U.S. patent application number 09/800023 was filed with the patent office on 2001-10-25 for tetra-substituted phenyl derivatives and processes for their preparation.
Invention is credited to Alexander, Rikki Peter, Warrellow, Graham John.
Application Number | 20010034450 09/800023 |
Document ID | / |
Family ID | 10757176 |
Filed Date | 2001-10-25 |
United States Patent
Application |
20010034450 |
Kind Code |
A1 |
Alexander, Rikki Peter ; et
al. |
October 25, 2001 |
Tetra-substituted phenyl derivatives and processes for their
preparation
Abstract
Compounds of general formula (1): 1 are described wherein
.dbd.W-- is (1) .dbd.C(Y)-- where Y is a halogen atom, or an alkyl,
or -X.sup.aR.sup.1 group where X.sup.a is --O--, --S(O).sub.m--
[where m is zero or an integer of value 1 or 2], or N(R.sup.a)-
[where R.sup.a is a hydrogen atom or an optionally substituted
alkyl group] and R.sup.1 is a hydrogen atom or an optionally
substituted alkyl group or, (2) .dbd.N--; X is as described above
for X.sup.a or is a chain --CR.dbd.C(R.sup.b)-- or
[--CH(R)].sub.q--CH(R.sup.b)- where R is a hydrogen or a fluorine
atom or a methyl group, R.sup.b is as described below for R.sup.2
and q is zero or the integer 1; R.sup.2 is (1) an optionally
substituted alkyl, alkenyl, cycloalkyl or cycloalkenyl group when X
is --O--, --S(O).sub.m-- or --N(R.sup.a)-; or is (2) when X is
other than --O--, --S(O).sub.m-- or --N(R.sup.a)-, a hydrogen atom,
or an optionally substituted straight or branched alkyl, alkenyl or
alkynyl, alkoxy, alkylthio, --CO.sub.2R.sup.9 (where R.sup.9 is a
hydrogen atom or an optionally substituted alkyl, aryl or aralkyl
group), --CONR.sup.10R.sup.11 (where R.sup.10 and R.sup.11 which
may be the same or different is as described for R.sup.9),
--CSNR.sup.10R.sup.11, --CN or NO.sub.2 group; or R.sup.2 and
R.sup.b, together with the carbon atom to which they are both
attached, are linked to form an optionally substituted cycloalkyl
or cycloalkenyl group optionally containing one or more X.sup.a
atoms or groups; R.sup.3 is an atom or group R.sup.13 or
-L.sup.1R.sup.13 where L.sup.1 is a linker group and R.sup.13 is
various substituents; R.sup.4 is a hydrogen atom or is as defined
for R.sup.6; R.sup.5 is a hydrogen or a fluorine atom, or an
OR.sup.c group where R.sup.c is a hydrogen atom or an optionally
substituted straight or branched alkyl, alkenyl, alkoxyalkyl,
alkanoyl, formyl, carboxamido, thiocarboxamido, cycloalkyl, or
cycloalkenyl group; R.sup.6 is a group --(CH.sub.2).sub.nAr where
Ar is an optionally substituted monocyclic or bicyclic aryl ring
optionally interrupted by one or more heteroatoms --O--, --S-- or
--N-- and n is zero or the integer 1, 2 or 3; R.sup.7 and R.sup.8,
which may be the same or different, is a hydrogen or a fluorine
atom, or an optionally substituted straight or branched alkyl
group; and the salts, solvates, prodrugs, hydrates 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 an unwanted inflammatory response
or muscular spasm is present.
Inventors: |
Alexander, Rikki Peter;
(High Wycombe, GB) ; Warrellow, Graham John;
(Northwood, GB) |
Correspondence
Address: |
Woodcock Washburn Kurtz
Mackiewicz & Norris LLP
One Liberty Place - 46th Floor
Philadelphia
PA
19103
US
|
Family ID: |
10757176 |
Appl. No.: |
09/800023 |
Filed: |
March 5, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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09800023 |
Mar 5, 2001 |
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09048608 |
Mar 26, 1998 |
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6197792 |
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Current U.S.
Class: |
546/296 ;
546/297; 562/426; 562/452; 562/465; 568/39; 568/626 |
Current CPC
Class: |
C07D 213/30
20130101 |
Class at
Publication: |
546/296 ;
546/297; 562/426; 562/452; 562/465; 568/39; 568/626 |
International
Class: |
C07D 213/69; C07D
213/70; C07D 213/72 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 22, 1994 |
GB |
9412571.3 |
Claims
1. A compound of formula (1) 29wherein .dbd.W-- is (1) .dbd.C(Y)--
where Y is a halogen atom, or an alkyl, or -X.sup.aR.sup.1 group
where X.sup.a is --O--, --S(O).sub.m-- [where m is zero or an
integer of value 1 or 2], or --N(R.sup.a)- [where R.sup.a is a
hydrogen atom or an optionally substituted alkyl group] and R.sup.1
is an optionally substituted alkyl group or, (2) .dbd.N--; X is as
described above for X.sup.a or is a chain --CR.dbd.C(R.sup.b)- or
--[--CH(R)].sub.q--CH(R.sup.b)- where R is a hydrogen or a fluorine
atom or a methyl group, R.sup.b is as described below for R.sup.2
and q is zero or the integer 1; R.sup.2 is (1) an optionally
substituted alkyl, alkenyl, cycloalkyl or cycloalkenyl group when X
is --O--, --S(O).sub.m-- or --N(R.sup.a)-; or when X is
--CR.dbd.C(R.sup.b)- or --[--CH(R)].sub.qCH(R.sup.b)- is (2) a
hydrogen atom, or an optionally substituted straight or branched
alkyl, alkenyl or alkynyl, alkoxy, alkylthio, --CO.sub.2R.sup.9
(where R.sup.9 is a hydrogen atom or an optionally substituted
alkyl, aryl or aralkyl group), --CONR.sup.10R.sup.11 (where
R.sup.10 and R.sup.11 which may be the same or different is as
described for R.sup.9), --CSNR.sup.10R.sup.11, --CN or NO.sub.2
group; or R.sup.2 and R.sup.b, together with the carbon atom to
which they are both attached, are linked to form an optionally
substituted cycloalkyl or cycloalkenyl group optionally containing
one or more X.sup.a atoms or groups; R.sup.3 is an atom or group
R.sup.13 or -L.sup.1R.sup.13 where L.sup.1 is a linker group and
R.sup.13 is a halogen atom or an Alk.sup.1 [where Alk.sup.1 is an
optionally substituted straight or branched C.sub.1-6alkyl,
C.sub.2-6alkenyl or C.sub.2-6alkynyl group optionally interrupted
by one, two, or three --O--, or --S-- atoms or --S(O).sub.p--,
[where p is an integer 1 or 2], or --N(R.sup.a)- groups], or an
amino (--NH.sub.2), substituted amino, nitro, cyano, hydroxyl
(--OH), substituted hydroxyl, cycloalkyl, cycloalkoxy, formyl
[HC(O)--], carboxyl (--CO.sub.2H), esterified carboxyl, thiol
(--SH), substituted thiol, --C(O)Alk.sup.1, --SO.sub.3H,
--SO.sub.2Alk.sup.1, --SO.sub.2NH.sub.2, --SO.sub.2NHAlk.sup.1,
--SO.sub.2N[Alk.sup.1].sub.2, --SO.sub.2NHAr [where Ar is as
defined below for R.sup.6], --SO.sub.2N(Alk.sup.1)Ar, --CONH.sub.2,
--CONHAlk.sup.1, --CON[Alk.sup.1].sub.2, --CONHAr,
--CON(Alk.sup.1)Ar, --NHSO.sub.2H, --NAlk.sup.1SO.sub.2H,
--NHSO.sub.2 Alk.sup.1, --NAlk.sup.1SO.sub.2Alk.sup.1,
--N[SO.sub.2Alk.sup.1].sub.2, --N(Alk.sup.1)SO.sub.2N(Alk.sup.1)Ar,
--NHSO.sub.2NH.sub.2, --N(Alk.sup.1)SO.sub.2NH.sub.2,
--NHSO.sub.2NHAlk.sup.1, --N(Alk.sup.1)SO.sub.2NHAlk.sup.1,
--NHSO.sub.2N[Alk.sup.1].sub.2, --NAlk.sup.1
SO.sub.2N[Alk.sup.1].sub.2, --NHSO.sub.2 NHAr,
--N(Alk.sup.1)SO.sub.2N HAr, --NHSO.sub.2N(Alk.sup.1)Ar,
--N(Alk.sup.1)SO.sub.2N(Alk.sup.1)Ar, --NHC(O)Alk.sup.1,
--N(Alk.sup.1)C(O)Alk.sup.1, --N[C(O)Alk.sup.1].sub.2,
--NHC(O)OAlk.sup.1, --N(Alk.sup.1)C(O)OAlk.sup.1, --Ar, -Het [where
Het is a C.sub.5-7 heterocycloalkyl group], --CONHet.sup.1 [where
--NHet.sup.1 is a C.sub.5-7 cycloamino group optionally containing
one or more --O-- or --S-- atoms or --N(R.sup.a)-- groups],
--SO.sub.2NHet.sup.1, --NHSO.sub.2NHet.sup.1, --CSAlk.sup.1,
--CSNH.sub.2, --CSNHAlk.sup.1, --CSN[Alk.sup.1].sub.2, --CSNHAr,
--CSN(Alk.sup.1 )Ar, --NHC(S)Alk.sup.1,
--N(Alk.sup.1)C(S)Alk.sup.1, --CSNHet.sup.1 group,
--N[C(S)Alk.sup.1].sub.2, --N[C(O)Alk.sup.1]SO.sub.- 2Alk.sup.1,
--N[C(S)Alk.sup.1]SO.sub.2Alk.sup.1, --NHC(O)NH.sub.2,
--NHC(O)NHAlk.sup.1, --NHC(O)N[Alk.sup.1].sub.2,
--N(Alk.sup.1)CONH.sub.2- , --N(Alk.sup.1)C(O)NHAlk.sup.1,
--N(Alk.sup.1)C(O)N[Alk.sup.1].sub.2, --NHC(S)NH.sub.2,
--NHC(S)NHAlk.sup.1, --NHC(S)N[Alk.sup.1].sub.2, --N
(Alk.sup.1)CSNH.sub.2, --N(Alk.sup.1 )C(S)NHAlk.sup.1, or
--N(Alk.sup.1)C(S)N[Alk.sup.1].sub.2, group; R.sup.4 is a hydrogen
atom or is as defined for R.sup.6; R.sup.5 is a hydrogen or a
fluorine atom, or an OR.sup.c group where R.sup.c is a hydrogen
atom or an optionally substituted straight or branched alkyl,
alkenyl, alkoxyalkyl, alkanoyl, formyl, carboxamido,
thiocarboxamido, cycloalkyl, or cycloalkenyl group; R.sup.6 is a
group --(CH.sub.2).sub.nAr where Ar is an optionally substituted
monocyclic or bicyclic aryl ring optionally interrupted by one or
more heteroatoms --O--, --S-- or --N-- and n is zero or the integer
1, 2 or 3; R.sup.7 and R.sup.8, which may be the same or different,
is a hydrogen or a fluorine atom, or an optionally substituted
straight or branched alkyl group; and the salts, solvates,
prodrugs, hydrates and N-oxides thereof.
