U.S. patent application number 09/805842 was filed with the patent office on 2002-10-03 for tri-substituted phenyl derivatives and processes for their preparation.
This patent application is currently assigned to Celltech Therapeutics, Limited. Invention is credited to Alexander, Rikki Peter, Boyd, Ewan Campbell, Warrellow, Graham John.
Application Number | 20020143011 09/805842 |
Document ID | / |
Family ID | 27451178 |
Filed Date | 2002-10-03 |
United States Patent
Application |
20020143011 |
Kind Code |
A1 |
Warrellow, Graham John ; et
al. |
October 3, 2002 |
Tri-substituted phenyl derivatives and processes for their
preparation
Abstract
Compounds of general formula (1) are described: 1 wherein
.dbd.W-- is (1) .dbd.C(Y)-- where Y is a halogen atom, or an alkyl
or --XR.sup.a group where X is --O--, --S(O).sub.m--[where m is
zero or an integer of value 1 or 2], or --N(R.sup.b)--[where
R.sup.b is a hydrogen atom or an optionally substituted alkyl
group] and R.sup.a is a hydrogen atom or an optionally substituted
alkyl group or, (2) .dbd.N--; L is (1) a
--C(R).dbd.C(R.sup.1)(R.sup.2) or [--CH(R)].sub.nCH(R.sup.1)(R.-
sup.2) group; is (2) a --(X.sup.a).sub.nAlk'Ar', or Alk'X.sup.aAr'
group; or is (3) X.sup.aR.sup.1; Z is a group (A), (B), (C) or (D):
2 wherein Ar is a monocyclic or bicyclic aryl group optionally
containing one or more heteroatoms selected from oxygen, sulphur or
nitrogen atoms; Z.sup.1 is a group --NR.sup.12C(O)--[where R.sup.12
is a hydrogen atom or an optionally substituted alkyl or
(Alk).sub.tAr group], --C(O)NR.sup.12--, --NR.sup.12C(S)--,
--C(S)NR.sup.12--, --C.ident.C--, --NR.sup.12SO.sub.2--, or
--SO.sub.2NR.sup.12--; Alk is an optionally substituted straight or
branched alkyl chain optionally interrupted by an atom or group X;
t is zero or an integer of value 1, 2 or 3; R.sup.3 is a hydrogen
or a fluorine atom or an optionally substituted straight or
branched alkyl group or an OR.sup.11 group [where R.sup.11 is a
hydrogen atom or an optionally substituted alkyl, alkenyl,
alkoxyalkyl, alkanoyl, formyl, carboxamido or thiocarboxamido
group]; R.sup.4 is a hydrogen atom or an optionally substituted
alkyl, --CO.sub.2R.sup.8, --CSNR.sup.9R.sup.10, --CN, --CH.sub.2CN,
or --(CH.sub.2).sub.tAr group where t is zero or an integer of
value 1, 2 or 3 and Ar is a monocyclic or bicyclic aryl group
optionally containing one or more heteroatoms selected from oxygen,
sulphur or nitrogen atoms; provided that when L is a group of type
(2) or (3) above then Z is a group of type (A) or type (B) in which
R.sup.4 is a --(CH.sub.2).sub.tAr group; R.sup.5 is a group
--(CH.sub.2).sub.tAr; R.sup.6 is a hydrogen or a fluorine atom, or
an optionally substituted alkyl or --CO.sub.2R.sup.8,
--CONR.sup.9R.sup.10, --CSNR.sup.9R.sup.10, --CN or --CH.sub.2CN
group; R.sup.7 is a hydrogen or a fluorine atom, an optionally
substituted straight or branched alkyl group, or an OR.sup.c group
where R.sup.c is a hydrogen atom or an optionally substituted alkyl
or alkenyl group, alkoxyalkyl, alkanoyl, formyl, carboxamido or
thiocarboxamido group; and the salts, solvates, hydrates, prodrugs
and N-oxides thereof. Compounds according to the invention are
phosphodiesterase type IV inhibitors and are useful in the
prophylaxis and treatment of disease such as asthma where unwanted
inflammatory response or muscular spasm is present.
Inventors: |
Warrellow, Graham John;
(Middlesex, GB) ; Boyd, Ewan Campbell; (Tullibody,
GB) ; Alexander, Rikki Peter; (High Wycombe,
GB) |
Correspondence
Address: |
Woodcock Washburn Kurtz
Mackiewicz & Norris LLP
One Liberty Place - 46th Floor
Philadelphia
PA
19103
US
|
Assignee: |
Celltech Therapeutics,
Limited
|
Family ID: |
27451178 |
Appl. No.: |
09/805842 |
Filed: |
March 14, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09805842 |
Mar 14, 2001 |
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08492855 |
Jun 20, 1995 |
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6245774 |
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Current U.S.
Class: |
514/227.8 ;
514/227.5; 514/231.2; 514/253.12; 514/255.03; 514/336; 514/345;
514/520; 514/570; 514/618; 514/622; 544/124; 544/162; 544/163;
544/360; 544/386; 544/59; 544/60; 546/268.1; 546/286; 546/290 |
Current CPC
Class: |
C07D 409/12 20130101;
C07D 213/30 20130101; A61P 43/00 20180101 |
Class at
Publication: |
514/227.8 ;
514/227.5; 514/231.2; 514/253.12; 514/255.03; 514/336; 514/345;
514/520; 514/570; 514/618; 514/622; 544/59; 544/60; 544/360;
544/124; 544/162; 544/163; 544/386; 546/268.1; 546/286;
546/290 |
International
Class: |
A61K 031/541; A61K
031/54; A61K 031/5377; A61K 031/535; A61K 031/496; A61K 031/495;
A61K 031/4439; A61K 031/277; A61K 031/195 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 21, 1994 |
GB |
9412386.6 |
Jun 21, 1994 |
GB |
9412384.1 |
Jun 22, 1994 |
GB |
9412493.0 |
Aug 5, 1994 |
GB |
9415836.7 |
Claims
1. A compound of formula (1) 37wherein .dbd.W-- is (1) .dbd.C(Y)--
where Y is a halogen atom, or an alkyl or --XR.sup.a group where X
is --O--, --S(O).sub.m--[where m is zero or an integer of value 1
or 2], or --N(R.sup.b)-- where R.sup.b is a hydrogen atom or an
optionally substituted alkyl group] and R.sup.a is a hydrogen atom
or an optionally substituted alkyl group or, (2) .dbd.N--; L is (1)
a --C(R).dbd.C(R.sup.1)(R.sup.2) or [--CH(R)].sub.nCH(Rl)(R.sup.2)
group where R is a hydrogen or a fluorine atom or a methyl group,
and R.sup.1 and R.sup.2, which may be the same or different, is
each a hydrogen or fluorine atom or an optionally substituted
alkyl, alkenyl, alkynyl, alkoxy, alkylthio, --CO.sub.2R.sup.8
[where R.sup.8 is a hydrogen atom or an optionally substituted
alkyl, aralkyl or aryl group], --CONR.sup.9R.sup.10 [where R.sup.9
and R.sup.10, which may be the same or different are defined for
R.sup.8], --CSNR.sup.9R.sup.10,--CN or --NO.sub.2 group, or R.sup.1
and R.sup.2, together with the C atom to which they are attached
are linked to form an optionally substituted cycloalkyl,
cycloalkenyl or heterocycloaliphatic group and n is zero or the
integer 1; or is (2)--(X.sup.a).sub.nAlk'Ar', or -Alk'X.sup.aAr'
where X.sup.a is a group X, Ar' is an optionally substituted
heterocycloaliphatic, or an optionally substituted monocylic or
bicyclic aryl group optionally containing one or more heteroatoms
selected from oxygen, sulphur or nitrogen atoms, Alk' is an
optionally substituted straight or branched alkylene, alkenylene or
alkynylene chain optionally interrupted by one or more L.sup.1
atoms or groups [where L.sup.1 is a linker atom or group] and n is
zero or the integer 1; or is (3) X.sup.aR' where R' Ar' or is an
optionally substituted polycycloalkyl or polycycloalkenyl group
optionally containing one or more --O--, or --S-- atoms or
--N(R.sup.b)-- groups; Z is a group (A), (B), (C) or (D): 38wherein
Ar is a monocyclic or bicyclic aryl group optionally containing one
or more heteroatoms selected from oxygen, sulphur or nitrogen
atoms; Z' is a group --NR.sup.12C(O)--[where R.sup.12 is a hydrogen
atom or an optionally substituted alkyl or (Alk).sub.tAr group],
--C(O)NR.sup.12--, --NR.sup.12C(S)--, --C(S)NR.sup.12--,
--C.ident.C--, --NR.sup.12SO.sub.2--, or --SO.sub.2NR.sup.12--; Alk
is an optionally substituted straight or branched alkyl chain
optionally interrupted by an atom or group X; t is zero or an
integer of value 1, 2 or 3; R.sup.3 is a hydrogen or a fluorine
atom or an optionally substituted straight or branched alkyl group
or an OR.sup.11 group (where R.sup.11 is a hydrogen atom or an
optionally substituted alkyl, alkenyl, alkoxyalkyl, alkanoyl,
formyl, carboxamido or thiocarboxamido group]; R.sup.4 is a
hydrogen atom or an optionally substituted alkyl, --CO.sub.2R8,
--CSNR.sup.9R.sup.10, --CN, --CH.sub.2CN, or --(CH.sub.2).sub.tAr
group where t is zero or an integer of value 1, 2 or 3 and Ar is a
monocyclic or bicyclic aryl group optionally containing one or more
heteroatoms selected from oxygen, sulphur or nitrogen atoms,
provided that when L is a group of type (2) or (3) above then Z is
a group of type (A) or type (B) in which R.sup.4 is a
--(CH.sub.2).sub.tAr group; R.sup.5 is a group
--(CH.sub.2).sub.tAr; R.sup.6 is a hydrogen or a fluorine atom, or
an optionally substituted alkyl or --CO.sub.2R8,
--CONR.sup.9R.sup.10, --CSNR.sup.9R.sup.10, --CN or --CH.sub.2CN
group; R.sup.7 is a hydrogen or a fluorine atom, an optionally
substituted straight or branched alkyl group, or an OR.sup.c group
where R.sup.c is a hydrogen atom or an optionally substituted alkyl
or alkenyl group, alkoxyalkyl, alkanoyl, formyl, carboxamido or
thiocarboxamido group; and the salts, solvates, hydrates, prodrugs
and N-oxides thereof.
2. A compound according to claim 1 wherein W is a .dbd.C(XRa)--
group.
3. A compound according to claim 2 wherein L is a
--C(R).dbd.C(R.sup.1)(R.- sup.2) group in which R.sup.1 and
R.sup.2, together with the C atom to which they are attached are
linked to form a cycloalkyl group.
4. A compound according to claim 1 wherein Z is a group (A) or (B),
in which R.sup.3, R.sup.6 and R.sup.7 is each a hydrogen atom,
R.sup.4 is an aryl group and R.sup.5 is a heteroaryl group.
5. A compound according to claim 4 wherein R.sup.4 is an optionally
substituted phenyl group and R.sup.5 is an optionally substituted
pyridyl group.
6. A compound which is:
4-{2-[4-Methoxy-3-(phenylpentyloxy)phenyl]-2-pheny-
lethyl}pyridine;
4-[2-(4-Methoxy-3-(3-thienyloxy)phenyl)-2-phenylethyl]pyr- idine;
4-{2-[3-(4-Biphenyloxy)-4-methoxyphenyl)-2-phenyl]ethyl}pyridine;
4-[2-(3-((2RS)-exo-Bicyclo[2.2.1
]hept-2-yloxy)-4-methoxyphenyl)-2-phenyl- ethyl]pyridine;
3-(3-Cyclopentylidenyl-4-methoxyphenyl)pyridine; the resolved
enantiomer; and the salts, solvates, hydrates, prodrugs and
n-oxides thereof
7. A pharmaceutical composition comprising a compound of formula
(1) 39wherein .dbd.W-- is (1) .dbd.C(Y)-- where Y is a halogen
atom, or an alkyl or --XR.sup.a group where X is --O--,
--S(O).sub.m--[where m is zero or an integer of value 1 or 2], or
--N(R.sup.b)--[where R.sup.b is a hydrogen atom or an optionally
substituted alkyl group] and R.sup.a is a hydrogen atom or an
optionally substituted alkyl group or, (2) .dbd.N--; L is (1) a
--C(R).dbd.C(R.sup.1)(R.sup.2) or [--CH(R)].sub.nCH(R.sup.1)(R-
.sup.2) group where R is a hydrogen or a fluorine atom or a methyl
group, and R.sup.1 and R.sup.2, which may be the same or different,
is each a hydrogen or fluorine atom or an optionally substituted
alkyl, alkenyl, alkynyl, alkoxy, alkylthio, --CO.sub.2R.sup.8
[where R.sup.8 is a hydrogen atom or an optionally substituted
alkyl, aralkyl or aryl group], --CONR.sup.9R.sup.10 [where R.sup.9
and R.sup.10, which may be the same or different are defined for
R.sup.8], --CSNR.sup.9R.sup.10,--CN or --NO.sub.2 group, or R.sup.1
and R.sup.2, together with the C atom to which they are attached
are linked to form an optionally substituted cycloalkyl,
cycloalkenyl or heterocycloaliphatic group and n is zero or the
integer 1; or is (2)--(X.sup.a).sub.nAlk'Ar', or -Alk'X.sup.aAr'
where X.sup.a is a group X, Ar' is an optionally substituted
heterocycloaliphatic, or an optionally substituted monocylic or
bicyclic aryl group optionally containing one or more heteroatoms
selected from oxygen, sulphur or nitrogen atoms, Alk' is an
optionally substituted straight or branched alkylene, alkenylene or
alkynylene chain optionally interrupted by one or more L.sup.1
atoms or groups [where L.sup.1 is a linker atom or group] and n is
zero or the integer 1; or is (3) X.sup.aR' where R' is Ar' or is an
optionally substituted polycycloalkyl or polycycloalkenyl group
optionally containing one or more --O--, or --S-- atoms or
--N(R.sup.b)-- groups; Z is a group (A), (B), (C) or (D): 40wherein
Ar is a monocyclic or bicyclic aryl group optionally containing one
or more heteroatoms selected from oxygen, sulphur or nitrogen
atoms; Z.sup.1 is a group --NR.sup.12C(O)--[where R.sup.12 is a
hydrogen atom or an optionally substituted alkyl or (Alk).sub.tAr
group], --C(O)NR.sup.12--, --NR.sup.12C(S)--, --C(S)NR.sup.12--,
--C.ident.C--, --NR.sup.12SO.sub.2--, or --SO.sub.2NR.sup.12--; Alk
is an optionally substituted straight or branched alkyl chain
optionally interrupted by an atom or group X; t is zero or an
integer of value 1, 2 or 3; R.sup.3 is a hydrogen or a fluorine
atom or an optionally substituted straight or branched alkyl group
or an OR.sup.11 group [where R.sup.11 is a hydrogen atom or an
optionally substituted alkyl, alkenyl, alkoxyalkyl, alkanoyl,
formyl, carboxamido or thiocarboxamido group]; R.sup.4 is a
hydrogen atom or an optionally substituted alkyl,
--CO.sub.2R.sup.8, --CSNR.sup.9R.sup.10, --CN, --CH.sub.2CN, or
--(CH.sub.2).sub.tAr group where t is zero or an integer of value
1, 2 or 3 and Ar is a monocyclic or bicyclic aryl group optionally
containing one or more heteroatoms selected from oxygen, sulphur or
nitrogen atoms, provided that when L is a group of type (2) or (3)
above then Z is a group of type (A) or type (B) in which R.sup.4 is
a --(CH.sub.2).sub.tAr group; R.sup.5 is a group
--(CH.sub.2).sub.tAr; R.sup.6 is a hydrogen or a fluorine atom, or
an optionally substituted alkyl or --CO.sub.2R.sup.8,
--CONR.sup.9R.sup.10, --CSNR.sup.9R.sup.10, --CN or --CH.sub.2CN
group; R.sup.7 is a hydrogen or a fluorine atom, an optionally
substituted straight or branched alkyl group, or an OR.sup.c group
where R.sup.c is a hydrogen atom or an optionally substituted alkyl
or alkenyl group, alkoxyalkyl, alkanoyl, formyl, carboxamido or
thiocarboxamido group; and the salts, solvates, hydrates, prodrugs
and N-oxides thereof; together with one or more pharmaceutically
acceptable carriers, excipients or diluents.
8. A process for the preparation of a compound of formula (1)
41wherein .dbd.W-- is (1) .dbd.C(Y)-- where Y is a halogen atom, or
an alkyl or --XR.sup.a group where X is --O--, --S(O).sub.m--[where
m is zero or an integer of value 1 or 2], or --N(R.sup.b)--[where
R.sup.b is a hydrogen atom or an optionally substituted alkyl
group] and R.sup.a is a hydrogen atom or an optionally substituted
alkyl group or, (2) .dbd.N--; L is (1) a
--C(R).dbd.C(R.sup.1)(R.sup.2) or
[--CH(R)].sub.nCH(R.sup.1)(R.sup.2) group where R is a hydrogen or
a fluorine atom or a methyl group, and R.sup.1 and R.sup.2, which
may be the same or different, is each a hydrogen or fluorine atom
or an optionally substituted alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, --C02R8 [where R8 is a hydrogen atom or an optionally
substituted alkyl, aralkyl or aryl group], --CONR.sup.9R.sup.10
[where R.sup.9 and R.sup.10, which may be the same or different are
defined for R.sup.8], --CSNR.sup.9R.sup.10,--CN or --NO.sub.2
group, or R.sup.1 and R.sup.2, together with the C atom to which
they are attached are linked to form an optionally substituted
cycloalkyl, cycloalkenyl or heterocycloaliphatic group and n is
zero or the integer 1; or is (2)--(X.sup.a).sub.nAlk'Ar', or
-Alk'X.sup.aAr' where X.sup.a is a group X, Ar' is an optionally
substituted heterocycloaliphatic, or an optionally substituted
monocylic or bicyclic aryl group optionally containing one or more
heteroatoms selected from oxygen, sulphur or nitrogen atoms, Alk'
is an optionally substituted straight or branched alkylene,
alkenylene or alkynylene chain optionally interrupted by one or
more L.sup.1 atoms or groups [where L.sup.1 is a linker atom or
group] and n is zero or the integer 1; or is (3) X.sup.aR' where R'
is Ar' or is an optionally substituted polycycloalkyl or
polycycloalkenyl group optionally containing one or more --O--, or
--S-- atoms or --N(R.sup.b)-- groups; Z is a group (A), (B), (C) or
(D): 42wherein Ar is a monocyclic or bicyclic aryl group optionally
containing one or more heteroatoms selected from oxygen, sulphur or
nitrogen atoms; Z.sup.1 is a group --NR.sup.12C(O)--[where R.sup.12
is a hydrogen atom or an optionally substituted alkyl or
(Alk).sub.tAr group], --C(O)NR.sup.12--, --NR.sup.12C(S)--,
--C(S)NR.sup.12--, --C.ident.C--, --NR.sup.12SO.sub.2--, or
--SO.sub.2NR.sup.12--; Alk is an optionally substituted straight or
branched alkyl chain optionally interrupted by an atom or group X;
t is zero or an integer of value 1, 2 or 3; R.sup.3 is a hydrogen
or a fluorine atom or an optionally substituted straight or
branched alkyl group or an OR.sup.11 group [where R.sup.11 is a
hydrogen atom or an optionally substituted alkyl, alkenyl,
alkoxyalkyl, alkanoyl, formyl, carboxamido or thiocarboxamido
group]; R.sup.4 is a hydrogen atom or an optionally substituted
alkyl, --CO.sub.2R.sup.8, --CSNR.sup.9R.sup.10, --CN, --CH.sub.2CN,
or --(CH.sub.2).sub.tAr group where t is zero or an integer of
value 1, 2 or 3 and Ar is a monocyclic or bicyclic aryl group
optionally containing one or more heteroatoms selected from oxygen,
sulphur or nitrogen atoms, provided that when L is a group of type
(2) or (3) above then Z is a group of type (A) or type (B) in which
R.sup.4 is a --(CH.sub.2).sub.tAr group; R.sup.5 is a group
--(CH.sub.2).sub.tAr; R.sup.6 is a hydrogen or a fluorine atom, or
an optionally substituted alkyl or --CO.sub.2R.sup.8,
--CONR.sup.9R.sup.10, --CSNR.sup.9R.sup.1, --CN or --CH.sub.2CN
group; R.sup.7 is a hydrogen or a fluorine atom, an optionally
substituted straight or branched alkyl group, or an OR.sup.c group
where R.sup.c is a hydrogen atom or an optionally substituted alkyl
or alkenyl group, alkoxyalkyl, alkanoyl, formyl, carboxamido or
thiocarboxamido group; and the salts, solvates, hydrates, prodrugs
and N-oxides thereof; which comprises in a final step: a) coupling
a compound of formula (3) 43i) where L.sup.2 is a group X.sup.aH
with a reagent L.sup.3Alk'Ar', or L.sup.3R' in which L.sup.3 is a
leaving group; or ii) where L.sup.2 is a group -Alk'L.sup.3 with a
reagent Ar'X.sup.aH; b) reacting a compound of formula (12) 44
where R.sup.4 is a hydrogen atom, or an alkyl or
--(CH.sub.2).sub.tAr group with a phosphonate ester to give a
compound of formula (1) wherein Z is a group (B); c) coupling a
compound of formula (18) 45 with an organopalladium compound to
give a compound of formula (1) wherein Z is a group (B); d)
reacting a compound of formula (19) 46 with an organometallic
reagent followed by dehydration of the corresponding alcohol to
give a compound of formula (1) wherein L is a group
--C(R).dbd.CH(R.sup.1); e) decarboxylating an acid of formula (21)
47 to give a compound of formula (1) wherein R.sup.3, R.sup.6 and
R.sup.7 is each a hydrogen atom; f) cyclisation of a compound of
formula (23) 48 where R.sup.16 is a carboxylic acid (CO.sub.2H) or
a reactive derivative thereof; or a nitrile (-CN) or an imine salt
with a bifunctional reagent W.sup.1R.sup.5aW.sup.2 and, where
necessary, a compound R.sup.5bW.sup.3 [where W.sup.1, W.sup.2 and
W.sup.3, which may be the same or different, is each a reactive
functional group or a protected derivative thereof; and R.sup.5a
and R.sup.5bare components of the heteroaryl group R.sup.5 such
that when added together with WI, W.sup.2 and W.sup.3 to the group
R.sup.16 in compounds of formula (19) the resulting group
--RW.sup.1R.sup.5aW.sup.2 or
--RW.sup.1R.sup.5aW.sup.2R.sup.5bW.sup.3 constitutes the heteroaryl
group R.sup.5]; to give a compound of formula (1) wherein R.sup.3,
R.sup.6 and R.sup.7 is each a hydrogen atom and R.sup.5 is a
heteroaryl group to give a compound of formula (1) wherein R.sup.3,
R.sup.6 and R.sup.7 is each a hydrogen atom and R.sup.5 is a
heteroaryl group; g) coupling a compound of formula (25) 49 where E
is a boronic acid --B(OH).sub.2 or a tin reagent Sn(R).sub.3, in
which R is an alkyl group with a reagent Z-L.sup.4, where L.sup.4
is a leaving group, in the presence of a complex metal catalyst; to
give a compound of formula (1) wherein Z is a group (C); h)
coupling a compound of formula (26) 50 where A is a --CO.sub.2H or
--NHR.sup.12 group, or an active derivative thereof with a compound
R.sup.12NH(Alk.sub.t(Xn)Ar or Ar(X).sub.nAlk).sub.tCO.sub.2H or an
active derivative thereof to give a compound of formula (1) wherein
Z is a group (D) in which --Z.sup.1 is --NR.sup.12C(O)-- or
--C(O)NR.sup.12--; i) reacting a compound of formula (29) 51 with a
reagent Ar(X).sub.n(Alk).sub.tL.sup.5 in which L.sup.5 is a leaving
group to give a compound of formula (1) wherein Z.sup.1 is a
--C.dbd.C-chain; j) reacting a compound of formula (30) 52 where
(i) W.sup.b is a --NHR.sup.12 group with a compound
Ar(X).sub.n(Alk).sub.tSO.- sub.2Hal (where Hal is a halogen atom);
or (ii) W.sup.b is a --SO.sub.2Hal group with a compound
Ar(X).sub.n(Alk).sub.tNHR.sup.12 to give a compound of formula (1)
wherein Z.sup.1 is a --NR.sup.12SO.sub.2-- or --SO.sub.2NR.sup.12--
group; k) reacting a compound of formula (31) 53 where Hall is a
halogen atom where a diazoalkane to give a compound of formula (1)
where L is a --CH(R.sup.1)(R.sup.2)group in which R.sup.2 is a
--CO.sub.2H group; or l) interconverting a compound of formula (1)
to another compound of formula (1).
