U.S. patent application number 12/830763 was filed with the patent office on 2011-01-06 for metalloproteinase inhibitors.
Invention is credited to Anders Eriksson, Matti Lepisto, Michael Lundkvist, Magnus Munck Af Rosenchold, Pavol Zlatoidsky.
Application Number | 20110003853 12/830763 |
Document ID | / |
Family ID | 20283374 |
Filed Date | 2011-01-06 |
United States Patent
Application |
20110003853 |
Kind Code |
A1 |
Eriksson; Anders ; et
al. |
January 6, 2011 |
Metalloproteinase Inhibitors
Abstract
Compounds of the formula (I) wherein z is SO.sub.2 or SO, useful
as metalloproteinase inhibitors, especially as inhibitors of
MMP12.
Inventors: |
Eriksson; Anders; (Lund,
SE) ; Lepisto; Matti; (Lund, SE) ; Lundkvist;
Michael; (Lund, SE) ; Munck Af Rosenchold;
Magnus; (Lund, SE) ; Zlatoidsky; Pavol; (Lund,
SE) |
Correspondence
Address: |
FISH & RICHARDSON P.C.
P.O BOX 1022
MINNEAPOLIS
MN
55440-1022
US
|
Family ID: |
20283374 |
Appl. No.: |
12/830763 |
Filed: |
July 6, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12115785 |
May 6, 2008 |
7754750 |
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12830763 |
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10471900 |
Jan 14, 2004 |
7427631 |
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PCT/SE02/00472 |
Mar 13, 2002 |
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12115785 |
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Current U.S.
Class: |
514/318 ;
546/193 |
Current CPC
Class: |
A61P 9/10 20180101; A61P
19/00 20180101; A61P 25/28 20180101; A61P 29/00 20180101; A61P
15/00 20180101; C07D 401/12 20130101; A61P 7/00 20180101; A61P
43/00 20180101; C07D 409/14 20130101; C07D 233/76 20130101; A61P
1/00 20180101; A61P 9/04 20180101; C07D 405/14 20130101; A61P 1/02
20180101; A61P 3/10 20180101; A61P 9/00 20180101; C07D 405/12
20130101; A61P 11/06 20180101; A61P 7/02 20180101; A61P 19/08
20180101; C07D 403/04 20130101; A61P 11/02 20180101; A61P 35/00
20180101; A61P 17/02 20180101; A61P 19/02 20180101; A61P 35/04
20180101; A61P 11/00 20180101; A61P 19/04 20180101; A61P 17/06
20180101; A61P 37/08 20180101; A61P 27/02 20180101; C07D 401/14
20130101; C07D 403/06 20130101; A61P 19/06 20180101; A61P 13/12
20180101; C07D 403/12 20130101; A61P 17/00 20180101; A61P 17/04
20180101; A61P 1/16 20180101; A61P 25/02 20180101; C07D 417/14
20130101; C07D 471/04 20130101; A61P 19/10 20180101; A61P 25/00
20180101; A61P 1/04 20180101 |
Class at
Publication: |
514/318 ;
546/193 |
International
Class: |
A61K 31/4545 20060101
A61K031/4545; C07D 401/14 20060101 C07D401/14; A61P 3/10 20060101
A61P003/10; A61P 9/00 20060101 A61P009/00; A61P 11/00 20060101
A61P011/00; A61P 17/00 20060101 A61P017/00; A61P 19/02 20060101
A61P019/02; A61P 29/00 20060101 A61P029/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 15, 2001 |
SE |
0100902-6 |
Claims
1-16. (canceled)
17.
(5S)-5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl-
]-5-methylimidazolidine-2,4-dione or a pharmaceutically acceptable
salt thereof or an in vivo hydrolysable ester thereof.
18.
(5S)-5-[{4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-
-5-methylimidazolidine-2,4-dione or a pharmaceutically acceptable
salt thereof.
19.
(5S)-5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl-
]-5-methylimidazolidine-2,4-dione.
20.
(5S)-5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl-
]-5-methylimidazolidine-2,4-dione in the form of a pharmaceutically
acceptable salt.
21. A pharmaceutical composition which comprises a compound or a
pharmaceutically acceptable salt thereof or an in vivo hydrolysable
ester thereof, as claimed in claim 17, and a pharmaceutically
acceptable carrier.
22. A pharmaceutical composition which comprises a compound or a
pharmaceutically acceptable salt thereof, as claimed in claim 18,
and a pharmaceutically acceptable carrier.
23. A pharmaceutical composition which comprises a compound as
claimed in claim 19 and a pharmaceutically acceptable carrier.
24. A pharmaceutical composition which comprises a pharmaceutically
acceptable salt as claimed in claim 20, and a pharmaceutically
acceptable carrier.
Description
[0001] The present invention relates to compounds useful in the
inhibition of metalloproteinases and in particular to
pharmaceutical compositions comprising these, as well as their
use.
[0002] The compounds of this invention are inhibitors of one or
more metalloproteinase enzymes. Metalloproteinases are a
superfamily of proteinases (enzymes) whose numbers in recent years
have increased dramatically. Based on structural and functional
considerations these enzymes have been classified into families and
subfamilies as described in N. M. Hooper (1994) FEBS Letters
354:1-6. Examples of metalloproteinases include the matrix
metalloproteinases (MMPs) such as the collagenases (MMP1, MMP8,
MMP13), the gelatinases (MMP2, MMP9), the stromelysins (MMP3,
MMP10, MMP1), matrilysin (MMP7), metalloelastase (MMP12),
enamelysin (MMP19), the MT-MMPs (MMP14, MMP15, MMP16, MMP17); the
reprolysin or adamalysin or MDC family which includes the
secretases and sheddases such as TNF converting enzymes (ADAM10 and
TACE); the astacin family which include enzymes such as procollagen
processing proteinase (PCP); and other metalloproteinases such as
aggrecanase, the endothelin converting enzyme family and the
angiotensin converting enzyme family.
[0003] Metalloproteinases are believed to be important in a
plethora of physiological disease processes that involve tissue
remodelling such as embryonic development, bone formation and
uterine remodelling during menstruation. This is based on the
ability of the metalloproteinases to cleave a broad range of matrix
substrates such as collagen, proteoglycan and fibronectin.
Metalloproteinases are also believed to be important in the
processing, or secretion, of biological important cell mediators,
such as tumour necrosis factor (TNF); and the post translational
proteolysis processing, or shedding, of biologically important
membrane proteins, such as the low affinity IgE receptor CD23 (for
a more complete list see N. M. Hooper et al., (1997) Biochem J.
321:265-279).
[0004] Metalloproteinases have been associated with many diseases
or conditions. Inhibition of the activity of one or more
metalloproteinases may well be of benefit in these diseases or
conditions, for example: various inflammatory and allergic diseases
such as, inflammation of the joint (especially rheumatoid
arthritis, osteoarthritis and gout), inflammation of the
gastro-intestinal tract (especially inflammatory bowel disease,
ulcerative colitis and gastritis), inflammation of the skin
(especially psoriasis, eczema, dermatitis); in tumour metastasis or
invasion; in disease associated with uncontrolled degradation of
the extracellular matrix such as osteoarthritis; in bone resorptive
disease (such as osteoporosis and Paget's disease); in diseases
associated with aberrant angiogenesis; the enhanced collagen
remodelling associated with diabetes, periodontal disease (such as
gingivitis), corneal ulceration, ulceration of the skin,
post-operative conditions (such as colonic anastomosis) and dermal
wound healing; demyelinating diseases of the central and peripheral
nervous systems (such as multiple sclerosis); Alzheimer's disease;
extracellular matrix remodelling observed in cardiovascular
diseases such as restenosis and atherosclerosis; asthma; rhinitis;
and chronic obstructive pulmonary diseases (COPD).
[0005] MMP12, also known as macrophage elastase or metalloelastase,
was initially cloned in the mouse by Shapiro et al [1992, Journal
of Biological Chemistry 267: 4664] and in man by the same group in
1995. MMP-12 is preferentially expressed in activated macrophages,
and has been shown to be secreted from alveolar macrophages from
smokers [Shapiro et al, 1993, Journal of Biological Chemistry, 268:
23824] as well as in foam cells in atherosclerotic lesions
[Matsumoto et al, 1998, Am J Pathol 153: 109]. A mouse model of
COPD is based on challenge of mice with cigarette smoke for six
months, two cigarettes a day six days a week. Wildtype mice
developed pulmonary emphysema after this treatment. When MMP12
knock-out mice were tested in this model they developed no
significant emphysema, strongly indicating that MMP-12 is a key
enzyme in the COPD pathogenesis. The role of MMPs such as MMP12 in
COPD (emphysema and bronchitis) is discussed in Anderson and
Shinagawa, 1999, Current Opinion in Anti-inflammatory and
Immunomodulatory Investigational Drugs 1(1): 29-38. It was recently
discovered that smoking increases macrophage infiltration and
macrophage-derived MMP-12 expression in human carotid artery
plaques Kangavari [Matetzky S, Fishbein M C et al., Circulation
102:(18), 36-39 Suppl. S, Oct. 31, 2000].
[0006] MMP13, or collagenase 3, was initially cloned from a cDNA
library derived from a breast tumour [J. M. P. Freije et al. (1994)
Journal of Biological Chemistry 269 (24):16766-16773]. PCR-RNA
analysis of RNAs from a wide range of tissues indicated that MMP13
expression was limited to breast carcinomas as it was not found in
breast fibroadenomas, normal or resting mammary gland, placenta,
liver, ovary, uterus, prostate or parotid gland or in breast cancer
cell lines (T47-D, MCF-7 and ZR75-1). Subsequent to this
observation MMP13 has been detected in transformed epidermal
keratinocytes [N. Johansson et al., (1997) Cell Growth Differ.
8(2):243-250], squamous cell carcinomas [N. Johansson et al.,
(1997) Am. J. Pathol. 151(2):499-508] and epidermal tumours [K.
Airola et al., (1997) J. Invest. Dermatol. 109(2):225-231]. These
results are suggestive that MMP13 is secreted by transformed
epithelial cells and may be involved in the extracellular matrix
degradation and cell-matrix interaction associated with metastasis
especially as observed in invasive breast cancer lesions and in
malignant epithelia growth in skin carcinogenesis.
[0007] Recent published data implies that MMP13 plays a role in the
turnover of other connective tissues. For instance, consistent with
MMP13's substrate specificity and preference for degrading type II
collagen [P. G. Mitchell et al., (1996) J. Clin. Invest.
97(3):761-768; V. Knauper et al., (1996) The Biochemical Journal
271:1544-1550], MMP13 has been hypothesised to serve a role during
primary ossification and skeletal remodelling [M. Stahle-Backdahl
et al., (1997) Lab. Invest. 76(5):717-728; N. Johansson et al.,
(1997) Dev. Dyn. 208(3):387-397], in destructive joint diseases
such as rheumatoid and osteo-arthritis [D. Wernicke et al., (1996)
J. Rheumatol. 23:590-595; P. G. Mitchell et al., (1996) J. Clin.
Invest. 97(3):761-768; O. Lindy et al., (1997) Arthritis Rheum
40(8):1391-1399]; and during the aseptic loosening of hip
replacements [S. Imai et al., (1998) J. Bone Joint Surg. Br.
80(4):701-710]. MMP13 has also been implicated in chronic adult
periodontitis as it has been localised to the epithelium of
chronically inflamed mucosa human gingival tissue [V. J. Uitto et
al., (1998) Am. J. Pathol 152(6):1489-1499] and in remodelling of
the collagenous matrix in chronic wounds [M. Vaalamo et al., (1997)
J. Invest. Dermatol. 109(1):96-101].
[0008] MMP9 (Gelatinase B; 92 kDa Type IV Collagenase; 92 kDa
Gelatinase) is a secreted protein which was first purified, then
cloned and sequenced, in 1989 [S. M. Wilhelm et al (1989) J. Biol.
Chem. 264(29): 17213-17221; published erratum in J. Biol. Chem.
(1990) 265(36): 22570]. A recent review of MMP9 provides an
excellent source for detailed information and references on this
protease: T. H. Vu & Z. Werb (1998) (In: Matrix
Metalloproteinases. 1998. Edited by W. C. Parks & R. P. Mecham.
pp 115-148. Academic Press. ISBN 0-12-545090-7). The following
points are drawn from that review by T. H. Vu & Z. Werb
(1998).
[0009] The expression of MMP9 is restricted normally to a few cell
types, including trophoblasts, osteoclasts, neutrophils and
macrophages. However, it's expression can be induced in these same
cells and in other cell types by several mediators, including
exposure of the cells to growth factors or cytokines. These are the
same mediators often implicated in initiating an inflammatory
response. As with other secreted MMPs, MMP9 is released as an
inactive Pro-enzyme which is subsequently cleaved to form the
enzymatically active enzyme. The proteases required for this
activation in vivo are not known. The balance of active MMP9 versus
inactive enzyme is further regulated in vivo by interaction with
TIMP-1 (Tissue Inhibitor of Metalloproteinases-1), a
naturally-occurring protein. TIMP-1 binds to the C-terminal region
of MMP9, leading to inhibition of the catalytic domain of MMP9. The
balance of induced expression of ProMMP9, cleavage of Pro- to
active MMP9 and the presence of TIMP-1 combine to determine the
amount of catalytically active MMP9 which is present at a local
site. Proteolytically active MMP9 attacks substrates which include
gelatin, elastin, and native Type IV and Type V collagens; it has
no activity against native Type I collagen, proteoglycans or
laminins.
[0010] There has been a growing body of data implicating roles for
MMP9 in various physiological and pathological processes.
Physiological roles include the invasion of embryonic trophoblasts
through the uterine epithelium in the early stages of embryonic
implantation; some role in the growth and development of bones; and
migration of inflammatory cells from the vasculature into
tissues.
[0011] MMP-9 release, measured using enzyme immunoassay, was
significantly enhanced in fluids and in AM supernatants from
untreated asthmatics compared with those from other populations
[Am. J. Resp. Cell & Mol. Biol., November 1997, 17(5):583-591].
Also, increased MMP9 expression has been observed in certain other
pathological conditions, thereby implicating MMP9 in disease
processes such as COPD, arthritis, tumour metastasis, Alzheimer's,
Multiple Sclerosis, and plaque rupture in atherosclerosis leading
to acute coronary conditions such as Myocardial Infarction.
[0012] MMP-8 (collagenase-2, neutrophil collagenase) is a 53 kD
enzyme of the matrix metalloproteinase family that is
preferentially expressed in neutrophils. Later studies indicate
MMP-8 is expressed also in other cells, such as osteoarthritic
chondrocytes [Shlopov et al, 1997, Arthritis Rheum, 40:2065]. MMPs
produced by neutrophils can cause tissue remodelling, and hence
blocking MMP-8 should have a positive effect in fibrotic diseases
of for instance the lung, and in degradative diseases like
pulmonary emphysema. MMP-8 was also found to be up-regulated in
osteoarthritis, indicating that blocking MMP-8 many also be
beneficial in this disease.
[0013] MMP-3 (stromelysin-1) is a 53 kD enzyme of the matrix
metalloproteinase enzyme family. MMP-3 activity has been
demonstrated in fibroblasts isolated from inflamed gingiva [Uitto
V. J. et al, 1981, J. Periodontal Res., 16:417-424], and enzyme
levels have been correlated to the severity of gum disease [Overall
C. M. et al, 1987, J. Periodontal Res., 22:81-88]. MMP-3 is also
produced by basal keratinocytes in a variety of chronic ulcers
[Saarialho-Kere U. K. et al, 1994, J. Clin. Invest., 94:79-88].
MMP-3 mRNA and protein were detected in basal keratinocytes
adjacent to but distal from the wound edge in what probably
represents the sites of proliferating epidermis. MMP-3 may thus
prevent the epidermis from healing. Several investigators have
demonstrated consistent elevation of MMP-3 in synovial fluids from
rheumatoid and osteoarthritis patients as compared to controls
[Walakovits L. A. et al, 1992, Arthritis Rheum., 35:35-42;
Zafarullah M. et al, 1993, J. Rheumatol., 20:693-697]. These
studies provided the basis for the belief that an inhibitor of
MMP-3 will treat diseases involving disruption of extracellular
matrix resulting in inflammation due to lymphocytic infiltration,
or loss of structural integrity necessary for organ function.
[0014] A number of metalloproteinase inhibitors are known (see for
example the review of MMP inhibitors by Beckett R. P. and Whittaker
M., 1998, Exp. Opin. Ther. Patents, 8(3):259-282]. Different
classes of compounds may have different degrees of potency and
selectivity for inhibiting various metalloproteinases.
[0015] Whittaker M. et al (1999, Chemical Reviews 99(9):2735-2776]
review a wide range of known MMP inhibitor compounds. They state
that an effective MMP inhibitor requires a zinc binding group or
ZBG (functional group capable of chelating the active site zinc(II)
ion), at least one functional group which provides a hydrogen bond
interaction with the enzyme backbone, and one or more side chains
which undergo effective van der Waals interactions with the enzyme
subsites. Zinc binding groups in known MMP inhibitors include
carboxylic acid groups, hydroxamic acid groups, sulfhydryl or
mercapto, etc. For example, Whittaker M. et al discuss the
following MMP inhibitors:
##STR00001##
The above compound entered clinical development. It has a
mercaptoacyl zinc binding group, a trimethylhydantoinylethyl group
at the P1 position and a leucinyl-tert-butyllglycinyl backbone.
##STR00002##
The above compound has a mercaptoacyl zinc binding group and an
imide group at the P1 position.
##STR00003##
The above compound was developed for the treatment of arthritis. It
has a non-peptidic succinyl hydroxamate zinc binding group and a
trimethylhydantoinylethyl group at the P1 position.
##STR00004##
The above compound is a phthalimido derivative that inhibits
collagenases. It has a non-peptidic succinyl hydroxamate zinc
binding group and a cyclic imide group at P1. Whittaker M. et al
also discuss other MMP inhibitors having a P1 cyclic imido group
and various zinc binding groups (succinyl hydroxamate, carboxylic
acid, thiol group, phosphorous-based group).
##STR00005##
The above compounds appear to be good inhibitors of MMP8 and MMP9
(PCT patent applications WO9858925, WO9858915). They have a
pyrimidin-2,3,4-trione zinc binding group.
[0016] The following compounds are not known as MMP
inhibitors:--
Lora-Tamayo, M et al (1968, An. Quim 64(6): 591-606) describe
synthesis of the following compounds as a potential anti-cancer
agent:
##STR00006##
Czech patent numbers 151744 (19731119) and 152617 (1974022)
describe the synthesis and the anticonvulsive activity of the
following compounds:
##STR00007##
R=4-NO2, 4-OMe, 2-NO2,
[0017] U.S. Pat. No. 3,529,019 (19700915) describes the following
compounds used as intermediates:
##STR00008##
PCT patent application number WO 00/09103 describes compounds
useful for treating a vision disorder, including the following
(compounds 81 and 83, Table A, page 47):
##STR00009##
[0018] We have now discovered a new class of compounds that are
inhibitors of metalloproteinases and are of particular interest in
inhibiting MMPs such as MMP-12. The compounds are metalloproteinase
inhibitors having a metal binding group that is not found in known
metalloproteinase inhibitors. In particular, we have discovered
compounds that are potent MMP12 inhibitors and have desirable
activity profiles. The compounds of this invention have beneficial
potency, selectivity and/or pharmacokinetic properties.
[0019] The metalloproteinase inhibitor compounds of the invention
comprise a metal binding group and one or more other functional
groups or side chains characterised in that the metal binding group
has the formula (k)
##STR00010##
wherein X is selected from NR1, O, S;
[0020] Y1 and Y2 are independently selected from O, S;
[0021] R1 is selected from H, alkyl, haloalkyl;
[0022] Any alkyl groups outlined above may be straight chain or
branched; any alkyl group outlined above is preferably (C1-7)alkyl
and most preferably (C1-6)alkyl.
[0023] A metalloproteinase inhibitor compound is a compound that
inhibits the activity of a metalloproteinase enzyme (for example,
an MMP). By way of non-limiting example the inhibitor compound may
show IC50s in vitro in the range of 0.1-10000 nanomolar, preferably
0.1-1000 nanomolar.
[0024] A metal binding group is a functional group capable of
binding the metal ion within the active site of the enzyme. For
example, the metal binding group will be a zinc binding group in
MMP inhibitors, binding the active site zinc(II) ion. The metal
binding group of formula (k) is based on a five-membered ring
structure and is preferably a hydantoin group, most preferably a -5
substituted 1-H,3-H-imidazolidine-2,4-dione.
[0025] In a first aspect of the invention we now provide compounds
of the formula I
##STR00011##
[0026] wherein
[0027] X is selected from NR1, O, S;
[0028] Y1 and Y2 are independently selected from O, S;
[0029] Z is selected from SO, SO.sub.2;
[0030] m is 1 or 2;
[0031] A is selected from a direct bond, (C1-6)alkyl,
(C1-6)haloalkyl, or (C1-6)heteroalkyl containing a hetero group
selected from N, O, S, SO, SO2 or containing two hetero groups
selected from N, O, S, SO, SO2 and separated by at least two carbon
atoms;
[0032] R1 is selected from H, (C1-3)alkyl, haloalkyl;
[0033] Each R2 and R3 is independently selected from H, halogen
(preferably fluorine), alkyl, heteroalkyl, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkyl-heteroaryl,
heteroalkyl-aryl, heteroalkyl-heteroaryl, aryl-alkyl,
aryl-heteroalkyl, heteroaryl-alkyl, heteroaryl-heteroalkyl,
aryl-aryl, aryl-heteroaryl, heteroaryl-aryl, heteroaryl-heteroaryl,
cycloalkyl-alkyl, heterocycloalkyl-alkyl, alkyl-cycloalkyl,
alkyl-heterocycloalkyl;
[0034] Each R4 is independently selected from H, halogen
(preferably fluorine), (C1-3)alkyl or haloalkyl;
[0035] Each of the R2 and R3 radicals may be independently
optionally substituted with one or more (preferably one) groups
selected from alkyl, heteroalkyl, aryl, heteroaryl, halo,
haloalkyl, hydroxy, alkoxy, haloalkoxy, thiol, alkylthiol,
arylthiol, alkylsulfon, haloalkylsulfon, arylsulfon, aminosulfon,
N-alkylaminosulfon, N,N-dialkylaminosulfon, arylaminosulfon, amino,
N-alkylamino, N,N-dialkylamino, amido, N-alkylamido,
N,N-dialkylamido, cyano, sulfonamino, alkylsulfonamino,
arylsulfonamino, amidino, N-aminosulfon-amidino, guanidino,
N-cyano-guanidino, thioguanidino, 2-nitro-ethene-1,1-diamin,
carboxy, alkyl-carboxy, nitro, carbamate;
[0036] Optionally R2 and R3 may join to form a ring comprising up
to 7 ring atoms, or R2 and R4 may join to form a ring comprising up
to 7 ring atoms, or R3 and R4 may join to form a ring comprising up
to 7 ring atoms;
[0037] R5 is a monocyclic, bicyclic or tricyclic group comprising
one, two or three ring structures each of up to 7 ring atoms
independently selected from cycloalkyl, aryl, heterocycloalkyl or
heteroaryl, with each ring structure being independently optionally
substituted by one or more substituents independently selected from
halogen, hydroxy, alkyl, alkoxy, haloalkoxy, amino, N-alkylamino,
N,N-dialkylamino, alkylsulfonamino, alkylcarboxyamino, cyano,
nitro, thiol, alkylthiol, alkylsulfonyl, haloalkylsulfonyl,
alkylaminosulfonyl, carboxylate, alkylcarboxylate, aminocarboxy,
N-alkylamino-carboxy, N,N-dialkylamino-carboxy, wherein any alkyl
radical within any substituent may itself be optionally substituted
with one or more groups selected from halogen, hydroxy, alkoxy,
haloalkoxy, amino, N-alkylamino, N,N-dialkylamino,
N-alkylsulfonamino, N-alkylcarboxyamino, cyano, nitro, thiol,
alkylthiol, alkylsulfonyl, N-alkylaminosulfonyl, carboxylate,
alkylcarboxy, aminocarboxy, N-alkylaminocarboxy,
N,N-dialkylaminocarboxy, carbamate;
[0038] when R5 is a bicyclic or tricyclic group, each ring
structure is joined to the next ring structure by a direct bond, by
--O--, by (C1-6)alkyl, by (C1-6)haloalkyl, by (C1-6)heteroalkyl, by
(C1-6)alkenyl, by (C1-6)alkynyl, by sulfone, by CO, by NCO, by CON,
by NH, by S, by C(OH) or is fused to the next ring structure;
[0039] Any heteroalkyl group outlined above is a hetero
atom-substituted alkyl containing one or more hetero groups
independently selected from N, O, S, SO, SO2, (a hetero group being
a hetero atom or group of atoms);
[0040] Any heterocycloalkyl or heteroaryl group outlined above
contains one or more hetero groups independently selected from N,
O, S, SO, SO2;
[0041] Any alkyl, alkenyl or alkynyl groups outlined above may be
straight chain or branched; unless otherwise stated, any alkyl
group outlined above is preferably (C1-7)alkyl and most preferably
(C1-6)alkyl.
[0042] Preferred compounds of the formula I are those wherein any
one or more of the following apply:
[0043] X is NR1;
[0044] Z is SO.sub.2 or SO; especially Z is SO.sub.2;
[0045] At least one of Y1 and Y2 is O; especially both Y1 and Y2
are O;
[0046] m is 1; [0047] R1 is H, (C1-3) alkyl, (C1-3) haloalkyl;
especially R1 is H, (C1-3)alkyl; most especially R1 is H;
[0048] R2 is H, alkyl, hydroxyalkyl, alkoxyalkyl, aryloxy alkyl,
aminoalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, arylalkyl,
alkylaryl, alkyl-heteroaryl, heteroalkyl, heterocycloalkyl-alkyl,
alkyl-heterocycloalkyl, heteroaryl-alkyl, heteroalkyl-aryl;
especially R2 is alkyl, aminoalkyl, alkyl-heteroaryl,
alkyl-heterocycloalkyl or heteroaryl-alkyl.
[0049] R3 and/or R4 is H;
[0050] R3 and/or R4 is methyl;
[0051] R5 comprises one, two or three optionally substituted aryl
or heteroaryl 5 or 6 membered rings;
[0052] R5 is a bicyclic or tricyclic group comprising two or three
optionally substituted ring structures.
[0053] Particularly preferred compounds of formula I are those
wherein R5 is a bicyclic or tricyclic group comprising two or three
optionally substituted ring structures.
[0054] The invention further provides compounds of the formula
II
##STR00012##
[0055] wherein
[0056] each of G1, G2 and G4 is a monocyclic ring structure
comprising each of up to 7 ring atoms independently selected from
cycloalkyl, aryl, heterocycloalkyl or heteroaryl, with each ring
structure being independently optionally substituted by one or two
substituents independently selected from halogen, hydroxy,
haloalkoxy, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro,
alkyl, alkoxy, alkyl sulfone, haloalkyl sulfone, alkylcarbamate,
alylamide, wherein any alkyl radical within any substituent may
itself be optionally substituted with one or more groups selected
from halogen, hydroxy, amino, N-alkylamino, N,N-dialkylamino,
cyano, nitro, alkoxy, haloalkoxy, aryloxy, heteroaryloxy,
carbamate;
[0057] Z is SO.sub.2;
[0058] Each of B and F is independently selected from a direct
bond, O, (C1-6)alkyl, (C1-6)heteroalkyl, alkynyl, CO, NCO, CON, NH,
S;
[0059] R2 is selected from H, alkyl, hydroxyalkyl, alkoxyalkyl,
aryloxy alkyl, aminoalkyl, (N-alkylamino)alkyl,
(N,N-dialkylamino)alkyl, amidoalkyl, thioalkyl cycloalkyl-alkyl,
alkyl-cycloalkyl, arylalkyl, alkylaryl, alkyl-heteroaryl,
heteroalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl,
heteroaryl-alkyl, heteroalkyl-aryl;
[0060] R3 and R4 are independently selected from H or
(C1-3)alkyl;
[0061] Optionally R2 and R3 may join to form a ring comprising up
to 7 ring atoms, or R2 and R4 may join to form a ring comprising up
to 7 ring atoms, or P3 and R4 may join to form a ring comprising up
to 7 ring atoms;
[0062] Any heteroalkyl group outlined above is a hetero
atom-substituted alkyl containing one or more hetero groups
independently selected from N, O, S, SO, SO2, (a hetero group being
a hetero atom or group of atoms);
[0063] Any heterocycloalkyl or heteroaryl group outlined above
contains one or more hetero groups independently selected from N,
O, S, SO, SO2;
[0064] Any alkyl alkenyl or alkynyl groups outlined above may be
straight chain or branched; unless otherwise stated, any alkyl
group outlined above is preferably (C1-7)alkyl and most preferably
(C1-6)alkyl.
[0065] Preferred compounds of the formula II include those wherein
R2 is alkyl, aminoalkyl, alkyl-heteroaryl, alkyl-heterocycloalkyl
or heteroaryl-alkyl.
[0066] The invention further provides compounds of the formula
IIa
##STR00013##
[0067] wherein
[0068] each of G1 and G2 is a monocyclic ring structure comprising
each of up to 7 ring atoms independently selected from cycloalkyl,
aryl, heterocycloalkyl or heteroaryl, with each ring structure
being independently optionally substituted by one or two
substituents independently selected from halogen, hydroxy,
haloalkoxy, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro,
alkyl, alkoxy, alkyl sulfone, haloalkyl sulfone, alkylcarbamate,
alkylamide, wherein any alkyl radical within any substituent may
itself be optionally substituted with one or more groups selected
from halogen, hydroxy, amino, N-alkylamino, N,N-dialkylamino,
cyano, nitro, alkoxy, haloalkoxy, aryloxy, heteroaryloxy,
carbamate;
[0069] Z is SO.sub.2;
[0070] B is selected from a direct bond, O, (C1-6)alkyl,
(C1-6)heteroalkyl, CO, NCO, CON, NH, S, akynyl;
[0071] R2 is selected from H, (C1-6)alkyl, haloalkyl, hydroxyalkyl,
alkoxyalkyl, aminoalkyl, (N-alkylamino)alkyl,
(N,N-dialkylamino)alkyl, amidoalkyl, thioalkyl, or R2 is a group of
formula III
##STR00014##
[0072] C and D are independently selected from a direct bond, H,
(C1-C6)alkyl, (C1-C6)haloalkyl, or (C1-C6)heteroalkyl containing
one or two hetero atoms selected from N, O or S such that when two
hetero atoms are present they are separated by at least two carbon
atoms;
[0073] G3 is a monocyclic ring structure comprising up to 7 ring
atoms independently selected from cycloalkyl, aryl,
heterocycloalkyl or heteroaryl, optionally substituted by one or
two substituents independently selected from halogen, hydroxy,
amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkyl, alkoxy,
alkyl sulfone, haloalkyl sulfone, or alkyl substituted with one or
more groups selected from halogen, hydroxy, amino, N-alkylamino,
N,N-dialkylamino, cyano, nitro, alkoxy, haloalkoxy;
[0074] Optionally R2 is substituted with halo, haloalkyl, hydroxy,
alkoxy, haloalkoxy, amino, aminoalkyl, N-alkylamino,
N,N-dialkylamino, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl,
alkylsulfone, aminosulfone, N-alkylamino-sulfone,
N,N-dialkylamino-sulfone, amido, N-alkylamido, N,N-dialkylamido,
cyano, sulfonamino, alkyl-sulfonamino, amidino,
N-aminosulfone-amidino, guanidino, N-cyano-guanidino,
thioguanidino, 2-nitroguanidino, carboxy, alkylcarboxy,
carbamate;
[0075] R3 and R4 are independently selected from H or
(C1-3)alkyl;
[0076] Optionally R2 and R3 may join to form a ring comprising up
to 7 ring atoms, or R2 and R4 may join to form a ring comprising up
to 7 ring atoms, or R3 and R4 may join to form a ring comprising up
to 7 ring atoms;
[0077] Any heteroalkyl group outlined above is a hetero
atom-substituted alkyl containing one or more hetero groups
independently selected from N, O, S, SO, SO2, (a hetero group being
a hetero atom or group of atoms);
[0078] Any heterocycloalkyl or heteroaryl group outlined above
contains one or more hetero groups independently selected from N,
O, S, SO, SO2;
[0079] Any alkyl, alkenyl or alkynyl groups outlined above may be
straight chain or branched; unless otherwise stated, any alkyl
group outlined above is preferably (C1-7)alkyl and most preferably
(C1-6)alkyl.
