U.S. patent application number 10/471500 was filed with the patent office on 2004-06-03 for metalloproteinase inhibitors.
Invention is credited to Af Rosenschold, Magnus Munck.
Application Number | 20040106659 10/471500 |
Document ID | / |
Family ID | 20283374 |
Filed Date | 2004-06-03 |
United States Patent
Application |
20040106659 |
Kind Code |
A1 |
Af Rosenschold, Magnus
Munck |
June 3, 2004 |
Metalloproteinase inhibitors
Abstract
Compounds of the formula (I) wherein z --O-- or --S--, useful as
metalloproteinase inhibitors, especially as inhibitors of
MMP12.
Inventors: |
Af Rosenschold, Magnus Munck;
(Lund, SE) |
Correspondence
Address: |
FISH & RICHARDSON PC
225 FRANKLIN ST
BOSTON
MA
02110
US
|
Family ID: |
20283374 |
Appl. No.: |
10/471500 |
Filed: |
January 6, 2004 |
PCT Filed: |
March 13, 2002 |
PCT NO: |
PCT/SE02/00473 |
Current U.S.
Class: |
514/369 ;
514/376; 514/389; 548/183; 548/226; 548/311.1; 548/317.1 |
Current CPC
Class: |
C07D 409/14 20130101;
A61P 1/16 20180101; A61P 19/04 20180101; C07D 417/14 20130101; A61P
25/00 20180101; A61P 29/00 20180101; C07D 233/76 20130101; A61P
43/00 20180101; A61P 19/00 20180101; A61P 19/08 20180101; A61P 7/02
20180101; A61P 9/00 20180101; A61P 37/08 20180101; A61P 35/00
20180101; A61P 1/02 20180101; A61P 11/06 20180101; A61P 19/02
20180101; A61P 25/02 20180101; C07D 405/12 20130101; A61P 7/00
20180101; A61P 9/04 20180101; C07D 471/04 20130101; A61P 11/00
20180101; A61P 13/12 20180101; C07D 403/04 20130101; A61P 11/02
20180101; A61P 1/04 20180101; A61P 9/10 20180101; C07D 401/12
20130101; A61P 17/06 20180101; A61P 35/04 20180101; C07D 403/12
20130101; A61P 3/10 20180101; A61P 19/06 20180101; A61P 17/00
20180101; A61P 19/10 20180101; A61P 27/02 20180101; A61P 25/28
20180101; C07D 403/06 20130101; A61P 1/00 20180101; A61P 15/00
20180101; A61P 17/02 20180101; C07D 401/14 20130101; C07D 405/14
20130101; A61P 17/04 20180101 |
Class at
Publication: |
514/369 ;
514/376; 514/389; 548/183; 548/226; 548/311.1; 548/317.1 |
International
Class: |
A61K 031/426; A61K
031/421; A61K 031/4178; A61K 031/4168; C07D 277/14; C07D
263/04 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 15, 2001 |
SE |
0100902-6 |
Claims
What we claim is:
1. A compound of the formula I or a pharmaceutically acceptable
salt or an in vivo hydrolysable ester thereof 68wherein X is
selected from NR1, O, S; Y1 and Y2 are independently selected from
O, S; Z is selected from O, S; 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; R1 is selected from H, (C1-3)alkyl,
haloalkyl; R2 and R3 are 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; R4 is selected from H, halogen (preferably
fluorine), (C1-3)alkyl or haloalkyl; 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; 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; 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; 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 S, or is
fused to the next ring structure; Provided that when X is NR1, R1
is H, Y1 is O, Y2 is O, Z is O, R2 is methyl, R3 is H, R4 is H, and
A is a direct bond, then R5 is not p-chloro-phenyl,
o-methoxyphenyl, p-methoxyphenyl, 3,4-dichlorophenyl,
o-nitrophenyl, p-nitrophenyl, 2-methoxy-4-aminophenyl,
2-methoxy-5-fluorophenyl or p-benzyloxyphenyl; when X is NR1, R1 is
H, Y1 is O, Y2 is O, Z is O, R2 is phenyl, R3 is H, R4 is H and A
is a direct bond, then R5 is not p-chloro-phenyl.
2. A compound of the formula I as claimed in claim 1 or a
pharmaceutically acceptable salt or an in vivo hydrolysable ester
thereof, wherein X is NR1, at least one of Y1 and Y2 is O, R1 is H,
(C1-3) alkyl or (C1-3) haloalky.
3. A compound of the formula I as claimed in either claim 1 or
claim 2 or a pharmaceutically acceptable salt or an in vivo
hydrolysable ester thereof, wherein 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.
4. A compound of the formula I as claimed in any of the preceding
claims or a pharmaceutically acceptable salt or an in vivo
hydrolysable ester thereof, wherein each of R3 and R4 is
independently selected from H, methyl.
5. A compound of the formula I as claimed in any of the preceding
claims or a pharmaceutically acceptable salt or an in vivo
hydrolysable ester thereof, wherein R5 comprises one, two or three
optionally substituted aryl or heteroaryl 5 or 6 membered
rings.