Description
[0001] This invention relates to a novel series of tri-substituted
phenyl derivatives, to processes for their preparation, to
pharmaceutical compositions containing them, and to their use in
medicine.
[0002] Many hormones and neurotransmitters modulate tissue function
by elevating intra-cellular levels of adenosine 3', 5'-cyclic
monophosphate (cAMP). The cellular levels of cAMP are regulated by
mechanisms which control synthesis and breakdown. The synthesis of
cAMP is controlled by adenyl cyclase which may be directly
activated by agents such as forskolin or indirectly activated by
the binding of specific agonists to cell surface receptors which
are coupled to adenyl cyclase. The breakdown of cAMP is controlled
by a family of phosphodiesterase (PDE) isoenzymes, which also
control the breakdown of guanosine 3',5'-cyclic monophosphate
(cGMP). To date, seven members of the family have been described
(PDE I-VII) the distribution of which varies from tissue to tissue.
This suggests that specific inhibitors of PDE isoenzymes could
achieve differential elevation of cAMP in different tissues, [for
reviews of PDE distribution, structure, function and regulation,
see Beavo & Reifsnyder (1990) TIPS, 11: 150-155 and Nicholson
et al (1991) TIPS, 12: 19-27].
[0003] There is clear evidence that elevation of cAMP in
inflammatory leukocytes leads to inhibition of their activation.
Furthermore, elevation of cAMP in airway smooth muscle has a
spasmolytic effect. In these tissues, PDE IV plays a major role in
the hydrolysis of cAMP. It can be expected, therefore, that
selective inhibitors of PDE IV would have therapeutic effects in
inflammatory diseases such as asthma, by achieving both
anti-inflammatory and bronchodilator effects.
[0004] The design of PDE IV inhibitors has met with limited success
to date, in that many of the potential PDE IV inhibitors which have
been synthesised have lacked potency and/or have been capable of
inhibiting more than one type of PDE isoenzyme in a non-selective
manner. Lack of a selective action has been a particular problem
given the widespread role of cAMP in viva and what is needed are
potent selective PDE IV inhibitors with an inhibitory action
against PDE IV and little or no action against other PDE
isoenzymes.
[0005] We have now found a novel series of tri-substituted phenyl
derivatives, members of which are potent inhibitors of PDE IV at
concentrations at which they have little or no inhibitory action on
other PDE isoenzymes. These compounds inhibit the human recombinant
PDE IV enzyme and also elevate cAMP in isolated leukocytes. The
compounds of the invention are therefore of use in medicine,
especially in the prophylaxis and treatment of asthma.
[0006] Thus according to one aspect of the invention, we provide a
compound of formula (1) 3
[0007] wherein
[0008] .dbd.W-- is (1) .dbd.C(Y)-- where Y is a halogen atom, or an
alkyl or --XR.sup.a group where X is --O--, --S(O).sub.m--[where m
is zero or an integer of value 1 or 2], or --N(R.sup.b)--[where
R.sup.b is a hydrogen atom or an optionally substituted alkyl
group] and R.sup.a is a hydrogen atom or an optionally substituted
alkyl group or, (2) .dbd.N--;
[0009] L is (1) a --C(R).dbd.C(R.sup.1)(R.sup.2) or
[--CH(R)].sub.nCH(R.sup.1)(R.sup.2) group where R is a hydrogen or
a fluorine atom or a methyl group, and R.sup.1 and R.sup.2, which
may be the same or different, is each a hydrogen or fluorine atom
or an optionally substituted alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, --CO.sub.2R.sup.8 [where R.sup.8 is a hydrogen atom or
an optionally substituted alkyl, aralkyl or aryl group],
--CONR.sup.9R.sup.10 [where R.sup.9 and R.sup.10, which may be the
same or different are defined for R.sup.8],
--CSNR.sup.9R.sup.10,--CN or --NO.sub.2 group, or R.sup.1 and
R.sup.2, together with the C atom to which they are attached are
linked to form an optionally substituted cycloalkyl, cycloalkenyl
or heterocycloaliphatic group and n is zero or the integer 1; or is
(2)--(X.sup.a).sub.nAlk'Ar', or -Alk'X.sup.aAr' where X.sup.a is a
group X, Ar' is an optionally substituted heterocycloaliphatic, or
an optionally substituted monocylic or bicyclic aryl group
optionally containing one or more heteroatoms selected from oxygen,
sulphur or nitrogen atoms, Alk' is an optionally substituted
straight or branched alkylene, alkenylene or alkynylene chain
optionally interrupted by one or more L.sup.1 atoms or groups
[where L.sup.1 is a linker atom or group] and n is zero or the
integer 1; or is (3) X.sup.aR' where R' is Ar' or is an optionally
substituted polycycloalkyl or polycycloalkenyl group optionally
containing one or more --O--, or --S-- atoms or --N(R.sup.b)--
groups;
[0010] Z is a group (A), (B), (C) or (D): 4
[0011] wherein
[0012] Ar is a monocyclic or bicyclic aryl group optionally
containing one or more heteroatoms selected from oxygen, sulphur or
nitrogen atoms;
[0013] Z.sup.1 is a group --NR.sup.12C(O)--[where R.sup.12 is a
hydrogen atom or an optionally substituted alkyl or (Alk).sub.tAr
group], --C(O)NR.sup.12--, --NR.sup.12C(S)--, --C(S)NR.sup.12--,
--C.ident.C--, --NR.sup.12SO.sub.2--, or --SO.sub.2NR.sup.12--;
[0014] Alk is an optionally substituted straight or branched alkyl
chain optionally interrupted by an atom or group X;
[0015] t is zero or an integer of value 1, 2 or 3;
[0016] R.sup.3 is a hydrogen or a fluorine atom or an optionally
substituted straight or branched alkyl group or an OR.sup.11 group
[where R.sup.11 is a hydrogen atom or an optionally substituted
alkyl, alkenyl, alkoxyalkyl, alkanoyl, formyl, carboxamido or
thiocarboxamido group];
[0017] R.sup.4 is a hydrogen atom or an optionally substituted
alkyl, --CO.sub.2R.sup.8, --CSNR.sup.9R.sup.10, --CN, --CH.sub.2CN,
or --(CH.sub.2).sub.tAr group where t is zero or an integer of
value 1, 2 or 3 and Ar is a monocyclic or bicyclic aryl group
optionally containing one or more heteroatoms selected from oxygen,
sulphur or nitrogen atoms, provided that when L is a group of type
(2) or (3) above then Z is a group of type (A) or type (B) in which
R.sup.4 is a --(CH.sub.2).sub.tAr group;
[0018] R.sup.5 is a group --(CH.sub.2).sub.tAr;
[0019] R.sup.6 is a hydrogen or a fluorine atom, or an optionally
substituted alkyl or --CO.sub.2R.sup.8, --CONR.sup.9R.sup.10,
--CSNR.sup.9R.sup.10, --CN or --CH.sub.2CN group;
[0020] R.sup.7 is a hydrogen or a fluorine atom, an optionally
substituted straight or branched alkyl group, or an OR.sup.c group
where R.sup.c is a hydrogen atom or an optionally substituted alkyl
or alkenyl group, alkoxyalkyl, alkanoyl, formyl, carboxamido or
thiocarboxamido group; and the salts, solvates, hydrates, prodrugs
and N-oxides thereof.
[0021] It will be appreciated that certain compounds of formula (1)
may have one or more chiral centres, depending on the nature of the
groups Alk, R.sup.1, R.sup.2, R.sup.3 R.sup.4, R.sup.5, R.sup.6 and
R.sup.7. Where one or more chiral centres is present, enantiomers
or diastereomers may exist, and the invention is to be understood
to extend to all such enantiomers, diastereomers and mixtures
thereof, including racemates.
[0022] Compounds of formula (1) in which L is a
--C(R).dbd.C(R.sup.1)(R.su- p.2) group and/or Z is the group (B),
may exist as geometric isomers depending on the nature of the
groups R, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.6, and the
invention is to be understood to extend to all such isomers and
mixtures thereof.
[0023] In the compounds of formula (1), when .dbd.W-- is
.dbd.C(Y)-- and Y is a halogen atom Y may be for example a
fluorine, chlorine, bromine or iodine atom.
[0024] When W in the compounds of formula (1) is a group
.dbd.C(Y)-- and Y is --XR.sup.a, R.sup.a may be, for example, a
hydrogen atom or an optionally substituted straight or branched
alkyl group, for example, an optionally substituted C.sub.1-6alkyl
group, such as a methyl, ethyl, n-propyl or 1-propyl group.
Optional substituents which may be present on R.sup.a groups
include one or more halogen atoms, e.g. fluorine, or chlorine
atoms. Particular R.sup.a groups include for example --CH.sub.2F,
--CH.sub.2Cl, --CHF.sub.2, --CHCl.sub.2, --CF.sub.3 or --CCl.sub.3
groups.
[0025] When .dbd.W-- in the compounds of formula (1) is a group
.dbd.C(Y)-- where --Y is --N(R.sup.b), .dbd.W-- may be a
.dbd.C(NH.sub.2)--, .dbd.C(NHCH.sub.3)-- or
.dbd.C(NHC.sub.2H.sub.5)-- group.
[0026] In compounds of formula (1), X may be an oxygen or a sulphur
atom, or a group --S(O)--, --S(O).sub.2--, --NH-- or C.sub.1-6
alkylamino, for example a C.sub.1-3 alkylamino, e.g. methylamino
[--N(CH.sub.3)--] or ethylamino [--N(C.sub.2H.sub.5)-] group.
[0027] Alkyl groups represented by Y, R.sup.1, R.sup.2 or R.sup.b
in the compounds of formula (1) include optionally substituted
straight or branched C.sub.1-6 alkyl groups optionally interrupted
by one or more X atoms or groups. Particular examples include
C.sub.1-3 alkyl groups such as methyl, ethyl, n-propyl or i-propyl
groups. Optional substituents on these groups include one, two or
three substituents selected from halogen atoms, e.g. fluorine,
chlorine, bromine or iodine atoms, or hydroxyl or C.sub.1-6 alkoxy
e.g. C.sub.1-3 alkoxy such as methoxy or ethoxy or
--CO.sub.2R.sup.8, --CONR.sup.9R.sup.10, --CSNR.sup.9R.sup.1l or
--CN groups. Particular substituted alkyl groups include for
example --CH.sub.2F, --CH.sub.2Cl, --CHF.sub.2, CHCl.sub.2,
--CH.sub.3 or --CCl.sub.3 groups.
[0028] Alkenyl groups represented by R.sup.1 or R.sup.2 in the
compounds of formula (1) include optionally substituted straight or
branched C.sub.2-6alkenyl groups optionally interrupted by one or
more X atoms or groups. Particular examples include ethenyl,
propen-1-yl and 2-methylpropen-1-yl groups. Optional substituents
include those described above in relation to alkyl groups
represented by the groups R.sup.1 or R.sup.2.
[0029] Alkynyl groups represented by R.sup.1 or R.sup.2 in
compounds of formula (1) include optionally substituted straight or
branched C.sub.2-6alkynyl groups optionally interrupted by one or
more X atoms or groups. Particular examples include ethynyl and
propyn-1-yl groups. Optional substituents include those described
above in relation to alkyl groups represented by the groups R.sup.1
or R.sup.2.
[0030] When R.sup.1 or R.sup.2 in compounds of formula (1) is an
alkoxy or alkylthio group it may be for example an optionally
substituted C.sub.1-6alkoxy or C.sub.1-6alkylthio group optionally
interrupted by one or more X atoms or groups. Particular examples
include C.sub.1-3alkoxy, e.g. methoxy or ethoxy, or
C.sub.1-3alkylthio e.g. methylthio or ethylthio groups. Optional
substituents include those described above in relation to alkyl
groups represented by the groups R.sup.1 or R.sup.2.
[0031] When R.sup.1 and R.sup.2 together with the carbon atom to
which they are attached in the compounds of formula (1) are linked
to form a cycloalkyl or cycloalkenyl group, the group may be for
example a C.sub.3-8cycloalkyl group such as a cyclobutyl,
cyclopentyl or cyclohexyl group or a C.sub.3-8 cycloalkenyl group
containing for example one or two double bonds such as a
2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl,
2,4-cyclopentadien-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl,
2,4-cyclohexadien-1-yl or 3,5-cyclohexadien-1-yl group, each
cycloalkyl or cycloalkenyl group being optionally substituted by
one, two or three substituents selected from halogen atoms, e.g.
fluorine, chlorine, bromine or iodine atoms, straight or branched
C.sub.1-6alkyl e.g. C.sub.1-3alkyl such as methyl or ethyl,
hydroxyl or C.sub.1-6alkoxy e.g. C.sub.1-3alkoxy such as methoxy or
ethoxy groups. The linker atoms represented by the group L.sup.1
include for example --O-- or --S-- atoms. Particular groups
represented by the linker group L.sup.1 are --S(O)--,
--S(O).sub.2--, --N(R.sup.b)--, --C(O)--, --C(O).sub.2--, --C(S)--,
--C(NR.sup.b)-- --CON(R.sup.b)--, --CSN(R.sup.b)--,
--N(R.sup.b)CO--, --N(R.sup.b)CS--, --SON(R.sup.b)--,
--S.sub.2N(R.sup.b)--, N(R.sup.b)SO-, --N(R.sup.b)SO.sub.2--,
N(R.sup.b)SO.sub.2N(R.sup.b)--, --N(R.sup.b)SON(R.sup.b)--,
--N(R.sup.b)CON(R.sup.b)-- or --N(R.sup.b)CSN(R.sup.b)-- groups. It
will be appreciated that when the chain Alk is interrupted by two
or more L.sup.1 atoms or groups, such atoms or groups may be
adjacent to one another, for example to form a group
--N(R.sup.b)--C(NR.sup.b)--N(R.sup.b- )-- or --O--CONH--.
[0032] When L is a --(X.sup.a).sub.nAlk'Ar' or Alk'X.sup.aAr' group
where Alk' is an alkylene chain L may be for example an optionally
substituted straight or branched C.sub.1-8alkylene chain optionally
interrupted by one or more L.sup.1 linker atoms or groups.
Particular examples include --CH.sub.2Ar', --(CH.sub.2).sub.2Ar',
--OAr', --SAr', --N(R.sup.b)Ar', --C(O)Ar', --C(S)Ar',
--CON(R.sup.b)Ar', --CSN (R.sup.b)Ar', --SOAr', --SON(R.sup.b)Ar',
--SO.sub.2Ar', --SO.sub.2N(R.sup.b)Ar', OCH.sub.2Ar',
--SCH.sub.2Ar', --N(R.sup.b)CH.sub.2Ar', --CH.sub.2OAr',
--CH.sub.2SAr', --CH.sub.2N(R.sup.b)Ar', --CH.sub.2C(O)Ar',
--CH.sub.2C(S)Ar', --CH.sub.2CON(R.sup.b)Ar',
--CH.sub.2CSN(R.sup.b)Ar', --CH.sub.2SOAr', --CH.sub.2 SO.sub.2Ar',
--(CH.sub.2).sub.2OCH.sub.2Ar', --(CH.sub.2).sub.2SCH.sub.2Ar',
--(CH.sub.2).sub.2SOCH.sub.2Ar',
--(CH.sub.2).sub.2SO.sub.2CH.sub.2Ar', --(CH.sub.2).sub.3Ar',
--O(CH.sub.2).sub.3Ar', --S(CH.sub.2).sub.3Ar',
--N(R.sup.b)(CH.sub.2).su- b.3Ar', --SO(CH.sub.2).sub.3Ar',
--SO.sub.2(CH.sub.2).sub.3Ar', --(CH.sub.2).sub.3OAr',
--(CH.sub.2).sub.3SAr', --(CH.sub.2).sub.3N(R.sup- .b)Ar',
--(CH.sub.2).sub.3SOAr' or --(CH.sub.2).sub.3SO.sub.2Ar' group.
Optional substituents on these groups include those mentioned above
in relation to the alkyl groups represented by Y, R.sup.1, R.sup.2
or R.sup.b.
[0033] When L is a --(X.sup.a).sub.nAlk'Ar' or Alk'X.sup.aAr' group
where Alk' is an alkenylene chain it may be an optionally
substituted straight or branched mono or polyunsaturated
C.sub.2-8alkenylene chain optionally interrupted by one or more
L.sup.1 linker atoms or groups. Particular examples include
--(CH.dbd.CH)Ar', --CH.dbd.CH--CH.sub.2Ar',
--CH.sub.2--CH.dbd.CHAr', --CH.dbd.CH--CH.sub.2Ar',
--CH.sub.2--CH.dbd.CHAr', --OCH.dbd.CH--CH.sub.2Ar',
--OCH.sub.2--CH.dbd.CHAr', --SCH.dbd.CH--CH.sub.2Ar',
--SCH.sub.2--CH.dbd.CHAr', --N(R.sup.b)CH.dbd.CH--CH.sub.2Ar',
--CH.dbd.CH--CH.sub.2--OAr', --CH.sub.2--CH.dbd.CH.sub.2--OAr' or
--CH.dbd.CH--CH.dbd.CHAr' group. Optional substituents on these
groups include those mentioned above in relation to the alkyl
groups represented by Y, R.sup.1, R.sup.2 or R.sup.b.
[0034] When L is a (X.sup.a).sub.nAlk'Ar' or Alk'X.sup.aAr' group
where Alk' is an alkynylene chain, it may be an optionally
substituted straight or branched mono or polyunsaturated
C.sub.2-8alkynylene chain optionally interrupted by one or more
L.sup.1 linker atoms or groups. Particular examples include
--C.ident.CAr', --C.ident.C--CH.sub.2Ar',
--CH.sub.2--C.ident.C--Ar', --OC--C--CH.sub.2Ar',
--OCH.sub.2--C.ident.CA- r', --SC.ident.C--CH.sub.2Ar',
--SCH.sub.2--C.ident.CAr', --N(R.sup.b)C.ident.C--CH.sub.2Ar',
--N(R.sup.b)CH.sub.2--C.ident.CAr', --C.ident.C--CH.sub.2OAr',
--CH.sub.2--C.ident.COAr', --C.ident.C--CH.sub.2SAr',
--CH.sub.2--C=--CSAr', --CH.sub.2--C.ident.CN(- R.sup.b)Ar' or
C=--C--CH.sub.2N(R.sup.b)Ar' group. Optional substituents on these
groups include those mentioned above in relation to the alkyl
groups represented by Y, R.sup.1, R.sup.2 or R.sup.b.
[0035] When R.sup.1 and R.sup.2, together with the C atom to which
they are attached are linked to form an optionally substituted
heterocycloaliphatic group, and/or when Ar' is a
heterocycloaliphatic group, the group may be for example an
optionally substituted C.sub.3-8 cycloalkyl or C.sub.3-8
cycloalkenyl group containing one or more --O--, or --S-- atoms, or
--N(R.sup.b)-- groups such as a pyrrolidinyl, dioxolanyl, e.g.
1,3-dioxolanyl, imidazolidinyl, pyrazolidinyl, piperidinyl,
1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl,
piperazinyl, 1,3,5-trithianyl, 3-pyrrolinyl, 2-imidazolinyl, or
2-pyrazolinyl group. Optional substituents which may be present on
such groups include one, two or three substituents selected from
halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms,
straight or branched C.sub.1-6 alkyl e.g. C.sub.1-3 alkyl such as
methyl or ethyl, hydroxyl or C.sub.1-6 alkoxy e.g. C.sub.1-3 alkoxy
such as methoxy or ethoxy groups.
[0036] Polycycloalkyl groups represented by R' in compounds of
formula (1) include optionally substituted C6-10 polycycloalkyl,
e.g. bicycloalkyl or tricycloalkyl groups optionally containing
one, two or more --O-- or --S-- atoms or --N(R.sup.b)-- groups.
Polycycloalkenyl groups represented by Ar' include optionally
substituted C.sub.6-10 polycycloalkenyl, e.g. bicycloalkenyl or
tricycloalkenyl groups optionally containing one, two or more --O--
or --S-- atoms or --N(R.sup.b) groups. The degree of unsaturation
of polycycloalkenyl groups may be varied widely and the term is to
be understood to include groups with one, two, three or more
--CH.dbd.CH-- groups. Optional substituents which may be present on
such groups include those mentioned above in relation to the Ar'
group when Ar' is a heterocycloaliphatic group.
[0037] When the group R.sup.7 in compounds of formula (1) is an
OR.sup.c group it may be for example a hydroxyl group; or a group
--OR.sup.c where R.sup.c is an optionally substituted straight or
branched C.sub.1-6alkyl group, e.g. a C.sub.1-3alkyl group such as
a methyl or ethyl group, a C.sub.2-6alkenyl group such as an
ethenyl or 2-propen-1-yl group, a C.sub.1-3alkoxyC.sub.1-3alkyl
group such as a methoxymethyl, ethoxymethyl or ethoxyethyl group, a
C.sub.1-6alkanoyl, e.g. C.sub.1-3alkanoyl group such as an acetyl
group, or a formyl [HC(O)--], carboxamido (CONR.sup.13R.sup.13a) or
thiocarboxamido (CSNR.sup.13R.sup.13a) group, where R.sup.13 and
R.sup.13a in each instance may be the same or different and is each
a hydrogen atom or an optionally substituted straight or branched
C.sub.1-6alkyl, e.g. C.sub.1-3alkyl group such as methyl or ethyl
group. Optional substituents which may be present on such R.sup.c,
R.sup.13 or R.sup.13a groups include those described below in
relation to the alkyl groups R.sup.3, R.sup.4, R.sup.6, R.sup.7 and
R.sup.12.
[0038] Alkyl groups represented by R.sup.3, R.sup.4, R.sup.6,
R.sup.7 or R.sup.12 in compounds of formula (1) include optionally
substituted straight or branched C.sub.1-6 alkyl groups, e.g.
