanol/0.2%
aqueous NH.sub.3(25%)) and recrystallised from ethyl acetate-hexane
to give 4-[4-Methoxy-3-(5-benzof- urazanyl)phenyl]pyridine as a
beige crystalline solid, m.p. 187-192.degree. C.
Example 6
[0090] 4-[2-Methoxy-3'-cyano-(1,1'-biphenyl)-5-yl]pyridine
[0091] a) 2-Methoxy-5-(4-pyridinyl)phenylboronic acid
[0092] A solution of n-butyllithium in hexane (1.7 mL of 2.5 M,
4.25 mmol) is added to a stirred solution of
4-(3-bromo-4-methoxyphenyl)pyridine (Example 1b; 1.06 g, 4 mmol)
and triethylborate (0.62 g, 4.2 mmol) in dry tetrahydrofuran (20
mL) at -85.degree. C. under an argon atmosphere. The mixture is
stirred for 15 min at -80.degree. C., then treated with a saturated
aqueous solution of ammonium chloride (60 mL) and extracted with
ethyl acetate (2.times.80 mL). The combined extracts are dried
(Na.sub.2SO.sub.4), filtered and the solvent is evaporated off
under reduced pressure to yield the crude product which is purified
by recrystallisation from ethyl acetate-hexane to give
2-methoxy-5-(pyridin-4-yl)phenylboronic acid as a beige crystalline
solid, m.p. 194-200.degree. C. and having the following physical
characteristics:
[0093] .sup.1H-NMR (.delta. DMSO-d.sub.6): 3.88 (s, 3H), 7.13 (d,
J=8.7 Hz, 1H), 7.68 (d, J=6.1 Hz, 2H), 7.88 (s, 1H), 7.85 (dd,
J=8.7Hz, J=2.4 Hz, 1H), 7.97 (d, J=2,4 Hz, 1H) and 8.60 (d, J=6.1
Hz, 2H).
[0094] b) 4-[2-(Methoxy)-3'-(cyano)biphenyl-5-yl]pyridine
[0095] A stirred mixture of 3-bromobenzonitrile (0.91 g, 5.0 mmol),
2-Methoxy-5-(pyridin-4-yl)phenylboronic acid (0.50 g. 2.3 mmol),
tri-o-tolylphosphine (0.152 g, 0.50 mmol), palladium (11) acetate
(0.056 g 0.25 mmol), sodium carbonate (1.59 g, 15 mmol) and water
(15 mL) in dimethylformamide (46 mL) is heated at 80.degree. C. for
5 h. The mixture is then treated with water (100 mL) and extracted
with ethyl acetate (3.times.80 mL). The combined extracts are dried
(Na.sub.2SO.sub.4), filtered and the solvent is evaporated off
under reduced pressure to yield the crude product which is purified
by chromatography (silica gel, ethyl acetate) to give
4-[4-methoxy-3-(phenyl)phenyl]pyridine base. The base is dissolved
in diethylether (5 mL), treated with methanolic HCl (excess),
evaporated to dryness under reduced pressure and recrystallised
from ethanol-ether to give
4-[2-methoxy-3'-cyano-biphenyl-5-yl]pyridine, hydrochloride as a
pale-yellow crystalline solid, m.p. 142-150.degree. C.
[0096] The following compounds are prepared analogously by
utilising the appropriate aryl bromides:
Example 7
[0097] 4-[2-(Methoxy)-3'-(chloro)biphenyl-5-yl]pyridine,
hydrochloride, m.p. 156-210.degree. C.
Example 8
[0098] 4-[2-(Methoxy)-3',4'-(methylenedioxy)biphenyl-5-yl]pyridine,
m.p. 168-171.degree. C.
Example 9
[0099] 4-[2-(Methoxy)-3'-(phenoxy)biphenyl-5-yl]pyridine,
hydrochloride, m.p. 184-204.degree. C.
Example 10
[0100] 4-[2-(Methoxy)-4'-(phenoxy)biphenyl-5-yl]pyridine,
hydrochloride, m.p. 173-218.degree. C.
Example 11
[0101]
4-[2-(Methoxy)-3'-(chloro)-4'-(fluoro)biphenyl-5-yl]pyridine,
hydrochloride, m.p. 115.degree..
[0102] Compounds of Formula I having benzamide or phenylcarboxy in
lieu of pyridyl are prepared analogously.
Example 12
[0103]
4'-Methoxy-3'-(benzofurazan-5-yl)-[1,1'-biphenyl]4-carboxamide
[0104] a) 4'-Methoxy-[1,1'-biphenyl]-4-carboxylic acid, ethyl
ester
[0105] A stirred mixture of 4-bromobenzoic acid, ethyl ester (23.6
g, 103 mmol), 4-methoxyphenylboronic acid (15.6 g, 103 mmol),
tetrakis(triphenylphosphine)palladium (0) (2.0 g, 1.73 mmol) and
powdered caesium fluoride (30.0 g, 200 mmol) in 1,2-dimethoxyethane
(300 mL) is heated at 85.degree. C. for 3 h. The mixture is then
treated with water (500 mL) and extracted with ethyl acetate
(3.times.100 mL). The combined extracts are washed (saturated
NaCl), dried (Na.sub.2SO.sub.4), filtered and the solvent is
evaporated off under reduced pressure to yield the crude product
which is purified by chromatography (silica gel, 5% ethyl
acetate/95% cyclohexane) to 4'-methoxy-[1,1'-biphenyl]-4-carboxylic
acid, ethyl ester as a colourless crystalline solid. m.p.
103-104.degree. C.
