U.S. patent application number 12/391855 was filed with the patent office on 2009-06-25 for morpholin-acetamide derivatives for the treatment of inflammatory diseases.
This patent application is currently assigned to GLAXO GROUP LIMITED. Invention is credited to Rachael Anne Ancliff, Simon Teanby Hodgson, Suzanne Elaine Keeling, Xiao Qing Lewell, Graeme Michael Robertson.
Application Number | 20090163495 12/391855 |
Document ID | / |
Family ID | 26245078 |
Filed Date | 2009-06-25 |
United States Patent
Application |
20090163495 |
Kind Code |
A1 |
Ancliff; Rachael Anne ; et
al. |
June 25, 2009 |
MORPHOLIN-ACETAMIDE DERIVATIVES FOR THE TREATMENT OF INFLAMMATORY
DISEASES
Abstract
There are provided according to the invention, novel compounds
of formula (I) ##STR00001## wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, X, a, b and Z are as defined in the
specification, processes for preparing them, formulations
containing them and their use in therapy for the treatment of
inflammatory diseases.
Inventors: |
Ancliff; Rachael Anne;
(Stevenage, GB) ; Hodgson; Simon Teanby;
(Stevenage, GB) ; Keeling; Suzanne Elaine;
(Stevenage, GB) ; Lewell; Xiao Qing; (Stevenage,
GB) ; Robertson; Graeme Michael; (Stevenage,
GB) |
Correspondence
Address: |
GLAXOSMITHKLINE;CORPORATE INTELLECTUAL PROPERTY, MAI B482
FIVE MOORE DR., PO BOX 13398
RESEARCH TRIANGLE PARK
NC
27709-3398
US
|
Assignee: |
GLAXO GROUP LIMITED
Greenford
GB
|
Family ID: |
26245078 |
Appl. No.: |
12/391855 |
Filed: |
February 24, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11284544 |
Nov 22, 2005 |
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12391855 |
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10381767 |
Aug 15, 2003 |
7101882 |
|
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PCT/GB01/04345 |
Sep 28, 2001 |
|
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11284544 |
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Current U.S.
Class: |
514/235.2 ;
544/143 |
Current CPC
Class: |
C07D 265/30 20130101;
A61P 19/02 20180101; A61P 1/04 20180101; A61P 11/06 20180101; A61P
33/10 20180101; A61P 27/02 20180101; A61P 31/18 20180101; A61P 3/10
20180101; A61P 9/14 20180101; A61P 17/04 20180101; A61P 33/02
20180101; A61P 9/10 20180101; A61P 25/00 20180101; A61P 29/00
20180101; A61P 37/08 20180101; A61P 37/02 20180101; A61P 43/00
20180101; A61P 33/12 20180101; A61P 33/00 20180101; A61P 11/02
20180101; A61P 17/00 20180101; A61P 25/28 20180101; C07D 413/12
20130101; C07D 413/14 20130101; C07D 417/14 20130101; A61P 17/06
20180101; C07D 417/12 20130101; A61P 37/06 20180101 |
Class at
Publication: |
514/235.2 ;
544/143 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 417/12 20060101 C07D417/12; A61P 11/06 20060101
A61P011/06 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 29, 2000 |
GB |
0023902.0 |
Mar 27, 2001 |
GB |
0107644.7 |
Claims
1. A compound which is
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(5-methoxy-2-methyl-1H-
-indol-3-yl)acetamide or a salt thereof.
2. The compound of claim 1, in which the salt is a physiologically
acceptable salt.
3. A pharmaceutical composition comprising: a compound of claim 2
and one or more physiologically acceptable diluents or
excipients.
4. A method for the treatment of an inflammatory condition of the
lung comprising administering to a patient an effective amount of a
compound of claim 1 or a pharmaceutically acceptable salt
thereof.
5. The method of claim 4, wherein the inflammatory condition of the
lung is asthma.
Description
[0001] This patent application is a divisional of U.S. patent
application Ser. No. 11/284,544, filed Nov. 22, 2005, now allowed,
which was a continuation of U.S. patent application Ser. No.
10/381,767 filed Aug. 15, 2003, now U.S. Pat. No. 7,101,882, which
was a 371 Application of PCT/GB01/04345 filed Sep. 28, 2001, which
claims priority to GB 0023902.0 filed on Sep. 29, 2000, and GB
0107644.7 filed Mar. 27, 2001 both in the United Kingdom.
[0002] This invention relates to novel chemical compounds,
processes for their preparation, pharmaceutical formulations
containing them and their use in therapy.
[0003] Inflammation is a primary response to tissue injury or
microbial invasion and is characterised by leukocyte adhesion to
the endothelium, diapedesis and activation within the tissue.
Leukocyte activation can result in the generation of toxic oxygen
species (such as superoxide anion), and the release of granule
products (such as peroxidases and proteases). Circulating
leukocytes include neutrophils, eosinophils, basophils, monocytes
and lymphocytes. Different forms of inflammation involve different
types of infiltrating leukocytes, the particular profile being
regulated by the profile of adhesion molecule, cytokine and
chemotactic factor expression within the tissue.
[0004] The primary function of leukocytes is to defend the host
from invading organisms, such as bacteria and parasites. Once a
tissue is injured or infected, a series of events occurs which
causes the local recruitment of leukocytes from the circulation
into the affected tissue. Leukocyte recruitment is controlled to
allow for the orderly destruction and phagocytosis of foreign or
dead cells, followed by tissue repair and resolution of the
inflammatory infiltrate. However in chronic inflammatory states,
recruitment is often inappropriate, resolution is not adequately
controlled and the inflammatory reaction causes tissue destruction.
There is increasing evidence that the bronchial inflammation which
is characteristic of asthma represents a specialised form of
cell-mediated immunity, in which cytokine products, such as IL-4
and IL-5 released by Th2 T lymphocytes, orchestrate the
accumulation and activation of granulocytes, in particular
eosinophils and to a lesser extent basophils. Through the release
of cytotoxic basic proteins, pro-inflammatory mediators and oxygen
radicals, eosinophils generate mucosal damage and initiate
mechanisms that underlie bronchial hyperreactivity. Therefore,
blocking the recruitment and activation of Th2 cells and
eosinophils is likely to have anti-inflammatory properties in
asthma. In addition, eosinophils have been implicated in other
disease types such as rhinitis, eczema, irritable bowel syndrome
and parasitic infections.
[0005] Chemokines are a large family of small proteins which are
involved in trafficking and recruitment of leukocytes (for review
see Luster, New Eng. J. Med., 338, 436-445 (1998)). They are
released by a wide variety of cells and act to attract and activate
various cell types, including eosinophils, basophils, neutrophils,
macrophages, T and B lymphocytes. There are two major families of
chemokines, CXC-(.alpha.) and CC-(.beta.) chemokines, classified
according to the spacing of two conserved cysteine residues near to
the amino terminus of the chemokine proteins. Chemokines bind to
specific cell surface receptors belonging to the family of
G-protein-coupled seven transmembrane-domain proteins (for review
see Luster, 1998). Activation of chemokine receptors results in,
amongst other responses, an increase in intracellular calcium,
changes in cell shape, increased expression of cellular adhesion
molecules, degranulation and promotion of cell migration
(chemotaxis).
[0006] To date, 9 members of CC chemokine receptors have been
identified (CCR-1 to 9). Of particular importance to the current
invention is the CC-chemokine receptor-3 (CCR-3), which is
predominantly expressed on eosinophils, and also on basophils, mast
cells and Th2 cells (Luster, 1998). Chemokines that act at CCR-3,
such as RANTES, MCP-3 and MCP-4, are known to recruit and activate
eosinophils. Of particular interest are eotaxin and eotaxin-2,
which specifically bind to CCR-3. The localization and function of
CCR-3 chemokines indicate that they play a central role in the
development of allergic diseases such as asthma. Thus, CCR-3 is
specifically expressed on all the major cell types involved in
inflammatory allergic responses. Chemokines that act at CCR-3 are
generated in response to inflammatory stimuli and act to recruit
these cell types to sites of inflammation, where they cause their
activation (e.g. Griffiths et al., J. Exp. Med., 179, 881-887
(1994), Lloyd et al., J. Exp. Med., 191, 265-273 (2000)). In
addition, anti-CCR-3 monoclonal antibodies completely inhibit
eotaxin interaction with eosinophils (Heath, H. et al., (1997) J.
Clin. Invest. 99 (2), 178-184), while an antibody for the CCR-3
specific chemokine, eotaxin, reduced both bronchial hyperreactivity
and lung eosinophilia in an animal model of asthma (Gonzalo et al.,
J. Exp. Med., 188, 157-167 (1998). Thus, many lines of evidence
indicate that antagonists at the CCR-3 receptor are very likely to
be of therapeutic use for the treatment of a range of inflammatory
conditions.
[0007] A number of patent applications relating to CCR-3
antagonists have published before the filing date of this
application. For example, EP 0 903 349, FR 2785902, WO 00/29377, WO
00/31032 and WO 00/31033 (all in the name of F. Hoffmann-La-Roche
AG) disclose pyrrolidine, piperidine and piperazine based compounds
which are all distinct from the compounds of the present
invention.
[0008] WO 99/55324, WO 00/04003, WO 00/27800, WO 00/27835, WO
00/27843, WO 00/41685 and WO 00/53172 (all in the name of
SmithKline Beecham Corporation) describe a variety of compounds as
CCR-3 antagonists which are unrelated to the compounds of the
present invention.
[0009] WO 00/34278 (Toray Industries Inc.) describe fused triazolo
derived compounds as chemokine inhibitors.
[0010] WO 00/35449, WO 00/35451, WO 00/35452, WO 00/35453, WO
00/35454, WO 00/35876 and WO 00/35877 (Du Pont Pharmaceuticals
Company) describe N-ureidoalkyl and heterocyclic piperidine
compounds as CCR-3 antagonists.
[0011] WO 00/51607 and WO 00/51608 (Merck & Co. Inc.) describe
a series of pyrrolidine modulators of chemokine receptor
activity.
[0012] WO 00/53600 (Banyu Pharmaceutical Co. Ltd.) describes
piperidine derivatives as inhibitors at the CCR-3 receptor.
[0013] WO 01/14333 (AstraZeneca UK Ltd.) describe substituted
piperidine compounds as modulators of chemokine receptor
activity.
[0014] EP 0 760 362 (Nisshin Flour Milling Co. Ltd.) describes
morpholinoalkylurea derivatives which are disclosed as being useful
in the treatment of digestive tract diseases.
[0015] JP 04208267A (Mitsui Seiyaku Kogyo KK) also describes
morpholinoalkylurea derivatives which are disclosed as being useful
as antiemetics, for activating peristalsis and ameliorating
gastrointestinal function.
[0016] EP 243959A (Dainippon Pharm KK) describes O-substituted
N-morpholinyl-alkyl-benzamide derivatives useful as
gastrointestinal motility enhancing agents.
[0017] JO 1117-882-A (Dainippon Pharm KK) describes heterocyclic
morpholinyl alkylenyl carboxamide derivatives useful as
anti-emetics.
[0018] WO 00/71518 (Sepracor Inc.) describes morpholinoalkylamide
derivatives useful in the treatment of pain, drug addiction and
tinnitus.
[0019] WO 97/48695 and WO 97/48397 (Klinge Pharma Gmbh) describe
pyridyl alkane, alkene and/or alkyne acid amide compounds useful as
cytostatic, immunomodulatory or immuno-suppressive agents.
[0020] Kato et al., (1992) Chem. Pharm. Bull. 40(3), 652-660, Kato
et al., (1991) J. Med. Chem. 34(2), 616-624 and Kato et al., (1990)
J. Med. Chem. 33(5), 1406-1413 describe a series of morpholine
benzamides which are disclosed as being selective and potent
gastrokinetic agents.
[0021] We have now found a novel group of CCR-3 antagonist
compounds which block migration/chemotaxis of eosinophils,
consequently effecting anti-inflammatory properties. These
compounds are therefore of potential therapeutic benefit,
especially in providing protection from eosinophil, basophil and
Th2-cell-induced tissue damage in diseases where such cell types
are implicated, particularly allergic diseases, including but not
limited to bronchial asthma, allergic rhinitis and atopic
dermatitis.
[0022] In addition to a key role in inflammatory disorders,
chemokines and their receptors also play a role in infectious
disease. Mammalian cytomegaloviruses, herpes viruses and pox
viruses express chemokine receptor homologues, which can be
activated by human CC chemokines such as RANTES and MCP-3 (for
review see Wells and Schwartz, Curr. Opin. Biotech., 8, 741-748,
1997). In addition, human chemokine receptors, such as CXCR-4,
CCR-5 and CCR-3, can act as co-receptors for the infection of
mammalian cells by microbes such as human immunodeficiency viruses
(HIV). CCR-3 serves as a co-receptor for certain clinical strains
of HIV-1 and facilitates viral entry (e.g. Choe, H. et al, Cell,
1996, 85, 1135-1148). A key ligand for CCR-3, eotaxin, blocked the
process of HIV entry. Thus, chemokine receptor antagonists,
including CCR-3 antagonists, may be useful in blocking infection of
CCR-3 expressing cells by HIV or in preventing the manipulation of
immune cellular responses by viruses such as cytomegaloviruses.
[0023] Thus, according to one aspect of the invention, we provide
compounds of formula (I):
##STR00002##
wherein:
[0024] R.sup.1 represents C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.2-6 alkynyl-Y.sup.1--, aryl-Y.sup.1--,
heteroaryl-Y.sup.1--, aryl-(O).sub.t-aryl-Y.sup.1--,
aryl-(O).sub.t-heteroaryl-Y.sup.1--,
heteroaryl-(O).sub.t-aryl-Y.sup.1--,
heteroaryl-(O).sub.t-heteroaryl-Y.sup.1--, C.sub.2-6
alkenyl-Y.sup.1--, aryl-O--Y.sup.1--, heteroaryl-O--Y.sup.1--,
C.sub.1-6 alkyl-SO.sub.2--Y.sup.1--, M-Y.sup.1--,
J.sup.2-Y.sup.1--, --CN or C.sub.3-8 cycloalkyl-Y.sup.1-- or
C.sub.3-8 cycloalkenyl-Y.sup.1--, which cycloalkyl or cycloalkenyl
may be optionally substituted by one or more hydroxyl or C.sub.1-6
alkyl groups;
[0025] R.sup.2 represents hydrogen or C.sub.1-6 alkyl;
[0026] X represents ethylene or a group of formula CR.sup.eR.sup.f
wherein R.sup.e and R.sup.f independently represent hydrogen or
C.sub.1-4 alkyl or R.sup.e and R.sup.f may together with the carbon
atom to which they are attached form a C.sub.3-8 cycloalkyl
group;
[0027] R.sup.3 and R.sup.4 independently represent hydrogen or
C.sub.1-4 alkyl;
[0028] Z represents a bond, CO, SO.sub.2,
CR.sup.9R.sup.6(CH.sub.2).sub.n, (CH.sub.2).sub.nCR.sup.9R.sup.6,
CHR(CH.sub.2).sub.nO, CHR.sup.6(CH.sub.2).sub.nS,
CHR.sup.6(CH.sub.2).sub.nOCO, CHR.sup.6(CH.sub.2).sub.nCO,
COCHR.sup.6(CH.sub.2).sub.n or
SO.sub.2CHR.sup.6(CH.sub.2).sub.n;
[0029] R.sup.5 represents C.sub.1-6 alkyl, C.sub.2-6 alkenyl, aryl,
heteroaryl, aryl-C.sub.2-6 alkenyl- or a group of formula
--Y.sup.2-J.sup.1;
[0030] R.sup.6 represents hydrogen, C.sub.1-4 alkyl,
CONR.sup.7R.sup.8 or COOC.sub.1-6 alkyl;
[0031] a and b represent 1 or 2, such that a+b represents 2 or
3;
[0032] n represents an integer from 0 to 4;
[0033] J.sup.1 and J.sup.2 independently represent a moiety of
formula (K):
##STR00003##
wherein X.sup.1 represents oxygen, NR.sup.13 or sulphur, X.sup.2
represents CH.sub.2, oxygen, NR.sup.10 or sulphur, m.sup.1
represents an integer from 1 to 3 and m.sup.2 represents an integer
from 1 to 3, provided that m.sup.1+m.sup.2 is in the range from 3
to 5, also provided that when both X.sup.1 and X.sup.2 represent
oxygen, NR.sup.13, NR.sup.10 or sulphur, m.sup.1 and m.sup.2 must
both not equal less than 2, wherein K is optionally substituted by
one or more (e.g. 1 or 2) --Y.sup.3-aryl, --Y.sup.3-heteroaryl,
--Y.sup.3--CO-aryl, --COC.sub.3-8cycloalkyl,
--Y.sup.3--CO-heteroaryl, --C.sub.1-6 alkyl,
--Y.sup.3--COOC.sub.1-6 alkyl, --Y.sup.3--CoC.sub.1-6 alkyl,
--Y.sup.3--W, --Y.sup.3--CO--W, --Y.sup.3--NR.sup.11R.sup.12,
--Y.sup.3--CONR.sup.11R.sup.12, hydroxy, oxo,
--Y.sup.3--SO.sub.2NR.sup.11R.sup.12, --Y.sup.3--SO.sub.2 C.sub.1-6
alkyl, --Y.sup.3--SO.sub.2aryl, --Y.sup.3--SO.sub.2heteroaryl,
--Y.sup.3--NR.sup.14C.sub.1-6 alkyl, --Y.sup.3--NR.sup.14SO.sub.2
C.sub.1-6 alkyl, --Y.sup.3--NR.sup.14CONR.sup.11R.sup.12,
--Y.sup.3--NR.sup.14COOR.sup.15 or --Y.sup.3--OCONR.sup.11R.sup.12
groups, and is optionally fused to a monocyclic aryl or heteroaryl
ring;
[0034] R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.13, R.sup.14 and
R.sup.15 independently represent hydrogen or C.sub.1-6 alkyl;
[0035] R.sup.11 and R.sup.12 independently represent hydrogen or
C.sub.1-6 alkyl or R.sup.11 and R.sup.12 together with the nitrogen
atom to which they are attached may form a morpholine, piperidine
or pyrrolidine ring;
[0036] M represents a C.sub.3-8 cycloalkyl or a C.sub.3-8
cycloalkenyl group fused to a monocyclic aryl or monocyclic
heteroaryl group;
[0037] W represents a saturated or unsaturated, non-aromatic 5-7
membered ring containing between 1 and 3 heteroatoms selected from
nitrogen, oxygen or sulphur, optionally substituted with one or
more C.sub.1-6 alkyl, halogen or hydroxy groups;
[0038] t represents 0 or 1.
[0039] Y.sup.1, Y.sup.2 and Y.sup.3 independently represent a bond
or a group of formula
--(CH.sub.2).sub.pCR.sup.cR.sup.d(CH.sub.2).sub.q-- wherein R.sup.c
and R.sup.d independently represent hydrogen or C.sub.1-4 alkyl or
R.sup.c and R.sup.d may together with the carbon atom to which they
are attached form a C.sub.3-8 cycloalkyl group, and p and q
independently represent an integer from 0 to 5 wherein p+q is an
integer from 0 to 5;
[0040] and salts and solvates thereof.
