U.S. patent application number 12/122954 was filed with the patent office on 2008-09-18 for inhibitors of matrix metalloproteinase.
This patent application is currently assigned to Glaxo Group Limited. Invention is credited to Ian Holmes, Stephen Paul Watson.
Application Number | 20080227858 12/122954 |
Document ID | / |
Family ID | 27637076 |
Filed Date | 2008-09-18 |
United States Patent
Application |
20080227858 |
Kind Code |
A1 |
Holmes; Ian ; et
al. |
September 18, 2008 |
Inhibitors of matrix metalloproteinase
Abstract
Compounds of formula (I): ##STR00001## wherein R.sup.1
represents optionally substituted C.sub.4-12 alkyl, optionally
substituted C.sub.2-6alkylaryl, or optionally substituted 5- or
6-membered aryl or heteroaryl; Z represents a bond, CH.sub.2, O, S,
SO, SO.sub.2, NR.sup.4, OCR.sup.4R.sup.5, CR.sup.4R.sup.5O, or Z,
R.sup.1 and Q together form an optionally substituted fused
tricyclic group; Q represents an optionally substituted 5- or
6-membered aryl or heteroaryl ring; X represents COR.sup.3 or
N(OR.sup.8)COR.sup.9; R.sup.2 represents SO.sub.2R.sup.10 or
SO.sub.2NR.sup.10R.sup.11; R.sup.3 represents
OR.sup.6NR.sup.6R.sup.7 or NR.sup.6OH; R.sup.4 and R.sup.5 each
independently represents H, C.sub.1-6 alkyl or C.sub.1-4 alkylaryl;
R.sup.6 and R.sup.7 each independently represents H, C.sub.1-6
alkyl, or C.sub.1-6 alkyl substituted with one or more heteroaryl
groups, or R.sup.6 and R.sup.7 together with the nitrogen atom to
which they are attached form a 5- or 6-membered ring which may
optionally include 1 or more further heteroatoms selected from O, S
and N; R.sup.8 and R.sup.9 each independently represents H or
C.sub.1-6 alkyl; R.sup.10 and R.sup.11 each independently
represents H or C.sub.1-6 alkyl; and and physiologically functional
derivatives thereof, with the exception of
N-(ethoxycarbonyl)-N-[4-(1H-tetrazol-1-yl)phenyl]glycine, processes
for their preparation, pharmaceutical formulations containing them
and their use as inhibitors of matrix metalloproteinase enzymes
(MMPs) are described.
Inventors: |
Holmes; Ian; (Stevenage,
GB) ; Watson; Stephen Paul; (Stevenage, GB) |
Correspondence
Address: |
GLAXOSMITHKLINE;Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
Glaxo Group Limited
|
Family ID: |
27637076 |
Appl. No.: |
12/122954 |
Filed: |
May 19, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10561055 |
Dec 16, 2005 |
7375248 |
|
|
PCT/EP2004/006553 |
Jun 16, 2004 |
|
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12122954 |
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Current U.S.
Class: |
514/521 ;
514/562; 558/406; 562/430 |
Current CPC
Class: |
A61P 37/00 20180101;
C07D 213/42 20130101; C07C 311/08 20130101; A61P 29/00 20180101;
A61P 37/02 20180101 |
Class at
Publication: |
514/521 ;
558/406; 514/562; 562/430 |
International
Class: |
A61K 31/277 20060101
A61K031/277; A61K 31/195 20060101 A61K031/195; C07C 311/30 20060101
C07C311/30 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 20, 2003 |
GB |
0314488.8 |
Claims
1. A compound of formula (I): ##STR00030## wherein: R.sup.1
represents optionally substituted C.sub.4-12 alkyl, optionally
substituted C.sub.2-6alkylaryl, or optionally substituted 5- or
6-membered aryl or heteroaryl; Z represents a bond, CH.sub.2, O, S,
SO, SO.sub.2, NR.sup.4, OCR.sup.4R.sup.5, CR.sup.4R.sup.50, or Z,
R.sup.1 and Q together form an optionally substituted fused
tricyclic group; Q represents an optionally substituted 5- or
6-membered aryl or heteroaryl ring; X represents COR.sup.3 or
N(OR.sup.8)COR.sup.9; R.sup.2 represents SO.sub.2R.sup.10 or
SO.sub.2NR.sup.10R.sup.9; R.sup.3 represents OR.sup.6,
NR.sup.6R.sup.7 or NR.sup.6OH; R.sup.4 and R.sup.5 each
independently represents H, C.sub.1-6 alkyl or C.sub.1-4 alkylaryl;
R.sup.6 and R.sup.7 each independently represents H, C.sub.1-6
alkyl, or C.sub.1-6 alkyl substituted with one or more heteroaryl
groups, or R.sup.6 and R.sup.7 together with the nitrogen atom to
which they are attached form a 5- or 6-membered ring which may
optionally include 1 or more further heteroatoms selected from O, S
and N; R.sup.8 and R.sup.9 each independently represents H or
C.sub.1-6 alkyl; R.sup.10 and R.sup.11 each independently
represents H or C.sub.1-6 alkyl; and and physiologically functional
derivatives thereof, with the exception of
N-(ethoxycarbonyl)-N-[4-(1H-tetrazol-1-yl)phenyl]glycine.
2. A compound of formula (Ia): ##STR00031## wherein: R.sup.10
represents H or C.sub.1-6 alkyl; R.sup.12 represents H, halo,
CF.sub.3, cyano, OCF.sub.3, nitro, OR.sup.3, SR.sup.3, COR.sup.13
or C.sub.1-6 alkyl; R.sup.13 represents C.sub.1-6 alkyl or
C.sub.1-4alkylaryl; and physiologically functional derivatives
thereof.
3. A method for treatment of a human or animal subject suffering
from or susceptible to an autoimmune disorder or an inflammatory
condition, which comprises administering to said human or animal
subject an effective amount of a compound of claim 1.
4. A pharmaceutical composition, comprising a compound of claim 1
and a pharmaceutically acceptable carrier therefor, and optionally
one or more other therapeutic agents.