[0106] The following compounds are prepared analogously by
utilising the appropriate bromobenzoic acid esters and aryl boronic
acids:
[0107] 4'-Methoxy-[1,1'-biphenyl]-3-carboxylic acid, ethyl
ester.
[0108] 4'-Methoxy-3-methyl-[1,1'-biphenyl]-3-carboxylic acid, ethyl
ester.
[0109] b) 3'--Bromo-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid,
ethyl ester
[0110] A solution of bromine (14.6 g, 91.3 mmol) in carbon
tetrachloride (100 mL) is added to a stirred mixture of
4'-Methoxy-[1,1'-biphenyl]4-car- boxylic acid, ethyl ester (23.4 g,
91.3 mmol) and silica gal (100 g of particle size 0.040-0.063 mm;
Merck 1.09385) in carbon tetrachloride (350 mL). The mixture is
stirred at 20.degree. C. for 4 h after which the silica gel is
removed by filtration. The filtrate is washed with aqueous sodium
hydrogen carbonate (200 mL of 1 M) followed by aqueous sodium
thiosulphate (50 mL of 2 M), dried (Na.sub.2SO.sub.4), filtered and
evaporated to dryness under reduced pressure to give the crude
product which is recrystallised from ether-cyclohexane to give
3'-bromo-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, ethyl ester
as a colourless crystalline solid, m.p. 114-115.degree. C.
[0111] The following compounds are prepared analogously by
utilising the appropriate esters:
[0112] 3'-Bromo-4'-methoxy-[1,1'-biphenyl]-3-carboxylic acid, ethyl
ester, m.p. 88-90.degree. C.
[0113] 3'-Bromo-4'-methoxy-3-methyl-[1,1'-biphenyl]-4-carboxylic
acid, ethyl ester, m.p. 84-87.degree. C.
[0114] c) 3'-Bromo-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid
[0115] A stirred mixture of
3'-bromo-4'-methoxy-[1,1'-biphenyl]-4-carboxyl- ic acid, ethyl
ester (28.8 g, 86 mmol) and aqueous sodium hydroxide (35 mL of 2 M)
in ethanol (690 mL) is heated at 90.degree. C. for 2 h. The cooled
mixture is then acidified with hydrochloric acid (200 mL of 1.0 M)
and the resulting precipitate is filtered off and dried to give
3'-bromo-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid as a
colourless crystalline solid.
[0116] d) 3'-Bromo-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid,
2,2-dimethylpropyl ester
[0117] A stirred mixture of
3'-bromo-4'-methoxy-[1,1'-biphenyl]4-carboxyli- c acid (19.2 g,
62.5 mmol) and dimethylformamide (0.1 mL) in toluene (200 mL) at
20.degree. C. is treated with oxalyl chloride (11.0 mL, 126
mmol).The mixture is then heated at 50.degree. C. for 1 h and then
evaporated to dryness under reduced pressure. The resulting crude
acid chloride is dissolved in dry tetrahydrofuran (250 mL) and
added dropwise to a stirred solution of lithium tert-butylate in
tetrahydrofuran (prepared by the slow addition of 32.5 mL of
n-butyl lithium to a solution of 23.5 mL of dry t-butanol in 200 mL
of dry tetrahydrofuran at 20.degree. C.). The mixture is stirred
for an additional 2 h, then treated with a saturated aqueous
solution of ammonium chloride (400 mL) and extracted with
t-butylethyl ether (2.times.300 mL). The combined extracts are
dried (Na.sub.2SO.sub.4), filtered and the solvent is evaporated
off under reduced pressure to yield the crude product which is
purified by chromatography (silica gel, 20% ethyl acetate in
cyclohexane) and recrystallised from t-butylethyl ether-hexane to
give 3'-bromo-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid,
2,2-dimethylpropyl ester as a colourless crystalline solid.
[0118] e) 4-(3-bromo-4-methoxyphenyl)benzamide
[0119] Utilizing the procedure of example 1b), but employing
4-(4-methoxyphenyl)benzamide in lieu of 4-(4-methoxyphenyl)pyridine
yields 4-(3-bromo-4-methoxyphenyl)benzamide as a beige crystalline
solid. m.p. 246-250.degree. C.
[0120] f) 4'-Methoxy-3'-(benzofurazan-5-yl
)-[1,1'-biphenyl]-4-carboxamide
[0121] Utilizing the procedure of example 5b), but employing
4-(3-bromo-4-methoxyphenyl)benzamide in lieu of
4-(3-Bromo-4-methoxypheny- l)pyridine yields a crude product which
is purified by chromatography (silica gel, ethyl acetate) and
recrystallized from ethanol-ethyl acetate to give the title
compound as a beige crystalline solid, m.p. 235-255.degree. C.
Example 13
[0122] 4'-Methoxy-3'-(3-nitrophenyl)-[1,1'-biphenyl]-4-carboxylic
acid, ethyl ester
[0123] A stirred mixture of
3'-bromo-4'-methoxy-[1,1'-biphenyl]-4-carboxyl- ic acid, ethyl
ester (26.6 g, 79.3 mmol), 3-nitrophenylboronic acid (21.2 g, 127
mmol), tri-o-tolylphosphine (2.51 g, 8.26 mmol), palladium (II)
acetate (0.91 g, 4.05 mmol), potassium carbonate (21.9 g, 159 mmol)
and water (100 mL) in dimethylformamide (400 mL) is heated at
60.degree. C. for 2 h. The mixture is then treated with water (1000
mL) and extracted with ethyl acetate (3.times.200 mL). The combined
extracts are dried (Na.sub.2SO.sub.4), filtered and the solvent is
evaporated off under reduced pressure to yield the crude product
which is purified by chromatography (silica gel, 10% ethyl acetate
in cyclohexane) to give
4'-methoxy-3'-(3-nitrophenyl)-[1,1'-biphenyl]4-carboxylic acid,
ethyl ester as a colourless crystalline solid, m.p. 106-108.degree.