C.sub.1-3 alkyl groups such as methyl, ethyl, n-propyl or 1-propyl
groups. Optional substituents which may be present on these groups
include one or more halogen atoms, e.g. fluorine, chlorine, bromine
or iodine atoms, or hydroxyl or C.sub.1-6alkoxy e.g.
C.sub.1-3alkoxy such as methoxy or ethoxy groups.
[0039] When R.sup.1, R.sup.2, R.sup.4 or R.sup.6 is a
--CO.sub.2R.sup.8, --CONR.sup.9R.sup.10 or CSNR.sup.9R.sup.10 group
it may be for example a --CO.sub.2H, --CONH.sub.2 or --CSNH.sub.2
group or a group --CO.sub.2R.sup.8, --CONR.sup.9R.sup.10,
--CSNR.sup.9R.sup.10, --CONHR.sup.10, or --CSNHR.sup.10 where
R.sup.8, R.sup.9 and R.sup.10 where present is a C.sub.1-3alkyl
group such as methyl or ethyl group, a C.sub.6-12aryl group, for
example an optionally substituted phenyl, or a 1-- or 2-- naphthyl
group, or a C.sub.6-12aryl C.sub.1-3alkyl group such as an
optionally substituted benzyl or phenethyl group. Optional
substituents which may be present on these aryl groups include
R.sup.14 substituents discussed below in relation to the group
Ar.
[0040] When the chain Alk is present in compounds of formula (1) it
may be an optionally subtituted straight or branched
C.sub.1-3alkylene chain optionally interrupted by an atom or group
X. Particular examples include --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--, --CH.sub.2OCH.sub.2--, --CH.sub.2SCH.sub.2--,
or --CH.sub.2N(R.sup.b)CH.s- ub.2, e.g. --CH.sub.2NHCH.sub.2-- or
--CH.sub.2N(CH.sub.3)CH.sub.2-- chains. Optional substituents
include those described in relation to the alkyl groups represented
by R.sup.3, R.sup.4, R.sup.6, R.sup.7 and R.sup.12
[0041] In the compounds of formula (1) when the group
--(Alk).sub.t(X).sub.nAr is present it may be a group --Ar,
--CH.sub.2Ar, --(CH.sub.2)2Ar, --(CH.sub.2).sub.3Ar, --CH.sub.2OAr,
--CH.sub.2OCH.sub.2Ar, --CH.sub.2N(R.sup.b)Ar or
--CH.sub.2N(R.sup.b)CH.s- ub.2Ar group.
[0042] Monocyclic or bicyclic aryl groups represented by the group
Ar, Ar', or R' in compounds of formula (1) include for example
C.sub.6-12 optionally substituted aryl groups, for example
optionally substituted phenyl, 1-or 2-naphthyl, indenyl or
isoindenyl groups.
[0043] When the monocyclic or bicyclic aryl group Ar, Ar' or R'
contains one or more heteroatoms it may be for example a C.sub.5-10
optionally substituted heteroaryl group containing for example one,
two, three or four heteroatoms selected from oxygen, sulphur or
nitrogen atoms. In general, Ar heteroaryl groups may be for example
monocyclic or bicyclic heteroaryl groups. Monocyclic heteroaryl
groups include for example five- or six-membered heteroaryl groups
containing one, two, three or four heteroatoms selected from
oxygen, sulphur or nitrogen atoms. Bicyclic heteroaryl groups
include for example nine- or ten-membered heteroaryl groups
containing one, two or more heteroatoms selected from oxygen,
sulphur or nitrogen atoms.
[0044] Examples of heteroaryl groups represented by Ar, Ar' or R'
include pyrrolyl, furyl, thienyl, imidazolyl, N-methylimidazolyl,
N-ethylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl,
pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl,
1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl, isobenzofuryl,
benzothienyl, isobenzothienyl, indolyl, isoindolyl, benzimidazolyl,
benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl,
pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl,
quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8-tetrahydroquinolinyl
and 5,6,7,8-tetrahydroisoquinoli- nyl. Example of bicyclic
heteroaryl groups include quinolinyl or isoquinolinyl groups.
[0045] The heteroaryl group represented by Ar, Ar' or R' may be
attached to the remainder of the molecule of formula (1) through
any ring carbon or heteroatom as appropriate. Thus, for example,
when the group Ar or Ar' is a pyridyl group it may be a 2-pyridyl,
3-pyridyl or 4-pyridyl group. When it is a thienyl group it may be
a 2-thienyl or 3-thienyl group, and, similarly, when it is a furyl
group it may be a 2-furyl or 3-furyl group. In another example,
when the group Ar is a quinolinyl group it may be a 2-, 3-, 4-, 5-,
6-, 7- or 8-quinolinyl and when it is an isoquinolinyl, it may be a
1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl group.
[0046] When in compounds of formula (1) the Ar, Ar' or R' group is
a nitrogen-containing heterocycle it may be possible to form
quaternary salts, for example N-alkyl quaternary salts and the
invention is to be understood to extend to such salts. Thus for
example when the group Ar is a pyridyl group, pyridinium salts may
be formed, for example N-alkylpyridinium salts such as
N-methylpyridinium.
[0047] The aryl or heteroaryl groups represented by Ar, Ar' or R',
in compounds of formula (1) may each optionally be substituted by
one, two, three or more substituents [R.sup.14]. The substituent
R.sup.14 may be selected from an atom or group R.sup.15 or
-Alk.sup.1(R.sup.15).sub.m wherein R.sup.15 is a halogen atom, or
an amino (--NH.sub.2), substituted amino, nitro, cyano, hydroxyl
(--OH), substituted hydroxyl, cycloalkoxy, cycloaliphatic, formyl
[HC(O)--], carboxyl (--CO.sub.2H), esterified carboxyl, thiol
(--SH), substituted thiol, --C(O)R" [where R" is a group Alk.sup.1
where Alk.sup.1 is a straight or branched C.sub.1-6 alkylene,
C.sub.2-6alkenylene, or C.sub.2-6alkynylene chain optionally
interrupted by one, two, or three --O--, or --S-- atoms or
--S(O).sub.z--, (where z is an integer 1 or 2) or --N(R.sup.b)--
groups; or is a group Ar" (where Ar" is as defined for Ar),
--SO.sub.3H, --SO.sub.2R", --SO.sub.2NH.sub.2, --SO.sub.2NHR"
--SO.sub.2N[R"].sub.2, --CONH.sub.2, --CONHR" --CON[R"]2,
--NHSO.sub.2H, --N(R")SO.sub.2H, --NHSO.sub.2R", --NR"SO.sub.2R",
--N[SO.sub.2R"1.sub.2, --NHSO.sub.2NH.sub.2, --NR"SO.sub.2
NH.sub.2, --NHSO.sub.2 NHR", --NR"SO.sub.2NHR",
--NHSO.sub.2NHR"].sub.2, --N(R")SO.sub.2N[R"].sub.2, --NHC(O)R",
--NR"C(O)R", --N[C(O)R"].sub.2, --NHC(O)H, --NR"C(O)H, --NHC(O)OR",
--NR"C(O)OR", --NHC(O)OH, --NR"C(O)OH, --NHCONH.sub.2, --NHCONHR",
--NHCON[R"].sub.2, --NR"CON[R"].sub.2, --C(S)R", --C(S)NH.sub.2,
--C(S)NHR", --C(S)N[R".sub.2, --NHC(S)R", --NR"C(S)R",
-N[[C(S)R"].sub.2, --NHC(S)H, --NR"C(S)H, --NHC(S)NH.sub.2,
--NHC(S)NHR", --NHC(S)N[R"].sub.2, --NR"C(S)N[R"].sub.2, "Ar" or
--XAr" group; and m is zero or an integer 1, 2 or 3.
[0048] When in the group -Alk.sup.1(R.sup.15).sub.m m is an integer
1, 2 or 3, it is to be understood that the substituent or
substituents R.sup.15 may be present on any suitable carbon atom in
-Alk.sup.1. Where more than one R.sup.15 substituent is present
these may be the same or different and may be present on the same
or different carbon atom in Alk.sup.1. Clearly, when m is zero and
no substituent R.sup.15 is present or when Alk.sup.1 forms part of
a group such as --SO.sub.2Alk.sup.1 the alkylene, alkenylene or
alkynylene chain represented by Alk.sup.1 becomes an alkyl, alkenyl
or alkynyl group.
[0049] When R.sup.15 is a substituted amino group it may be a group
--NH[Alk.sup.1(R.sup.15a)m] [where Alk.sup.1 and m are as defined
above and R.sup.15a is as defined above for R.sup.15 but is not a
substituted amino, a substituted hydroxyl or a substituted thiol
group] or a group --N[Alk.sup.1 (R.sup.15a)m]2 wherein each
-Alk.sup.1 (R.sup.15a).sub.m group is the same or different.
[0050] When R.sup.15 is a halogen atom it may be for example a
fluorine, chlorine, bromine, or iodine atom.
[0051] When R.sup.15 is a cycloalkoxy group it may be for example a
C.sub.5-7cycloalkoxy group such as a cyclopentyloxy or
cyclohexyloxy group. When R.sup.15 is a substituted hydroxyl or
substituted thiol group it may be a group
--OAlk.sup.1(R.sup.15a).sub.m or --SAlk.sup.1(R.sup.15a).sub.m
respectively, where Alk.sup.1, R.sup.5a and m are as just
defined.
[0052] Esterified carboxyl groups represented by the group R.sup.15
include groups of formula --CO.sub.2Alk.sup.2 wherein Alk.sup.2 is
a straight or branched, optionally substituted C.sub.1-8alkyl group
such as a methyl, ethyl, n-propyl, 1-propyl, n-butyl, 1-butyl,
s-butyl or t-butyl group; a C.sub.6-12arylC.sub.1-8alkyl group such
as an optionally substituted benzyl, phenylethyl, phenylpropyl,
1-naphthylmethyl or 2-naphthylmethyl group; a C.sub.6-12aryl group
such as an optionally substituted phenyl, 1-naphthyl or 2-naphthyl
group; a C.sub.6-12aryloxyC.sub.1-8alkyl group such as an
optionally substituted phenyloxymethyl, phenyloxyethyl,
1-naphthyloxymethyl, or 2-naphthyloxymethyl group; an optionally
substituted C1-8alkanoyloxyC.sub.6-8alkyl group, such as a
pivaloyloxymethyl, propionyloxyethyl or propionyloxypropyl group;
or a C.sub.6-12aroyloxyC.sub.1-8alkyl group such as an optionally
substituted benzoyloxyethyl or benzoyloxy-propyl group. Optional
substituents present on the Alk.sup.2 group include R.sup.14
substituents described above.
[0053] When the group R.sup.15 in compounds of formulae (1) and (2)
is an optionally substituted C.sub.3-9cycloaliphatic group, it may
be a C.sub.3-9cycloalkyl or C.sub.3-9cycloalkenyl group such as a
C5-7cycloalkyl or C5-7Cycloalkenyl group, containing 1, 2, 3 or
more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
Particular examples of such R.sup.15 groups include pyrrolyl, e.g.
2H-pyrrolyl, pyrrolinyl, e.g. 2-- or 3-pyrrolinyl, pyrrolidinyl,
1,3-dioxolanyl, imidazolinyl, e.g. 2-imidazolinyl, imidazolidinyl,
pyrazolinyl, e.g. 2-pyrazolinyl, pyrazolidinyl, pyranyl, e.g. 2--
or 4-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl,
1,4-dithianyl, thiomorpholinyl, piperazinyl, 1,3,5-trithianyl,
3H-pyrrolyl, 2H-imidazolyl, dithiolyl, e.g. 1,2-- or 1,3-dithiolyl,
oxathiolyl, e.g. 3H-1-2 or 1,3-oxathiolyl, 5H-1,2,5-oxathiozolyl,
1,3-dioxinyl, oxazinyl, e.g. 2H-1,3-, 6H-1,3-, 6H-1,2-,
1,4-2H-1,2-- or 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, isoxazinyl,
e.g. -o- or p- isoxazinyl, oxathiazinyl, e.g. 1,2,5-,
1,2,6-oxathiazinyl, 1,3,5,2-oxadiazinyl, or 1,2,4-diazepinyl
groups. Optional substituents which may be present on such groups
include those substituents discussed above in relation to the group
Ar' where Ar' is a heterocycloaliphatic group.
[0054] It will be appreciated that the group Ar, Ar' or R' may be
attached to the remainder of the molecule of formula (1) through
either a ring carbon atom or heteroatom.
[0055] Particular examples of the group Alk.sup.1 when present
include methylene, ethylene, n-propylene, 1-propylene, n-butylene,
1-butylene, s-butylene, t-butylene, ethenylene, 2-propenylene,
2-butenylene, 3-butenylene, ethynylene, 2-propynylene, 2-butynylene
or 3-butynylene chain, optionally interrupted by one, two, or three
--O-- or --S-- atoms or --S(O)--, --S(O)2-- or --N(R.sup.b)--
groups.
[0056] Particularly useful atoms or groups represented by R.sup.14
include fluorine, chlorine, bromine or iodine atoms, or
C.sub.1-6alkyl, e.g. methyl or ethyl, C.sub.1-6alkylamino, e.g.
methylamino or ethylamino, C.sub.1-6 hydroxyalkyl, e.g.
hydroxymethyl or hydroxyethyl, C.sub.1-6alkylthiol e.g. methylthiol
or ethylthiol, C.sub.1-6-alkoxy, e.g. methoxy or ethoxy,
C.sub.5-7cycloalkyl e.g. cyclopentyl, C.sub.5-7 cycloalkoxy, e.g.
cyclopentyloxy, haloC.sub.1-6alkyl, e.g. trifluoromethyl, C.sub.1-6
alkylamino, e.g. methylamino or ethylamino, amino (--NH.sub.2),
aminoC.sub.1-6alkyl, e.g. aminomethyl or aminoethyl,
C.sub.1-6-dialkylamino, e.g. dimethylamino or diethylamino, nitro,
cyano, hydroxyl (--OH), formyl [HC(O)--], carboxyl (--CO.sub.2H),
--CO.sub.2Alk.sup.2 [where Alk.sup.2 is as defined above],
C.sub.1-6 alkanoyl e.g. acetyl, thiol (--SH), thioC.sub.1-6alkyl,
e.g. thiomethyl or thioethyl, sulphonyl (--SO.sub.3H),
C.sub.1-6alkylsulphonyl, e.g. methylsulphonyl, aminosulphonyl
(--SO.sub.2NH.sub.2), C.sub.1-6alkylaminosulphonyl, e.g.
methylaminosulphonyl or ethyl-aminosulphonyl,
C.sub.1-6dialkylaminosulphonyl, e.g. dimethylaminosulphonyl or
diethylaminosulphonyl, phenylaminosulphonyl, carboxamido
(--CONH.sub.2), C.sub.1-6alkylaminocarbonyl, e.g.
methylaminocarbonyl or ethylaminocarbonyl,
C.sub.1-6dialkylaminocarbonyl, e.g. dimethylaminocarbonyl or
diethylamino-carbonyl, phenylaminocarbonyl, sulphonylamino
(--NHSO.sub.2H), C.sub.1-6alkyl-sulphonylamino, e.g.
methylsulphonylamino or ethylsulphonylamino, C.sub.1-6
dialkylsulphonylamino, e.g. dimethylsulphonylamino or
diethylsulphonyl-amino, aminosulphonylamino (--NHSO.sub.2NH.sub.2),
C.sub.1-6alkylaminosulphonyl-amino, e.g. methylaminosulphonylamino
or ethylaminosulphonylamino, C.sub.1-6dialkylaminosulphonylamino,
e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino,
phenylaminosulphonylamino, C.sub.1-6alkanoyl-amino, e.g.
acetylamino, C.sub.1-6alkanoylaminoCi 6alkyl, e.g.
acetylamino-methyl or C.sub.1-6 alkoxycarbonylamino, e.g.
methoxycarbonylamino, ethoxy-carbonylamino or
t-butoxycarbonylamino, thiocarboxamido (--CSNH.sub.2), C.sub.1-6
alkylaminothiocarbonyl, e.g. methylaminothiocarbonyl or
ethylamino-thiocarbonyl, C.sub.1-6dialkylaminothiocarbonyl, e.g.
dimethylaminothio-carbonyl or diethylaminothiocarbonyl,
aminocarbonylamino, C.sub.1-6alky-aminocarbonylamino, e.g.
methylaminocarbonylamino or ethylamino-carbonylamino,
C.sub.1-6dialkylaminocarbonylamino, e.g.
dimethylamino-carbonylamino or diethylaminocarbonylamino,
aminothiocarbonylamino, C.sub.1-6alkylaminothiocarbonylamino, e.g.
methylaminothiocarbonylamino or ethylaminothiocarbonylamino,
C.sub.1-6dialkylaminothiocarbonylamino, e.g.
dimethylaminothiocarbonylamino, or diethylaminothiocarbonylamino,
aminocarbonylC.sub.1-6alkylamino, e.g. aminocarbonylmethylamino or
amino-carbonylethylamino, aminothiocarbonylC.sub.1-6alkylamino e.g.
aminothio-carbonylmethylamino or aminothiocarbonylethylamino,
formylaminoC.sub.1-6 alkylsulphonylamino, e.g.
formylaminomethylsulphonyl- amino or
formyl-aminoethylsulphonylamino, thioformylaminoC.sub.1-6alkylsul-
phonylamino, e.g. thioformylaminomethylsulphonylamino or
thioformylethylsulphonylamino, C.sub.1-6acylaminosulphonylamino,
e.g. acetylaminosulphonylamino,
C.sub.1-6thio-acylaminosulphonylamino, e.g.
thioacetylaminosulphonylamino groups, --Ar", e.g. phenyl, --XAr"
e.g. phenoxy, or -Alk' Ar" e.g. benzyl or phenethyl groups.
[0057] Where desired, two R.sup.14 substituents may be linked
together to form a cyclic group such as a cyclic ether, e.g. a
C.sub.2-6alkylenedioxy group such as ethylenedioxy.
[0058] It will be appreciated that where two or more R.sup.14
substituents are present, these need not necessarily be the same
atoms and/or groups. The R.sup.14 substituents may be present at
any ring carbon atom away from that attached to the rest of the
molecule of formula (1). Thus, for example, in phenyl groups
represented by Ar any substituent may be present at the 2-, 3-, 4-,
5- or 6-positions relative to the ring carbon atom attached to the
remainder of the molecule.
[0059] Particular examples of the chain Z.sup.1 in compounds of
formula (1) include --NHCO--, --CONH--, --NHCS--, --CSNH--,
--NHSO.sub.2--, --SO.sub.2NH-- and --C.dbd.C--.
[0060] In the compounds of formula (1), when an ester group is
present, for example a group --CO.sub.2R.sup.8 or
--CO.sub.2Alk.sup.2 this may advantageously be a metabolically
labile ester.
[0061] The presence of certain substituents in the compounds of
formula (1) may enable salts of the compounds to be formed.
Suitable salts include pharmaceutically acceptable salts, for
example acid addition salts derived from inorganic or organic
acids, and salts derived from inorganic and organic bases.
[0062] Acid addition salts include hydrochlorides, hydrobromides,
hydroiodides, alkylsulphonates, e.g. methanesulphonates,
ethanesulphonates, or isethionates, arylsulphonates, e.g.
p-toluenesulphonates, besylates or napsylates, phosphates,
sulphates, hydrogen sulphates, acetates, trifluoroacetates,
propionates, citrates, maleates, fumarates, malonates, succinates,
lactates, oxalates, tartrates and benzoates.
[0063] Salts derived from inorganic or organic bases include alkali
metal salts such as sodium or potassium salts, alkaline earth metal
salts such as magnesium or calcium salts, and organic amine salts
such as morpholine, piperidine, dimethylamine or diethylamine
salts.
[0064] Prodrugs of compounds of formula (1) include those
compounds, for example esters, alcohols or aminos, which are
convertible in vivo by metabolic means, e.g. by hydrolysis,
reduction, oxidation or trans-esterification, to compounds of
formula (1).
[0065] Particularly useful salts of compounds according to the
invention include pharmaceutically acceptable salts, especially
acid addition pharmaceutically acceptable salts. In the compounds
of formula (1) the group .dbd.W-- is preferably a .dbd.C(Y)--
group. In compounds of this type Y is preferably a --XR.sup.a group
where X is --O-- and R.sup.a is an optionally substituted ethyl
group or, especially, an optionally substituted methyl group.
Especially useful substituents which may be present on R.sup.a
groups include one, two or three fluorine or chlorine atoms.
[0066] The group L in compounds of formula (1) is preferably a
--CH.dbd.C(R.sup.1)(R.sup.2) group. In compounds of this type
R.sup.1 and R.sup.2 are preferably linked together with the C atom
to which they are attached to form an optionally substituted
cycloalkyl or cycloalkenyl group, especially a substituted
cyclopentyl or cyclohexyl or, especially, a cyclopentyl or
cyclohexyl group.
[0067] In the compounds of formula (1) where Z is the group (A),
one preferred group of compounds are those where the group R.sup.3
is a hydrogen atom; the group R.sup.6 is a methyl group, or
especially a hydrogen atom; the group R.sup.7 is a methyl group, or
especially a hydrogen atom; and R.sup.4 and R.sup.5 are as defined
for formula (1). In compounds of this type R.sup.6 and R.sup.7 in
one preference, is each a methyl group; in another preference, one
of R.sup.6 or R.sup.7 is a methyl group and the other is a hydrogen
atom, in general, however, R.sup.6 and R.sup.7 is each especially a
hydrogen atom.
[0068] The groups R.sup.4 and R.sup.5 when present in compounds of
formula (1) are each, independently, preferably a --CH.sub.2Ar
group, or, especially, an --Ar group. Particularly useful R.sup.4
or R.sup.5 groups of this type include those groups in which Ar is
a monocyclic aryl group optionally containing one or more
heteroatoms selected from oxygen, sulphur, or, in particular,
nitrogen atoms, and optionally substituted by one, two, three or
more R.sup.14 substituents. In these compounds, when the group
represented by Ar is a heteroaryl group it is preferably a
nitrogen-containing monocyclic heteroaryl group, especially a
six-membered nitrogen-containing heteroaryl group. Thus, in one
preferred example, the groups R.sup.4 and R.sup.5 may each be a
six-membered nitrogen-containing heteroaryl group. In another
preferred example R.sup.4 may be a monocyclic aryl group or a
monocyclic or bicyclic heteroaryl group containing one or more
oxygen, sulphur or nitrogen atom and R.sup.5 may be a six-membered
nitrogen-containing heteroaryl group. In these examples, the
six-membered nitrogen-containing heteroaryl group may be an
optionally substituted pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl
or imidazolyl group. Particular examples include optionally
substituted 2-pyridyl, 3-pyridyl, 5-imidazolyl, or, especially,
4-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl,
2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl or
3-pyrazinyl. The monocyclic aryl group may be a phenyl group or a
substituted phenyl group, and the monocyclic or bicyclic heteroaryl
group containing one or more oxygen, sulphur or nitrogen atom may
be an optionally substituted 2-furyl, 3-furyl, 2-thienyl,
3-thienyl, 2-thiazolyl, 2-benzo(b)thiophenyl, 2-benzo(b)furyl or
4-isoquinolinyl group.