5. A process for preparation of compounds of formula (I) according
to claim 1, which comprises: (A) preparing a compound of formula
(I), wherein Z represents a bond and R.sup.1 represents an
optionally substituted C.sub.2-6alkylaryl or an optionally
substituted 5- or 6-membered aryl or heteroaryl, by reacting a
compound of formula (II): ##STR00032## wherein R.sup.2, Q and X are
as previously defined for formula (I) and L represents a leaving
group, with a reagent suitable to introduce the group R.sup.1; or
(B) preparing a compound of formula (I), wherein Z represents a
bond and R.sup.1 represents an optionally substituted
C.sub.4-12alkyl, by reacting a compound of formula (III):
##STR00033## wherein R.sup.2, Q and X are as previously defined for
formula (I), with a reagent suitable to introduce the group
R.sup.1; or (C) preparing a compound of formula (I), wherein Z
represents OS, SO, SO.sub.2, NR.sup.4 or OCR.sup.4R.sup.5, and
R.sup.1 represents an optionally substituted C.sub.4-12alkyl, by
reacting a compound of formula (IV): ##STR00034## wherein X,
R.sup.2 and Q are as previously defined for formula (I), and Y
represents OH, SH, NR.sup.4H or HCR.sup.4R.sup.5, with a reagent
suitable to introduce group R.sup.1, provided that when Y is SH it
is followed by optional oxidation of sulphide to sulfoxide or
sulfone; or (D) preparing a compound of formula (I), wherein Z
represents OS, SO, SO.sub.2, or NR.sup.4, and R.sup.1 represents an
optionally substituted C.sub.2-6alkylaryl or an optionally
substituted 5- or 6-membered aryl or heteroaryl, by reacting a
compound of formula (IV): ##STR00035## wherein X, R.sup.2 and Q are
as previously defined for formula (I), and Y represents OH, SH or
NR.sup.4H, with a reagent suitable to couple to group R.sup.1,
provided that when Y is SH it is followed by optional oxidation of
the sulphide to sulfoxide or sulfone; or (E) preparing a compound
of formula (I), wherein Z represents OCR.sup.4R.sup.5 and R.sup.1
represents an optionally substituted C.sub.2-6alkylaryl or an
optionally substituted 5- or 6-membered aryl or heteroaryl, by
reacting a compound of formula (V): ##STR00036## wherein X, R.sup.2
and Q are as defined for formula (I) and L.sup.4 is a suitable
leaving group, with a reagent suitable to introduce group
R.sup.1--O; or (F) preparing a compound of formula (I), wherein Z
represents CR.sup.4R.sup.50, by reacting a compound of formula
(IV): ##STR00037## wherein R.sup.2 and Q are as defined for formula
(I), and Y represents OH, with a reagent suitable to introduce
group R.sup.1CR.sup.4R.sup.5--; or (G) preparing a compound of
formula (I), wherein Z represents CH.sub.2, by reacting a compound
of formula (III): ##STR00038## wherein R.sup.2, Q and X are as
defined for formula (I), with a reagent suitable to introduce group
R.sup.1CH.sub.2; (H) reacting a compound of formula (VI)
##STR00039## or a protected derivative thereof, wherein R.sup.1, Z,
Q and X are as defined for formula (I), with a reagent suitable to
introduce group R.sup.2 as defined for formula (I): or (J) carrying
out a process selected from processes (A) to (G) followed by
interconversion of one or more functional groups.
Description
CROSS REFERENCE TO PRIOR APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 10/561,055 filed 16 Dec. 2005 (allowed), which is a 371
application of PCT/EP2004/006553 filed 16 Jun. 2004 which claims
priority to GB application 0314488.8 filed 20 Jun. 2003.
FIELD OF THE INVENTION
[0002] This invention relates to novel chemical compounds,
processes for their preparation, pharmaceutical formulations
containing them and their use in therapy.
SUMMARY OF THE INVENTION
[0003] The compounds of the invention are inhibitors of matrix
metalloproteinase enzymes (MMPs).
BACKGROUND OF THE INVENTION
[0004] Matrix metalloproteinase enzymes play a major role in
extracellular matrix component degradation and remodelling.
Examples of MMPs include collagenase 1, 2 and 3, gelatinase A and
B, stromelysin 1, 2 and 3, matrilysin, macrophage metalloelastase,
enamelysin and membrane type 1, 2, 3 and 4 MMP. The enzymes are
secreted by connective tissue cells and inflammatory cells. Enzyme
activation can not only initiate tissue damage but induce increased
inflammatory cell infiltration into the tissue, leading to more
enzyme production and subsequent tissue damage. For example,
elastin fragments produced by MMP degradation are believed to
stimulate inflammation by attracting macrophages to the site of MMP
activity. Inhibition of MMPs provides a means for treating disease
states wherein inappropriate metalloprotease activity results in
degradation of connective tissue and inflammation.
DETAILED DESCRIPTION OF THE INVENTION
[0005] In one aspect, the present invention provides compounds of
formula (I):
##STR00002##
wherein: R.sup.1 represents optionally substituted C.sub.4-12
alkyl, optionally substituted C.sub.2-6alkylaryl, or optionally
substituted 5- or 6-membered aryl or heteroaryl; Z represents a
bond, CH.sub.2, O, S, SO, SO.sub.2, NR.sup.4, OCR.sup.4R.sup.5,
CR.sup.4R.sup.5O, or Z, R.sup.1 and Q together form an optionally
substituted fused tricyclic group; Q represents an optionally
substituted 5- or 6-membered aryl or heteroaryl ring; X represents
COR.sup.3 or N(OR.sup.8)COR.sup.9; R.sup.2 represents
SO.sub.2R.sup.10 or SO.sub.2NR.sup.10R.sup.11; R.sup.3 represents
OR.sup.6, NR.sup.6R.sup.7 or NR.sup.6OH; R.sup.4 and R.sup.5 each
independently represents H, C.sub.1-6 alkyl or C.sub.1-4 alkylaryl;
R.sup.5 and R.sup.7 each independently represents H, C.sub.1-6
alkyl, or C.sub.1-6 alkyl substituted with one or more heteroaryl
groups, or R.sup.6 and R.sup.7 together with the nitrogen atom to
which they are attached form a 5- or 6-membered ring which may
optionally include 1 or more further heteroatoms selected from O,
S, and N; R.sup.8 and R.sup.9 each independently represents H or
C.sub.1-6 alkyl; R.sup.10 and R.sup.11 each independently
represents H or C.sub.1-6 alkyl; and and physiologically functional
derivatives thereof, with the exception of
N-(ethoxycarbonyl)-N-[4-(1H-tetrazol-1-yl)phenyl]glycine.
[0006] References to `aryl` include references to monocyclic
carbocyclic aromatic rings (e.g. phenyl) and bicyclic carbocyclic
aromatic rings (e.g. naphthyl) and references to `heteroaryl`
include references to mono- and bicyclic heterocyclic aromatic
rings containing 1-3 hetero atoms selected from nitrogen, oxygen
and sulphur. Examples of monocyclic heterocyclic aromatic rings
include e.g. pyridinyl, pyrimidinyl, thiophenyl, furanyl, pyrrolyl,
oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl or
imidazolyl, and examples of bicyclic heterocyclic aromatic rings
include e.g. benzimidazolyl, quinolinyl or indolyl. Carbocyclic and
heterocyclic aromatic rings may be optionally substituted, e.g. by
one or more C.sub.1-6 alkyl C.sub.2-6 alkenyl, halogen,
(CH.sub.2).sub.0-4OR.sup.6, (CH.sub.2).sub.0-4SR.sup.6,
SO.sub.2R.sup.6, COR.sup.6, aryloxy, thioaryl, cyano, hydroxy,
nitro, NR.sup.6R.sup.7, --NR.sup.6COR.sup.7, --OCF.sub.3,
--CF.sub.3, COOR.sup.7, --OCHCF.sub.2, --SCF.sub.3,
--CONR.sup.6R.sup.7, --SO.sub.2NR.sup.6R.sup.7, or like groups.
