U.S. patent application number 10/425307 was filed with the patent office on 2003-11-06 for hydroxamic and carboxylic acid derivatives having mmp and tnf inhibitory activity.
Invention is credited to Baxter, Andrew Douglas, Keily, John Fraser, Montana, John Gary, Owen, David Alan, Watson, Robert John.
Application Number | 20030207889 10/425307 |
Document ID | / |
Family ID | 27451504 |
Filed Date | 2003-11-06 |
United States Patent
Application |
20030207889 |
Kind Code |
A1 |
Owen, David Alan ; et
al. |
November 6, 2003 |
Hydroxamic and carboxylic acid derivatives having MMP and TNF
inhibitory activity
Abstract
Hydroxamic and carboxylic acid derivatives having MMP and TNF
inhibitory activity.
Inventors: |
Owen, David Alan;
(Cambridge, GB) ; Montana, John Gary; (Cambridge,
GB) ; Keily, John Fraser; (Cambridge, GB) ;
Watson, Robert John; (Cambridge, GB) ; Baxter, Andrew
Douglas; (Cambridge, GB) |
Correspondence
Address: |
SALIWANCHIK LLOYD & SALIWANCHIK
A PROFESSIONAL ASSOCIATION
2421 N.W. 41ST STREET
SUITE A-1
GAINESVILLE
FL
326066669
|
Family ID: |
27451504 |
Appl. No.: |
10/425307 |
Filed: |
April 29, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10425307 |
Apr 29, 2003 |
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10011031 |
Nov 13, 2001 |
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6566384 |
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10011031 |
Nov 13, 2001 |
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09209627 |
Dec 11, 1998 |
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09209627 |
Dec 11, 1998 |
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08908397 |
Aug 7, 1997 |
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6118001 |
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Current U.S.
Class: |
514/252.05 ;
514/341; 514/389; 514/417; 514/425; 544/236; 544/238; 546/274.4;
548/319.1; 548/477; 548/547 |
Current CPC
Class: |
C07D 207/48 20130101;
C07C 317/44 20130101; C07C 2601/08 20170501 |
Class at
Publication: |
514/252.05 ;
546/274.4; 544/236; 544/238; 548/319.1; 548/477; 548/547; 514/341;
514/389; 514/417; 514/425 |
International
Class: |
A61K 031/501; A61K
031/4439; A61K 031/4162; A61K 031/4035; A61K 031/4015; C07D
43/02 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 7, 1996 |
GB |
9616599.8 |
Apr 11, 1997 |
GB |
9707427.2 |
Claims
We claim:
1. A compound of formula (Ic)
B--SO.sub.2--CH.sub.2--CHR.sup.1--CO--NHOH (Ic) wherein R.sup.1 is
C.sub.1-6 alkyl substituted with R.sup.9; B is aryl or heteroaryl,
either of which is optionally substituted by a substituent selected
from R.sup.5, C.sub.1-6 alkyl-R.sup.5, C.sub.2-6 alkenyl-R.sup.5,
aryl (optionally substituted with R.sup.5), aryl-C.sub.1-6
alkyl-R.sup.5, C.sub.1-6 alkyl-aryl (optionally substituted with
R.sup.5), C.sub.1-6 alkyl-heteroaryl (optionally substituted with
R.sup.5), aryl-C.sub.2-6 alkenyl-R.sup.7, heteroaryl (optionally
substituted with R.sup.5), heteroaryl-C.sub.1-6 alkyl-R.sup.5,
cycloalkyl (optionally substituted with R.sup.5), benzofused
cycloalkyl (optionally substituted with R.sup.5), heterocycloalkyl
(optionally substituted with R.sup.5), benzofused heterocycloalkyl
(optionally substituted with R.sup.5), and the groups: 15R.sup.2 is
H or C.sub.1-6 alkyl; R.sup.5 is C.sub.1-6 alkyl, C.sub.2-6
alkenyl-R.sup.7, halogen, CN, NO.sub.2, N(R.sup.6).sub.2, OR.sup.6,
COR.sup.6, CO.sub.2R.sup.2, CON(R.sup.6).sub.2, NR.sup.6R.sup.7,
S(O).sub.0-2R.sup.8 or SO.sub.2N(R.sup.6).sub.2; R.sup.6 is H or a
group selected from C.sub.1-6 alkyl, aryl, C.sub.1-6 alkyl-aryl,
heteroaryl, C.sub.1-6 alkyl-heteroaryl, cycloalkyl, C.sub.1-6
alkyl-cycloalkyl, heterocycloalkyl and C.sub.1-6
alkyl-heterocycloalkyl, wherein said group is optionally
substituted with R.sup.8, COR.sup.8, SO.sub.0-2R.sup.8,
CO.sub.2R.sup.8, OR.sup.8, CONR.sup.2R.sup.8, NR.sup.2R.sup.8,
halogen, CN, SO.sub.2NR.sup.2R.sup.8 or NO.sub.2, and for each case
of N(R.sup.6).sub.2 the R.sup.6 groups are the same or different or
N(R.sup.6).sub.2 is heterocycloalkyl optionally substituted with
R.sup.8, COR.sup.8, SO.sub.0-2R.sup.8, CO.sub.2R.sup.8, OR.sup.8,
CONR.sup.2R.sup.8, NR.sup.2R.sup.8, halogen, CN,
SO.sub.2NR.sup.2R.sup.8 or NO.sub.2; R.sup.7 is COR.sup.6,
CON(R.sup.6).sub.2, CO.sub.2R.sup.8 or SO.sub.2R.sup.8; R.sup.8 is
C.sub.1-6 alkyl, aryl, C.sub.1-6 alkyl-aryl, heteroaryl or
C.sub.1-6 alkyl-heteroaryl; and R.sup.9 is phthalimido, succinimido
or the group: 16or an N-oxide, salt, solvate, hydrate, protected
amino or protected carboxy derivative thereof.
2. The compound according to claim 1, wherein R.sup.1 is ethyl or
propyl.
3. The compound according to claim 1, wherein R.sup.2 is
methyl.
4. The compound according to claim 1, wherein B is optionally
substituted phenyl, furanyl, thiophenyl, pyridyl or
pyridyl-N-oxide.
5. The compound according to claim 1, wherein R.sup.5 is OR.sup.6
or COR.sup.6.
6. The compound according to claim 5, wherein R.sup.6 is optionally
substituted C.sub.1-6 alkyl, aryl, C.sub.1-6 alkyl-aryl, heteroaryl
or C.sub.1-6 alkyl-heteroaryl.
7. The compound according to claim 6, wherein R.sup.6 is optionally
substituted methyl, phenyl, furanyl, thiophenyl, pyridyl,
pyridyl-N-oxide, methyl-pyridyl, ethyl-pyridyl, methyl-furanyl,
ethyl-furanyl, methyl-thiophenyl or ethyl-thiophenyl.
8. The compound according to claim 1, wherein R.sup.6 is
substituted with R.sup.8, OR.sup.8, F, Cl, Br, I or CN.
9. The compound according to claim 8, wherein R.sup.6 is
substituted with phenyl, OCH.sub.3 or Cl.
10. The compound according to claim 1, selected from the group
consisting of:
2-(4-Methoxyphenylsulfonylmethyl)-5-phthalimido-pentanoic Acid
N-Hydroxy Amide;
2-(4-Methoxyphenylsulfonylmethyl)-4-phthalimido-butanoic Acid
N-Hydroxy Amide;
2-(4-Methoxyphenylsulfonylmethyl)-5-succinimido-pen- tanoic Acid
N-Hydroxy Amide; 2-(4-Benzoylphenyl)sulfonylmethyl-5-succinimi-
do-pentanoic Acid N-Hydroxy Amide;
2-(4-Methoxyphenylsulfonylmethyl)-5-(3,-
3,4-trimethylhydantoin-1-yl)pentanoic Acid N-Hydroxy Amide;
2-(4-Methoxyphenylsulfonylmethyl)-4-(3,3,4-trimethylhydantoin-1-yl)butano-
ic Acid N-Hydroxy Amide;
2-((4-Trifluoromethoxyphenylsulfonyl)methyl)-5-(1-
,5,5-trimethylhydantoin-3-yl)pentanoic Acid N-Hydroxy Amide;
2-(4-benzoylphenyl)sulfonylmethyl-4-(3,3,4-trimethylhydantoin-1-yl)butano-
ic Acid N-Hydroxy Amide;
2-((4-Benzoylphenyl)sulfonylmethyl)-5-(3,3,4-trim-
ethylhydantoin-1-yl)pentanoic Acid N-Hydroxy Amide;
2-((4-(4-Pyridinoyl)phenyl)sulfonylmethyl)-5-(3,3,4-trimethylhydantoin-1--
yl)pentanoic Acid N-Hydroxy Amide;
2-((4-(2-Thienoyl)phenyl)sulfonylmethyl-
)-5-(3,3,4-trimethylhydantoin-1-yl)pentanoic Acid N-Hydroxy Amide;
and
2-(1-Oxy-pyridine-4-sulfonylmethyl)-5-(3,4,4-trimethyl-2,5-dioxo-imidazol-
idin-1-yl)pentanoic acid hydroxyamide.
11. A method for the treatment or prevention of a condition
associated with matrix metalloproteinases or that is mediated by
TNF .alpha. or enzymes involved in the shedding of L-selectin, the
TNF receptors or IL-6 receptors, which comprises administration of
a compound of claim 1 to a patient in need thereof.
12. The method according to claim 11, wherein the condition is
selected from the group consisting of cancer, inflammation and
inflammatory diseases, tissue degeneration, periodontal disease,
ophthalmological disease, dermatological disorders, fever,
cardiovascular effects, haemorrhage, coagulation and acute phase
response, cachexia, anorexia, acute infection, HIV infection, shock
states, graft versus host reactions, autoimmune disease,
reperfusion injury, meningitis, migraine, and aspirin-independent
anti-thrombosis.
13. The method according to claim 11, wherein the condition is
selected from the group consisting of tumour growth, angiogenesis,
tumour invasion and spread, metastases, malignant ascites, and
malignant pleural effusion.
14. The method according to claim 11, wherein the condition is
selected from the group consisting of cerebral ischaemia, ischaemic
heart disease, rheumatoid arthritis, osteoarthritis, osteoporosis,
asthma, multiple sclerosis, neurodegeneration, Alzheimer's,
atherosclerosis, stroke, vasculitis, Crohn's disease, and
ulcerative colitis.
15. The method according to claim 11, wherein the condition is
selected from the group consisting of corneal ulceration,
retinopathy, and surgical wound healing.
16. The method according to claim 11, wherein the condition is
selected from the group consisting of psoriasis, atopic dermatitis,
chronic ulcers, and epidermolysis bullosa.
17. The method according to claim 11, wherein the condition is
selected from the group consisting of periodontitis, and
gingivitis.
18. The method according to claim 11, wherein the condition is
selected from the group consisting of rhinitis, allergic
conjunctivitis, eczema, and anaphylaxis.
19. The method according to claim 11, wherein the condition is
selected from the group consisting of restenosis, congestive heart
failure, endometriosis, atherosclerosis, and endosclerosis.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This Application is a continuation-in-part of application
Ser. No. 09/209,627, filed Dec. 11, 1998, which is a continuation
of application Ser. No. 08/908,397, filed Aug. 7, 1997, now U.S.
Pat. No. 6,118,001.
FIELD OF THE INVENTION
[0002] This invention relates to hydroxamic and carboxylic acid
derivatives, and to their use in medicine.
BACKGROUND OF THE INVENTION
[0003] Metalloproteinases, including matrix metalloproteinase
(MMP), (human fibroblast) collagenase, gelatinase and TNF
convertase (TACE), and their modes of action, and also inhibitors
thereof and their clinical effects, are described in WO-A-9611209,
WO-A-9712902 and WO-A-9719075, the contents of which are
incorporated herein by reference. MMP inhibitors may also be useful
in the inhibition of other mammalian metalloproteinases such as the
adamalysin family (or ADAMs) whose members include TNF convertase
(TACE) and ADAM-10, which can cause the release of TNF.alpha. from
cells, and others, which have been demonstrated to be expressed by
human articular cartilage cells and also involved in the
destruction of myelin basic protein, a phenomenon associated with
multiple sclerosis.
[0004] Compounds which have the property of inhibiting the action
of metalloproteinases involved in connective tissue breakdown, such
as collagenase, stromelysin and gelatinase, have been shown to
inhibit the release of TNF both in vitro and in vivo. See Gearing
et al (1994), Nature 370:555-557; McGeehan et al (1994), Nature
370:558-561; GB-A-2268934; and WO-A-9320047. All of these reported
inhibitors contain a hydroxamic acid zinc-binding group, as do the
imidazole-substituted compounds disclosed in WO-A-9523790. Other
compounds that inhibit MMP and/or TNF are described in
WO-A-9513289, WO-A-9611209, WO-A-96035687, WO-A-96035711,
WO-A-96035712 and WO-A-96035714.
[0005] WO-A-9718188 discloses MMP inhibitors of the formula
Ph.sup.1-Ph.sup.2-X--(CH.sub.2).sub.0-6--(CZ).sub.0-1-(CHR.sup.1).sub.0-1--
-CO--NHOH
[0006] wherein Ph.sup.1 and Ph.sup.2 are each
optionally-substituted phenyl; X is absent, O, NH or S, Z is
--CONR.sup.2R.sup.3; and R.sup.1 is H, alkyl, alkenyl, OH,
optionally-substituted phenylalkyl or phenyl-SO.sub.0-2-alkyl, or
alkyl-COOR.sup.7.
[0007] EP-A-0780386 discloses compounds having MMP and TNF
inhibitory activity, of the formula
Y--CO--CR.sup.1R.sup.2--CR.sup.3R.sup.4--S(O).sub.nR.sup.5
[0008] wherein n is 0, 1 or 2; Y is OH or NHOH; R.sup.1 is H or
lower alkyl; R.sup.2 is H, lower alkyl, heteroalkyl, aryl, aralkyl,
arylheteroalkyl, cycloalkyl, heteroaryl, heteroaralkyl,
heteroarylheteroalkyl, heterocyclo, heterocyclo-lower alkyl,
heterocyclo-lower heteroaryl or NR.sup.6R.sup.7; R.sup.3 is H,
lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,
heteroaryl, heteroaralkyl, heteroalkyl or lower alkoxy; R.sup.4 is
H, lower alkyl, cycloalkyl or cycaloalkylalkyl; and R.sup.5 is
lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl
or heteroaralkyl.
[0009] Compounds of EP-A-0780386 first disclosed in U.S.
application Ser. No. 8939, filed Dec. 20, 1995, are of the same
formula, wherein R.sup.1 is H; R.sup.2 is H, lower alkyl, aralkyl,
cycloalkyl, cycloalkylalkyl, heterocyclo or NR.sup.6R.sup.7;
R.sup.3 is H, lower alkyl, cycloalkyl, cycloalkylalkyl or aralkyl;
R.sup.4 is H or lower alkyl; and R.sup.5 is lower alkyl, aryl,
aralkyl, heteroaryl or heteroaralkyl.
[0010] U.S. Pat. No. 4,325,964 discloses certain benzhydryl
sulphinyl hydroxamates, as having utility in neuropsychic
ailments.
[0011] Zayed et al, Zeitschrift fur Naturforschung (1966) 180-182,
discloses 3-phenylsulphonylpropanoic acid N-hydroxyamide, as a
fungicide.
SUMMARY OF THE INVENTION
[0012] The invention encompasses novel compounds of formula (I)
which are useful inhibitors of matrix metalloproteinases and/or
TNF.alpha.-mediated diseases, including degenerative diseases and
certain cancers.
[0013] Novel compounds according to the invention are of the
general type represented by formula (I):
B--X--(CH.sub.2).sub.n--CHR.sup.1--(CH.sub.2).sub.m--COY (I)
[0014] wherein m and n are both independently 0 or 1, but are not
both 0;
[0015] X is O, NR.sup.3 or S(O).sub.0-2;
[0016] Y is OR.sup.2 or NHOH;
[0017] R.sup.1 is H or a group (optionally substituted with
R.sup.9) selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, aryl,
C.sub.1-6 alkyl-aryl, heteroaryl, C.sub.1-6 alkyl-heteroaryl,
heterocycloalkyl, C.sub.1-6 alkyl-heterocycloalkyl, cycloalkyl and
C.sub.1-6 alkyl-cycloalkyl;
[0018] R.sup.2 is H or C.sub.1-6 alkyl;
[0019] R.sup.3 is H, C.sub.1-6 alkyl, COR.sup.2, CON(R.sup.2).sub.2
where each R.sup.2 is the same or different, CO.sub.2R.sup.4 or
SO.sub.2R.sup.4, and
[0020] R.sup.4 is C.sub.1-6 alkyl;
[0021] B is C.sub.1-6 alkyl-aryl, C.sub.1-6 alkyl, cycloalkyl,
C.sub.1-6 alkyl-cycloalkyl, cycloalkenyl, heterocycloalkenyl,
C.sub.1-6 alkyl-heteroaryl, heterocycloalkyl, C.sub.1-6
alkyl-heterocycloalkyl, aryl or heteroaryl, any of which groups is
optionally substituted by a substituent selected from R.sup.5,
C.sub.1-6 alkyl-R.sup.5, C.sub.2-6 alkenyl-R.sup.5, aryl
(optionally substituted with R.sup.5), aryl-C.sub.1-6
alkyl-R.sup.5, C.sub.1-6 alkyl-aryl (optionally substituted with
R.sup.5), C.sub.1-6 alkyl-heteroaryl (optionally substituted with
R.sup.5), aryl-C.sub.2-6 alkenyl-R.sup.7, heteroaryl (optionally
substituted with R.sup.5), heteroaryl-C.sub.1-6 alkyl-R.sup.5,
cycloalkyl (optionally substituted with R.sup.5), benzofused
cycloalkyl (optionally substituted with R.sup.5), heterocycloalkyl
(optionally substituted with R.sup.5), benzofused heterocycloalkyl
(optionally substituted with R.sup.5), and the groups: 1
[0022] provided that B is not benzhydryl when X is SO and R.sup.1
is H;
[0023] R.sup.5 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl-R.sup.7,
halogen, CN, NO.sub.2, N(R.sup.6).sub.2, OR.sup.6, COR.sup.6,
CO.sub.2R.sup.2, CON(R.sup.6).sub.2, NR.sup.6R.sup.7,
S(O).sub.0-2R.sup.8 or SO.sub.2N(R.sup.6).sub.2,
[0024] R.sup.6 is H or a group selected from C.sub.1-6 alkyl, aryl,
C.sub.1-6 alkyl-aryl, heteroaryl, C.sub.1-6 alkyl-heteroaryl,
cycloalkyl, C.sub.1-6 alkyl-cycloalkyl, heterocycloalkyl and
C.sub.1-6 alkyl-heterocycloalkyl, wherein said group is optionally
substituted with R.sup.8, COR.sup.8, SO.sub.0-2R.sup.8,
CO.sub.2R.sup.8, OR.sup.8, CONR.sup.2R.sup.8, NR.sup.2R.sup.8,
halogen, CN, SO.sub.2NR.sup.2R.sup.8 or NO.sub.2, and for each case
of N(R.sup.6).sub.2 the R.sup.6 groups are the same or different or
N(R.sup.6).sub.2 is heterocycloalkyl optionally substituted with
R.sup.8, COR.sup.8, SO.sub.0-2R.sup.8, CO.sub.2R.sup.8, OR.sup.8,
CONR.sup.2R.sup.8, NR.sup.2R.sup.8, halogen, CN,
SO.sub.2NR.sup.2R.sup.8 or NO.sub.2;
[0025] R.sup.7 is COR.sup.6, CON(R.sup.6).sub.2, CO.sub.2R.sup.8 or
SO.sub.2R.sup.8;
[0026] R.sup.8 is C.sub.1-6 alkyl, aryl, C.sub.1-6 alkyl-aryl,
heteroaryl or C.sub.1-6 alkyl-heteroaryl; and
[0027] R.sup.9 is OR.sup.6, COR.sup.6, CO.sub.2R.sup.2,
CON(R.sup.6).sub.2, NR.sup.6R.sup.7, S(O).sub.0-2R.sup.8,
SO.sub.2N(R.sup.6).sub.2, phthalimido, succinimido or the group
2
[0028] and the salts, solvates, hydrates, protected amino and
protected carboxy derivatives thereof;
[0029] provided that the compound is not 3-phenylsulfonylpropanoic
acid N-hydroxy amide.
[0030] Combinations of substituents and/or variables are only
permissible if such combinations result in stable compounds.
DESCRIPTION OF THE INVENTION
[0031] Preferred compounds of the invention are those wherein any
one or more of the following apply:
[0032] X is S, SO or SO.sub.2;
[0033] R.sup.1 is H or a group (optionally substituted with
R.sup.9) selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.1-6 alkyl-aryl, C.sub.1-6 alkyl-heteroaryl, C.sub.1-6
alkyl-heterocycloalkyl and C.sub.1-6 alkyl-cycloalkyl;
[0034] B is C.sub.1-6 alkyl-aryl, C.sub.1-6 alkyl, cycloalkyl,
cycloalkenyl, heterocycloalkenyl, C.sub.1-6 alkyl-heteroaryl, aryl
or heteroaryl, any of which groups is optionally substituted by a
substituent selected from R.sup.5, C.sub.1-6 alkyl-R.sup.5, aryl
(optionally substituted with R.sup.5), aryl-C.sub.1-6
alkyl-R.sup.5, C.sub.1-6 alkyl-aryl (optionally substituted with
R.sup.5), C.sub.1-6 alkyl-heteroaryl (optionally substituted with
R.sup.5), heteroaryl (optionally substituted with R.sup.5),
heteroaryl-C.sub.1-6 alkyl-R.sup.5, heteroaryl-C.sub.1-6
alkyl-R.sup.5 cycloalkyl (optionally substituted with R.sup.5),
benzofused cycloalkyl (optionally substituted with R.sup.5),
heterocycloalkyl optionally substituted with R.sup.5), benzofused
heterocycloalkyl (optionally substituted with R.sup.5), and the
groups: 3
[0035] R.sup.5 is halogen, CN, NO.sub.2, N(R.sup.6).sub.2,
OR.sup.6, COR.sup.6, CON(R.sup.6).sub.2, NR.sup.6R.sup.7, or
S(O).sub.0-2R.sup.8;
[0036] R.sup.7 is COR.sup.6; and
[0037] R.sup.9 is OR.sup.6, CO.sub.2R.sup.2, CON(R.sup.6).sub.2,
phthalimido, succinimido or the group 4
[0038] One group of compounds of the invention is represented by
the formula (Ib)
B--X--(CH.sub.2).sub.n--CHR.sup.1--(CH.sub.2).sub.m--COY (Ib)
[0039] wherein
[0040] m is 0;
[0041] n is 1;
[0042] X is SO.sub.2;
[0043] Y is NHOH;
[0044] R.sup.1 is C.sub.1-6 alkyl optionally substituted with
R.sup.9;
[0045] R.sup.2 is H or C.sub.1-6 alkyl;
[0046] B is C.sub.1-6 alkyl substituted by R.sup.5;
[0047] R.sup.5 is OR.sup.6;
[0048] R.sup.6 is a group selected from C.sub.1-6 alkyl, aryl,
C.sub.1-6 alkyl-aryl, heteroaryl, C.sub.1-6 alkyl-heteroaryl,
cycloalkyl, C.sub.1-6 alkyl-cycloalkyl, heterocycloalkyl and
C.sub.1-6 alkyl-heterocycloalkyl, wherein said group is optionally
substituted with R.sup.8, COR.sup.8, SO.sub.0-2R.sup.8,
CO.sub.2R.sup.8, OR.sup.8, CONR.sup.2R.sup.8, NR.sup.2R.sup.8,
halogen, CN, SO.sub.2NR.sup.2R.sup.8 or NO.sub.2, and for each case
of N(R.sup.6).sub.2 the R.sup.6 groups are the same or different or
N(R.sup.6).sub.2 is heterocycloalkyl optionally substituted with
R.sup.8, COR.sup.8, SO.sub.0-2R.sup.8, CO.sub.2R.sup.8, OR.sup.8,
CONR.sup.2R.sup.8, NR.sup.2R.sup.8, halogen, CN,
SO.sub.2NR.sup.2R.sup.8 or NO.sub.2;
[0049] R.sup.7 is COR.sup.6, CON(R.sup.6).sub.2, CO.sub.2R.sup.8 or
SO.sub.2R.sup.8;
[0050] R.sup.8 is C.sub.1-6 alkyl, aryl, C.sub.1-6 alkyl-aryl,
heteroaryl or C.sub.1-6 alkyl-heteroaryl; and
[0051] R.sup.9 is phthalimido, succinimido or the group 5
[0052] and the salts, solvates, hydrates, protected amino and
protected carboxy derivatives thereof;
[0053] R.sup.1 in compounds of formula (Ib) is preferably
optionally substituted ethyl, propyl or isopropyl. Especially
preferred is where R.sup.1 is isopropyl or R.sup.1 is propyl
substituted by R.sup.9, where R.sup.9 is in particular the group:
6
[0054] In compounds of this type each R.sup.2 group is preferably
methyl.
[0055] In compounds of formula (Ib), B is preferably substituted
ethyl, propyl or butyl, especially substituted propyl.
[0056] One preferred group of compounds of formula (Ib) s where
R.sup.6 is optionally substituted aryl, heteroaryl, cycloalkyl or
C.sub.1-6 alkyl-cycloalkyl. Particular R.sup.6 groups of interest
are optionally substituted phenyl, pyridyl, furanyl, thiophenyl,
cycloburyl, cyclopentyl, cyclohexyl, methyl-cyclobutyl,
methyl-cyclopentyl, methyl-cyclohexyl, ethyl-cyclobutyl,
ethyl-cyclopenyl or ethyl-cyclohexyl, especially optionally
substituted phenyl, pyridyl, cyclohexyl or methyl-cyclohexyl.
[0057] When R.sup.6 in compounds of formula (Ib) is substituted, it
is preferably substituted by R.sup.8, particularly where R.sup.8 is
phenyl, OR.sup.8, particularly where OR.sup.8 is OCH.sub.3, F, Cl,
Br, I or CN, especially phenyl, OCH.sub.3 or Cl.
[0058] In another embodiment of the invention, a particular group
of compounds is presented by the formula (Ic):
B--X--(CH.sub.2).sub.n--CHR.sup.1--(CH.sub.2).sub.m--COY (Ic)
[0059] wherein
[0060] m is 0;
[0061] n is 1;
[0062] X is SO.sub.2;
[0063] Y is NHOH;
[0064] R.sup.1 is C.sub.1-6 alkyl substituted with R.sup.9;
[0065] R.sup.2 is H or C.sub.1-6 alkyl;
[0066] B is aryl or heteroaryl, either of which is optionally
substituted by a substituent selected from R.sup.5, C.sub.1-6
alkyl-R.sup.5, C.sub.2-6 alkenyl-R.sup.5, aryl (optionally
substituted with R.sup.5), aryl-C.sub.1-6 alkyl-R.sup.5, C.sub.1-6
alkyl-aryl (optionally substituted with R.sup.5), C.sub.1-6
alkyl-heteroaryl (optionally substituted with R.sup.5),
aryl-C.sub.2-6 alkenyl-R.sup.7, heteroaryl (optionally substituted
with R.sup.5), heteroaryl-C.sub.1-6 alkyl-R.sup.5, cycloalkyl
(optionally substituted with R.sup.5), benzofused cycloalkyl
(optionally substituted with R.sup.5), heterocycloalkyl (optionally
substituted with R.sup.5), benzofused heterocycloalkyl (optionally
substituted with R.sup.5), and the groups: 7
[0067] R.sup.5 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl-R.sup.7,
halogen, CN, NO.sub.2, N(R.sup.6).sub.2, OR.sup.6, COR.sup.6,
CO.sub.2R.sup.2, CON(R.sup.6).sub.2, NR.sup.6R.sup.7,
S(O).sub.0-2R.sup.8 or SO.sub.2N(R.sup.6).sub.2;
[0068] R.sup.6 is H or a group selected from C.sub.1-6 alkyl, aryl,
C.sub.1-6 alkyl-aryl, heteroaryl, C.sub.1-6 alkyl-heteroaryl,
cycloalkyl, C.sub.1-6 alkyl-cycloalkyl, heterocycloalkyl and
C.sub.1-6 alkyl-heterocycloalkyl, wherein said group is optionally
substituted with R.sup.8, COR.sup.8, SO.sub.0-2R.sup.8,
CO.sub.2R.sup.8, OR.sup.8, CONR.sup.2R.sup.8, NR.sup.2R.sup.8,
halogen, CN, SO.sub.2NR.sup.2R.sup.8 or NO.sub.2, and for each case
of N(R.sup.6).sub.2 the R.sup.6 groups are the same or different or
N(R.sup.6).sub.2 is heterocycloalkyl optionally substituted with
R.sup.8, COR.sup.8, SO.sub.0-2R.sup.8, CO.sub.2R.sup.8, OR.sup.8,
CONR.sup.2R.sup.8, NR.sup.2R.sup.8, halogen, CN,
SO.sub.2NR.sup.2R.sup.8 or NO.sub.2;
[0069] R.sup.7 is COR.sup.6, CON(R.sup.6).sub.2, CO.sub.2R.sup.8 or
SO.sub.2R.sup.8;
[0070] R.sup.8 is C.sub.1-6 alkyl, aryl, C.sub.1-6 alkyl-aryl,
heteroaryl or C.sub.1-6 alkyl-heteroaryl; and
[0071] R.sup.9 is phthalimido, succinimido or the group 8
[0072] and the salts, solvates, hydrates, protected amino and
protected carboxy derivatives thereof;
[0073] R.sup.1 in compounds of formula (Ic) is preferably
substituted ethyl or propyl.