[0069] One particularly useful group of compounds of formula (1)
when Z is a group (A) or (B) is that wherein R.sup.4 and R.sup.5 is
each a pyridyl or, especially, a monosubstituted pyridyl, or
preferably a disubstituted pyridyl group, or R.sup.4 is a phenyl,
thienyl or furyl, or substituted phenyl, thienyl or furyl group and
R.sup.5 is a pyridyl or, especially a monosubstituted pyridyl, or
preferably a disubstituted pyridyl group.
[0070] In this particular group of compounds and also in general in
compounds of formula (1) when R.sup.4 and/or R.sup.5 is a
substituted phenyl group it may be for example a mono-, di- or
trisubstituted phenyl group in which the substituent is an atom or
group R.sup.14 as defined above. When the R.sup.4 and/or R.sup.5
group is a monosubstituted phenyl group the substituent may be in
the 2-, or preferably 3-, or especially 4-position relative to the
ring carbon atom attached to the remainder of the molecule. When
the R.sup.4 and/or R.sup.5 group is a disubstituted phenyl group,
the substituents may be in the 2,6 position relative to the ring
carbon atom attached to the remainder of the molecule.
[0071] When in compounds of formula (1) R.sup.4 and/or R.sup.5 is a
substituted pyridyl group it may be for example a mono-or
disubstituted pyridyl group, such as a mono- or disubstituted
2-pyridyl, 3-pyridyl or especially 4-pyridyl group substituted by
one or two atoms or groups R.sup.14 as defined above, in particular
one or two halogen atoms such as fluorine or chlorine atoms, or
methyl, methoxy, hydroxyl or nitro groups. Particularly useful
pyridyl groups of these types are 3-monosubstituted-4-pyridyl or
3,5-disubstituted-4-pyridyl, or 2-- or 4-monosubstituted-3-pyridyl
or 2,4-disubstituted-3-pyridyl groups.
[0072] Other particularly useful groups of compounds of formula (1)
where Z is the group (B), include those where R.sup.4 is a
--CH.sub.3 group or a hydrogen atom; R.sup.5 is a hydrogen atom, a
--CN or a --CH.sub.3 group; R.sup.6 is as just described for
R.sup.4 and R.sup.5 in the compounds of formula (1) where Z is the
group (A).
[0073] Another particularly useful group of compounds of formula
(1) when Z is a group (C) is that wherein Ar is a phenyl, naphthyl,
pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl,
pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, quinolinyl,
isoquinolinyl, 5,6,7,8-tetrahydroquinolinyl or
5,6,7,8-tetrahydro-isoquinolinyl group. In compounds of this type
when Ar is a quinolinyl group it may be for example a mono- or
disubstituted quinolinyl group such as a
2-monosubstituted-4-quinolinyl group; when it is a pyridyl group,
it may be an optionally substituted 3-- or 4-- pyridyl, e.g. a
2,3,5,6-tetrasubstituted-4-pyridyl or
2,4,6-trisubstituted-3-pyridyl group; when it is a pyrimidinyl
group, it may be for example a 5-pyrimidinyl group or a
2-substituted 5-pyrimidinyl group; and when it is an isoquinolinyl
group, it may be a 4-isoquinolinyl group.
[0074] Other especially useful groups of compounds of formula (1)
include those where Z is a group (D) in which (1) --Z.sup.1 is a
--C(O)NR.sup.12-- group, where R.sup.12 is a hydrogen atom. In
compounds of this type, t is preferably zero and Ar is a
2-nitrophenyl or 4-(3,5-dichloro)pyridyl group, or (2) those where
--Z.sup.1-- is a --NR.sup.12C(O)-- group, where R.sup.12 is a
hydrogen atom, t is zero and Ar is a 4-pyridyl or
4-(3,5-dichloro)pyridyl, benzyl or 2-methylbenzoate group, or t is
an integer of value 1 and Ar is a 2-- or 3-nitrophenyl, phenyl or
2-methylphenyl group.
[0075] A particularly useful group of compounds of formula (1) has
the formula (2): 5
[0076] where (1) --L is a --CH.dbd.C(R.sup.1)(R.sup.2) or
--CH.sub.2CH(R.sup.1)(R.sup.2) group where R.sup.1 and R.sup.2 are
linked together with the carbon atom to which they are attached to
form a cycloalkyl group: or (2) L is a group --OAlkAr' where Alk is
a C.sub.1-6alkylene chain and Ar' is a monocyclic aryl or
heteroaryl group. Particular examples of such L groups include
benzyloxy, thienyloxy or phenyl-pentyloxy groups; or (3) L is a
group OR' where R' is an optionally substituted polycyloalkyl or
polycycloalkenyl group or is as described above for Ar'. Preferred
examples of such R' groups include optionally substituted
bicycylo[2.2.1]heptyl or bicyclo[2.2.1]heptenyl group. In
particular R' is a bicyclo[2.2.1]hept-2-yl group; and Z is as
defined for formula (1); and the salts, solvates, hydrates,
prodrugs and N-oxides thereof.
[0077] In compounds of formula (2) where R.sup.3, R.sup.6 or
R.sup.7 is present it is each preferably a hydrogen atom.
[0078] A particularly useful group of compounds according to the
invention has the formula (2) wherein L is a OR' group and Z is the
group (A). In this particular group of compounds R.sup.3, R.sup.6
and R.sup.7 is each a hydrogen atom and R.sup.4 and R.sup.5 are as
defined for compounds of formula (1) and the salts, solvates,
hydrates and N-oxides thereof. Compounds of this type in which R'
is a bicyclo [2.2.1] heptyl, particularly a bicyclo [2.2.1]
hept-2-yl group are particularly useful. In this group of
compounds, R.sup.4 is preferably a monocyclic aryl group,
particularly a phenyl or substituted phenyl group or R.sup.4 is a
six-membered nitrogen-containing monocyclic heteroaryl group,
particularly a pyridyl or substituted pyridyl group and R.sup.5 is
a six-membered nitrogen-containing monocyclic heteroaryl group,
especially a pyridyl or substituted pyridyl group, in particular a
4-pyridyl or substituted 4-pyridyl group.
[0079] Other particularly useful groups of compounds of formulae
(1) or (2) where L is a group --C(R).dbd.C(R.sup.1)(R.sup.2) or
--(X.sup.a).sub.nAlk'Ar' and Z is the group (B), include those
where R.sup.4 is a --CH.sub.3 group or a hydrogen atom; R.sup.5 is
a hydrogen atom, a --CN or a --CH.sub.3 group; R.sup.6 is as just
described for R.sup.4 and R.sup.5 in the compounds of formulae (1)
or (2) where Z is the group (A).
[0080] Particular compounds according to the invention are:
[0081] (2R)-4-{2-[3-((2RS)-exo-Bicyclo[2.2.1
]hept-2-yloxy)-4-methoxypheny- l]-2-phenylethyl}pyridine;
[0082]
(.+-.)-4-[2-(3-Benzyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine;
[0083]
(.+-.)-4-{2-[4-Methoxy-3-(3-thienyloxy)phenyl]-2-phenylethyl}pyridi-
ne;
[0084]
(.+-.)-4-[2-(3-Cyclopentylidenyl-4-methoxyphenyl)-2-phenylethyl]pyr-
idine;
[0085]
(.+-.)-4-[2-(3-Cyclohexylidenyl-4-methoxyphenyl)-2-phenylethyl]pyri-
dine;
[0086] (E,
Z)-3-(3-Cyclopentylidenyl-4-methoxyphenyl)-2-(2,6-dichloropheny- l)
propenenitrile;
[0087] (E,
Z)-3-(3-Cyclopentylidenyl-4-methoxyphenyl)-2-(2,6-difluoropheny- l)
propenenitrile;
[0088] (E,
Z)-4-[2-(3-Cyclopentylidenyl-4-methoxyphenyl)ethenyl]-3,5-dichl-
oro-pyridine;
[0089] 3-(3-Cyclopentylidenyl-4-methoxyphenyl)pyridine;
[0090] 5-(3-Cyclopentylidenyl-4-methoxyphenyl)pyrimidine;
[0091] 4-(3-Cyclopentylidenyl-4-methoxyphenyl)nitrobenzene;
[0092] 3-(3-Cyclopentylmethyl-4-methoxyphenyl)pyridine;
[0093]
N-(3-Cyclopentylidenyl-4-methoxyphenyl)-3,5-dichloro-4-pyridenecarb-
ox-amide;
[0094]
4-[2-(3-Cyclopentylidenyl-4-methoxyphenyl)ethyl]pyridine;
[0095]
N-{4-[2-(3-Cyclopentylidenyl-4-methoxyphenyl)ethyl]-3-pyridyl}pheny-
l-sulphonamide;
[0096] 3-Cyclopentylidenyl-4-methoxy-N-(2-nitrobenzoyl)aniline;
[0097] N-(3-Cyclopentylidenyl-4-methoxyphenyl)-4-pyridinecarboxam
ide;
[0098] N-Phenyl-3-cyclopentylidenyl-4-methoxybenzam ide;
[0099]
N-(2--Nitrophenyl)-3-cyclopentylidenyl-4-methoxybenzamide;
[0100]
N-(3,5-Dichloropyrid-4-yl)-3-cyclopentylidenyl-4-methoxybenzamide;
[0101] and the salts, solvates, hydrates, prodrugs and N-oxides
thereof.
[0102] Compounds according to the invention are selective and
potent inhibitors of PDE IV. The ability of the compounds to act in
this way may be simply determined by the tests described in the
Examples hereinafter.
[0103] Particular uses to which the compounds of the invention may
be put include the prophylaxis and treatment of asthma, especially
inflamed lung associated with asthma, cystic fibrosis, or in the
treatment of inflammatory airway disease, chronic bronchitis,
eosinophilic granuloma, psoriasis and other benign and malignant
proliferative skin diseases, endotoxic shock, septic shock,
ulcerative colitis, Crohn's disease, reperfusion injury of the
myocardium and brain, inflammatory arthritis, chronic
glomerulonephritis, atopic dermatitis, urticaria, adult respiratory
distress syndrome, diabetes insipidus, allergic rhinitis, allergic
conjunctivitis, vernal conjunctivitis, arterial restenosis and
artherosclerosis.
[0104] Compounds of the invention may also suppress neurogenic
inflammation through elevation of cAMP in sensory neurones. They
are, therefore, analgesic, anti-tussive and anti-hyperalgesic in
inflammatory diseases associated with irritation and pain.
[0105] Compounds according to the invention may also elevate cAMP
in lymphocytes and thereby suppress unwanted lymphocyte activation
in immune-based diseases such as rheumatoid arthritis, ankylosing
spondylitis, transplant rejection and graft versus host
disease.
[0106] Compounds according to the invention may also reduce gastric
acid secretion and therefore can be used to treat conditions
associated with hypersecretion.
[0107] Compounds of the invention may suppress cytokine synthesis
by inflammatory cells in response to immune or infectious
stimulation. They are, therefore, useful in the treatment of
bacterial, fungal or viral induced sepsis and septic shock in which
cytokines such as tumour necrosis factor (TNF) are key mediators.
Also compounds of the invention may suppress inflammation and
pyrexia due to cytokines and are, therefore, useful in the
treatment of inflammation and cytokine-mediated chronic tissue
degeneration which occurs in diseases such as rheumatoid or
osteo-arthritis.
[0108] Over-production of cytokines such as TNF in bacterial,
fungal or viral infections or in diseases such as cancer, leads to
cachexia and muscle wasting. Compounds of the invention may
ameliorate these symptoms with a consequent enhancement of quality
of life.
[0109] Compounds of the invention may also elevate cAMP in certain
areas of the brain and thereby counteract depression and memory
impairment.
[0110] Compounds of the invention may suppress cell proliferation
in certain tumour cells and can be used, therefore, to prevent
tumour growth and invasion of normal tissues.
[0111] For the prophylaxis or treatment of disease the compounds
according to the invention may be administered as pharmaceutical
compositions, and according to a further aspect of the invention we
provide a pharmaceutical composition which comprises a compound of
formula (1) together with one or more pharmaceutically acceptable
carriers, excipients or diluents.
[0112] Pharmaceutical compositions according to the invention may
take a form suitable for oral, buccal, parenteral, nasal, topical
or rectal administration, or a form suitable for administration by
inhalation or insufflation.
[0113] For oral administration, the pharmaceutical compositions may
take the form of, for example, tablets, lozenges or capsules
prepared by conventional means with pharmaceutically acceptable
excipients such as binding agents (e.g. pregelatinised maize
starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose);
fillers (e.g. lactose, microcrystalline cellulose or calcium
hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or
silica); disintegrants (e.g. potato starch or sodium glycollate);
or wetting agents (e.g. sodium lauryl sulphate). The tablets may be
coated by methods well known in the art. Liquid preparations for
oral administration may take the form of, for example, solutions,
syrups or suspensions, or they may be presented as a dry product
for constitution with water or other suitable vehicle before use.
Such liquid preparations may be prepared by conventional means with
pharmaceutically acceptable additives such as suspending agents,
emulsifying agents, non-aqueous vehicles and preservatives. The
preparations may also contain buffer salts, flavouring, colouring
and sweetening agents as appropriate.
[0114] Preparations for oral administration may be suitably
formulated to give controlled release of the active compound.
[0115] For buccal administration the compositions may take the form
of tablets or lozenges formulated in conventional manner.
[0116] The compounds of formulae (1) and (2) may be formulated for
parenteral administration by injection e.g. by bolus injection or
infusion. Formulations for injection may be presented in unit
dosage form, e.g. in glass ampoule or multi dose containers, e.g.
glass vials. The compositions for injection may take such forms as
suspensions, solutions or emulsions in oily or aqueous vehicles,
and may contain formulatory agents such as suspending, stabilising,
preserving and/or dispersing agents. Alternatively, the active
ingredient may be in powder form for constitution with a suitable
vehicle, e.g. sterile pyrogen-free water, before use.
[0117] In addition to the formulations described above, the
compounds of formulae (1) and (2) may also be formulated as a depot
preparation. Such long acting formulations may be administered by
implantation or by intramuscular injection.
[0118] For nasal administration or administration by inhalation,
the compounds for use according to the present invention are
conveniently delivered in the form of an aerosol spray presentation
for pressurised packs or a nebuliser, with the use of suitable
propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethan- e, carbon dioxide or other suitable gas
or mixture of gases.
[0119] The compositions may, if desired, be presented in a pack or
dispenser device which may contain one or more unit dosage forms
containing the active ingredient. The pack or dispensing device may
be accompanied by instructions for administration.
[0120] The quantity of a compound of the invention required for the
prophylaxis or treatment of a particular inflammatory condition
will vary depending on the compound chosen, and the condition of
the patient to be treated. In general, however, daily dosages may
range from around 100 ng/kg to 100 mg/kg, e.g. around 0.01 mg/kg to
40 mg/kg body weight for oral or buccal administration, from around
10 ng/kg to 50 mg/kg body weight for parenteral administration and
around 0.05 mg to around 1000 mg e.g. around 0.5 mg to around 1000
mg for nasal administration or administration by inhalation or
insufflation.
[0121] The compounds according to the invention may be prepared by
the following processes. The symbols W, L, Z, X, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 when used in the
formulae below are to be understood to represent those groups
described above in relation to formula (1) unless otherwise
indicated. In the reactions described below it may be necessary to
protect reactive functional groups, for example hydroxy, amino,
thio, carboxy or aldehyde groups, where these are desired in the
final product, to avoid their unwanted participation in the
reactions. Conventional protecting groups may be used in accordance
with standard practice (see, for example, Green, T. W. in
"Protective Groups in Organic Synthesis" John Wiley and Sons,
1981].
[0122] Thus, according to a further aspect of the invention,
compounds of general formula (1) where L is X.sup.aAlk'Ar',
Alk'X.sup.aAr' or X.sup.aR' may be prepared by coupling an
intermediate of formula (3) 6
[0123] a) where L.sup.2 is a group --X.sup.aH with a reagent
L.sup.3Alk'Ar', or L.sup.3R' where L.sup.3 is a leaving group;
or
[0124] b) where L.sup.2 is a group -Alk'L.sup.3 with a reagent
Ar'X.sup.aH.
[0125] Leaving groups represented by L.sup.3 include halogen atoms
such as iodine, chlorine or bromine atoms, sulphonyloxy groups such
as arylsulpyhonyl-oxy groups, e.g. ptoluenesulphonyloxy or hydroxyl
groups.
[0126] The coupling reaction may be carried out in the presence of
a base, e.g. an inorganic base such as a carbonate, e.g. caesium or
potassium carbonate, an alkoxide, e.g. potassium t-butoxide, or a
hydride, e.g. sodium hydride, in a dipolar aprotic solvent such as
an amide, e.g. a substituted amide, such as dimethylformamide or an
ether, e.g. diethylether or a cyclic ether such as tetrahydrofuran
or halogenated solvents, such as dichloromethane. The temperature
of the reaction mixture may vary from ambient temperature or above,
e.g. around 40.degree. C. to the reflux temperature. Where
necessary, an activator may be used, such as diethyl-,
diisopropyl-, or dimethylazodicarboxylate, in the presence of a
phosphine, such as triphenylphosphine and a base, such as an amine,
e.g. triethylamine.
[0127] Intermediates of formula (3) where L.sup.2 is a group
-Alk'L.sup.3 wherein L.sup.3 is a halogen atom may be prepared by
reaction of an intermediate of formula (3) wherein Alk'L.sup.3 is a
-Alk'OH group with a halogenating agent, such as an inorganic acid
halide e.g. thienylchloride, or an anhydride such as an
arylsulphonic anhydride, e.g. p.toluenesulphonic anhydride, using
conventional procedures.
[0128] Intermediates of formula (3) where L.sup.2 is a group
--X.sup.aH may be prepared by deprotection of a protected compound
of formula (4) 7
[0129] where P is a hydroxy, thio, or amino protecting group.
Examples of hydroxy protecting groups include, for example ether
groups, such as a cyclopentyloxy group. The deprotection reaction
may take place in an aqueous solvent, such as an aqueous ether,
e.g. dioxane-water, in the presence of an acid, e.g. sulphuric acid
at an elevated temperature. e.g. around 90.degree. C. Another
example of protecting group P include t-butyidimethylsilyloxy group
which can be cleaved by treatment with tetrabutylammonium fluoride
to regenerate the free hydroxy group.
[0130] Intermediates of formula (3) where Z is a group (A) in which
R.sup.3 is a hydroxyl group and R.sup.7 is a hydrogen atom may be
prepared by reacting a ketone of formula (5) 8
[0131] with an organometallic reagent R.sup.5R.sup.6 CHM, where M
is a metal atom.
[0132] Metal atoms represented by Z include, for example, a lithium
atom.
[0133] The reaction may be performed in a solvent such as an ether,
e.g. a cyclic ether such as tetrahydrofuran, at a low temperature
e.g. around -70.degree. C. to ambient temperature. This reaction is
particularly suitable for the preparation of compounds of formula
(3) wherein R.sup.5 is an electron deficient group such as a 2-- or
4-pyridyl group.
[0134] Reagents R.sup.5R.sup.6CHM are either known compounds or may
be prepared, preferably in situ during the above process, by
reaction of a compound AlkCH.sub.2M [where Alk is an alkyl group
such as n-propyl] with a compound R.sup.5R.sup.6CH.sub.2 where
necessary in the presence of a base such as an amine e.g.
diisopropylamine using the above-mentioned conditions.
[0135] Intermediates of formula (5) where L.sup.2 is a group
--X.sup.aH in which --X.sup.a-- is --NH-and R.sup.4 is a hydrogen
atom may be prepared from the known compound of formula (6) 9
[0136] by reduction with a reducing agent, such as a lithium
aluminium hydride, to give the alcohol derivative. This in turn may
be oxidised, for example with manganese dioxide to afford an
aldehyde of formula (5).
[0137] Intermediates of formula (3) where Z is a group (A) in which
R.sup.3 is a hydroxyl group may be prepared by reacting a ketone of
formula (5) with a reagent R.sup.5CHR.sup.6R.sup.7 using a base,
such as an organometallic base, for example an organolithium
reagent e.g. n-butyllithium, in a solvent, such as an ether, e.g.
tetrahydrofuran, at around -70.degree. C. to room temperature.
Ketones of formula (5) may be prepared by oxidation of an alcohol
of formula (7) 10
[0138] using an oxidising agent, such as manganese (IV) oxide, in a
solvent, such as dichloromethane, at room temperature.
[0139] Alternatively, ketones of formula (5) may be prepared by
reaction of a halide of formula (8) 11
[0140] [where Hal is a halogen atom such as a bromine or chlorine
atom] by halogen-metal exchange with a base such as n-butyllithium
followed by reaction with a nitrile R.sup.4CN, an acid chloride
R.sup.4COCl or an ester R.sup.4CO.sub.2A (where A is an alkyl
group, e.g. a methyl group), in a solvent such as tetrahydrofuran
at a low temperature, e.g. around -70.degree. C., and subsequent
treatment with an acid such as hydrochloric acid at e.g.
-20.degree. C. to ambient temperature.
[0141] Alcohols of Formula (7) may be Prepared
[0142] (1) by reacting a halide of formula (8) e.g. a bromide, with
an aldehyde R.sup.4CHO, in the presence of a base, such as
n-butyllithium, in a solvent, e.g. tetrahydrofuran, at a
temperature from around -70.degree. C. to room temperature; or
[0143] (2) by reacting an aldehyde of formula (9) where W.sup.a is
a --CHO group (as described hereinbelow) with an organometallic
compound, such as an organolithium R.sup.4Li, or a Grignard
R.sup.4MgBr, in a solvent, such as tetrahydrofuran, at a low
temperature, e.g. around -55.degree. C. to 0.degree. C.
[0144] Intermediates of formula (3) where Z is a group (B) may be
prepared by condensing an intermediate of formula (9) 12
[0145] where
[0146] (a) W.sup.a is a --C(O)R.sup.4 group wherein R.sup.4 is as
defined for formula (1) but is not a --CN or --CH.sub.2CN group,
with a compound R.sup.5CH.sub.2R.sup.6; or where
[0147] (b) W.sup.a is a --CH.sub.2R.sup.4 group with an aldehyde or
ketone R.sup.5COR.sup.6 where R.sup.5 is as just defined for
R.sup.4; or where
[0148] (c) W.sup.a is a --C(O)R.sup.4 group with a silane
derivative (Alk.sup.a).sub.3SiCH(R.sup.5)(R.sup.6), where Alk.sup.a
is an alkyl group; in each instance in the presence of a base or an
acid in a suitable solvent.
[0149] Bases for use in these reactions include inorganic bases,
for example alkali and alkaline earth metal bases, e.g. hydroxides,
such as sodium or potassium hydroxide; alkoxides, for example
sodium ethoxide; organic bases, for example amines such as
piperidine; and organolithium bases, such as alkyllithium, e.g.
n-butyllithium bases. Suitable solvents include alcohols such as
ethanol, or ethers such as tetrahydrofuran. Acids for use in the
reactions include organic acids, e.g. carboxylic acids such as
acetic acid.
[0150] The reactions may be performed at any suitable temperature,
for example from around -78.degree. C. to ambient temperature or to
the reflux temperature depending on the nature of the starting
materials.