6. A compound of the formula I as claimed in any of the preceding
claims or a pharmaceutically acceptable salt or an in vivo
hydrolysable ester thereof, wherein R5 is a bicyclic or tricyclic
group comprising two or three optionally substituted ring
structures.
7. A compound of the formula II or a pharmaceutically acceptable
salt or an in vivo hydrolysable ester thereof 69wherein 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; Z is O or S; B is
selected from a direct bond, O, (C1-6)alkyl, (C1-6)heteroalkyl; 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 70C 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; 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; 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, alkoxycarbonyl, carboxy,
alkylcarboxy, carbamate; R3 and R4 are independently selected from
H or (C1-3)alkyl; 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.
8. A compound of the formula II as claimed in claim 7 or a
pharmaceutically acceptable salt or an in vivo hydrolysable ester
thereof, wherein B is a direct bond or O.
9. A compound of the formula II as claimed in either claim 7 or
claim 8 or a pharmaceutically acceptable salt or an in vivo
hydrolysable ester thereof, wherein 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-sulfon- e,
amido, N-alkylamido, N,N-dialkylamido, cyano, sulfonamino,
alkyl-sulfonamino, amidino, N-aminosulfone-amidino, carboxy,
alkylcarboxy, alkoxycarbonyl, carbamate.
10. A compound of the formula II as claimed in any of claims 7 to 9
or a pharmaceutically acceptable salt or an in vivo hydrolysable
ester thereof, wherein each of R3 and R4 is H.
11. A compound of the formula II as claimed in any of claims 7 to
10 or a pharmaceutically acceptable salt or an in vivo hydrolysable
ester thereof, wherein each of G1 and G2 is an optionally
substituted monocyclic group with each ring structure comprising up
to 6 ring atoms independently selected from aryl or heteroaryl.
12. A compound of the formula II as claimed in claim 11 or a
pharmaceutically acceptable salt or an in vivo hydrolysable ester
thereof, wherein G1 is substituted with halogen, hydroxy,
haloalkoxy, amido, amino, N-alkylamino, N,N-dialkylamino, cyano,
alkyl, haloalkyl, alkoxy, 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, alkoxy, haloalkoxy, cyano, carbamate.
13. A pharmaceutical composition which comprises a compound of the
formula I as claimed in claim 1 or a compound of the formula II as
claimed in claim 7 or a pharmaceutically acceptable salt or an in
vivo hydrolysable ester thereof and a pharmaceutically acceptable
carrier.
14. 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 formulae I or
II or a pharmaceutically acceptable salt or in vivo hydrolysable
ester thereof.
15. Use of a compound of the formulae I or II 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.
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, MMP11), 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 atheroscelerosis; 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 MC 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):225-23 1]. 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 TypeIV 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.
pp115-148. 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 supernantants 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: 1
[0016] 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.
2
[0017] The above compound has a mercaptoacyl zinc binding group and
an imide group at the P1 position. 3
[0018] 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.
4
[0019] 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. Whitaker 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). 5
[0020] 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.
[0021] The following compounds are not known as MMP inhibitors:
[0022] Lora-Tamayo, M et al (1968, An. Quim 64(6: 591-606) describe
synthesis of the following compounds as a potential anti-cancer
agent: 6
[0023] Czech patent numbers 151744 (19731119) and 152617 (1974022)
describe the synthesis and the anticonvulsive activity of the
following compounds: 7
[0024] R=4-NO2, 4-OMe, 2-NO2,
[0025] U.S. Pat. No. 3,529,019 (19700915) describes the following
compounds used as intermediates: 8
[0026] 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): 9
[0027] 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.
[0028] 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) 10
[0029] wherein X is selected from NR1, O, S;
[0030] Y1 and Y2 are independently selected from O, S;
[0031] R1 is selected from H, alkyl, haloalkyl;
[0032] 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.
[0033] 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
in the range of 0.1-1000 nanomolar.
[0034] 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, chelating 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.
[0035] In a first aspect of the invention we now provide compounds
of the formula I 11
[0036] wherein
[0037] X is selected from NR1, O, S;
[0038] Y1 and Y2 are independently selected from O, S;
[0039] Z is selected from O, S;
[0040] 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;
[0041] R1 is selected from H, (C1-3)alkyl, haloalkyl;
[0042] R2 and R3 are 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;
[0043] R4 is selected from H, halogen (preferably fluorine),
(C1-3)alkyl or haloalkyl;
[0044] 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;
[0045] 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;
[0046] 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;
[0047] 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 S, or is
fused to the next ring structure;
[0048] 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);
[0049] Any heterocycloalkyl or heteroaryl group outlined above
contains one or more hetero groups independently selected from N,
O, S, SO, SO2;
[0050] 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;
[0051] Provided that
[0052] when X is NR1, R1 is H, Y1 is O, Y2 is O, Z is O, R2 is
methyl, R3 is H, R4 is H, and A is a direct bond, then R5 is not
p-chloro-phenyl, o-methoxyphenyl, p-methoxyphenyl,
3,4-dichlorophenyl, o-nitrophenyl, p-nitrophenyl,
2-methoxy-4-aminophenyl, 2-methoxy-5-fluorophenyl or
p-benzyloxyphenyl;
[0053] when X is NR1, R1 is H, Y1 is O, Y2 is O, Z is O, R2 is
phenyl, R3 is H, R4 is H and A is a direct bond, then R5 is not
p-chloro-phenyl.