[0074] Each R.sup.2 group is in particular methyl.
[0075] In compounds of formula (Ic), B is especially optionally
substituted phenyl, furanyl, thiophenyl or pyridyl or
pyridyl-N-oxide, especially optionally substituted phenyl, pyridyl
or pyridyl-N-oxide.
[0076] One preferred group of compounds of formula (Ic) is where
R.sup.5 is OR.sup.6 or COR.sup.6. R.sup.6 compounds of this type is
in particular optionally substituted C.sub.1-6 alkyl, aryl,
C.sub.1-6 alkyl-aryl, heteroaryl or C.sub.1-6 alkyl-heteroaryl,
especially optionally substituted C.sub.1-6 alkyl, aryl, heteroaryl
or C.sub.1-6 alkyl-heteroaryl. Particular R.sup.6 groups are
optionally substituted methyl, phenyl, furanyl, thiophenyl,
pyridyl, pyridyl-N-oxide, methyl-pyridyl, ethyl-pyridyl,
methyl-furanyl, ethyl-furanyl, methyl-thiophenyl or
ethyl-thiophenyl, especially optionally substituted methyl, phenyl,
thiophenyl, pyridyl, pyridyl-N-oxide, or methyl-pyridyl.
[0077] When R.sup.6 in compounds of formula (Ic) is substituted, it
is in particular substituted by OR.sup.8, particularly where
OR.sup.8 is OCH.sub.3, F, Cl, Br, I or CN especially F, Cl or
CN.
[0078] A further group of compounds of the invention is represented
by the formula (Id)
B--X--(CH.sub.2).sub.n--CHR.sup.1--(CH.sub.2).sub.m--COY (Id)
[0079] wherein
[0080] m is 0;
[0081] n is 1;
[0082] X is SO.sub.2;
[0083] Y is NHOH;
[0084] R.sup.1 is H or a group (optionally substituted with
R.sup.9) selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, aryl,
C.sub.1-6 alkyl-aryl, heteroaryl, C.sub.1-6 alkyl-heteroaryl,
heterocycloalkyl, C.sub.1-6 alkyl-heterocycloalkyl, cycloalkyl and
C.sub.1-6 alkyl-cycloalkyl;
[0085] R.sup.2 is H or C.sub.1-6 alkyl;
[0086] B is aryl or heteroaryl, either of which is substituted by
R.sup.5;
[0087] R.sup.2 is H or C.sub.1-6 alkyl;
[0088] R.sup.5 is OR.sup.6a, S(O).sub.1-2R.sup.8 or
NR.sup.6R.sup.7;
[0089] R.sup.6 is H or a group selected from C.sub.1-6 alkyl, aryl,
C.sub.1-6 alkyl-aryl, heteroaryl, C.sub.1-6 alkyl-heteroaryl,
cycloalkyl, C.sub.1-6 alkyl-cycloalkyl, heterocycloalkyl and
C.sub.1-6 alkyl-heterocycloalkyl, wherein said group is optionally
substituted with R.sup.8, COR.sup.8, SO.sub.0-2R.sup.8,
CO.sub.2R.sup.8, OR.sup.8, CONR.sup.2R.sup.8, NR.sup.2R.sup.8,
halogen, CN, SO.sub.2NR.sup.2R.sup.8 or NO.sub.2;
[0090] R.sup.6a is selected from C.sub.1-6 alkyl-heteroaryl,
C.sub.1-6 alkyl-cycloalkyl and C.sub.1-6 alkyl-heterocycloalkyl
wherein said group is optionally substituted with R.sup.8,
COR.sup.8, SO.sub.0-2R.sup.8, CO.sub.2R.sup.8, OR.sup.8,
CONR.sup.2R.sup.8, NR.sup.2R.sup.8, halogen, CN,
SO.sub.2NR.sup.2R.sup.8 or NO.sub.2, or R.sup.6a is C.sub.1-6
alkyl-aryl substituted with R.sup.8, COR.sup.8, SO.sub.0-2R.sup.8,
CO.sub.2R.sup.8, OR.sup.8, CONR.sup.2R.sup.8, NR.sup.2R.sup.8,
halogen, CN, SO.sub.2NR.sup.2R.sup.8 or NO.sub.2;
[0091] R.sup.7 is CON(R.sup.6).sub.2, or SO.sub.2R.sup.8;
[0092] R.sup.8 is C.sub.1-6 alkyl, aryl, C.sub.1-6 alkyl-aryl,
heteroaryl or C.sub.1-6 alkyl-heteroaryl; and
[0093] R.sup.9 is OR.sup.6, COR.sup.6, CO.sub.2R.sup.2,
CON(R.sup.6).sub.2, NR.sup.6R.sup.7, S(O).sub.0-2R.sup.8,
SO.sub.2N(R.sup.6).sub.2, phthalimido, succinimido or the group
9
[0094] and the salts, solvates, hydrates, protected amino and
protected carboxy derivatives thereof;
[0095] R.sup.1 in compounds of formula (Id) is in particular
optionally substituted C.sub.1-6 alkyl. Especially preferred is
isopropyl.
[0096] In compounds of formula (Id), B is preferably substituted
aryl, especially substituted phenyl.
[0097] A preferred group of compounds has the formula (Ic) wherein
R.sup.5 is NR.sup.6R.sup.7. Especially preferred is where R.sup.7
is CON(R.sup.6).sub.2. In compounds of this type, R.sup.6 is in
particular a hydrogen atom or a C.sub.1-6 alkyl group, especially a
hydrogen atom.
[0098] Another group of compounds of the invention is represented
by the formula (Ie):
B--X--(CH.sub.2).sub.n--CHR.sup.1--(CH.sub.2).sub.m--COY (Ie)
[0099] wherein
[0100] m is 0;
[0101] n is 1;
[0102] X is SO.sub.2;
[0103] Y is NHOH;
[0104] R.sup.1 is aryl or heteroaryl, either of which is optionally
substituted with R.sup.9;
[0105] R.sup.2 is H or C.sub.1-6 alkyl;
[0106] B is heteroaryl optionally substituted by a substituent
selected from R.sup.5, C.sub.1-6 alkyl-R.sup.5, C.sub.2-6
alkenyl-R.sup.5, aryl (optionally substituted with R.sup.5),
aryl-C.sub.1-6 alkyl-R.sub.5, C.sub.1-6 alkyl-aryl (optionally
substituted with R.sup.5), C.sub.1-6 alkyl-heteroaryl (optionally
substituted with R.sup.5), aryl-C.sub.2-6 alkenyl-R.sup.7,
heteroaryl (optionally substituted with R.sup.5),
heteroaryl-C.sub.1-6 alkyl-R.sup.5, cycloalkyl (optionally
substituted with R.sup.5), benzofused cycloalkyl (optionally
substituted with R.sup.5), heterocycloalkyl (optionally substituted
with R.sup.5), benzofused heterocycloalkyl (optionally substituted
with R.sup.5), and the groups: 10
[0107] R.sup.5 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl-R.sup.7,
halogen, CN, NO.sub.2, N(R.sup.6).sub.2, OR.sup.6, COR.sup.6,
CO.sub.2R.sup.2, CON(R.sup.6).sub.2, NR.sup.6R.sup.7,
S(O).sub.0-2R.sup.8 or SO.sub.2N(R.sup.6).sub.2;
[0108] R.sup.6 H is or a group selected from C.sub.1-6 alkyl, aryl,
C.sub.1-6 alkyl-aryl, heteroaryl, C.sub.1-6 alkyl-heteroaryl,
cycloalkyl, C.sub.1-6 alkyl-cycloalkyl, heterocycloalkyl and
C.sub.1-6 alkyl-heterocycloalkyl, wherein said group is optionally
substituted with R.sup.8, COR.sup.8, SO.sub.0-2R.sup.8,
CO.sub.2R.sup.8, OR.sup.8, CONR.sup.2R.sup.8, NR.sup.2R.sup.8,
halogen, CN, SO.sub.2NR.sup.2R.sup.8 or NO.sub.2, and for each case
of N(R.sup.6).sub.2 the R.sup.6 groups are the same or different or
N(R.sup.6).sub.2 is heterocycloalkyl optionally substituted with
R.sup.8, COR.sup.8, SO.sub.0-2R.sup.8, CO.sub.2R.sup.8, OR.sup.8,
CONR.sup.2R.sup.8, NR.sup.2R.sup.8, halogen, CN,
SO.sub.2NR.sup.2R.sup.8 or NO.sub.2;
[0109] R.sup.7 is COR.sup.6, CON(R.sup.6).sub.2, CO.sub.2R.sup.8 or
SO.sub.2R.sup.8;
[0110] R.sup.8 is C.sub.1-6 alkyl, aryl, C.sub.1-6 alkyl-aryl,
heteroaryl or C.sub.1-6 alkyl-heteroaryl; and
[0111] R.sup.9 is OR.sup.6, COR.sup.6, CO.sub.2R.sup.2,
CON(R.sup.6).sub.2, NR.sup.6R.sup.7, S(O).sub.0-2R.sup.8,
SO.sub.2N(R.sup.6).sub.2, phthalimido, succinimido or the group
11
[0112] and the salts, solvates, hydrates, protected amino and
protected carboxy derivatives thereof;
[0113] R.sup.1 in compounds of formula (Ie) is in particular
optionally substituted aryl. R.sup.1 is especially phenyl.
[0114] In compounds of formula (Ie), B is in particular optionally
substituted furanyl, thiophenyl or pyridyl, especially optionally
substituted thiophenyl. Especially preferred is where B is
thiophenyl.
[0115] The compounds of the Examples are particularly
preferred.
[0116] It will be appreciated that the compounds according to the
invention can contain one or more asymmetrically substituted carbon
atoms. The presence of one or more of these asymmetric centres in a
compound of formula (I) can give rise to stereoisomers, and in each
case the invention is to be understood to extend to all such
stereoisomers, including enantiomers and diastereomers, and
mixtures including racemic mixtures thereof.
[0117] As used in this specification, alone or in combination, the
term "C.sub.1-6 alkyl" refers to straight or branched chain alkyl
moiety having from one to six carbon atoms, including for example,
methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl
and the like.
[0118] The term "C.sub.2-6 alkenyl" refers to a straight or
branched chain alkyl moiety having two to six carbon atoms and
having in addition one double bond, of either E or Z
stereochemistry where applicable. This term would include for
example, vinyl, 1-propenyl, 1- and 2-butenyl, 2-methyl-2-propenyl
etc.
[0119] The term "cycloalkyl" refers to a saturated alicyclic moiety
having from three to six carbon atoms and includes for example
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
"Benzofused cycloalkyl" includes indanyl and
tetrahydronaphthyl.
[0120] The term "heterocycloalkyl" refers to a saturated
heterocyclic moiety having from three to six carbon atoms and one
or more heteroatom from the group N, O, S and includes for example
azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and the
like. "Benzofused hetercycloalkyl" includes indolinyl and
tetrahydroquinolinyl.
[0121] The term "cycloalkenyl" refers to an alicyclic moiety having
from three to six carbon atoms and having in addition one double
bond. This term would include for example cyclopentenyl or
cyclohexenyl
[0122] The term "heterocycloalkenyl" refers to an alicyclic moiety
having from three to six carbon atoms and one or more heteroatoms
from the group N, O, S and having in addition one double bond. This
term includes, for example, dihydropyranyl.
[0123] The term "aryl" means an optionally substituted phenyl or
naphthyl group with the substituent(s) being selected, for example,
from halogen, trifluoromethyl, C.sub.1-6 alkyl, alkoxy, phenyl and
the like.
[0124] The term "heteroaryl" refers to aromatic ring systems of
five to ten atoms of which at least one atom is selected from O, N
and S, and includes for example furanyl, thiophenyl, pyridyl,
indolyl, quinolyl and the like.
[0125] The term "alkoxy" refers to a straight chain or branched
chain alkoxy group containing a maximum of six carbon atoms, such
as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and
the like.
[0126] The terms "halogen" means fluorine, chlorine, bromine or
iodine.
[0127] The terms "protected amino" and "protected carboxy" mean
amino and carboxy groups which can be protected in a manner
familiar to those skilled in the art. For example, an amino group
can be protected by a benzyloxycarbonyl, tert-butoxycarbonyl,
acetyl or like group, or may be in the form of a phthalimido or
like group. A carboxyl group can be protected in the form of a
readily-cleavable ester such as the methyl, ethyl, benzyl or
tert-butyl ester.
[0128] Salts of compounds of formula (I) include
pharmaceutically-acceptab- le salts, for example acid addition
salts derived from inorganic or organic acids, such as
hydrochlorides, hydrobromides, p-toluenesulphonates, phosphates,
sulphates, perchlorates, acetates, trifluoroacetates, propionates,
citrates, malonates, succinates, lactates, oxalates, tartrates and
benzoates.
[0129] Salts may also be formed with bases. Such salts include
salts derived from inorganic or organic bases, for example alkali
metal salts such as magnesium or calcium salts, and organic amine
salts such as morpholine, piperidine, dimethylamine or diethylamine
salts.
[0130] When the "protected carboxy" group in compounds of the
invention is an esterified carboxyl group, it may be a
metabolically-labile ester of formula CO.sub.2R.sup.10 where
R.sup.10 may be an ethyl, benzyl, phenethyl, phenylpropyl, .alpha.-
or .beta.-naphthyl, 2,4-dimethylphenyl, 4-tert-butylphenyl,
2,2,2-trifluoroethyl, 1-(benzyloxy)benzyl, 1-(benzyloxy)ethyl,
2-methyl-1-propionyloxypropyl, 2,4,6-trimethylbenzyloxymethyl or
pivaloylmethyl group.
[0131] Compounds of the general formula (I) may be prepared by any
suitable method known in the art and/or by the following
processes.
[0132] It will be appreciated that, where a particular stereoisomer
of formula (I) is required, the synthetic processes described
herein may be used with the appropriate homochiral starting
material and/or isomers maybe resolved from mixtures using
conventional separation techniques (e.g. HPLC).
[0133] The compounds according to the invention may be prepared by
the following process. In the description and formulae below the
groups R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9, R.sup.10, B, X and Y are as defined
above, except where otherwise indicated. It will be appreciated
that functional groups, such as amino, hydroxyl or carboxyl groups,
present in the various compounds described below, and which it is
desired to retain, may need to be in protected form before any
reaction is initiated. In such instances, removal of the protecting
group may be the final step in a particular reaction. Suitable
protecting groups for such functionality will be apparent to those
skilled in the art. For specific details see Greene et al,
"Protective Groups in Organic Synthesis", Wiley Interscience.
[0134] A process for preparing compounds of general formula (I)
comprises alkylating a compound of formula B--XH (II) wherein B and
X are as previously defined, with an alkylating agent of formula
Z-(CH.sub.2).sub.n--CHR.sup.1--(CH.sub.2).sub.m--COY (III), using
for example an amine base, such as triethylamine in
N,N-dimethylformamide (DMF); or (when m=0) an acrylate of formula
CH.sub.2.dbd.CR.sup.1--COY (IV) wherein R.sup.1 and Y are as
defined previously and Z represents a suitable leaving group (e.g.
a halogen such as bromine, or an alkylsulphonate ester such as
methanesulphonate).
[0135] Alkylating agents (III) can be obtained in chiral or racemic
form. Many of these derivatives can be readily obtained from
commercially available starting materials using methods known to
those skilled in the art (see WO-A-9005719).
[0136] Acrylates of formula (IV) may be prepared by the Mannich
reaction (ie. with paraformaldehyde and piperidine in a suitable
organic solvent, such as 1,4-dioxane) on a dicarboxylic acid of
general formula HO.sub.2C--CHR.sup.1--CO.sub.2H (V). This reaction
involves an eliminative decarboxylation step resulting in the
formation of an .alpha.,.beta.-unsaturated carboxylic acid (i.e.
where Y.dbd.OH) directly. This carboxylic acid can then be
elaborated using standard chemistry, known to those skilled in the
art, to provide esters (Y.dbd.OR.sup.2) or hydroxamides
(NHOR.sup.11) where R.sup.11 is a suitable protecting group such as
benzyl, tert-butyl or tert-butyldimethylsilyl (TBDMS).
[0137] Dicarboxylic acids of formula (V) may be prepared by the
alkylation of, for instance, diethyl malonate with an alkylating
agent of formula R.sup.1-Z (VI), wherein Z is as defined above,
followed by hydrolysis under basic conditions.
[0138] Compounds of formula (II) in which B includes includes an
aryl, heteroaryl, functional or other group as a substituent on a
core part thereof (B'), may be prepared by palladium-catalysed
coupling of an aryl, heteroaryl, functionalising or other compound
with a compound of general formula A-B'--XR.sup.12 (VII) wherein
R.sup.12 is a suitable protecting group such as a methyl,
tert-butyl, benzyl or trityl, and A is a halide such as iodide,
bromide or, in some instances, chloride. This is followed by
removal of any protecting groups.
[0139] Many such palladium-catalysed coupling reactions are known
to those skilled in the art and can provide compounds of formula
(II) bearing substituents described by R.sup.5 such as COR.sup.6,
CO.sub.2R.sup.2 or CON(R.sup.6).sub.2 as well as aryl, heteroaryl,
alkenyl or alkyl groups optionally substitute by R.sup.5. Other
groups described by B and/or R.sup.5 can be introduced by standard
chemical transformations known to those skilled in the art.
[0140] Many compounds of general formulae (II), (VI) and (VII) are
commercially available or may be prepared, by standard aromatic,
heteroaromatic or other chemistry known to those skilled in the
art, from commercially-available materials.
[0141] If required, intermediates of general formulae (VIII) and
(IX) 12
[0142] may be prepared by Friedel-Crafts acylation of a simple
aromatic system Ph-XH (X) with phthalic or maleic anhydride,
followed by treatment with a hydrazine of general formula
H.sub.2N--NHR.sup.2(XI).
[0143] Compounds of formula (I) may also be prepared by
interconversion of other compounds of formula (I). Thus, for
example, a compound of formula (I) wherein R.sup.1 is a C.sub.1-6
alkyl group may be prepared by hydrogenation (using palladium on
carbon in suitable solvent, such as an alcohol, e.g. ethanol) of a
compound of formula (I) wherein R.sup.2 is a C.sub.2-6 alkenyl
group. Alternatively, acetylsulfanyl-tert-butyl esters (XII), where
R.sup.1 is in general one of the groups isopropyl,
propylsuccinimide or propylhydantoin, may be reacted with bromides
(XI) (commercially available or prepared according to the
literature or via the methods described below) for example, in
methanol with sodium bis(trimethylsilyl)amide to give
sulfanyl-tert-butyl esters of general formula (I). These may be
deprotected using trifluoroacetic acid to afford the desired
sulfanyl-acids of general formula (I), as shown in scheme A. 13
[0144] Further, a compound of formula (I) wherein X is S(O).sub.1-2
may be prepared by oxidation of a compound of formula (I) wherein X
is S, for example using Oxone.RTM. in methanol/water. Carboxylic
acids of general formula (I) (Y.dbd.OH) may be converted to other
compounds of formula (I) such as esters (Y.dbd.OR.sup.2) or
hydroxamic acids (Y.dbd.NHOH) using methods known to those skilled
in the art. For example, the acids of general formula (I) may be
reacted with oxalyl chloride and catalytic DMF in dichloromethane
to afford the corresponding acid chlorides which are treated with
hydroxylamine in THF/water. Alternatively, the acids of general
formula (I) may be coupled with O-tert-butyldimethylsilyl-protect-
ed hydroxylamine using, for example,
1-(3-dimethylaminopropyl)-3-ethylcarb- odiimide hydrochloride and
4-dimethylaminopyridine in dichloromethane and the resulting
products deprotected using, for example, either tetrabutylammonium
fluoride in dichloromethane or hydrogen chloride in diethyl ether.
These interconversions of compounds of general formula (I) are
illustrated in the general scheme B. 14
[0145] Any mixtures of final products or intermediates obtained can
be separated on the basis of the physico-chemical differences of
the constituents, in known manner, into the pure final products or
intermediates, for example by chromatography, distillation,
fractional crystallization, or by formation of a salt if
appropriate or possible under the circumstances.
[0146] The compounds according to the invention exhibit in vitro
inhibiting activities with respect to the stromelysins,
collagenases and gelatinases. Compounds according to the invention
also exhibit in vitro inhibition of TNF release, TNF receptor
shedding, IL-6 receptor shedding and L-selectin shedding.
[0147] The 80 kD TNF receptor (TNFR.sub.80) is proteolytically
cleaved at the cell surface (shed), releasing a soluble
ligand-binding receptor fragment. Interestingly, the processing of
TNF.alpha. and shedding of TNFR.sub.80 have been demonstrated to
occur concurrently in activated T-cells, arousing speculation that
a common protease may be involved. It has been shown by Crowe et
al, J. Exp. Med., (1995) 181:1205, that a synthetic inhibitor of
TNF processing also blocks the shedding of TNFR.sub.80, suggesting
that these processes may be coordinatedly regulated during T-cell
activation. Notably, the protease cleavage site in pro-TNF(Ala-Val)
is also present in the extracellular domain of TNFR.sub.80
(Ala.sup.213-Val.sup.214) at a site consistent with the observed
molecular weight of the shed receptor fragment. Thus,
metalloproteinase inhibitors may offer protection from the
deleterious systemic effects of TNF.alpha. at two levels
simultaneously, firstly by preventing the release of soluble
TNF.alpha., and secondly by blocking the accumulation of shed
TNFR.sub.80.
[0148] Synergistically with TNF, metalloproteinase inhibitors also
inhibit the release of APO-1/Fas (CD95) ligand (APO-1L) which
induces apoptosis in sensitive target cells. The shedding APO-1/Fas
(CD95), a type I transmembrane glycoprotein belonging to the nerve
growth factor/TNF receptor sub-family is also blocked by known
metalloproteinase inhibitors but not by common inhibitors of
serine/cysteine proteases; see Mariani et al, Eur. J. Immunol.,
(1995) 25:2303. Several other important receptors expressed by
activated T- and B-cells have also been demonstrated to be shed
from the cell surface by the action of metalloproteinases. These
enzymes, collectively known as sheddases, provide new targets for
inhibitors of metalloproteinases, including compounds of the
present invention.
[0149] The activity and selectivity of the compounds may be
determined by use of the appropriate enzyme inhibition test, for
example as described in Examples A-M, below. Certain compounds of
this invention have selective inhibitory activity, in particular
inhibition of MMP substantially without inhibition of TNF release
and related activities as defined above. This may be of particular
value where such activities are associated with reduced
side-effects.
[0150] This invention also relates to a method of treatment for
patients (including man and/or mammalian animals raised in the
dairy, meat or fur industries or as pets) suffering from disorders
or diseases which can be attributed to stromelysin as previously
described, and more specifically, a method of treatment involving
the administration of the matrix metalloproteinase inhibitors of
formula (I) as the active constituents.
[0151] Accordingly, the compounds of formula (I) can be used among
other things in the treatment of osteoarthritis and rheumatoid
arthritis, and in diseases and indications resulting from the
over-expression of these matrix metalloproteinases such as found in
certain metastatic tumour cell lines.
[0152] As mentioned above, compounds of formula (I) are useful in
human or veterinary medicine since they are active as inhibitors of
TNF and MMPs. Accordingly in another aspect, this invention
concerns:
[0153] a method of management (by which is meant treatment of
prophylaxis) of disease or conditions mediated by TNF and/or MMPs
in mammals, in particular in humans, which method comprises
administering to the mammal an effective, amount of a compound of
formula (I) above, or a pharmaceutically acceptable salt thereof;
and
[0154] a compound of formula (I) for use in human or veterinary
medicine, particularly in the management (by which is meant
treatment or prophylaxis) of diseases or conditions mediated by TNF
and/or MMPs; and
[0155] the use of a compound of formula (I) in the preparation of
an agent for the management (by which is meant treatment or
prophylaxis) of diseases or conditions mediated by TNF and/or
MMPs.
[0156] The disease or conditions referred to above include
inflammatory diseases, autoimmune diseases cancer, cardiovascular
diseases, diseases involving tissue breakdown such as rheumatoid
arthritis, osteoarthritis, osteoporosis, neurodegeneration,
Alzheimer's disease, stroke, vasculitis, Crohn's disease,
ulcerative colitis, multiple sclerosis, periodontitis, gingivitis
and those involving tissue breakdown such as bone resorption,
haemorrhage, coagulation, acute phase response, cachexia and
anorexia, acute infections, HIV infections, fever, shock states,
graft versus host reactions, dermatological conditions, surgical
wound healing, psoriasis, atopic dermatitis, epidermolysis bullosa,
tumour growth, angiogenesis and invasion by secondary metastases,
ophthalmological disease, retinopathy, corneal ulceration,
reperfusion injury, migraine, meningitis, asthma rhinitis, allergic
conjunctivitis, eczema, anaphylaxis, restenosis, congestive heart
failure, endometriosis, atherosclerosis, endosclerosis and
aspirin-independent anti-thrombosis.
[0157] For the treatment of rheumatoid arthritis, osteoarthritis,
and in diseases and indications resulting from the over-expression
of matrix metalloendoproteinases such as found in certain
metastatic tumour cell lines or other diseases mediated by the
matrix metalloendoproteinases or increased TNF production, the
compounds of formula (I) may be administered orally, topically,
parenterally, by inhalation spray or rectally in dosage unit
formulations containing non-toxic pharmaceutically acceptable
carriers, adjuvants and vehicles. The term parenteral as used
herein includes subcutaneous injections, intravenous,
intramuscular, intrasternal injection or infusion techniques. In
addition to the treament of warm-blooded animals such as mice,
rats, horses, cattle, sheep, dogs, cats etc, the compounds of the
invention are effective in the treatment of humans.
[0158] The pharmaceutical composition containing the active
ingredient may be in a form suitable for oral use, for example, as
tablets, troches, lozenges, aqueous or oily suspensions,
dispersible powders or granules, emulsions, hard or soft capsules,
or syrups or elixirs. Compositions intended for oral use may be
prepared according to any method known to the art for the
manufacture of pharmaceutical compositions and such compositions
may contain one or more agents selected from the group consisting
of sweetening agents, flavouring agents, colouring agents and
preserving agents in order to provide pharmaceutically elegant and
palatable preparations. Tablets contain the active ingredient in
admixture with non-toxic pharmaceutically acceptable excipients
which are suitable for the manufacture of tablets. These excipients
may be for example, inert diluents, such as calcium carbonate,
sodium carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example corn starch, or
alginic acid; binding agents, for example starch, gelatin or
acacia, and lubricating agents, for example magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be
coated by known techniques to delay disintegration and absorption
in the gastointestinal tract and thereby provide a sustained action
over a longer period. For example, a time delay material such as
glyceryl monostearate or glyceryl distearate may be employed. They
may also be coated by the techniques described in the U.S. Pat.
Nos. 4,256,108; 4,166,452; and 4,265,874, to form osmotic
therapeutic tablets for control release.
[0159] Formulations for oral use may also be presented as hard
gelatin capsules where in the active ingredient is mixed with an
inert solid diluent, for example calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, for example peanut
oil, liquid paraffin or olive oil.