2. A compound according to claim 1 wherein .dbd.W-- is
.dbd.C(X.sup.aR.sup.1)- and X is --O--, --S(O).sub.m-- or
--N(R.sup.a)-.
3. A compound according to claim 2 wherein R.sup.2 is an optionally
substituted cyclopentyl group.
4. A compound according to claim 2 wherein R.sup.5, R.sup.7 and
R.sup.8 is each a hydrogen atom.
5. A compound according to claim 4 wherein R.sup.4 is a hydrogen
atom or a phenyl or substituted phenyl group.
6. A compound according to claim 5 wherein R.sup.6 is an optionally
substituted pyridyl group.
7. A compound according to claim 6 wherein R.sup.3 is a halogen
atom, or an alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl,
heteroaryl or heteroaralkyl group.
8. A compound which is:
4-[2-(5-Cyclopentyloxy-2-iodo-4-methoxyphenyl)ethy- l]pyridine;
4-[2-(5-Cyclopentyloxy-4-methoxy-2-phenyl)ethyl]pyridine;
4-{2-[5-Cyclopentyloxy-4-methoxy-2-(2-phenylethenyl)phenyl]ethyl}pyridine-
;
4-{2-[5-Cyclopentyloxy-4-methoxy-2-(2-phenylethyl)phenyl]ethyl}pyridine;
4-{2-[5-Cyclopentyloxy-4-methoxy-2-(1
-naphthyl)phenyl]ethyl}pyridine;
4-{2-[5-Cyclopentyloxy-4-methoxy-2-(2-naphthyl)phenyl]ethyl}pyridine;
4-{2-[5-Cyclopentyloxy-4-methoxy-2-(3-pyridyl)phenyl]ethyl}pyridine;
or each isomer or enantiomer, and/or the salts, hydrates, solvates,
prodrugs and N-oxides thereof.
9. A pharmaceutical composition comprising a compound of formula
(1) 30wherein .dbd.W-- is (1) .dbd.C(Y)-- where Y is a halogen
atom, or an alkyl, or -X.sup.aR.sup.1 group where X.sup.a is --O--,
--S(O).sub.m-- [where m is zero or an integer of value 1 or 2], or
--N(R.sup.a)- [where R.sup.a is a hydrogen atom or an optionally
substituted alkyl group] and R.sup.1 is an optionally substituted
alkyl group or, (2) .dbd.N--; X is as described above for X.sup.a
or is a chain CR.dbd.C(R.sup.b)- or --[--CH(R)].sub.q--CH(R.sup.b)-
where R is a hydrogen or a fluorine atom or a methyl group, R.sup.b
is as described below for R.sup.2 and q is zero or the integer 1;
R.sup.2 is (1) an optionally substituted alkyl, alkenyl, cycloalkyl
or cycloalkenyl group when X is --O--, --S(O).sub.m-- or
--N(R.sup.a)-; or when X is --CR.dbd.C(R.sup.b)- or
--[--CH(R)].sub.qCH(R.sup.b)- is (2) a hydrogen atom, or an
optionally substituted straight or branched alkyl, alkenyl or
alkynyl, alkoxy, alkylthio, --CO.sub.2R.sup.9 (where R.sup.9 is a
hydrogen atom or an optionally substituted alkyl, aryl or aralkyl
group), --CONR.sup.10R.sup.11 (where R.sup.10 and R.sup.11 which
may be the same or different is as described for R.sup.9),
--CSNR.sup.10R.sup.11, --CN or NO.sub.2 group; or R.sup.2 and
R.sup.b, together with the carbon atom to which they are both
attached, are linked to form an optionally substituted cycloalkyl
or cycloalkenyl group optionally containing one or more X.sup.a
atoms or groups; R.sup.3 is an atom or group R.sup.13 or
-L.sup.1R.sup.13 where L.sup.1 is a linker group and R.sup.13 is a
halogen atom or an Alk.sup.1 [where Alk.sup.1 is an optionally
substituted straight or branched C.sub.1-6 alkyl, C.sub.2-6alkenyl
or C.sub.2-6alkynyl group optionally interrupted by one, two, or
three --O--, or --S-- atoms or --S(O).sub.p--, [where p is an
integer 1 or 2], or --N(R.sup.a)- groups], or an amino
(--NH.sub.2), substituted amino, nitro, cyano, hydroxyl (--OH),
substituted hydroxyl, cycloalkyl, cycloalkoxy, formyl [HC(O)--],
carboxyl (--CO.sub.2H), esterified carboxyl, thiol (--SH),
substituted thiol, --C(O)Alk.sup.1, --SO.sub.3H,
--SO.sub.2Alk.sup.1, --SO.sub.2NH.sub.2, --SO.sub.2NHAlk.sup.1,
--SO.sub.2N[Alk.sup.1].sub.2, --SO.sub.2NHAr [where Ar is as
defined below for R.sup.6], --SO.sub.2N(Alk.sup.1)Ar, --CONH.sub.2,
--CONHAlk.sup.1, --CON[Alk.sup.1].sub.2, --CONHAr,
--CON(Alk.sup.1)Ar, --NHSO.sub.2H, --NAlk.sup.1SO.sub.2H,
--NHSO.sub.2Alk.sup.1, --NAlk.sup.1SO.sub.2Alk.sup.1,
--N[SO.sub.2Alk.sup.1].sub.2, --N(Alk.sup.1)SO.sub.2N(Alk.sup.1)Ar,
--NHSO.sub.2NH.sub.2, --N(Alk.sup.1)SO.sub.2NH.sub.2,
--NHSO.sub.2NHAlk.sup.1, --N(Alk.sup.1)SO.sub.2NHAlk.sup.1,
--NHSO.sub.2N[Alk.sup.1].sub.2,
--NAlk.sup.1SO.sub.2N[Alk.sup.1].sub.2, --NHSO.sub.2NHAr,
--N(Alk.sup.1)SO.sub.2NHAr, --NHSO.sub.2N(Alk.sup.1)Ar,
--N(Alk.sup.1)SO.sub.2N(Alk.sup.1)Ar, --NHC(O)Alk.sup.1,
--N(Alk.sup.1)C(O)Alk.sup.1, --N[C(O)Alk.sup.1].sub.2,
--NHC(O)OAlk.sup.1, --N(Alk.sup.1)C(O)OAlk.sup.1, --Ar, --Het
[where Het is a C.sub.5-7 heterocycloalkyl group], --CONHet.sup.1
[where --NHet.sup.1 is a C.sub.5-7 cycloamino group optionally
containing one or more --O-- or --S-- atoms or --N(R.sup.a)--
groups], --SO.sub.2NHet.sup.1, --NHSO.sub.2NHet.sup.1,
--CSAlk.sup.1, --CSNH.sub.2, --CSNHAlk.sup.1,
--CSN[Alk.sup.1].sub.2, --CSNHAr, --CSN(Alk.sup.1)Ar,
--NHC(S)Alk.sup.1, --N(Alk.sup.1)C(S)Alk.sup.1, --CSNHet.sup.1
group, --N[C(S)Alk.sup.1].sub.2, --N[C(O)Alk.sup.1]SO.sub.-
2Alk.sup.1, --N[C (S)Alk.sup.1]SO.sub.2Alk.sup.1, --NHC(O)NH.sub.2,
--NHC(O)NHAlk.sup.1, --NHC(O)N[Alk.sup.1].sub.2,
--N(Alk)CONH.sub.2, --N(Alk.sup.1)C(O)NHAlk.sup.1,
--N(Alk.sup.1)C(O)N[Alk.sup.1].sub.2, --NHC(S)NH.sub.2,
--NHC(S)NHAlk.sup.1, --NHC(S)N[Alk.sup.1].sub.2,
--N(Alk.sup.1)CSNH.sub.2, --N(Alk.sup.1)C(S)NHAlk.sup.1, or
--N(Alk.sup.1)C(S)N[Alk.sup.1].sub.2, group; R.sup.4 is a hydrogen
atom or is as defined for R.sup.6; R.sup.5 is a hydrogen or a
fluorine atom, or an OR.sup.c group where R.sup.c is a hydrogen
atom or an optionally substituted straight or branched alkyl,
alkenyl, alkoxyalkyl, alkanoyl, formyl, carboxamido,
thiocarboxamido, cycloalkyl, or cycloalkenyl group; R.sup.6 is a
group --(CH.sub.2).sub.nAr where Ar is an optionally substituted
monocyclic or bicyclic aryl ring optionally interrupted by one or
more heteroatoms --O--, --S-- or --N-- and n is zero or the integer
1, 2 or 3; R.sup.7 and R.sup.8, which may be the same or different,
is a hydrogen or a fluorine atom, or an optionally substituted
straight or branched alkyl group; and the salts, solvates,
prodrugs, hydrates and N-oxides thereof.