[0007] References to `alkyl` include references to both straight
chain and branched chain aliphatic isomers of the corresponding
alkyl. It will be appreciated that references to `alkylene` and
`alkoxy` shall be interpreted similarly.
Suitably, R.sup.1 represents optionally substituted aryl, such as
substituted or unsubstituted phenyl. Suitably, Q represents
optionally substituted aryl, such as unsubstituted phenyl. Suitably
R.sup.2 represents SO.sub.2R.sup.10, such as SO.sub.2C.sub.1-4
alkyl, for example SO.sub.2CH.sub.3. Suitably R.sup.3 represents OH
or NR.sup.6R.sup.7. In particular, X suitably represents CO.sub.2H.
Suitably Z represents a bond.
[0008] When R.sup.6 or R.sup.7 represents C.sub.1-6alkyl
substituted with one or more heteroaryl groups, suitably the
C.sub.1-6 alkyl group will be methyl or ethyl; suitably the alkyl
group will be substituted with one heteroaryl group. Suitably, one
of R.sup.6 or R.sup.7 represents H.
[0009] One subgroup of compounds of formula (I) is represented by
formula (Ia):
wherein R.sup.10 represents H or C.sub.1-6 alkyl, preferably
C.sub.1-4 alkyl, most preferably methyl; R.sup.12 represents H,
halo, CF.sub.3, cyano, OCF.sub.3, nitro, OR.sup.13, SR.sup.3,
COR.sup.13 or C.sub.1-6 alkyl, for example, methyl;
[0010] R.sup.13 represents C.sub.1-6 alkyl or
C.sub.1-4alkylaryl;
and physiologically functional derivatives thereof.
[0011] Preferably R.sup.12 is in the meta or para position. Most
preferably R.sup.12 is in the para position.
[0012] A further or alternative subgroup of compounds of formula
(I) is represented by formula (Ia) wherein R.sup.10 represents H or
C.sub.1-6 alkyl, such as C.sub.1-4 alkyl, for example methyl;
R.sup.12 represents H, halo, CF.sub.3, cyano, OCF.sub.3, nitro,
OR.sup.13, SR.sup.13, or CoR.sup.13; R.sup.13 represents H,
C.sub.1-6 alkyl or C.sub.1-4alkylaryl; and physiologically
functional derivatives thereof.
[0013] Preferably R.sup.12 is in the meta or para position. Most
preferably R.sup.12 is in the para position.
[0014] By the term "physiologically functional derivative" is meant
a chemical derivative of a compound of formula (I) having the same
physiological function as the free compound of formula (I), for
example, by being convertible in the body thereto and includes any
pharmaceutically acceptable esters, amides and carbamates, salts
and solvates of compounds of formula (I) which, upon administration
to the recipient, are capable of providing (directly or indirectly)
compounds of formula (I) or active metabolite or residue
thereof.
[0015] Salts of compounds of formula (I) are also provided by the
invention. Suitable salts of the compounds of formula (I) include
physiologically acceptable salts and salts which may not be
physiologically acceptable but may be useful in the preparation of
compounds of formula (I) and physiologically acceptable salts
thereof. If appropriate, acid addition salts may be derived from
inorganic or organic acids, for example hydrochlorides,
hydrobromides, sulphates, phosphates, acetates, benzoates,
citrates, succinates, lactates, tartrates, fumarates, maleates,
1-hydroxy-2-naphthoates, palmoates, methanesulphonates, formates or
trifluoroacetates.
[0016] Examples of solvates include hydrates.
[0017] When compounds of formula (I) contain chiral centres, the
invention extends to mixtures of enantiomers (including racemic
mixtures) and diastereoisomers as well as to individual
enantiomers. Generally it is preferred to use a compound of formula
(I) in the form of a purified single enantiomer.
[0018] The compounds of formula (I) and salts and solvates thereof
may be prepared by the methodology described hereinafter,
constituting a further aspect of this invention.
[0019] A first process (A) according to the invention for preparing
a compound of formula (I) wherein Z represents a bond and R.sup.1
represents an optionally substituted C.sub.2-6alkylaryl or an
optionally substituted 5- or 6-membered aryl or heteroaryl,
comprises reacting a compound of formula (II):
##STR00003##
wherein R.sup.2, Q and X are as previously defined for formula (I)
and L represents a leaving group, with a reagent suitable to
introduce the group R.sup.1, such as a compound R.sup.1B(OH).sub.2,
suitably in the presence of a catalyst, such as a nobel metal
catalyst e.g. palladium, and a suitable base, such as an alkali
metal carbonate, e.g. caesium carbonate. The reaction is
conveniently carried out in a suitable solvent, such as a polar
organic solvent, e.g. dimethyl formamide. Suitable leaving groups
represented by L include halides, especially bromide or iodide.
[0020] For example, for the synthesis of a (optionally substituted)
[(1,1'-biphenyl-4-yl)(methyl-sulfonyl)amino]acetic acid according
to the invention a phenyl boronic acid may be reacted with
[(4-bromophenyl)(methylsulfonyl)amino]acetic acid in the presence
of a suitable catalyst:
[0021] A second process (B) according to the invention for
preparing a compound of formula (I) wherein Z represents a bond and
R.sup.1 represents an optionally substituted C.sub.4-12alkyl,
comprises reacting a compound of formula (III):
##STR00004##
wherein R.sup.2, Q and X are as previously defined for formula (I),
with a reagent suitable to introduce the group R.sup.1, such as a
compound R.sup.1-L, wherein L is a suitable leaving group, for
example halide, suitably in the presence of a catalyst, for example
a Lewis acid catalyst such as AlCl.sub.3. A Friedel-Crafts reaction
may accordingly be appropriate.
[0022] A third process (C) according to the invention for preparing
a compound of formula (I) wherein Z represents O, S, SO, SO.sub.2,
NR.sup.4 or OCR.sup.4R.sup.5, and R.sup.1 represents an optionally
substituted C.sub.4-12alkyl comprises reacting a compound of
formula (IV):
##STR00005##
wherein X, R.sup.2 and Q are as previously defined for formula (I),
and Y represents OH, SH, NR.sup.4H or HOCR.sup.4R.sup.5, with a
reagent suitable to introduce the group R.sup.1, such as a compound
R.sup.1-L, wherein L is a suitable leaving group. The reaction is
conveniently carried out in a suitable solvent, such as an alcohol
solvent, e.g. ethanol, under basic conditions, for example in the
presence of an aqueous hydroxide such as sodium hydroxide. Suitable
leaving groups represented by L include halides, especially bromide
or iodide.
[0023] For compounds in which Z represents SO or SO.sub.2, the
compound of formula (I) may conveniently be prepared by initial
preparation of the compound in which Z represents S, followed by
oxidation of the sulphide to the sulfoxide or the sulfone. The
oxidation step may be carried out using methods known in the art
such as oxidation with hydrogen peroxide in the case of the
sulfone, or oxidation with Oxone.RTM. (potassium peroxymonosulfate)
in the case of the sulfoxide.