[0080] Preferred compounds of the formula IIa are those wherein one
or more of the following apply:
[0081] B is selected from a direct bond, O, CO, S, alkynyl;
especially B is a direct bond, O, S, or alkynyl;
[0082] R2 is selected from H, (C1-6)alkyl, aryl-(C1-6)alkyl or
heteroaryl-(C1-6)alkyl optionally substituted with halo, haloalkyl,
hydroxy, alkoxy, haloalkoxy, amino, aminoalkyl, N-alkylamino,
N,N-dialkylamino, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl,
alkylsulfone, aminosulfone, N-alkylamino-sulfone,
N,N-dialkylamino-sulfone, amido, N-alkylamido, N,N-dialkylamido,
carbamate, cyano, sulfonamino, alkyl-sulfonamino, amidino,
N-aminosulfone-amidino, guanidino, N-cyano-guanidino,
thioguanidino, 2-nitroguanidino, 2-nitro-ethene-1,1-diamino,
carboxy, alkylcarboxy, carbamate;
[0083] Each of R3 and R4 is H;
[0084] G2 is a nitrogen containing six-membered ring;
[0085] G1 is para substituted.
[0086] Particularly preferred compounds of formula IIa are those
wherein each of R3 and R4 is H.
[0087] For example, particular compounds of the invention include
compounds of formula IIa wherein B is a direct bond, O, S or
alkynyl; and R2 is selected from H, (C1-6)alkyl, aryl-(C1-6)alkyl
or heteroaryl-(C1-6)alkyl optionally substituted with cyckloalkyl,
heterocycloalkyl, halo, haloalkyl, hydroxy, alkoxy, aryloxy,
haloalkoxy, amino, aminoalkyl, N-alkylamino, N,N-dialkylamino,
(N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, alkylsulfonyl,
aminosulfonyl, N-alkylamino-sulfonyl, N,N-dialkylamino-sulfonyl,
amido, N-alkylamido, N,N-dialkylamido, cyano, sulfonamino,
alkyl-sulfonamino, amidino, N-aminosulfone-amidino, guanidino,
N-cyano-guanidino, thioguanidino, 2-nitroguanidino, carbamate,
carboxy, alkylcarboxy; and each of R3 and R4 is H.
[0088] Particularly preferred compounds of the invention are those
of Formula IIb:
##STR00015##
wherein G2 is optionally substituted piperidine or piperazine, and
G1, B, and R2 are as described for Formula IIa. In a compound of
Formula IIb, preferably G2 is unsubstituted and G1 is optionally
substituted, preferably G1 is para substituted.
[0089] Suitable values for R2 include the following:
##STR00016## ##STR00017##
[0090] Suitable values for R5 include the following:
##STR00018##
[0091] It will be appreciated that the particular substituents and
number of substituents in compounds of the invention are selected
so as to avoid sterically undesirable combinations.
[0092] Each exemplified compound represents a particular and
independent aspect of the invention.
[0093] Where optically active centres exist in the compounds of the
invention, we disclose all individual optically active forms and
combinations of these as individual specific embodiments of the
invention, as well as their corresponding racemates. Racemates may
be separated into individual optically active forms using known
procedures (cf. Advanced Organic Chemistry: 3rd Edition: author J
March, p 104-107) including for example the formation of
diastereomeric derivatives having convenient optically active
auxiliary species followed by separation and then cleavage of the
auxiliary species.
[0094] It will be appreciated that the compounds according to the
invention may contain one or more asymmetrically substituted carbon
atoms. The presence of one or more of these asymmetric centres
(chiral centres) in a compound of the invention 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.
[0095] Where tautomers exist in the compounds of the invention, we
disclose all individual tautomeric forms and combinations of these
as individual specific embodiments of the invention.
[0096] As previously outlined the compounds of the invention are
metalloproteinase inhibitors, in particular they are inhibitors of
MMP12. Each of the above indications for the compounds of the
invention represents an independent and particular embodiment of
the invention.
[0097] Certain compounds of the invention are of particular use as
inhibitors of MMP13 and/or MMP9 and/or MMP8 and/or MMP3.
[0098] Compounds of the invention show a favourable selectivity
profile. Whilst we do not wish to be bound by theoretical
considerations, the compounds of the invention are believed to show
selective inhibition for any one of the above indications relative
to any MMP1 inhibitory activity, by way of non-limiting example
they may show 100-1000 fold selectivity over any MMP1 inhibitory
activity.
[0099] The compounds of the invention may be provided as
pharmaceutically acceptable salts. These include acid addition
salts such as hydrochloride, hydrobromide, citrate and maleate
salts and salts formed with phosphoric and sulphuric acid. In
another aspect suitable salts are base salts such as an alkali
metal salt for example sodium or potassium, an alkaline earth metal
salt for example calcium or magnesium, or organic amine salt for
example triethylamine.
[0100] They may also be provided as in vivo hydrolysable esters.
These are pharmaceutically acceptable esters that hydrolyse in the
human body to produce the parent compound. Such esters can be
identified by administering, for example intravenously to a test
animal, the compound under test and subsequently examining the test
animal's body fluids. Suitable in vivo hydrolysable esters for
carboxy include methoxymethyl and for hydroxy include formyl and
acetyl, especially acetyl.
[0101] In order to use a metalloproteinase inhibitor compound of
the invention (a compound of the formula I or II, IIa or IIb) or a
pharmaceutically acceptable salt or in vivo hydrolysable ester
thereof for the therapeutic treatment (including prophylactic
treatment) of mammals including humans, it is normally formulated
in accordance with standard is pharmaceutical practice as a
pharmaceutical composition.
[0102] Therefore in another aspect the present invention provides a
pharmaceutical composition which comprises a compound of the
invention (a compound of the formula I or II, IIa or IIb) or a
pharmaceutically acceptable salt or an in vivo hydrolysable ester
and pharmaceutically acceptable carrier.
[0103] The pharmaceutical compositions of this invention may be
administered in standard manner for the disease or condition that
it is desired to treat, for example by oral, topical, parenteral,
buccal, nasal, vaginal or rectal administration or by inhalation.
For these purposes the compounds of this invention may be
formulated by means known in the art into the form of, for example,
tablets, capsules, aqueous or oily solutions, suspensions,
emulsions, creams, ointments, gels, nasal sprays, suppositories,
finely divided powders or aerosols for inhalation, and for
parenteral use (including intravenous, intramuscular or infusion)
sterile aqueous or oily solutions or suspensions or sterile
emulsions.
[0104] In addition to the compounds of the present invention the
pharmaceutical composition of this invention may also contain, or
be co-administered (simultaneously or sequentially) with, one or
more pharmacological agents of value in treating one or more
diseases or conditions referred to hereinabove.
[0105] The pharmaceutical compositions of this invention will
normally be administered to humans so that, for example, a daily
dose of 0.5 to 75 mg/kg body weight (and preferably of 0.5 to 30
mg/kg body weight) is received. This daily dose may be given in
divided doses as necessary, the precise amount of the compound
received and the route of administration depending on the weight,
age and sex of the patient being treated and on the particular
disease or condition being treated according to principles known in
the art.
[0106] Typically unit dosage forms will contain about 1 mg to 500
mg of a compound of this invention.
[0107] Therefore in a further aspect, we provide a compound of the
formula I or a pharmaceutically acceptable salt or in vivo
hydrolysable ester thereof for use in a method of therapeutic
treatment of the human or animal body or for use as a therapeutic
agent. We disclose use in the treatment of a disease or condition
mediated by one or more metalloproteinase enzymes. In particular we
disclose use in the treatment of a disease or condition mediated by
MMP12 and/or MMP13 and/or MMP9 and/or MMP8 and/or MMP3; especially
use in the treatment of a disease or condition mediated by MMP12 or
MMP9; most especially use in the treatment of a disease or
condition mediated by MMP12.
[0108] In particular we provide a compound of the formula II, IIa
or IIb or a pharmaceutically acceptable salt or in vivo
hydrolysable ester thereof for use in a method of therapeutic
treatment of the human or animal body or for use as a therapeutic
agent (such as use in the treatment of a disease or condition
mediated by MMP12 and/or MMP13 and/or MMP9 and/or MMP8 and/or MMP3;
especially MMP12 or MMP9; most especially MMP12).
[0109] In yet a further aspect we provide a method of treating a
metalloproteinase mediated disease or condition which comprises
administering to a warm-blooded animal a therapeutically effective
amount of a compound of the formula I or a pharmaceutically
acceptable salt or in vivo hydrolysable ester thereof. We also
disclose the use of a compound of the formula I or a
pharmaceutically acceptable salt or in vivo hydrolysable precursor
thereof in the preparation of a medicament for use in the treatment
of a disease or condition mediated by one or more metalloproteinase
enzymes.
[0110] For example we provide a method of treating a
metalloproteinase mediated disease or condition which comprises
administering to a warm-blooded animal a therapeutically effective
amount of a compound of the formula II, IIa or IIb (or a
pharmaceutically acceptable salt or in vivo hydrolysable ester
thereof). We also provide the use of a compound of the formula II,
IIa or IIb (or a pharmaceutically acceptable salt or in vivo
hydrolysable precursor thereof) in the preparation of a medicament
for use in the treatment of a disease or condition mediated by one
or more metalloproteinase enzymes.
[0111] Metalloproteinase mediated diseases or conditions include
asthma, rhinitis, chronic obstructive pulmonary diseases (COPD),
arthritis (such as rheumatoid arthritis and osteoarthritis),
atherosclerosis and restenosis, cancer, invasion and metastasis,
diseases involving tissue destruction, loosening of hip joint
replacements, periodontal disease, fibrotic disease, infarction and
heart disease, liver and renal fibrosis, endometriosis, diseases
related to the weakening of the extracellular matrix, heart
failure, aortic aneurysms, CNS related diseases such as Alzheimer's
disease and Multiple Sclerosis (MS), hematological disorders.
Preparation of the Compounds of the Invention
[0112] In another aspect the present invention provides a process
for preparing a compound of the formula I or II, IIa, IIb or a
pharmaceutically acceptable salt or in vivo hydrolysable ester
thereof, as described in (a) to (d) below. It will be appreciated
that many of the relevant starting materials are commercially or
otherwise available or may be synthesised by known methods or may
be found in the scientific literature.
[0113] (a) Compounds of formula I in which Y1 and Y 2 are each O, Z
is SO.sub.2, R2 is as defined in formula I, A is a direct bond and
R5 comprises a nitrogen directly attached to Z, or A is (C1-6)
N-alkyl, may be prepared by reacting a compound of the formula IV
in which R5 is defined as in formula I with the known compounds of
the formula V in which X and m are as defined in formula I:
##STR00019##
The reaction is preferably performed in suitable solvent optionally
in the presence of base for 1 to 24 h at ambient to reflux
temperature. Preferably, solvents such as pyridine,
dimethylformamide, tetrahydrofurane, acetonitrile or dichlorometane
are used with bases like triethylamine, N-methylmorpholine,
pyridine or alkali metal carbonates at ambient temperature for 2-16
h reaction time, or until end of reaction is achieved as detected
by chromatographic or spectroscopic methods. Reactions of sulfonyl
chlorides of formula V with various primary and secondary amines
are previously described in the literature, and the variations of
the conditions will be evident for those skilled in the art.
[0114] Synthesis of compounds of formula V is described in the
literature and can be prepared from e.g. cystein or homocystein
(Mosher, J.: J. Org. Chem. 23, 1257(1958). Sulfonylchlorides of
formula V, in which m=1, X=NR1 (R1=H) and R2 is as described in
formula I, are conveniently prepared by oxidative chlorination of
compounds of formula Va, in which R2 is as described in formula I
(Griffith, O.: J. Biol. Chem., 1983, 258, 3, 1591).
##STR00020##
[0115] (b) Compounds of formula I in which Y1 and Y2 are each O, Z
is S, and X and R5 are as described in formula I may be prepared by
reacting a compound of formula VI in which K is a leaving group
(e.g. chloride, or sulfonate ester) and R5 as described in formula
I,
##STR00021##
with a compound of formula VII, in which G is a sulfhydryl (SH), X
and m as described in formula I. The reaction is preferably
performed in the presence of base such as diethyl isopropyl amine
or cesium carbonate and in the presence of a suitable solvent e.g.
DMF.
[0116] Alternatively, the compounds under process (b) may be
prepared in the same manner as in process (b), by reacting the
compounds of formula VI and VII, but in which K in compound VI is
the sulfhydryl (SH) or a hydroxyl group and G in formula VII
represents a leaving group.
[0117] (c) Compounds of the formula I in which Y1 and Y2 are each
O, Z is SO2 or S(O), and X, A, and R5 are as described in formula
I, may be prepared by oxidizing the final products described under
process (b) and in which Z is S, with oxidizing agents like
peroxide reagents, preferably m-chloroperbenzoic acid or oxone.
[0118] (d) Compounds of the formula I in which Y1 and Y2 are each
O, X is NR1 (R1=H), m is 1, and R2, R3, R4, R5 are as described in
formula I may be prepared by reacting a compound of formula XI in
which R2, R3, R4, R5 and A are as described in formula I,
##STR00022##
with ammonium and cyanide salts in protic solvents, preferably in
the presence of excess ammonium carbonate and potassium cyanide in
ethanol in a sealed vessel at 40-80 C for 4-24 hours.
[0119] The ketones of formula XI are conveniently prepared by
treating sulfonamides of formula XII in which R3 is H and R5 is as
described in formula I, with excess strong base and then treatment
with esters of formula XIII, in which R is an alkyl or aryl residue
and R2 are as described for formula I, in non-protic solvents.
Preferable conditions are 2-3 equivalents of lithium bases like
lithium diisopropylamide or lithium hexamethyldisilazane or butyl
lithium in dried etheral solvents like tetrahydrofurane.
##STR00023##
[0120] The ketones of formula XI, in which R3 and R4 are each alkyl
or form a ring, R5 is aryl or heteroaryl and R2 is alkyl or aryl,
can also be prepared by treating sulfinates of formula XIV in which
R5 is aryl or heteroaryl as described in formula I, with a base
such as tetrabutylammonium bromide and a ketone of formula XV in
which R2 is alkyl or aryl (Crandall et al J. Org. Chem. 1985, (8)
50, 1327-1329). R3 and R4 are then introduced by reaction with
alkyl halides or alkyl dihalides. The reaction is preferably
performed in the presence of base such as potassium carbonate or
caesium carbonate and in the presence of a suitable solvent e.g.
DMF or DMSO at 50-100.degree. C.
##STR00024##
[0121] The compounds of the invention may be evaluated for example
in the following assays:
Isolated Enzyme Assays
Matrix Metalloproteinase Family Including for Example MMP12,
MMP13
[0122] Recombinant human MMP12 catalytic domain may be expressed
and purified as described by Parkar A. A. et al, (2000), Protein
Expression and Purification, 20:152. The purified enzyme can be
used to monitor inhibitors of activity as follows: MMP12 (50 ng/ml
final concentration) is incubated for 30 minutes at RT in assay
buffer (0.1M Tris-HCl, pH 7.3 containing 0.1M NaCl, 20 mM
CaCl.sub.2, 0.040 mM ZnCl and 0.05% (w/v) Brij 35) using the
synthetic substrate Mac-Pro-Cha-Gly-Nva-His-Ala-Dpa-NH2 in the
presence or absence of inhibitors. Activity is determined by
measuring the fluorescence at .lamda.ex 328 nm and .lamda.em 393
nm. Percent inhibition is calculated as follows: % Inhibition is
equal to the [Fluorescence.sub.plus
inhibitor-Fluorescence.sub.background] divided by the
[Fluorescence.sub.minus inhibitor-Fluorescence.sub.background].
[0123] Recombinant human proMMP13 may be expressed and purified as
described by Knauper et al. [V. Knauper et al., (1996) The
Biochemical Journal 271:1544-1550 (1996)]. The purified enzyme can
be used to monitor inhibitors of activity as follows: purified
proMMP13 is activated using 1 mM amino phenyl mercuric acid (APMA),
20 hours at 21.degree. C.; the activated MMP13 (11.25 ng per assay)
is incubated for 4-5 hours at 35.degree. C. in assay buffer (0.1M
Tris-HCl, pH 7.5 containing 0.1M NaCl, 20 mM CaCl2, 0.02 mM ZnCl
and 0.05% (w/v) Brij 35) using the synthetic substrate
7-methoxycoumarin-4-yl)acetyl.Pro.Leu.Gly.Leu.N-3-(2,4-dinitrophenyl)-L-2-
,3-diaminopropionyl.Ala.Arg.NH.sub.2 in the presence or absence of
inhibitors. Activity is determined by measuring the fluorescence at
.lamda.ex 328 nm and .lamda.em 393 nm. Percent inhibition is
calculated as follows: % Inhibition is equal to the
[Fluorescence.sub.plus inhibitor-Fluorescence.sub.background]
divided by the [Fluorescence.sub.minus
inhibitor-Fluorescence.sub.background].
[0124] A similar protocol can be used for other expressed and
purified pro MMPs using substrates and buffers conditions optimal
for the particular MMP, for instance as described in C. Graham
Knight et al., (1992) FEBS Lett. 296(3):263-266.
Adamalysin Family Including for Example TNF Convertase
[0125] The ability of the compounds to inhibit proTNF.alpha.
convertase enzyme may be assessed using a partially purified,
isolated enzyme assay, the enzyme being obtained from the membranes
of THP-1 as described by K. M. Mohler et al., (1994) Nature
370:218-220. The purified enzyme activity and inhibition thereof is
determined by incubating the partially purified enzyme in the
presence or absence of test compounds using the substrate
4',5'-Dimethoxy-fluoresceinyl
Ser.Pro.Leu.Ala.Gln.Ala.Val.Arg.Ser.Ser.Ser.Arg.Cys(4-(3-succinimid-1-yl)-
-fluorescein)-NH.sub.2 in assay buffer (5 mM Tris HCl, pH 7.4
containing 0.1% (w/v) Triton X-100 and 2 mM CaCl.sub.2), at
26.degree. C. for 18 hours. The amount of inhibition is determined
as for MMP13 except .lamda.ex 490 nm and .lamda.em 530 nm were
used. The substrate was synthesised as follows. The peptidic part
of the substrate was assembled on Fmoc-NH-Rink-MBHA-polystyrene
resin either manually or on an automated peptide synthesiser by
standard methods involving the use of Fmoc-amino acids and
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU) as coupling agent with at least a 4- or
5-fold excess of Fmoc-amino acid and HBTU. Ser.sup.1 and Pro.sup.2
were double-coupled. The following side chain protection strategy
was employed; Ser.sup.1 (But), Gln.sup.5 (Trityl), Arg.sup.8,12
(Pmc or Pbf), Ser.sup.9,10,11 (Trityl), Cys.sup.13 (Trityl).
Following assembly, the N-terminal Fmoc-protecting group was
removed by treating the Fmoc-peptidyl-resin with in DMF. The
amino-peptidyl-resin so obtained was acylated by treatment for
1.5-2 hr at 70.degree. C. with 1.5-2 equivalents of
4',5'-dimethoxy-fluorescein-4(5)-carboxylic acid [Khanna &
Ullman, (1980) Anal Biochem. 108:156-161) which had been
preactivated with diisopropylcarbodiimide and
1-hydroxybenzotriazole in DMF]. The dimethoxyfluoresceinyl-peptide
was then simultaneously deprotected and cleaved from the resin by
treatment with trifluoroacetic acid containing 5% each of water and
triethylsilane. The dimethoxyfluoresceinyl-peptide was isolated by
evaporation, trituration with diethyl ether and filtration. The
isolated peptide was reacted with 4-(N-maleimido)-fluorescein in
DMF containing diisopropylethylamine, the product purified by
RP-HPLC and finally isolated by freeze-drying from aqueous acetic
acid. The product was characterised by MALDI-TOF MS and amino acid
analysis.
Natural Substrates
[0126] The activity of the compounds of the invention as inhibitors
of aggrecan degradation may be assayed using methods for example
based on the disclosures of E. C. Arner et al., is (1998)
Osteoarthritis and Cartilage 6:214-228; (1999) Journal of
Biological Chemistry, 274(10), 6594-6601 and the antibodies
described therein. The potency of compounds to act as inhibitors
against collagenases can be determined as described by T. Cawston
and A. Barrett (1979) Anal. Biochem. 99:340-345.
Inhibition of Metalloproteinase Activity in Cell/Tissue Based
Activity
Test as an Agent to Inhibit Membrane Sheddases Such as TNF
Convertase
[0127] The ability of the compounds of this invention to inhibit
the cellular processing of TNF.alpha. production may be assessed in
THP-1 cells using an ELISA to detect released TNF essentially as
described K. M. Mohler et al., (1994) Nature-370:218-220. In a
similar fashion the processing or shedding of other membrane
molecules such as those described in N. M. Hooper et al., (1997)
Biochem. J. 321:265-279 may be tested using appropriate cell lines
and with suitable antibodies to detect the shed protein.
Test as an Agent to Inhibit Cell Based Invasion
[0128] The ability of the compound of this invention to inhibit the
migration of cells in an invasion assay may be determined as
described in A. Albini et al., (1987) Cancer Research
47:3239-3245.
Test as an Agent to Inhibit Whole Blood TNF Sheddase Activity
[0129] The ability of the compounds of this invention to inhibit
TNF.alpha. production is assessed in a human whole blood assay
where LPS is used to stimulate the release of TNF.alpha..
Heparinized (10 Units/ml) human blood obtained from volunteers is
diluted 1:5 with medium (RPMI1640+bicarbonate, penicillin,
streptomycin and glutamine) and incubated (160 .mu.l) with 20 .mu.l
of test compound (triplicates), in DMSO or appropriate vehicle, for
30 min at 37.degree. C. in a humidified (5% CO.sub.2/95% air)
incubator, prior to addition of 20 .mu.l LPS (E. coli. 0111:B4;
final concentration 10 .mu.g/ml). Each assay includes controls of
diluted blood incubated with medium alone (6 wells/plate) or a
known TNF.alpha. inhibitor as standard. The plates are then
incubated for 6 hours at 37.degree. C. (humidified incubator),
centrifuged (2000 rpm for 10 min; 4.degree. C.), plasma harvested
(50-100 .mu.l) and stored in 96 well plates at -70.degree. C.
before subsequent analysis for TNF.alpha. concentration by
ELISA.
Test as an Agent to Inhibit In Vitro Cartilage Degradation
[0130] The ability of the compounds of this invention to inhibit
the degradation of the aggrecan or collagen components of cartilage
can be assessed essentially as described by K. M. Bottomley et al.,
(1997) Biochem J. 323:483-488.
Pharmacodynamic Test
[0131] To evaluate the clearance properties and bioavailability of
the compounds of this invention an ex vivo pharmacodynamic test is
employed which utilises the synthetic substrate assays above or
alternatively HPLC or Mass spectrometric analysis. This is a
generic test which can be used to estimate the clearance-rate of
compounds across a range of species. Animals (e.g. rats, marmosets)
are dosed iv or po with a soluble formulation of compound (such as
20% w/v DMSO, 60% w/v PEG400) and at subsequent time points (e.g.
5, 15, 30, 60, 120, 240, 480, 720, 1220 mins) the blood samples are
taken from an appropriate vessel into IOU heparin. Plasma fractions
are obtained following centrifugation and the plasma proteins
precipitated with acetonitrile (80% w/v final concentration). After
30 mins at -20.degree. C. the plasma proteins are sedimented by
centrifugation and the supernatant fraction is evaporated to
dryness using a Savant speed vac. The sediment is reconstituted in
assay buffer and subsequently analysed for compound content using
the synthetic substrate assay. Briefly, a compound
concentration-response curve is constructed for the compound
undergoing evaluation. Serial dilutions of the reconstituted plasma
extracts are assessed for activity and the amount of compound
present in the original plasma sample is calculated using the
concentration-response curve taking into account the total plasma
dilution factor.
In Vivo Assessment
Test as an Anti-TNF Agent
[0132] The ability of the compounds of this invention as ex vivo
TNF.alpha. inhibitors is assessed in the rat. Briefly, groups of
male Wistar Alderley Park (AP) rats (180-210 g) are dosed with
compound (6 rats) or drug vehicle (10 rats) by the appropriate
route e.g. peroral (p.o.), intraperitoneal (i.p.), subcutaneous
(s.c.). Ninety minutes later rats are sacrificed using a rising
concentration of CO.sub.2 and bled out via the posterior vena cavae
into 5 Units of sodium heparin/ml blood. Blood samples are
immediately placed on ice and centrifuged at 2000 rpm for 10 min at
4.degree. C. and the harvested plasmas frozen at -20.degree. C. for
subsequent assay of their effect on TNF.alpha. production by
LPS-stimulated human blood. The rat plasma samples are thawed and
175 .mu.l of each sample are added to a set format pattern in a 96
U well plate. Fifty .mu.l of heparinized human blood is then added
to each well, mixed and the plate is incubated for 30 min at
37.degree. C. (humidified incubator). LPS (25 .mu.l; final
concentration 10 .mu.g/ml) is added to the wells and incubation
continued for a further 5.5 hours. Control wells are incubated with
25 .mu.l of medium alone. Plates are then centrifuged for 10 min at
2000 rpm and 200 .mu.l of the supernatants are transferred to a 96
well plate and frozen at -20.degree. C. for subsequent analysis of
TNF concentration by ELISA.
[0133] Data analysis by dedicated software calculates for each
compound/dose:
Percent inhibition of TNF .alpha. = Mean TNF .alpha. ( Controls ) -
Mean TNF .alpha. ( Treated ) .times. 100 Mean TNF .alpha. (
Controls ) ##EQU00001##
Test as an Anti-Arthritic Agent
[0134] Activity of a compound as an anti-arthritic is tested in the
collagen-induced arthritis (CIA) as defined by D. E. Trentham et
al., (1977) J. Exp. Med. 146:857. In this model acid soluble native
type II collagen causes polyarthritis in rats when administered in
Freunds incomplete adjuvant. Similar conditions can be used to
induce arthritis in mice and primates.
Test as an Anti-Cancer Agent
[0135] Activity of a compound as an anti-cancer agent may be
assessed essentially as described in I. J. Fidler (1978) Methods in
Cancer Research 15:399-439, using for example the B16 cell line
(described in B. Hibner et al., Abstract 283 p 75 10th NCI-EORTC
Symposium, Amsterdam Jun. 16-19 1998).
Test as an Anti-Emphysema Agent
[0136] Activity of a compound as an anti-emphysema agent may be
assessed essentially as described in Hautamaki et al (1997)
Science, 277: 2002.
[0137] The invention will now be illustrated but not limited by the
following Examples:
General analytical methods: .sup.1H-NMR spectra were recorded on
either a Varian .sup.UnityInova 400 MHz or Varian Mercury-VX300 MHz
instrument. The central solvent peak of chloroform-d (.delta..sub.H
7.27 ppm), dimethylsulfoxide-d.sub.6 (.delta..sub.H 2.50 ppm) or
methanol-d.sub.4 (.delta..sub.H 3.31 ppm) were used as internal
references. Low resolution mass spectra were obtained on a Agilent
1100 LC-MS system equipped with an APCI ionization chamber.
EXAMPLE 1
5-(2-{[4-(4'-fluoro[1,1'-biphenyl]-4-yl)-1-piperazinyl]sulfonyl}ethyl)-2,4-
-imidazolidinedione
##STR00025##
[0139] To the solution of 1-(4-fluorophenyl)-phenylpiperazin (0.125
mg, 0.48 mmol) in 5 ml of dichloromethane was added triethylamin
(0.06 ml, 0.5 mmol) and
2-(2,5-dioxo-4-imidazolidinyl)-1-ethanesulfonyl chloride (0.113 ml
0.48 mol). The mixture was stirred for 18 hrs, diluted with DCM to
25 ml, extracted with 1N HCl (5 ml) sat. NaHCO3 (5 ml) and dried,
evaporated, crystallised. (EtOH-dioxan).
[0140] LC-MS (APCI) m/z 446.9 (MH+).
[0141] 1H NMR .delta. 1.95 m (1H); 2.1 m (1.15H), 3.2 m (13.3H),
4.1 m (1H), 7.05 d (2H), 7.25 d (2.1H), 7.65 d (2.2H), 7.80 d
(1.8H), 8.0 bs (NH).
[0142] The starting materials were prepared as follows:
2-(2,5-dioxo-4-imidazolidinyl)-1-ethanesulfonyl chloride
[0143] To the suspension of
5-(2-{[2-(2,5-dioxo-4-imidazolidinyl)ethyl]disulfanyl}ethyl)-2,4-imidazol-
idinedione (6.9 mol) in the mixture of 25 ml AcOH and 2 ml water
stirred violently in three necked flask with gas-inlet tube,
thermometer and short reflux condenser, placed in the ice bath, was
bubbled chlorine gas for 15 min (until all precipitate dissolved)
at max. temp. +5.degree. C. Then, it was stirred 15 min more,
evaporated to a small volume in vacuo (max. temp 30.degree. C.),
dissolved in 50 ml of dichloromethane, shaken carefully with sat.
NaHCO3 (ca 25 ml), then with 10% sodium thiosulfate, dried,
evaporated, crystallised from THF-hexane (Lora-Tamayo, M. et al,
1968, An. Quim., 64(6):591-606);
[0144] .sup.1H NMR: .delta. 2.55 m (1.1H), 2.65 m (1.8H), 2.70 m
(1H), 4.55 m (1H).
5-(2-{[2-(2,5-dioxo-4-imidazolidinyl)ethyl]disulfanyl}ethyl)-2,4-imidazoli-
dinedione
[0145] Commercially available RS homocystine (0.18 mol) was
suspended in 25 ml water and of potassium cyanate 1.5 g (0.2 mol)
was added and the mixture was stirred at 100.degree. C. for 45 min.
Then it was allowed to cool partially and 10 ml of 10% HCl were
added at once and the mixture was stirred at 100.degree. C. again
for 50 min. It was placed in the fridge overnight, crystals were
filtered and washed successively with water and dried in vacuo.
[0146] LC-MS (APCI) m/z 319.1 (MH+).
[0147] The overall generalised reaction scheme is shown below:
##STR00026##
EXAMPLE 2
(5R)-5-{[(4-phenyl-1-piperazinyl)sulfonyl]methyl}-2,4-imidazolidinedione
[0148] The title compound was prepared according to the scheme
shown in Example 1. To the solution of
R-(2,5-dioxo-4-imidazolidinyl)methanesulfonyl chloride (100 mg,
0.47 mmol) in 2.5 ml THF was added the solution of
1-phenylpiperazine (85 mg, 0.52 mmol) and 65 ul of triethylamine
(0.52 mmol) in 2.5 ml THF via syringe at once. The mixture was
stirred for 3 hrs, precipitated triethylammonium chloride was
filtered, washed with two small portions of THF, evaporated and
recrystallised from EtOH and a small amount of AcOH.
[0149] LC-MS (APCI) m/z 339.1 (MH+).
[0150] .sup.1H NMR .delta. 2.5 m (2H), 3.1 bs (6.5H), 3.3 m (2.5H),
4.55 m (1H), 6.8 t (1H), 6.9 d (1.88H), 7.2 t (2.05H), 9.1 bs
(1.7H).
[0151] The starting materials were prepared as follows:
R-(2,5-dioxo-4-imidazolidinyl)methanesulfonyl chloride
[0152] To the suspension of
R-5-({[(2,5-dioxo-4-imidazolidinyl)methyl]disulfanyl}methyl)-2,4-imidazol-
idinedione (6.9 mol) in the mixture of 25 ml AcOH and 2 ml water
stirred violently in three necked flask with gas-inlet tube,
thermometer and short reflux condenser, placed in the ice bath, was
bubbled chlorine gas for 15 min (until all precipitate dissolved)
at max. temp. +5.degree. C. Then, it was stirred 15 min more,
evaporated to a small volume in vacuo (max. temp 30.degree. C.),
dissolved in 50 ml of dichloromethane, shaken carefully with sat.
NaHCO3 (ca 25 ml), then with 10% sodium thiosulfate, dried,
evaporated, crystallised from THF-hexane (Lora-Tamayo, M. et al,
1968, An. Quim., 64(6):591-606);
[0153] .sup.1H NMR (DMSO-d.sub.6): .delta. 3.21 m (1.1H), 3.3 m
(0.7H) 4.65 m (1H).
R-5-({[(2,5-dioxo-4-imidazolidinyl)methyl]disulfanyl}methyl)-2,4-imidazoli-
dinedione
[0154] Commercially available R cystine (0.18 mol) was suspended in
25 ml water and of potassium cyanate 1.5 g (0.2 mol) was added and
the mixture was stirred at 100.degree. C. for 45 min. Then it was
allowed to cool partially and 10 ml of 10% HCl were added at once
and the mixture was stirred at 100.degree. C. again for 50 min. It
was placed in the fridge overnight, crystals were filtered and
washed successively with water and dried in vacuo.