10. A process for the preparation of a compound of formula (1)
31wherein .dbd.W-- is (1) .dbd.C(Y)-- where Y is a halogen atom, or
an alkyl, or -X.sup.aR.sup.1 group where X.sup.a is --O--,
--S(O).sub.m-- [where m is zero or an integer of value 1 or 2], or
--N(R.sup.a)- [where R.sup.a is a hydrogen atom or an optionally
substituted alkyl group] and R.sup.1 is an optionally substituted
alkyl group or, (2) .dbd.N--; X is as described above for X.sup.a
or is a chain --CR.dbd.C(R.sup.b)- or --[--CH(R)].sub.qCH(R.sup.b)-
where R is a hydrogen or a fluorine atom or a methyl group, R.sup.b
is as described below for R.sup.2 and q is zero or the integer 1;
R.sup.2 is (1) an optionally substituted alkyl, alkenyl, cycloalkyl
or cycloalkenyl group when X is --O--, S(O).sub.m-- or
--N(R.sup.a)--; or when X is --CR.dbd.C(R.sup.b)- or
--[--CH(R)].sub.qCH(R.sup.b)- is (2) a hydrogen atom, or an
optionally substituted straight or branched alkyl, alkenyl or
alkynyl, alkoxy, alkylthio, --CO.sub.2R.sup.9 (where R.sup.9 is a
hydrogen atom or an optionally substituted alkyl, aryl or aralkyl
group), --CONR.sup.10R.sup.11 (where R.sup.10 and R.sup.11 which
may be the same or different is as described for R.sup.9),
--CSNR.sup.10R.sup.11, --CN or NO.sub.2 group; or R.sup.2 and
R.sup.b, together with the carbon atom to which they are both
attached, are linked to form an optionally substituted cycloalkyl
or cycloalkenyl group optionally containing one or more X.sup.a
atoms or groups; R.sup.3 is an atom or group R.sup.13 or
-L.sup.1R.sup.13 where L.sup.1 is a linker group and R.sup.13 is a
halogen atom or an Alk.sup.1 [where Alk.sup.1 is an optionally
substituted straight or branched C.sub.1-6 alkyl, C.sub.2-6alkenyl
or C.sub.2-6alkynyl group optionally interrupted by one, two, or
three --O--, or --S-- atoms or --S(O).sub.p--, [where p is an
integer 1 or 2], or --N(R.sup.a)- groups], or an amino
(--NH.sub.2), substituted amino, nitro, cyano, hydroxyl (--OH),
substituted hydroxyl, cycloalkyl, cycloalkoxy, formyl [HC(O)--],
carboxyl (--CO.sub.2H), esterified carboxyl, thiol (--SH),
substituted thiol, --C(O)Alk.sup.1, --SO.sub.3H,
--SO.sub.2Alk.sup.1, --SO.sub.2NH.sub.2, --SO.sub.2NHAlk.sup.1,
--SO.sub.2N[Alk.sup.1].sub.2, --SO.sub.2NHAr [where Ar is as
defined below for R.sup.6], --SO.sub.2N(Alk.sup.1)Ar, --CONH.sub.2,
--CONHAlk.sup.1, --CON[Alk.sup.1].sub.2, --CONHAr,
-CON(Alk.sup.1)Ar, --NHSO.sub.2H, --NAlk.sup.1SO.sub.2H, --NH
SO.sub.2 Alk.sup.1, --NAlk.sup.1SO.sub.2Alk.sup.1,
--N[SO.sub.2Alk.sup.1].sub.2, --N(Alk.sup.1)SO.sub.2N(Alk.sup.1)Ar,
--NHSO.sub.2NH.sub.2, --N(Alk.sup.1)SO.sub.2NH.sub.2,
--NHSO.sub.2NHAlk.sup.1, --N(Alk.sup.1)SO.sub.2NHAlk.sup.1,
--NHSO.sub.2N[Alk.sup.1].sub.2,
--NAlk.sup.1SO.sub.2N[Alk.sup.1].sub.2, --NHSO.sub.2NHAr,
--N(Alk.sup.1)SO.sub.2N HAr, --NHSO.sub.2N(Alk.sup.1)Ar,
--N(Alk.sup.1)SO.sub.2N(Alk.sup.1)Ar, --NHC(O)Alk.sup.1,
--N(Alk.sup.1)C(O)Alk.sup.1, --N[C(O)Alk.sup.1].sub.2,
--NHC(O)OAlk.sup.1, --N(Alk.sup.1)C(O)OAlk.sup.1, --Ar, -Het [where
Het is a C.sub.5-7 heterocycloalkyl group], --CONHet.sup.1 [where
--NHet.sup.1 is a C.sub.5-7 cycloamino group optionally containing
one or more --O-- or --S-- atoms or --N(R.sup.a)- groups],
--SO.sub.2NHet.sup.1, --NHSO.sub.2NHet.sup.1, --CSAlk.sup.1,
--CSNH.sub.2, --CSNHAlk.sup.1, --CSN[Alk.sup.1].sub.2, --CSNHAr,
--CSN(Alk.sup.1)Ar, --NHC(S)Alk.sup.1, --N(Alk.sup.1)C(S)Alk.sup.1,
--CSNHet.sup.1 group, --N[C(S)Alk.sup.1].sub.2,
--N[C(O)Alk.sup.1SO.sub.2Alk.sup.1,
--N[C(S)Alk.sup.1]SO.sub.2Alk.sup.1, --NHC(O)NH.sub.2,
--NHC(O)NHAlk.sup.1, --NHC(O)N(Alk.sup.1].sub.2,
--N(Alk.sup.1)CONH.sub.2- , --N(Alk.sup.1)C(O)NHAlk.sup.1,
--N(Alk.sup.1)C(O)N[Alk.sup.1].sub.2, --NHC(S)NH.sub.2,
--NHC(S)NHAlk.sup.1, --NHC(S)N[Alk.sup.1].sub.2,
--N(Alk.sup.1)CSNH.sub.2, --N(Alk.sup.1)C(S)NHAlk.sup.1, or
--N(Alk.sup.1)C(S)N[Alk.sup.1].sub.2, group; R.sup.4 is a hydrogen
atom or is as defined for R.sup.6; R.sup.5 is a hydrogen or a
fluorine atom, or an OR.sup.c group where R.sup.c is a hydrogen
atom or an optionally substituted straight or branched alkyl,
alkenyl, alkoxyalkyl, alkanoyl, formyl, carboxamido,
thiocarboxamido, cycloalkyl, or cycloalkenyl group; R.sup.6 is a
group --(CH.sub.2).sub.nAr where Ar is an optionally substituted
monocyclic or bicyclic aryl ring optionally interrupted by one or
more heteroatoms --O--, --S-- or --N-- and n is zero or the integer
1, 2 or 3; R.sup.7 and R.sup.8, which may be the same or different,
is a hydrogen or a fluorine atom, or an optionally substituted
straight or branched alkyl group; and the salts, solvates,
prodrugs, hydrates and N-oxides thereof. which comprises in a final
step a) cross-coupling an intermediate of formula (3) 32 where Hal
is an iodine or bromine atom with a coupling reagent to give a
compound of formula (1) where R.sup.3 is a group L.sup.1R.sup.13;
b) hydrogenation of a compound of formula (16) 33 to give a
compound of formula (1) wherein R.sup.8 and R.sup.5 is each a
hydrogen atom; c) alkylation of a compound of formula (17) 34 where
X is --O--, --S-- or --N(R.sup.a)- with a reagent R.sup.2L where L
is a leaving group; d) coupling an intermediate of formula (19) 35
wherein R is a hydrogen atom or a methyl group; with an olefination
agent to give a compound of formula (1) wherein X is a chain
--C(R).dbd.C(R.sup.b)- in which R is a hydrogen atom or a methyl
group. e) alkylation of a compound of formula (25) 36 with a
reagent R.sup.1L where L is a leaving group to give a compound of
formula (1) in which .dbd.W-- is .dbd.C(OR.sup.1)--; f)
halogenation of a compound of formula (4) 37 to give a compound of
formula (1) where R.sup.3 is a halogen atom; or g) interconverting
a compound of formula (1) to another compound of formula (1).
Description
[0001] This invention relates to a novel series of
tetra-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 vivo 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 tetra-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) 2
[0007] wherein
[0008] .dbd.W-- is (1) .dbd.C(Y)- where Y is a halogen atom, or an
alkyl, or -X.sup.aR.sup.1 group where X.sup.a is --O--,
--S(O).sub.m-- [where m is zero or an integer of value 1 or 2], or
--N(R.sup.a)- [where R.sup.a is a hydrogen atom or an optionally
substituted alkyl group] and R.sup.1 is an optionally substituted
alkyl group or, (2) .dbd.N--; X is as described above for X.sup.a
or is a chain --CR.dbd.C(R.sup.b)- or
--[--CH(R)].sub.q--CH(R.sup.b)- where R is a hydrogen or a fluorine
atom or a methyl group, R.sup.b is as described below for R.sup.2
and q is zero or the integer 1;
[0009] R.sup.2 is (1) an optionally substituted alkyl, alkenyl,
cycloalkyl or cycloalkenyl group when X is --O--, --S(O).sub.m-- or
--N(R.sup.a)-; or when X is --CR.dbd.C(R.sup.b)- or
--[--CH(R)].sub.qCH(R.sup.b)-- is (2) a hydrogen atom, or an
optionally substituted straight or branched alkyl, alkenyl or
alkynyl, alkoxy, alkylthio, --CO.sub.2R.sup.9 (where R.sup.9 is a
hydrogen atom or an optionally substituted alkyl, aryl or aralkyl
group), --CONR.sup.10R.sup.11 (where R.sup.10 and R.sup.11 which
may be the same or different is as described for R.sup.9),
--CSNR.sup.10R.sup.11, --CN or NO.sub.2 group; or R.sup.2 and
R.sup.b, together with the carbon atom to which they are both
attached, are linked to form an optionally substituted cycloalkyl
or cycloalkenyl group optionally containing one or more X.sup.a
atoms or groups;
[0010] R.sup.3 is an atom or group R.sup.13 or -L.sup.1R.sup.13
where L.sup.1 is a linker group and R.sup.13 is a halogen atom or
an Alk.sup.1 [where Alk.sup.1 is an optionally substituted straight
or branched C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl
group optionally interrupted by one, two, or three --O--, or --S--
atoms or --S(O)p-, [where p is an integer 1 or 2], or --N(R.sup.a)-
groups], or an amino (--NH.sub.2), substituted amino, nitro, cyano,
hydroxyl (--OH), substituted hydroxyl, cycloalkyl, cycloalkoxy,
formyl [HC(O)--], carboxyl (--CO.sub.2H), esterified carboxyl,
thiol (--SH), substituted thiol, --C(O)Alk.sup.1, --SO.sub.3H,
--SO.sub.2Alk.sup.1, --SO.sub.2NH.sub.2, --SO.sub.2NHAlk.sup.1,
--SO.sub.2N[Alk.sup.1]2, --SO.sub.2NHAr [where Ar is as defined
below for R.sup.6], --SO.sub.2N(Alk.sup.1)Ar, --CONH.sub.2,
--CONHAlk.sup.1, --CON[Alk.sup.1].sub.2, --CONHAr,
--CON(Alk.sup.1)Ar, --NHSO.sub.2H, --NAlk.sup.1SO.sub.2H,
--NHSO.sub.2Alk.sup.1, --NAlk.sup.1SO.sub.2Alk.sup.1,
--N[SO.sub.2Alk.sup.1].sub.2, --N(Alk.sup.1)SO.sub.2N(Alk.sup.1)Ar,
--NHSO.sub.2NH.sub.2, --N(Alk.sup.1)SO.sub.2NH.sub.2,
--NHSO.sub.2NHAlk.sup.1, --N(Alk.sup.1)SO.sub.2NHAlk.sup.1,
--NHSO.sub.2N[Alk.sup.1].sub.2,
--NAlk.sup.1SO.sub.2N[Alk.sup.1].sub.2, --NHSO.sub.2NHAr,
--N(Alk.sup.1)SO.sub.2NHAr, --NHSO.sub.2N(Alk.sup.1)Ar,
--N(Alk.sup.1l)SO.sub.2N(Alk.sup.1)Ar, --NHC(O)Alk.sup.1,
--N(Alk.sup.1)C(O)Alk.sup.1, --N[C(O)Alk.sup.1].sub.2,
--NHC(O)OAlk.sup.1, --N(Alk.sup.1)C(O)OAlk.sup.1, --Ar, -Het [where
Het is a C.sub.5-7 heterocycloalkyl group], --CONHet.sup.1 [where
--NHet.sup.1 is a C.sub.5-7 cycloamino group optionally containing
one or more --O-- or --S-- atoms or --N(R.sup.a)-- groups],
--SO.sub.2NHet.sup.1, --NHSO.sub.2NHet.sup.1, --CSAlk.sup.1,
--CSNH.sub.2, --CSNHAlk.sup.1, --CSN[Alk.sup.1].sub.2, --CSNHAr,
--CSN(Alk.sup.1)Ar, --NHC(S)Alk.sup.1, --N(Alk.sup.1)C(S)Alk.sup.1,
--CSNHet.sup.1 group, --N[C(S)Alk.sup.1].sub.2,
--N[C(O)Alk.sup.1]SO.sub.- 2Alk.sup.1,
--N[C(S)Alk.sup.1]SO.sub.2Alk.sup.1, --NHC(O)NH.sub.2,
--NHC(O)NHAlk.sup.1, --NHC(O)N[Alk.sup.1].sub.2,
--N(Alk.sup.1)CONH.sub.2- , --N(Alk.sup.1)C(O)NHAlk.sup.1,
--N(Alk.sup.1)C(O)N[Alk.sup.1].sub.2, --NHC(S)NH.sub.2,
--NHC(S)NHAlk.sup.1, --NHC(S)N[Alk.sup.1].sub.2,
--N(Alk.sup.1)CSNH.sub.2, --N(Alk.sup.1)C(S)NHAlk.sup.1, or
--N(Alk.sup.1)C(S)N[Alk.sup.1].sub.2, group;
[0011] R.sup.4 is a hydrogen atom or is as defined for R.sup.6;
[0012] R.sup.5 is a hydrogen or a fluorine atom, or an OR.sup.c
group where R.sup.c is a hydrogen atom or an optionally substituted
straight or branched alkyl, alkenyl, alkoxyalkyl, alkanoyl, formyl,
carboxamido, thiocarboxamido, cycloalkyl, or cycloalkenyl
group;
[0013] R.sup.6 is a group --(CH.sub.2).sub.nAr where Ar is an
optionally substituted monocyclic or bicyclic aryl ring optionally
interrupted by one or more heteroatoms --O--, --S-- or --N-- and n
is zero or the integer 1, 2 or 3;
[0014] R.sup.7 and R.sup.8, which may be the same or different, is
a hydrogen or a fluorine atom, or an optionally substituted
straight or branched alkyl group; and the salts, solvates,
prodrugs, hydrates and N-oxides thereof.