[0041] Specific groups of compounds of formula (I) which may be
mentioned are those as defined above with the proviso that the
compound of formula (I) is not a compound of formula (I).sup.a:
##STR00004##
wherein R.sup.ai represents hydrogen, halogen, nitro,
SO.sub.2NH.sub.2, or mono- or di-(C.sub.1-4 alkylsulphamoyl;
R.sup.b1 represents hydrogen, halogen, amino, nitro,
--N(CH.sub.3).sub.2 or C.sub.2-5 alkanoylamino (provided that at
least one of R.sup.ai and R.sup.bi is not hydrogen); R.sup.ci
represents halogen, hydroxy, C.sub.1-6 alkoxy, cyano, C.sub.3-6
cycloalkyl, --SCH.sub.3, amino or C.sub.2-5 alkoxycarbonyl; X.sup.i
represents methylene or ethylene; b.sup.i represents 1 or 2;
R.sup.3i and R.sup.4i represent hydrogen or C.sub.1-4 alkyl; and
wherein the moiety -Z.sup.i-R.sup.5i represents heteroarylC.sub.1-3
alkyl (wherein heteroaryl represents furyl, thienyl, pyridyl or
1,2-benzisoxazolyl), phenyl-C.sub.3-5 alkenyl, naphthyl,
--C.sub.1-5 alkylenenaphthyl, --C.sub.1-5 alkyleneOnaphthyl,
--C.sub.1-5 alkyleneCOnaphthyl, phenyl, --C.sub.1-5 alkylenephenyl,
--C.sub.1-5 alkyleneOphenyl or --C.sub.1-5 alkyleneCOphenyl
(wherein phenyl is substituted by one to five members each
independently selected from the group consisting of a halogen,
C.sub.1-4 alkyl, trifluoromethyl, C.sub.1-4 alkoxy, nitro, cyano or
amino) (compounds of formula (I).sup.a are described in
EP0243959A1); and/or
[0042] the proviso that the compound of formula (I) is not a
compound of formula (I).sup.b:
##STR00005##
wherein Het represents a heteroaryl moiety; R.sup.aii, R.sup.bii
and R.sup.cii represent hydrogen, halogen, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, amino or NMe.sub.2; X.sup.ii represents methylene
or ethylene; R.sup.3ii represents hydrogen or C.sub.1-4 alkyl;
b.sup.ii represents 1 or 2; and wherein the moiety
-Z.sup.ii-R.sup.5ii represents optionally substituted
aryl-C.sub.1-5 alkyl-(compounds of formula (I).sup.b are described
in J011 17-882A); and/or
[0043] the proviso that the compound of formula (I) is not a
compound of formula (I).sup.c:
##STR00006##
wherein R.sup.1iii represents C.sub.1-6 alkyl, C.sub.3-8
cycloalkyl, heteroaryl or aryl; R.sup.2iii represents C.sub.1-6
alkyl; X.sup.iii represents ethylene or a group of formula
CR.sup.eiiiR.sup.fiii wherein R.sup.eiii and R.sup.fiii
independently represent hydrogen or C.sub.1-4 alkyl; R.sup.3iii
represents hydrogen or C.sub.1-4 alkyl; b.sup.iii represents 1 or
2; Z.sup.iii represents CR.sup.9iiiR.sup.6iii(CH.sub.2).sub.niii
(wherein R.sup.6iii represents hydrogen or C.sub.1-4 alkyl and
R.sup.9iii represents hydrogen or C.sub.1-6 alkyl and niii
represents 0 to 3); and R.sup.5iii represents C.sub.1-6 alkyl,
aryl, heteroaryl or C.sub.2-6 alkenyl (compounds of formula
(I).sup.c are described in WO00/71518A2); and/or
[0044] the proviso that the compound of formula (I) is not a
compound of formula (I).sup.d:
##STR00007##
wherein R.sup.aiv represents hydrogen, halogen, --CN, --CF.sub.3,
--OH, --CONH.sub.2, --COOH, C.sub.1-6 alkyl, --C.sub.2-6 alkenyl,
--C.sub.1-6 alkoxy, --SCH.sub.3, C.sub.3-8 cycloalkyl,
--COOC.sub.1-6 alkyl, --NHCOC.sub.1-6 alkyl, --CON(C.sub.1-6
alkyl).sub.2, --N(CH.sub.3).sub.2; R.sup.biv represents hydrogen,
halogen, --CN, OH, --CF.sub.3, C.sub.1-6 alkyl or C.sub.1-6 alkoxy;
R.sup.civ represents hydrogen, halogen, C.sub.1-6 alkyl,
--CF.sub.3; Y.sup.1iv represents C.sub.1-6 alkylene; R.sup.2iv
represents hydrogen or C.sub.1-6 alkyl; X.sup.iv represents
methylene or ethylene; R.sup.3iv represents hydrogen or C.sub.1-4
alkyl; R.sup.4iv represents hydrogen or C.sub.1-4 alkyl; b.sup.iv
represents 2; Z.sup.iv represents
CR.sup.9ivR.sup.6iv(CH.sub.2).sub.niv,
CHR.sup.6iv(CH.sub.2).sub.nivCO (wherein R.sup.6iv represents
hydrogen or C.sub.1-4 alkyl and R.sup.9iv represents hydrogen or
methyl and niv represents 0 to 3) or
SO.sub.2CHR.sup.6iv(CH.sub.2).sub.niv (wherein R.sup.6iv represents
hydrogen and niv represents 0); and R.sup.5iv represents C.sub.1-6
alkyl, C.sub.3-6 alkenyl, phenyl, J.sup.1 or heteroaryl (wherein
said phenyl or heteroaryl may be optionally substituted by 1-3
halogen, CN, C.sub.1-6 alkyl, --CF.sub.3, C.sub.3-8 cycloalkyl,
hydroxy, C.sub.1-6 alkoxy, --SCH.sub.3, COOH, COOC.sub.1-6 alkyl,
nitro, amino or --N(CH.sub.3).sub.2) (compounds of formula
(I).sup.d are described in WO97/48695A1 and WO97/48397A1);
and/or
[0045] the proviso that the compound of formula (I) is not a
compound of formula (I).sup.e:
##STR00008##
wherein R.sup.av represents chlorine; R.sup.bv represents amino;
R.sup.cv represents methoxy or ethoxy; and the moiety
-Z.sup.v-R.sup.5v represents phenyl or C.sub.1-6 alkyl (such
compounds of formula (I).sup.e are described in Kato et al., (1992)
Chem. Pharm. Bull. 40(3), 652-660); also wherein R.sup.av
represents chlorine; R.sup.bv represents amino; R.sup.cv represents
methoxy or ethoxy; and the moiety -Z.sup.v-R.sup.5v represents
--CH.sub.2-phenyl wherein phenyl is substituted by 2-, 3- or
4-chlorine, 2-, 3- or 4-fluorine, 3- or 4-CF.sub.3, 3- or
4-methoxy, 4-methyl, 4-nitro, 4-amino, 4-carboxymethyl, 3- or
4-cyano, 3,4-dichloro, 2,4-difluoro, 3,4-difluoro, 3,5-difluoro,
2,4,6-trimethyl (such compounds of formula (I).sup.e are described
in Kato et al., (1991) J. Med. Chem. 34(2), 616-624); also wherein
R.sup.av represents hydrogen, bromine, chlorine, nitro or
SO.sub.2NH.sub.2; R.sup.bv represents amino, --NMe.sub.2,
--NEt.sub.2 or --NHCOCH.sub.3; R.sup.cv represents methoxy, ethoxy,
hydroxy or chlorine; and the moiety -Z.sup.v-R.sup.5v represents
--CH.sub.2-phenyl (such compounds of formula (I).sup.e are
described in Kato et al., (1990) J. Med. Chem. 33(5),
1406-1413).
[0046] A preferred set of compounds of formula (I) include
compounds wherein R.sup.1 represents C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.2-6 alkynyl-Y.sup.1--,
aryl-Y.sup.1--, heteroaryl-Y.sup.1--,
aryl-(O).sub.t-aryl-Y.sup.1--, aryl-(O).sub.t-heteroaryl-Y.sup.1--,
heteroaryl-(O).sub.t-aryl-Y.sup.1--,
heteroaryl-(O).sub.t-heteroaryl-Y.sup.1--, C.sub.2-6
alkenyl-Y.sup.1--, aryl-O--Y.sup.1--, heteroaryl-O--Y.sup.1--,
C.sub.1-6 alkyl-SO.sub.2--Y.sup.1--, M-Y.sup.1-- or C.sub.3-8
cycloalkyl-Y.sup.1-- or C.sub.3-8 cycloalkenyl-Y.sup.1, which
cycloalkyl or cycloalkenyl may be optionally substituted by one or
more hydroxyl or C.sub.1-6 alkyl groups; and
[0047] J.sup.1 represents a moiety of formula (K):
##STR00009##
wherein X.sup.1 represents oxygen, NR.sup.13 or sulphur, X.sup.2
represents CH.sub.2, oxygen, NR.sup.10 or sulphur, m.sup.1
represents an integer from 1 to 3 and m.sup.2 represents an integer
from 1 to 3, provided that m.sup.1+m.sup.2 is in the range from 3
to 5, also provided that when both X.sup.1 and X.sup.2 represent
oxygen, NR.sup.13, NR.sup.10 or sulphur, m.sup.1 and m.sup.2 must
both not equal less than 2, wherein K is optionally substituted by
one or more (e.g. 1 or 2) --Y.sup.3-aryl, --Y.sup.3-heteroaryl,
--Y.sup.3--CO-aryl, --Y.sup.3--CO-heteroaryl, --C.sub.1-6 alkyl,
--Y.sup.3--COOC.sub.1-6 alkyl, --Y.sup.3--CoC.sub.1-6 alkyl,
--Y.sup.3--W, --Y.sup.3--CO--W, --Y.sup.3--NR.sup.11R.sup.12,
--Y.sup.3--CONR.sup.11R.sup.12, hydroxy, oxo,
--Y.sup.3--SO.sub.2NR.sup.11R.sup.12, --Y.sup.3--SO.sub.2 C.sub.1-6
alkyl, --Y.sup.3--SO.sub.2aryl, --Y.sup.3--SO.sub.2heteroaryl,
--Y.sup.3--NR.sup.14c.sub.1-6 alkyl, --Y.sup.3--NR.sup.14SO.sub.2
C.sub.1-6 alkyl, --Y.sup.3--NR.sup.14CONR.sup.11R.sup.12,
--Y.sup.3--NR.sup.14COOR.sup.15 or --Y.sup.3--OCONR.sup.11R.sup.12
groups, and is optionally fused to a monocyclic aryl or heteroaryl
ring.
[0048] A preferred subset of compounds of formula (I) include
compounds wherein R.sup.1 represents C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, aryl-Y.sup.1--, heteroaryl-Y.sup.1--,
aryl-(O).sub.t-aryl-Y.sup.1--, aryl-(O).sub.t-heteroaryl-Y.sup.1--,
heteroaryl-(O).sub.t-aryl-Y.sup.1--,
heteroaryl-(O).sub.t-heteroaryl-Y.sup.1--, C.sub.2-6
alkenyl-Y.sup.1--, aryl-O--Y.sup.1--, heteroaryl-O--Y.sup.1--,
C.sub.1-6 alkyl-SO.sub.2--Y.sup.1-, M-Y.sup.1- or C.sub.3-8
cycloalkyl-Y.sup.1- or C.sub.3-8 cycloalkenyl-Y.sup.1--, which
cycloalkyl or cycloalkenyl may be optionally substituted by one or
more hydroxyl or C.sub.1-6 alkyl groups;
[0049] Z represents a bond, CO, CR.sup.9R.sup.6(CH.sub.2).sub.n,
CHR.sup.6(CH.sub.2).sub.nO, CHR.sup.6(CH.sub.2).sub.nS,
CHR.sup.6(CH.sub.2).sub.nOCO, CHR.sup.6(CH.sub.2).sub.nCO; and
[0050] J.sup.1 represents a moiety of formula (K):
##STR00010##
wherein X.sup.1 represents oxygen, nitrogen, NR.sup.13 or sulphur,
X.sup.2 represents CH.sub.2, oxygen, nitrogen, NR.sup.10 or
sulphur, m.sup.1 represents an integer from 1 to 3, m.sup.2
represents an integer from 1 to 3, provided that m.sup.1+m.sup.2 is
in the range from 3 to 5, also provided that when X.sup.2
represents oxygen, nitrogen, NR.sup.10 or sulphur, m.sup.1 and
m.sup.2 must both not equal less than 2, wherein K is optionally
substituted by one or more (e.g. 1 or 2) --Y.sup.3-aryl,
--Y.sup.3-heteroaryl, --Y.sup.3--CO-aryl, --Y.sup.3--CO-heteroaryl,
--C.sub.1-6 alkyl, --Y.sup.3--COOC.sub.1-6 alkyl,
--Y.sup.3--COC.sub.1-6 alkyl, --Y.sup.3--W, --Y.sup.3--CO--W,
--Y.sup.3--NR.sup.11R.sup.12, --Y.sup.3--CONR.sup.11R.sup.12,
hydroxy, oxo, --Y.sup.3--SO.sub.2NR.sup.11R.sup.12,
--Y.sup.3--SO.sub.2 C.sub.1-6 alkyl, --Y.sup.3--SO.sub.2aryl,
--Y.sup.3--SO.sub.2heteroaryl, --Y.sup.3--NR.sup.14c.sub.1-6 alkyl,
--Y.sup.3--NR.sup.14SO.sub.2 C.sub.1-6 alkyl,
Y.sup.3--NR.sup.14CONR.sup.11R.sup.12,
--Y.sup.3--NR.sup.14COOR.sup.15 or --Y.sup.3--OCONR.sup.11R.sup.12
groups, and is optionally fused to a monocyclic aryl or heteroaryl
ring.
[0051] 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. References to `heteroaryl` may also be extended to
include references to mono- and bicyclic heterocyclic aromatic
rings containing 4 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,
imidazolyl. Further examples of monocyclic heterocyclic aromatic
rings include pyrazinyl or tetrazolyl. Examples of bicyclic
heterocyclic aromatic rings include e.g. benzimidazolyl, quinolinyl
or indolyl. Further examples of bicyclic heterocyclic aromatic
rings include e.g. benzotriazolyl, pyrrolopyridine, benzothiazolyl
and quinoxalinyl. 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, C.sub.1-6 alkoxy, cyano, hydroxy,
nitro, amino, W, --N(CH.sub.3).sub.2, --NHCOC.sub.1-6 alkyl,
--OCF.sub.3, --CF.sub.3, --COOC.sub.1-6 alkyl, --OCHF.sub.2,
--SCF.sub.3, --SO.sub.2N(CH.sub.3).sub.2, --SO.sub.2CH.sub.3,
--SCH.sub.3, --CONR.sup.16R.sup.17 or --SO.sub.2NR.sup.16R.sup.17
groups (wherein R.sup.16 and R.sup.17 independently represent
hydrogen or C.sub.1-6 alkyl; R.sup.16 and R.sup.17 may also
independently represent C.sub.3-8 cycloalkyl). Further substituents
of carbocyclic and heterocyclic aromatic rings include --COOH and
--NHSO.sub.2CH.sub.3. Yet further substituents include
--N(C.sub.1-6alkyl)SO.sub.2 C.sub.1-6alkyl, --N(SO.sub.2
C.sub.1-6alkyl).sub.2, --NHCOCH.sub.2N(C.sub.1-6alkyl).sub.2,
--NHCONHC.sub.1-6alkyl, --CONH(CH.sub.2).sub.2OC.sub.1-6alkyl,
--CONH(CH.sub.2).sub.2N(C.sub.1-6alkyl).sub.2,
CON(C.sub.1-6alkyl).sub.2, C.sub.3-8cycloalkyl, morpholinyl,
--COmethylpiperazinyl and COmorpholinyl.
[0052] Examples of group J.sup.1 include indolinyl, which may be
optionally substituted.
[0053] Examples of group J.sup.2 include thiomorpholinyl and
piperidinyl, which may be optionally substituted, for example by
t-butoxycarbonyl.
[0054] Examples of group M include tetrahydronaphthalenyl.
[0055] Examples of group W include piperidinyl, pyrrolidinyl,
morpholinyl and piperazinyl which may be optionally
substituted.
[0056] 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.
[0057] References to C.sub.3-8 cycloalkyl include references to all
alicyclic (including branched) isomers of the corresponding
alkyl.
[0058] Preferably, R.sup.1 represents C.sub.1-6 alkyl (particularly
butyl and --(CH.sub.2).sub.2CH(CH.sub.3).sub.2), C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl-Y.sup.1--, heteroaryl-Y.sup.1--,
aryl-(O).sub.t-aryl-Y.sup.1--,
aryl-(O).sub.t-heteroaryl-Y.sup.1--(particularly wherein aryl
represents phenyl and heteroaryl represents tetrazolyl,
oxadiazolyl, thiazolyl or oxazolyl),
heteroaryl-(O).sub.t-aryl-Y.sup.1--,
heteroaryl-(O).sub.t-heteroaryl-Y.sup.1-- (particularly wherein
heteroaryl represents oxazolyl, thiazolyl, thiophenyl, pyrazolyl,
pyrazinyl, furanyl, pyridinyl or tetrazolyl), C.sub.2-6
alkenyl-Y.sup.1--, aryl-O--Y.sup.1-- (particularly wherein aryl
represents phenyl), heteroaryl-O--Y.sup.1--, C.sub.1-6
alkyl-SO.sub.2--Y.sup.1-- (particularly wherein C.sub.1-6 alkyl
represents methyl), M-Y.sup.1--, --CN, J.sup.2-Y.sup.1-- or
C.sub.3-8 cycloalkyl-Y.sup.1-- (particularly cyclopropyl and
cyclohexyl) or C.sub.3-8 cycloalkenyl-Y.sup.1--, which cycloalkyl
or cycloalkenyl may be optionally substituted by one or more
hydroxyl or C.sub.1-6 alkyl groups.
[0059] Particularly, R.sup.1 represents C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, aryl-Y.sup.1--, heteroaryl-Y.sup.1--,
aryl-(O).sub.t-aryl-Y.sup.1--, aryl-(O).sub.t-heteroaryl-Y.sup.1--,
heteroaryl-(O).sub.t-aryl-Y.sup.1--,
heteroaryl-(O).sub.t-heteroaryl-Y.sup.1--, C.sub.2-6
alkenyl-Y.sup.1--, aryl-O--Y.sup.1--, heteroaryl-O--Y.sup.1--,
C.sub.1-6 alkyl-SO.sub.2--Y.sup.1--, M-Y.sup.1-- or C.sub.3-8
cycloalkyl-Y.sup.1-- or C.sub.3-8 cycloalkenyl-Y.sup.1--, which
cycloalkyl or cycloalkenyl may be optionally substituted by one or
more hydroxyl or C.sub.1-6 alkyl groups.
[0060] More preferably, R.sup.1 represents aryl-Y.sup.1--,
aryl-O--Y.sup.1--, heteroaryl-Y.sup.1--,
aryl-(O).sub.t-heteroaryl-Y.sup.1 or
heteroaryl-(O).sub.t-heteroaryl-Y.sup.1--, especially
aryl-Y.sup.1--, heteroaryl-Y.sup.1,
heteroaryl-(O).sub.t-heteroaryl-Y.sup.1-- or
aryl-(O).sub.t-heteroaryl-Y.sup.1--. In this definition, aryl
preferably represents phenyl optionally substituted by one or more
--SO.sub.2--N(CH.sub.3).sub.2, --SO.sub.2CH.sub.3, halogen
(especially fluorine or chlorine), C.sub.1-6 alkyl (especially
methyl), CH.sub.3CONH--, --CF.sub.3, CH.sub.3O--, --CONH.sub.2,
(CH.sub.3).sub.2N-- or --SCH.sub.3 groups. Further preferred phenyl
substituents include
[0061] --NHSO.sub.2CH.sub.3, --COOH, --COOCH.sub.3 and --CON
H-cyclopropyl. Yet further preferred phenyl substituents include
--SO.sub.2NHcyclopropyl, --SO.sub.2NHCH.sub.2CH.sub.3,
--SO.sub.2NHCH.sub.3, --N(CH.sub.3)SO.sub.2CH.sub.3,
--N(SO.sub.2CH.sub.3).sub.2, --NHCOCH.sub.2N(CH.sub.3).sub.2,
--NHCOCH(CH.sub.3).sub.2, --NH.sub.2, --SO.sub.2NH.sub.2,
--NHCONHCH.sub.3, --NO.sub.2, --CONH(CH.sub.2).sub.2OCH.sub.3,
--CONHCH(CH.sub.3).sub.2, --CONH(CH.sub.2).sub.2OH,
--CONH(CH.sub.2).sub.2N(CH.sub.3).sub.2, --CON(CH.sub.3).sub.2,
--CONHCH.sub.2CH.sub.3, --CONHCH.sub.3, --COCH.sub.3,
--COCH(CH.sub.3).sub.2, --CN, --OH, --CO-4-methyl-1-piperazinyl and
--COmorpholinyl. Heteroaryl preferably represents indolyl,
thiophenyl, oxazolyl, pyrazolyl, thiazolyl, pyrimidinyl or furanyl
optionally substituted with one or more C.sub.1-6 alkyl (especially
methyl), CH.sub.3O-- or halogen (especially bromine) groups.
Heteroaryl also preferably represents tetrazolyl or pyrazinyl.
Further preferred groups which heteroaryl may represent include
benzotriazolyl, pyrrolopyridine, benzothiazolyl, pyridinyl,
quinoxalinyl and imidazolyl. Suitable heteroaryl substituents
include halogen (especially bromine), --COCH.sub.3, --COOCH.sub.3,
--CH.sub.3, --CH(CH.sub.3).sub.2, morpholinyl, cyclopropyl,
--CH.sub.2CH(CH.sub.3).sub.2 and --CH.dbd.C(CH.sub.3).sub.2.
[0062] A most particularly preferred group of compounds are those
in which R.sup.1 is aryl-(O).sub.t-heteroaryl-Y.sup.1-- especially
wherein heteroaryl represents optionally substituted oxazolyl,
(especially oxazolyl substituted by methyl), aryl represents phenyl
and t represents 0.
[0063] Especially preferred R.sup.1 is aryl-Y.sup.1--, particularly
when aryl represents phenyl optionally substituted by any of the
above substituents, most especially phenyl substituted by
--SO.sub.2NH.sub.2.
[0064] Preferably, Y.sup.1 represents a bond, C.sub.1-6 alkylene,
C.sub.3-8 cycloalkyl or --CHCH.sub.3, particularly C.sub.1-6
alkylene or C.sub.3-8 cycloalkyl, most preferably methylene,
ethylene or cyclopropyl, especially methylene or cyclopropyl, most
especially methylene.
[0065] Preferably, R.sup.2 represents hydrogen.
[0066] Preferably, X represents methylene.
[0067] Preferably, R.sup.3 and R.sup.4 independently represent
hydrogen or methyl, especially hydrogen.
[0068] Preferably, Z represents a bond, CO,
CR.sup.9R.sup.6(CH.sub.2).sub.n, CHR.sup.6(CH.sub.2).sub.nO,
CHR.sup.6(CH.sub.2).sub.nS, CHR.sup.6(CH.sub.2).sub.nOCO or
CHR.sup.6(CH.sub.2).sub.nCO.
[0069] More preferably, Z represents a bond, CO,
CHR.sup.6(CH.sub.2).sub.n, CHR.sup.6(CH.sub.2).sub.nO (particularly
(CH.sub.2).sub.2O) or CHR.sup.6(CH.sub.2).sub.nCO, more
particularly CHR.sup.6(CH.sub.2).sub.n or
CHR.sup.6(CH.sub.2).sub.nCO, most preferably CH.sub.2,
(CH.sub.2).sub.3, CHCH.sub.3 or CH.sub.2CO, especially CH.sub.2 or
CH.sub.2CO, most especially CH.sub.2.
[0070] Preferably, R.sup.5 represents C.sub.2-6 alkenyl
(particularly --CH.sub.2CH(CH.sub.3).dbd.CH.sub.2), aryl,
heteroaryl or a group of formula --Y.sup.2-J.sup.1, more preferably
aryl, heteroaryl or a group of formula --Y.sup.2-J.sup.1, most
preferably monocyclic aryl, heteroaryl or a group of formula
--Y.sup.2-J.sup.1, especially aryl or --Y.sup.2-J.sup.1,
particularly phenyl which may be optionally substituted. We also
especially prefer R.sup.5 to represent heteroaryl, particularly
thiophenyl which may be optionally substituted. Other groups which
heteroaryl preferably represents include benzoxadiazolyl,
benzothiadiazolyl or benzothiophenyl which may be optionally
substituted. We most particularly prefer R.sup.5 to represent
phenyl optionally substituted by one or more (e.g. 1, 2 or 3)
halogen groups. Other preferred substituents for phenyl include
--CN and --CF.sub.3. We also most particularly prefer R.sup.5 to
represent thiophenyl optionally substituted by one or more (e.g. 1,
2 or 3) halogen groups.
[0071] Especially preferred R.sup.5 groups are dichlorophenyl,
difluorophenyl, fluorophenyl, chlorothiophenyl, chlorophenyl and
trifluorophenyl, most especially dichlorophenyl, difluorophenyl,
fluorophenyl and chlorothiophenyl.
[0072] Most preferred R.sup.5 is dichlorophenyl (particularly
3,4-dichlorophenyl, 2,3-dichlorophenyl and 2,5-dichlorophenyl),
4-fluorophenyl and 3,4-difluorophenyl.
[0073] Most especially preferred R.sup.5 is dichlorophenyl,
particularly 3,4-dichlorophenyl.
[0074] Preferably, Y.sup.2 represents a bond.
[0075] Preferably, J.sup.1 represents indolinyl, particularly
indolin-1-yl.