[0160] Aqueous suspensions contain the active materials in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydroxy-propylmethylcellulose, sodium alginate
polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents may be a naturally occurring phosphatide, for
example lecithin, or condensation products of an alkylene oxide
with fatty acids, for example polyoxyethylene stearate, or
condensation produces of ethylene oxide with long chain aliphatic
alcohols, for example heptadecaethyleneoxycetanol, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and a hexitol such a polyoxyethylene with partial esters
derived from fatty acids and hexitol anhydrides, for example
polyoxyethylene sorbitan monooleate. The aqueous suspensions may
also contain one or more preservatives, for example ethyl, or
n-propyl, p-hydroxybenzoate, one or more colouring agents, one or
more flavouring agents, and one or more sweetening agents, such as
sucrose or saccharin.
[0161] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavouring agents may be added
to provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0162] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified, for
example sweetening, flavouring and colouring agents, may also be
present.
[0163] The pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, for example olive oil or arachis oil, or a mineral
oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents may be naturally-occurring gums, for example gum
acacia or gum tragacanth, naturally-occurring phosphatides, for
example soya bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol anhydrides, for example sorbitan
monooleate and condensation products of the said partial esters
with ethylene oxide, for example polyoxyethylene sorbitan
monooleate. The emulsions may also contain sweetening and
flavouring agents.
[0164] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative and
flavouring and colouring agents. The pharmaceutical compositions
may be in the form of a sterile injectable aqueous or oleagenous
suspension. This suspension may be formulated according to the
known art using those suitable dispersing or wetting agents and
suspending agents which have been mentioned above. The sterile
injectable preparation may also be in a sterile injectable solution
or suspension in a non-toxic parenterally-acceptable diluent or
solvent, for example as a solution in 1,3-butane diol. Among the
acceptable vehicles and solvents that may be employed are water,
Ringer's solution and isotonic sodium chloride solution. In
addition, sterile, fixed oils are conventionally employed as a
solvent or suspending medium. For this purpose any bland fixed oil
may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid find use in the
preparation of injectables.
[0165] The compounds of formula (I) may also be administered in the
form of suppositories for rectal administration of the drug. These
compositions can be prepared by mixing the drug with a suitable
non-irritating excipient which is solid at ordinary temperatures
but liquid at the rectal temperature and will therefore melt in the
rectum to release the drug. Such materials are cocoa butter and
polyethylene glycols.
[0166] For topical use, creams, ointments, jellies, solutions or
suspensions, etc containing the compounds of Formula (I) are
employed. For the purposes of this specification, topical
application includes mouth washes and gargles.
[0167] Dosage levels of the order of from about 0.05 mg to about
140 mg per kilogram of body weight per day are useful in the
treatment of the above-indicated conditions (about 2.5 mg to about
7 g per patient per day). For example, inflammation may be
effectively treated by the administration of from about 0.01 to 50
mg of the compound per kilogram of body weight per day (about 0.5
mg to about 3.5 g per patient per day).
[0168] The amount of active ingredient that may be combined with
the carrier materials to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. For example, a formulation intended for the oral
administration of humans may vary from about 5 to about 95% of the
total composition. Dosage unit forms will generally contain between
from about 1 mg to about 500 mg of active ingredient.
[0169] It will be understood, however, that the specific dose level
for any particular patient will depend upon a variety of factors
including the activity of the specific compound employed, the age,
body weight, general health, sex, diet time of administration,
route of administration, rate of excretion, drug combination and
the severity of the particular disease undergoing therapy.
[0170] The following Examples illustrate the invention.
[0171] In the Examples, the following abbreviations are used:
1 TNF.alpha. Tumour Necrosis Factor .alpha. LPS Lipopolysaccharide
ELISA Enzyme linked immunosorbant assay EDC
1-Ethyl-2-dimethylaminopropylcarbodiimide RT Room Temperature THF
Tetrahydrofuran MTBE terr-Butyl methyl ether DMF
N,N-Dimethylformamide
[0172] Intermediate 1 4-Acetylthiophenol
[0173] Was prepared according to EP 302321.
[0174] TLC R.sub.f 0.3 (5% methanol-dichloromethane)
[0175] Intermediate 2 Bis(4-Benzenecarboxylate)disulfide
[0176] Iodine (1.23 g) was added portionwise to a solution of
4-mercaptobenzoic acid (1.5 g) in methanol (30 ml) at room
temperature. Stirring was continued for three hours. Water (1 ml)
and sodium sulfite (0.2 g) were added, and the reaction was stirred
for 30 minutes. Methanol was removed in vacuo and the title
compound was isolated by filtration as a white solid (1.38 g,
93%).
[0177] TLC R.sub.f 0.05 (2.5% methanol-dichloromethane)
[0178] Intermediate 3
Bis(4-N,N-Dimethylcarboxamidebenzene)disulfide
[0179] A solution of intermediate 2 (0.5 g) in a mixture of
tetrahydrofuran (15 ml) and DMF (7 ml) was stirred at room
temperature. Dimethylamine hydrochloride (0.27 g), triethylamine
(1.37 ml) and EDAC (0.63 g) were added and the reaction was stirred
overnight. Solvents were removed in vacuo and the residue
partitioned between water and ethyl acetate. The aqueous phase was
extracted with ethyl acetate and the combined organics were dried
over MgSO.sub.4, filtered, and concentrated in vacuo to give the
crude product, which was purified by column chromatography on
silica eluting with 5% methanol in dichloromethane. The title
compound was isolated as a white solid (0.245 g, 42%).
[0180] TLC R.sub.f 0.24 (5% methanol-dichloromethane)
[0181] Intermediate 4 4-Sulfanyl-N,N-dimethylbenzamide
[0182] Sodium borohydride (0.076 g) was added portionwise to a
solution of intermediate 3 (0.245 g) in ethanol (10 ml) at room
temperature, and the mixture was stirred for 16 h. The solvent was
then removed in vacuo and the residue was taken up in water. The
resulting solution was acidified to pH 2, then extracted with ethyl
acetate. Removal of the solvents gave the title compound as a white
solid (0.23 g 93%).
[0183] TLC R.sub.f 0.41 (5% methanol-dichloromethane)
[0184] Intermediate 5 1-Bromo-5-phenylpentan-2-one
[0185] Diazomethane preparation: The reaction vessel of a standard
diazomethane kit (fitted with a CO.sub.2 condenser and trap and an
addition funnel) was charged with a solution of potassium hydroxide
(5.00 g) in water (8 ml) and ethanol (10 ml). The vessel was heated
to 65.degree. C. and a solution of N-methyl-N-nitroso-4-toluene
sulfonamide (Diazald,.RTM. 5.00 g) in diethyl ether (45 ml) was
added dropwise over 30 min from an addition funnel. Diazomethane
solution was collected by continuous distillation. Ethyl
chloroformate was added dropwise to a stirred solution of
4-phenylbutyric acid (1.36 g) and N-methylmorpholine (1.28 ml) in
THF (15 ml) at -12.degree. C. under a nitrogen atmosphere. A white
precipitate began to form, which was removed by filtration after 90
min. The filtrate was treated with a pre-formed solution of
diazomethane (16.6 mmol) in diethyl ether at 0.degree. C. The
combined solution of diazomethane and anhydride was stirred at
0.degree. C. for 3.5 h and room temperature for 1 h. A solution of
hydrogen bromide in acetic acid (45%, 10 ml) and water (10 ml) was
added slowly. The mixture was stirred for 20 min before a saturated
aqueous solution of NaHCO.sub.3 (200 ml) was added. The mixture was
extracted with ethyl acetate (3.times.200 ml) and the combined
extracts were washed with brine and dried (MgSO.sub.4). The solvent
was removed in vacuo and the residue was eluted from a column of
silica with 10% diethyl ether in hexane to provide the title
compound as a colourless liquid (765 mg, 38%).
[0186] TLC R.sub.f 0.6 (3:1 hexane-diethyl ether).
[0187] Intermediate 6
1-(4-Methoxyphenylsulfanyl)-5-phenylpentan-2-one
[0188] A solution of intermediate 5 (365 mg) and
4-methoxythiophenol (0.186 ml) in DMF (15 ml) at room temperature
under a nitrogen atmosphere was treated with triethylamine (0.210
ml). The mixture was stirred for 4 h before being poured into 0.5 N
HCl (100 ml). The mixture was extracted with ethyl acetate
(3.times.100 ml) and the combined exacts were washed with brine and
dried (MgSO.sub.4). The solvent was removed in vacuo and the
residue was eluted from a column of silica with 10% diethyl ether
in hexane to provide the title compound as a colourless solid (375
mg, 83%).
[0189] TLC R.sub.f 0.3 (3:1 hexane-diethyl ether).
[0190] Intermediate 7 Methyl
3-(4-Methoxyphenylsulfanyl)methyl-6-phenylhex- -2-enoate
[0191] Methyl diethyl phosphonoacetate (0.246 ml) was added
dropwise to a stirred solution of potassium hexamethyldisilazide
(0.5 M in toluene, 2.67 ml) in THF (20 ml) at -12.degree. C. under
a nitrogen atmosphere. The mixture was stirred for 20 min before a
solution of intermediate 6 (365 mg) in THF (20 ml) at -12.degree.
C. was added via a double-tipped needle under pressure of nitrogen.
The mixture was stirred at a temperature not exceeding 0.degree. C.
for 1 h before being allowed to warm to room temperature and then
heated to 40.degree. C. for a period of 20 h. A saturated aqueous
solution of NH.sub.4Cl (100 ml) was added. The mixture was
extracted with ethyl acetate (3.times.100 ml) and the combined
extracts were washed with brine and dried (MgSO.sub.4). The solvent
was removed in vacuo and the residue was eluted from a column of
silica with 10% diethyl ether in hexane to provide the title
compound as an equal mixture of E and Z isomers as a colourless
liquid (265 mm 61%).
[0192] TLC R.sub.f 0.25 and 0.35 (5:1 hexane-diethyl ether).
[0193] Intermediate 8
Methyl-3-(4-Methoxyphenylsulfanyl)methyl-6-phenyl-he- xanoate
[0194] A solution of intermediate 7 (265 mg) in ethyl acetate (20
ml) was added to an evacuated hydrogenation flask containing 10%
palladium on charcoal (150 mg). The mixture was degassed before
being flushed with hydrogen and agitated overnight. The catalyst
was then removed by filtration over Celite.RTM. and the solvent was
removed in vacuo to give the title compound as a pale yellow liquid
(242 mg, 91%).
[0195] TLC R.sub.f 0.4 (5:1 hexane-diethyl ether)
[0196] Intermediate 9 Bis(4-Hydroxybenzene)disulfide
[0197] Iodine (5.12 g) was added portionwise to a stirred solution
of 4-hydroxythiophenol (5.09 g) in methanol (50 ml) at ambient
temperature. After stirring for 2 hours, water (2 ml) and sodium
sulfite (0.62 g) were added to decolourise the solution, and after
brief stirring the mixture was concentrated to dryness in vacuo.
The residual orange solid was partitioned between diethyl ether (50
ml) and water, and the layers were separated. The organic layer
washed with water (3.times.20 ml), saturated brine (10 ml), dried
(MgSO.sub.4) and concentrated to dryness in vacuo to provide the
title compound as a yellow solid (5.06 g, 100%).
[0198] TLC R.sub.f 0.29 (5% methanol-dichloromethane)
[0199] Intermediate 10
Bis(4-Carbamoylmethyloxybenzene)disulfide
[0200] Intermediate 9 (3.00 g), 2-bromoacetamide (3.47 g) and
potassium carbonate (3.48 g) were heated in acetone (100 ml) at
reflux. After 7 hours the mixture was cooled in ice, and a white
solid which precipitated was removed by filtration, washed with
acetone, water and acetone and dried to constant weight in vacuo to
provide the title compound (3.659 g 84%) as a colourless solid.
[0201] TLC R.sub.f 0.23 (5% methanol-dichloromethane)
[0202] Intermediate 11 2-(4-Sulfanylphenoxy)acetamide
[0203] Intermediate 10 (1.46 g) and sodium borohydride (0.45 g)
were heated to reflux in absolute ethanol for 90 minutes. Sodium
borohydride was added to the refluxing mixture (CAUTION) until the
reaction was complete by thin layer chromatography. After cooling,
the solution was concentrated to dryness in vacuo, and the residue
suspended in water (40 ml). The basic aqueous mixture was acidified
with concentrated hydrochloric acid and extracted with diethyl
ether (100 ml). The ethereal solution was washed with water
(2.times.50 ml), saturated brine (20 ml), dried (MgSO.sub.4) and
concentrated to dryness in vacuo to provide the title compound
(1.22 g, 84%) as an orange solid.
[0204] TLC R.sub.f 0.54 (5% methanol-dichloromethane)
[0205] Intermediate 12 Dibenzyl (3-Succinimidopropyl)malonate
[0206] Sodium hydride (60% dispersion in mineral oil, 4.4 g) was
added to a solution of dibenzyl malonate (29.5 g) in THF 300 ml)
and the mixture was stirred at room temperature for 30 min, then a
solution of 1-bromo-3-chloropropane (10 ml) in THF (30 ml) was
added dropwise. The solution was heated at reflux for 18 h, then
cooled and evaporated in vacuo. The oily residue was dissolved in
hexane (500 ml) and washed with water and brine, then dried
(MgSO.sub.4) and evaporated to give a colourless oil. This oil was
dissolved in acetone (300 ml) and sodium iodide (20 g) was added.
The solution was stirred at room temperature for 18 h, then
evaporated and the residue partitioned between water and hexane.
The layers were separated and the organic layer was dried
(MgSO.sub.4) and evaporated to give a pale yellow oil which was
dissolved in dry DMF. Potassium succinimide (15 g) was added and
the mixture was heated at 80.degree. C. for 18 h. The mixture was
cooled, poured into water (500 ml) and extracted with diethyl ether
(3.times.200 ml). The ether layers were combined, washed with
water, dried and evaporated. The residue was purified by column
chromatography, eluting with diethyl ether, to give the title
compound (9.65 g, 23%) as a colourless oil.
[0207] TLC R.sub.f 0.45 (diethyl ether)
[0208] Intermediate 13
1-(2-Bromoethyl)-3,4,4-trimethylhydantoin
[0209] Sodium hydride (60% dispersion in mineral oil, 1.7 g) was
added to a solution of 3,4,4-trimethylhydantoin (5.5 g) in DMF (20
ml) at room temperature. The mixture was stirred for 30 min, then
dibromoethane (3.5 ml) was added dropwise and the solution was
stirred overnight. The mixture was added to water (200 ml) and
extracted with diethyl ether. The ether layer was washed with
water, dried (MgSO.sub.4) and evaporated and the residue was
purified by column chromatography, eluting with diethyl ether, to
give the title compound (4.2 g, 50%) as a colourless solid.
[0210] TLC R.sub.f 0.5 (diethyl ether).
[0211] Intermediate 14
1-(3-Iodopropyl)-3,4,4-trimethylhydantoin
[0212] Sodium hydride (2.2 g) was added to a solution of
3,4,4-trimethylhydantoin (7.1 g) in DMF (50 ml) at room temperature
and the mixture was stirred for 1 h. 3-Chloro-1-bromopropane (4.9
ml) was then added and the solution was stirred overnight. The
mixture was then poured into water (300 ml) and extracted with
diethyl ether; the ether layer was dried (MgSO.sub.4) and
evaporated and the residue was dissolved in acetone (100 ml) to
which was added sodium iodide (10 g). The mixture was heated at
reflux for 18 h, then evaporated and the residue was dissolved in
diethyl ether and washed with water, then dried (MgSO.sub.4) and
evaporated to give the title compound (11 g, 70%) as a brown
oil.
[0213] TLC R.sub.f 0.85 (diethyl ether)
[0214] Intermediate 15 4-Benzoylbenzenethiol
[0215] A stirred solution of sodium hydrosulfide monohydrate (43 g)
in N-methylpyrrolidinone (400 ml) under a nitrogen atmosphere was
heated at 160.degree. C. under Dean and Stark conditions; 10 ml of
water azeotrope was collected over 90 min. The mix was cooled to
140.degree. C. and 4-chlorobenzophenone (50 g) was added. The
mixture was stirred at 160.degree. C. for 3 h before being allowed
to cool to room temperature overnight. The N-methylpyrrolidinone
was removed in vacuo and the black oily residue was dissolved in
water (500 ml). The solution was acidified with 6 N HCl and the
mixture was extracted with ethyl acetate (3.times.300 ml). The
combined extracts were washed with brine and the solvent was
removed in vacuo to give a brown solid (41 g). The solid was
dissolved in ethyl acetate (500 ml) and the solution was extracted
with NaOH (5%, 4.times.200 ml). The combined extracts were
acidified to pH 3 with 6 N HCl and the resulting precipitate was
collected by filtration, washed with water and dried in vacuo to
give the title compound as a beige solid (21 g, 43%).
[0216] TLC R.sub.f 0.4 (3:1 hexane-ethyl acetate)
[0217] Intermediate 16 Benzo[1,3]dioxole-5-thiol
[0218] Was prepared according to Hitotsuyangi et al (J. Chem. Soc.,
Perkin Trans. 1, 1995, 1387-1390) from 5-bromobenzo[1,3]dioxole, as
a colourless oil (7.48 g, 61%).
[0219] TLC R.sub.f 0.5 (10% ethyl acetate/hexane)
[0220] Intermediate 17 4-Acetylsulfanyltetrahydropyran
[0221] Diethyl azodicarboxylate (7.24 ml) was added to a stirred
solution of triphenylphosphine (12.1 g) in THF (80 ml), and stirred
at room temperature for 10 min. Thiolacetic acid (3.29 ml) and
tetrahydro-4H-pyran-4-ol (2.3 g) were added (CAUTION: exotherm),
and the mixture stirred at room temperature for a further 18 h.
After removal of the THF under reduced pressure, stirring with
hexane (50 ml) and water (50 ml) gave a precipitate, which was
removed by filtration. The biphasic filtrate was separated, and the
aqueous phase extracted once with hexane (50 ml). The combined
hexane extracts were washed with water (30 ml), brine (10 ml),
dried (MgSO.sub.4) and evaporated to leave a yellow liquid (2.73
g). Purification by chromatography on silica, eluting with
hexane/diethyl ether (10:1), provided the title compound as a pale
yellow liquid (0.98 g, 27%).
[0222] TLC R.sub.f 0.20 (hexane/diethyl ether (10:1))
[0223] Intermediate 18 Tetrahydropyran-thiol
[0224] Sodium borohydride (0.278 g) was added to a stirred solution
of intermediate 17 in methanol (15 ml) at 0.degree. C. under
nitrogen. After 2 h a further portion of sodium borohydride (0.370
g) was added, and the mixture allowed to warm to room temperature
and stirred for a further 18 h. The reaction was then quenched with
1 M hydrochloric acid (50 ml) and extracted with diethyl ether
(2.times.30 ml). The combined organic extracts were washed with
brine (10 ml), dried (MgSO.sub.4) and concentrated in vacuo to
provide the title compound as a colourless liquid (0.472 g,
60%).
[0225] TLC R.sub.f 0.70 (hexane/ethyl acetate (3:1))
[0226] Intermediate 19 1-Benzoyl-4-bromopiperidine
[0227] Benzoyl chloride (1.41 g) was added to a solution of
4-bromopiperidine hydrobromide (2.45 g) in THF (30 ml) at 0.degree.
C., followed by triethylamine (2.2 g, 2.2 eq). The solution was
stirred at room temperature for 1 h, and evaporated and. The
residue was dissolved in dichloromethane (100 ml), washed with
water, 1M HCl and saturated sodium bicarbonate, dried and
evaporated to give the title compound as colourless oil (2.76 g,
100%).
[0228] TLC R.sub.f0.55 (ether).
[0229] Intermediate 20 1-Benzoyl-4-(acetylsulfanyl)piperidine
[0230] Potassium thioacetate (2.3 g) was added to a solution of
intermediate 19 in DMF (50 ml) at room temperature. The mixture was
stirred at room temperature for 3 days, then added to water and
extracted with ether. The solvent was washed with water and sodium
bicarbonate solution, dried and evaporated to give the title
compound as pale amber oil (2.6 g, 100%).
[0231] TLC R.sub.f 0.45 (ether).
[0232] Intermediate 21 1-Benzoylpiperidine-4-thiol
[0233] A solution of the thioacetate intermediate 20 (2.6 g) in
methanol (100 ml) was treated with sodium borohydride (1.2 g) and
the mixture was stirred at room temperature for 4 h, then
evaporated and the residue dissolved in water. The solution was
acidified with solid citric acid and extracted with dichloromethane
(2.times.100 ml). The solvent was washed with brine, dried and
evaporated to give the title compound as brown oil (2.0 g).
[0234] TLC R.sub.f 0.30 (ether).
[0235] Intermediate 22
1-tert-Butyloxycarbonyl-4-bromopiperidine
[0236] A solution of di-tert-butyldicarbonate (4.4 g) in
dichloromethane was added to a suspension of 4-bromopiperidine
hydrobromide (5 g) in dichloromethane (100 ml) at 0.degree. C.,
followed by triethylamine (5.1 g). The solution was stirred for 3 h
at room temperature, then washed with water, 0.5 M HCl and
saturated sodium bicarbonate, dried and evaporated to give the
title compound as colourless oil (5.3 g, 99%).
[0237] TLC R.sub.f 0.70 (ether).
[0238] Intermediate 23
1-tert-Butyloxycarbonyl-4-(acetylsulfanyl)piperidin- e
[0239] Potassium thioacetate (4.4 g) was added to a solution of
intermediate 22 (5.3 g) in DMF (100 ml) and the mixture was heated
to 100.degree. C. for 4 h, then cooled and added to water. The
mixture was extracted with ether, and the solvent then washed with
water and sodium bicarbonate, dried and evaporated to give the
title compound (5.10 g, 96%).
[0240] TLC R.sub.f 0.60 (ether).
[0241] Intermediate 24 4-(4-Sulfanylbenzoyl)pyridine
[0242] A suspension of sodium hydrogen sulfide (6 g) in DMF (100
ml) was heated to reflux for 1 h, then cooled and
4-(4-chlorobenzoyl)pyridine (5 g) was added. The mixture was heated
at reflux for 2 h, then cooled and added to water. The brown
solution was washed with ether, then acidified with citric acid and
extracted with dichloromethane (2.times.100 ml). The solvent was
dried and evaporated to give the title compound as beige powder
(2.4 g, 50%).
[0243] TLC R.sub.f 0.45 (ether).
[0244] Similarly prepared was:
[0245] Intermediate 25 2-(4-Sulfanylbenzoyl)thiophene
[0246] From 2-(4-fluorobenzoyl)thiophene (10 g) as beige solid
(4.50 g, 42%).
[0247] TLC R.sub.f 0.65 (ether).
[0248] Intermediate 26
4-Methoxy-1-(2-Phenylethylsulfanyl)benzene
[0249] A solution of 4-methoxybenzene thiol (5.7 g), triethylamine
(4.1 g) and 2-bromoethylbenzene (5.6 ml) in DMF (50 ml) at
0.degree. C. was stirred for 2 h, then added to water and extracted
with ether. The solvent was washed with water, 1M NaOH and brine,
then dried and evaporated to give the title compound as colourless
oil (8.9 g, 95%).
[0250] TLC R.sub.f 0.80 (ether)
[0251] Intermediate 27 Dibenzyl-2-(3-phthalimidopropyl)malonate
[0252] A solution of dibenzyl malonate (20 g) in anhydrous THF (200
ml) was treated at 0.degree. C. with sodium hydride (60% dispersion
in mineral oil, 3.1 g). The mixture was allowed to warm to room
temperature and stirred for 30 minutes under nitrogen. The mixture
was then treated with a solution of N-(3-bromopropyl)phthalimide
(20.5 g) in THF (100 ml) and heated at reflux for 12 hours. The
reaction was then cooled, filtered, and the filtrate evaporated in
vacuo. The residue was partitioned between ethyl acetate (200 ml)
and saturated aqueous ammonium chloride (150 ml). The organic layer
was washed with water (100 ml), brine (100 ml), dried (MgSO.sub.4),
filtered and the filtrate evaporated in vacuo. The residue was
purified by column chromatography on silica gel eluting with 20%
ethyl acetate in hexane to yield the title compound (17.5 g, 50%)
as a white solid.
[0253] TLC R.sub.f 0.16 (20% ethyl acetate-hexane)
[0254] Similarly prepared were:
[0255] Intermediate 28 Dibenzyl 2-(2-Phthalimidoethyl)malonate
[0256] From dibenzyl malonate (20 g) and
N-(2-bromoethyl)phthalimide (18.7 g), as a clear gum (32 g,
100%).
[0257] TLC R.sub.f 0.15 (20% ethyl acetate-hexane)
[0258] Intermediate 29 Dibenzyl
(2-(3,4,4-Trimethylhydantoin-1-yl)ethyl)ma- lonate
[0259] From dibenzyl malonate (4.8 g) and intermediate 13 (4.2 g),
as a colourless oil (7.2 g, 100%).
[0260] TLC R.sub.f 0.4 (diethyl ether)
[0261] Intermediate 30 Dibenzyl
(3-(3,4,4-Trimethylhydantoin-1-yl)propyl)m- alonate
[0262] From dibenzyl malonate (5.7 g) and intermediate 14 (6.2 g)
as a colourless oil (7.1 g, 80%).
[0263] TLC R.sub.f 0.53 (diethyl ether)
[0264] Intermediate 31 Dibenzyl (3-Phenylpropyl)malonate
[0265] From dibenzyl malonate (30 g) and 1-bromo-3-phenylpropane
(21 g) as a colourless oil (34 g, 80%).
[0266] TLC R.sub.f 0.48 (20% ethyl acetate-hexane)
[0267] Intermediate 32 Dibenzyl propylmalonate
[0268] From dibenzyl malonate (22 ml) and 1-bromopropane (7.3 g) as
a colourless oil (25.9 g, 100%).
[0269] TLC R.sub.f 0.31 (20% ethyl acetate-hexane)
[0270] Intermediate 33 Diethyl
(3-(Ethoxycarbonyl)propyl)malonate
[0271] From diethyl malonate (5.0 g) and ethyl 4-bromobutyrate
(6.65 g), as a clear gum (3.79 g, 45%).
[0272] TLC R.sub.f 0.29 (20% ethyl acetate in hexane)
[0273] Intermediate 34 2-Methylene-5-phthalimidopentanoic Acid
[0274] A solution of intermediate 27 (16.75 g) in dioxane (200 ml)
was treated with 10% palladium on charcoal (1.7 g) and hydrogenated
at atmospheric pressure until the hydrogen uptake had ceased. The
catalyst was removed by filtration through Celite.RTM. and the
filtrate treated with piperidine (3.2 g) at room temperature. After
30 minutes the reaction was treated with formaldehyde (37% solution
in water, 15 ml), stirred for two hours at room temperature and
then heated at 80.degree. C. for two hours. The mixture was cooled,
the solvent removed in vacuo and the residue partitioned between
ethyl acetate (200 ml) and 10% aqueous citric acid (100 ml). The
organic layer was washed with water (100 ml), brine (100 ml), dried
over magnesium sulfate, filtered and the filtrate evaporated in
vacuo. The residue was purified by column chromatography on silica
gel eluting with 40% ethyl acetate in hexane to yield the title
compound (12.2 g, 70%) as a white solid.
[0275] TLC R.sub.f 0.44 (50% ethyl acetate-hexane)
[0276] Similarly prepared were:
[0277] Intermediate 35 2-Methylene-4-phthalimidobutanoic Acid
[0278] From intermediate 28 (10 g) as a white solid (5 g, 93%).
[0279] TLC R.sub.f 0.12 (50% ethyl acetate-hexane)
[0280] Intermediate 36 2-Methylene-5-succinimidopentanoic Acid
[0281] From intermediate 12 (9.65 g) as colourless oil (2.85 g
59%).
[0282] TLC R.sub.f 0.6 (diethyl ether).
[0283] Intermediate 37
2-Methylene-4-(3,4,4-trimethylhydantoin-1-yl)butana- noic Acid
[0284] From intermediate 29 (7.2 g) as a colourless solid (1.5 g,
37%).
