U.S. patent application number 10/473727 was filed with the patent office on 2004-06-17 for sulphones which modulate the action of gamma secretase.
Invention is credited to Churcher, Ian, Dinnell, Kevin, Harrison, Timothy, Kerrad, Sonia, Nadin, Alan John, Oakley, Paul Joseph, Owens, Andrew Pate, Pineiro, Jose Luis Castro, Shaw, Duncan Edward, Teall, Martin Richard, William, Susannah, Williams, Brian John.
Application Number | 20040116404 10/473727 |
Document ID | / |
Family ID | 9912329 |
Filed Date | 2004-06-17 |
United States Patent
Application |
20040116404 |
Kind Code |
A1 |
Pineiro, Jose Luis Castro ;
et al. |
June 17, 2004 |
Sulphones which modulate the action of gamma secretase
Abstract
Disclosed are sulphones which modulate the action of
gamma-secretase. The compounds are useful in the treatment or
prevention of Alzheimer's disease.
Inventors: |
Pineiro, Jose Luis Castro;
(Bishops Stortford, GB) ; Churcher, Ian; (Great
Dunmow, GB) ; Dinnell, Kevin; (Much Hadham, GB)
; Harrison, Timothy; (Great Dunmow, GB) ; Kerrad,
Sonia; (Huningue, FR) ; Nadin, Alan John;
(Sawbridgeworth, GB) ; Oakley, Paul Joseph; (South
Benfleet, GB) ; Owens, Andrew Pate; (Huntingdon,
GB) ; Shaw, Duncan Edward; (Bishops Stortford,
GB) ; Teall, Martin Richard; (Bishops Stortford,
GB) ; William, Susannah; (Basingstoke, GB) ;
Williams, Brian John; (Great Dunmow, GB) |
Correspondence
Address: |
Merck & Company Inc
126 East Lincoln Avenue
Rahway
NJ
07065
US
|
Family ID: |
9912329 |
Appl. No.: |
10/473727 |
Filed: |
October 1, 2003 |
PCT Filed: |
August 21, 2001 |
PCT NO: |
PCT/GB01/03741 |
Current U.S.
Class: |
514/210.01 ;
514/217.11; 514/227.5; 514/231.2; 514/255.02; 514/317; 514/424 |
Current CPC
Class: |
C07C 2601/14 20170501;
C07D 213/40 20130101; A61P 25/28 20180101; C07D 211/18 20130101;
C07D 241/18 20130101; C07D 309/10 20130101; C07C 2601/04 20170501;
C07C 317/24 20130101; C07D 295/096 20130101; C07D 263/44 20130101;
C07D 213/65 20130101; C07D 491/10 20130101; A61P 43/00 20180101;
C07D 211/54 20130101; C07C 2601/02 20170501; C07D 211/42 20130101;
C07C 317/30 20130101; C07D 211/46 20130101; C07D 207/12 20130101;
C07C 2601/16 20170501; C07D 317/48 20130101; C07D 285/12 20130101;
C07D 233/40 20130101; C07D 295/182 20130101; C07D 233/32 20130101;
C07C 2601/08 20170501; C07D 233/56 20130101; C07D 211/60 20130101;
C07D 249/04 20130101; C07F 7/0812 20130101; C07D 271/06 20130101;
C07D 213/64 20130101; C07D 249/12 20130101; C07D 309/08 20130101;
C07D 295/088 20130101; C07C 317/20 20130101; C07C 317/46 20130101;
C07D 249/08 20130101; C07C 317/14 20130101; C07D 207/27 20130101;
C07D 231/12 20130101; C07D 233/64 20130101; C07D 307/52 20130101;
C07D 317/72 20130101; C07D 257/04 20130101; C07D 263/38 20130101;
C07D 211/62 20130101; C07D 277/26 20130101; C07C 2601/10 20170501;
C07D 207/404 20130101; C07C 2601/18 20170501 |
Class at
Publication: |
514/210.01 ;
514/217.11; 514/227.5; 514/231.2; 514/255.02; 514/317; 514/424 |
International
Class: |
A61K 031/397; A61K
031/55; A61K 031/54; A61K 031/4965; A61K 031/537; A61K 031/445 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 5, 2001 |
GB |
0108591.9 |
Claims
1. A pharmaceutical composition comprising, in a pharmaceutically
acceptable carrier, a compound of formula I: 278wherein: A
represents the atoms necessary to complete a saturated or
unsaturated ring containing 4, 5, 6 or 7 ring atoms, at most 2 of
which are selected from nitrogen, oxygen and sulphur, the remainder
being carbon, said ring bearing, in addition to Ar.sup.2 and
Ar.sup.1SO.sub.2, 0-3 substituents independently selected from
.dbd.X, halogen, CN, NO.sub.2, N.sub.3, R.sup.2, CF.sub.3,
N(R.sup.1).sub.2, OR.sup.1, COR.sup.1, CO.sub.2R.sup.1,
CON(R.sup.1).sub.2, OCOR.sup.1, OCO.sub.2R.sup.2,
OCON(R.sup.1).sub.2, N(R.sup.1)COR.sup.2,
N(R.sup.1)CO.sub.2R.sup.2, OSO.sub.2R.sup.2 and
N(R.sup.1)SO.sub.2R.sup.2; X represents C(R.sup.1).sub.2,
CHCO.sub.2R.sup.1, O, S, NOR.sup.1, CHCON(R.sup.1).sub.2,
NNHCOR.sup.2, or the atoms necessary to complete a spiro-linked 5-
or 6-membered carbocyclic or heterocyclic ring; Ar.sup.1 represents
C.sub.6-10aryl or heteroaryl, either of which bears 0-3
substituents independently selected from halogen, CN, NO.sub.2,
CF.sub.3, OH, OCF.sub.3, C.sub.1-4alkoxy or C.sub.1-4alkyl which
optionally bears a substituent selected from halogen, CN, NO.sub.2,
CF.sub.3, OH and C.sub.1-4alkoxy; Ar.sup.2 represents
C.sub.6-10aryl or heteroaryl, either of which bears 0-3
substituents independently selected from halogen, CN, NO.sub.2,
CF.sub.3, OH, OCF.sub.3, C.sub.1-4alkoxy or C.sub.1-4alkyl which
optionally bears a substituent selected from halogen, CN, NO.sub.2,
CF.sub.3, OH and C.sub.1-4alkoxy; R.sup.1 represents H or R.sup.2,
or two R.sup.1 groups together with a nitrogen atom to which they
are mutually attached may complete an N-heterocyclyl group bearing
0-3 substituents selected from .dbd.O, .dbd.S, .dbd.NOR.sup.1,
halogen, CN, NO.sub.2, R.sup.2, CF.sub.3, N(R.sup.1a).sub.2,
OR.sup.1, COR.sup.1, CO.sub.2R.sup.1 and CON(R.sup.1a).sub.2;
R.sup.1a represents H or R.sup.2, or two R.sup.1a groups together
with a nitrogen atom to which they are mutually attached may
complete an N-heterocyclyl group bearing 0-3 substituents selected
from .dbd.O, .dbd.S, halogen, C.sub.1-4alkyl CN, NO.sub.2,
CF.sub.3, OH, C.sub.1-4alkoxy, C.sub.1-4alkoxycarbonyl, amino,
C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino, carbamoyl, Ar and
COAr; R.sup.2 represents C.sub.1-6alkyl, C.sub.3-9cycloalkyl,
C.sub.3-6cycloalkylC.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl or C-heterocyclyl, any of which may bear up to 3
substituents independently selected from halogen, CN, NO.sub.2,
N.sub.3, CF.sub.3, OR.sup.2a, N(R.sup.2a).sub.2, CO.sub.2R.sup.2a,
COR.sup.2a, OCOR.sup.2a, CON(R.sup.2a).sub.2, OCON(R.sup.2a).sub.2,
CONR.sup.2a(OR.sup.2a), CONHC(.dbd.NOH)R.sup.2a,
CON(R.sup.2a)N(R.sup.2a).sub.2, heterocyclyl, phenyl and
heteroaryl, said heterocyclyl, phenyl and heteroaryl substituents
themselves bearing 0-3 substituents selected from halogen, CN,
NO.sub.2, CF.sub.3, OR.sup.2a, N(R.sup.2a).sub.2, CO.sub.2R.sup.2a,
COR.sup.2a, CON(R.sup.2a).sub.2 and C.sub.1-4alkyl; or R.sup.2
represents Ar; or 2 OR.sup.2 groups attached to adjacent carbon
atoms may complete a 1,3-dioxolane ring; R.sup.2a represents H,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-6cycloalkylC.sub.1-6alkyl, C.sub.2-6alkenyl, any of which
optionally bears a substituent selected from halogen, CN, NO.sub.2,
CF.sub.3, OR.sup.2b, CO.sub.2R.sup.2b, N(R.sup.2b).sub.2,
CON(R.sup.2b).sub.2, Ar and COAr; or R.sup.2a represents Ar; or two
R.sup.2a groups together with a nitrogen atom to which they are
mutually attached may complete an N-heterocyclyl group bearing 0-4
substituents independently selected from .dbd.O, .dbd.S, halogen,
C.sub.1-4alkyl, CN, NO.sub.2, CF.sub.3, OH, C.sub.1-4alkoxy,
C.sub.1-4alkoxycarbonyl, CO.sub.2H, amino, C.sub.1-4alkylamino,
di(C.sub.1-4alkyl)amino, carbamoyl, Ar and COAr; R.sub.2b
represents H, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-6cycloalkylC.sub.1-6alkyl, C.sub.2-6alkenyl, any of which
optionally bears a substituent selected from halogen, CN, NO.sub.2,
CF.sub.3, OH, C.sub.1-4alkoxy, C.sub.1-4alkoxycarbonyl, CO.sub.2H,
amino, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino, carbamoyl, Ar
and COAr; or R.sup.2b represents Ar; or two R.sup.2b groups
together with a nitrogen atom to which they are mutually attached
may complete an N-heterocyclyl group bearing 0-4 substituents
independently selected from .dbd.O, .dbd.S, halogen,
C.sub.1-4alkyl, CN, NO.sub.2, CF.sub.3, OH, C.sub.1-4alkoxy,
C.sub.1-4alkoxycarbonyl, CO.sub.2H, amino, C.sub.1-4alkylamino,
di(C.sub.1-4alkyl)amino, carbamoyl, Ar and COAr; Ar represents
phenyl or heteroaryl bearing 0-3 substituents selected from
halogen, C.sub.1-4alkyl, CN, NO.sub.2, CF.sub.3, OH,
C.sub.1-4alkoxy, C.sub.1-4alkoxycarbonyl, amino,
C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino, carbamoyl,
C.sub.1-4alkylcarbamoyl and di(C.sub.1-4alkyl)carbamoyl;
"heterocyclyl" at every occurrence thereof means a cyclic or
polycyclic system of up to 10 ring atoms selected from C, N, O and
S, wherein none of the constituent rings is aromatic and wherein at
least one ring atom is other than C; and "heteroaryl" at every
occurrence thereof means a cyclic or polycyclic system of up to 10
ring atoms selected from C, N, O and S, wherein at least one of the
constituent rings is aromatic and wherein at least one ring atom of
said aromatic ring is other than C; or a pharmaceutically
acceptable salt thereof.
2. A compound of formula I as defined in claim 1, or a
pharmaceutically acceptable salt thereof, with the proviso that if
A represents --CH.sub.2--CH(CO.sub.2R)--CO--CH.sub.2CH.sub.2-- or
--CH.dbd.C(CO.sub.2R)--CO--CH.sub.2CH.sub.2--, where R represents
methyl, ethyl, n-propyl or n-butyl, and Ar.sup.1 represents phenyl,
4-methylphenyl or 4-chlorophenyl, then Ar.sup.2 does not represent
phenyl, 4-halophenyl or 2,4-dihalophenyl where the halogens are
independently Cl or F.
3. A compound according to claim 2 wherein A is selected from:
--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.pCH.dbd.CH(CH.sub.2).sub.q--,
--(CH.sub.2).sub.r--O--(CH.sub.2).sub.s--,
--(CH.sub.2).sub.r--NR.sup.1--- (CH.sub.2).sub.s--,
--(CH.sub.2).sub.r--CF.sub.2--(CH.sub.2).sub.s--,
--(CH.sub.2).sub.r--CR.sup.1R.sup.2--(CH.sub.2).sub.s--, 279where n
is an integer in the range 4-6; p and q are both 0-4 such that p+q
is an integer in the range 2-4; r and s are 0-5 such that r+s is an
integer in the range 2-5, and Y represents OR.sup.1,
N(R.sup.1).sub.2, N(R.sup.1)COR.sup.2, OCOR.sup.2,
OCON(R.sup.1).sub.2, CO.sub.2R.sup.1, CON(R.sup.1).sub.2 or CN.
4. A compound according to claim 3 wherein each of p, q, r and s is
at least 1; p+q is 2 or 3; and r+s is 3 or 4.
5. A compound according to claim 2 of formula II: 280or a
pharmaceutically acceptable salt thereof, wherein v is 1 and w is
0, 1 or 2, or v is 2and w is 0 or 1; bond a indicated by the dotted
line may be single or double; R.sup.3 represents H, OR.sup.1,
N(R.sup.1).sub.2 or N(R.sup.1)COR.sup.2; and R.sup.4 represents H,
R.sup.2, OR.sup.1, OCOR.sup.2, CN, CO.sub.2R.sup.1 or
CON(R.sup.1).sub.2.
6. A compound according to claim 5 in which v is 2, bond a is
single and R.sup.3 is H.
7. A compound according to claim 5 wherein v is 2, bond a is
single, R.sup.3 is H and R.sup.4 is R.sup.2.
8. A compound according to claim 7 of formula IIA: 281wherein m is
0 or 1; Z represents halogen, CN, NO.sub.2, N.sub.3, CF.sub.3,
OR.sup.2a, N(R.sup.2a).sub.2, CO.sub.2R.sup.2a, OCOR.sup.2a,
COR.sup.2a, CON(R.sup.2a).sub.2, OCON(R.sup.2a).sub.2,
CONR.sup.2a(OR.sup.2a), CON(R.sup.2a)N(R.sup.2a).sub.2,
CONHC(.dbd.NOH)R.sup.2a, heterocyclyl, phenyl or heteroaryl, said
heterocyclyl, phenyl or heteroaryl bearing 0-3 substituents
selected from halogen, CN, NO.sub.2, CF.sub.3, OR.sup.2a,
N(R.sup.2a).sub.2, CO.sub.2R.sup.2a, COR.sup.2a,
CON(R.sup.2a).sub.2 and C.sub.1-4alkyl; R.sup.1b represents H,
C.sub.1-4alkyl or OH; and R.sup.1c represents H or C.sub.1-4alkyl;
with the proviso that when m is 1, R.sup.1b and R.sup.1c do not
both represent C.sub.1-4alkyl; or a pharmaceutically acceptable
salt thereof
9. A compound according to claim 2 of formula III: 282or a
pharmaceutically acceptable salt thereof, wherein v is 1 and w is
0, 1 or 2, or v is 2 and w is 0 or 1; X represents
C(R.sup.1).sub.2, CHCO.sub.2R.sup.1, O, NOR.sup.1,
CHCON(R.sup.1).sub.2, NNHCOR.sup.2, or the atoms necessary to
complete a spiro-linked 5- or 6-membered carbocyclic or
heterocyclic ring; and R.sup.5 represents H, CO.sub.2R.sup.1 or
CON(R.sup.1).sub.2.
10. A compound according to claim 2 of formula IV, or a
pharmaceutically acceptable salt thereof: 283wherein: W represents
--NR.sup.6--(CH.sub.2).sub.t--, --O--CHR.sup.7--, or
--CF.sub.2CH.sub.2--; R.sup.6 represents R.sup.1, COR.sup.2 or
CO.sub.2R.sup.2; R.sup.7 represents H or OR.sup.1; and t is 0 or
1.
11. A compound according to claim 2 of formula V, or a
pharmaceutically acceptable salt thereof: 284
12. A compound according to any of claims 2-11 wherein Ar.sup.1 is
selected from: 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl,
4-trifluoromethylphenyl, 4-methylphenyl, 3,4-difluorophenyl,
3,4-dichlorophenyl, 4-methoxyphenyl and 6-chloro-3-pyridyl; and
Ar.sup.2 is selected from: 2,5-dichlorophenyl, 2,5-difluorophenyl,
2-bromo-5-fluorophenyl, 5-bromo-2-fluorophenyl,
5-iodo-2-fluorophenyl and 2-hydroxymethyl-5-fluorophenyl.
13. A compound of formula I as defined in claim 1 or a
pharmaceutically acceptable salt thereof for use in a method of
treatment of the human body.
14. The use of a compound of formula I as defined in claim 1 or a
pharmaceutically acceptable salt thereof in the manufacture of a
medicament for treating or preventing Alzheimer's disease.
15. A method of treatment of a subject suffering from or prone to
Alzheimer's disease which comprises administering to that subject
an effective amount of a compound according to formula I as defined
in claim 1 or a pharmaceutically acceptable salt thereof.
Description
[0001] The present invention relates to a novel class of compounds,
their salts, pharmaceutical compositions comprising them, processes
for making them and their use in therapy of the human body. In
particular, the invention relates to novel sulphones which modulate
the processing of APP by .gamma.-secretase, and hence are useful in
the treatment or prevention of Alzheimer's disease.
[0002] Alzheimer's disease (AD) is the most prevalent form of
dementia. Although primarily a disease of the elderly, affecting up
to 10% of the population over the age of 65, AD also affects
significant numbers of younger patients with a genetic
predisposition. It is a neurodegenerative disorder, clinically
characterized by progressive loss of memory and cognitive function,
and pathologically characterized by the deposition of extracellular
proteinaceous plaques in the cortical and associative brain regions
of sufferers. These plaques mainly comprise fibrillar aggregates of
.beta.-amyloid peptide (A.beta.), and although the exact role of
the plaques in the onset and progress of AD is not fully
understood, it is generally accepted that suppressing or
attenuating the secretion of A.beta. is a likely means of
alleviating or preventing the condition. (See, for example, ID
research alert 1996 1(2):1-7; ID research alert 1997 2(1):1-8;
Current Opinion in CPNS Investigational Drugs 1999 1(3):327-332;
and Chemistry in Britain, January 2000, 28-31.)
[0003] A.beta. is a peptide comprising 39-43 amino acid residues,
formed by proteolysis of the much larger amyloid precursor protein.
The amyloid precursor protein (APP or A.beta.PP) has a
receptor-like structure with a large ectodomain, a membrane
spanning region and a short cytoplasmic tail. Different isoforms of
APP result from the alternative splicing of three exons in a single
gene and have 695, 751 and 770 amino acids respectively.
[0004] The A.beta. domain encompasses parts of both extra-cellular
and transmembrane domains of APP, thus its release implies the
existence of two distinct proteolytic events to generate its
NH.sub.2- and COOH-termini. At least two secretory mechanisms exist
which release APP from the membrane and generate the soluble,
COOH-truncated forms of APP (APP.sub.s). Proteases which release
APP and its fragments from the membrane are termed "secretases".
Most APP.sub.s is released by a putative .alpha.-secretase which
cleaves within the A.beta. domain (between residues Lys.sup.6 and
Leu.sup.17) to release .alpha.-APP.sub.s and precludes the release
of intact A.beta.. A minor portion of APP.sub.s is released by a
.beta.-secretase, which cleaves near the NH.sub.2-terminus of
A.beta. and produces COOH-terminal fragments (CTFs) which contain
the whole A.beta. domain. Finding these fragments in the
extracellular compartment suggests that another proteolytic
activity (.gamma.-secretase) exists under normal conditions which
can generate the COOH-terminus of A.beta..
[0005] It is believed that .gamma.-secretase itself depends for its
activity on the presence of presenilin-1. In a manner that is not
fully understood presenilin-1 appears to undergo autocleavage.
[0006] There are relatively few reports in the literature of
compounds with inhibitory activity towards .beta.- or
.gamma.-secretase, as measured in cell-based assays. These are
reviewed in the articles referenced above. Many of the relevant
compounds are peptides or peptide derivatives.
[0007] Japanese Patent Publication No. 56 026847 discloses certain
4-aryl-4-arylsulphonylcyclohexanone derivatives as intermediates in
the synthesis of substituted salicylic acids.
[0008] The present invention provides a novel class of non-peptidic
compounds which are useful in the treatment or prevention of AD by
modulating the processing of APP by the putative .gamma.-secretase,
thus arresting the production of A.beta..
[0009] The present invention provides a pharmaceutical composition
comprising, in a pharmaceutically acceptable carrier, a compound of
formula I: 1
[0010] wherein:
[0011] A represents the atoms necessary to complete a saturated or
unsaturated ring containing 4, 5, 6 or 7 ring atoms, at most 2 of
which are selected from nitrogen, oxygen and sulphur, the remainder
being carbon, said ring bearing, in addition to Ar.sup.2 and
Ar.sup.1SO.sub.2, 0-3 substituents independently selected from
.dbd.X, halogen, CN, NO.sub.2, N.sub.3, R.sup.2, CF.sub.3,
N(R.sup.1).sub.2, OR.sup.1, COR.sup.1, CO.sub.2R.sup.1,
CON(R.sup.1).sub.2, OCOR.sup.1, OCO.sub.2R.sup.2,
OCON(R.sup.1).sub.2, N(R.sup.1)COR.sup.2,
N(R.sup.1)CO.sub.2R.sup.2, OSO.sub.2R.sup.2 and
N(R.sup.1)SO.sub.2R.sup.2- ;
[0012] X represents C(R.sup.1).sub.2, CHCO.sub.2R.sup.1, O, S,
NOR.sup.1, CHCON(R.sup.1).sub.2, NNHCOR.sup.2, or the atoms
necessary to complete a spiro-linked 5- or 6-membered carbocyclic
or heterocyclic ring;
[0013] Ar.sup.1 represents C.sub.6-10aryl or heteroaryl, either of
which bears 0-3 substituents independently selected from halogen,
CN, NO.sub.2, CF.sub.3, OH, OCF.sub.3, C.sub.1-4alkoxy or
C.sub.1-4alkyl which optionally bears a substituent selected from
halogen, CN, NO.sub.2, CF.sub.3, OH and C.sub.1-4alkoxy;
[0014] Ar.sup.2 represents C.sub.6-10 aryl or heteroaryl, either of
which bears 0-3 substituents independently selected from halogen,
CN, NO.sub.2, CF.sub.3, OH, OCF.sub.3, C.sub.1-4alkoxy or
C.sub.1-4alkyl which optionally bears a substituent selected from
halogen, CN, No.sub.2, CF.sub.3, OH and C.sub.1-4alkoxy;
[0015] R.sup.1 represents H or R.sup.2, or two R.sup.1 groups
together with a nitrogen atom to which they are mutually attached
may complete an N-heterocyclyl group bearing 0-3 substituents
selected from .dbd.O, .dbd.S, .dbd.NOR.sup.1, halogen, CN,
NO.sub.2, R.sup.2, CF.sub.3, N(R.sup.1a).sub.2, OR.sup.1,
COR.sup.1, CO.sub.2R.sup.1 and CON(R.sup.1a).sub.2;
[0016] R.sup.1a represents H or R.sup.2, or two R.sup.1a groups
together with a nitrogen atom to which they are mutually attached
may complete an N-heterocyclyl group bearing 0-3 substituents
selected from .dbd.O, .dbd.S, halogen, C.sub.1-4alkyl CN, NO.sub.2,
CF.sub.3, OH, C.sub.1-4alkoxy, C.sub.1-4alkoxycarbonyl, amino,
C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino, carbamoyl, Ar and
COAr;
[0017] R.sup.2 represents C.sub.1-6alkyl, C.sub.3-9cycloalkyl,
C.sub.3-6cycloalkylC.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl or C-heterocyclyl, any of which may bear up to 3
substituents independently selected from halogen, CN, NO.sub.2,
N.sub.3, CF.sub.3, OR.sup.2a, N(R.sup.2a).sub.2, CO.sub.2R.sup.2a,
COR.sup.2a, OCOR.sup.2a, CON(R.sup.2a).sub.2, OCON(R.sup.2a).sub.2,
CONR.sup.2a(OR.sup.2a), CONHC(.dbd.NOH)R.sup.2a,
CON(R.sup.2a)N(R.sup.2a).sub.2, heterocyclyl, phenyl and
heteroaryl, said heterocyclyl, phenyl and heteroaryl substituents
themselves bearing 0-3 substituents selected from halogen, CN,
NO.sub.2, CF.sub.3, OR.sup.2a, N(R.sup.2a).sub.2, CO.sub.2R.sup.2a,
COR.sup.2a, CON(R.sup.2a).sub.2 and C.sub.1-4alkyl; or R.sup.2
represents Ar; or 2 OR.sup.2 groups attached to adjacent carbon
atoms may complete a 1,3-dioxolane ring;
[0018] R.sup.2a represents H, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-6-cycloalkylC.sub.1-6alkyl, C.sub.2-6alkenyl, any of which
optionally bears a substituent selected from halogen, CN, NO.sub.2,
CF.sub.3, OR.sup.2b, CO.sub.2R.sup.2b, N(R.sup.2b).sub.2,
CON(R.sup.2b).sub.2, Ar and COAr; or R.sub.2a represents Ar; or two
R.sup.2a groups together with a nitrogen atom to which they are
mutually attached may complete an N-heterocyclyl group bearing 0-4
substituents independently selected from .dbd.O, .dbd.S, halogen,
C.sub.1-4alkyl, CN, NO.sub.2, CF.sub.3, OH, C.sub.1-4alkoxy,
C.sub.1-4alkoxycarbonyl, CO.sub.2H, amino, C.sub.1-4alkylamino,
di(C.sub.1-4alkyl)amino, carbamoyl, Ar and COAr;
[0019] R.sup.2b represents H, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-6cycloalkylC.sub.1-6alkyl, C.sub.2-6alkenyl, any of which
optionally bears a substituent selected from halogen, CN, NO.sub.2,
CF.sub.3, OH, C.sub.1-4alkoxy, C.sub.1-4alkoxycarbonyl, CO.sub.2H,
amino, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino, carbamoyl, Ar
and COAr; or R.sup.2b represents Ar; or two R.sup.2b groups
together with a nitrogen atom to which they are mutually attached
may complete an N-heterocyclyl group bearing 0-4 substituents
independently selected from .dbd.O, .dbd.S, halogen,
C.sub.1-4alkyl, CN, NO.sub.2, CF.sub.3, OH, C.sub.1-4alkoxy,
C.sub.1-4alkoxycarbonyl, CO.sub.2H, amino, C.sub.1-4alkylamino,
di(C.sub.1-4alkyl)amino, carbamoyl, Ar and COAr;
[0020] Ar represents phenyl or heteroaryl bearing 0-3 substituents
selected from halogen, C.sub.1-4alkyl, CN, NO.sub.2, CF.sub.3, OH,
C.sub.1-4alkoxy, C.sub.1-4alkoxycarbonyl, amino,
C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino, carbamoyl,
C.sub.1-4alkylcarbamoyl and di(C.sub.1-4alkyl)carbamoyl;
[0021] "heterocyclyl" at every occurrence thereof means a cyclic or
polycyclic system of up to 10 ring atoms selected from C, N, O and
S, wherein none of the constituent rings is aromatic and wherein at
least one ring atom is other than C; and
[0022] "heteroaryl" at every occurrence thereof means a cyclic or
polycyclic system of up to 10 ring atoms selected from C, N, O and
S, wherein at least one of the constituent rings is aromatic and
wherein at least one ring atom of said aromatic ring is other than
C;
[0023] or a pharmaceutically acceptable salt thereof.
[0024] In a subset of the compounds of formula I,
[0025] A represents the atoms necessary to complete a saturated or
unsaturated ring containing 5, 6 or 7 ring atoms, at most 2 of
which are selected from nitrogen, oxygen and sulphur, the remainder
being carbon, said ring bearing 0-3 substituents independently
selected from .dbd.C(R.sup.1).sub.2, .dbd.CHCO.sub.2R.sup.1,
.dbd.O, .dbd.S, .dbd.NOR.sup.1, halogen, CN, NO.sub.2, N.sub.3,
R.sup.2, CF.sub.3, N(R.sup.1).sub.2, OR.sup.1, COR.sup.1,
CO.sub.2R.sup.1, CON(R.sup.1).sub.2, OCOR.sup.1, OCO.sub.2R.sup.2,
N(R.sup.1)COR.sup.2, N(R.sup.1)CO.sub.2R.sup.2, OSO.sub.2R.sup.2
and N(R.sup.1)SO.sub.2R.sup.2- ;
[0026] Ar.sup.1 represents C.sub.6-10aryl or heteroaryl, either of
which bears 0-3 substituents independently selected from halogen,
CN, NO.sub.2, CF.sub.3, OH, C.sub.1-4alkoxy or C.sub.1-4alkyl which
optionally bears a substituent selected from halogen, CN, NO.sub.2,
CF.sub.3, OH and C.sub.1-4alkoxy;
[0027] Ar.sup.2 represents C.sub.6-10aryl or heteroaryl, either of
which bears 0-3 substituents independently selected from halogen,
CN, NO.sub.2, CF.sub.3, OH, C.sub.1-4alkoxy or C.sub.1-4alkyl which
optionally bears a substituent selected from halogen, CN, NO.sub.2,
CF.sub.3, OH and C.sub.1-4alkoxy;
[0028] R.sup.1 represents H or R.sup.2, or two R.sup.1 groups
together with a nitrogen atom to which they are mutually attached
may complete an N-heterocyclyl group bearing 0-3 substituents
selected from .dbd.O, .dbd.S, .dbd.NOR.sup.1, halogen, CN,
NO.sub.2, R.sup.2, CF.sub.3, N(R.sup.1a).sub.2, OR.sup.1,
COR.sup.1, CO.sub.2R.sup.1 and CON(R.sup.1a).sub.2;
[0029] R.sup.1a represents H or R.sup.2, or two R.sup.1a groups
together with a nitrogen atom to which they are mutually attached
may complete an N-heterocyclyl group bearing 0-3 substituents
selected from .dbd.O, .dbd.S, halogen, C.sub.1-4alkyl CN, NO.sub.2,
CF.sub.3, OH, C.sub.1-4alkoxy, C.sub.1-4alkoxycarbonyl, amino,
C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino, carbamoyl, Ar and
COAr,
[0030] R.sup.2 represents C.sub.1-6alkyl, C.sub.3-9cycloalkyl,
C.sub.3-6cycloalkylC.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl or C-heterocyclyl, any of which may bear a
substituent selected from halogen, CN, NO.sub.2, CF.sub.3,
OR.sup.2a, N(R.sup.2a).sub.2, CO.sub.2R.sup.2a, COR.sup.2a,
CON(R.sup.2a).sub.2, heterocyclyl, phenyl and heteroaryl, said
heterocyclyl, phenyl and heteroaryl substituents themselves bearing
0-3 substituents selected from halogen, CN, NO.sub.2, CF.sub.3,
OR.sup.2a, N(R.sup.2 a).sub.2, CO.sub.2R.sup.2a, COR.sup.2a,
CON(R.sup.2a).sub.2 and C.sub.1-4alkyl, or R.sup.2 represents
Ar;
[0031] R.sup.2a represents H, C.sub.1-4alkyl, or Ar; or two
R.sup.2a groups together with a nitrogen atom to which they are
mutually attached may complete an N-heterocyclyl group bearing 0-3
substituents selected from .dbd.O, .dbd.S, halogen, C.sub.1-4alkyl
CN, NO.sub.2, CF.sub.3, OH, C.sub.1-4alkoxy,
C.sub.1-4alkoxycarbonyl, amino, C.sub.1-4alkylamino,
di(C.sub.1-4alkyl)amino, carbamoyl, Ar and COAr, and
[0032] Ar represents phenyl or heteroaryl bearing 0-3 substituents
selected from halogen, C.sub.1-4alkyl, CN, NO.sub.2, CF.sub.3, OH,
C.sub.1-4alkoxy, C.sub.1-4alkoxycarbonyl, amino,
C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino, carbamoyl,
C.sub.1-4alkylcarbamoyl and di(C.sub.1-4alkyl)carbamoyl.
[0033] The invention further provides a compound of formula I or a
pharmaceutically acceptable salt thereof, with the proviso that if
A represents --CH.sub.2--CH(CO.sub.2R)--CO--CH.sub.2CH.sub.2-- or
--CH.dbd.C(CO.sub.2R)--CO--CH.sub.2CH.sub.2--, where R represents
methyl, ethyl, n-propyl or n-butyl, and Ar.sup.1 represents phenyl,
4-methylphenyl or 4-chlorophenyl, then Ar.sup.2 does not represent
phenyl, 4-halophenyl or 2,4-dihalophenyl where the halogens are
independently Cl or F.