[0155] LC-MS (APCI) m/z 291 (MH+).
EXAMPLE 3
(5S)-5-{[(4-phenyl-1-piperazinyl)sulfonyl]methyl}-2,4-imidazolidinedione
[0156] The title compound was prepared according to the scheme
shown in Example 1. To the solution of
S-(2,5-dioxo-4-imidazolidinyl)methanesulfonyl chloride (100 mg,
0.47 mmol) in 2.5 ml THF was added the solution of
1-phenylpiperazine (85 mg, 0.52 mmol) and 65 ul of triethylamine
(0.52 mmol) in 2.5 ml THF via syringe at once. The mixture was
stirred for 3 hrs, precipitated triethylammonium chloride was
filtered, washed with two small portions of THF, evaporated and
recrystallised from EtOH and a small amount of AcOH.
[0157] LC-MS (APCI) m/z 339.1 (MH+).
[0158] .sup.1H NMR: .delta. 2.5 m (2H), 3.1 bs (6.5H), 3.3 m
(2.5H), 4.55 m (1H), 6.8 t (1H), 6.9 d (1.88H), 7.2 t (2.05H), 9.1
bs (1.7H)
[0159] The starting materials were prepared as follows:
S-(2,5-dioxo-4-imidazolidinyl)methanesulfonyl chloride
[0160] To the suspension of
S-5-({[(2,5-dioxo-4-imidazolidinyl)methyl]disulfanyl}methyl)-2,4-imidazol-
idinedione (6.9 mol) in the mixture of 25 ml AcOH and 2 ml water
stirred violently in three necked flask with gas-inlet tube,
thermometer and short reflux condenser, placed in the ice bath, was
bubbled chlorine gas for 15 min (until all precipitate dissolved)
at max. temp. +5.degree. C. Then, it was stirred 15 min more,
evaporated to a small volume in vacuo (max. temp 30.degree. C.),
dissolved in 50 ml of dichloromethane, shaken carefully with sat.
NaHCO3 (ca 25 ml), then with 10% sodium thiosulfate, dried,
evaporated, crystallised from THF-hexane (Lora-Tamayo, M. et al,
1968, An. Quim., 64(6):591-606);
[0161] .sup.1H NMR (DMSO-d.sub.6): .delta. 3.2 m (0.9H, 3.35 m
(0.9H), 4.50 m (1H).
S-5-({[(2,5-dioxo-4-imidazolidinyl)methyl]disulfanyl}methyl)-2,4-imidazoli-
dinedione
[0162] Commercially available S cystine (0.18 mol) was suspended in
25 ml water and of potassium cyanate 1.5 g (0.2 mol) was added and
the mixture was stirred at 100.degree. C. for 45 min. Then it was
allowed to cool partially and 10 ml of 10% HCl were added at once
and the mixture was stirred at 100.degree. C. again for 50 min. It
was placed in the fridge overnight, crystals were filtered and
washed successively with water and dried in vacuo.
[0163] LC-MS (APCI) m/z 291.1 (MH+).
EXAMPLE 4
(R)-5-(([4-(4'-fluoro[1,1'-biphenyl]-4-yl)-1-piperazinyl]sulfonyl)methyl)--
2,4-imidazolidinedione
##STR00027##
[0164] [(R)-2,5-Dioxoimidazolidinyl]methanesulfonyl chloride
(0.0127 g, 0.060 mmol), 1-(4'-fluoro[1,1'-biphenyl]-4-yl)piperazine
(0.0154 g, 0.060 mmol), triethylamine (0.0084 mL, 0.060 mmol) and
dry tetrahydrofuran (0.70 mL) were stirred at room temperature over
night. Polystyrene methylisocyanate (0.025 g, 0.030 mmol) was added
and the mixture was shaken over night. The white suspension was
carefully transferred to a round-bottomed flask, the resin was
rinsed with tetrahydrofuran (2.times.1 mL) and washings were
transferred to the bulk of suspension. The solvent was evaporated,
the white solid was suspended in water (5 mL), collected on a
filter, washed with water (2.times.1 mL), sucked free of water and
dried in vacuo at 45.degree. C. over night to afford approx. 0.010
g of the title compound.
[0165] LC-MS (APCI) m/z 434 (MH+).
[0166] .sup.1H NMR (DMSO-d.sub.6) .delta. 10.8 (1H, bs), 7.98 (1H,
d, J=2 Hz), 7.63 (2H, dd, J.sub.1=5 Hz, J.sub.2=9 Hz), 7.53 (2H, d,
J=9 Hz), 7.23 (2H, t, J=9 Hz), 7.05 (2H, d, J=9 Hz), 4.45 (1H, ddd,
J.sub.1=2 Hz, J.sub.2=4 Hz, J.sub.3=6 Hz), 3.51 (1H, dd, J.sub.1=15
Hz, J.sub.2=7 Hz), 3.44 (1H, dd, J.sub.1=15 Hz, J.sub.2=4 Hz),
3.35-3.25 (8H, m's; obscured by water signal) ppm.
[0167] .sup.13C NMR (DMSO-d.sub.6) .delta. 173.7, 161.3 (d, J=243
Hz), 157.3, 149.8, 136.4 (d, J=3 Hz), 130.1, 127.7 (d, J=8 Hz),
127.2, 116.2, 115.5 (d, J=21 Hz), 53.4, 49.4, 48.0, 44.9.
[0168] The starting materials were prepared as follows:
[(R)-2,5-Dioxoimidazolidinyl]methanesulfonyl chloride was prepared
according to Mosher et al, 1958, J. Org. Chem 23:1257.
1-(4'-Fluoro[1,1'-biphenyl]-4-yl)piperazine
[0169] 4-Bromo-4'-fluorobiphenyl (4.46 g, 17.8 mmol),
N-tert-butoxycarbonyl piperazine (3.97 g, 21.3 mmol), sodium
tert-butoxide (2.39 g, 24.9 mmol), racemic
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (rac-BINAP) (0.082 g,
0.131 mmol), bis-(dibenzylideneacetone)palladium (0) (0.041 g,
0.045 mmol) and dry toluene (45 mL) were stirred at 80.degree. C.
under nitrogen atmosphere for six hours. The warm mixture was
filtered, the solids were washed twice with warm toluene and the
filtrate was concentrated in vacuo giving an orange-red crude,
which was stirred with ether (50 mL) for two hours. The solid was
filtered off, washed with small volumes of ether and dried in vacuo
at 45.degree. C. over night to give 5.57 g (88% yield) of
tert-butyl
4-(4'-fluoro[1,1'-biphenyl]-4-yl)-1-piperazinecarboxylate. This
product (5.52 g, 15.5 mmol) was dissolved in dioxane (150 mL) and
stirred with 4M hydrochloric acid (8.1 mL) at RT over night.
Concentrated hydrochloric acid (3.0 mL) was added and stirring was
continued at 45.degree. C. for 1.5 hours and at 60.degree. C. for 1
hour. The solution was concentrated to dryness and the solid was
triturated with ether (100 mL), filtered, washed with small volumes
of ether and dried in vacuo at 45.degree. C. for two hours to give
5.26 g (103% yield) of 1-(4'-fluoro[1,1'-biphenyl]-4-yl)piperazine
dihydrochloride as a light-yellow salt.
[0170] LC-MS (APCI) m/z 257 (MH+).
[0171] .sup.1H NMR (DMSO-d.sub.6) .delta. 9.40 (2H, bs), 7.64 (2H,
dd, J.sub.1=6 Hz, J.sub.2=9 Hz), 7.55 (2H, d, J=9 Hz), 7.24 (2H, t,
J=9 Hz), 7.07 (2H, d, J=9 Hz), 3.46-3.41 (4H, m), 3.25-3.17 (4H,
m).
The salt was treated with aqueous sodium hydroxide solution and the
base was taken up in dichloro-methane. Drying with
Na.sub.2SO.sub.4, filtering and concentrating the organic phase
gave the title compound as an off white solid.
[0172] .sup.1H NMR (DMSO-d.sub.6) .delta. 7.61 (2H, dd, J.sub.1=6
Hz, J.sub.2=9 Hz), 7.49 (2H, d, J=9 Hz), 7.22 (2H, t, J=9 Hz), 6.98
(2H, d, J=9 Hz), 3.10-3.06 (4H, m), 2.86-2.81 (4H, m).
EXAMPLE 5
[0173] Using an analogous procedure to that described in Example 4,
[(4R)-2,5-dioxoimidazolidinyl]methanesulfonyl chloride was reacted
with the appropriate primary or secondary amine to give the
compounds listed below. All the amines employed are commercially
available.
##STR00028##
The Table below gives the Amine group for each compound of the
above structure.
TABLE-US-00001 ##STR00029## MW. 353.40 m/z 354 (MH+) ##STR00030##
MW. 355.39 m/z 356 (MH+) ##STR00031## MW. 357.36 m/z 358 (MH+)
##STR00032## MW. 421.52 m/z 422 (MH+) ##STR00033## MW. 422.29 m/z
423 (MH+) ##STR00034## MW. 433.49 m/z 434 (MH+) ##STR00035## MW.
437.91 m/z 438 (MH+)
EXAMPLE 6
(S)-5-(([4-(4'-fluoro[1,1'-biphenyl]-4-yl)-1-piperazinyl]sulfonyl)methyl)--
2,4-imidazolidinedione
##STR00036##
[0174] [(S)-2,5-Dioxoimidazolidinyl]methanesulfonyl chloride
(0.0127 g, 0.060 mmol), 1-(4'-fluoro[1,1'-biphenyl]-4-yl)piperazine
(0.0154 g, 0.060 mmol), triethylamine (0.0084 mL, 0.060 mmol) and
dry tetrahydrofuran (0.70 mL) were stirred at room temperature over
night. Polystyrene methylisocyanate (0.025 g, 0.030 mmol) was added
and the mixture was shaken over night. The white suspension was
carefully transferred to a round-bottomed flask, the resin was
rinsed with tetrahydrofuran (2.times.1 mL) and washings were
transferred to the bulk of suspension. The solvent was evaporated,
the white solid was suspended in water (5 mL), collected on a
filter, washed with water (2.times.1 mL), sucked free of water and
dried in vacuo at 45.degree. C. over night to afford approx. 0.010
g of the title compound.
[0175] LC-MS (APCI) m/z 433 (MH+).
[0176] .sup.1H NMR (DMSO-d.sub.6) .delta. 10.8 (1H, br s), 7.98
(1H, d, J=2 Hz), 7.63 (2H, dd, J.sub.1=5 Hz, J.sub.2=9 Hz), 7.53
(2H, d, J=9 Hz), 7.23 (2H, t, J=9 Hz), 7.05 (2H, d, J=9 Hz), 4.45
(1H, ddd, J.sub.1=2 Hz, J.sub.2=4 Hz, J.sub.3=6 Hz), 3.51 (1H, dd,
J.sub.1=15 Hz, J.sub.2=7 Hz), 3.44 (1H, dd, J.sub.1=15 Hz,
J.sub.2=4 Hz), 3.35-3.25 (8H, m's; obscured by water signal).
[0177] .sup.13C NMR (DMSO-d.sub.6) .delta. 173.7, 161.3 (d, J=243
Hz), 157.3, 149.8, 136.4 (d, J=3 Hz), 130.1, 127.7 (d, J=8 Hz),
127.2, 116.2, 115.5 (d, J=21 Hz), 53.4, 49.4, 48.0, 44.9.
The starting materials were prepared as follows:
[(S)-2,5-Dioxoimidazolidinyl]methanesulfonyl chloride was prepared
according to Mosher et al, 1958, J. Org. Chem 23:1257.
1-(4'-Fluoro[1,1'-biphenyl]-4-yl)piperazine was prepared according
to Example 4.
EXAMPLE 7
[0178] Using an analogous procedure to that described in Example 6,
[(4S)-2,5-dioxoimidazolidinyl]methanesulfonyl chloride was reacted
with the appropriate primary or secondary amine to give the
compounds listed below. All the amines employed are commercially
available.
##STR00037##
The Table below gives the Amine group for each compound of the
above structure.
TABLE-US-00002 ##STR00038## MW. 353.40 m/z 354 (MH+) ##STR00039##
MW. 355.39 m/z 356 (MH+) ##STR00040## MW. 357.36 m/z 358 (MH+)
##STR00041## MW. 421.52 m/z 422 (MH+) ##STR00042## MW. 422.29 m/z
423 (MH+) ##STR00043## MW. 433.49 m/z 434 (MH+) ##STR00044## MW.
437.91 m/z 438 (MH+)
EXAMPLE 8
[0179] Hydantoins with the following general structure were
synthesised (where E is carbon or a heteroatom):
##STR00045##
Representative Synthetic Route:
(5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonylmethyl]-5-methyl-imidaz-
olidine 2,4-dione
##STR00046##
[0180] Sulfonyl-amide Intermediates
TABLE-US-00003 [0181] Structure Analysis.sup.(1) ##STR00047## m/z
258 (MH+) ##STR00048## m/z 291 (MH+) ##STR00049## m/z 310 (MH+)
##STR00050## m/z 267 (MH+) ##STR00051## m/z 259 (MH+) ##STR00052##
m/z 273 (MH+) ##STR00053## m/z 243 (MH+) ##STR00054## m/z 274 (MH+)
.sup.(1)For NMR-data see experimental part.
4-(4-Fluoro-phenyl)-1-methanesulfonyl-piperidine
[0182] 4-(4-Fluoro-phenyl)piperidine hydrochloride (2.16 g; 10
mmol) and diisopropylethylamine (4.35 ml; 25 mmol) was dissolved in
DCM (60 ml) and cooled under nitrogen on a ice/water bath.
Methanesulfonyl chloride (1.56 ml; 10.1 mmol) was dissolved in DCM
(5 ml) and added dropwise during 2 min. The reaction mixture was
stirred for 2.5 h on the ice/water bath. The reaction mixture was
washed with dilute HCl (aq), pH=2, H.sub.2O, and 1M
Na.sub.2CO.sub.3. The organic phase was dried (Na.sub.2SO.sub.4),
filtered and evaporated to give a crude product that was
recrystallised from THF/n-Heptane. The colourless crystals was
removed by filtration and dried under vacuum at 45.degree. C.
[0183] Obtained 1.96 g (76% yield) of the title compound.
[0184] LC-MS (APCI) m/z 258 (MH+).
[0185] .sup.1H NMR (DMSO-d.sub.6): .delta. 7.31 (m, 2H), 7.12 (m,
2H), 3.67 (m, 2H), 2.80 (dt, 2H), 2.64 (m, 1H), 1.85 (m, 2H), 1.65
(m, 2H).
5-Chloro-2-(1-methanesulfonyl-piperidine-4-yloxy)-pyridine
[0186] The title compound was prepared as described in the
synthesis of 4-(4-Fluoro-phenyl)-1-methanesulfonyl-piperidine.
5-Chloro-2-(piperidine-4-yloxy)-pyridine (2.13 g; 10 mmol)
(preparation of this compound was made as described in WO
99-GB2801), diisopropylethylamine (2.20 ml; 12.5 mmol) and
Methanesulfonyl chloride (1.56 ml; 10.1 mmol) gave 2.14 g (74%) of
the title compound.
[0187] LC-MS (APCI) m/z 291 (MH+).
[0188] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.20 (d, 1H), 7.81 (dd,
1H), 6.87 (d, 1H), 5.09 (m, 1H), 3.41-3.30 (m, 2H), 3.15-3.06 (m,
2H), 2.90 (s, 3H), 2.04 (m, 2H), 1.75 (m, 2H).
1-(methylsulfonyl)-4-[5-(trifluoromethyl)pyridin-2-yl]piperazine
[0189] 1-[5-(Trifluoromethyl)-Pyridin-2-yl]-piperazine (1.0 g; 4.3
mmol) and Diisopropylethylamine (0.9 ml; 5.4 mmol) was dissolved in
DCM (10 ml). Molecular sieves (4 A) was added and the solution was
cooled on a ice/water bath. Methanesulfonylchloride (0.9 ml; 12
mmol) was added and a slurry formed that was stirred for 15 min,
the reaction mixture was allowed to reach room temperature and
after 1 h. the reaction was quenched by adding 5% KHCO.sub.3.
Evaporation of solvents and the residue was dissolved between DCM
and 5% KHCO.sub.3. Separation and extraction of the waterphase with
DCM (1.times.). The combined organic phases was dried (MgSO.sub.4),
filtered and evaporated to give a crude product as a slightly
yellow solid.
[0190] Recrystallised (3.times.) from EtOAc/Heptan gave the title
compound as colourless crystals.
[0191] Obtained 1.06 g (79% yield) of the title compound.
[0192] Purity>95% (HPLC, 254 nm)
[0193] LC-MS (APCI) m/z 310 (MH+).
[0194] .sup.1H-NMR (DMSO-d.sub.6): .delta. 8.44 (1H, bs), 7.85 (1H,
dd), 7.02 (1H, d), 3.77 (4H, bt), 3.20 (4H, bt), 2.90 (3H, s).
[0195] The following compounds were prepared as described in the
synthesis of
1-(methylsulfonyl)-4-[5-(trifluoromethyl)pyridin-2-yl]piperazine
6-[4-(methylsulfonyl)piperazine-1-yl]pyridine-3-carbonitrile
[0196] 6-(1-piperazino)-pyridine-3-carbonitrile (2.07 g; 11 mmol),
Diisopropylethylamine (2.4 ml; 13.8 mmol) and
Methanesulfonylchloride (0.86 ml; 11 mmol) in DCM (20 ml) gave 2.53
g (86%) of the title compound.
[0197] Purity>95% (NMR).
[0198] LC-MS (APCI) m/z 267 (MH+).
[0199] .sup.1H-NMR (DMSO-d.sub.6): .delta. 8.52 (1H, dd), 7.90 (1H,
dd), 7.00 (1H, d), 3.79 (4H, brt), 3.19 (4H, bt), 2.90 (3H, s).
1-(4-fluorophenyl)-4-(methylsulfonyl)piperazine
[0200] 1-(4-Fluorophenyl)-piperazine (1.98 g; 11 mmol),
Diisopropylethylamine (2.4 ml; 13.8 mmol) and
Methanesulfonylchloride (0.86 ml; 11 mmol) in DCM (20 ml) gave 2.46
g (86%) of the title compound.
[0201] Purity>95% (NMR).
[0202] LC-MS (APCI) m/z 259 (MH+).
[0203] .sup.1H-NMR (DMSO-d.sub.6): .delta. 7.11-6.96 (4H, m),
3.28-3.20 (4H, m), 3.20-3.14 (4H, m), 2.92 (3H, s).
1-[(4-fluorophenyl)methyl]-4-(methylsulfonyl)piperazine
[0204] 1-(4-Fluor-benzyl)-piperazine (2.14 g; 11 mmol),
Diisopropylethylamine (2.4 ml; 13.8 mmol) and
Methanesulfonylchloride (0.86 ml; 11 mmol) in DCM (20 ml) gave 1.97
g (65%) of the title compound.
[0205] Purity>95% (NMR)
[0206] LC-MS (APCI) m/z 273 (MH+).
[0207] .sup.1H-NMR (DMSO-d.sub.6): .delta. 7.40-7.28 (2H, m),
7.21-7.10 (2H, m), 3.50 (2H, bs), 3.10 (4H, m), 2.87 (3H, bs), 2.44
(4H, m).
2-[4-(methylsulfonyl)piperazin-1-yl)pyrimidine
[0208] 1-(2-Pyrimidyl)-piperazine dihydrochloride (2.61 g; 11 mmol)
and Diisopropylethylamine (7.2 ml; 41.3 mmol) was stirred in DCM
(20 ml) for 30 min. The precipitated salts was removed by
filtration and solvents evaporated, residue was redissolved in DCM
(20 ml). Diisopropylethylamine (2.4 ml; 11 mmol) and 4 A mol.
sieves was added, the yellow solution was cooled on ice/water bath
and Methanesulfonylchloride (0.86 ml; 11 mmol) was added. The
resulting red solution was stirred for 15 min, the reaction mixture
was allowed to reach room temperature and after 1 h. the reaction
was quenched by adding 5% KHCO.sub.3. Evaporation of solvents and
the residue was dissolved between DCM and 5% KHCO.sub.3. Separation
difficult due to foam formation. Waterphase was saturated with NaCl
and pH adjusted to 10-11. Extraction with EtOAc (3.times.). The
combined organic phases was dried (K.sub.2CO.sub.3), filtered and
evaporated to give a crude product as a red solid.
[0209] Recrystallised (3.times.) from EtOAc/Heptan gave the title
compound as a red powder.
[0210] Obtained 0.6 g (22%) of the title compound.
[0211] Purity>95% (NMR).
[0212] LC-MS (APCI) m/z 243 (MH+).
[0213] .sup.1H-NMR (DMSO-d.sub.6): .delta. 8.39 (2H, d), 6.68 (1H,
t), 3.85 (4H, bt), 3.17 (4H, bt), 2.88 (3H, s).
4-(4-chlorophenyl)-1-(methylsulfonyl)piperidine
[0214] The title compound was prepared as described in the
synthesis of 4-(4-Fluoro-phenyl)-1-methanesulfonyl-piperidine.
[0215] 4-(4-Chlorophenyl)piperidine hydrochloride (0.9 g, 3.9
mmol), diisopropylethylamine (1.7 ml, 9.7 mmol) and
methanesulfonylchloride (0.33 ml, 4.3 mmol) in DCM (30 ml) and gave
0.82 g (78%) of the title compound after recrystallisation from
EtOAc/Heptane.
[0216] Purity>95%.
[0217] LC-MS (APCI) m/z 274 (MH+).
[0218] .sup.1H NMR CDCl.sub.3: .delta. 1.83 (2H, dd); 1.92-2.01
(2H, m); 2.55-2.68 (1H, m); 2.79 (2H, dt); 2.85 (3H, s); 3.97 (2H,
d); 7.16 (2H, d); 7.32 (2H, d).
Ester Intermediates
TABLE-US-00004 [0219] Structure Analysis ##STR00055## m/z 195 (MH+)
.sup.1H-NMR ##STR00056## m/z 181 (MH+) ##STR00057## m/z 158 (MH+ -
boc)
All other esters used are commercially available or earlier
described.
4-Pyrimidin-2-yl-butyric acid ethyl ester
[0220] 2-Bromopyrimidine (11.0 g, 6.3 mmol) was slurried in dry THF
(8 mL). N.sub.2 (g) was bubbled through the slurry for 5 min.
Pd(CH.sub.3CN).sub.2Cl.sub.2 (8 mg, 0.03 mmol) and PPh.sub.3 (23.6
mg, 0.09 mmol) was added. Under N.sub.2-atmosphere
4-Ethoxy-4-oxo-butylzincbromide (0.5M/THF) (15 mL, 7.5 mL) was
added in one portion. The resulting brown solution was stirred at
room temperature for 2 h. H.sub.2O (5 mL) was added and the mixture
stirred for 60 min. before evaporation of solvents. The residue was
redissolved in DCM (150 mL) and washed with 0.5M trisodiumcitrate
(100 mL), H.sub.2O (100 mL) and brine (100 mL), dried (MgSO.sub.4),
filtered and evaporated to give 1.3 g of an orange oil. The crude
product was purified on 70 g of Si-60 gel using a gradient of 100%
Heptane to 100% EtOAc as eluent. The fractions containing the
product was collected and solvent evaporated to give a yellow oil.
Purity by NMR>95% was considered enough for our need. Obtained
1.12 g (92% yield) of the title compound.
[0221] LC-MS (APCI) m/z 195 (MH+).
[0222] .sup.1H-NMR (CDCl.sub.3): .delta. 8.67 (d, 2H), 7.14 (t,
1H), 4.12 (q, 2H), 3.02 (t, 2H), 2.41 (t, 2H), 2.18 (q, 2H), 1.25
(t, 3H).
3-Pyrimidin-2-yl-propionic acid ethyl ester
[0223] 2-Bromopyrimidine (1.0 g, 6.3 mmol) was dissolved in THF (8
mL) and bubbled through with nitrogen. Pd(MeCN).sub.2Cl.sub.2 (8
mg, 0.03 mmol) and PPh.sub.3 (23.6 mg, 0.09 mmol) was added
followed by addition of 3-ethoxy-3-oxopropylzinkbromid (15 mL, 7.5
mmol). The reaction was stirred at rt for several days. The crude
product was purified on silica with Heptane-EtOAc 3:1 as eluent
giving 0.60 g (52%) of the title compound.
[0224] LC-MS (APCI) m/z 181 (MH+).
tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate
[0225] tert-Butyl
4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (3.6 g, 14
mmol.) and 10% Pd/C moistened with water (0.8 g) was mixed in MeOH
(75 mL) and stirred under H.sub.2 (1 atm) for 4 h. The mixture was
filtered through Celite and concentrated to give the title compound
(3.6 g, 99%).
[0226] LC-MS (APCI) m/z 158 (MH+-boc).
[0227] .sup.1H NMR (CDCl.sub.3): .delta. 4.07 (2H, bs); 3.68 (3H,
s); 2.72 (2H, t); 2.25 (2H, d, J=7.1 Hz); 2.01-1.86 (1H, m); 1.68
(2H, d); 1.46 (9H, s); 1.23-1.08 (2H, m).
Ketone Intermediates
TABLE-US-00005 ##STR00058## [0228] R E R2 Analysis ##STR00059## CH
Me m/z 300 (MH+) ##STR00060## CH ##STR00061## H-NMR. see exp. part.
##STR00062## CH ##STR00063## m/z 394 (MH+) ##STR00064## CH
##STR00065## m/z 406 (MH+).sup.(1) ##STR00066## CH Me m/z 333
(MH+).sup.(1) ##STR00067## CH ##STR00068## m/z 423 (MH+).sup.(1)
##STR00069## CH ##STR00070## m/z 427 (MH+).sup.(1) ##STR00071## CH
##STR00072## m/z 439 (MH+).sup.(1) ##STR00073## CH ##STR00074## m/z
347 (MH+).sup.(1) ##STR00075## CH ##STR00076## m/z 361
(MH+).sup.(1) ##STR00077## CH ##STR00078## m/z 375 (MH+).sup.(1)
##STR00079## CH ##STR00080## m/z 425 (MH+).sup.(1) ##STR00081## CH
##STR00082## m/z 423 (MH+).sup.(1) ##STR00083## CH ##STR00084## m/z
417 (MH+).sup.(1) ##STR00085## CH ##STR00086## m/z 446
(MH+).sup.(1) ##STR00087## CH ##STR00088## m/z 372 (MH+).sup.(1)
##STR00089## CH ##STR00090## m/z 476 (MH+).sup.(1) ##STR00091## CH
##STR00092## m/z 432 (MH+).sup.(1) ##STR00093## CH ##STR00094## m/z
395 (MH+).sup.(1) ##STR00095## CH ##STR00096## m/z 413
(MH+).sup.(1) ##STR00097## CH ##STR00098## m/z 385 (MH+).sup.(1)
##STR00099## CH ##STR00100## ##STR00101## CH ##STR00102## m/z 414
(MH+).sup.(1) ##STR00103## CH ##STR00104## m/z 392 (MH+).sup.(1)
##STR00105## CH ##STR00106## m/z 384 (MH+).sup.(1) ##STR00107## CH
##STR00108## m/z 405 (MH+).sup.(1) ##STR00109## CH ##STR00110## m/z
352 (MH+).sup.(1) ##STR00111## CH ##STR00112## m/z 400
(MH+).sup.(1) ##STR00113## CH ##STR00114## m/z 429 (MH+).sup.(1)
##STR00115## N Me m/z 352 (MH+).sup.(1) ##STR00116## N Me m/z 309
(MH+).sup.(1) ##STR00117## N Me m/z 301 (MH+).sup.(1) ##STR00118##
N Me m/z 315 (MH+).sup.(1) ##STR00119## N Me m/z 285 (MH+).sup.(1)
##STR00120## CH ##STR00121## m/z 517 (MH+).sup.(1) .sup.(1)crude
products, no NMR available, mtrl. used directly in next synthetic
step.
1-[4-4(Fluoro-phenyl)-piperidine-1-sulfonyl]-propan-2-one
[0229] 4-(4-Fluoro-phenyl)-1-methanesulfonyl-piperidine (100 mg;
0.39 mmol) was dissolved in dry THF (3 mL) under a protective
nitrogen atmosphere. Lithium bis(trimethylsilyl)amide as a 1.0 M
solution in THF (11.0 mL; 11.0 mmol) was added in one portion at
room temperature, the resulting yellow solution was stirred for 45
min. Methylacetate (50 mg; 0.68 mmol) dissolved in dry THF (0.5 mL)
was added, the mixture was stirred at room temperature for 40 min.
The reaction was quenched by adding NH.sub.4Cl (sat.) (2 mL). The
mixture was evaporated and the resulting solid was dissolved in a
mixture of DCM and H.sub.2O. The organic phase was separated and
washed with brine, dried (MgSO.sub.4), filtrated and evaporated.
The crude product was purified on 20 g of Si-60 gel using a
gradient of 100% Heptane to 50% EtOAc, a flow of 20 mL/min was used
and UV=254 nm was used for detection. The fractions containing the
product was evaporated and this gave the title compound as a
colourless solid.
[0230] Obtained 70 mg (59% yield).
[0231] TLC(Si-60; EtOAc:Heptane (2:1)): R.sub.f=0.65
[0232] LC-MS (APCI) m/z 300.1 (MH+).
[0233] .sup.1H-NMR (CDCl.sub.3): .delta. 7.17 (m, 2H), 7.01 (m,
2H), 4.02 (s, 2H), 3.93 (m, 2H), 2.94 (dt, 2H), 2.63 (m, 1H), 2.46
(s, 3H), 1.91 (m, 2H), 1.77 (m, 2H).
[0234] The following compounds were prepared as described in the
synthesis of
1-[4-4(Fluoro-phenyl)-piperidine-1-sulfonyl]-propan-2-one.
1-[4-4(Fluoro-phenyl)-piperidine-1-sulfonyl]-4-phenyl-butan-2-one
[0235] 4-(4-Fluoro-phenyl)-1-methanesulfonyl-piperidine (100 mg;
0.39 mmol), Methyl-3-phenylpropionate (112 mg; 0.68 mmol) and
Lithium bis(trimethylsilyl)amide 1.0 M/THF (1.0 mL; 1.0 mmol) gave
93 mg (61%) of the title compound.
[0236] TLC(Si-60; EtOAc:Heptane (2:1)): R.sub.f=0.68
[0237] .sup.1H-NMR (CDCl.sub.3): .delta. 7.30-7.10 (m, 7H), 6.99
(m, 2H), 3.97 (s, 2H), 3.79 (m, 2H), 3.11 (t, 2H), 2.94 (t, 2H),
2.83 (dt, 2H) 2.57 (m, 1H), 1.83 (m, 2H), 1.70 (m, 2H).
1-[4-4(Fluoro-phenyl)-piperidine-1-sulfonyl]-5-imidazol-pentan-2-one
[0238] 4-(4-Fluoro-phenyl)-1-methanesulfonyl-piperidine (100 mg;
0.39 mmol), 4-imidazol-1yl-butyric acid ethyl ester (127 mg; 0.70
mmol) and Lithium bis(trimethylsilyl)amide 1.0 M/THF (1.0 mL; 1.0
mmol) gave 75 mg (48%) of the title compound.
[0239] LC-MS (APCI) m/z 394 (MH+).
[0240] .sup.1H-NMR (CDCl.sub.3): .delta. 7.48 (s, 1H), 7.16 (m,
2H), 7.08 (s, 1H), 7.02 (m, 2H), 6.93 (s, 2H), 4.00 (t, 2H), 3.97
(s, 2H), 3.90 (m, 2H), 2.92 (dt, 2H), 2.77 (t, 2H), 2.63 (m, 1H),
2.12 (q, 2H), 1.92 (m, 2H), 1.77 (m, 2H).
1-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonyl]-5-pyrimidin-2-yl-pentan-2-on-
e
[0241] 4-(4-Fluoro-phenyl)-1-methanesulfonyl-piperidine (150 mg;
0.39 mmol) was dissolved in dry THF (3 mL) and cooled on an
ice/brine mixture. Lithium bis(trimethylsilyl)amide as a 1.0 M
solution in THF (1.5 mL; 1.5 mmol) was added and the mixture was
stirred for 40 min. 4-Pyrimidin-2-yl-butyric acid ethyl ester (169
mg; 0.87 mmol) in THF (0.5 mL) was added, the reaction was stirred
for 30 min and then allowed to reach room temperature. After 2 h.