[0076] Preferably, J.sup.2 represents optionally substituted
piperidinyl (particularly piperidinyl substituted by
--COOC.sub.1-6alkyl e.g. --COOC(CH.sub.3).sub.3) or thiomorpholinyl
(particularly dioxidothiomorpholinyl) or
dioxidothiomorpholinyl.
[0077] Preferably, Y.sup.3 represents a bond.
[0078] Preferably, R.sup.6 represents hydrogen.
[0079] Preferably, R.sup.7 and R.sup.8 represent hydrogen.
[0080] Preferably, R.sup.9 represents hydrogen.
[0081] Preferably, R.sup.10 and R.sup.13 independently represent
hydrogen or methyl, especially hydrogen.
[0082] Preferably, R.sup.11 and R.sup.12 independently represent
hydrogen or methyl or R.sup.11 and R.sup.12 together with the
nitrogen atom to which they are attached may form a morpholine,
piperidine or pyrrolidine ring, especially hydrogen or methyl.
[0083] Preferably, R.sup.14 and R.sup.15 independently represent
hydrogen or methyl.
[0084] Preferably, R.sup.16 and R.sup.17 independently represent
hydrogen, methyl, ethyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl,
cyclopropyl or 2-(dimethylamino)ethyl. Most preferably, R.sup.16
and R.sup.17 independently represent hydrogen or cyclopropyl.
[0085] Preferably, R.sup.c and R.sup.d independently represents
hydrogen or methyl, most preferably hydrogen or R.sup.c and R.sup.d
together with the carbon atom to which they are attached preferably
forms cyclopropyl.
[0086] Preferably, R.sup.e and R.sup.f both represent hydrogen.
[0087] Preferably, a and b both represent 1.
[0088] Preferably, n represents 0, 1 or 2, more preferably 0.
[0089] Preferably, p and q independently represent 0 or 1 such that
p+q represent 0-1. Most preferably, p and q both represent 0.
[0090] Preferably, t represents 0.
[0091] Preferably, W represents pyrrolidinyl or piperidinyl,
especially pyrrolidinyl.
[0092] Preferably, X.sup.1 represents sulphur, oxygen or NR.sup.11.
More preferably, X.sup.1 represents oxygen or NR.sup.11.
[0093] Preferably, X.sup.2 represents CH.sub.2, oxygen or
NR.sup.12.
[0094] Preferably, m.sup.1 and m.sup.2 independently represent an
integer from 1 to 2, such that m.sup.1+m.sup.2 is in the range from
3 to 4.
[0095] 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. Examples of solvates include hydrates.
[0096] 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 single enantiomer.
[0097] 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.
[0098] A process according to the invention for preparing a
compound of formula (I) which comprises:
(a) acylation of a compound of formula (II)
##STR00011##
or a protected derivative thereof wherein R.sup.2, R.sup.3,
R.sup.4, R.sup.5, X, Z, a and b are as described above, with a
compound of formula R.sup.1COOH or an activated derivative thereof,
wherein R.sup.1 is as described above; or (b) reacting a compound
of formula (III)
##STR00012##
or a protected derivative thereof wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4, X, a and b are as defined above, with a compound
of formula L.sup.1-Z-R.sup.5, wherein Z and R.sup.5 are as defined
above and L.sup.1 represents a suitable leaving group; or (c)
deprotecting a compound of formula (I) which is protected; or (d)
interconversion of other compounds of formula (I).
[0099] We also provide a further process according to the invention
for preparing a compound of formula (I) which comprises:
(e) forming a compound of formula (I) wherein R.sup.1 represents
heteroaryl-Y.sup.1--, aryl-(O).sub.t-heteroaryl-Y.sup.1-- or
heteroaryl-(O).sub.t-heteroaryl-Y.sup.1-- (wherein said Y.sup.1
group is attached to heteroaryl via a heterocyclic nitrogen atom)
and R.sup.2 represents hydrogen which comprises reacting a compound
of formula (IV)
##STR00013##
or a protected derivative thereof wherein R.sup.3, R.sup.4,
R.sup.5, X, Y.sup.1, Z, a and b are as defined above, L.sup.2
represents a suitable leaving group, such as a halogen atom e.g.
bromine and P.sup.1 represents a solid phase resin bound protecting
group, such as one described for process (c), with a heterocyclic
compound defined by the R.sup.1 groups heteroaryl,
aryl-(O).sub.t-heteroaryl or heteroaryl-(O).sub.t-heteroaryl above
wherein said heteroaryl group contains at least one NH atom,
followed by removal of the solid phase resin bound protecting
group; or (f) forming a compound of formula (I) wherein Z
represents CR.sup.9R.sup.6(CH.sub.2).sub.n and R.sup.9 represents
hydrogen which comprises reacting a compound of formula (III) or a
protected derivative thereof with a compound of formula
R.sup.6CO(CH.sub.2).sub.nR.sup.5, followed by reduction of the
resultant imine; or (g) forming a compound of formula (I) wherein Z
represents CO by reacting a compound of formula (III) or a
protected derivative thereof with a compound of formula R.sup.5COOH
or an activated derivative thereof.
[0100] Process (a) may be effected simply by the reaction of a
compound of formula (II) with R.sup.1COOH which may typically be
achieved using an oven e.g. a microwave oven at a power of 600 W
for 4 minutes. Examples of activated derivatives of R.sup.1COOH
which may be employed in this reaction include acid halides and
anhydride derivatives (e.g. the acid chloride). Alternatively,
process (a) may be performed in the presence of
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylammonium
hexafluorophosphate (HATU) and a suitable base, e.g.
N,N-diisopropylethylamine in a suitable solvent, e.g.
N,N-dimethylformamide at a suitable temperature, e.g. room
temperature. Process (a) may also be performed in the presence of
1-hydroxybenzotriazole and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in the
presence of a suitable base, e.g. N,N-diisopropylethylamine and a
suitable solvent, e.g. dichloromethane or N,N-dimethylformamide, at
a suitable temperature, e.g. room temperature. Further, process (a)
may be performed in the presence of 1,1'-carbonyldiimidazole in the
presence of a suitable solvent, e.g. N,N-dimethylformamide at a
suitable temperature, e.g. room temperature. Process (a) may also
be performed in the presence of a suitable base such as
polyvinylpyridine and a suitable solvent, such as dichloromethane
at a suitable temperature such as room temperature.
[0101] Process (b) may be performed in the presence of a suitable
solvent e.g. N,N-dimethylformamide, optionally in the presence of
N,N-diisopropylethylamine at a suitable temperature e.g. room
temperature. Examples of suitable leaving groups (L.sup.1) include
halogen, e.g. chlorine.
[0102] In process (c), examples of protecting groups and the means
for their removal can be found in T. W. Greene and P. G. M. Wuts
`Protective Groups in Organic Synthesis` (J. Wiley and Sons, 3rd
Ed. 1999). Suitable amine protecting groups include sulphonyl (e.g.
tosyl), acyl (e.g. benzyloxycarbonyl or t-butoxycarbonyl) and
arylalkyl (e.g. benzyl), which may be removed by hydrolysis or
hydrogenolysis as appropriate. Other suitable amine protecting
groups include trifluoroacetyl (--COCF.sub.3) which may be removed
by base catalysed hydrolysis, or a solid phase resin bound benzyl
group, such as a Merrifield resin bound 2,6-dimethoxybenzyl group
(Ellman linker) or a
2,6-dimethoxy-4-[2-(polystyrylmethoxy)ethoxy]benzyl, which may be
removed by acid catalysed hydrolysis, for example with
trifluoroacetic acid.
[0103] Process (d) may be performed using conventional
interconversion procedures such as epimerisation, oxidation,
reduction, alkylation, nucleophilic aromatic substitution, ester
hydrolysis or amide bond formation. Alternative conditions for
process (d) include t-butoxycarbonyl group addition or removal and
sulphonylation.
[0104] Process (e) may be performed using a suitable base, e.g.
potassium tert-butoxide and a suitable solvent, e.g.
N,N-dimethylformamide, at a suitable temperature, e.g. 60.degree.
C.
[0105] Process (f) may be performed in the presence of a suitable
acid e.g. acetic acid and a suitable reducing agent, e.g. sodium
triacetoxyborohydride in a suitable solvent, e.g. dichloromethane
at a suitable temperature, e.g. room temperature.
[0106] Process (g) may be performed in the presence of suitable
reagents, e.g. 1,-(3-dimethylaminopropyl)-3-ethyl-carbodiimide
hydrochloride and 1-hydroxybenzotriazole in the presence of a
suitable base, e.g. N,N-diisopropylethylamine and a suitable
solvent e.g. N,N-dimethylformamide at a suitable temperature, e.g.
room temperature.
[0107] Compounds of formula (II) may be prepared according to the
following process:
##STR00014##
wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, X, a, b and Z are as
defined above and L.sup.1 represents a suitable leaving group e.g.
chlorine and P.sup.2 represents a suitable protecting group e.g.
one mentioned above, such as --COCF.sub.3. Step (i) comprises the
use of a suitable solvent e.g. N,N-dimethylformamide in the
presence of suitable reagents e.g. sodium iodide and potassium
carbonate at a suitable temperature e.g. room temperature.
Alternatively step (i) may comprise the use of a suitable solvent
e.g. N,N-dimethylformamide, in the presence of a suitable base such
as N,N-diisopropylethylamine at a suitable temperature e.g. room
temperature. Step (ii) comprises deprotection under conventional
conditions appropriate for the protecting groups. When P.sup.2
represents --COCF.sub.3, deprotection may be achieved by the use of
water and methanol in the presence of potassium carbonate at room
temperature.
[0108] Compounds of formula (II).sup.p may also be prepared by
reductive amination of compounds of formula (V) in an analogous
manner to that described in process (f) above.
[0109] Compounds of formula (II) wherein R.sup.2 represents
hydrogen, X represents methylene, a and b represent 1 and R.sup.3
and R.sup.4 are both attached to the morpholine ring at the
5-position may be prepared according to the following process:
##STR00015##
wherein R.sup.3, R.sup.4 and R.sup.5 and Z are as defined above and
L.sup.1 represents a suitable leaving group e.g. chlorine. Step (i)
comprises heating in the absence of solvent at between 50 and
60.degree. C. Step (ii) comprises heating with
2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione at 80.degree. C.
under nitrogen, followed by stirring with concentrated sulphuric
acid at 150.degree. C.
[0110] Compounds of formula (II) wherein R.sup.2 represents H may
be prepared according to the following process:
##STR00016##
wherein R.sup.3, R.sup.4, R.sup.5, X, a, b and Z are as defined
above and L.sup.1 represents a suitable leaving group e.g.
chlorine. Step (i) comprises heating a compound of formula (VIII;
Merrifield Resin) with sodium carbonate in a suitable solvent e.g.
dimethylsulphoxide at a suitable temperature e.g. 150.degree. C.
Step (ii) comprises reacting a compound of formula (IX) with a
compound of formula (X) in the presence of a suitable solvent e.g.
tetrahydrofuran at a suitable temperature e.g. room temperature.
Step (iii) comprises the use of suitable solvent e.g.
N,N-dimethylformamide and a suitable base e.g.
N,N-diisopropylethylamine at a suitable temperature e.g. 70.degree.
C., followed by deprotection under conventional conditions
appropriate for the Merrifield resin protecting group e.g. acid
catalysed hydrolysis.
[0111] Compounds of formula R.sup.1COOH used in process (a) above
(and activated derivatives thereof) are either known compounds or
may be synthesised by known methods.
[0112] For example, compounds of formula R.sup.1COOH wherein
R.sup.1 represents heteroaryl-Y.sup.1,
aryl-(O).sub.t-heteroaryl-Y.sup.1-- or
heteroaryl-(O).sub.t-heteroaryl-Y.sup.1-- (wherein the heteroaryl
moiety linked to Y.sup.1 represents 1,3-oxazol-4-yl and t
represents 0) may be prepared according to the following
process:
##STR00017##
wherein R.sup.w represents a suitable substituent described above
for a heteroaryl group, especially C.sub.1-6 alkyl, R.sup.x
represents C.sub.1-6 alkyl, aryl or heteroaryl, R.sup.z represents
C.sub.1-6 alkyl, especially ethyl, Hal represents a halogen atom,
especially bromine and Y.sup.1 is as defined above.
[0113] Compounds of formula (XII) may be prepared by following the
procedure described in Svendsen and Boll (1973) Tetrahedron 29,
4251-4258.
[0114] Step (i) may typically be performed in the presence of a
suitable solvent, e.g. toluene at a suitable temperature e.g. at
140.degree. C. and using suitable conditions, e.g. Dean-Stark
conditions.
[0115] Step (ii) may typically be performed in the presence of a
suitable alkali, e.g. sodium hydroxide and suitable solvents, e.g.
water and ethanol at a suitable temperature, e.g. 70.degree. C.
[0116] Compounds of formula R.sup.1COOH wherein R.sup.1 represents
heteroaryl-Y.sup.1, aryl-(O).sub.t-heteroaryl-Y.sup.1-- or
heteroaryl-(O).sub.t-heteroaryl-Y.sup.1-- (wherein the heteroaryl
moiety linked to Y.sup.1 represents 1,3-oxazol-4-yl and t
represents 0) may also be prepared according to the following
process:
##STR00018##
wherein R.sup.V represents C.sub.1-6 alkyl, especially methyl,
R.sup.w represents a suitable substituent described above for a
heteroaryl group, especially C.sub.1-6 alkyl, R.sup.x represents
C.sub.1-6 alkyl, aryl or heteroaryl, Hal represents a halogen atom,
especially chlorine and Y.sup.1 is as defined above.
[0117] Step (i) may typically be performed in the presence of a
suitable base, e.g. pyridine, at a suitable temperature, e.g. from
0.degree. C. to room temperature.
[0118] Step (ii) may typically be performed in the presence of a
suitable base, e.g. pyridine at a suitable temperature, e.g.
90.degree. C., followed by the addition of water at a suitable
temperature, e.g. 90.degree. C.
[0119] Step (iii) may typically be performed in the presence of a
suitable reagent, e.g. phosphorus oxychloride and a suitable
solvent, e.g. toluene, under suitable conditions, e.g. 110.degree.
C.
[0120] Step (iv) may typically be performed in the presence of a
suitable alkali e.g. 2M aqueous sodium hydroxide, and a suitable
solvent, e.g. ethanol at a suitable temperature, e.g. room
temperature.
[0121] Compounds of formula (III) as the R-isomer, wherein R.sup.2
represents hydrogen, X represents methylene, a and b represent 1
and R.sup.3 and R.sup.4 both represent hydrogen may be prepared
according to the following process:
##STR00019##
wherein R.sup.1 is as defined above and P.sup.3 is a suitable
protecting group, e.g. benzyl.
[0122] Compounds of formula (XXII) may be prepared as described in
EP0995746.
[0123] Step (i) typically comprises the use of
1-hydroxybenzotriazole and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in the
presence of a suitable base, e.g. N,N-diisopropylethylamine and a
suitable solvent, e.g. N,N-dimethylformamide, at a suitable
temperature, e.g. room temperature.
[0124] Step (ii) typically comprises a simple deprotection
reaction, e.g. which may comprise the use of 10% palladium on
activated carbon in the presence of ammonium formate and a suitable
solvent, e.g. ethanol.
[0125] Compounds of formula (III) as the S-isomer, wherein R.sup.1
is as defined above, may be prepared by an analogous process.
[0126] Compounds of formula (IV) may be prepared according to the
following process:
##STR00020##
wherein R.sup.3, R.sup.4, R.sup.5, X, Y.sup.1, Z, a and b are as
defined above, L.sup.2 represents a suitable leaving group, such as
a halogen atom, e.g. bromine and P.sup.1 represents a solid phase
resin bound protecting group, such as one described in process
(c).
[0127] Step (i) typically comprises the use of a suitable reagent,
e.g. 1,3-diisopropylcarbodiimide in the presence of one or more
suitable solvents, e.g. dichloromethane and
N,N-dimethylformamide.
[0128] Compounds of formula (V), (VI), (VIII), (X), (XII), (XIII),
(XVI), (XVII), (XIX) and (XXII) are either known or may be prepared
in accordance with known procedures.
[0129] Compounds of formula L.sup.1-Z-R.sup.5,
R.sup.6CO(CH.sub.2).sub.nR.sup.5, R.sup.5COOH,
L.sup.2-Y.sup.1--COOH and heterocyclic compounds defined by the
R.sup.1 groups heteroaryl, aryl-(O).sub.t-heteroaryl or
heteroaryl-(O).sub.t-heteroaryl above are also either known or may
be prepared in accordance with known procedures.
[0130] Compounds of formula (III) may be prepared in accordance
with processes analogous to those described above for compounds of
formula (I), employing suitable protection for the morpholine (or
analogue) NH, e.g. t-butoxycarbonyl protection.
[0131] Compounds of formula (II), (III) and (IV) in their protected
and deprotected form and salts and solvates thereof are also
claimed as an aspect of the invention.
[0132] Compounds of the invention may be tested for in vitro and in
vivo biological activity in accordance with the following
assays.
(a) CCR-3 Binding Assay
[0133] A CCR-3 competition binding SPA (scintillation proximity
assay) was used to assess the affinity of novel compounds for
CCR-3. Membranes prepared from K562 cells stably expressing CCR-3
(2.5 .mu.g/well) were mixed with 0.25 mg/well wheat-germ agglutinin
SPA beads (Amersham) and incubated in binding buffer (HEPES 50 mM,
CaCl.sub.2 1 mM, MgCl.sub.2 5 mM, 0.5% BSA) at 4.degree. C. for 1.5
hr. Following incubation, 20 pM of [.sup.125I] eotaxin (Amersham)
and increasing concentrations of compound (1 pM to 30 .mu.M) were
added and incubated in a 96 well plate for 2 hr at 22.degree. C.
then counted on a Microbeta plate counter. The total assay volume
was 100 .mu.l. Competition binding data were analysed by fitting
the data with a four parameter logistic equation. Data are
presented as the mean plC.sub.50 values (negative logarithm of the
concentration of compound which inhibits [.sup.125I] eotaxin
binding by 50%) from at least two experiments.
(b) Eosinophil Chemotaxis Assay.
[0134] Compounds were evaluated for their inhibitory effect on
eosinophil chemotaxis. Eosinophils were purified from human
peripheral blood by standard CD16 cell depletion using a Miltenyi
cell separation column and a magnetic Super Macs magnet as
previously described (Motegi & Kita, 1998; J. Immunology.
161:4340-6). Cells were re-suspended in RPMI 1640/10% FCS solution
and incubated with calcein-AM (Molecular Probes) at 37.degree. C.
for 30 mins. Following incubation, the eosinophils were centrifuged
at 400 g for 5 min and re-suspended in RPMI/FCS at 2.2 million/ml.
Cells were then incubated in the presence of increasing
concentration of compounds (1 pM to 30 .mu.M) at 37.degree. C. for
30 mins. For control responses cells were incubated with RPMI/FCS
only. The agonist eotaxin (either a concentration response curve or
for the functional inhibition curves an EC.sub.80 concentration)
was added to the lower chamber of a 96 well chemotaxis plate (5
.mu.m filter: Receptor Technologies). Eosinophils (50 .mu.l of 2
million/ml cells) were added to the top chamber of the filter plate
and incubated at 37.degree. C. for 45 mins. Cells remaining on top
of the chemotaxis filter were removed and the number of eosinophils
which had migrated were quantified by reading the plate on a
fluorescent plate reader. Inhibition curves for the effect of
compounds on eosinophil chemotaxis were analysed by fitting the
data with a four parameter logistic equation. Functional pK.sub.i
values (fpK.sub.i) were generated using the equation below
(Lazareno & Birdsall, 1995. Br. J. Pharmacol 109: 1110-9).
fpKi = IC 50 1 + [ [ Agonist ] EC 50 ] ##EQU00001##
(c) Guinea-Pig Ovalbumin Model
Inhibition of Eosinophil Infiltration and Hyper-Reactivity in the
Guinea Pig
[0135] In a method based on that described by Danahay et al., 1997,
ovalbumin sensitised guinea pigs were dosed with mepyramine (30 mg
kg.sup.-1 ip) to protect against anaphylactic bronchospasm. Test
compounds, dissolved in 10% DMSO and 90% PEG200, were given by the
oral route, 30 minutes before ovalbumin challenge (10 minutes
breathing of an aerosol generated from a 0.5% solution of
ovalbumin). Hyper-reactivity of the airways to the thromboxane
mimetic U46619, was measured 24 hours after ovalbumin challenge in
un-restrained animals using a whole body plethysmograph (Buxco
Ltd., USA). The guinea pigs were then sacrificed and the lungs
lavaged. Total and differential leukocyte counts were then obtained
for the bronchoalveolar lavage fluid and the percentage reduction
in eosinophil accumulation determined (Sanjar et al., 1992). Data
was presented as the inhibitory effect of the specified dose
expressed as a percentage of the vehicle control response.
[0136] Examples of disease states in which the compounds of the
invention have potentially beneficial anti-inflammatory effects
include diseases of the respiratory tract such as bronchitis
(including chronic bronchitis), asthma (including allergen-induced
asthmatic reactions), chronic obstructive pulmonary disease (COPD)
and rhinitis. Another disease of the respiratory tract in which the
compounds of the invention have potentially beneficial effects is
sinusitis. Other relevant disease states include diseases of the
gastrointestinal tract such as intestinal inflammatory diseases
including inflammatory bowel disease (e.g. Crohn's disease or
ulcerative colitis) and intestinal inflammatory diseases secondary
to radiation exposure or allergen exposure. Furthermore, compounds
of the invention may be used to treat nephritis, skin diseases such
as psoriasis, eczema, allergic dermatitis and hypersensitivity
reactions and diseases of the central nervous system which have an
inflammatory component e.g. Alzheimer's disease, meningitis,
multiple sclerosis and AIDS dementia. Compounds of the present
invention may also be of use in the treatment of nasal polyposis,
conjunctivitis or pruritis. Additionally, the compounds of the
present invention may be of use in the treatment of viral diseases
such as HIV.
[0137] Further examples of disease states in which compounds of the
invention have potentially beneficial effects include
cardiovascular conditions such as atherosclerosis, peripheral
vascular disease and idiopathic hypereosinophilic syndrome. Other
diseases for which the compounds of the present invention may be
beneficial are other hypereosinophilic diseases such as
Churg-strauss syndrome. Additionally, eosinophilia is commonly
found in parasitic diseases, especially helminth infections, and
thus the compounds of the present invention may be useful in
treating inflammation arising from hyper-eosinophilic states of
diseases such as hydatid cyst (Echinococcus sp.), tapeworm
infections (Taenia sp.), blood flukes (schistosomiasis), and
nematode (round worms) infections such as: Hookworm (Ancylostoma
sp.), Ascaris, Strongyloides, Trichinella, and particularly
lymphatic filariasis including Onchocerca, Brugia, Wucheria
(Elephantiasis).