[0015] It will be appreciated that compounds of formula (1) may
have one or more chiral centres depending on the nature of the
groups X, R, 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 diasteromers
may exist, and the invention is to be understood to extend to all
such enantiomers, diastereomers and mixtures thereof, including
racemates.
[0016] Compounds of formula (1) where X is a chain
--CR.dbd.C(R.sup.b) may exist as geometric isomers depending on the
nature of the groups R, R.sup.b and R.sup.2, and the invention is
to be understood to extend to all such isomers and mixtures
thereof.
[0017] In the compounds of formula (1), when Y is a halogen atom it
may be for example a fluorine, chlorine, bromine or iodine
atom.
[0018] When .dbd.W-- in the compounds of formula (1) is a group
.dbd.C(Y)-- where Y is a group -X.sup.aR.sup.1, R.sup.1 may be, for
example, 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 i-propyl group. Optional
substitutents which may be present on R.sup.1 groups include one or
more halogen atoms, e.g. fluorine, or chlorine atoms. Particular
R.sup.1 groups include for example --CH.sub.2F, --CH.sub.2Cl,
--CHF.sub.2, --CHCl.sub.2, --CF.sub.3 or --CCl.sub.3 groups.
[0019] When .dbd.W-- in compounds of formula (1) is a group
.dbd.C(Y)-- where Y is X.sup.aR.sup.1 in which X.sup.a is a
--N(R.sup.a)- group, X.sup.a may be a --NH--, --NCH.sub.2-- or
--NC.sub.2H.sub.4-- group.
[0020] Alkyl groups represented by R.sup.1, R.sup.2, R.sup.6,
R.sup.7, or R.sup.8 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 or ethyl 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 groups.
[0021] Alkenyl groups represented by R.sup.2, or R.sup.c in
compounds of formula (1) include optionally substituted straight or
branched C.sub.2-6alkenyl groups such as ethenyl, propen-1-yl and
2-methylpropen-1-yl. Optional substituents include those described
above in relation to the alkyl groups represented by R.sup.2.
[0022] Alkynyl groups represented by R.sup.2, or R.sup.b in
compounds of formula (1) include optionally substituted straight or
branched C.sub.2-6alkynyl groups optionally interrupted by one or
more X.sup.a 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
R.sup.2.
[0023] When R.sup.2, or R.sup.b or R.sup.2 and R.sup.b, together
with the carbon atom to which they are both attached, are an
optionally substituted 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.
[0024] When the group .dbd.W-- in compounds of formula (1) is a
group .dbd.C(Y)-- in which Y is a halogen atom Y may be for example
a fluorine, chlorine, bromine or iodine atom.
[0025] Particular examples of --(CH.sub.2).sub.nAr groups
represented by R.sup.4 and/or R.sup.6 include --Ar, --CH.sub.2Ar,
--(CH.sub.2).sub.2Ar or --(CH.sub.2).sub.3Ar groups.
[0026] Monocyclic or bicyclic aryl groups represented by the group
Ar 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.
[0027] When the monocyclic or bicyclic aryl group Ar contains one
or more heteroatoms it may be for example a C.sub.1-9 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
or sulphur atoms or a group --N(R.sup.a)-.
[0028] Examples of heteroaryl groups represented by Ar 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-tetrahydroisoquinolinyl.
[0029] The heteroaryl group represented by Ar 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 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.
[0030] When in compounds of formula (1) the Ar 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.
[0031] The aryl or heteroaryl groups represented by Ar in compounds
of formula (1) may each optionally be substituted by one, two,
three or more R.sup.13 substituents.
[0032] When R.sup.13 in compounds of formula (1) is a substituted
amino group it may be a group
--NH[Alk.sup.1(R.sup.13a).sub.z][where z is zero or an integer 1, 2
or 3 and R.sup.13a is as defined above for R.sup.13 but is not a
substituted amino, a substituted hydroxyl or a substituted thiol
group] or a group --N[Alk.sup.1(R.sup.13a).sub.z].sub.2 wherein
each --Alk.sup.1(R.sup.13a).sub.z group is the same or
different.
[0033] When R.sup.13 is a cycloalkoxy group it may be for example a
C.sub.5-7cycloalkoxy group such as a cyclopentyloxy or
cyclohexyloxy group.
[0034] When R.sup.13 is a substituted hydroxyl or substituted thiol
group it may be a group --OAlk.sup.1(R.sup.13a).sub.z or
--SAlk.sup.1(R.sup.13a).sub.z respectively, where Alk.sup.1,
R.sup.13a and z are as just defined.
[0035] Esterified carboxyl groups represented by the group R.sup.13
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, i-propyl, n-butyl, i-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 C.sub.1-8alkanoyloxyC.sub.1-8alkyl 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 benzoyloxypropyl group. Optional
substituents present on the Alk.sup.2 group include R.sup.13
substituents described above.
[0036] Particular examples of -Het groups represented by the group
R.sup.13 include optionally substituted 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 alkyl groups
represented by R.sup.1, R.sup.2, R.sup.6, R.sup.7 or R.sup.8.
[0037] Examples of the group Alk.sup.1 in compounds of formula (1)
include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
s-butyl, t-butyl, ethenyl, 2-propenyl, 2-butenyl, 3-butenyl,
ethynyl, 2-propynyl, 2-butynyl or 3-butynyl groups optionally
interrupted by one, two or three --O-- or --S-- atoms or --S(O)--,
--S(O).sub.2-- or --N(R.sup.a)- groups.
[0038] Particularly useful atoms or groups represented by R.sup.13
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.1-6hydroxyalkyl, e.g.
hydroxymethyl or hydroxyethyl, C.sub.1-6alkylthiol e.g. methylthiol
or ethylthiol, C.sub.1-6alkoxy, e.g. methoxy or ethoxy, C.sub.5-7
cycloalkyl, e.g. cyclopentyl, C.sub.5-7 cycloalkoxy, e.g.
cyclopentyloxy, haloC.sub.1-6alkyl, e.g. trifluoromethyl,
C.sub.1-6alkylamino, e.g. methylamino or ethylamino, amino
(--NH.sub.2), aminoC.sub.1-6alkyl, e.g. aminomethyl or aminoethyl,
C.sub.1-6dialkylamino, 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.1-6alkanoyl e.g. acetyl, thiol (--SH), thioC.sub.1-6alkyl,
e.g. thiomethyl or thioethyl, optionally substituted phenyl or
naphthyl (where the optional substituents are selected from one or
more atoms or groups R.sup.13 or L.sup.1R.sup.13), a group -Het as
just described above, 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 ethylaminosulphonyl,
C.sub.1-6dialkylaminosulphon- yl, e.g. dimethylaminosulphonyl or
diethylaminosulphonyl, phenylaminosulphonyl, carboxamido
(--CONH.sub.2), C.sub.1-6alkylaminocarb- onyl, e.g.
methylaminocarbonyl or ethylaminocarbonyl, C.sub.1-6
dialkylaminocarbonyl, e.g. dimethylaminocarbonyl or
diethylaminocarbonyl, phenylaminocarbonyl, sulphonylamino
(--NHSO.sub.2H), C.sub.1-6 alkylsulphonylamino, e.g.
methylsulphonylamino or ethylsulphonylamino,
C.sub.1-6dialkylsulphonylamino, e.g. dimethylsulphonylamino or
diethylsulphonylamino, aminosulphonylamino (--NHSO.sub.2NH.sub.2),
C.sub.1-6alkylaminosulphonylamino, e.g. methylaminosulphonylamino
or ethylaminosulphonylamino, C.sub.1-6dialkylaminosulphonylamino,
e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino,
phenylaminosulphonylamino, C.sub.1-6 alkanoylamino, e.g.
acetylamino, C.sub.1-6alkanoylamino, C.sub.1-6alkyl, e.g.
acetylaminomethyl or C.sub.1-6alkoxycarbonylamino, e.g.
methoxycarbonylamino, ethoxycarbonylamino, or
t-butoxycarbonylamino, thiocarboxamido (--CSNH.sub.2), C.sub.1-6
alkylaminothiocarbonyl, e.g. methylaminothiocarbonyl or
ethylaminothiocarbonyl, C.sub.1-6dialkylaminothiocarbonyl, e.g.
dimethylaminothiocarbonyl or diethylaminothiocarbonyl,
phenylaminothiocarbonyl, aminocarbonylamino,
C.sub.1-6alkylaminocarbonylamino, e.g. methylaminocarbonylamino or
ethylaminocarbonylamino, C.sub.1-6dialkylaminocarbonylamino, e.g.
dimethylaminocarbonylamino or diethylaminocarbonylamino,
aminothiocarbonylamino, C.sub.1-6alkylaminothiocarbonylamino, e.g.
methylaminothiocarbonylamino or ethylaminothiocarbonylamino,
C.sub.1-6 dialkylaminothiocarbonylamino, e.g.
dimethylaminothiocarbonylamino, or diethylaminothiocarbonylamino,
aminocarbonylC.sub.1-6alkylamino, e.g. aminocarbonylmethylamino or
aminocarbonylethylamino, aminothiocarbonylC.sub.1-6alkylamino e.g.
aminothiocarbonylmethylamino or aminothiocarbonylethylamino,
formylaminoC.sub.1-6 alkylsulphonylamino, e.g.
formylaminomethylsulphonylamino or formylaminoethylsulphonylamino,
thioformylaminoC.sub.1-6alkylsulphonylamino, e.g.
thioformylaminomethylsu- lphonylamino or
thioformylethylsulphonylamino, C.sub.1-6acylaminosulphonyl- amino,
e.g. acetylaminosulphonylamino,
C.sub.1-6thioacylaminosulphonylamin- o, e.g.
thioacetylaminosulphonylamino groups.
[0039] In the compounds of formula (1), when R.sup.3 is a L.sup.1
R.sup.13 group the linker group L.sup.1 may be any divalent linking
group. Particular examples of L.sup.1 groups include groups of
formula --(Alk.sup.a).sub.r(X.sup.a).sub.s(Alk.sup.b).sub.t- where
Alk.sup.a and Alk.sup.b is each an optionally substituted straight
or branched C.sub.1-6alkylene, C.sub.2-6alkenylene or
C.sub.2-6alkynylene chain optionally interrupted by one or more,
e.g. one, two or three heteroatoms or carbocyclic or
heteroatom-containing groups, X.sup.a is an --O-- or --S-- atom or
a --S(O)--, --S(O).sub.2-- or --N(R.sup.b)- group, r is zero or the
integer 1, t is zero or the integer 1 and s is zero or the integer
1, provided that when one of r, s, or t is zero at least one of the
remainder is the integer 1.