[0054] Preferred compounds of the formula I are those wherein any
one or more of the following apply:
[0055] X is NR1;
[0056] At least one of Y1 and Y2 is O; especially both Y1 and Y2
are O;
[0057] R1 is H, (C1-3) alkyl, (C1-3) haloalkyl; especially R1 is
H;
[0058] 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.
[0059] R3 and/or R4 is H;
[0060] R3 and/or R4 is methyl;
[0061] R5 comprises one, two or three optionally substituted aryl
or heteroaryl 5 or 6 membered rings;
[0062] R5 is a bicyclic or tricyclic group comprising two or three
optionally substituted ring structures.
[0063] Particularly preferred compounds of formula I are those
wherein R5 is a bicyclic or tricyclic group comprising two or three
optionally substituted ring structures.
[0064] Further preferred compounds of the invention are compounds
of the formula II 12
[0065] wherein
[0066] 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;
[0067] Z is O or S;
[0068] B is selected from a direct bond, O, (C1-6)alkyl,
(C1-6)heteroalkyl;
[0069] 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 13
[0070] 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;
[0071] 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-allylamino,
N,N-dialkylamino, cyano, nitro, alkoxy, haloalkoxy;
[0072] Optionally R2 is substituted with halo, haloalkyl, hydroxy,
alkoxy, haloalkoxy, amino, aminoalkyl, N-alkylamino,
N,N-dialkylamino, (N4-alkylamino)alkyl, (N,N-dialkylamino)alkyl,
alkylsulfone, aminosulfone, N-alkylamino-sulfone,
N,N-dialkylaminosulfone, amido, N-alkylamido, N,N-dialkylamido,
cyano, sulfonamino, alkyl-sulfonamino, amidino,
N-aminosulfone-amidino, guanidino, N-cyano-guanidino,
thioguanidino, 2-nitroguanidino, alkoxycarbonyl, carboxy,
alkylcarboxy, carbamate;
[0073] R3 and R4 are independently selected from H or
(C1-3)alkyl;
[0074] 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;
[0075] 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);
[0076] Any heterocycloalkyl or heteroaryl group outlined above
contains one or more hetero groups independently selected from N,
O, S, SO, SO2;
[0077] 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.
[0078] Preferred compounds of the formula II are those wherein one
or more of the following apply:
[0079] B is a direct bond or O;
[0080] 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-dialkylaminosulfone- , amido, N-alkylamido, N,N-dialkylamido,
cyano, sulfonamino, alkyl-sulfonamino, amidino,
N-aminosulfone-amidino, carboxy, alkylcarboxy, alkoxycarbonyl,
carbamate;
[0081] Each of R3 and R4 is H;
[0082] Each of G1 and G2 is an optionally substituted monocyclic
group with each ring structure comprising up to 6 ring atoms
independently selected from aryl or heteroaryl; preferably G1 is
substituted with halogen, hydroxy, haloalkoxy, amido, amino,
N-alkylamino, N,N-dialkylamino, cyano, alkyl, haloalkyl, alkoxy,
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, alkoxy,
haloalkoxy, cyano, carbamate.
[0083] For example, particular compounds of the invention include
compounds of formula II wherein B is a direct bond or O; and Z is O
or S; and 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 and each of R3 and R4 is H; and each of G1 and G2
is a monocyclic group with each ring structure comprising up to 6
ring atoms independently selected from aryl or heteroaryl;
preferably G1 is substituted with halogen, hydroxy, haloalkoxy,
amido, amino, N-alkylamino, N,N-dialkylamino, cyano, alkyl,
haloalkyl, alkoxy, 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, alkoxy, haloalkoxy, cyano, carbamate.
[0084] Suitable values for R2 include the following: 1415
[0085] Suitable values for R5 include the following: 16
[0086] R=F, Cl, Br, CF3, CF3O, CH3O, OH, CF3CH2, CN, NCOMe
[0087] It will be appreciated that the particular substituents and
number of substituents in compounds of formula I are selected so as
to avoid sterically undesirable combinations.
[0088] Each exemplified compound represents a particular and
independent aspect of the invention.
[0089] Where optically active centres exist in the compounds of
formula I, 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, p104-107) including for example the formation of
diastereomeric derivatives having convenient optically active
auxiliary species followed by separation and then cleavage of the
auxiliary species.
[0090] 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 formula I can give rise to
stereoisomers, and in each case the invention is to be understood
to extend to all such stereoisomers, including enantiomers and
diastereomers, and mixtures including racemic mixtures thereof.
[0091] Where tautomers exist in the compounds of formula I, we
disclose all individual is tautomeric forms and combinations of
these as individual specific embodiments of the invention.
[0092] 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
formula I represents an independent and particular embodiment of
the invention.