[0138] Compounds of the invention may be useful as
immunosuppressive agents and so have use in the treatment of
auto-immune diseases such as allograft tissue rejection after
transplantation, rheumatoid arthritis and diabetes.
[0139] Compounds of the invention may also be useful in inhibiting
metastasis.
[0140] Diseases of principal interest include asthma, COPD and
inflammatory diseases of the upper respiratory tract involving
seasonal and perennial rhinitis. Preferred diseases of principle
interest include asthma and inflammatory diseases of the upper
respiratory tract involving seasonal and perennial rhinitis.
Further diseases also of principle interest include inflammatory
diseases of the gastrointestinal tract such as inflammatory bowel
disease.
[0141] 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.
[0142] As mentioned above, compounds of formula (I) are useful as
pharmaceuticals, in particular as anti-inflammatory agents.
[0143] There is thus provided as a further aspect of the invention
a compound of formula (I) or a physiologically acceptable salt or
solvate thereof for use as pharmaceuticals, particularly in the
treatment of patients with inflammatory conditions, e.g. asthma or
rhinitis.
[0144] According to another aspect of the invention, there is
provided the use of a compound of formula (I) or a physiologically
acceptable salt or solvate thereof for the manufacture of a
medicament for the treatment of patients with inflammatory
conditions, e.g. asthma or rhinitis.
[0145] In a further or alternative aspect there is provided a
method for the treatment of a human or animal subject with an
inflammatory condition e.g. asthma or rhinitis, which method
comprises administering to said human or animal subject an
effective amount of a compound of formula (I) or a physiologically
acceptable salt or solvate thereof.
[0146] 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 for use in anti-inflammatory therapy, comprising a
compound of formula (I) or a physiologically acceptable salt or
solvate thereof together, if desirable, with one or more
physiologically acceptable diluents or carriers.
[0147] There is also provided a process for preparing such a
pharmaceutical formulation which comprises mixing the
ingredients.
[0148] The compounds according to the invention may, for example,
be formulated for oral, inhaled, intranasal, buccal, parenteral or
rectal administration, preferably for oral administration.
[0149] 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.
[0150] For buccal administration the compositions may take the form
of tablets or lozenges formulated in conventional manner.
[0151] The compounds may also be formulated as suppositories, e.g.
containing conventional suppository bases such as cocoa butter or
other glycerides.
[0152] 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.
[0153] 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, 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),
anti-histamines (e.g. methapyrilene or loratadine) or antiinfective
agents (e.g. antibiotics, antivirals).
[0154] 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.
[0155] Compounds of the invention may conveniently be administered
in amounts of, for example, 0.001 to 500 mg/kg body weight,
preferably 0.01 to 500 mg/kg body weight, more preferably 0.01 to
100 mg/kg body weight, 1 to 4 times daily. The precise dose will of
course depend on the age and condition of the patient and the
particular route of administration chosen.
[0156] The compounds of the invention have the advantage that they
may be more efficacious, show greater selectivity, have fewer side
effects, have a longer duration of action, be more bioavailable
when administered by the oral route, have more ready and economic
synthesis, or have other more desirable properties than similar
known compounds.
[0157] The invention may be illustrated by reference to the
following examples:
EXAMPLES
General Experimental Details
Standard Automated Preparative HPLC Column, Conditions and
Eluent
[0158] Automated preparative high performance liquid chromatography
(autoprep. HPLC) was carried out using a Supelco+5 .mu.m (100
mm.times.22 mm internal diameter) column eluted with a mixture of
solvents consisting of i) 0.1% trifluoroacetic acid in water and
ii) 0.1% trifluoroacetic acid in acetonitrile, the eluent being
expressed as the percentage of ii) in the solvent mixture, at a
flow rate of 4 ml per minute.
Mass Directed Automated Preparative HPLC Column, Conditions and
Eluent
[0159] Mass directed automated preparative high performance liquid
chromatography was carried out using an LCABZ+5 .mu.m (5
cm.times.10 mm internal diameter) column, employing gradient
elution using two solvent systems, (A) 0.1% formic acid in water,
and (B) 95% acetonitrile and 0.5% formic acid in water, at a flow
rate of 8 ml min.sup.-1. Mass spectrometry was carried out using a
VG Platform Mass Spectrometer, with an HP1100 Diode Array Detector
and Accurate Flow Splitter.
Normal Phase Automated Preparative HPLC Column-Conditions
[0160] Normal phase automated preparative high performance liquid
chromatography (normal phase autoprep HPLC) was carried out using a
Nucleosil silica 5 .mu.m (100 mm.times.20 mm internal diameter)
column eluted with an ethyl acetate:heptane two-step gradient (i)
0% to 25% ethyl acetate over 7 min followed by (ii) 25% to 100%
ethyl acetate over 5.5 min; at a flow rate of 30 ml/min.
LC/MS System
[0161] Three alternative Liquid Chromatography Mass Spectroscopy
(LC/MS) Systems were used:
System A
[0162] This system used a 3 .mu.m ABZ+PLUS (3.3 cm.times.4.6 mm
internal diameter) column, eluting with solvents: A--0.1% v/v
formic acid+0.077% w/v ammonium acetate in water; and B--95:5
acetonitrile:water+0.05% v/v formic acid, at a flow rate of 3 ml
per minute. The following gradient protocol was used: 100% A for
0.7 mins; A+B mixtures, gradient profile 0-100% B over 3.5 mins;
hold at 100% B for 1.1 mins; return to 100% A over 0.2 mins.
System B
[0163] This system used a 3 .mu.m ABZ+PLUS (3.3 cm.times.4.6 mm
internal diameter) column, eluting with solvents: A--0.1% v/v
formic acid+0.077% w/v ammonium acetate in water; and B--95:5
acetonitrile:water+0.05% v/v formic acid, at a flow rate of 1 ml
per minute. The following gradient protocol was used: 100% A for
1.0 min; A+B mixtures, gradient profile 0-100% B over 9.0 mins;
hold at 100% B for 3.0 mins; return to 100% A over 2.0 mins.
System C
[0164] This system used a 3 .mu.m ABZ+PLUS (3.3 cm.times.4.6 mm
internal diameter) column, eluting with solvents: A--0.1% v/v
formic acid+0.077% w/v ammonium acetate in water; and B--95:5
acetonitrile:water+0.05% v/v formic acid, at a flow rate of 1 ml
per minute. The following gradient protocol was used: 100% A for
2.0 mins; A+B mixtures, gradient profile 0-100% B over 20 mins;
hold at 100% B for 5.0 mins; return to 100% A over 2.0 mins; hold
at 100% A for 1.0 mins.
[0165] All LC/MS systems (apart from the Mass Directed Automated
Preparative HPLC system) used a micromass spectrometer, with
electrospray ionisation mode, positive and negative ion switching,
mass range 80-1000 a.m.u.
Thermospray Mass Spectra
[0166] Thermospray Mass Spectra were determined on a HP 5989A
engine mass spectrometer, +ve thermospray, source temperature
250.degree. C., probe temperatures 120.degree. C. (stem),
190.degree. C. (tip), detection mass range 100-850 a.m.u. Compounds
were injected in 10 .mu.l of a mixture of solvents comprising 65%
methanol and 35% 0.05M aqueous ammonium acetate, at a flow rate of
0.7 ml/min.
Normal Phase Analytical HPLC Method
[0167] Normal phase automated analytical high performance liquid
chromatography (normal phase analytical HPLC) was carried out using
a Nucleosil silica 3 .mu.m (150 mm.times.4.6 mm internal diameter)
column eluted with an ethyl acetate:heptane two-step gradient (i)
0% to 40% ethyl acetate over 7 min followed by (ii) 40% to 100%
ethyl acetate over 2.5 min; at a flow rate of 2 ml/min.
Standard Chiral Analytical HPLC System
[0168] This system used a 250.times.4.6 mm Chiralpak AD 10 .mu.m
column, eluting with absolute ethanol:heptane mixtures at a flow
rate of 1 ml per minute, with UV detection at 215 nm.
Standard Chiral Preparative HPLC System
[0169] This system used a Chiralpak AD column (2 cm.times.25 cm),
eluting with absolute ethanol:heptane mixtures (15 ml/min over 25
mins, UV detection at 215 nm).
Solid Phase Extraction (Ion Exchange)
[0170] `SCX` refers to Isolute Flash SCX-2 sulphonic acid solid
phase extraction cartridges.
Organic/Aqueous Phase Separation with Hydrophobic Frits
[0171] `Hydrophobic frit` refers to a Whatman polypropylene filter
tube fitted with a PTFE frit, pore size 5.0 .mu.m.
[0172] All temperatures are in .degree. C.
Intermediates
[0173] Intermediate 1:
[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methylamine
[0174] A mixture of 2-[(3,4-dichlorobenzyl)amino]ethanol (Chem Abs
No. 40172-06-3, 0.980 g) and
2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione (1.10 g) was
heated at 80.degree. C. under nitrogen for 3 h. The resulting solid
mass was treated with concentrated sulphuric acid (1.5 ml) then
stirred at 150.degree. C. for 24 h. The mixture was treated with
water (100 ml) then washed with ethyl acetate (2.times.100 ml). The
dark aqueous phase was basified to .about.pH 12 using 5M aqueous
sodium hydroxide, then extracted with ethyl acetate (2.times.100
ml). The combined organic extracts were washed with water and
brine, dried (Na.sub.2SO.sub.4) and concentrated under vacuum to
give the title compound as a brown oil (1.02 g).
[0175] LC-MS (System A): Rt 1.6 min.
Intermediate 1 (Alternative Procedure):
[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methylamine
[0176] To a stirred solution of Intermediate 42 (2.97 g) in
methanol (15 ml) and water (5 ml) was added potassium carbonate
(5.53 g). The mixture was stirred at 22.degree. C. for 18 h before
the methanol was removed in vacuo. Water (25 ml) was added and the
mixture extracted with ethyl acetate (3.times.30 ml). The combined
organic phases were washed with water (5 ml) and saturated aqueous
sodium chloride solution (10 ml) before drying over sodium
sulphate, filtering and evaporation of the solvent in vacuo to give
a pale yellow oil. The oil was purified by Biotage flash
chromatography on a 90 g silica cartridge eluting with 75:8:1
dichloromethane/ethanol/0.880 ammonia solution. The required
fractions were combined and the solvent evaporated in vacuo to give
the title compound as a colourless oil (1.85 g).
[0177] LC/MS (System A) R.sub.t 1.77 min, Mass Spectrum m/z 275
[MH.sup.+].
Intermediate 1A: [4-(3,4-Dichlorobenzyl)morpholin-2-yl]methylamine
Salt with Para-toluenesulphonic Acid 1:1
[0178] A solution of 2-[(3,4-dichlorobenzyl)amino]ethanol (2.25 g)
and 2-chloroacrylonitrile (1.0 ml) in tetrahydrofuran (3 ml) was
heated at 40.degree. C. for 66 h. The solvent was evaporated in
vacuo to leave a gum. The residue was redissolved in
tetrahydrofuran (20 ml) and cooled to 0-5.degree. C. Potassium
tert-butoxide (1.2 g) was added portionwise to this solution over
10 min and the mixture was stirred at 0-5.degree. C. for a further
45 min. The mixture was diluted with water (20 ml) and ethyl
acetate (20 ml), the phases were separated and the organic phase
was washed with 20% w/w aqueous sodium chloride solution. The
organic phase was dried over sodium sulfate and the solvent was
evaporated in vacuo to leave a gum (2.75 g).
[0179] A portion of this gum (0.22 g) in tetrahydrofuran (1 ml) was
treated dropwise with a 1 M solution of borane.tetrahydrofuran
complex in tetrahydrofuran (2.44 ml) at 15-25.degree. C. The
mixture was stirred at 15-25.degree. C. for 16 h, and methanol (3
ml) was added dropwise. The mixture was stirred for a further 5 h
and the solvent was evaporated in vacuo. The residue was
redissolved in ethyl acetate (4 ml) and p-toluenesulfonic acid
monohydrate (0.123 g) was added. The mixture was heated at
50.degree. C. for 20 min, and the suspension was cooled to
15-25.degree. C. and stirred for 15 min. The mixture was filtered,
washed with ethyl acetate and dried to give the title compound
(0.123 g) as a white solid.
[0180] LC/MS (System A) R.sub.t 1.75 min. Mass spectrum m/z 275/277
[MH.sup.+]
Intermediate 2:
2-[(3,4-Dichlorobenzyl)amino]-2-methylpropan-1-ol
[0181] 3,4-Dichlorobenzyl chloride (3.95 g) was added to
2-amino-2-methylpropan-1-ol (17.8 g) and the mixture was stirred at
60.degree. C. under nitrogen for 2 h. Excess amine was removed by
distillation under vacuum and the residue was partitioned between
saturated aqueous sodium bicarbonate (100 ml) and ethyl acetate
(100 ml). The phases were separated, the organic layer was washed
with water (4.times.100 ml) and brine (100 ml), dried
(Na.sub.2SO.sub.4) and concentrated under vacuum to give the title
compound as a white solid (4.7 g).
[0182] LC-MS (System A): Rt 2.07 min.
Intermediate 3:
1-[4-(3,4-Dichlorobenzyl)-5,5-dimethylmorpholin-2-yl]methanamine
[0183] A mixture of Intermediate 2 (0.260 g) and
2-(oxiran-2-ylmethyl)-1H-isoindole-13(2H)-dione (0.205 g) was
heated at 80.degree. C. under nitrogen for 3 h. The mixture was
treated with concentrated sulphuric acid (0.3 ml) then stirred at
150.degree. C. for 18 h. The mixture was treated with water (25 ml)
then washed with ethyl acetate (2.times.25 ml). The dark aqueous
phase was basified to .about.pH 11 using 5M aqueous sodium
hydroxide then extracted with ethyl acetate (2.times.25 ml). The
combined organic extracts were washed with water and brine, dried
(Na.sub.2SO.sub.4) and concentrated under vacuum to give the title
compound as a brown oil (0.225 g).
[0184] LC-MS (System A): Rt 1.92 min.
Intermediate 4: 2-[(3,4-Dichlorobenzyl)amino]propan-1-ol
[0185] 3,4-Dichlorobenzyl chloride (0.988 g) was added to
2-amino-1-propanol (4.10 g) and the mixture was stirred at
50.degree. C. under nitrogen for 2 h. The mixture was partitioned
between saturated aqueous sodium bicarbonate (100 ml) and ethyl
acetate (100 ml) and the phases were separated. The organic layer
was washed with water (4.times.100 ml) and brine, dried
(Na.sub.2SO.sub.4) then concentrated under vacuum to give the title
compound as a white solid (0.935 g).
[0186] LC-MS (System A): Rt 2.13 min.
Intermediate 5:
1-[(cis)-4-(3,4-Dichlorobenzyl)-5-methylmorpholin-2-yl]methanamine
(2:1 Mixture with Trans Isomer)
[0187] A mixture of Intermediate 4 (0.470 g) and
2-(oxiran-2-ylmethyl)-1H-isoindole-13(2H)-dione (0.410 g) was
heated at 80.degree. C. under nitrogen for 5 h. The mixture was
treated with concentrated sulphuric acid (0.6 ml) then stirred at
150.degree. C. for 42 h. The mixture was treated with water (50 ml)
then washed with ethyl acetate (2.times.50 ml). The dark aqueous
phase was basified to .about.pH 11 using 5M aqueous sodium
hydroxide then extracted with ethyl acetate (2.times.50 ml). The
combined organic extracts were washed with water and brine, dried
(Na.sub.2SO.sub.4) and concentrated under vacuum to give the title
compound as a brown oil (0.42 g).
[0188] LC-MS (System A): Rt 1.74 min.
Intermediate 6: 2-{[3-(3,4-Dichlorophenyl)propyl}amino]ethanol
[0189] 4-(3-Bromopropyl)-1,2-dichlorobenzene (Chem Abs No.
29648-26-8, 1.30 g) was added to ethanolamine (2.8 ml) and the
mixture stirred at 60.degree. C. under nitrogen for 2 h. The
mixture was concentrated under vacuum at 80.degree. C. and the
residue was partitioned between saturated aqueous sodium
bicarbonate (100 ml) and ethyl acetate (100 ml). The phases were
separated, the aqueous layer was re-extracted with ethyl acetate
(100 ml) and the combined organic extracts were washed with water
(2.times.100 ml) and brine then dried (Na.sub.2SO.sub.4). The
solution was concentrated under vacuum to give the title compound
as a pale yellow liquid (1.10 g).
[0190] LC-MS (System A): Rt 2.40 min.
Intermediate 7:
1-{4-[3-(3,4-Dichlorophenyl)propyl]morpholin-2-yl}methanamine
[0191] A mixture of Intermediate 6 (1.05 g) and
2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione (1.10 g) were
heated at 80.degree. C. under nitrogen for 2 h. The mixture was
treated with concentrated sulphuric acid (1.5 ml) then stirred at
150.degree. C. for 18 h. The mixture was treated with water (100
ml) then washed with ethyl acetate (2.times.100 ml). The dark
aqueous phase was basified to .about.pH 11 using 5M aqueous sodium
hydroxide then extracted with ethyl acetate (2.times.100 ml). The
combined organic extracts were washed with water and brine, dried
(Na.sub.2SO.sub.4) and concentrated under vacuum to give the title
compound as a brown oil (0.980 g).
[0192] LC-MS (System A): Rt 2.05 min.
Intermediate 8: 1-[4-(2,3-Dichlorobenzyl)morpholin-2-yl]methanamine
Hydrochloride
[0193] A mixture of chloromethylpolystyrene-divinylbenzene
(Merrifield resin, loaded at 4.0 mmol g.sup.-1) (5.0 g) and sodium
hydrogen carbonate (14.5 g) in dimethylsulphoxide (80 ml) was
heated at 150.degree. C. for 8 h. The solution was allowed to cool,
left to stand for 24 h, then filtered. The solid was washed
successively with water (3.times.100 ml), tetrahydrofuran
(3.times.100 ml) and diethyl ether (3.times.100 ml), then dried in
vacuo to give the formylpolystyrene as a yellow solid which was not
characterised. A portion of this solid (1.0 g) was washed with
tetrahydrofuran (5.times.10 ml) and transferred to a round bottomed
flask. 1-Morpholin-2-ylmethanamine dihydrochloride (0.435 g) was
dissolved in methanol (10 ml) and loaded equally onto two solid
phase extraction columns (Isolute SCX sulphonic acid, 10 g each)
which had been prepared by application of methanol. Elution with
methanol, then 0.880 ammonia:methanol 10:90 gave a clear colourless
oil (0.280 g). This was added in tetrahydrofuran (2.3 ml) to the
round bottomed flask containing formylpolystyrene and the mixture
stirred for 24 h at 20.degree. C. The mixture was then filtered,
and the solid washed with tetrahydrofuran:methanol 1:1 to leave
N-{[4-(polystyrene
resin)phenyl]methylidene}-1-morpholin-2-ylmethanamine as a yellow
solid which was not characterised. Two portions of this solid
(2.times.50 mg) in two thick walled glass vials (Reactivials) were
each treated with N,N-dimethylformamide (1.25 ml),
N,N-diisopropylethylamine (0.097 ml) and
1,2-dichloro-3-(chloromethyl)benzene (0.076 ml), and the mixture
was stirred at 70.degree. C. for 20 h, then allowed to cool. The
mixtures were combined, filtered and washed sequentially with
N,N-dimethylformamide (10.times.10 ml) and tetrahydrofuran
(5.times.10 ml), then treated with tetrahydrofuran: 2M aqueous
hydrochloric acid solution 3:1 (3 ml). After 2 h shaking at
20.degree. C., the mixture was filtered, washed with
tetrahydrofuran (4.times.5 ml) and the filtrate and washings
concentrated in vacuo to give the title compound as white crystals
(0.060 g).
[0194] 1 HNMR (MeOD) 7.85 (1H, dd,aromatic CH), 7.78 (1H,
dd,aromatic CH), 7.53 (1H, t,aromatic CH), 4.72 (2H,AB,CH.sub.2),
4.30-4.23 (2H, m,2.times.CH), 4.05 (1H,br.t, CH), 3.65 (1H,br.d,
CH), 3.58 (1H,br.d, CH), 3.47 (1H, dd, CH), 3.30-3.22 (2H,
m,2.times.CH), 3.08 (1H,br.m, CH).
Intermediate 9:
1-[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methanamine
[0195] Intermediate 1 (racemic mixture, 8 g) was separated into its
single enantiomers by preparative chiral-HPLC. The separation was
carried out using a 2''.times.22 cm Chiralpak AD 20 .mu.m column,
Merck self pack DAC system, eluting with 95:5:0.1 (v/v) heptane:
absolute ethanol: diethylamine (flow rate: 55 ml/min over 40 min,
UV detection 225 nm); sample load preparation: 400 mg sample in 20
ml 3:2 (v/v) absolute ethanol: system eluent.
[0196] The title compound (2.49 g) was obtained with preparative
HPLC retention time 23.0 min.
Intermediate 9A:
1-[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methanamine Salt with
D-Tartaric Acid 1:1
[0197] 35% Hydrazine in water (1.8 ml) was added to a slurry of
Intermediate 41 (5 g) in industrial methylated spirits (75 ml), and
the mixture was heated to reflux. Chloroform (75 ml) was added and
the mixture was heated under reflux for 65 h. The reaction mixture
was cooled to 0-4.degree. C. and allowed to stand for 15 min. The
by-product phthalhydrazide was removed by vacuum filtration and
washed with chloroform (50 ml). The filtrate was washed with water
(50 ml, 25 ml), dried (MgSO.sub.4), and the solvent evaporated in
vacuo to give an oil. This was dissolved in methanol (20 ml), which
was evaporated in vacuo to give an oil. The oil was dissolved in
methanol (100 ml) and D-tartaric acid (1.05 g) was added. The
mixture was heated to and maintained at reflux for 30 min. The
solution was cooled to 45-50.degree. C., then seeded. The slurry
was held at this temperature for 30 min, then cooled to 0-4.degree.
C. and allowed to stand for 30 min. The product was isolated by
filtration to give the title compound as a white solid (2.59
g).