[0040] The heteroatoms which may interrupt the Alk.sup.a or
Alk.sup.b chains include for example --O-- or --S-- atoms.
Carbocyclic groups include for example cycloalkyl, e.g. cyclopentyl
or cyclohexyl, or cycloalkenyl e.g. cyclopentenyl or cyclohexenyl,
groups. Particular heteroatom-containing groups which may interrupt
Alk.sup.a or Alk.sup.b include oxygen-, sulphur- or
nitrogen-containing groups such as --S(O)--, --S(O).sub.2--,
N(R.sup.b)-, --C(O)--, --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)-, --SO.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 chains Alk.sup.a or Alk.sup.b are interrupted by two or more
heteroatoms, carbocyclic or heteroatom-containing 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--.
[0041] Optional substituents which may be present on Alk.sup.a or
Alk.sup.b chains include those described above in relation to the
group R.sup.1 when it is an alkyl group.
[0042] In the group -L.sup.1R.sup.13 particular examples of
Alk.sup.a or Alk.sup.b when present include optionally substituted
methylene, ethylene, propylene, butylene, ethenylene,
2-propenylene, 2-butenylene, 3-butenylene, ethynylene,
2-propynylene, 2-butynylene or 3-butynylene chains, optionally
interrupted by one, two or three heteroatoms, carbocyclic or
heteroatom-containing groups as described above.
[0043] Particular groups represented by -L.sup.1R.sup.13 include
for example --CH.sub.2Ar, --(CH.sub.2).sub.2Ar, --CH.dbd.CHAr,
--(CH.sub.2).sub.3Ar, --CH.sub.2CH.dbd.CHAr, --OCH.sub.2Ar,
--CH.sub.2OAr, --CH.sub.2OCH.sub.2Ar, --CH.sub.2N(R.sup.a)Ar or
--CH.sub.2N(R.sup.a)CH.sub.2Ar groups.
[0044] The group R.sup.3 in compounds of formula (1) may in general
be attached to the remainder of the molecule through a carbon atom
adjacent to the group
--C(R.sup.4)(R.sup.5)C(R.sup.6)(R.sup.7)(R.sup.8) or the group
W.
[0045] 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.
[0046] 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.
[0047] 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.
[0048] Particularly useful salts of compounds according to the
invention include pharmaceutically acceptable salts, especially
acid addition pharmaceutically acceptable salts.
[0049] In compounds of formula (1), the group .dbd.W-- is
preferably a .dbd.C(Y)-- group in which Y is an --OR.sup.1 group,
especially where R.sup.1 is an optionally substituted ethyl group,
or an optionally substituted methyl group. Especially useful
substituents which may be present on R.sup.1 groups include one,
two or three fluorine or chlorine atoms.
[0050] The group X in compounds of formula (1) is preferably
--O--.
[0051] Particularly useful groups of compounds of formula (1) have
the formula (2) 3
[0052] where R.sup.2 is an optionally substituted cycloalkyl group;
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as
defined for formula (1); and the salts, solvates, hydrates,
prodrugs and N-oxides thereof.
[0053] In the compounds of formulae (1) and (2), R.sup.2 is
preferably an optionally substituted methyl or cyclopentyl group.
In particular R.sup.2 is a cyclopentyl group.
[0054] In the compounds of formulae (1) and (2) R.sup.4 is
preferably a hydrogen atom or an --Ar or --CH.sub.2Ar group, where
Ar is an optionally substituted aryl or heteroaryl group,
particularly a phenyl or nitrogen containing heteroaryl group such
as a pyridyl group. In general however in compounds of formulae (1)
and (2) R.sup.4 is especially a hydrogen atom.
[0055] The groups R.sup.5, R.sup.7 and R.sup.8 in compounds of
formulae (1) and (2) is each preferably a fluorine atom or
especially a hydrogen atom.
[0056] In the compounds of formulae (1) and (2) the group R.sup.6
is preferably an --Ar group, especially a nitrogen containing
monocyclic heteroaryl group. Particularly useful groups of this
type are optionally substituted pyridyl groups, particularly
optionally substituted 4-pyridyl groups.
[0057] In the compounds of formulae (1) and (2) R.sup.3 is
preferably a halogen atom or an optionally substituted
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.6-12
mono- or bicyclic aryl, arC.sub.1-3alkyl or arC.sub.1-3alkenyl, or
C.sub.1-9 mono- or bicyclic heteroaryl or heteroarC.sub.1-3alkyl
group. Optional substituents which may be present on these groups
include, for alkyl, alkenyl or alkynyl groups, those substituents
described above in relation to the group R.sup.1, and for aryl,
aralkyl, heteroaryl or heteroaralkyl groups, R.sup.13 substituents
as described above.
[0058] Particular examples of aryl or aralkyl groups include
optionally substituted phenyl, naphthyl, phenC.sub.1-3alkyl or
naphthylC.sub.1-3alkyl groups. Examples of heteroaryl or
heteroaralkyl groups include optionally substitued pyridyl or
pyridylC.sub.1-3alkyl groups.
[0059] Particular examples of R.sup.3 in the compounds of formulae
(1) and (2) include bromine, chlorine or iodine atoms or, methyl,
ethyl, ethenyl 2-propenyl, ethynyl, 2-propynyl, phenyl, naphthyl,
benzyl, phenylethyl, phenylethenyl, phenylpropen-1-yl,
phenylpropen-2-yl, 2-, 3- or 4-pyridyl, 2-, 3- or 4- pyridylmethyl,
or 2-, 3- or 4-pyridylethyl, each of said phenyl or pyridyl groups
being optionally substituted by one or more R.sup.13
substituents.
[0060] The group R.sup.3 may in particular be positioned on one of
the two ring carbon atoms between the group W and the group
--C(R.sup.4)(R.sup.5)C(R.sup.6)(R.sup.7)(R.sup.8) either adjacent
to the group W or adjacent to the group
--C(R.sup.4)(R.sup.5)C(R.sup.6)(R.sup.7)- (R.sup.8).
[0061] Particularly useful compounds according to the invention
are:
[0062]
4-[2-(5-Cyclopentyloxy-2-iodo-4-methoxyphenyl)ethyl]pyridine;
[0063]
4-[2-(5-Cyclopentyloxy-4-methoxy-2-phenyl)ethyl]pyridine;
[0064]
4-{2-[5-Cyclopentyloxy-4-methoxy-2-(2-phenylethenyl)phenyl]ethyl}py-
ridine;
[0065]
4-{2-[5-Cyclopentyloxy-4-methoxy-2-(2-phenylethyl)phenyl]ethyl}pyri-
dine;
[0066]
4-{2-[5-Cyclopentyloxy-4-methoxy-2-(1-naphthyl)phenyl]ethyl}pyridin-
e;
[0067]
4-{2-[5-Cyclopentyloxy-4-methoxy-2-(2-naphthyl)phenyl]ethyl}pyridin-
e;
[0068]
4-{2-[5-Cyclopentyloxy-4-methoxy-2-(3-pyridyl)phenyl]ethyl}pyridine-
;
[0069] or each isomer and enantiomer, and/or the salts, hydrates,
solvates, prodrugs and N-oxides thereof.
[0070] 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.
[0071] The compounds according to the invention are thus of
particular use in the prophylaxis and treatment of human diseases
where an unwanted inflammatory response or muscular spasm (for
example bladder or alimentary smooth muscle spasm) is present and
where the elevation of cAMP levels may be expected to prevent or
alleviate the inflammation and relax muscle.
[0072] 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.
[0073] Compounds of the invention 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.
[0074] 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.
[0075] Compounds according to the invention have also been found to
reduce gastric acid secretion and therefore can be used to treat
conditions associated with hypersecretion.
[0076] Compounds of the invention 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 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 osteoarthritis.
[0077] 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 ameliorate
these symptoms with a consequent enhancement of quality of
life.
[0078] Compounds of the invention also elevate cAMP in certain
areas of the brain and thereby counteract depression and memory
impairment.
[0079] Compounds of the invention suppress cell proliferation in
certain tumour cells and can be used, therefore, to prevent tumour
growth and invasion of normal tissues.
[0080] 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.
[0081] 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.
[0082] 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.
[0083] Preparations for oral administration may be suitably
formulated to give controlled release of the active compound.
[0084] For buccal administration the compositions may take the form
of tablets or lozenges formulated in conventional manner.
[0085] The compounds of formula (1) 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.
[0086] In addition to the formulations described above, the
compounds of formula (1) may also be formulated as a depot
preparation. Such long acting formulations may be administered by
implantation or by intramuscular injection.
[0087] 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.
[0088] 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.
[0089] 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.
[0090] The compounds according to the invention may be prepared by
the following processes. The symbols W, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8 and X, 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.] It may be that deprotection
will form the last step in the synthesis of compounds of formula
(1).
[0091] Thus according to a further aspect of the invention, a
compound of formula (1) where R.sup.3 is a group -L.sup.1R.sup.13
may be prepared by a cross-coupling reaction of compound of formula
(3) 4
[0092] where Hal is an iodine or bromine atom with a coupling
reagent.
[0093] The reaction may be carried out in the presence of a metal
catalyst, such as a metal complex catalyst, for example a palladium
complex e.g.
dichloro-[1,4-bis(diphenylphosphino)ferrocene]palladium, tetrakis
(triphenylphosphine)palladium, or palladium (II) acetate, or a
nickel complex such as dichloro-[1,3-bis
(diphenylphosphino)propane] nickel.
[0094] The coupling reagents include organometallic reagents, such
as organo magnesium reagents R.sup.13L.sup.1MgX, where X is a
halogen atom, such as a chlorine or bromine atom, organozinc
reagents R.sup.13L.sup.1ZnX; boronic acid derivatives, for example
R.sup.13L.sup.1B(OH).sub.2 in the presence of a base, such as a
carbonate e.g. sodium carbonate; or an olefin reagent for example
R.sup.13L.sup.1CH.dbd.CH.sub.2 in the presence of a phosphine, e.g.
tri-0-tolylphosphine and a base such as triethylamine.
[0095] The reaction may take place in a solvent, for example an
ether, such as diethylether or a cyclic ether, e.g. tetrahydrofuran
or dioxane, or a nitrile, e.g. acetonitrile, at a temperature
varied from room temperature to an elevated temperature, e.g.
140.degree. C.
[0096] The coupling reagents are either known compounds or may be
prepared using reagents and conditions similar to those used for
the preparation of the known compounds.
[0097] It is to be understood that compounds of formula (3) are
compounds of formula (1) in which R.sup.3 is a halogen atom.
Therefore, in a further aspect of the invention compounds of
formula (1) wherein R.sup.3 is a halogen atom may be prepared by
halogenation of a compound of formula (4) 5
[0098] This reaction is particularly suitable for preparing
compounds in which R.sup.3 is a chlorine, bromine or iodine atom.
Thus for example bromination and chlorination may be achieved by
using bromine or chlorine in the presence of a catalyst, such as a
Lewis acid, e.g. AlBr.sub.3, AlCl.sub.3, or FeCl.sub.3 respectively
or an organic acid, e.g. acetic acid where necessary in a solvent
for example a halogenated hydrocarbon, e.g. dichloromethane.