LC/MS analysis of the reaction mixture showed >98% conversion of
the starting material and the reaction was quenched by adding
saturated NH.sub.4Cl (aq) (2 mL). The mixture was evaporated and
the resulting solid was dissolved in a mixture of DCM and 5%
KHCO.sub.3. The organic phase was separated and the water phase was
extracted once with DCM. The combined organic phases was washed
with brine, dried (MgSO.sub.4), filtered, and evaporated to give a
yellow oil. The oil was dissolved in EtOAc and isoHexane was added
until a solid formed. Evaporation of solvent gave a yellow solid
crude product. This material was analysed using LC/MS only and used
without further purification in the next step.
[0242] Obtained 234 mg of the crude title compound.
[0243] LC-MS (APCI) m/z 406.1 (MH+).
[0244] The following compounds were prepared as described in the
synthesis of
1-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonyl]-5-pyrimidin-2-yl-pentan--
2-one. They were obtained as crude products and used without
further purification.
1-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonyl]-propan-2-one
[0245] Starting from
5-Chloro-2-(1-methanesulfonyl-piperidine-4-yloxy)-pyridine (150 mg;
0.51 mmol), Methylacetate (61 mg; 0.82 mmol) and Lithium
bis(trimethylsilyl)amide 1.0M/THF (1.3 ml; 1.3 mmol).
[0246] Obtained 161 mg of the crude title compound. Used without
further purification.
[0247] LC-MS (APCI) m/z 333.1 (MH+).
1-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonyl]-4-phenyl-butan-2-on-
e
[0248] Starting from
5-Chloro-2-(1-methanesulfonyl-piperidine-4-yloxy)-pyridine (150 mg;
0.51 mmol), Methyl-3-phenylpropionate (126 mg; 0.77 mmol) and
Lithium bis(trimethylsilyl)amide 1.0 M/THF (1.3 ml; 1.3 mmol).
[0249] Obtained 258 mg of the crude title compound. Used without
further purification.
[0250] LC-MS (APCI) m/z 423.2 (MH+).
1-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonyl]-5-imidazol-1-yl-pen-
tan-2-one
[0251] Starting from
5-Chloro-2-(1-methanesulfonyl-piperidine-4-yloxy)-pyridine (150 mg;
0.51 mmol), 4-imidazol-1yl-butyric acid ethyl ester (140 mg; 0.77
mmol) and Lithium bis(trimethylsilyl)amide 1.0 M/THF (1.3 ml; 1.3
mmol).
[0252] Obtained 268 mg of the crude title compound. Used without
further purification.
[0253] LC-MS (APCI) m/z 427.2 (MH+).
1-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonyl]-5-pyrimidin-2-yl-pe-
ntan-2-one
[0254] Starting from
5-Chloro-2-(1-methanesulfonyl-piperidine-4-yloxy)-pyridine (150 mg;
0.51 mmol), 4-Pyrimidin-2-yl-butyric acid ethyl ester (147 mg; 0.76
mmol) and Lithium bis(trimethylsilyl)amide 1.0 M/THF (1.3 ml; 1.3
mmol).
[0255] Obtained 244 mg of the crude title compound. Used without
further purification.
[0256] LC-MS (APCI) m/z 439.2 (MH+).
1-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonyl]-butan-2-one
[0257] LC-MS (APCI) m/z 347 (MH+)
1-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonyl]-pentan-2-one
[0258] LC-MS (APCI) m/z 361 (MH+)
1-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonyl]-4-methyl-pentan-2-o-
ne
[0259] LC-MS (APCI) m/z 375 (MH+)
1-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonyl]-4-pyrimidin-2-yl-bu-
tan-2-one
[0260] LC-MS (APCI) m/z 425 (MH+)
1-({4-[(5-Chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-3-(3-methylpheny-
l)propan-2-one
[0261] LC-MS (APCI) m/z 423 (MH+)
1-({4-[(5-Chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-3-tetrahydro-2H--
pyran-4-ylpropan-2-one
[0262] LC-MS (APCI) m/z 417 (MH+)
1-({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-5-morpholin-4-yl-
pentan-2-one
[0263] LC-MS (APCI) m/z 446 (MH+)
5-({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-4-oxopentanenitr-
ile
[0264] LC-MS (APCI) m/z 372 (MH+)
1,1-dimethylethyl
5-({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-4-oxopentylcarb-
amate
[0265] LC-MS (APCI) m/z 476 (MH+)
1-({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-4-morpholin-4-yl-
butan-2-one
[0266] LC-MS (APCI) m/z 432 (MH+)
2-({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-1-phenylethanone
[0267] LC-MS (APCI) m/z 395 (MH+)
2-({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-1-(4-fluoropheny-
l)ethanone
[0268] LC-MS (APCI) m/z 413 (MH+)
2-({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-1-(1H-imidazol-4-
-yl)ethanone
[0269] LC-MS (APCI) m/z 385 (MH+)
4-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)acetyl]benzamide
[0270] n.d.
1-({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-4-(1H-1,2,4-tria-
zol-1-yl)butan-2-one
[0271] LC-MS (APCI) m/z 414 (MH+)
1-{[4-(4-fluorophenyl)piperidin-1-yl]sulfonyl}-4-pyrimidin-2-ylbutan-2-one
[0272] LC-MS (APCI) m/z 392 (MH+)
1-{[4-(4-fluorophenyl)piperidin-1-yl]sulfonyl}-3-tetrahydro-2H-pyran-4-ylp-
ropan-2-one
[0273] LC-MS (APCI) m/z 384 (MH+)
4-({[4-(4-fluorophenyl)piperidin-1-yl]sulfonyl}acetyl)benzamide
[0274] LC-MS (APCI) m/z 405 (MH+)
2-{[4-(4-fluorophenyl)piperidin-1-yl]sulfonyl}-1-(H-imidazol-4-yl)ethanone
[0275] LC-MS (APCI) m/z 352 (MH+)
1-{[4-(4-chlorophenyl)piperidin-1-yl]sulfonyl}-3-tetrahydro-2H-pyran-4-ylp-
ropan-2-one
[0276] LC-MS (APCI) m/z 400 (MH+)
1-{[4-(4-chlorophenyl)piperidin-1-yl]sulfonyl}-5-morpholin-4-ylpentan-2-on-
e
[0277] LC-MS (APCI) m/z 429 (MH+)
1-({4-[5-(trifluoromethyl)pyridin-2-yl]piperazine-1-yl}sulfonyl)propan-2-o-
ne
[0278] LC-MS (APCI) m/z 352.1 (MH+)
6-{4-[(2-oxopropyl)sulfonyl]piperazin-1-yl}pyridine-3-carbonitrile
[0279] LC-MS (APCI) m/z 309.1 (MH+)
1-{[4-(4-fluorophenyl)piperazine-1-yl]sulfonyl}propan-2-one
[0280] LC-MS (APCI) m/z 301.1 (MH+)
1-({4-[(4-fluorophenyl)methyl]piperazine-1-yl}sulfonyl)propan-2-one
[0281] LC-MS (APCI) m/z 315.1 (MH+)
1-[(4-pyrimidin-2-ylpiperazine-1-yl)sulfonyl]propan-2-one
[0282] LC-MS (APCI) m/z 285.1 (MH+)
1,1-dimethylethyl
4-[3-({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-2-oxopropyl]-
piperidine-1-carboxylate
[0283] LC-MS (APCI) m/z 517 (MH+).
Hydantoins of Formula I
TABLE-US-00006 ##STR00122## [0284] R E R2 Analysis ##STR00123## CH
Me m/z 370 (MH+).sup.(1) ##STR00124## CH ##STR00125## m/z 460
(MH+).sup.(1) ##STR00126## CH ##STR00127## m/z 464 (MH+).sup.(1)
##STR00128## CH ##STR00129## m/z 476 (MH+).sup.(1) ##STR00130## CH
Me m/z 403 (MH+).sup.(1) ##STR00131## CH ##STR00132## m/z 493
(MH+).sup.(1) ##STR00133## CH ##STR00134## m/z 497 (MH+).sup.(1)
##STR00135## CH ##STR00136## m/z 509 (MH+).sup.(1) ##STR00137## CH
##STR00138## m/z 417 (MH+).sup.(1) ##STR00139## CH ##STR00140## m/z
431 (MH+).sup.(1) ##STR00141## CH ##STR00142## m/z 445
(MH+).sup.(1) ##STR00143## CH ##STR00144## m/z 495 (MH+).sup.(1)
##STR00145## CH ##STR00146## m/z 493 (MH+).sup.(1) ##STR00147## CH
##STR00148## m/z 487 (MH+).sup.(1) ##STR00149## CH ##STR00150## m/z
517 (MH+).sup.(1) ##STR00151## CH ##STR00152## m/z 442
(MH+).sup.(1) ##STR00153## CH ##STR00154## m/z 547, 490 (MH+), -
tBu.sup.(1) ##STR00155## CH ##STR00156## m/z 502 (MH+).sup.(2)
##STR00157## CH ##STR00158## m/z 465 (MH+).sup.(2) ##STR00159## CH
##STR00160## m/z 483 (MH+).sup.(2) ##STR00161## CH ##STR00162## m/z
455 (MH+).sup.(2) ##STR00163## CH ##STR00164## m/z 508
(MH+).sup.(2) ##STR00165## CH ##STR00166## m/z 484 (MH+).sup.(2)
##STR00167## CH ##STR00168## m/z 462 (MH+).sup.(1) ##STR00169## CH
##STR00170## m/z 454 (MH+).sup.(1) ##STR00171## CH ##STR00172## m/z
475 (MH+).sup.(1) ##STR00173## CH ##STR00174## m/z 422
(MH+).sup.(2) ##STR00175## CH ##STR00176## m/z 470 (MH+).sup.(1)
##STR00177## CH ##STR00178## m/z 499 (MH+).sup.(1) ##STR00179## N
Me m/z 422 (MH+).sup.(1) ##STR00180## N Me m/z 379 (MH+).sup.(1)
##STR00181## N Me m/z 371 (MH+).sup.(1) ##STR00182## N Me m/z 385
(MH+).sup.(1) ##STR00183## N Me m/z 355 (MH+).sup.(1) ##STR00184##
CH ##STR00185## m/z 446 (MH+).sup.(1) ##STR00186## CH ##STR00187##
m/z 472 (MH+).sup.(1) ##STR00188## CH ##STR00189## m/z 4o3
(MH+).sup.(1) ##STR00190## CH ##STR00191## m/z 466 (MH+).sup.(1)
##STR00192## CH ##STR00193## m/z 530 (MH + - boc).sup.(1)
##STR00194## CH ##STR00195## m/z 486 (MH + - boc).sup.(1)
##STR00196## CH ##STR00197## m/z 524 (MH+).sup.(1) .sup.(1)NMR
available, see experimental part. .sup.(2)Not purified.
(5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonylmethyl]-5-methyl-imidaz-
olidine-2,4-dione
[0285] The ketone
1-[4-4(Fluorophenyl)-piperidine-1-sulfonyl]-propan-2-one (68 mg;
0.23 mmol), KCN (30 mg; 0.46 mmol) and (NH.sub.4).sub.2CO.sub.3
(111 mg; 1.16 mmol) was suspended in 50% EtOH/H.sub.2O (8 mL) in a
22 mL sealed tube and heated to 70.degree. C., a solution was
formed. The mixture was stirred at 70.degree. C. for 17 h. a solid
formed in the tube, the mixture was cooled to room temperature and
solvent evaporated, the residue was suspended in water and pH
adjusted to pH=6 using 1.0M HCl and precipitated product removed by
filtration and washed with water. The water phase was saturated
with NaCl and extracted with MeCN. The solid material and MeCN
solutions was combined and evaporated. The crude product was
purified using a semipreparative HPLC system and a C-18 column with
MeCN/H.sub.2O+0.1% TFA as eluent. Fractions containing the product
was combined and solvent removed by evaporation to give the title
compound as a colourless solid.
[0286] Obtained 53 mg (62% yield).
[0287] Purity by NMR>98%
[0288] LC-MS (APCI) m/z 370.0 (MH+).
[0289] .sup.1H-NMR (DMSO-d.sub.6): .delta. 10.74 (s, 1H), 8.02 (s,
1H), 7.31 (m, 2H), 7.12 (m, 2H), 3.61 (m, 2H), 3.51 (d, 1H), 3.34
(d, 1H), 2.86 (m, 2H), 2.63 (m, 1H), 1.82 (m, 2H), 1.63 (m, 2H),
1.34 (s, 3H).
(5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonylmethyl]-5-phenethyl-imi-
dazolidine-2,4-dione
[0290] The title compound was prepared as described in the
synthesis of
(5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonylmethyl]-5-methyl-imida-
zolidine-2,4-dione.
1-[4-4(Fluorophenyl)-piperidine-1-sulfonyl]-4-phenyl-butan-2-one
(93 mg; 0.24 mmol), KCN (40 mg; 0.61 mmol) and (NH).sub.2CO.sub.3
(117 mg; 1.22 mmol) gave 37 mg (33%) of the title compound.
[0291] LC-MS (APCI) m/z 460.1 (MH+).
[0292] .sup.1H-NMR (DMSO-d.sub.6): .delta. 10.87 (s, 1H), 8.13 (s,
1H), 7.30 (m, 4H), 7.15 (m, 5H), 3.63 (m, 2H), 3.56 (d, 1H), 3.41
(d, 1H), 2.87 (m, 2H), 2.61 (m, 2H), 2.39 (m, 1H), 1.92 (bt, 2H),
1.83 (m, 2H), 1.63 (m, 2H).
(5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonylmethyl]-5-(3-imidazol-1-
-yl-propyl)-imidazolidine-2,4-dione
[0293]
1-[4-4(Fluorophenyl)-piperidine-1-sulfonyl]-5-imidazol-butan-2-one
(75 mg; 0.19 mmol), KCN (30 mg; 0.46 mmol) and
(NH.sub.4).sub.2CO.sub.3 (91 mg; 0.95 mmol) was dissolved in
EtOH/H.sub.2O (1/1) (10 mL) in a sealed 22 mL tube and stirred for
17.5 h at 70.degree. C. Another portion of KCN (40 mg; 0.61 mmol)
and (NH.sub.4)CO.sub.3 (250 mg; 2.60 mmol) was added and the
mixture was stirred at 70.degree. C. for another 16 h. Evaporation
of solvent and the residual material was suspended in H.sub.2O,
precipitating crude product was removed by filtration and purified
using a semipreparative HPLC system and a C-18 column with
MeCN/H.sub.2O+0.1% TFA as eluent. Fractions containing the product
was combined and MeCN was removed by evaporation, the acidic
waterphase was made basic, pH=-8-9, using 5% KHCO.sub.3 and the
precipitating product was extracted using EtOAc. Organic phase
dried (Na.sub.2SO.sub.4), filtered and evaporated to give the title
compound as a colourless solid.
[0294] Obtained 60 mg (68% yield)
[0295] LC-MS (APCI) m/z 464.2 (MH+).
[0296] .sup.1H-NMR (DMSO-d.sub.6): .delta. 10.75 (bs, 1H), 8.06 (s,
1H), 7.59 (s, 1H), 7.30 (m, 2H), 7.16-7.08 (m, 3H), 6.88 (s, 1H),
3.95 (m, 2H), 3.60 (m, 2H), 3.47 (d, 1H), 3.35 (d, 1H), 2.86 (m,
2H), 2.62 (m, 1H), 1.86-1.50 (m, 8H).
(5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonylmethyl]-5-(3-pyrimidin--
2-yl-propyl)-imidazolidine-2,4-dione
[0297] Crude
1-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonyl]-5-pyrimidin-2-yl-pentan-2-o-
ne (234 mg; max 0.58 mmol), KCN (151 mg; 2.3 mmol) and
(NH.sub.4).sub.2CO.sub.3 (557 mg; 5.8 mmol) was suspended in
EtOH(H.sub.2O (1/1) (26 mL) in a 40 mL sealed tube. The mixture was
heated 70.degree. C. and the resulting yellow solution was stirred
for 16 h. LC/MS analysis showed that 15% unreacted ketone remained
and another portion of KCN (65 mg; 1 mmol) and
(NH.sub.4).sub.2CO.sub.3 (245 mg; 2.55 mmol) was added and the
mixture was heated to 70.degree. C. for another 16 h. Solvent was
removed by evaporation and the residue was treated with H.sub.2O
(25 mL). The precipitating crude product was removed by filtration
and purified using semipreparative HPLC system and a C-18 column
with MeCN/H.sub.2O+0.1% TFA as eluent. Fractions containing the
product was combined and MeCN was removed by evaporation, the
acidic waterphase was made basic, pH=8-9, using 5% KHCO.sub.3 and
the precipitating product was filtered off, washed with water and
dried in a desiccator under reduced pressure at 40.degree. C. over
night. This gave the title compound as a colourless solid.
Purity>98% by NMR.
[0298] Obtained 120 mg (43% yield, 2 steps).
[0299] LC-MS (APCI) m/z 476.2 (MH+).
[0300] .sup.1H-NMR (DMSO-d.sub.6): .delta. 10.77 (s, 1H), 8.72 (d,
2H), 8.03 (s, 1H), 7.36-7.27 (m, 3H), 7.15-7.09 (m, 2H), 3.60 (m,
2H), 3.50 (d, 1H), 3.34 (d, 1H), 2.92-2.80 (m, 4H), 2.62 (m, 1H),
1.86-1.54 (m, 8H).
[0301] The following compounds were prepared as described in the
synthesis of
(5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonylmethyl]-5-(3-pyrimi-
din-2-yl-propyl)-imidazolidine-2,4-dione.
(5R,S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-meth-
yl-imidazolidine-2,4-dione
[0302] Purification not needed, after evaporation of reaction
mixture and addition of water the precipitating product was pure
enough >98% by HPLC (220 nm, 254 nm) and NMR.
[0303] Obtained 147 mg (71% yield, 2 steps) of the title compound
as a colorless solid.
[0304] LC-MS (APCI) m/z 403.1 (MH+).
[0305] .sup.1H-NMR (DMSO-d.sub.6): .delta. 10.73 (bs, 1H), 8.20 (d,
1H), 8.01 (s, 1H), 7.81 (dd, 1H), 6.87 (d, 1H), 5.09 (m, 1H), 3.52
(d, 1H), 3.35 (d, 1H), 3.42-3.26 (m, 2H+H.sub.2O), 3.18-3.06 (m,
2H), 2.08-1.96 (m, 2H), 1.79-1.65 (m, 2H), 1.33 (s, 3H).
(5S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-methyl-
-imidazolidine-2,4-dione and
(5R)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-methy-
l-imidazolidine-2,4-dione
[0306] The corresponding racemic material (74 mg), was dissolved in
36 mL of isoHexane/EtOH (25/75) and separated into the pure
enantiomers by using the following Gilson HPLC system: Column:
CHIRALCEL OD, 2.0.times.25 cm, flow=6.0 mL/min,
eluent=isoHexane/EtOH (25/75), temp=ambient, detector UV=220 nm.
The enantiomers were collected and analysed on a CHIRALCEL OD-H,
0.46.times.25 cm, 0.5 mL/min, isoHexane/EtOH (25/75), ambient
temperature, 220 nm.
[0307] Rt=9.88 min. ee>99% for the faster eluting enantiomer, 29
mg (39%).
[0308] Rt=11.45 min. ee=98.7% for the slower eluting enantiomer, 27
mg (36%).
[0309] LC-MS (APCI) m/z 403.1 (MH+).
(5R,S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-phen-
ethyl-imidazolidine-2,4-dione
[0310] Starting from crude
1-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonyl]-4-phenyl-butan-2-o-
ne (258 mg; max 0.51 mmol). Purification of crude product was made
on 70 g Si-60 gel using DCM+5% MeOH as eluent.
[0311] Purity>96% by NMR and HPLC (220 nm, 254 nm).
[0312] Obtained 201 mg (80% yield, 2 steps) of the title compound
as a colourless solid.
[0313] LC-MS (APCI) m/z 493.0 (MH+).
[0314] .sup.1H-NMR (DMSO-d.sub.6): .delta. 10.86 (bs, 1H), 8.21
(bd, 1H), 8.13 (s, 1H), 7.81 (dd, 1H), 7.33-7.24 (m, 2H), 7.22-7.14
(m, 3H), 6.87 (d, 1H), 5.10 (m, 1H), 3.56 (d, 1H), 3.42 (d, 1H),
3.43-3.28 (m, 2H+H.sub.2O), 3.20-3.08 (m, 2H), 2.66-2.52 (m, 1H),
2.45-2.31 (m, 1H), 2.08-1.96 (m, 2H), 1.96-1.83 (m, 2H), 1.81-1.65
(m, 2H.
(5R,S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-(3-i-
midazol-1yl-propyl)-imidazolidine-2,4-dione
[0315] Starting from crude
1-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonyl]-5-imidazol-1-yl-pe-
ntan-2-one (268 mg; max 0.51 mmol).
[0316] Obtained 151 mg (59% yield, 2 steps) of the title compound
as a colourless solid.
[0317] Purity>98% by NMR.
[0318] LC-MS (APCI) m/z 497.2 (MH+).
[0319] .sup.1H-NMR (DMSO-d.sub.6): .delta. 10.81 (bs, 1H), 8.20 (d,
1H), 8.05 (s, 1H), 7.81 (dd, 1H), 7.59 (bs, 1H), 7.13 (bs, 1H),
6.88 (bs, 1H), 6.87 (d, 1H), 5.08 (m, 1H), 3.47 (d, 1H), 3.40-3.28
(m, 3H+H.sub.2O), 3.17-3.06 (m, 2H), 2.07-1.95 (m, 2H), 1.79-1.64
(m, 3H), 1.61-1.48 (m, 3H).
(5R,S)-5-[4-(5-Chloro-Pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-(3-p-
yrimidin-2-yl-propyl)-imidazolidine-2,4-dione
[0320] Starting from crude
1-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonyl]-5-pyrimidin-2-yl-p-
entan-2-one (244 mg; max 0.51 mmol).
[0321] Obtained 105 mg (49% yield, 2 steps) of the title compound
as a colourless solid.
[0322] Purity>98% by NMR
[0323] .sup.1H-NMR (DMSO-d.sub.6): .delta. 10.77 (bs, 1H), 8.72 (d,
2H), 8.20 (d, 1H), 8.03 (s, 1H), 7.81 (dd, 1H), 7.34 (t, 1H), 6.87
(d, 1H), 5.08 (m, 1H), 3.50 (d, 1H), 3.41-3.29 (m, 3H+H.sub.2O),
3.16-3.07 (m, 2H), 2.83 (t, 2H), 2.06-1.96 (m, 2H), 1.81-1.66 (m,
5H), 1.63-1.51 (m, 1H).
(5S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-(3-pyr-
imidin-2-yl-propyl)-imidazolidine-2,4-dione and
(5R)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-(3-py-
rimidin-2-yl-propyl)-imidazolidine-2,4-dione
[0324] The corresponding racemic material (40 mg), was dissolved in
26 mL of isoHexane/EtOH (25/75) and separated into the pure
enantiomers by using the same conditions as described for
separation of
(5R,S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-met-
hyl-imidazolidine-2,4-dione.
[0325] Rt=17.6 min. ee>99% for the faster eluting enantiomer, 17
mg (42%).
[0326] Rt=21.0 min. ee=98.9% for the slower eluting enantiomer, 15
mg (37%).
[0327] LC-MS (APCI) m/z 509 (MH+).
5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-ethyli-
midazolidine-2,4-dione
[0328] LC-MS (APCI) m/z 417 (MH+).
[0329] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.76 (3H, t); 1.63 (2H,
q); 1.66-1.76 (2H, m); 1.96-2.06 (2H, m); 3.12 (2H, bt); 3.48, 3.35
(1H each, ABq, J=14.9); 3.32-3.41 (2H, m); 5.04-5.12 (1H, m); 6.86
(1H, d); 7.80 (1H, dd); 7.96 (1H, s); 8.19 (1H, d); 10.73 (1H,
s).
[0330] LC-MS (APCI) m/z 417 (MH+).
5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-propyl-
imidazolidine-2,4-dione
[0331] LC-MS (APCI) m/z 431 (MH+).
[0332] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.84 (3H, t); 1.03-1.16
(1H, m); 1.20-1.35 (1H, m); 1.58 (2H, t); 1.65-1.77 (2H, m);
1.96-2.06 (2H, m); 3.11 (2H, t); 3.21-3.42 (3H, D.sub.2O); 3.48
(1H, half ABq, J=14.9); 5.04-5.12 (1H, m); 6.86 (1H, d); 7.80 (1H,
dd); 7.99 (1H, s); 8.19 (1H, d); 10.74 (1H, s).
5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-(2-met-
hylpropyl)imidazolidine-2,4-dione
[0333] LC-MS (APCI) m/z 445 (MH+).
[0334] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.81 (3H, d); 0.88 (3H,
d); 1.50-1.59 (3H, m); 1.64-1.78 (2H, m); 1.95-2.05 (2H, m);
3.06-3.16 (2H, m); 3.22-3.41 (3H, D.sub.2O); 3.46 (1H half Abq,
J=15.1); 5.03-5.12 (1H, m); 6.86 (1H, d); 7.80 (1H, dd); 7.99 (1H,
bs); 8.19 (1H, d); 10.71 (1H, bs).
5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-(2-pyr-
imidin-2-ylethyl)imidazolidine-2,4-dione
[0335] LC-MS (APCI) m/z 495 (MH+).
[0336] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.66-1.78 (2H, m);
1.96-2.16 (4H, m); 2.64-2.76 (1H, m); 2.84-2.95 (1H, m); 3.08-3.18
(2H, m); 3.33-3.41 (2H, m); 3.43, 3.57 (1H each, ABq, J=14.9);
5.04-5.12 (1H, m); 6.86 (1H, d); 7.34 (1H, t); 7.80 (1H, dd); 8.12
(1H, d); 8.19 (1H, d); 8.70 (1H, d); 10.84 (1H, s).
5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-[(3-me-
thylphenyl)methyl]imidazolidine-2,4-dione
[0337] LC-MS (APCI) m/z 493 (MH+).
[0338] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.66-1.78 (2H, m);
1.96-2.07 (2H, m); 2.23 (3H, s); 2.84 (2H, s); 3.09-3.20 (2H, m);
3.34-3.43 (2H, m); 3.45, 3.69 (1H each, ABq, J=14.7 Hz); 5.06-5.13
(1H, m); 6.87 (1H, d); 6.93-6.98 (2H, m); 7.01-7.06 (1H, m);
7.10-7.17 (1H, m); 7.81 (1H, dd); 8.08 (1H, s); 8.20 (1H, d); 10.35
(1H, s).
5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-(tetra-
hydro-2H-pyran-4-ylmethyl)imidazolidine-2,4-dione
[0339] LC-MS (APCI) m/z 487 (MH+).
[0340] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.06-1.26 (2H, m);
1.39-1.77 (7H, m); 1.95-2.05 (2H, m); 3.06-3.27 (4H, m); 3.27-3.41
(3H, D.sub.2O); 3.48 (1H half ABq, J=15.0 Hz); 3.69-3.79 (2H, m);
5.03-5.12 (1H, m); 6.85 (1H, d); 7.80 (1H, dd); 8.03 (1H, bs); 8.19
(1H, d); 10.79 (1H, s).
5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-(3-mor-
pholin-4-ylpropyl)imidazolidine-2,4-dione trifluoroacetic acid
[0341] LC-MS (APCI) m/z 517 (MH+).
[0342] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.40-1.78 (6H, m);
1.96-2.06 (2H, m); 2.94-3.18 (6H, m); 3.31-3.44 (5H, m); 3.54 (1H
half Abq, J=14.9 Hz); 3.60 (2H, t); 3.90-4.01 (2H, m); 4.25-6.27
(1H); 6.85 (1H, d); 7.80 (1H, dd); 8.05 (1H, bs); 8.19 (1H, d);
9.52 (1H, bs); 10.88 (1H, s).
3-{4-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-2,5-d-
ioxoimidazolidin-4-yl}propanenitrile
[0343] LC-MS (APCI) m/z 442 (MH+).
[0344] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.66-1.78 (2H, m);
1.95-2.05 (4H, m); 2.37-2.57 (2H, DMSO-d.sub.6); 3.07-3.17 (2H, m);
3.25-3.40 (2H, D.sub.2O); 3.42, 3.52 (1H each, Abq, J=14.7);
5.04-5.12 (1H, m); 6.86 (1H, d); 7.80 (1H, dd); 7.99 (1H, bs); 8.20
(1H, d); 10.91 (1H, s).
1,1-dimethylethyl
3-{4-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-2,5--
dioxoimidazolidin-4-yl}propylcarbamate
[0345] LC-MS (APCI) m/z 547, 490 (MH+); (MH+)-tBu.
[0346] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.10-1.27 (1H, m);
1.27-1.43 (9H, s); 1.52-1.77 (4H, m); 1.94-2.06 (2H, m); 2.80-2.90
(2H, m); 3.06-3.16 (2H, m); 3.22-3.40 (4H, D.sub.2O); 3.47 (1H half
ABq, J=15.1 Hz); 5.03-5.12 (1H, m); 6.76-6.88 (2H, m); 7.80 (1H,
dd); 7.95 (1H, bs); 8.19 (1H, d); 10.73 (1H, bs).
5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-(2-mor-
pholin-4-ylethyl)imidazolidine-2,4-dione
[0347] Not purified.
[0348] LC-MS (APCI) m/z 502 (MH+).
5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-phenyl-
imidazolidine-2,4-dione
[0349] Not purified.
[0350] LC-MS (APCI) m/z 465 (MH+).
5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-(4-flu-
orophenyl)imidazolidine-2,4-dione
[0351] Not purified.
[0352] LC-MS (APCI) m/483 (MH+).
5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-(1H-im-
idazol-4-yl)imidazolidine-2,4-dione
[0353] Not purified.
[0354] LC-MS (APCI) m/z 455 (MH+).
4-{4-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-2,5-d-
ioxoimidazolidin-4-yl}benzamide
[0355] Not purified.
[0356] LC-MS (APCI) m/z 508 (MH+).
5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-[2-(1H-
-1,2,4-triazol-1-yl)ethyl]imidazolidine-2,4-dione
[0357] Not purified.
[0358] LC-MS (APCI) m/z 484 (MH+).
5-({[4-(4-fluorophenyl)piperidin-1-yl]sulfonyl}methyl)-5-(2-pyrimidin-2-yl-
ethyl)imidazolidine-2,4-dione
[0359] LC-MS (APCI) m/z 462 (MH+).
[0360] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.62 (2H, dq); 1.77-1.86
(2H, m); 2.07-2.19 (2H, m); 2.57-2.76 (2H, m); 2.81-2.96 (3H, m);
3.42, 3.56 (1H each, ABq, J=14.6 Hz); 3.59-3.68 (2H, m); 7.11 (2H,
t); 7.27-7.36 (3H, m); 8.08 (1H, bs); 8.71 (1H, d); 10.84 (1H,
bs).
5-({[4-(4-fluorophenyl)piperidin-1-yl]sulfonyl}methyl)-5-(tetrahydro-2H-py-
ran-4-ylmethyl)imidazolidine-2,4-dione
[0361] LC-MS (APCI) m/z 454 (MH+).
[0362] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.07-1.28 (2H, m);
1.40-1.68 (7H, m); 1.77-1.85 (2H, m); 2.56-2.67 (1H, m); 2.85 (2H,
dq); 3.22 (2H, dq); 3.39-3.45 (1H, m); 3.48 (1H half ABq, J=14.5
Hz); 3.53-3.66 (2H, m); 3.75 (2H, dt); 7.11 (2H, t); 7.26-7.33 (2H,
m); 8.00 (1H, bs); 10.68 (1H, bs).
4-[4-({[4-(4-fluorophenyl)piperidin-1-yl]sulfonyl}methyl)-2,5-dioxoimidazo-
lidin-4-yl]benzamide
[0363] LC-MS (APCI) m/z 475 (MH+).
[0364] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.61 (2H, dq); 1.77-1.88
(2H, m); 2.58-2.69 (1H, m); 2.85-3.01 (2H, m); 3.60 (1H half ABq,
J=14.6 Hz); 3.60-3.69 (2H, m); 7.12 (2H, t); 7.26-7.34 (2H, m);
7.42 (1H, bs); 7.65 (2H, d); 7.91 (2H, d); 8.01 (1H, bs); 8.85 (1H,
s); 10.95 (1H, bs).
5-({[4-(4-fluorophenyl)piperidin-1-yl]sulfonyl}methyl)-5-(1H-imidazol-4-yl-
)imidazolidine-2,4-dione
[0365] Not purified.
[0366] LC-MS (APCI) m/z 422 (MH+).