[0198] A sample of the crude D-tartrate salt (500 mg) was dissolved
in water (1.4 ml). Methanol (23 ml) was added to give a slurry
which was heated to reflux to give a solution. The mixture was
stirred at reflux for 30 min, then cooled slowly, seeding at
55.degree. C. The resultant slurry was cooled to 0-4.degree. C. and
allowed to stand 30 min. The product was isolated by filtration to
give the title compound as a white solid (0.355 g).
[0199] ee: 91.6% ee
[0200] LC/MS (System A) R.sub.t 1.75 min. Mass spectrum m/z 275/277
[MH.sup.+]
[0201] Chiral analytical HPLC (Chiralpak AD column, 4.6.times.250
mm, eluent 50:50:0.1 MeOH: EtOH: Butylamine, flow rate 0.5 ml/min,
UV detection at 220 nm), Rt 8.9 min.
Intermediate 9A (Alternative Procedure):
1-[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methanamine Salt with
D-tartaric Acid 1:1
[0202] Intermediate 1 (0.613 g) was dissolved in methanol (12.3
ml). D-Tartaric acid (0.335 g) was added and the slurry was heated
to reflux for 50 min. The mixture was allowed to cool to
0-5.degree. C. and the precipitate isolated by filtration to give
the title compound as a white solid (0.4 g).
[0203] ee: 76% ee
[0204] Chiral analytical HPLC (Chiralpak AD column, 4.6.times.250
mm, eluent 50:50:0.1 MeOH: EtOH: Butylamine, flow rate 0.5 ml/min,
UV detection at 220 nm), Rt 8.9 min.
Intermediate
10:1-[(2R)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methanamine
[0205] Intermediate 10 was prepared in an analogous manner to
Intermediate 9 yielding the title compound (2.24 g) with
preparative HPLC retention time 27.8 min.
Intermediate 10A:
1-[(2R)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methanamine Salt with
L-Tartaric Acid 1:1
[0206] [4-(3,4-Dichlorobenzyl)morpholin-2-yl]methylamine
(Intermediate 1) (0.500 g) was dissolved in methanol (5 ml).
L-Tartaric acid (0.273 g) was added and the mixture was heated to
.about.65.degree. C. to give a milky slurry, and maintained at this
temperature for 1 h. Further methanol (5 ml) was added and the
mixture left to cool slowly to 15-25.degree. C., then cooled
further to 0-4.degree. C. The mixture was stirred for 30 min at
this temperature and the product isolated by filtration to give the
title compound as a white solid (0.38 g).
[0207] ee: 78%
[0208] LC/MS (System A) R.sub.t 1.75 min. Mass spectrum m/z 275/277
[MH.sup.+]
[0209] Chiral analytical HPLC (Chiralpak AD column, 4.6.times.250
mm, eluent 50:50:0.1 MeOH: EtOH: Butylamine, flow rate 0.5 ml/min,
UV detection at 220 nm), Rt 10.5 min.
Intermediate 11: Ethyl
[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]acetate
[0210] A suspension of 4-fluorobenzamide (12.9 g) and ethyl
4-bromo-3-oxopentanoate (Chem Abs No. 36187-69-6; 5.24 g) in
anhydrous toluene (120 ml) was heated at 140.degree. C. for 19 h,
using a Dean-Stark trap. The solution was allowed to cool,
filtered, and the residual solid washed with toluene (30 ml). The
combined filtrate and washings were concentrated in vacuo to give a
brown oil, which was purified by Biotage flash chromatography on
silica gel (90 g column), eluting with ethyl acetate:cyclohexane
(5:95, 7.5:92.5, 10:90), to give the title compound as a yellow
solid (2.98 g).
[0211] LC/MS (System A) Rt 3.26 min. Mass spectrum m/z 264
[MH.sup.+].
Intermediate 12:
[2-(4-Fluorophenyl)-5-methyl-1,3-oxazol-4-yl]acetic Acid
[0212] Intermediate 11 (2.98 g) in ethanol (25 ml) was treated with
aqueous sodium hydroxide (2.5M, 18 ml) and the solution stirred at
70.degree. C. for 3.5 h then allowed to cool. The material was
concentrated in vacuo to remove the ethanol, then the aqueous phase
was washed with ethyl acetate (30 ml). The aqueous phase was
adjusted to pH1 by addition of aqueous hydrochloric acid (5M) and
the desired acid was extracted into ethyl acetate (1.times.100 ml,
1.times.50 ml). The combined organic phases were washed with dilute
aqueous sodium chloride, dried (Na.sub.2SO.sub.4), filtered and the
solution concentrated in vacuo to give the title compound as a
cream solid (2.54 g).
[0213] LC/MS (System A) Rt 2.85 min. Mass Spectrum m/z 236
[MH.sup.+].
Intermediate 13:
1-[4-[(5-Chlorothien-2-yl)methyl]morpholin-2-yl]methanamine
[0214] Intermediate 13 was prepared in an analogous manner to
Intermediate 1 (Alternative procedure) from Intermediate 19 and
2-chloro-5-(chloromethyl)thiophene, followed by a deprotection
reaction yielding the title compound.
Intermediate 14:
1-{(2S)-4-[(5-Chlorothien-2-yl)methyl]morpholin-2-yl}methanamine
[0215] Intermediate 13 was separated into its single enantiomers by
chiral preparative HPLC to give the title compound in an analogous
manner to the separation of Intermediate 1 to yield Intermediate
9.
[0216] LCMS (system A) R.sub.t 25.2 min.
[0217] Chiral Preparative HPLC retention time 25.2 min
Intermediate 14A:
1-{(2R)-4-[(5-Chlorothien-2-yl)methyl]morpholin-2-yl}methanamine
[0218] Intermediate 14A was prepared in an analogous manner to
Intermediate 14 yielding the title compound.
[0219] LCMS (system A) R.sub.t 34 min.
[0220] Chiral Preparative HPLC retention time 34 min.
Intermediate 15:
N-{[(2S)-4-Benzylmorpholin-2-yl]methyl}-2-(5-methyl-2-phenyl-1,3-oxazol-4-
-yl)acetamide
[0221] A mixture of (5-methyl-2-phenyl-oxazol-4-yl)-acetic acid
(0.263 g), 1-hydroxylbenzotriazole (0.163 g), and
N,N-diisopropylethylamine (0.211 ml) in N,N-dimethylformamide (3
ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (0.232 g). The mixture was stirred for 5 min, treated
with 1-[(2S)-4-benzylmorpholin-2-yl]methanamine (prepared in
accordance with EP 0 995 746 A1; 0.192 g), and the solution was
stirred at 22.degree. C. for 18 h. The mixture was partitioned
between dichloromethane (20 ml) and saturated aqueous sodium
hydrogen carbonate (10 ml). The phases were separated in a
hydrophobic frit; the organic phase was loaded onto a solid phase
extraction cartridge (10 g SCX) and eluted with methanol, followed
by 0.880 ammonia:methanol 10:90 to give the title compound as a
colourless gum (0.394 g).
[0222] LC/MS (System A) R.sub.t 2.42 min. Mass spectrum m/z 406
[MH.sup.+].
[0223] Chiral analytical HPLC, eluent 10% EtOH/n-heptane, R.sub.t
18.55 min.
Intermediate 15A:
N-{[(2R)-4-Benzylmorpholin-2-yl]methyl}-2-(5-methyl-2-phenyl-1,3-oxazol-4-
-yl)acetamide
[0224] Prepared in an analogous manner to Intermediate 15 from
1-[(2R)-4-benzylmorpholin-2-yl]methanamine (prepared in accordance
with EP 0 995 746 A1) to obtain the R isomer.
[0225] Chiral analytical HPLC eluent 10% EtOH/n-heptane, R.sub.t
16.296 min.
Intermediate 16:
2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)-N-[(2R)-morpholin-2-ylmethyl]acetam-
ide
[0226] A mixture of Intermediate 15 (0.192 g) and ammonium formate
(0.4 g) in absolute ethanol (2 ml) was treated with 10% palladium
on activated carbon (0.1 g). After 1.5 h the mixture was treated
with ammonium formate (0.6 g) and stirred under nitrogen for a
further 15.5 h.
[0227] The mixture was filtered through celite and the residue
washed with absolute ethanol (20 ml). The solvent was removed at
reduced pressure to leave a gum. The residue was partitioned
between ethyl acetate (20 ml) and 2N sodium hydroxide (20 ml). The
phases were separated and the aqueous phase extracted with ethyl
acetate (10 ml). The combined organic extracts were filtered
through Whatman silicone treated filter paper and the solvent
removed at reduced pressure to give the title compound (0.077 g) as
a colourless gum.
[0228] LC/MS (System A) R.sub.t 2.14 min. Mass spectrum m/z 316
[MH.sup.+].
Intermediate 17:
2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)-N-[(2S)-morpholin-2-yl
methyl]acetamide
[0229] Intermediate 17 was prepared in an analogous manner to
Intermediate 16 from Intermediate 15A yielding the title
compound.
Intermediate 18: {3-[(Methylsulfonyl)amino]phenyl}acetic Acid
[0230] Methanesulphonylchloride (1.70 ml) was added to a stirred
mixture of 3-aminophenylacetic acid (3.2 g) and sodium carbonate
(5.44 g) in water (36 ml), and the mixture was heated at 85.degree.
C. with stirring for 4 h, allowed to cool and acidified with conc.
hydrochloric acid to pH2. After leaving to stand at approximately
4.degree. C. for 18 h, a solid was filtered off, and the residue
washed with water and ether. The aqueous and ether filtrates were
combined and evaporated in vacuo to give a solid, which was
dissolved in hot water; the solution was filtered whilst still hot
and the filtrate left to cool before standing at 4.degree. C. for
18 h. The precipitated solid was filtered, washed with a small
quantity of cold water and dried in vacuo to give the title
compound as a pale yellow solid (0.417 g).
[0231] .sup.1H nmr (400 MHz, d.sub.6 DMSO) 12.35 (1H, br, s, COOH),
9.74 (1H, s, NH), 7.27 (1H, dd, CH), 7.13-7.08 (2H, m, 2.times.CH),
6.99 (1H, br, d, CH), 3.54 (2H, s, CH.sub.2), 2.98 (3H, s
CH.sub.3)
[0232] LCMS (system A) R.sub.t 2.07 min. Mass Spectrum m/z=247
[MNH.sub.4.sup.+]m/z=228 [MH.sup.-].
Intermediate 19:
2,2,2-Trifluoro-N-(morpholin-2-ylmethyl)acetamide
[0233] To a stirred solution of morpholin-2-ylmethylamine (3.1 g)
in methanol (70 ml) under nitrogen was added an ethereal solution
of ethyl-.alpha.,.alpha.,.alpha.-trifluoroacetate (5 ml in 20 ml
ether) which had been washed with saturated aqueous sodium
bicarbonate, water and brine, and dried. The mixture was stirred
for 30 min at 22.degree. C. before removal of all volatiles in
vacuo. The residue was dissolved in methanol (10 ml) and the
volatiles again removed in vacuo to give the title compound as a
white crunchy foam (4.9 g).
[0234] Thermospray Mass Spectrum m/z 213 [MH.sup.+].
Intermediate
20:1-[4-(3,4-Difluorobenzyl)morpholin-2-yl]methanamine
[0235] Intermediate 20 was prepared in an analogous manner to
Intermediate 1 (Alternative Procedure) from Intermediate 19 and
3,4-difluorobenzyl bromide, followed by deprotection to yield the
title compound.
Intermediate 21:
1-[4-(4-Fluorobenzyl)morpholin-2-yl]methanamine
[0236] Intermediate 21 was prepared in an analogous manner to
Intermediate 1 (Alternative Procedure) from Intermediate 19 and
4-fluorobenzyl chloride, followed by deprotection to yield the
title compound.
Intermediate 22:
1-[(2S)-4-(4-Fluorobenzyl)morpholin-2-yl]methanamine
[0237] Intermediate 21 was separated into its single enantiomers by
chiral preparative HPLC to give the title compound in an analogous
manner to the separation of Intermediate 1 to yield Intermediate
9.
[0238] LCMS (system A) R.sub.t 18.43 min.
[0239] Chiral Preparative HPLC Retention time 18.43 min.
Intermediate 23:
1-[(2R)-4-(4-Fluorobenzyl)morpholin-2-yl]methanamine
[0240] Intermediate 23 was prepared in an analogous manner to
Intermediate 22 yielding the title compound.
[0241] LCMS (system A) R.sub.t 26.56 min.
[0242] Chiral Preparative HPLC Retention time 26.56 min.
Intermediate 24:
[(2S)-4-(3-chlorobenzyl)morpholin-2-yl]methylamine
[0243] Intermediate 24 was prepared in an analogous manner to
Intermediate 9. Preparative chiral HPLC retention time 26.1 min
Intermediate 25:
[(2S)-4-(2,3-dichlorobenzyl)morpholin-2-yl]methylamine
[0244] Intermediate 25 was prepared in an analogous manner to
Intermediate 9. Preparative chiral HPLC retention time 25.3 min
Intermediate 26:
[(2S)-4-(3,4-difluorobenzyl)morpholin-2-yl]methylamine
[0245] Intermediate 26 was prepared in an analogous manner to
Intermediate 9. Preparative chiral HPLC retention time 28.3
Intermediate 27:
1-[(cis)-4-(2,5-dichlorobenzyl)-5-methylmorpholin-2-yl]methanamine
(2:1 Mixture with Trans Isomer)
[0246] Intermediate 27 was made in an analogous manner to
Intermediate 5.
[0247] LC-MS (System A): Rt 1.88 mins Mass Spectrum m/z 289
[MH.sup.+]
Intermediate 28:
2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]-N-[(2R)-morpholin-2-ylmet-
hyl]acetamide
[0248] Intermediate 28 was prepared in an analogous manner to
Intermediate 16.
[0249] LC-MS (System A): Rt 2.21 mins Mass Spectrum m/z 334
[MH.sup.+]
Intermediate 29: [4-(3-Fluorobenzyl)morpholin-2-yl]methylamine
[0250] A mixture of Intermediate 19 (0.300 g) and
N,N-diisopropylethylamine (0.372 ml) in N,N-dimethylformamide (5
ml) was treated with 3-fluorobenzyl bromide (0.295 g). The solution
was stirred at 20.degree. C. under nitrogen for 24 h. The mixture
was partitioned between dichloromethane (10 ml) and saturated
aqueous potassium carbonate (10 ml). The phases were separated and
the organic phase applied to an ion exchange cartridge (10 g
Isolute SCX, prewashed with methanol). The SCX cartridge was eluted
with methanol (40 ml) followed by 10% 0.880 ammonia in methanol (40
ml) and the appropriate fractions were concentrated in vacuo. The
residue was dissolved in methanol (2 ml) and treated with aqueous
2N sodium hydroxide (2 ml). The solution was stirred at 20.degree.
C. for 24 h. The mixture was partitioned between dichloromethane
(15 ml) and water (20 ml). The aqueous extract was washed with
dichloromethane (15 ml) and the combined organic extracts
concentrated to give the title compound as a colourless gum (0.150
g).
[0251] Thermospray Mass spectrum m/z 225 [MH.sup.+].
Intermediate 30: tert-Butyl
[(2S)-4-(3,4-dichlorobenzoyl)morpholin-2-yl]-methylcarbamate
[0252] A mixture of 3,4-dichlorobenzoic acid (0.5 g),
1-hydroxybenzotriazole (0.376 g),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.432
g), and N,N-diisopropylethylamine (0.485 ml) in
N,N-dimethylformamide (10 ml) was stirred at 20.degree. C. for 10
min. The mixture was treated with tert-butyl
(2R)-morpholin-2-ylmethylcarbamate (0.500 g, known compound WO
9639407A1) and stirred at 20.degree. C. for 24 h. The mixture was
partitioned between ethyl acetate (75 ml) and 2N aqueous
hydrochloric acid (50 ml). The phases were separated and the
organic extract washed with 2N aqueous hydrochloric acid (50 ml),
saturated aqueous sodium hydrogen carbonate (2.times.50 ml), dried
(MgSO.sub.4) and filtered. The solvent was removed in vacuo to give
the title compound as a yellow oil, (0.774 g).
[0253] LCMS (system A) R.sub.t 3.24 min Mass Spectrum m/z 389
[MH.sup.+].
Intermediate 31:
1-[(2S)-4-(3,4-dichlorobenzoyl)morpholin-2-yl]methanamine
Hydrochloride
[0254] Intermediate 30 (0.770 g) was treated with 4.0M hydrogen
chloride in dioxane (8 ml). The mixture was stirred at 20.degree.
C. for 30 min. The solvent was removed in vacuo to give the title
compound as a white solid (0.592 g).
[0255] LCMS (system A) R.sub.t 2.04 min Mass Spectrum m/z 289
[MH.sup.+]
Intermediate 32: Methyl
4-oxo-3-[(pyridin-3-ylcarbonyl)amino]pentanoate
[0256] Nicotinyl chloride hydrochloride (178 mg) was added to a
stirred suspension of aspartic acid .beta.-methyl ester
hydrochloride (183 mg) in pyridine at 0.degree. C. with stirring
under nitrogen, and the mixture was stirred at 0.degree. C. for 1.5
h and at room temperature for 0.5 h. Acetic anhydride (0.37 ml) was
added, and the mixture was heated at 90.degree. C. for 2 h. Water
(0.6 ml) was added and heating continued for 15 min before the
mixture was partitioned between saturated aqueous sodium
bicarbonate and dichloromethane. The organic layer was evaporated
in vacuo to give a yellow oil (110 mg).
[0257] LC-MS (System A) Rt 1.86 min. Mass Spectrum m/z 251
[MH.sup.+].
Intermediate 33: Methyl
(5-methyl-2-pyridin-3-yl-1,3-oxazol-4-yl)acetate
[0258] Intermediate 32 (1110 mg) was treated with phosphorous
oxychloride (0.51 ml) in toluene (2 ml) and the mixture heated
under reflux for 3.5 h. The mixture was poured into ice cold
saturated aqueous sodium bicarbonate (30 ml) and extracted with
dichloromethane (20 ml). The organic layer was evaporated in vacuo
to give a yellow gum (111 mg).
[0259] LC-MS (System A) Rt 2.30 min. Mass Spectrum m/z 233
[MH.sup.+].
Intermediate 34: (5-Methyl-2-pyridin-3-yl-1,3-oxazol-4-yl)acetic
Acid
[0260] Intermediate 33 (111 mg) was dissolved in tetrahydrofuran (2
ml) and water (0.2 ml) and lithium hydroxide (12 mg) added. The
mixture was stirred at 22.degree. C. for 17 h and heated at
60.degree. C. for 2 h. Ethanol (3 ml) and 2N aqueous sodium
hydroxide (1 ml) were added, and stirring was continued at
22.degree. C. for 2 h. The mixture was applied to a sulphonic acid
ion exchange cartridge (10 g Isolute SCX) and eluted with methanol
followed by 10% triethylamine in methanol. Evaporation of the
triethylamine containing fraction gave the title compound as a gum
(46 mg).
[0261] LC-MS (System A) Rt 2.12 min. Mass Spectrum m/z 219
[MH.sup.+].
Intermediate 35: Ethyl 4-(methylthio)butanoate
[0262] A solution of ethyl 4-bromobutyrate (0.26 g) in
N,N-dimethylformamide (3 ml) was treated with sodium thiomethoxide
(0.103 g), and the mixture stirred at room temperature overnight.
The mixture was partitioned between water (10 ml) and
dichloromethane (10 ml), and the organic layer was washed with 1:1
saturated aqueous sodium chloride and water (10 ml). The organic
layers were evaporated in vacuo to give the title compound as a
clear oil (0.135 g).
[0263] NMR (CDCl.sub.3) 4.06 .delta.(2H, q, CH.sub.2), 2.46
.delta.(2H, t, CH.sub.2), 2.35 .delta.(2H, t, CH.sub.2), 2.03
.delta.(3H, s, CH.sub.3), 1.85 .delta.(2H, m, CH.sub.2), 1.18
.delta.(3H, t, CH.sub.3).
Intermediate 36: Ethyl 4-(methylsulfonyl)butanoate
[0264] A solution of Intermediate 35 (0.126 g) in dry
dichloromethane (5 ml) was treated with m-chloroperoxybenzoic acid
(0.27 g) portion-wise over .about.5 min. The mixture was stirred at
room temperature overnight, treated with saturated aqueous sodium
carbonate solution (10 ml) and stirred for .about.5 min. The
organic layers were separated using a hydrophobic frit and
evaporated in vacuo to give the title compound as a pale yellow oil
(0.133 g).
[0265] NMR (CDCl.sub.3) 4.15 .delta.(2H, q, CH.sub.2), 3.11
.delta.(2H, t, CH.sub.2), 2.93 .delta.(3H, s, CH.sub.3), 2.52
.delta.(2H, t, CH.sub.2), 2.17 .delta.(2H, m, CH.sub.2), 1.28
.delta.(3H, t, CH.sub.3).
Intermediate 37: 4-(Methylsulfonyl)butanoic Acid
[0266] To a solution of Intermediate 36 (0.130 g) in ethanol (2
ml), was added 2N aqueous sodium hydroxide (0.75 ml). The mixture
was stirred at room temperature under nitrogen overnight. The
solution was evaporated in vacuo to remove the ethanol, and applied
to a solid phase extraction cartridge (Isolute SCX sulphonic acid
column, 2 g). The cartridge was eluted with methanol (15 ml) and
the solvent concentrated in vacuo to give the title compound as a
clear oil (0.110 g).
[0267] NMR (MeOD) 3.09 .delta.(2H, m, CH.sub.2), 2.88 .delta.(3H,
s, CH.sub.3), 2.41 .delta.(2H, t, CH.sub.2), 1.98 .delta.(2H, m,
CH.sub.2).
Intermediate 38: Methyl [5-(4-fluorophenyl)-1,
2,4-oxadiazol-3-yl]acetate
[0268] A mixture of 4-fluorobenzamidoxime (1.54 g) and dimethyl
malonate (5.7 ml) was heated under reflux in para-xylene (20 ml)
for 2 h. The mixture was cooled, washed with 1 M aqueous
hydrochloric acid, the organic phase separated and dried
(MgSO.sub.4) and the solvent evaporated in vacuo. The colourless
oily residue was diluted with toluene and the toluene evaporated
three times; the residue was re-dissolved in dichloromethane and
the solvent evaporated under a stream of nitrogen to give the title
compound as colourless crystals (1.59 g).