[0034] Where a variable occurs more than once in formula I or in a
substituent thereof, the individual occurrences of that variable
are independent of each other, unless otherwise specified.
[0035] As used herein, the expression "C.sub.1-xalkyl" where x is
an integer greater than 1 refers to straight-chained and branched
alkyl groups wherein the number of constituent carbon atoms is in
the range 1 to x. Particular alkyl groups include methyl, ethyl,
n-propyl, isopropyl and t-butyl. Derived expressions such as
"C.sub.2-6alkenyl", "hydroxyC.sub.1-6alkyl",
"heteroaryl"C.sub.1-6alkyl, "C.sub.2-6alkynyl" and
"C.sub.1-6alkoxy" are to be construed in an analogous manner.
[0036] The expression "C.sub.3-9cycloalkyl" as used herein refers
to nonaromatic monocyclic or fused bicyclic hydrocarbon ring
systems comprising from 3 to 9 ring atoms. Examples include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and
bicyclo[2.2.1]heptyl.
[0037] The expression "C.sub.3-6cycloalkylC.sub.1-6alkyl" as used
herein includes cyclopropylmethyl, cyclobutylmethyl,
cyclopentylmethyl and cyclohexylmethyl.
[0038] The expression "C.sub.6-10aryl" as used herein includes
phenyl and naphthyl.
[0039] The expression "heterocyclyl" as used herein means a cyclic
or polycyclic system of up to 10 ring atoms selected from C, N, O
and S, wherein none of the constituent rings is aromatic and
wherein at least one ring atom is other than carbon. Preferably not
more than 3 ring atoms are other than carbon. Examples of
heterocyclyl groups include azetidinyl, pyrrolidinyl,
terahydrofuryl, piperidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl,
2,5-diazabicyclo[2.2.1]heptyl, 2-aza-5-oxabicyclo[2.2.1]he- ptyl
and 1,4-dioxa-8-azaspiro[4.5]decanyl. Unless otherwise indicated,
heterocyclyl groups may be bonded through a ring carbon atom or a
ring nitrogen atom where present. "C-heterocyclyl" indicates
bonding through carbon, while "N-heterocyclyl" indicates bonding
through nitrogen.
[0040] The expression "heteroaryl" as used herein means a cyclic or
polycyclic system of up to 10 ring atoms selected from C, N, O and
S, wherein at least one of the constituent rings is aromatic and
wherein at least one ring atom is other than carbon. Where a
heteroaryl ring comprises two or more atoms which are not carbon,
not more than one of said atoms may be other than nitrogen.
Examples of heteroaryl groups include pyridinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, pyrrolyl, furyl, thienyl, pyrazolyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,
oxadiazolyl, triazolyl and thiadiazolyl groups and benzo-fused
analogues thereof. Further examples of heteroaryl groups include
tetrazole, 1,2,4-triazine and 1,3,5-triazine.
[0041] The term "halogen" as used herein includes fluorine,
chlorine, bromine and iodine, of which fluorine and chlorine are
preferred.
[0042] For use in medicine, the compounds of formula I may
advantageously be in the form of pharmaceutically acceptable salts.
Other salts may, however, be useful in the preparation of the
compounds of formula I or of their pharmaceutically acceptable
salts. Suitable pharmaceutically acceptable salts of the compounds
of this invention include acid addition salts which may, for
example, be formed by mixing a solution of the compound according
to the invention with a solution of a pharmaceutically acceptable
acid such as hydrochloric acid, sulphuric acid, methanesulphonic
acid, fumaric acid, maleic acid, succinic acid, acetic acid,
benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic
acid or phosphoric acid. Furthermore, where the compounds of the
invention carry an acidic moiety, suitable pharmaceutically
acceptable salts thereof may include alkali metal salts, e.g.
sodium or potassium salts; alkaline earth metal salts, e.g. calcium
or magnesium salts; and salts formed with suitable organic ligands,
e.g. quaternary ammonium salts.
[0043] Where the compounds according to the invention have at least
one asymmetric centre, they may accordingly exist as enantiomers.
Where the compounds according to the invention possess two or more
asymmetric centres, they may additionally exist as
diastereoisomers. It is to be understood that all such isomers and
mixtures thereof in any proportion are encompassed within the scope
of the present invention.
[0044] Regardless of the presence or absence of asymmetric centres,
certain compounds in accordance with the invention may exist as
enantiomers by virtue of the asymmetry of the molecule as a whole.
It is to be understood that in such cases both enantiomers, and
mixtures thereof in any proportion, are included within the scope
of the invention, and that structural formulae depicting molecules
of this type shall be representative of both of the possible
enantiomers, unless otherwise indicated.
[0045] In the compounds of formula I, A completes a saturated or
unsaturated ring system containing 4, 5, 6 or 7 ring atoms, at most
2 of which are selected from nitrogen, oxygen or sulphur, the
remainder being carbon, which optionally bears up to 3 additional
substituents as defined previously. Preferably, A completes a 4-,
5-, 6-, or 7-membered ring in which at most 1 ring atom is oxygen
or nitrogen and the remainder carbon, and in certain embodiments
when A completes a 4-membered ring, said ring is carbocyclic.
Examples of rings completed by A include cycloheptane, cyclohexane,
cyclohexene, cyclopentane, cyclopentene, cyclobutane, piperidine,
pyrrolidine and pyran, with cycloheptarie, cyclohexane,
cyclohexene, cyclopentane, cyclopentene and pyran preferred.
[0046] The ring completed by A may bear up to 3 substituents in
addition to those shown in formula I, but when A completes a
4-membered ring, said ring typically bears at most 2 additional
substituents, preferably at most 1 additional substituent. Where
three additional substituents are present, two of them are
preferably attached to the same ring carbon atom. Preferred
substituents include .dbd.X; halogen; azide; hydroxy or alkoxy
represented by OR.sup.1; alkylsulphonyloxy represented by
OSO.sub.2R.sup.2; amino or N-heterocyclyl represented by
N(R.sup.1).sub.2; optionally substituted alkyl, alkenyl, aryl or
heteroaryl represented by R.sup.2; carboxylic acid or
alkoxycarbonyl represented by CO.sub.2R.sup.1; carbamoyl
represented by CON(R.sup.1).sub.2; carbamoyloxy represented by
OCON(R.sup.1).sub.2; and amido represented by
N(R.sup.1)COR.sup.2.
[0047] When A completes a cyclobutyl ring, it is aptly substituted
by OR.sup.1.
[0048] When the ring completed by A bears one additional
substituent which is connected to the ring by a single bond, that
substituent may be either cis or trans with respect to the
Ar.sup.1SO.sub.2 group, but the cis configuration is preferred.
[0049] Typical embodiments of .dbd.X include alkylidene represented
by .dbd.C(R.sup.1).sub.2, .dbd.CHCON(R.sup.1).sub.2 or
.dbd.CHCO.sub.2R.sup.1; oxo represented by .dbd.O; oximino or
alkoximino represented by .dbd.NOR.sup.1; .dbd.N--NHCOR.sup.2; or
the atoms necessary to complete a spiro-linked 5- or 6-membered
carbocyclic or heterocyclic ring such as: 2
[0050] In certain embodiments, the ring positions adjacent to the
carbon bonded to the Ar.sup.1SO.sub.2 group are occupied by
unsubstituted methylene groups.
[0051] Examples of fragments represented by A include, but are not
limited to:
[0052] --(CH.sub.2).sub.n--,
--(CH.sub.2).sub.pCH.dbd.CH(CH.sub.2).sub.q--- ,
--(CH.sub.2).sub.r--O--(CH.sub.2).sub.s--,
--(CH.sub.2).sub.r--NR.sup.1-- -(CH.sub.2).sub.s--,
--(CH.sub.2).sub.r--CF.sub.2--(CH.sub.2).sub.s--,
--(CH.sub.2).sub.r--CR.sup.1R.sup.2--(CH.sub.2).sub.s--, 3
[0053] where n is an integer in the range 4-6;
[0054] p and q are both 0-4 such that p+q is an integer in the
range 2-4;
[0055] r and s are 0-5 such that r+s is an integer in the range
2-5, and
[0056] Y represents OR.sup.1, N(R.sup.1).sub.2,
N(R.sup.1)COR.sup.2, OCOR.sup.2, OCON(R.sup.1).sub.2,
CO.sub.2R.sup.1, CON(R.sup.1).sub.2 or CN.
[0057] Preferably, each of p, q, r and s is at least 1.
[0058] Preferably, p+q is 2 or 3, most preferably 3.
[0059] Preferably, r+s is 3 or 4, most preferably 4.
[0060] R.sup.1 represents H or R.sup.2, or two R.sup.1 groups
together with a nitrogen atom to which they are mutually attached
may complete an N-heterocyclyl group. Examples of N-heterocyclyl
groups represented by N(R.sup.1).sub.2 include pyrrolidin-1-yl,
piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl
and 1,4-dioxa-8-azaspiro[4.5]decan-8-y- l, each optionally bearing
up to 3 substituents as defined previously. Preferably, such
heterocyclyl groups bear at most 2 substituents selected from
.dbd.O, CF.sub.3, OH, R.sup.2, CO.sub.2R.sup.1 and
N(R.sup.1a).sub.2.
[0061] R.sup.1a represents H or R.sup.2, or two R.sup.1a groups
together with a nitrogen atom to which they are mutually attached
may complete an N-heterocyclyl group, optionally substituted as
defined previously, an example being piperidin-1-yl.
[0062] R.sup.2 represents C.sub.1-6alkyl, C.sub.3-9cycloalkyl,
C.sub.3-6cycloalkylC.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl or C-heterocyclyl (any of which is optionally
substituted as defined previously), or Ar. Alternatively, two
OR.sup.2 groups attached to adjacent carbon atoms may complete a
1,3-dioxolane ring such as 2,2-dimethyl-1,3-dioxolane. Preferred
substituents on groups represented by R.sup.2 include CN, phenyl,
heteroaryl (such as imidazolyl, furyl, thiazolyl, pyrazolyl,
thiadiazolyl, oxadiazolyl, triazolyl, tetrazolyl and pyridyl),
C-heterocyclyl (such as 1-t-butoxycarbonylpyrrolidin-2-yl),
COR.sup.2a, OR.sup.2a, N(R.sup.2a).sub.2, CO.sub.2R.sup.2a,
CON(R.sup.2).sub.2, OCON(R.sup.2a).sub.2, CONR.sup.2a(OR.sup.2a),
and CON(R.sup.2a)N(R.sup.2a).sub.2. Typically, not more than 2
substituents are present on R.sup.2.
[0063] R.sup.2a represents H, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.3-6cycloalkylC.sub.1-6alkyl, C.sub.2-6alkenyl, any of which
optionally bears a substituent as defined previously; or R.sup.2a
represents Ar; or two R.sup.2a groups together with a nitrogen atom
to which they are mutually attached may complete an N-heterocyclyl
group which is optionally substituted as defined previously.
Particular values of R.sup.2a include H, aryl (such as phenyl),
heteroaryl (such as pyridyl), C.sub.3-6cycloalkyl (such as
cyclopropyl, cyclobutyl and cyclopentyl),
C.sub.3-6cycloalkylC.sub.1-6alkyl (such as cyclopropylmethyl),
C.sub.2-6alkenyl (such as allyl), and linear or branched
C.sub.1-6alkyl which is optionally substituted with CF.sub.3, Ar,
OR.sup.2b, N(R.sup.2b).sub.2, CO.sub.2R.sup.2b or
CON(R.sup.2b).sub.2.
[0064] Examples of N-heterocyclyl groups represented by
N(R.sup.2a).sub.2 include piperidin-1-yl (optionally substituted
with OH, CO.sub.2H, CO.sub.2C.sub.1-4alkyl, Me or Ph),
piperazin-1-yl (optionally substituted with Me or Ph),
morpholin-4-yl, thiomorpholin-4-yl, 1,1-dioxo-thiomorpholin-4-yl,
2-oxo-imidazolidin-1-yl, 5,5-dimethyl-2,2-dioxo-oxazolidin-3-yl,
2,5-dioxo-imidazolidin-1-yl, 2-oxo-oxazolidin-3-yl,
2-oxo-pyridin-1-yl, and 2-oxo-pyrrolidin-1-yl.
[0065] R.sup.2b typically represents H or C.sub.1-4alkyl.
[0066] Typically, R.sup.2 represents C.sub.2-6alkenyl (such as
allyl) or C.sub.1-6alkyl, such as methyl, ethyl, n-propyl or
t-butyl, which is optionally substituted as described above.
[0067] Ar.sup.1 represents C.sub.6-10aryl or heteroaryl, either of
which bears 0-3 substituents independently selected from halogen,
CN, NO.sub.2, CF.sub.3, OH, C.sub.1-4alkoxy or C.sub.1-4alkyl which
optionally bears a substituent selected from halogen, CN, NO.sub.2,
CF.sub.3, OH and C.sub.1-4alkoxy. Preferably, Ar.sup.1 represents
optionally substituted phenyl or heteroaryl. Typical heteroaryl
embodiments of Ar.sup.1 include optionally substituted pyridyl, in
particular optionally substituted 3-pyridyl. Preferably, Ar.sup.1
bears 0-2 substituents, more preferably 1 or 2 substituents, and
most preferably 1 substituent which is preferably in the
para-position relative to the sulphone group. Typical substituents
include halogen (especially chlorine, bromine and fluorine),
C.sub.1-4alkyl (such as methyl), C.sub.1-4alkoxy (such as methoxy),
and CF.sub.3. Examples of groups represented by Ar.sup.1 include
4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl,
4-trifluoromethylphenyl, 4-methylphenyl, 3,4-difluorophenyl,
3,4-dichlorophenyl, 4-methoxyphenyl and 6-chloro-3-pyridyl. Most
preferably, Ar.sup.1 represents 4-chlorophenyl, 4-bromophenyl or
4-trifluoromethylphenyl.
[0068] Ar.sup.2 represents C.sub.6-10aryl or heteroaryl bearing 0-3
substituents independently selected from halogen, CN, NO.sub.2,
CF.sub.3, OH, C.sub.1-4alkoxy or C.sub.1-4alkyl which optionally
bears a substituent selected from halogen, CN, NO.sub.2, CF.sub.3,
OH and C.sub.1-4alkoxy. Preferably, Ar.sup.2 represents phenyl
bearing 1 or 2 substituents as indicated, and most preferably,
Ar.sup.2 represents 2,5-disubstituted phenyl. Preferred
substituents include halogen (especially bromine, chlorine and
fluorine) and substituted alkyl, such as hydroxymethyl. Examples of
groups represented by Ar.sup.2 include 2,5-dichlorophenyl,
2,5-difluorophenyl, 2-bromo-5-fluorophenyl, 5-bromo-2-fluorophenyl,
5-iodo-2-fluorophenyl and 2-hydroxymethyl-5-fluor- ophenyl. Very
aptly, Ar.sup.2 represents 2,5-difluorophenyl.
[0069] A subclass of the compounds of the invention comprises the
compounds of formula II: 4
[0070] and the pharmaceutically acceptable salts thereof,
wherein
[0071] v is 1 and w is 0, 1 or 2, or v is 2 and w is 0 or 1;
[0072] bond a (indicated by the dotted line) may be single or
double;
[0073] R.sup.3 represents H, OR.sup.1, N(R.sup.1).sub.2 or
N(R.sup.1)COR.sup.2;
[0074] R.sup.4 represents H, R.sup.2, OR.sup.1, OCOR.sup.2, CN,
CO.sub.2R.sup.1 or CON(R.sup.1).sub.2;
[0075] and Ar.sup.1, Ar.sup.2, R.sup.1 and R.sup.2 have the same
meanings as before.
[0076] When R.sup.3 represents N(R.sup.1).sub.2 or
N(R.sup.1)COR.sup.2, bond a is preferably single and R.sup.4 is
preferably H.
[0077] When bond a is single, R.sup.3 may be cis or trans relative
to Ar.sup.1SO.sub.2--, but is preferably cis.
[0078] Examples of compounds within this subclass include those
wherein Ar.sup.1 represents 4-chlorophenyl, Ar.sup.2 represents
2,5-difluorophenyl, v is 1 and w, a, R.sup.3 and R.sup.4 are as
indicated in the following table:
1 w Bond a R.sup.3 R.sup.4 0 Single H H 0 Double H H 0 Single OH H
1 Single H H 1 Double H H 1 Single OH H 1 Double OH CO.sub.2Me 1
Double O-allyl CO.sub.2Me 1 Double O--CH.sub.2Ph CO.sub.2Me 1
Single OH CH.sub.2OH 1 Double OMe CO.sub.2Me 1 Double OH CONH.sub.2
1 Single NH.sub.2 H 1 Single NMe.sub.2 H 1 Single NHCH.sub.2Ph H 1
Single morpholin-4-yl H 1 Single thiomorpholin-4-yl H 1 Single
NHCH.sub.2CO.sub.2Me H 1 Single 5 H 1 Single 6 H 1 Single 7 H 1
Single 8 H 1 Single 9 H 1 Single 10 H 1 Single 11 H 1 Single 12 H 1
Single 13 H 1 Single 14 H 1 Single 15 H 1 Single 16 H 1 Single
--NHCH(Me)CO.sub.2Me H 1 Single 17 H 1 Single 18 H 1 Single 19 H 1
Single 20 H 1 Single 21 H 1 Single 22 H 1 Single 23 H 1 Single
--NHCO(CH.sub.2).sub.3NMe.sub.2 H 1 Single 24 H 1 Single
--NHCOCH.sub.2NMe.sub.2 H 1 Single --NHCOPh H 1 Single --NHCOMe H 1
Single NHCH.sub.2CH.sub.2OH H 1 Single
NHCH(CONH.sub.2)CH.sub.2CH(Me).su- b.2 H 1 Single
NHCH.sub.2CONH.sub.2 H 1 Single OMe H 2 Double H H 2 Single H H 2
Single morpholin-4-yl H 1 Single H OH 1 Single H OCOMe 1 Single H
OEt 1 Single H O-allyl 1 Single --O--C(Me).sub.2--O-- 1 Single OH
OH 1 Single OCH.sub.2CONH.sub.2 H 1 Single OCH.sub.2CO.sub.2H H
[0079] and pharmaceutically acceptable salts thereof.
[0080] A subset of the compounds of formula II are those in which v
is 2, bond a is single and R.sup.3 is H. Particular examples of
compounds within this subset include those in which w is 0 and
Ar.sup.1, Ar.sup.2 and R.sup.4 have the identities shown in the
following table:
2 Ar.sup.1 Ar.sup.2 R.sup.4 3,4-di-Cl--C.sub.6H.sub.3
2,5-di-F--C.sub.6H.sub.3 H 4-Cl--C.sub.6H.sub.4 2-F--C.sub.6H.sub.4
H 4-Cl--C.sub.6H.sub.4 2,5-di-F--C.sub.6H.sub.3 CO.sub.2Me
4-Cl--C.sub.6H.sub.4 2,5-di-F--C.sub.6H.sub.3 OCOMe
4-Cl--C.sub.6H.sub.4 2,5-di-F--C.sub.6H.sub.3 1,2,3-triazol-1-yl
4-Br--C.sub.6H.sub.4 2,5-di-F--C.sub.6H.sub.3 H 4-F--C.sub.6H.sub.4
2,5-di-F--C.sub.6H.sub.3 H 4-Cl--C.sub.6H.sub.4
2-Br-5-F--C.sub.6H.sub.3 H 4-Me--C.sub.6H.sub.4
2,5-di-F--C.sub.6H.sub.3 H 4-Cl--C.sub.6H.sub.4
2,5-di-F--C.sub.6H.sub.3 CN 4-(CF.sub.3O)--C.sub.6H.sub.4
2,5-di-F--C.sub.6H.sub.3 H 3-Cl--C.sub.6H.sub.4
2,5-di-F--C.sub.6H.sub.3 H 4-Cl--C.sub.6H.sub.4 C.sub.6H.sub.5
H
[0081] and pharmaceutically acceptable salts thereof.
[0082] In a further subset of the compounds of formula II, v is 2,
bond a is single, R.sup.3 is H and R.sup.4 is R.sup.2. Within this
subset, there is the group of compounds defined by formula IIA:
25
[0083] wherein m is 0 or 1;
[0084] Z represents halogen, CN, NO.sub.2, N.sub.3, CF.sub.3,
OR.sup.2a, N(R.sup.2a).sub.2, CO.sub.2R.sup.2a, OCOR.sup.2a,
COR.sup.2a, CON(R.sup.2a).sub.2, OCON(R.sup.2a).sub.2,
CONR.sup.2a(OR.sup.2a), CON(R.sup.2a)N(R.sup.2a).sub.2,
CONHC(.dbd.NOH)R.sup.2a, heterocyclyl, phenyl or heteroaryl, said
heterocyclyl, phenyl or heteroaryl bearing 0-3 substituents
selected from halogen, CN, NO.sub.2, CF.sub.3, OR.sup.2a,
N(R.sup.2a).sub.2, CO.sub.2R.sup.2a, COR.sup.2a,
CON(R.sup.2a).sub.2 and C.sub.1-4alkyl;
[0085] R.sup.1b represents H, C.sub.1-4alkyl or OH;
[0086] R.sup.1c represents H or C.sub.1-4alkyl;
[0087] with the proviso that when m is 1, R.sup.1b and R.sup.1c do
not both represent C.sub.1-4alkyl;
[0088] and Ar.sup.1, Ar.sup.2 and R.sup.2a have the same meanings
as before;
[0089] and the pharmaceutically acceptable salts thereof
[0090] When m is 1 and R.sup.1b is OH, Z preferably represents
optionally substituted phenyl or heteroaryl.
[0091] In the compounds of formula IIA, Ar.sup.1 is typically
selected from phenyl groups substituted in the 4-position with
halogen, methyl or trifluoromethyl and phenyl groups substituted in
the 3- and 4-positions by halogen; and Ar.sup.2 is typically
selected from phenyl groups substituted in the 2- and 5-positions
by halogen. In particular embodiments, Ar.sup.1 is 4-chlorophenyl
or 4-trifluoromethylphenyl and Ar.sup.2 is 2,5-difluorophenyl.
[0092] R.sup.1b typically represents H, methyl or OH, preferably
H.
[0093] R.sup.1c typically represents H or methyl, preferably H.
[0094] Z is typically selected from CN, N.sub.3, OR.sup.2a,
N(R.sup.2a).sub.2, CO.sub.2R.sup.2a, COR.sup.2a,
CON(R.sup.2a).sub.2, OCON(R.sup.2a).sub.2, CONR.sup.2a(OR.sup.2a),
CON(R.sup.2a)N(R.sup.2a).su- b.2, and optionally substituted phenyl
or heteroaryl.
[0095] When Z represents OR.sup.2a, R.sup.2a aptly represents H, Ar
(especially heteroaryl such as pyridyl), alkyl (such as methyl,
ethyl, propyl or butyl), or substituted alkyl (especially
CH.sub.2Ar such as benzyl or pyridylmethyl).
[0096] When Z represents N(R.sup.2a).sub.2, the R.sup.2a groups
aptly complete an N-heterocyclyl group which is optionally
substituted as described above. Preferred substituents include
.dbd.O and methyl. Specific examples of N-heterocyclyl groups
represented by Z include morpholin-4-yl, 2-oxo-imidazolidin-1-yl,
5,5-dimethyl-2,2-dioxo-oxazolidi- n-3-yl,
2,5-dioxo-imidazolidin-1-yl, 2-oxo-oxazolidin-3-yl,
2-oxo-pyridin-1-yl, and 2-oxo-pyrrolidin-1-yl.
[0097] When Z represents CO.sub.2R.sup.2a, R.sup.2a aptly
represents H or alkyl (such as methyl, ethyl, propyl or butyl).
[0098] When Z represents COR.sup.2a, R.sup.2a aptly represents Ar,
especially heteroaryl, and in particular 5-membered heteroaryl such
as 1,2,4-triazol-3-yl.
[0099] When Z represents CON(R.sup.2a).sub.2 or
OCON(R.sup.2a).sub.2, the R.sup.2a groups independently represent H
or optionally substituted alkyl, cycloalkyl, cycloalkylalkyl or
alkenyl, or together complete an N-heterocyclyl group. Very aptly,
one R.sup.2a represents H and the other represents alkyl (such as
methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl
or 1-ethylpropyl), alkenyl (such as allyl), cycloalkyl (such as
cyclopropyl, cyclobutyl or cyclopentyl), cycloalkylalkyl (such as
cyclopropylmethyl) or substituted alkyl (such as alkyl substituted
with Ar, especially 2-pyridylethyl, 3-(imidazol-1-yl)propyl or
2-phenylethyl; or alkyl substituted with CF.sub.3,
CO.sub.2R.sup.2b, or CON(R.sup.2b).sub.2, especially
2,2,2-trifluoromethyl, methoxycarbonylmethyl or carbamoylmethyl).
Alternatively, the two R.sup.2a groups complete an N-heterocyclyl
group, such as morpholine, thiomorpholine,
thiomorpholine-1,1-dioxide, 4-methylpiperazine, 4-phenylpiperazine,
piperidine, 4-hydroxypiperidine or piperidine which is substituted
in the 3- or 4-position with CO.sub.2R.sup.2b and/or
C.sub.1-4alkyl, especially 3- or 4-carboxypiperidine, 3- or
4-ethoxycarbonylpiperidine, 3-carboxy-3-methylpiperidine and
3-ethoxycarbonyl-3-methylpiperidine.
[0100] When Z represents CONR.sup.2a(OR.sup.2a), each R.sup.2a
aptly represents H or alkyl, such as methyl.
[0101] When Z represents CON(R.sup.2a)N(R.sup.2a).sub.2, each
R.sup.2a aptly represents H or alkyl. Specific examples include
CONHNH.sub.2 and CONHNH.sup.tBu.
[0102] When Z represents CONHC(.dbd.NOH)R.sup.2a, R.sup.2a aptly
represents alkyl such as methyl or ethyl.
[0103] Heteroaryl groups represented by Z are very aptly
5-membered, such as tetrazole, triazole, thiazole, thiadiazole,
oxadiazole, pyrazole and imidazole, which are typically
unsubstituted or substituted with methyl or hydroxy groups. The
keto-tautomers of hydroxy-substituted heteroaryl groups are to be
considered interchangeable with the enol forms. Specific examples
include 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-2-yl,
1,2,3,4-tetrazol-5-yl, 3-hydroxy-1,2,4-triazol-5-yl,
1,2,4-triazol-3-yl, 5-methyl-1,2,4-triazol-3-yl,
2,5-dimethyl-1,2,4-triazol-3-yl, 1,3,4-oxadiazol-2-yl,
5-methyl-1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl,
3-methyl-1,2,4-oxadiazol-5-yl, imidazol-2-yl, imidazol-1-yl,
4-methylthiazol-2-yl, pyrazol-1-yl, 1,2,3-triazol-1-yl,
1,2,4-triazol-1-yl, and 1,2,3-triazol-2-yl.
[0104] Examples of individual compounds in accordance with formula
IIA are provided in the Examples section appended hereto.
[0105] A second subclass of the compounds of the invention
comprises the compounds of formula III: 26
[0106] and the pharmaceutically acceptable salts thereof,
wherein
[0107] v is 1 and w is 0, 1 or 2, or v is 2 and w is 0 or 1;
[0108] X represents C(R.sup.1).sub.2, CHCO.sub.2R.sup.1, O,
NOR.sup.1, CHCON(R.sup.1).sub.2, NNHCOR.sup.2, or the atoms
necessary to complete a spiro-linked 5- or 6-membered carbocyclic
or heterocyclic ring;
[0109] R.sup.5 represents H, CO.sub.2R.sup.1 or
CON(R.sup.1).sub.2;
[0110] and R.sup.1, R.sup.2, Ar.sup.1 and Ar.sup.2 have the same
meanings as before.
[0111] Preferably, v is 1 and w is 0 or 1. Most preferably, v and w
are both 1.
[0112] Examples of compounds within this subclass include those
wherein Ar.sup.1 represents 4-chlorophenyl, Ar.sup.2 represents
2,5-difluorophenyl, v and w are both 1 and X, R.sup.1 and R.sup.5
are as indicated in the following table:
3 .dbd.X R.sup.1 R.sup.5 .dbd.0 H H .dbd.0 CH.sub.2Ph CO.sub.2Me
.dbd.0 H CONH.sub.2 .dbd.0 H CO.sub.2Me .dbd.0 Me CO.sub.2Me .dbd.0
allyl CO.sub.2Me .dbd.N--OH H H .dbd.N--OMe H H .dbd.N--OCH.sub.2Ph
H H .dbd.N--OCH.sub.2CH.dbd.CH.sub.2 H H .dbd.N--O.sup.tBu H H 27 H
H 28 H H 29 H H .dbd.CH.sub.2 H H .dbd.CHCO.sub.2H H H 30 H H 31 H
H 32 H H 33 H H 34 H H 35 H H 36 H H .dbd.N--NH--COMe H H
.dbd.CHCH.sub.2CH.sub.2CO.sub.2Et H H .dbd.N--O--CH.sub.2CO.sub.2H
H H
[0113] and the pharmaceutically acceptable salts thereof.
[0114] Further examples of compounds in accordance with formula III
include those in which R.sup.1 and R.sup.5 are both H, and v, w,
Ar.sup.1, Ar.sup.2 and X are as shown in the following table:
4 v w Ar.sup.1 Ar.sup.2 .dbd.X 2 0 4-Cl--C.sub.6H.sub.4
2,5-di-F--C.sub.6H.sub.3 .dbd.O 1 2 4-Cl--C.sub.6H.sub.4
2,5-di-F--C.sub.6H.sub.3 .dbd.O 1 1 4-CF.sub.3--C.sub.6H.sub.4
2,5-di-F--C.sub.6H.sub.3 .dbd.CHCO.sub.2Et 1 0 4-Cl--C.sub.6H.sub.4
2,5-di-F--C.sub.6H.sub.3 37 1 1 4-Cl--C.sub.6H.sub.4
5-Br-2-F--C.sub.6H.sub.3 .dbd.O 1 1 4-Cl--C.sub.6H.sub.4
2-F-5-I--C.sub.6H.sub.3 .dbd.O 1 1 4-MeO--C.sub.6H.sub.4
2,5-di-F--C.sub.6H.sub.3 .dbd.O
[0115] and the pharmaceutically acceptable salts thereof.
[0116] A third subclass of the compounds of the invention is
defined by formula IV and the pharmaceutically acceptable salts
thereof: 38
[0117] wherein:
[0118] W represents --NR.sup.6--(CH.sub.2).sub.t--,
--O--CHR.sup.7--, or --CF.sub.2CH.sub.2--;
[0119] R.sup.6 represents R.sup.1, COR.sup.2 or
CO.sub.2R.sup.2;
[0120] R.sup.7 represents H or OR.sup.1;
[0121] t is 0 or 1; and
[0122] Ar.sup.1, Ar.sup.2, R.sup.1 and R.sup.2 have the same
meanings as before.
[0123] Examples of groups represented by R.sup.6 include H,
optionally substituted C.sub.1-6alkyl (such as methyl, ethyl,
benzyl and CH.sub.2CO.sub.2Me), C.sub.2-6alkenyl (such as allyl),
t-butoxycarbonyl, and acyl (such as
COCH.sub.2CH.sub.2CO.sub.2Me).
[0124] A fourth subclass of the compounds of the invention is
defined by formula V and the pharmaceutically acceptable salts
thereof: 39
[0125] wherein Ar.sup.1, Ar.sup.2 and R.sup.1 have the same
meanings as before.
[0126] Within this subclass, R.sup.1 aptly represents H,
C.sub.1-6alkyl such as methyl, ethyl or propyl, any of which is
optionally substituted with OR.sup.2a, CO.sub.2R.sup.2a or
CON(R.sup.2a).sub.2, where R.sup.2a has the same meaning as before,
or C.sub.2-6alkenyl such as allyl.
[0127] Individual compounds within this subclass are described in
the Examples appended hereto, in particular Examples 150-159. and
the pharmaceutically acceptable salts thereof.
[0128] It will be apparent that certain compounds of formula III
are tautomers of compounds of formula II. In particular, compounds
of formula III wherein X represents O and R.sup.1 is H may
tautomerise to corresponding compounds of formula II wherein
R.sup.3 represents OH and bond a is double. It is to be understood
that both tautomeric forms are within the scope of the invention,
regardless of which tautomeric form is present in the greater
amount under any particular set of conditions.
[0129] The compounds of formula I have an activity as modulators of
the processing of APP by .gamma. secretase.