[0093] Certain compounds of the invention are of particular use as
inhibitors of MMP13 and/or MMP9 and/or MMP8 and/or MMP3.
[0094] 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 TACE inhibitory activity, by way of non-limiting example
they may show 100-1000 fold selectivity over any TACE inhibitory
activity.
[0095] 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.
[0096] 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.
[0097] In order to use a metalloproteinase inhibitor compound of
the invention (a compound of the formula I or II) 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 pharmaceutical practice as a
pharmaceutical composition.
[0098] 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) or a pharmaceutically
acceptable salt or an in vivo hydrolysable ester and
pharmaceutically acceptable carrier.
[0099] 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 adminstration 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.
[0100] 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.
[0101] 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.
[0102] Typically unit dosage forms will contain about 1 mg to 500
mg of a compound of this invention.
[0103] 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.
[0104] In particular we provide a compound of the formula II 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).
[0105] 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 forumal 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.
[0106] 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 (or a pharmaceutically
acceptable salt or in vivo hydrolysable ester thereof). We also
provide the use of a compound of the formula II (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.
[0107] 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.
[0108] Preparation of the Compounds of the Invention
[0109] In another aspect the present invention provides a process
for preparing a compound of the formula I or II or a
pharmaceutically acceptable salt or in vivo hydrolysable ester
thereof, as described 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.
[0110] (a) Compounds of formula I in which each of Y1 and Y2 is O,
Z is O, and X and R5 is 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, 17
[0111] with a compound of formula VII, in which G is a sulfhydryl
(SH) or a hydroxyl group, and X is 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.
[0112] Alternatively, the compounds may be prepared in the same
manner 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 VIII represents a leaving group.
[0113] (b) Compounds of formula I in which Y1 and Y2 are each O, X
is NR1(R1=H), Z is S or O, and R2, R3, R4, R5 are as described in
formula I may be prepared by reacting a compound of formula VIII in
which R2, R3, R4, R5 and A are as described in formula I, 18
[0114] with ammonium and cyanide salts in protic solvents,
preferably in the presence of excess ammonium carbonat and
potassium cyanide in ethanol in a sealed vessel at 40-80 C. for
4-24 hours.
[0115] The ketones of formula VIII are conveniently prepared by
treating alkohols or thiols of formula IX, in which R5 and A are as
described in formula I, with haloketones of formula X, in which R2
is as described for formula I, and excess base. 19
[0116] The compounds of the invention may be evaluated for example
in the following assays:
[0117] Isolated Enzyme Assays
[0118] Matrix Metalloproteinase Family Including for Example MMP12,
MMP13.
[0119] 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-NH- 2 in the
presence or absence of inhibitors. Activity is determined by
measuring the fluorescence at .lambda.ex 328 nm and .lambda.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].
[0120] 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 .lambda.ex 328 nm and .lambda.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].
[0121] 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.
[0122] Adamalysin Family Including for Example TNF Convertase
[0123] 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 TBP-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 (50 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 .lambda.ex 490 nm and
.lambda.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'-t-
etramethyluronium 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.
[0124] Natural Substrates
[0125] 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., (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.
[0126] 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.
[0128] Test as an Agent to Inhibit Cell Based Invasion
[0129] 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.
[0130] Test as an Agent to Inhibit Whole Blood TNF Sheddase
Activity
[0131] 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.
[0132] Test as an Agent to Inhibit In Vitro Cartilage
Degradation
[0133] 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. Bottomnley et
al., (1997) Biochem J. 323:483-488.
[0134] Pharmacodynamic Test
[0135] 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 10U 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.
[0136] In Vivo Assessment Test as an Anti-TNF Agent
[0137] 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 96U
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.
[0138] Data analysis by dedicated software calculates for each
compound/dose: 1 Percent inhibition of TNF = Mean TNF ( Controls )
- Mean TNF ( Treated ) .times. 100 Mean TNF ( Controls )
[0139] Test as an Anti-arthritic Agent
[0140] Activity of a compound as an anti-arthritic is tested in the
collagen-induced arthritis (CIA) as defmed by D. E. Trentham et
al., (1977) J. Exp. Med. 14,: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.
[0141] Test as an Anti-cancer Agent
[0142] 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 p75 10th NCI-EORTC
Symposium, Amsterdam Jun. 16-19 1998).
[0143] Test as an Anti-emphysema Agent
[0144] Activity of a compound as an anti-emphysema agent may be
assessed essentially as described in Hautamaki et al (1997)
Science, 277: 2002.