[0269] Thermospray Mass Spectrum m/z 237 [MH.sup.+], 254
[MNH.sub.4.sup.+]
Intermediate 39: Methyl [3-(aminosulfonyl)phenyl]acetate
[0270] 0.880 Ammonia (0.027 ml) was added to a stirred solution of
methyl [3-(chlorosulfonyl)phenyl]acetate (0.35 g) in a 1:1 mixture
of dichloromethane and acetonitrile (1.75 ml), and the mixture was
stirred at 22.degree. C. for 2 h. The mixture was allowed to stand
for a further 18 h, and the solvent was evaporated in vacuo. The
residue was re-dissolved in dichloromethane and applied to a silica
gel cartridge (10 g Varian Bond Elut, pre-conditioned with
dichloromethane). The cartridge was eluted with dichloromethane,
chloroform, ether, ethyl acetate, acetone, acetonitrile and
methanol (1 column volume each), the fractions containing the
product evaporated in vacuo, and the residue passed down a 5 g
silica gel cartridge which was prepared and eluted in an identical
manner. The product containing fractions were evaporated in vacuo
to give a residue which was further purified using mass-directed
preparative HPLC, to give the title compound as a colourless gum
(0.018 g).
[0271] LCMS (System A) R.sub.t 2.12 min Mass Spectrum m/z 230
[MH.sup.+], 247[MNH.sub.4.sup.+]
Intermediate 40: [3-(Aminosulfonyl)phenyl]acetic Acid Compound with
N,N,N-triethylamine (1:1)
[0272] A portion (0.120 ml) of a solution of sodium hydroxide
(0.123 g) in water (3.05 ml) was added to a stirred solution of
Intermediate 39 (0.018 g) in methanol (2 ml) and water (1 ml), and
stirring was continued at 22.degree. C. for 7 h. The pH of the
mixture was adjusted to approximately 8, and the mixture was
applied to an aminopropyl ion exchange cartridge (2 g Isolute SPE,
pre-conditioned with methanol). Elution with methanol (3 column
volumes) followed by of 10% triethylamine in methanol (2 column
volumes), and evaporation of the basic fractions in vacuo gave the
title compound as a colourless gum (0.022 g).
[0273] LCMS (System A) R.sub.t 1.75 min Mass Spectrum m/z 214
[MH-1,233 [MNH.sub.4.sup.+]
Intermediate 41:
2-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-1H-isoindole-1,
3(2H)-dione
[0274] To a solution of
2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione (2 g) in
tetrahydrofuran (4 ml) was added
2-[(3,4-dichlorobenzyl)amino]ethanol (2.16 g) with stirring, under
a nitrogen atmosphere. The mixture was heated to 66.degree. C. for
22 h, then cooled to 0.degree. C. A further portion of
tetrahydrofuran (10 ml) was added, followed by triphenylphosphine
(2.88 g). Diisopropyl azodicarboxylate (2.2 g) was then added over
10 min. The mixture was stirred at 0.degree. C. for a further 30
min, and at room temperature for 14 h. To the crude solution was
added ethyl acetate (100 ml), then 2M aqueous hydrochloric acid
(250 ml). The resulting white precipitate was isolated by
filtration, and dried in vacuo to give the title compound as its
white crystalline hydrochloride salt (2.01 g). This was partitioned
between 8% aqueous sodium bicarbonate (200 ml) and ethyl acetate
(50 ml). The organic phase was separated, dried over magnesium
sulfate and the solvent evaporated in vacuo to give a solid.
Dichloromethane (20 ml) was added to the residue and the solvent
again evaporated in vacuo to give the title compound as a white
solid (1.1 g).
[0275] LC/MS R.sub.t 2.91 min. Mass Spectrum m/z 405 [MH.sup.+]
Intermediate 42:
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2,2,2-trifluoroacetamide
[0276] To a stirred solution of Intermediate 19 (3.3 g) in
N,N-dimethylformamide (50 ml) under nitrogen was added potassium
carbonate (2.46 g) and sodium iodide (2.12 g). A solution of
3,4-dichlorobenzyl chloride (2 ml) in N,N-dimethylformamide (10 ml)
was added dropwise to the mixture. The mixture was stirred at
22.degree. C. for 18 h before the volatiles were removed in vacuo.
The residue was partitioned between dichloromethane (100 ml) and
saturated aqueous sodium carbonate solution (50 ml). The organic
phase was subsequently washed with additional saturated aqueous
sodium carbonate solution (2.times.50 ml) and water (50 ml) before
drying over magnesium sulphate, filtering and evaporation of the
solvent in vacuo to give a pale yellow oil. The oil was purified by
Biotage flash chromatography on a 90 g silica cartridge eluting
with 25% ethyl acetate in cyclohexane, to give the title compound
as a colourless oil (2.97 g).
[0277] LC/MS (System A) R.sub.t 2.63 min, Mass Spectrum m/z 371
[MH.sup.+].
EXAMPLES
Example 1
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-phenylacetamide
[0278] A mixture of Intermediate 1 (0.028 g) and phenylacetic acid
(0.015 g) was treated with 1-methyl-2-pyrrolidinone (0.015 ml) then
heated in a 600 W microwave oven, at full power, for 4 min. The
crude mixture was purified by chromatography on silica gel (Varian
Bond-Elut, 1 g) eluting with cyclohexane/ethyl acetate (4:1
followed by 2:1) to give the title compound as a colourless gum
(0.029 g).
[0279] LC-MS (System A): Rt 2.63 min, Mass Spectrum m/z 393
[MH.sup.+].
Example 2
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl)phen-
yl]acetamide Salt with Formic Acid (1:1)
[0280] Example 2 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.055 g) and
[4-(methylsulfonyl)phenyl]acetic acid (0.043 g) to give the title
compound (0.03 g).
[0281] LC-MS (System A): Rt 2.32 mins, Mass Spectrum m/z 471
[MH.sup.+].
Example 3
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(3-fluorophenyl)acetami-
de
[0282] Example 3 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.055 g) and
(3-fluorophenyl)acetic acid (0.031 g) to give the title compound
(0.041 g).
[0283] LC-MS (System A): Rt 2.65 mins, Mass Spectrum m/z 411
[MH.sup.+].
Example 4
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-fluorophenyl)acetami-
de
[0284] Example 4 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.055 g) and
(4-fluorophenyl)acetic acid (0.031 g) to give the title compound
(0.019 g).
[0285] LC-MS (System A): Rt 2.72 mins, Mass Spectrum m/z 411
[MH.sup.+].
Example 5
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylthio)phenyl]a-
cetamide
[0286] Example 5 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.055 g) and
4-(methylthio)phenylacetic acid (0.036 g) to give the title
compound (0.028 g).
[0287] LC-MS (System A): Rt 2.77 mins, Mass Spectrum m/z 439
[MH.sup.+].
Example 6
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(3,4-difluorophenyl)ace-
tamide
[0288] Example 6 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.055 g) and
(3,4-difluorophenyl)acetic acid (0.034 g) to give the title
compound (0.0195 g).
[0289] LC-MS (System A): Rt 2.84 mins, Mass Spectrum m/z 429
[MH.sup.+].
Example 7
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(dimethylamino)sulf-
onyl]phenyl}acetamide Salt with Formic Acid (1:1)
[0290] Example 7 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.055 g) and
{4-[(dimethylamino)sulfonyl]phenyl}acetic acid (0.049 g) to give
the title compound (0.031 g).
[0291] LC-MS (System A): Rt 2.46 mins, Mass Spectrum m/z 500
[MH.sup.+].
Example 8
2-(3-Chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetami-
de
[0292] Example 8 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.055 g) and
(3-chlorophenyl)acetic acid (0.034 g) to give the title compound
(0.034 g).
[0293] LC-MS (System A): Rt 2.64 mins, Mass Spectrum m/z 427
[MH.sup.+].
Example 9
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-methylphenyl)acetami-
de
[0294] Example 9 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.055 g) and
(4-methylphenyl)acetic acid (0.03 g) to give the title compound
(0.024 g).
[0295] LC-MS (System A): Rt 2.64 mins, Mass Spectrum m/z 407
[MH.sup.+].
Example 10
4-[2-({[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]benz-
amide
[0296] Example 10 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.055 g) and
[4-(aminocarbonyl)phenyl]acetic acid (0.036 g) to give the title
compound (0.01 g).
[0297] LC-MS (System A): Rt 2.20 mins, Mass Spectrum m/z 436
[MH.sup.+].
Example 11
2-(4-Chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetami-
de
[0298] Example 11 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.028 g) and
(4-chlorophenyl)acetic acid (0.019 g) to give the title compound
(0.033 g).
[0299] LC-MS (System A): Rt 2.86 min, Mass Spectrum m/z 427
[MH.sup.+].
Example 12
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(dimethylamino)pheny-
l]acetamide Salt with Formic Acid (1:1)
[0300] Example 12 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.055 g) and
[4-(dimethylamino)phenyl]acetic acid (0.036 g) to give the title
compound (0.025 g).
[0301] LC-MS (System A): Rt 2.27 mins, Mass Spectrum m/z 436
[MH.sup.+].
Example 13
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,5-dichlorophenyl)ace-
tamide
[0302] Example 13 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.055 g) and
(2,5-dichlorophenyl)acetic acid (0.041 g) to give the title
compound (0.025 g).
[0303] LC-MS (System A): Rt 2.89 mins, Mass Spectrum m/z 463
[MH.sup.+].
Example 14
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(trifluoromethyl)phe-
nyl]acetamide
[0304] Example 14 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.055 g) and
[4-(trifluoromethyl)phenyl]acetic acid (0.041 g) to give the title
compound (0.015 g).
[0305] LC-MS (System A): Rt 3.00 mins, Mass Spectrum m/z 463
[MH.sup.+].
Example 15
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(3,4-dichlorophenyl)ace-
tamide
[0306] Example 15 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.055 g) and
(3,4-dichlorophenyl)acetic acid (0.041 g) to give the title
compound (0.015 g).
[0307] LC-MS (System A): Rt 2.93 mins, Mass Spectrum m/z 461
[MH.sup.+].
Example 16
2-(2-Chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetami-
de
[0308] Example 16 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.055 g) and
(2-chlorophenyl)acetic acid (0.034 g) to give the title compound
(0.025 g).
[0309] LC-MS (System A): Rt 2.67 mins, Mass Spectrum m/z 429
[MH.sup.+].
Example 17
2-[3,5-Bis(trifluoromethyl)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-y-
l]methyl}acetamide
[0310] Example 17 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.055 g) and
[3,5-bis(trifluoromethyl)phenyl]acetic acid (0.054 g) to give the
title compound (0.04 g).
[0311] LC-MS (System A): Rt 3.24 mins, Mass Spectrum m/z 529
[MH.sup.+].
Example 18
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,4-dichlorophenyl)ace-
tamide
[0312] Example 18 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.055 g) and
(2,4-dichlorophenyl)acetic acid (0.041 g) to give the title
compound (0.019 g).
[0313] LC-MS (System A): Rt 2.72 mins, Mass Spectrum m/z 463
[MH.sup.+].
Example 19
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-fluoro-2-methylpheny-
l)acetamide
[0314] Example 19 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.055 g) and
(4-fluoro-2-methylphenyl)acetic acid (0.034 g) to give the title
compound (0.014 g).
[0315] LC-MS (System A): Rt 2.77 mins, Mass Spectrum m/z 425
[MH.sup.+].
Example 20
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,6-dichlorophenyl)ace-
tamide
[0316] Example 20 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.055 g) and
(2,6-dichlorophenyl)acetic acid (0.041 g) to give the title
compound (0.011 g).
[0317] LC-MS (System A): Rt 2.81 mins, Mass Spectrum m/z 463
[MH.sup.+].
Example 21
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-phenoxyacetamide
[0318] Example 21 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.028 g) and phenoxyacetic acid
(0.017 g) to give the title compound (0.026 g).
[0319] LC-MS (System A): Rt 2.74 min, Mass Spectrum m/z 409
[MH.sup.+].
Example 22
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-methoxyphenyl)acetam-
ide
[0320] Example 22 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.028 g) and
(4-methoxyphenyl)acetic acid (0.018 g) to give the title compound
(0.02 g).
[0321] LC-MS (System A): Rt 2.66 min, Mass Spectrum m/z 423
[MH.sup.+].
Example 23
2-(4-Chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)-5,5-dimethylmorpholin-2-yl]m-
ethyl}acetamide
[0322] A mixture of Intermediate 3 (0.030 g) and
4-chlorophenylacetic acid (0.020 g) were treated with
1-methyl-2-pyrrolidinone (0.015 ml) then heated in a 600 W
microwave oven, at full power, for 4 min. The crude mixture was
purified by chromatography on silica gel (Varian Bond-Elut
cartridge, 1 g) eluting with cyclohexane/ethyl acetate (19:1
followed by 1:1) to give a brown solid which was triturated with
ether to give the title compound as an off-white solid (0.018
g).
[0323] LC-MS (System A): Rt 3.21 min, Mass Spectrum m/z 455
[MH.sup.+].
Example 24
N-{[(cis)-4-(3,4-Dichlorobenzyl)-5-methyl
morpholin-2-yl]methyl}-2-phenylacetamide
[0324] A mixture of Intermediate 5 (0.060 g) and phenylacetic acid
(0.027 g) was treated with 1-methyl-2-pyrrolidinone (0.015 ml) then
heated in a 600 W microwave oven, at full power, for 4 min. The
crude mixture was purified by normal phase preparative HPLC to give
the title compound as a colourless gum (27 mg).
[0325] LC-MS (System A): Rt 2.85 min, Mass Spectrum m/z 407
[MH.sup.+].
Example 25
N-{[(trans)-4-(3,4-Dichlorobenzyl)-5-methylmorpholin-2-yl]methyl}-2-phenyl-
acetamide
[0326] Example 25 was prepared in an analogous manner to Example 24
using a mixture of Intermediate 5 (0.06 g) and phenylacetic acid
(0.027 g) to give the title compound as a colourless gum (18
mg).
[0327] LC-MS (System A): Rt 2.85 min, Mass Spectrum m/z 407
[MH.sup.+].
Example 26
2-(4-Chlorophenyl)-N-{[(cis)-4-(3,4-dichlorobenzyl)-5-methylmorpholin-2-yl-
]methyl}acetamide
[0328] Example 26 was prepared in an analogous manner to Example 24
using a mixture of Intermediate 5 (0.06 g) and
(4-chlorophenyl)acetic acid (0.034 g) to give the title compound
(0.027 g).
[0329] LC-MS (System A): Rt 3.10 min, Mass Spectrum m/z 441
[MH.sup.+].
Example 27
2-(4-Chlorophenyl)-N-{[(trans)-4-(3,4-dichlorobenzyl)-5-methylmorpholin-2--
yl]methyl}acetamide
[0330] Example 27 was prepared in an analogous manner to Example 24
using a mixture of Intermediate 5 (0.06 g) and
(4-chlorophenyl)acetic acid (0.034 g) to give the title compound
(0.018 g).
[0331] LC-MS (System A): Rt 3.10 min, Mass Spectrum m/z 441
[MH.sup.+].
Example 28
N-([4-[3-(3,4-Dichlorophenyl)propyl]morpholin-2-yl]methyl)-2-phenylacetami-
de
[0332] A mixture of Intermediate 7 (0.030 g) and phenylacetic acid
(0.015 g) was treated with 1-methyl-2-pyrrolidinone (0.015 ml) then
heated in a 600 W microwave oven, at full power, for 4 min. The
crude mixture was purified by chromatography on silica gel (Varian
Bond-Elut, 1 g) eluting with cyclohexane/ethyl acetate (4:1
followed by 2:1) to give the title compound as a colourless gum
(0.004 g).
[0333] LC-MS (System A): Rt 2.74 min, Mass Spectrum m/z 421
[MH.sup.+].
Example 29
2-(4-Chlorophenyl)-N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}acetami-
de Trifluoroacetate
[0334] Intermediate 8 (0.060 g) was dissolved in methanol (10 ml)
and loaded onto a solid phase extraction column (2 g Isolute SCX
sulphonic acid) which had been prepared by application of methanol.
Elution with methanol, then 0.880 ammonia:methanol 10:90 gave a
clear colourless gum (0.027 g). This was treated with
(4-chlorophenyl)acetic acid (0.017 g) and N-methyl-2-pyrrolidinone
(1 drop) and subjected to microwave irradiation (600 W, full power,
4 min). Purification by automated preparative HPLC (gradient
profile 30-60% (ii) over 20 mins, R.sub.t 13 mins) gave the title
compound (0.018 g) as a white solid.
[0335] LC/MS (System A): R.sub.t 2.87 min, Mass spectrum m/z 429
[MH.sup.+].
Example 30
1-(4-Chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}cyclopr-
opanecarboxamide Trifluoroacetate
[0336] Example 30 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.055 g) and
1-(4-chlorophenyl)cyclopropanecarboxylic acid (0.039 g) to give the
title compound (0.008 g).
[0337] LC-MS (System A): Rt 3.03 mins, Mass Spectrum m/z 455
[MH.sup.+].
Example 31
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(5-methoxy-2-methyl-1H--
indol-3-yl)acetamide
[0338] Example 31 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.056 g) and
(5-methoxy-2-methyl-1H-indol-3-yl)acetic acid (0.044 g) to give the
title compound (0.019 g).
[0339] LC-MS (System A): Rt 2.63 mins, Mass Spectrum m/z 476
[MH.sup.+].
Example 32
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-thien-3-ylacetamide
[0340] Example 32 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.056 g) and thien-3-ylacetic
acid (0.028 g) to give the title compound (0.016 g).
[0341] LC-MS (System A): Rt 2.50 mins, Mass Spectrum m/z 399
[MH.sup.+].
Example 33
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(5-methyl-2-phenyl-1,3--
oxazol-4-yl)acetamide
[0342] Example 33 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.056 g) and
(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetic acid (0.043 g) to give
the title compound (0.036 g).
[0343] LC-MS (System A): Rt 2.80 mins, Mass Spectrum m/z 474
[MH.sup.+].
Example 34
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(5-methyl-1-phenyl-1H-p-
yrazol-4-yl)acetamide
[0344] Example 34 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.056 g) and
(5-methyl-1-phenyl-1H-pyrazol-4-yl)acetic acid (0.043 g) to give
the title compound (0.014 g).
[0345] LC-MS (System A): Rt 2.61 mins, Mass Spectrum m/z 473
[MH.sup.+].
Example 35
2-(4-Bromo-3,5-dimethyl-1H-pyrazol-1-yl)-N-{[4-(3,4-dichlorobenzyl)morphol-
in-2-yl]methyl}acetamide
[0346] Example 35 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.056 g) and
(4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)acetic acid (0.047 g) to give
the title compound (0.032 g).
[0347] LC-MS (System A): Rt 2.70 mins, Mass Spectrum m/z 491
[MH.sup.+].
Example 36
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(2-phenyl-1,3-thiazol-4-
-yl)acetamide
[0348] Example 36 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.056 g) and
(2-phenyl-1,3-thiazol-4-yl)acetic acid (0.042 g) to give the title
compound (0.049 g).
[0349] LC-MS (System A): Rt 2.85 mins, Mass Spectrum m/z 476
[MH.sup.+].
Example 37
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(2-pyrazin-2-yl-1,3-thi-
azol-4-yl)acetamide
[0350] Example 37 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.056 g) and
(2-pyrazin-2-yl-1,3-thiazol-4-yl)acetic acid (0.044 g) to give the
title compound (0.05 g).
[0351] LC-MS (System A): Rt 2.43 mins, Mass Spectrum m/z 478
[MH.sup.+].
[0352] Chiral analytical HPLC, eluent 60% EtOH/n-heptane: Rt 9.22
min and 12.42 min.
Example 38
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(2-furyl)acetamide
[0353] Example 38 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.056 g) and 2-furylacetic acid
(0.025 g) to give the title compound (0.044 g).
[0354] LC-MS (System A): Rt 2.38 mins, Mass Spectrum m/z 383
[MH.sup.+].
Example 39
N-{[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl-
)phenyl]acetamide (Single Enantiomer of Example 2)
[0355] Example 39 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 9 (0.055 g) and
4-(methylsulphonyl)phenylacetic acid (0.050 g) to give the title
compound (0.045 g).
[0356] Chiral analytical HPLC, eluent 35% EtOH/n-heptane, Rt 20.56
min
Example 40
N-{[(2R)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl-
)phenyl]acetamide
[0357] Example 40 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 10 (0.055 g) and
4-(methylsulphonyl)phenylacetic acid (0.050 g) to give the title
compound (0.046 g).
[0358] Chiral analytical HPLC, eluent 35% EtOH/n-heptane, Rt 17.16
min
Example 41
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-[2-(4-fluorophenyl)-5-m-
ethyl-1,3-oxazol-4-yl]acetamide
[0359] Intermediate 12 (0.050 g) was treated with
N,N-dimethylformamide (0.5 ml) followed by 1-hydroxybenzotriazole
hydrate (0.027 g), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (0.044 g) and Intermediate 1 (0.042 g) in
N,N-dimethylformamide (0.5 ml) and N,N-diisopropylethylamine (0.027
ml). The mixture was stirred at 22.degree. C. for 20 h, then left
to stand for 6 days. The solution was diluted with dichloromethane
(10 ml) and washed successively with dilute aqueous sodium hydrogen
carbonate (10 ml) and dilute aqueous sodium chloride (2.times.10
ml). The organic phase was isolated using a hydrophobic frit (6 ml)
and drained directly onto an SCX column (2 g Isolute SPE) which had
been prepared by application of methanol. Elution with methanol,
then 0.880 ammonia:methanol 10:90 gave the title compound (0.048 g)
as an orange glassy solid.
[0360] LC/MS (System A) Rt 2.93 min. Mass spectrum m/z 492
[MH.sup.+].
Example 42
N-{[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(2-pyrazin-2-yl-1,-
3-thiazol-4-yl)acetamide
[0361] Chiral separation from the racemic mixture of Example
37:
[0362] Example 37 was separated into its single enantiomers with a
chiral preparative HPLC system. The separation was carried out
using a Chiralpak AD column (2 cm.times.25 cm), eluting with 60%
ethanol in heptane (15 ml/min over 25 mins, UV detection
.lamda.=215 nm) to give the S isomer.
[0363] Chiral analytical HPLC, eluent 60% EtOH/n-heptane: Rt 12.22
min.
Example 43
N-{[(2R)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(2-pyrazin-2-yl-1,-
3-thiazol-4-yl)acetamide
[0364] Example 43 was prepared in an analogous manner to Example 42
which similarly obtained the R isomer.
[0365] Chiral analytical HPLC, eluent 60% EtOH/n-heptane: Rt 9.20
min.