[0024] A fourth process (D) according to the invention for
preparing a compound of formula (I) wherein Z represents O, S, SO,
SO.sub.2, or NR.sup.4, and R.sup.1 represents an optionally
substituted C.sub.2-6alkylaryl or an optionally substituted 5- or
6-membered aryl or heteroaryl, comprises reacting a compound of
formula (IV):
##STR00006##
wherein X, R.sup.2 and Q are as previously defined for formula (I),
and Y represents OH, SH or NR.sup.4H, with a reagent suitable to
introduce the group R.sup.1, such as a compound R.sup.1-L, wherein
L is a suitable leaving group. The reaction is conveniently carried
out in a suitable solvent, such as a solvent containing a
heteroatom, e.g. pyridine, in the presence of a suitable catalyst,
for example palladium catalyst (preferred for Y.dbd.NR.sup.4H) or a
copper catalyst (preferred for Y.dbd.OH or SH). Suitable leaving
groups represented by L include halides, especially bromide or
iodide.
[0025] For compounds in which Z represents SO or SO.sub.2, the
compound of formula (I) may conveniently be prepared by initial
preparation of the compound in which Z represents S, followed by
oxidation of the sulphide to the sulfoxide or the sulfone. The
oxidation step may be carried out using methods known in the art
such as oxidation with hydrogen peroxide in the case of the
sulfone, or oxidation with Oxone.RTM. (potassium peroxymonosulfate)
in the case of the sulfoxide.
[0026] A fifth process (E) according to the invention for preparing
a compound of formula (I) wherein Z represents OCR.sup.4R.sup.5 and
R.sup.1 represents an optionally substituted C.sub.2-6alkylaryl or
an optionally substituted 5- or 6-membered aryl or heteroaryl,
comprises reacting a compound of formula (V):
##STR00007##
wherein X, R.sup.2 and Q are as previously defined for formula (I)
and L.sup.4 is a suitable leaving group, with a reagent suitable to
introduce the group R'--O such as a compound R.sup.1--OH. The
reaction is conveniently carried out in a suitable solvent, such as
an alcohol solvent, e.g. ethanol, under basic conditions, for
example in the presence of an aqueous hydroxide such as sodium
hydroxide. Suitable leaving groups represented by L.sup.4 include
halides, especially bromide or iodide.
[0027] A sixth process (F) according to the invention for preparing
a compound of formula (I) wherein Z represents CR.sup.4R.sup.5O,
comprises reacting a compound of formula (IV):
##STR00008##
wherein X, R.sup.2 and Q are as previously defined for formula (I),
and Y represents OH, with a reagent suitable to introduce the group
R.sup.1CR.sup.4R.sup.5 such as a compound R.sup.1CR.sup.4R.sup.5-L,
wherein L is a suitable leaving group. The reaction is conveniently
carried out in a suitable solvent, such as an alcohol solvent, e.g.
ethanol, under basic conditions, for example in the presence of an
aqueous hydroxide such as sodium hydroxide. Suitable leaving groups
represented by L include halides, especially bromide or iodide.
[0028] A seventh process (G) according to the invention for
preparing a compound of formula (I) wherein Z represents CH.sub.2,
comprises reacting a compound of formula (III):
##STR00009##
wherein R.sup.2, Q and X are as previously defined for formula (I),
with a reagent suitable to introduce the group R.sup.1CH.sub.2,
such as a compound R.sup.1CH.sub.2-L, wherein L is a suitable
leaving group, for example halide, suitably in the presence of a
catalyst, for example a Lewis acid catalyst such as AlCl.sub.3. A
Friedel-Crafts reaction may accordingly be appropriate.
[0029] An eighth process (H) according to the invention comprises
reacting a compound of formula (VI)
##STR00010##
or a protected derivative thereof, wherein R.sup.1, Z. Q and X are
as previously defined for formula (I), with a reagent suitable to
introduce the group R.sup.2 as previously defined for formula (I).
An example of such a reagent is R.sup.2-L wherein R.sup.2 is as
previously defined for formula (I) and L is a suitable leaving
group, for example a halide, such as a chloride, in the presence of
a base, such as a tertiary amine, for example a trialkyl amine such
as triethylamine.
[0030] A ninth process (J) according to the invention comprises
carrying out a process selected from processes (A) to (H) followed
by interconversion of one or more functional groups.
[0031] Compounds of formula (II) may be prepared for example by
reaction of a compound of formula L-Q-NH--CH.sub.2X (formula (VII))
with a compound of formula R.sup.2-L.sup.2 wherein L, Q, X and
R.sup.2 are as previously defined for formula (II) and L.sup.2
represents a leaving group, in the presence of a base. In turn
compounds of formula (VII) may be prepared by reaction of a
compound of formula L-Q-NH.sub.2 with a compound of formula
X--CH.sub.2L.sup.3 wherein L, Q and X are as previously defined and
L.sup.3 represents a leaving group. The reaction is preferably
carried out in a polar organic solvent (for example dimethyl
formamide) in the presence of a base (for example potassium
carbonate).
[0032] Compounds of formula (III) may be prepared in an analogous
fashion to compounds of formula (II) starting from a compound of
formula H-Q-NH--CH.sub.2X (formula (VIII)) in place of a compound
of formula (VII). In turn compounds of formula (VIII) may be
prepared by reaction of a compound of formula H-Q-NH.sub.2 with a
compound of formula X--CH.sub.2L.sup.3 wherein Q and X are as
previously defined and L.sup.3 represents a leaving group. The
reaction is preferably carried out in a polar organic solvent (for
example dimethyl formamide) in the presence of a base (for example
potassium carbonate).
[0033] Similarly, compounds of formula (IV) may be prepared in an
analogous fashion to the compounds of formula (II) starting from a
compound of formula Y-Q-NH--CH.sub.2X (formula (IX)) wherein Y
represents OH, SH, NR.sup.4H or HCR.sup.4R.sup.5, in place of a
compound of formula (VII). In turn compounds of formula (IX) may be
prepared by reaction of a compound of formula Y-Q-NH.sub.2 with a
compound of formula X--CH.sub.2L.sup.3 wherein Y, Q and X are as
previously defined and L.sup.3 represents a leaving group. The
reaction is preferably carried out in a polar organic solvent (for
example dimethyl formamide) in the presence of a base (for example
potassium carbonate).
[0034] Similarly, compounds of formula (V) may be prepared in an
analogous fashion to the compounds of formula (II) starting from a
compound of formula L.sup.4CR.sup.4R.sup.5-Q-NH--CH.sub.2X (formula
(X)) in place of a compound of formula (VII). In turn compounds of
formula (X) may be prepared by reaction of a compound of formula
L.sup.4CR.sup.4R.sup.5-Q-NH.sub.2 with a compound of formula
X--CH.sub.2L.sup.3 wherein L.sup.4, Q and X are as previously
defined and L.sup.3 represents a leaving group. The reaction is
preferably carried out in a polar organic solvent (for example
dimethyl formamide) in the presence of a base (for example
potassium carbonate).