C.
[0124] The following compounds are prepared analogously by
utilising the appropriate bromobenzoic acid esters and aryl boronic
acids:
Example 14
[0125] 4'-Methoxy-3'-(3-nitrophenyl)-[1,1'-biphenyl]-3-carboxylic
acid, ethyl ester m.p. 87-89.degree. C.
Example 15
[0126]
4'-Methoxy-3-methyl-3'-(3-nitrophenyl)-[1,1'-biphenyl]4-carboxylic
acid, ethyl ester m.p. 88-90.degree. C.
Example 16
[0127]
3'-(5-Benzofurazanyl)-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid,
ethyl ester m.p. 166-168.degree. C.
Example 17
[0128]
3'-(5-Benzofurazanyl)-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid,
2,2)-dimethylpropyl ester m.p. 131-136.degree. C.
Example 18:
[0129]
3'-(5-Benzofurazanyl)-4'-methoxy-[1,1'-biphenyl]-4-carboxylic
acid
[0130] A stirred mixture of
4'-methoxy-3'-(3-nitrophenyl)-[1,1'-biphenyl]-- 4-carboxylic acid,
ethyl ester (1.88 g. 5 mmol) and aqueous sodium hydroxide (20 mL of
2 M) in ethanol (30 mL) is heated at 90.degree. C. for 3 h. The
cooled mixture was then acidified with hydrochloric acid (100 mL of
1.0 M) and the resulting precipitate is filtered off and dried to
give 4'-methoxy-3'-(3-nitrophenyl)-[1,1'-biphenyl]-4-carboxylic
acid as a colourless crystalline solid, m.p. 270-274.degree. C.
[0131] The following compounds are prepared analogously by
utilising the appropriate esters:
Example 19
[0132] 4'-Methoxy-3'-(3-nitrophenyl)-[1,1'-biphenyl]-3-carboxylic
acid m.p. 223-228.degree. C.
Example 20
[0133]
4'-Methoxy-3-methyl-3'-(3-nitrophenyl)-[1,1'-biphenyl]-4-carboxylic
acid m.p. 278-281.degree. C.
Example 21
[0134]
3'-(5-Benzofurazanyl)-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid
m.p. >300.degree. C.
Example 22
[0135] 4'-Methoxy-3'-(3-chlorophenyl)-[1,1'-biphenyl]-4-carboxylic
acid m.p. 250-252.degree. C.
Example 23
[0136] 4'-Methoxy-3'-(3-cyanophenyl)-[1,1'-biphenyl]-4-carboxylic
acid m.p. 280-285.degree. C.
Example 24
[0137]
4'-Methoxy-3'-(3-nitrophenyl)-[1,1'-biphenyl]-4-carboxamide
[0138] A solution of trimethylaluminium in toluene (10 mL of 2.0 M)
is added over 30 minutes to a stirred suspension of ammonium
choride (1.07 g, 20 mmol) in toluene (20 mL) at 5.degree. C. under
an argon atmosphere. The mixture is stirred at 20.degree. C. for 2
h, treated with a solution of
4'-methoxy-3'-(3-nitrophenyl)-[1,1'-biphenyl]-4-carboxylic acid,
ethyl ester (l.65 g, 4.3 mmol) in toluene (40 mL) and stirred at
60.degree. C. for 18 h. The cooled mixture is washed with
hydrochloric acid (50 mL of 0.5 M) followed by saturated aqueous
sodium chloride (50 mL), dried (Na.sub.2SO.sub.4), filtered and the
solvent is evaporated off under reduced pressure to yield the crude
product which is purified by crystallisation from ethyl
acetate-t-butylethyl ether to give
4'-methoxy-3'-(3-nitrophenyl)-[1,1'-biphenyl]-4-carboxamide as a
colourless crystalline solid, m.p. 201-205.degree. C.
[0139] The following compounds are prepared analogously by
utilising the appropriate esters:
Example 25
[0140] 4'-Methoxy-3'-(3-nitrophenyl)-[1,1'-biphenyl]-3-carboxamide
m.p. 118-120.degree. C.
Example 26
[0141]
4'-Methoxy-3-methyl-3'-(3-nitrophenyl)-[1,1'-biphenyl]-4-carboxamid-
e m.p. 179-184.degree. C.
Example 27
[0142]
N-Methyl-4'-methoxy-3'-(3-nitrophenyl)-[1,1'-biphenyl]-4-carboxamid-
e
[0143] Utilising the procedure described in Example 24, but
employing methylamine hydrochloride in lieu of ammonium chloride
yields a crude product which is purified by chromatography (silica
gel, 50% ethyl acetate in cyclohexane) and recrystallised from
tetrahydrofuran-cyclohexa- ne to give
N-methyl-4'-methoxy-3'-(3-nitrophenyl)-[1,1'-biphenyl]-4-carbox-
amide as a pale-yellow crystalline solid, m.p. 171-172.degree.
C.
[0144] A representative imidazopyridine compound is prepared as
follows.