Example 44
N-{[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(5-phenyl-2H-tetra-
azol-2-yl)acetamide
[0366] A solution of (5-phenyl-2H-tetraazol-2-yl)acetic acid (0.082
g) in N,N-dimethylformamide (2 ml) under nitrogen was treated with
O-(7-azabenzotriazol-1-yl)-N,N,N'N'-tetramethylammonium
hexafluorophosphate (0.152 g) and N,N-diisopropylethylamine (0.139
ml) followed by a solution of Intermediate 9 (0.110 g) in
N,N-dimethylformamide (3 ml), and the mixture was stirred at
22.degree. C. for 4 h. The solvent was removed in vacuo and the
residue dissolved in ethyl acetate (20 ml). The solution was washed
with 10% aqueous citric acid (20 ml), brine (20 ml), saturated
aqueous sodium hydrogen carbonate (20 ml) and brine (20 ml), dried
(MgSO.sub.4) and evaporated in vacuo. Purification by flash
chromatography on silica gel (Merck 9385), eluting with ethyl
acetate, followed by trituration of the resultant product with
diethyl ether, gave the title compound as a white solid (0.184
g).
[0367] LC-MS (System A): Rt 2.85 min. Mass Spectrum m/z 461
[MH.sup.+].
Example 45
N-{[4-(3,4-Difluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)ami-
no]phenyl}acetamide
[0368] Example 45 was prepared in an analogous manner to Example 44
using a mixture of Intermediate 24 (0.014 g) and
{4-[(methylsulfonyl)amino]phenyl}acetic acid (0.013 g) to give the
title compound (0.022 g).
[0369] LC-MS (System A) Rt 2.09 mins. Mass Spectrum m/z 454
[MH.sup.+].
Example 46
N-{[(2S)-4-(4-Fluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)am-
ino]phenyl}acetamide
[0370] Example 46 was prepared in an analogous manner to Example 44
using a mixture of Intermediate 24 (0.09 g) and
4-(methylsulphonylamino)phenylacetic acid (0.1 g) to give the title
compound (0.077 g).
[0371] LC-MS (System A) Rt 2.05 mins. Mass Spectrum m/z 436
[MH.sup.+].
[0372] Chiral analytical HPLC, eluent 15% EtOH/n-heptane: Rt 23.09
min.
Example 47
N-{[(2R)-4-(4-Fluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)am-
ino]phenyl}acetamide
[0373] Example 47 was prepared in an analogous manner to Example 44
using a mixture of Intermediate 24 (0.023 g) and
4-(methylsulphonylamino)phenylacetic acid (0.025 g) to give the
title compound (0.01 g).
[0374] LC-MS (System A) Rt 2.06 mins. Mass Spectrum m/z 436
[MH.sup.+].
[0375] Chiral analytical HPLC, eluent 15% EtOH/n-heptane: Rt 18.78
min.
Example 48
N-{[4-(4-Fluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)amino]p-
henyl}acetamide
[0376] Example 48 was prepared in an analogous manner to Example 44
using a mixture of Intermediate 24 (0.013 g) and
4-(methylsulphonylamino)phenylacetic acid (0.013 g), with the
exception that 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide
hydrochloride and 1-hydroxybenzotriazole were used as the coupling
reagents to give the title compound (0.019 g).
[0377] LC-MS (System A) Rt 2.01 mins Mass Spectrum m/z 436
[MH.sup.+].
[0378] Chiral analytical HPLC, eluent 15% EtOH/n-heptane: Rt 19.40
min and 23.51 min.
Example 49
N-({(2S)-4-[(5-Chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{3-[(methy-
lsulfonyl)amino]phenyl}acetamide
[0379] Example 49 was prepared in an analogous manner to Example 44
using a mixture of Intermediate 14 (0.1 g) and Intermediate 18 (0.1
g) to give the title compound (0.102 g).
[0380] LC-MS (System A) Rt 2.23 mins. Mass Spectrum m/z 458
[MH.sup.+].
[0381] Chiral analytical HPLC, eluent 20% EtOH/n-heptane: Rt 13.18
min.
Example 50
N-({(2R)-4-[(5-Chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{3-[(methy-
lsulfonyl)amino]phenyl}acetamide
[0382] Example 50 was prepared in an analogous manner to Example 44
using a mixture of Intermediate 14A (0.1 g) and Intermediate 18
(0.1 g) to give the title compound (0.085 g).
[0383] LC-MS (System A) Rt 2.27 mins. Mass Spectrum m/z 458
[MH.sup.+].
[0384] Chiral analytical HPLC, eluent 20% EtOH/n-heptane: Rt 10.65
min.
Example 51
N-({4-[(5-Chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{3-[(methylsulf-
onyl)amino]phenyl}acetamide
[0385] Example 51 was prepared in an analogous manner to Example 44
using a mixture of Intermediate 24 (0.007 g) and Intermediate 18
(0.007 g) with the exception that
1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride and
1-hydroxybenzotriazole were used as the coupling reagents to give
the title compound (0.0077 g).
[0386] LC-MS (System A) Rt 2.29 mins. Mass Spectrum m/z 458
[MH.sup.+].
[0387] Chiral analytical HPLC, eluent 20% EtOH/n-heptane: Rt 10.67
min and 13.23 min.
Example 52
N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,6-difluorophenyl)ace-
tamide
[0388] Example 52 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 1 (0.055 g) and
2,6-difluorophenylacetic acid (0.035 g) to give the title compound
(0.057 g).
[0389] LC-MS (System A) Rt 2.70 mins. Mass Spectrum m/z 429
[MH.sup.+].
Example 53
N-Cyclopropyl-3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-
-oxoethyl]benzamide
[0390] A mixture of Example 57 (0.300 g), 1-hydroxybenzotriazole
(0.171 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (0.098 g) was stirred in N,N-dimethylformamide (6.6
ml) and N,N-diisopropylethylamine (0.190 ml) was added. The mixture
was stirred at 20.degree. C. until a clear solution was obtained. A
portion of the mixture (1.1 ml) was transferred into a flask,
cyclopropylamine (0.0077 ml) was added, and the mixture was stirred
at 20.degree. C. under nitrogen for 17 h. Polystyrene
methylisocyanate (Argonaut Technologies, 0.034 g, loading 1.57
mmol/g) and macroporous triethylammonium methylpolystyrene
carbonate (Argonaut Technologies, 0.015 g, loading 3.2 mmol/g) were
added, and stirring was continued for 1 h. The mixture was
filtered, the resin beads washed with methanol and the combined
filtrates reduced in volume to approximately 1 ml and purified by
solid phase extraction (2 g SCX cartridge), eluting with methanol
followed by 10% 0.880 ammonia in methanol. The product was isolated
by evaporation of the solvent from the basic fraction and was
further purified by solid phase extraction (5 g Varian Bondelut
silica gel cartridge), eluting successively with one column volume
of dichloromethane, chloroform, ether, ethylacetate, acetone,
acetonitrile and methanol, to give the title compound as a
colourless gum (0.034 g).
LCMS (system A) R.sub.t 2.65 min. Mass Spectrum m/z 476, 478
[MH.sup.+].
Example 54
N-{[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(5-methyl-2-phenyl-
-1,3-oxazol-4-yl)acetamide
[0391] Intermediate 16 (0.077 g) in anhydrous N,N-dimethylformamide
(2 ml) was treated with N,N-diisopropylethylamine (0.044 ml) and
3,4-dichlorobenzyl chloride (0.035 ml). The mixture was stirred at
22.degree. C. for 19 h, and partitioned between chloroform (15 ml)
and saturated aqueous sodium bicarbonate (15 ml). The phases were
separated using a hydrophobic frit and the organic phase loaded
onto a solid phase extraction column (10 g SCX). Elution with
methanol, then 0.880 ammonia:methanol 10:90 gave a clear colourless
gum. The crude mixture was purified by flash chromatography on
silica gel (Trikonex Flashtube.TM.2008, 8 g), eluting with ethyl
acetate, to give the title compound as a colourless gum (0.0023
g).
[0392] LC/MS (System A) R.sub.t 2.88 min. Mass spectrum m/z 474
[MH.sup.+].
[0393] Chiral analytical HPLC, eluent 10% EtOH/n-heptane, R.sub.t
12.39 min.
Example 54 (Alternative Procedure)
N-{[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(5-methyl-2-phenyl-
-1,3-oxazol-4-yl)acetamide
[0394] Example 54 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 9 (0.055 g) and
2-phenyl-5-methyl-4-oxazolylacetic acid (0.050 g) to give the title
compound (0.046 g).
[0395] LC-MS (System A) Rt 2.88 mins. Mass Spectrum m/z 474
[MH.sup.+].
Example 55
N-{[(2R)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(5-methyl-2-phenyl-
-1,3-oxazol-4-yl)acetamide
[0396] Example 55 was prepared in an analogous manner to that
described in Example 54 using Intermediate 17 (0.081 g) and
3,4-dichlorobenzyl chloride (0.037 ml) to give a colourless gum
(0.011 g).
[0397] LC/MS (System A) R.sub.t 2.87 min. Mass spectrum m/z 474
[MH.sup.+].
[0398] Chiral analytical HPLC, eluent 10% EtOH/n-heptane, R.sub.t
9.812 min.
Example 55 (Alternative Procedure)
N-{[(2R)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(5-methyl-2-phenyl-
-1,3-oxazol-4-yl)acetamide
[0399] Example 55 was prepared in an analogous manner to Example 1
using a mixture of Intermediate 10 (0.055 g) and
2-phenyl-5-methyl-4-oxazolylacetic acid (0.050 g) to give the title
compound (0.042 g).
[0400] LC-MS (System A) Rt 2.88 mins. Mass Spectrum m/z 474
[MH.sup.+].
[0401] A mixture of Examples 54 and 55: Chiral analytical HPLC,
eluent 10% EtOH/n-heptane, R.sub.t 9.73 and 12.42 min.
Example 56
Methyl
3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoeth-
yl]benzoate
[0402] A mixture of [3-(methoxycarbonyl)phenyl]acetic acid (0.200
g), Intermediate 1 (0.284 g), 1-hydroxybenzotriazole (0.182 g) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.316
g) was stirred in dichloromethane (10 ml), and
N,N-diisopropylethylamine (0.352 ml) was added to the solution.
Stirring at 20.degree. C. under nitrogen was continued for 8 h. The
mixture was purified by solid phase extraction (2.times.10 g Varian
Bondelut silica gel cartridges), eluting successively with one
column volume of dichloromethane, chloroform, ether, ethyl acetate,
acetone, acetonitrile and methanol, to give the title compound as a
colourless gum, (0.266 g).
[0403] LCMS (system A) R.sub.t 2.70 min. Mass Spectrum m/z=451, 453
[MH.sup.+].
Example 57
3-[2-({[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]benz-
oic Acid Compound with N,N,N-triethylamine (1:1)
[0404] To a solution of Example 56 (0.261 g) in a mixture of water
(4 ml) and methanol (12 ml) was added a solution of sodium
hydroxide (0.054 g) in water (0.5 ml) and the mixture was stirred
at 20.degree. C. for 72 h. The pH of the mixture was adjusted to
approximately 6 by the addition of 2N hydrochloric acid and the
mixture was purified by solid phase extraction (10 g SCX
cartridge), eluting with methanol followed by 10% triethylamine in
methanol. Evaporation of the basic fraction in vacuo gave the title
compound as a colourless gum, (0.319 g).
[0405] LCMS (system A) R.sub.t 2.66 min. Mass Spectrum m/z 437, 439
[MH.sup.+].
Examples 58-85
TABLE-US-00001 [0406] Preparation Name analogous to Characterising
Data 58 2-[3-(acetylamino)phenyl]-N-{[4- Example 1 LC-MS (System
A): (3,4-dichlorobenzyl)morpholin-2- Rt 2.33 mins.
yl]methyl}acetamide Mass Spectrum m/z 450 [MH.sup.+]. 59
2-(3-acetyl-1-benzothien-4-yl)-N- Example 1 LC-MS (System A):
{[4-(3,4-dichlorobenzyl)morpholin-2- Rt 2.90 mins.
yl]methyl}acetamide trifluoroacetate Mass Spectrum m/z 491
[MH.sup.+]. 60 2-(5-bromopyridin-3-yl)-N-{[4-(3,4- Example 1 LC-MS
(System A): dichlorobenzyl)morpholin-2- Rt 2.57 mins.
yl]methyl}acetamide compound with Mass Spectrum m/z formic acid
(1:1) 474 [MH.sup.+]. 61 N-{[4-(3,4- Example 1 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.51 mins. yl]methyl}-2-(2,3- Mass
Spectrum m/z dimethylquinoxalin-6-yl)acetamide 473 [MH.sup.+]. 62
2-(4-acetylphenyl)-N-{[4-(3,4- Example 1 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.57 mins. yl]methyl}acetamide
trifluoroacetate Mass Spectrum m/z 435 [MH.sup.+]. 63
2-(4-acetylphenyl)-N-{[4-(3,4- Example 41 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.57 mins. yl]methyl}acetamide Mass
Spectrum m/z 435 [MH.sup.+]. 64 N-{[4-(3,4- Example 1 LC-MS (System
A): dichlorobenzyl)morpholin-2- Rt 2.84 mins. yl]methyl}-2-(4- Mass
Spectrum m/z isobutyrylphenyl)acetamide 463 [MH.sup.+].
trifluoroacetate 65 methyl 4-[2-({[4-(3,4- Example 1 LC-MS (System
A): dichlorobenzyl)morpholin-2- Rt 2.65 mins. yl]methyl}amino)-2-
Mass Spectrum m/z oxoethyl]benzoate trifluoroacetate 451
[MH.sup.+]. 66 methyl 4-[2-({[4-(3,4- Example 56 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.73 mins. yl]methyl}amino)-2- Mass
Spectrum m/z oxoethyl]benzoate 451 [MH.sup.+]. 67
2-(4-cyanophenyl)-N-{[4-(3,4- Example 1 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.60 mins. yl]methyl}acetamide
trifluoroacetate Mass Spectrum m/z 418 [MH.sup.+]. 68
2-(4-cyanophenyl)-N-{[4-(3,4- Example 41 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.63 mins. yl]methyl}acetamide Mass
Spectrum m/z 418 [MH.sup.+]. 69 N-{[(2S,5R)-4-(3,4-dichlorobenzyl)-
Example 24 LC-MS (System A): 5-methylmorpholin-2-yl]methyl}-2- from
(2R)-2- Rt 2.88 mins. phenylacetamide aminopropan- Mass Spectrum
m/z 1-ol 407 [MH.sup.+]. 70 2-(4-chlorophenyl)-N-{[(2S,5R)-4-
Example 24 LC-MS (System A): (3,4-dichlorobenzyl)-5- Rt 3.13 mins.
methylmorpholin-2- Mass Spectrum m/z yl]methyl}acetamide 441
[MH.sup.+]. 71 N-{[4-(3,4- Example 1 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.66 mins. yl]methyl}-2-(3-fluoro-4-
Mass Spectrum m/z hydroxyphenyl)acetamide 427 [MH.sup.+].
trifluoroacetate 72 N-{[(2S)-4-(3,4- Example 42 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.38 mins.
yl]methyl}-2-(2-furyl)acetamide Mass Spectrum m/z 383 [MH.sup.+].
Chiral Analytical HPLC Eluent 20% EtOH/heptane Rt 9.97 mins. 73
N-{[4-(3,4- Example 53 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.25 mins.
yl]methyl}-2-{4-[(4-methylpiperazin- Mass Spectrum m/z
1-yl)carbonyl]phenyl}acetamide 519 [MH.sup.+]. 74 4-[2-({[4-(3,4-
Example 53 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.13
mins. yl]methyl}amino)-2-oxoethyl]-N-[2- Mass Spectrum m/z
(dimethylamino)ethyl]benzamide 507 [MH.sup.+]. 75 4-[2-({[4-(3,4-
Example 53 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.53
mins. yl]methyl}amino)-2-oxoethyl]-N,N- Mass Spectrum m/z
dimethylbenzamide 464 [MH.sup.+]. 76 4-[2-({[4-(3,4- Example 53
LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.57 mins.
yl]methyl}amino)-2-oxoethyl]-N- Mass Spectrum m/z ethylbenzamide
464 [MH.sup.+]. 77 4-[2-({[4-(3,4- Example 53 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.28 mins.
yl]methyl}amino)-2-oxoethyl]-N-(2- Mass Spectrum m/z
hydroxyethyl)benzamide 480 [MH.sup.+]. 78 N-{[4-(3,4- Example 53
LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.45 mins.
yl]methyl}-2-[4-(morpholin-4- Mass Spectrum m/z
ylcarbonyl)phenyl]acetamide 506 [MH.sup.+]. 79 N-{[(2S)-4-(3,4-
Example LC-MS (System A): dichlorobenzyl)morpholin-2- 162 Rt 2.66
mins. yl]methyl}-2-{3- Mass Spectrum m/z
[(dimethylamino)sulfonyl]phenyl}acetamide 500 [MH.sup.+]. 80
N-{[(2R)-4-(3,4- Example 42 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.81 mins. yl]methyl}-2-{4- Mass
Spectrum m/z [(dimethylamino)sulfonyl]phenyl}acetamide 500
[MH.sup.+]. Chiral Analytical HPLC Eluent 40% EtOH/heptane Rt 13.10
min. 81 N-{[(2S)-4-(3,4- Example LC-MS (System A):
dichlorobenzyl)morpholin-2- 162 Rt mins 2.62. yl]methyl}-2-{4- Mass
Spectrum m/z [(dimethylamino)sulfonyl]phenyl}acetamide 500
[MH.sup.+]. 82 4-[2-({[4-(3,4- Example 53 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.49 mins.
yl]methyl}amino)-2-oxoethyl]-N- Mass Spectrum m/z methylbenzamide
450 [MH.sup.+]. 83 4-[2-({[4-(3,4- Example 53 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.69 mins.
yl]methyl}amino)-2-oxoethyl]-N- Mass Spectrum m/z
isopropylbenzamide 478 [MH.sup.+]. 84 N-cyclopropyl-4-[2-({[4-(3,4-
Example 53 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.61
mins. yl]methyl}amino)-2- Mass Spectrum m/z oxoethyl]benzamide 476
[MH.sup.+]. 85 4-[2-({[4-(3,4- Example 53 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.57 mins.
yl]methyl}amino)-2-oxoethyl]-N-(2- Mass Spectrum m/z
methoxyethyl)benzamide 494 [MH.sup.+].
Example 86
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(5-phenyl-2H-tetraazol--
2-yl)acetamide
[0407] 2-(3,5-Dimethoxy-4-formylphenoxy)ethoxymethyl polystyrene
resin (Novabiochem, loading 0.9 mmol/g, 1 g) was swollen with the
minimum quantity of 1% acetic acid/N,N-dimethylformamide to form a
slurry. Intermediate 1 (0.969 g) was added to this mixture in
N,N-dimethylformamide (2 ml) and the mixture shaken at room
temperature for 100 min. 1% Acetic acid/N,N-dimethylformamide (10
ml) was added followed by sodium triacetoxyborohydride (333 mg).
The mixture was then shaken for 20 min before further sodium
triacetoxyborohydride (0.300 g) was added, and shaking was
continued at room temperature for 18 h. The reaction solution was
then drained off and the resin washed with (N,N-dimethylformamide:
5.times.10 ml, methanol: 5.times.10 ml, dichloromethane: 5.times.10
ml, diethyl ether: 3.times.10 ml). The resin was then dried in
vacuo.
[0408] The resin (0.100 g) was then swollen with dichloromethane,
and excess solvent drained off. A solution of
diisopropylcarbodiimide (0.0705 ml) and bromo acetic acid (0.125 g)
in 1:1 dichloromethane/dimethyl formamide (1 ml), was made and
stirred for ca. 5 min, before adding to the resin. The resin was
then shaken at room temperature for 2 h. The solution was drained
off and the resin washed with (N,N-dimethylformamide: 5.times.10
ml, methanol: 5.times.10 ml, dichloromethane: 5.times.10 ml).
[0409] A solution of potassium tert-butoxide (0.050 g) and the
azole 5-phenyl-1-H-tetrazole (0.131 g) in N,N-dimethylformamide (1
ml) was prepared and stirred for 5 min before this was added to the
resin. The reaction mixture was heated to 60.degree. C. and shaken
for 18 h. The reaction solution was then drained off and the resin
washed with (N,N-dimethylformamide: 5.times.1 ml, methanol:
5.times.1 ml, dichloromethane: 5.times.1 ml).
[0410] 1:1 trifluoroacetic acid/dichloromethane solution (1 ml) was
then added to the resin, and the mixture shaken for 90 min. The
resin was filtered off, washed with dichloromethane (1 ml), and the
combined filtrate and washings evaporated. The resulting solid was
purified by mass directed preparative HPLC to give the title
compound (15 mg).
[0411] LC-MS (System A) R.sub.t 2.77 min. Mass Spectrum m/z 461
[MH.sup.+].
Examples 87-90
TABLE-US-00002 [0412] Preparation Name analogous to Characterising
Data 87 2-(4-bromo-1H-imidazol-1-yl)- Example 86 LC-MS (System A):
N-{[4-(3,4- Rt 2.34 mins. dichlorobenzyl)morpholin-2- Mass Spectrum
m/z yl]methyl}acetamide 462 [MH.sup.+]. 88 N-{[4-(3,4- Example 56
LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.92 mins.
yl]methyl}-2-(4- Mass Spectrum m/z nitrophenyl)acetamide 438
[MH.sup.+]. 89 N-{[4-(3,4- Example 56 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt mins 2.92. yl]methyl}-2-(3- Mass
Spectrum m/z nitrophenyl)acetamide 438 [MH.sup.+]. 90
2-[3-(acetylamino)phenyl]- Example 91 LC-MS (System A): N-{[4-(3-
Rt 2.13 mins. fluorobenzyl)morpholin-2- Mass Spectrum m/z
yl]methyl}acetamide 400 [MH.sup.+].
Example 91
N-{[4-(3-fluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)amino]p-
henyl}acetamide
[0413] A mixture of Intermediate 29 (0.0134 g),
{4-[(methylsulfonyl)amino]phenyl}acetic acid (0.0137 g, known
compound WO 9929655 A1), 1-hydroxybenzotriazole (0.0097 g) and
N,N-diisopropylethylamine (0.01 ml) in N,N-dimethylformamide (0.5
ml) was treated with a solution of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(0.00138 g) in N,N-dimethylformamide (0.5 ml). The mixture was
stirred at 20.degree. C. for 24 h. The mixture was partitioned
between dichloromethane (4 ml) and saturated aqueous sodium
hydrogen carbonate (4 ml). The phases were separated and the
organic phase applied to an ion exchange cartridge (2 g Isolute
SCX, prewashed with methanol). The SCX cartridge was eluted with
methanol (10 ml) followed by 10% 0.880 ammonia in methanol (10 ml)
and the appropriate fractions were concentrated in vacuo to give
the title compound as a colourless gum (0.0174 g).