[0035] Compounds of formula (VI) may be prepared from compounds of
formula R.sup.1ZQNH.sub.2 (formula (XI)) wherein R.sup.1, Z and Q
are as previously defined for formula (I), by reaction with a
reagent suitable to introduce the group CH.sub.2X, wherein X is as
previously defined for formula (I). An example of such a reagent is
L-CH.sub.2X, wherein X is as previously defined for formula (I) and
L is a suitable leaving group, for example a halide, such as a
bromide, in the presence of a base (for example potassium
carbonate). Compounds of formula (XI) may be prepared by
conventional methods well known to those skilled in the art, for
example, by reduction of a compound of formula
R.sup.1ZQNO.sub.2.
[0036] Compounds of formula R.sup.2-L.sup.2, L-Q-NH.sub.2,
X--CH.sub.2L.sup.3, H-Q-NH.sub.2, Y-Q-NH.sub.2, and
L.sup.4CR.sup.4R.sup.5-Q-NH.sub.2 are known or may be prepared by
known methods.
[0037] Depending on the identity of the group X, it may be
preferable for that group to be protected during the steps of the
synthesis of a compound of formula (II). Suitable protecting groups
are known to those skilled in the art. Protecting groups may be any
conventional protecting groups, for example as described in
"Protective Groups in Organic Synthesis" by Theodora Greene and
Peter G. M. Wuts (John Wiley and Sons Inc. 1999). Suitable
carboxylic acid protecting groups include but are not limited to
carboxylic acid esters, for example, methyl ester, ethyl ester,
t-butyl ester, aryl esters e.g. benzyl ester.
[0038] For example, a compound of formula (II) in which X is
COR.sup.3, R.sup.3 is OH, R.sup.2 is SO.sub.2Me, Q is phenyl and L
is 4-bromo may be prepared by the following scheme in which the
free acid group of the final product is protected as the t-butyl
ester during the synthesis substitution reactions:
##STR00011##
[0039] It will be appreciated by those skilled in the art that
compounds of formula (I) may also be prepared from other compounds
of formula (I) by interconversion using processes such as
oxidation, reduction, substitution, deprotection etc., standard in
the art of synthetic chemistry.
[0040] The enantiomeric compounds of the invention may be obtained
(a) by the separation of the components of the corresponding
racemic mixture, for example, by chiral chromatography, enzymatic
resolution methods or preparing and separating suitable
diastereoisomers, (b) by direct synthesis from the appropriate
chiral starting materials by the methods described above, or (c) by
methods analogous to those described above using chiral
reagents.
[0041] Optional conversion of a compound of formula (I) to a
corresponding salt may conveniently be effected by reaction with
the appropriate acid or base. Optional conversion of a compound of
formula (I) to a corresponding solvate or other physiologically
functional derivative may be effected by methods known to those
skilled in the art.
[0042] Compounds of formula (I) may be useful for the treatment of
any conditions in which inhibition of matrix metalloproteinase
would be beneficial, especially in the treatment of inflammatory
diseases and autoimmune disorders.
[0043] Examples of inflammatory conditions and autoimmune disorders
in which the compounds of the invention have potentially beneficial
effects include diseases of the respiratory tract such as asthma
(including allergen-induced asthmatic reactions), cystic fibrosis,
bronchitis (including chronic bronchitis), chronic obstructive
pulmonary disease (COPD), adult respiratory distress syndrome
(ARDS), chronic pulmonary inflammation, rhinitis and upper
respiratory tract inflammatory disorders (URID), ventilator induced
lung injury, silicosis, pulmonary sarcoidosis, idiopathic pulmonary
fibrosis, bronchopulmonary dysplasia, arthritis, e.g. rheumatoid
arthritis, osteoarthritis, infectious arthritis, psoriatic
arthritis, traumatic arthritis, rubella arthritis, Reiter's
syndrome, gouty arthritis and prosthetic joint failure, gout, acute
synovitis, spondylitis and non-articular inflammatory conditions,
e.g. herniated/ruptured/prolapsed intervertebral disk syndrome,
bursitis, tendonitis, tenosynovitic, fibromyalgic syndrome and
other inflammatory conditions associated with ligamentous sprain
and regional musculoskeletal strain, inflammatory disorders of
the
gastrointestinal tract, e.g. ulcerative colitis, diverticulitis,
Crohn's disease, inflammatory bowel diseases, irritable bowel
syndrome and gastritis, multiple sclerosis, systemic lupus
erythematosus, scleroderma, autoimmune exocrinopathy, autoimmune
encephalomyelitis, diabetes, tumor angiogenesis and metastasis,
cancer including carcinoma of the breast, colon, rectum, lung,
kidney, ovary, stomach, uterus, pancreas, liver, oral, laryngeal
and prostate, melanoma, acute and chronic leukemia, periodontal
disease, neurodegenerative disease, Alzheimer's disease,
Parkinson's disease, epilepsy, muscle degeneration, inguinal
hernia, retinal degeneration, diabetic retinopathy, macular
degeneration, ocular inflammation, bone resorption diseases,
osteoporosis, osteopetrosis, graft vs. host reaction, allograft
rejections, sepsis, endotoxemia, toxic shock syndrome,
tuberculosis, usual interstitial and cryptogenic organizing
pneumonia, bacterial meningitis, systemic cachexia, cachexia
secondary to infection or malignancy, cachexia secondary to
acquired immune deficiency syndrome (AIDS), malaria, leprosy,
leishmaniasis, Lyme disease, glomerulonephritis,
glomerulosclerosis, renal fibrosis, liver fibrosis, pancreatitis,
hepatitis, endometriosis, pain, e.g. that associated with
inflammation and/or trauma, inflammatory diseases of the skin, e.g.
dermatitis, dermatosis, skin ulcers, psoriasis, eczema, systemic
vasculitis, vascular dementia, thrombosis, atherosclerosis,
restenosis, reperfusion injury, plaque calcification, myocarditis,
aneurysm, stroke, pulmonary hypertension, left ventricular
remodeling and heart failure.
[0044] Diseases of principal interest include COPD and inflammatory
diseases of the respiratory tract and joints and vascular
diseases.
[0045] It will be appreciated by those skilled in the art that
reference herein to treatment extends to prophylaxis as well as the
treatment of established conditions.
[0046] There is thus provided as a further aspect of the invention
a compound of formula (I) or a physiologically acceptable
derivative thereof for use in medicine.
[0047] According to another aspect of the invention, there is
provided the use of a compound of formula (I) or a physiologically
acceptable derivative thereof for the manufacture of a medicament
for the treatment of inflammatory conditions or autoimmune
disorders.
[0048] In a further or alternative aspect there is provided a
method for the treatment of a human or animal subject suffering
from or susceptible to an autoimmune disorder or an inflammatory
condition which method comprises administering to said human or
animal subject an effective amount of a compound of formula (I) or
a physiologically functional derivative thereof.
[0049] The compounds according to the invention may be formulated
for administration in any convenient way, and the invention
therefore also includes within its scope pharmaceutical
compositions comprising a compound of formula (I) or a
physiologically acceptable derivative thereof together, if
desirable, with one or more physiologically acceptable diluents or
carriers.