[0130] The invention provides pharmaceutical compositions
comprising one or more compounds of formula I or the
pharmaceutically acceptable salts thereof and a pharmaceutically
acceptable carrier. Preferably these compositions are in unit
dosage forms such as tablets, pills, capsules, powders, granules,
sterile parenteral solutions or suspensions, metered aerosol or
liquid sprays, drops, ampoules, transdermal patches, auto-injector
devices or suppositories; for oral, parenteral, intranasal,
sublingual or rectal administration, or for administration by
inhalation or insufflation. For preparing solid compositions such
as tablets, the principal active ingredient is mixed with a
pharmaceutical carrier, e.g. conventional tableting ingredients
such as corn starch, lactose, sucrose, sorbitol, talc, stearic
acid, magnesium stearate, dicalcium phosphate or gums or
surfactants such as sorbitan monooleate, polyethylene glycol, and
other pharmaceutical diluents, e.g. water, to form a solid
preformulation composition containing a homogeneous mixture of a
compound of the present invention, or a pharmaceutically acceptable
salt thereof. When referring to these preformulation compositions
as homogeneous, it is meant that the active ingredient is dispersed
evenly throughout the composition so that the composition may be
readily subdivided into equally effective unit dosage forms such as
tablets, pills and capsules. This solid preformulation composition
is then subdivided into unit dosage forms of the type described
above containing from 0.1 to about 500 mg of the active ingredient
of the present invention. Typical unit dosage forms contain from 1
to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active
ingredient. The tablets or pills of the novel composition can be
coated or otherwise compounded to provide a dosage form affording
the advantage of prolonged action. For example, the tablet or pill
can comprise an inner dosage and an outer dosage component, the
latter being in the form of an envelope over the former. The two
components can be separated by an enteric layer which serves to
resist disintegration in the stomach and permits the inner
component to pass intact into the duodenum or to be delayed in
release. A variety of materials can be used for such enteric layers
or coatings, such materials including a number of polymeric acids
and mixtures of polymeric acids with such materials as shellac,
cetyl alcohol and cellulose acetate.
[0131] The present invention also provides a compound of formula I
or a pharmaceutically acceptable salt thereof for use in a method
of treatment of the human body. Preferably the treatment is for a
condition associated with the deposition of .beta.-amyloid.
Preferably the condition is a neurological disease having
associated .beta.-amyloid deposition such as Alzheimer's
disease.
[0132] The present invention further provides the use of a compound
of formula I or a pharmaceutically acceptable salt thereof in the
manufacture of a medicament for treating or preventing Alzheimer's
disease.
[0133] Also disclosed is a method of treatment of a subject
suffering from or prone to Alzheimer's disease which comprises
administering to that subject an effective amount of a compound
according to formula I or a pharmaceutically acceptable salt
thereof.
[0134] The liquid forms in which the novel compositions of the
present invention may be incorporated for administration orally or
by injection include aqueous solutions, suitably flavoured syrups,
aqueous or oil suspensions, and flavoured emulsions with edible
oils such as cottonseed oil, sesame oil, coconut oil or peanut oil,
as well as elixirs and similar pharmaceutical vehicles. Suitable
dispersing or suspending agents for aqueous suspensions include
synthetic and natural gums such as tragacanth, acacia, alginate,
dextran, sodium carboxymethylcellulose, methylcellulose,
poly(vinylpyrrolidone) or gelatin.
[0135] For treating or preventing Alzheimer's Disease, a suitable
dosage level is about 0.01 to 250 mg/kg per day, preferably about
0.01 to 100 mg/kg per day, and especially about 0.01 to 10 mg/kg of
body weight per day. The compounds may be administered on a regimen
of 1 to 4 times per day. In some cases, however, dosage outside
these limits may be used.
[0136] The compounds of formula I may be synthesised by a variety
of routes starting from the benzyl sulphones:
Ar.sup.2--CH.sub.2--SO.sub.2--Ar.sup.1 (1)
[0137] wherein Ar.sup.1 and Ar.sup.2 have the same meanings as
before. The sulphones (1) are prepared by oxidation of thioethers
Ar.sup.2--CH.sub.2--SAr.sup.1 (2), which in turn are formed by
reaction of thiols Ar.sup.1SH (3) with benzyl derivatives
Ar.sup.2CH.sub.2-L (4), where L is a leaving group such as chloride
or bromide and Ar.sup.1 and Ar.sup.2 have the same meanings as
before. The reaction between (3) and (4) takes place in an inert
solvent such as dichloromethane in the presence of a base such as
triethylamine, while the oxidation of (2) to (1) is conveniently
effected by m-chloroperoxybenzoic acid, also in an inert solvent
such as dichloromethane.
[0138] In a first process, bis-alkylation of (1) with L-A-L (5)
(where L and A have the same meanings as before) provides the
compounds of formula I directly. The reaction may be carried out in
the presence of sodium hydride in DMF at room temperature, and is
particularly suitable when A represents a fragment such as
--CH.sub.2CH.sub.2OCH.sub.2CH.sub.2--.
[0139] In a second process, sequential alkylation of (1) with
L-CH.sub.2(CH.sub.2).sub.wCH.dbd.CH.sub.2 and
L-(CH.sub.2).sub.vCH.dbd.CH- .sub.2 provides the bis-olefins (6)
which give the cycloalkenes (7) on treatment with a rhodium
catalyst: 40
[0140] where v, w, L, Ar.sup.1 and Ar.sup.2 have the same meanings
as before. The alkylations take place at ambient temperature in an
aprotic solvent such as DMF or THF in the presence of strong base
such as sodium hydride or potassium t-butoxide. Suitable catalysts
for the cyclisation of (6) to (7) include
bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride,
the reaction taking place at room temperature in an inert solvent
such as dichloromethane.
[0141] In a third process, reaction of (1) with at least two
equivalents of an acrylate ester (8) provides enols (9) which are
tautomeric with keto-esters (10): 41
[0142] where R.sup.2, Ar.sup.1 and Ar.sup.2 have the same meanings
as before. On the basis of NMR spectral data, the products are
believed to exist predominantly as the enols (9). The reaction may
be carried out at ambient temperature in an inert solvent such as
THF in the presence of strong base such as potassium
t-butoxide.
[0143] In a fourth process, sequential treatment of (1) with BuLi,
Me.sub.3SiCl and formaldehyde provides vinyl sulphones (11), which
react with amine derivatives (12) in the presence of
trifluoroacetic acid to provide pyrrolidines (13): 42
[0144] where R.sup.2, Ar.sup.1 and Ar.sup.2 have the same meanings
as before. The reaction to form (11) is carried out at -78.degree.
C. in THF, while the formation of (13) may be carried out in
dichloromethane at 0.degree. C.
[0145] An alternative route to compounds of formula I involves
reaction of styrene derivatives (27) with thiophenols Ar.sup.1SH in
the presence of perchloric acid, with subsequent oxidation by
m-chloroperoxybenzoic acid: 43
[0146] where A, Ar.sup.1 and Ar.sup.2 have the same meanings as
before. The styrenes (27) are available by reaction of the
triflates (28) with Ar.sup.2--B(OH).sub.2 in the presence of a
Pd(0) catalyst, and the triflates may be formed by treatment of the
ketones (29) with N-phenyl triflamide and strong base such as
lithium di-isopropylamide at low temperatures under anhydrous
conditions: 44
[0147] where Tf represents trifluoromethanesulphonyl and A,
Ar.sup.1 and Ar.sup.2 have the same meanings as before.
[0148] Compounds in accordance with formula I, prepared by any of
the above processes, may be converted into other compounds in
accordance with formula I by the application of conventional
synthesis methodology.
[0149] For example, the compounds of formulae (9) or (10) may be
reacted with R.sup.2-L in the presence of base to provide a mixture
of O-alkyl and C-alkyl derivatives (14) and (15): 45
[0150] where L, R.sup.2, Ar.sup.1 and Ar.sup.2 have the same
meanings as before. The reaction is typically carried out in
refluxing acetone in the presence of potassium carbonate, and the
products separated by conventional chromatographic techniques.
[0151] The esters (9), (10), (14) and (15) may be hydrolysed to the
corresponding carboxylic acids, which may be coupled with amines to
provide the corresponding amides, or with alcohols to provide
alternative esters. Alternatively, the esters (9), (10), (14) and
(15) themselves may be reacted with amines or alcohols to provide
amides or alternative esters.
[0152] Reduction f the esters (9) or (10) with sodium borohydride
provides the diols (16): 46
[0153] The cycloalkenes (7) may be reduced to the corresponding
cycloalkanes (17): 47
[0154] where v, w, Ar.sup.1 and Ar.sup.2 have the same meanings as
before. The reaction is typically carried out by hydrogenation over
Pd/C. at 45 psi. in a solvent such as ethyl acetate.
[0155] Alternatively, the cycloalkenes (7) may be treated
sequentially with borane in THF and alkaline hydrogen peroxide to
provide the alkanols (18): 48
[0156] where v, w, Ar.sup.1 and Ar.sup.2 have the same meanings as
before. The alkanols may be reacted with methanesulphonyl chloride
to provide the corresponding mesylates, which may be subjected to
nucleophilic displacement by a variety of nucleophiles such as
halide, cyanide and azide (e.g. at 90.degree. C. in DMF solution).
Azides formed in this way may be reduced to the primary amines
(19): 49
[0157] where v, w, Ar.sup.1 and Ar.sup.2 have the same meanings as
before. The reduction may be effected by treatment with
triphenylphosphine in refluxing aqueous THF.
[0158] The alkanols (18) may also be oxidised to ketones (20):
50
[0159] where v, w, Ar.sup.1 and Ar.sup.2 have the same meanings as
before. Any of the conventional oxidants may be used, such as
pyridinium dichromate, but an alternative route to the ketones (20)
in which v and w are both 1 is by decarboxylation of the compounds
(9)/(10), which may be accomplished by heating at 150.degree. C. in
DMSO in the presence of sodium chloride and water. The latter
procedure, followed by reduction of the carbonyl group with
borohydride, provides an alternative route to the alkanols (18) in
which v=w=1.
[0160] The ketones (20) react with R.sup.1--ONH.sub.2 to form
oximes and alkoximes (21): 51
[0161] where R.sup.1, v, w, Ar.sup.1 and Ar.sup.2 have the same
meanings as before. The reaction may be carried out in a mixture of
pyridine and ethanol at 80.degree. C.
[0162] The ketones (20) may alternatively be converted to the
amines (22) by reaction with (R.sup.1).sub.2NH and sodium
triacetoxyborohydride: 52
[0163] where R.sup.1, v, w, Ar.sup.1 and Ar.sup.2 have the same
meanings as before. The reaction takes place at ambient temperature
in dichloromethane, and is particularly suitable for the synthesis
of secondary and tertiary amines wherein at least one of the
R.sup.1 groups is other than H.
[0164] The ketones (20) may converted to the difluorides (23) by
reaction with (diethylamino)sulphur trifluoride: 53
[0165] where v, w, Ar.sup.1 and Ar.sup.2 have the same meanings as
before. The reaction may be carried out in dichloromethane at
ambient temperature.
[0166] The ketones (20) may alternatively be condensed with ylides
such as Ph.sub.3P.dbd.CH(R.sup.1).sub.2 and
Ph.sub.3P.dbd.CHCO.sub.2R.sup.2 to form alkylidene derivatives (24)
and (25): 54
[0167] where v, w, R.sup.1, R.sup.2, Ar.sup.1 and Ar.sup.2 have the
same meanings as before. The ylides are formed by treatment of the
corresponding phosphonium bromides with butyllithium in an aprotic
solvent at low temperature, and are reacted in situ with the
ketones (20).
[0168] The primary amines (19) may be alkylated and/or acylated in
accordance with standard techniques. In particular, they may be
coupled with acids R.sup.2CO.sub.2H to form the amides (26) using
any of the well known processes for amide bond formation: 55
[0169] where R.sup.2, v, w, Ar.sup.1 and Ar.sup.2 have the same
meanings as before. Suitable processes include conversion of the
carboxylic acid to the acid chloride prior to reaction with amine
(19), and the use of coupling agents such as dimethylaminopyridine,
hydroxybenzotriazole, dicyclohexylcarbodiimide, carbonyldiimidazole
and the like.
[0170] Compounds of formula IIA in which m is 0 and Z is
CO.sub.2R.sup.2a, CON(R.sup.2a).sub.2, CONR.sup.2a(OR.sup.2a),
CON(R.sup.2a)N(R.sup.2a).sub- .2 or CONHC(.dbd.NOH)R.sup.2a may be
prepared by coupling of a carboxylic acid (30) with (respectively)
R.sup.2aOH, HN(R.sup.2a).sub.2, HNR.sup.2a(OR.sup.2a),
HN(R.sup.2aa)N(R.sup.2a).sub.2 or H.sub.2NC(.dbd.NOH)R.sup.2a,
56
[0171] where Ar.sup.1, Ar.sup.2, R.sup.1c and R.sup.2a have the
same meanings as before. Any of the standard coupling techniques
may be used, including the use of coupling agents such as
dimethylaminopyridine, hydroxybenzotriazole,
dicyclohexylcarbodiimide, carbonyldiimidazole and the like. In one
preferred method, the acid is converted to the corresponding acid
chloride (e.g. by treatment with oxalyl chloride in DMF solution)
and reacted directly with the desired nucleophile. In another
preferred method, the acid is converted to an active ester
derivative such as the pentafluorophenol ester (e.g. by coupling
with the phenol in the presence of dicyclohexyl carbodiimide), and
this intermediate is reacted with the desired nucleophile.
[0172] The acids (30) are available by hydrolysis of the esters
(31), typically under alkaline conditions such as treatment with
LiOH in ethanol solution: 57
[0173] where Ar.sup.1, Ar.sup.2, R.sup.1c and R.sup.2 have the same
meanings as before. In this context, R.sup.2 is typically methyl or
ethyl.
[0174] The esters (31) are available by reduction of the alkylidene
derivatives (25) in which v=w=1, optionally followed by alkylation
with (C.sub.1-4alkyl)-L where L is a leaving group (especially
bromide or iodide) when R.sup.1c is other than H. The reduction may
be carried out using sodium borohydride and nickel(II) chloride in
ethanol, while the optional alkylation may be effected by treating
the ester (31, R.sup.1c.dbd.H)) with strong base (e.g. sodium
bis(trimethylsilyl)amide) in an aprotic solvent at low temperature,
followed by treatment with (C.sub.1-4alkyl)-L and warming to room
temperature.
[0175] Alternatively, the unsaturated esters (25, v=w=1) may be
hydrolysed to the corresponding acids and converted to amides by
reaction with HN(R.sup.2a).sub.2 prior to reduction.
[0176] Compounds of formula IIA in which m is 0 and Z is COR.sup.2c
may be prepared by treatment of the corresponding compounds in
which Z is CONR.sup.2c(OR.sup.2c) with R.sup.2c--Li, where R.sup.2c
represents R.sup.2a which is other than H. The reaction is
typically carried out in an aprotic solvent at low temperature, and
is particularly useful when R.sup.2c in COR.sup.2c represents aryl
or heteroaryl. In such cases, subsequent reduction of the carbonyl
group (e.g. using sodium borohydride) provides the compounds of
formula IIA in which m is 1, R.sup.1b is OH and Z is aryl or
heteroaryl.
[0177] Compounds of formula IIA in which m is 0 and Z is halogen,
CN, N.sub.3, OR.sup.2a, N(R.sup.2a).sub.2 or heteroaryl bonded
through N may be obtained by reaction of a sulph nate ester (32)
with (respectively) halide ion, cyanide ion, azide ion, R.sup.2aOH,
HN(R.sup.2a).sub.2 or heteroaryl comprising NH in the ring: 58
[0178] where L.sup.1 represents a sulphonate leaving group (such as
mesylate, tosylate or triflate) and Ar.sup.1, Ar.sup.2 and R.sup.2a
have the same meanings as before. The displacement reaction may be
carried out in DMF at elevated temperature, e.g. about 80.degree.
C. When the nucleophile is R.sup.2aOH, HN(R.sup.2a).sub.2 or
heteroaryl comprising NH in the ring, it is advantageous to
generate the corresponding anion by treatment with sodium hydride
prior to reaction with (32).
[0179] The sulphonates (32) are prepared by reaction of the
alcohols (33) with the appropriate sulphonyl chloride (e.g. under
anhydrous conditions at low temperature in the presence of a
tertiary amine). 59
[0180] The alcohols (33) are available from the hydroboration of
alkylidenes (24) in which one of the R.sup.1 groups is H and the
other is H or C.sub.1-4alkyl. The process typically involves
reaction with borane in THF at room temperature, followed by
treatment with alkaline hydrogen peroxide and separation of the
desired cis isomer by chromatography.
[0181] An alternative route to the alcohols (33) in which R.sup.1c
is H involves converting an alcohol (18) in which v=w=1 to the
corresponding mesylate (or equivalent leaving group), effecting
nucleophilic displacement with cyanide ion, hydrolysing the
resulting nitrile to the corresponding carboxylic acid, followed by
reduction to the primary alcohol. The hydrolysis is typically
carried out under acid conditions (e.g. in a mixture of acetic acid
and conc. HCl at 110.degree. C.) and the reduction is conveniently
carried out by sequential treatment with isobutyl chloroformate and
borohydride in THF.
[0182] Compounds of formula IIA in which m is 0 and Z is
OCOR.sup.2a or OCON(R.sup.2a).sub.2 are available by reaction of
alcohols (33) with (respectively) R.sup.2aCOCl or R.sup.2a--NCO in
accordance with standard procedures.
[0183] Compounds of formula IIA in which m is 0 and Z represents
aryl or heteroaryl bonded through C may be prepared by reaction of
a sulphonyl derivative (32) with the appropriate aryllithium or
heteroaryllithium. Alternatively, the corresponding compounds in
which Z represents a functional group such as CN, CO.sub.2H,
CONH.sub.2, CONHNH.sub.2 or CONHC(.dbd.NOH)R.sup.2a may be
converted to heteroaryl derivatives using conventional techniques
of heterocyclic synthesis. Examples of such conversions
include:
[0184] treatment of a nitrile derivative with azide to form a
tetrazol-5-yl derivative;
[0185] treatment of a nitrile derivative with methanol and HCl,
followed by a hydrazide, to form a
5-substituted-1,3,4-oxadiazol-3-yl derivative;
[0186] treatment of a hydrazide derivative with
triethylorthoformate to form a 1,3,4-oxadiazol-3-yl derivative;
[0187] treatment of a hydrazide derivative with acetamidine to form
a 5-methyl-1,2,4-triazol-3-yl derivative;
[0188] treatment of an amide derivative with Lawesson's reagent,
followed by a chloromethyl ketone, to form a
4-substituted-thiazol-2-yl derivative;
[0189] treatment of a carboxylic acid derivative (or active ester
thereof) with semicarbazide to form a 1,2,4-triazol-3-one
derivative;
[0190] treatment of a carboxylic acid derivative (or active ester
thereof) with a hydrazide, followed by Lawesson's reagent, to form
a 5-substituted-1,3,4-thiadiazol-2-yl derivative; and
[0191] treatment of a CONHC(.dbd.NOH)R.sup.2a derivative with
strong base (e.g. potassium t-butoxide) to form a
3-substituted-1,2,4-oxadiazol-5-yl derivative.
[0192] Illustrations of these conversions are provided in the
Examples appended hereto.
[0193] Compounds of formula IIA in which m is 1 and R.sup.1b is H
or C.sub.1-4alkyl may be obtained via oxidation of an alcohol (33)
to the corresponding aldehyde or ketone, and elaboration of the
carbonyl group thereof in the manner described previously in
connection with conversion of the ketones (20) into compounds of
formula IIA in which m is 0.
[0194] Compounds of formula V may be obtained by treatment of the
sulphones (1) with an alkyllithium (e.g. BuLi) and epichlorohydrin,
and optional alkylation of the resulting cyclobutanol with
R.sup.1-L, where R.sup.1 and L have the same meanings as before.
The reaction of (1) with epichlorohydrin is typically carried out
at low temperature in THF, and the optional alkylation is typically
effected by treatment of the cyclobutanol with sodium hydride in
DMF and reaction of the resulting alkoxide with R.sup.1-L.
[0195] Where they are not themselves commercially available, the
starting materials and reagents employed in the above-described
synthetic schemes may be obtained by the application of standard
techniques of organic synthesis to commercially available
materials.
[0196] It will be appreciated that many of the above-described
synthetic schemes may give rise to mixtures of stereoisomers. In
particular, certain products may be formed as mixtures of cis and
trans isomers in which a particular ring substituent is on the same
or opposite side of the ring as the arylsulphonyl group. Such
mixtures may be separated by conventional means such as fractional
crystallisation and preparative chromatography.
[0197] Certain compounds according to the invention may exist as
optical isomers due to the presence of one or more chiral centres
or because of the overall asymmetry of the molecule. Such compounds
may be prepared in racemic form, or individual enantiomers may be
prepared ither by enantiospecific synthesis or by resolution. The
novel compounds may, for example, be resolved into their component
enantiomers by standard techniques such as preparative HPLC, or the
formation of diastereomeric pairs by salt formation with an
optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid
and/or (+)-di-p-toluoyl-1-tartaric acid, followed by fractional
crystallization and regeneration of the free base. The novel
compounds may also be resolved by formation of diastereomeric
esters or amides, followed by chromatographic separation and
removal of the chiral auxiliary.
[0198] During any of the above synthetic sequences it may be
necessary and/or desirable to protect sensitive or reactive groups
on any of the molecules concerned. This may be achieved by means of
conventional protecting groups, such as those described in
Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum
Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective
Groups in Organic Synthesis, John Wiley & Sons, 1991. The
protecting groups may be removed at a convenient subsequent stage
using methods known from the art.
[0199] A typical assay which can be used to determine the level of
activity of compounds of the present invention is as follows:
[0200] (1) Mouse neuroblastoma neuro 2a cells expressing human
app695 are cultured at 50-70% confluency in the presence of sterile
10 mM sodium butyrate.
[0201] (2) Cells are placed in 96-well plates at 30,000/well/100
.mu.L in minimal essential medium (MEM) (phenol red-free)+10%
foetal bovine serum (FBS), 50 mM HEPES buffer (pH7.3), 1%
glutamine, 0.2 mg/ml G418 antibiotic, 10 mM sodium butyrate.
[0202] (3) Make dilutions of the compound plate. Dilute stock
solution to 5.5% DMSO/101 .mu.M compound. Mix compounds vigorously
and store at 4.degree. C. until use.
[0203] (4) Add 10 .mu.L compound/well. Mix plate bri fly, and leave
for 18 h in 37.degree. C. incubator.
[0204] (5) Remove 90 .mu.L of culture supernatant and dilute 1:1
with ice-cold 25 mM HEPES (pH0.3), 0.1% BSA, 1.0 mM EDTA (+broad
spectrum protease inhibitor cocktail; pre-aliquotted into a 96-well
plate). Mix and keep on ice or freeze at -80.degree. C.
[0205] (6) Add back 100 .mu.L of warm MEM+10% PBS, 50 mM HEPES
(pH7.3), 1% glutamine, 0.2 mg/ml G418, 10 mM sodium butyrate to
each well, and return plate to 37.degree. C. incubator.
[0206] (7) Prepare reagents necessary to determine amyloid peptide
levels, for example by ELISA assay.
[0207] (8) To determine if compounds are cytotoxic, cell viability
following compound administration is assessed by the use of redox
dye reduction. A typical example is a combination of redox dye MTS
(Promega) and the electron coupling reagent PES. This mixture is
made up according to the manufacturer's instructions and left at
room temperature.
[0208] (9) Quantitate amyloid beta 40 and 42 peptides using an
appropriate volume of diluted culture medium by standard ELISA
techniques.
[0209] (10) Add 15 .mu.L/well MTS/PES solution to the cells; mix
and leave at 37.degree. C.
[0210] (11) Read plate when the absorbance values are approximately
1.0 (mix briefly before reading to disperse the reduced formazan
product).
[0211] Alternative assays are described in Biochemistry, 2000,
39(30), 8698-8704.
[0212] The Examples of the present invention all had an ED.sub.50
of less than 10 .mu.M, preferably less than 1 .mu.M and most
preferably less than 100 nM in at least one of the above
assays.
[0213] The following examples illustrate the present invention.
EXAMPLES
[0214] Intermediate 1 60
[0215] 4-Chlorothiophenol (3.6 g, 0.025 mol) in dichloromethane
(100 ml) was treated with 2,5-difluorobenzyl bromide (5.17 g, 0.025
mol) and triethylamine (3.9 ml, 0.028 mol), reaction was stirred
for 2 hours then diluted with dichloromethane (250 ml) and washed
with water (100 ml) and brine (100 ml). The separated organic layer
was dried (MgSO.sub.4) and evaporated to dryness. Product was
purified by passing down a plug of silica eluting with hexane-ethyl
acetate mixtures. 5.12 g. .sup.1H NMR CDCl.sub.3 7.23 (4H,s),
6.69-6.86 (3H,m) and 4.04 (2H,s).
[0216] This thioether (5.12 g, 0.018 mol) was dissolved in
dichloromethane (100 ml) and treated with m-chloroperoxybenzoic
acid (14.3 g, 0.042 mol (50% w/w)) and stirred for 2 hours. The
reaction was then washed with Na.sub.2S.sub.2O.sub.5 (5% solution,
100 ml), brine (50 ml), dried (MgSO.sub.4) and evaporated to
dryness. The sulphone product was purified on silica eluting with
hexane-ethyl acetate mixtures, 3.6 g. .sup.1H NMR CDCl.sub.3 7.61
(2H,d, J=8.6 Hz), 7.45 (2H,d, J=8.6 Hz), 7.13-7.08 (1H,m),
7.05-7.01 (1H,m), 7.05-7.00 (1H,m), 6.99-6.87 (1H,m) and 4.36
(2h,s).
[0217] Intermediate 2 61
[0218] Intermediate 1 (500 mg, 1.66 mmol) in N,N-dimethylformamide
(DMF) (2.5 ml) was treated with sodium hydride (73 mg, 60% w/w in
mineral oil, 1.82 mmol), then allyl bromide (216 .mu.l, 2.49 mmol).
The mixture was stirred at room temperature for 16 hours, a further
portion of sodium hydride (36 mg, 60% w/w in mineral oil, 0.91
mmol) added and stirring at room temperature continued for another
5.5 hours. The reaction mixture was diluted with water (40 ml) and
extracted with ethyl acetate (3.times.50 ml), and the combined
organics washed with brine (sat., 100 ml), dried (Mg SO.sub.4) and
evaporated to dryness, giving an orange oil (506 mg). This material
was chromatographed on silica, eluting with 0-5% ethyl acetate in
hexanes to give product 199 mg. .sup.1H NMR (400 MHz, CDCl.sub.3),
2.79-2.88 (1H, m), 3.17-3.23 (1H, m), 4.57-4.61 (1H, m), 5.00-5.10
(2H, m), 5.50-5.60 (1H, m), 6.79-6.85 (1H, m), 6.94-7.00 (1H, m),
7.23-7.28 (1H, m), 7.38-7.41 (2H, m), 7.53-7.56 (2H, m).
[0219] This mono-allyl derivative (50 mg, 0.15 mmol) in
tetrahydrofuran (2 ml) was treated with allyl bromide (14 .mu.l,
0.16 mmol). Potassium tert-butoxide (161 .mu.l, 1M solution in
tetrahydrofuran, 0.16 mmol) was then dripped in slowly and mixture
stirred at room temperature for 2 hours. The reaction mixture was
diluted with ethyl acetate (20 ml), washed with water (30 ml) and
then brine (sat., 30 ml), then dried (MgSO.sub.4) and evaporated to
dryness, giving 39 mg crude material. This was purified by
preparative t.l.c., eluting with 5% ethyl acetate in hexanes,
giving product 10.6 mg. .sup.1H NMR (400 MHz, CDCl.sub.3),
3.08-3.15 (2H, m), 3.20-3.30 (2H, m), 5.14-5.24 (4H, m), 5.75-5.90
(2H, m), 6.75-6.82 (1H, m), 6.94-7.00 (2H, m), 7.37 (4H, d, J=8.0
Hz).
[0220] Intermediat 3 62
[0221] Intermediate 1 (1.01 g, 3.34 mmol) in DMF (3 ml) was dripped
into a stirring suspension of sodium hydride (134 mg, 60% w/w in
mineral oil, 3.34 mmol) in DMF (2 ml), and the mixture treated with
4-bromo-1-butene (508 .mu.l, 5.01 mmol) and stirred at room
temperature for 1.5 hours. The reaction mixture was diluted with
water (150 ml) and extracted with ethyl acetate (3.times.100 ml).
The combined organics were washed with brine (sat., 150 ml), dried
(MgSO.sub.4) and evaporated in vacuo to give 1.05 g crude material
which was chromatographed on silica, eluting with 0-5% ethyl
acetate in hexanes to give product. 720 mg. .sup.1H NMR (360 MHz,
CDCl.sub.3), 1.85-1.96 (1H, m), 2.06-2.25 (2H, m), 2.49-2.58 (1H,
m), 4.54 (1H, dd, J=11.2 Hz and J=2.5 Hz), 4.97 (2H, dq, J=12.9 Hz
and J=1.2 Hz), 5.64-5.75 (1H, m), 6.80-6.86 (1H, m), 6.96-7.02 (1H,
m), 7.22-7.27 (1H, m), 7.36-7.40 (2H, m), 7.51-7.55 (2H, m).
[0222] This homoallyl derivative (720 mg, 2.02 mmol) in DMF (10 ml)
was dripped into a stirring suspension of sodium hydride (202 mg,
60% w/w in mineral oil, 5.06 mmol) in DMF (7 ml). The mixture was
treated with allyl bromide (875 .mu.l, 10.1 mmol) and stirred at
room temperature for 64 hours, then diluted with water (150 ml) and
extracted with ethyl acetate (3.times.100 ml). The combined
organics were washed with brine (sat., 200 ml), dried (MgSO.sub.4)
and evaporated in vacuo to give 910 mg crude material which was
chromatographed on silica, eluting with 0-5% ethyl acetate in
hexanes to give product (794 mg.) A portion of this material (44
mg) was further purified by preparative t.l.c., eluting with 10%
ethyl acetate in hexanes to give 36 mg pure product. .sup.1H NMR
(400 MHz, CDCl.sub.3), 1.8-1.95 (1H, m), 2.27-2.33 (1H,m),
2.41-2.46 (2H, m), 3.03 (1H, dd, J=14.8 Hz and J=7.0 Hz), 3.31 (1H,
dd, J=15.4 Hz and J=6.3 Hz), 4.99-5.06 (2H, m), 5.18-5.28 (2H, m),
5.73-5.84 (1H, m), 5.90-6.00 (1H, m), 6.78-6.86 (1H, m), 7.00-7.08
(2H, m), 7.31-7.37 (4H, m).
[0223] Intermediate 4 63
[0224] Prepared as for Intermediate 1, using
4-trifluoromethylthiophenol, and obtained as a solid. .sup.1H NMR
(360 MHz, CDCl.sub.3) .delta. 7.85-7.83 (2H, m), 7.76-7.74 (2H, m),
7.15-7.10 (1H, m), 7.06-7.0 (1H, m), 6.92-6.86 (1H, m) and 4.46
(2H, s).
[0225] Intermediate 5 64
[0226] Prepared as for Intermediate 1, using
3,4-dichlorothiophenol, and obtained as a solid. .sup.1H NMR (360
MHz, CDCl.sub.3) .delta. 7.76 (1H, d, J=2 Hz), 7.76 (1H, d, J=8.4
Hz), 7.51-7.48 (1H, m), 7.17-7.11 (1H, m), 7.08-7.05 (1H,m),
6.96-6.90 (1H, m) and 4.37 (2h, s).
[0227] Intermediate 6 65
[0228] Prepared as for Intermediate 1 using 4-chlorothiophenol and
2-fluorobenzyl bromide as starting materials to obtain product as a
solid. .sup.1H NMR (360 MHz, CDCl.sub.3) .delta. 7.59-7.56 (2H, m),
7.44-7.41 (2H, m), 7.36-7.29 (2H,m), 7.16-7.12 (1H, m), 6.95-6.90
(1H,m) and 4.40 (2H, s).
[0229] Intermediate 7 66
[0230] Prepared as for Intermediate 3, substituting
5-bromo-1-pentene for 4-bromo-1-butene.