[0285] TLC R.sub.f 0.35 (ethyl acetate)
[0286] Intermediate 38 2-Methylene-5-phenylpentanoic Acid
[0287] From intermediate 31 (17.6 g) as a colourless oil (5.0 g,
60%)
[0288] TLC R.sub.f 0.31 (20% ethyl acetate-hexane)
[0289] Intermediate 39
2-Methylene-5-(3,4,4-trimethylhydantoin-1-yl)pentan- oic Acid
[0290] From intermediate 30 (10 g) as a colourless oil (5.40 g,
95%).
[0291] TLC R.sub.f 0.4 (ethyl acetate)
[0292] Intermediate 40 2-Methylene-3-phenylpropanoic Acid
[0293] From dibenzyl benzylmalonate (10 g) as a colourless oil (4.5
g, 100%).
[0294] TLC R.sub.f 0.34 (diethyl ether)
[0295] Intermediate 41 2-Methylenepentanoic Acid
[0296] From intermediate 32 (25.9 g) as a colourless oil (5.8 g,
64%). TLC R.sub.f 0.33 (ethyl acetate)
[0297] Intermediate 42 1-Methylenebutane-1,4-dicarboxylic acid
[0298] A solution of intermediate 33 (3.79 g) in ethanol (10 ml)
was treated with water (50 ml) and potassium hydroxide (4.65 g).
The reaction was heated at 100.degree. C. for two hours and the
organic solvent removed in vacuo. The aqueous residue was washed
with ethyl acetate (50 ml) separated and the basic layer acidified
to pH 1 with 6 M hydrochloric acid. The product was extracted with
ethyl acetate (3.times.100 ml), the extracts combined, dried over
magnesium sulfate and filtered. The filtrate was evaporated in
vacuo and the residue treated with piperidine (0.7 g) at room
temperature. After 30 minutes the reaction was treated with
formaldehyde (37% solution in water, 3.3 ml), stirred for two hours
at room temperate and then heated at 80.degree. C. for two hours.
The mixture was cooled, the solvent removed in vacuo and the
residue partitioned between ethyl acetate (100 ml) and 10% aqueous
citric acid (50 ml). The organic layer was washed with water (50
ml), brine (50 ml), dried over magnesium sulfate, filtered and the
filtrate evaporated in vacuo. The residue was purified by column
chromatography on silica gel eluting with 50% ethyl acetate in
hexane to yield the title compound as a white solid (1.0 g,
49%).
[0299] TLC R.sub.f 0.28 (50% ethyl acetate in hexane)
[0300] Intermediate 43 2-Methylene-3-methylbutanoic Acid
[0301] Piperidine (6 ml) was added to a solution of
isopropylmalonic acid (5 g) in dioxan (70 ml) and the reaction was
stirred for 0.5 h. Formaldehyde (37% aqueous, 6 ml) was added and
the reaction was stirred for 16 hours. The reaction was heated to
80.degree. C. for 2 h, cooled to room temperature, and partitioned
between ethyl acetate and water. The aqueous phase was acidified to
pH 1 and extracted with dichloromethane. Combined organic phases
were dried and the solvents removed in vacuo to give the title
compound as a colourless oil (3.1 g, 79%).
[0302] TLC R.sub.f 0.5 (5% methanol/dichloromethane)
[0303] Similarly prepared was:
[0304] Intermediate 44 2-Methylene-4-(pyrid-2-yl)butanoic Acid
[0305] From 2-(2-pyridylethyl)malonic acid (2.5 g) as colourless
solid (1.80 g, 90%).
[0306] TLC R.sub.f 0.3 (EtOAc).
[0307] Intermediate 45 2-Bromomethyl-5-phthalimidopentanoic
Acid
[0308] Intermediate 34 (1.0 g) was treated with 45% hydrogen
bromide in acetic acid (30 ml) at room temperature. After three
hours the solution was poured into water (300 ml) and the product
extracted with ethyl acetate (3.times.100 ml). The extracts were
combined, washed with water (100 ml), brine (100 ml), dried over
magnesium sulfate, filtered and the filtrate evaporated in vacuo.
The residue was dried by azeotrope with toluene (2.times.10 ml) to
yield the title compound as a white solid (1.3 g, 100%).
[0309] TLC R.sub.f 0.34 (50% ethyl acetate-hexane)
[0310] Similarly prepared were:
[0311] Intermediate 46 2-Bromomethyl-4-phthalimidobutanoic Acid
[0312] From intermediate 35 (4.7 g), as a white solid (5.3 g,
85%).
[0313] TLC R.sub.f 0.36 (50% ethyl acetate-hexane)
[0314] Intermediate 47 2-Bromomethyl-5-succinimidopentanoic
Acid
[0315] From intermediate 36 (2.86 g) as colourless sold (2.50 g,
63%).
[0316] TLC R.sub.f 0.3 (ethyl acetate)
[0317] Intermediate 48
2-Bromomethyl-4-(3,4,4-trimethylhydantoin-1-yl)buta- noic Acid
[0318] From intermediate 37 (1.5 g) as colourless solid (0.80 g,
45%).
[0319] TLC R.sub.f 0.2 (5% methanol-dichloromethane)
[0320] Intermediate 49
2-Bromomethyl-5-(3,4,4-trimethylhydantoin-1-yl)-pen- tanoic
Acid
[0321] From intermediate 39 (5.4 g) as a viscous oil (4.0 g,
56%).
[0322] TLC R.sub.f 0.35 (ethyl acetate)
[0323] Intermediate 50 2-Bromomethyl-3-phenylpropanoic Acid
[0324] From intermediate 40 (26.2 g) as a colourless oil (33.2 g,
86%).
[0325] TLC R.sub.f 0.45 (1:1 ethyl acetate-hexane)
[0326] Intermediate 51 2-(Bromomethyl)pentanoic Acid
[0327] From intermediate 41 (4.8 g) as a colourless oil (7.0 g,
85%).
[0328] TLC R.sub.f 0.36 (20% ethyl acetate-hexane)
[0329] Intermediate 52 2-Bromomethyl-5-phenylpentanoic Acid
[0330] From intermediate 38 (3.4 g) as a colourless oil (4.2 g,
87%).
[0331] TLC R.sub.f 0.32 (20% ethyl acetate-hexane)
[0332] Intermediate 53 1-(Bromomethyl)butane-1,4-dicarboxylic
Acid
[0333] From intermediate 42 (0.6 g), as a white solid (0.8 g,
88%)TLC R.sub.f 0.38 (50% ethyl acetate in hexane)
[0334] Intermediate 54 2-Bromomethyl-3-methylbutanoic Acid
[0335] From intermediate 43 (3.1 g) as a colourless oil (4.6 g,
87%).
[0336] MS 196MH.sup.+
[0337] Intermediate 55 2-Bromomethyl-4-(2-pyridyl)butanoic Acid
Hydrobromide
[0338] Intermediate 44 (1.80 g) was dissolved in 48% HBr/acetic
acid (20 ml) and stirred for 2 h, then evaporated in vacuo and
azeotroped with isopropanol (4.times.100 ml) to give the title
compound as beige solid (3.3 g, 90%).
[0339] TLC R.sub.f 0.40 (1:4:4 water/EtOAc/MeOH).
[0340] Intermediate 56 Methyl
2-(Bromomethyl)-5-phenylpentanoate
[0341] Intermediate 52 (5.0 g) was treated with a solution of
diazomethane in diethyl ether. Removal of the solvent in vacuo gave
the title compound as a colourless oil (5.2 g, 100%).
[0342] TLC R.sub.f 0.31 (5% ethyl acetate-hexane)
[0343] Intermediate 57 Methyl
2-Acetylsulfanylmethyl-5-phenylpentanoate
[0344] A solution of intermediate 56 in DMF was treated with
potassium thioacetate (6.0 g) at 60.degree. C. for 18 h. The
mixture was added to water and extracted with ether, them the
solvent was washed with water and brine, dried and evaporated to
give the title compound as a brown oil (8.5 g, 90%).
[0345] TLC R.sub.f 0.80 (ether).
[0346] Intermediate 58 Methyl
2-Chlorosulfonylmethyl-5-phenylpentanoate
[0347] Chlorine was passed through a suspension of intermediate 57
(0.7 g) in iced water (20 ml) for 30 min. The yellow suspension was
then extracted with dichloromethane and the solvent was washed with
water, sodium metabisulfite and brine, then dried and evaporated to
give a the title compound (0.7 g, 100%) as colourless oil.
[0348] TLC R.sub.f 0.45 (ether).
[0349] Intermediate 59 2-(4-Hydroxy-3,5-dimethylbenzoyl)benzoic
Acid
[0350] Was prepared according to Chem Ber., 1983, 116, 970.
[0351] Intermediate 60
4-(4-Hydroxy-3,5-dimethylphenyl)-2-methyl-1(2H)phth- alazinone
[0352] Was prepared according to Chem Ber., 1983, 116, 970.
[0353] Intermediate 61 1-tert-Butoxycarbonylpiperidine-4-thiol
[0354] Sodium borohydride (5.0 g) was added to a solution of
intermediate 23 (5.1 g) in methanol (200 ml). The solution was
stirred at room temperature for two hours and then evaporated in
vacuo. The residue was carefully dissolved in water and citric acid
added (5.0 g). The product was extracted with dichloromethane
(2.times.100 ml), the extracts combined, dried over magnesium
sulfate, filtered and the filtrate evaporated in vacuo to give the
title compound as a pale yellow oil (4.70 g, 98%)
[0355] TLC R.sub.f 0.40 (ether).
[0356] Intermediate 62
2-(4-Benzoylphenylsulfanylmethyl)-5-phthalimidopent- an-oic
Acid
[0357] A solution of intermediate 45 (1.0 g) in THF (20 ml) was
purged with nitrogen for 5 minutes and treated with intermediate 15
(0.7 g) and triethylamine (1.0 ml). The mixture was stirred at room
temperature for 24 hours and then the solvent removed in vacuo. The
residue was partitioned between ethyl acetate (100 ml) and water
(100 ml). The aqueous layer was extracted with ethyl acetate (50
ml), the extracts combined, washed with brine, dried over magnesium
sulfate and filtered. The filtrate was evaporated in vacuo and the
residue was purified by column chromatography on silica gel eluting
with 50% ethyl acetate in hexane to yield the title compound (0.5
g, 35%) as a clear gum.
[0358] TLC R.sub.f 0.33 (50% ethyl acetate-hexane)
[0359] Similarly prepared were:
[0360] Intermediate 63 3-(4Benzoylphenylsulfanyl)propanoic Acid
[0361] From intermediate 15 (1.5 g) and 3-bromopropionic acid (1.07
g), as a white solid (0.32 g, 16%).
[0362] TLC R.sub.f 0.05 (50% ethyl acetate-hexane)
[0363] Intermediate 64
2-(4-Acetylphenylsulfanylmethyl)-5-phenylpentanoic Acid
[0364] From intermediate 1 (0.37 g) and intermediate 52 (1.34 g) as
an orange oil (0.5 g, 41%).
[0365] TLC R.sub.f 0.47 (5% methanol-dichloromethane)
[0366] Intermediate 65
2-(Thiazol-2-ylsulfanylmethyl)-5-phenylpentanoic Acid
[0367] From intermediate 52 (1.16 g) and 2-mercaptothiazole (0.5 g)
as a colourless oil (0.125 g, 9%).
[0368] TLC R.sub.f 0.6 (5% metanol-dichloromethane)
[0369] Intermediate 66
2-(4-N,N-Dimethylcarbamoylphenlylsulfanylmethyl)-5--
phenylpentanoic Acid
[0370] From intermediate 52 (0.2g) and intermediate 4 (0.344 g) as
a colourless oil (0.29 g, 59%).
[0371] TLC R.sub.f 0.22 (5% methanol-dicloromethane)
[0372] Intermediate 67
2-(4-Methoxybenzenesulfanylmethyl)-5-phenylpentanoi- c Acid.
[0373] From 4-methoxybenzenethiol (0.556 g) and intermediate 52
(1.08 g) as a pale yellow oil (1.021 g, 78%).
[0374] TLC R.sub.f 0.80 (50% ethyl acetate-hexane)
[0375] Intermediate 68
2-(4-Methoxyphenylsulfanylmethyl)-5-phthalimidopent- anoic Acid
[0376] From intermediate 45 (1.0 g) and 4-methoxybenzenethiol (0.45
g), as a clear gum (1.1 g, 94%).
[0377] TLC R.sub.f 0.62 (4% methanol-dichloromethane)
[0378] Intermediate 69
2-(4-Methoxyphenylsulfanylmethyl)-4-phthalimidobuta- noic Acid
[0379] From intermediate 46 (1.0 g) and 4-methoxybenzenethiol (0.47
g), as a clear gum (0.92 g, 78%).
[0380] TLC R.sub.f 0.19 (2% methanol-dichloromethane)
[0381] TLC R.sub.f 0.41 (50% ethyl acetate-hexane)
[0382] Intermediate 70 5-Phenyl-2-(phenylsulfanylmethyl)pentanoic
Acid
[0383] From benzenethiol (0.107 g) and intermediate 52 (0.248 g),
as a milky white oil (0.223 g, 82%).
[0384] TLC R.sub.f 0.46 (4:1 hexane-ethyl acetate)
[0385] Intermediate 71
2-(2-Methoxyphenylsulfanylmethyl)-5-phenylpentanoic Acid
[0386] From 2-methoxybenzenethiol (0.324 g) and intermediate 52
(0.597 g), as a colourless oil (0.539 g, 74%).
[0387] TLC R.sub.f 0.29 (20% ethyl acetate-hexane)
[0388] Intermediate 72
2-(3-Methoxyphenylsulfanylmethyl)-5-phenylpentanoic Acid
[0389] From 3-methoxybenzenethiol (0.318 g) and intermediate 52
(0.585 g), as a colourless oil (0.662 g, 93%).
[0390] TLC R.sub.f 0.29 (20% ethyl acetate-hexane)
[0391] Intermediate 73
2-(4-(Carbamoylmethyloxy)phenylsulfanylmethyl)-5-ph- enylpentanoic
Acid
[0392] From intermediate 11 (0.503 g) and intermediate 52 (0.744
g), as a white solid (0.884 g, 86%).
[0393] TLC R.sub.f 0.41 (5% methanol-dichloromethane)
[0394] Intermediate 74
2-(4-Benzoylphenylsulfanylmethyl)-5-phenylpentanoic Acid
[0395] From intermediate 52 (5.6 g) and intermediate 15 (4.6 g) as
a pale amber oil (7.5 g, 92%).
[0396] TLC R.sub.f 0.32 (3:1 hexane-ethyl acetate)
[0397] Intermediate 75
2-(Pyrid-4-ylsulfanylmethyl)-5-phenylpentanoic Acid
[0398] From 4-mercaptopyridine (0.33 g) and intermediate 52 (0.84
g) as a white solid (0.53 g, 58%).
[0399] TLC R.sub.f 0.45 (ethyl acetate)
[0400] Intermediate 76
2-(4-Methoxyphenylsulfanylmethyl)-5-succinimido-pen- tanoic
Acid
[0401] From intermediate 47 (1.5 g) and 4-methoxybenzenethiol (0.71
g) as a colourless oil (1.56 g, 80%).
[0402] TLC R.sub.f 0.3 (diethyl ether)
[0403] Intermediate 77
2-(4Benzoylphenylsulfanylmethyl)-5-succinimido-pent- anoic Acid
[0404] From intermediate 15 (0.21 g) and intermediate 47 (0.29 g)
as a white solid (0.34 g, 80%).
[0405] TLC R.sub.f 0.27 (ethyl acetate)
[0406] Intermediate 78
2-(4-Acetamidophenylsulfanylmethyl)-5-phenylpentano- ic Acid
[0407] From 4-acetamidobenzenethiol (0.17 g) and intermediate 52
(0.28 g) as a colourless oil (0.25 g, 45%).
[0408] TLC R.sub.f 0.5 (diethyl ether)
[0409] Intermediate 79
2-((1-Methylimidazol-2-yl)methylsulfanyl)-5-phenyl-- pentanoic
Acid
[0410] From 2-mercapto-1-methylimidazole (1.14 g) and intermediate
52 (2.8 g) as a white solid 0.5 g, 16%).
[0411] TLC R.sub.f 0.30 (6% methanol-dichloromethane)
[0412] Intermediate 80
2-(4-Methoxyphenylsulfanylmethyl)-5-(3,3,4-trimethy-
lhydantoin-1-yl)pentanoic Acid
[0413] From 4-methoxybenzenethiol (0.28 g) and intermediate 49
(0.68 g) as a white solid (0.64 g, 80%).
[0414] TLC R.sub.f 0.4 (ethyl acetate)
[0415] Intermediate 81
2-(4-Methoxyphenylsulfanylmethyl-4-(3,3,4-trimethyl-
hydantoin-1-yl)butanoic Acid
[0416] From intermediate 48 (0.48 g) and 4-methoxybenzenethiol
(0.21 g) as a white solid (0.49 g, 87%).
[0417] TLC R.sub.f 0.31 (ethyl acetate)
[0418] Intermediate 82
2-(4-Methoxyphenylsulfanylmethyl)-3-phenylpropanoic Acid
[0419] From intermediate 50 (2.43 g) and 4-methoxybenzenethiol (1.4
g) as a white solid (2.95 g, 98%).
[0420] TLC R.sub.f 0.55 (ethyl acetate)
[0421] Intermediate 83 Ethyl
4-(4-Methoxyphenyl)sulfanylbutanoate
[0422] From 4-methoxythiophenol (10.0 g) and ethyl 4-bromobutyrate
(10.2 ml) as a colourless liquid (16.7 g, 92%).
[0423] TLC R.sub.f 0.5 (3:1 hexane-diethyl ether)
[0424] Intermediate 84 2-(4-Methoxyphenylsulfanylmethyl)-pentanoic
Acid
[0425] From intermediate 51 (2.0 g) and 4-methoxybenzenethiol (1.3
ml) as a yellow oil (2.6 g, 99%).
[0426] TLC R.sub.f 0.40 (50% ethyl acetate-hexane)
[0427] Intermediate 85
1-(4Methoxyphenylsulfanylmethyl)butane-1,4-dicarbox- ylic Acid
[0428] From intermediate 53 (0.6g) and 4-methoxybenzenethiol (0.38
g), as a clear gum (0.57 g, 76%).
[0429] TLC R.sub.f 0.36 (50% ethyl acetate in hexane)
[0430] Intermediate 86
3-Methyl-2-(4-methoxyphenylsulfanylmethyl)butanoic Acid
[0431] From intermediate 54 (3.5 g) and 4-methoxybenzenethiol (2.51
g), as a colourless oil (3.26 g, 71%).
[0432] TLC R.sub.f 0.25 (5% methanol/dichloromethane)
[0433] Intermediate 87
2-[(Benzo(1,3)dioxole-5-yl)sulfanylmethyl]-5-phenyl- pentanoic
Acid
[0434] From intermediate 16 (2.0 g) and intermediate 52 (3.52g), as
a yellow-brown oil (3.78 g, 85%).
[0435] TLC R.sub.f 0.52 (5% methanol/dichloromethane)
[0436] Intermediate 88
2-[(4-Trifluoromethoxyphenylsulfanyl)methyl]-5-(1,5-
,5-trimethylhydantoin-3-yl)pentanoic Acid
[0437] From intermediate 49 (0.51 g) and
4-trifluoromethoxybenzenethiol (0.29 g), as a colourless oil (0.47
g, 70%).
[0438] TLC R.sub.f 0.32 (50% hexane/ethyl acetate with trace acetic
acid)
[0439] Intermediate 89
2-[(4-Trifluoromethoxyphenylsulfanyl)methyl]pentano- ic Acid
[0440] From intermediate 51 (2.00 g) and
4-trifluoromethoxybenzenethiol (1.99 g), as a pale yellow oil (2.78
g, 88%).
[0441] TLC R.sub.f 0.50 (hexane/ethyl acetate/acetic acid
(200:50:3))
[0442] Intermediate 90
2-(Quinolin-2-ylsulfanyl)methyl-5-phenylpentanoic Acid
[0443] From 2-mercaptoquinoline (256 mg) and intermediate 52 (0.3
g) as a colourless solid (0.3 g, 50%)
[0444] TLC R.sub.f 0.40 (ethyl acetate)
[0445] MS 352 [MH.sup.30 ]
[0446] Intermediate 91
2-(4-Benzoylphenyl)sulfanylmethyl-4-(3,3,4-trimethy-
lhydantoin-1-yl)butanoic Acid
[0447] From 4-mercaptobenzophenone (0.17 g) and intermediate 48
(0.20 g) as white solid (0.20 g, 85%).
[0448] TLC R.sub.f 0.50 (ether)
[0449] MS 470[M.sup.+]
[0450] Intermediate 92
2-(4-Benzoylphenyl)sulfanylmethyl-5-(3,3,4-trimethy-
lhydantoin-1-yl)pentanoic acid
[0451] From 4-mercaptobenzophenone (0.34 g) and intermediate 49
(0.40 g) as a pale amber oil (0.52 g, 62%)
[0452] TLC R.sub.f 0.45 (ethyl acetate)
[0453] MS 468 [M.sup.+]
[0454] Intermediate 93
2-(4-Benzoylphenyl)sulfanylmethyl-3-phenylpropanoic Acid
[0455] From 4-mercaptobenzophenone (0.85 g) and intermediate 50
(0.80 g) as a pale yellow gum (1.01 g, 59%).
[0456] TLC R.sub.f 0.60 (ether)
[0457] MS 372 [MH.sup.+]
[0458] Intermediate 94
2-(4-Methoxyphenyl)sulfanylmethyl-4-(pyrid-2-yl)but- anoic Acid
[0459] From intermediate 55 (1.0 g) and 4-methoxybenzenethiol (0.42
g) as a colourless oil (0.25 g, 25%).
[0460] TLC R.sub.f 0.25 (10% MeOH/dichloromethane).
[0461] MS 318 [MH.sup.+]
[0462] Intermediate 95
2-(4-(4-Pyridinoyl)phenylsulfanyl)methyl-5-phenylpe- ntanoic
Acid
[0463] From intermediate 24 (1.1 g) and intermediate 52 (1.4 g) as
white solid (1.62 g, 80%).
[0464] TLC R.sub.f 0.6 (EtOAc).
[0465] MS 406 [M.sup.+]
[0466] Intermediate 96
2-(4-(2-Thienoyl)phenylsulfanyl)methyl-5-phenylpent- anoic Acid
[0467] From intermediate 25 (1.3 g) and intermediate 52 (1.4 g) as
white solid (1.8 g, 85%).
[0468] TLC R.sub.f 0.60 (ether).
[0469] MS 410 [MH.sup.+]
[0470] Intermediate 97
2-(4-(4-Pyridinoyl)phenyl)sulfanylmethyl-5-(3,3,4-t-
rimethylhydantoin-1-yl)pentanoic Acid
[0471] From intermediate 24 (0.21 g) and intermediate 49 (0.34 g)
as white solid (0.25 g, 65%).
[0472] TLC R.sub.f 0.50 (10% MeOH/dichloromethane)
[0473] MS 469 [MH.sup.+]
[0474] Intermediate 98
2-(4-(2-Thienoyl)phenyl)sulfanylmethyl-5-(3,3,4-tri-
methylhydantoin-1-yl)pentanoic Acid
[0475] From intermediate 25 (0.66 g) and intermediate 49 (1.0 g) as
white solid (1.3 g, 90%).
[0476] TLC R.sub.f 0.70 (EtOAc)
[0477] Intermediate 99
2-(4-Hydroxyphenyl)sulfanylmethyl-5-phenylpentanoic Acid
[0478] From 4-mercaptophenol (1.26 g) and intermediate 52 as
colourless oil (3.0 g, 95%).
[0479] TLC R.sub.F 0.63 (ether).
[0480] Intermediate 100
2-((Quinolin-8yl)sulfanylmethyl)-5-phenylpentanoic Acid
[0481] From 8-quinoline thiol (120 mg) and intermediate 52 (170 mg)
as colourless solid (105 mg, 50%).
[0482] TLC R.sub.f 0.50 (ether).
[0483] Intermediate 101
2-(Furan-2ylmethylsulfanyl)methyl-5-phenylpentanoi- c Acid
[0484] Potassium tert-butoxide (415 mg) was added to a stirred
solution of furfuryl thiol (0.186 ml) in dichloromethane (20 ml) at
0.degree. C. under a nitrogen atmosphere. The mixture was stirred
for 3 min before a solution of intermediate 37 (500 mg) in
dichloromethane (5 ml) was added. The mixture was allowed to warm
to room temperature and stirred for 6 h before being poured into
HCl (0.5 M, 100 ml). The mixture was extracted with ethyl acetate
(2.times.100 ml). The combined organic phases were washed with
brine and dried (MgSO.sub.4). The solvent was removed in vacuo to
give the title compound as a yellow oil (560 mg, 99%).
[0485] TLC R.sub.f 0.3 (4:1 hexane-ethyl acetate)
[0486] Similarly prepared were:
[0487] Intermediate 102
2-(Cyclopentylsulfanyl)methyl-5-phenylpentanoic Acid
[0488] From intermediate 52 (500 mg), and cyclopentanethiol (0.198
ml) as a pale yellow oil (540 mg, 99%).
[0489] TLC R.sub.f 0.4 (4:1 hexane-ethyl acetate)
[0490] Intermediate 103 2-(Benzylsulfanylmethyl)-5-phenylpentanoic
Acid
[0491] From benzylmercaptan (0.059 g) and intermediate 52 (0.128 g)
as a colourless oil (0.116 g, 78%).
[0492] TLC R.sub.f 0.49 (hexane-ethyl acetate-acetic acid
(200:50:3)
[0493] Intermediate 104
5-Phenyl-2-[(tetrahydropyran-4-ylsulfanyl)methyl]-- pentanoic
Acid
[0494] From intermediate 18 (0.40 g) and intermediate 52 (0.700 g),
as a pale yellow oil (0.99 g, 94%).
[0495] TLC R.sub.f 0.50 (hexane/diethyl ether (1:1))
[0496] MS 373 (M+NH.sub.4.sup.+)
[0497] Intermediate 105
2-(2-Phenylethylsulfanylmethyl)-5phenylpentanoic Acid
[0498] Potassium hexamethyldisilazide (0.5 M in toluene, 20 ml) was
added to a solution of phenethyl mercaptan (0.7 g) in THF (50 ml)
at -78.degree. C. and the solution was stirred for 10 min, then a
solution of intermediate 52 (1.4 g) in THF (10 ml) was added
dropwise and the mixture was stirred for 3 hours, warming to room
temperature. The mixture was added to water and the solution was
washed with diethyl ether, acidified with acetic acid and extracted
with ether. The ether layer was washed with water and brine, dried
and evaporated and the residue purified by column chromatography,
eluting with 20% ethyl acetate in hexane to give the title compound
(1.30 g, 78%) as a colourless oil,
[0499] TLC R.sub.f 0.3 (20% ethyl acetate-hexane)
[0500] Similarly prepared were:
[0501] Intermediate 106
2-(3-Phenylpropylsulfanyl)methyl-5-phenylpentanoic Acid
[0502] From phenpropyl mercaptan (1.5 g) and intermediate 52 (2.8
g) as colourless oil (1.6 g, 50%).
[0503] TLC R.sub.f 0.86 (ether).
[0504] Intermediate 107
2-(2-Methylpropylsulfanylmethyl)-5-phenylpentanoic Acid
[0505] From isobutyl mercaptan (0.9 g) and intermediate 52 (2.8 g)
as a colourless oil (2.6 g, 93%).
[0506] TLC R.sub.f 0.83 (diethyl ether).
[0507] Intermediate 108
2-(1-Benzoylpiperidine-4-yl)sulfanylmethyl-5-pheny- lpentanoic
Acid
[0508] From intermediate 21 (2.0 g) and intermediate 52 (2.0 g) as
colourless oil (1.6 g).
[0509] TLC R.sub.f 0.34 (ether)
[0510] Intermediate 109
2-((1-tert-Butyloxycarbonyl)piperidin-4-yl)sulfany-
lmethyl-5-phenylpentanoic Acid
[0511] From intermediate 61 (4.2 g) and intermediate 52 (5.2 g) as
colourless oil (4.5 g, 53%).
[0512] TLC R.sub.f 0.3 (1:1 ether/hexanes).