[0050] There is also provided a process for preparing such a
pharmaceutical formulation which comprises mixing the
ingredients.
[0051] The compounds according to the invention may, for example,
be formulated for oral, inhaled, intranasal, topical, buccal,
parenteral or rectal administration, preferably for oral
administration.
[0052] Tablets and capsules for oral administration may contain
conventional excipients such as binding agents, for example syrup,
acacia, gelatin, sorbitol, tragacanth, mucilage of starch,
cellulose or polyvinyl pyrrolidone; fillers, for example, lactose,
microcrystalline cellulose, sugar, maize-starch, calcium phosphate
or sorbitol; lubricants, for example, magnesium stearate, stearic
acid, talc, polyethylene glycol or silica; disintegrants, for
example, potato starch, croscarmellose sodium or sodium starch
glycollate; or wetting agents such as sodium lauryl sulphate. The
tablets may be coated according to methods well known in the art.
Oral liquid preparations may be in the form of, for example,
aqueous or oily suspensions, solutions, emulsions, syrups or
elixirs, or may be presented as a dry product for constitution with
water or other suitable vehicle before use. Such liquid
preparations may contain conventional additives such as suspending
agents, for example, sorbitol syrup, methyl cellulose,
glucose/sugar syrup, gelatin, hydroxymethyl cellulose,
carboxymethyl cellulose, aluminium stearate gel or hydrogenated
edible fats; emulsifying agents, for example, lecithin, sorbitan
mono-oleate or acacia; non-aqueous vehicles (which may include
edible oils), for example almond oil, fractionated coconut oil,
oily esters, propylene glycol or ethyl alcohol; or preservatives,
for example, methyl or propyl p-hydroxybenzoates or sorbic acid.
The preparations may also contain buffer salts, flavouring,
colouring and/or sweetening agents (e.g. mannitol) as
appropriate.
[0053] Compounds according to the invention for topical
administration may be formulated as creams, gels, ointments or
lotions or as a transdermal patch. Such compositions may for
example be formulated with an aqueous or oily base with the
addition of suitable thickening, gelling, emulsifying, stabilising,
dispersing, suspending, and/or colouring agents.
[0054] Lotions may be formulated with an aqueous or oily base and
will in general also contain one or more emulsifying agents,
stabilising agents, dispersing agents, suspending agents,
thickening agents, or colouring agents. They may also contain a
preservative.
[0055] For buccal administration the compositions may take the form
of tablets or lozenges formulated in conventional manner.
[0056] The compounds may also be formulated as suppositories, e.g.
containing conventional suppository bases such as cocoa butter or
other glycerides.
[0057] The compounds according to the invention may also be
formulated for parenteral administration by bolus injection or
continuous infusion and may be presented in unit dose form, for
instance as ampoules, vials, small volume infusions or pre-filled
syringes, or in multi-dose containers with an added preservative.
The compositions may take such forms as solutions, suspensions, or
emulsions in aqueous or non-aqueous vehicles, and may contain
formulatory agents such as anti-oxidants, buffers, antimicrobial
agents and/or tonicity adjusting agents. Alternatively, the active
ingredient may be in powder form for constitution with a suitable
vehicle, e.g. sterile, pyrogen-free water, before use. The dry
solid presentation may be prepared by filling a sterile powder
aseptically into individual sterile containers or by filling a
sterile solution aseptically into each container and
freeze-drying.
[0058] The pharmaceutical compositions according to the invention
may also be used in combination with other therapeutic agents, for
example anti-inflammatory agents (such as corticosteroids (e.g.
fluticasone propionate, beclomethasone dipropionate, mometasone
furoate, triamcinolone acetonide or budesonide) or NSAIDs (e.g.
sodium cromoglycate, nedocromil sodium, PDE-4 inhibitors,
leukotriene antagonists, CCR-3 antagonists, iNOS inhibitors,
tryptase and elastase inhibitors, beta-2 integrin antagonists and
adenosine 2a agonists)) or beta adrenergic agents (such as
salmeterol, salbutamol, formoterol, fenoterol or terbutaline and
salts thereof) or antiinfective agents (e.g. antibiotics,
antivirals).
[0059] It will be appreciated that when the compounds of the
present invention are administered in combination with other
therapeutic agents normally administered by the inhaled or
intranasal route, that the resultant pharmaceutical composition may
be administered by the inhaled or intranasal route.
[0060] Compounds of the invention may conveniently be administered
in amounts of, for example, 0.01 to 100 mg/kg body weight,
preferably 0.1 to 25 mg/kg body weight, more preferably 0.3 to 5
mg/kg body weight. The compounds may be given more than once daily
to be equivalent to the total daily dose. The precise dose will of
course depend on the age and condition of the patient and the
particular route of administration chosen and will ultimately be at
the discretion of the attendant physician.
[0061] No toxicological effects are expected when a compound
according to the present invention is administered in the above
mentioned dose range.
[0062] Compounds of the invention may be tested for in vitro
activity in accordance with the following assay:
[0063] The fluorescent peptide substrate used in the MMP-12 assay
is FAM-Gly-Pro-Leu-Gly-Leu-Phe-Ala-Arg-Lys(TAMRA), where FAM
represents carboxyfluorescein, and TAMRA represents
tetramethylrhodamine. MMP12 catalytic domain (residues 106-268)
protein was expressed in E. coli in the form of insoluble inclusion
bodies & stored in concentrated solution under denaturing
conditions (8M guanidine hydrochloride). Enzyme was refolded into
active form in situ by direct dilution into assay reactions. The 51
uL reactions are run in NUNC-brand black, square 384-well plates,
each well containing 2 uM substrate, 20 nM enzyme, and 0.001-100 uM
inhibitor, in 50 mM HEPES, pH 7.5, 150 mM NaCl, 10 mM CaCl.sub.2, 1
uM ZnAc, 0.6 mM CHAPS, and 2% DMSO. Postitive control wells contain
no inhibitor. Negative control wells are effected by either
pre-dispensing the EDTA quench (see below) or by omiting enyme.
Reactions are incubated at ambient temperature for 120 min, then
quenched by the addition of 15 uL of 100 mM EDTA. Product formation
in each well is quantified by measuring flourescense with a
Molecular Devices Acquest. The excitation wavelength is set at 485
nM, and the emmision wavelength is 530 nM. IC.sub.50 values were
obtained by first calculating the percent inhibition (% I) at each
inhibitor concentration (% I=100*(1-(I-C2)/(C1-C2)), where C1 is
the mean of the positive controls, and C2 is the mean of the
negative controls), then fitting the % I vs. inhibitor
concentration [I] data to: % I=A+((B-A)/(1+((C/[I] D))), where A is
the lower asymptote, B is the upper asymptote, C is the IC50 value,
and D is the slope factor. When tested in this assay, compounds of
Examples 1 to 11 had IC50s below 100 micromolar.