[0231] .sup.1H NMR (400 MHz, CDCl.sub.3), 1.20-1.31 (1H, m),
1.54-1.68 (1H, m), 2.06-2.12 (2H, m), 2.33-2.38 (2H, m), 2.99-3.05
(1H, m), 3.28 (1H, dd, J=15.6 Hz and J=6.4 Hz), 4.97-5.05 (2H, m),
5.16-5.26 (2H, m), 5.70-5.78 (1H, m), 5.87-5.98 (1H, m), 6.78-6.84
(1H, m), 6.99-7.06 (2H, m), 7.29-7.37 (4H, m).
Example 1
[0232] 67
[0233] Intermediate 1 (1 g, 3.31 mmol) and methyl acrylate (0.84
ml, 9.27 mmol) in tetrahydrofuran (30 ml) were treated dropwise
with potassium .sup.tbutoxide (3.64 ml 1M solution in
tetrahydrofuran, 3.64 mmol). The reaction was stirred for 2 hours,
diluted with ethyl acetate (100 ml) and washed with water (50 ml)
and brine (50 ml). The organic phase was separated, dried
(MgSO.sub.4) and evaporated to dryness, and the product purified on
silica eluting with hexane-ethyl acetate mixtures. (1.0 g). .sup.1H
NMR CDCl.sub.3 12.0 (1H,s), 7.41 (4H,s), 7.06-7.0 (2H,m), 6.87-6.81
(1H,s), 3.81 (3H,s), 3.38 (1H,dd, J=3.2,15.8 Hz), 3.02-2.92 (2H,m),
2.52 (1H,dd, J=5.7, 18.5 Hz), 2.3-2.2 (1H,m) and 2.2-2.1
(1H,m).
Example 2
[0234] 68
[0235] The ester from Ex.1 (1.0 g, 2.25 mmol) in dimethylsulfoxide
(10 ml) was treated with NaCl (0.3 g, 4.96 mmol) and water (0.9 ml,
4.96 mmol) and heated at 150.degree. C. for 2 hours. The cooled
reaction mixture was diluted with ethyl acetate (100 ml), washed
with saturated NH.sub.4Cl (100 ml), and the organic phase
separated, dried (MgSO.sub.4) and evaporated to dryness. The
product was purified on silica eluting with hexane-ethyl acetate
mixtures, 0.5 g. .sup.1H NMR CDCl.sub.3 7.43-7.37 (4H,m), 7.22-7.1
(2H,m), 6.97-6.9 (1H,m), 3.05-2.98 (2H,m) and 2.61-2.53 (2H,m).
Example 3
[0236] 69
[0237] The ketone from Ex.2 (0.14 g, 0.36 mmol) and morpholine
(0.048 ml, 0.54 mmol) in dichloroethane (10 ml) were treated with
sodium triacetoxyborohydride (0.23 g, 1.08 mmol) and stirred at
room temperature for 18 hours. The reaction was diluted with ethyl
acetate (50 ml), washed with saturated sodium bicarbonate
(2.times.50 ml) and brine (50 ml), and the organic phase separated,
dried (MgSO.sub.4) and evaporated to dryness. The cis and trans
products were purified on silica eluting with hexane-ethyl acetate
mixtures, 0.04 and 0.06 g.
[0238] Isomer A .sup.1H NMR CDCl.sub.3 7.36-7.32 (4H,m), 7.14-7.09
(2H,m), 7.06-7.01 (1H, m), 3.75-3.73 (4H,m),2.67-2.60 (2H,m),
2.50-2.45 (4H,m), 2.36-2.32 (2H,m), 2.09-2.04 (3H,m) and 1.31-1.21
(2H,m). MS (MH+) 456.
[0239] Isomer B .sup.1H NMR CDCl.sub.3 7.38-7.32 4H, m), 7.1-7.0
(2H,m), 6.87-6.80 (1H,m), 3.64-3.62 (4H,m), 3.0-2.6 (2H,br m),
2.45-2.26 (4H,m), 2.32-2.04 (5H,m) and 1.19-1.12 (2H,m). MS (MH+)
456.
Example 4
[0240] 70
[0241] prepared as in example 3, substituting benzylamine for
morpholine. MS (MH+) 477(479)
Examples 5-16
[0242] 71
[0243] To the ketone from Ex.2 (50 mg, 0.13 mmol) in dichloroethane
(2 ml) was added the appropriate amine (0.95 eq) and then sodium
triacetoxyborohydride (42 mg, 0.2 mmol). The reaction was stirred
at room temperature until the starting amine was consumed
(typically 24-48 h), then sat. aq sodium hydrogen carbonate (1 ml)
was added, followed by dilution with dichloromethane (2 ml). The
organic layer was removed and transferred to a SCX Varian Bond
Elut.TM. cartridge and the organic layer passed through the
cartridge by suction filtration. The product was liberated from the
cartridge by passing a solution of ammonia in methanol (2.0 M)
through it. Evaporation to dryness afforded the product, usually as
a white solid.
[0244] By this method, the following were obtained as mixtures of
cis and trans isomers:
5 Example No. --N(R.sup.1).sub.2 MS (MH+) 5 72 438 6 73 467 7 74
529 8 75 510 9 76 510 10 77 468 11 78 468 12 79 467 13
--NHCH.sub.2CO.sub.2Me 492 14 80 543 15 81 556 16 82 538
Examples 17-21
[0245] 83
[0246] The ketone from Ex. 2 (0.13 g, 0.33 mmol) and hydroxylamine
or alkoxylamine H.sub.2NOR.sup.1 (0.92 mmol) were dissolved in
pyridine-ethanol (9 ml, 2:1) and heated at 80.degree. C. for 3
hours. The reaction was then diluted with ethyl acetate (50 ml),
washed with 2N HCl (5.times.25 ml), dried (MgSO.sub.4) and
evaporated to dryness. Product were purified on silica eluting with
hexane-ethyl acetate mixtures.
[0247] By this route there were obtained:
6 Example No. R.sup.1 17 H 18 methyl 19 CH.sub.2CH.dbd.CH.sub.2 20
t-butyl 21 benzyl
[0248] with yields and spectral data as follows:
Example 17
[0249] Yield 69 mg, .sup.1H NMR CDCl.sub.3 7.60 (1H,br), 7.41-7.36
(4H, m), 7.17-7.07 (2H, m), 6.93-6.87 (1H, m), 3.47-3.43 (1H,m),
2.88-2.83 (2H, m), 2.31-2.23 (2H,m), 2.07-2.04 (1H,m) and 1.71-1.68
(1H,m). MS MH+ 399.
Example 18
[0250] Yield 22 mg. .sup.1H NMR CDCl.sub.3 7.41-7.39 (4H, m),
7.16-7.06 (2H, m), 6.93-6.86 (1H, m), 3.76 (3H, s), 3.4-3.33 (1H,
m), 2.85-2.65 (2H, m), 2.55-2.52 (1H, m), 2.30-2.21 (2H, m),
2.04-2.02 (1H, m) and 1.68-1.61 (1H, m).
Example 19
[0251] Yield 28 mg. .sup.1H NMR CDCl.sub.3 7.41-7.36 (4H, m),
7.15-7.05 (2H, m), 6.93-6.86 (1H, m), 5.98-5.88 (1H, m), 5.27-5.16
(2H, m), 4.49-4.48 (2H, m), 3.43-3.39 (1H, m), 2.91-2.81 (2H, m),
2.57-2.34 (1H, m), 2.34-2.19 (2H, m), 2.07-1.98 (1H, m) and
1.75-1.61 (1H, m).
Example 20
[0252] Yield 32 mg. .sup.1H NMR CDCl.sub.3 7.42-7.35 (1H, m),
7.18-7.05 (2H, m), 6.81-6.85 (1H, m), 3.42-3.36 (1H, m), 2.82-2.76
(2H, m), 2.58-2.54 (1H, m), 2.34-2.18 (2H, m), 2.2-1.87 (1H, m),
1.7-1.62 (1H, m) and 1.21 (9JH, s).
Example 21
[0253] Yield 38 mg. .sup.1H NMR CDCl.sub.3 7.40-7.25 (9H, m),
7.15-7.05 (2H, m), 6.92-6.85 (1H, m), 5.02 (2H, s), 3.45-3.41 (1H,
m), 2.90-2.80 (2H, m), 2.57-2.53 (1H, m), 2.32-2.16 (2H, m),
2.06-1.98 (1H, m) and 1.74-1.67 (1H, m).
Example 22
[0254] 84
[0255] The ketone from example 2, (0.1 g, 0.26 mmol) in methanol (2
ml) was treated with NaBH.sub.4 (0.098 g, 0.26 mmol) and stirred
for 1 hour. The reaction was quenched with HCl (1N, 10 ml), diluted
with ethyl acetate (20 ml), then the organic phase was separated,
dried (MgSO.sub.4) and evaporated to dryness. The cis and trans
products were purified on silica eluting with hexane-ethyl acetate
mixtures.
[0256] (a) (trans) 0.052 g. .sup.1H NMR CDCl.sub.3 7.39-7.33
(4H,m), 7.11-7.02 (2H,m), 6.88-6.82 (1H,m), 3.80-3.73 (1H,m),
2.80-2.60 (2H,m), 2.22-2.16 (2H,m), 2.08-2.04 (2H,m), 1.53(1H,br)
and 1.27-1.13 (2H,m).
[0257] (b) (cis) .sup.1H NMR (CDCl.sub.3) 7.40 (4H,s), 7.16-7.03
(2H,m), 6.90-6.83 (1H,m), 3.97-3.95 (1H, m), 3.77-3.68 (1H, m),
3.51-3.49 (1H, m), 2.61-2.53 (2H,m), 1.91-1.83 (2H, m) and
1.50-1.42 (2H, m).
Example 23
[0258] 85
[0259] The ester from Ex. 1, (0.1 g, 0.22 mmol) in methanol was
saturated with ammonia at 0.degree. C., sealed and stirred for 18
hours. The reaction was then evaporated to dryness and the product
purified on silica eluting with hexane-ethyl acetate mixtures,
0.056 g. .sup.1H NMR d.sub.6-DMSO 7.64 (2H,d,J=8.5 Hz), 7.53
(2H,d,J=8.6 Hz), 7.48-7.42 (2H,m), 7.34-7.29(1H,m), 7.19-7.10
(2H,m), 3.35-3.21(2H,m), 2.85-2.76 (2H,m), 2.43-2.37 (1H,m),
2.19-2.14(1H,m) and 2.0-1.95 (1H,m).
Examples 24 and 25
[0260] 86
[0261] The product from Ex.1 (400 mg, 0.88 mmol) and potassium
carbonate (234 mg, 1.66 mmol) in acetone (10 ml) were treated
dropwise with methyl iodide (0.28 ml, 4.4 mmol). After stirring for
72 hours at reflux and then evaporation to dryness, the residue was
partitioned between ethyl acetate (3.times.100 ml) and water (50
ml) and brine (50 ml). The organic phase was separated, dried
(MgSO.sub.4) and evaporated to dryness. Product was purified on
silica eluting with hexane-ethyl acetate mixtures, 0.42 g. A
portion of this material was purified by preparative tlc, and the
C-methyl product 24 [.sup.1H NMR CDCl.sub.3 7.41 (2H,d, J=8.6 Hz),
7.27 (2H,d, J=10.1 Hz), 7.12-7.06 (2H,m), 6.89-6.84 (1H,m),
3.52-3.35 (1H, m), 3.22 (3H,s), 2.81-2.57 (5H,m) and 1.43 (3H,s).]
and the O-methyl product 25 [.sup.1H NMR CDCl.sub.3 7.39 (2H,d,
J=8.6 Hz), 7.36 (2H,d, J=8.6 Hz), 7.12-7.08 (2H,m), 6.92-6.85
(1H,m), 3.80 (3H,s), 3.59 (1H, dd, J=14.8 and 1.4 Hz ), 2.99-2.76
(4H,m), 2.52-2.46 (1H,m) and 1.54 (3H,s).] were obtained.
Examples 26 and 27
[0262] 87
[0263] The product from Ex.1 (200 mg, 0.45 mmol) in acetone (4 ml)
was treated with potassium carbonate (125 mg, 0.90 mmol) and allyl
bromide (58.7 .mu.l, 0.68 mmol). After stirring at reflux for 2.5
hours, a further portion of allyl bromide (39 .mu.l, 0.45 mmol) was
added and stirring at reflux continued for a further 5 hours. The
cooled reaction mixture was evaporated in vacuo and the resulting
colourless oil diluted with water (20 ml), then extracted with
ethyl acetate (3.times.20 ml). The combined organics were dried
(MgSO.sub.4) then evaporated in vacuo, giving a white foam (230 mg)
which was chromatographed on silica, eluting with 0-15% ethyl
acetate in hexanes to give the C-allyl product 26 (106 mg) and the
O-allyl product 27 (31 mg).
[0264] A portion of 26 (30 mg, 0.06 mmol) was purified further by
preparative t.l.c., eluting with 25% ethyl acetate in hexanes to
give 13.7 mg. .sup.1H NMR (360 MHz, CD.sub.3OD), 2.50-2.61 (4H, m),
2.68-2.75 (2H, m), 2.85-2.95 (1H, br), 3.20 (3H, s), 3.36-3.40 (1H,
m), 5.11-5.17 (2H, m), 5.72-5.83 (1H, m), 6.95-7.05 (1H, br),
7.20-7.25 (2H, m), 7.38-7.41 (2H, m), 7.50-7.53 (2H, m).
[0265] O-allyl 27 .sup.1H NMR (360 MHz, CD.sub.3OD), 2.10-2.25 (1H,
m), 2.28-2.40 (1H, m), 2.71 (1H, dd, J=18.3 Hz and J=5.9 Hz),
2.98-3.02 (2H, m), 3.46 (1H, dd, J=16.4 Hz and J=3.6 Hz), 3.71 (3H,
s), 4.32-4.35 (2H, m), 4.91-5.08 (2H, m), 5.67-5.75 (1H, m),
6.94-7.02 (1H, m), 7.03-7.09 (1H, m), 7.14-7.18 (1H, m), 7.46 (2H,
dd, J=6.8 Hz and J=2.0 Hz), 7.54 (2H, dd, J=6.7 Hz and J=1.9
Hz).
Examples 28 and 29
[0266] 88
[0267] The product from Ex.1 (100 mg, 0.23 mmol) in acetone (2 ml)
was treated with potassium carbonate (62 mg, 0.45 mmol) and benzyl
bromide (41 .mu.l, 0.35 mmol) and stirred at reflux for 16 hours.
The cooled reaction mixture was evaporated in vacuo and the
resulting colourless oil diluted with water (20 ml), then extracted
with ethyl acetate (3.times.20 ml). The combined organics were
dried (MgSO.sub.4) then evaporated in vacuo, giving a white foam
(144 mg). This material was purified by preparative t.l.c., eluting
with 25% ethyl acetate in hexanes to give the C-benzyl product 28
(85 mg) .sup.1H NMR (360 MHz, CD.sub.3OD), 2.30-2.40 (1H, m),
2.44-2.55 (1H, m), 2.58-2.62 (2H, m), 2.74-2.90 (2H, m), 3.10-3.14
(1H, m), 3.15 (3H, s), 3.38-3.45 (1H, m), 7.00-7.11 (1H, m),
7.18-7.30 (7H, m), 7.36 (2H, dd, J=7.0 Hz and J=1.9 Hz), 7.49 (2H,
d, J=8.7 Hz) and the O-benzyl product 29. 14 mg. .sup.1H NMR (360
MHz, CD.sub.3OD), 2.02-2.18 (1H, m), 2.22-2.35 (1H, m), 2.73 (1H,
dd, J=18.2 Hz and J=5.7 Hz), 2.90-3.02 (2H, m), 3.44 (1H, dd,
J=13.2 Hz and J=2.9 Hz), 3.73 (3H, s), 4.91 (2H, d, J=4.0 Hz),
6.83-6.96 (2H, m), 7.06-7.17 (6H, m), 7.43 (2H, d, J=8.6 Hz), 7.52
(2H, d, J=8.6 Hz).
Example 30
[0268] 89
[0269] Intermediate 1 (3 g, 9.9 mmol), in tetrahydrofuran (100 ml)
was treated with butyl lithium (6.8 ml, 10.9 mmol, 1.6M solution in
hexanes) at -78.degree. C. for 0.5 hours before adding
chlorotrimethylsilane (1.4 mL, 10.9 mmol), and allowing the mixture
to warm to r.t. for 1 hour. The reaction was then recooled to
-78.degree. C. and treated with further butyl lithium (7.5 ml, 12
mmol, 1.6M solution in hexanes), then stirred at 0.degree. C. for 2
hrs before bubbling through gaseous formaldehyde for 15 mins. The
mixture was allowed to warm to r.t. over 16 hours and was then
diluted with water and the products extracted into ethyl acetate
(100 ml). The organic phase was separated washed with brine (50
ml), dried (MgSO.sub.4) and evaporated to dryness. Product was
purified on silica eluting with hexane-ethyl acetate mixtures, 0.49
g. .sup.1H NMR CDCl.sub.3 7.63-7.59 (2H,m), 7.49-7.39 (2H,m),
7.08-6.86 (2H,m), 6.88 (1H,s) and 6.09 (1H, s).
[0270] The resulting vinyl derivative (0.05 g, 0.16 mmol), and
methoxymethyltrimethylsilylmethylbenzylamine (0.2 ml, 0.64 mmol) in
dichloromethane (2 ml) at 0.degree. C. were treated with
trifluoroacetic acid (0.12 mL, 0.016 mmol, 1.3M in dichloromethane)
and stirred at r.t. for 16 hours. The reaction was diluted with
sodium hydrogen carbonate (sat aq, 3 mL), the products extracted
into ethyl acetate (100 ml), and the organic phase separated,
washed with brine (50 ml), dried (MgSO.sub.4) and evaporated to
dryness. Product was purified on silica eluting with hexane-ethyl
acetate mixtures, 0.006 g. .sup.1H NMR CDCl.sub.3 7.49 (2H,d, J=8.6
Hz), 7.38-7.18 (5H,m), 7.05-6.96 (2H,m), 6.90-6.83 (1H,m), 3.79
(1H, dd, , J=11.5 and 1.0 Hz), 3.63 (2H, s), 3.14-2.89 (3H,m) and
2.58-2.50 (2H, m).
Example 31
[0271] 90
[0272] Intermediate 2 (110 mg, 0.29 mmol) in dichloromethane (37
ml) was treated with bis(tricylcohexylphosphine)benzylidine
ruthenium (IV) dichloride (12 mg, 0.014 mmol) and the mixture
stirred at room temperature for 16 hours, then evaporated to
dryness in vacuo to give 146 mg crude material. This was
chromatographed on silica, eluting with 0-7.5% ethyl acetate in
hexanes, giving product 84 mg. .sup.1H NMR (400 MHz, CDCl.sub.3),
3.10 (2H, d, J=17.3 Hz), 3.61-3.66 (2H, m), 5.65 (2H, s), 6.88-6.93
(1H, m), 7.01-7.06 (2H, m), 7.38-7.41 (2H, m), 7.49-7.52 (2H,
m).
Example 32
[0273] 91
[0274] The product of Ex. 31 (74 mg, 0.21 mmol) in ethyl acetate (7
ml) was treated with 10% palladium on carbon (20 mg) and the
mixture stirred under an atmosphere of hydrogen at 1 atm at room
temperature for 19 hours. The catalyst was filtered off through
Hyflo.TM. and the solvent removed in vacuo to give 79 mg crude
product. This was purified by preparative t.l.c., eluting with 10%
ethyl acetate in hexanes to provide the pure product .sup.1H NMR
(360 MHz, CDCl.sub.3), 1.73-1.82 (2H, m), 2.08-2.17 (2H, m),
2.24-2.32 (2H, m), 2.90-2.94 (2H, m), 6.75-6.81 (1H, m), 6.95-7.04
(2H, m), 7.35 (4H, s).
Example 33
[0275] 92
[0276] The cyclopentene from Ex. 31 (104 mg, 0.29 mmol) in
tetrahydrofuran (2 ml) at 0.degree. C. was treated with
borane-tetrahydrofuran complex (1.0 ml, 1.0M solution in
tetrahydrofuran, 1.0 mmol) and the mixture was stirred for 1 hour,
warming to room temperature. A solution of hydrogen peroxide (27%
w/w, 3 ml) in sodium hydroxide (4M, 3 ml) was added and stirring at
room temperature continued for 1 hour. The reaction mixture was
extracted with ethyl acetate (2.times.25 ml) and the combined
organics were washed with brine (sat., 30 ml), dried (MgSO.sub.4)
and evaporated in vacuo to give 116 mg crude product. This was
chromatographed on silica, eluting with 30% ethyl acetate in
hexanes to give product. 78 mg.
[0277] .sup.1H NMR (400 MHz, CDCl.sub.3), 1.75-1.84 (1H, m),
2.37-2.49 (2H, m), 2.51-2.62 (1H, m), 2.88-2.96 (1H, m), 3.22-3.30
(1H, m), 4.72-4.80 (1H, m), 6.74-6.82 (1H, m), 6.98-7.02 (2H, m),
7.30-7.37 (4H, m).
Example 34
[0278] 93
[0279] Intermediate 3 (750 mg, 1.89 mmol) in dichloromethane (200
ml) was treated with bis(tricylcohexylphosphine)benzylidine
ruthenium(IV) dichloride (78 mg, 0.095 mmol) and the mixture
stirred at room temperature for 16 hours. Evaporation to dryness in
vacuo gave 750 mg material which was chromatographed on silica,
eluting with 5-7.5% ethyl acetate in hexanes, giving product 539
mg. .sup.1H NMR (360 MHz, CDCl.sub.3), 1.82-1.92 (1H, br),
2.20-2.35 (2H, m), 2.80-2.92 (1H, m), 2.94-2.98 (2H, br), 5.50-5.56
(1H, m), 5.64-5.670 (1H, m), 6.75-6.88 (1H, m), 6.95-7.10 (2H, m),
7.39 (4H, s).
Example 35
[0280] 94
[0281] The cyclohexene from Example 34 (52.1 mg, 0.14 mmol) in
ethyl acetate (5 ml) was treated with 10% palladium on carbon (15
mg) and the mixture shaken under an atmosphere of hydrogen at 45
psi for 1 hour. Catalyst was removed by filtration through
Hyflo.TM. and the filtrate evaporated to dryness in vacuo to give
47 mg crude material. This was purified by preparative t.l.c.,
eluting with 10% ethyl acetate in hexanes to give product. 43 mg.
.sup.1H NMR (400 MHz, CDCl.sub.3), 1.10-1.25 (2H, m), 1.26-1.40
(1H, m), 1.58-1.64 (1H, m), 1.76-1.82 (2H, m), 2.04-2.12 (2H, m),
2.65-2.80 (2H, br), 6.81-6.88 (1H, m), 7.01-7.11 (2H, m), 7.36 (4H,
s).
Example 36
[0282] 95
[0283] To a solution of Intermediate 1 (0.41 g, 1.36 mmol) in DMF
(4 ml) was added sodium hydride (60% suspension in oil, 0.12 g, 3.0
mmol). After the effervescence had subsided 2-bromoethyl ether (0.2
ml, 1.59 mmol) was added and the solution was stirred at room
temperature for 1 h. Water (20 ml) and ethyl acetate (20 ml) were
added and the organic phase was washed further with water (four
times) and saturated brine. After drying (MgSO.sub.4) and
evaporating to dryness, the residue, dissolved in dichloromethane,
was applied to a column containing silica gel. The product was
eluted with 10% ethyl acetate in isohexane to give an oil which
crystallised on treatment with diethyl ether to give the desired
product (0.15 g). .sup.1H NMR (360 MHz, CDCl.sub.3) .delta.
2.50(2H, m), 2.59(2H, broad m), 3.32(2H, t J 12 Hz),4.02(2H, dt J
12 Hz and 3 Hz), 6.89(1H, m), 7.10(2H,m), 7.38(4H, m).
Example 37
[0284] 96
[0285] The trans cyclohexanol from Ex. 22(a) (2.7 g, 6.9 mmol) and
triethylamine (1.45 mL, 10.3 mmol) in dichloromethane (50 mL) were
treated with methane sulphonyl chloride (0.645 mL, 8.9 mmol) at
-30.degree. C. After 30 mins the mixture was washed with water (20
mL), 10% aqueous citric acid (20 mL) and saturated aqueous sodium
hydrogen carbonate (50 mL), dried (MgSO.sub.4) and evaporated to
dryness. The solid was triturated with ether to give the mesylate
(2.6 g) .sup.1H NMR (CDCl.sub.3) 7.40-7.37 (4H,m), 7.12-7.07
(2H,m), 6.92-6.83 (1H,m), 4.78-4.65 (1H, m), 2.96 (3H, s),
2.88-2.52 (2H, m), 2.29-2.21 (4H, m) and 1.59-1.47 (2H, m).
Example 38
[0286] 97
[0287] The mesylate from Ex. 37 (1.5 g, 3.2 mmol) in DMF (5 mL) was
treated with sodium azide (315 mg, 4.8 mmol) and heated to
90.degree. C. for 6 hrs. The mixture was treated with water (80
mL), and extracted with diethyl ether (3.times.50 mL), dried
(MgSO.sub.4) and evaporated to dryness. The solid was triturated
with ether to give the azide (1.4 g) .sup.1H NMR (CDCl.sub.3)
7.40-7.34 (4H,m), 7.12-7.03 (2H,m), 6.90-6.83 (1H,m), 3.78-3.76
(1H, m), 2.62-2.41 (4H, m), 1.97-1.91 (2H, m) and 1.51-1.41 (2H,
m).
Example 39
[0288] 98
[0289] The azide from Ex. 38 (1 g, 2.55 mmol), dissolved in
tetrahydrofuran (10 mL) and water (1 mL), was treated with
triphenylphosphine (740 mg, 2.8 mmol) at room temperature for 15
mins and then water (5 mL) was added and the mixture was heated at
reflux for 4 hrs. The mixture was allowed to cool to r.t. and then
passed through SCX Varian Bond Elut.TM. cartridge. The basic
fraction was evaporated and a portion was purified by preparative
t.l.c. to give the primary amine. .sup.1H NMR (CDCl.sub.3) 7.35
(4H,s), 7.12-7.01 (2H,m), 6.88-6.81 (1H,m), 3.13-3.11 (1H, m),
2.64-2.44 (4H, m), 1.78-1.68 (2H, m) and 1.52-1.39 (2H, m). MS MH+
386(388)
Example 40
[0290] 99
[0291] n-Butyllithium (1.6M solution in hexanes, 15.6 mL) was added
slowly to a stirred, cooled (0.degree. C.) suspension of methyl
triphenylphosphonium bromide (9.26 g, 26.0 mmol) in tetrahydrofuran
(100 mL) and the mixture was stirred at room temperature for 3 h.
The mixture was cooled to 0.degree. C. and ketone from Ex. 2 (4 g,
10.4 mmol) in tetrahydrofuran (30 mL) was added. The mixture was
stirred at room temperature for 1 h. then under reflux for 3 h. The
mixture was cooled, poured into water and extracted with ethyl
acetate. The combined organic fractions were dried (MgSO.sub.4) and
the solvent was evaporated under reduced pressure. The residue was
purified by flash column chromatography on silica gel, eluting with
isohexane:EtOAc (20:80), to give the desired product as a white
solid (2.63 g, 66%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.38
(4H, s), 7.16-7.11 (1H, m), 7.09-7.03 (1H, m), 6.91-6.84 (1H, m),
4.68-4.67 (2H, m), 2.81 (2H, br m), 2.41-2.37 (2H, m), 2.20-2.13
(2H, m), and 2.00-1.93 (2H, m).
Example 41
[0292] 100
[0293] Prepared by the procedures of examples 1 and 2 using
Intermediate 4 to give the product as a solid. (0.3 g) .sup.1H NMR
(360 MHz, CDCl.sub.3) .delta. 7.71-7.69 (2H, d, J=7.5 Hz),
6.62-6.60 (2H, d, J=7.4 Hz), 7.22-7.11 (2H, m), 6.95-6.88 (1H, m),
3.02-2.99 (2H, m), 2.63-2.54 (4H, m) and 2.25-2.16 (2H, m).
Example 42
[0294] 101
[0295] Intermediate 5 (0.54 g, 1.71 mM) was dissolved in
tetrahydrofuran (20 ml) and treated with 1,5-dibromopentane (231
.mu.l, 1.71 mM) and .sup.tBuOK in tetrahydrofuran (3.42 mL, 1.0M
solution). The reaction was left stirring for 18 hours, then
diluted with water (100 mL) and the products extracted into ethyl
acetate (3.times.500 mL). The combined organic phases were dried
(MgSO.sub.4) and evaporated to dryness. The product was purified on
SiO.sub.2 eluting with 2-8% ethyl acetate in isohexane to obtain
pure product, 0.18 g. .sup.1H NMR (360 MHz, CDCl.sub.3) .delta.
7.49-7.47 (1H, m), 7.42 (1H, d, J=2 Hz), 7.27-7.25 (1H, m),
7.13-7.04 (2H, m), 6.90-6.83 (1H, m), 2.90-2.60 (2H, m), 2.12-2.04
(2H, m), 1.83-1.80 (2H, m), 1.64-1.56 (1H, m) and 1.40-1.15 (3H
m).
Example 43
[0296] 102
[0297] Prepared as for Example 42, using Intermediate 6.
[0298] .sup.1H NMR (360 MHz, CDCl.sub.3) .delta. 7.38-7.27 (6H, m),
7.14 (1H, t, J=1.3 and 7.8 Hz), 6.90-6.83 (1H, m), 2.80-2.60
(2H,m), 2.14-2.04 (2H, m), 1.80-1.77 (2H, m), 1.61-1.55 (1H, m) and
1.38-1.15 (3H, m).
Example 44
[0299] 103
[0300] Borane-tetrahydrofuran complex (1M in tetrahydrofuran, 2 mL,
2 mmol) was added to a solution of the olefin from Example 40 (383
mg, 1 mmol) in tetrahydrofuran (15 mL) and the mixture was stirred
at room temperature for 3 h. Aqueous sodium hydroxide (4M, 2.5 mL)
and aqueous hydrogen peroxide (27%, 2.5 mL) were added and the
mixture was stirred at room temperature for 2 h. Water was added
and the mixture was extracted with ethyl acetate. The combined
organic fractions were dried (MgSO.sub.4) and the solvent was
evaporated under reduced pressure to give the desired product as a
white foam (350 mg, 88%) as a 1:1 mixture of cis and trans isomers.
.sup.1H NMR (360 MHz, CDCl.sub.3) .delta. 7.39-7.31 (8H, m),
7.11-7.01 (4H, m), 6.88-6.81 (2H, m), 3.73 (2H, d, J=7.5 Hz), 3.35
(2H, d, J=6.2 Hz), 2.42-2.30 (4H, m), 2.23-2.12 (2H, m), 1.91-1.85
(4H, m), 1.77-1.67 (4H, m), 1.51-1.45 (2H, m), 1.02-0.89 (2H,
m).
Example 45
[0301] 104
[0302] Methanesulfonyl chloride (77 .mu.L, 0.998 mm 1) was added to
a solution of the cis and trans alcohol mixture from Example 44
(200 mg, 0.499 mmol) and triethylamine (208 .mu.L, 1.50 mmol) in
dichloromethane (10 mL) and the mixture was stirred at room
temperature for 24 h. The solvent was evaporated under reduced
pressure and the residue was dissolved in ethyl acetate. The
mixture was washed with aqueous citric acid (10%), aqueous sodium
hydroxide (1M), dried (MgSO.sub.4) and the solvent was evaporated
under reduced pressure. The residue was purified by flash column
chromatography on silica gel, eluting with isohexane:EtOAc (20:80),
to give the product as a white foam (105 mg, 44%). .sup.1H NMR (400
MHz, DMSO-d6) .delta. 7.62-7.60 (2H, m), 7.35-7.33 (3H, m),
7.21-7.09 (2H, m), 4.24 (2H, d, J=7.6 Hz), 3.21 (3H, s), 2.51-2.44
(2H, m), 2.27-2.18 (2H, m), 1.98-1.89 (1H, m), 1.81-1.73 (2H, m),
1.46-1.35 (2H, m).
Example 46
[0303] 105
[0304] Morpholine (91 .mu.L, 1.04 mmol) was added to a solution of
the cis-mesylate from Example 45 (50 mg, 0.104 mmol) in
acetonitrile (2 mL) and the mixture was stirred at 80.degree. C.
for 3 days. The mixture was cooled and the solvent was evaporated
under reduced pressure and the residue was dissolved in ethyl
acetate. The mixture was washed with aqueous sodium hydroxide (1M),
dried (MgSO.sub.4) and the solvent was evaporated under reduced
pressure. The residue was purified by flash column chromatography
on silica gel, eluting with isohexane:EtOAc (1:1), to give the
product as a white foam (30 mg, 61%). .sup.1H NMR (360 MHz,
CD.sub.3OD) .delta. 7.51-7.48 (2H, m), 7.44-7.38 (2H, m), 7.19-7.09
(2H, m), 7.00-6.93 (1H, m), 3.70-3.67 (4H, m), 2.56-2.24 (10H, m),
1.85-1.81 (3H, m), 1.50-1.42 (2H, m).