Example 28
[0145]
6-[4-Methoxy-3-(5-benzofurazanyl)phenyl]imidazo[1,2-a]pyridine
[0146] a) 5-(2-Hydroxyphenyl)benzofurazan
[0147] A stirred mixture of 5-bromobenzofurazan (11.94 g, 60 mmol),
2-hydroxyphenylboronic acid (9.10 g. 66 mmol), tri-o-tolylphosphine
(1.82 g, 6 mmol), palladium (II) acetate (0.672 g, 3 mmol),
potassiunm carbonate (12.4 g 90 mmol), and water (90 mL) in
dimethylformamide (180 mL) is heated at 80.degree. C. under an
argon atmosphere for 30 minutes. The mixture is then treated with
water (300 mL) and extracted with ethyl acetate (3.times.100 mL).
The combined extracts are washed (saturated NaCl), dried
(Na.sub.2SO.sub.4), filtered and the solvent is evaporated off
under reduced pressure to yield the crude product which is purified
by chromatography (silica gel. 20% -100% ethyl acetate in
cyclohexane) and recrystallised from ethyl acetate-hexane to give
5-(2-hydroxyphenyl)benzofurazan as a pale-yellow crystalline solid,
m.p. 166-169.degree. C.
[0148] b) 5-(3-Bromo-5-hydroxyphenyl)benzofurazan
[0149] A stirred mixture of 5-(2-hydroxyphenyl)benzofurazan (11.2
g, 52.8 mmol), and tetrabutylammonium tribromide (25.5 g, 52.8
mmol) in dichoromethane (530 mL) is stirred at 18.degree. C. for 18
h. The solvent is evaporated off under reduced pressure to yield a
residue which is treated with water (300 mL) and extracted with
ethyl acetate (3.times.100 mL). The combined extracts are washed
(saturated NaCl), dried (Na.sub.2SO.sub.4), filtered and the
solvent is evaporated off under reduced pressure to yield the crude
product which is purified by recrystallisation from ethyl
acetate-hexane to give 5-(3-bromo-5-hydroxyphenyl)benzofurazan as a
pale-yellow crystalline solid, m.p. 179-181.degree. C.
[0150] c) 5-(3-Bromo-5-methoxyphenyl)benzofurazan
[0151] A stirred mixture of 5-(3-bromo-5-hydroxyphenyl)benzofurazan
(8.70 g, 30 mmol), potassium carbonate (14.42 g, 90 mmol) and
methyl iodide (2.83 mL, 45 mmol) in dimethylformamide (100 mL) is
stirred at 18.degree. C. for 16 h. The mixture is then treated with
water (600 mL) and extracted with ethyl acetate (3.times.150 mL).
The combined extracts are washed (saturated NaCl). dried
(Na.sub.2SO.sub.4), filtered and the solvent is evaporated off
under reduced pressure to yield the crude product which is purified
by recrystallisation from t-butylmethyl ether-hexane to give
5-(3-bromo-5-methoxyphenyl)benzofurazan as a beige crystalline
solid. m.p. 135-137.degree. C.
[0152] d) 6-(Trimethylstannyl)imidazo[1,2-a]pyridine
[0153] A stirred mixture of 6-bromoimidazo[1,2-a]pyridine (2.36 g,
12 mmol), hexamethylditin (5.0 g, 15.3 mmol), triphenylphosphine
(496 mg, 1.89 mmol), and bis(dibenzylidineacetone)palladium(0) (270
mg, 0.47 mmol) in toluene (120 mL) is heated at 118.degree. C.
under an argon atmosphere for 6 h. The mixture is then treated with
aqueous potassium fluoride solution (300 mL of 0.50 M) and
extracted toluene (3.times.50 mL). The combined extracts are dried
(Na.sub.2SO.sub.4), filtered and the solvent is evaporated off
under reduced pressure to yield the crude product which is purified
by chromatography (silica gel, 50% ethyl acetate in cyclohexane) to
give 6-(trimethylstannyl)imidazo[1,2-a]pyridine as a colourless
oil.
[0154] e)
6-[4-Methoxy-3-(5-benzofurazanyl)phenyl]imidazo[1,2-a]pyridine
[0155] A stirred mixture of 5-(3-bromo-5-methoxyphenyl)benzofurazan
(2.44 g, 8 mmol), 6-(trimethylstannyl)imidazo[1,2-a]pyridine (2,2
g, 7.9 mmol), triphenylphosphine (336 mg, 1.28 mmol), and
bis(dibenzylidineacetone)pall- adium(0) (186 mg, 0.32 mmol) in
dimethylformamide (60 mL) is heated at 125.degree. C. under an
argon atmosphere for 36 h. The solvent is evaporated off under
reduced pressure to yield a crude product which is purified by
chromatography (silica gel, 95% ethyl acetate/4.5% ethanol/0.5%
aqueous NH3 (25%)) and recrystallised from ethyl acetate
-t-butylmethyl ether to give
6-[4-methoxy-3-(5-benzofurazanyl)phenyl]imid- azo[1,2-a]pyridine as
a pale-yellow crystalline solid, m.p. 190-196.degree. C.
[0156] The AGENTS OF THE INVENTION as defined above, e.g., of
formula Ia or Ib, particularly as exemplified, in free or
pharmaceutically acceptable acid addition salt form, exhibit
pharmacological activity and are useful as pharmaceuticals, e.g.
for therapy, in the treatment of diseases and conditions as
hereinafter set forth.
[0157] In particular AGENTS OF THE INVENTION exhibit cyclic
nucleotide phosphodiesterase (PDE) isoenzymc inhibiting activity,
selective for type 4 isoenzyme.
[0158] AGENTS OF THE INVENTION possess anti-inflammatory,
anti-airways hyperreactivity and bronchodilator properties. They
further possess immunosuppressive, TNF.alpha. secretion inhibitory
and other pharmacological activities as may be demonstrated in
standard test methods for example as follows:
[0159] A. PDE4 inhibition: Recombinant PDE4A, PDE4B, PDE4C and
PDE4D isoenzyme inhibition assays.