[0513] Intermediate 110
2-(4-Methoxyphenylsulfanylmethyl)-5-(methoxycarbon- yl)pentanoic
Acid
[0514] A solution of intermediate 85 (0.5 g) in methanol (10 ml)
was treated with 4-toluenesulfonic acid (16 mg) at room
temperature. The mixture was heated at 40.degree. C. under nitrogen
for 2 h, then allowed to cool and the solvent was removed in vacuo.
The residue was partitioned between ethyl acetate (100 ml) and
water (50 ml). The organic layer was separated, dried over
magnesium sulfate, filtered and the filtrate evaporated in vacuo.
The residue was purified by column chromatography on silica gel
eluting with 40% ethyl acetate in hexane to give the title compound
as a while solid (0.38 g, 72%).
[0515] TLC R.sub.f 0.48 (50% ethyl acetate in hexane)
[0516] Intermediate 111 Methyl
2-(4-Bromophenylsulfanylmethyl)-5-phenylpen- tanoate
[0517] A solution of intermediate 46 (4.70 g) and 4-bromothiophenol
(4.79 g) in tetrahydrofuran (50 ml) was treated with 10% sodium
hydroxide in water (4.0 ml) and heated at reflux for 3 hours. The
reaction mixture was concentrated to an aqueous residue in vacuo
and partitioned between diethyl ether (250 ml) and water (150 ml).
The organic phase was dried over magnesium sulfate, concentrated
onto silica in vacuo and purified by chromatography on silica
eluting with 20% ethyl acetate in hexane to give the title compound
as a colourless oil (6.46 g, 71%)
[0518] TLC R.sub.f 0.2 (3% ethyl acetate-heptane)
[0519] Intermediate 112 Methyl
3-(4-Methoxyphenylsulfanyl)propanoate
[0520] 4-Methoxythiophenol (4.80 g) was added to a stirred solution
of methyl acrylate (3.08 ml) in dichloromethane (60 ml) at
0.degree. C. Potassium carbonate (4.72 g) was added and the mixture
was allowed to warm to room temperature overnight. The mixture was
filtered over a plug of Celite.RTM. and the solvent was removed in
vacuo to give the title compound as a yellow liquid (7.70 g,
100%).
[0521] TLC R.sub.f 0.3 (2:1 hexane-ethyl acetate)
[0522] Similarly prepared was:
[0523] Intermediate 113 Methyl 3-(4-Bromophenylsulfanyl)propanoate
From 4-bromothiophenol (6.26 g) as a yellow oil (8.75 g 96%).
[0524] TLC R.sub.f 0.5 (60% ethyl acetate-hexane)
[0525] Intermediate 114 Methyl
3-[4-(Chlorophenyl)phenylsulfanylmethyl]pro- panoate
[0526] A solution of intermediate 113 (2.80 g) and
4-chlorobenzeneboronic acid (1.91 g) in THF (80 ml) at room
temperature under a nitrogen atmosphere was treated with dichloro
bis(triphenylphosphine)palladium(II) (1.43 g). Aqueous sodium
carbonate solution (2 M) was added and the mixture was heated at
reflux overnight. The residue was cooled to room temperature and
the THF was removed in vacuo. The residue was dissolved in diethyl
ether, washed with brine and dried (MgSO.sub.4). The solvent was
removed in vacuo and the residue was eluted from a column of silica
with 10% dietyl ether in hexane to provide the title compound as a
white solid (700 mg, 22%).
[0527] TLC R.sub.f 0.2 (5% diethyl ether-hexane)
[0528] MS 323 MNH.sub.4.sup.+
[0529] Similarly prepared was:
[0530] Intermediate 115 Methyl
2-[4-(4-Chlorophenyl)phenylsulfanyl)methyl]-
-5-phenylpentanoate
[0531] From intermediate 111 (5.20 g) and 4-chlorobenzeneboronic
acid (2.48 g), as a colourless oil (4.07 g, 74%).
[0532] TLC R.sub.f 0.3 (10% diethyl ether-heptane)
[0533] MS 425 MH.sup.+
[0534] Intermediate 116 3-(4-Bromophenylsulfanyl)propanoic Acid
[0535] A solution of intermediate 113 (1.01 g) in THF (15 ml) and
water (5 ml) at 0.degree. C. was treated with lithium hydroxide
(154 mg). The mixture was allowed to warm slowly to room
temperature and stirred overnight. The mixture was acidified to pH
5 with 10% aqueous citric acid and diluted with water (75 ml) and
ethyl acetate (100 ml). The aqueous phase was extracted with ethyl
acetate (100 ml) and the combined organic phases were washed with
brine and dried (MgSO.sub.4). The solvent was removed in vacuo to
give the title compound as a white solid (890 mg, 93%).
[0536] TLC R.sub.f 0.3 (1:2 hexane-ethyl acetate)
[0537] MS 261 MH.sup.+
[0538] Similarly prepared were:
[0539] Intermediate 117 3-[4-(Chlorophenyl)phenylsulfanyl]propanoic
Acid
[0540] From intermediate 114 (450 mg), as a white solid (430 mg,
100%).
[0541] TLC R.sub.f 0.3 (10% diethyl ether-hexane)
[0542] MS 244
[0543] Intermediate 118 3-(4-Methoxyphenyl)sulfanylpropanoic
Acid
[0544] From intermediate 112 (5.00 g), as a white solid (4.40 g,
94%).
[0545] TLC R.sub.f 0.4 (1:1 hexane-ethyl acetate)
[0546] MS 330MNH.sub.4.sup.+
[0547] Intermediate 119
3-(4-Methoxyphenylsulfanylmethyl)-6-phenylhexanoic Acid
[0548] From intermediate 8 (240 mg), as a colourless oil (234 mg,
100%).
[0549] TLC R.sub.f 0.1 (3:1 hexane-diethyl ether)
[0550] Intermediate 120 4-(4-Methoxyphenylsulfanyl)butanoic
Acid
[0551] From intermediate 83 (5.00 g), as a white solid (4.10 g,
92%).
[0552] TLC R.sub.f 0.1 (3:1 hexane-diethyl ether)
[0553] Intermediate 121
2-[4-(4-Chlorophenyl)phenylsulfanylmethyl]-5-pheny- l-pentanoic
Acid
[0554] From intermediate 115 (1.57 g), as a white solid (1.42 g,
93%).
[0555] TLC R.sub.f 0.3 (10 % diethyl ether-heptene)
[0556] MS 428MNH.sub.4.sup.+
EXAMPLE 1
[0557] 2-(4-Benzoylphenylsulfanylmethyl)-5-phenylpentanoic Acid
[0558] A solution of intermediate 74 (84 mg) in dichloromethane (10
ml) was cooled to 0.degree. C. and treated with 4-chloroperbenzoic
acid (73 mg). The reaction was warmed to room temperature and
stirred for 3 hours. The reaction was concentrated onto silica in
vacuo and purified by chromatography on silica eluting with 1%
acetic acid and 1% methanol in dichloromethane to give the title
compound as a colourless oil (42 mg, 48%).
[0559] TLC R.sub.f 10 (30% ethyl acetate-hexane)
[0560] MS 421 MH.sup.+
[0561] Similarly prepared was:
[0562] Intermediate 122 3-4-Methoxyphenylsulfinyl)propanoic
Acid
[0563] From intermediate 118 (1.00 g), as a white solid (688 mg,
63%).
[0564] TLC R.sub.f 0.1 (1:2 hexane-ethyl acetate)
[0565] MS 229 MH.sup.+
EXAMPLE 2
[0566] 2-(4-Benzoylphenylsulfonylmethyl)-5-phthalimido-pentanoic
Acid
[0567] A solution of intermediate 62 (0.4 g) in methanol (50 ml)
was treated at room temperature with a solution of Oxone.RTM. (0.52
g) in water (10 ml). The mixture was stirred for 24 hours and the
organic solvent removed in vacuo. The residue was diluted with
water (100 ml) and extracted with ethyl acetate (3.times.100 ml).
The organic extracts were combined washed with brine (40 ml), dried
over magnesium sulfate and filtered. The filtrate was evaporated in
vacuo and the residue was purified by column chromatography on
silica gel eluting with 2% methanol in dichlorometane to yield the
title compound as a white solid (0.37 g, 87%).
[0568] TLC R.sub.f 0.24 (2% methanol-dichloromethane)
[0569] MS 506 MH.sup.+
[0570] Similarly prepared were:
[0571] Intermediate 123 3-(4-Benzoylphenylsulfonyl)propanoic
Acid
[0572] From intermediate 63 (0.257 g) as a white solid (0.20 g,
69%)
[0573] TLC R.sub.f 0.3 (ethyl acetate)
[0574] MS 319 MH.sup.+
EXAMPLE 3
[0575] 2-(4-Acetylphenylsulfonylmethyl)-5-phenylpentanoic Acid
[0576] From intermediate 64 (0.12 g) as a cream solid (0.094 g,
72%).
[0577] TLC R.sub.f 0.43 (10% metanol-dichloromethane)
[0578] MS 374 MH.sup.+
[0579] Intermediate 124
2-(2-Thiazolylsulfonylmethyl)-5-phenylpentanoic Acid
[0580] From intermediate 65 (0.125 g) as a colourless oil (0.094 g,
67%).
[0581] TLC R.sub.f 0.4 (5% methanol-dichloromethane)
[0582] MS 341MH.sup.+
EXAMPLE 4
[0583] 2-(4-N,N-Dimethylcarbamoylsulfonylmethyl)-5-phenyl pentanoic
Acid
[0584] From intermediate 66 (0.289 g) as a colourless oil (0.250 g,
83%).
[0585] TLC R.sub.f 0.36 (10% methanol-dichloromethane)
[0586] MS 404 MH.sup.+
EXAMPLE 5
[0587] 2-(4-Methoxyphenylsulfonylmethyl)-5-phthalimido-pentanoic
Acid
[0588] From intermediate 68 (0.9 g) as a white solid (0.7 g,
72%).
[0589] TLC R.sub.f 0.58 (5% methanol-dichloromethane)
[0590] MS432 MH.sup.+EXAMPLE 6
[0591] 2-(4-Methoxyphenylsulfonylmethyl)-4-phthalimido-butanoic
Acid
[0592] From intermediate 69 (0.9 g), as a white solid (0.8 g,
82%).
[0593] TLC R.sub.f 0.19 (4% methanol-dichloromethane)
[0594] MS 418 MH.sup.+
[0595] Intermediate 125 3-(4-Bromophenylsulfonyl)propanoic Acid
[0596] From intermediate 116 (260 mg) as a white solid (241 mg,
83%).
[0597] TLC R.sub.f 0.3 (1:2 hexane-ethyl acetate)
[0598] MS 294 MH.sup.+
[0599] Intermediate 126 3-[4-(Chlorophenyl)phenylsulfonyl]propanoic
Acid
[0600] From intermediate 117 (195 mg), as a white solid (196 mg,
90%).
[0601] TLC R.sub.f 0.2 (10% diethyl ether-hexane)
[0602] MS 341 MNH.sub.4.sup.+
[0603] Intermediate 127 3-(4-Methoxyphenylsulfonyl)propanoic
Acid
[0604] From intermediate 118 (1.00 g), as a white solid (1.13 g,
98%).
[0605] TLC R.sub.f 0.2 (1:2 hexane-ethyl acetate)
[0606] MS 262 MNH.sub.4.sup.+
EXAMPLE 7
[0607] 2-(Furan-2-ylmethylsulfonylmethyl)-5-phenylpentanoic
Acid
[0608] From intermediate 101 (560 mg), as a colourless oil (401 mg,
64%).
[0609] TLC R.sub.f 0.3 (3:1 hexane-ethyl acetate)
[0610] MS 354 MNH.sub.4.sup.+
EXAMPLE 8
[0611] 2-(Cyclopentylsulfonylmethyl)-5-phenlypentanoic Acid
[0612] From intermediate 102 (540 mg), as a colourless oil (387 mg,
64%).
[0613] TLC R.sub.f 0.3 (3:1 hexane-ethyl acetate)
[0614] MS 342 MNH.sub.4.sup.+
EXAMPLE 9
[0615] 3-(4-Methoxyphenylsulfonylmethyl)-6-phenylhexanoic Acid
[0616] From intermediate 119 (230 mg), as a colourless oil (157 mg,
62%).
[0617] TLC R.sub.f 0.2 (1:2 hexane-ethyl acetate)
[0618] MS 394 MNH.sub.4.sup.+
EXAMPLE 10
[0619] 2-(4-Methoxyphenylsulfonylmethyl)-5-phenylpentanoic Acid
[0620] From intermediate 67 (0.50 g) as a white solid (0.52 g,
95%).
[0621] TLC R.sub.f 0.61 (50% ethyl acetate-hexane)
[0622] MS 380 MNH.sub.4.sup.+
EXAMPLE 11
[0623] 2-(Benzylsulfonylmethyl)-5-phenylpentanoic Acid
[0624] From intermediate 103 (0.569 g), as a white solid (0.613 g,
98%).
[0625] TLC R.sub.f 0.53 (50% ethyl acetate-hexane)
[0626] MS 364MNH.sub.4.sup.+
EXAMPLE 12
[0627] 5-Phenyl-2-(phenylsulfonylmethyl)pentanoic Acid
[0628] From intermediate 70 (0.494 g), as a white solid (0.543 g,
100%).
[0629] TLC R.sub.f 0.52 (50% ethyl acetate-hexane)
[0630] MS 348 MNH.sub.4.sup.-
EXAMPLE 13
[0631] 2-(2-Methoxybenzenesulfonylmethyl)-5-phenylpentanoic
Acid
[0632] From intermediate 71 (0.539 g), as a colourless oil (0.561
g, 95%).
[0633] TLC R.sub.f 0.47 (50% ethyl acetate-hexane)
[0634] MS 380 MNH.sub.4.sup.+
EXAMPLE 14
[0635] 2-(3-Methoxyphenylsulfonylmethyl)-5-phenylpentanoic Acid
[0636] From intermediate 72 (0.610 g), as a colourless oil (0.617
g, 92%).
[0637] TLC R.sub.f 0.58 (50% ethyl acetate-hexane)
[0638] MS 380 MNH.sub.4.sup.+
[0639] Intermediate 128
2-(4-(Carbamoylmethyloxy)phenylsulfonylmethyl)-5-p- henylpentanoic
Acid
[0640] From intermediate 73 (0.864 g), as a white solid (0.653 g,
70%).
[0641] TLC R.sub.f 0.29 (5% methanol-dichloromethane)
[0642] MS 423 MNH.sub.4.sup.+
EXAMPLE 15
[0643] 2-(4-Benzoylphenylsulfonylmethyl)-5-phenylpentanoic Acid
[0644] From intermediate 74 (7.5 g) as a colourless solid (7.4 g,
91%).
[0645] TLC R.sub.f 0.3 (1:1 ethyl acetate-hexane).
[0646] MS 437 MH.sup.+
EXAMPLE 16
[0647] 2-(Pyrid-4-ylsulfonylmethyl)-5-phenylpentanoic Acid
[0648] From intermediate 75 (0.52 g) as a white solid (0.55 g,
96%).
[0649] TLC R.sub.f 0.25 (5% methanol-dichloromethane).
[0650] MS 334 MH.sup.+
[0651] Intermediate 129
2-((4-Acetylamino)phenylsulfonylmethyl-5-phenyl-pe- ntanoic
Acid
[0652] From intermediate 78 (0.20 g) as a colourless solid (0.12 g,
56%).
[0653] TLC R.sub.f 0.3 (ethyl acetate).
[0654] MS 390MH.sup.+
[0655] Intermediate 130
2-((1-Methylimidazol-2-yl)sulfonylmethyl)-5-phenyl- -pentanoic
Acid
[0656] From intermediate 79 (0.5 g) as a white solid (0.35 g,
64%).
[0657] TLC R.sub.f 0.2 (6% methanol-dichloromethane).
[0658] MS 337 MH.sup.+
EXAMPLE 17
[0659] 2-(2-Phenylethylsulfonylmethyl)-5-phenylpentanoic Acid
[0660] From intermediate 105 (1.35 g) as a white solid (1.40 g,
94%).
[0661] TLC R.sub.f 5 (diethyl ether).
[0662] MS 361 MH.sup.+
EXAMPLE 18
[0663] 2-((2-Methylpropyl)sulfonylmethyl)-5-phenylpentanoic
Acid
[0664] From intermediate 107 (2.6 g) as a white solid (1.70 g,
59%).
[0665] TLC R.sub.f 0.5 (40% diethyl ether-hexane).
[0666] MS312 M.sup.+
EXAMPLE 19
[0667] 2-(4-Methoxyphenylsulfonylmethyl)-5-succinimido-pentanoic
Acid
[0668] From intermediate 76 (1.56 g ) as a white solid (1.4 g,
82%).
[0669] TLC R.sub.f 0.15 (ethyl acetate)
[0670] MS 383 M.sup.+
EXAMPLE 20
[0671] 2-(4-Benzoylphenyl)sulfonylmethyl-5-succinimidopentan-oic
Acid
[0672] From intermediate 77 (0.34 g) as a white solid (0.28 g,
78%).
[0673] TLC R.sub.f 0.2 (ethyl acetate)
[0674] MS 457 M.sup.+
EXAMPLE 21
[0675]
2-(4-Methoxyphenylsulfonylmethyl)-5-(3,3,4-trimethyl-hydantoin-1-yl-
)pentanoic Acid
[0676] From intermediate 80 (0.8 g) as a white solid (0.6 g,
70%).
[0677] TLC R.sub.f 0.4 (6% methanol-dichloromethane)
[0678] MS 427 MH.sup.+
EXAMPLE 22
[0679]
2-(4-Methoxyphenylsulfonylmethyl)-4-(3,3,4trimethyl-hydantoin-1-yl)-
butanoic Acid
[0680] From intermediate 81 (0.57 g) as a white solid (0.50 g,
79%).
[0681] TLC R.sub.f 0.35 (10% methanol-dichloromethane)
[0682] MS 413 MH.sup.+
EXAMPLE 23
[0683] 2-(4-Methoxyphenylsulfonylmethyl)-3-phenylpropanoic Acid
[0684] From intermediate 82 (2.95 g) as a white solid (3.0 g,
90%).
[0685] TLC R.sub.f 0.43 (ethyl acetate)
[0686] MS 334 M.sup.+
[0687] Intermediate 131 4-(4-Methoxyphenylsulfonyl)butanoic
Acid
[0688] From intermediate 120 (1.00 g), as a white solid (1.12 g,
98%).
[0689] TLC R.sub.f 0.2 (2:1 hexane-ethyl acetate)
[0690] MS 259 MH.sup.+
EXAMPLE 24
[0691]
2-[4-(4-Chlorophenyl)phenylsulfonyl)methyl]-5-phenylpentanoic
Acid
[0692] From intermediate 121 (1.24 g), as a white solid (1.01 g,
75%).
[0693] TLC R.sub.f 0.2 (10% diethyl ether-heptane)
[0694] MS 443 MH.sup.+
EXAMPLE 25
[0695] 2-[4-Methoxyphenylsulfonylmethyl]pentanoic Acid
[0696] From intermediate 84 (2.6 g) as a white solid (2.2 g,
74%).
[0697] TLC R.sub.f 0.32 (5% methanol-dichloromethene)
[0698] MS 287 (M+H).
[0699] Intermediate 132
2-(4-Methoxyphenylsulfonylmethyl)-5-(methoxycarbon- yl)pentanoic
Acid
[0700] From intermediate 110 (0.3 g), as a white solid (0.2 g,
61%)
[0701] TLC R.sub.f 0.19 (50% ethyl acetate in hexane)
[0702] MS 345 MH.sup.+
EXAMPLE 26
[0703] 3Methyl-2-(4-methoxyphenylsulfonylmethyl)butanoic Acid
[0704] From intermediate 86 (3.26 g) as a white solid (2.3 g,
63%)
[0705] TLC R.sub.f 0.43 (10% methanol/dichloromethane)
[0706] Intermediate 133
2-((Benzo[1,3]dioxole-5-yl)sulfonylmethyl)-5-pheny- lpentanoic
Acid
[0707] From intermediate 87 as a colourless oil (3.4 g, 81%)
[0708] TLC R.sub.f 0.48 (10% methanol/dichloromethane)
EXAMPLE 27
[0709]
2-](4-Trifluoromethoxyphenylsulfonyl)methyl]-5-(1,5,5-trimethylhyda-
ntoin-3yl)pentanoic Acid
[0710] From intermediate 88 (0.47 g) as a white solid (0.49 g,
96%).
[0711] TLC R.sub.f 0.43 (hexane/ethyl acetate (1:2) with trace
acetic acid)
[0712] MS 481 (MH.sup.+)
EXAMPLE 28
[0713] 2-[(4-Trifluoromethoxyphenylsulfonyl)methyl]pentanoic
Acid
[0714] From intermediate 89 (2.77 g) as a white solid (2.79 g,
91%).
[0715] TLC R.sub.f 0.73 (50% hexane/ethyl acetate with trace acetic
acid)
[0716] MS 358 (M+NH.sub.4.sup.+)
[0717] Intermediate 134
5-Phenyl-2-((tetrahydropyran-4-ylsulfonyl)methyl)-- pentanoic
Acid
[0718] From intermediate 104 (0.99 g), as a waxy white solid (0.62
g, 57%).
[0719] TLC R.sub.f 0.10 (ethyl acetate/hexane/acetic acid
(49:49:2))
EXAMPLE 29
[0720] 2-((Quinolin-2-yl)sulfanylmethyl)-5-phenylpentanoic Acid
[0721] From intermediate 90 (0.2 g) as a pale yellow gum (0.10
g).
[0722] TLC R.sub.f 0.53 (60% EtOAc-hexanes).
[0723] MS 384 (MH.sup.+).
EXAMPLE 30
[0724]
2-(4-Benzoylphenyl)sulfonylmethyl-4-(3,3,4-trimethylhydantoin-1-yl)-
butanoic Acid
[0725] From intermediate 91 (0.3 g) as white solid (0.20 g,
66%).
[0726] TLC R.sub.f 0.54 (10% MeOH/dichloromethane)
[0727] MS 486 (M.sup.+)
EXAMPLE 31
[0728]
2-(4-Benzoylphenyl)sulfonylmethyl-5-(3,3,4-trimethylhydantoin-1-yl)-
pentanoic Acid
[0729] From intermediate 92 (0.6g) as white solid (0.25 g, 40%)
[0730] TLC R.sub.f 0.50 (10% MeOH/dichloromethane)
[0731] MS 500 (M.sup.+)
EXAMPLE 32
[0732] 2-((4-Benzoylphenylsulfonyl)methyl)-3-phenylpropanoic
Acid
[0733] From intermediate 93 (1.10 g) as white solid (0.80 g,
60%).
[0734] TLC R.sub.f 0.60 (10% MeOH/dichloromethane).
[0735] MS 408 (M.sup.+).
[0736] Intermediate 135
2-((1-Benzoylpiperidine-4-yl)sulfonylmethyl)-5-phe- nylpentanoic
Acid
[0737] From intermediate 108 (1.6 g) as white solid (1.05 g,
26%).
[0738] TLC R.sub.f 0.57 (EtOAc).
[0739] MS 443 (M.sup.+)
EXAMPLE 33
[0740] 2-((4-Methoxyphenyl)sulfonylmethyl)-4-(2-pyridyl)butanoic
Acid
[0741] From intermediate 94 (0.25 g), as a white solid (0.26 g,
100%).
[0742] TLC R.sub.f 0.22 (10% MeOH/dichloromethane).
[0743] MS 350 (MH.sup.+).
[0744] Intermediate 136
2-(4-(4-Pyridimoyl)phenylsulfonylmethyl)-5-phenylp- entanoic
Acid
[0745] From intermediate 95 (1.62 g) as white solid (1.20 g,
65%).
[0746] TLC R.sub.f 0.65 (10% MeOH/dichloromethane).
[0747] MS
[0748] Intermediate 137
2-(4-(2-Thienoyl)phenylsulfonylmethyl)-5-phenylpen- tanoic Acid
[0749] From intermediate 96 (1.8 g) as white solid (1.60 g,
80%).
[0750] TLC R.sub.f 0.60 (10% MeOH/dichloromethane).
[0751] MS 442 (M.sup.+).
[0752] Intermediate 138
2-(4-(4-Pyridinoyl)phenylsulfonylmethyl)-5-(3,3,4--
trimethylhydantoin-1-yl)pentanoic Acid
[0753] From intermediate 97 (0.25 g), as white solid (0.12 g,
50%).
[0754] TLC R.sub.f 0.45 (EtOAc)
[0755] MS 502 (MH.sup.+).
[0756] Intermediate 139
2-(4-(2-Thienoyl)phenylsulfonylmethyl)-5-(3,3,4-tr-
imebylhydantoin-1-yl)pentanoic Acid
[0757] From intermediate 98 (1.3 g), as white solid (1.2 g,
85%).
[0758] TLC R.sub.f 0.45 (EtOAc)
[0759] MS 506 (M.sup.+).
[0760] Intermediate 140
2-((4-Hydroxyphenyl)sulfonylmethyl)-5-phenylpentan- oic Acid
[0761] From intermediate 99 (3.0 g) as white solid (3.1 g,
95%).
[0762] TLC R.sub.f 0.30 (EtOAc).
[0763] MS 348 (M.sup.+).
EXAMPLE 34
[0764] 2-((Quinolin-8-yl)sulfonylmethyl)-5-phenylpentanoic Acid
[0765] From intermediate 100 (100 mg) as white solid (60 mg,
55%).
[0766] TLC R.sub.f 0.30 (EtOAc).
[0767] MS 391 (M.sup.+).
EXAMPLE 35
[0768] 2-(3-Phenylpropylsulfonyl)methyl-5-phenylpentanoic Acid
[0769] From intermediate 106 (1.6 g), as colourless solid (1.45 g,
90%).
[0770] TLC 0.75 (ether)
[0771] MS 374 (M.sup.+).
[0772] Intermediate 141
4-Methoxy-1-(2-phenylmethylsulfonyl)benzene
[0773] From intermediate 26 (8.9 g), as white solid (10.0 g,
100%).
[0774] TLC R.sub.f 0.75 (ether).
EXAMPLE 36
[0775] 3-(4Methoxybenzenesulfonyl)-4-phenylbutanoic Acid
[0776] n-Butyllithium (12.5 mmol) was added to a solution of
intermediate 141 (2.75 g) in THF at -78.degree. C. and the solution
was stirred for 4 h at that temperature, then a solution of lithium
bromoacetate (10 mmol) was added dropwise. The mixture was stirred
at -78.degree. C. For 2 h, then warmed to room temperature,
quenched with dilute aqueous HCl and evaporated in vacuo. The
residue was dissolved in dilute NaOH, washed with ether, acidified
with aqueaous HCl and extracted with ethyl acetate. The ethyl
acetate extracts were combined, washed with water, dried and
evaporated and the residue purified by flash column chromatography,
eluting with 40% EtOAc in hexane, to give the title compound as
colourless solid (150 mg, 7%).
[0777] TLC R.sub.f 0.40 (40% EtOAc/hexanes).
[0778] Intermediate 142
2-(1-tert-Butyloxycarbonylpiperidin-4-yl)sulfonylm-
ethyl)-5-phenylpentanoic Acid
[0779] Oxone.RTM. (13 g) was added to a solution of intermediate
109 (4.5 g) and sodium acetate (5 g) in methanol 200 ml) and water
(50 ml) at room temperature and the mixture was stirred for 18 h,
then evaporated, diluted with water and the product collected by
filtration to give the title compound as white solid (3.50 g,
75%).
[0780] TLC R.sub.f 0.35 (EtOAc)
[0781] MS 439 (M.sup.+).
[0782] Intermediate 143 Methyl
2-((Pyrrolidin-1-yl)sulfonylmethyl)-5-pheny- l-pentanoate
[0783] Pyrrolidine (0.2 ml) was added to a solution of intermediate
58 (0.7 g) and triethylamine (0.5 ml) in dichloromethane (20 ml) at
-10.degree. C. and the solution was stirred for 18 h, then washed
with water, sodium bicarbonate and 0.5 M HCl. The solvent was dried
and evaporated and the residue was purified by flash column
chromatography, eluting with 40% a ether/hexanes, to give the title
compound as colourless oil (0.16 g, 25%)
[0784] TLC R.sub.f 0.28 (40% ether/hexanes).