Example 47
[0305] 106
[0306] Ethyl (diethoxyphosphinyl)acetate (5.16 mL, 26 mmol) was
added dropwise to a slurry of sodium hydride (60% dispersion in
mineral oil, 988 mg, 24.7 mmol) in tetrahydrofuran (60 mL) and the
mixture was stirred at room temperature for 1 h. The ketone from
Example 2 (5 g, 13 mmol) in tetrahydrofuran (50 mL) was added
dropwise over 20 min. and the mixture was stirred at room
temperature for 18 h. Water was added and the mixture was extracted
with ethyl acetate. The combined organic fractions were washed with
water, dried (MgSO.sub.4) and the solvent was evaporated under
reduced pressure. The residue was purified by flash column
chromatography on silica gel, eluting with isohexane:EtOAc (85:15),
to give the product as a white solid (5.2 g, 88%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.41-7.36 (4H, m), 7.18-7.13 (1H, m),
7.11-7.05 (1H, m), 6.93-6.86 (1H, m), 5.64 (1H, s), 4.14-4.10 (2H,
m), 3.99-3.96 (1H, m), 2.91-2.80 (2H, m), 2.42-2.38 (1H, m),
2.31-2.04 (3H, m), 1.89-1.78 (1H, m), 1.28-1.24 (3H, m).
Example 48
[0307] 107
[0308] Sodium borohydride (313 mg, 8.23 mmol) was added to a
mixture of the unsaturated ester from Example 47 (3.74 g, 8.23
mmol) and nickel (II) chloride (2.67 g, 20.6 mmol) in ethanol (100
mL). The mixture was stirred at room temperature for 20 min., then
water (100 mL) was added. The mixture was filtered through
Hyflo.TM. , washing with ethanol and ethyl acetate. The solvent was
evaporated under reduced pressure and the residue was partitioned
between ethyl acetate and water. The organic layer was collected,
dried (MgSO.sub.4) and the solvent was evaporated under reduced
pressure. The residue was purified by flash column chromatography
on silica gel, eluting with isohexane:EtOAc (85:15), to give the
faster running cis-isomer, as an oil (1.36 g, 36%), .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.37-7.30 (4H, m), 7.09-7.00 (2H, m),
6.86-6.79 (1H, m), 4.14 (2H, q, J=7.1 Hz), 2.47 (2H, d, J=7.6 Hz),
2.46-2.38 (2H,m), 2.19-2.14 (1H, m), 1.76-1.71 (2H, m), 1.57-1.48
(4H, m), 1.27 (3H, t, J 7.1 Hz);
[0309] and the slower running trans-isomer, as an oil (200 mg,
5.3%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.39-7.34 (4H, m),
7.10-7.03 (2H, m), 6.88-6.82 (1H, m), 4.08 (2H, q, J=7.1 Hz),
2.98-2.85 (1H, m), 2.67-2.53 (1H, m), 2.22-2.11 (2H, m), 2.06 (2H,
d, J=6.9 Hz), 2.01-1.85 (3H, m), 1.20 (3H, t, J=7.1 Hz), 1.01-0.90
(2H, m).
Example 49
[0310] 108
[0311] Lithium hydroxide (132 mg, 5.5 mmol) was added to a solution
of the unsaturated ester from Example 47 (500 mg, 1.1 mmol) in
ethanol (40 mL). The mixture was degassed and stirred at room
temperature under nitrogen gas for 24 h. The mixture was poured
into aqueous hydrochloric acid (1M) and extracted with ethyl
acetate. The organic extract was dried (MgSO.sub.4) and the solvent
was evaporated under reduced pressure to give the product as a
white solid (430 mg, 92%). .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 7.53-7.51 (2H, m), 7.45-7.39 (2H, m), 7.27-7.18 (2H, m),
7.07-7.00 (1H, m), 5.67 (1H, s), 3.97-3.93 (1H, m), 2.96-2.90 (2H,
m), 2.47-2.43 (1H, m), 2.26-2.09 (3H, m), 1.84-1.77 (1H, m).
Example 50
[0312] 109
[0313] Lithium hydroxide (350 mg, 14.57 mmol) was added to a
solution of the cis-ester from Example 48, (1.33 g, 2.91 mmol) in
ethanol (40 mL). The mixture was degassed and stirred at room
temperature under nitrogen gas for 5 h. The mixture was poured into
aqueous hydrochloric acid (1M) and extracted with ethyl acetate.
The organic extract was dried (MgSO.sub.4) and the solvent was
evaporated under reduced pressure to give a white solid which was
then crystallized from IPA to give the product as a white solid
(950 mg, 76%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.51-7.49
(2H, m), 7.40-7.37 (2H, m), 7.19-7.10 (2H, m), 7.00-6.94 (1H, m),
2.51-2.35 (6H, m), 2.13-2.10 (1H, m), 1.78-1.74 (2H, m), 1.57-1.50
(2H, m).
Example 51
[0314] 110
[0315] The acid from Example 50 (50 mg, 0.117 mmol), morpholine (30
.mu.L, 0.351 mmol), 1-hydroxybenzotriazole (24 mg, 0.176 mmol) and
triethylamine (65 .mu.L, 0.468 mmol) was stirred in tetrahydrofuran
at room temperature under nitrogen gas for 10min.
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimi- de hydrochloride (45
mg, 0.234 mmol) was added to the mixture and stirred for 24 h. The
mixture was poured into aqueous sodium hydroxide (1M) and extracted
with ethyl acetate. The organic extract was dried (MgSO.sub.4) and
the solvent was evaporated under reduced pressure. The residue was
purified by flash column chromatography on silica gel, eluting with
5 to 10% methanol in dichloromethane, to give the product as a
white foam (50 mg, 86%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
7.50 (2H, d, J 8.6 Hz), 7.37 (2H, d, J 8.6 Hz), 7.19-7.09 (2H, m),
7.00-6.93 (1H, m), 3.69-3.63 (4H, m), 3.59-3.56 (4H, m), 2.55 (2H,
d, J 7.4 Hz), 2.47-2.39 (4H, m), 2.16-2.07 (1H, m), 1.78-1.74 (2H,
m), 1.58-1.51 (2H, m). m/z (ES+) (M+1) 498+500.
Examples 52-63
[0316] The following compounds were prepared according to the
method of Example 51, using the appropriate amine in place of
morpholine.
7 111 m/z (ES+) Ex. --NR.sub.2 Formula M.W. (M + 1) 52 112
C.sub.25H.sub.29ClF.sub.2N.sub.2O.sub.3S 510 512 511 513 53 113
C.sub.30 H.sub.31ClF.sub.2N.sub.2O.sub.3S 572 574 573 575 54 114
C.sub.25H.sub.28ClF.sub.2NO.sub.4S 511 513 512 514 55 115
C.sub.27H.sub.27ClF.sub.2N.sub.2O.sub.3S 532 534 533 535 56 116
C.sub.26H.sub.28ClF.sub.2N.sub.3O.sub.3S 535 537 536 538 57 117
C.sub.28H.sub.32ClF.sub.2NO.sub.5S 567 569 568 570 58 118
C.sub.28H.sub.32ClF.sub.2NO.sub.5S 567 569 568 570 59 119
C.sub.28H.sub.32ClF.sub.2NO.sub.5S 567 569 568 570 60 120
C.sub.28H.sub.32ClF.sub.2NO.sub.5S 567 569 568 570 61 121
C.sub.25H.sub.28ClF.sub.2NO.sub.3S 495 497 496 498 62 122
C.sub.29H.sub.34ClF.sub.2NO.sub.5S 581 583 582 584 63 123
C.sub.29H.sub.34ClF.sub.2NO.sub.5S 581 583 582 584
Example 64
[0317] 124
[0318] Lithium hydroxide (20 mg, 0.833 mmol) was added to a
solution of Example 57 (95 mg, 0.167 mmol) in ethanol (12 ml) and
water (4 ml). The mixture was degassed and stirred at room
temperature under nitrogen gas for 18 h. The mixture was poured
into aqueous hydrochloric acid (1M) and extracted with ethyl
acetate. The organic extract was dried MgSO.sub.4) and the solvent
was evaporated under reduced pressure to give the product as a
white solid (75 mg, 83%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
7.50 (2H, d, J 8.6 Hz), 7.38 (2H, d, J 8.6 Hz), 7.19-7.10 (2H, m),
7.00-6.93 (1H, m), 4.37-4.32 (1H, m), 3.98-3.90 (1H, m), 3.26-3.18
(1H, m), 2.90-2.82 (1H, m), 2.64-2.38 (7H, m), 2.10-2.06 (1H, m),
2.00-1.91 (2H, m), 1.78-1.49 (6H, m). m/z (ES+) (M+1) 540+542.
Examples 65-69
[0319] The following compounds were prepared according to the
method of Example 64 using the appropriate esters from Examples
58-63.
8 125 Ex. --NR.sub.2 Formula M.W m/z (ES+) (M + 1) 65 126
C.sub.26H.sub.28ClF.sub.2NO.sub.5S 539 541 540 542 66 127
C.sub.28H.sub.32ClF.sub.2NO.sub.5S 539 541 540 542 67 128
C.sub.28H.sub.32ClF.sub.2NO.sub.5S 539 541 540 542 68 129
C.sub.27H.sub.30ClF.sub.2NO.sub.5S 553 555 554 556 69 130
C.sub.27H.sub.30ClF.sub.2NO.sub.5S 553 555 554 556
Example 70
[0320] 131
[0321] The acid from Exampl 49 (30 mg, 0.0703 mmol) was coupled
with morpholine (18.4 .mu.L, 0.211 mmol) following the procedure of
Example 51 to give the product as a white foam (30 mg, 86%).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.53-7.51 (2H, d, m),
7.45-7.41 (2H, d, m), 7.26-7.19 (2H, m), 7.07-7.00 (1H, m), 5.88
(1H, s), 3.64-3.58 (6H, m), 3.51-3.49 (2H, m), 2.98-2.92 (3H, m),
2.48-2.44 (1H, m), 2.23-2.06 (3H, m), 1.87-1.80 (1H, m).
Example 71
[0322] 132
[0323] Prepared from the acid from Example 49 and
4-hydroxypiperidine according to the method of Example 51. .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 7.54-7.51 (2H, m), 7.43-7.41 (2H,
m), 7.25-7.19 (2H, m), 7.07-7.00 (1H, m), 5.88 (1H, s), 4.12-4.02
(1H, m), 3.86-3.76 (2H, m), 3.26-3.12 (2H, m), 3.00-2.83 (3H, m),
2.48-2.44 (1H, m), 2.23-2.05 (3H, m), 1.87-1.78 (3H, m), 1.43-1.40
(2H, m).
Example 72
[0324] 133
[0325] Prepared from the acid from Example 49 (30 mg, 0.0703 mmol)
and 1-methylpiperazine (23 .mu.L, 0.211 mmol) by the method of
Example 51 to give the product as a white foam (25 mg, 70%).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.53-7.51 (2H, m),
7.44-7.41 (2H, m), 7.25-7.19 (2H, m), 7.07-7.00 (1H, m), 5.88 (1H,
s), 3.66-3.60 (2H, m), 3.53-3.48 (2H, m), 2.93-2.89 (3H, m),
2.48-2.39 (5H, m), 2.30 (3H, s), 2.23-2.08 (3H, m), 1.86-1.80 (1H,
m). m/z (ES+) (M+1) 509+511.
Examples 73-75
[0326] The following compounds were prepared according to the
method of Example 70, using the appropriate amine in place of
morpholine.
9 134 m/z (ES+) Ex. --NR.sub.2 Formula M.W. (M + 1) 73 135
C.sub.30H.sub.29ClF.sub.2N.sub.2O.sub.3S 570 572 571 573 74 136
C.sub.27H.sub.25ClF.sub.2N.sub.2O.sub.3S 530 532 531 533 75 137
C.sub.26H.sub.26ClF.sub.2N.sub.3O.sub.3S 533 535 534 536
Examples 76-86
[0327] The following were prepared as mixtures of cis and trans
isomers by the procedure outlined for Examples 5-16:
10 138 Example No --NR.sup.2 MS(MH+) 76 139 549 77 140 599 78 141
561 79 142 567 80 143 561 81 144 429 82 145 476 83 146 476 84 147
476 85 148 471 86 149 499
[0328] In the case of Examples 81-86, the cis and trans isomers
were separated by flash chromatography using ethyl acetate/methanol
mixtures.
Example 87
[0329] 150
[0330] The cis alcohol from Example 22(b) (100 mg, 0.26 mmol) in
dry THF was treated with NaH (60% dispersion, 16 mg, 0.39 mmol) and
methyl iodide (0.2 ml, excess) and heated in a sealed tube at
70.degree. C. for 18 h. The reaction was quenched with sat. aq.
ammonium chloride and the products extracted with ethyl acetate
(3.times.20 ml). The organics were washed with brine, dried
(MgSO.sub.4), filtered and evaporated. The crude oil was purified
by flash chromatography eluting with 2:1 .sup.ihexane/ethyl acetate
to give 35 mg of product.
[0331] .sup.1H NMR .delta. (ppm) (CDCl.sub.3): 1.26 (3 H, t, J=7.0
Hz), 1.99 (2 H, s), 2.04 (1 H, s), 2.48 (3 H, d, J=0.7 Hz),
3.26-3.32 (3 H, m), 6.82-6.90 (1 H, m), 7.01-7.13 (2 H, m), 7.37 (4
H, s).
Example 88
[0332] 151
[0333] The cis alcohol from Example 22(b) (100 mg, 0.26 mmol) in
dry DCM (5 ml) under nitrogen was treated with triethylamine (53
mg, 0.52 mmol) and acetyl chloride (41 mg, 0.52 mmol) using
catalytic DMAP. The reaction was stirred at room temperature for 12
h. Reaction was diluted with DCM, washed with water, brine, dried
(MgSO.sub.4), filtered and evaporated. The crude oil was purified
by flash chromatography eluting with 1:1 .sup.ihexane/ethyl
acetate) to give 45 mg of product.
[0334] .sup.1H NMR .delta. (ppm) (CDCl.sub.3): 1.24 (1 H, d, J=6.3
Hz), 1.42 (2 H, t, J=14.7 Hz), 1.97 (1 H, s), 2.03 (1 H, d, J=10.9
Hz), 2.11 (3 H, s), 2.53 (3H, d, J=11.6 Hz), 4.88-4.91 (1 H, m),
6.82-6.89 (1 H, m), 7.03-7.12 (2 H, m), 7.35-7.37 (4H, m)
Example 89
[0335] 152
[0336] The ketone from Example 2 (200 mg, 0.52 mmol) in dry toluene
(7 ml) was treated with ethanediol (0.1 ml, 1.56 mmol),
p-toluenesulfonic acid (10 mg) and 4A molecular sieves (30 mg). The
mixture was heated at reflux for 18 h. The reaction was neutralised
with solid NaHCO.sub.3, filtered and evaporated. The residue was
dissolved in DCM, washed with aqueous NaHCO.sub.3, dried
(MgSO.sub.4), filtered and evaporated. The crude oil was purified
by flash chromatography (SiO.sub.2, 2:1 .sup.ihexane/ethyl acetate
to 1:1) to give the product (65 mg).
[0337] .sup.1H NMR .delta. (ppm) (CDCl.sub.3): 1.24 (1 H, d, J=6.3
Hz), 1.42 (2 H, t, J=14.7 Hz), 1.97 (1 H, s), 2.03 (1 H, d, J=10.9
Hz), 2.11 (3 H, s), 2.53 (3H, d, J=11.6 Hz), 4.88-4.91 (1 H, m),
6.82-4.89 (1 H, m), 7.03-7.12 (2 H, m), 7.35-7.37 (4H, m)
Example 90
[0338] 153
[0339] The cis amino-ester from Example 13 (100 mg, 0.23 mmol)
(obtained by flash chromatography of the cis/trans mixture using
ethyl acetate/methanol) was treated with a 2.0M solution of ammonia
in methanol (3 ml). The solution was heated in a sealed tube for 18
hours, the reaction concentrated and the residue purified by flash
chromatography (SiO.sub.2, ethyl acetate to 3:1 ethyl
acetate/methanol to give 70 mg. product amide. .sup.1H NMR .delta.
(ppm) (CDCl.sub.3): 1.41-1.49 (2 H, m), 1.79-1.83 (2 H, m),
2.42-2.58 (4 H, m), 2.76 (1 H, t, J=3.1 Hz), 3.28 (2 H, s),
5.43-5.47 (1 H, m), 6.81-6.88 (1 H, m), 6.98-7.11 (2 H, m),
7.32-7.38 (4 H, m).
Example 91
[0340] 154
[0341] Prepared from Intermediate 7 (2.10 g, 5.12 mmol), using the
method of Example 34. Yield 2.00 g. .sup.1H NMR (400 MHz,
CDCl.sub.3), 1.28-1.35 (1H, m), 1.81-1.87 (1H, m), 2.14-2.18 (2H,
m), 2.30-2.37 (1H, m), 2.86-2.90 (1H, m), 3.04-3.07 (1H, m),
3.30-3.36 (1H, m), 5.63-5.68 (1H, m), 5.79-5.84 (1H, m), 6.81-6.87
(1H, m), 6.92-7.04 (2H, m), 7.37 (4H, s).
Example 92
[0342] 155
[0343] The product of Example 91 (57.8 mg, 0.151 mmol) in ethyl
acetate (5 ml) was hydrogenated by the method of Example 35 to give
the cycloheptane (46 mg). .sup.1H NMR (400 MHz, CDCl.sub.3),
1.38-1.46 (4H, m), 1.51-1.60 (2H, m), 1.84-1.92 (2H, m), 2.32-2.39
(2H, m), 2.67-2.72 (2H, m), 6.85-6.91 (1H, m), 6.98-7.06 (2H, m),
7.33-7.38 (4H, m).
Example 93
[0344] 156
[0345] The cyclohexene from Example 34 (352 mg, 0.957 mmol) in
tetrahydrofuran (6 ml) was treated with borane-tetrahydrofuran
complex (1M in tetrahydrofuran, 4.8 ml, 4.78 mmol) at 0.degree. C.
Hydrogen peroxide (27% w/w in water, 10 ml) was mixed with sodium
hydroxide solution (4N, 10 ml), then added slowly to the reaction
and stirring continued for a further hour at room temperature. The
reaction mixture was extracted with ethyl acetate (2.times.100 ml),
and the combined organics washed with brine (sat., 100 ml), dried
(MgSO.sub.4) and evaporated in vacuo to giv 415 mg mixture of 4
isomers. The isomers were separated by chromatography on silica,
eluting with 30-50% ethyl acetate in hexanes. Fractions rich in
3-hydroxy isomers (198 mg) were purified by preparative t.l.c,
eluting with 30% ethyl acetate in hexanes followed by two
crystallisations from diethyl ether in hexanes to give the
cis-3-alcohol product. 1.9 mg. .sup.1H NMR (400 MHz, CDCl.sub.3),
1.23-1.39 (2H, m), 1.89-2.09 (4H, m), 2.55-3.10 (2H, br), 3.48-3.54
(1H, m), 6.82-6.89 (1H, m), 7.02-7.25 (2H, m), 7.35-7.40 (4H,
m).
Example 94
[0346] 157
[0347] A mixture of cis-3- and cis-4-alcohols (2.52 g, 6.53 mmol)
(from Example 93) in dichloromethane (80 ml) at 0.degree. C. was
treated with triethylamine (1.36 ml, 9.79 mmol) then methansulfonyl
chloride (603 .mu.l, 7.83 mmol). The mixture was stirred for 3.5
hours, slowly warming to room temperature, then washed with water
(200 ml), citric acid (10% aq., 200 ml) and sodium hydrogen
carbonate (sat. aq., 200 ml), dried (MgSO.sub.4) and evaporated in
vacuo to give 2.97 g mixture of 2 isomers. Isomers were separated
by chromatography on silica, eluting with 100% dichloromethane
giving cis-3-mesylate (182 mg), cis-4 mesylate (185 mg) and mixed
fractions (2.19 g).
[0348] Cis-3-mesylate (52 mg) was purified by preparative t.l.c.,
eluting with 100% dichloromethane to give product. 48 mg. .sup.1H
NMR (400 MHz, CDCl.sub.3), 1.24-1.31 (1H, m), 1.63 (1H, dq, J=4.4
Hz and J=12.4 Hz), 1.96-2.20 (3H, br), 2.31 (1H, dt, J=2.4 Hz and
J=12.4 Hz), 2.50-2.90 (1H, br), 3.01 (3H, s), 3.10-3.25 (1H, br),
4.40-4.54 (1H, m), 6.88-6.93 (1H, m), 7.07-7.11 (2H, m), 7.34-7.41
(4H, m).
Example 95
[0349] 158
[0350] The cis-4-mesylate fraction from Example 94 (46 mg) was
purified by preparative t.l.c., eluting with 100% dichloromethane
to give product. 31 mg. .sup.1H NMR (400 MHz, CDCl.sub.3),
1.40-1.10 (2H, br), 2.15-2.25 (2H, br), 2.50-2.60 (4H, br), 3.08
(3H, s), 4.89 (1H, t, J=2.8 Hz), 6.80-6.90 (1H, m), 7.06-7.10 (2H,
m), 7.33-7.40 (4H, m).
Example 96
[0351] 159
[0352] Cis-3-mesylate from Example 94 (66 mg, 0.142 mmol) in
N,N-dimethylformamide (2 ml) was treated with sodium azide (14 mg,
0.213 mmol) and the mixture heated to 95.degree. C. for 16 hours. A
further portion of sodium azide (9 mg, 0.142 mmol) was added and
stirring at 95.degree. C. continued for a further 24 hours. The
reaction was diluted with water (40 ml), extracted with 20% ethyl
acetate in diethyl ether (3.times.60 ml) and the combined organics
washed with brine (sat., 100 ml), dried (MgSO.sub.4) and evaporated
in vacuo to give 46 mg crude product. This was purified by
chromatography on silica, eluting with 15% ethyl acetate in hexanes
to give 12 mg product which was further purified by preparative
t.l.c., eluting with 15% ethyl acetate in hexanes to give pure
product. 7.2 mg. .sup.1H NMR (400 MHz, CDCl.sub.3), 1.62-1.71 (2H,
m), 1.82-1.95 (2H, m), 2.30-2.50 (2H, br), 2.65-2.82 (2H, br),
4.18-4.23 (1H, m), 6.79-6.86 (1H, m), 6.70-7.04 (2H, m), 2.28-2.38
(4H, m).
Example 97
[0353] 160
[0354] A mixture of cis-3- and trans-3-alcohols (650 mg, 1.68 mmol,
isomer ratio 3:1) (from Example 93) in dichloromethane (20 ml) was
treated with acetic anhydride (159 .mu.l, 1.68 mmol) and
dimethylaminopyridine (21 mg, 0.168 mmol). After 1 hour stirring at
room temperature, the reaction was quenched with water (30 ml),
washed with citric acid (10% aq., 30 ml) then sodium hydrogen
carbonate (sat., aq., 30 ml). The organics were dried (MgSO.sub.4)
and evaporated in vacuo to give 843 mg mixture of isomers.
Separation by chromatography on silica, eluting with 15-20% ethyl
acetate in hexanes, gave the cis-isomer (209 mg). .sup.1H NMR (360
MHz, CDCl.sub.3), 1.20-1.50 (2H, br), 1.90-2.00 (2H, br), 2.05 (3H,
s), 2.05-2.20 (2H, br), 2.50-3.05 (2H, br), 4.54-4.60 (1H, br),
6.82-6.90 (1H, m), 7.02-7.08 (2H, m), 7.33-7.39 (4H, m).
Example 98
[0355] 161
[0356] The trans-acetate fraction from Example 97 (220 mg) was
purified by chromatography on silica, eluting with 100%
dichloromethane, then 20% ethyl acetate in hexanes to give 90 mg
material which was further purified by preparative t.l.c., eluting
with 5% ethyl acetate in dichloromethane to give product. 49 mg.
.sup.1H NMR (400 MHz, CDCl.sub.3), 1.55-1.88 (3H, m), 2.09 (3H, s),
2.28-2.36 (1H, m), 2.49-2.54 (1H, m), 2.58-2.65 (1H, br), 2.92-3.04
(2H, m), 5.40-5.44 (1H, m), 6.79-6.84 (1H, m), 7.01-7.07 (2H, m),
7.31-7.38 (4H, m).
Example 99
[0357] 162
[0358] A degassed solution of trans-3-acetate from Example 98 (44
mg, 0.103 mmol) in methanol/water/tetrahydrofuran (3:1:1, 2 ml) was
treated with lithium hydroxide (12 mg, 0.50 mmol). After 1 hour
stirring at room temperature, a further portion of lithium
hydroxide (12 mg, 0.50 mmol) was added, and after stirring at room
temperature for 16 hours, the reaction was heated to 75.degree. C.
for 4 hours, cooled, diluted with water (10 ml), acidified with
hydrochloric acid (1N, 3 ml), then extracted with ethyl acetate
(3.times.20 ml). The combined organics were washed with brine
(sat., 70 ml), dried (MgSO.sub.4) and evaporated to give 35 mg
crude product. This was purified by preparative t.l.c., eluting
with 30% ethyl acetate in hexanes to give product. 11.3 mg. .sup.1H
NMR (400 MHz, CDCl.sub.3), 1.63-1.84 (4H, m), 2.31-2.36 (1H, br),
2.45-2.57 (2H, br), 2.84-2.92 (1H, br), 4.37-4.45 (1H, br),
6.77-6.84 (1H, m), 6.97-7.05 (2H, m), 7.29-7.38 (4H, m).
Example 100
[0359] 163
[0360] Cis-3-alcohol (Example 93) (49 mg, 0.128 mmol) in
tetrahydrofuran (2 ml) was dripped into a stirring suspension of
sodium hydride (5.6 mg, 60% w/w in mineral oil, 0.140 mmol) in
tetrahydrofuran (1 ml) and the mixture heated to reflux for 2
hours. After cooling to 0.degree. C., bromoethane (38 .mu.l, 0.512
mmol) was added, the mixture stirred at room temperature for 16
hours, then further portions of sodium hydride (11 mg, 60% w/w in
mineral oil, 0.256 mmol) and bromoethane (29 .mu.l, 0.384 mmol)
were added. After stirring at reflux for 24 hours, the reaction was
cooled to room temperature, acidified with hydrochloric acid (2N, 2
ml) and extracted with diethyl ether (3.times.20 ml). The combined
organics were washed with brine (sat., 50 ml), dried (MgSO.sub.4)
and evaporated to give 86 mg crude product. This was purified by
preparative t.l.c., eluting with 30% ethyl acetate in hexanes to
give product. 10 mg. .sup.1H NMR (360 MHz, CDCl.sub.3), 1.15-1.35
(6H, m), 1.87-2.04 (4H, m), 2.50-2.80 (1H, br), 3.06-3.20 (1H, br),
3.42-3.56 (2H, m), 6.84-6.91 (1H, m), 7.02-7.15 (2H, m), 7.39 (4H,
s).
Example 101
[0361] 164
[0362] Prepared by the method of Example 100, substituting allyl
bromide for bromoethane. The crude product was purified by
preparative t.l.c., eluting with 15% ethyl acetate in hexanes to
give product. 23 mg. .sup.1H NMR (360 MHz, CDCl.sub.3), 1.15-1.40
(3H, m), 1.85-2.02 (4H, m), 2.50-3.00 (1H, br), 3.12-3.24 (1H, br),
3.98-4.00 (2H, m), 5.14-5.26 (2H, m), 5.82-5.95 (1H, m), 6.84-6.90
(1H, m), 7.03-7.08 (2H, m), 7.40 (4H, s).
Example 102
[0363] 165
[0364] The amine from Example 39 (50 mg, 0.13 mmol) was dissolved
in dichloromethane (1 mL) and was treated with triethylamine (27
.mu.L, 0.2 mmol) and then acetic anhydride (18 .mu.L, 0.2 mmol) and
the mixture was stirred at r.t. for 24 hrs. The mixture was diluted
with water (2 mL) and separated on a Bond Elut.TM. cartridge before
purifying by preparative t.l.c to give the amide. .sup.1H NMR
(CDCl.sub.3) 7.36 (2H, d, J=8.6 Hz), 7.29 (2H, d, J=9.3 Hz),
7.08-7.03 (2H,m), 6.88-6.83 (1H,m), 5.98-5.96 (1H, m), 4.04-4.01
(1H, m), 2.58-2.50 (2H, m), 2.41-2.34 (2H, m), 2.04 (3H, s),
1.97-1.91 (2H, m) and 1.54-1.46 (2H, m).
Example 103
[0365] 166
[0366] The amine from Example 39 (50 mg, 0.13 mmol) was dissolved
in dichloromethane (1 mL) and was treated with triethylamine (54
.mu.L, 0.4 mmol), benzoic acid (21 mg, 0.17 mmol) and 1-(3
dimethylaminopropyl)-3-et- hylcarbodiimide hydrochloride (32 mg,
0.17 mmol) and the mixture was stirred at r.t. for 24 hrs. The
mixture was diluted with water (2 mL) and separated on a Bond
Elut.TM. cartridge before purifying by preparative t.l.c to give
the amide. .sup.1H NMR (CDCl.sub.3) 7.77-7.72 (2H, m), 7.69-7.45
(3H, m), 7.39 (2H, d, J=11.2 Hz), 7.31 (2H, d, J=11.8 Hz),
7.26-7.03 (2H,m), 6.90-6.83 (1H, m), 6.43-6.40 (1H, m), 4.24-4.20
(1H, m), 2.63-2.58 (2H, m), 2.48-2.41 (2H, m), 2.12-2.07 (2H, m)
and 1.68-1.54 (2H, m).
Examples 104-107
[0367] 167
[0368] Using the method of Example 103, the following were
prepared:
11 Example R MS (MH+) 104 Dimethylaminomethyl 470 (472) 105
2-(piperidin-1-yL)ethyl 525 (527) 106 3-(dimethylamino)propyl 499
(501) 107 (1H-imidazol-5-yl)methyl 493 (495)
Example 108
[0369] 168
[0370] The amine from Example 39 (50 mg, 0.13 mmol) was dissolved
in methanol (1 mL) and was treated with alumina (50 mg) and
furfuraldehyde (2.5 .mu.L, 0.26 mmol) and the mixture was stirred
at r.t. for 16 hrs. Sodium borohydride was then added and the
mixture was stirred for a further 16 hrs. The mixture was separated
on a SCX Varian Bond Elut.TM. cartridge before purifying the basic
fraction by preparative t.l.c to give the product. .sup.1H NMR
(CDCl.sub.3) 7.38-7.32 (4H, m), 7.11-7.00 (2H, m), 6.87-6.80
(1H,m), 6.29 (1H, dd, J=2.8 and 1.6 Hz), 6.13 (1H, d, J=2.8 Hz),
3.76 (2H, s), 2.76-2.73 (1H, m), 2.64-2.56 (2H, m), 2.46-2.38 (2H,
m), 1.82-1.76 (2H, m) and 1.41-1.34 (2H, m); MS MH+ 465(467).
Example 109
[0371] 169
[0372] Prepared as in Example 108, substituting
4(5)-imidazolecarboxaldehy- de for furfural. MS MH+ 465(467).
Example 110
[0373] 170
[0374] The amine from Example 39 (50 mg, 0.13 mmol) was dissolved
in dichloroethane (1 mL) and treated with N-benzoyl-4-piperidone
(53 mg, 0.26 mmol) and sodium triacetoxyborohydride (55 mg, 0.26
mmol) and the mixture was stirred at r.t. for 16 hrs. The mixture
was diluted with saturated aqueous sodium bicarbonate (1 mL) and
was separated on a Bond Elut.TM. cartridge before passing through a
SCX Bond Elut.TM. cartridge. The basic fraction was purified by
preparative t.l.c to give the amide. .sup.1H NMR (CDCl.sub.3)
7.41-7.30 (9H, m), 7.10-7.01 (2H, m), 6.87-6.80 (1H,m), 4.62-4.50
(1H,m), 3.78-3.71 (1H, m), 3.08-2.91 (3H, m), 2.79-2.72 (1H, m),
2.61-2.43 (4H, m), 2.03-1.75 (4H, m) and 1.44-1.24 (4H, m); MS MH+
573(575).