[0099] Iodination may be carried out by the use of iodine in the
presence of an oxidising agent, such as HNO.sub.3, HIO.sub.3 or
peracetic acid, or salts, such as copper salts, antimony salts e.g.
SbCl.sub.5 or sulphonates, e.g. silver trifluoromethanesulphonate,
where necessary in a solvent such as a halogenated hydrocarbon,
e.g. dichloromethane.
[0100] Intermediates of formula (4) where R.sup.5 is a hydroxyl
group may be prepared by reaction of a compound of formula (5)
6
[0101] with
[0102] (a) an organometallic reagent R.sup.6R.sup.7R.sup.8CM where
M is a metal atom, such as lithium, or a Grignard reagent
R.sup.6R.sup.7R.sup.8MgHal, where Hal is a halogen atom, e.g. a
bromine atom, or
[0103] (b) a compound R.sup.6R.sup.7R.sup.8CHal, where Hal is a
halogen atom, such as a bromine atom, using a base, such as
t-butyllithium.
[0104] Intermediates of formula (4), where R.sup.5 is a fluorine
atom may be prepared by reacting an intermediate of formula (4),
where R.sup.5 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.
[0105] Ketones of formula (5) may be prepared by oxidation of a
corresponding alcohol of formula (6) 7
[0106] using an oxidising agent such as manganese dioxide in a
solvent such a dichloromethane at ambient temperature.
[0107] Alcohols of formula (6) may be prepared by reaction of an
aldehyde of formula (7) 8
[0108] with an organometallic compound, such as organolithium
compound R.sup.4Li, or a Grignard reagent R.sup.4MgBr, in a
solvent, such as tetrahydrofuran, at a low temperature, e.g. around
-50.degree. C. to 0.degree. C.
[0109] Aldehydes of formula (7) where .dbd.W-- is .dbd.C(Y)-- may
be prepared by alkylation of a corresponding compound of formula
(8): 9
[0110] using a compound R.sup.2Hal [where Hal is as previously
defined] using the reagents and conditions described hereinafter
for the alkylation of intermediates of formula (15).
[0111] Intermediates of formula (8) 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.
[0112] Intermediates of formula (7) wherein .dbd.W-- is .dbd.N--
may be prepared from an intermediate of formula (9) 10
[0113] by successive oxidation and reduction reactions.
[0114] For example a first oxidation of intermediate (9) by
SeO.sub.2 or potassium permanganate gives the carboxylic acid
derivative. This in turn may be reduced by a reducing agent, for
example lithium aluminium hydride to afford the corresponding
alcohol, which upon oxidation with manganese dioxide gives the
desired intermediate (7).
[0115] Intermediates of formula (9) may be prepared by reacting a
halide of formula (10) 11
[0116] where Hal is a halogen atom, e.g. a bromine, chlorine or
iodine atom with a compound RXH, where X is --O--, --S-- or --NH--
in the presence of a base.
[0117] Bases used in this reaction include hydrides, such as sodium
hydride, or organometallic bases, such as butyllithium in a
solvent, such as an amide, for example dimethylformamide at a
temperature from room temperature to above, e.g. around 80.degree.
C.
[0118] Intermediates of formula (10) may be prepared by reacting
the commercially available amine of formula (11) 12
[0119] 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 (1) halide
for example CuBr or Cul, or halogen, e.g. bromine, chlorine or
iodine.
[0120] Alternatively ketones of formula (5) may be prepared by
reaction of a halide of formula (12) 13
[0121] [where Hal is a halogen atom such as bromine or chlorine
atom] by halogen metal exchange with a base such as n-butyllithium
followed by reaction with a nitrite R.sup.4CN, an acid chloride
R.sup.4COCl or an ester R.sup.4CO.sub.2Alk (where Alk 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.
[0122] Halides of formula (12) may be prepared by alkylation of a
compound of formula (13): 14
[0123] using the reagents and conditions discussed below in
relation to the alkylation of intermediates of formula (15).
[0124] Halides of formula (13) where X is --O-- may be prepared by
oxidation of an aldehyde of formula (14): 15
[0125] 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.
[0126] Aldehydes of formula (14) and halides of formula (13) where
X is --S-- or --N(R.sup.8)-- 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.
[0127] Intermediates of formula (5) where X is --O--, --S-- or
--N(R.sup.a)- may also be prepared by alkylation of a compound of
formula (15) 16
[0128] using a reagent R.sup.2L, where L is a leaving group.
[0129] Leaving groups represented by L include halogen atoms such
as iodine, chlorine or bromine atoms, or sulphonyloxy groups such
as aryl-sulphonyloxy groups, e.g. p-toluenesulphonyloxy.
[0130] The alkylation reaction may be carried out in the presence
of a 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 dimethyl-formamide, 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.
[0131] Intermediates of formula (15) are known compounds or may be
prepared in a manner similar to the preparation of the known
compounds.
[0132] In yet another process according to the invention, compounds
of formula (1) where R.sup.8 and R.sup.5 is each a hydrogen atom
may be prepared by hydrogenation of a compound of formula (16)
17
[0133] 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 rodhium. 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.
[0134] 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 formates, 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 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.
[0135] Intermediate alkenes of formula (16) may be obtained by
reaction of a corresponding aldehyde of formula (5) [where R.sup.4
is a hydrogen atom] using an olefination agent and the reagents and
conditions similar to those described below for the production of a
compound of formula (1) from an intermediate of formula (19).
[0136] In another process according to the invention, a compound of
formula (1) where X is --O--, --S-- or --N(R.sup.a)- may be
prepared by alkylation of a compound of formula (17) 18
[0137] using a reagent R.sup.2L, as described above for the
production of a compound of formula (5) from a compound of formula
(15).
[0138] Intermediates of formula (17) may be obtained from the
corresponding protected compounds of formula (18) 19
[0139] wherein X.sup.1 is a protected hydroxy, thio, amino or
aldehyde group using conventional deprotection procedures [see
Green, T. W. ibid]. Thus for example where X.sup.1 is a
t-butyldimethylsilyloxy group, the required hydroxyl group may be
obtained by treatment of the protected intermediate with
tetra-butylammonium fluoride. In another example where X.sup.1 is a
dioxanyl group, the required aldehyde group may be obtained by acid
hydrolysis of the protected intermediate 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.
[0140] The protected intermediates of formula (18) may be prepared
in an analogous manner to the compounds of formula (1) using the
reactions described herein and appropriately protected
intermediates.
[0141] In a further aspect of the invention, compounds of general
formula (1) where X is a chain --C(R)=C(R.sup.b)-, in which R is a
hydrogen atom or a methyl group, may be prepared by coupling a
compound of formula (19) 20
[0142] where R is as defined above with an olefination agent
[0143] Particular examples of olefination agents include
phosphonium salts such as compounds
(R.sup.b)(R.sup.2)CHP(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.b)(R.sup.2)C.dbd.P(D).sub.3; phosphonates
(DO).sub.2P(O)CH(R.sup.b- )(R.sup.2); or silane derivatives, for
example compounds of formula (D).sub.3SiC(R.sup.5)(R.sup.6), e.g.
trialkylsilanes such as (CH.sub.3).sub.3SiC(R.sup.b)(R.sup.2).
[0144] 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.
[0145] 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.
[0146] 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 may be prepared by
reacting a halide (R.sup.b)(R.sup.2)CHHal 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 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.
[0147] According to a further aspect of the invention compounds of
formula (1) where X is a group --C(R)=CH(R.sup.b) and R.sup.2 is an
optionally substituted alkyl, alkenyl or alkynyl group may also be
prepared by reaction of an intermediate of formula (19) with an
organometallic reagent, for example as described above in
connection with the preparation of intermediates of formula (4),
followed by dehydration of the corresponding alcohol. The
dehydration may be performed using an acid, for example an organic
acid such as p-toluene sulphonic acid or trifluoroacetic acid, in
the presence of a base, such as an amine, e.g. triethylamine.
[0148] Intermediates of formula (19) may be prepared by
deprotecting an intermediate of formula (20) 21
[0149] where X.sup.1 is an aldehyde or ketone protecting group.
[0150] Intermediates of formula (20) may be prepared by reaction of
a compound of formula (21) 22
[0151] with an organometallic reagent or a halide in an analogous
manner to the preparation of intermediates of formula (4) from
intermediates of formula (5)
[0152] Intermediates of formula (21) may be prepared by oxidation
of an alcohol of formula (22) 23
[0153] using an oxidising agent, such as manganese (IV) oxide, in a
solvent, such as dichloromethane, at room temperature.
[0154] Intermediates of formula (22) may be prepared by reaction of
a halide of formula (23) 24
[0155] with an aldehyde R.sup.4CHO, in the presence of a base, such
as n-butyl-lithium, in a solvent, e.g. tetrahydrofuran, at a
temperature from around -70.degree. C. to room temperature.
[0156] Intermediates of formula (23) may be prepared by protecting
an aldehyde of formula (24) 25
[0157] using the reagents and conditions described herein
above.
[0158] Intermediates of formula (24) are either known compounds or
may be prepared in a similar manner to the known compounds.
[0159] In another aspect of the invention, a compound a formula (1)
in which .dbd.W-- is a .dbd.C(X.sup.aR.sup.1)- group in which
X.sup.a is --O-- may be prepared by alkylating an intermediate of
formula (25) 26
[0160] using a reagent R.sup.1L where L is a leaving group as
described above.
[0161] The reaction may be performed using the reagents and
conditions described above for the production of a compound of
formula (5) from a compound of formula (15).
[0162] Intermediates of formula (25) where R.sup.3 is propen-2-yl
may be prepared in a Claisen rearrangement by heating an allylic
aryl ether of formula (26) 27
[0163] at elevated temperature.
[0164] Intermediates of formula (23) may be prepared by reacting an
intermediate of formula (4) where W is a .dbd.C(OCH.sub.3)-- group
with a thiol reagent, such as propanethiol, in the presence of a
base, such as a hydride, e.g. sodium or potassium hydride, or an
amide, e.g. sodium bis (trimethylsilyl)amide. The reaction may be
performed in a solvent, such as dimethylformamide at an elevated
temperature, e.g. the reflux temperature.
[0165] Intermediates of formula (25) may also be prepared by
deprotecting a compound of formula (26) 28
[0166] where X.sup.2 is a protected hydroxyl group, e.g. methoxy,
using iodotrimethylsilane in chloroform.
[0167] Intermediates of formula (24) may be prepared using similar
protected reagents and conditions to those used for the preparation
of intermediates of formula (4).
[0168] Compounds of formula (1) may also be prepared by
interconversion of other compounds of formula (1). These reactions
will generally involve the group R.sup.13, whether present as the
group R.sup.3 or as a substituent on a group Ar in R.sup.4 or
R.sup.6. Thus, in one example of an interconversion process a
compound of formula (1) which contains a --CH.sub.2NH.sub.2
substituent may be prepared by reduction of a corresponding
compound of formula (1) which contains a nitrile group, using for
example a complex metal hydride such as lithium aluminium hydride
in a solvent such as an ether e.g. diethylether.
[0169] In a further example, a compound of formula (1) with an
alkanoylamino or alkanoylaminoalkyl substituent may be prepared by
acylation of a corresponding compound of formula (1) containing a
--NH.sub.2 or alkylamino group by reaction with an acyl halide in
the presence of a base, such as a tertiary amine e.g. triethylamine
in a solvent such as dichloromethane.