[0785] Intermediate 144
2-((Pyrrolidin-1-yl)sulfonylmethyl)-5-phenylpentan- oic Acid
[0786] Lithium hydroxide (100 mg) was added to a solution of the
ester intermediate 143 (0.16 g) in methanol (5 ml) THF (10 ml) and
water (5 ml) and the solution was stirred for 6 h, then evaporated
in vacuo and the residue dissolved in water. The aqueous solution
was washed with ether, then acidified with citric acid and
extracted with dichloromethane. The dichloromethane exacts were
combined and washed with water, dried and evaporated to give the
crude product. This material was purified by flash column
chromatography, eluting with 60% ether/hexanes, to give the title
compound as colourless oil (60 mg, 40%).
[0787] TLC R.sub.f 0.40 (60% ether/hexanes).
EXAMPLE 37
[0788] 2-(4-Benzoylphenylsulfonylmethyl)-5-phthalimido-pentanoic
Acid N-Hydroxyamide
[0789] A solution of example 2 (0.1 g) in anhydrous THF (10 ml) was
treated at room temperature with
O-(tert-butyldimethylsilyl)hydroxylamine (0.032 8) and
1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (0.042
g). The mixture was stirred for 24 hours and the organic solvent
removed in vacuo. The residue was partitioned between water (30 ml)
and ethyl acetate (50 ml). The organic extract were was washed with
brine (40 ml), dried over magnesium sulfate and filtered. The
filtrate was evaporated in vacuo and the residue dissolved in THF
(10 ml). The solution was treated at 0.degree. C. with a 1.0 M
solution of tetrabutylammonium fluoride in THF (1.0 ml) and stirred
for 1 hour. The solvent was removed in vacuo and the residue
partitioned between ethyl acetate (50 ml) and water (40 ml). The
organic layer was washed with brine (20 ml), dried over magnesium
sulfate, filtered and the filtrate evaporated in vacuo. The residue
was purified by column chromatography on silica gel eluting with 2%
methanol in dichloromethane to yield the title compound as a white
solid (0.06 g, 58%).
[0790] TLC R.sub.f 0.74 (ethyl acetate)
[0791] MS 521 MH.sup.+
[0792] Similarly prepared were:
EXAMPLE 38
[0793] 3-(4-Benzoylphenylsulfonyl)propanoic Acid N-Hydroxy
Amide
[0794] From intermediate 123 (0.158 g) as a white solid (0.032 g,
20%).
[0795] TLC R.sub.f 0.15 (5% methanol-dichloromethane)
[0796] MS 334 MH.sup.+
EXAMPLE 39
[0797] 2-(4-Acethylphenylsulfonylmethyl)-5-phenylpentanoic Acid
N-Hydroxy Amide
[0798] From example 3 (0.080 g) as a white solid (0.022 g,
30%).
[0799] TLC R.sub.f 0.36 (5% methanol-dichloromethane)
[0800] MS 389MH.sup.+
EXAMPLE 40
[0801] 2-(Thiazol-2-ylsulfonylmethyl)-5-phenylpentanoic Acid
N-Hydroxy Amide
[0802] From intermediate 124 (0.125 g) as an oily semi-solid (0.023
g, 26%).
[0803] TLC R.sub.f 0.3 (5% methanol-dichloromethane)
[0804] MS 354 MH.sup.+
EXAMPLE 41
[0805]
2-(4-N,N-Dimethylcarbamoylphenylsulfanylmethyl)-5-phenylpentanoic
Acid N-Hydroxy Amide
[0806] From example 4 (0.232 g) as a white solid (0.046 8,
25%).
[0807] TLC R.sub.f 0.49 (10% methanol-dichloromethane)
[0808] MS 419MH.sup.+
EXAMPLE 42
[0809] 2-(4-Methoxyphenylsulfonylmethyl)-5-phthalimido-pentanoic
Acid N-Hydroxy Amide
[0810] From example 5 (0.35 g), as a white solid (0.12 g, 43%).
[0811] TLC R.sub.f 0.52 (5% metanol-dichloromethane)
[0812] MS 447 MH.sup.+
EXAMPLE 43
[0813] 2-(4-Methoxyphenylsulfonylmethyl)-4-phthalimido-butanoic
Acid N-Hydroxy Amide
[0814] From example 6 (0.3 g), as a white solid (0.11 g, 35%).
[0815] TLC R.sub.f 0.48 (5% methanol-dichloromethane)
[0816] MS 433MH.sup.+
EXAMPLE 44
[0817] 3-(4-Bromophenylsulfonyl)propanoic Acid N-Hydroxy Amide
[0818] From intermediate 125 (130 mg) as a white solid (87 mg,
64%).
[0819] TLC R.sub.f 0.1 (1:2 hexane-ethyl acetate)
[0820] MS 310 MH.sup.+
EXAMPLE 45
[0821] 3-[4-(Chlorophenyl)phenylsulfonyl]propanoic Acid N-Hydroxy
Amide
[0822] From intermediate 126 (123 mg), as a white solid (39 mg,
30%).
[0823] TLC R.sub.f 0.1 (10% diethyl ether-hexane)
[0824] MS 341 MH.sup.+
EXAMPLE 46
[0825] 3-(4-Methoxyphenylsulfonyl)propanoic Acid N-Hydroxy
Amide
[0826] From intermediate 127 (764 mg), as a white solid (100 mg,
12%).
[0827] TLC R.sub.f 0.1 (1:2 hexane-ethyl acetate)
[0828] MS 277 MNH.sub.4.sup.+
EXAMPLE 47
[0829] 3-(4-Methoxyphenylsulfinyl)propanoic Acid N-Hydroxy
Amide
[0830] From intermediate 122 (200 mg), as a colourless oil (32 mg,
15%).
[0831] TLC R.sub.f 0.1 (1,1 hexane-ethyl acetate)
[0832] MS 261 MNH.sub.4.sup.+
EXAMPLE 48
[0833] 2-[(4-Benzoylphenyl)sulfinylmethyl]-5-phenylpentanoic Acid
N-Hydroxy Amide
[0834] From example 1 (450 mg), as a white solid (42 mg, 9%).
[0835] TLC R.sub.f 0.3 (ethyl acetate)
[0836] MS 436MH+
EXAMPLE 49
[0837] 2-(Furan-2-ylmethylsulfonylmethyl)-5-phenylpentanoic Acid
N-Hydroxy Amide
[0838] From example 7 (350 mg), as a colourless oil (228 mg,
62%).
[0839] TLC R.sub.f 0.4 (1:2 hexane-ethyl acetate)
[0840] MS 369 MNH.sub.4.sup.+
EXAMPLE 50
[0841] 2-(Cyclopentylsulfonylmethyl)-5-phenylpentanoic Acid
N-Hydroxy Amide
[0842] From example 8 (342 mg), as a colourless oil (265 mg,
75%).
[0843] TLC R.sub.f 0.2 (1:2 hexane-ethyl acetate)
[0844] MS 357 MNH.sub.4.sup.+
EXAMPLE 51
[0845] 3-(4-Methoxyphenylsulfonylmethyl)-6-phenylhexanoic Acid
N-Hydroxy Amide
[0846] From example 9 (135 mg), as a colourless oil (86 mg,
61%).
[0847] TLC R.sub.f 0.2 (1:2 hexane-ethyl acetate)
[0848] MS 392 MH.sup.+
EXAMPLE 52
[0849] 2-(Phenylmethylsulfonylmethyl)-5-phenylpentanoic Acid
N-Hydroxy Amide
[0850] From example 11 (0.559 g) as a white solid (0.500 g,
86%).
[0851] TLC R.sub.f 0.41 (ethyl acetate-hexane (2:1))
[0852] MS 362 MH.sup.+
EXAMPLE 53
[0853] 5-Phenyl-2-(phenylsulfonylmethyl)pentanoic Acid N-Hydroxy
Amide
[0854] From example 12 (0.478 g), as a white solid (0.394 g,
79%).
[0855] TLC R.sub.f 0.51 (ethyl acetate-hexane (2:1))
[0856] MS 348 MH.sup.+
EXAMPLE 54
[0857] 2-(2-Methoxyphenylsulfonylmethyl)-5-phenylpentanoic Acid
N-Hydroxy Amide
[0858] From example 13 (0.547 g), as a white solid (0.392 g,
69%).
[0859] TLC R.sub.f 0.25 (ethyl acetate-hexane (2:1))
[0860] MS 378 MH.sup.+
EXAMPLE 55
[0861] 2-(3-Methoxyphenylsulfonylmethyl)-5-phenylpentanoic Acid
N-Hydroxy Amide
[0862] From example 14 (0.636 g), as a white solid (0.460 g,
70%).
[0863] TLC R.sub.f 0.48 (ethyl acetate-hexane (2:1))
[0864] MS 378 MH.sup.+
EXAMPLE 56
[0865]
2-(4-(4-Chlorophenyl)phenylsulfonylmethyl)-5-phenyl-pentanoic Acid
N-Hydroxy Amide
[0866] From example 24 (0.511 g), as a white solid (0.348 g,
66%)
[0867] TLC R.sub.f 0.61 (ethyl acetate-hexane (2:1))
[0868] MS 459, 461 (M-O+NH.sub.4.sup.30)
EXAMPLE 57
[0869]
2-(4-(Carbamoylmethyloxy)benzenesulfonylmethyl)-5-phenylpentanoic
Acid, N-Hydroxy Amide
[0870] From intermediate 128 (0.297 g) as a white solid (0.049 g,
16%).
[0871] TLC R.sub.f 0.18 (ethyl acetate)
[0872] MS 427 M-O+NH.sub.4.sup.+
EXAMPLE 58
[0873] 2-(4Benzoylphenylsulfonylmethyl)-5-phenylpentanoic Acid
N-Hydroxy Amide
[0874] From example 15 (7.4 g) as a colourless solid (3.80 g,
50%).
[0875] TLC R.sub.f 0.42 (10% methanol-dichloromethane)
[0876] MS 452 MH.sup.+
EXAMPLE 59
[0877] 2-(4-Methoxyphenylsulfonylmethyl)-5-phenylpentanoic Acid
N-Hydroxy Amide
[0878] From example 10 (0.425 g) as a white solid (0.185 g,
40%).
[0879] TLC R.sub.f 0.31 (ethyl acetate-hexane (2:1))
[0880] MS 378 MH.sup.+
EXAMPLE 60
[0881] 2-(Pyrid-4-ylsulfonylmethyl)-5-phenylpentanoic Acid
N-Hydroxy Amide
[0882] From example 16 (0.23 g), as a colourless solid (0.2 g,
80%).
[0883] TLC R.sub.f 0.2 (5% methanol-dichloromethane)
[0884] MS 337 M+
EXAMPLE 61
[0885] 2-(4-Acetylaminophenylsulfonylmethyl)-5-phenylpentanoic Acid
N-Hydroxy Amide
[0886] From intermediate 129 (0.12 g) as a beige solid (0.04 g,
32%).
[0887] TLC R.sub.f 0.2 (5% methanol-dichloromethane)
[0888] MS 406 MH+
EXAMPLE 62
[0889] 2-(1-Methylimidazol-2-ylsulfonylmethyl)-5-phenylpentan-oic
Acid N-Hydroxy Amide
[0890] From intermediate 130 (0.20 g) as a white solid (0.06 g,
31%).
[0891] TLC R.sub.f 0.35 (10% methanol-dichloromethane)
[0892] MS 352 (MH+).
EXAMPLE 63
[0893] 2-(2-Phenylethyl)sulfonylmethyl)-5-phenylpentanoic Acid
N-Hydroxy Amide
[0894] From example 17 (0.50 g) as a white powder (0.23 g,
42%).
[0895] TLC R.sub.f 0.4 (diethyl ether).
[0896] MS 376(MH+).
EXAMPLE 64
[0897] 2-(2-Methylpropyl)sulfonylmethyl-5-phenylpentanoic Acid
N-Hydroxy Amide
[0898] From example 18 (1.7 g) as a white solid (0.85 g, 47%).
[0899] TLC R.sub.f 0.32 (diethyl ether).
[0900] MS 328 (MH+).
EXAMPLE 65
[0901] 2-(4-Methoxyphenylsulfonylmethyl-5-phenylpentanoic Acid
N-Hydroxy Amide
[0902] From example 19 (1.15 g) as a white solid (0.90 g, 74%).
[0903] TLC R.sub.f 0.35 (10% methanol-dichloromethane).
[0904] MS 398 (M+).
EXAMPLE 66
[0905] 2-(4-Benzoylphenyl)sulfonylmethyl-5-succinimido-pentanoic
Acid N-Hydroxy Amide
[0906] From example 20 (0.26 g) as a white solid (0.22 g, 79%).
[0907] TLC R.sub.f 0.45 (10% methanol-dichloromethane).
[0908] MS 471 (M+).
EXAMPLE 67
[0909]
2-(4-Methoxyphenylsulfonlylmethyl-5-(3,3,4-trimethyl-hydantoin-1-yl-
)pentanoic Acid N-Hydroxy Amide
[0910] From example 21 (0.6 g) as a white solid (0.45 g, 70%).
[0911] TLC R.sub.f 0.55 (10% methanol-dichloromethane).
[0912] MS 442 (MH+)
EXAMPLE 68
[0913]
2-(4-Methoxyphenylsulfonylmethyl-4-(3,3,4-trimethyl-hydantoin-1-yl)-
butanoic Acid-N-Hydroxy Amide
[0914] From example 22 (0.42 g) as a white solid (0.22 g, 53%).
[0915] TLC R.sub.f 0.32 (10% methanol-dichloromethane).
[0916] MS 428 (MH+).
EXAMPLE 69
[0917] 2-(4-Methoxyphenylsulfonylmethyl)-3-phenylpropanoic Acid
N-Hydroxy Amide
[0918] From example 23 (1.7 g) as a white solid (1.4 g, 78%).
[0919] TLC R.sub.f 0.55 (10% methanol-dichloromethane).
[0920] MS 349 (M+).
EXAMPLE 70
[0921] 4-(4-Methoxyphenylsulfonyl)butanoic Acid N-Hydroxy Amide
[0922] From intermediate 131 (500 g), as a white solid (210 mg,
40%).
[0923] TLC R.sub.f 0.1 (1:2 hexane-ethyl acetate)
[0924] MS 291 MNH.sub.4.sup.+
EXAMPLE 71
[0925] 2-[4-Methoxyphenylsulfonylmethyl]pentanoic Acid N-Hydroxy
Amide
[0926] From example 25 (500 mg), as a white solid (390 g, 73%).
[0927] TLC R.sub.f 0.29 (5% methanol-dichloromethane)
[0928] MS 302MH.sup.+
EXAMPLE 72
[0929]
2-(4-Methoxyphenylsulfonylmethyl)-5-(methoxycarbonyl)pentanoic Acid
N-Hydroxy Amide
[0930] From intermediate 132 (0.2 g), as a white solid (0.08 g,
38%)
[0931] TLC R.sub.f 0.45 (10% methanol in dichloromethane)
[0932] MS 360 MH.sup.+
EXAMPLE 73
[0933] 2-(4-Methyoxyphenylsulfonylmethyl)-3-methylbutanoic Acid
N-Hydroxy Amide
[0934] From example 26 (2.2 g), as a white solid (0.46 g, 34%)
[0935] TLC R.sub.f 0.2 (10% methanol/dichloromethane)
[0936] MS 302MH.sup.+
EXAMPLE 74
[0937] 2-((Benzo[1,3]dioxole-5-yl)sulfanylmethyl)-5-phenylpentanoic
Acid N-Hydroxy Amide
[0938] From intermediate 133 as a tan solid (1.636 g, 70%)
[0939] TLC Rf 0.36 (10% methanol/dichloromethane)
[0940] MS 392 MH.sup.+
EXAMPLE 75
[0941]
2-((4-Trifluoromethoxyphenylsulfonyl)methyl)-5-(1,5,5-trimethylhyda-
ntoin-3-yl)pentanoic Acid N-Hydroxy Amide
[0942] From example 27 (0.46 g), as a white solid (0.36 g,
71%).
[0943] TLC R.sub.f 0.16 (ethyl acetate/hexane (3:1) with trace
acetic acid)
[0944] MS 496 (MH.sup.+)
EXAMPLE 76
[0945] 2-((4-Trifluoromethoxybenzenesulfonylmethyl)pentanoic Acid
N-Hydroxy Amide
[0946] From example 28 (2.70 g), as a white solid (2.09 g,
74%).
[0947] TLC R.sub.f 0.53 (10% methanol/dichloromethane)
[0948] MS 373 (M+NH.sub.4.sup.+)
EXAMPLE 77
[0949] 5-Phenyl-2-((tetrahydropyran-4-ylsulfonyl)methyl)-pentanoic
Acid N-Hydroxy Amide
[0950] From intermediate 134 (0.60 g), as a white solid (0.40 g,
65%).
[0951] TLC R.sub.f 0.20 (ethyl acetate/hexane (5:1) with trace
acetic acid)
[0952] MS 373 (M+NH.sub.4.sup.+)
EXAMPLE 78
[0953] 2-(Quinoline-2-yl)sulfonylmethyl)-5-phenylpentanoic Acid
N-Hydroxy Amide
[0954] From example 29 (100 mg), as pale yellow solid (0.046 g,
42%)
[0955] TLC R.sub.f 0.5 (6% MeOH/dichloromethane).
[0956] MS 396 (MH.sup.+)
EXAMPLE 79
[0957]
2-(4-benzoylphenyl)sulfonylmethyl-4-(3,3,4-trimethyl-hydantoin-1-yl-
)butanoic Acid N-Hydroxy Amide
[0958] From example 30 (0.25 g) as white solid (0.20 g, 80%).
[0959] TLC R.sub.f 0.55 (6% MeOH/dichloromethane)
[0960] MS 501 (M.sup.+).
EXAMPLE 80
[0961]
2-((4-Benzoylphenyl)sulfonylmethyl)-5-(3,3,4-trimethyl-hydantoin-1--
yl)pentanoic Acid N-Hydroxy Amide
[0962] From example 31 (0.25 g) as white solid (0.20 g).
[0963] TLC R.sub.f 0.50 (6% MeOH/dichloromethane).
[0964] MS 515 (M.sup.+).
EXAMPLE 81
[0965] 2-((4-Benzoylphenyl)sulfonylmethyl)-3-phenylpropanoic Acid
N-Hydroxy Amide
[0966] From example 32 (0.80 g), as white solid (0.43 g, 50%).
[0967] TLC R.sub.f 0.43 (10% MeOH/dichloromethane).
[0968] MS 423 (M.sup.+)
EXAMPLE 82
[0969]
2-((1-Benzoylpiperidine-4-yl)sulfonylmethyl)-5-phenyl-pentanoic
Acid N-Hydroxy Amide
[0970] From intermediate 135 (1.05 g) as white solid (0.85 g,
80%).
[0971] TLC R.sub.f 0.43 (7% MeOH/dichloromethane)
[0972] MS 458 (M.sup.+).
EXAMPLE 83
[0973]
2-((1-tert-Butyloxycarbonylpiperidin-4-yl)sulfonylmethyl)-5-phenylp-
entanoic Acid N-Hydroxy Amide
[0974] From intermediate 142 (3.5 g), as white foam (2.40 g,
66%).
[0975] TLC R.sub.f 0.7 (7% MeOH/dichloromethane).
[0976] MS 454 (M.sup.+).
EXAMPLE 84
[0977] 2-(4-Methoxyphenyl)sulfonylmethyl)-4-(pyrid-2-yl)butanoic
Acid N-Hydroxy Amide
[0978] From example 33 (0.26 g), as white solid (0.20 g, 75%).
[0979] TLC R.sub.f 0.5 (10% MeOH/dichloromethane).
[0980] MS 365 (MH.sup.+).
EXAMPLE 85
[0981] 2-((4-Pyridinoylphenyl)sulfonylmehthyl)-5-phenylpentanoic
Acid N-hydroxy Amide
[0982] From intermediate 136 (1.08 g), as white solid (0.75 g,
67%).
[0983] TLC R.sub.f 0.40 (7% MeOH/dichloromethane).
[0984] MS 453 (MH.sup.+)
EXAMPLE 86
[0985] 2(4-(2-Thienoyl)phenylsulfonylmethyl)-5-phenylpentanoic Acid
N-Hydroxy Amide
[0986] From intermediate 137 (1.4 g) as white solid (0.85 g,
57%).
[0987] TLC R.sub.f 0.63 (10% MeOH/dichloromethane).
[0988] MS 457 (M.sup.+).
EXAMPLE 87
[0989]
2-((4-(4-Pyridinoyl)phenyl)sulfonylmethyl)-5-(3,3,4-trimethylhydant-
oin-1-yl)pentanoic Acid N-Hydroxy Amide
[0990] From intermediate 138 (0.10 g), as white solid (0.025 g,
26%).
[0991] TLC R.sub.f 0.60 (10% MeOH/dichloromethane).
[0992] MS 517(MH.sup.+).
EXAMPLE 88
[0993]
2-((4-(2-Thienoyl)phenyl)sulfonylmethyl)-5-(3,3,4-trimethylhydantoi-
n-1-yl)pentanoic Acid N-Hydroxy Amide
[0994] From intermediate 139 (1.2 g), as white solid (0.66 g,
60%).
[0995] TLC R.sub.f 0.52 (7% MeOH/dichloromethane)
[0996] MS 521 (M.sup.+).
EXAMPLE 89
[0997] 2-((4-Hydroxyphenyl)sulfonylmethyl)-5-phenylpentanoic Acid
N-Hydroxy Amide
[0998] From intermediate 140 (0.35 g), as white solid (0.20 g,
60%).
[0999] TLC R.sub.f 0.40 (7% MeOH/dichloromethane).
[1000] MS 363 (M.sup.+)
EXAMPLE 90
[1001] 2-((Pyrrolidin-1-yl)sulfonylmethyl)-5-phenylpentanoic Acid
N-Hydroxy Amide
[1002] From intermediate 144 (60 mg) as colourless solid (30 mg,
50%).
[1003] TLC R.sub.f 0.40 (7% MeOH/dichloromethane).
[1004] MS 340 (M.sup.+).
EXAMPLE 91
[1005] 2-((Quinolin-8-yl)sulfonylmethyl-5-phenylpentanoic Acid
N-Hydroxy Amide
[1006] From example 34 (60 mg) as white solid (20 mg, 30% ).
[1007] TLC R.sub.f 0.30 (5% MeOH/dichloromethane).
[1008] MS 396 (MH.sup.+)
EXAMPLE 92
[1009] 3-(4-Methoxyphenylsulfonyl)-4-phenylbutanoic Acid N-Hydroxy
Amide
[1010] From example 36 (100 mg), as white solid (60 mg, 60%).
[1011] TLC R.sub.f 0.30 (6% MeOH/dichloromethane).
[1012] MS 348 (M.sup.+)
EXAMPLE 93
[1013] 2-(3-Phenylpropylsulfonylmethyl)-5-phenylpentanoic Acid
N-Hydroxy Amide
[1014] From example 35 (1.45 g), as white solid (1.35 g, 90%).
[1015] TLC R.sub.f 0.42 (5% MeOH/dichloromethane).
[1016] MS 389 (M.sup.+)
EXAMPLE 94
[1017] 3-(4-Chlorophenylsulfonyl)butanoic Acid N-Hydroxy Amide
[1018] From 3-(4-chlorophenylsulfonyl)butanoic acid (2.63 g), as a
colourless solid (1.00 g, 37%).
[1019] TLC R.sub.f 0.37 (5% MeOH/dichloromethane).
[1020] MS 277 (M.sup.+).
EXAMPLE 95
[1021] 2-(4-Methoxyphenylsulfanyl)-5-phenylpentanoic Acid N-Hydroxy
Amide
[1022] From intermediate 67 (0.53 g) as a colourless solid (0.17 g,
31%)
[1023] TLC R.sub.f 0.25 (5% MeOH/dichloromethane)
[1024] MS 345 (M.sup.+)
EXAMPLE 96
[1025] 5-Phenyl-2-(4-(phenylmethyl)phenylsulfonylmethyl)-pentanoic
Acid N-Hydroxy Amide
[1026] Example 58 (0.203 g) and triethylsilane (0.42 ml) were held
at reflux in trifluoroacetic acid (10 ml) for 30 h. The solvent was
removed in vacuo, and the residue triturated with hexane (twice) to
leave, after vacuum drying, a red solid (0.253 g). The crude red
product was then purified by chromatography on silica, with 4%
methanol/dichloromethane as eluent collecting fractions at R.sub.f
0.27 to give a white solid. Further column purification of the
white solid with 2% mehanol/dicloromethane eluent collecting at
R.sub.f 0.14 provided a white solid (0.10 g). In order to remove
residual traces of the starting hydroxamic acid, the residue was
further purified as follows: 2,4-Dinitrophenylhydrazine (0.15 g)
was suspeded in methanol and treated with concentrated sulfonic
acid (0.3 ml), and the warm filtered. To this was added a solution
of the column purified product in methanol (3 ml), and the mixture
briefly warmed. Acetone (1 ml) was added and the mixture left to
crystallise. The solids were then removed by filtration, and the
residue obtained by concentration of the filtrate was diluted with
water (20 ml) and extracted with ethyl acetate (2.times.30 ml). The
combined organic extracts were then washed with water (2.times.10
ml), brine (10 ml), dried (MgSO.sub.4) and evapourated in vacuo.
Purification of the red oil by chromatography on silica, with 4%
methanol/dichloromethane as eluent, provided the title compound as
a pale orange solid (0.061 g, 31%).
[1027] TLC R.sub.f 0.29 (4% methanol/dichloromethane)
[1028] MS 439 (M-O+NH.sub.4.sup.+)
EXAMPLE 97
[1029] 2-((Piperidin-4-yl)sulfonylmethyl)-5-phenylpentanoic Acid
N-Hydroxy Amide Trifluoroacetate
[1030] Trifluoracetic acid (20 ml) was added to a solution of the
acid example 83 (2.4 g) in dichloromethane (20 ml) at room
temperature and the solution was stirred for 2 h, then evaporated
in vacuo and the residue azeotroped with toluene (2.times.50 ml).
The resulting solid was then precipitated from methanol by addition
of ether to give the title compound (1.54 g, 65%)
[1031] TLC R.sub.f 0.25 (10% MeOH/dichloromethane 2%
NH.sub.4OH).
[1032] MS 323 (MH.sup.+).
EXAMPLE 98
[1033]
2-((1-Benzylpiperidin-4-yl)sulfonylmethyl)-5-phenyl-pentanoic Acid
N-Hydroxy Amide
[1034] Sodium triacetoxyborohydride (0.22 g) was added to a
solution of example 97(0.23 g), triethylamine (60 mg) and
benzaldehyde (106 mg) in a mixture of dichloromethane (10 ml) and
methanol (2 ml). The mixture was stirred at room temperature for 6
h, then evaporated in vacuo and the residue partitioned between
water and dichloromethane. The organic solvent was washed with
water, dried and evaporated and the residue purified by
chromatography, eluting with 6% MeOH in dichloromethane and 1%
NH.sub.4OH, to give the title compound as white solid (60 mg,
25%).
[1035] TLC R.sub.f 0.35 (6% MeOH/dichloromethane 1%
NH.sub.4OH).
[1036] MS 445 (MH.sup.+).
[1037] Similarly prepared was:
EXAMPLE 99
[1038]
2-((1-(4-Cyanobenzyl)piperidin-4-yl)sulfonylmethyl-5-phenylpentanoi-
c Acid N-Hydroxy Amide
[1039] From example 97 (0.23 g) and 4-cyanobenzaldehyde (65 mg) as
white solid (35 mg, 14 %).
[1040] TLC R.sub.f 0.40 (6% MeOH/dichloromethane).
[1041] MS 410 (MH.sup.+).
[1042] Intermediate 145
2-((4-Hydroxyphenyl)sulfonylmethyl)-5-phenylpentan- oic Acid
N-tert-Butyloxy Amide
[1043] EDC (2.0 g) was added to a solution of intermediate 140 (3.5
g), triethylamine (1.0 g) and O-tert-butylhydroxylamine
hydrochloride (1.3 g) in dichloromethane (100 ml) at room
temperature and the mixture was stirred for 18 h. The mixture was
then washed with water, 1M HCl and saturated sodium bicarbonate,
dried and evaporated to give the title compound as colourless solid
(4.0 g, 95%)
[1044] TLC R.sub.f 0.46 (ether)
[1045] Intermediate 146
2-((4-Benzyloxyphenyl)sulfonylmethyl)-5-phenylpent- anoic Acid
[1046] N-tert-Butyloxy AmideBenzyl bromide (0.16 g) was added to a
suspension of intermediate 145 (0.42 g) and caesium carbonate (0.33
g) in DMF (10 ml) and the mixture was stirred for 18 h at room
temperature, then added to water and extracted with ether. The
solvent was washed with water and brine, dried and evaporated. The
residue was purified by flash column chromatography, eluting with
ether, to give the title compound as colourless oil (0.25 g 50%
).