[0145] The invention will now be illustrated but not limited by the
following Examples:
[0146] General analytical methods: .sup.1H-NMR spectra were
recorded on either a Varian .sup.UnityInova 400 MHz or Varian
Mercury-VX 300 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
[0147] 20
5-(Biphenyl-4-yloxymethyl)-5-ethyl-imidazolidine-2,4-dione
[0148] 4-Hydroxy-biphenyl (84 mg, 0.5 mmol) was added to
1-bromo-2-butanone (0.055 ml, 0.55 mmol) and anhydrous potassium
carbonate (95 mg, 0.69 mmol) in dry aceton (2.5 ml). The 21
[0149] mixture was stirred for 2 hours at ambidient temperature,
then diluted with ethylacetate (2.5 ml). The supernantant was
evaporated. The afforded oil was stirred at 75.degree. C.
overnight, in a sealed vial, together with ammonium carbonate (290
mg, 3.0 mmol) and potassium cyanide (79 mg, 1.2 mmol) in 50%
ethanol (3 ml). The resulting solution was pured out on
ethylacetate (20 ml), ether (10 ml) and water (15 ml), together
with saturated ammonium chloride (aq, 2 ml). The organic phase was
washed additionally once with water (10 ml), then evaporated
together with heptane to afford the title compound (112 mg, 0.36
mmol) as a white solid in 72% yield.
[0150] .sup.1HNMR (300 MHz, DMSO-d.sub.6): .delta. 10.57 (1H, bs);
8.00 (1H, s); 7.63-7.58 (4H, m); 7.43 (2H, m); 7.01 (2H, d); 4.07
(2H, dd); 1.67 (2H, m); 0.86 (3H, t). LC-MS (APCI) m/z 311.1
(MH+).
EXAMPLE 2
[0151] Compounds with the general formula 22
[0152] were synthesised according to the method described in
Example 1
1 R R2 R3 Analysis 23 Me Me m/z 311 (MH+) 24 Et H m/z 336 (MH+) 25
Me H m/z 331 (MH+) 26 Me H m/z 322 (MH+) 27 tBu H m/z 364 (MH+) 28
Ph H m/z 384 (MH+) 29 Me H m/z 381 (MH+) CN 30 H m/z 338 (MH+) CN
31 H m/z 386 (MH+) CN 32 H m/z 308 (MH+) Br 33 H m/z 393 (MH+) Br
34 H m/z 443 (MH+) Br 35 H m/z 363 (MH+) OMe 36 H m/z 343 (MH+) OMe
37 H m/z 393 (MH+) OMe 38 H m/z 313 (MH+) Me 39 H m/z 327 (MH+) Me
40 H m/z 377 (MH+) Me 41 H m/z 297 (MH+) H 42 H m/z 313 (MH+) H 43
H m/z 363 (MH+) H 44 H m/z 283 (MH+) 45 m/z 281 (MH+) 46 Me H m/z
303 (MH+).sup.(1) 47 Me H m/z 365 (MH+).sup.(1) 48 Me H m/z 326
(MH+) 49 Me H m/z 315 (MH+).sup.(1) 50 Me H m/z 354 (MH+).sup.(1)
51 Me H m/z 327 (MH+).sup.(1) 52 Et H m/z 341 (MH+).sup.(1) 53 Et H
m/z 378 (MH+).sup.(1) 54 Et H m/z 340 (MH+).sup.(1) 55 Et H m/z 395
(MH+).sup.(1) 56 Et H m/z 317 (MH+).sup.(1) 57 Ph H m/z 426
(MH+).sup.(1) 58 tBu H m/z 340 (MH+).sup.(1) 59 tBu H m/z 368
(MH+).sup.(1) 60 tBu H m/z 406 (MH+).sup.(1) 61 tBu H m/z 407
(MH+).sup.(1) 62 63 H m/z 360 (MH+).sup.(1) .sup.(1)For NMR-data
see experimental part.
5-[1-(Biphenyl-4-yloxy)-ethyl]-5-methyl-imidazolidine-2,4-dione
[0153] LC-MS (APCI) m/z 311.2 (MH+).
5-(4'-Cyano-biphenyl-4-yloxymethyl)-5-ethyl-imidazolidine-2,4-dione
[0154] LC-MS (APCI) m/z 336.2 (MH+).
5-(4'-Chloro-biphenyl-4-yloxymethyl)-5-methyl-imidazolidine-2,4-dione
[0155] LC-MS (APCI) m/z 331.2 (MH+).
5-(4'-Cyano-biphenyl-4-yloxymethyl)-5-methyl-imidazolidine-2,4-dione
[0156] LC-MS (APCI) m/z 322.2 (MH+).
5-(4'-Cyano-biphenyl-4-yloxymethyl)-5-tert-butyl-imidazolidine-2,4-dione
[0157] LC-MS (APCI) m/z 364 (MH+).
5-(4'-Cyano-biphenyl-4-yloxymethyl)-5-phenyl-imidazolidine-2,4-dione
[0158] LC-MS (APCI) m/z 384 (MH+).
5-Methyl-5-[4-(4-trifluoromethyl-phenoxy)-phenoxymethyl]-imidazolidine-2,4-
-dione
[0159] LC-MS (APCI) m/z 381.4 (MH+).
5-(4-Cyano-phenoxymethyl)-5-(3-methoxy-phenyl)-imidazolidine-2,4-dione
[0160] LC-MS (APCI) m/z 338.2 (MH+).
5-(4-Cyano-phenoxymethyl)-5-(3-bromo-phenyl)-imidazolidine-2,4-dione
[0161] LC-MS (APCI) m/z 386.1 (MH+).