[0151] In general, the base, acid, solvent and reaction conditions
may be selected depending on the nature of the starting materials,
from a range of known alternatives for reactions of this type.
[0152] In silane derivatives of formula
(Alk.sup.a).sub.3SiCH(R.sup.5)(R.s- up.6), Alk.sup.a may be for
example a C.sub.1-6alkyl group such as a methyl group. Derivatives
of this type may be prepared for example by reacting a compound
R.sup.5--CH.sub.2--R.sup.6 with a silane derivative, such as a
chlorotrialkylsilane, e.g. chlorotrimethyl-silane in the presence
of a base, e.g. lithium diisopropylamide, in a solvent, e.g.
tetrahydrofuran, at a low temperature, e.g. around -10.degree.
C.
[0153] The starting materials R.sup.5COR.sup.6 and R.sup.5
CH.sub.2R.sup.6 are either known compounds or may be prepared from
known starting materials by methods analogous to those used for the
preparation of the known compounds.
[0154] Intermediates of formula (9) where --W.sup.a is a
--C(O)R.sup.4 group where R.sup.4 is an alkyl or aryl group
(CH.sub.2).sub.tAr group, may be prepared by reacting an aldehyde
of formula (9) where --W.sup.a is a --CHO group with an
organometallic reagent in a solvent, e.g. tetrahydrofuran, at low
temperature, e.g. around 10.degree. C., followed by oxidation with
an oxidising agent, such as manganese dioxide, in a solvent, e.g.
dichloromethane.
[0155] Intermediates of formula (9) where --W.sup.a is --CHO may be
prepared by reacting a compound of formula (8) described above with
an organo-metallic reagent, such as n-butyllithium, in a solvent,
such as an amide, e.g. dimethylformamide, at a low temperature,
e.g. below -60.degree. C.
[0156] Intermediates of formula (8) may be prepared by deprotecting
a compound of formula (10) 13
[0157] using reagents and conditions described herein for the
obtention of an intermediate of formula (3) from an intermediate of
formula (4) where L.sup.2 is a group X.sup.aH.
[0158] Intermediates of formula (10) may be prepared by protecting
a compound of formula (11) 14
[0159] Examples of protecting groups include hydroxy, thio or amino
protecting groups using conventional procedures [see Green, T. W.
ibid]. Thus for example, where X.sup.a is an oxygen atom, the
hydroxyl group may be protected as an ether group, using a reagent
Alk.sup.bL.sup.3, where Alk.sup.b is an alkyl group and L.sup.3 is
a leaving group. Alkyl groups represented by Alk.sup.b include
cycloalkyl groups, such as cyclopentyl group, and leaving groups
L.sup.3 include halogen atoms such as iodine, chlorine or bromine
atoms or sulphonyloxy groups such as arylsulphonyloxy groups, e.g.
p.toluene-sulphonyloxy groups.
[0160] The reaction may be carried out in the presence of a base,
e.g. an inorganic base such as a carbonate, e.g. caesium or
potassium carbonate, an alkoxide, e.g. potassium-t-butoxide, or a
hydride, e.g. sodium hydride, in a dipolar aprotic solvent such as
an amide, e.g. a substituted amide such as dimethylformamide or an
ether, e.g. a cyclic ether such as tetrahydrofuran, at ambient
temperature or above. e.g. around 40.degree. C. to 50.degree.
C.
[0161] Halides of formula (11) where X.sup.a is --O-- may be
prepared by oxydation of an aldehyde of formula (17) (where R is a
hydrogen atom) as described below using an oxidising agent such as
3-chloroperoxybenzoic acid in a halogenated hydrocarbon such as
chloroform at a temperature from around 0.degree. C. to room
temperature. Halides of formula (11) where X.sup.a is --S-- or
--N(R.sup.b)-- are either known compounds or may be prepared from
known starting materials by methods analogous to those used for the
preparation of the known compounds.
[0162] Compounds of formula (1) where Z is a group (A) in which
R.sup.3 is a hydroxyl group and R.sup.7 is as described for
compounds of formula (1) may be prepared by reacting a compound or
formula (11) with a reagent R.sup.5R.sup.6CHM or
R.sup.5CHR.sup.6R.sup.7 using the conditions described hereinabove
for the obtention of an intermediate of formula (3) from a ketone
of formula (5).
[0163] In another process according to the invention, compounds of
formula (1) where Z is a group (B) and R.sup.4 is a hydrogen atom
or an alkyl or --(CH.sub.2).sub.tAr group may be prepared by
reacting a compound of formula (12) 15
[0164] with a phosphonate ester
(R.sup.dO)(OR.sup.e)P(O)CH(R.sup.5)(R.sup.- 6) [where Rd and Re,
which may be the same or different is an alkyl, or aralkyl group]
in the presence of a base in a suitable solvent.
[0165] Suitable bases include organometallic bases such as
organolithium, e.g. n-butyllithium, alkoxides, for example alkali
metal alkoxides such as sodium ethoxide or sodium methoxide and a
hydride such as potassium hydride or sodium hydride. Solvents
include ethers, e.g. diethylether or cyclic ethers such as
tetrahydrofuran and alcohol, e.g. methanol or ethanol.
[0166] The phosphonate derivatives used in this reaction are either
known compounds or may be prepared by reacting a phosphite
P(ORd).sub.2(OR.sup.e) with a compound R.sup.5CHR.sup.6Hal [where
Hal is a halogen atom, for example a bromine atom] using
conventional methods.
[0167] Intermediates of formula (12) where R.sup.4 is a hydrogen
atom may be prepared by reacting a halide of formula (13) 16
[0168] where Hal is a halogen atom, e.g. a bromine or chlorine atom
with an organometallic reagent using the same reagents and
conditions described above for the preparation of intermediates of
formula (9) where W.sup.a is --CHO from intermediates of formula
(8).
[0169] Intermediates of formula (2) where .dbd.W-- is =N-- and
R.sup.4 is H may be prepared from an acid of formula (14) 17
[0170] using the conditions described above for the preparation of
an intermediate of formula (5) from an acid of formula (6).
[0171] Intermediates of formula (14) where L is X.sup.aAlk'Ar' or
X.sup.aR' and --X.sup.a is --O--, --S-- or --NH--, may be prepared
by reacting a halide of formula (15) 18
[0172] where Hal is a halogen atom, e.g. a bromine, chlorine or
iodine atom with a compound ArAlk'X.sup.aH, where --X.sup.a is
--O--, --S-- or --NH-- in the presence of a base.
[0173] Bases used in this reaction include a hydride, such as
sodium hydride, or an organometallic base such as butyllithium in a
solvent, such as an amide, for example dimethylformamide at a
temperature from room temperature to above, e.g. 80%.
[0174] Intermediates of formula (15) may be prepared by reacting
the known amine of formula (16) 19
[0175] with nitrous acid (made in situ by reacting sodium nitrite
with an acid, for example sulphuric acid or hydrobromic acid) to
produce the diazonium salt. This in turn may be reacted with a
haloacid, e.g. hydrobromic, hydrochloride or hydriodic acid if
necessary in the presence of the corresponding copper (I), halide
(CuBr or Cul) or halogen Br.sub.2, Cl.sub.2 or I.sub.2.
[0176] Intermediates of formula (13) where L is a
--C(R).dbd.C(R.sup.1)(R.- sup.2) group may be prepared by coupling
a compound of formula (17) 20
[0177] where Hal is a halogen atom, e.g. a bromine atom with a
phosphonium salt (R.sup.1)(R.sup.2)CHP(D).sub.3Hal as described
below for the preparation of compounds of formula (1) from
intermediates of formula (19).
[0178] Intermediates of formula (12) where R.sup.4 is an alkyl or
--(CH.sub.2).sub.tAr group may be prepared by reaction of the
corresponding compound of formula (12) where R.sup.4 is a hydrogen
atom with an organometallic reagent, followed by oxidation, as
described previously for the preparation of intermediates of
formula (9) where W.sup.a is --C(O)R.sup.4 where R.sup.4 is an
alkyl or aryl group (CH.sub.2).sub.tAr from intermediates of
formula (9) where R.sup.4 is a hydrogen atom.
[0179] In another process for the preparation of compounds of
formula (1) where Z is the group (B), an intermediate of formula
(18) 21
[0180] may be coupled in a Heck reaction with an organopalladium
compound derived from a compound R.sup.5Hal [where Hal is a halogen
atom such as a bromine atom] and a palladium salt such as palladium
acetate in the presence of a phosphine such as tri-o-tolylphosphine
and a base such as triethylamine at an elevated temperature and
pressure.
[0181] Intermediate alkenes of formula (18) may be obtained by
reaction of a corresponding intermediate of formula (12) using a
Wittig reaction employing a phosphonium salt such as
methyltriphenylphosphonium bromide in the presence of a base such
as n-butylithium and an inert solvent such as tetrahydrofuran at,
for example, 0.degree. C. to ambient temperature.
[0182] Intermediates of formula (3) where L.sup.2 is a -Alk'L.sup.3
group in which Alk' is an alkenylene chain --C.dbd.C-Alk'- and
L.sup.3 is a hydroxyl group may be prepared by coupling a compound
of formula (19) 22
[0183] where R is a hydrogen atom or an alkyl group such as a
methyl group, with an olefination agent.
[0184] Particular examples of olefination agents include
phosphonium salts such as compounds HOAlk'P(D).sub.3Hal [where the
hydroxyl group may need to be protected using conventional
protecting group] where Hal is a halogen atom, such as a bromine
atom and D is an optionally substituted alkyl, e.g. methyl, or
aryl, especially phenyl group; phosphoranes HOAlk.degree.
C.=P(D).sub.3; phosphonates (DO).sub.2P(O)Alk'OH; or silane
derivatives, for example compounds of formula (D).sub.3SiAlk'OH
e.g. trialkylsilanes such as (CH.sub.3).sub.3SiAlk'OH.
[0185] Intermediates of formula (19) where R is an alkyl group, may
be prepared by reacting an intermediate of formula (19) where R is
a hydrogen atom with an organometallic reagent, such as an
alkyllithium or an organomagnesium RMgHal, using the conditions
described above, followed by oxidation of the resulting alcohol,
using an oxidising agent, e.g. manganese dioxide.
[0186] Intermediates of formula (19) where R is a hydrogen atom may
be prepared by deprotecting a protected aldehyde of formula (20)
23
[0187] where P.sup.1 is a protected aldehyde group, e.g. a dioxanyl
group, using acid hydrolysis e.g. by reaction with trifluoroacetic
acid or p-toluene sulphonic acid, in the presence of a solvent,
e.g. acetone, or a mixture of solvents, e.g. chloroform and
water.
[0188] Intermediates of formula (20) may be prepared by protecting
an aldehyde or ketone of formula (19) with an aldehyde or ketone
protecting group, using for example a suitable diol, e.g.
1,3-propanediol, in the presence of an acid catalyst, e.g.
4-toluene sulphonic acid, in a solvent, such as an aromatic
solvent, e.g. toluene, at an elevated temperature.
[0189] In general, this reaction may be used when it is desired to
protect an aldehyde in any intermediate described herein.
[0190] Compounds of formula (1) where L is a group
--C(R).dbd.C(R.sup.1)(R- .sup.2) or Alk'Ar' where Alk' is an
alkenylene chain --C.dbd.C-Alk' may be prepared from an
intermediate of formula (19) using an appropriate olefination
agent.
[0191] Particular examples of olefination agents include
phosphonium salts such as compounds
(R.sup.1)(R.sup.2)CHP(D).sub.3Hal or Ar'Alk'P(D).sub.3Hal where Hal
is a halogen atom, such as a bromine atom, and D is an optionally
substituted alkyl, e.g. methyl, or aryl, especially phenyl, group;
phosphoranes (R.sup.1)(R.sup.2)C.dbd.P(D).sub.3 or
Ar'Alk'=P(D).sub.3; phosphonates (DO).sub.2P(O)CH(R.sup.1)(R.sup.2)
or (DO.sub.2)P(O)Alk'Ar'; or silane derivatives, for example
compounds of formula (D.sub.3)SiC(R.sup.1)(R.sup.2) or
(D.sub.3)SiAlk'Ar', e.g. trialkylsilanes such as
(CH.sub.3).sub.3SiC(R.sup.1)(R.sup.2) or
(CH.sub.3).sub.3SiAlk'Ar'.
[0192] Bases for use in the above reaction include organometallic
bases, for example, an organolithium compound such as an
alkyllithium e.g. n-butyllithium, a hydride, such as sodium or
potassium hydride or an alkoxide, such as a sodium alkoxide, e.g.
sodium methoxide.
[0193] The reaction may be performed in a suitable solvent, for
example a polar aprotic solvent, such as an alkyl sulphoxide, e.g.
methyl sulphoxide, an amide such as N,N-dimethylformamide or
hexamethylphosphorous triamide; a non-polar solvent, such as an
ether, e.g. tetrahydrofuran or diethyl ether or an aromatic solvent
such as benzene, toluene or xylene; or a polar protic solvent, such
as an alcohol, for example ethanol. Preferably the reaction is
carried out at a low temperature, for example from around
-78.degree. C. to around room temperature.
[0194] The olefination agents used in this reaction are either
known compounds or may be prepared from known starting materials
using reagents and conditions similar to those used to prepare the
known compounds. For example, a phosphorane may be prepared in situ
by reaction of a phosphonium salt with a base of the type described
above. In another example, a phosphonate reagent may be prepared by
reacting a halide Alk'Hal with a phosphite (DO).sub.3P, as
described in the Arbuzov reaction. Silane derivatives may be
prepared by reaction of a halosilane (D).sub.3SiHal where Hal is a
halogen atom, for example a chlorine atom, with a base, such as
lithium diisopropylamide, in a solvent, such as an ether, for
example a cyclic ether, e.g. tetrahydrofuran, at low temperature,
e.g. -10.degree. C.
[0195] According to a further aspect of the invention, compounds of
formula (1) where L is a group --C(R).dbd.CH(R.sup.1) and R.sup.1
is an optionally substituted alkyl, alkenyl or alkenyl group may
also be prepared by reaction of an intermediate of formula (19)
with an organometallic reagent, followed by dehydration of the
corresponding alcohol.
[0196] Examples of organometallic reagents include organolithium
R.sup.1Li or organomagnesium R.sup.1MgHal reagents. The reaction
with the organo-metallic reagent may be performed in a solvent such
as an ether, e.g. diethyl ether or for example a cyclic ether such
as tetrahydrofuran, at a low temperature for example -10.degree. C.
to room temperature. The dehydration may be performed using an
acid, for example an organic acid such as p.toluene sulphonic acid
or trifluoracetic acid, in the presence of a base, such as an
amine, e.g. triethylamine.
[0197] In yet another process according to the invention, compounds
of formula (1) wherein R.sup.3, R.sup.6 and R.sup.7 is each a
hydrogen atom may be prepared by decarboxylation of an acid of
formula (21): 24
[0198] The reaction may be carried out by treatment of the compound
of formula (21) with a base, for example an inorganic base such as
a hydroxide, e.g. sodium hydroxide in a solvent such as an alcohol,
e.g. ethanol, at an elevated temperature e.g. the reflux
temperature, followed by acidification of the reaction mixture to a
pH of around pH4 to around pH.sub.6 using an acid such as an
inorganic acid, e.g. hydrochloric acid, at an elevated temperature,
e.g. the reflux temperature.
[0199] If desired, the acid of formula (21) may be generated in
situ from the corresponding ester or nitrite using the above
reaction conditions, or by initial treatment with an acid.
[0200] Intermediates of formula (21) may be prepared by reacting a
compound of formula (22) 25
[0201] [where R.sup.15 is an ester of an acid --CO.sub.2H (e.g. an
alkyl ester such as an ethyl ester) or a nitrite --CN], with a
Grignard reagent R.sup.4MgBr, in the presence of a complexing
agent, e.g. a copper (I) bromide-dimethyl sulphide complex, or a
copper (I) chloride, or with an organolithium compound, e.g.
R.sup.4Li, in a solvent, e.g. tetrahydrofuran, at low temperature,
e.g. around -40.degree. C., followed by treatment with a base or an
acid to yield the acid of formula (21). The Grignard and the
lithium reagents are either known compounds or may be prepared in a
manner similar to that used to synthesise the known compounds.
[0202] Compounds of formula (22) may be obtained by reacting an
adehyde of formula (12) with an ester or nitrile
R.sup.5CH.sub.2R.sup.15 in an acid solvent, such as acetic acid, at
an elevated temperature, for example the reflux temperature, in the
presence of a base, such as ammonium acetate.
[0203] In a further process according to the invention a compound
of formula (1) wherein R.sup.3, R.sup.6 and R.sup.7 is each a
hydrogen atom and R.sup.5 is a heteroaryl group may be generally
prepared by cyclisation of a compound of formula (23): 26
[0204] where R.sup.16 is a carboxylic acid [--CO.sub.2H] group or a
reactive derivative thereof; or a nitrile [--CN] or an imine salt
with a bifunctional reagent W.sup.1R.sup.5aW.sup.2 and, where
necessary, a compound R.sup.5bW.sup.3 [where W.sup.1, W.sup.2 and
W.sup.3, which may be the same or different, is each a reactive
functional group or a protected derivative thereof; and R.sup.5a
and R.sup.5bare components of the heteroaryl group R.sup.5 such
that when added together with W.sup.1, W.sup.2 and W.sup.3 to the
group R.sup.16 in compounds of formula (23) the resulting group
-RW.sup.1 R.sup.5aW.sup.2 or --RW.sup.1
R.sup.5aW.sup.2R.sup.5bW.sup.3 constitutes the heteroaryl group
R.sup.5].
[0205] Reactive derivatives of carboxylic acids for use in this
reaction include acid halides, (e.g. acid chlorides), amides,
including thioamides, or esters, including thioesters. Imine salts
include for example salts of formula [e.g.
--C(OAlk).dbd.NH.sub.2+A.sup.-, where Alk is a C.sub.1-4alkyl group
and A.sup.- is a counterion e.g. a chloride ion].
[0206] In this general reaction the reactive functional groups
represented by W.sup.1, W.sup.2 or W.sup.3 may be any suitable
carbon, nitrogen, sulphur or oxygen nucleophiles. Particular
examples include simple nucleophiles such as carbanions [e.g.
generated by the coupling of an alkyl group with an organometallic
compound], amino, thiol and hydroxyl groups.
[0207] In general, the cyclisation reaction will initially be
performed in a solvent, for example an inert solvent such as a
halocarbon, e.g. dichloromethane, an ether, e.g. a cyclic ether
such as tetrahydrofuran, or a hydrocarbon, e.g. an aromatic
hydrocarbon such as toluene, from a low temperature, e.g. around
-70.degree. C., to around the reflux temperature, where necessary
in the presence of a base or a thiation reagent, e.g. Lawesson's
reagent, followed if necessary by heating, to an elevated
temperature, e.g. the reflux temperature.
[0208] Thus, in one particular example, compounds of formula (1)
wherein R.sup.3, R.sup.6 and R.sup.7 is each a hydrogen atom and
R.sup.5 is a benzothiazolyl, benzoxazolyl or benzimidazolyl group
may be prepared by reaction of a compound of formula (19) where
R.sup.16 is an acid halide, e.g. acid chloride, with a reagent
W.sup.1R.sup.5aW.sup.2 which is 2-aminothiophenol, 2-hydroxyphenol,
or 1,2-diaminobenzene respectively in the presence of a base e.g.
an organic amine such as pyridine, in a solvent e.g. a halocarbon
such as dichloromethane, from around -70.degree. C. to the reflux
temperature.
[0209] In another example of the general cyclisation process, a
compound of formula (23) where R.sup.16 is an acid halide as
described above may be reacted with a compound WI R.sup.5aW.sup.2
which is a monoalkylmalonate, e.g. ethyl hydrogen malonate,
followed by reaction with a compound R.sup.5bW.sup.3 which is
hydrazine to give a compound of formula (1) wherein R.sup.3,
R.sup.6 and R.sup.7 is each a hydrogen atom and R.sup.5 is a
5-hydroxypyrazolyl group.
[0210] In another variation of the cyclisation process, the halide
of formula (23) may be reacted with a compound
W.sup.1R.sup.5aW.sup.2 which is
BrMg(CH.sub.2).sub.3[--O(CH.sub.2).sub.2O--] followed by reaction
in an acid solution with a compound R.sup.5bW.sup.3 which is
methylamine to yield a compound of formula (1) wherein R.sup.3,
R.sup.6 and R.sup.7 is each a hydrogen atom and R.sup.5 is a
N-methyl pyrrole group.
[0211] In a further example of the cyclisation process, the acid
halide of formula (23) may be reacted with a compound
W.sup.1R.sup.5aW.sup.2 which is H.sub.2NNHCSNH.sub.2 in an aromatic
hydrocarbon such as toluene, at an elevated temperature, e.g.
around 150.degree. C., followed by treatment with a base, e.g. an
inorganic base such as sodium bicarbonate to give a compound of
formula (1) wherein R.sup.3, R.sup.6 and R.sup.7 is each a hydrogen
atom and R.sup.5 is a 1,2,4-triazolyl-5-thiolate group.
[0212] Intermediate compounds of formula (23) are particularly
useful and form a further aspect of the invention. Active
derivatives of the acids of formula (23) and other compounds of
formula (23) where R.sup.16 is a nitrile or an imine salt may be
prepared from the corresponding acids [where R.sup.16 is
--CO.sub.2H] using conventional procedures for converting
carboxylic acids to such compounds, for example as described in the
Examples hereinafter.
[0213] Acids of formula (23) [where R.sup.16 is --CO.sub.2H] may be
prepared by hydrolysing a diester of formula (24) 27
[0214] where A.sup.1 is a C14alkyl group, e.g. an ethyl group, with
a base, e.g. sodium hydroxide, in a solvent, e.g. dioxane, at an
elevated temperature, e.g. the reflux temperature, followed by
acidification at an elevated temperature.
[0215] Diesters of formula (24) may be prepared by reacting a
diester of formula (24) 28
[0216] with an organometallic reagent, such as a Grignard reagent
using the conditions described above for the preparation of
alcohols of formula (1).
[0217] In yet another process according to the invention, a
compound of formula (1) where Z is a group (C) may be prepared by
coupling a compound of formula (25), 29
[0218] where E is a boronic acid --B(OH)2 or a tin reagent
Sn(R).sub.3, in which R is an alkyl group, for example a methyl
group, with a reagent Z-L.sup.4, where L.sup.4 is a leaving group,
in the presence of a complex metal catalyst.
[0219] Particular leaving groups L.sup.4 include for example
halogen atoms, e.g. bromine, iodine or chlorine atoms and an alkyl
sulphonate, such as trifluoromethanesulphonate.
[0220] Suitable catalysts include heavy metal catalysts, for
example palladium catalysts, such as tetrakis
(triphenylphosphine)palladium. The reaction may be performed in an
inert solvent, for example an aromatic hydrocarbon such as toluene
or benzene, or an ether, such as dimethoxyethane or dioxane, if
necessary in the presence of a base, e.g. an alkali carbonate such
as sodium carbonate, at an elevated temperature, e.g. the reflux
temperature. In general, the metal catalyst and reaction conditions
may be selected, depending on the nature of the compound of formula
(25) and/or the compound Z-L.sup.4 from a range of known
alternatives for reactions of this type [see for example Miyaura, N
etal, Synth. Comm. (1981), 11, 513; Thompson, W. J. and Gaudino,
J., J. Org. Chem, (1984), 49, 5237 and Sharp, M. J. etal,
Tetrahedron Lett. (1987), 28, 5093].