Example 111
[0375] 171
[0376] The cyclopentene from Example 31 (296 mg, 0.84 mmol) was
dissolved in dichloromethane (40 mL), methanol (40 mL) and was
stirred at -78.degree. C. and purged with oxygen over 5 mins
followed by bubbling through ozone until the blue colour persisted.
The solution was then re-purged with oxygen and treated with sodium
borohydride (316 mg, 8.4 mmol), and allowed to warm to r.t. over 16
hrs. The solvent was removed in vacuo and the residue was
partitioned between ethyl acetate (100 mL) and saturated aqueous
sodium bicarbonate (100 mL). The organic layer was separated, dried
(MgSO.sub.4) and evaporated. The yellow oil obtained was purified
by column chromatography on silica gel eluting with 20-100% ethyl
acetate in hexanes, to give the lactol. .sup.1H NMR (CDCl.sub.3)
7.41-7.30 (4H, m), 7.15-7.06 (2H, m), [1H, 5.48-5.46 (m) and 4.60
(d, J=8.8 Hz)], [1H, 4.11-4.07 (m) and 3.91-3.98(m)], 3.41-3.40
(2H, m), and 2.95-2.12 (3H,m)
Example 112
[0377] 172
[0378] The lactol from Example 111 (30 mg, 0.07 mmol) was dissolved
in dichloromethane (3 mL), methanol (1 mL) and was treated with
Amberlyst 15 (10 mg) at r.t. over 16 hrs. The mixture was filtered
and evaporated to give a pale oil (30 mg) which was purified by
preparative t.l.c to give the ethyl acetal. .sup.1H NMR
(CDCl.sub.3) 7.40-7.26 (4H, m), 7.02-6.88 (2H, m), 6.80-6.73 (1H,
m), [1H, 5.01-4.99 (m) and 4.26 (d, J=8.8 Hz)], [2H, 4.11-4.07 (m)
and 3.87-3.78(m)], 3.49-3.18 (2H, m), 2.90-2.16 (4H,m) and [3H,
1.20 (t, J=6.8 Hz) and 0.80 (t, J=7.2)]
Example 113
[0379] 173
[0380] Intermediate 1 (2.5 g, 8.3 mmol) was dissolved in
dimethylformamide (6 mL), and added dropwise to a suspension of 60%
sodium hydride in mineral oil (635 mg 16.6 mmol) in
dimethylformamide (6 mL). When the effervescence had ceased the
solution was treated with a solution of
N-Boc-bis-(2-chloroethyl)amine (3.75 g, 12 mmol) in
dimethylformamide (3 mL). The mixture was stirred at r.t. for 36
hrs. Water (800 mL) was added and the solution was washed with
ethyl acetate (2.times.500 mL). The organic phase was washed with
brine (500 mL), dried (MgSO.sub.4) and evaporated. The clear oil
obtained was purified by column chromatography on silica gel
eluting with 5-20% ethyl acetate in hexanes. The oil obtained was
then further purified by column chromatography on silica gel
eluting with dichloromethane to give the Boc-piperidine. .sup.1H
NMR (CDCl.sub.3) 7.41-7.34 (4H, m), 7.13-7.05 (2H, m), 6.91-6.83
(1H, m), 4.25-4.15 (2H, m), 2.72-2.56 (4H, m), 2.34-2.23 (2H, m)
and 1.43 (9H, s)
Example 114
[0381] 174
[0382] The Boc piperidine from Example 113 (300 mg, 0.64 mmol) was
dissolved in dichloromethane (150 mL), and was treated with
trifluoroacetic acid (30 mL). The mixture was stirred at r.t. for
30 mins and then the solvent was removed in vacuo and saturated
aqueous sodium bicarbonate (100 mL) was added. The solution was
washed with dichloromethane (3.times.100 mL). The organic phase was
dried (MgSO.sub.4) and evaporated, to give the piperidine as a
white solid. .sup.1H NMR (CDCl.sub.3) 7.40-7.36 (4H, m), 7.12-7.03
(2H, m), 6.91-6.84 (1H, m), 3.18-3.14 (2H, m), 2.75-2.54 (4H, m)
and 2.30-2.24 (2H, m); MS MH+ =371(373).
Example 115
[0383] 175
[0384] The piperidine from Example 114 (100 mg, 0.3 mmol) was
dissolved in toluene (3 mL) and ethyl acetate (2 mL) and was
treated with methyl bromoacetate (125 .mu.L, 1.5 mmol) and was
heated at 90.degree. C. for 1 hr. The solvent was evaporated and
the clear oil obtained was purified by column chromatography on
silica gel eluting with 5-20% ethyl acetate in hexanes, to give the
N-alkylpiperidine. .sup.1H NMR (CDCl.sub.3) 7.43-7.38 (4H, m),
7.13-7.04 (2H, m), 6.91-6.84 (1H, m), 3.66(3H, s), 3.12 (2H, s),
3.02-2.97 (2H, m), 2.90-2.60 (2H, m), 2.51-2.44 (2H, m) and
2.22-2.15 (2H, m); MS MH+ =443(445).
Example 116
[0385] 176
[0386] The piperidine from Example 114 (35 mg, 0.09 mmol) was
dissolved in dichloromethane (2 mL) and was treated with
triethylamine (20 .mu.L, 0.14 mmol), methyl succinate mono-ester
(15 mg, 0.11 mmol) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (24 mg,
0.12 mmol) and the mixture was stirred at r.t. for 24 hrs. The
mixture was diluted with water (2 mL) and separated on a Bond
Elut.TM. cartridge before purifying by preparative t.l.c to give
the amide. .sup.1H NMR (CDCl.sub.3) 7.42-7.35 (4H, m), 7.14-7.07
(2H, m), 6.94-6.88 (1H, m), 4.70-4.64 (1H, m), 4.03-3.97 (1H, m),
3.67 (3H, s), and 3.08-2.25 (10H, m); MS MH+ =485(487).
Example 117
[0387] 177
[0388] The piperidine from Example 114 (56 mg, 0.15 mmol) was
dissolved in dimethylformamide (2 mL) and was treated with allyl
bromide (17 .mu.L, 0.18 mmol), and potassium carbonate (63 mg, 0.45
mmol) and the mixture was stirred at r.t. for 4 hrs. The mixture
was diluted with water (2 mL) and the solution was washed with
ethyl acetate (3.times.10 mL). The organic phase was dried
(MgSO.sub.4) and evaporated to give a pale oil which was purified
by column chromatography on silica gel eluting with 80% ethyl
acetate in hexanes to give the N-allylpiperidine. .sup.1H NMR
(CDCl.sub.3) 7.42-7.37 (4H, m), 7.13-7.02 (2H, m), 6.90-6.83 (1H,
m), 5.83-5.71 (1H, m), 5.12-5.08 (2H, m), 2.99-2.95 (2H, m), 2.86
(2H, d, J=6.5 Hz), 2.84-2.38 (4H, m), and 1.91-1.85 (2H, m); MS MH+
=412(414).
Example 118
[0389] 178
[0390] The azide from Example 38 (130 mg, 0.31 mmol) was dissolved
in trimethylsilylacetylene (1.7 mL) and toluene (4 mL) and was
heated at 90.degree. C. for 7 hrs. The mixture was evaporated to
dryness and purified by column chromatography on silica gel eluting
with 20% ethyl acetate in hexanes to give the TMS triazole which
was dissolved in tetrahydrofuran (16 mL) and was treated with
acetic acid (0.3 mL) and TBAF (1M in tetrahydrofuran, 2 mL). The
mixture was stirred at r.t. for 16 hrs. The solvent was removed in
vacuo and saturated aqueous sodium bicarbonate (10 mL) was added.
The solution was washed with ethyl acetate (3.times.100 mL). The
organic phase was dried (MgSO.sub.4) and evaporated, to give a pale
oil which was purified by column chromatography on silica gel
eluting with 80% ethyl acetate in hexanes to give the triazole as a
white solid. .sup.1H NMR (CDCl.sub.3) 7.77 (1H, s), 7.69 (1H, s),
7.39-7.32 (4H, m), 7.15-7.06 (2H, m), 6.91-6.86 (1H, m), 4.59-4.55
(1H, m), 3.28-3.23 (2H, m), 2.68-2.52 (5H, m) and 1.97-1.92 (2H,
m); MS MH+ =437(439).
Example 119
[0391] 179
[0392] Th cycloh ptene from Example 91 (1.43 g, 3.75 mmol) in
tetrahydrofuran (20 ml) at 0.degree. C. was treated with borane
(18.7 ml, 18.7 mmol, 1M solution in tetrahydrofuran), and the
reaction mixture stirred for 1 hour at 0 .degree.C. Hydrogen
peroxide (27% w/w in water, 30 ml) was mixed with sodium hydroxide
solution (4N, 30 ml), then added slowly to the reaction, and
stirring continued for a further hour, warming to room temperature.
The reaction mixture was extracted with ethyl acetate (3.times.100
ml), and the combined organics were washed with brine (sat., 200
ml), dried (MgSO.sub.4) and evaporated in vacuo to give 1.31 g
mixture of isomeric cycloheptanols.
Example 120, 121
[0393] 180
[0394] The cycloheptanol mixture from Example 119 (48 mg, 0.12
mmol) was dissolved in dichloromethane (5 mL) and treated with
Dess-Martin periodinate (61 mg, 0.12 mmol), and the mixture stirred
at r.t. for 1 hr. The mixture was diluted with saturated aqueous
sodium bisulphite (5 mL) and after 15 mins was treated with
saturated aqueous sodium bicarbonate, (10 mL) then extracted with
dichloromethane (3.times.50 mL). The organic phase was dried
(MgSO.sub.4) and evaporated, to give a pale oil which was purified
by preparative t.l.c to give the cycloheptan-3-one (Ex. 107):
.sup.1H NMR (CDCl.sub.3) 7.42-7.33 (4H, m), 7.11-7.01 (2H, m),
6.94-6.87 (1H, m), 3.66 (1H, dt, J=16.4 and 2.8 Hz), 2.50 (1H, dd,
J=16.4 and 5.6 Hz), 2.32-2.16 (2H, m), 1.86-1.78 (2H, m), and
1.67-1.52 (2H, m);
[0395] and the cycloheptan-4-one (Ex. 108): .sup.1H NMR
(CDCl.sub.3) 7.41-7.34 (4H, m), 7.13-7.07 (1H, m), 7.01-6.97 (1H,
m), 6.95-6.88 (1H, m), 3.06-3.00 (2H, m), 2.65-2.44 (4H, m),
2.41-2.33 (1H, m), 2.09-2.01 (1H, m), and 1.58-1.50 (2H, m).
Example 122
[0396] 181
[0397] The ketone from Example 121 (40 mg, 0.1 mmol) was dissolved
in dichloroethane (3 mL) and was treated with morpholine (16 mg,
0.26 mmol) and sodium triacetoxyborohydride (42 mg, 0.26 mmol) and
the mixture stirred at r.t. for 16 hrs. The mixture was diluted
with saturated aqueous sodium bicarbonate (1 mL) and was separated
on a Bond Elut.TM. cartridge before passing through a SCX Bond
Elut.TM. cartridge. The basic fraction was purified by preparative
t.l.c to give the amine. .sup.1H NMR (CDCl.sub.3) 7.38-7.31 (4H,
m), 7.07-6.95 (2H, m), 6.91-6.84 (1H,m), 3.73-3.61 (5H,m) and
2.72-1.21 (11H, m); MS MH+ 469(471).
Example 123
[0398] 182
[0399] The cycloheptan-4-one from Example 121 (200 mg, 0.5 mmol)
was dissolved in acetic acid (18 mL) and water (2 mL) and was
treated with ceric ammonium nitrate (138 mg, 0.25 mmol) and bromine
(40 mg; 0.25 mmol) and the mixture was heated at 50.degree. C. for
16 hrs. The mixture was diluted with water (100 mL) and was
extracted with ether (3.times.75 mL), the organic layer was dried
(MgSO.sub.4) and evaporated, give a mixture of bromoketones, which
were dissolved in glyme (7.5 mL) and treated with sodium methoxide
(43 mg, 3 eq). The mixture was stirred at room temperature for 2
hrs before quenching with acetic acid (0.5 mL), the mixture was
diluted with water (30 mL) and extracted with ethyl acetate
(3.times.25 mL). The organic layer was dried (MgSO.sub.4) and
evaporated, to give a mixture of esters. The 4-isomer was isolated
by preparative t.l.c. .sup.1H NMR (CDCl.sub.3) 7.38-7.32 (4H, m),
7.09-7.02 (2H, m), 6.89-6.83 (1H,m), 3.74 (3H, s), 2.62-2.53
(3H,m), 2.33-2.24 (4H, m) and 1.51-1.41 (2H, m); MS MH+
469(471).
Example 124
[0400] 183
[0401] Step (1)
[0402] The ketone from Example 2 (5 g, 13 mmol) was dissolved in
tetrahydrofuran (100 ml) and was added at -78.degree. C. to a
solution of LDA (28.6 mmol) in tetrahydrofuran (200 ml). The
mixture was warmed to -30.degree. C. over 1 hr and then recooled to
-78.degree. C. before treating with N-phenyl triflamide (4.65 g, 13
mmol) and the mixture was allowed to warm to rt over 16 hr. The
mixture was diluted with water (2 ml) and the solution was washed
with ethyl acetate (2.times.500 ml). The organic phase was washed
with brine (500 ml), dried (MgSO.sub.4) and evaporated. The clear
oil obtained was purified by column chromatography on silica gel
eluting with 5-20% ethyl acetate in hexanes. The oil obtained was
then further purified by column chromatography on silica gel
eluting with 5-10% ethyl acetate in hexane to give
4-(2,5difluorophenyl)-4-(4-chlorophenylsulphonyl)-1-trifluoromethylsulpho-
nylcyclohex-1-ene.
[0403] .sup.1H NMR (CDCl.sub.3) 7.42-7.36 (4H, m), 7.10-7.04 (2H,
m), 6.91-6.83 (1H, m), 5.77-5.76 (1H, m), 3.14-3.12 (2H, m),
3.01-2.95 (1H, m), 2.57-2.44 (2H, m) and 2.24-2.14 (1H, m).
[0404] Step (2)
[0405] The triflate from step (1) (260 mg, 0.6 mmol), cesium
carbonate (357 mg, 1.2 mmol) and phenyl boronic acid (94 mg, 0.76
mmol) were dissolved in dimethoxyethane/water [9:1] (20 ml). The
flask was degassed and then tetrakistriphenylphosphine palladium
(25 mg) was added, the mixture warmed to reflux over 4 hr and then
cooled to rt. The solution was filtered through Celite.TM. and was
diluted with water (20 ml) The solution was washed with ethyl
acetate (2.times.100 ml). The organic phase was washed with brine
(100 ml), dried (MgSO.sub.4) and evaporated. The clear oil obtained
was purified by column chromatography on silica gel eluting with 5%
ethyl acetate in hexanes, to give the desired product. .sup.1H NMR
(CDCl.sub.3) 7.44-7.38 (4H, m), 7.25-7.17 (5H, m), 7.13-7.07 (1H,
m), 7.01-6.96 (2H, m), 6.86-6.79 (1H, m), 6.09-6.07 (1H, m),
3.16-3.14 (2H, m), 3.07-3.02 (1H, m), 2.73-2.67 (1H,m), 2.49-2.45
(1H, m) and 2.28-2.25 (1H, m).
Example 125
[0406] 184
[0407] The alkene from Example 124 (60 mg, 0.13 mmol) was dissolved
in ethanol (5 ml). The flask was degassed and then 5% palladium on
carbon (5 mg) was added the mixture was stirred under an atmosphere
of hydrogen for 45 mins. The solution was filtered through
Celite.TM. and evaporated. The clear oil obtained was purified by
preparative tlc eluting with 5% ethyl acetate in hexanes. The oil
obtained was then further purified by column chromatography on
silica gel eluting with 5% ethyl acetate in hexane to give the cis
isomer; .sup.1H NMR (CDCl.sub.3) 7.38 (4H, s), 7.25-7.00 (7H, m),
6.91-6.84 (1H, m), 3.08-3.06 (1H, m), 2.75-2.69 (2H, m), 2.38-2.31
(2H, m), 2.04-2.00 (2H, m) and 1.44-1.38 (2H, m); and the trans
isomer .sup.1H NMR (CDCl.sub.3) 7.42-7.37 (8H, m), 7.34-7.00 (3H,
m), 6.91-6.83 (1H, m), 2.87-2.75 (3H, m), 2.49-2.40 (1H, m),
2.37-2.26 (2H, m) and 1.90-1.80 (1H, m).
Example 126
[0408] 185
[0409] The trans mesylate from Example 37 (103 mg, 0.22 mmol) was
dissolved in toluene (20 ml) and added to a pre-azeotroped sample
of tetrabutylammonium cyanide (354 mg, 1.32 mmol). and the mixture
was warmed to 70.degree. C. over 18 hr and then cooled to rt. The
solution was diluted with water (10 ml) and washed with ethyl
acetate (2.times.50 ml). The organic phase was washed with brine
(10 ml), dried (MgSO.sub.4) and evaporated. The clear oil obtained
was purified by column chromatography on silica gel eluting with
10-20% ethyl acetate in hexanes, to give the cyanide. .sup.1H NMR
(CDCl.sub.3) 7.42-7.36 (4H, s), 7.10-7.05 (2H, m), 6.89-6.84 (1H,
m), 2.88-2.86 (1H, m), 2.76-2.72 (2H, m), 2.52-2.45 (1H,m),
2.12-2.07 (1H, m) and 1.56-1.49 (1H, m).
Example 127
[0410] 186
[0411] The cyanide from Example 126 (143 mg, 0.36 mmol) was
dissolved/suspended in a mixture of glacial acetic acid (10 ml) and
conc. HCl (6 ml) and heated at 110.degree. C. for 15 hours. The
mixture was cooled, diluted with ethyl acetate and washed with
water (.times.3), dried (MgSO.sub.4) and evaporated to dryness.
This crude residue (153 mg) was purified by preparative tlc (5%
methanol in dichloromethane/1% acetic acid). .sup.1H NMR
(CDCl.sub.3) 7.38-7.35 (4H, s), 7.08-7.06 (2H, m), 6.90-6.84 (1H,
m), 2.65-2.58 (2H, m), 2.38-2.33 (3H, m), and 1.75-1.49 (4H,
m).
Example 128
[0412] 187
[0413] The cyanide from Example 126 (50 mg, 0.12 mmol) was
dissolved in a mixture of tetrahydrofuran (4.5 ml) and water (0.5
ml) and stirred at 20.degree. C. The mixture was treated with
hydrogen peroxide (20 ml, 0.6 mmol) and then with lithium hydroxide
(6 mg, 0.25 mmol) for 2 hours. Hydrogen peroxide (20 ml, 0.6 mmol)
and then with lithium hydroxide (6 mg, 0.25 mmol) were added and
the mixture was stirred at rt. for 72 hrs. The mixture was cooled,
diluted with ethyl acetate and washed with water (.times.2) and
sat. sodium bisulphite, dried (MgSO.sub.4) and evaporated to
dryness. This crude residue (51 mg) was purified by preparative tlc
(20% ethyl acetate in hexanes) .sup.1H NMR (CDCl.sub.3) 7.37 (4H,
s), 7.10-7.02 (2H, m), 6.90-6.84 (1H, m), 5.57 (2H, brs), 2.54-2.48
(3H, m), 2.43-2.39 (1H, m), 2.19-2.15 (2H, m) and 1.62-1.50 (3H,
m).
Example 129
[0414] 188
[0415] Step (1)
[0416] 1-Trifluoromethylsulphonylcyclohex-1-ene (3 g, 13 mmol),
cesium carbonate (8.4 g, 26 mmol) and 2,5-difluorophenyl boronic
acid (2.88 g, 18 mmol) were dissolved in dimethoxyethane/ water
[9:1] (200 ml). The flask was degassed and then
tetrakistriphenylphosphine palladium (125 mg) was added, the
mixture warmed to 80.degree. C. over 4 hr and then cooled to r.t.
The solution was filtered through Celite.TM., diluted with water
(20 ml) and the solution washed with ethyl acetate (2.times.100
ml). The organic phase was washed with brine (100 ml), dried
(MgSO.sub.4) and evaporated. The clear oil obtained was purified by
column chromatography on silica gel eluting with hexanes, to give
1-(2,5-difluorophenyl)cyclohe- x-1-ene. .sup.1H NMR (CDCl.sub.3)
6.97-6.73 (3H, m), 5.97-5.96 (1H, m), 2.35-2.31 (2H, m), 2.23-2.14
(2H, m) and 1.79-1.68 (1H, m).
[0417] Step (2)
[0418] The styrene from Step (1) (100 mg, 0.5 mmol) and
4-bromothiophenol (96 mg 0.5 mmol) were dissolved in
dichloromethane (5 ml) and then 70% aqueous perchloric acid (15 ml)
was added. The mixture was stirred at rt. over 24 hr and then
treated with m-chloroperoxybenzoic acid in dichloromethane (10 ml)
with stirring at rt. for a further 6 hrs. The mixture was diluted
with 2N sodium hydroxide (2 ml) and separated on a Varian Bond
Elut.TM. cartridge. The organic phase was dried (MgSO.sub.4) and
evaporated. The clear oil obtained was purified by column
chromatography on silica gel eluting with 2-5% ethyl acetate in
hexanes, to give the sulphone. .sup.1H NMR (CDCl.sub.3) 7.53 (2H,
d, J=8.6 Hz), 7.27 (2H, d, J=8.6 Hz), 7.08-7.03 (2H, m), 6.84-6.80
(1H, m), 2.82-2.63 (2H, m), 2.12-2.04 (2H, m), 1.82-1.78 (2H, m)
1.64-1.54 (1H, m) and 1.40-1.18 (3H, m).
[0419] Following the procedure of Example 129, using the
appropriate thiophenol in Step (2), the compounds of Examples
130-132 were obtained:
Example 130
[0420] 189
[0421] .sup.1H NMR (CDCl.sup.3) 7.30 (2H, d, J=8.6 Hz), 7.18 (2H ,
d, J=8.6 Hz), 7.03-6.97 (2H, m), 6.85-6.79 (1H, m), 2.85-2.65 (2H,
m), 2.41 (3H, s), 2.10-2.03 (2H, m), 1.81-1.75 (2H, m) 1.61-1.57
(1H, m) and 1.35-1.13 (3H, m).
Example 131
[0422] 190
[0423] .sup.1H NMR (CDCl.sub.3) 7.44-7.40 (1H, m), 7.10-7.00 (4H,
m), 6.86-6.80 (1H, m), 2.82-2.61 (2H, m), 2.12-2.07 (2H, m),
1.82-1.78 (2H, m) 1.62-1.54 (1H, m) and 1.45-1.15 (3H, m).
Example 132
[0424] 191
[0425] .sup.1H NMR (CDCl.sub.3) 7.58-7.54 (1H, m), 7.34-7.33
(3H,m), 7.10-7.03 (2H, m), 6.98-6.81 (1H, m), 2.82-2.61 (2H, m),
2.18-2.07 (2H, m), 1.85-1.79 (2H, m) 1.63-1.58 (1H, m) and
1.40-1.17 (3H, m).
Example 133
[0426] 192
[0427] To the cis alcohol from Example 22 (1.8 g, 4.7 mmol) in dry
THF (10 ml) under nitrogen were added sodium hydride (60%
dispersion, 740 mg, 18.6 mmol) and potassium .sup.tbutoxide (1M in
THF solution, 0.47 ml, 0.47 mmol). Allyl bromide (1.2 ml, 14.1
mmol) was added and the reaction heated at 60.degree. C. for 18 h.,
diluted with water and extracted with ethyl acetate (.times.3).
Organic extracts were washed with brine, dried (MgSO.sub.4),
filtered and evaporated. Crude product purified by flash column
chromatography (2:1 .sup.ihexane/ethyl acetate) to give a light
yellow semi-solid (1.0 g). .sup.1H NMR (CDCl3) 1.24-1.32 (2H, m),
1.97 (1H, s), 2.03 (1H, d, J=9.5 Hz), 2.51 (4H, d, J=11.2 Hz), 3.47
(1H, t, J=2.8 Hz), 3.94 (1H, t, J=1.6 Hz), 3.96 (1H, t, J=1.4 Hz),
5.17-5.27 (2H, m), 5.86-5.96 (1H, m), 6.83-6.90 (1H, m), 7.02-7.14
(2H, m), 7.38 (4H, s).
Example 134
[0428] 193
[0429] The allyl ether (200 mg, 0.47 mmol) from example 133 was
dissolved in carbon tetrachloride (10 ml), water (1 ml), and
acetonitrile (1 ml). The solution was stirred vigorously and sodium
metaperiodate (402 mg, 1.88 mmol) and ruthenium trichloride hydrate
(2 mg) were added. After 2 h the reaction was diluted with DCM and
filtered through Celite.TM.. The filtrate was concentrated and
partitioned between ethyl acetate and water. Organic extracts were
washed with brine, dried (MgSO.sub.4), filtered and evaporated.
Crude product purified by flash column chromatography (ethyl
acetate) to give a white solid (80 mg). .sup.1H NMR (CDCl3) 2.04
(5H, br), 2.30-2.59 (4H, m), 3.63-3.67 (1H, br), 4.05 (2H, br),
6.79 (1H, br), 6.99 (2H, br), 7.29 (4H, br).
Example 135
[0430] 194
[0431] The allyl ether (120 mg, 0.28 mmol) from Example 133 was
dissolved in dry THF (5 ml). To the solution under nitrogen and
cooled to 0.degree. C. was added a borane-THF solution (1M, 0.56
ml, 0.56 mmol), via a syringe, over 5 minutes. The reaction was
stirred at this temperature for 4 h and then water (0.5 ml) was
added followed by aq. sodium hydroxide (2M, 0.5 ml) and 30%
hydrogen peroxide (0.4 ml). Reaction was stirred for 15 h at room
temperature, concentrated, and partitioned between ethyl acetate
and water. Organic extracts were washed with brine, dried
(MgSO.sub.4), filtered and evaporated. Crude product purified by
flash column chromatography (1:1 .sup.ihexane/ethyl acetate) to
give a colourless oil (80 mg). .sup.1H NMR (CDCl3) 1.81-1.88 (2H,
m), 1.98 (1H, s), 2.03 (2H, d, J=8.4 Hz), 2.07 (1H, s), 2.46 (5H,
dd, J=0.7, 0.7 Hz), 3.44 (1H, t, J=2.8 Hz), 3.57 (2H, t, J=5.8 Hz),
3.78 (2H, s), 6.83-6.90 (1H, m), 7.02-7.13 (2H, m), 7.38 (4H,
s).
Example 136
[0432] 195
[0433] Step (1)
[0434] The acid from Example 134 (560 mg, 1.2 mmol) was dissolved
in ethyl acetate (100 ml) under nitrogen and pentafluorphenol (330
mg, 1.8 mmol) was added. The solution was cooled to 0.degree. C,
dicyclohexylcarbodiimide (370 mg, 1.8 mmol) added, and the reaction
was allowed to warm to room temperature and stirred for 1 h. The
reaction mixture was filtered through a pad of Celite.TM., the
filtrate evaporated and purified by flash chromatography (2:1
.sup.ihexane/ethyl acetate) to give the pentafluorophenol ester as
a white solid (760 mg).
[0435] Step (2)
[0436] To this ester (115 mg, 0.18 mmol) was added a 2M solution of
ammonia in methanol (3 ml), and the mixture heated at 50.degree. C.
in a sealed tube for 3 h. The reaction mixture was concentrated and
purified by flash chromatography (1:1 .sup.ihexane/ethyl acetate to
9:1 ethyl acetate/methanol) to give a white solid (54 mg). .sup.1H
NMR (CDCl3) 1.32-1.40 (2H, m), 2.04 (2H, br), 2.51-2.54 (4H, m),
3.54 (1H, t, J=2.8 Hz), 3.95 (2H, s), 5.45-5.54 (1H, br), 6.50-6.59
(1H, br), 6.83-6.90 (1H, m), 7.03-7.14 (2H, m), 7.36-7.40 (4H,
m)
Example 137
[0437] 196
[0438] To the pentafluorophenol ester prepared in Example 136 (125
mg, 0.2 mmol) dissolved in DCM (3 ml) and under nitrogen was added
N-methyl piperazine (70 .mu.l, 0.8 mmol). After 1 h the reaction
was concentrated, diluted with ethyl acetate, washed with aq.
sodium carbonate, water, brine, dried (MgSO.sub.4), filtered and
evaporated. Purified by flash column chromatography (1:1
.sup.ihexanelethyl acetate to 9:1 ethyl acetate/methanol+2%
triethylamine) to give a colourless glassy solid (50 mg). .sup.1H
NMR (CDCl3) 1.34 (2H, m), 2.02 (4H, m), 2.34 (2H, m), 2.40-2.55
(8H, m), 3.55 (1H, t, J=2.8 Hz), 3.63 (2H, t, J=4.9 Hz), 4.14 (3H,
s), 6.82-6.89 (1H, m), 7.02-7.12 (2H, m), 7.36 (4H, d, J=4.6
Hz).
Example 138
[0439] 197
[0440] Prepared as in Example 137, using thiomorpholine sulfone
hydrochloride (120 mg, 0.7 mmol) and triethylamine (0.1 ml) in
place of N-methylpiperazine, to give a white solid (50 mg). .sup.1H
NMR (CDCl3) 1.31-1.39 (2H, m), 2.00 (1H, s), 2.05 (1H, s),
2.38-2.45 (3H, m), 2.51-2.65 (1H, m), 3.09 (2H, d, J=1.1 Hz), 3.22
(2H, s), 3.58 (1H, t, J=2.5 Hz), 4.13 (4H, d, J=3.2 Hz), 4.18 (2H,
s), 6.82-6.89 (1H, m), 7.03-7.12 (2H, m), 7.34 (3H, d, J=14.7 Hz),
7.39 (1H, s).
Example 139
[0441] 198
[0442] To the alcohol prepared in Exampl 22b (150 mg, 0.39 mmol) in
dry THF (5 ml) cooled to 0.degree. C. and under nitrogen was added
chlorosulfonyl isocyanate (50 .mu.l, 0.54 mmol). The reaction was
stirred for 1 h and then sodium metabisulfite (220 mg, 1.17 mmol)
in water (2 ml) was added dropwise over 5 min. Reaction was allowed
to warm to room temperature and stirred for 16 h., diluted with
water and extracted with ethyl acetate (.times.3). Organic extracts
were washed with brine, dried (MgSO.sub.4), filtered and
evaporated. The carbamate was isolated by trituration with ether to
give a white solid (40 mg). MS (EI+) 427 (M-2H)
Example 140
[0443] 199
[0444] To 3-(ethoxycarbonyl)propyltriphenylphosphonium bromide (238
mg, 0.52 mmol) in dry toluene (5 ml) and under nitrogen was added
dropwise potassium hexamethyldisilazide (0.5 M in toluene, 1.2 ml).
The ketone from Example 2 (100 mg, 0.26 mmol) in dry toluene (3 ml)
was added, the reaction stirred at 100.degree. C. for 5 h., cooled,
diluted with water and the organic layer removed. The aqueous layer
was extracted with ethyl acetate (.times.3). Organic extracts were
washed with brine, dried (MgSO.sub.4), filtered and evaporated.
Crude product purified by flash column chromatography (2:1
.sup.ihexane/ethyl acetate) to give a white foam (70 mg). .sup.1H
NMR (CDCl3) 1.24 (3H, t, J=7.2 Hz), 1.64-1.71 (2H, m), 1.93-2.38
(5H, m) 2.70-2.80 (4H, m),4.13 (2H, q, J=7.1 Hz), 5.12 (1H, s),
6.83-6.91 (1H, m), 7.02-7.16 (3H, m), 7.37 (4H, s).
Example 141
[0445] 200
[0446] The trans-3-alcohol from Example 99 (40.0 mg, 0.104 mmol) in
N,N-dimethylformamide (2 ml) was treated with allyl bromide (26.4
.mu.l, 0.312 mmol), followed by sodium hydride (6.2 mg, 60% w/w in
mineral oil, 0.156 mmol) and stirred at room temperature. After 2
hours, further portions of allyl bromide (26.4 .mu.l, 0.312 mmol)
and sodium hydride (6.2 mg, 60% w/w in mineral oil, 0.156 mmol)
were added and stirring at room temperature continued. After 4
hours, reaction was quenched with water (60 ml), extracted with
ethyl acetate (3.times.40 ml). Combined organics were washed with
brine (sat., 150 ml), dried (MgSO.sub.4) and concentrated in vacuo
to give crude product (45 mg). This material was purified by
preparative t.l.c., eluting with 15% ethyl acetate in hexanes to
give product (25 mg, 56%). .sup.1H NMR (400 MHz, CDCl.sub.3)
1.53-1.81 (3H, m), 2.29-2.35 (1H, m), 2.45 (2H, d, J=13.8 Hz)
2.95-3.00 (1H, br), 3.80-3.82 (2H, m), 3.91-3.92 (2H, m), 4.89-4.98
(2H, m), 5.58-5.68 (1H, m), 6.74-6.80 (1H, m), 6.93-7.02 (2H, m),
7.29-7.38 (4H, m).