[1047] TLC R.sub.f 0.70 (ether).
[1048] Similarly prepared were
[1049] Intermediate 147
2-(4-(1-Methyleth-1-yloxy)phenylsulfonylmethyl)-5-- phenylpentanoic
Acid N-tert-Butyloxy Amide
[1050] From intermediate 145 (0.42 g), as colourless oil (0.35 g,
80%).
[1051] TLC R.sub.f 0.65 (ether).
[1052] Intermediate 143
2-((4-Butyloxy)phenylsulfonylmethyl)-5-phenylpenta- noic Acid
N-tert-Butyloxy Amide
[1053] From intermediate 145 (0.42 g), as colourless oil (0.40 g,
90%).
[1054] TLC R.sub.f 0.75 (ether).
[1055] Intermediate 149
2-((4-Cyclopentyloxy)phenylsulfonylmethyl)-5-pheny- l-pentanoic
Acid N-tert-Butyloxy Amide
[1056] From intermediate 145 (0.42 g), as colourless oil (0.40 g,
90%).
[1057] TLC R.sub.f 0.68 (ether).
[1058] Intermediate 150
2-(4-(4-Cyanobenzyloxy)phenylsulfonylmethyl)-5-phe- nyl-pentanoic
Acid N-tert-Butyloxy Amide
[1059] From intermediate 145 (0.42 g) as colourless oil (0.35 g,
75%).
[1060] TLC R.sub.f 0.63 (ether).
[1061] Intermediate 151 2-Bromomethyl-3-methyl-butyric acid
tert-butyl ester
[1062] To a solution of 2-bromomethyl-3-methyl-butyric acid (52.1
g, 0.267 mol) in dichloromethane (150 ml) was added concentrated
sulphuric acid (2.85 ml) and isobutylene (150 ml). The mixture was
stirred in a Parr vessel a room temperature for 24 hours. The
mixture was slowly added to a saturated solution of sodium
hydrogencarbonate (300 ml) and extracted with dichloromethane (50
ml). The organic layer was washed with brine (100 ml), separated,
dried over magnesium sulphate, filtered and the solvent removed in
vacuo to afford the title compound as a pale yellow oil (66.4 g,
99%).
[1063] TLC R.sub.f 0.59 (20% ethyl acetate/hexane).
[1064] Intermediate 152 2-Acetylsulfanylmethyl-3-methyl-butyric
acid tert-butyl ester
[1065] To solution of intermediate 151 (66.4 g, 0.264 mol) in dry
DMF (330 ml) under nitrogen cooled to 0.degree. C. was added
portionwise potassium thioacetate (36.2 g, 0.317 mol). The mixture
was allowed to warm to room temperature and stirred for 18 hours.
After cooling to 0.degree. C., water (350 ml) was added and the
aqueous layer extracted with MTBE (2.times.300 ml). The combined
organic layers were washed with water (2.times.250 ml), washed with
brine (250 ml), separated, dried over magnesium sulphate, filtered
and the solvent removed in vacuo to afford the title compound as a
yellow oil (63.5 g, 98%)
[1066] TLC R.sub.f 0.49 (20% ethyl acetate/hexane).
[1067] Intermediate 153
1-[4-(3-Bromo-propoxymethyl)-cyclohexyl]-4-methoxy- -benzene
[1068] To a mixture of (4methoxy-cyclohexyl)-methanol (1.25 g, 8.7
mmol) and trifluoro-methanesulfonic acid 3-bromo-propyl ester (2.58
g, 9.55 mmol) in nitromethane (15 ml) was added
2,6di-tert-butylpyridine (1.83 ml, 9.55 mmol). The reaction mixture
was heated at 80.degree. C. for 18 hours. The mixture was
concentrated in vacuo and the residue purified by flash column
chromatography on silica eluting with 20% ethyl acetate in hexane
to give the title compound as a yellow oil (1.4 g, 61%).
[1069] TLC R.sub.f 0.81 (20% ethyl acetate/hexane).
[1070] The following compound was prepared in a similar way to that
described above.
[1071] Intermediate 154 [4-(3Bromo-propoxy)-cyclohexyl]-benzene
[1072] From 4-phenyl-cyclohexanol (1.3 g, 7.5 mmol) and
trifluoro-methanesulfonic acid 3-bromo-propyl ester (4.1 g, 15
mmol) as a yellow oil (1.6 g, 72%)
[1073] TLC R.sub.f 0.54 (10% ethyl acetate/hexane).
[1074] Intermediate 155
2-(3-Hydroxy-propylsulfanoylmethyl)-3-methyl-butyr- ic acid
tert-butyl ester
[1075] To a solution of intermediate 152 (1.32 g, 5.36 mmol) in
methanol (10 ml) cooled to 0.degree. C. was added dropwise a
solution of sodium bis(trimethylsilyl)amide (1.0M in THF, 5.4 ml,
5.36 mmol). After stirring for 5 mins, a solution of
3-bromo-1-propanol (0.48 ml, 5.36 mmol) was added and the reaction
mixture was allowed to warm to room temperature and stirred for 90
mins. The mixture was concentrated in vacuo and the residue
purified by flash column chromatography on silica eluting with 25%
ethyl acetate in hexane to give the title compound as a clear
colourless oil (1.13 g, 72%).
[1076] TLC R.sub.f 0.29 (25% ethyl acetate/hexane).
[1077] The following compounds were prepared in a similar way to
that described above.
[1078] Intermediate 156
3-Methyl-2-(3-phenoxy-propanesulfanylmethyl)-butyr- ic acid
tert-butyl ester
[1079] From intermediate 152 (0.7 g, 2.8 mmol) and 3-phenoxypropyl
bromide (0.44 ml, 2.8 mmol) as a clear oil (943 mg,
quantitative).
[1080] TLC R.sub.f 0.32 (10% ethyl acetate/heptane).
[1081] Intermediate 157
2-[3-(4-methoxy-cyclohexylmethoxy)-propane-1-sulfa-
nylmethyl]-3-methyl-butyric acid tert-butyl ester
[1082] From intermediate 152 (700 mg, 2.84 mmol) and intermediate
153 (751 mg, 2.84 mmol) as a yellow oil (368 mg, 33%).
[1083] TLC R.sub.f 0.27 (10% ethyl acetate/heptane).
[1084] Intermediate 158
3-methyl-2-[3-(4-phenyl-cyclohexyloxy)-propane-1-s-
ulfanylmethyl]-butyric acid tert-butyl ester
[1085] From intermediate 152 (700 mg, 2.84 mmol) and intermediate
154 (700 mg, 2.84 mmol) as a clear oil (612 mg, 52%).
[1086] TLC R.sub.f 0.33 (10% ethyl acetate/heptane).
[1087] Intermediate 159
2-[3-(4-Chloro-phenoxy)-propane-1-sulfanylmethy]-3- -methyl-butyric
acid tert-butyl ester
[1088] To a solution of intermediate 155 (1.0 g, 3.82 mmol) in dry
THF (25 ml) under nitrogen cooled to 0.degree. C. was added
triphenylphosphine (891 mg, 3.40 mmol) followed by
diethylazodicarboxylate (0.54 ml, 3.40 mmol). After stirring for 5
mins, 4-chlorophenol (437 mg, 3.40 mmol) was added and the reaction
mixture allowed to warm to room temperature and stirred for 18
hours. Concentration in vacuo and purification by flash column
chromatography eluting with 30% ethyl acetate in hexane afforded
the title compound as a yellow oil (855 mg, 60%).
[1089] TLC R.sub.f 0.24 (hexane).
[1090] The following compound was prepared in a similar way to that
described above:
[1091] Intermediate 160
3-Methyl-2-[3-(pyridin-3-yloxy)-propylsulfanylmeth- yl]-butyric
acid tert-butyl ester
[1092] From intermediate 155 (1.05 g, 3.6 mmol) and
3-hydroxypyridine (0,34 g, 3.6 mmol) as a clear oil (802 mg,
69%).
[1093] TLC R.sub.f 0.42 (50% ethyl acetate/hexane)
[1094] Intermediate 161
3-Methyl-2-(3-phenoxy-propanesulfanylmethyl)-butyr- ic acid
[1095] To a solution of intermediate 156 (940 mg, 2.8 mmol) in
dichloromethane (20 ml) was added trifluoroacetic acid (3.7 ml) and
the mixture stirred at room temperature for 3 hours. The mixture
was concentrated in vacuo and the residue partitioned between ethyl
acetate (25 ml) and water (25 ml). The organic layer was washed
with water (25 ml), dried over magnesium sulphate, filtered and
concentrated in vacuo to afford the title compound as a clear
colourless gum (577 mg, 74%).
[1096] TLC R.sub.f 0.56 (5% methanol/dichloromethane).
[1097] The following compounds were prepared in a similar way to
that described above.
[1098] Intermediate 162
2-[3-(4-Chloro-phenoxy)-propane-1-sulfanylmethyl]--
3-methyl-butyric acid
[1099] From Intermediate 159 (855 mg, 2.29 mmol) as a pale yellow
gum (692 mg, 95%).
[1100] TLC R.sub.f 50 (30% ethyl acetate/hexane).
[1101] Intermediate 163
3-Methyl-2-[3-(pyridin-3-yloxy)-propylsulfanylmeth- yl]-butyric
acid
[1102] From intermediate 160 (801 mg). Purification by flash column
chromatography on silica eluting with 5% methanol in
dichloromethane afforded the title compound as clear oil (318 mg,
69%).
[1103] TLC R.sub.f 0.39 (10% methanol/dichloromethane).
[1104] Intermediate 164
2-[3-(4-methoxy-cyclohexylmethoxy)-propane-1-sulfa-
nylmethyl]-3-methyl-butyric acid
[1105] From intermediate 157 (368 mg, 0.95 mmol) as a clear oil
(220 mg, 82%).
[1106] TLC R.sub.f 0.31 (25% ethyl acetate/heptane)
[1107] Intermediate 165
3-methyl-2-[3-(4-phenyl-cyclohexyloxy)-propane-1-s-
ulfanylmethyl]-butyric acid
[1108] From intermediate 158 (612 mg, 1.5 mmol) as a clear
colourless gum (120 mg, 23%).
[1109] TLC R.sub.f 0.61 (10% methanol/dichloromethane).
[1110] Intermediate 166
3-Methyl-2(3-phenoxy-propane-1-sulfonylmethyl)-but- yric acid
[1111] To a solution of intermediate 161 (576 mg, 2.04 mmol) in
methanol (15 ml) was added a solution of oxone (2.6 g, 4.08 mmol)
in water (15 ml). The reaction mixture was stirred at room
temperature for 20 hours. The methanol was removed in vacuo and the
residue partitioned between ethyl acetate (50 ml) and water (50
ml). The aqueous layer was extracted with ethyl acetate (50 ml),
the organic layers were combined, washed with water (2.times.100
ml), dried over magnesium sulphate, filtered and concentrated in
vacuo to afford the title compound as a white solid (544 mg,
85%).
[1112] TLC R.sub.f 0.28 (5% methanol/dichloromethane).
[1113] The following compounds were prepared in a similar way to
that described above.
[1114] Intermediate 167
2-[3-(4-Chloro-phenoxy)-propane-1-sulfonylmethyl]--
3-methyl-butyric acid
[1115] From intermediate 162 (692 mg, 2.18 mmol) as a white solid
(689 mg, 91%).
[1116] TLC R.sub.f 0.6 (40% ethyl acetate/hexane).
[1117] Intermediate 168
3-Methyl-2-[3-pyridin-3-yloxy)-propane-1-sulfonylm- ethyl]-butyric
acid
[1118] From intermediate 163 (317 mg, 1.12 mmol). Purification by
flash column chromatography on silica eluting with 5% methanol in
dichloromethane afforded the title compound as a white solid (92
mg, 26%).
[1119] TLC R.sub.f 0.19 (10% methanol/dichloromethane).
[1120] Intermediate 169
2-[3-(4-Methoxy-cyclohexylmethoxy)-propane-1-sulfo-
nylmethyl]-3-methyl-butyric acid
[1121] From intermediate 164 (220 mg, 0.8 mmol) as a clear oil (240
mg, quantitative).
[1122] TLC R.sub.f 0.19 (50% ethyl acetate/heptane).
[1123] Intermediate 170
3-Methyl-2-[3-(4-phenyl-cyclohexyloxy)-propane-1-s-
ulfonylmethyl]-butyric acid
[1124] From intermediate 165 (118 mg, 0.3 mmol) as a clear
colourless oil (116 mg, 90%).
[1125] TLC R.sub.f 0.47 (10% methanol/dichloromethane).
[1126] Intermediate 171
2-(Pyridin-4-ylsulfanylmethylmethyl-5-(3,4,4-trime-
thyl-2,5-dioxo-imidazolidin-1-yl)-pentanoic acid
[1127] To a solution of intermediate 49 (500 mg, 1.56 mmol) in THF
(10 ml) under nitrogen was added 4-mercaptopyridine (173 mg, 1.56
mmol) and triethylamine (0.5 ml, 3.12 mmol) and the mixture was
stirred at room temperature overnight. The mixture was concentrated
in vacuo and the residue purified by flash column chromatography on
silica eluting with 10% methanol in dichloromethane to give the
title compound as a colourless oil (281 mg, 50%).
[1128] TLC R.sub.f 0.46 (10% methanol/dichloromethane).
[1129] Intermediate 172
2-(1-Oxy-pyridine-4-sulfonylmethyl)-5-(3,4,4-trime-
thyl-2,5-dioxo-imidazolidin-1-yl)-pentanoic acid
[1130] Was prepared in a similar way to intermediate 166 from
intermediate 171 (281 mg, 0.77 mmol). Purification by flash column
chromatography on silica eluting with 5% methanol in
dichloromethane to afford the title compound as a colourless oil
(60 mg, 20%).
[1131] TLC R.sub.f 0.19 (10% methanol/dichloromethane).
[1132] Intermediate 173
2-Bromoethyl-5-(3,4,4-trimethyl-2,5-dioxo-imidazol-
idin-1-yl)-pentanoic acid tert-butyl ester
[1133] To a solution of intermediate 49 (3.5 g, 10.4 mmol) in
dichloromethane (50 ml) was added isobutylene (20 ml) and
concentrated sulphuric acid (0.5 ml). The mixture was stirred at
room temperature in a sealed vessel for 24 hours. The mixture was
poured into sodium hydrogencabonate solution (300 ml) and extracted
with dichloromethane (200 ml). The organic layer was washed with
water (100 ml), separated, dried over magnesium sulphate, filtered
and concentrated in vacuo to afford the title compound as a pale
amber oil (2.8 g, 69%).
[1134] TLC R.sub.f 0.75 (ethyl acetate).
[1135] Intermediate 174
2-acetylsulfanylmethyl-5-(3,4,4-trimethyl-2,5-diox-
o-imidozolidin-1-yl-pentanoic acid tert-butyl ester
[1136] To a solution of intermediate 173 (2.8 g, 7.2 mmol) in dry
DMF (30 ml) under nitrogen was added potassium thioacetate (2.0 g,
17.5 mmol) and the mixture stirred at room temperature for 12
hours. The mixture was poured into water (50 ml) and extracted with
diethyl ether (200 ml). The organic layer was washed with water
(6.times.50 ml), washed with brine (50 ml), separated, dried over
magnesium sulphate, filtered and concentrated in vacuo to give the
title compound as a pale yellow oil (2.2 g, 82%).
[1137] TLC R.sub.f 0.45 (65% diethyl ether/hexane).
[1138] Intermediate 175
2-[3-(4-Methoxy-cyclohexylmethoxy)-propylsulfanylm-
ethyl]-5-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)pentanoic
acid tert-butyl ester
[1139] Was prepared in a similar way to intermediate 155 from
intermediate 174 (500 mg, 1.34 mmol) and intermediate 153 (531 mg,
2.0 mmol) as a clear oil (198 mg, 28%).
[1140] TLC R.sub.f 0.18 (25% ethyl acetate/hexane).
[1141] Intermediate 176
2-[3-(4-Phenyl-cyclohexyloloxy)-propylsulfanylmeth-
yl]-5-(3,4,4-trimethyl-2,5-diaxo-imidazolidin-1-yl)pentanoic acid
tert-butyl ester
[1142] Was prepared in a similar way to intermediate 155 from
intermediate 174 (500 mg, 1.34 mmol) and intermediate 154 (500 mg,
2.01 mmol) as a clear oil (517 mg, 69%). TLC R.sub.f 0.42 (50%
ethyl acetate/hexane).
[1143] Intermediate 177
2-[3-(4-Methoxy-cyclohexylmethoxy)-propylsulfonylm-
ethyl]-5-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)pentanoic
acid tert-butyl ester
[1144] Was prepared in a similar way to intermediate 166 from
intermediate 175 (198 mg, 0.38 mmol) as a clear oil (193 mg,
91%).
[1145] TLC R.sub.f 0.16 (25% ethyl acetate/hexane).
[1146] Intermediate 178
2-[3(4-Phenyl-cyclohexyloloxy)-propylsulfonylmethy-
l]-5-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-pentanoic acid
tert-butyl ester
[1147] Was prepared in a similar way to intermediate 166 from
intermediate 176 (510 mg, 0.91 mmol) as a clear oil (463 mg,
86%).
[1148] TLC R.sub.f 0.16 (50% ethyl acetate/hexane).
[1149] Intermediate 179
2-[3-(4-Methoxy-cyclohexylmethoxy)-propylsulfonylm-
ethyl]-5-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-pentanoic
acid
[1150] Was prepared in a similar way to intermediate 161 from
intermediate 177 (193 mg, 0.35 mmol) as a clear oil (236 mg,
quantitative).
[1151] TLC R.sub.f 0.40 (ethyl acetate).
[1152] Intermediate 180
2-[3-(4-Phenyl-cyclohexyloloxy)-propylsulfonylmeth-
yl]-5-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1yl)-pentanoic
acid
[1153] Was prepared in a similar way to intermediate 161 from
intermediate 178 (463 mg, 0.78 mmol) as a clear oil (500 mg,
quantitative).
[1154] MS 537 M.sup.+
[1155] Intermediate 181 1-(3-Bromo-propoxy)-4-chloro-benzene
[1156] To a solution of 4-chlorophenol (5.0 g, 38.9 mmol) in dry
THF (80 ml) under nitrogen cooled to 0.degree. C. was added
portionwise sodium hydride (60% in mineral oil, 1.71 g, 42.8 mmol).
After stirring at 0.degree. C. for 15 mins and room temperature for
30 mins, this mixture was added to a solution of 1,3dibromopropane
(4 ml, 77.8 mmol) in THF (20 ml) under nitrogen cooled to 0.degree.
C. The reaction mixture was stirred at room temperature for 30 mins
and then heated at reflux for 5 hours. Saturated ammonium chloride
solution (50 ml) was added and the mixture concentrated in vacuo.
The residue was partitioned between ethyl acetate (150 ml) and
water (150 ml). The organic layer was washed with brine (150 ml),
dried over magnesium sulphate, filtered and concentrated in vacuo.
Purification was by flash chromatography on silica eluting with
dichloromethane afforded the title compound as a clear oil (2.6 g,
30%).
[1157] TLC R.sub.f 0.95 (dichloromethane).
[1158] Intermediate 182 Thioacetic acid
S-[3-(4-chloro-phenoxy)-propyl] ester
[1159] Was prepared in a similar way to intermediate 174 from
intermediate 181 (2.55 g, 10.2 mmol). Purification by flash
chromatography on silica eluting with dichloromethane afforded the
title compound as a clear oil (1.5 g, 64%).
[1160] TLC R.sub.f 0.60 (dichloromethane).
[1161] Intermediate 183
2-[3-(4Choro-phenoxy)-propane-1-sulfanylmethyl]-5--
(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-pentanoic acid
[1162] Was prepared in a similar way to intermediate 155 from
intermediate 182 (0.75 g, 3.22 mmol) and intermediate 49 (1.08 g,
3.22 mmol) as a clear oil (300 mg, 16%).
[1163] TLC R.sub.f 0.40 (5% methanol/dichloromethane).
[1164] Intermediate 184
2-[3-(4-Choro-phenoxy)-propane-1-sulfonylmethyl]-5-
-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-pentanoic acid
[1165] Was prepared in a similar way to intermediate 166 from
intermediate 183 (0.91 g, 2.0 mmol). Purification by flash
chromatography on silica eluting with ethyl acetate afforded the
title compound as a white solid (550 mg, 60%).
[1166] TLC R.sub.f 0.20 (5% methanol/dichloromethane).
[1167] Intermediate 185
(4-Mercapto-phenyl)-pyridin-4-yl-methanone
[1168] To a solution of 4-(4-chlorobenzoyl)-pyridine (50 g, 230
mmol) in N-methylpyrrolidine (400 ml) was added sodium thiolate (40
g, 230 mmol) and the mixture heated at 100.degree. C. for 3 hours.
The mixture was poured into water (100 ml), acidified to pH 5 with
citric acid and extracted with dichloromethane (2.times.200 ml).
The combined organic layers were washed with water (100 ml),
separated, dried over magnesium sulphate, filtered and concentrated
in vacuo to give a beige oil. This was dissolved in methanol (400
ml) and tributyl phosphine (40 ml) and water (100 ml) were added.
The resulting yellow solution was stirred at room temperature for
30 mins. The methanol was removed in vacuo, the solution diluted
with water (100 ml) and citric acid (20 g) added. The mixture was
extracted with dichoromethane (2.times.100 ml) and the combined
organic layers were extracted with sodium hydrogencarbonate
solution (5.times.75 ml). The combined aqueous layers were
carefully acidified with citric acid and the resulting solid
collected by filtration. This was dried in vacuo to afford the
title compound as a beige powder (24.2 g, 50%).
[1169] TLC R.sub.f 0.2 (diethyl ether).
[1170] The following compound was prepared in a similar way to that
described above:
[1171] Intermediate 186
(4-Mercapto-phenyl)-thiophen-2-yl-methanone
[1172] From 4-fluorophenyl-2-thienyl ketone (25 g, 121 mmol) as a
beige powder (16.0 g, 60%).
[1173] Intermediate 187
4-(Tetrahydro-pyran-2-ylsulfanyl)-phenol
[1174] To a solution of 4-hydroxythiophenol (10 g, 79 mmol) and
p-toluenesulphonic acid (100 mg) in dichloromethane (100 ml) was
added dihydropyran (16.7 g, 19.8 mmol) and the mixture stirred at
room temperature for 18 hours. The mixture was concentrated in
vacuo and the residue dissolved in THF (100 ml) and 0.5M sulphuric
acid (20 ml). The mixture was stirred at room temperature for 18
hours and concentrated in vacuo. The residue was dissolved in
dichloromethane (200 ml) and washed with water (50 ml) and brine
(50 ml). The organic layer was separated, dried over magnesium
sulphate, filtered and concentrated in vacuo. Purification by flash
column chromatography on silica eluting with 25% diethyl ether in
hexane afforded the title compound as a white solid (11.5 g,
66%).
[1175] TLC R.sub.f 0.3 (25% diethyl ether/hexane)
[1176] Intermediate 188
4-[4-(Tetrahydro-pyran-2-ylsulfanyl)-phenoxymethyl- ]-pyridine
[1177] To a suspension of intermediate 186 (4.4 g, 20 mmol) and
caesium carbonate (6.5 g, 20 mmol) in dry DMF (30 ml) under
nitrogen was added 4-picolyl chloride (3.4 g, 20 mmol) and the
mixture stirred at room temperature for 2 hours. The mixture was
poured into water (100 ml) and extracted with diethyl ether
(3.times.100 ml). The combined organic layers were washed with
water (3.times.75 ml), washed with brine (75 ml), separated, dried
over magnesium sulphate, filtered and concentrated in vacuo.
Purification by flash column chromatography on silica eluting with
ethyl acetate afforded the title compound as a colourless oil (3.5
g, 88%).
[1178] TLC R.sub.f 0.35 (dietyl ether).
[1179] Intermediate 189 4-(Pyridin-4-ylmethoxy)-benzenthiol
[1180] A solution of intermediate 187 (3.0 g, 10 mmol) in
concentrated hydrochloric acid (56 ml) was left standing at room
temperature for 3 days. The mixture was diluted with water (200 ml)
and washed with diethyl ether (3.times.100 ml). The aqueous layer
was basified to pH7 with sodium hydroxide and sodium
hydrogencarbonate and extracted with dichloromethane (2.times.200
ml). The organic layers were combined, dried over magnesium
sulphate, filtered and concentrated in vacuo to give the title
compound as a pale yellow solid.
[1181] TLC R.sub.f 0.25 (ethyl acetate)
[1182] Intermediate 190 4-(Pyridin-4-yloxy)-benzenethiol
[1183] To a mixture of crushed ice (10 g) and concentrated
hydrochloric acid (10 ml) was added portionwise
4-(pyridin-4yloxy)-phenylamine (10 g, 62 mmol). After cooling to
0.degree. C. a solution of sodium nitrite (4.5 g, 65 mmol) in water
(7.5 ml) was added dropwise. The mixture was stirred at 0.degree.
C. for 30 mins before being added to a solution of potassium
ethylxanthate (11.9 g, 0.074) at room temperature. The reaction
mixture was allowed to stir at room temperature for 90 mins. The
mixture was extracted with ethyl acetate (3.times.50 ml) and the
organic layers combined, washed with 10% sodium hydroxide solution
(50 ml), washed with water (3.times.25 ml), separated, dried over
magnesium sulphate, filtered and concentrated in vacuo to give a
brown oil. This was dissolved in ethanol (50 ml) and potassium
hydroxide (11 g) added slowly after which the mixture was heated at
reflux for 18 hours. The mixture was concentrated in vacuo and to
the residue was added water (60 ml). The aqueous layer was washed
with MTBE (2.times.50 ml) and ethyl acetate (2.times.50 ml),
acidified to pH 5 with acetic acid and extracted with MTBE
(3.times.50 ml). The combined organic layers were washed with water
(50 ml), separated, dried over magnesium sulphate and concentrated
in vacuo to give the title compound as a brown oil (9.6 g,
97%).
[1184] TLC R.sub.f 0.53 (ethyl acetate).
[1185] Intermediate 191
2-(4-(4-Pyridinoyl)phenylsulphonyl)methyl-5-(3,4,4-
-trimethylhydantoin-1-yl)pentanoic acid N-oxide
[1186] A solution of intermediate 185 (14 g, 65 mmol), intermediate
49 (20 g, 60 mmol) and triethylamine (20 ml, 140 mmol) in dry DMF
(200 ml) under nitrogen was stirred at room temperature for 18
hours. The mixture was poured into water (600 ml), acidified with
citric acid and extracted with dichloromethane (3.times.200 ml).
The combined organic layers were washed with water (200 ml) and
brine (200 ml), separated, dried over magnesium sulphate, filtered
and concentrated in vacuo to give a brown oil. This was dissolved
in methanol (400 ml), a solution of oxone (60 g, 100 mmol) m water
(100 ml) was added and the mixture stirred at room temperature for
18 hours. The mixture was reduced to half its volume in vacuo,
sodium acetate (30 g) was added and the mixture was extracted with
ethyl acetate (4.times.100 ml). The organic layers were combined,
dried over magnesium sulphate, filtered and concentrated in vacuo.
Trituration in ethyl acetate afforded the title compound as a white
solid (13 g, 42%).
[1187] TLC R.sub.f 0.45 (10% methanol/dichloromethane).
[1188] The following compounds were prepared in a similar way to
that described above.
[1189] Intermediate 192
2-(4-(4-pyridinoyl)phenylsulphonyl)methyl-5-succin- imidopentanoic
acid
[1190] From intermediate 185 (2.2 g, 10 mmol) and intermediate 47
(2.9 g, 10 mmol) as a white powder (2.4 g, 52%).
[1191] TLC R.sub.f 0.6 (9% methanol/dichloromethane).
[1192] Intermediate 193
2-(4-(2-thienoyl)phenylsulphonylmethyl)-5-succinim- idopentanoic
acid
[1193] From intermediate 186 (2.2 g, 10 mmol) and intermediate 47
(2.9 g, 10 mmol) as a white foam (2.9 g, 63%).