[0160] Cloning and expression: PDE4 cDNA coding for the four
isoenzymes, human PDE4A (as described by Sullivan et al., Cell
Signal 1994; 6:793-812), rat PDE4B (as described by Colicelli et
al., Proc. Natl. Acad. Sci. USA 1989; 86:3599-3903), human PDE4C
(as described by Engels et al., FEBS Lett. 1995; 358:305-310), and
human PDE4D (as described by Baecker et al., Gene 1994;
138:253-256) is cloned either into an extrachromosomal yeast
expression vector (PDE4C, PDE4D) or integrated (PDE4A, PDE4B;
single copy) at the pep4 locus of a Saccharomyces cerevisiae strain
lacking both of the wild-type yeast PDE genes. Yeast strains
expressing PDE4 isoenzymes are grown in 1 l cultures at 30.degree.
C., pelleted and frozen until homogenization.
[0161] Homogenization: Pelleted yeast (5 mL) is suspended in 50 mL
of buffer (10 mM tris-hydroxymethylaminomethane. 1 mM
ethylenediamine-tetraacetic acid, 1 mg/mL each of leupeptin and
pepstatin A, 175 mg/mL phenylmethylsulphonyl fluoride, 1 mM
dithiothreitol, pH 7.4 with HCl). After centrifugation, 15 g of
glass beads (425-600 mm, acid washed, Sigma Chemical Co.) washed
with buffer are added to the pellet. To this slurry, 1 mL of buffer
and 60 mg of cholamidopropane sulphonic acid are added and the
slurry is vigorously agitated for 4 h at 4.degree. C. The yeast
cells are disintegrated, as observed microscopically
(phase-contrast optics) as dark cells and is >30% (usually 50%).
The slurry is transferred to a coarse glass funnel and the
homogenate collected by suction and washing of the glass beads with
a total of 15 mL buffer. Cell fragments are separated from cytosol
by centrifugation (2000.times.g, 10 min. 4.degree. C.). The pellet
is resuspended in 15 mL of buffer and assayed for PDE activity
together with the cytosol.
[0162] PDE assay: The assay protocol is based upon the two-step
method described by Thompson et al. (Adv. Second Messenger
Phosphoprotein Res. 1979; 10:69-92), modified for 96-well
microtitre plates. Briefly, enzyme is diluted with homogenization
buffer (see above) in order to obtain between 10% and 30% total
substrate hydrolysis during the assay. To start the reaction, 25 mL
of diluted enzyme is added to 25 mL of substrate ([3H]-cAMP, 1.25
mM, 740 Bq) and 75 mL of inhibitor solution (see below). After 30
minutes at 37.degree. C., the reaction is stopped in a hot water
bath (65.degree. C., 5 minutes). Plates are cooled on ice and
incubated for 10 minutes at 37.degree. C. with 25 mL of
5'-nucleotidase (Snake venom, from oiophaghus hannah, Sigma
Chemical Co., 0.1 mg/mL in water). The unreacted substrate is
separated from [3H]adenosine by sequentially adding aliquots
(100+50+50 mL, at 5 min intervals) of 30% (v/v) Dowex 1.times.2
slurry (acetate form) in 0.2% (v/v) acetic acid. The Dowex is
pelleted by centrifugation (150.times.g, 5 min). Aliquots of the
supernates are transferred onto 96-well, solid-phase scintillation
plates (LumaPlate, Canberra Packard) using an automated pipetting
device (Hamilton MicroLab 2200), dried (at least 4 h at 50.degree.
C.) and counted (Canberra Packard TopCount).
[0163] Inhibitors: Inhibitor stock solutions are prepared in
dimethylsulphoxide (DMSO) and diluted with water/DMSO to achieve 7
concentrations selected to cover the range of 30% to 70%
inhibition. The concentration of DMSO is kept constant at 50 mL/mL
throughout the assay.
[0164] Determination of inhibition parameters: The concentration at
which half-maximal inhibition occurs (IC50) and the steepness of
the dose-response curve (Hill's coefficient) are determined from
concentration-inhibition curves by non-linear least-squares fitting
to the two-parameter logistic equation. Results are expressed as
the negative decimal logarithm of inhibitor concentration at which
half-maximal inhibition is observed (IC50) (in mol/L; pIC50). 95%
confidence intervals were estimated and expressed as pL and pU
(negative decimal logarithms of the lower and upper confidence
limits, respectively). Concentrations which cause a visible
precipitation in the assay are excluded from the analysis.
[0165] In this test method AGENTS OF THE INVENTION predominantly
inhibit PDE isoenzymes of type 4 having relatively little effect in
relation to types 1, 2, 3 and 7. Within the PDE type 4 isoenzyme
croup (i.e. PDE types 4A to D) AGENTS OF THE INVENTION generally
exhibit selectivity for inhibition of PDE type 4 D isoenzyme in
comparison with the PDE type 4A, 4B and 4C isoenzymes.
[0166] B. Anti-inflammatory activity: Inhibition of eosinophil
activation by formyl-MetLeuPhe (fMLP)
[0167] Purified human eosinophils (10.sup.4/well in 0.2 ml HBSS)
are stimulated with fMLP (1 .mu.M) in the presence of lucigenin (25
.mu.M). Inhibition of the oxidative burst (measured as changes in
chemiluminescence) is determined from dose response curves using
the logistic equation.
[0168] AGENTS OF THE INVENTION are active in test methods A and B
at concentrations of the order of from 0.001 to 5 .mu.M, generally
in the low nM range.