5-(4-Cyano-phenoxymethyl)-5-phenyl-imidazolidine-2,4-dione
[0162] LC-MS (APCI) m/z 308.1 (MH+).
5-(4-Bromo-phenoxymethyl)-5-(3-methoxy-phenyl)-imidazolidine-2,4-dione
[0163] LC-MS (APCI) m/z 393.1 (MH+).
5-(4-Bromo-phenoxymethyl)-5-(3-bromo-phenyl)-imidazolidine-2,4-dione
[0164] LC-MS (APCI) m/z 442.9 (MH+).
5-(4-Bromo-phenoxymethyl)-5-phenyl-imidazolidine-2,4-dione
[0165] LC-MS (APCI) m/z 363.1 (MH+).
5-(4-Methoxy-phenoxymethyl)-5-(3-methoxy-phenyl)-imidazolidine-2,4-dione
[0166] LC-MS (APCI) m/z 343.2(MH+).
5-(4-Methoxy-phenoxymethyl)-5-(3-bromo-phenyl)-imidazolidine-2,4-dione
LC-MS (APCI) m/z 393.2 (MH+).
5-(4-Methoxy-phenoxymethyl)-5-phenyl-imidazolidine-2,4-dione
[0167] LC-MS (APCI) m/z 313.2 (MH+).
5-(4-Methyl-phenoxymethyl)-5-(3-methoxy-phenyl)-imidazolidine-2,4-dione
[0168] LC-MS (APCI) m/z 327.1 (MH+).
5-(4-Methyl-phenoxymethyl)-5-(3-bromo-phenyl)-imidazolidine-2,4-dione
[0169] LC-MS (APCI) m/z 377.1 (MH+).
5-(4-Methyl-phenoxymethyl)-5-phenyl-imidazolidine-2,4-dione
[0170] LC-MS (APCI) m/z 297.1 (MH+).
5-Phenoxymethyl-5-(3-methoxy-phenyl)-imidazolidine-2,4-dione
[0171] LC-MS (APCI) m/z 313.2 (MH+).
5-Phenoxymethyl-5-(3-bromo-phenyl)-imidazolidine-2,4-dione
[0172] LC-MS (APCI) m/z 363 (MH+).
5-Phenoxymethyl-5-phenyl-imidazolidine-2,4-dione
[0173] LC-MS (APCI) m/z 283.2 (MH+).
6-(4-Chloro-phenoxy)-1,3-diaza-spiro[4,4]nonane-2,4-dione
[0174] LC-MS (APCI) m/z 281 (MH+).
5-Methyl-5-[(4-thiophen-2-yl-phenoxymethyl)-imidazolidine-2,4-dione
[0175] 1-(4-Thien-2-ylphenoxy)acetone (114 mg, 0.49 mmol), sodium
cyanide (40 mg, 0.81 mmol), ammonium carbonate (222 mg, 2.85 mmol)
water (5 ml) and ethanol were mixed and heated at 80.degree. C. for
10 hours. After cooling the reaction mixture was treated with
water, the solid was filtered off and dried to give 105 mg
product.
[0176] LC-MS (APCI) m/z 303 (MH+). .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.31 (3H, s); 3.95, 4.10 (2H, abq, J=9.8 Hz); 6.95 (2H, d);
7.08 (1H, dd); 7.37 (1H, d); 7.45 (1H, d); 7.55 (2H, d); 8.03 (1H,
s).
[0177] The starting materials were prepared as follows:
[0178] 1(4-Iodophenoxy)acetone
[0179] 4-lodophenol (4.9 g, 22 mmol) was stirred together with
potassium carbonate (4.7 g, 33 mmol), chloroacetone (4.5 ml, 55
mmol) and acetone at reflux for 18 hours. The reaction mixture was
poured into water (100 mL), extracted with ethyl acetate
(3.times.50 mL), the extracts were brine washed, dried over sodium
sulphate and evaporated. The residue was purified by flash
chromatography eluting with dichloromethane.
[0180] LC-MS (APCI) /z 275 (MH+). .sup.1H NMR (CDCl.sub.3): .delta.
2.26 (3H, s); 4.51 (2H, s); 6.65 (2H, 4); 7.57 (2H, d).
[0181] 1-(4-Thien-2-ylphenoxy)acetone
[0182] 1-(4-Iodophenoxy)acetone (192 mg, 0.69 mmol) was treated
with thiophen-2-boronic acid (102 mg, 0.79 mmol),
[1,1'-bis(diphenylphosphino)- ferrocene]dichloro palladium (II)
complex with dichloromethane (1:1) (36 mg), dimethylformamide (12
mL) and ammonium acetate (135 mg) were stirred together at 80
.degree. C. for 3 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 50 % ethyl acetate: iso-hexane to give 114 mg
product.
[0183] LC-MS (APCI) m/z 232 (MH+).