[1194] TLC R.sub.f 0.40 (ethyl acetate).
[1195] Intermediate 194
2-(4-(4-Chlorobenzoyl)phenylthio)methyl-5-succinim- idopentanoic
acid
[1196] From (4-chloro-phenyl)-(4-mercapto-phenyl)-methanone (2.5 g,
10 mmol) and intermediate 47 (2.9 g, 10 mmol) as a white solid (3.4
g, 69%).
[1197] TLC R.sub.f 0.35 (ethyl acetate).
[1198] Intermediate 195
2-(4-(4-Cyanophenoxy)phenylsulphonyl)methyl-5-succ-
inimidopentanoic acid
[1199] From 4-(4-mercapto-phenoxy)-benzonitrile (0.60 g, 2.64 mmol)
and intermediate 47 (0.78 g, 10 mmol) as a white powder (0.5 g,
40%).
[1200] TLC R.sub.f 0.45 (ethyl acetate).
[1201] Intermediate 196
2-(4-(4-Pyridylmethoxy)phenylsulphonyl)methyl-5-su-
ccinimidopentanoic acid
[1202] From intermediate 189 (0.70 g, 3.2 mmol) and intermediate 47
(0.94 g, 3.2 mmol) as a white solid (0.26 g, 18%).
[1203] TLC R.sub.f 0.25 (7% methanol/dichloromethane).
[1204] Intermediate 197
2-(4-Phenoxyphenylsulphonyl)methyl-5-succinimidope- ntanoic
acid
[1205] From 4-phenoxy-benzenethiol (1.87 g, 9.3 mmol) and
intermediate 47 (2.7 g, 3.2 mmol) as white solid (3.5 g, 85%).
[1206] TLC R.sub.f 0.45 (ethyl acetate).
[1207] Intermediate 198
2-(4-(3-Pyridyloxy)phenyl)sulphonylmethyl-5-succin- imidopentanoic
acid
[1208] From intermediate 190 (2.03 g, 10 mmol) and intermediate 47
(2.9 g, 10 mmol) as a beige solid (2.0 g, 45%).
[1209] TLC R.sub.f 0.45 (10% methanol/dichloromethane with 1%
acetic acid).
[1210] Intermediate 199 2-Phenyl-3-(thiophene-2-sulfonyl)-propionic
acid
[1211] From 2-thiophene thiol (230 mg, 2 mmol) and
3-bromo-2-phenyl-propio- nic acid (460 mg, 2 mmol). Purification by
flash column chromatography on silica eluting with 66% diethyl
ether in hexane with 1% acetic acid afforded the title compound as
a white solid (35 mg, 6%).
[1212] TLC R.sub.f 0.43 (66% diethyl ether/hexane with 1% acetic
acid).
[1213] Intermediate 200
3-Methyl-2-(4-nitro-phenylsulfanylmethyl)-butyric acid
[1214] A solution of 4-nitrophenol (1.0 g, 6.5 mmol),
2-bromomethyl-3-methyl-butyric acid (1.26 g, 6.5 mmol) and
triethylamine (20 ml, 140 mmol) in dry DMF (200 ml) under nitrogen
was stirred at room temperature for 18 hours. The mixture was
poured into water (30 ml), washed with ethyl acetate (2.times.30
ml), acidified with citric acid and extracted with ethyl acetate
(3.times.75 ml). The combined organic layers were dried over
magnesium sulphate, filtered and concentrated in vacuo to give an
off-white solid (1.82 g, quantitative).
[1215] TLC R.sub.f 0.48 (5% methanol/dichloromethane).
[1216] Intermediate 201
2-(4-Amino-phenylsulfanylmethyl)-3-methyl-butyric acid
[1217] To a solution of intermediate 200 (700 mg, 2.6 mmol) in
ethanol (30 ml) was added 10% palladium on activated charcoal and
the mixture stirred under an atmosphere of hydrogen gas for 18
hours. The mixture was filtered through celite and concentrated in
vacuo to afford the title compound as an off-white solid (715 mg,
quantitative).
[1218] TLC R.sub.f 0.45 (5% methanol/dichloromethane).
[1219] Intermediate 202
3-Methyl-2-(4-ureidobezenesulanylmethyl)-butyric acid
[1220] To a solution of intermediate 201 (300 mg. 1.25 mmol) in
acetic acid (5 ml) was added a solution of potassium cyanate (0.51
g, 6.28 mmol) in water (8 ml) and the mixture stirred at room
temperature for 18 hours. The mixture was concentrated in vacuo to
afford the title compound as an off-white solid (350 mg,
quantitative).
[1221] MS 283 (M+1).sup.+
EXAMPLE 100
[1222] 2-((4-Benzyloxyphenyl)sulfonylmethyl)-5-phenylpentanoic Acid
N-Hydroxy Amide
[1223] A solution of intermediate 146 (0.17 g) in TFA (10 ml) and
dichloromethane (10 ml) was stirred overnight and the evaporated in
vacuo. The residue was azeotroped with toluene, then purified by
flash column chromatography, eluting with 7% MeOH/dichloromethane,
to give the title compound as colourless solid (0.06 g, 40%).
[1224] TLC R.sub.f 0.45 (5% MeOH/dichloromethane).
[1225] MS 453 (M.sup.+)
EXAMPLE 101
[1226]
2-(4-(1-Methyleth-1-yloxy)phenylsulfonylmethyl)-5-phenylpentanoic
Acid N-Hydroxy Amide
[1227] From intermediate 147 (0.35 g) as white solid (0.20 g,
48%).
[1228] TLC R.sub.f 0.25 (5% MeOH/dichloromethane).
[1229] MS 405 (M.sup.+).
EXAMPLE 102
[1230] 2-((4-Butyloxy)phenylsulfonylmethyl)-5-phenylpentanoic Acid
N-Hydroxy Amide
[1231] From intermediate 148 (0.40 g) as white solid (0.20 g,
45%).
[1232] TLC R.sub.f 0.30 (5% MeOH/dichloromethane).
[1233] MS 419 (M.sup.+)
EXAMPLE 103
[1234] 2-((4-Cyclopentyloxyphenyl)sulfonylmethyl)-5-phenylpentanoic
Acid N-Hydroxy Amide
[1235] From intermediate 149 (0.40 g), as white solid (0.15 g,
33%).
[1236] TLC R.sub.f 0.30 (5% MeOH/dichloromethane).
[1237] MS 431 (M.sup.+).
EXAMPLE 104
[1238]
2-(4-(4-Cyanobenzyloxy)phenylsulfonylmethyl)-5-phenyl-pentanoic
Acid N-Hydroxy Amide
[1239] From intermediate 150 (0.25 g) as white solid (0.265 g,
100%).
[1240] TLC R.sub.f 0.25 (6% MeOH/dichloromethane).
[1241] MS 469 (M.sup.+).
EXAMPLE 105
[1242]
2-((4-(1-Hydroxy-1-phenylmethyl)phenyl)sulfonyl-methyl)-5-phenylpen-
tanoic Acid N-Hydroxy Amide
[1243] Sodium borohydride (0.38 g) was added to a solution of
example 58 (0.45 g) in MeOH (100 ml) and the solution was stirred
for 2 h, then evaporated and the residue dissolved in water,
acidified with citric acid and extracted with ethyl acetate. The
organic layer was washed with brine, dried and evaporated to give
the crude product, which was purified by column chromatography,
eluting with 7% MeOH in dichloromethane to give the title compound
(0.43 g, 95%) as white solid.
[1244] TLC R.sub.f 0.53 (7% MeOH/dichloromethane).
[1245] MS 454 (M.sup.+).
EXAMPLE 106
[1246] 2-(Pyrid-4-ylsulfonylmethyl)-5-phenylpentananoic Acid
N-Hydroxy Amide Hydrochloride
[1247] Example 60 was dissolved in dichloromethane and treated with
excess 1M HCl in diethyl ether and then evaporated to give the
title compound (0.20 g) as a pale yellow solid.
EXAMPLE 107
[1248]
4-[4-(Methoxycarbonyl)methoxy-3,5-dimethyphenyl]-2-methyl-1(2H)phth-
alazinone
[1249] Intermediate 60 (1.40 g) was added to a suspension of sodium
hydride (0.24 g) in DMF (30 ml) at 0.degree. C. After stirring for
30 min, methyl bromoacetate (1.15 g) was added and the mixture
stirred for 18 h. Water (90 ml) was added and the result
precipitate was collected by filtration and dried in vacuo to
provide the title compound as a white solid (1.54 g)
[1250] MS 353 MH.sup.+
EXAMPLE 108
[1251]
4-[4-(Carboxy)methoxy-3,5-dimethyphenyl]-2-methyl-1(2H)phthalazinon-
e
[1252] Lithium hydroxide monohydrate (0.22 g) was added to a
solution of example 107 (1.52 g) in aqueous tetrahydrofuran (1:150
ml) and the reaction stirred 18 h. the mixture was the concentrated
in vacuo and the residual slurry acidified with 10% hydrochloric
acid.
[1253] The resulting precipitate was collected to give the title
compound as a white solid (1.36 g).
[1254] MS 338MH.sup.+
EXAMPLE 109
[1255]
4-[4-(Hydroxyaminocarbonyl)methoxy-3,5-dimethyphenyl]-2-methyl-1(2H-
)phthalazinone
[1256] A solution of example 108 (1.15 g) in dichloromethane (30
ml) at 0.degree. C. was treated with triethylamine (0.52 g)
followed by isopropenyl chloroformate (0.41 g), and the mixture was
stirred for 1 h. O-tert-butyldimethylsilylhydroxylamine (0.50 g)
was then added and the mixture was stirred for a further 18 h. The
reaction mixture was washed with 10% citric acid (20 ml), saturated
sodium bicarbonate (20 ml) and the concentrated to dryness in
vacuo. A solution of the residual solid in tetrahydrofuran (30 ml)
and water (5 ml) was then treated with a 1.0 M solution of
tetrabutylammonium fluoride in tetrahydrofuran (1 ml) and stirred 1
h. the resultant crude mixture was concentrated on to silica and
purified by chromatography, eluting with 5% methanol in
dichloromethane, to provide the title compound as a white solid
(0.10 g).
[1257] R.sub.f0.18 (5% methanol in dichloromethane)
EXAMPLE 110
[1258]
2-(3-Phenoxy-propane-1-sulfonylmethyl)-N-hydroxy-3-methyl-butyramid-
e
[1259] To a solution/suspension of intermediate 166 (543 mg, 1.7
mmol) in dichloromethane (15 ml) under nitrogen was added DMF (3
drops) followed by oxalyl chloride (0.15 ml, 1.7 mmol) dropwise.
After string at room temperature for 60 mins, the mixture was
concentrated in vacuo. The residue was dissolved in THF (15 ml), a
solution of hydroxylamine added slowly (50% in water, 4 ml) and the
reaction mixture stirred at room temperature for 60 mins. The
mixture was concentrated in vacuo and the residue partitioned
between ethyl acetate (25 ml) and water (25 ml). The organic layer
was washed with water (25 ml), separated, dried over magnesium
sulphate and concentrated in vacuo to give the title compound as a
white solid (470 mg, 83%).
[1260] TLC R.sub.f0.51 (10% methanol/dichloromethane).
[1261] MS 330 (M+1).sup.+
[1262] The following compounds were prepared in a similar way to
that described above.
EXAMPLE 111
[1263]
2-[3-(4Chloro-phenoxy)-propane-1-sulfonylmethyl]-N-hydroxy-3methyl--
butyramide
[1264] From intermediate 167 (689 mg, 1.98 mmol) as a white solid
(654 mg, 91%).
[1265] TLC R.sub.f0.64 (ethyl acetate).
[1266] MS364M.sup.+
EXAMPLE 112
[1267]
N-Hydroxy-2-[3(4methoxy-cyclohexylmethoxy)-propane-1-sulfonylmethyl-
]-3-methyl-butyramide
[1268] From intermediate 169 (240 mg, 0.76 mmol). Purification by
flash column chromatography afforded the title compound as a clear
gum (180 mg, 72%).
[1269] TLC R.sub.f0.38 (10% methanol/dichloromethane).
[1270] MS 380 M.sup.+
EXAMPLE 113
[1271]
N-Hydroxy-3-methyl-2-[3-(4-phenyl-cyclohexyloxy)-propane-1-sulfonyl-
methyl]-butyramide
[1272] From intermediate 170 (116 mg, 0.3 mmol) as a clear gum (62
mg, 51%).
[1273] TLC R.sub.f0.44 (10% methanol/dichloromethane).
[1274] MS 412 M.sup.+
EXAMPLE 114
[1275]
2-(1-Oxy-pyridine-4-sulfonylmethyl)-5-(3,4,4-trimethyl-2,5-dioxo-im-
idazolidin-1-yl)-pentanoic acid hydroxyamide
[1276] From intermediate 172 (60 mg 0.15 mmol). Purification by
flash chromatography on silica eluting with 5% methanol in
dichloromethne afforded the title compound as a clear oil (35 mg,
54%). TLC R.sub.f0.16 (5% methanol/dichloromethane).
[1277] MS 430 (M+1).sup.+
EXAMPLE 115
[1278]
2-[3-(4-Methoxy-cyclohexylmethoxy)-propylsulfonylmethyl]-5-(3,4,4-t-
rimethyl-2,5-diazo-imidazolidin-1-yl)-pentanoic acid
hydroxyamide
[1279] From intermediate 179 (166 mg, 0.35 mmol) as a clear oil (25
mg, 14%).
[1280] TLC R.sub.f0.14 (ethyl acetate).
[1281] MS 520 M.sup.+
EXAMPLE 116
[1282]
2-[3-(4Phenyl-cyclohexyloloxy)-propylsulfonylmethyl]-5-(3,4,4trimet-
hyl-2,5-dioxo-imidazolidin-1-yl)-pentanoic acid hydroxyamide
[1283] From intermediate 180 (418 mg, 0.78 mmol) as a yellow oil
(374 mg, 87%).
[1284] TLC R.sub.f0.17 (ethyl acetate).
[1285] MS 552 M.sup.+
EXAMPLE 117
[1286]
N-Hydroxy-3-methyl-2-[3-pyridin-3-yloxy)-propane-1-sulfonylmethyl]--
butyramide
[1287] To a suspension of intermediate 168 (90 mg, 0.28 mmol) in
dry dichloromethane (5 ml) under nitrogen was added
1,3-dimethylaminopropyl-3- -ethylcarbodiimide (66 mg, 0.34 mmol).
After stirring at room temperature for 5 mins,
tert-butyldimethylsilyl hydroxylamine (50 mg, 0.34 mmol) and
4-dimethylaminopyridine (3 mg) were added and the mixture stirred
for a further 2 hours. The mixture was washed with water (20 ml)
and sodium hydrogencarbonate solution (20 ml), the organic layer
was separated, dried over magnesium sulphate, filtered and
concentrated in vacuo. The residue was redissolved in
dichloromethane (5 ml) and a solution of tetrabutylammonium
fluoride (1.0M in THF, 0.28 ml, 0.28 mmol) added. The reaction
mixture was stirred at room temperature for 2 mins. The mixture was
concentrated in vacuo and the residues purified by flash column
chromatography on silica eluting with 5% methanol in
dichloromethane to give the title compound as a white solid (48 mg,
51%).
[1288] TLC R.sub.f0.20 (10% methanol/dichloromethane).
[1289] MS 331 (M+1).sup.+
EXAMPLE 118
[1290]
2-[3-(4-Chloro-phenoxy)-propane-sulfonylmethyl]-5-(3,4,4-trimethyl--
2,5-dioxo-imidazolidin-1-yl)-pentanoic acid hydroxyamide
[1291] To a suspension of intermediate 184 (550 mg, 1.1 mmol) in
dry dichloromethane (30 ml) under nitrogen was added
1,3-dimethylaminopropyl-- 3-ethylcarbodiimide (324 mg, 1.7 mmol).
After stirring at room temperature for 15 mins,
tert-butyldimethylsilyl hydroxylamine (165 mg, 1.1 mmol) was added
and the mixture stirred for a further 2 hours. The mixture was
partitioned between dichloromethane (100 ml) and water (100 ml).
The organic layer was washed with sodium hydrogencarbonate solution
(100 ml), washed with brine (100 ml), separated, dried over
magnesium sulphate, filtered and concentrated in vacuo. The residue
was triturated in hexane to give a sticky solid. This was dissolved
in chloroform (15 ml) and a solution of hydrogen chloride (1.0M in
diethyl ether, 2 ml) added and the mixture stirred at room
temperature for 45 mins. The mixture was concentrated in vacuo and
the residue triturated in diethyl ether to give the title compound
as a white solid.
[1292] TLC R.sub.f0.10 (5% methanol in dichloromethane).
[1293] MS 504 M.sup.+
Example A
[1294] Collagenase Inhibition Activity
[1295] The potency of compounds of general formula (I) to act as
inhibitors of collagenase was determined by the procedure of
Cawston and Barrett, (Anal. Biochem, 9:340-345, 1979) whereby a 1
mM solution of the inhibitor being tested or dilutions thereof was
incubated at 37.degree. C. for 16 hours with collagen and
collagenase (buffered with 50 mM Tris, pH 7.6 containing 5 mM
CaCl.sub.2, 0.05% Brij 35, 60 mM NaCl and 0.02% NaN.sub.3). The
collagen was acetylated .sup.3H or .sup.14C-collagen prepared by
the method of Cawston and Murphy (Methods in Enzymolgy, 80:711,
1981). The choice of radiolabel did not alter the ability of
collagenase to degrade the collagen substrate. The samples were
centrifuged to sediment undigested collagen and an aliquot of the
radioactive supernatant removed for assay on a scintillation
counter as a measure of hydrolysis. The collagenase activity in the
presence of 1 mM inhibitor, or a dilution thereof, was compared to
activity in a control devoid of inhibitor and the results reported
as that inhibitor concentration effecting 50% inhibition of the
collagenase (IC.sub.50).
Example B
[1296] Stromelysin Inhibition Activity
[1297] The potency of compounds of general formula (I) to act as
inhibitors of stromelysin was determined using the procedure of
Nagase et al (Methods in Enzymology Vol 254, 1994), whereby a 0.1
mM solution of the inhibitor being tested or dilutions thereof was
incubated at 37.degree. C. for 16 hours with stromelysin and
.sup.3H transferrin (buffered with 50 mM Tris, pH 7.6 containing 10
mM CaCl.sub.2, 150M NaCl, 0.05% Brij, 35, and 0.02% NaN.sub.3). The
transferrin was carboxymethylated with .sup.3H iodoacetic acid. The
stromes activity in the presence of 1mM, or a dilution thereof, was
compared to activity in a control devoid of inhibitor and the
results reported as that inhibitor concentration effecting 50%
inhibition of the stromelysin (IC.sub.50)
Example C
[1298] Gelatinase Inhibition Activity
[1299] The potency of the compounds of general formula (I) to act
as inhibitors of gelatinase was determined using the procedure of
Harris & Krane (Biochem Biophys. Acta, 258:566-576, 1972),
whereby a 1 mM solution of the inhibitor being tested or dilutions
thereof was incubated at 37.degree. C. for 16 hours with gelatinase
and heat denatured .sup.3H or .sup.14C-acetylated collagen
(buffered with 50 mM Tris, pH 7.6 containing 5 mM CaCl.sub.2, 0.05%
Brij 35 and 0.02% NaN.sub.3). The .sup.3H or .sup.14C gelatin was
prepared by denaturing .sup.3H or .sup.14C-collagen produced
according to the method of Cawston and Murphy (Methods in
Enzymology, 80;711, 1981) by incubation at 60.degree. C. for 30
minutes. Undigested gelatin was precipitated by addition of
trichloroacetic acid and centrifugation. The gelatinase activity in
the presence of 1 mM, or dilution thereof, was compared to the
activity in a control devoid of inhibitor and results reported as
that inhibitor concentration effecting 50% inhibition of the
gelatinase (IC.sub.50).
Example D
[1300] MMP Inhibition Activity-Fluorimetic Assay
[1301] The potency of compounds of general formula (I) to act as
inhibitors of collagenase-1(MMP-1), collagenase-2 (MMP-8),
collagenase-3 (MMP-13), gelatinase-A (MMP-2), gelatinase-B (MMP-9)
and stromelysin-1 (MMP-3) was determined using the following
procedure:
[1302] Inhibitors are dissolved in dimethysulphoxide containing
0.02% .beta.-mercaptoethanol and serial dilutions are prepared.
Activated enzyme is incubated in assay buffer containing 500M Tris,
pH 7.4, 5 mM CaCl.sub.2, 0.002% NaN.sub.3 and Brij 35 in the
presence and absence of inhibitor. Samples are preincubated at
37.degree. C. for 15 minutes before the addition of the
fluorimetric substrate (Mca-Pro-Leu-Gly-Leu-Dp- a-Ala-Arg-NH.sub.2)
to a final concentration of 10 .mu.M. The assay is incubated for
20-30 min at 37.degree. C. and then read in a Fluoroscan II at
.lambda..sub.cm (340 nm) and .lambda..sub.cm (405 nm).
[1303] The enzyme activity was compared to activity in a control
devoid of inhibitor and the results reported as that inhibitor
concentration effecting 50% inhibition of the stromelysin
(IC.sub.50).
Example E
[1304] Inhibition of TNF .alpha. Production
[1305] The potency of the compounds of general formula (I) to act
as inhibitors of the production of TNF .alpha. is determined using
the following procedure. A 100 .mu.M solution of the inhibitor
being tested or dilutions thereof is incubated at 37.degree. C. in
an atmosphere of 5% CO.sub.2 with TFP-1 cells (human monocytes)
suspended in RPM1 1640 medium and 20 .mu.M .beta.-mercaptoethanol
at a cell density of 1.times.10.sup.6/ml and stimulated with LPS.
After 18 hours the supernatant is assayed for the levels of TNF
.alpha. using a commercially available ELISA kit (R & D
Systems).
[1306] The activity in the presence of 0.1 mM inhibitor or
dilutions thereof is compared to activity in a control devoid of
inhibitor and results reported as that inhibitor concentration
effecting 50% inhibition of the production of TNF.alpha..
Example F
[1307] Inhibition of L-Selectin Shedding
[1308] Compounds of general formula (I) are evaluated in an assay
of L-selectin shedding by peripheral blood mononuclear cells
(PBMC). PBMC are isolated from buffy coats by standard procedures
using Ficoll. A 100 .mu.M solution of the inhibitor being tested or
dilutions thereof is incubated for 20 min at 37.degree. C. in an
atmosphere of 5% CO.sub.2 with 4.times.10.sup.6/ml PBMC stimulated
with PMA. The cells are centrifuged down and the supernatants
tested for sL-selectin un a commercially available ELISA kit (R
& D Systems).
[1309] The activity in the presence of 100 .mu.M inhibitor or
dilutions thereof was compared to activity in a control devoid of
inhibitor and results reported as that inhibitor concentration
effecting 50% inhibition of the shedding of L-selectin.
Example G
[1310] Inhibition of sIl-1RII Shedding
[1311] Compounds of general formula (I) are evaluated in an assay
of sIl-1RII shedding by peripheral blood mononuclear cells (PBMC).
PBMC are isolated from buffy coats by standard procedures using
Ficoll. A 100 .mu.M solution of the inhibitor being tested or
dilutions thereof are incubated for 18 h at 37.degree. C. in an
atmosphere of 5% CO.sub.2 with 2.times.10.sup.6/ml PBMC stimulated
with Il-13. The cells are centrifuged down and the supernatants
tested for sIl-1RII using a commercially available ELISA kit (R
& D Systems).
[1312] The activity in the presence of 100 .mu.M inhibitor or
dilutions thereof is compared to activity in a control devoid of
inhibitor and results reported as that inhibitor concentration
effecting 50% inhibition of the shedding of sIl-1RII.
Example H
[1313] Inhibition of Il-6R Shedding
[1314] Compounds of general formula (I) are evaluated in an assay
of sIl-6R shedding by HL-60 cells. PBMC are isolated from b coats
by standard procedures using Ficoll. A 100 .mu.M solution of the
inhibitor being tested or dilutions thereof is incubated or 24 h at
37.degree. C. in an atmosphere of 5% CO.sub.2 with
2.times.10.sup.6/ml HL-60 cells stimulated with PMA. The cells are
centrifuged down and the supernatants tested for sIl-6R using a
commercially available ELISA kit (R & D Systems).
[1315] The activity in the presence of 100 82 M inhibitor or
dilutions thereof is compared to activity in a control devoid of
inhibitor and results reported as that inhibitor concentration
effecting 50% inhibition of the shedding of Il-6R.
Example I
[1316] Inhibition of TNF RII Shedding
[1317] The potency of the compounds of general formula (I) to act
as inhibitors of the shedding of TNF RII is determined using the
following procedure. A 100 .mu.M solution of the inhibitor being
tested or dilutions thereof are incubated at 37.degree. C. in an
atmosphere of 5% CO.sub.2 with THP-1 cells (human monocytes)
suspended in RPM1 1640 medium and 20 .mu.M .beta.-mercaptoethanol
at a cell density of 1.times.10.sup.6/ml and stimulated with LPS.
After 18 hours the supernatant is assayed for the levels of sTNF
RII using a commercially available ELISA it (R & D
Systems).
[1318] The activity in the presence of 0.1 mM inhibitor or
dilutions thereof is compared to act in a control devoid of
inhibitor and results reported as that inhibitor concentration
effecting 50% inhibition of the shedding of TNF RII.
Example J
[1319] Adjuvant Arthritic Rat Model
[1320] Compounds of general formula (I) were evaluated in an
adjuvant arthritis model in the rat based on the methods employed
by B. B. Newbould (1963), Br. J. Pharmacol, 21, 127-136 and C. M.
Pearson and F. D. Wood (1959), Arthritis R 2, 440-459. Briefly male
Wistar rats (180-200 g) were injected at the base of the tail with
Freund's adjuvant. Twelve days later the responding animals were
randomised into experimental groups. Compounds of general formula
(I) were dosed either orally as a suspension in 1% methyl cellulose
or intrapentoieally in 0.2% carboxymethylcellulose from day 12 to
the end of the experiment on day 22. Hind paw volumes were measured
evey two days from day 12 onwards and X-rays were taken of the hind
feet on completion of the experiment. Results were expressed as the
percent increase of foot volume over day 12 values.
Example K
[1321] Mouse Ovarian Carcinoma Xenograft Model
[1322] Compounds of general formula (I) were evaluated in an
ovarian carcinoma xenograft model of cancer, based on that
described by B. Davies et al (1993), Cancer Research, 53, 2087-2091
This model, in brief, consists of inoculating female nu/nu mice
with 1.times.10.sup.9 OVCAR3-icr cells into the peritoneal cavity.
Compounds of general formula (I) are administered by the oral route
as a suspension in 1% methyl cellulose or intraperitoneally as a
suspension in phosphate buffered saline in 0.01% Tween-20. At the
conclusion of the experiment (4-5 weeks) the number of peritoneal
cells are counted and any solid tumour deposits weighed. In some
experiments tumour development is monitored by measurement of
tumour specific antigens.
Example L
[1323] Rat Mammary Carcinoma Model
[1324] Compounds of general formula (I) were evaluated in a HOSP.1
rat mammary carcinoma model of cancer (S. Eccles et al (1995),
Cancer Research, in press). This model consists of the intravenous
inoculation of female CBH/cbi rats with 2.times.10.sup.4 tumour
cells into the jugular vein. Compounds of general formula (I) are
administered by the oral route as a suspension in 1% methyl
cellulose or intraperitoneally as a suspension in phosphate
buffered saline +0.01% Tween-20. At the conclusion of the
experiment (4-5 weeks) the animals are killed, the lungs are
removed and individual tumours counted after 20 hours fixation in
Methacarn.
Example M
[1325] Mouse B16 Melanoma Model
[1326] The anti-metastatic potential of compounds of general
formula (I) is evaluated in a B16 melanoma model in C57BL/6. Mice
are injected intravenously with 2.times.10.sup.5 B16/F10 murine
tumour cells harvested from in vitro cultures. Inhibitors are
administered by the oral route as a suspension in 1% methyl
cellulose or intraperitoneally as a suspension in phosphate
buffered saline pH7.2+0.01% Tween-20. Mice are killed 14 days after
cell inoculation and the lungs removed and weighed prior to fixing
in Bouin's solution. The number of colonies present on the surface
of each set of lungs is then counted by eye.
* * * * *