5-({[4-(4-chlorophenyl)piperidin-1-yl]sulfonyl}methyl)-5-(tetrahydro-2-pyr-
an-4-ylmethyl)imidazolidine-2,4-dione
[0367] LC-MS (APCI) m/z 470 (MH+).
[0368] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.07-1.28 (2H, m);
1.40-1.68 (7H, m); 1.76-1.85 (2H, m); 2.56-2.68 (1H, m); 2.85 (2H,
q); 3.22 (2H, q); 3.48 (1H half ABq, J=14.5 Hz); 3.53-3.67 (2H, m);
3.75 (2H, t); 7.26-7.37 (4H, m); 8.02 (1H, bs); 10.79 (1H, bs).
5-({[4-(4-chlorophenyl)piperidin-1-yl]sulfonyl}methyl)-5-(3-morpholin-4-yl-
propyl)imidazolidine-2,4-dione trifluoroacetic acid
[0369] LC-MS (APCI) m/z 499 (MH+).
[0370] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.41-1.87 (8H, m);
2.56-2.69 (1H, m); 2.86 (2H, q); 2.95-3.14 (4H, m); 3.33-3.44 (3H,
m); 3.52 (1H half ABq, J=14.6 Hz); 3.55-3.69 (4H, m); 3.90-4.00
(2H, m); 7.25-7.37 (4H, m); 8.07 (1H, s); 9.89 (1H, bs); 10.87 (1H,
s).
(5R,S)-5-Methyl-5-[({4-[5-(trifluoromethyl)pyridin-2-yl]piperazine-1-yl}su-
lfonyl)methyl]imidazolidine-2,4-dione
[0371] LC-MS (APCI) m/z 422.1 (MH+).
[0372] Purity>95% by NMR.
[0373] .sup.1H-NMR (DMSO-d.sub.6): .delta. 10.75 (1H, s); 8.44 (1H,
d); 8.02 (1H, s); 7.85 (1H, dd); 7.03 (1H, d); 3.75 (4H, m); 3.55
(1H, d); 3.35 (1H, d); 3.21 (4H, m); 1.31 (3H, s).
6-(4-{[({4R,S}-4-methyl-2,5-dioxoimidazolidin-4-yl)methyl]sulfonyl}piperaz-
in-1-yl)pyridine-3-carbonitril
[0374] LC-MS (APCI) m/z 379.1 (MH+).
[0375] Purity>99% by NMR.
[0376] .sup.1H-NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 8.52 (1H,
d); 8.00 (1H, s); 7.90 (1H, dd); 7.00 (1H, d); 3.78 (4H, m); 3.55
(1H, d); 3.36 (1H, d); 3.20 (4H, m); 1.31 (3H, s).
(5R,S)-5-({[4-(4-fluorophenyl)piperazine-1-yl]sulfonyl}methyl)-5-methylimi-
dazolidine-2,4-dione
[0377] LC-MS (APCI) m/z 371.1 (MH+).
[0378] Purity>98% by NMR.
[0379] .sup.1H-NMR (DMSO-d.sub.6): .delta. 10.75 (1H, s); 8.03 (1H,
s); 7.11-6.95 (4H, m); 3.56 (1H, d); 3.36 (1H, d); 3.25 (4H, m);
3.15 (4H, m); 1.33 (3H, s).
(5R,S)-5-[({4-[(4-fluorophenyl)methyl]piperazine-1-yl}sulfonyl)methyl]-5-m-
ethylimidazolidine-2,4-dione
[0380] LC-MS (APCI) m/z 385.1 (MH+).
[0381] Purity>95% by NMR.
[0382] .sup.1H-NMR (DMSO-d.sub.6): .delta. 10.72 (1H, s); 7.99 (1H,
s); 7.33 (2H, m); 7.15 (2H, m); 3.50 (2H, s); 3.49 (1H, d); 3.30
(1H, d); 3.12 (4H, m); 2.42 (4H, m); 1.32 (3H, s).
(5R,S)-5-methyl-5-{[4-pyrimidin-2-ylpiperazine-1-yl)sulfonyl]methyl}imidaz-
olidine-2,4-dione
[0383] LC-MS (APCI) m/z 355.1 (MH+).
[0384] Purity>99% by NMR.
[0385] .sup.1H-NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 8.40 (2H,
d); 8.01 (1H, s); 6.68 (1H, t); 3.83 (4H, m); 3.53 (1H, d); 3.33
(1H, d); 3.18 (4H, m); 1.31 (3H, s).
5-(3-aminopropyl)-5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfony-
l)methyl]imidazolidine-2,4-dione trifluoroacetic acid
[0386] 1,1-dimethylethyl
3-{4-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-2,5--
dioxoimidazolidin-4-yl}propylcarbamate (426 mg, 0.78 mmol) was
dissolved in 10 mL CH.sub.2Cl.sub.2 and 4 mL of TFA was added. The
reaction was stirred at rt for 1 hour. The solvent was removed to
give 408 mg (93%) of the title compound as a white solid.
[0387] LC-MS (APCI) m/z 446 (MH+).
[0388] .sup.1H NMR (CD.sub.3OD): .delta. 1.48-1.63 (1H, m);
1.69-1.96 (5H, m); 2.01-2.12 (2H, m); 2.93 (2H, t); 3.20-3.29 (2H,
m); 3.40, 3.60 (1H each ABq, J=14.6 Hz); 3.44-3.54 (2H, m); 4.85
(4H, D.sub.2O); 5.14-5.22 (1H, m); 6.78 (1H, d); 7.67 (1H, dd);
8.08 (1H, d).
5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-piperidin-4-
-yl-imidazolidine-2,4-dion hydro chloride
[0389]
4-{4-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-2,5-
-dioxo-imidazolidin-4-yl}-piperidine-1-carboxylic acid tert-butyl
ester (100 mg, 0.16 mmol) was solved in 2 M hydrogen chloride
(ethyl acetate, 30 ml) and methanol (5 ml). The solution was
stirred at 50.degree. C. for 1 hour. Evaporation afforded 90.5 mg
(0.16 mmol) of the title compound
5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-piperidin--
4-yl-imidazolidine-2,4-dion hydro chloride in quantitative
yield.
[0390] LC-MS (APCI) m/z 472.3 (MH+).
[0391] .sup.1H NMR (DMSO-d.sub.6): .delta.10.88 (1H, s); 9.05 (1H,
d); 8.48 (1H, m); 8.21 (1H, d); 7.82 (1H, dd); 6.87 1H, d); 5.10
1H, m); 3.47 (2H, s); 3.43-3.13 (7H, m); 2.78 (2H, m); 2.02-1.39
(9H, m).
4-{4-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-2,5-dioxo--
imidazolidin-4-yl}-piperidine-1-carboxylic acid tert-butyl
ester
[0392] For preparation of the reacting ester,
piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester,
see for example Albert A Carr et al, Journal of Organic Chemistry
(1990), 55 (4), 1399-401.
[0393] LC-MS (APCI) m/z 472.3 (MH+-Boc).
5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-(tetrahydro-
-pyran-4-yl)-2,4-dion
[0394] LC-MS (APCI) m/z 403.2 (MH+).
[0395] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.77 (1H, s); 8.20 (1H,
d); 8.19 (1H, s); 7.81 (1H, dd); 6.87 (1H, d); 5.09 (1H, m); 3.88
(2H, t); 3.45 (2H, s); 3.38 (2H, m); 3.21 (2H, t); 3.13 (2H, m);
2.02 (2H, m); 1.84 (1H, t); 1.72 (2H, m); 1.60 (1H, d); 1.32 (4H,
m).
5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-pyridin-4-y-
l-imidazolidine-2,4-dion trifluoroacetic acid
[0396] LC-MS (APCI) m/z 466.2 (MH+).
[0397] .sup.1H NMR (DMSO-d.sub.6): .delta. 11.15 (1H, s); 8.97 (1H,
s); 8.76 (2H, d); 8.20 (1H, d); 7.82 (2H, dd); 7.80 (1H, d); 6.86
(1H, d); 5.10 (1H, m); 4.17 (1H, m); 3.73 (1H, d); 3.41 (2H, m);
3.17 (2H, m); 2.08 (2H, m); 1.72 (2H, m).
1,1-dimethylethyl
4-({4-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-2,5-
-dioxoimidazolidin 4-yl}methyl)piperidine-1-carboxylate
[0398] The title compound was prepared essentially as described in
the synthesis of
(5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonylmethyl]-5-methyl-imida-
zolidine-2,4-dione
[0399] LC-MS (APCI) m/z 530 (MH+-boc).
[0400] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.88-1.10 (2H, m);
1.30-1.77 (16H, m); 1.94-2.06 (2H, m); 2.53-2.77 (2H, m); 3.05-3.17
(2H, m); 3.21-3.41 (4H, D.sub.2O); 3.48 (1H half ABq, J=14.7 Hz);
3.73-3.88 (2H, m); 5.03-5.12 (1H, m); 6.86 (1H, d); 7.80 (1H, dd);
8.04 (1H, bs); 8.19 (1H, d); 10.55 (1H, bs).
5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-(piper-
idin-4-ylmethyl)imidazolidine-2,4-dione trifluoroacetate
[0401] The title compound was prepared as described in the
synthesis of
5-(3-aminopropyl)-5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfon-
yl)methyl]imidazolidine-2,4-dione trifluoroacetic acid.
[0402] LC-MS (APCI) m/z 486 (MH+).
[0403] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.17-1.40 (2H, m);
1.47-1.81 (7H, m); 1.94-2.07 (2H, m); 2.75-2.93 (2H, m); 3.06-3.42
(7H, m); 3.50 (1H half ABq, J=15.6 Hz); 5.04-5.12 (1H, m); 6.85
(1H, d); 7.80 (1H, dd); 8.06 (1H, s); 8.08-8.22 (2H, m); 8.45 (1H,
bd); 10.85 (1H, s).
N-(3-{4-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-2,-
5-dioxoimidazolidin-4-yl}propyl)methanesulfonamide
[0404]
5-(3-Aminopropyl)-5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}-
sulfonyl)methyl]imidazolidine-2,4-dione trifluoroacetic acid (100
mg, 0.18 mmol) was slurried in 2 mL DCM. DIPEA (62 .mu.L, 0.36
mmol) was added and the slurry was stirred for some minutes.
Sulfonylchloride (16 .mu.L, 0.18 mmol) was added and the reaction
was stirred at rt over night. The crude product was purified by
preparative HPLC.
[0405] LC-MS (APCI) m/z 524 (MH+).
[0406] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.19-1.52 (2H, m);
1.58-1.77 (4H, m); 1.95-2.06 (2H, m); 2.85 (3H, s); 2.83-2.93 (2H,
m); 3.12 (2H, t); 3.19-3.46 (3H, D.sub.2O); 3.50 (1H half ABq,
J=15.7 Hz); 5.04-5.12 (1H, m); 6.86 (1H, d); 6.97 (1H, t); 7.80
(1H, dd); 8.01 (1H, s); 8.19 (1H, d); 10.79 (1H, s).
EXAMPLE 9
(5R,S)-5-[4-(5-Chloro-pyridin-2-yl)-piperazine-1-sulfonylmethyl]-5-(3-pyri-
midin-2-yl-propyl)-imidazolidine-2,4-dione
##STR00198##
[0407]
1-([4-(5-Chloro-2-pyridinyl)-1-piperazinyl]sulfonyl)-5-(2-pyrimidin-
yl)-2-pentanone 0.397 g, 0.936 mmol), potassium cyanide (0.122 g,
1.87 mmol), ammonium carbonate 0.500 g, 4.68 mmol) and 50% ethanol
(4 mL) were stirred in a sealed vial at 75.degree. C. (oil temp)
for 17 hours. The ethanol was removed by rotary evaporation, pH was
adjusted to 6 with 1M HCl, the suspension was filtered, the solid
was washed with a little water, collected and dried in vacuo at
45.degree. C. Some more product was recovered from the aqueous
filtrate by adding solid sodium chloride to saturation and
extracting the mixture with acetonitrile (2.times.10 mL). Drying
with Na.sub.2SO.sub.4, filtering and concentrating the organic
phase gave a second crop. The combined crops were dissolved in
tetrahydrofuran (5-10 mL), adsorbed on silica. (3 g) and applied on
a short silica column. Elution with EtOAc followed by EtOAc-MeCN
(1:1) gave 0.30 g (65% yield) of the title compound as a white
crystalline solid.
[0408] LC-MS (APCI) m/z 494 (MH+).
[0409] .sup.1H NMR (DMSO-d.sub.6) .delta. 10.78 (1H, bs); 8.70 (2H,
d, J=5 Hz); 8.13 (1H, d, J=3 Hz); 8.02 (1H, s); 7.63 (1H, dd,
J.sub.1=3 Hz, J.sub.2=9 Hz); 7.33 (1H, t, J=5 Hz); 6.93 (1H, d,
J=10 Hz); 3.63-3.56 (4H, m); 3.52 (1H, d, J=14 Hz); 3.34 (1H, d,
J=14 Hz; obscured by water signal), 3.24-3.14 (4H, m); 2.82 (2H, t,
J=7 Hz) and 1.79-1.50 (4H, m's). .sup.13C NMR (DMSO-d.sub.6)
.delta. 175.6, 169.5, 157.2, 157.0, 156.5, 145.6, 137.3, 119.2,
119.1, 108.8, 62.4, 52.7, 44.5, 38.2, 36.4 and 21.2.
[0410] The starting materials were prepared as follows:
1-([4-(5-Chloro-2-pyridinyl)-1-piperazinyl]sulfonyl)-5-(2-pyrimidinyl)-2-p-
entanone
##STR00199##
[0411] A stirred solution of
1-(5-Chloro-2-pyridinyl)-1-methylsulfonyl piperazine (0.64 g, 2.32
mmol) in dry THF (25 mL, 40 rel vol), under nitrogen, was cooled to
-10.degree. C. causing the sulfonamide to precipitate out of
solution. LHMDS 1M in THF (4.64 mL, 4.64 mmol) was added dropwise,
over 4 min, to the suspension of sulfonamide, the mixture was then
stirred for 40 min. 4-(2-Pyrimidinyl)-butyric acid ethyl ester
(0.68 g, 3.48 mmol) (example 8) in dry THF (6.4 mL, 10 rel vol) was
added dropwise, over 4 min, and the mixture stirred for 30 min. The
mixture was quenched with saturated NH.sub.4Cl (0.64 mL, 1 rel vol)
and evaporated to a semi-solid residue. The residue was taken up in
DCM (20 rel vol) and the organic layer was washed with water (15
mL, 24 rel vol), brine (15 mL, 24 rel vol), and dried with
MgSO.sub.4. Removal of the solvent by rotary evaporation gave the
crude product as an off white solid (0.84 g, 85%). The crude
product was purified by Biotage FLASH chromatography, using ethyl
acetate/isohexane (90:10) as eluant, to give pure ketone as a white
amorphous solid.
1-(5-Chloro-2-pyridinyl)-1-methylsulfonyl piperazine
[0412] To a solution containing 1-(5-Chloro-2-pyridinyl)-piperazine
(1 eq.) in toluene (25 volumes) is added triethylamine (1.1 eq),
and the mixture is cooled down to 5.degree. C. in an ice bath.
Methanesulfonyl chloride diluted with toluene (0.5 vols) is slowly
added to the cooled 0 solution, keeping the temperature below
10.degree. C. Once the addition is finished, the reaction is
allowed to warm-up to room temperature. Water (6.6 vols) is added
and the mixture is filtered and cake slurried in Toluene (2 vols).
The cake is then washed with Toluene (2 vols) and dried in a vacuum
oven at 40.degree. C. overnight.
1-(5-Chloro-2-pyridinyl)-piperazine
##STR00200##
[0413] Piperazine (4 eq) is charged in the reaction vessel as a
solid. At room temperature pyridine (1.43 vols) is added to the
vessel followed by toluene (2.14 vols). The final slurry is stirred
and heated to reflux at 120.degree. C. to obtain a complete
solution. To a separate vessel charge 2,5-dichloropyridine (DCP)
followed by Toluene (1.43 vols) to dissolve the solid. The
dissolution is endothermic, and it is necessary to warm up the
solution to 30.degree. C. to get complete solution. The solution
containing DCP is then slowly discharged into the reaction vessel
over 5 hours. At this point the remaining amount of DCP should be
about 20%. The reaction is left refluxing overnight to reach
completion. The reaction mixture is allowed to cool to room
temperature, then water is added (6 vols). The two layers are
separated, and the aqueous phase is re-extracted with Toluene (5
vols). The two organic layers are combined and re-washed with
H.sub.2O (6 vols). Finally, the organic layer is washed with brine
(6 vols).
(5S)-5-[4-(5-Chloro-pyridin-2-yl)-piperazine-1-sulfonylmethyl]-5-(3-pyrimi-
din-2-yl-propyl)-imidazolidine-2,4-dione and
(5R)-5-[4-(5-Chloro-pyridin-2-yl)-piperazine-1-sulfonylmethyl]-5-(3-pyrim-
idin-2-yl-propyl)-imidazolidine-2,4-dione
[0414] The corresponding racemic material (23 mg) was dissolved in
8 mL of isoHexane/EtOH (25/75) and separated into the pure
enantiomers by using the following Gilson HPLC system: Column:
CHIRALCEL OD, 2.0.times.25 cm, flow=6.0 mL/min,
eluent=isoHexane/EtOH (25/75), temp=ambient, detector UV=230 nm.
The enantiomers were collected and analysed on a CHIRALCEL OD-H,
0.46.times.25 cm, 0.5 mL/min, isoHexane/EtOH (25/75), ambient
temperature, 220 nm.
[0415] Rt=11.5 min. ee>99% for the faster eluting enantiomer,
8.7 mg (37%).
[0416] LC-MS (APCI) m/z 494.1 (MH+).
[0417] [.alpha.].sub.D=-26.4.degree.. (c=0.0022 g/mL, EtOH,
t=20.degree. C.)
[0418] Rt=14.5 min. ee=98% for the slower eluting enantiomer, 9 mg
(39%).
[0419] LC-MS (APCI) m/z 494.1 (MH+).
[0420] [.alpha.].sub.D=+24.5.degree. (c=0.0026 g/mL, EtOH,
t=20.degree. C.)
EXAMPLE 10
[0421] The following compounds were prepared using a method
analogous to that described in Example 8 or 9.
##STR00201##
EXAMPLE 11
[0422] Compounds with the general formula
##STR00202##
were synthesised according to the method described in Example 8
TABLE-US-00007 R R2 z Analysis.sup.(1) ##STR00203## Me S GC/MS m/z
242 (M.sup.+) ##STR00204## Me S GC/MS m/z 267 (M.sup.+)
##STR00205## Me S GC/MS m/z 326 (M.sup.+) ##STR00206## Me SO2 LC/MS
m/z 275 (MH+) ##STR00207## Me SO2 -- .sup.(1)For NMR-data see
experimental part.
1-(1,1'-biphenyl-4-ylthio)propan-2-one
[0423] 1-[(4-bromophenyl)thio]propan-2-one (357 mg, 1.46 mmol) was
treated with phenyl boronic acid (231 mg, 1.89 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloro palladium (II)
complex with dichloromethane (1:1) (36 mg), toluene (20 ml),
methanol (7.5 ml), saturated sodium carbonate solution (3.5 ml) and
were stirred together at 80.degree. C. for 18 hours. After cooling
the reaction mixture was treated with dilute hydrochloric acid and
extracted into ethyl acetate. The product was purified by flash
chromatography on silica, eluting with 25% ethyl acetate:
iso-hexane to give 277 mg product.
[0424] GC/MS m/z: 242 [M.sup.+].
[0425] .sup.1H NMR (CDCl.sub.3): .delta. 2.33 (3H, s); 3.73 (2H,
s); 7.37 (1H, s); 7.42-7.48 (4H, m); 7.54-7.59 (4H, m).
[0426] The following compounds were prepared as described in the
synthesis of 1-(1,1'-biphenyl-4-ylthio)propan-2-one
4'-[(2-oxopropyl)thio]-1,1'-biphenyl-4-carbonitrile
[0427] GC/MS m/z 267 [M+].
[0428] .sup.1H NMR (CDCl.sub.3): .delta. 2.34 (3H, s); 3.75 (2H,
s); 7.44, 7.54 (4H, abq, J=8.5 Hz); 7.67, 7.74 (4H, abq, J=8.5
Hz).
1-({4'-[(trifluoromethyl)oxy]-1,1'-biphenyl-4-yl}thio)propan-2-one
[0429] GC/MS m/z: 326 [M+].
[0430] .sup.1H NMR (CDCl.sub.3): .delta. 2.34 (3H, s); 3.73 (2H,
s); 7.30 (2H, d); 7.43 (2H, d); 7.51 (2H, d); 7.58 (2H, d).
1-(1,1'-biphenyl-4-ylsulfonyl)propan-2-one
[0431] 1-(1,1'-biphenyl-4-ylthio)propan-2-one (69 mg, 0.28 mmol)
was stirred at room temperature with sodium bicarbonate (72 mg,
0.85 mmol), oxone ((525 mg, 0.85 mmol), water (5 ml) and methanol
(10 ml) for 3 hours. Water (50 ml) was added and the product
extracted into ethyl acetate (3.times.25 ml). The extracts were
brine washed, sodium sulphate dried and evaporated to give 78 mg
(99%) product that was of sufficient purity to use with out ether
purification.
[0432] LC-MS (APCI) m/z 275 (MH+).
[0433] .sup.1H NMR (CDCl.sub.3): .delta. 2.47 (3H, s); 4.22 (2H,
s); 7.44-7.54 (3H, m); 7.64 (2H, d); 7.80, 7.97 (4H, abq, J=8.6
Hz).
4'-[(2-oxopropyl)sulfonyl]-1,1'-biphenyl-4-carbonitrile
[0434] The title compound was prepared as described in the
synthesis of 1-(1,1'-biphenyl-4-ylsulfonyl)propan-2-one.
[0435] .sup.1H NMR (DMSO-d.sub.6): .delta. 2.48 (3H, s); 4.23 (2H,
s); 7.74 (2H, d); 7.81 (4H, t); 8.02 (2H, d).
Hydantoins of Formula I
[0436] The following compounds were prepared as described in the
synthesis of
(5R,S)-5-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonylmethyl]-5-methyl-im-
idazolidine-2,4-dione (Example 8).
TABLE-US-00008 R R2 z Analysis.sup.(1) ##STR00208## Me SO2 m/z 396
(MH+) ##STR00209## Me S(O) m/z 413 (MH+) ##STR00210## Me SO2 m/z
345 (MH+) ##STR00211## Me SO2 m/z 370 (MH+) .sup.(1)For NMR-data
see experimental part.
(5R,S)-[4-(5-Chloro-pyridin-2-yloxy)-benzenesulfonylmethyl]-5-methyl-imida-
zolidine-2,4-dione
[0437] LC-MS (APCI) m/z 396 (MH+).
[0438] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.27 (3H, s); 3.71, 3.78
(1H each, ABq, J=15.0); 7.23 (1H, d); 7.36-7.41 (2H, m); 7.82-7.87
(3H, m); 8.04 (1H, dd); 8.27 (1H, d); 10.79 (1H, s).
5-chloro-2-{[4-(methylsulfonyl)phenyl]oxy}pyridine
[0439] 2,5-dichloropyridine (1.48 g; 10 mmol),
4-methylsulfonylphenol (1.89 g; 11 mmol) and Cs.sub.2CO.sub.3 (4.24
g; 13 mmol) was slurried in 75 mL of NMP. The slurry was heated to
approx 170.degree. C. over night. After cooling the
Cs.sub.2CO.sub.3 was filtered off and the solvent was extracted
between H.sub.2O and EtOAc. The organic phase was dried over
Na.sub.2SO.sub.4 and evaporated. Heptane:EtOAc 2:1 was added to the
residue and the crystals was filtered off. 1.42 g (50%).
[0440] LC-MS (APCI) m/z 284 (MH+).
[0441] .sup.1H NMR CDCl.sub.3: .delta. 3.09 (3H, s); 7.02 (1H, d);
7.33 (2H, d); 7.76 (1H, dd); 8.00 (2H, d); 8.17 (1H, s).
5-methyl-5-[({4'-[(trifluoromethyl)oxy]-1,1'-biphenyl-4-yl}sulfinyl)methyl-
]imidazolidine-2,4-dione
[0442]
5-methyl-5-[({4'-[(trifluoromethyl)oxy]-1,1'-biphenyl-4-yl}thio)met-
hyl]imidazolidine-2,4-dione (48 mg, 0.112 mmol) was stirred at room
temperature with oxone (50 mg), sodium bicarbonate (50 mg), water
(5 ml) and Methanol (10 ml) for 18 hours. The solid was filtered
off and crystallized from ethanol to give 20 mg of the title
compound.
[0443] LC-MS (APCI) m/z very weak 413 (MH+).
[0444] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.41 (3H, s); 3.04-3.27
(2H, m); 7.47 (2H, d); 7.67-7.73 (2H, m); 7.78-7.90 (5H, m); 8.21
and 8.37 (1H, 2 s); 10.79 and 10.91 (1H, 2 s)
5-methyl-5-[({4'-[(trifluoromethyl)oxy]-1,1'-biphenyl-4-yl}thio)methyl]imi-
dazolidine-2,4-dione
[0445] LC-MS (APCI) m/z very weak 397 (MH+).
[0446] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.33 (3H, s); 3.29 (2H,
s); 7.42-7.45 (4H, m); 7.61 (2H, d); 7.77 (2H, d); 7.99 (1H, s);
10.75 (1H, s).
5-[(1,1'-biphenyl-4-ylsulfonyl)methyl]-5-methylimidazolidine-2,4-dione
[0447] LC-MS (APCI) m/z 345 (MH+).
[0448] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.27 (3H, s); 3.72, 3.81
(2H, abq, J=15.3 Hz); 7.45 (1H, t); 7.52 (2H, t); 7.76 (2H, d);
7.82 (1H, s); 7.88, 7.94 (4H, abq, J=8.9 Hz); 10.80 (1H, bs).
4'-{[(4-methyl-2,5-dioxoimidazolidin-4-yl)methyl]sulfonyl}-1,1'-biphenyl-4-
-carbonitrile
[0449] LC-MS (APCI) m/z very weak 370 (MH+).
[0450] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.26 (3H, s); 3.74, 3.84
(2H, abq, J=16.0 Hz); 7.81 (1H, s); 7.91-8.03 (8H, m); 10.81 (1H,
s).
EXAMPLE 12
Synthesis of Enantiomeric Pure Hydantoins
##STR00212##
[0451] Representative synthetic route is shown overleaf.
##STR00213##
Experimental Procedures
(5S)-5-({[4-(4-fluorophenyl)piperidin-1-yl}sulfonyl]methyl)-5-methylimidaz-
olidine-2,4-dione
[0452] 4-(4-Fluorophenyl)piperidine hydrochloride (63 mg, 0.29
mmol) was taken up in 3 mL of dry THF, neutralized with
diisopropylethylamine (50 .mu.L, 0.29 mmol) and cooled on an
ice-water bath.
[(4S)-4-methyl-2,5-dioxo-imidazolodin-4-yl]methanesulfonyl chloride
(80 mg, 0.35 mmol) was added and after stirring for 10 min,
diisopropylethylamine (50 .mu.L, 0.29 mmol) was added and the
reaction mixture was stirred at ambient temperature until LC-MS
(APCI) indicated consumption of the amine. The reaction mixture was
evaporated and the residue taken up in EtOH and heated to
50.degree. C. and allowed to cool before water was added. The
precipitated product was collected and washed with EtOH/water and
dried in vacuum to yield 87 mg.
[0453] LC-MS (APCI) m/z 370 (MH+).
[0454] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.73 (1H, s); 8.01 (1H,
s); 7.29 (2H, dd); 7.11 (2H, dd); 3.61 (2H, dd); 3.50, 3.33 (1H
each, ABq, J=14.7 Hz); 2.91-2.80 (2H, m); 2.67-2.57 (1H, m); 1.82
(2H, d); 1.62 (2H, ddd); 1.33 (3H, s).
[0455] The starting materials were prepared as follows:
5-methyl-5-{[(phenylmethyl)thio]methyl}imidazolidine-2,4-dione
[0456] A steel vessel was charged with ethanol and water (315
mL/135 mL). 31.7 g (0.175 mol) of benzylthioacetone, 22.9 g (0.351
mol) of potassium cyanide and 84.5 g (0.879 mol) of ammonium
carbonate was added. The closed reaction vessel was kept in an oil
bath (bath temperature 90.degree. C.) under vigorous stirring for 3
h. The reaction vessel was cooled with ice-water (0.5 h), the
yellowish slurry was evaporated to dryness and the solid residue
partitioned between 400 mL water and 700 mL ethylacetate and
separated. The water-phase was extracted with ethylacetate (300
mL). The combined organic phases were washed with saturated brine
(150 mL), dried (Na.sub.2SO.sub.4), filtered and evaporated to
dryness. If the product did not crystallize, 300 mL of
dichloromethane was added to the oil. Evaporation gave the product
as a slightly yellowish powder, 43.8 g (90%).
[0457] LC-MS (APCI) m/z 251.1 (MH+).
[0458] .sup.1H NMR (DMSO-d.sub.6) .delta.: 10.74 (1H, s); 8.00 (1H,
s); 7.35-7.20 (5H, m); 3.76 (2H, s); 2.72, 2.62 (1H each, ABq,
J=14.0 Hz); 1.29 (3H, s).
[0459] .sup.13C NMR (DMSO-d.sub.6) .delta.: 177.30, 156.38, 138.11,
128.74, 128.24, 126.77, 62.93, 37.96, 36.39, 23.15.
(5S)-5-methyl-5-{[(phenylmethyl)thio]methyl}imidazolidine-2,4-dione
[0460] The title compound was prepared by chiral separation of the
racemic material using a 250 mm.times.50 mm column on a Dynamic
Axial Compression Preparative HPLC system. The stationary phase
used was CHIRALPAK AD, eluent=Methanol, flow=89 mL/min,
temp=ambient, UV=220 nm, sample conc=150 mg/mL, injection volume=20
mL.
[0461] Retention time for title compound=6 min.
[0462] Analysis of chiral purity was made using a 250 mm.times.4.6
ml CHIRALPAK-AD column from Daicel, flow=0.5 mL/min,
eluent=Ethanol, UV=220 nm, temp=ambient.
[0463] Retention time for title compound=9.27 min.
[0464] Purity estimated to >99% ee.
[0465] LC-MS (APCI) m/z 251.1 (MH+).
[0466] [.alpha.].sub.D=-30.3.degree. (c=0.01 g/mL, MeOH,
T=20.degree. C.).
[0467] .sup.1H NMR (DMSO-d.sub.6) .delta.: 10.74 (1H, s); 8.00 (1H,
s); 7.35-7.20 (5H, m); 3.76 (2H, s); 2.72, 2.62 (1H each, ABq,
J=14.0 Hz); 1.29 (3H, s).
[0468] .sup.13C NMR (DMSO-d.sub.6) .delta.: 177.30, 156.28, 138.11,
128.74, 128.24, 126.77, 62.93, 37.96, 36.39, 23.15.
(5R)-5-methyl-5-{[(phenylmethyl)thio]methyl}imidazolidine-2,4-dione
[0469] The title compound was prepared by chiral separation of the
racemic material using a 250 mm.times.50 mm column on a Dynamic
Axial Compression Preparative HPLC system. The stationary phase
used was CHIRALPAK AD, eluent-Methanol, flow=89 mL/min,
temp=ambient, UV=220 nm, sample conc=150 mg/mL, injection volume=20
mL.
[0470] Retention time for title compound=10 min.
[0471] Analysis of chiral purity was made using a 250 mm.times.4.6
mm CHIRALPAK-AD column from Daicel, flow=0.5 mL/min,
eluent=Ethanol, UV=220 nm, temp=ambient.
[0472] Retention time for title compound=17.81 min.
[0473] Chiral purity estimated to >99% ee.
[0474] LC-MS (APCI) m/z 251.0 (MH+).
[0475] [.alpha.].sub.D=+30.3.degree. (c=0.01 g/mL, MeOH,
T=20.degree. C.).
[0476] .sup.1H NMR (DMSO-d.sub.6) .delta.: 10.74 (1H, s); 8.00 (1H,
s); 7.35-7.20 (5H, m); 3.76 (2H, s); 2.72, 2.62 (1H each, ABq,
J=14.0 Hz); 1.29 (3H, s).
[0477] .sup.13C NMR (DMSO-d.sub.6) .delta.: 177.31, 156.30, 138.11,
128.74, 128.25, 126.77, 62.94, 37.97, 36.40, 23.16.