[0221] Intermediates Z-L.sup.4 are either known compounds or may be
prepared from known starting materials by methods analogous to
those used for the preparation of the known compounds. Thus, for
example, where it is desired to obtain a compound Z-L.sup.4 where
L.sup.4 is a halogen atom such as bromine or chlorine atom and this
compound is not readily available, such a compound may be prepared
by (1) treatment of the corresponding amine with t-butyl nitrite
and anhydrous CuCl.sub.2 or CuBr.sub.2 at elevated temperature, or
(2) with t-butyl thionitrite or t-butyl thionitrate and CuCl.sub.2
or CuBr.sub.2 at room temperature followed by reaction with an
appropriate copper (I) halide such as cuprous chloride or bromide
in an aqueous acid.
[0222] Intermediates of formula (25) may be prepared by
halogen-metal exchange between a compound of formula (13) where Hal
is a bromine atom and an organometallic agent such as n-butyl or
t-butyllithium followed by reaction with a borate such as
triisopropylborate or a tin reagent (R).sub.3SnX, where R is as
described above and X is a halogen atom, such as chlorine atom,
optionally at a low temperature e.g. around -70.degree. C., in a
solvent such as tetrahydrofuran.
[0223] According to another aspect of the invention, a compound of
formula (1) where Z is a group (D) in which -Z.sup.1 is
--NR.sup.12C(O)-- or --C(O)NR.sup.12-- may be prepared by coupling
a compound of formula (26) 30
[0224] where --A is a --CO.sub.2H or --NHR.sup.12 group,
[0225] or an active derivative thereof with a compound
R.sup.12NH(Alk).sub.t(X).sub.nAr or Ar(X).sub.n(Alk).sub.tCO.sub.2H
or an active derivative thereof. Active derivatives of acids of
formula (26) or Ar(X).sub.n(Alk).sub.tCO.sub.2H include, for
example, acid anhydrides, or acid halides, such as acid
chlorides.
[0226] The coupling reaction may be performed using standard
conditions for reactions of this type. Thus for example, the
reaction may be carried out in a solvent, for example an inert
organic solvent such as an ether, e.g. a cyclic ether such as
tetrahydrofuran, an amide, e.g. a substituted amide such as
dimethylformamide, or a halogenated hydrocarbon such as
dichloromethane, at a low temperature, e.g. -30.degree. C. to
ambient temperature such as -20.degree. C. to 0.degree. C.,
optionally in the presence of a base, e.g. an organic base such as
an amine, e.g. triethylamine or a cyclic amine such as
N-methylmorpholine. Where an acid of formula (17) or
Ar(X).sub.n(Alk).sub.tCO.sub.2H is used, the reaction may
additionally be performed in the presence of a condensing agent,
for example a diimide such as N,N'-dicyclohexylcarbodiimide,
advantageously in the presence of a triazole such as
1-hydroxybenzotriazole. Alternatively, the acid may be reacted with
a chloroformate, for example ethylchloroformate, prior to reaction
with the amine.
[0227] Intermediate acids of formula (26) where A is a --CO.sub.2H
group may be prepared by hydrolysis of a corresponding ester of
formula (27) 31
[0228] where Alk.sup.a is an alkyl group; by heating in the
presence of a base, for example an alkali metal hydroxide such as
lithium hydroxide in a solvent such as an alcohol, e.g.
methanol.
[0229] Intermediates of formula (26) where A is a --NHR.sup.12
group and R.sup.12 is a hydrogen atom, may be prepared by
hydrogenation of a corresponding nitro compound of formula (28)
32
[0230] using the reagents described below for the hydrogenation of
a compound of formula (1) where --L is a
--CH.dbd.C(R.sup.1)(R.sup.2) chain to a compound of formula (1)
where --L is a --CH.sub.2CH(R.sup.1)(R.sup.2- ) chain.
[0231] Intermediates of formula (26) where A is a NHR.sup.12 group
in which R.sup.12 is an alkyl group may be prepared by alkylation
of an intermediate of formula (26) in which R.sup.12 is a hydrogen
atom, using an alkyl halide e.g. an alkyl iodide in a solvent, such
as an aromatic solvent, for example benzene.
[0232] Intermediates of formulae (27) and (28) and the reagents
R.sup.12NH(Alk).sub.t(X).sub.nAr and
Ar(X).sub.n(Alk).sub.tCO.sub.2H are known compounds or may be
prepared from known starting materials by methods analogous to
those used for the preparation of the known compounds.
[0233] In yet another aspect of the invention compounds of formula
(1) where Z is a group(D) in which Z.sup.1 is a --C.ident.C-- chain
and n and t is each zero may be prepared by reacting a compound of
formula (29) 33
[0234] with a reagent Ar(X).sub.n(Alk).sub.tL.sup.5 (where L.sup.5
is a leaving group) in the presence of a metal complex catalyst,
and in a solvent
[0235] Examples of L.sup.5 leaving groups include halogen atoms
such as bromine, iodine or chlorine atoms or alkyl triflate such as
trifluoromethane sulphonate. Suitable solvents include for example
an amine, for example a tertiary amine, e.g. triethylamine, a
secondary amine, e.g. dimethylamine or a primary amine e.g.
n-butylamine.
[0236] Metal complex catalysts include palladium catalysts, such as
Pd(Hal).sub.2(PPh.sub.3).sub.2 or Pd(PPh.sub.3) 4 (where Hal is a
halogen atom e.g. a chlorine atom) in the presence of copper (I)
iodide, at a temperature from room temperature to an elevated
temperature, e.g. the reflux temperature. (Comprehensive organic
synthesis, vol. 3., 531-541; Trost, Fleming. Pergamon Press,
1991).
[0237] Intermediates of formula (29) may be prepared by reacting a
dihalide of formula (30) 34
[0238] where Hal is a halogen atom, e.g. a bromine atom, with a
base such as an organometallic base, for example an organolithium,
e.g. n-butyllithium, in a solvent such as an ether, e.g.
tetrahydrofuran or diethylether, at a temperature from around
-78.degree. C. to room temperature.
[0239] Intermediates of formula (30) may be prepared by reacting an
aldehyde of formula (12) (where R.sup.4 is a hydrogen atom) with a
reagent Hal.sub.2C.dbd.P(Ar.sup.1).sub.3 (where Hal is a halogen
atom, such as a bromine atom and Ar.sup.1 is an aryl group, such as
phenyl or -tolyl), prepared in situ from C(Hal)4 and
P(Ar.sup.1).sub.3 in the presence of a base, such a an
organometallic base, for example an organolithium, e.g.
n-butyllithium).
[0240] In a futher aspect of the invention, compounds of formula
(1) where Z is a group (D) in which Z.sup.1 is a
--NR.sup.12SO.sub.2-- or --SO.sub.2NR.sup.12-- group may be
prepared by reaction of a compound of formula (30) 35
[0241] where (a) W.sup.b is a --NHR.sup.12 group with a compound
Ar(X).sub.n(Alk).sub.tSO.sub.2Hal [where Hal is a halogen atom,
e.g. a bromine or chlorine atom], if necessary in the presence of a
base; or,
[0242] (b) W.sup.b is a --SO.sub.2Hal group with a compound
Ar(X).sub.n(Alk).sub.tNHR.sup.12 using the reagents and conditions
described in (a) above.
[0243] Examples of bases used in this reaction include amine, such
as tertiary amine, for example triethylamine, in a solvent such as
an ether, for example a cyclic ether, e.g. tetrahydrofuran.
[0244] Compounds Ar (X).sub.n(Alk).sub.tNHR.sup.12 and compounds of
formula (30) where Wb is a --NHR.sup.12 group are known compounds
or may be prepared using similar reagents and conditions to those
used to prepare the known compounds.
[0245] Compounds of formula (30) where W.sup.b is --SO.sub.2Hal,
may be prepared by reacting an intermediate halide of formula (13)
with an organometallic reagent, such as an organolithium, e.g.
n-butyllithium in a solvent, such as an ether, e.g.
tetrahydrofuran, at a low temperature e.g. around -60.degree. C. to
-100.degree. C. followed by reaction with sulphuryl chloride, in a
solvent, such as an aliphatic solvent, e.g. n-hexane, at a low
temperature, e.g. around 0.degree. C.
[0246] Compounds of formula (1) where L is a group
--CH(R.sup.1)(R.sup.2) where R.sup.2 is a --CO.sub.2H group may be
prepared by reacting a compound of formula (31) 36
[0247] where Hal.sup.1 is a halogen atom, such as a chlorine or a
bromine atom, with a diazoalkane CH(R.sup.1)N.sub.2 to give the
corresponding diazoketone derivative which is then treated with
water and silver oxide or with silver benzoate and
triethylamine.
[0248] Intermediates of formula (31) may be prepared by oxidation
of an aldehyde of formula (19), using an oxidising agent, such as
permanganate or chromic acid, to give the corresponding carboxylic
acid which is then reacted with a halide reagent, such as
thionylchloride, phosphorous pentachloride or phosphorous
pentabromide.
[0249] Compounds of formula (1) may also be prepared by
interconverting other compounds of formula (1). Thus, for example
where Z is a group (A) in which R.sup.3 is a hydrogen atom may be
prepared by hydrogenation of a compound of formula (1) where Z is a
group (B).
[0250] The hydrogenation may be performed using for example
hydrogen in the presence of a catalyst. Suitable catalysts include
metals such as platinum or palladium optionally supported on an
inert carrier such as carbon or calcium carbonate; nickel, e.g.
Raney nickel, or rhodium. The reaction may be performed in a
suitable solvent, for example an alcohol such as methanol or
ethanol, an ether such as tetrahydrofuran or dioxane, or an ester
such as ethyl acetate, optionally in the presence of a base, for
example a tertiary organic base such as triethylamine, at for
example ambient temperature.
[0251] Alternatively, the reaction may be accomplished by transfer
hydrogenation using an organic hydrogen donor and a transfer agent.
Suitable hydrogen donors include for example acids, such as formic
acid, formates, e.g. ammonium formate, alcohols, such as benzyl
alcohol or ethylene glycol, hydrazine, and cycloalkenes such as
cyclohexene or cyclohexadiene. The transfer agent may be for
example a transition metal, for example palladium or platinum,
optionally supported on an inert carrier as discussed above,
nickel, e.g. Raney nickel, ruthenium, e.g. tris
(triphenylphosphine) ruthenium chloride or copper. The reaction may
generally be performed at an ambient or elevated temperature,
optionally in the presence of a solvent, for example an alcohol
such as ethanol or an acid such as acetic acid.
[0252] In a second example of an interconversion process, compounds
of formula (1) where Z is a group (A) in which R.sup.7 is an
OR.sup.c group where R.sup.c is an alkyl or alkenyl group, may be
prepared by reacting a compound of formula (1) where Z is a group
(A) in which R.sup.7 is a --OH group, with a reagent RC--OH, in the
presence of an acid, such as sulphuric acid.
[0253] In another example of an interconversion process, compounds
of formula (1) where Z is a group (A) in which R.sup.7 is an
OR.sup.c group where R.sup.c is a carboxamido or thiocarboxamido
group may be prepared by reaction of a compound of formula (1)
where Z is a group (A) in which R.sup.7 is a --OH group, with an
isocyanate R.sup.cN.dbd.C.dbd.O or an isothiocyanate
R.sup.cN.dbd.C.dbd.S in the presence of a base, such as sodium
hydride, in a solvent, such as tetrahydrofuran. Compounds
R.sup.cN.dbd.C.dbd.O and R.sup.cN.dbd.C.dbd.S are known compounds
or may be prepared using the reagents and conditions used for the
preparation of the known compounds. When R.sup.cN.dbd.C.dbd.S is
not available, a compound of formula (1) where R.sup.c is a
thiocarboxamido group may be prepared by interconverting a compound
of formula (1) where R.sup.c is a carboxamido group using a
thiation reagent, such as Lawesson's reagent
[2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-di-sulphide],
in an aromatic solvent, such as xylene or toluene.
[0254] In a yet another example of an interconversion process, a
compound of formula (1) where Z is a group (A) in which R.sup.3 is
a fluorine atom may be prepared by reacting a compound of formula
(1) where Z is a group (A) in which R.sup.3 is a hydroxyl group,
with a fluorinating reagent, such as diethylaminosulphur
trifluoride (DAST), in a solvent, for example a chlorinated
solvent, e.g. dichloromethane, at a low temperature, e.g. around
0.degree. C.
[0255] In a still further example of an interconversion process, a
compound of formula (1) where Z is a group (A) in which R.sup.3 is
an alkyl group, may be prepared by alkylation of a compound of
formula (1) where Z is a group (A), and R.sup.3 is a hydrogen atom,
with a reagent R.sup.3L.sup.3 using a base, for example
n-butyllithium or lithium diisopropylamide. In this process,
R.sup.4 in the starting material is preferably an electron
withdrawing group.
[0256] In a still further example of interconversion process, a
compound of formula (1) where L is (X.sup.a).sub.nAlk'Ar' or
Alk'X.sup.aAr' where Alk' is an alkylene chain, may be prepared by
hydrogenation of a compound of formula (1) where Alk' is an
alkenylene or alkynylene chain, using for example hydrogen in the
presence of a metal catalyst, as described above for the
hydrogenation of a compound of formula (1) where Z is a group (B)
to give a compound of formula (1) where Z is the group A.
[0257] Compounds of formula (1) where Z is the group (B) may also
be prepared by dehydrating a compound of formula (1) where Z is the
group (A) and R.sup.3 is a hydroxyl group, by using an acid, e.g.
trifluoroacetic acid, in the presence of a base, such as an amine,
e.g. triethylamine, in a solvent, such as dichloromethane, at a low
temperature, e.g. around -10.degree. C.
[0258] Where it is desired to obtain a particular enantiomer of a
compound of formula (1) this may be produced from a corresponding
mixture of enantiomers using any suitable conventional procedure
for resolving enantiomers.
[0259] Thus for example diastereomeric derivatives, e.g. salts, may
be produced by reaction of a mixture of enantiomers of formula (1)
e.g. a racemate, and an appropriate chiral compound, e.g. a chiral
acid or base. Suitable chiral acids include, for example, tartaric
acid and other tartrates such as dibenzoyl tartrates and ditoluoyl
tartrates, sulphonates such as camphor sulphonates, mandelic acid
and other mandelates and phosphates such as
1,1'-binaphthalene-2,2'-diyl hydrogen phosphate. The diastereomers
may then be separated by any convenient means, for example by
crystallisation and the desired enantiomer recovered, e.g. by
treatment with an acid or base in the instance where the
diastereomer is a salt.
[0260] In another resolution process a racemate of formula (1) may
be separated using chiral High Performance Liquid Chromatography.
Alternatively, if desired a particular enantiomer may be obtained
by using an appropriate chiral intermediate in one of the processes
described above. N-oxides of compounds of formula (1) may be
prepared for example by oxidation of the corresponding nitrogen
base using an oxidising agent such as hydrogen peroxide in the
presence of an acid such as acetic acid, at an elevated
temperature, for example around 70.degree. C. to 80.degree. C., or
alternatively by reaction with a peracid such as peracetic acid in
a solvent, e.g. dichloromethane, at ambient temperature.
[0261] Salts of compounds of formula (1) may be prepared by
reaction of a compound of formula (1) with an appropriate acid or
base in a suitable solvent or mixture of solvents e.g. an organic
solvent such as an ether e.g. diethylether, or an alcohol, e.g.
ethanol using conventional procedures.
[0262] The following Examples illustrate the invention. In the
Examples, the following abbreviations are used DME--ethylene glycol
dimethyl ether; THF--tetrahydrofuran; CH.sub.2Cl.sub.2--
dichloromethane; Et.sub.2O--ether; EtOH--ethanol; RT--room
temperature; DMF--N, N-dimethylformamide; EtOAc--ethyl acetate;
MeOH--methanol.
[0263] Intermediates 1-6 were prepared as described in
International Patent Specification No. WO 94/14742.
[0264] Intermediate 1
[0265] 3-Cyclopentyloxy 4-methoxybenzaldehyde
[0266] Intermediate 2
[0267] (3-Cyclopentyloxy-4-methoxyphenyl)phenylketone
[0268] Intermediate 3
[0269]
(.+-.)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-hydroxy-2-phenyl-e-
thyl] pyridine
[0270] Intermediate 4
[0271] (E) and (Z) isomers of
4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-ph- enylethenyl]
pyridine
[0272] Intermediate 5
[0273] (.+-.)4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]
pyridine
[0274] Intermediate 6
[0275] (i)
(+)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyrid-
ine
[0276] (ii) (-)
4-[2-(3-Cyclopentyloxy4-methoxyphenyl)-2-phenylethyl]pyrid- ine
[0277] Intermediate 7
[0278] a) (R)
4-[2-(3-Hydroxy-4-methoxyphenyl)-2-phenylethyl]pyridine
[0279] Intermediate 6 (i) (430 mg) in dioxane/water (20 ml:lOml)
containing concentrated H.sub.2SO.sub.4 (10 ml) was heated at
90.degree. C. for 1 h. The reaction mixture was cooled, neutralised
with aqueous NaHCO.sub.3 then concentrated in vacuo. The residue
was partitioned between EtOAc (25 ml) and H.sub.2O (15 ml), and the
organic phase separated. The extract was washed with brine (25 ml),
dried (MgSO.sub.4) and concentrated in vacuo. The residue was
recrystallised (EtOH) to afford the title compound (240 mg) as an
off-white crystalline solid m.p. 195-197.degree. C. (Found: C,
78.66;H, 627; N, 4.59. C.sub.20H.sub.19NO.sub.2 requires C,
78.64;H, 6.18; N, 4.42%); .delta..sub.H (CDCl.sub.3) 3.30 (2H, d, J
8 Hz, CHCH.sub.2), 3.86 (3H, s, OMe), 4.13 (1H, t, J 8 Hz,
CHCH.sub.2), 5.7 (1H, br s, OH, 6.63 (1H, dd, J 8.3 Hz, ArH para to
OH), 6.71 (1H, d, J 8.3 Hz, ArH ortho to OMe), 6.80 (1H, d, J 2.2
Hz, ArH ortho to OH), 6.93 (2H, dd, J 4.5, 1.5 Hz, pyridine
H.sub.3, H.sub.5), 7.1-7.3 (5H, m, C.sub.6H.sub.5), and 8.37 (2H,
dd, J 4.5, 1.5 Hz, pyridine H.sub.3, H.sub.6).
[0280] The following Intermediate was prepared in a manner similar
to Intermediate 7a)
[0281] b) (E)-4-[2-(3-Hydroxy-4-methoxyphenyl)ethenyl]pyridine
[0282] From Intermediate 20 (8.0 g, 27.1 mmol) in toluene (200 ml)
and p-toluenesulphonic acid H.sub.2O (10.3 g, 54.2 mmol) under a
nitrogen atmosphere. Recrystallisation (EtOH) gave the title
compound (3.8 g) as an amorphous yellow solid. m.p. 196-199.degree.
C. (Found C, 73.73;H, 6.03; N, 6.06. C.sub.14H.sub.13NO.sub.2
requires C, 73.99;H, 5.77; N, 6.16%). .delta..sub.H (300 MHz;
CDCl.sub.3) 3.92 (3H, s, OCH.sub.3), 6.22 (1H, br s, OH), 6.86 (1H,
d, H 8.3 Hz, ArH.sub.4), 6.86 (1H, d, J 16.2 Hz, HC.dbd.C (trans)),
7.01 (1H, dd, J 8.3, 2.1 Hz, ArH.sub.6), 7.17-7.26 (2H, m,
ArH.sub.2 and HC.dbd.C), 7.34 (2H, dd, J 4.6, 1.6 Hz, pyridine
H.sub.3, H.sub.5), and 8.55 (2H, t, J 4.6, 1.4 Hz, pyridine
H.sub.2, H.sub.6).
[0283] Intermediate 8
[0284] 2-Methoxy4(3-pyridyl)benzaldehyde
[0285] A mixture of 5-bromo-2-methoxybenzaldehyde (10.00 g, 1.82
mmol) and tetrakis (triphenylphosphine)palladium (0) (2.10 g, 1.82
mmol, 3.9 mol %) in DME (filtered through A1.sub.2O.sub.3) (50 ml)
was stirred at RT for 0.25 h. Sodium carbonate (2M, 50 ml, 0.10mol
%) and diethyl (3-pyridyl)borane (6.817 g, 46.36 mmol) were added,
the mixture heated to reflux for 5.5 h then allowed to stand at RT
overnight. The dark brown reaction mixture was partitioned between
water (50 ml) and Et.sub.2O (lOOml) and the organic layer separated
and combined with two further Et.sub.2O extracts (1.times.50 ml,
1.times.25 ml). The organic phase was extracted with 2N
hydrochloric acid (2.times.50 ml) then the aqueous extract was
basified with 3M NaOH and extracted with Et.sub.2O (1.times.150 ml,
2.times.50 ml). The combined organic extract was washed with brine
(50 ml), dried (Na.sub.2SO.sub.4), concentrated in vacuo then
submitted to column chromatography [SiO2; Et.sub.2O] to furnish the
title compound (3.318 g) as a pale yellow solid (Found: C, 73.40;H,
5.20; N, 6.44. C.sub.1-3H.sub.11NO.sub.2 requires C, 73.23;H, 5.20;
N, 6.57%.)
[0286] Intermediate 9
[0287] 2-(S-Bromo-2-methoxyphenyl1,3-dioxane
[0288] A mixture of 5-bromo-2-methoxybenzaldehyde (52.3 g, 243
mmol), 1,3-propanediol (30 ml, 31.69, 415 mmol), and
4-toluenesulphonic acid (0.3 g) in toluene (350 ml) was heated to
reflux in a Dean--Stark apparatus for 20 h. The mixture was cooled
to RT, washed with saturated NaHCO.sub.3 solution (100 ml), then
the organic layer was separated and combined with a
CH.sub.2Cl.sub.2 solution (100 ml). The extract was washed (brine;
50 ml), dried (Na.sub.2SO.sub.4), and concentrated in vacuo to give
a brown oil (66.2 g). The crude product was distilled to afford the
title compound (58.2 g) as a colourless viscous oil b.p.
115-120.degree. C., 0.02 mmHg .delta..sub.H (80 MHz; CDCl.sub.3)
1.2-1.5 (1H, br m, CH.sub.2CHHCH.sub.2), 1.9-2.4 (1H, m,
CH.sub.2CHHCH.sub.2), 3.78 (3H, s, OMe), 3.6-4.4 (4H, m,
CH.sub.2CH.sub.2CH.sub.2), 5.76 (1H, s, OCH), 6.67 (1H, d, J 8.8
Hz, ArH ortho to OMe), 7.33 (1H, dd, J 8.8, 2.3 Hz, ArH para to
acetal), and 7.68 (1H, d, J 2.3 Hz, ArH ortho to acetal); mLz (El)
274 (44%), 273 (31), 272 (45), 271 (27), 216 (34), 215 (47), 214
(35), 213 (44), 193 (34), 135 (22), and 87 (100).