Example 142
[0447] 201
[0448] The cis-3-alcohol from Example 93 (87.0 mg, 0.226 mmol) in
N,N-dimethylformamide (3 ml) was dripped into a suspension of
sodium hydride (27.1 mg, 60% w/w in mineral oil, 0.678 mmol) in
N,N-dimethylformamide (1 ml). Ethyl bromoacetate (75.2 .mu.l, 0.678
mmol) was added and reaction stirred at room temperature. After 2
hours a further portion of ethyl bromoacetate (75.2 .mu.l, 0.678
mmol) was added, the mixture stirred at room temperature for a
further 4 hours, then heated to 90.degree. C. for 3.5 hours.
Reaction was then cooled, further portions of sodium hydride (27.1
mg, 60% w/w in mineral oil, 0.678 mmol) and ethyl bromoacetate
(75.2 .mu.l, 0.678 mmol) added, and heated again to 90.degree. C.
After 4 hours at this temperature, reaction was cooled, diluted
with water (150 ml) and extracted with ethyl acetate (3.times.100
ml). Combined organics were washed with brine (sat., 250 ml), dried
(MgSO.sub.4) and evaporated in vacuo to give crude (263 mg). Crude
material was chromatographed on silica, eluting with 15% ethyl
acetate in hexanes to give impure product (32 mg) which was
purified further by preparative t.l.c., eluting with 15% ethyl
acetate in hexanes, followed by a second preparative t.l.c.,
eluting with 100% dichloromethane to give product (7 mg, 7%).
.sup.1H NMR (400 MHz, CDCl.sub.3), 1.22-1.38 (3H, m), 1.89-1.94
(1H, m), 2.00-2.05 (3H, br), 2.60-3.15 (2H, m), 3.19-3.26 (1H, m),
4.07 (2H, s), 4.16-4.26 (4H, m), 6.84-6.95 (1H, m), 7.02-7.11 (2H,
m), 7.39 (4H, s).
Example 143
[0449] 202
[0450] The cis-allyl ether from Example 101 (50.0 mg, 0.108 mmol)
in carbon tetrachloride (0.2 ml), water (0.3 ml) and acetonitrile
(0.2 ml) was treated with sodium (meta)periodate (95.0 mg, 0.444
mmol) followed by ruthenium(III) chloride hydrate (2.2 mol %, 0.5
mg, 2.38 nmol). After stirring at room temperature for 2 hours,
dichloromethane (2 ml) was added and the phases separated. Aqueous
phase was extracted with dichloromethane (3.times.5 ml). Combined
organics were dried (MgSO.sub.4) and evaporated in vacuo to give a
brown residue (44 mg). This residue was diluted in diethyl ether
(10 ml) and filtered through a pad of Celite.TM., then concentrated
in vacuo to give crude (34 mg). This material was purified by
preparative t.l.c., eluting with 5% methanol, 1% acetic acid in
dichloromethane to give product (27 mg, 56%). .sup.1H NMR (400 MHz,
(CD.sub.3).sub.2SO), 0.99-1.23 (2H, br), 1.70-1.86 (2H, br),
1.87-1.99 (1H, br), 2.55-3.05 (2H, br), 3.09-3.22 (1H, br),
3.24-3.40 (2H, br), 3.85-4.05 (1H, br), 7.10-7.20 (2H, br),
7.25-7.35 (1H, br), 7.41 (2H, d, J=7.9 Hz), 7.64 (2H, d, J=8.0 Hz),
12.10-12.80 (1H, br).
Example 144
[0451] 203
[0452] The cis-allyl ether from Example 101 (100 mg, 0.235 mmol) in
dichloromethane/methanol (1:1, 10 ml) was cooled to -78.degree. C.
The flask was purged with oxygen, then with ozone until saturated,
then with oxygen again and finally nitrogen. The mixture was warmed
to room temperature and dimethyl sulphide (159 .mu.l, 2.35 mmol)
added. The reaction was then allowed to warm to room temperature
and stirring continued for a further 16 hours. Solvent was removed
in vacuo and the residue partitioned between water (10 ml) and
ethyl acetate (10 ml). The aqueous phase was separated and
extracted with ethyl acetate (2.times.10 ml). Combined organics
were washed with brine (sat., 40 ml), dried (MgSO.sub.4) and
evaporated in vacuo to give the cyclohexyloxyacetaldehyd- e
derivative (102 mg, >99%). .sup.1H NMR (400 MHz, CDCl.sub.3),
1.16-1.25 (1H, br), 1.32-1.40 (1H, br), 1.90-1.96 (2H, m),
2.02-2.10 (2H, br), 2.30-3.00 (2H, br), 3.18-3.23 (1H, m), 4.09
(2H, s), 6.84-6.91 (1H, m), 7.03-7.09 (2H, m), 7.36-7.41 (4H, m),
9.68 (1H, s).
[0453] The aldehyde (102 mg, 0.238 mmol) in dichloroethane (10 ml)
was then treated with morpholine (22.9 .mu.l, 0.262 mmol). After
stirring at room temperature for 2 hours, the mixture was treated
with sodium triacetoxyborohydride (202 mg, 0.852 mmol) and glacial
acetic acid (1 ml). After a further 1.5 hours at room temperature,
solvent was removed in vacuo and the residue partitioned between
dichloromethane (5 ml) and sodium hydrogen carbonate (sat. aq., 5
ml). The organic phase was separated on a Varian Bond Elut.TM.
cartridge and purified on a SCX Varian Bond Elut.TM. cartridge.
Solvent was removed in vacuo to give product (80 mg, 67%). .sup.1H
NMR (400 MHz, CDCl.sub.3), 1.15-1.32 (2H, m), 1.87-1.99 (4H, m),
2.47-2.49 (4H, m), 2.54 (2H, t, J=6.0 Hz), 2.60-3.00 (2H, br),
3.08-3.16 (1H, br), 3.56-3.63 (2H, m), 3.70 (4H, t, J=4.6 Hz),
6.84-6.90 (1H, m), 7.03-7.08 (2H, m), 7.36-7.41 (4H, m); ms. (ES+),
500 (M.sup.++1), 324 (M.sup.+175), 193 (M.sup.+306).
Example 145
[0454] 204
[0455] The cyclohexene from Example 34 (493 mg, 1.34 mmol) and
N-methylmorpholine-N-oxide (204 mg, 1.74 mmol) in
tetrahydrofuran/water (3:1, 8 ml) were stirred during the addition
of osmium tetroxide (107 .mu.l, 2.5 wt. % in .sup.tBuOH, 0.342
mmol). Mixture was stirred for 24 hours at room temperature, then
another portion of osmium tetroxide (107 .mu.L, 2.5 wt. % in
.sup.tBuOH, 0.342 mmol) was added and stirring continued for a
further 5 hours. The reaction mixture was diluted with sodium
hydrogen sulfite (sat., aq., 16 ml) then extracted with ethyl
acetate (3.times.15 ml). Combined organics were washed with brine
(sat., 50 ml), dried (MgSO.sub.4) and evaporated in vacuo to give
product (88:12 cis:trans) (509 mg, 94%). .sup.1H NMR (400 MHz,
CD.sub.3OD), 1.31-1.39 (1H, m), 1.92 (1H, qd, J=14.6 Hz and J=3.1
Hz), 2.40-2.62 (4H, br), 3.33-3.38 (1H, m), 3.78 (1H, d, J=2.7 Hz),
6.97-7.10 (1H, m), 7.16-7.21 (2H, m), 7.43 (2H, d, J=8.5 Hz), 7.52
(2H, d, J=8.6 Hz).
Example 146
[0456] 205
[0457] The mixture of diols from Example 145 (100 mg, 0.249 mmol)
in acetone (3 ml) was treated with para-toluenesulphonic acid
monohydrate (30.0 mg, 0.158 mmol) and the mixture stirred at room
temperature. After 4 hours, a further portion of
para-toluenesulphonic acid monohydrate (50.0 mg, 0.263 mmol) was
added and the reaction mixture heated to 60.degree. C. for 1 hour,
then stirring continued at room temperature for a further 24 hours.
Solvent was then removed in vacuo and the residue partitioned
between ethyl acetate (10 ml) and sodium hydrogen carbonate (sat.
aq., 10 ml). The aqueous phase was separated and extracted with
ethyl acetate (2.times.10 ml). Combined organics were then washed
with brine (sat., 50 ml), dried (MgSO.sub.4) and evaporated in
vacuo to give crude (77 mg). This material was chromatographed on
silica, eluting with 20% ethyl acetate in hexanes, followed by
further purification by preparative t.l.c., eluting with 30% ethyl
acetate in hexanes to give product (7.7 mg, 7%). .sup.1H NMR (400
MHz, CDCl.sub.3), 1.31 (3H, s), 1.54 (3H, s), 1.59-1.66 (1H, m),
2.14-2.20 (1H, m), 2.26-2.32 (1H, m), 2.35-2.42 (1H, m), 2.54-2.58
(1H, br), 2.81-2.86 (1H, br), 3.95-4.03 (2H, m), 6.83-6.89 (1H, m),
7.03-7.11 (2H, m), 7.36-7.41 (4H, m).
Example 147
[0458] 206
[0459] The mixture of diols from Example 145 (100 mg, 0.249 mmol)
in toluene (3 ml) was treated with N-Fmoc-4-piperidone (240 mg,
0.747 mmol) and para-toluenesulphonic acid monohydrate (10 mg).
This mixture was heated to reflux under Dean-Stark conditions.
After 3 hours, solvent was removed in vacuo to give crude (420 mg).
This material was chromatographed on silica, eluting with 25% ethyl
acetate in hexanes to give protected acetal (148 mg, 84%).
[0460] This material was treated with 20% diethylamine in
dichloromethane (5 ml). After stirring at room temperature for 16
hours, solvent was removed in vacuo to give crude (343 mg). This
material was chromatographed on silica, eluting with
dichloromethane/methanol/ammonia (90:8:1) to give material which
was purified further by preparative t.l.c., eluting with
dichloromethane/methanol/ammonia (90:8:1) giving product (40 mg,
39%). .sup.1H NMR (360 MHz, CDCl.sub.3), 1.58-1.70 (3H, br),
1.83-1.88 (2H, m), 2.17 (1H, dt, J=10.2 Hz and J=2.0 Hz), 2.31-2.58
(3H, br), 2.84-3.02 (3H, m), 3.00 (2H, t, J=5.7 Hz), 3.97-4.03 (2H,
m), 6.81-6.88 (1H, m), 7.02-7.11 (2H, m), 7.34-7.40 (4H, m).
Example 148
[0461] 207
[0462] Prepared by the methods of Examples 1 and 2. The sulphone
used for the process of Example 1 was obtained in the same manner
as Intermediate 1, using 2-fluoro-5-iodobenzyl bromide in place of
2,5-difluorobenzyl bromide. .sup.1H NMR (360 MHz, CDCl.sub.3) 2.18
(2H, dt, J=5.5, 16.4 Hz), 2.52-2.59 (4H, m), 2.97-3.06 (2H, m),
6.76 (1H, dd, J=8.6, 12.7 Hz), 7.36-7.44 (4H, m), 7.56 (1H, dd,
J=2.1, 7.5 Hz), 7.69-7.73 (1H, m).
Example 149
[0463] 208
[0464] Prepared by the methods of Examples 1 and 2. The sulphone
used for the process of Example 1 was obtained in the same manner
as Intermediate 1, using 2-fluoro-5-bromobenzyl bromide in place of
2,5-difluorobenzyl bromide.. .sup.1H NMR (360 MHz, CDCl.sub.3) 2.19
(2H, dt, J=5.2, 16.3 Hz), 2.53-2.59 (4H, m), 2.98-3.06 (2H, m),
6.88 (1H, dd, J=8.7, 12.5 Hz), 7.37-7.55 (6H, m).
Example 150
[0465] 209
[0466] A solution of Intermediate 1 (10 g) in THF (100 ml) was
cooled to -30.degree. C. and treated slowly with n-BuLi (1.6 M in
hexane, 22 ml). The reaction was stirred for 30 mins, then treated
with epichlorohydrin, warmed to room temperature and refluxed for
30 min. The reaction mixture was cooled, evaporated and partitioned
between water/EtOAc. The aqueous layer was dried, filtered and
evaporated. Purification by column chromatography gave the alcohol
(5 g, 42%) as a white solid. .sup.1H NMR (360 MHz, CDCl.sub.3)
7.41-7.35 (4H, m), 7.04-6.97 (1H, m), 6.85-6.76 (2H, m), 4.34-4.24
(1H, m), 3.69 (1H, d, J=10.7 Hz), 3.13-3.11 (4H, m).
Example 151
[0467] 210
[0468] A solution of the alcohol from Example 150 (3 g) in DMF (20
ml) was treated with sodium hydride (1.5 equiv.) and allyl bromide
(2 equiv.) and stirred at room temperature for 1 h. The reaction
mixture was diluted with 1N HCl and ethyl acetate. The organic
phase was washed, dried, filtered and evaporated. Purification by
column chromatography gave the allyl ether (3 g, 89%) as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.39-7.34 (4H, m),
7.04-6.99 (1H, m), 6.95-6.91 (1H, m), 6.85-6.79 (1H; m), 5.94-5.85
(1H, m), 5.29-5.17 (2H, m), 3.94-3.84 (3H, m), 3.23-3.18 (2H, m),
3.00-2.95 (2H, m).
Example 152
[0469] 211
[0470] A solution of the allyl ether from Example 151 (2 g) was
dissolved in .sup.tBuOH (20 ml), THF (20 ml) and water (1 ml) and
treated with N-methylmorpholine-N-oxide (3 equiv.) and OsO.sub.4
(2.5 wt % solution in .sup.tBuOH, 2 ml) and stirred at room
temperature for 1 h. The reaction mixture was treated with sodium
sulfite (3 equiv.), stirred for 10 min, then diluted with
water/EtOAc. The organic phase was dried, filtered and evaporated.
Purification by column chromatography gave the diol (2.1 g, 97%) as
a white solid. .sup.1H NMR (360 MHz, CDCl.sub.3) 7.37 (4H, s),
7.05-6.98 (1H, m), 6.93-6.88 (1H, m), 6.83-6.77 (1H, m), 3.99-3.87
(2H, m), 3.79-3.64 (2H, m), 3.53-3.44 (2H, m), 3.25-3.19 (2H, m),
3.03-2.97 (2H, m), 2.83 (1H, d, J=4.8 Hz), 2.09 (1H, t, J=6.1
Hz).
Example 153
[0471] 212
[0472] A solution of the diol from Example 152 (2 g) was dissolved
in methanol (20 ml) and water (20 ml) and treated with sodium
periodate (3 equiv.) and stirred at room temperature for 10 min.
The reaction mixture was diluted with ether and water. The organic
layer was washed, dried, filtered and evaporated in vacuo to give
the corresponding aldehyde. This compound was dissolved in
.sup.tBuOH (20 ml) and water (6 ml) and treated with NaClO.sub.2 (3
equiv.) and NaH.sub.2PO.sub.4.2H.sub.2O (1.05 equiv.) and stirred
at room temperature for 1 h. The reaction mixture was quenched with
1N HCl, ethyl acetate and water. The organic phase was washed,
dried, filtered and evaporated. Purification by column
chromatography gave the acid as a white solid (1.2 g, 81%). .sup.1H
NMR (360 MHz, DMSO) 12.8 (1H, brs), 7.62-7.60 (2H, m), 7.43-7.39
(2H, m),7.32-7.03 (3H, m), 3.99 (2H, s), 3.92 (1H, qt, J=7.4 Hz),
3.07-2.96 (4H, m).
Example 154
[0473] 213
[0474] A solution of the acid from Example 153 (0.8 g) was
dissolved in ethyl acetate (10 ml) and treated with
C.sub.6F.sub.5OH (1.5 equiv.) and DCC (1.5 equiv.) and stirred at
room temperature for 15 min. The reaction mixture was filtered and
evaporated in vacuo and used without further purification.
[0475] A solution of the resulting active ester (ca. 0.64 mmol) in
DCM (3.33 ml) was treated with ammonia gas and stirred at room
temperature for 10 min. The reaction mixture was evaporated in
vacuo and purified by column chromatography to give the amide (120
mg, 45%) as a white solid. .sup.1H NMR (400 MHz, DMSO) 7.61 (2H, d,
J=8.7 Hz), 7.41 (2H, d, J=8.7 Hz), 7.30-6.99 (5H, m), 3.95-3.88
(1H, m), 3.76 (2H, s), 3.09-2.93 (4H, m).
Example 155
[0476] 214
[0477] Prepared in 47% yield by a procedure analogous to Example
154. .sup.1H NMR (400 MHz, DMSO) 7.70 (1H, brd), 7.63-7.61 (2H, m),
7.41-7.40 (2H, m), 7.32-7.27 (1H, m), 7.17-7.09 (1H, m), 7.07-7.02
(1H, m), 3.95-3.85 (1H, m), 3.80 (2H, s), 3.04-3.01 (4H, m), 2.61
(3H, d, J=4.8 Hz).
Example 156
[0478] 215
[0479] Prepared in 35% yield in a procedure analogous to Example
154. .sup.1H NMR (400 MHz, DMSO) 7.63-7.61 (2H, m), 7.42-7.40 (2H,
m), 7.33-7.25 (1H, m), 7.17-7.01 (2H, m), 4.10 (2H, s), 3.95-3.85
(1H, m), 3.08-2.94 (4H, m), 2.88 (3H, s), 2.79 (3H, s).
Example 157
[0480] 216
[0481] A solution of the allyl ether from Example 151 (0.6 g) in
THF (15 ml) was cooled to -10.degree. C. and treated with a
solution of borane in THF (1.0M, 1.5 equiv.) The reaction mixture
was stirred at room temperature for 1 h, then re-cooled to
-10.degree. C. and treated with 4N NaOH and H.sub.2O.sub.2. The
reaction mixture was warmed to room temperature, washed with brine,
dried, filtered and evaporated. Purification by column
chromatography gave the alcohol (350 mg, 56%) as a white solid.
.sup.1H NMR (360 MHz, CDCl.sub.3) 7.37 (4H, s), 7.05-6.98 (1H, m),
6.94-6.89 (1H, m), 6.85-6.78 (1H, m), 3.91-3.78 (3H, m), 3.54 (2H,
t, J=5.8 Hz), 3.22-3.17 (2H, m), 2.99-2.96 (2H, m), 2.01 (1H, brs),
1.84 (2H, qt, J=5.8 Hz).
Example 158
[0482] 217
[0483] A solution of the alcohol from Example 157 (330 mg) was
dissolved in CCl.sub.4 (2 ml), MeCN (2 ml), water (3 ml) and
treated with RuO.sub.2.H.sub.2O (5 mg) and sodium periodate (800
mg) and stirred vigorously for 1 h. The reaction mixture was
diluted with DCM, and the organic layer was dried, filtered and
evaporated. Purification by column chromatography gave the acid as
a solid (100 mg, 29%). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.37 (4H,
s), 7.04-6.99 (1H, m), 6.94-6.90 (1H, m), 6.84-6.78 (1H, m), 3.89
(1H, qt, J=7.4 Hz), 3.67-3.64 (2H, m), 3.23-3.18 (2H, m), 3.01-2.96
(2H, m), 2.66-2.63 (2H, m).
Example 159
[0484] 218
[0485] A solution of the acid from Example 158 was converted into
the corresponding amide in 81% yield using the conditions described
in Example 154. .sup.1H NMR (360 MHz, CDCl.sub.3) 7.38 (4H, s),
7.05-6.99 (1H, m), 6.93-6.88 (1H, m), 6.84-6.77 (1H, m), 6.42 (1H,
brs), 5.39 (1H, brs), 3.95 (1H, qt, J=7.4 Hz), 3.65-3.62 (2H, m),
3.27-3.20 (2H, m), 3.05-2.99 (2H, m), 2.54 (2H, t, J=5.6 Hz).
Examples 160-177
[0486] 219
[0487] These Examples were prepared by the following method, using
the appropriate amine free base or amine salt with prior
neutralization.
[0488] To a stirred suspension of cis
4-(4-chlorobenzenesulphonyl)-4-(2,5--
difluorophenyl)cyclohexaneacetic acid (Example 50, 0.15 g, 0.35
mmol) in dichloromethane (5 ml) was added oxalyl chloride (0.05 ml,
0.57 mmol) and dimethylformamide (1 drop). After 30 minutes the
solution was evaporated to a small volume and to a solution of the
residue in dichloromethane (5 ml) was added the desired amine (1.75
mmol). After stirring the solution for 20 minutes the solvent was
removed in vacuo and the residue purified by chromatography on
silica gel eluting with increasing concentrations of ethyl acetate
in isohexane (25%, 50%). The fractions containing the product were
evaporated to give the product amide. Chromatographic purification
was performed on silica gel using appropriate concentrations of
ethyl acetate in isohexane, ethyl acetate or methanol in ethyl
acetate where appropriate.
12 MS m/z Example No. R (M + H) m.p. 160 NH-cyclobutyl 482,484
192-193.degree. C. 161 NH.sub.2 428,430 187-189.degree. C. 162 NHMe
442,444 200-201.degree. C. 163 NHEt 456,458 146-147.degree. C. 164
NH.sup.nPr 470,472 150-151.degree. C. 165 NH.sup.iPr 470,472
124-125.degree. C. 166 NMe.sub.2 456,458 167 NHCH.sub.2CH.sub.2Ph
532,534 168 NHCH.sub.2CF.sub.3 510,512 169 220 546,548 170
NHCH.sub.2-cyclopropyl 482,484 187-188.degree. C. 171
NH-cyclopentyl 496,498 182-183.degree. C. 172 NH-cyclopropyl
468,470 145-147.degree. C. 173 NH.sup.nBu 484,486 oil 174
NH.sup.tBu 484,486 102-110.degree. C. 175 NHCH(Et).sub.2 498,500
89-92.degree. C. 176 NH-allyl 468,470 132-134.degree. C. 177
NHNH.sup.tBu 499,501
Example 178
[0489] 221
[0490] Step (1)
[0491] To a solution of the acid from Example 50 (1 g) in DCM (50
ml) and ethyl acetate (30 ml) was added pentafluorophenol (1.5
equiv.) and DCC (1.5 equiv.) and stirred at room temperature for 1
h. The reaction mixture was evaporated in vacuo, taken up in ethyl
acetate and filtered. The filtrate was evaporated in vacuo to yield
the pentafluorophenol ester of sufficient purity to use in
subsequent reactions without further purification.
[0492] Step (2)
[0493] To the active ester prepared in Step (1) (200 mg, 0.33 mmol)
dissolved in dry THF (3 ml) and under nitrogen was added hydrazine
(1 M solution in THF, 1.3 ml, 1.32 mmol). After 3 h the reaction
was concentrated diluted with water, extracted with ethyl acetate
(.times.3), washed with, water, brine, dried (MgSO.sub.4), filtered
and evaporated. Purified by flash column chromatography (1:1
.sup.ihexane/ethyl acetate to ethyl acetate+3% triethylamine) to
give a white solid (50 mg). MS(EI+) 444 (MH+)
Example 179
[0494] 222
[0495] A solution of th active ester from step (1) of Example 178
in DMF was treated with acetamidoxime at room temperature. The
reaction mixture was stirred for 0.5 h, diluted with ethyl acetate,
washed with water, dried, filtered and evaporated in vacuo.
Purification by column chromatography gave the desired product as a
white solid (180 mg, 100%). MS MH+ 485(487).
Example 180
[0496] 223
[0497] A solution of the oxime from Example 179 (100 mg) in THF (5
ml) was treated with potassium tert-butoxide solution (3 equiv.)
and stirred at room temperature for 15 mins. The reaction mixture
was diluted with water and ethyl acetate. The organic phase was
washed, dried, filtered and evaporated. Purification by column
chromatography gave the desired product (65 mg, 62%) as a white
solid. MS MH+ 467(469).
Example 181
[0498] 224
[0499] A solution of the amide from Example 161 (100 mg) was
dissolved in dioxane and treated with Lawesson's reagent and
stirred at room temperature overnight. The reaction mixture was
filtered and the filtrate was evaporated in vacuo. Purification by
column chromatography gave the thioamide (50 mg, 52%) as a white
solid. A solution of the foregoing thioamide (40 mg) in ethanol (2
ml) was treated with chloroacetone (1.3 equiv.) and refluxed for 4
h. The reaction mixture was evaporated in vacuo. Trituration from
hexane-ethyl acetate gave the desired product (26 mg, 59%) as a
white solid. MS MH+ 482(484).
Example 182
[0500] 225
[0501] A solution of the active ester from Example 178 step (1) in
DMF was treated with acetic hydrazide and stirred at room
temperature for 15 min. The reaction mixture was diluted with ether
and the precipitate was collected by filtration and washed several
times with ether to give the intermediate diacyl hydrazide as a
white solid. A solution of the foregoing compound (100 mg) in
dioxane was treated with Lawesson's reagent (2 equiv.) and stirred
at room temperature for 1 h. The reaction mixture was evaporated in
vacuo. Purification by column chromatography gave the desired
product (55 mg, 52%) as a white solid. MS MH+ 483(485).
Example 183
[0502] 226
[0503] To a solution of the cis amide from Example 128 (46 mg) and
pyridine (0.053 ml) in tetrahydrofuran (1 ml) was added
trifluoroacetic anhydride (0.056 ml). The solution was stirred at
room temperature for 2 hours when 0.5M-HCl (aqueous) and ethyl
acetate were added. The organic phase was dried (MgSO.sub.4),
evaporated to a small volume and purified by chromatography on
silica gel, eluting with isohexane:ethyl acetate (5:1) to give the
desired product as a colourless solid. .sup.1H NMR (360 MHz,
CDCl.sub.3) .delta. 1.61-1.70 (2H, m), 1.86-1.94 (2H, m), 2.03-2.10
(1H, m), 2.42-2.45 (4H, m), 2.51(2H, d J 8.0 Hz), 6.8 (1H, m),
7.02-7.09(2H, m), 7.30 (2H, d J 8.6 Hz), 7.36(2H, d J 8.7 Hz).
Example 184
[0504] 227
[0505] To a solution of the nitrile from Example 183 (0.43 g) in
dimethylformamide (0.5 ml) was added ammonium chloride (0.15 g) and
sodium azide (0.15 g) and the mixture was heated at 100.degree. C.
for 12 h. 0.2M-HCl (5 ml) and ethyl acetate (5 ml) were added and
the organic phase was washed with water (5 times) and dried
(MgSO.sub.4). The solvent was removed in vacuo and the residue was
purified by chromatography on silica gel (eluting with ethyl
acetate, 5% methanol in ethyl acetate) to give the desired product
MS m/z 451 (M-H)
Example 185
[0506] 228
[0507] The nitrile from Example 183 (300 mg) was dissolved in
methanol (3 ml) and ether (20 ml), cooled to 0.degree. C. and
treated with HCl gas for 10 minutes. The reaction vessel was
stoppered and left to stand at room temperature overnight. The
reaction mixture was evaporated in vacuo to give the imidate ether
hydrochloride salt (350 mg, ca 100%) as a white solid.
[0508] A solution of the foregoing imidate ether hydrochloride salt
(100 mg) in methanol (10 ml) was treated with acetic hydrazide (1.5
equiv.) and stirred at room temperature for 5 min. The reaction
mixture was evaporated in vacuo and taken up in Dowtherm A, treated
with ammonium chloride (100 mg) and heated at 190.degree. C. for 2
h. The reaction mixture was cooled and purified by column
chromatography to give the desired product (24 mg, 24%) as a white
solid. MS MH+ 467(469).
Example 186
[0509] 229
[0510] A suspension of the hydrazide of Example 178 (160 mg) in
methanol (10 ml) was treated with a solution of acetamidine (2
equiv.) in ethanol (1 ml) and stirred at room temperature
overnight, then refluxed for 2 h. The reaction mixture was
evaporated in vacuo, dissolv d in N-methylpyrrolidinone (2 ml) and
xylene (30 ml) and refluxed overnight with the azeotropic removal
of water. The reaction mixture was evaporated in vacuo, dissolved
in ethyl acetate and washed with water (three times). The organic
phase was dried, filtered and evaporated. Purification by column
chromatography gave the desired product (137 mg, 76%) as a white
solid. MS MH+ 466(468).
Example 187
[0511] 230
[0512] A solution of the triazole from Example 186 (50 mg) in DMF
(1 ml) was treated with sodium hydride (1.1 equiv.) and, after 5
minutes, methyl iodide (1.5 equiv.). After 1 h, the reaction
mixture was diluted with ethyl acetate and water. The organic layer
was washed with water, dried, filtered and evaporated in vacuo.
Purification by column chromatography gave the desired product (33
mg, 64%) as a white foam. .sup.1H NMR indicated this compound to be
a mixture of N1/N2 methylated regioisomers. MS MH+ 480(482).
Example 188
[0513] 231
[0514] A solution of the active ester from Example 178 step (1)
(200 mg) in toluene was treated with a suspension of semicarbazide
hydrochloride (1.1 equiv.) in DMF and triethylamine (2.2 equiv.)
and stirred at room temperature for half an hour. The reaction
mixture was diluted with ether and filtered. The residue was washed
with ether to give the crude acyl semicarbazide as a white
solid.
[0515] A suspension of this material (150 mg) in 1 M NaOH solution
(20 ml) and a small amount of 1,4-dioxane was refluxed overnight.
The reaction mixture was cooled and acidified with 1 M HCl. The
resulting precipitate was collected by filtration, washed with
water and ether several times and dried in vacuo to give the
desired product as a white solid. MS MH+ 468(470).
Example 189
[0516] 232
[0517] The hydrazide prepared in Example 178 (40 mg, 0.09 mmol)was
dissolved in triethyl orthoformate (3 ml) and heated at 150.degree.
C. for 18 h. Reaction was concentrated and purified by flash
chromatography (1:1 .sup.ihexane/ethyl acetate) to give a
colourless glassy solid (12 mg). .sup.1H NMR (CDCl3) 1.55-1.62 (2H,
m), 1.77-1.82 (2H, m), 2.20-2.28 (1H, m), 2.44 (1H, s), 2.50 (3H,
dd, J=5.5, 14.5 Hz), 3.07 (2H, d, J=7.8 Hz), 6.80-6.87 (1H, m),
7.01-7.09 (2H, m), 7.31-7.38 (4H, m), 8.36 (1H, s).
Example 190
[0518] 233
[0519] To the acid prepared in Example 50 (1.0 g, 2.3 mmol)
dissolved in THF (80 ml) under nitrogen and cooled to 0.degree. C.
were added triethylamine (0.4 ml, 2.8 mmol) and
isobutylchloroformate (0.36 ml, 2.8 mmol). Reaction was stirred at
0.degree. C. for 2 h and then the solid in the reaction mixture was
removed by filtration. The filtrate was recooled to 0.degree. C.
and sodium borohydride (435 mg) in water (10 ml) added dropwise and
the reaction was stirred for 1 h. Reaction was concentrated,
diluted with ethyl acetate, washed with water, brine, dried
(MgSO.sub.4), filtered and evaporated. Purified by flash
chromatography (1:1 .sup.ihexane/ethyl acetate) to give the alcohol
(0.96 g).
[0520] To the alcohol (400 mg, 0.97 mmol) dissolved in DCM (20 ml)
was added Dess-Martin periodinane (453 mg, 1.1 mmol). Reaction
stirred for 1 h and then filtered through a pad of Celite.TM. and
the filtrate evaporated and the residue purified by flash
chromatography (2:1 .sup.ihexane/ethyl acetate) to give the
aldehyde (250 mg) which was dissolved in ethanol (5 ml), cooled to
0.degree. C. and treated with glyoxal (40% w/w aq solution, 0.2 ml)
and ammonia (25% w/w aq. solution, 1 ml). After 30 min the reaction
was allowed to warm to room temperature and stirred for 15 h. After
concentration the residue was diluted with brine and extracted with
ethyl acetate (.times.3). Organic extracts were dried (MgSO.sub.4),
filtered and evaporated to give the imidazole as a white solid (150
mg). .sup.1H NMR (CDCl3) 1.45-1.55 (2H, m), 1.70-1.75 (2H, m),
2.17-2.22 (1H, m), 2.46 (4H, dd, J=5.6, 14.0 Hz), 2.88 (2H, d,
J=7.7 Hz), 6.78-6.85 (1H, m), 6.98 (2H, s), 7.00-7.05 (2H, m),
7.31-7.36 (4H, M), 9.1-9.8 (1H, br).