[0169] C. Influence on allergen-induced pulmonary eosinophilia
[0170] Exposure of Brown Norway rats to inhaled antigen (ovalbumin,
OA) evokes pulmonary eosinophilia that is maximal 48 hours later.
In addition to eosinophil numbers, the activation status of these
cells can be assessed by means of enzymatic activity of the
eosinophil granule enzyme eosinophil peroxidase (EPO). In the
present experiments, inhibition of pulmonary cosinophil
accumulation by the AGENTS OF THE INVENTION is assessed.
[0171] Ovalbumin (10 .mu.g/ml) is mixed (i hour on ice) in a
blender with aluminum hydroxide (10 mg/ml) and injected s.c.
coincidentally with a B. pertussis vaccine (0.25 ml/rat i.p.) into
male Brown Norway rats (ca. 200 g). Injection of OA together with
adjuvant is repeated 15 and 21 days later. On day 28, sensitized
animals are restrained in plastic tubes and exposed for one hour to
an acrosal of OA (3.2 mg/ml) using a nose only exposure system.
Animals are killed 48 hours later with phenobarbital (250 mg/kg
i.p.). The lungs are lavaged using 3 aliquots (4 ml) of Hank's
solution (HBSS.times.10, 100 ml; EDTA 100 mM, 100 ml; HEPES 1 M, 10
ml; 1 liter water). recovered cells are pooled, smeared air dried
and stained to differentiate cell types. Cells are identified and
counted under oil immersion (.times.1,000). A minimum of 500 cells
per smear are counted and the total population of each cell type is
calculated.
[0172] Test substance is administered intratracheally 1 hour prior
to and 24 hours after OA challenge.
[0173] In untreated animals OA challenge induces increase of all
cell types in BAL fluid 24 hours after challenge. Prior
administration of AGENTS OF THE INVENTION at dosages of the order
of from 0.01 to 10 mg/kg reduces eosinophil count in BAL in a dose
dependent manner as compared with untreated controls. Cell counts
for other leucocytes (macrophages, neutrophils) are also
reduced.
[0174] Having regard to their anti-inflammatory activity, their
influence on airways hyperreactivity and their profile in relation
to PDE isoenzyme inhibition, in particular as selective type IV
inhibitors. AGENTS OF THE INVENTION are useful for the treatment,
in particular prophylactic treatment, of obstructive or
inflammatory airways disease. Thus by continued and regular
administration over prolonged periods of time AGENTS OF THE
INVENTION are useful in providing advance protection against
recurrence of bronchoconstrictor or other symptomatic attack
consequential to obstructive or inflammatory airways disease or for
the control, amelioration or reversal of basal status of such
disease.
[0175] Having regard to their bronchodilator activity AGENTS OF THE
INVENTION are useful as bronchodilators, e.g. for the treatment of
chronic or acute broncho-constriction, e.g. for the symptomatic
treatment of obstructive or inflammatory airways disease.
[0176] The words "treatment" and "treating" as used throughout the
present specification and claims in relation to obstructive or
inflammatory airways disease are to be understood accordingly as
embracing both prophylactic and symptomatic modes of therapy.
[0177] In accordance with the foregoing the present invention
further provides
[0178] A. A method
[0179] a) for the treatment of airways hyperreactivity,
[0180] b) of effecting bronchodilation or, in particular,
[0181] c) of treating obstructive or inflammatory airways disease,
in a subject in need thereof, which method comprises administering
to said subject an effective amount of an AGENT OF THE
INVENTION.
[0182] Obstructive or inflammatory airways diseases to which the
present invention applies include asthma, pneumoconiosis, chronic
obstructive airways or pulmonary disease (COAD or COPD) and adult
respiratory distress syndrome (ARDS), as well as exacerbation of
airways hyperreactivity consequent to other drug therapy, e.g.
aspirin or .beta.-agonist therapy.
[0183] The present invention is applicable to the treatment of
asthma of whatever type or genesis, including intrinsic and,
especially, extrinsic asthma. It is applicable to the treatment of
allergic (atopic/IgE-mediated) asthma. It is also applicable to the
treatment of non-atopic asthma, including e.g. bronchitic, exercise
induced and occupational asthma, asthma induced following bacterial
infection and other non-allergic asthmas. It is further applicable
to the treatment of wheezy infant syndrome (infant, incipient
asthma).
[0184] The invention is applicable to the treatment of
pneumoconiosis of whatever type or genesis including, for example,
aluminosis, anthracosis, asbestosis, chalicosis, ptilosis,
siderosis, silicosis, tobacoosis and byssinosis.
[0185] The invention is applicable to the treatment of COPD or COAD
including chronic bronchitis, pulmonary emphysaema or dyspnea
associated therewith.
[0186] The invention is also applicable to the treatment of
bronchitis of whatever type or genesis including, e.g. acute,
arachidic, catarrhal, chronic, croupus or phthinoid bronchitis
etc..
[0187] Having regard to their activity as selective inhibitors of
TNF-.alpha. release, AGENTS OF THE INVENTION are also useful for
the down-regulation or inhibition of TNF-.alpha. release, e.g. for
the treatment of diseases or conditions in which TNF-.alpha.
release is implicated or plays a mediating role, e.g. diseases or
conditions having an aetiology involving or comprising morbid, for
example undesirable, excessive or unregulated TNF-.alpha. release,
in particular for the treatment of cachexia or endotoxin shock and
in treatment of AIDS [cf. Sharief et al, Mediators of Inflammation,
1 323-338(1992)].