[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl
chloride
[0478]
(5S)-5-methyl-5-{[(phenylmethyl)thio]methyl}imidazolidine-2,4-dione
(42.6 g; 0.17 mol) was dissolved in a mixture of AcOH (450 mL) and
H.sub.2O (50 mL). The mixture was immersed in an ice/water bath,
Cl.sub.2 (g) was bubbled through the solution, the flow of gas was
adjusted so that the temperature was kept below +15.degree. C.
After 25 min the solution became yellow-green in colour and a
sample was withdrawn for LC/MS and HPLC analysis. It showed that
starting material was consumed. The yellow clear solution was
stirred for 30 min and an opaque solution/slurry was formed. The
solvent was removed on a rotary evaporator using waterbath with
temperature held at +37.degree. C. The yellowish solid was
suspended in Toluene (400 mL) and solvent removed on the same
rotary evaporator. This was repeated once more. The crude product
was then suspended in iso-Hexane (400 mL) and warmed to +40.degree.
C. while stirring, the slurry was allowed to cool to room
temperature before the insoluble product was removed by filtration,
washed with iso-Hexane (6.times.100 mL), and dried under reduced
pressure at +50.degree. C. over night. This gave the product as a
slightly yellow powder.
[0479] Obtained 36.9 g (95%) of the title compound.
[0480] Purity by HPLC=99%, NMR supported that purity.
[0481] [.alpha.].sub.D=-12.4.degree. (c=0.01 g/mL, THF,
T=20.degree. C.).
[0482] .sup.1H NMR (THF-d.sub.8): .delta. 9.91 (1H, bs); 7.57 (1H,
s); 4.53, 4.44 (1H each, ABq, J=14.6 Hz); 1.52 (s, 3H,
CH.sub.3).
[0483] .sup.13C NMR (THF-d.sub.8): .delta. 174.96; 155.86; 70.96;
61.04; 23.66.
[(4R)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl
chloride
[0484] Following the procedure described for
[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride.
Starting from
(5R)-5-methyl-5-{[(phenylmethyl)thio]methyl}imidazolidine-2,4-dione
(10.0 g, 40 mmol).
[0485] Obtained 8.78 g (96% yield) of the title compound.
[0486] Purity by NMR>98%.
[0487] [.alpha.].sub.D=+12.8.degree. (c=0.01 g/mL, THF,
T=20.degree. C.).
[0488] .sup.1H NMR (THF-d.sub.8): .delta. 9.91 (1H, brs); 7.57 (1H,
s); 4.53, 4.44 (1H each, ABq, J=14.6 Hz); 1.52 (s, 3H,
CH.sub.3).
[0489] .sup.13C NMR (THF-dg): .delta. 174.96; 155.84; 70.97; 61.04;
23.66.
EXAMPLE 13
[0490] Compounds with the general formula
##STR00214##
were synthesised according to the method described in Example
12.
Amine Intermediates
TABLE-US-00009 [0491] Amine Analysis ##STR00215## m/z 246 (MH+);
.sup.1H NMR data ##STR00216## m/z 185 (MH+); .sup.1H NMR data
##STR00217## m/z 198 (MH+); .sup.1H NMR data ##STR00218## m/z
218/220 3:1 (MH+); .sup.1H NMR data ##STR00219## m/z 247 (MH+);
.sup.1H NMR data ##STR00220## m/z 204 (MH+); .sup.1H NMR data
##STR00221## .sup.1H NMR data ##STR00222## .sup.1H NMR data
##STR00223## .sup.1H NMR data ##STR00224## .sup.1H NMR data
##STR00225## .sup.1H NMR data ##STR00226## .sup.1H NMR data
##STR00227## m/z 225 (MH+) ##STR00228## m/z 240 (MH+) ##STR00229##
m/z 235 (MH+) ##STR00230## m/z 203 (MH+) ##STR00231## m/z 208 (MH+)
##STR00232## m/z 262 (MH+) ##STR00233## m/z 214 (MH+) ##STR00234##
m/z 212 (MH+) ##STR00235## m/z 203 (MH+) ##STR00236## m/z 208 (MH+)
##STR00237## m/z 246 (MH+) ##STR00238## m/z 214 (MH+) ##STR00239##
m/z 235 (MH+) ##STR00240## m/z 220 (MH+) ##STR00241## m/z 220 (MH+)
##STR00242## m/z 197 (MH+); .sup.1H NMR data ##STR00243## m/z 285
(MH+) ##STR00244## m/z 195 (MH+); .sup.1H NMR data ##STR00245## m/z
257, 259 (MH+) ##STR00246## m/z 258 (MH+) ##STR00247## m/z 270
(MH+) ##STR00248## m/z 274, 276 (MH+) ##STR00249## m/z 324 (MH+)
##STR00250## m/z 230 (MH+) ##STR00251## m/z 229 (MH+) ##STR00252##
m/z 241 (MH+) ##STR00253## m/z 265 (MH+)
[0492] All other amines used are commercially available or earlier
described.
4-{4-[(trifluoromethyl)oxy]phenyl}piperidine trifluoroacetic
acid
[0493] Pd(PPh.sub.3).sub.4 (87 mg, 0.0075 mmol), LiCl (190 mg, 4.5
mmol), tert-butyl
4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate
(0.50 g 1.5 mmol), 4-(trifluoromethoxy)phenylboronic acid (0.43 g,
2.1 mmol) and aq Na.sub.2CO.sub.3 (2 mL, 2N solution) were mixed in
5.2 mL DME and heated at 85.degree. C. for 3 h followed by cooling
to room temperature and concentrated under reduced pressure. The
residue was partitioned between DCM (10 mL), aq Na.sub.2CO.sub.3
(10 mL, 2N solution) and conc NH.sub.4OH (0.6 mL). The layers were
separated and the aqueous layer extracted with DCM (3.times.10 mL).
The combined organic layers were dried (Na.sub.2SO.sub.4) and
concentrated. Purification by column chromatography (Si O.sub.2,
Heptane/Ethylacetate/DCM 5:1:1) gave tert-butyl
4-[4-(trifluoromethoxy)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate
(0.27 g, 52%). The product and 5% Pd/C (30 mg) was mixed in MeOH (3
mL) and stirred under H.sub.2 (1 atm) for 24 h. The mixture was
filtered through Celite and concentrated to give tert-butyl
4-[4-(trifluoromethoxy)phenyl]piperidine-1-carboxylate-(0.23 g,
86%). The crude product was dissolved in a mixture of TFA (2 mL)
and DCM (4 mL) and stirred at RT for 2 h. The reaction mixture was
concentrated and purified by preparative HPLC to give the title
compound (0.14 g, 58%, three steps 26%).
[0494] LC-MS (APCI) m/z 246 (MH+).
[0495] .sup.1H NMR (CDCl.sub.3): .delta. 9.38 (1H, bs); 8.97 (1H,
bs); 7.26 (2H, d); 7.20 (2H, d); 3.60 (2H, bd); 3.07 (2H, q);
2.88-2.72 (1H, m); 2.18-2.01 (4H, m).
[0496] .sup.19F NMR (CDCl.sub.3): .delta. -58.35 (3F), -76.19
(3F).
4-[(4-chlorophenyl)ethynyl]-1,2,3,6-tetrahydropyridine
hydrochloride
[0497] PdCl.sub.2(PPh.sub.3).sub.2 (47 mg, 0.07 mmol) and CuI (13
mg, 0.07 mmol) were dissolved in Et.sub.3N (2.7 mL) and THF (8.4
mL) under a stream of argon and stirred for 10 min. A solution of
tert-butyl
4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate
(0.46 g 1.4 mmol) and 2-ethynylpyridine (152 .mu.L, 1.5 mmol) in
3.5 mL TH-F was added. The reaction mixture was stirred at RT for 2
h, diethyl ether was added and the precipitate was filtered off.
The clear solution was washed with saturated aqueous NH.sub.4Cl,
water, Brine and dried (Na.sub.2SO.sub.4). Concentration and
purification by column chromatography (SiO.sub.2, Heptane/Diethyl
ether 1:2) gave tert-butyl
4-[(4-chlorophenyl)ethynyl]-3,6-dihydropyridine-1(2H)-carboxylate
(0.26 g, 58%). The product was dissolved in THP (3 mL) and conc HCl
(3 mL) and stirred at RT for 30 min. Concentration several times
with toluene and EtOH gave the title compound (0.20 g, 98%, two
steps 57%).
[0498] LC-MS (APCI) m/z 218/220 3:1 (MH+).
[0499] .sup.1H NMR (DMSO-d.sub.6): .delta. 9.25 (2H, bs); 7.49-7.44
(4H, m); 6.24-6.11 (1H, m); 3.75-3.63 (2H, m); 3.25-3.15 (2H, m);
2.48-2.42 (2H, m).
[0500] The following amines were prepared in a similar way as
described for
4-[(4-chlorophenyl)ethynyl]-1,2,3,6-tetrahydropyridine
hydrochloride.
2-(1,2,3,6-tetrahydropyridine-4-ylethynyl)pyridine
[0501] LC-MS (APCI) m/z 185 (MH+)
[0502] .sup.1H NMR (CDCl.sub.3): .delta. 8.59-8.55 (1H, m); 7.64
(1H, dt); 7.43-7.39 (1H, m); 7.20 (1H, ddd); 6.30 (1H, bs); 3.51
(2H, q); 3.04 (2H, t); 2.37-2.31 (2H, m).
4-[(4-methylphenyl)ethynyl]-1,2,3,6-tetrahydropyridine
[0503] LC-MS (APCI) m/z 198 (MH+).
[0504] .sup.1H NMR (CDCl.sub.3): .delta. 8.91 (1H, bs); 7.33 (2H,
d); 7.15 (2H, d); 6.06 (1H, bs); 3.93-3.80 (2H, m); 3.49-3.335 (2H,
m); 2.73-2.60 (2H, m); 2.37 (3H, s).
2-(Piperidin-4-yloxy)-5-trifluoromethyl-pyridine
[0505] Sodium hydride (0.52 g, 12 mmol, 55% in oil) was washed
twice in hexane, and suspended in dry dimethoxyethane (30 ml).
4-hydroxypiperidine (1.21 g, 12 mmol) and
2-chloro-5-trifluoromethylpyridine was dissolved in dry
dimethoxyethane (30 ml). The solution was added dropwise to the
sodium hydride-suspension. The reaction was stirred at 80.degree.
C. under nitrogen over night. After cooling. Water was carefully
added to the mixture and the solvents were removed by rotary
evaporation. The residue was dissolved in water and extracted with
ethyl acetate. The organic phase was dried over Na.sub.2SO.sub.4
and evaporated. The residue was chromatographed on silica gel
eluting with 80:20:2 EtOAc/MeOH/Et.sub.3N affording 1.7 g (63%) of
the title compound as a yellow oil, which crystallised after a few
hours.
[0506] LC-MS (APCI) m/z 247.1 (MH+).
[0507] .sup.1H NMR (CDCl.sub.3): .delta. 8.40 (1H, s); 7.74 (1H,
dd, J=2.52, 8.70 Hz); 6.78 (1H, d, J=8.74 Hz); 5.25-5.17 (1H, m);
3.19-3.08 (2H, m); 2.83-2.73 (2H, m); 2.10-2.00 (2H, m); 1.83 (1H,
s); 1.73-1.62 (2H, m).
[0508] The following amines were prepared in a similar way as
described in the synthesis of
2-(Piperidin-4-yloxy)-5-trifluoromethyl-pyridine.
6-(Piperidin-4-yloxy)-nicotinonitrile
[0509] LC-MS (APCI) m/z 204.2 (MH+).
[0510] .sup.1H NMR (CDCl.sub.3): .delta. 8.45 (1H, s); 7.76 (1H,
dd, J=2.40, 8.77 Hz); 6.78 (1H, d, J=8.77 Hz); 5.28-5.17 (1H, m);
3.19-3.09 (2H, m); 2.83-2.74 (2H, m); 2.10-2.01 (2H, m); 1.74-1.63
(2H, m).
5-Methyl-2-(piperidin-4-yloxy)-pyridine
[0511] .sup.1H NMR (Methanol-d.sub.4): .delta. 7.90 (1H, s); 7.46
(1H, dd, J=2.47, 8.46 Hz); 6.68 (1H, d, J=8.50 Hz); 5.07-4.98 (1H,
m); 3.15-3.07 (2H, m); 2.82-2.73 (2H, m); 2.23 (3H, s); 2.07-1.97
(2H, m); 1.84-1.74 (2H, m).
2-Methoxy-6-(piperidin-4-yloxy)-pyridine
[0512] .sup.1H NMR (CDCl.sub.3): .delta. 7.44 (1H, t, J=7.90 Hz);
7.25 (2H, dd, J=1.83, 7.90 Hz); 5.19-5.11 (1H, m); 3.82 (3H, s);
3.23-3.16 (2H, m); 2.96-2.88 (2H, m); 2.13-2.05 (2H, m); 1.89-1.79
(2H, m).
2-chloro-6-piperidine-4-yloxy)-pyridine
[0513] .sup.1H NMR (Methanol-d.sub.4): .delta. 7.64 (1H, dd,
J=7.60, 8.22 Hz); 6.96 (1H, dd, J=0.66, 7.60 Hz); 6.73 (1H, dd,
J=0.60, 8.19 Hz); 5.25-5.14 (1H, m); 3.28-3.18 (2H, m); 3.05-2.94
(2H, m); 2.19-2.07 (2H, m); 1.93-1.80 (2H, m).
5-Fluoro-2-(piperidin-4-yloxy)-pyrimidine
[0514] .sup.1H NMR (CDCl.sub.3): .delta. 8.36 (2H, s); 5.16-5.06
(1H, m); 3.29-3.18 (2H, m); 2.98-2.87 (2H, m); 2.21-2.08 (2H, m);
1.97-1.81 (2H, m).
2-(Piperidin-4-yloxy)-4-trifluoromethyl-pyrimidine
[0515] .sup.1H NMR (CDCl.sub.3): .delta. 8.75 (1H, d, J=4.93 Hz);
7.27 (1H, d, J=5.07 Hz); 5.39-5.30 (1H, m); 3.44-3.33 (2H, m);
3.28-3.17 (2H, m); 2.35-2.10 (4H, m).
5-Ethyl-2-(piperidin-4-yloxy)-pyrimidine
[0516] .sup.1H NMR (Methanol-d.sub.4): .delta. 8.40 (2H, s);
5.16-5.08 (1H, m); 3.16-3.06 (2H, m); 2.77-2.70 (2H, m); 2.60 (2H,
q, J=7.66, 15.28 Hz); 2.10-2.00 (2H, m); 1.76-1.66 (2H, m); 1.23
(3H, t, J=7.63 Hz).
5-Methoxy-2-(piperidin-4-yloxy)-pyridine; hydrochloride
[0517] 4-(5-Methoxy-pyridin-2-yloxy)-piperidine-1-carboxylic acid
tert-butyl ester (45 mg, 0.14 mmol) was dissolved in THF (3 ml) and
conc. HCl (2 ml) was added. The reaction was stirred at room
temperature for 2 hrs after which the solvents were removed in
vacuo and the remaining water was removed by azeotropic evaporation
using EtOH/Toulene affording 35 mg (97%) of the title compound as
oily crystals.
[0518] LC-MS (APCI) m/z 225.1 (MH+).
[0519] The starting material was prepared as follows:
2-Chloro-5-methoxy-pyridine 1-oxide
[0520] 2-chloro-5-methoxy-pyridine (200 mg, 1.39 mmol) and mCPBA
(360 mg, 2.09 mmol) was dissolved in CH.sub.2Cl.sub.2 (10 ml). The
mixture was stirred at room temperature for 2 days. The mixture was
then diluted with CH.sub.2Cl.sub.2 and washed with 10% aqueous
K.sub.2CO.sub.3 and brine and dried over Na.sub.2SO.sub.4. The
solvent were removed in vacuo affording 140 mg (63%) of the title
compound as white crystals.
[0521] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.30 (1H, d, J=2.72 Hz);
7.68 (1H, d, J=9.23 Hz); 7.08 (1H, dd, J=2.70, 9.23 Hz); 3.31 (3H,
s).
4-(5-Methoxy-1-oxy-pyridin-2-yloxy)-piperidine-1-carboxylic acid
tert-butyl ester
[0522] Potassium tert-butoxide (128 mg, 1.14 mmol) was dissolved in
dry THF (10 ml) and 4-Hydroxy-piperidine-1-carboxylic acid
tert-butyl ester (177 mg, 0.88 mmol) dissolved in dry THF (5 ml)
was added under nitrogen. The mixture was stirred at room
temperature for 10 minutes after which 2-Chloro-5-methoxy-pyridine
1-oxide (140 mg, 0.88 mmol) dissolved in dry THF (5 ml) was added.
The reaction was stirred for 3 days at room temperature. The
solvent were removed and the residue was partitioned between
H.sub.2O and CHCl.sub.3. The organic phase was washed with brine
and dried over Na.sub.2SO.sub.4. The solvent were removed in vacuo
affording 245 mg (86%) of the title compound as a brown oil.
[0523] .sup.1H NMR (CDCl.sub.3): .delta. 7.95-7.93 (1H, m);
6.86-6.84 (2H, m); 4.95-4.85 (1H, m); 3.79 (3H, s); 3.25-3.14 (2H,
m); 3.07-2.96 (2H, m); 1.98-1.79 (4H, m); 1.46 (9H, s).
4-(5-Methoxy-pyridin-2-yloxy)-piperidine-1-carboxylic acid
tert-butyl ester
[0524] 4-(5-Methoxy-1-oxy-pyridin-2-yloxy)-piperidine-1-carboxylic
acid tert-butyl ester (200 mg, 0.62 mmol) was dissolved in EtOH (5
ml). Indium (498 mg, 4.34 mmol) and saturated aqueous NH.sub.4Cl (4
ml) was added to the solution and the reaction was refluxed for 4
days. The mixture was filtered through celite after cooling and the
solvents were removed in vacuo. The residue was chromatographed on
silica gel eluting with 5:1 Heptane/EtOAc affording 50 mg (26%) of
the title compound as a yellowish oil.
[0525] .sup.1H NMR (CDCl.sub.3): .delta. 7.77 (1H, d, J=3.06 Hz);
7.20 (1H, dd, J=3.07, 8.89 Hz); 6.66 (1H, B d, J=8.99 Hz);
5.14-5.07 (1H, m); 3.80 (3H, s); 3.79-3.72 (2H, m); 3.31-3.23 (2H,
m); 2.00-1.91 (2H, m); 1.75-1.64 (2H, m); 1.47 (9H, s).
4-(4-Pyridin-3-yl-phenyl)piperazine; hydrochloride
[0526] 4-(4-Pyridin-3-yl-phenyl)piperazine-1-carboxylic acid
tert-butyl ester (60 mg, 0.18 mmol) in THF (3 ml) and conc. HCl (3
ml) was stirred for 1 hr. The solvents were removed in vacuo and
the remaining water was removed by azeotropic evaporation using
EtOH/Toulene, affording 50 mg (100%) of the title compound as a
yellow powder.
[0527] LC-MS (APCI) m/z 240.2 (MH+).
[0528] The starting material was prepared as follows:
4-(4-Iodophenyl)piperazine-1-carboxylic acid tert-butyl ester
[0529] was prepared according to La Clair in Angew. Chem. Int. Ed.
1998, 37 (3), 325-329 in 55% overall yield starting from
N-phenylpiperazine (19 mmol).
4-(4-Pyridin-3-yl-phenyl)piperazine-1-carboxylic acid tert-butyl
ester
[0530] (Ref. Wellmar et al. J. Heterocycl. Chem. 32 (4), 1995,
1159-1164). 4-(4-Iodophenyl)piperazine-1-carboxylic acid tert-butyl
ester (0.272 g, 0.70 mmoles), 3-pyridylboronic acid (0.078 g, 0.64
mmoles), tetrakis(triphenylphosphine)palladium (0.024 g, 0.02
mmoles), 1 M sodium hydrogencarbonate (1.0 mL) and
1,2-dimethoxyethane (1.5 mL) were stirred under nitrogen at
84.degree. C. for 3 hours, taken up in ethyl acetate and washed
with water and brine. The organic phase was dried over anhydrous
sodium sulfate, filtered, concentrated with silica (1 g) by rotary
evaporation to give a solid which was applied on a short silica
column. Elution with dichloromethane, dichloromethane/ethyl acetate
(4:1) and neat ethyl acetate gave 0.060 g (32% yield) of the title
compound as a white solid and 0.060 g of starting material (the
iodide), respectively. Yield was calculated from amount of
converted iodide.
[0531] LC-MS (APCI) m/z 340.3 (MH+).
[0532] .sup.1H NMR (Methanol-d.sub.4): .delta. 8.75 (1H, d, J=2.0
Hz); 8.43 (1H, m); 8.04 (1H, m); 7.58 (2H, d, J=8.0 Hz); 7.47 (1H,
m); 7.10 (2H, d, J=8.0 Hz); 3.59 (4H, m); 3.22 (4H, m); 1.50 (9H,
s).
N-[3-(Piperidin-4-yloxy)-phenyl]-acetamide; hydrochloride
[0533] 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (300
mg, 1.5 mmol) was dissolved in dry CH.sub.2Cl.sub.2 and cooled to
-10.degree. C. Polymer bound triphenylphosphine (750 mg, 2.25 mmol)
was added and allowed to swell. N-(3-Hydroxy-phenyl)-acetamide (340
mg, 2.25 mmol) dissolved in dry THF was added and the reaction was
stirred at -10.degree. C. for 10 minutes after which DEAD (0.35 ml,
2.25 mmol) was added dropwise to the mixture. The reaction was
stirred over night allowing the temperature rise to room
temperature. The polymer was filtered off, using a short plug of
silica with Toluene/EtOAc (5:1) as eluent. The volume of the
combined fractions was reduced by rotary evaporation and the
solution was washed with 5% aqueous KOH and water, dried over
Na.sub.2SO.sub.4 and the solvent removed in vacuo. The resulting
white powder was dissolved in THF (10 ml) and conc. HCl (10 ml) and
stirred at ambient temperature for 1 hr. The solvents were removed
in vacuo and the remaining water was removed by azeotropic
evaporation using EtOH/Toulene, affording 230 mg (57%) of the title
compound as a white powder.
[0534] LC-MS (APCI) IT/Z 235.1 (MH+).
[0535] The following amines were prepared in a similar way as
described in the synthesis
N-[3-(Piperidin-4-yloxy)-phenyl]-acetamide.
3-(Piperidin-4-yloxy)-benzonitrile
[0536] LC-MS (APCI) m/z 203.2 (MH+).
4-(3-Methoxy-phenoxy)-piperidine
[0537] LC-MS (APCI) m/z 208.2 (MH+).
4-(3-Trifluoromethoxy-phenoxy)-piperidine
[0538] LC-MS (APCI) m/z 262.1 (MH+).
4-(2,4-Difluoro-phenoxy)-piperidine
[0539] LC-MS (APCI) m/z 214.2 (MH+).
4-(4-Chloro-phenoxy)-piperidine
[0540] LC-MS (APCI) m/z 212.2 (MH+).
4-(Piperidin-4-yloxy)-benzonitrile
[0541] LC-MS (APCI) m/z 203.2 (MH+).
4-(4-Methoxy-phenoxy)-piperidine
[0542] LC-MS (APCI) m/z 208.2 (MH+).
4-(3,4-Dichloro-phenoxy)-piperidine
[0543] LC-MS (APCI) m/z 246.1 (MH+).
4-(3,4-Difluoro-phenoxy)-piperidine
[0544] LC-MS (APCI) m/z 214.2 (MH+).
N-[4-(Piperidin-4-yloxy)-phenyl]-acetamide
[0545] LC-MS (APCI) m/z 235.1 (MH+).
4-{[(3,4-dimethylphenyl)methyl]oxy}piperidine hydrochloride
[0546] LC-MS (APCI) m/z 220 (MH+).
4-{[(2,5-dimethylphenyl)methyl]oxy}piperidine hydrochloride
[0547] LC-MS (APCI) m/z 220 (MH+).
5-chloro-2-piperidin-4-ylpyridine hydrochloride
[0548] Zn dust (225 mg, 3.5 mmol) was stirred in THF (1 mL) under
Ar and 1,2-dibromoethane (50 .mu.L) was added at room temperature.
The mixture was heated to 65.degree. C. for 3 min and allowed to
cool to room temperature before trimethylsilyl chloride (70 .mu.L)
was added and the mixture was stirred at room temperature for 30
min. A solution of 4-iodo-N-Boc-piperidine (840 mg, 2.7 mmol) in
THF (1.5 mL) was slowly added and the reaction mixture was stirred
at 40.degree. C. for 2 h. Pd.sub.2(dba).sub.3 (22 mg, 0.024 mmol)
and P(2-furyl).sub.3 (23 mg, 0.10 mmol) were mixed in THF (0.5 mL),
the mixture stirred at room temperature for 10 min and then added
to the organozink reagent solution, followed by
2-bromo-5-chloro-pyridine (624 mg, 3.24 mmol) in THF (1 mL) and DMA
(4 mL). The reaction mixture was heated at 80.degree. C. for 3 h,
allowed to cool to room temperature and then filtered through
Celite and diluted with EtOAc. The filtrate was washed with
saturated aqueous NaHCO.sub.3 and brine, dried Na.sub.2SO.sub.4 and
concentrated. Purification on SiO.sub.2 eluting with heptane/EtOAc
95:5 to 2:1 gave tert-butyl
4-(5-chloropyridin-2-yl)piperidine-1-carboxylate as an yellow oil
(128 mg, 16%). The oil was dissolved in THF (1.5 mL) and conc HCl
(1.5 mL) and stirred at RT for 30 min. Concentration several times
with toluene and EtOH gave the title compound (89 mg, 89%)
[0549] LC-MS (APCI) m/z 197 (MH+).
[0550] .sup.1H NMR (MeOD-d.sub.4): .delta. 8.54 (1H, d); 7.86 (1H,
dd); 7.38 (1H, d); 3.55-3.45 (2H, m); 3.22-3.06 (3H, m); 2.19-2.09
(2H, m); 2.08-1.98 (2H, m).
5-Benzyloxy-2-(piperidin-4-yloxy)-pyridine; hydrochloride
[0551] The amine was prepared in the same way as described in the
synthesis of 5-Methoxy-2-(piperidin-4-yloxy)-pyridine.
[0552] LC-MS (APCI) m/z 285 (MH+).
[0553] The starting material was prepared as follows:
2-Chloro-5-benzyloxypyridine
[0554] Sodium hydride (55% in oil, 236 mg, 5.40 mmol) washed in
Hexane and 2-Chloro-5-hydroxypyridine (350 mg, 2.70 mmol) was
suspended in dry DMF (20 ml). After 10 minutes at room temperature
Benzylbromide (0.32 ml, 2.70 mmol) was added and the mixture was
stirred for an additional 2 hrs. The reaction was diluted with
water and extracted with EtOAc (3*50 ml). The combined organic
layers were washed with water and brine, and dried over
Na.sub.2SO.sub.4. The solvent was removed by rotary evaporation,
affording 520 mg (88%) of the title compound as a yellow oil.
[0555] LC-MS (APCI) m/z 220 (MH+).
[0556] .sup.1H NMR (CDCl.sub.3): .delta. 8.19 (1H, d, J=3.00 Hz);
7.55 (1H, dd, J=3.15, 8.81 Hz); 7.48-7.31 (6H, m); 5.19 (2H,
s).
2-Chloro-5-benzyloxy-pyridine 1-oxide
[0557] The amine was prepared in the same way as described in the
synthesis of 2-Chloro-5-methoxy-pyridine 1-oxide.
[0558] LC-MS (APCI) m/z 236 (MH+).
[0559] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.38 (1H, d, J=2.61 Hz);
7.69 (1H, d, J=9.28 Hz); 7.47-7.33 (5H, m); 7.15 (1H, dd, J=2.69,
9.15 Hz); 5.19 (2H, s).
4-(5-Benzyloxy-1-oxy-pyridin-2-yloxy)-piperidine-1-carboxylic acid
tert-butyl ester
[0560] The compound was prepared as described in the synthesis of
4-(5-Methoxy-1-oxy-pyridin-2-yloxy)-piperidine-1-carboxylic acid
tert-butyl ester.
[0561] LC-MS (APCI) m/z 401 (MH+).
[0562] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.12 (1H, d, J=2.79 Hz);
7.48-7.32 (5H, m); 7.19 (1H, d, J=9.16 Hz); 7.07 (1H, dd, J=2.88,
9.18 Hz); 5.13 (2H, s); 4.84-4.76 (1H, m); 3.20-3.11 (2H, m);
3.00-2.87 (2H, m); 1.86-1.78 (2H, m); 1.59-1.49 (2H, m); 1.40 (9H,
s).
4-(5-Benzyloxy-pyridin-2-yloxy)-piperidine-1-carboxylic acid
tert-butyl ester
[0563] The compound was prepared as described in the synthesis of
4-(5-Methoxy-pyridin-2-yloxy)-piperidine-1-carboxylic acid
tert-butyl ester.
[0564] LC-MS (APCI) m/z 385 (MH+).
[0565] .sup.1H NMR (CDCl.sub.3): .delta. 7.86 (1H, d, J=3.10 Hz);
7.46-7.32 (5H, m); 7.28 (1H, dd, J=3.16, 9.04 Hz); 6.67 (1H, d,
J=9.04 Hz); 5.16-5.08 (1H, m); 5.05 (2H, s); 3.84-3.72 (2H, m);
3.33-3.25 (2H, m); 2.02-1.93 (2H, m); 1.76-1.66 (2H, m); 1.49 (9H,
s).
5-Hydroxy-2-(piperidin-4-yloxy)-pyridine trifluoroacetic acid
[0566]
4-(5-Benzyloxy-1-oxy-pyridin-2-yloxy)-piperidine-1-carboxylic acid
tert-butyl ester (476 mg, 1.19 mmol) was dissolved in Methanol (20
ml) and Pd(OH).sub.2 (30 mg) was added. The mixture was
hydrogenated at 1 atm and room temperature for 24 hrs. The catalyst
was filtered off, and the mixture was purified using preparative
HPLC affording, after freeze drying, 110 mg (30%) of the title
compound as a TFA-salt and 34 mg (10%) of the neutral Boc-protected
intermediate.
[0567] LC-MS (APCI) m/z 195 (MH+).
[0568] .sup.1H NMR (DMSO-d.sub.6): .delta. 7.66 (1H, d, J=2.94 Hz);
7.20 (1H, dd, J=3.07, 8.82 Hz); 6.68 (1H, d, J=8.93 Hz); 5.12-5.00
(1H, m); 3.29-3.00 (4H, m); 2.16-2.02 (2H, m); 1.93-1.75 (2H,
m).
5-Bromo-2-(piperidin-4-yloxy)-pyridine hydrochloride
[0569] The amine was prepared in the same way as described in the
synthesis of 5-Methoxy-2-(piperidin-4-yloxy)-pyridine.
[0570] LC-MS (APCI) m/z 257+259 (MH+)
The starting material was prepared as described in the synthesis of
4-(5-Methoxy-pyridin-2-yloxy)-piperidine-1-carboxylic acid
tert-butyl ester:
4-(5-Bromo-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl
ester
[0571] LC-MS (APCI) m/z 357+359 (MH+).
[0572] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.26 (1H, dd, J=0.53,
2.67 Hz); 7.88 (1H, dd, J=2.66, 8.81 Hz); 6.80 (1H, dd, J=0.53,
8.79 Hz); 5.15-5.07 (1H, m); 3.72-3.64 (2H, m); 3.20-3.09 (2H, m);
1.97-1.88 (2H, m); 1.58-1.48 (2H, m); 1.40 (9H, s).
4-(5-(4-Fluoro-phenyl)-pyridine-2-yl)-piperazine hydrochloride
[0573]
4-(5-(4-Fluoro-phenyl)-pyridine-2-yl)-piperazine-1-carbaldehyde (98
mg, 0.34 mmol) was dissolved in MeOH (5 ml) and conc. HCl (12M, 5
ml) was added. The mixture was stirred at room temperature over
night. The solvents were removed in vacuo and the remaining water
was removed by azeotropic evaporation using EtOH/Toulene affording
102 mg (100%) of the title compound as a yellow powder.
[0574] LC-MS (APCI) m/z 258 (MH+).