[0289] Intermediate 10
[0290] 3-[2-(1,3-Dioxanyl)]-4methoxybenzaldehyde
[0291] n-BuLi (1,6M solution in hexane) (125 ml, 200 mmol, 1.06
equiv.) was added dropwise to a solution of Intermediate 9 (51.65
g, 189 mmol) in THF (250 ml) at below -65.degree. C. After 3.5 h,
DMF (20 ml, 258 mmol, 1.37 equiv.) was added at below -60.degree.
C. The reaction mixture was allowed to warm to RT then poured into
hydrochloric acid (0.05 M; 500 ml) and immediately extracted with
CH.sub.2Cl.sub.2 (500 ml, 2.times.150 ml). The extract was washed
(brine; 200 ml), dried (K.sub.2CO.sub.3), and concentrated in vacuo
to give a pale yellow oil (44.0 g). The crude product was
triturated with warm hexane (250 ml) to afford the title compound
(38.75 g) as an off-white crystalline solid .delta..sub.H (80 MHz;
CDCl.sub.3) 1,3-1.6 (1H, br m, CH.sub.2CHHCH.sub.2), 1.8-2.5 (1H,
m, CH.sub.2CHHCH.sub.2), 3.89 (3H, s, OMe), 3.7-4.4 (4H, m,
CH.sub.2CH.sub.2CH.sub.2), 5.82 (1H, s, OCH), 6.93 (1H, d, J 8.4
Hz, ArH ortho to OMe), 7.82 (1H, dd, J 8.4, 2.2 Hz, ArH para to
acetal), 8.12 (1H, d, J 2.2 Hz, ArH ortho to acetal), and 9.84 (1H,
s, CHO).
[0292] Intermediate 11
[0293]
3-[3-(1,3-Dioxan-2-methoxyphenyl]-2-(4-pyridyl)propenenitrile
[0294] A mixture of Intermediate 10 (15.0 g, 67.5 mmol) and
4-pyridylacetonitrile hydrochloride (10.75 g, 69.5 mmol) was
stirred at RT in a mixture of EtOH (300 ml) and NaOH solution (3M;
40 ml, 150 mmol). After 1 h, the precipitate was collected by
filtration, washed with EtOH (50 ml), then Et.sub.2O (25 ml) and
dried in vacuo to afford the title compound (15.85 g) as a very
pale yellow solid SH (80 MHz; CDCl.sub.3) 1,3-1.7 (1H, br m,
CH.sub.2CHHCH.sub.2), 2.0-2.4 (1H, m, CH.sub.2CHHCH.sub.2), 3.90
(3H, s, OMe), 3.8-4.4 (4H, m, CH.sub.2CH.sub.2CH.sub.2), 5.83 (1H,
s, OCH), 6.95 (1H, d, J 8.5 Hz, ArH ortho to OMe), 7.47 (2H, dd, J
4.6, 1.7 Hz, pyridine H.sub.3, H.sub.5), 7.63 (1H, s, CH.dbd.C),
7.96 (1H, d, J 2.4 Hz, ArH ortho to acetal), 8.20 (1H, dd, J 8.5,
2.4 Hz, ArH para to acetal), and 8.61 (2H, dd, J 4.6, 1.7 Hz,
pyridine H.sub.2, H.sub.6).
[0295] Intermediate 12
[0296] 5-Bromo-2-methoxybenzylidenecyclopentane
[0297] n-BuLi (1.6M solution in hexane) (72.5 ml, 116 mmol) was
added dropwise at 0.degree. C. to a solution of
cyclopentyltriphenylphosphonium bromide (45.8 g, 111 mmol) in THF
(300 ml). The red solution was stirred at 0.degree. C. for 0.5 h
then treated with a solution of 5-bromo-2-methoxybenzaldehyde (23.5
g, 109 mmol) in THF (150 ml). The reaction mixture was stirred at
RT overnight, concentrated in vacuo, then partitioned between
CH.sub.2Cl.sub.2 (250 ml) and water (150 ml). The organic phase was
separated and combined with further CH.sub.2Cl.sub.2 extracts
(2.times.50 ml). The organic phase was washed (brine; 50 ml), dried
(Na.sub.2SO.sub.4), and concentrated in vacuo. The residue was
subjected to chromatography (SiO.sub.2; CH.sub.2Cl.sub.2) to afford
the title compound (24.6 g), as a colourless oil .delta..sub.H (80
MHz; CDCl.sub.3) 1.6-1.9 (4H, br m, CH.sub.2(CH.sub.2).sub.2),
2.3-2.6 (4H, br m, CH.sub.2(CH.sub.2).sub.2CH.sub.2), 3.76 (3H, s,
OMe), 6.4-6.5 (1H, br m, CH.dbd.C), 6.65 (1H, d, J 8.5 Hz, ArH
ortho to OMe), 7.18 (1H, dd, J 8.5, 2.4 Hz, ArH oara to olefin),
and 7.39 (1H, d, J 2.4 Hz, ArH ortho to olefin).
[0298] Intermediate 13
[0299] 5-Formyl-2-methoxbenzylidenecyclopentane
[0300] n-BuLi (1.6M solution in hexane) (22 ml, 27.7 mmol, 1.1
equiv) was added dropwise at below -70.degree. C. to a solution of
Intermediate 12 (6.81 g, 25.5 mmol) in THF (50 ml). The resulting
orange solution was stirred for a further 0.5 h then DMF (3.0 ml,
39 mmol, 1.5 equiv) was added at below -60.degree. C. The reaction
mixture was allowed to warm to RT, stirred for 1 h, then treated
with hydrochloric acid (10%; 100 ml). After 1 h, the mixture was
extracted with CH.sub.2Cl.sub.2 (150 ml, 2.times.50 ml). The
extract was washed (brine; 50 ml), dried (Na.sub.2SO.sub.4), and
concentrated in vacuo to give a yellow oil (7.0 g). The crude
product was subjected to chromatography (SiO.sub.2;
Et.sub.2O-hexane, 1:3) to afford the title compound (4.58 g) as a
colouriess oil .delta..sub.H (80 MHz; CDCl.sub.3) 1.6-1.9 (4H, br
m, CH.sub.2(CH.sub.2).sub.2), 2.4-2.65 (4H, br m,
CH.sub.2(CH.sub.2).sub.2CH- .sub.2), 3.88 (3H, s, OMe), 6.45-6.6
(1H, br m, CH.dbd.C), 6.89 (1H, d, J 8.6 Hz, ArH ortho to OMe),
7.59 (1H, d, J 2.2 Hz, ArH ortho to olefin), 7.75 (1H, dd, J 8.6,
2.2 Hz, ArH para to olefin), and 9.81 (1H, s, CHO).
[0301] Intermediate 14
[0302] 2-[2-Methoxy-5-(phenylhydroxymethyl)]-1,3-dioxane
[0303] n-BuLi (1.6M solution in hexane) (115 ml, 184 mmol) was
added dropwise at ca -70.degree. C. to a solution of Intermediate 9
(50.3 g, 184 mmol) in THF (1000 ml). A solution of benzaldehyde
(20.5 g, 193 mmol) in THF (100 ml) was added dropwise at ca
-70.degree. C. and the reaction mixture allowed to warm to RT over
3 h. The mixture was quenched with 10% aqueous NH.sub.4Cl solution
(200 ml) and the organic layer separated and combined with EtOAc
extracts (3.times.100 ml). The extract was dried (MgSO.sub.4) and
concentrated in vacuo to afford the title compound (61.0 g) as a
pale yellow crystalline solid. .delta..sub.H (CDCl.sub.3) 1.47 (1H,
br d, J ca 13 Hz, CH.sub.2CHCH.sub.2), 2.15-2.35 (2H, complex m,
CH.sub.2CHCH.sub.2+OH), 3.82 (3H, s, OMe), 3.99 (2H, ca. t, J ca.
11 Hz, CHCH.sub.2CH), 4.23 (2H, dd, J ca. 11.4 Hz, CHCH.sub.2CH),
5.81 (1H, s, ArCH), 5.85 (1H, s, ArCH), 6.83 (1H, d, J 8.6HZ, ArH
ortho to OMe), 7.2-7.4 (6H, m, C.sub.6H.sub.5+ArH para to
dioxolane), and 7.68 (1H, d, J 2.3 Hz, ArH ortho to dioxolane).
[0304] Intermediate 15
[0305] [3-(2-Dioxan-1,3-yl)4methoxy1benzophenone
[0306] A mixture of Intermediate 14 (60.0 g, 200 mmol) and
manganese dioxide (174 g, 2.0 mol) in CH.sub.2Cl.sub.2 (1000 ml)
was stirred at RT for 18 h. The reaction mixture was filtered
through Celite and the filtrate concentrated in vacuo. The residue
was recrystallised from diisopropyl ether-toluene to afford the
title compound (41.0 g) as a white solid. .delta..sub.H
(CDCl.sub.3) 1.41 (1H, br d, J 13.5 Hz, CH.sub.2CHCH.sub.2),
2.1-2.3 (1H, complex m, CH.sub.2CHCH.sub.2), 3.93 (3H, s, OMe),
3.99 (2H, dt, J 2.1, 12.3 Hz, CHCH.sub.2CH), 4.23 (2H, dd, J 4.5,
11.5 Hz, CHCH.sub.2CH), 5.87 (1H, s, ArCH), 6.94 (1H, d, J 8.6HZ,
ArH ortho to OMe), 7.4-7.6 (3H, m, meta and para C.sub.6H.sub.5),
7.75 (2H, d, J 8.4 Hz ortho C.sub.6H.sub.5), 7.84 (1H, dd, J. 2.3,
8.6 Hz, ArH para to dioxane), and 8.15 (1H, dd, J 2.3 Hz, ArH ortho
to dioxane).
[0307] Intermediate 16
[0308]
(.+-.)-1-{3-[2-(1,3-Dioxanyl)]-methoxyphenyl}-1-phenyl-2-(4-pyridyl-
) ethanol
[0309] n-BuLi (2.5M solution in hexane) (55.6 ml, 139 mmol,
1.05equiv.) was added to a solution of 4-methylpyridine (11.9 ml,
133 mmol) in THF (500 ml) at -70.degree. C. The mixture was allowed
to stir at -70.degree. C. for 0.5 h then a solution of Intermediate
15 (40.0 g, 133 mmol) in THF (250 ml) was added dropwise and
allowed to warm to RT overnight. The reaction mixture was quenched
with 10% aqueous NH.sub.4Cl solution (lOOml) and extracted with
CH.sub.2Cl.sub.2 (300 ml, 100 ml). The extract was separated, dried
(Na.sub.2SO.sub.4), and concentrated in vacuo. The residue was
recrystallised from EtOAc to afford the title compound (28.9 g) as
a white crystalline solid .delta..sub.H (CDCl.sub.3) 1.41 (1H, br
d, J 13.5 Hz, CH.sub.2CHCH.sub.2), 2.15-2.25 (1H, complex m,
CH.sub.2CHCH.sub.2), 2.4 (1H, br s, OH), 3.54 (1H, d, J 13.1 Hz,
pyridine CH),3.62 (1H, d, J 13.1 Hz, pyridine CH), 3.82 (3H, s,
OMe), 3.99 (2H, dt, J 2.1, 12.3 Hz, CHCH.sub.2CH), 4.23 (2H, dd, J
5.1,10.7 Hz, CHCH.sub.2CH), 5.84 (1H, s, ArCH), 6.75-6.85 (3H, m,
ArH meta/para to dioxane +C.sub.6H.sub.5 para H), 7.15-7.35 (6H, m
pyridine H.sub.3, H.sub.5+C.sub.6H.sub.5 ortho/meta H), 7.76 (1H,
d, J 2,3HZ, ArH ortho to dioxane), and 8.30 (1H, dd, J 1.5, 4.5 Hz,
pyridine H.sub.2, H.sub.6)
[0310] Intermediate 17
[0311] (E,
Z)4-{-2-[3-(2-Dioxan-1,3-yl-4methoxyphenyl]ethenyl}pyridine
[0312] Trifluoroacetic anhydride (11.3 ml, 80.2 mmol) was added
dropwise at ca. -10.degree. C. to a solution of Intermediate 16
(28.59 g, 72.9 mmol) and triethylamine (15.2 ml, 109.3 mmol) in
CH.sub.2Cl.sub.2 (500 ml). The reaction mixture was stirred at
-10.degree. C. for 0.5 h then quenched with 10% aqueous sodium
carbonate solution (250 ml). The organic layer was separated and
combined with further CH.sub.2Cl.sub.2 extracts (3.times.50 ml),
then dried (Na.sub.2SO.sub.4) and concentrated in vacua. The
residue was subjected to chromatography (SiO.sub.2; 5% MeOH
CH.sub.2Cl.sub.2) to afford the title compound (20.0 g) as a yellow
solid. .delta..sub.H (CDCl.sub.3) ('Hnmr indicates a 3:1 mlxture of
isomers; data for major isomer, possibly (E)--, presented) 1.43
(1H, br d, J 12.6 Hz, CH.sub.2CHCH.sub.2), 2.15-2.35 (1H, complex
m, CH.sub.2CHCH.sub.2), 3.84 (3H, s, OMe), 4.01 (2H, ca. t, J 11.5
Hz, CHCH.sub.2CH), 4.26 (2H, dd, J 4.9, 11.5 Hz, CHCH.sub.2CH),
5.88 (1H, s, ArCH), 6.77 (1H, d, J 8.6 Hz, ArH ortho to OMe), 6.81
(2H, d, J 5.8 Hz, pyridine H.sub.3, H.sub.5), 6.85 (1H, s,
C.dbd.CH), 7.03 (1H, dd, J 2.3, 8.6 Hz, ArH para to dioxane),
7.1-7.2 (2H, m, C.sub.6H.sub.3H.sub.2), 7.3-7.35 (3H, m,
C.sub.6H.sub.3H.sub.2), 7.83 (1H, d, J 2.4 Hz, ArH ortho to
dioxane) and 8.30 (2H, d, J 5.8 Hz, pyridine H.sub.2, H.sub.6)
[0313] Intermediate 18
[0314] 2-Methoxy-5-yl-phenyl-2-(4-pyridyl)ethyl]benzaldehyde
[0315] A solution of Intermediate 17 (17.5 g, 46.8 mmol) in
THF-MeOH (5:1; 1200 ml) containing 10% Pd/C (0.5 g) was
hydrogenated at RT over 1 h. The reaction mixture was filtered
through Celite and then concentrated in vacuo. The crude alkane
(15.0 g) in THF (750 ml) and 10% hydrochloric acid (75 ml) was
vigorously stirred at RT for 0.5 h, then quenched with aqueous
NaHCO.sub.3 (2M; 100 ml). The organic solvent was removed in vacua
and the aqueous phase extracted with EtOAC (3.times.100 ml). The
extract was dried (MgSO.sub.4) and concentrated in vacuo to afford
the title compound (12.6 g). .delta..sub.H (CDCl.sub.3) 3.34 (2H,
d, J 8.0 Hz, CHCH.sub.2pyridine), 3.87 (3H, s, OMe), 4.22 (1H, t, J
8.0 Hz, CHCH.sub.2pyridine), 6.87 (1H, d, J 8.6 Hz, ArH ortho to
OMe), 6.92 (2H, d, J 6.0 Hz, H.sub.2, H.sub.6 of C.sub.6H.sub.5),
7.1-7.3 (5H, m, pyridine H.sub.3, H.sub.5+H.sub.3, H.sub.4, H.sub.5
of C.sub.6H.sub.5), 7.32 (1H, dd,J 2.4, 8.6 Hz, ArHpara to CHO),
7.74 (1H, d, J 2.4 Hz, ArH ortho to CHO), 8.38 (2H, ca. d, J 4.5
Hz, pyridine H.sub.2, H.sub.6) and 10.42 (1H, s, ArCHO).
[0316] Intermediate 19
[0317] (.+-.)4-[2-(3-Cyclopentyloxy
4methoxyphenyl)-2-hydroxyethylpyridine
[0318] The title compound was prepared as described in the
International Patent Application No. WO94/20446.
[0319] Intermediate 20
[0320]
(E)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)ethenyl]pyridine
[0321] The title compound was prepared as described in the
International Patent Application No. WO94/20446.
[0322] Intermediate 21
[0323] 5-Phentylpentylbromide
[0324] To a stirred solution of 5-phenyl-1-pentanol (2.80 g, 17.07
mmol) in dry CH.sub.2Cl.sub.2 (80 ml) at 0.degree. C. under a
nitrogen atmosphere was added PBr3 (4.62 g, 1.62 ml. 17.07 mmol).
The mixture was stirred at RT for 34 min and quenched cautiously
with saturated NaHCO.sub.3 solution (100 ml). The layers were
separated and the aqueous layer extracted with CH.sub.2Cl.sub.2
(2.times.60 ml). The combined organic extract was washed with water
(80 ml), dried (MgSO.sub.4)and the residue subjected to
chromatography (SiO.sub.2) to give the title compound (0.69 g) as a
clear oil.
EXAMPLE 1
[0325] a)
(R)-4-[2-(3-Benzyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine
[0326] Potassium tert-butoxide (180 mg, 1.57 mmol) was added to a
stirred solution of Intermediate 7 (400 mg, 1.31 mmol) in THF (15
ml) and DMF (5 ml). The mixture was stirred at RT for 0.25 h then
treated with benzyl bromide (246 mg, 1.44 mmol). After 0.5 h at RT,
the reaction mixture was quenched with water (5 ml) and
concentrated in vacuo. The residue was partitioned between water
(20 ml) and EtOAc (30 ml). The organic layer was separated and
combined with further EtOAC extracts (2.times.30 ml). The extract
was dried (MgSO.sub.4) and concentrated in vacuo to give a pale
brown oil which was subjected to chromatography (SiO.sub.2;
EtOAc-hexane, 17:3) to afford the title compound (434 mg) as a
colourless oil SH (CDCl.sub.3) 3.18 (1H, dd, J 13.6, 8.4 Hz,
CHCH.sub.AH.sub.B), 3.25 (1H, dd, J 13.6, 7.4 Hz,
CHCH.sub.AH.sub.B), 3.84 (3H, s, OMe), 4.09 (1H, t, J 7.9 Hz,
CHCH.sub.AH.sub.B), 5.08 (2H, S, OCH.sub.2), 6.58-6.8 (3H, m,
C.sub.6H.sub.3), 6.82 (2H, dd, J 4.5,1.6 Hz, pyridine H.sub.3,
H.sub.5), 7.05-7.4 (10H, m, 2.times.C.sub.6H.sub.5), and 8.35 (2H,
dd, J 4.5,1.6 Hz, pyridine H.sub.2,H.sub.6).
[0327] The following Example was prepared in a manner similar to
compound of Example 1a).
[0328] b)
4-{2-(R)[4-Methoxy3-(phenylpentloxy)phenyl]-2-phenylethyl}
pyridine
[0329] From Intermediate 7a) (0.29 g, 0.95 mmol) in THF (5 ml) and
DMF (3 ml), potassium t-butoxide (0.12 g, 1.04 mmol) and
5-phenylbromopentane (0.26 g, 1.14 mmol) in THF (5 ml).
Chromatography (SiO.sub.2; EtOAc-hexane, 1:1) gave the title
compound (0.339) as a clear colourless oil. (Found C, 82.16;H,
7.38; N, 3.06. C.sub.31H.sub.33NO2 requires C, 82.45;H, 7.37; N,
3.10%) .delta..sub.H (300 MHz: CDCl.sub.3) 1.40-1.85 (6H, m,
(CH.sub.2).sub.3), 2.63 (2H, t, J 7.6 Hz, C.sub.6H.sub.5CH.sub.2)-
, 3.31 (2H, d, J 7.9 Hz, CH.sub.2 pyridine), 3.81 (3H, s,
OCH.sub.3), 3.90 (2H, dt, J 6.8, 1.6 Hz, OCH.sub.2), 4.15 (1H, t, J
9 Hz, CH.sub.2CH), 6.65 (1H, d, J 1.8 Hz, ArH.sub.2), 6.7-6.8 (2H,
m, ArH), 6.92 (2H, dd, J 4.6, 1.4 Hz, pyridine H.sub.3, H.sub.5),
7.15-7.30 (10H, m, 2.times.C.sub.6H.sub.5), and 8.38 (2H ,dd, J
4.5, 1.5 Hz, H.sub.2, H.sub.6, pyridine).
[0330] c)
(E)-4-[4-Methoxy-3-(5-phenylpentyloxy)phenylethenyl]pyridine
[0331] From Intermediate 7b) (0.68 g, 3.0 mmol) potassium
t-butoxide (0.40 g, 3.6 mmol) and Intermediate 21 (0.68 g, 3.0
mmol). Chromatography (SiO.sub.2; EtOAc-hexane, 3:1) gave a
slightly off-white solid (0.874 g). A small portion (0.34 g) was
recrystallised (diisopropylether; 9 ml) to give the title compound
(0.312 g) as an amorphous white solid (0.312 g). m.p.
98-100.degree. C. (Found C, 80.31;H, 7.27; N, 3.56.
C.sub.25H.sub.27NO.sub.2 requires C, 80.40;H, 7.29; N, 3.7%).
.delta..sub.H (300 MHz; CDCl.sub.3) 1.5-2.0 (6H, m,
(CH.sub.2).sub.3), 2.67 (2H. t. J. 7.7 Hz, ArCH.sub.2), 3.89 (3H,
s, OCH.sub.3), 4.07 (2H, t, J 6.8 Hz, OCH.sub.2), 6.86 (1H, d, J
16.3,HC.dbd.C), 6.88 (1H, d, J 8.9 Hz, ArH), 7.07-7.31 (6H, m, ArH
and HC.dbd.C), 7.33 (2H, dd, J 4.6, 1.5 Hz, pyridine H.sub.3,
H.sub.5) and 8.55 (2H, dd, J 4.6,1.5 Hz pyridine
H.sub.2,H.sub.6).
EXAMPLE 2
[0332] a)
(R)-4-[2-(4-Methoxy-3-(3-thienyloxy)phenyl)-2-phenylethyl]
pyridine
[0333] A mixture of Intermediate 7a) (500 mg, 1.64 mmol), anhydrous
potassium carbonate (450 mg, 3.28 mmol) and 3-bromothiophene (3.48
g, 21.3 mmol) in pyridine (4 ml) was heated to Ca 90.degree. C.
Copper (II) oxide (330 mg, 4.1 mmol) was added and the reaction
mixture heated to reflux for 52 h. CH.sub.2Cl.sub.2 (20 ml) was
added to the cooled reaction mixture which was then filtered. The
filtrate was concentrated in vacuo and the residue subjected to
chromatography (SiO2; EtOAc-hexane, 17:3) to afford the title
compound (315 mg), as a colourless oil. (Found C, 74.15;H, 5.40; N,
3.50. C.sub.24H.sub.21NO.sub.2S requires C, 74.39;H, 5.46; N,
3.61%) .delta..sub.H (CDCl.sub.3) 3.24 (1H, dd, J 13.6, 8.5 Hz,
CHxCH.sub.AH.sub.B), 3.30 (1H, dd, J 13.6, 7.4 Hz,
CHxCH.sub.AH.sub.B), 3.81 (3H, s, OMe), 4.14 (1H, t, J ca. 8.0 Hz,
CHxCH.sub.AH.sub.B), 6.28 (1H, dd, J 3.3, 1.5 Hz, thiophene H),
6.74 (1H, dd, J 5.2, 1.5 Hz, thiophene H), 6.8-6.95 (5H, m),
7.1-7.3 (6H, m), and 8.39 (2H, br s, pyridine H.sub.2,
H.sub.6).