[0170] Compounds of formula (1) where X is a chain
[--CH(R)].sub.q--CH(R.s- up.b)- may be prepared by hydrogenation of
a compound of formula (1) where X is a chain --C(R)=C(R.sup.b)-
using the reagents and conditions described above for the
production of a compound of formula (1) from an intermediate of
formula (13).
[0171] In yet another example of an interconversion process,
compounds of formula (1) containing an ester [CO.sub.2Alk.sup.2],
e.g. an ethanoate, may be prepared by esterification of a
corresponding compound of formula (1) containing a carboxylic acid,
using an acid halide, such as an acid chloride, e.g. acetyl
chloride, in an alcohol, such as ethanol, at an elevated
temperature, such as the reflux temperature.
[0172] Compounds of formula (1) containing a carboxylic acid may be
prepared from the corresponding compound of formula (1) containing
a formyl group, by oxidation with an oxidising agent, e.g.
potassium permanganate, in a solvent, such as an alcohol, e.g.
tert-butanol, at ambient temperature.
[0173] In a further interconversion reaction, compounds of formula
(1) which contain an aminoalkyl group, such as dimethylaminomethyl,
may be prepared by reductive amination of a corresponding compound
of formula (1) which contains a formyl group, using an amine, e.g.
dimethylamine, in the presence of a reducing agent, e.g. sodium
cyanoborohydride, if necessary in the presence of a catalyst, e.g.
ethanolic HCl, in a solvent, such as an alcohol, e.g. methanol, at
ambient temperature.
[0174] In another example of an interconversion reaction a compound
of formula (1) which contains a formyl group, may be reduced to the
corresponding alcohol, using a reducing agent, e.g. sodium
borohydride, in a solvent, such as an alcohol, e.g. ethanol, at a
temperature from around 0.degree. C. to ambient temperature. The
resulting alcohol may then be converted to a corresponding alkoxy
derivative, e.g. methoxymethyl, by reaction with an alkyl halide or
alkyl sulphonate using the methods and reagents described above for
the alkylation of intermediates of formula (9).
[0175] In a further example of an interconversion process compounds
of formula (1) which contain a carboxamido (--CONHAlk.sup.1) or an
aminocarbonyl (--NHCOAlk.sup.1) group may be prepared by reaction
of the corresponding compound containing a --CO.sub.2H or a
--NH.sub.2 group respectively by reaction with a carbamate, such as
i-butyl chloroformate or ethyl chloroformate, in the presence of a
base, such as an amine, e.g. triethylamine or N-methylmorpholine,
in a solvent, such as dichloromethane, or a mixture of solvents,
e.g. tetrahydrofuran and dimethylformamide, at a temperature from
around -20.degree. C. to room temperature.
[0176] In a still further interconversion reaction, compounds of
formula (1) which contain a --NHCONHAlk.sup.1 group may be prepared
by reacting a corresponding compound of formula (1) which contains
an amino (--NH.sub.2) group, with an isocyanate, e.g. ethyl
isocyanate, in a solvent, e.g. dichloromethane, at ambient
temperature.
[0177] In another example of an interconversion process, compounds
of formula (1) wherein R.sup.7 is an alkyl group, may be prepared
by interconversion of a compound of formula (1) where R.sup.7 is a
hydrogen atom by reaction with a compound R.sup.7L, where L is a
leaving group, for example a halogen atom, such as chlorine, in the
presence of a base, for example lithium diisopropylamide, in a
solvent such as tetrahydrofuran, at low temperature, such as
0.degree. C.
[0178] Compounds of formula (1) wherein R.sup.5 is an OR.sup.c
group where R.sup.c is an alkyl, alkoxyalkyl, formyl or alkanoyl
group, may be prepared in another example of an interconversion
process by reaction of a compound of formula (1) where R.sup.5 is a
--OH group with a compound R.sup.cL (where R.sup.c is as just
defined and L is a leaving group as described above), in a solvent,
such as dichloromethane or tetrahydrofuran in the presence of a
base, for example triethylamine or potassium tert-butoxide, at room
temperature.
[0179] In a further interconversion process compounds of formula
(1) wherein R.sup.c is a carboxamido (--CONHAlk.sup.1) or a
thiocarboxamido (--CSNHAlk.sup.1) group, may be prepared by
reaction of a compound of formula (1) wherein R.sup.5 is a hydroxyl
group with an isocyanate Alk.sup.1NCO or an isothiocyanate
Alk.sup.1NCS, in a solvent, for example chloroform, in the presence
of a base, for example diisopropylethylamine, at ambient
temperature. The isocyanate Alk.sup.1NCO and isothiocyanate
Alk.sup.1NCS are known compounds or may be prepared in a
conventional manner.
[0180] In a further example, a compound of formula (1) wherein
R.sup.c is a CON[Alk.sup.1].sub.2 group may be prepared by reaction
of a compound of formula (1) wherein R.sup.c is a CONHAlk.sup.1
group with a reagent Alk.sup.1L (where L is a leaving group as
described above) in the presence of a base, for example sodium
hydride, in a solvent, such as tetrahydrofuran, at low temperature,
for example 0.degree. C.
[0181] In another example, an isothiocyanate of formula (1) where
R.sup.c is --CSN[Alk.sup.1l].sub.2 may be prepared by reacting a
compound of formula (1) wherein R.sup.c is a --CON[Alk.sup.1].sub.2
group with a thiation reagent, such as Lawesson's Reagent, in an
anhydrous solvent, for example toluene, at elevated temperature,
such as the reflux temperature.
[0182] 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.
[0183] 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.
[0184] 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.
[0185] 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 dltoluoyl
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
[0186] In another resolution process a racemate of formula (1) may
be separated using chiral High Performance Liquid
Chromatography.
[0187] Alternatively, if desired a particular enantiomer may be
obtained by using an appropriate chiral intermediate in one of the
processes described above.
[0188] The following examples illustrate the invention. The
following abbreviations are used: DMF--dimethylformamide;
THF--tetrahydrofuran; DME--dimethoxyethane; EtOAc--ethyl acetate;
Et.sub.2O--diethylether; Et.sub.3N--triethylamine;
BuLi--butyllithium; LDA--lithium diisopropylamide; EtOH--ethanol;
CHCl.sub.3--chloroform; CH.sub.2Cl.sub.2--dichloromethane;
MEOH--methanol; RT--room temperature.
[0189] All .sup.1Hnmr spectra were obtained at 300 MHz unless
specified otherwise.
Intermediate 1
3-Cyclopentyloxy-4-methoxybenzaldehyde
[0190] The title compound was prepared as described for
Intermediate 9 in International Patent Specification No. WO
94/14742.
Intermediate 2
(.+-.)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-hydroxyethyl]pyridine
[0191] The title compound was prepared as described in Example 2b)
in International Patent Specification No. WO 94/20446.
Intermediate 3
(E)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)ethenyl]pyridine
[0192] The title compound was prepared as described for
Intermediate 5c) in International Patent Specification No. WO
94/20446.
Intermediate 4
4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)ethyl]pyridine
[0193] The title compound was prepared as decribed in Example 3f)
iin International Patent Specification No. WO 94/20446.
Intermediate 5
(R)-(+)-4-[2-(3-Hydroxy-4-methoxyphenyl)-2-phenylethyl]pyridine
[0194] To a stirred solution of NaH (60% dispersion in mineral oil)
(0.483 g, 12.075 mmol) in DMF under nitrogen at RT was added
propanethiol (1.09 ml, 12.07 mmol) and the mixture stirred for 30
min. A solution of
(R)-(+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine
(made as described in WO 94/14742) (1.8 g, 4.83 mmol) in DMF was
added, the mixture heated to reflux for 5 h, allowed to cool (the
reaction was followed by tic) and concentrated in vacuo. The
residue was taken up in CH.sub.2Cl.sub.2 and washed with aqueous
NaHCO.sub.3 solution. The aqueous phase was extracted with
CH.sub.2Cl.sub.2, the combined organic phase dried (MgSO.sub.4),
filtered and concentrated in vacuo. The residue was subjected to
chromatography (SiO.sub.2; Et.sub.2O) then recrystallised
(i-propylether) to give the title compound (6.00 g) as a white
solid. m.p. 158-159.degree. C. (Found C, 79.37; H, 6.96; N. 3.66.
C.sub.24H.sub.25O.sub.2N requires C, 80.19; H, 7.01; N, 3.90%).
.delta.H (CDCl.sub.3) 1.5-1.9 (8H, m, (CH.sub.2), 3.39 (2H, dd, J8,
1Hz, CH.sub.2 pyridine), 4.12 (1H, t, J8 Hz, CHCH.sub.2), 4.62 (1H,
m, OCH), 5.52 (1H, br s, OH), 6.57 (1H, m, C.sub.6H.sub.3), 6.6-6.7
(1H, m, C.sub.6H.sub.3), 6.75-6.8 (1H, m, C.sub.6H.sub.3), 6.91
(2H, d, J6.Hz, H.sub.3, H.sub.5 pyridine), 7.1-7.3 (5H, m,
C.sub.6H.sub.5), and 8.38 (2H, d, J6Hz, H.sub.2, H.sub.6
pyridine).
Intermediate 6
4-[2-(R)-(3-Cyclopentyloxy-4-prop-2-enyloxyphenyl)-2-phenylethyl]-pyridine
hyrochloride
[0195] To a stirred soution of Intermediate 5 (2.031 g, 5.66 mmol)
in THF (60 ml) and DMF (20 ml) at RT, under nitrogen, was added
potassium t-butoxide (0.8 g, 6.77 mmol). After 20 min, allyl
bromide (0.56 ml, 6.47 mmol) was added, the mixture stirred at RT
for 20 min then quenched with water and extracted with EtOAc. The
combined organic phase was dried (MgSO.sub.4), filtered and
concentrated in vacuo to give the title compound free base (2.2 g)
as a yellow gum.
[0196] A small amount of the free base was treated with etheral HCl
to give the title compound as an off-white solid (Found C, 71.18;
H, 6.58; N, 2.93. C.sub.27H.sub.31NO.sub.2Cl. H.sub.2O requires C,
71.26; H, 6.86; N, 3.08%). m/z (ESI) (M+, 400, 100%). .delta.H
(CD.sub.3OD) 1.05-1.85 (5H, m), 3.7 (2H, d, J 9.0Hz), 4.45-4.52
(3H, m), 4.7 (1H, m), 5.19 (1H, dd, J 3.01, 6.0Hz), 5.3 (1H, dd,
J3.0, 9.0Hz), 5.9-6.1 (1H, m), 6.7-6.82 (3H, m), 7.1-7.39 (5H, m),
7.82 (2H, d, J 6.0Hz) and 8.6 (2H, d, J 6.0Hz).
Intermediate 7
4-{2-(R)-[3-Cyclopentyloxy-4-hydroxy-5-prop-3-enylphenyl]-2-phenyl}ethylpy-
ridine hydrochloride
[0197] Intermediate 6 (2.2 g, 5.51 mmol) was heated in a silicon
oil bath at 230.degree. C. for 2 h under nitrogen. The crude
product was subjected to chromatography (SiO.sub.2;
MeOH--CH.sub.2Cl.sub.2, 5:95) to give the free base (1.41 g) as a
yellow gum.
[0198] A small amount of the free base was treated with ethereal
HCl to give the title compound as an off-white solid. m/z (ESI)
(M+H, 400, 50%) (Found C, 71.57; H, 6.58; N, 3.00.