[0184] The following compounds were prepared as described in the
synthesis of
5-methyl-5-[(4-thien-2-ylphenoxy)methyl]imidazolidine-2,4-dione
5-Methyl-5-(4'-(trifluoromethyl-biphenyl-4-yloxymethyl)-imidazolidine-2,4--
dione
[0185] LC-MS (APCI) m/z 365 (MH+). .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.46 (3H, s); 4.05, 4.22 (2H, ABq, J=9.9 Hz); 7.04 (2H, d);
7.61 (2H, d); 7.04, 7.61 (4H, ABq, J=9.8 Hz).
5-(4'-(Methoxy-biphenyl-4-yloxymethyl)-5-methyl-imidazolidine-2,4-dione
[0186] LC-MS (APCI) m/z 326 (MH+).
5-(4'-(Fluoro-biphenyl-4-yloxymethyl)-5-methyl-imidazolidine-2,4-dione
[0187] LC-MS (APCI) m/z 315 (MH+). .sup.1H NMR (DMSO-d.sub.6):
.delta.1,45 (3H, s); 4.02, 4.20 (2H, abq, J=9.9 Hz); 6.99 (2H, d);
7.12 (2H, t); 7.50 (2H, d); 7.55 (2H, dd).
N-[4'(4-Methyl-2,5-dioxo-imidazolidin-4-ylmethoxy)-biphenyl-3-yl]-acetamid-
e
[0188] LC-MS (APCI) m/z 354 (MH+). .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.46 (3H, s); 2.14 (3H, s); 2.15 (1H, s); 4.05, 4.20 (2H,
abq, J=9.6 Hz); 7.00 (2H, d); 7.28-7.40 (3H, m); 7.46 (1H, bd);
7.53 (2H, d); 7.78-7.81 (1H, m).
5-(3'-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-imidazolidine-2,4-dione
[0189] LC-MS (APCI) m/z 327 (MH+). .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.45 (3H, s); 3.83 (3H, s); 4.04, 4.20 (2H, abq, J=9.6 Hz);
6.85 (1H, dd); 6.99 (2H, d); 7.08 (1H, m); 7.12 (1H, d); 7.30 (1H,
t); 7.53 (2H, d).
5-Ethyl-5-(4'-(methoxy-biphenyl-4-yloxymethyl)-imidazolidine-2,4-dione
[0190] LC-MS (APCI) m/z 341 (MH+). .sup.1H NMR (DMSO-d.sub.6):
.delta. 0.48 (3H, t); 1.56-1.74 (2H, m); 3.77 (3H, s); 3.97, 4.11
(2H, abq, J=10.0 Hz); 6.94-7.00 (4H, m); 7.49-7.54 (4H, m); 7.97
(1H, s); 10.71 (1H, brs)
5-Ethyl-5-(4'-(trifluoromethyl-biphenyl-4-yloxymethyl)-imidazolidine-2,4-d-
ione
[0191] LC-MS (APCI) m/z 378 (MH+). .sup.1H NMR (DMSO-d.sub.6):
.delta. 0.83 (3H, t); 1.66 (2H, oct); 4.01, 4.14 (2H, abq, J=9.8
Hz); 7.04 (2H, d); 7.67 (2H, d); 7.75 (2H, d); 7.84 (2H, d); 8.01
(1H, s); 10.75 (1H, bs).
5-Ethyl-5-(3'-(methoxy-biphenyl-4-yloxymethyl)-imidazolidine-2,4-dione
[0192] LC-MS (APCI) m/z 340 (MH+). .sup.1H NMR (DMSO-d.sub.6):
.delta. 0.83 (3H, t); 1.65 (2H, oct); 3.76 (3H, s); 3.97, 4.10 (2H,
abq, J=9.7 Hz); 6.93-6.99 (3H, m); 7.49-7.53 (3H, m); 7.99 (1H, s);
10.74 (1H, bs).
5-Ethyl-5-(4'-(trifluoromethoxy-biphenyl-4-yloxymethyl)-imidazolidine-2,4--
dione
[0193] LC-MS (APCI) m/z 395 (MH+). .sup.1H NMR (DMSO-d.sub.6):
.delta. 0.84 (3H, t); 1.56-1.74 (2H, m); 4.00, 4.13 (2H, abq,
J=10.9 Hz); 7.01 (2H, d); 7.40 (2H, d); 7.61, 7.72 (4H, abq, J=8.9
Hz); 7.79 (1H, s); 10.72 (1H, bs).
5-Ethyl-5-[(4-thiophen-2-yl-phenoxymethyl)-imidazolidine-2,4-dione
[0194] LC-MS (APCI) m/z 317 (MH+). .sup.1H NMR (DMSO-d.sub.6):
.delta. 0.82 (3H, t); 1.54-1.74 (2H, m); 3.97, 4.12 (2H, abq,
J=10.0 Hz); 6.95 (2H, d); 7.08 (1H, dd); 7.37 (1H, dd); 7.44 (1H,
dd); 7.55 (2H, d); 7.98 (1H, s); 10.67 (1H, s).