[0188] The method of the invention is applicable to the treatment
of cachexia associated with morbid TNF-.alpha. release or
TNF-.alpha. blood-serum levels of whatever origin, including
cachexia consequential to, e.g. bacterial, viral or parasitic,
infection or to deprivation or deterioration of humoral or other
organic, e.g. renal function. It is for example applicable to the
treatment of cancerous, malarial and vermal cachexia, cachexia
resulting from dysfunction of the pituitary, thyroid or thymus
glands as well as uremic cachexia. It is in particular applicable
to the treatment of AIDS-related cachexia, i.e. cachexia
consequential to or associated with to HIV infection.
[0189] The method of the invention is also applicable to the
treatment of septic shock, e.g., shock conditions resulting from
bacterial infection, for example toxic or endotoxic shock. In this
regard it is to be noted that the present invention provides a
method for the treatment of septic shock as such as well as of
conditions consequential to or symptomatic of septic or shock, for
example ARDS (adult respiratory distress syndrome). The method of
the invention is also applicable to other severe acute inflammatory
conditions, for example severe burns, menengitis, and
pneumonia.
[0190] The method of the invention is further applicable to the
treatment of disease consequential to HIV infection. e.g. AIDS,
e.g. to the amelioration or control of the advance of such
disease.
[0191] Having regard to their profile in relation to inhibition of
PDE isoenzymes and/or TNF.alpha. release inhibition, as well as
their immunosuppressive activity, AGENTS OF THE INVENTION are also
useful as immunosuppressive agents, e.g. for the treatment of
autoimmune diseases, in particular for the treatment of autoimmune
diseases in which inflammatory processes are implicated or which
have an inflammatory component or aetiology, or as
anti-inflammatory agents for the treatment of inflammatory disease
in particular for the treatment of inflammatory disease in which
autoimmune reactions are implicated or having an autoimmune
component or aetiology.
[0192] Examples of such disease to which the present invention is
applicable include autoimmune hematological disorders (e.g.
hemolytic anaemia, aplastic anaemia, pure red cell anaemia and
idiopathic thrombocytopenia), systemic lupus erythematosus,
polychondritis, scleroderma, Wegener granulomatosis,
dermatomyositis, chronic active hepatitis, myasthenia gravis,
Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory
bowel disease (e.g. ulcerative colitis and Crohn's disease)
endocrine ophthalmopathy, Grave's disease, sarcoidosis, alveolitis,
chronic hypersensitivity pneumonitis, multiple sclerosis, primary
biliary cirrhosis, juvenile diabetes (diabetes mellitus type I),
uveitis (anterior and posterior), keratoconjunctivitis sicca and
vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic
arthritis and glomerulonephritis (with and without nephrotic
syndrome, e.g. including idiopathic nephrotic syndrome or minimal
change nephropathy), as well as inflammatory and/or
hyperproliferative skin diseases such as psoriasis atopic
dermatitis, pemphigus and, in particular, contact dermatitis. e.g.
allergic contact dermatitis.
[0193] AGENTS OF THE INVENTION are in particular useful for the
treatment of arthritis, and other rheumatic or inflammatory
disease, especially for the treatment of rheumatoid arthritis.
[0194] As immunosuppressants AGENTS OF THE INVENTION are further
indicated for use in the prevention of craft rejection, e.g. for
the maintenance of allogenic organ transplants or the like, e.g. in
relation to kidney, liver, lung, heart, heart-lung, bowel,
bone-marrow, skin, or corneal transplant.
[0195] Having regard to their anti-inflammatory activity, in
particular in relation to inhibition of eosinophil activation,
AGENTS OF THE INVENTION are also useful for the treatment of
eosinophil related disorders, e.g. eosinophilia, in particular
eosinophil related disorders of the airways (e.g. involving morbid
eosinophilic infiltration of pulmonary tissues) including
hypereosinophilia as it effects the airways and/or lungs as well
as, for example, eosinophil-related disorders of the airways
consequential or concomitant to Loffler's syndrome, eosinophilic
pneumonia, parasitic (in particular metazoal) infestation
(including tropical eosinophilia), bronchopulmonary aspergillosis,
polyarteritis nodosa (including Churg-Strauss syndrome),
eosinophilic granuloma and eosinophil-related disorders affecting
the airways occasioned by drug-reaction.
[0196] Having regard to their profile in relation to inhibition of
PDE isoenzymes, in particular their profile as selective type IV
inhibitors, AGENTS OF THE INVENTION are further useful as type IV
PDE inhibitors, for example for the treatment of disease involving
tissue calcium depletion, in particular degenerative diseases of
the bone and joint involving calcium depletion, especially
osteoporosis. In this regard they are further useful for the
treatment of allergic inflammatory diseases such as rhinitis,
conjunctivitis, atopic dermatitis, urticaria and gastro-intestinal
allergies; as vasodilators, e.g. for the treatment of angina,
hypertension, congestive heart failure and multi-infarct dementia;
and for the treatment of other conditions where inhibition of PDE
IV is indicated, for example, depression, conditions and diseases
characterized by impaired cognitive function including Alzheimer's
disease, Parkinson's disease and stroke.
[0197] Having regard to their ability to interact synergistically
with immunosuppressive and/or anti-inflammatory drug substances.