[0575] The starting material was prepared as follows:
4-(5-(4-Fluoro-phenyl)-pyridine-2-yl)-piperazine-1-carbaldehyde
[0576] 4-(5-Bromo-pyridine-2-yl)-piperazine-1-carbaldehyde (100 mg,
0.37 mmol), 4-Fluorobenzeneboronic acid (55 mg, 0.39 mmol),
(1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (10
mg, 0.01 mmol), Toluene (2 ml), EtOH (0.5 ml) and 2M
Na.sub.2CO.sub.3 solution (0.5 ml, 1 mmol) were heated at
80.degree. C. under N.sub.2 overnight. After cooling the mixture
was diluted with toluene and separated. The organic phase was
washed with water and brine, filtered through a pad of celite and
dried over Na.sub.2SO.sub.4. The solvent were removed in vacuo
affording 100 mg (94%) of the title product as a beige powder.
[0577] LC-MS (APCI) m/z 286 (MH+).
[0578] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.44 (1H, d, J=2.66 Hz);
8.10 (1H, s); 7.97 (1H, dd, J=2.52, 8.82 Hz); 7.70-7.31 (2H, m);
7.31-7.21 (2H, m); 6.97 (1H, d, J=8.97 Hz); 3.65-3.43 (8H, m).
[0579] The following compounds were synthesised as described in the
synthesis of 4-(5-(4-Fluoro-phenyl)-pyridine-2-yl)-piperazine
hydrochloride:
4-(5-(4-Methoxy-phenyl)-pyridine-2-yl)-piperazine hydrochloride
[0580] LC-MS (APCI) m/z 270 (MH+).
4-(5-(4-Chloro-phenyl)-pyridine-2-yl)-piperazine hydrochloride
[0581] LC-MS (APCI) m/z 274, 276 (MH+).
4-(5-(4-Trifluoromethoxy-phenyl)-pyridine-2-yl)-piperazine
hydrochloride
[0582] LC-MS (APCI) m/z 324 (MH+).
4-(5-Furan-2-yl-pyridine-2-yl)-piperazine hydrochloride
[0583] LC-MS (APCI) m/z 230 (MH+).
4-(5-(1H-Pyrrol-2-yl)-pyridine-2-yl)-piperazine dihydrochloride
[0584] The title compound was prepared from
2-(6-(4-Formyl-piperazine-1-yl)-pyridine-3-yl)-pyrrole-1-carboxylic
acid tert-butyl ester.
[0585] LC-MS (APCI) m/z 229 (MH+).
4-[3,3']-Bipyridinyl-6-yl-piperazine hydrochloride
[0586] LC-MS (APCI) m/z 241 (MH+).
4-(6-piperazine-1-yl-pyridine-3-yl)-benzonitrile hydrochloride
[0587] LC-MS (APCI) m/z 265 (MH+).
Hydantoins of Formula I
TABLE-US-00010 [0588] Hydantoin Analysis.sup.(1) ##STR00254## m/z
380 (MH+) ##STR00255## m/z 382 (MH+) ##STR00256## m/z 402/403 3:1
(MH+) ##STR00257## m/z 382 (MH+) ##STR00258## m/z 420 (MH+)
##STR00259## m/z 420 (MH+) ##STR00260## m/z 488 (MH+) ##STR00261##
m/z 384/386 3:1 (MH+) ##STR00262## m/z 370 (MH+) ##STR00263## m/z
370 (MH+) ##STR00264## m/z 366 (MH+) ##STR00265## m/z 366 (MH+)
##STR00266## m/z 359 (MH+) ##STR00267## m/z 408 (MH+) ##STR00268##
m/z 436 (MH+) ##STR00269## m/z 386/388 3:1 (MH+) ##STR00270## m/z
345 (MH+) ##STR00271## m/z 375 (MH+) ##STR00272## m/z 395 (MH+)
##STR00273## m/z 462 (MH+) ##STR00274## m/z 276 (MH+) ##STR00275##
m/z 274 (MH+) ##STR00276## m/z 408 (MH+) ##STR00277## m/z 393 (MH+)
##STR00278## m/z 375 (MH+) ##STR00279## m/z 388 (MH+) ##STR00280##
m/z 408 (MH+) ##STR00281## m/z 436 (MH+) ##STR00282## m/z 437 (MH+)
##STR00283## m/z 394 (MH+) ##STR00284## m/z 382 (MH+) ##STR00285##
m/z 436 (MH+) ##STR00286## m/z 393 (MH+) ##STR00287## m/z 398 (MH+)
##STR00288## m/z 404 (MH+) ##STR00289## m/z 402 (MH+) ##STR00290##
m/z 398 (MH+) ##STR00291## m/z 438 (MH+) ##STR00292## m/z 383 (MH+)
##STR00293## m/z 398 (MH+) ##STR00294## m/z 388 (MH+) ##STR00295##
m/z 399 (MH+) ##STR00296## m/z 403 (MH+) ##STR00297## m/z 393 (MH+)
##STR00298## m/z 398 (MH+) ##STR00299## m/z 425 (MH+) ##STR00300##
m/z 402 (MH+) ##STR00301## m/z 452 (MH+) ##STR00302## m/z 452 (MH+)
##STR00303## m/z 405 (MH+) ##STR00304## m/z 386 (MH+) ##STR00305##
m/z 386 (MH+) ##STR00306## m/z 386 (MH+) ##STR00307## m/z 399 (MH+)
##STR00308## m/z 430 (MH+) ##STR00309## m/z 369 (MH+) ##STR00310##
m/z 410 (MH+) ##STR00311## m/z 368 (MH+) ##STR00312## m/z 413 (MH+)
##STR00313## m/z 410 (MH+) ##STR00314## m/z 387 (MH+) ##STR00315##
m/z 475 (MH+) ##STR00316## m/z 403 (MH+) ##STR00317## m/z 385 (MH+)
##STR00318## m/z 418 (MH+) ##STR00319## m/z 450 (MH+) ##STR00320##
m/z 385 (MH+) ##STR00321## m/z 425 (MH+) ##STR00322## m/z 415 (MH+)
##STR00323## m/z 413 (MH+) ##STR00324## m/z 447, 449 (MH+)
##STR00325## m/z 448 (MH+) ##STR00326## m/z 460 (MH+) ##STR00327##
m/z 464, 466 (MH+) ##STR00328## m/z 514 (MH+) ##STR00329## m/z 420
(MH+) ##STR00330## m/z 419 (MH+) ##STR00331## m/z 431 (MH+)
##STR00332## m/z 455 (MH+) .sup.(1)For NMR-data see experimental
part.
[0589] The following compounds were prepared in the same way as
(5S)-5-({[4-(4-s
fluorophenyl)piperidin-1-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-di-
one (Example 12) and purified either by precipitation and washing
with EtOH/water or by preparative HPLC.
(5S)-5-methyl-5-({[4-[4-(methyloxy)phenyl]-3,6-dihydropyridin-1
(2H)-yl}sulfonyl]methyl)imidazolidine-2,4-dione
[0590] LC-MS (APCI) m/z 380 (MH+).
[0591] .sup.1H NMR (Methanol-d.sub.4): .delta. 7.35 (2H, d, J=8.9
Hz); 6.87 (2H, d, J=8.9 Hz); 6.01 (1H, dd); 3.92 (2H, dd); 3.78
(3H, s); 3.56, 3.41 (1H each, ABq, J=14.6 Hz); 3.51-3.46 (2H, m);
2.62-2.57 (2H, m); 1.47 (3H, s).
(5S)-5-methyl-5-[({4-[4-(methyloxy)phenyl]piperidin-1-yl}sulfonyl)methyl]i-
midazolidine-2,4-dione
[0592] LC-MS (APCI) m/z 382 (MH+).
[0593] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.73 (1H, s); 8.01 (1H,
s); 7.17 (2H, d); 6.85 (2H, d); 3.71 (3H, s); 3.60 (2H, dd); 3.50
(1H, part of ABq, J=14.8 Hz); 2.85 (2H, q); 2.54 (1H, t); 1.79 (2H,
d); 1.64-1.53 (2H, m); 1.33 (3H, s).
(5S)-5-({[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]sulfonyl}methyl)-5-me-
thylimidazolidine-2,4-dione
[0594] LC-MS (APCI) m/z 402/404 3:1 (MH+).
[0595] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.72 (1H, s); 8.01 (1H,
s); 7.51 (2H, d); 7.37 (2H, d); 5.22 (1H, s); 3.49, 3.34 (1H each,
ABq, J=14.9 Hz); 3.47-3.35 (2H, m); 3.15 (2H, q); 1.93 (2H, t);
1.64 (2H, d); 1.33 (3H, s).
(5S)-5-methyl-5-[({4-[2-(methyloxy)phenyl]piperidin-1-yl}sulfonyl)methyl]i-
midazolidine-2,4-dione
[0596] LC-MS (APCI) m/z 382 (MH+).
[0597] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.72 (1H, s); 8.01 (1H,
s); 7.24-7.14 (2H, m); 6.96 (1H, d); 6.90 (1H, t); 3.78 (3H, s);
3.60 (2H, dd); 3.51, 3.33 (1H each, ABq, J=14.7 Hz); 3.02-2.94 (1H,
m); 2.88 (2H, q); 1.77 (2H, d); 1.66-1.56 (2H, m); 1.33 (3H,
s).
(5S)-5-methyl-5-[({4-[4-(trifluoromethyl)phenyl]piperidin-1-yl}sulfonyl)me-
thyl]imidazolidine-2,4-dione
[0598] LC-MS (APCI) m/z 420 (MH+).
[0599] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.73 (1H, s); 8.01 (1H,
s); 7.66 (2H, d); 7.50 (2H, d); 3.63 (2H, dd); 3.52, 3.34 (1H each,
ABq, J=14.9 Hz); 2.88 (2H, ddd); 2.79-2.68 (1H, m); 1.86 (2H, d);
1.67 (2H, ddd); 1.33 (3H, s).
(5S)-5-methyl-5-[({4-[3-(trifluoromethyl)phenyl]piperidin-1-yl}sulfonyl)me-
thyl]imidazolidine-2,4-dione
[0600] LC-MS (APCI) m/z 420 (MH+).
[0601] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 8.02 (1H,
s); 7.63-7.52 (4H, m); 3.63 (2H, dd); 3.52 (1H, part of ABq, J=14.9
Hz); 2.87 (2H, ddd); 2.79-2.70 (1H, m); 1.87 (2H, d); 1.75-1.63
(2H, m); 1.33 (3H, s).
(5S)-5-[({4-[3,5-bis(trifluoromethyl)phenyl]piperidin-1-yl}sulfonyl)methyl-
]-5-methylimidazolidine-2,4-dione
[0602] LC-MS (APCI) m/z 488 (MH+).
[0603] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 8.02 (1H,
s); 8.00 (2H, s); 7.93 (1H, s); 3.64 (2H, dd); 3.52 (1H, part of
ABq, J=14.9 Hz); 2.95-2.81 (3H, m); 1.89 (2H, d); 1.83-1.69 (2H,
m); 1.34 (3H, s).
(5S)-5-({[4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl]sulfonyl}methyl)--
5-methylimidazolidine-2,4-dione
[0604] LC-MS (APCI) m/z 384/386 3:1 (MH+).
[0605] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 8.03 (1H,
s); 7.47 (2H, d); 7.40 (2H, d); 6.23 (1H, app s); 3.85 (2H, app s);
3.52, 3.39 (1H each, ABq, J=14.7 Hz); 3.39-3.32 (2H, m); 2.55 (2H,
br s); 1.32 (3H, s).
(5S)-5-({[4-(3-fluorophenyl)piperidin-1-yl]sulfonyl}methyl)-5-methylimidaz-
olidine-2,4-dione
[0606] LC-MS (APCI) m/z 370 (MH+).
[0607] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.73 (1H, s); 8.01 (1H,
s); 7.38-7.31 (1H, m); 7.15-7.08 (2H, m); 7.05-6.98 (1H, m); 3.62
(2H, dd); 3.51, 3.33 (1H each, ABq, J=14.7 Hz); 2.95-2.80 (2H, m);
2.68-2.60 (1H, m); 1.82 (2H, br d); 1.69-1.58 (2H, m); 1.33 (3H,
s).
(5S)-5-({[4-(2-fluorophenyl)piperidin-1-yl]sulfonyl}methyl)-5-methylimidaz-
olidine-2,4-dione
[0608] LC-MS (APCI) m/z 370 (MH+).
[0609] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.73 (1H, s); 8.01 (1H,
s); 7.36 (1H, t); 7.30-7.20 (1H, m); 7.18-7.12 (2H, m); 3.63 (2H,
dd); 3.52, 3.33 (1H each, ABq); 2.96-2.85 (3H, m); 1.80 (2H, brd);
1.69 (2H, ddd); 1.33 (3H, s).
(5S)-5-methyl-5-({[4-(4-methylphenyl)piperidin-1-yl]sulfonyl}methyl)imidaz-
olidine-2,4-dione
[0610] LC-MS (APCI) m/z 366 (MH+).
[0611] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.73 (1H, s); 8.01 (1H,
s); 7.15-7.07 (4H, m); 3.60 (2H, dd); 3.50, 3.32 (1H each, ABq);
2.85 (2H, q); 2.59-2.51 (1H, m); 2.25 (3H, s); 1.79 (2H, br d);
1.60 (2H, ddd).
(5S)-5-methyl-5-({[4-(phenylmethyl)piperidin-1-yl]sulfonyl}methyl)imidazol-
idine-2,4-dione
[0612] LC-MS (APCI) m/z 366 (MH+).
[0613] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.70 (1H, s); 7.96 (1H,
s); 7.29-7.15 (5H, m); 3.46 (2H, t); 3.41, 3.24 (1H each, ABq,
J=14.9 Hz); 2.68 (2H, dt); 2.52 (2H, d); 1.54-1.51 (3H, m); 1.30
(3H, s).
(5S)-5-[(1,4'-bipiperidin-1'-ylsulfonyl)methyl]-5-methylimidazolidine-2,4--
dione trifluoroacetic acid
[0614] LC-MS (APCI) m/z 359 (MH+).
[0615] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 9.25 (1H,
br s); 8.02 (1H, s); 3.63 (2H, t); 3.51, 3.34 (1H each, ABq, J=14.8
Hz); 3.39 (2H, d); 3.24 (1H, t); 2.92 (2H, q); 2.81 (2H, t); 2.07
(2H, d); 1.82 (2H, d); 1.74-1.58 (5H, m); 1.45-1.34 (1H, m); 1.31
(3H, s).
[0616] .sup.19F NMR (DMSO-d.sub.6): .delta. -74.48.
(5S)-5-({[4-(3-furan-2-yl-1H-pyrazol-5-yl)piperidin-1-yl]sulfonyl}methyl)--
5-methylimidazolidine-2,4-dione
[0617] LC-MS (APCI) m/z 408 (MH+).
[0618] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.73 (1H, s); 8.01 (1H,
s); 7.66 (1H, s); 6.64 (1H, s); 6.53 (1H, s); 6.34 (1H, s);
3.61-3.49 (2H, m); 3.49 (1H, half ABq, J=14.9 Hz); 2.94-2.84 (2H,
m); 2.81-2.72 (1H, m); 1.98 (2H, br d); 1.70-1.58 (2H, m); 1.32
(3H, s).
(5S)-5-methyl-5-{[(4-{4-[(trifluoromethyl)oxy]phenyl}piperidin-1-yl)sulfon-
yl]methyl}imidazolidine-2,4-dione
[0619] LC-MS (APCI) m/z 436 (MH+).
[0620] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.73 (1H, s); 8.01 (1H,
s); 7.40 (2H, d); 7.28 (2H, d); 3.70-3.55 (2H, m); 3.51, 3.33 (1H
each, ABq, J=14.7 Hz); 2.94-2.80 (2H, m); 2.73-2.61 (2H, m); 1.86
(2H, d); 1.71-1.57 (2H, m); 1.33 (3H, s).
(5S)-5-({[4-(4-chlorophenyl)piperidin-1-yl]sulfonyl}methyl)-5-methylimidaz-
olidine-2,4-dione
[0621] LC-MS (APCI) m/z 386/388 3:1 (MH+).
[0622] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.73 (1H, s); 8.01 (1H,
s); 7.36-7.28 (4H, m); 3.66-3.54 (2H, m); 3.51, 3.33 (1H each, ABq,
J=14.9 Hz); 2.92-2.80 (2H, m); 2.67-2.58 (1H, m); 1.81 (2H, br d);
1.68-1.56 (2H, m); 1.33 (3H, s).
(5S)-5-dimethyl-5-{[(4-pyrrolidin-1-ylpiperidin-1-yl)sulfonyl]methyl}imida-
zolidine-2,4-dione trifluoroacetic acid
[0623] LC-MS (APCI) m/z 345 (MH+).
[0624] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 9.61 (1H,
br s); 8.01 (1H, s); 3.60 (2H, t); 3.51, 3.36 (1H each, ABq, J=14.8
Hz); 3.55-3.47 (2H, m); 3.27-3.15 (1H, m); 3.13-3.02 (2H, m); 2.80
(2H, t); 2.12 (2H, br d); 2.07-1.94 (2H, m); 1.86-1.77 (2H, m);
1.62-1.49 (2H, m); 1.32 (3H, s).
[0625] .sup.19F NMR (DMSO-d.sub.6): .delta. -74.02
(5S)-5-methyl-5-({[4-(tetrahydrofuran-2-ylcarbonyl)piperazin-1-yl]sulfonyl-
}methyl)imidazolidine-2,4-dione
[0626] LC-MS (APCI) m/z 375 (MH+).
[0627] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.73 (1H, s); 8.01 (1H,
s); 4.65 (1H, dd); 3.80-3.68 (2H, m); 3.60-3.42 (3H and water, m);
3.33 (1H, half ABq, J=14.9 Hz); 3.19-3.00 (4H, m); 2.09-1.92 (2H,
m); 1.87-1.75 (2H, m); 1.30 (3H, s).
N-[1-({[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)piperidin-
-4-yl]benzamide
[0628] LC-MS (APCI) m/z 395 (MH+).
[0629] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.72 (1H, s); 8.30 (1H,
d); 8.01 (1H, s); 7.82 (2H, d); 7.51 (1H, t); 7.45 (2H, t);
3.96-3.85 (1H, m); 3.52 (2H, t); 3.50, 3.32 (1H each, ABq, J=14.7
Hz); 2.92 (2H, t); 1.88 (2H, d); 1.55 (2H, q); 1.33 (3H, s).
(5S)-5-{[(4-{[2-(1,1-dimethylethyl)-1H-indol-5-yl]amino}piperidin-1-yl)sul-
fonyl]methyl}-5-methylimidazolidine-2,4-dione
[0630] LC-MS (APCI) m/z 462 (MH+).
[0631] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.72 (1H, s); 10.37
(1H, s); 8.00 (1H, s); 7.02 (1H, d, J=8.4 Hz); 6.58 (1H, s); 6.45
(1H, d, J=8.4 Hz); 5.86 (1H, s); 4.65 (1H, Br s); 3.48, 3.29 (1H
each, ABq, J=14.7 Hz); 3.46 (2H, t); 2.93 (2H, t); 1.95 (2H, t);
1.45-1.35 (2H, m); 1.33 (3H, s); 1.29 (9H, s).
(5S)-5-methyl-5-[(piperidin-1-ylsulfonyl)methyl]imidazolidine-2,4-dione
[0632] LC-MS (APCI) m/z 276 (MH+).
[0633] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.70 (1H, s); 7.97 (1H,
s); 3.44, 3.23 (1H each, ABq, J=14.8 Hz); 3.13-3.01 (4H, m);
1.58-1.42 (6H, m); 1.30 (3H, s).
(5S)-5-[(3,6-dihydropyridin-1(2H)-ylsulfonyl)methyl]-5-methylimidazolidine-
-2,4-dione
[0634] LC-MS (APCI) m/z 274 (MH+).
[0635] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.72 (1H, s); 8.00 (1H,
s); 5.85-5.78 (1H, m); 5.74-5.68 (1H, m); 3.67-3.62 (2H, m); 3.47,
3.33 (1H each, ABq, J=14.7 Hz); 3.22 (2H, dd); 2.14-2.10 (2H, m);
1.31 (3H, s).
(5S)-5-methyl-5-({[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-y-
l]sulfonyl}methyl)imidazolidine-2,4-dione
[0636] LC-MS (APCI) m/z 408 (MH+).
[0637] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.86 (1H, s); 10.75
(1H, s); 8.02 (1H, s); 7.27-7.17 (1H, m); 7.05-6.91 (3H, m);
4.38-4.20 (1H, m); 3.65 (2H, t); 3.56, 3.38 (1H each, ABq, J=14.8
Hz); 3.03-2.90 (2H, m); 2.41-2.24 (2H, m); 1.76 (2H, d); 1.34 (3H,
s).
(5S)-5-({[4-(1H-1,2,3-benzotriazol-1-yl)piperidin-1-yl]sulfonyl}methyl)-5--
methylimidazolidine-2,4-dione
[0638] LC-MS (APCI) m/z 393 (MH+).
[0639] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.77 (1H, s); 8.05 (1H,
s); 8.05 (1H, d); 7.93 (1H, d); 7.56 (1H, t); 7.41 (1H, t);
5.12-4.97 (1H, m); 3.71 (2H, t); 3.58, 3.43 (1H each, ABq, J=14.7
Hz); 3.19-3.03 (2H, m); 2.29-2.16 (4H, m); 1.35 (3H, s).
(5S)-5-methyl-5-({[4-(pyridin-2-ylethynyl)-3,6-dihydropyridin-1(2H)-yl}sul-
fonyl]methyl)imidazolidine-2,4-dione trifluoroacetic acid
[0640] LC-MS (APCI) m/z 375 (MH+).
[0641] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.57 (1H, s); 8.56 (1H,
d); 8.03 (1H, s); 7.82 (1H, t); 7.53 (1H, d); 7.38 (1H, dd); 6.31
(1H, br s); 3.83 (2H, d); 3.54, 3.41 (1H each, ABq, J=14.8 Hz);
3.36-3.25 (2H, m); 2.42-2.34 (2H, m); 1.32 (3H, s).
[0642] .sup.19F NMR (DMSO-d.sub.6): .delta. -75.10
(5S)-5-methyl-5-({[4-[(4-methylphenyl)ethynyl]-3,6-dihydropyridin-1(2H)-yl-
]sulfonyl}methyl)imidazolidine-2,4-dione
[0643] LC-MS (APCI) m/z 388 (MH+).
[0644] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 8.02 (1H,
s); 7.32 (2H, d); 7.19 (2H, d); 6.17 (1H, br s); 3.80 (2H, d);
3.52, 3.39 (1H each, ABq, J=14.8 Hz); 3.29 (2H, t); 2.39-2.32 (2H,
m); 2.30 (3H, s); 1.32 (3H, s).
(5S)-5-({[4-[(4-chlorophenyl)ethynyl]-3,6-dihydropyridin-1(2H)-yl]sulfonyl-
}methyl)-5-methylimidazolidine-2,4-dione
[0645] LC-MS (APCI) m/z 408 (MH+).
[0646] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 8.02 (1H,
s); 7.54-7.38 (4H, m); 6.23 (1H, br s); 3.87-3.76 (2H, m); 3.53,
3.41 (1H each, ABq, J=14.9 Hz); 3.34-2.25 (2H, m); 2.42-2.29 (2H,
m); 1.32 (3H, s).
(5S)-5-[4-(3,4-Dichloro-phenoxy)-piperidine-1-sulfonylmethyl]-5-methyl-imi-
dazolidine-2,4-dione
[0647] LC-MS (APCI) m/z (APCI) m/z 436.1 (MH+).
[0648] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 8.01 (1H,
s); 7.53 (1H, d, J=9.2 Hz); 7.31 (1H, d, J=2.9 Hz); 7.02 (1H, dd,
J=9.2, 2.9 Hz); 4.65-4.57 (1H, m); 3.51, 3.34 (1H each, ABq, J=15.2
Hz); 3.39-3.27 (2H, m); 3.17-3.08 (2H, m); 2.00-1.90 (2H, m);
1.75-1.65 (2H, m); 1.33 (3H, s).
(5S)-5-[4-(5-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-methyl
imidazolidine-2,4-dione
[0649] LC-MS (APCI) m/z 403.3 (MH+).
[0650] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 8.20 (1H,
d, J=2.7 Hz); 7.81 (1H, dd, J=8.7, 2.7 Hz); 6.87 (1H, d, J=2.7 Hz);
5.16-5.03 (1H, m); 3.52, 3.35 (1H each, ABq, J=15.0 Hz); 3.43-3.28
(2H, m); 3.19-3.07 (2H, m); 2.08-1.95 (2H, m); 1.80-1.65 (2H, m);
1.33 (3H, s).
(5S)-5-Methyl-5-[4-(5-trifluoromethyl-pyridin-2-yloxy)-piperidine-1-sulfon-
ylmethyl]imidazolidine-2,4-dione
[0651] LC-MS (APCI) m/z 437 (MH+).
[0652] .sup.1H NMR (CDCl.sub.3): .delta. 8.95 (1H, s); 8.42-8.38
(1H, m); 7.79 (1H, dd, J=8.8, 2.5 Hz); 6.81 (1H, d, J=8.8 Hz); 6.71
(1H, s); 5.40-5.28 (1H, m); 3.52-3.39 (2H, m); 3.40-3.28 (2H, m);
3.32 (2H, ABq, J=24.6, 14.0 Hz); 2.16-2.02 (2H, m); 2.02-1.84 (2H,
m); 1.67 (3H, s).
6-[1-((4S)-4-Methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl)-piperidin--
4-yloxy]-nicotinonitrile
[0653] LC-MS (APCI) m/z 394.3 (MH+).
[0654] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.72 (1H, s); 8.68 (1H,
d, J=2.3 Hz); 8.14 (1H, dd, J=8.7, 2.3 Hz); 8.00 (1H, s); 6.98 (1H,
d, J=8.7 Hz); 5.27-5.14 (1H, m); 3.56-3.28 (4H, m); 3.18-3.06 (2H,
m); 2.08-1.96 (2H, m); 1.81-1.66 (2H, m); 1.31 (3H, s).
(5S)-5-Methyl-5-(4-p-tolyloxy-piperidine-1-sulfonylmethyl)-imidazolidine-2-
,4-dione
[0655] LC-MS (APCI) m/z 382.5 (MH+).
[0656] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.73 (1H, s); 8.01 (1H,
s); 7.09 (2H, d, J=8.4 Hz); 6.87 (2H, d, J=8.4 Hz); 4.50-4.42 (1H,
m); 3.50, 3.34 (1H each, ABq, J=14.8 Hz); 3.38-3.29 (2H, m);
3.17-3.09 (2H, m); 2.23 (3H, s); 1.99-1.89 (2H, m); 1.73-1.63 (2H,
m); 1.33 (3H, s).
(5S)-5-Methyl-5-[4-(4-trifluoromethyl-phenoxy)-piperidine-1-sulfonylmethyl-
]-imidazolidine-2,4-dione
[0657] LC-MS (APCI) m/z 436.3 (MH+).
[0658] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.71 (1H, brs); 8.02
(1H, s); 7.65 (2H, d, J=8.8 Hz); 7.17 (2H, d, J=8.8 Hz); 4.72-4.64
(1H, m); 3.52, 3.35 (1H each, ABq, J=14.7 Hz); 3.40-3.28 (2H, m);
3.19-3.10 (2H, m); 2.05-1.95 (2H, m); 1.78-1.68 (2H, m); 1.33 (3H,
s).
4-[1-(4S)-4-Methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl)-piperidin-4-
-yloxy]-benzonitrile
[0659] LC-MS (APCI) M/Z 393.2 (MH+).
[0660] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.73 (1H, s); 8.00 (1H,
s); 7.76 (2H, d, J=8.8 Hz); 7.15 (2H, d, J=8.8 Hz); 4.74-4.65 (1H,
m); 3.51, 3.34 (1H each, ABq, J=14.9 Hz); 3.40-3.27 (2H, m);
3.17-3.07 (2H, m); 2.03-1.94 (2H, m); 1.77-1.66 (2H, m); 1.32 (3H,
s).
(5S)-5-[4-(4-Methoxy-phenoxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidaz-
olidine-2,4-dione
[0661] LC-MS (APCI) m/z 398.2 (MH+).
[0662] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.73 (1H, s); 8.01 (1H,
s); 6.89 (4H, ABq, J=29.1, 9.1 Hz); 4.43-4.34 (1H, m); 3.70 (3H,
m); 3.51, 3.33 (1H, ABq, J=15.0 Hz); 3.38-3.28 (2H, m); 3.16-3.05
(2H, m); 1.97-1.87 (2H, m); 1.73-1.62 (2H, m); 1.33 (3H, s).
(5S)-5-[4-(3,4-Difluoro-phenoxy)-piperidine-1-sulfonylmethyl]-5-methyl-imi-
dazolidine-2,4-dione
[0663] LC-MS (APCI) m/z 404.2 (MH+).
[0664] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 8.01 (1H,
s); 7.35 (1H, q, J=19.6, 9.2 Hz); 7.19-7.11 (1H, m); 6.86-6.80 (1H,
m); 4.57-4.48 (1H, m); 3.51, 3.34 (1H each, ABq, J=14.9 Hz);
3.38-3.28 (2H, m); 2.16-2.06 (2H, m); 2.00-1.90 (2H, m); 1.74-1.64
(2H, m); 1.33 (3H, s).
(5S)-5-[4-(4-Chloro-phenoxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazo-
lidine-2,4-dione
[0665] LC-MS (APCI) m/z 402 (MH+).
[0666] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.73 (1H, s); 8.00 (1H,
s); 7.32 (2H, d, J=8.8 Hz); 7.00 (2H, d, J=8.8 Hz); 4.56-4.48 (1H,
m); 3.50, 3.33 (1H each, ABq, J=14.8 Hz); 3.37-3.28 (2H, m);
3.16-3.06 (2H, m); 2.00-1.90 (2H, m); 1.73-1.63 (2H, m); 1.32 (3H,
s).
(5S)-5-[4-(5-Ethyl-pyrimidin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-methy-
l-imidazolidine-2,4-dione
[0667] LC-MS (APCI) m/z 398 (MH+).
[0668] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 8.47 (2H,
s); 8.02 (1H, s); 5.11-5.03 (1H, m); 3.52, 3.35 (1H each, ABq,
J=14.8 Hz); 3.42-3.28 (2H, m); 3.19-3.10 (2H, m); 2.54 (2H, q,
J=15.2, 7.6 Hz); 2.06-1.98 (2H, m); 1.81-1.71 (2H, m); 1.33 (3H,
s); 1.17 (3H, t, J=7.2 Hz).
(5S)-5-Methyl-5-[4-(4-trifluoromethyl-pyrimidin-2-yloxy)-piperidine-1-sulf-
onylmethyl]-imidazolidine-2,4-dione
[0669] LC-MS (APCI) m/z 438 (MH+).
[0670] .sup.1H NMR (CDCl.sub.3): .delta. 8.84-8.76 (1H, m); 8.02
(1H, s); 7.31 (1H, d, J=4.8 Hz); 6.33 (1H, s); 5.41-5.34 (1H, m);
4.54-4.42 (4H, m); 3.35, 3.24 (1H each, ABq, J=12.9 Hz); 2.17-2.07
(4H, m); 2.02 (3H, s).
(5S)-5-Methyl-5-[4-(5-methyl-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-
-imidazolidine-2,4-dione
[0671] LC-MS (APCI) m/z 383 (MH+).
[0672] .sup.1H NMR (CDCl.sub.3): .delta. 8.14 (1H, s); 8.06-7.99
(2H, m); 7.19 (1H, s); 7.09 (1H, d, J=1.6 Hz); 5.28-5.21 (1H, m);
3.70-3.41 (6H, m); 2.44 (3H, s); 2.13-1.96 (4H, m); 1.62 (3H,
s).
(5S)-5-[4-(4-Fluoro-benzoyl)-piperidine-1-sulfonylmethyl]-5-methyl-imidazo-
lidine-2,4-dione
[0673] LC-MS (APCI) m/z 398 (MH+).
[0674] .sup.1H NMR (DMSO-d.sub.6): .delta. 8.06 (2H, q, J=9.2, 6.0
Hz); 7.40 (2H t, J=8.8 Hz); 3.61-3.41 (4H, m); 3.00-2.91 (2H, m);
1.90-1.81 (2H, m); 1.62-1.50 (2H, m); 1.33 (3H, s).
(5S)-5-[4-(5-Fluoro-pyrimidin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-meth-
yl-imidazolidine-2,4-dione
[0675] LC-MS (APCI) m/z 388 (MH+).
[0676] .sup.1H NMR (CDCl.sub.3): .delta. 8.42 (2H, s); 8.30 (1H,
s); 6.40 (1H, s); 5.30-5.23 (1H, m); 3.53-3.35 (4H, m); 3.36, 3.21
(1H each, ABq, J=14.4 Hz); 2.10-2.02 (4H, m); 1.70 (3H, s).