[0064] The invention may be illustrated by reference to the
following examples, which should not be construed as a limitation
thereto:
EXAMPLES
General Experimental Details
[0065] LC/MS data were obtained under the following conditions:
[0066] Column: 3.3 cm.times.4.6 mm ID, 3 um ABZ+PLUS [0067] Flow
Rate: 3 ml/min [0068] Injection Volume: 5 .mu.l [0069] Temp: RT
[0070] UV Detection Range: 215 to 330 nm Solvents: A: 0.1% Formic
Acid+10 mMolar Ammonium Acetate. [0071] B: 95% Acetonitrile+0.05%
Formic Acid
TABLE-US-00001 [0071] Time A % B % Gradient: 0.00 100 0 0.70 100 0
4.20 0 100 5.30 0 100 5.50 100 0
[0072] .sup.1HNMR spectra were obtained at 400 MHz on a
Bruker-Spectrospin Ultrashield 400 spectrophotometer.
[0073] All synthesis starting materials and reagents were used as
obtained from commercial suppliers.
Example 1
##STR00012##
[0074] [(4'-Cyano-1,1'-biphenyl-4-yl)(methylsulfonyl)amino]acetic
acid
[0075] A solution of [(4-bromophenyl)(methylsulfonyl)amino]acetic
acid (intermediate 3, 20 mg, 65 .mu.mol) in dimethoxyethane (1 mL)
was added in one portion to a mixture of 4-cyanophenyl-boronic acid
(9.5 mg, 65 .mu.mol) and fibrecat FC1001 (2.71% Pd; 25 mg, 6.5
.mu.mol) in a Smith microwave reaction vial. Aqueous sodium
carbonate solution (1.0 M; 130 .mu.L, 130 .mu.mol) was added and
the vial capped. The crude reaction mixture was heated at
150.degree. C. for 15 min using a Smith Synthesiser microwave
reactor. On cooling the vial was opened and the contents were
filtered through a Whatman 5 .mu.M filter tube, washing the filter
cake with methanol (2.times.1 mL). The filtrate was evaporated and
the resulting residue was purified using mass directed
auto-preparative reverse phase HPLC to give the title compound (1.1
mg, 5%) as a white solid. LC/MS: 2.94 min; z/e 329, calcd (M-1)
329. .sup.1H NMR (400 MHz: MeOD): 7.80 (4H), 7.75 (2H), 7.65 (2H),
4.45 (2H), 3.10 (3H).
Example 2
##STR00013##
[0076]
{(Methylsulfonyl)[4'-(trifluoromethoxy)-1,1'-biphenyl-4-yl]amino}ac-
etic acid
[0077] Prepared analogously to Example 1. LC/MS: 3.41 min; z/e 407,
calcd (M+18) 407.
Example 3
##STR00014##
[0078] [(4'-Acetyl-1,1'-biphenyl-4-yl)(methylsulfonyl)amino]acetic
acid
[0079] Prepared analogously to Example 1. LC/MS: 2.98 min; z/e 365,
calcd (M+18) 365.
Example 4
##STR00015##
[0080] [(4'-Methoxy-1,1'-biphenyl-4-yl)(methylsulfonyl)amino]acetic
acid
[0081] Prepared analogously to Example 1. LC/MS: 3.17 min; z/e 353,
calcd (M+18) 353.
Example 5
##STR00016##
[0082] [(4'-Methyl-1,1'-biphenyl-4-yl)(methylsulfonyl)amino]acetic
acid
[0083] Prepared analogously to Example 1. LC/MS: 3.24 min; z/e 337,
calcd (M+18) 337.
Example 6
##STR00017##
[0084] [(3'-Cyano-1,1'-biphenyl-4-yl)(methylsulfonyl)amino]acetic
acid
[0085] Prepared analogously to Example 1. LC/MS: 3.05 min; z/e 348,
calcd (M+18) 348.
Example 7
##STR00018##
[0086] [(3'-Acetyl-1,1'-biphenyl-4-yl)(methylsulfonyl)amino]acetic
acid
[0087] Prepared analogously to Example 1. LC/MS: 2.82 min; z/e 365,
calcd (M+18) 365.
Example 8
##STR00019##
[0088] [(4'-Ethoxy-1,1'-biphenyl-4-yl)(methylsulfonyl)amino]acetic
acid
[0089] Prepared analogously to Example 1. LC/MS: 3.24 min; z/e 367,
calcd (M+18) 367.
Example 9
##STR00020##
[0090] [(1,1'-Biphenyl-4-yl)(methylsulfonyl)amino]acetic acid
[0091] Prepared analogously to Example 1. LC/MS: 3.04 min; z/e 323,
calcd (M+18) 323.
Example 10
##STR00021##
[0092] [(pyridin-3-ylphenyl-4-yl)(methylsulfonyl)amino]acetic acid
(i.e. N-(methylsulfonyl)-N-(4-pyridin-3-ylphenyl)glycine)
[0093] Prepared analogously to Example 1. LC/MS: 1.86 min; z/e 307,
calcd (M+1) 307.
Example 11
##STR00022##
[0094]
N-{4-[(3-Methylbutyl)oxy]phenyl}-N-(methylsulfonyl)glycine
[0095] Trifluoroacetic acid (2.5 mL) was added in one portion to a
stirred solution of 1,1-dimethylethyl
N-{4-[(3-methylbutyl)oxy]phenyl}-N-(methylsulfonyl)glycinate
(intermediate 7, 140 mg, 0.378 mmol) in dichloromethane (5 mL) at
room temperature under an atmosphere of nitrogen. The resulting
mixture was stirred for 3 h then the volatiles evaporated. A
portion of the crude orange product was purified by reverse phase
mass directed preparative HPLC to give the title compound as a
white solid (20 mg). LC/MS: 3.22 min; z/e 333, calcd (M+18) 333.
.sup.1H NMR (400 MHz; MeOD): 0.95 (6H), 1.75 (2H), 1.85 (1H), 3.05
(3H), 4.05 (2H), 4.35 (2H), 6.90 (2H), 7.40 (2H).
Intermediate 1
##STR00023##
[0096] tert-Butyl [(4-bromophenyl)amino]acetate
[0097] t-Butylbromoacetate (6.24 g, 4.72 mL, 32.0 mmol) was added
in one portion to a stirred suspension of 4-bromonaniline (5.00 g,
29.1 mmol) and potassium carbonate (4.02 g, 29.1 mmol) in
dimethylformamide (100 mL) at room temperature under nitrogen. The
resulting mixture was stirred for 14 h then the volatiles were
evaporated. The residue was partitioned between dichloromethane (50
mL) and water (50 mL). The aqueous phase was extracted with
dichloromethane (3.times.50 mL) then the organic extracts were
combined, dried (magnesium sulfate) and the solvent evaporated. The
residue was chromatographed on silica gel (20% ethyl acetate:
cyclohexane) to give the title compound as a white solid (5.86 g,
70%). LC/MS: 3.65 min; z/e 286 and 288, calcd (M+1) 286 and 288.
.sup.1H NMR (400 MHz: CDCl.sub.3): 7.30(2H), 6.50 (2H), 4.35 (1H),
3.75 (2H), 1.45 (9H).