AGENTS OF THE INVENTION are also useful as co-therapeutic agents
for use in conjunction with such drugs, e.g. as potentiators of
therapeutic activity of such drugs or as means of reducing required
dosaging or potential side effects of such drugs. Drug substances
with which AGENTS OF THE INVENTION may suitably be co-administered
include, e.g. cyclopeptide, cyclopeptolide or macrolide
immunosuppressive or anti-inflammatory drug substances, for
examples drugs belonging to the cyclosporin class, e.g.
cyclosporins A or G, the drug substances tacrolimus (also known as
FK 506), ascomycin and rapamycin and their various known congeners
and derivatives, as well as glucocorticosteroid drugs. Diseases to
which such co-therapy may be applied include e.g. any disease or
condition requiring immunosuppressive or anti-inflammatory drug
therapy, e.g. as hereinbefore set forth. In particular AGENTS OF
THE INVENTION are suitable for use in co-therapy as aforesaid, e.g.
for the purposes of immunosuppressive, anti-inflammatory or
anti-asthmatic treatment, e.g. to achieve cyclosporin, e.g.
cyclosporin A-, macrolide- or steroid-sparing effect.
[0198] In accordance with the foregoing the present invention also
provides:
[0199] B. A method
[0200] a) for the down-regulation or inhibition of TNF-.alpha.
release,
[0201] b) for the inhibition of PDE IV isoenzyme activity,
[0202] c) of effecting immunosuppression,
[0203] d) for the treatment of inflammatory disease, or
[0204] e) for the treatment of any particular condition or disease
as hereinabove set forth,
[0205] in a subject in need thereof, which method comprises
administering to said subject an effective amount of an AGENT OF
THE INVENTION.
[0206] The present invention also provides:
[0207] C. An AGENT OF THE INVENTION for use as a pharmaceutical,
for example for use in any method or in the treatment of any
disease or condition as hereinbefore set forth, e.g. as defined
under A or B above.
[0208] Dosages employed in practicing the present invention will of
course vary depending, e.g. on the particular disease or condition
to be treated, the particular AGENT OF THE INVENTION used, the mode
of administration and the therapy desired. In general, however,
satisfactory results. e.g. for the treatment of diseases as
hereinbefore set forth are indicated to be obtained on oral
administration at dosages of the order from about 0.01 to 2.0
mg/kg. In larger mammals, for example humans, an indicated daily
dosage for oral administration will accordingly be in the range of
from about 0.75 to 150 mg, conveniently administered 1.times. or in
divided doses 2 to 4.times. daily or in sustained release form.
Unit dosage forms for oral administration thus suitably comprise
from about 0.2 to 75 or 150, e.g. from about 0.2 or 2.0 to 50, 75
or 100 mg AGENT OF THE INVENTION, together with a pharmaceutically
acceptable diluent or carrier therefor.
[0209] For use in the treatment of chronic or obstructive airways
disease, e.g. asthma AGENTS OF THE INVENTION may also be
administered by the inhaled route. Again dosages employed will
vary, e.g. depending on the particular disease or condition, the
particular AGENT OF THE INVENTION employed, the particular mode of
administration (e.g. whether by dry powder inhalation or otherwise)
and the effect desired. In general, however, an indicated inhaled
daily dosage will be of the order of from about 2.5 to about 130.0
.mu.g/kg/day e.g. from about 13.0 to about 60.0 .mu.g/kg/day. For
larger mammals, for example humans, an indicated daily dosage for
administration by inhalation, e.g. in the treatment of asthma, will
be in the range of from about 0.2 to about 10.0 mg. e.g. from about
1 to about 5 mg, conveniently given in one single administration or
2 or 3 separate administrations throughout the day. An appropriate
dosage per administration will thus be of the order of from about
200 .mu.g to about 3.3 mg, with administration up to 3 times daily,
suitably administered from a dry powder inhalation delivery device
in a series of 2 to 8 puffs at each administration.
[0210] AGENTS OF THE INVENTION may also be administered by any
other appropriate route, e.g. by infusion, for example for the
treatment of endotoxin shock; nasally, for example for the
treatment of rhinitis; ocularly for example for the treatment of
autoimmune diseases of the eye dermally, i.e. topically to the
skin, for example for the treatment of dermatoses or psoriasis, or
rectally, e.g. via enemation or suppository, for example for the
treatment of inflammator bowel disease. Suitable dosages for
application by such routes will generally be of the order of 10 to
100.times. less than those required for oral administration.
[0211] Pharmaceutical compositions comprising AGENTS OF THE
INVENTION may be prepared using conventional diluents or excipients
and techniques known in the galenic art. Thus oral dosage forms may
include tablets, capsules and the like. Formulations for dermal
administration may take the form of creams, ointments, gels, or
transdermal delivery systems, e.g. patches and, in addition to
inert diluents or carriers, may suitably contain skin penetration
enhancing agents, again as known in the art.
[0212] Compositions for inhalation may comprise aerosol or other
atomizable formulations as well as inhalable dry powder
formulations, with or without diluent, for administration by any
appropriate dry powder inhalation system as known in the art. For
the preparation of dry powder forms for inhalation, AGENTS OF THE
INVENTION are suitably employed in pharmaceutically acceptable acid
addition salt form. The said salt form is suitably milled, e.g.
using an air-jet or ceramic mill to provide a finely divided
inhalable powder, e.g. having an average particle diameter of ca.
2-3.mu.. Appropriately at least 90% of the material will have an
average particle diameter of less than 7.8.mu., more preferably of
less than 4.8.mu.. In order to ensure obtention of an appropriate
and consistent particulate product suitable for administration by
inhalation in dry powder from, it may be preferable to effect
milling of the active ingredient premixed with an appropriate
inhalable carrier medium, e.g. lactose, under conditions of reduced
temperature.
[0213] In accordance with the foregoing the present invention also
provides: a pharmaceutical composition comprising an AGENT OF THE
INVENTION together with a pharmaceutically acceptable diluent or
carrier therefor, e.g. for use in any method as hereinbefore
defined.
* * * * *