(5S)-5-[4-(6-Methoxy-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-methy-
l-imidazolidine-2,4-dione
[0677] LC-MS (APCI) m/z 399 (MH+).
[0678] .sup.1H NMR (MeOD): .delta. 7.54 (1H, t, J=8.4 Hz);
6.33-6.28 (2H, m); 5.24-5.14 (1H, m); 3.86 (3H, s); 3.53-3.42 (2H,
m); 3.58, 3.39 (1H each, ABq, J=14.4 Hz); 3.30-3.22 (2H, m);
2.13-2.02 (2H, m); 1.96-1.82 (2H, m); 1.47 (3H, s).
(5S)-5-[4-(6-Chloro-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-methyl
imidazolidine-2,4-dione
[0679] LC-MS (APCI) m/z 403 (MH+).
[0680] .sup.1H NMR (MeOD): .delta. 7.65 (1H, t, J=7.8 Hz); 6.97
(1H, d, J=7.2 Hz); 6.73 (1H, d, J=7.2 Hz); 5.25-5.14 (1H, m);
3.55-3.44 (2H, m); 3.58, 3.39 (1H each, ABq, J=14.4 Hz); 3.28-3.19
(2H, m); 2.14-2.02 (2H, m); 1.92-1.79 (2H, m); 1.47 (3H, s).
3-[1-((4S)-4-Methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl)-piperidin--
4-yloxy]-benzonitrile
[0681] LC-MS (APCI) m/z 393 (MH+).
[0682] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 8.02 (1H,
s); 7.52-7.47 (2H, m); 7.42-7.38 (1H, m); 7.36-7.31 (1H, m);
4.69-4.61 (1H, m); 3.52, 3.35 (1H each, ABq, J=17.2 Hz); 3.18-3.07
(2H, m); 2.02-1.95 (2H, m); 1.79-1.65 (2H, m); 1.33 (3H, s).
(5S)-5-[4-(3-Methoxy-phenoxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidaz-
olidine-2,4-dione
[0683] LC-MS (APCI) m/z 398 (MH+).
[0684] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 8.01 (1H,
s); 7.21-7.15 (1H, m); 6.58-6.50 (3H, m); 4.57-4.49 (1H, m); 3.73
(3H, s); 3.51, 3.34 (1H each, ABq, J=14.4 Hz); 3.17-3.08 (2H, m);
2.01-1.91 (2H, m); 1.74-1.64 (2H, m); 1.33 (3H, s).
N-{4-[1-(4S)-4-Methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl)-piperidi-
n-4-yloxy]-phenyl}-acetamide
[0685] LC-MS (APCI) m/z 425 (MH+).
[0686] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.69 (1H, brs); 9.78
(1H, s); 8.00 (1H, s); 7.47 (2H, d, J=9.2 Hz); 6.91 (2H, d, J=9.2
Hz); 4.48-4.41 (1H, m); 3.51 (1H from ABq, J=14.4 Hz); 3.16-3.06
(2H, m); 2.00 (3H, s); 1.98-1.90 (2H, m); 1.73-1.63 (2H, m); 1.33
(3H, s).
(5S)-5-[4-(3-Chloro-phenoxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazo-
lidine-2,4-dione
[0687] LC-MS (APCI) m/z 402 (MH+).
[0688] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.76 (1H, brs); 7.99
(1H, s); 7.31 (1H, t, J=8.4 Hz); 7.08 (1H, t, J=2.2 Hz); 7.02-6.95
(2H, m); 4.64-4.56 (1H, m); 3.51 (1H from ABq, J=14.4 Hz);
3.17-3.09 (2H, m); 2.00-1.91 (2H, m); 1.75-1.65 (2H, m); 1.33 (3H,
s).
(5S)-5-Methyl-5-[4-(4-trifluoromethoxy-phenoxy)-piperidine-1-sulfonylmethy-
l]-imidazolidine-2,4-dione
[0689] LC-MS (APCI) m/z 452 (MH+).
[0690] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 8.01 (1H,
s); 7.29 (2H, d, J=8.8 Hz); 7.08 (2H, d, J=9.2 Hz); 4.60-4.52 (1H,
m); 3.51 (1H from ABq, J=14.8 Hz); 3.17-3.08 (2H, m); 2.02-1.93
(2H, m); 1.75-1.65 (2H, m); 1.33 (3H, s).
(5S)-5-Methyl-5-[4-(3-trifluoromethoxy-phenoxy)-piperidine-1-sulfonylmethy-
l]-imidazolidine-2,4-dione
[0691] LC-MS (APCI) m/z 452 (MH+).
[0692] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 8.01 (1H,
s); 7.41 (1H, t, J=8.4 Hz); 7.06-6.91 (3H, m); 4.65-4.58 (1H, m);
3.51 (1H from ABq, J=14.8 Hz); 3.18-3.08 (2H, m); 2.02-1.93 (2H,
m); 1.76-1.65 (2H, m); 1.33 (3H, s).
(5S)-5-[4-(2,4-Difluoro-phenoxy)-piperidine-1-sulfonylmethyl]-5-methyl
imidazolidine-2,4-dione
[0693] LC-MS (APCI) m/z 404 (MH+).
[0694] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 8.02 (1H,
s); 7.34-7.23 (2H, m); 7.06-6.97 (1H, m); 4.50-4.41 (1H, m); 3.50
(1H from ABq); 3.17-3.06 (2H, m); 2.02-1.90 (2H, m); 1.78-1.65 (2H,
m); 1.33 (3H, s).
(5S)-5-[4-(4-Fluoro-phenoxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazo-
lidine-2,4-dione
[0695] LC-MS (APCI) m/z 386 (MH+).
[0696] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.75 (1H, s); 8.02 (1H,
s); 7.17-6.97 (2H, m); 4.52-4.43 (1H, m); 3.17-3.06 (2H, m);
2.00-1.89 (2H, m); 1.75-1.62 (2H, m); 1.33 (3H, s).
(5S)-5-[4-(3-Fluoro-phenoxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazo-
lidine-2,4-dione
[0697] LC-MS (APCI) m/z 386 (MH+).
[0698] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.72 (1H, s); 8.02 (1H,
s); 7.36-7.26 (1H, m); 6.91-6.71 (3H, m); 4.62452 (1H, m);
3.18-3.06 (2H, m); 2.02-1.91 (2H, m); 1.78-1.63 (2H, m); 1.33 (3H,
s).
(5S)-5-[4-(2-Fluoro-phenoxy)-piperidine-1-sulfonylmethyl]-5-methyl-imidazo-
lidine-2,4-dione
[0699] LC-MS (APCI) m/z 386 (MH+).
[0700] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 8.01 (1H,
s); 7.28-7.17 (2H, m); 7.17-7.08 (1H, m); 7.02-6.97 (1H, m);
4.59-4.47 (1H, m); 2.04-1.92 (2H, m); 1.80-1.67 (2H, m); 1.33 (3H,
s).
(5S)-5-[4-(5-Methoxy-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-methy-
l-imidazolidine-2,4-dione
[0701] LC-MS (APCI) m/z 399 (MH+).
[0702] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 8.01 (1H,
s); 7.89 (1H, d, J=3.16 Hz); 7.39 (1H, dd, J=3.18, 9.07 Hz); 6.77
(1H, d, J=8.95 Hz); 5.08-4.96 (1H, m); 3.76 (3H, s); 3.51, 3.34 (1H
each, ABq, J=14.7 Hz); 3.43-3.29 (2H, m); 3.18-3.05 (2H, m);
2.05-1.94 (2H, m); 1.77; 1.61 (2H, m); 1.33 (3H, s).
(5S)-5-Methyl-5-[4-(4-pyridin-3-yl-phenyl)-piperazine-1-sulfonylmethyl]-im-
idazolidine-2,4-dione
[0703] LC-MS (APCI) m/z 430 (MH+).
[0704] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.76 (1H, s); 8.99 (1H,
s); 8.60 (1H, d, J=4.91 Hz); 8.35 (1H, d, J=7.81 Hz); 8.04 (1H, s);
7.70 (2H, d, J=8.87 Hz); 7.12 (2H, d, J=8.91 Hz); 3.57 (1H from
ABq); 3.35 (4H, m); 3.27 (4H, m); 1.33 (3H, s).
(5S)-5-methyl-5-({[4-(pyridin-2-yloxy)piperidin-1-yl]sulfonyl}methyl)imida-
zolidine-2,4-dione
[0705] LC-MS (APCI) m/z 369 (MH+).
[0706] .sup.1H NMR (CDCl.sub.3): .delta. 1.73 (3H, s); 1.96-2.04
(2H, m); 2.04-2.13 (2H, m); 3.21 (1H, d); 3.36-3.42 (3H, m);
3.45-3.50 (2H, m); 5.29-5.33 (1H, m); 6.30 (1H, bs); 6.78 (1H, d);
6.93 (1H, t); 7.65 (1H, t); 7.70 (1H, bs); 8.16 (1H, d).
(5S)-5-[({4-[(3,4-dimethylbenzyl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-met-
hylimidazolidine-2,4-dione
[0707] (NB. contains 30% of the 2,3-dimethyl isomer which was in
the starting material)
[0708] LC-MS (APCI) m/z 410 (MH+).
[0709] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.3 (3H, s); 1.53-1.64
(2H, m); 1.83-1.89 (2H, m); 2.18 (3H, s); 2.20 (3H, s); 2.95-3.33
(2H, m); 3.25-3.31 (3H, m); 3.45 (1H, d); 3.45-3.53 (1H, m); 4.42
(2H, s); 7.01-7.15 (3H, m); 7.97 (1H, s); 10.70 (1H, s).
(5S)-5-methyl-5-{[(4-phenoxypiperidin-1-yl)sulfonyl]methyl}imidazolidine-2-
,4-dione
[0710] LC-MS (APCI) m/z 368 (MH+).
[0711] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.30 (3H, s); 1.64-1.73
(2H, m); 1.92-2.00 (2H, m); 3.08-3.15 (2H, m); 3.28-3.44 (4H, m);
4.49-4.54 (1H, m); 6.92 (1H, t); 6.96 (2H, d); 7.28 (2H, t); 7.69
(1H, bs); 10.7 (1H, bs).
4-Fluoro-N-[1-((4S)-4-methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl)-p-
iperidin-4-yl]-benzamide
[0712] LC-MS (APCI) m/z 413 (MH+).
[0713] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.73 (1H, s); 8.34 (1H,
d, J=7.50 Hz); 8.02 (1H, s); 7.94-7.88 (2H, m); 7.33-7.26 (2H, m);
3.96-3.86 (1H, m); 3.58-3.47 (2H, m); 3.51, 3.32 (1H each, ABq,
J=14.81 Hz); 2.97-2.88 (2H, m); 1.92-1.84 (2H, m); 1.62-1.48 (2H,
m); 1.33 (3H, s).
(5S)-5-[({4-[(2,5-dimethylbenzyl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-met-
hylimidazolidine-2,4-dione
[0714] LC-MS (APCI) m/z 410 (MH+).
[0715] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.30 (3H, s); 1.54-1.62
(2H, m); 1.85-1.91 (2H, m); 2.21 (3H, s); 2.24 (3H, s); 2.97-3.03
(2H, m); 3.27-3.34 (3H, m); 3.45 (1H, d); 3.49-3.55 (1H, m);
6.97-7.04 (2H, m); 7.11 (1H, s); 7.98 (1H, s); 10.70 (1H, s).
(5S)-5-{[4-(5-chloropyridin-2-yl)piperidin-1-yl]sulfonyl}-5-methylimidazol-
idine-2,4-dione
[0716] LC-MS (APCI) m/z 387 (MH+).
[0717] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.72 (1H, s); 8.54 (1H,
d); 8.01 (1H, s); 7.86 (1H, dd); 7.38 (1H, d); 3.61 (2H, bt); 3.50,
3.32 (1H each, ABq, J=14.9 Hz); 2.96-2.76 (3H, m); 1.92 (2H, brd);
1.77-1.62 (2H, m); 1.33 (3H, s).
(5S)-5-[4-(5-Benzyloxy-pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-met-
hyl-imidazolidine-2,4-dione
[0718] LC-MS (APCI) m/z 475 (MH+).
[0719] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.73 (1H, s); 8.01 (1H,
s); 7.90 (1H, d, J=3.13 Hz); 7.48-7.30 (6H, m); 6.76 (1H, d, J=8.97
Hz); 5.10 (2H, s); 5.05-4.98 (1H, m); 3.51 (1H (from ABq), J=14.84
Hz); 3.40-3.30 (3H, m); 3.15-3.07 (2H, m); 2.07-1.95 (2H, m);
1.74-1.64 (2H, m); 1.33 (3H, s).
(5S)-5-[4-(6-Chloro-pyridine-3-yloxy)-piperidine-1-sulfonylmethyl]-5-methy-
l-imidazolidine-2,4-dione
[0720] LC-MS (APCI) m/z 403 (MH+).
[0721] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 8.17 (1H,
d, J=3.10 Hz); 8.61 (1H, s); 7.56 (1H, dd, J=3.18, 8.80 Hz); 7.44
(1H, d, J=8.77 Hz); 4.67-4.59 (1H, m); 3.52, 3.35 (2H, ABq, J=15.22
Hz); 3.39-3.28 (2H, m); 3.17-3.08 (2H, m); 2.03-1.93 (2H, m);
1.77-1.67 (2H, m); 1.33 (3H, s).
(5S)-5-[4-(5-Hydroxy-pyridine-2-yloxy)-piperidine-1-sulfonylmethyl]-5-meth-
yl-imidazolidine-2,4-dione
[0722] LC-MS (APCI) m/z 385 (MH+).
[0723] .sup.1H NMR (Methanol-d.sub.4): .delta. 7.73 (1H, d, J=3.01
Hz); 7.53 (1H, dd, J=3.11, 9.03 Hz); 7.04 (1H, d, J=9.04 Hz);
3.80-3.67 (1H, m); 3.58, 3.41 (2H, ABq, J=15.04 Hz); 3.53-3.42 (2H,
m); 3.36-3.18 (2H, m); 2.17-2.02 (2H, m), 1.96-1.81 (2H, m); 1.48
(3H, s).
(5S)-5-[4-(4-Chloro-phenylsulfanyl)-piperidine-1-sulfonylmethyl]-5-methyl--
imidazolidine-2,4-dione
[0724] LC-MS (APCI) m/z 418 (MH+).
[0725] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 8.00 (1H,
s); 7.45-7.39 (4H, m); 2.97-2.89 (2H, m); 2.00-1.91 (2H, m);
1.56-1.45 (2H, m); 1.31 (3H, s).
(5S)-5-[4-(4-Chloro-benzenesulfonyl)-piperidine-1-sulfonylmethyl]-5-methyl-
-imidazolidine-2,4-dione
[0726] LC-MS (APCI) m/z 450 (MH+).
[0727] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.73 (1H, s); 7.99 (1H,
s); 7.86 (2H, d, J=8.77 Hz); 7.77 (2H, d, J=8.75 Hz); 3.66-3.54
(2H, m); 3.50-3.41 (1H, m); 3.44, 3.32 (1H each, ABq, J=14.63 Hz);
2.82-2.73 (2H, m); 1.97-1.88 (2H, m); 1.57-1.42 (2H, m); 1.30 (3H,
s).
(5S)-5-[4-(4-Fluoro-phenylamino)-piperidine-1-sulfonylmethyl]-5-methyl-imi-
dazolidine-2,4-dione
[0728] LC-MS (APCI) m/z 385 (MH+).
[0729] .sup.1H NMR (Methanol-d.sub.4): .delta. 7.20-7.11 (4H, m);
3.84-3.71 (2H, m); 3.60-3.48 (1H, m); 3.56, 3.39 (1H each, ABq,
J=14.96 Hz); 2.97-2.84 (2H, m); 2.10-2.00 (2H, m); 1.69-1.53 (2H,
m); 1.46 (3H, s).
N-{3-[1-((4S)-4-Methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl)-piperid-
in-4-yloxy]-phenyl}-acetamide
[0730] LC-MS (APCI) m/z 425 (MH+).
[0731] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 9.89 (1H,
s); 8.01 (1H, s); 7.37-7.33 (1H, m); 7.21-7.14 (1H, m); 7.08-7.03
(1H, m); 6.65 (1H, dd, J=1.89, 8.04 Hz); 4.49-4.42 (1H, m); 3.51,
3.34 (1H each, ABq, J=14.73 Hz); 3.39-3.28 (2H, m); 3.18-3.08 (2H,
m); 2.02 (3H, s); 2.00-1.92 (2H, m); 1.76-1.65 (2H, m); 1.33 (3H,
s).
(5S)-5-[4-(4-Chloro-benzoyl)-piperazine-1-sulfonylmethyl]-5-methyl-imidazo-
lidine-2,4-dione
[0732] LC-MS (APCI) m/z 415 (MH+).
[0733] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.75 (1H, s); 8.04 (1H,
s); 7.54 (2H, d, J=8.38 Hz); 7.45 (2H, d, J=8.38 Hz); 3.79-3.55
(2H, bs); 3.56, 3.35 (1H each, ABq, J=14.84 Hz); 3.51-3.31 (2H,
bs); 3.27-3.06 (4H, bs); 1.33 (3H, s).
1-(4S)-4-Methyl-2,5-dioxo-imidazolidine-4-ylmethanesulfonyl)-piperidine-4--
carboxylic acid (4-fluoro-phenyl)-amide
[0734] LC-MS (APCI) m/z 413 (MH+).
[0735] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.74 (1H, s); 9.97 (1H,
s); 8.02 (1H, s); 7.65-7.58 (2H, m); 7.16-7.09 (2H, m); 3.62-3.52
(2H, m); 3.49, 3.33 (1H each, ABq, J=14.94 Hz); 2.87-2.77 (2H, m);
2.48-2.39 (1H, m); 1.91-1.84 (2H, m); 1.70-1.57 (2H, m); 1.33 (3H,
s).
(5S)-5-[4-(5-Bromo-Pyridin-2-yloxy)-piperidine-1-sulfonylmethyl]-5-methyl--
imidazolidine-2,4-dione
[0736] LC-MS (APCI) m/z 447, 449 (MH+).
[0737] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.73 (1H, s); 8.28 (1H,
d, J=2.64 Hz); 8.01 (1H, s); 7.91 (1H, dd, J=2.60, 8.84 Hz); 6.83
(1H, d, J=8.79 Hz); 5.12-5.05 (1H, m); 3.52, 3.35 (1H each, ABq,
J=14.85 Hz); 3.41-3.34 (2H, m); 3.17-3.08 (2H, m); 2.06-1.97 (2H,
m); 1.78-1.67 (2H, m); 1.33 (3H, s).
(5S)-5-[4-(5-(4-Fluoro-phenyl)-pyridin-2-yl)-piperazine-1-sulfonylmethyl]--
5-methyl-imidazolidine-2,4-dione
[0738] LC-MS (APCI) m/z 448 (MH+).
[0739] .sup.1H NMR (DMSO-d.sub.6): .delta. 10.75 (1H, s); 8.45 (1H,
d, J=2.51 Hz); 8.02 (1H, s); 7.88 (1H, dd, J=2.57, 8.86 Hz);
7.70-7.62 (2H, m); 7.30-7.22 (2H, m); 6.98 (1H, d, J=8.94 Hz);
3.70-3.62 (4H, m); 3.55, 3.36 (1H each, ABq, J=14.73 Hz); 3.26-3.19
(4H, m); 1.32 (3H, s)
(5S)-5-[4-(5-(4-Methoxy-Phenyl)-pyridin-2-yl)-piperazine-1-sulfonylmethyl]-
-5-methyl-imidazolidine-2,4-dione
[0740] LC-MS (APCI) m/z 460 (MH+).
(5S)-5-[4-(5-(4-Chloro-phenyl)-pyridin-2-yl)-piperazine-1-sulfonylmethyl]--
5-methyl-imidazolidine-2,4-dione
[0741] LC-MS (APCI) m/z 464, 466 (MH+).
(5S)-5-[4-(5-(4-Trifluoromethoxy-phenyl)-pyridin-2-yl)-piperazine-1-sulfon-
ylmethyl]-5-methyl-imidazolidine-2,4-dione
[0742] LC-MS (APCI) m/z 514 (MH+).
(5S)-5-[4-(5-Furan-2-yl-pyridin-2-yl)-piperazine-1-sulfonylmethyl]-5-methy-
l-imidazolidine-2,4-dione
[0743] LC-MS (APCI) m/z 420 (MH+).
(5S)-5-Methyl-5-(4-[5-(1H-pyrrol-2-yl)-pyridine-2-yl]-piperazine-1-sulfony-
lmethyl)-imidazolidine-2,4-dione
[0744] LC-MS (APCI) m/z 419 (MH+).
(5S)-5-(4-[3,3']-Bipyridinyl-6-yl-piperazine-1-sulfonylmethyl)-5-methyl-im-
idazolidine-2,4-dione
[0745] LC-MS (APCI) m/z 431 (MH+).
(4S)-4-(6-[4-(4-Methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl)-piperaz-
ine-1-yl]-pyridine-3-yl)-benzonitrile
[0746] LC-MS (APCI) m/z 455 (MH+).
EXAMPLE 14
[0747] Compounds with the general formula
##STR00333##
were synthesised according to the method described in Example
12.
TABLE-US-00011 R R2 Analysis ##STR00334## ##STR00335## m/z 543
(MH+).sup.(1) ##STR00336## ##STR00337## m/z 562 (MH+).sup.(1)
##STR00338## ##STR00339## m/z 511 (MH+).sup.(1) ##STR00340##
##STR00341## m/z 523 (MH+).sup.(1) ##STR00342## m/z 443
(MH+).sup.(1) .sup.(1)NMR available, see experimental part.
5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-[(3,4,-
4-trimethyl-2,5-dioxoimidazolidin-1-yl)methyl]imidazolidine-2,4-dione
[0748] The title compound was prepared as described in Example 12
from racemic
{2,5-dioxo-4-[(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)methyl]-
imidazolidin-4-yl}methanesulfonyl chloride and
5-chloro-2-(piperidin-4-yloxy)-pyridine.
[0749] LC-MS (APCI) m/z 543 (MH+).
[0750] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.28 (6H, s); 1.63-1.74
(2H, m); 1.95-2.05 (2H, m); 2.77 (3H, s); 3.14 (4H, d); 3.53-3.73
(3H, m); 4.14 (1H, q); 5.04-5.1.1 (1H, m); 6.85 (1H, d); 7.80 (1H,
dd); 7.94 (1H, s); 8.19 (1H, d); 10.83 (1H, s).
[0751] The starting material was prepared as follows:
3-[3-(benzylthio)-2-oxopropyl]-1,5,5-trimethylimidazolidine-2,4-dione
[0752] Benzyl mercaptan (256 .mu.l, 2.2 mmol) was stirred with
cesium carbonate (712 mg, 2.2 mmol) in dimethyl formamide (5 ml) at
room temperature for 1 hour.
3-(3-bromo-2-oxopropyl)-1,5,5-trimethylimidazolidine-2,4-dione (552
mg, 1.99 mmol) prepared as in WO99/06361 was added and the mixture
stirred 18 hours at room temperature. The reaction mixture was
treated with water, extracted into ethyl acetate (3.times.25 ml),
the organic phases combined, brine washed and dried. The product
was purified by silica chromatography, eluting with 50% ethyl
acetate/iso-hexane to give 300 mg product.
[0753] LC-MS (APCI) m/z 321 (MH+).
[0754] .sup.1H NMR (CDCl.sub.3): .delta. 1.45 (6H, s); 2.91 (3H,
s); 3.16 (2H, s); 3.70 (2H, s); 4.53 (2H, s); 7.22-7.33 (5H,
m).
5-[(benzylthio)methyl]-5-[(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)meth-
yl]imidazolidine-2,4-dione
[0755] The title compound was prepared as described in the
synthesis of 5-methyl-5-s
{[(phenylmethyl)thio]methyl}imidazolidine-2,4-dione in Example
12.
[0756] LC-MS (APCI) m/z 391 (MH+).
[0757] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.28 (6H, s); 2.64 and
2.76 (2H, abq, J=114.2 Hz); 2.78 (3H, s); 3.54 & 3.64 (2H, abq,
J=14.2 Hz); 3.73 (2H, s); 7.20-7.32 (5H, m); 7.98 (1H, s); 10.83
(1H, s).
{2,5-dioxo-4-[(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)methyl]imidazoli-
din-4-yl}methanesulfonyl chloride
[0758] The title compound was prepared as described in the
synthesis of [(48) and
(4R)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride
in Example 12.
[0759] .sup.1H NMR (CD.sub.3OD): .delta. 1.38 (6H, s); 2.89 (3H,
s); 3.81 and 3.92 (2H, abq, J=14.3 Hz); 4.61 (2H, s).
[0760] The following compounds were prepared as described in the
synthesis of
5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-[(-
3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)methyl]imidazolidine-2,4-dione.
5-[({4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}sulfonyl)methyl]-5--
[(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)methyl]imidazolidine-2,4-dion-
e
[0761] LC-MS (APCI) m/z 562 (MH+).
[0762] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.26 (6H, s); 2.76 (3H,
s); 3.16-3.22 (4H, m); 3.48-3.76 (8H, m); 7.02 (1H, d); 7.81-7.76
(2H, m); 8.43 (1H, s); 10.83 (1H, s).
5-[4-(4-Fluoro-phenyl-piperazine-1-sulfonylmethyl]-5-[(3,4,4-trimethyl-2,5-
-dioxoimidazolidin-1-yl)methyl]imidazolidine-2,4-dione
[0763] LC-MS (APCI) m/z 511 (MH+).
[0764] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.28 (6H, s); 2.77 (3H,
s); 3.10-3.16 (4H, m); 3.21-3.26 (4H, m); 3.48-3.71 (4H, m);
6.95-7.09 (4H, m); 7.88 (1H, s); 10.84 (1H, bs).
5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-{2-[(p-
henylmethyl)oxy]ethyl}imidazolidine-2,4-dione
[0765] The title compound was prepared as described in the
synthesis of
5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-5-[(3,4-
,4-trimethyl-2,5-dioxoimidazolidin-1-yl)methyl]imidazolidine-2,4-dione
starting from 5-Chloro-2-(piperidine-4-yloxy)-pyridine
hydrochloride and
(2,5-dioxo-4-{2-[(phenylmethyl)oxy]ethyl}imidazolidin-4-yl)methanesulfony-
l chloride.
[0766] LC-MS (APCI) m/z 523 (MH+).
[0767] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.37-1.79 (3H, m);
1.83-2.08 (4H, m); 3.00-3.56 (7H, m partially obscured by
D.sub.2O); 4.33-4.44 (2H, m); 5.01-5.12 (1H, m); 6.85 (1H, d);
7.21-7.36 (5H, m); 7.80 (1H, dd); 8.02 (1H, s); 8.19 (1H, d); 10.70
(1H, bs).
6-({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)-1,3-diazaspiro[4-
.5]decane-2,4-dione
[0768] LC-MS (APCI) m/z 443 (MH+).
[0769] The starting material was prepared as follows:
6-[(phenylmethyl)thio]-1,3-diazaspiro[4.5]decane-2,4-dione
[0770] Benzylmercaptan (937 mg, 7.5 mmol) was dissolved in 70 mL of
THF. NaH (362 mg 60%, 9.0 mmol) was added and the slurry was
stirred for some minutes. 2-chlorocyclohexanone (11.0 g, 7.5 mmol)
was added and the reaction was stirred at rt over night. The solid
was filtered of and the solvent was removed by rotary evaporation.
Potassium cyanide (4 eq), (NH.sub.4).sub.2CO.sub.3 (8 eq) and 25 mL
of ethanol was added. The reaction was stirred in a sealed vial at
80.degree. C. over night. The suspension was filtered and the solid
was recrystallised from DMSO and water to give the title compound
as a white solid
[0771] LC-MS (APCI) m/z 291 (MH+).
[0772] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.21-1.81 (8H, m); 2.79
(1H, dd); 3.67-3.76 (2H, m); 7.18-7.32 (5H, m); 8.43 (1H, s); 10.68
(1H, s).
EXAMPLE 15
##STR00343##
[0773]
5-Methyl-5-(1-(toluene-4-sulfonyl)-cyclopentyl)-imidazolidine-2,4-d-
ione
[0774] 1-(1-(Toluene-4-sulfonyl)-cyclopentyl))-ethanone (0.10 g,
0.38 mmol), potassium cyanide (0.049 g, 0.75 mmol), ammonium
carbonate (0.18 g, 1.9 mmol), 50% ethanol in water (1.6 mL) were
stirred in a sealed tube (2 mL volume) at 90.degree. C. for 70
hours. The solution was acidified with 10% acetic acid to pH 6 and
concentrated by rotary evaporation to half of its original volume
upon which part of the product fell out. The solution and its solid
contents were taken up in ethyl acetate, the aqueous phase was
separated and washed twice with ethyl acetate. The combined organic
phases were washed with brine, dried over anhydrous sodium sulfate,
filtered and concentrated by rotary evaporation to give 0.74 g of a
white solid. The crude product was dissolved in methanol (5 mL),
concentrated with silica (1 g) by rotary evaporation and applied on
a short silica column. Elution with ethyl acetate/n-heptane (1:2
and 2:1) gave 0.060 g (48%) of the title product as colourless
needles.
[0775] LC-MS (APCI) m/z 337 (MH+).
[0776] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.96-1.10 (1H, m);
1.32-1.44 (1H, m); 1.36 (3H, s); 1.47-1.58 (2H, m); 2.10-2.30 (4H,
m); 2.40 (3H, s); 7.41 (2H, d, J=8 Hz); 7.72 (2H, d, J=8 Hz); 7.80
(1H, bs) and 10.7 (1H, bs).
[0777] .sup.13C NMR (DMSO-d.sub.6): .delta. 21.0, 22.60, 22.64,
26.1, 26.3, 30.8, 31.5, 64.1, 78.9, 129.2, 130.3, 135.3, 144.2,
156.0 and 176.2.
The starting material was prepared as follows:
1-(Toluene-4-sulfonyl)-propan-2-one
[0778] was prepared according to Crandall et al. J. Org. Chem.
1985, (8) 50, 1327-1329 from sodium p-toluenesulfinate dihydrate
(4.2 g, 18 mmol), chloroacetone (1.0 mL, 12 mmol),
n-tetrabutylammonium bromide (0.30 g) and water-benzene-acetone
4:3:3 (10 mL). Work-up and chromatography on silica of the crude
using ethyl acetate/n-heptane (1:3 through 1:2) as eluent gave 2.4
g (95%) of the title product as an oil which crystallised on
standing in the fridge.
[0779] LC-MS (APCI) m/z 213 (MH+).
[0780] .sup.1H NMR (CDCl.sub.3): .delta.2.38 (3H, s); 2.42 (3H, s);
4.10 (2H, s); 7.35 (d2H, d, J=8 Hz); 7.74 (d, 2H, d, J=8 Hz).
[0781] .sup.13C NMR (CDCl.sub.3): .delta. 21.7, 31.4, 67.7, 128.0,
129.8, 135.5, 145.3 and 195.9.
1-(1-(Toluene-4-sulfonyl)-cyclopentyl))-ethanone
[0782] 1-(Toluene-4-sulfonyl)-propan-2-one (0.10 g, 0.47 mmol),
1,4-diiodobutane (0.068 mL, 0.52 mmol), finely ground potassium
carbonate (0.14 g, 1.0 mmol) and dry dimethylsulfoxide (0.80 mL)
were stirred at 50.degree. C. (oil bath temperature) for 22 hours.
The heating was shut off and stirring was continued at 22.degree.
C. for 22 hours. The crude product was taken up in ethyl acetate,
washed with water (5.times.50 mL) and brine (1.times.50 mL), dried
over anhydrous sodium sulfate, filtered and concentrated by rotary
evaporation. The oily residue was chromatographed on silica using
ethyl acetate/n-heptane (1:4 through 1:3) to give 0.10 g (80%) of
the title product as a colourless oil.
[0783] LC-MS (APCI) m/z 267 (MH+).
[0784] .sup.1H NMR (CDCl.sub.3): .delta. 1.52 (2H, m); 1.77 (2H,
m); 2.26 (2H, m); 2.37 (2H, m); 2.42 (3H, s); 2.48 (3H, s); 7.30
(2H, d, J=8 Hz) and 7.60 (2H, d, J=8 Hz).
[0785] .sup.13C NMR (CDCl.sub.3): .delta. 21.7, 25.4, 28.0, 31.3,
83.9, 129.4, 129.5, 133.2, 145.0 and 202.5.
* * * * *