[0334] The following Examples were prepared in a manner similar to
compound of Example 2a).
[0335] b)
4-{2-(R)-r3-(4-Biphenyloxy)4methoxyphenyl)-2-phenyl]ethyl}
pyridine
[0336] From Intermediate 7a) (0.4 g, 1.131 mmol), anhydrous
potassium carbonate (0.36 g, 2.62 mmol), 4-bromobiphenyl (0.4 g,
1.70 mmol) and copper (II) oxide (0.26 g, 3.3 mmol). Chromatography
(SiO2; EtOAc-hexane, 1:1 then 7:3) gave the title compound (0.383
g) as a clear colourless foamy oil. (Found C, 83.40;H, 5.89; N,
3.03. C.sub.32H.sub.27NO.sub.2 requires C, 83.92;H, 5.95; N,
3.06%). .delta..sub.H (300 MHz; CDCl.sub.3) 3.25 (1H, dd, J 13.6,
8.5 Hz, pyridine CH.sub.AH.sub.B), 3.25 (1H, dd, J 13.6, 7.5 Hz,
pyridine CH.sub.AH.sub.B) 3.80 (3H, s, OCH.sub.3), 4.16 (1H, t,
C6H.sub.3CH), 6.85-7.0 (7H, m, ArH, pyridine H.sub.3, H.sub.5), 7,
15-7.6 (12H, m, ArH) and 8.40 (2H, br s, pyridine H.sub.2,
H.sub.6).
[0337] c)
4-[2-(R)-(4-Methoxy-3-phenyloxyphenyl)-2-phenylethyl]pyridine
[0338] From Intermediate 7a) (0.4 g, 1.31 mmol), anhydrous
potassium carbonate (0.36 g, 2.62 mmol), bromobenzene (2.98 g, 2.0
ml, 19 mmol) and copper (11) oxide (0.26 g, 3.3 mmol).
Chromatography (SiO.sub.2; EtOAc-hexane, 17:3) gave the title
compound (0.433 g) as a clear oil. (Found C, 81.45;H, 5.97; N,
3.48. C.sub.26H.sub.32NO2 requires C, 81.86;H, 6.08; N, 3.67%).
.delta..sub.H (300 MHz; CDCl.sub.3) 3.24 (1H, dd, J 13.6, 8.7 Hz,
pyridine CH.sub.AH.sub.B), 3.29(1H, dd, J 13.6, 7.4 Hz, pyridine
CH.sub.AH.sub.B), 3.78 (3H, s, OCH.sub.3), 4.14 (1H, t, J 7.9 Hz,
CH.sub.2CH), 6.80-6.94 (7H, m, ArH, pyridine H.sub.3, H.sub.5),
7.00-7.06 (1H, m, ArH), 7,15-7.3 (7H, m, ArH) and 8.39 (2H, dd, J
4.5, 1.6 Hz, pyridine H.sub.2, H.sub.6).
EXAMPLE 3
[0339]
(2R)-4-[2(3-((2RS)exo-Bicyclo[2.2.1]hept-2-yloxy)4-methoxyphenyl)-2-
-phenylethyl]pyridine
[0340] Diethylazodicarboxylate (522 mg, 3.0 mmol) was added to a
mixture of Intermediate 7a) (610 mg, 2.0 mmol),
(+)-endo-2-norborneol (224 mg, 2.0 mmol), and triphenylphosphine
(787 mg, 3.0 mmol) in THF (5 ml) and the mixture heated to reflux
for 40 h. The reaction mixture was poured into saturated NaHCO3
solution (lOml) and extracted with CH.sub.2Cl.sub.2 (2.times.25
ml). The extract was dried (Na.sub.2SO.sub.4), concentrated in
vacuo, and then subjected to chromatography (SiO2; Et.sub.2O) to
afford the title compound (256 mg) as a colourless oil. SH
(CDCl.sub.3) 1.0-1.75 (8H, m, norbornyl H's), 2.2-2.4 (2H, br m,
norbornyl H's), 3.25-3.4 (2H, m, CHCH.sub.2), 3.77 (3H, s, OMe),
4.05 (1H, br d, J 5.6 Hz, OCH), 4.14 (1H, t, J 7.9 Hz, CHCH.sub.2),
6.6-6.8 (3H, m, C.sub.6H.sub.3), 6.92 (2H, ca d, J 4.5 Hz, pyridine
H.sub.3, H.sub.5), 7.1-7.3 (5H, m, C.sub.6H.sub.5), 8.38 (2H,
ca.d., J 4.5 Hz, pyridine H.sub.2, H.sub.6); mLz (El) 399 (M.sup.+,
8%), 307 (13), 305 (18), 213 (100), 152 (18), 95 (51), 93 (19), and
67 (37).
EXAMPLE 4
[0341] a) 3-(3-Cyclopentylidenyl-4-methoxyphenyl)pyridine
hydrochloride
[0342] To a solution of cyclopentyl triphenylphosphonium bromide
(3.66 g, 8.9 mmol) in THF (50 ml) was added dropwise n-BuLi (1.6M
in hexane) (5.6 ml, 9.0 mmol) at 0.degree. C. The red solution was
stirred and left to warm up to RT for 1 h then treated with a
solution of Intermediate 8 (1.9 g, 8.9 mmol) in THF (25 ml) at
0.degree. C. After stirring for 1 h at RT the reaction mixture was
quenched with water (50 ml) and extracted with CH.sub.2Cl.sub.2
(1.times.75, 1.times.50, 1.times.25 ml). The extract was washed
(brine), dried (Na.sub.2SO.sub.4) and concentrated in vacua to give
a colourless syrup which crystallised to give a white solid.
Purification by column chromatography [SiO.sub.2; EtOAc] furnished
the title compound free base (1.80 g) as a white solid.
[0343] A portion of the free base (388 mg) was treated with
ethanolic HCl and diluted with a little Et.sub.2O. The precipitate
was decanted, washed (Et.sub.2O) and dried in vacua to furnish the
title compound (420 mg) as a pale yellow solid (Found: C, 71.56;H,
6.68; N, 4.74. C.sub.18H.sub.1gNO. HCl requires C, 71.63;H, 6.68;
N, 4.64%). .delta..sub.H (80 MHz; CDCl.sub.3) 1.6-1.9 (4H, br m,
CH.sub.2(CH.sub.2).sub.2CH.sub.2), 2.4-2.65 (4H, br m,
CH.sub.2(CH.sub.2).sub.2CH.sub.2), 3.89 (3H, s, OMe), 6.5-6.6 (1H,
br m, HC.dbd.C), 6.97 (1H, d, J 8.6 Hz, ArH ortho to OMe), 7.40
(1H, dd, J. 8.6, 2.2 Hz, ArH para to C.dbd.C), 7.53 (1H, d J 2.2
Hz, ArH ortho to C.dbd.C), 7.9 (1H, dd, J. 5.6, 8.3 Hz, pyridine
H.sub.5), 8.4-8.7 (2H, m, pyridine H.sub.4, H.sub.6) and 8.85 (1H,
d, J 2.2 Hz, pyridine H.sub.2).
[0344] b)
4-[2-(3-Cyclopentylidenylmethyl4-methoxyphenyl)-2-phenyl-ethyl]p-
yridine hyrochloride hemihydrate
[0345] From n-BuLi (1,6M solution in hexane) (2.1 ml, 3.55 mmol,
1.06 equiv), cyclopentyltriphenylphosphonium bromide (1.43 g, 3.46
mmol, 1.1 equiv) in THF (30 ml) and Intermediate 18 (1.00 g, 3.15
mmol) in THF (20 ml). Chromatography (SiO.sub.2; 2%
MeOH--CH.sub.2Cl.sub.2) afforded the title compound free base (420
mg). .delta..sub.H (CDCl.sub.3) 1.6-1.8 (4H, br m,
CH.sub.2(CH.sub.2).sub.2CH.sub.2), 2.2-2.35 (2H, br m,
CH(CH.sub.2)2CH), 2.4-2.55 (2H, br m, CH(CH.sub.2).sub.2CH), 3.22
(2H, d, J 7.8 Hz, CHCH.sub.2 pyridine), 3.78 (3H, s, OMe), 4.17
(1H, t, J 7.8 Hz, CHCH.sub.2 pyridine), 6.51 (1H, ca. t, J 2.2 Hz,
HC.dbd.CCH.sub.2), 6.72 (1H, d, J 8.4 Hz, ArH ortho to OMe),
6.85-7.0 (3H, m, H of C.sub.6H.sub.3+pyridine H.sub.3, H.sub.5),
7.1-7.3 (6H, m, C.sub.6H.sub.5+H of C6H.sub.3) and 8.38 (2H, ca. d,
J 5.7 Hz, pyridine H.sub.2, H.sub.6).
[0346] The base (420 mg) was dissolved in Et.sub.2O (5 ml) and
treated dropwise with ethanolic HCl. The precipitated product was
collected by filtration and dried in vacua to afford the title
compound as a white solid (Found: C, 75.23;H, 6.72; N, 3.11;
C.sub.26H.sub.28NO. 0.5H.sub.2O requires C, 75.25;H, 7.04; N,
3.38%). .delta..sub.H (CDCl.sub.3) 1.6-1.8 (4H, br m,
CH.sub.2(CH.sub.2).sub.2CH.sub.2), 2.2-2.35 (2H, br m,
CH(CH.sub.2)2CH), 2.4-2.55 (2H, br m, CH(CH.sub.2).sub.2CH), 3.59
(2H, d, J 8.0 Hz, CHCH.sub.2 pyridine), 3.80 (3H, s, OMe),
[0347] 4.18 (1H, t, J 8.0 Hz, CHCH.sub.2 pyridine), 6.51 (1H, ca.
t, J 2.0 Hz, CH.dbd.CCH.sub.2), 6.73 (1H, d, J 8.4 Hz, ArH ortho to
OMe), 6.87 (1H, dd, J 2.2, 8.4 Hz, ArH para to olefin), 7.1-7.45
(6H, m, C.sub.6H.sub.5+ArH ortho to olefin), 7.46 (2H, ca. d, J ca.
6.4 Hz, pyridine H.sub.3, H.sub.5), and 8.50 (2H, ca. d, J ca. 6.4
Hz, pyridine H.sub.2, H.sub.6); m/z (ESI) 370 (M.sup.++1-HCl, 18%),
369 (M.sup.+-HCl, 95), 277 (100), 178 (55), 165 (75), and 152
(45).
[0348] c)
4-[2-(3-Cyclohexylidenylmethyl-4-methoxyphenyl)-2-phenyl-ethyl]p-
yridine hydrochloride
[0349] From Intermediate 18 (1.00 g, 3.15 mmol),
cyclohexyltriphenylphosph- onium bromide (1.47 g, 3.46 mmol, 1.1
equiv) and n-BuLi (1.6 M solution in hexane) (2.1 ml, 3.36 mmol,
1.07 equiv). The crude product was subjected to chromatography
(SiO2; 2% MeOH--CH.sub.2Cl.sub.2) to afford the title compound free
base (1.07 g).
[0350] A portion of the free base (400 mg) was dissolved in
Et.sub.2O (5 ml) and treated with ethanolic HCl to afford the title
compound as a white solid (Found: C, 77.32;H, 7.15; N, 3.24.
C.sub.27H.sub.30CINO requires C, 77.21;H, 7.20; N, 3.34%).
.delta..sub.H (CDCl.sub.3) 1.4-1.75 (6H, br m,
CH.sub.2(CH.sub.2).sub.3CH.sub.2), 2.0-2.1 (2H, br m,
CH(CH.sub.2).sub.3CH), 2.2-2.3 (2H, br m, CH(CH.sub.2).sub.3CH),
3.58(2H, d, J 8.0 Hz, CHCH.sub.2 pyridine), 3.78 (3H, s, OMe), 4.18
(1H, t, J 8.0 Hz, CHCH.sub.2 pyridine), 6.15 (1H, ca. s,
HC.dbd.CCH.sub.2), 6.73 (1H, d, J 9.0 Hz, ArH ortho to OMe),
6.85-6.95 (2H, m, ArH), 7.1-7.35 (5H, m, ArH), 7.46 (2H, d, J 5.8
Hz, pyridine H.sub.3, H.sub.5), and 8.50 (2H, d. J 5.8 Hz, pyridine
H.sub.2, H.sub.6); m/z (ESI) 384 (M.sup.++1-HCl, 37%), 383
(M.sup.+-HCl, 85), 291 (100), 178 (32), 165 (50), 152 (28) and 91
(33).
[0351] d)
4-{2(R)-[3-(Phenyl-1,3-butedienyl)-4-methoxyphenyl]-2-phenylethy-
l}pyridine
[0352] From n-BuLi (1.6M solution in hexane) (1.2 ml, 2.93 mmol,
1.05equiv).` cinnamyltriphenylphosphonium bromide (930.6 mg, 2.02
mmol) and Intermediate 9 (583.9 mg, 1.84 mmol). Chromatography
(SiO.sub.2; EtOAc-hexane, 1:1) gave the title compound.
EXAMPLE 5
[0353] a) 3-(3-Cyclopentylmethyl-4-methoxyphenyl) pyridine
hydro-chloride
[0354] The compound of Example 4a) (485 mg) was hydrogenated over
the weekend in EtOH (25 ml) in the presence of 5% Pd/C (50 mg). The
reaction mixture was filtered through Celite and concentrated in
vacuo to give the title compound free base (464 mg) as a colourless
oil.
[0355] The free base was dissolved in warm ethanolic HCl,
precipitated with Et.sub.2O, decanted and dried in vacuo to yield
the title compound (485 mg) as a white solid. (Found: C, 70.98;H,
7.31; N, 4.62. C.sub.18H.sub.21NO. HCl requires C, 71.16;H, 7.30;
N, 4.61%). SH (80 MHz; CDCb) 1.5-1.8 ((H, v.br m, cyclopentyl H's),
2.67 (2H, d, J 6.8 Hz,CH.sub.2 cyclopentyl), 3.87 (3H, s, OMe),
6.95 (1H, d, J 8.0 Hz, ArH ortho to OMe), 7.35-7.50 (2H, m, 2xArH
meta to OMe), 7.8-8.0 (1H, m, pyridine H.sub.5), 8.4-8.65 (2H, m,
pyridine H) and 8.87 (1H, .about.d, J 2.0 Hz, pyridine
H.sub.2).
[0356] The following compound was prepared in a manner similar to
the compound of Example 5a)
[0357] b)
4{-2-r4-Methoxy-3-(5-phenylpentyloxy)phenylethyl}pyridine
[0358] From the compound of Example 1c) (0.534 g, 1.43 mmol) and 5%
Pd/C catalyst (40 mg). Chromatography (SiO.sub.2; EtOAc-hexane,
3:1) gave a clear colourless oil which solidified to give the title
compound (0.45 g) as a white amorphous solid. m.p. 59-62.degree. C.
(Found C, 79.63;H, 7.79; N, 3.57. C.sub.25H.sub.29NO.sub.2 requires
C, 79.96;H, 7.78; N, 3.73%) .delta..sub.H (300 MHz; CDCl.sub.3)
1.4-1.9 (6H, br m, (CH.sub.2).sub.3), 2.65 (2H, t, J 7.7 Hz,
ArCH.sub.2), 2.83-2.91 (4H, m, (CH.sub.2).sub.2), 3.83 (3H, s,
OCH.sub.3), 3.94 (2H, t, J 6.8 Hz, OCH.sub.2), 6.63 (1H, d, J 2.0
Hz, ArH.sub.2), 6.66 (1H, dd, J 8.0, 2.0 Hz, ArH.sub.6), 6.78 (1H,
d, J 8.1 Hz, ArH.sub.4), 7.06 (2H, dd, J 4.4, 1.6 Hz, pyridine
H.sub.3, H.sub.5), 7.15-7.3 (5H, m, ArH), and 8.47 (2H, dd, J 4.4,
1.6 Hz, pyridine H.sub.2, H.sub.6).
[0359] c) 4-[2-(4-Methoxy-3-butylphenyl)-2-phenylethyl]pyridine
hydrochloride
[0360] From the compound of Example 4d). Chromatography (SiO.sub.2;
EtOAc-hexane, 1:9) gave the title compound free base as a
colourless oil. The free base was treated with ethanolic HCl to
give the title compound as an off-white solid. (Found C, 78.13;H,
6.98; N, 3.02 C.sub.30H.sub.32NOCl requires C, 78.67;H, 7.04; N,
3.06%). .delta..sub.H (CDCl.sub.3) 1.55 (4H, m,
CH.sub.2(CH.sub.2)CH.sub.2), 2.60 (4H, m,
CH.sub.2(CH.sub.2).sub.2CH.sub.2), 3.55 (2H, d, pyridine
(CH.sub.2), 3.75 (3H, s, OCH.sub.3), 4.15 (1H, t, ARCH), 6.70 (m,
ArH), 6.90 (2H, m, ArH), 7.10-7.30 (10 H, m, 2xC.sub.6H.sub.5), 7.4
(2H, d, ArH) and 8.55 (2H, d, ArH).
EXAMPLE 6
[0361] Methyl 3-[Cyclopentylidenyl4methoxyphenyl]propenoate
[0362] A mixture of trimethylphosphonoacetate (2.7 g, 14.8 mmol)
and Intermediate 13 (3.00 g, 13.9 mmol) in MeOH (30 ml) was added
to a solution of sodium methoxide [prepared from sodium (0.4 g,
17.4 mmol) in MeOH (50 ml) at RT]. The reaction mixture was stirred
at RT overnight then the crystalline product collected by
filtration, washed with MeOH (2.times.10 ml), and dried in vacuo to
afford the title compound (2.70 g) as a white solid (Found: C,
74.73;H, 7.43 C.sub.17H2003 requires: C, 74.97;H, 7.40%);
.delta..sub.H (80 MHz; CDCl.sub.3) 1.5-1.8 (4H, br m,
CH.sub.2(CH.sub.2).sub.2), 2.4-2.6 (4H, br m,
CH.sub.2(CH.sub.2).sub.2CH.- sub.2), 3.77 (3H, s, OMe), 6.25 (1H,
d, J 15.8 Hz, CH.dbd.CH), 6.45-6.55 (1H, br m, CH.dbd.CCH.sub.2),
6.80 (1H, d, J 8.7 Hz, ArH ortho to OMe), 7.28 (1H, dd, J 8.7, 2.6
Hz, ArH para to cyclopentylidene), 7.48 (1H, d, J 2.6 Hz, ArH ortho
to cyclopentylidene), and 7.61 (1H, d, J 15.8 Hz, CH.dbd.CH); m/z
(El) 273 (M.sup.++1, 18%), 272 (100), 241 (11), 239 (11), 225 (11),
205 (19), 192 (17), 175 (11), 161 (17), and 115 (18).
[0363] The activity and selectivity of compounds according to the
invention was demonstrated in the following tests. In these tests
the abbreviation FMLP represents the peptide
N-formyl-met-leu-phe.
[0364] 1. Isolated Enzyme
[0365] The potency and selectivity of the compounds o f the
invention was
1 i. PDE I, rabbit heart ii. PDE II, rabbit heart iii. PDE III,
rabbit heart, Jurkat cells iv. PDE IV, HL60 cells, rabbit brain,
rabbit kidney and human recombinant PDE IV v. PDE V, rabbit lung,
guinea pig lung
[0366] A gene encoding human PDE IV has been cloned from human
monocytes (Livi, et al., 1990, Molecular and Cellular Biology, 10,
2676). Using similar procedures we have cloned human PDE IV genes
from a number of sources including eosinophils, neutrophils,
lymphocytes, monocytes, brain and neuronal tissues. These genes
have been transfected into yeast using an inducible vector and
various recombinant proteins have been expressed which have the
biochemical characteristics of PDE IV (Beavo and Reifsnyder, 1990,
TIPS, 11, 150). These recombinant enzymes, particularly the human
eosinophil recombinant PDE IV, have been used as the basis of a
screen for potent, selective PDE IV inhibitors.
[0367] The enzymes were purified to isoenzyme homogeneity using
standard chromatographic techniques.
[0368] Phosphodiesterase activity was assayed as follows. The
reaction was conducted in 150 .mu.l of standard mixture containing
(final concentrations): 50 mM
2--[[tris(hydroxymethyl)methyl]amino]-1-ethanesulp- honic acid
(TES)-NaOH buffer (pH 7.5), 10 mM MgCl.sub.2, 0.1 .mu.M
[.sup.3H]-cAMP and vehicle or various concentrations of the test
compounds. The reaction was initiated by addition of enzyme and
conducted at 30.degree. C. for between 5 to 30 min. The reaction
was terminated by addition of 50 .mu.l 2% trifluoroacetic acid
containing [.sup.14C]-5'AMP for determining recovery of the
product. An aliquot of the sample was then applied to a column of
neutral alumina and the [.sup.3H]-cAMP eluted with 10 ml 0.1
TES--NaOH buffer (pH8). The [.sup.3H]-5'-AMP product was eluted
with 2 ml 2M NaOH into a scintillation vial containing 10 ml of
scintillation cocktail. Recovery of [3H]-5'AMP was determined using
the [.sup.14C]-5'AMP and all assays were conducted in the linear
range of the reaction.
[0369] Compounds according to the invention such as compounds of
the Examples herein cause a concentration-dependent inhibition of
recombinant PDE IV at 0.1-1000 nM with little or no activity
against PDE I, II, III or V at concentrations up to 100 .mu.M.
[0370] 2. The Elevation of CAMP in Leukocytes
[0371] The effect of compounds of the invention on intracellular
cAMP was investigated using human neutrophils or guinea pig
eosinophils.
[0372] Human neutrophils were separated from peripheral blood,
incubated with dihydrocytochalasin B and the test compound for 10
min and then stimulated with FMLP. Guinea pig eosinophils were
harvested by peritoneal lavage of animals previously treated with
intra-peritoneal injections of human serum. Eosinophils were
separated from the peritoneal exudate and incubated with
isoprenaline and test compound. With both cell types, suspensions
were centrifuged at the end of the incubation, the cell pellets
were resuspended in buffer and boiled for 10 min prior to
measurement of cAMP by specific radioimmunoassay (DuPont).
[0373] The most potent compounds according to the Examples induced
a concentration -dependent elevation of cAMP in neutrophils and/or
eosinophils at concentrations of 0.1nM to 1 .mu.M.
[0374] 3. Suppression of Leukocyte Function
[0375] Compounds of the invention were investigated for their
effects on superoxide generation, chemotaxis and adhesion of
neutrophils and eosinophils. Isolated leukocytes were incubated
with dihydrocyto-chalasin B for superoxide generation only and test
compound prior to stimulation with FMLP. The most potent compounds
of the Examples caused a concentration-dependent inhibition of
superoxide generation, chemotaxis and adhesion at concentrations of
0.1 nM to 1 .mu.M.
[0376] Lipopolysaccharide (LPS)-induced synthesis of tumour
necrosis factor (TNF) by human peripheral blood monocytes (PBM) is
inhibited by compounds of the Examples at concentrations of 0.01 nM
to 1 .mu.M.
[0377] 4. Adverse Effects
[0378] In general, in our tests, compounds of the invention have
had no observed toxic effects when administered to animals at
pharmacologically effect doses.
* * * * *