5-Phenyl-5-(4'-(trifluoromethyl-biphenyl-4-yloxymethyl)-imidazolidine-2,4--
dione
[0195] LC-MS (APCI) m/z 426 (MH+). .sup.1H NMR (DMSO-d.sub.6):
.delta. 4.21, 4.62 (2H, abq, J=10.1 Hz); 7.10 (2H, d); 7.38-7.47
(3H, m); 7.61-7.69 (4H, m); 7.76, 7.84 (4H, abq, J=8.8 Hz); 8.76
(1H, s); 10.92 (1H, bs).
5-tert-Butyl-5-(4-pyridin-3-yl-phenoxymethyl)-imidazolidine-2,4-dione
[0196] LC-MS (APCI) m/z 340 (MH+) .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.02 (9H, s); 4.15, 4.36 (2H, abq, J=9.9 Hz); 7.10 (2H, d);
7.70-7.75 (3H, m); 8.08 (1H, s); 8.39 (1H, dd); 8.65 (1H, dd); 9.00
(1H, s).
5-tert-Butyl-5-(4'-methoxy-biphenyl-4-yloxymethyl)-imidazolidine-2,4-dione
[0197] LC-MS (APCI) m/z 368 (MH+). .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.01 (9H, s); 3.76 (3H, s); 4.10, 4.31 (2H, abq, J=9.7 Hz);
6.95-7.01 (4H, dd); 7.48-7.55 (4H, dd); 8.05 (1H, s); 10.59 (1H,
bs).
5-tert-Butyl-5-(3'-trifluoromethyl-biphenyl-4-yloxymethyl)-imidazolidine-2-
,4-dione
[0198] LC-MS (APCI) m/z 406 (MH+). .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.01 (9H, s); 4.14, 4.35 (2H, abq, J=9.6 Hz); 7.06 (2H, d);
7.65-7.69 (4H, m); 7.89 (1H, s); 7.93 (1H, t); 8.08 (1H, s); 10.65
(1H, s).
5-tert-Butyl-5-(4'-trifluoromethyl-biphenyl-4-yloxymethyl)-imidazolidine-2-
,4-dione
[0199] LC-MS (APCI) m/z 407 (MH+). .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.03 (9H, s); 4.15, 4.36 (2H, abq, J=10.0 Hz); 7.07, 7.68
(4H, abq, J=8.9 Hz); 7.76, 7.84 (4H, abq, J=8.9 Hz); 8.08 (1H, s);
10.67 (1H, s).
5-(Biphenyl-4-yloxymethyl)-5-pyridin-4-yl-imidazolidine-2,4-dione
[0200] LC-MS (APCI) m/z 360 (MH+). .sup.1H NMR (CD.sub.3OD):
.delta. 4.41, 4.71 (2H, ABq, J=9.7 Hz); 7.02 (2H, d); 7.28 (1H, t);
7.39 (2H, t); 7.55 (2H, d); 8.14 (2H, d); 8.81 (2H, d).
EXAMPLE 3
[0201] Compounds with the general formula 64
[0202] were synthesised according to the method described in
Example 1
2 R R2 Analysis.sup.(1) 65 Me m/z 313 (MH+) 66 Me -- 67 Me m/z 397
(MH+) .sup.(1)For NMR-data see experimental part.
5-[(1,1'-biphenyl-4-ylthio)methyl]-5-methylimidazolidine-2,4-dione
[0203] LC-MS(APCI) m/z 313 (MH+). .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.36 (3H, s); 3.28 (2H, s); 7.34 (1H, t); 7.44 (4H, t);
7.60 (2H, d); 7.64 (2H, d); 7.97 (1H, s); 10.74 (1H, bs).
[0204] The starting material was prepared as follows:
[0205] 1-(1,1'-biphenyl-4-ylthio)propan-2-one
[0206] 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.
[0207] GC/MS m/z: 242 [M+]. .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); 7.45-7.59
(4H, m).
[0208] The following compounds were prepared as described in the
synthesis of
5-[(1,1'-biphenyl-4-ylthio)methyl]-5-methylimidazolidine-2,4-dione
4'-{[(4-methyl-2,5-dioxoimidazolidin-4-yl)methyl]thio}-1,1'-biphenyl-4-car-
bonitrile
[0209] The starting material,
4'-[(2-oxopropyl)thio]-1,1'-biphenyl-4-carbo- nitrile, was prepared
as described in the synthesis of
1-(1,1'-biphenyl-4-ylthio)propan-2-one. .sup.1H NMR (DMSO-d.sub.6):
.delta. 1.37 (3H, s); 3.30 (2H, s); 7.45, 7.67 (4H, abq, J=7.5 Hz);
7.88 (4H, q); 7.99 (1H, s); 10.75 (1H, bs).
5-methyl-5-[({4'-[(trifluoromethyl)oxy]-1,1'-biphenyl-4-yl}thio)methyl]imi-
dazolidine-2,4-dione
[0210] The starting material,
1-({4'-[(trifluoromethyl)oxy]-1,1'-biphenyl--
4-yl}thio)propan-2-one, was prepared as described in the synthesis
of 1-(1,1'-biphenyl-4-ylthio)propan-2-one.
[0211] LC-MS(APCI) m/z very weak 397 (MH+). .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).
* * * * *