Example 191
[0521] 234
[0522] The imidazole prepared in Example 190 (35 mg, 0.078 mmol)
was dissolved in dry DMF (2 ml) and treated with potassium
carbonate (53 mg, 0.39 mmol) and iodomethane (6 .mu.l, 0.096 mmol)
and allowed to stir for 48 h. The reaction was diluted with water
and extracted with ethyl acetate (.times.3). Organic extracts were
dried (MgSO.sub.4), filtered and evaporated and purified by flash
chromatography (ethyl acetate) to give a white solid (8 mg).
.sup.1H NMR (CDCl3) 1.51-1.59 (1H, m), 1.80 (4H, dd, J=3.9, 10.5
Hz), 2.19-2.26 (1H, m), 2.42-2.57 (3H, m), 2.80 (2 H, d, J=7.7 Hz),
3.60 (3 H, s), 6.79 (1 H, d, J=1.1 Hz), 6.81-6.86 (1 H, m), 6.94
(1H, d, J=1.4 Hz), 7.00-7.08 (2H, m), 7.34 (4H, d, J=4.2 Hz).
Example 192
[0523] 235
[0524] The acid from Example 127 (153 mg) was dissolved in dry THF
(10 ml) and cooled to 0.degree. C. under nitrogen. Triethylamine
(61 .mu.L, 0.43 mmol) and isobutylchloroformate (57 .mu.L, 0.43
mmol) were added and the mixture stirred at 0.degree. C. for one
hour. The precipitate that had formed was removed by filtration and
washed with a further 5 ml of dry THF. The combined THF layers were
recooled to 0.degree. C. and sodium borohydride (70 mg, 1.84 mmol)
as a solution in water (2 ml) was added with effervescence. After
stirring for 30 minutes at 0.degree. C., the reaction was diluted
with ethyl acetate, washed with ammonium chloride solution, sodium
bicarbonate solution and brine then dried (MgSO.sub.4) and
evaporated to dryness. The residue was purified by column
chromatography eluting with ethyl acetate:hexane (1:3) to afford
the desired alcohol (75 mg). .sup.1H NMR (CDCl.sub.3) 7.39-7.31
(4H, m), 7.10-7.01 (2H, m), 6.88-6.81 (1H, m), 3.71 (2H, d, J=7.5
Hz), 2.46-2.32 (4H, m), 1.90-1.85 (2H, m), 1.78-1.74 (1H, m) and
1.54-1.44 (2H, m). m/z=423 [MNa].sup.+
Example 193
[0525] 236
[0526] A stirred solution of the alcohol from Example 192 (294 mg,
0.74 mmol) in DCM (10 ml) was cooled to -30.degree. C.
Triethylamine (155 .mu.l, 1.11 mmol) then methanesulfonyl chloride
(68 .mu.l, 0.89 mmol) were added and the mixture stirred for 30
minutes at -30.degree. C. The reaction was diluted with water,
warmed to ambient temperature and extracted with DCM. The organic
layer was washed with citric acid solution and sodium bicarbonate
solution, dried (MgSO.sub.4) and evaporated to dryness. The residue
(321 mg) could be used without further purification or purified by
column chromatography eluting with ethyl acetate:hexane (1:3) to
remove small quantities of the trans isomer to afford the desired
product. (272 mg). .sup.1H NMR (CDCl.sub.3) 7.36 (2H, d, J=8.5 Hz),
7.31 (2H, d, J=8.5 Hz), 7.08-7.02 (2H, m), 6.87-6.83 (1H, m), 4.29
(1H, d, J=7.5 Hz), 3.05 (3H, s), 2.46-2.42 (4H, m), 2.05-2.02 (1H,
m), 1.93-1.88 (2H, m) and 1.62-1.55 (2H, m). m/z=501
[MNa].sup.+
Example 194
[0527] 237
[0528] To a stirred solution of the alcohol from Example 192 (59
mg, 0.15 mmol) in dry THF (5 ml) cooled to 0.degree. C. under
nitrogen was added chlorosulfonyl isocyanate (18 .mu.l, 0.21 mmol).
The mixture was stirred for 45 minutes at this temperature then
sodium metabisulfite (84 mg, 0.44 mmol) as a solution in water (1
ml) was added and stirring continued for 16 hours at room
temperature. Ethyl acetate was added and the mixture washed with
water (.times.2), brine, dried (MgSO.sub.4) and evaporated to leave
a residual solid (73 mg) which was triturated with ether and
filtered to afford the desired product (35 mg). .sup.1H NMR (DMSO)
7.61 (2H, d, J=8.5 Hz), 7.36 (2H, d, J=8.5 Hz), 7.35-7.30 (1H, m),
7.25-7.10 (2H, m), 6.47 (2H, br s), 3.95 (2H, d, J=7.5 Hz), 3.16
(1H, m), 2.44 (1H, m), 2.23-2.14 (2H, m), 1.85-1.67 (3H, m) and
1.38-1.26 (2H, m). m/z=444 [MH].sup.+
Example 195
[0529] 238
[0530] A stirred solution of 1,2,4-triazole sodium derivative (95
mg, 1.04 mmol) in DMSO (5 ml) and the mesylate from Example 193
(100 mg, 0.21 mmol) were heated to 100.degree. C. for 17 hours. The
reaction was cooled, diluted with dichloromethane and washed with
water, brine (.times.2), dried (MgSO.sub.4) and evaporated to leave
a residue which was purified by preparative thin layer
chromatography eluting with ether:dichloromethane 1:1 to afford the
desired product. .sup.1H NMR (CDCl.sub.3) 8.09 (1H, s), 7.95 (1H,
s), 7.36 (2H, d, J=8.5 Hz), 7.31 (2H, d, J=8.5 Hz), 7.07-7.02 (2H,
m), 6.85-6.81 (1H, m), 4.27 (2H, d, J=8 Hz), 2.58-2.39 (4H, m),
2.28-2.22 (1H, m), 1.75-1.68 (2H, m) and 1.6-1.48 (2H, m). m/z=452
[MH].sup.+.
Example 196
[0531] 239
[0532] To a stirred solution of the alcohol from Example 192 (114
mg, 0.29 mmol) in dry THF (10 ml) was added 3-hydroxypyridine (30
mg, 0.32 mmol), triphenylphosphine (164 mg, 0.63 mmol) and
diethylazodicarboxylate (55 .mu.l, 0.35 mmol) and the resulting
solution stirred at ambient temperature for 20 hours. The mixture
was evaporated and purified by column chromatography eluting with
ethyl acetate:hexane (1:1) to afford the desired product. (52 mg).
.sup.1H NMR (CDCl.sub.3) 8.33 (1H, s), 8.24 (1H, s), 7.37-7.30 (4H,
m), 7.25-7.20 (2H, m), 7.11-7.03 (2H, m), 6.88-6.82 (1H, m), 4.07
(2H, d, J=7.5 Hz), 2.50-2.43 (4H, m), 2.13-2.09 (1H, m), 2.01-1.96
(2H, m) and 1.67-1.56 (2H, m). m/z=478[MH].sup.+
Example 197
[0533] 240
[0534] To a stirred solution of pyrrolidin-2-one (23 mg, 0.27 mmol)
in DMF (10 ml) under nitrogen was added sodium hydride (11 mg of a
60% dispersion in mineral oil, 0.27 mmol) and the mixture stirred
at ambient temperature for 20 minutes. After this time, a solution
of the mesylate from Example 193 (44 mg, 0.09 mmol) in DMF (2 ml)
was added and the mixture heated to 80.degree. C. for 4 hours. The
reaction was cooled, diluted with ethyl acetate and washed with
ammonium chloride solution, sodium bicarbonate solution, brine,
dried (MgSO.sub.4) and evaporated to leave a residue which was
purified by preparative thin layer chromatography eluting with
ethyl acetate:hexanes 3:1 to afford the desired product (9 mg).
.sup.1H NMR (CDCl.sub.3) 7.37 (4H, s), 7.08-7.00 (2H, m), 6.88-6.81
(1H, m), 3.38-3.34 (4H, m), 2.51-2.38 (6H, m), 2.06-1.98 (2H, m),
1.92-1.87 (1H, m), 1.70-1.64 (2H, m) and 1.51-1.42 (2H, m).
m/z=292[M-ArSO.sub.2--].sup.+
[0535] Using the general procedure of Example 197, and substituting
the appropriate nucleophile for pyrrolidin-2-one, the following
were prepared:
13 241 Example No. NR.sub.2 m/z 198 242 294 [M--ArSO.sub.2--]+ 199
243 292 [M--ArSO.sub.2--]+ 200 244 275 [M--ArSO.sub.2--]+451 [MH]+
201 245 302 [M--ArSO.sub.2--]+478 [MH]+ 202 246 321
[M--ArSO.sub.2--]+497 [MH]+ 203 247 307 [M--ArSO.sub.2--]+483 [MH]+
204 248 *** 205* 249 452 [MH]+ 206* 250 452 [MH]+ 207 251 451 [MH]+
208** 252 453 [MH]+ 209** 253 453 [MH]+ 210 254 482 [MH]+ *obtained
as a mixture using 1,2,3-triazole as nucleophile, and separated by
preparative TLC (2:1 DCM/hexane 2% MeOH). **obtained as a mixture
using 1,2,3,4-tetrazole as nucleophile, and separated by
preparative TLC. ***.sup.1H NMR (CDCl.sub.3) 7.36 (4H, br s),
7.06-7.04 (2H, m), 6.89-6.80(1H, m), 3.64-3.62 (2H, d, J=7.5 Hz),
2.53-2.46 (4H, m), 2.04-2.01 (1H, m), 1.69-1.68 (2H, m) and
1.51-1.50 (2H, m).
Example 211
[0536] 255
[0537] A stirred solution of 2-hydroxypyridine (60 mg, 0.63 mmol)
in DME (4 ml) and DMF (1 ml) under nitrogen was cooled to 0.degree.
C. Sodium hydride (28 mg of a 60% dispersion in mineral oil, 1.15
mmol) was then added and the suspension stirred at 0.degree. C.
LiBr (109 mg, 1.26 mmol) was added 10 minutes later. After this
time, the mixture was warmed to ambient temperature and stirred for
15 minutes. A solution of the mesylate from Example 193 (60 mg,
0.13 mmol) in DMF (2 ml) was added and the mixture heated to
65.degree. C. for 18 hours. The reaction was cooled, diluted with
ethyl acetate and washed with ammonium chloride solution, sodium
bicarbonate solution and brine then dried (MgSO.sub.4) and
evaporated to leave a residue which was purified by preparative
thin layer chromatography eluting with EtOAc:Hexane 1:5 to afford
the desired product (4 mg).
[0538] .sup.1H NMR (CDCl.sub.3) 7.55-7.30 (5H, m), 7.25-7.22 (1H,
dd J=7.0, 2.0 Hz), 7.09-7.00 (2H, m), 6.85-6.78 (1H, m), 6.58-6.55
(1H, d, J=9.0 Hz), 6.18-6.14 (1H, m), 4.02-3.99 (2H, d, J=8.0 Hz),
2.62-2.55 (2H, m), 2.44 (2H, m), 2.19-2.17 (1H, m), 1.80-1.76 (2H,
m) and 1.6-1.5 (2H, m).
Example 212
[0539] 256
[0540] To a stirred solution of the mesylate from Example 193 (90
mg, 0.19 mmol) in DMF (10 ml) under nitrogen was added sodium azide
(49 mg, 0.76 mmol) and the mixture stirred and heated to
100.degree. C. for 2 hours. After this time, the reaction was
cooled, diluted with water and extracted with ethyl acetate
(.times.2), the combined organic layers were washed with water,
dried (MgSO.sub.4) and evaporated to leave a residue (76 mg) which
was purified by preparative thin layer chromatography eluting with
4% EtOAc:Hexane to afford the desired product.
[0541] .sup.1H NMR (CDCl.sub.3) 7.38-7.30 (4H, m), 7.09-7.01 (2H,
m), 6.87-6.80 (1H, m), 3.43-3.41 (2H, d, J=8.0 Hz), 2.46-2.35 (4H,
m), 1.87-1.79 (3H, m), 1.56-1.50 (2H, m).
Example 213
[0542] 257
[0543] Step (1)
[0544] The alcohol from Example 192 (181 mg, 0.46 mmol) was
dissolved in THF and pyridine (37 .mu.l, 0.46 mmol) added followed
by 4-nitrophenyl chloroformate (103 mg, 0.51 mmol). The reaction
was stirred overnight at room temperature then the solvent removed
in vacuo and the reaction taken up in ether and washed with water
(.times.2) and brine (.times.2), dried (MgSO.sub.4) and evaporated
to a foam (247 mg). Product was purified by flash column
chromatography (1% MeOH, 99% DCM) to yield the desired
4-nitrophenylcarbonate (230 mg)
[0545] Step (2)
[0546] The carbonate (74 mg, 0.14 mmol) was dissolved in DMF (2 ml)
and isopropylamine (23 .mu.l, 0.28 mmol) added. The reaction was
stirred for 10 minutes then diluted with ethyl acetate and washed
with 2N NaOH (.times.3) and brine (.times.3), dried (MgSO.sub.4)
and evaporated to dryness. The crude product was purified by prep
plate (2:1 hexane:ethyl acetate) affording the desired product (18
mg). .sup.1H NMR (CDCl.sub.3) 7.38-7.30 (4H, m), 7.09-6.99 (2H, m),
6.88-6.79 (1H, m) 4.57-4.48 (1H, s, broad), 4.13 (2H, d, J=8.5 Hz),
3.88-3.71 (1H, m), 2.49-2.38 (4H, m), 1.92-1.80 (3H, m) 1.55-1.41
(2H, m), and 1.16 (6H, d, J=6.5 Hz).
Example 214
[0547] 258
[0548] The carbonate from Example 213 step (1) (56 mg, 0.14 mmol)
was dissolved in THF (2 ml) and ethylamine (0.4 ml, 0.28 mmol, 2M
solution in THF) added. The reaction was stirred for 10 minutes
then evaporated to a foam. The reaction was taken up in ethyl
acetate and washed with 2N NaOH (.times.3) and brine (.times.3),
dried (MgSO.sub.4) and evaporated to dryness. The crude product was
purified by prep plate (2:1 hexane:ethyl acetate) affording the
desired product (18 mg). .sup.1H NMR (CDCl.sub.3) 7.38-7.30 (4H,
m), 7.09-6.99 (2H, m), 6.88-6.79 (1H, m) 4.61-4.70 (1H, s, broad),
4.14 (2H, d, J=7 Hz), 3.28-3.15 (2H, m), 2.49-2.38 (4H, m),
1.90-1.79 (3H, m) 1.55-1.42 (2H, m) and 1.15 (3H, t, J=7 Hz).
Example 215
[0549] 259
[0550] Prepared as for Example 214 using dimethylamine (2M solution
in THF) as starting material. Yield 7 mg. .sup.1H NMR (CDCl.sub.3)
7.38-7.30 (4H, m), 7.09-6.99 (2H, m), 6.88-6.78 (1H, m), 4.15 (2H,
d, J=7 Hz), 2.91 (6H, s), 2.49-2.38 (4H, m), 1.95-1.80 (3H, m) and
1.55-1.48 (2H, m).
Example 216
[0551] 260
[0552] Prepared as for Example 214 using cyclopropylmethylamine as
starting material. Yield 11 mg. .sup.1H NMR (CDCl.sub.3) 7.38-7.30
(4H, m), 7.09-7.00 (2H, m), 6.88-6.78 (1H, m), 4.87-4.75 (1H, s,
broad), 4.14 (2H, d, J=7 Hz), 3.08-2.97 (2H, m), 2.47-2.38 (4H, m),
1.98-1.79 (3H, m), 1.55-1.41 (2H, m), 1.0-0.88 (1H, m), 0.53-0.46
(2H, m) and 0.20-0.12 (2H, m).
Example 217
[0553] 261
[0554] Prepared as for Example 214 using methylamine (8M solution
in EtOH) as starting material. Yield 7 mg. .sup.1H NMR (CDCl.sub.3)
7.38-7.30 (4H, m), 7.09-7.00 (2H, m), 6.88-6.78 (1H, m), 4.68-4.56
(1H, s, broad), 4.14 (2H, d, J=7 Hz), 2.81 (3H, d, J=4.89),
2.48-2.38 (4H, m), 1.91-1.76 (3H, m) and 1.56-1.41 (2H, m).
Example 218
[0555] 262
[0556] To the pentafluorophenol ester prepared in Example 178 step
(1) (140 mg, 0.23 mmol) dissolved in DCM (3 ml) and under nitrogen
were added methoxyamine hydrochloride (80 mg, 0.92 mmol) and
triethylamine (0.1 ml). After 1 h the reaction was concentrated,
diluted with ethyl acetate, washed with aq. sodium carbonate,
water, brine, dried (MgSO.sub.4), filtered and evaporated. Purified
by flash column chromatography (1:1 .sup.ihexane/ethyl acetate to
ethyl acetate/methanol) to give a white solid (50 mg). .sup.1H NMR
(CDCl3) 1.56 (2H, br), 1.76 (2H, br), 2.25 (4H, br), 2.44 (4H, br),
3.78 (3H, s), 6.78-6.86 (1H, m), 7.01-7.06 (2H, m), 7.29-7.37 (4H,
m).
Example 219
[0557] 263
[0558] To a stirred suspension of cis
4-(4-chlorobenzenesulphonyl)-4-(2,5--
difluorophenyl)cyclohexaneacetic acid (Example 50, 0.224 g, 0.52
mmol) in dichloromethane (5 ml) was added oxalyl chloride (0.075
ml, 0.86 mmol) and dimethylformamide (1 drop). After 30minutes the
solution was evaporated to a small volume and to a solution of the
residue in dichloromethane (5 ml) was added
N,O-dimethylhydroxylamine hydrochloride (0.068 g, 0.58 mmol) and
diisopropylethylamine (0.2 ml, 1.14 mmol). After stirring the
solution for 30 minutes the solvent was removed in vacuo and the
residue purified by chromatography on silica gel eluting with
increasing concentrations of ethyl acetate in isohexane (33%, 50%).
The fractions containing the product were evaporated to give the
desired product as a foam. .sup.1H NMR (360 MHz, CDCl.sub.3)
.delta. 1.50-1.56 (2H, m), 1.72-1.77 (2H, m), 2.24 (1H, m), 2.44
(4H, m),2.57 (2H, d J 7.3 Hz), 3.2 (3H, s),3.7 (3H, s), 6.80-6.88
(1H, m), 7.01-7.08 (2H, m), 7.31 (2H, dd J 6.7 Hz and 2.3 Hz), 7.36
(2H, dd J 6.7 Hz and 2.3 Hz).
Example 220
[0559] 264
[0560] To the pentafluorophenol ester prepared in Example 178 step
(1) (155 mg, 0.25 mmol) dissolved in DMF (3 ml) and under nitrogen
were added glycine methyl ester hydrochloride (125 mg, 1.0 mmol)
and triethylamine (0.15 ml). After 2 h the reaction was diluted
with water, extracted with ethyl acetate (.times.3), washed with,
water, brine, dried (MgSO.sub.4), filtered and evaporated. Purified
by flash column chromatography (1:1 .sup.ihexane/ethyl acetate to
9:1 ethyl acetate/methanol) to give a white solid (55 mg). .sup.1H
NMR (CDCl3) 1.08-1.16 (1H, m), 1.30-1.37 (1H, m), 1.67-1.71 (1H,
m), 1.75-1.79 (2H, m), 1.91-1.95 (1H, m), 2.20-2.26 (1H, m), 2.41
(4 H, d, J=7.8 Hz), 3.77 (3H, s), 4.05 (2H, d, J=5.1 Hz), 6.19 (1H,
br), 6.79-6.85 (1H, m), 7.00-7.07 (2H, m), 7.30-7.37 (4H, m).
Example 221
[0561] 265
[0562] The glycine ester prepared in Example 220 (50 mg, 0.1 mmol)
in a sealed tube and dissolved in a 2M ammonia in methanol solution
(3 ml) was heated to 50.degree. C. for 3 h. After cooling to room
temperature the reaction mixture was concentrated and purified by
trituration with ether to give a white solid (28 mg). MS(EI+): 485
(MH+)
Example 222
[0563] 266
[0564] The alcohol from Example 192 (4 g, 10 mmol) was dissolved in
dichloromethane (280 ml) and was treated with Dess Martin
periodinane (4.66 g, 11 mmol) and the mixture was stirred for 45
mins before adding saturated aqueous sodium bisulphite (100 ml) and
after 5 mins the mixture was separated and the organic phase as
washed with saturated aqueous sodium bicarbonate (100 ml) dried
(MgSO.sub.4) and evaporated to dryness. The crude residue (4 g) was
dissolved in dry dichloromethane (100 ml) and treated with methyl
triphenylphosphinoacetate (4.7 g 14 mmol), stirring at rt. for 16
hrs. The solvent was evaporated and the residue was purified by
column chromatography on silica gel eluting with 10-20% ethyl
acetate in hexanes, to give the product. .sup.1H NMR (CDCl.sub.3)
7.37-7.36 (4H, m), 7.10-7.02 (3H, m), 6.87-6.83 (1H, m),5.91 (1H,
d, J=16 Hz), 3.77 (3H, s), 2.55-2.45 (3H, m), 2.40-2.38 (2H, m),
1.95-1.90 (2H,m) and 1.65-1.52 (1H, m).
Example 223
[0565] 267
[0566] The alkene from Example 222 (3.6 g, 9 mmol) was dissolved in
ethyl acetate (350 ml). The flask was degassed and then 10%
palladium on carbon (400 mg) was added and the mixture stirred
under an atmosphere of hydrogen for 45 mins. The solution was
filtered through Celite.TM. and evaporated. The clear oil obtained
was purified by preparative tlc eluting with 5% ethyl acetate in
hexanes. The oil obtained was then further purified by column
chromatography on silica gel eluting with 5-10% ethyl acetate in
hexane to give the product. .sup.1H NMR (CDCl.sub.3) 7.37-7.34 (4H,
m), 7.08-7.00 (2H, m), 6.85-6.81 (1H, m), 3.67 (3H, s), 2.45-2.39
(4H, m), 2.33 (2H, t, J=8.4 Hz), 1.81 (2H, q, J=8.4 Hz), 1.72-1.68
(2H,m) and 1.60-1.43 (3H, m).
Example 224
[0567] 268
[0568] The ester from Example 223 (104 mg, 0.23 mmol) was dissolved
in a mixture of ethanol (10 ml) and water (3 ml) and stirred at
20.degree. C. The flask was degassed and then lithium hydroxide (27
mg, 1.15 mmol) was added. The mixture was stirred for 3 hrs. at
room temperature. 1N Hydrochloric acid was then added and the
mixture was washed with ethyl acetate (2.times.50 ml). The organic
phase was washed with brine (50 ml), dried (MgSO.sub.4) and
evaporated. The oil obtained was then further purified by
preparative tlc eluting with ethyl acetate to give the acid.
.sup.1H NMR (CDCl.sub.3) 7.37-7.30 (4H, m), 7.09-6.99 (2H, m),
6.85-6.79 (1H, m), 2.42-2.36 (6H, m), 1.85-1.79 (2H, m), 1.73-1.69
(2H,m), 1.63-1.58 (1H,m) and 1.53-1.45 (2H, m).
Example 225
[0569] 269
[0570] The acid from Example 224 (52 mg, 0.118 mmol) in
dichloromethane (2 ml) was treated with oxalyl chloride (88 .mu.l,
2 M solution in dichloromethane, 0.176 mmol). A drop of
N,N-dimethylformamide was added and the solution allowed to stir
for 2 hours. After this time, solvent was removed in vacuo and the
residue redissolved in dichloromethane (1 ml). This solution was
dripped into methanolic ammonia (2 M, 2 ml). The reaction was
evaporated in vacuo and the residue chromatographed on silica,
eluting with 80% ethyl acetate in hexanes. The resulting material
was purified further by preparative t.l.c., eluting with 100% ethyl
acetate followed by recrystallisation from hot hexane to give
product (7.4 mg, 14%). .sup.1H NMR (360 MHz, CDCl.sub.3), 1.45-1.53
(2H, m), 1.57-1.65 (1H, br), 1.70-1.75 (2H, m), 1.78-1.84 (2H, m),
2.32 (2H, t, J=15.3 Hz), 2.38-2.44 (4H, br), 2.95 (3H, s), 3.02
(3H, s), 6.79-6.86 (1H, m), 7.00-7.09 (2H, m), 7.31-7.37 (4H, m);
ms. (ES.sup.+), 470 (M.sup.+1), 294 (M.sup.+175).
Example 226
[0571] 270
[0572] The acid from Example 224 (52 mg, 0.118 mmol) in
dichloromethane (2 ml) was treated with
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (45 mg,
0.235 mmol), triethylamine (32.7 .mu.l, 0.235 mmol) and
tert-butylamine (24.6 .mu.l, 0.235 mmol). After 2 hours stirring at
room temperature, reaction was washed with hydrochloric acid (1 N,
10 ml), organics dried (MgSO.sub.4) and evaporated in vacuo to give
crude (55 mg). This material was chromatographed on silica, eluting
with 20-30% ethyl acetate in hexanes to give product (25 mg, 43%).
.sup.1H NMR (400 MHz, CDCl.sub.3), 1.35 (9H, s), 1.45-1.62 (3H, m),
1.67-1.74 (2H, m), 1.76-1.80 (2H, m), 2.08-2.12 (2H, m), 2.38-2.42
(4H, br), 5.72-5.78 (1H, br), 6.76-6.88 (1H, m), 7.00-7.10 (2H, m),
7.31-7.37 (4H, m).
Exampl 227
[0573] 271
[0574] To a cooled (-80.degree. C.) solution of
1-(trimethylsilylethyloxym- ethyl)triazole (0.109 g, 0.55 mmol) in
tetrahydrofuran (2 ml) was added a solution of n-butyl lithium
(2.5M in hexanes, 0.22 ml). The solution was stirred at -80.degree.
C. for 15 minutes, warmed to 0.degree. C. for 5 minutes and then
recooled to -80.degree. C. To the cooled solution was added a
solution of cis 4-(4-chlorobenzenesulphonyl)-4-(2,5-difluoropheny-
l)cyclohexaneacetic acid N,O-dimethylhydroxamate (Example 219) (217
mg, 0.46 mmol) in tetrahydrofuran (3 ml). After stirring the
mixture at -80.degree. C. for 15 minutes a saturated solution of
aqueous ammonium chloride was added and the product extracted with
ethyl acetate. The organic phase was dried (MgSO.sub.4), evaporated
to dryness and purified by chromatography on silica gel (eluting
with 25% ethyl acetate in hexane) to give the desired product as a
crystalline solid. MS m/z 610,612 (M+H)
Example 228
[0575] 272
[0576] Th triazole from Example 227 (0.117 g) was heated in a
mixture of ethanol (10 ml) and 6M-HCl (aqueous) (5 ml) and
concentrated HCl (2 ml) for 2 hours at 60.degree. C. Water and
ethyl acetate were added and the organic phase was dried
(MgSO.sub.4), evaporated in vacuo and the residue purified by
chromatography on silica gel (eluting with 50% ethyl acetate in
hexane, 100% ethyl acetate) to give the desired product as a solid
which was washed with hexane mp 147-154.degree. C. MS m/z 480,482
(M+H). .sup.1H NMR (360 MHz, CD.sub.4OD) 1.51-1.60 (2H, m), 1.76
(2H, dd, J=14.3 Hz and 3.1 Hz), 2.37 (1H, m), 2.5 (4H m),3.26 (2H,
d, J=7.3 Hz), 6.96 (1H, m), 7.16 (2H, m), 7.40 (2H, dt, J=8.7 Hz
and 2.23 Hz), 7.51 (2H, dt, J=8.7 Hz and 2.23 Hz), 8.51 (1H,
s).
Example 229
[0577] 273
[0578] To a solution of the product of Example 228, (50 mg) in
methanol (2 ml) was added sodium borohydride (4.5 mg 0.11 mmol).
After 30 minutes ethyl acetate and water were added followed by
addition of solid citric acid (50 mg). The organic phase was dried
(MgSO.sub.4), evaporated to dryness and the residue chromatographed
on silica gel (eluting with ethyl acetate then 5% methanol in ethyl
acetate) to give the desired product as a colourless solid after
washing the residue with hexane. MS m/z 482, 484(M+H)). .sup.1H NMR
(360 MHz, CD.sub.4OD) 1.43-1.54 (2H, m), 1.75-1.88 (3H, m),
1.54-2.0 (1H, m), 2.01-2.16 (1H,m), 2.35-2.55(5H,m), 6.93-7.00 (1H,
m), 7.09-7.18 (2H, m), 7.37 (2H, d, J=8.6 Hz), 7.48 (2H,d, J=8.6
Hz), 8.1 (1H, v.broad s).
Example 230
[0579] 274
[0580] The ester from Example 48 (669 mg, 1.467 mmol) in
tetrahydrofuran (14 ml) was cooled to -78.degree. C., treated with
sodium bis(trimethylsilyl)amide (2.20 ml, 1 M solution in
tetrahydrofuran, 2.20 mmol) and stirred while warming to room
temperature over 2 hours. Methyl iodide (457 .mu.l, 7.36 mmol) was
then added to the mixture at -20.degree. C. and stirring continued,
again warming to room temperature, for 2 hours. The reaction was
quenched with glacial acetic acid (132 .mu.l, 2.20 mmol), diluted
with ammonium chloride (50% aq., 80 ml) and extracted with ethyl
acetate (3.times.100 ml). Combined organics were then washed with
brine (sat., 200 ml), dried (MgSO.sub.4) and evaporated in vacuo to
give crude (670 mg). This material was chromatographed on silica,
eluting with 8% ethyl acetate in hexanes to give product (272 mg,
40%). .sup.1H NMR (400 MHz, CDCl.sub.3), 1.16 (3H, d, J=6.9 Hz),
1.28 (3H, t, J=7.1 Hz), 1.45-1.51 (2H, m), 1.71-1.77 (2H, m),
1.89-1.94 (1H, m), 2.28-2.48 (3H, br), 2.54-2.60 (1H, br),
2.70-2.74 (1H, m),
Example 231
[0581] 275
[0582] A solution of .alpha.-methyl ethyl ester from Example 230
(13 mg, 0.028 mmol) in methanol/water/tetrahydrofuran (3:1:1, 1 ml)
was degassed and treated with lithium hydroxide (3.3 mg, 0.138
mmol) and the mixture heated to 90.degree. C. After 1 hour at this
temperature, the reaction was cooled to room temperature, acidified
with hydrochloric acid (1 N, 2 ml), diluted with water (5 ml) and
extracted with ethyl acetate (3.times.10 ml). Combined organics
were washed with brine (sat., 30 ml), dried (MgSO.sub.4) and
evaporated in vacuo to give crude. This material was purified by
preparative t.l.c., eluting with 3% methanol, 1% acetic acid in
dichloromethane to give product (7 mg, 57%). .sup.1H NMR (360 MHz,
CDCl.sub.3), 1.22 (3H, d, J=6.9 Hz), 1.48-1.58 (2H, m), 1.74-1.96
(3H, m), 2.30-2.50 (3H, br), 2.53-2.62 (1H, br), 2.71-2.81 (1H, m),
6.78-6.84 (1H, m), 7.00-7.09 (2H, m), 7.30-7.37 (4H, m).
Example 232
[0583] 276
[0584] Prepared from the ketone of Example 41, following the
procedures of Examples 47, 48 and 50. .sup.1H NMR (360 MHz, CDCl3)
1.52-1.61 (2H, m), 1.76-1.81 (2H, m), 2.20-2.26 (1H, m), 2.39 (2H,
d, J=7.6 Hz), 2.40-2.50 (4H, m), 5.37 (1H, br), 5.51 (1H, br),
6.75-6.83 (1H, m), 7.01-7.08 (2H, m), 7.51 (2H, d, J=8.3 Hz) and
7.64 (2H, d, J=8.3 Hz).
Example 233
[0585] 277
[0586] Prepared from the acid of Example 232 by the procedure of
Example 178, using ammonia in the second step. MS MH+ 462(463).
* * * * *