C.sub.27H.sub.30NO.sub.2Cl requires C, 71.42; H, 6.66; N, 3.08%).
.delta.H (CD.sub.3OD) 1.5-1.98 (5H, m), 3.3 (2H, dd, J 3.0, 6.0Hz),
3.68 (2H, dd, J 3.0, 6.0Hz), 3.7 (2H, dd, J 3.0, 6.0Hz), 4.32-4.45
(1H, m), 4.78 (1H,m), 4.9 (2H, dd, J 3.0, 9.0Hz under HOD), 5.8-6.0
(1H, m), 6.6 (2H, dd, J 3.0, 30Hz), 7.1-7.4 (5H, m), 7.81 (2H, d, J
3.0Hz) and 8.6 (2H, d, J 3.0Hz).
EXAMPLE 1
[0199] a)
4-[2-(5-Cyclopentyloxy-2-iodo-4-methoxyphenyl)ethyl]pyridine
[0200] Silver triflate (2.57 g, 10.0 mmol) was added to a solution
of Intermediate 4 (3.00 g, 10.0 mmol) in CHCl.sub.3 (100 ml) at RT.
A solution of iodine (2.54 g, 10.0 mmol) in CHCl.sub.3 (100 ml) was
added dropwise and the mixture allowed to stir for a further 1 h at
RT. Sodium thiosulphate solution (100 ml) was added and the organic
layer separated and combined with a CH.sub.2Cl.sub.2 portion (50
ml). The extract was dried (MgSO.sub.4) and concentrated in vacuo.
The residue was subjected to chromatography (SiO.sub.2; Et.sub.2O)
to afford the title compound (3.89 g) as a pale yellow solid;
.delta.H (CDCl.sub.3) 1.4-1.9 (8H, br m, (CH.sub.2).sub.4), 2.8-3.0
(4H, m, CH.sub.2CH.sub.2 pyridine), 3.81 (3H, s, OMe), 4.60 (1H, br
m, OCH), 6.55 (1H, s, ArH meta to methoxy), 7.12 (2H, dd, J 4.5,
1.5 Hz, pyridine H.sub.3, H.sub.5), 7.22 (1H, s, ArH ortho to
methoxy), and 8.50 (2H, dd, J 4.5, 1.5 Hz, pyridine H.sub.2,
H.sub.6).
[0201] The following compound was prepared in a manner similar to
the compound of Example 1a):
[0202] b)
(R)-4-[2-(3-Cyclopentyloxy-6-iodo-4-methoxyphenyl)-2-phenyl-ethy-
l]pyridine
[0203] From
(R)-(+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]-
pyridine (made as described in International Patent Specification
No. WO 94/14742) (1.82 g, 4.88 mmol) in CHCl.sub.3 (50 ml)m, silver
triflate (1.26 g, 4.88 mmol) and iodine (1.24 g, 4.88 mmol).
Chromatography (SiO.sub.2;EtOAc) afforded the title compound (2.2
g) as a colourless gum. (Found C, 59.23; H, 5.32; N, 2.67.
C.sub.23H.sub.26NO.sub.2I requires C, 60.13; H, 5.25; N, 2.81)
.delta.H (CDCl.sub.3) 1.5-1.9 (8H, m,CH.sub.2).sub.4), 3.25 (1H, d,
J 5Hz, CH.sub.2pyridine), 3.27 (1H, d, J 5Hz, CH.sub.2 pyridine),
3.74 (3H, s, OCH.sub.3), 4.6-4.7 (1H, m, OCH), 4.64 (1H, t, J 8Hz,
CH phenyl), 6.74 (1H, s, C.sub.6H.sub.2), 7.01 (2H, d, J 5Hz,
H.sub.3, H.sub.5 pyridine), 7.24 (1H, s, C.sub.6H.sub.2), 7.25-7.4
(5H, m, C.sub.6H.sub.5), and 8.39 (2H, d, J 5Hz, H.sub.2, H.sub.6
pyridine). m/z 500 (M+, 100%), 406 (25) and 212 (14).
EXAMPLE 2
[0204] 4-[2-(5-Cyclopentyloxy-4-methoxy-2-phenyl)ethyl]pyridine
hydrochloride
[0205] A solution of the compound of Example 1 (1.06 g, 2.5 mmol)
in dioxane (10 ml) was added to a solution of tetrakis
(triphenylphosphine)palladium (0.144 g, 0.125 mmol) in dioxane (20
ml) and the mixture stirred at RT for 0.5 h. Sodium carbonate
solution (2M; 3.25 ml) and phenylboronic acid (0.305 g, 2.5 mmol)
were then added and the mixture heated to reflux for 16 h. The
cooled reaction mixture was poured into sodium hydrogen carbonate
solution (20 ml) and extracted with CH.sub.2Cl.sub.2 (2.times.25
ml). The extract was dried (MgSO.sub.4), concentrated in vacuo, and
the residue subjected to chromatography (SiO.sub.2; Et.sub.2O) to
afford the title compound free base.
[0206] The base was dissolved in Et.sub.2O (20 ml) and treated with
ethanolic HCl to afford the title compound (320 mg) as a pale
yellow solid m.p. 179-180.degree. C.; .delta.H (CDCl.sub.3) 1.5-2.0
(8H, br m, (CH.sub.2).sub.4), 2.6-2.7 (2H, m, CH.sub.2CH.sub.2),
2.8-2.9 (2H, m, CH.sub.2CH.sub.2), 3.80 (3H, s, OMe), 4.74 (1H, br
m, OCH), 6.69 (1H, s, ArH ortho to alkoxy), 6.72 (1H, s, ArH ortho
to alkoxy), 6.80 (2H, dd, J 4.5, 1.5 Hz, pyridine H.sub.3,
H.sub.5), 7.2-7.5 (5H, m, C.sub.6H.sub.5), and 8.37 (2H, dd, J 4.5,
1.5 Hz, pyridine H.sub.2, H.sub.6); m/z (El) 373 (M+, 12%) 305
(17), 182 (18), 181 (100), 153 (28), 152 (22), 94 (17), 93 (46),
and 69 (23).
EXAMPLE 3
[0207] (E)- and (Z)-isomers of
4-[2-(5-Cyclopentyloxy-4-methoxy-2-(2-pheny- l-ethenyl))
ethyl]pyridine
[0208] A mixture of the compound of Example 1 (1.27 g, 3.0 mmol),
styrene (417 mg, 4.0 mmol), Et.sub.3N (404 mg, 4.0 mmol), palladium
(II) acetate (34 mg, 0.15 mmol), and tri-O-tolylphosphine (41 mg,
0.5 mmol) in acetonitrile (5 ml) was heated in a bomb at
140.degree. C. for 24 h. The cooled reaction mixture was poured
into sodium hydrogen carbonate solution (10 ml) and extracted with
CH.sub.2Cl.sub.2 (2.times.25 ml). The extract was dried
(MgSO.sub.4), concentrated in vacuo, and the residue subjected to
chromatography (SiO.sub.2; Et.sub.2O) to afford the title compound
(1.05 g) as a cream solid m.p. 91-94.degree. C. .delta.H
(CDCl.sub.3) 1.5-1.7 and 1.75-1.95 (8H, m, (CH.sub.2).sub.4),
2.8-3.1 (4H, m, (CH.sub.2).sub.2 pyridine), 3.90 (3H, s, OMe),
4.60-4.75 (1H, m, OCH), 6.51 (1H, s, ArH), 6.6-7.5 (8H, m,
ArH+(CH.sub.2+C.sub.6H.sub.5), 7.07 (2H, d, J 7.5Hz, H.sub.3,
H.sub.5 pyridine), and 8.47 (2H, d, J 7.5 Hz, H.sub.2, H.sub.6
pyridine).
EXAMPLE 4
[0209]
4-{2-(R)-[3-Cyclopentyloxy-4-methoxy-5-prop-3-enylphenyl]-2-phenyl}-
ethylpyridine
[0210] To a stirred solution of Intermediate 7 (243 mg) in dry
THF-DMF (8 ml; 3:1) at RT was added potassium tert-butoxide (90
mg). After 20 min, iodomethane (0.042 ml) was added and the
solution stirred a further 40-min, then quenched with H.sub.2O. The
reaction mixture was partitioned between H.sub.2O-EtOAc and the
aqueous phase extracted with EtOAc. The combined organic phase was
dried (MgSO.sub.4) then evaporated. Chromatography (SiO.sub.2;
EtOAc-hexane, 30-50%) afforded the title compound (0.167 g) as a
yellow oil. Found (C, 80.43; H, 7.52; N, 3.55.
C.sub.28H.sub.31NO.sub.2 requires C, 81.32; H, 7.56; N, 3.36%).
.delta.H (CDCl.sub.3) 1.55-1.8 (8H, br m), 3.3 (4H, dd, J 6.0Hz),
3.61 (31H, s), 4.13 (1H, t, J 9.0Hz), 4.58 (1H, s), 4.92-5.08 (2H,
m), 5.82-5.97 (1H, m), 6.6 (2H, dd, J 3.0, 6.0Hz), 6.92 (2H, d, J
6.0Hz), 7.15-7.3 (5H, m), 8.4 (2H, d, J 6.0Hz). m/z (ESI) 414 (M+H
414, 100%).
Formulation Examples
[0211] The compounds of the invention may be formulated for
pharmaceutical use in a number of forms using any suitable
excipients. Thus, for example, for oral use the compounds of the
invention such as the compounds of the Examples may be formulated
as a solid dosage form, by mixing an appropriate weight of compound
(for example 50 mg) with maize starch (50-99% w/w), anhydrous
colloidal silica (0-10% w/w) and organic or inorganic acid (up to
1% w/w), to fill capsules of an appropriate size, e.g. white opaque
hard gelatine capsules size 3. If desired the same mixture may be
compressed into tablets.
[0212] 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.
[0213] Isolated Enzyme
[0214] The potency and selectivity of the compounds of the
invention was determined using distinct PDE isoenzymes as
follows:
[0215] i. PDE I, rabbit heart
[0216] ii. PDE II, rabbit heart
[0217] iii. PDE III, rabbit heart, Jurkat cells
[0218] iv. PDE IV, HL60 cells, rabbit brain, rabbit kidney and
human recombinant PDE IV
[0219] v. PDE V, rabbit lung, guinea pig lung
[0220] A gene encoding human PDE IV has been cloned from human
monocytes (Livi, et al., 1990, Molecular and Cellular Biology, 10,
2678). 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.
[0221] The enzymes were purified to isoenzyme homogeneity using
standard chromatographic techniques.
[0222] 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-ethane-sulp- 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 mins. 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 [.sup.3H]-5'AMP was determined
using the [.sup.14C]-5'AMP and all assays were conducted in the
linear range of the reaction.
[0223] Compounds according to the invention such as the most potent
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.
[0224] 2. The Elevation of cAMP In Leukocytes
[0225] The effect of compounds of the invention on intracellular
cAMP was investigated using human neutrophils or guinea pig
eosinophils. 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).
[0226] The most potent compounds according to the Examples induced
a concentration -dependent elevation of cAMP in neutrophils and/or
eosinophils at concentrations of 0.1 nM to 1 .mu.M.
[0227] 3. Suppression of Leukocyte Function
[0228] 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
[0229] 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 10 .mu.M.
[0230] 4. Adverse Effects
[0231] In general, in our tests above, compounds of the invention
have had no observed toxic effects when administered to animals at
pharmacologically effective doses.
* * * * *