Intermediate 2
##STR00024##
[0098] tert-Butyl [(4-bromophenyl)(methylsulfonyl)amino]acetate
[0099] A solution of tert-butyl [(4-bromophenyl)amino]acetate
(intermediate 1, 5.86 g, 20.5 mmol), methanesulfonyl chloride (2.58
g, 1.74 mL, 22.5 mmol), triethylamine (4.15 g, 5.71 mL, 41.0 mmol)
and 4-dimethylaminopyridine (260 mg, 2.05 mmol) in dichloromethane
(100 mL) was heated at reflux for 14 h. A second portion of
methanesulfonyl chloride (2.58 g, 1.74 mmol, 22.5 mmol) was added
and heating at reflux continued for a further 48 h. The reaction
was cooled to room temperature and extracted with aqueous
hydrochloric acid solution (1.0 M; 3.times.50 mL). The organic
phase was dried (magnesium sulfate) and evaporated to dryness. The
residue was chromatographed on silica gel (10% diethyl ether:
cyclohexane) to give the title compound as a pale cream solid (2.37
g, 32%). LC/MS: 3.35 min; z/e 381 and 383, calcd (M+18) 381 and
383. .sup.1H NMR (400 MHz: CDCl.sub.3): 7.55 (2H), 7.35 (2H), 4.30
(2H), 3.10 (3H), 1.45 (9H).
Intermediate 3
##STR00025##
[0100] [(4-Bromophenyl)(methylsulfonyl)amino]acetic acid
[0101] A suspension of tert-butyl
[(4-bromophenyl)(methylsulfonyl)amino]acetate (intermediate 2, 1.00
g, 2.74 mmol) and silica gel (13.7 g) in toluene (88 mL) was heated
at reflux for 4 h. The reaction was cooled to room temperature and
filtered, the filter cake was washed with methanol/dichloromethane
(20/80; 2.times.100 mL). Evaporation of the combined organic
filtrates gave the title compound as a white solid (0.81 g, 95%).
LC/MS: 2.81 min; z/e 325 and 327, calcd (M+18) 325 and 327. .sup.1H
NMR (400 MHz: MeOD): 7.45 (2H), 7.35 (2H), 4.45 (2H), 3.05
(3H).
Intermediate 4
##STR00026##
[0102] 1-[(3-Methylbutyl)oxy]-4-nitrobenzene
[0103] 1-Bromo-3-methylbutane (7.07 g, 5.60 mL, 46.8 mmol) was
added in one portion to a stirred suspension of 4-nitrophenol (5.00
g, 35.9 mmol) and potassium carbonate (5.46 g, 49.5 mmol) in
dimethylformamide (50 mL) at room temperature under a nitrogen
atmosphere. The resulting mixture was stirred at room temperature
for 16 h then the volatiles were evaporated. The residue was
partitioned between diethyl ether (50 mL) and water (50 mL) and the
phases separated. The aqueous phase was extracted with ether
(2.times.50 mL) then the organic extracts were combined and dried
(magnesium sulfate). The solvent was evaporated and the residue
chromatographed on silica gel (10% diethyl ether: cyclohexane) to
give the title compound as a pale yellow oil (6.63 g, 88%). LC/MS:
3.69 min. .sup.1H NMR (400 MHz; CDCl.sub.3): 0.95 (6H), 1.75 (2H),
1.85 (1H), 4.05 (2H), 6.95 (2H), 8.20 (2H).
Intermediate 5
##STR00027##
[0104] {4-[(3-Methylbutyl)oxy]phenyl}amine
[0105] 5% Palladium on charcoal (100 mg) was added in one portion
to a stirred solution of 1-[(3-methylbutyl)oxy]-4-nitrobenzene
(intermediate 4, 2.00 g, 9.56 mmol) in ethyl acetate (40 mL) at
room temperature under a nitrogen atmosphere. The nitrogen was
replaced with hydrogen and stirring was continued for 4 h. The
hydrogen was replaced with nitrogen then the crude reaction mixture
was filtered through a plug of celite. The solute was evaporated to
dryness to give the title compound as a colourless oil (1.71 g,
100%) which was used without purification. LC/MS: 2.29 min; z/e
180, calcd (M+1) 180. .sup.1H NMR (400 MHz; CDCl.sub.3): 0.95 (6H),
1.65 (2H), 1.85 (1H), 3.10 (2H), 3.90 (2H), 6.65 (2H), 6.75
(2H).
Intermediate 6
##STR00028##
[0106] 1,1-Dimethylethyl
N-{4-[(3-methylbutyl)oxy]phenyl}glycinate
[0107] t-Butylbromoacetate (1.12 g, 0.85 mL, 5.76 mmol) was added
drop wise over 5 min to a stirred suspension of
{4-[(3-methylbutyl)oxy]phenyl}amine (intermediate 5, 0.85 g, 4.8
mmol) and potassium carbonate (0.66 g, 4.8 mmol) in
dimethylformamide (23.4 mL) at room temperature under a nitrogen
atmosphere. After stirring for 14 h the volatiles were evaporated
and the residue partitioned between dichloromethane (50 mL) and
water (50 mL). The phases were separated and the aqueous phase
washed with dichloromethane (2.times.50 mL). The organic phases
were combined, dried (magnesium sulfate) then the solvent
evaporated. The residue was chromatographed on silica gel (10%
diethyl ether: cyclohexane) to give the title compound (inseparable
10:1 mixture of mono- to di-substitution) as a colourless oil (1.38
g). Mono-product: LC/MS: 3.77 min; z/e 294, calcd (M+1) 294.
.sup.1H NMR (400 MHz; CDCl.sub.3): 0.90 (6H), 1.45 (9H), 1.65 (2H),
1.85 (1H), 3.75 (2H), 3.90 (2H), 6.55 (2H), 6.80 (2H).
Intermediate 7
##STR00029##
[0108] 1,1-Dimethylethyl
N-{4-[(3-methylbutyl)oxy]phenyl}-N-(methylsulfonyl)glycinate
[0109] Methanesulfonylchloride (93 mg, 63 .mu.L, 0.82 mmol) was
added in one portion to a stirred solution of 1,1-dimethylethyl
N-{4-[(3-methylbutyl)oxy]phenyl}glycinate (intermediate 6, 0.20 g,
0.68 mmol) and triethylamine (138 mg, 189 .mu.L, 1.36 mmol) in
dichloromethane (2 mL) at room temperature under a nitrogen
atmosphere. Stirring was continued for 3 h then aqueous
hydrochloric acid (1.0 M; 2 mL) was added. The organic phase was
separated and the aqueous phase washed with dichloromethane
(3.times.5 mL). The organic phases were combined, dried (magnesium
sulfate) then evaporated to dryness. The residue was
chromatographed on silica gel (30% diethyl ether: cyclohexane) to
give the title compound as a white solid (140 mg, 56%). LC/MS: 3.72
min; z/e 389, calcd (M+18) 389. .sup.1H NMR (400 MHz; CDCl.sub.3):
0.95 (6H), 1.45 (9H), 1.70 (2H), 1.85 (1H), 3.10 (3H), 3.95 (2H),
4.30 (2H), 6.85 (2H), 7.35 (2H).
* * * * *