LCMS (system A) R.sub.t 2.14 min. Mass Spectrum m/z 436
[MH.sup.+].
Examples 92-134
TABLE-US-00003 [0414] Preparation Name analogous to Characterising
Data 92 2-[3-(acetylamino)phenyl]-N-{[4- Example 91 LC-MS (System
A): (3,4-difluorobenzyl)morpholin-2- Rt 2.31 mins.
yl]methyl}acetamide Mass Spectrum m/z 418 [MH.sup.+]. 93
2-[4-(acetylamino)phenyl]-N-{[4- Example 91 LC-MS (System A):
(3,4-difluorobenzyl)morpholin-2- Rt 2.10 mins. yl]methyl}acetamide
Mass Spectrum m/z 418 [MH.sup.+]. 94 N-{[4-(3,4- Example 91 LC-MS
(System A): difluorobenzyl)morpholin-2- Rt 2.09 mins.
yl]methyl}-2-(2-pyrazin-2-yl-1,3- Mass Spectrum m/z
thiazol-4-yl)acetamide 554 [MH.sup.+]. 95 N-{[4-(3,4- Example 91
LC-MS (System A): difluorobenzyl)morpholin-2- Rt 2.13 mins.
yl]methyl}-2-{3- Mass Spectrum m/z
[(methylsulfonyl)amino]phenyl}acetamide 446 [MH.sup.+]. 96
N-{[4-(3,4- Example 91 LC-MS (System A):
difluorobenzyl)morpholin-2- Rt 2.04 mins. yl]methyl}-2-[3- Mass
Spectrum m/z (methylsulfonyl)phenyl]acetamide 439 [MH.sup.+]. 97
N-{[4-(3-chlorobenzyl)morpholin-2- Example 91 LC-MS (System A):
yl]methyl}-2-[4- Rt 2.09 mins. (methylsulfonyl)phenyl]acetamide
Mass Spectrum m/z 437 [MH.sup.+]. 98
N-{[4-(3-chlorobenzyl)morpholin-2- Example 91 LC-MS (System A):
yl]methyl}-2-[3- Rt 2.11 mins. (methylsulfonyl)phenyl]acetamide
Mass Spectrum m/z 437 [MH.sup.+]. 99
2-[3-(acetylamino)phenyl]-N-{[4-(4- Example 91 LC-MS (System A):
fluorobenzyl)morpholin-2- Rt 1.95 mins. yl]methyl}acetamide Mass
Spectrum m/z 400 [MH.sup.+]. 100
2-[4-(acetylamino)phenyl]-N-{[4-(4- Example 91 LC-MS (System A):
fluorobenzyl)morpholin-2- Rt 1.91 mins. yl]methyl}acetamide Mass
Spectrum m/z 400 [MH.sup.+]. 101 N-{[4-(4-fluorobenzyl)morpholin-2-
Example 91 LC-MS (System A): yl]methyl}-2-(2-pyrazin-2-yl-1,3- Rt
2.10 mins. thiazol-4-yl)acetamide Mass Spectrum m/z 428 [MH.sup.+].
102 N-{[4-(2,3- Example 91 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.36 mins. yl]methyl}-2-[4- Mass
Spectrum m/z (methylsulfonyl)phenyl]acetamide 471 [MH.sup.+]. 103
2-[3-(acetylamino)phenyl]-N-{[4- Example 91 LC-MS (System A):
(2,3-dichlorobenzyl)morpholin-2- Rt 2.30 mins. yl]methyl}acetamide
Mass Spectrum m/z 450 [MH.sup.+]. 104 N-{[4-(2,3- Example 91 LC-MS
(System A): dichlorobenzyl)morpholin-2- Rt 2.37 mins.
yl]methyl}-2-{4- Mass Spectrum m/z
[(methylsulfonyl)amino]phenyl}acetamide 486 [MH.sup.+]. 105
N-{[4-(2,3- Example 91 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.24 mins. yl]methyl}-2-(4- Mass
Spectrum m/z {[(methylamino)carbonyl]amino}phenyl)acetamide 465
[MH.sup.+]. 106 N-{[4-(2,3- Example 91 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.44 mins.
yl]methyl}-2-(2-pyrazin-2-yl-1,3- Mass Spectrum m/z
thiazol-4-yl)acetamide 478 [MH.sup.+]. 107 N-({4-[(5-chlorothien-2-
Example 91 LC-MS (System A): yl)methyl]morpholin-2-yl}methyl)-2- Rt
2.16 mins. [4- Mass Spectrum m/z (methylsulfonyl)phenyl]acetamide
443 [MH.sup.+]. 108 2-[3-(acetylamino)phenyl]-N-({4- Example 91
LC-MS (System A): [(5-chlorothien-2- Rt 2.13 mins.
yl)methyl]morpholin-2- Mass Spectrum m/z yl}methyl)acetamide 422
[MH.sup.+]. 109 N-({4-[(5-chlorothien-2- Example 91 LC-MS (System
A): yl)methyl]morpholin-2-yl}methyl)-2- Rt 2.18 mins.
{4-[(methylsulfonyl)amino]phenyl}acetamide Mass Spectrum m/z 458
[MH.sup.+]. 110 N-({4-[(5-chlorothien-2- Example 91 LC-MS (System
A): yl)methyl]morpholin-2-yl}methyl)-2- Rt 2.26 mins.
(2-pyrazin-2-yl-1,3-thiazol-4- Mass Spectrum m/z yl)acetamide 450
[MH.sup.+]. 111 2-[3-(acetylamino)phenyl]-N-{[4-(3- Example 91
LC-MS (System A): chlorobenzyl)morpholin-2- Rt 2.37 mins.
yl]methyl}acetamide Mass Spectrum m/z 416 [MH.sup.+]. 112
N-{[4-(3-chlorobenzyl)morpholin-2- Example 91 LC-MS (System A):
yl]methyl}-2-{4- Rt 2.37 mins.
[(methylsulfonyl)amino]phenyl}acetamide Mass Spectrum m/z 452
[MH.sup.+]. 113 2-[4-(acetylamino)phenyl]-N-{[4-(3- Example 91
LC-MS (System A): chlorobenzyl)morpholin-2- Rt 2.31 mins.
yl]methyl}acetamide Mass Spectrum m/z 416 [MH.sup.+]. 114
N-{[4-(3-chlorobenzyl)morpholin-2- Example 91 LC-MS (System A):
yl]methyl}-2-(4- Rt 2.31 mins.
{[(methylamino)carbonyl]amino}phenyl)acetamide Mass Spectrum m/z
431 [MH.sup.+]. 115 N-{[4-(3-chlorobenzyl)morpholin-2- Example 91
LC-MS (System A): yl]methyl}-2-(2-pyrazin-2-yl-1,3- Rt 2.46 mins.
thiazol-4-yl)acetamide Mass Spectrum m/z 444 [MH.sup.+]. 116
2-[4-(acetylamino)phenyl]-N-{[4- Example 91 LC-MS (System A):
(2,3-dichlorobenzyl)morpholin-2- Rt 2.51 mins. yl]methyl}acetamide
Mass Spectrum m/z 450 [MH.sup.+]. 117 N-{[4-(2,3- Example 91 LC-MS
(System A): dichlorobenzyl)morpholin-2- Rt 2.43 mins.
yl]methyl}-2-[3- Mass Spectrum m/z (methylsulfonyl)phenyl]acetamide
471 [MH.sup.+]. 118 2-[4-(aminosulfonyl)phenyl]-N-{[4- Example 41
LC-MS (System A): (3,4-dichlorobenzyl)morpholin-2- Rt 2.37 mins.
yl]methyl}acetamide Mass Spectrum m/z 472 [MH.sup.+]. 119
2-[2-(acetylamino)phenyl]-N-{[4- Example 41 LC-MS (System A):
(3,4-dichlorobenzyl)morpholin-2- Rt 2.44 mins. yl]methyl}acetamide
Mass Spectrum m/z 450 [MH.sup.+]. 120 2-(3-cyanophenyl)-N-{[4-(3,4-
Example 41 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.64
mins. yl]methyl}acetamide Mass Spectrum m/z 418 [MH.sup.+]. 121
N-{[(2S,5R)-4-(2,5-dichlorobenzyl)- Example 24 LC-MS (System A):
5-methylmorpholin-2-yl]methyl}-2- Rt 2.73 mins. phenylacetamide
Mass Spectrum m/z 407 [MH.sup.+]. 122
2-(4-chlorophenyl)-N-{[(2S,5R)-4- Example 24 LC-MS (System A):
(2,5-dichlorobenzyl)-5- Rt 3.02 mins. methylmorpholin-2- Mass
Spectrum m/z yl]methyl}acetamide 441 [MH.sup.+]. 123 N-{[4-(3,4-
Example 1 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.67
mins. yl]methyl}-2-(2- Mass Spectrum m/z fluorophenyl)acetamide 411
[MH.sup.+]. 124 N-{[4-(3,4- Example 1 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.75 mins. yl]methyl}-2-(2,3- Mass
Spectrum m/z difluorophenyl)acetamide 429 [MH.sup.+]. 125
N-{[4-(3,4- Example 1 LC-MS (System A): dichlorobenzyl)morpholin-2-
Rt 2.74 mins. yl]methyl}-2-(2,4- Mass Spectrum m/z
difluorophenyl)acetamide 429 [MH.sup.+]. 126 N-{[4-(3,4- Example 1
LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.73 mins.
yl]methyl}-2-(2,5- Mass Spectrum m/z difluorophenyl)acetamide 429
[MH.sup.+]. 127 3-[2-({[4-(3,4- Example 53 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt mins 2.57.
yl]methyl}amino)-2-oxoethyl]-N-(2- Mass Spectrum m/z
methoxyethyl)benzamide 494 [MH.sup.+]. 128 3-[2-({[4-(3,4- Example
53 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt mins 2.65.
yl]methyl}amino)-2-oxoethyl]-N- Mass Spectrum m/z ethylbenzamide
464 [MH.sup.+]. 129 3-[2-({[4-(3,4- Example 53 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.61 mins.
yl]methyl}amino)-2-oxoethyl]-N,N- Mass Spectrum m/z
dimethylbenzamide 464 [MH.sup.+]. 130 3-[2-({[4-(3,4- Example 53
LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.27 mins.
yl]methyl}amino)-2-oxoethyl]-N-[2- Mass Spectrum m/z
(dimethylamino)ethyl]benzamide 507 [MH.sup.+]. 131 N-{[4-(3,4-
Example 53 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.25
mins. yl]methyl}-2-{3-[(4-methylpiperazin- Mass Spectrum m/z
1-yl)carbonyl]phenyl}acetamide 519 [MH.sup.+]. 132
2-(3-aminophenyl)-N-{[4-(3,4- Example 56 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.26 mins. yl]methyl}acetamide Mass
Spectrum m/z 408 [MH.sup.+]. 133 2-(4-aminophenyl)-N-{[4-(3,4-
Example 56 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.29
mins. yl]methyl}acetamide Mass Spectrum m/z 408 [MH.sup.+]. 134
N-{[(2S)-4-(3,4- Example 54 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.90 mins.
yl]methyl}-2-(5-methyl-2-phenyl- Mass Spectrum m/z
1,3-oxazol-4-yl)acetamide 474 [MH.sup.+]. hydrochloride
Example 135
N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(5-methyl-2-phenyl-
-1,3-oxazol-4-yl)acetamide Fumarate Salt
[0415] Example 54 (1 g) was dissolved in acetonitrile (10 ml) and
methanol (3 ml). Fumaric acid (0.245 g) was added forming a slurry.
The slurry was heated to and held at reflux for 1 h, during which
time the reaction mixture became a solution. After 1 h heating, the
solution was allowed to cool slowly to 23.degree. C. Product was
filtered off and washed with acetonitrile (2.times.5 ml), then
dried in a vacuum oven at 50.degree. C. for 16 h, to give the title
compound as a white solid (0.35 g).
[0416] .sup.1H nmr (400 MHz, d.sub.6 DMSO) 13 .delta.(2H, v.br.s,
fumaric acid COOH), 8.03 .delta.(1H, br.t, NH), 7.92-7.87
.delta.(2H, m, aromatic CH's), 7.56 .delta.(1H, d, aromatic CH),
7.52-7.46 .delta.(4H, m, aromatic CH's), 7.27 .delta.(1H, dd,
aromatic CH), 6.62 .delta.(2H, s, fumaric acid CH), 3.78
.delta.(1H, ddd, CH), 3.53-3.44 .delta.(2H, m, 2.times.CH), 3.43
.delta.(2H, s, CH.sub.2), 3.35 .delta.(2H, s, CH.sub.2), 3.12
.delta.(2H, br.t, CH.sub.2), 2.68 .delta.(1H, br. dd, CH), 2.56
.delta.(1H, dddd, CH), 2.31 .delta.(3H, s, CH.sub.3), 2.05
.delta.(TH, ddd, CH), 1.82 .delta.(TH, dd, CH).
Examples 136-138
TABLE-US-00004 [0417] Preparation analogous Name to Characterising
Data 136 2-[4-(acetylamino)phenyl]-N- Example LC-MS (System A):
{[4-(3,4- 139 Rt mins 2.49. dichlorobenzyl)morpholin-2- Mass
Spectrum m/z yl]methyl}acetamide 450 [MH.sup.+]. 137
N-{4-[2-({[4-(3,4- Example LC-MS (System A):
dichlorobenzyl)morpholin-2- 139 Rt 2.77 mins. yl]methyl}amino)-2-
Mass Spectrum m/z oxoethyl]phenyl}-2- 478 [MH.sup.+].
methylpropanamide 138 N-{3-[2-({[4-(3,4- Example LC-MS (System A):
dichlorobenzyl)morpholin-2- 139 Rt 2.77 mins. yl]methyl}amino)-2-
Mass Spectrum m/z oxoethyl]phenyl}-2- 478 [MH.sup.+].
methylpropanamide
Example 139
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(methylsulfonyl)ami-
no]phenyl}acetamide
[0418] Methanesulphonylchloride (0.022 ml) was added to a stirred
solution of Example 132 (0.114 g) in dichloromethane (5 ml), and
stirring was continued at 22.degree. C. for 2 h. After leaving to
stand for a further 112 h, tris-(2-aminoethyl)amine polystyrene
resin (0.026 g) was added and stirring continued for a further 2 h.
N,N-Dimethylformamide (1 ml) was added and the mixture applied to a
10 g ion exchange cartridge (Isolute SCX, pre-conditioned with
methanol). Elution with methanol (3 column volumes) followed by 10%
0.880 ammonia in methanol (2 column volumes) and evaporation of the
first basic fraction gave a residue, which was re-dissolved in
dichloromethane, treated with polystyrene methylisocyanate resin
(3.85 mmol/g, 0.026 g), and left to stand for 1 h. The mixture was
applied to a 10 g silica gel cartridge (Varian Bond Elut,
pre-conditioned with dichloromethane), and eluted with 1 column
volume each of dichloromethane, chloroform, ether, ethyl acetate,
acetone, acetonitrile and methanol. The appropriate fraction was
evaporated in vacuo to give the title compound as a colourless gum
(0.115 g).
[0419] LC/MS (system A) R.sub.t 2.65 min Mass Spectrum m/z 486
[MH.sup.+]
Examples 140-150
TABLE-US-00005 [0420] Preparation Name analogous to Characterising
Data 140 N-{[(2S,5R)-4-(3,4-dichlorobenzyl)- Example 24 LC-MS
(System A): 5-methylmorpholin-2-yl]methyl}-2- Rt 2.93 mins.
(5-methyl-2-phenyl-1,3-oxazol-4- Mass Spectrum m/z yl)acetamide 488
[MH.sup.+]. Normal Phase Analytical HPLC RT 14.31 mins. 141
N-{[4-(3,4- Example LC-MS (System A): dichlorobenzyl)morpholin-2-
139 Rt 2.57 mins. yl]methyl}-2-{4- Mass Spectrum m/z
[(methylsulfonyl)amino]phenyl} 486 [MH.sup.+]. acetamide 142
N-{3-[2-({[4-(3,4- Example LC-MS (System A):
dichlorobenzyl)morpholin-2- 136 Rt 2.29 mins. yl]methyl}amino)-2-
Mass Spectrum m/z oxoethyl]phenyl}-2- 493 [MH.sup.+].
(dimethylamino)acetamide 143 2-{4- Example LC-MS (System A):
[bis(methylsulfonyl)amino]phenyl}- 139 Rt 2.62 mins. N-{[4-(3,4-
Mass Spectrum m/z 564, dichlorobenzyl)morpholin-2- 566 [MH.sup.+].
yl]methyl}acetamide 144 N-{[4-(3,4- Example 41 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 3.05 mins.
yl]methyl}-2-(5-methyl-2-phenyl- Mass Spectrum m/z
1,3-thiazol-4-yl)acetamide 490 [MH.sup.+]. 145 N-{[4-(3,4- Example
41 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.60 mins.
yl]methyl}-2-(5-methyl-2-pyrazin-2- Mass Spectrum m/z
yl-1,3-thiazol-4-yl)acetamide 492 [MH.sup.+]. 146 N-{[4-(3,4-
Example 56 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.61
mins. yl]methyl}-2-[3- Mass Spectrum m/z
(methylsulfonyl)phenyl]acetamide 471 [MH.sup.+]. 147 N-{[4-(3,4-
Example 41 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.6
mins. yl]methyl}-2-[4-(methylsulfonyl)-2- Mass Spectrum m/z
nitrophenyl]acetamide 518 [MH.sup.+]. 148 N-{[4-(3,4- Example 41
LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.52 mins.
yl]methyl}-2-(2- Mass Spectrum m/z hydroxyphenyl)acetamide 409
[MH.sup.+]. 149 N-{[4-(3,4- Example 41 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.78 mins.
yl]methyl}-2-(2-phenyl-1,3-oxazol- Mass Spectrum m/z 4-yl)acetamide
460 [MH.sup.+]. 150 N-{[4-(3,4- Example LC-MS (System A):
dichlorobenzyl)morpholin-2- 151 Rt 2.73 mins. yl]methyl}-2-{4- Mass
Spectrum m/z [methyl(methylsulfonyl)amino] 500 [MH.sup.+].
phenyl}acetamide
Example 151
N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[methyl(methylsulfon-
yl)amino]phenyl}acetamide
[0421] Potassium carbonate (0.035 g) and iodomethane (0.015 ml)
were added to a stirred solution of Example 139 (0.115 g) in
acetone (1 ml), and stirring was continued at 22.degree. C. for 72
h before a further portion of iodomethane (0.003 ml) was added.
After stirring for a further 24 h, more iodomethane (0.003 ml) and
potassium carbonate (0.007 g) were added, and the mixture stirred
for a further 48 h. The mixture was applied in two equal portions
to two ion exchange cartridges (2 g Isolute SCX, pre-conditioned
with methanol). Elution with methanol (3 column volumes) followed
by 10% 0.880 ammonia in methanol (2 column volumes), and
evaporation of the first basic fraction from each elution in vacuo
gave the title compound as a pale yellow gum (0.038 g).
[0422] LC/MS (system A) R.sub.t 2.73 min Mass Spectrum m/z 500
[MH.sup.+]
Examples 152-157
TABLE-US-00006 [0423] Preparation Name analogous to Characterising
Data 152 N-{[(2S)-4-(3,4- Example 44 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.18 mins. yl]methyl}-4- Mass
Spectrum m/z (methylsulfonyl)butanamide 423 [MH.sup.+] 153
N-{[4-(3,4- Example 41 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.87 mins. yl]methyl}-2-[5-methyl-
Mass Spectrum m/z 2-(5-methylthien-2-yl)-1,3- 494 [MH.sup.+].
oxazol-4-yl]acetamide 154 2-[2-amino-4- Example 41 LC-MS (System
A): (methylsulfonyl)phenyl]- Rt 2.36 mins. N-{[4-(3,4- Mass
Spectrum m/z dichlorobenzyl)morpholin-2- 486 [MH.sup.+].
yl]methyl}acetamide 155 N-{[4-(3,4- Example 41 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.79 mins. yl]methyl}-2-(5-methyl-2-
Mass Spectrum m/z thien-2-yl-1,3-oxazol-4- 480 [MH.sup.+].
yl)acetamide 156 N-{[4-(3,4- Example 41 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.64 mins. yl]methyl}-2-[2-(2- Mass
Spectrum m/z furyl)-5-methyl-1,3-oxazol- 464 [MH.sup.+].
4-yl]acetamide 157 N-{[4-(3,4- Example 1 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.30 mins. yl]methyl}pent-4-ynamide
Mass Spectrum m/z 355 [MH.sup.+].
Example 158
N-{[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(5-methyl-2-pyridi-
n-3-yl-1,3-oxazol-4-yl)acetamide Compound With Formic Acid
(1:1)
[0424] N,N'-carbonyldiimidazole (15 mg) was added to a stirred
solution of Intermediate 34 (20 mg) at 22.degree. C. under
nitrogen, and the mixture was stirred at 22.degree. C. for 1 h.
Intermediate 9 (26 mg) was added and the mixture stirred at
22.degree. C. for 24 h. The mixture was applied directly to a
sulphonic acid ion exchange cartridge (Isolute SCX, 2 g) and eluted
with methanol followed by 10% 0.880 ammonia in methanol.
Evaporation of the methanolic ammonia fraction gave a gum (50 mg)
which was further purified by solid phase extraction on silica gel
(1 g Varian Bondelut cartridge), eluting with chloroform, ether,
ethyl acetate, acetone and methanol to give a gum (38 mg). The gum
was partitioned between dichloromethane and water, and the organic
layer treated with polystyrene methylisocyanate resin (Argonaut, 95
mg, 1.6 mmol/g). After shaking for 4 h the resin was filtered off
and the filtrate evaporated to give a gum (29 mg), which was
further purified by chromatography on silica gel, eluting with
dichloromethane: ethanol: 0.880 ammonia 100:0:0-95:5:0.5, followed
by mass directed preparative HPLC to give the title compound (7.6
mg).
[0425] LC-MS (System A) Rt 2.48 min. Mass Spectrum m/z 475
[MH.sup.+].
[0426] Examples 159-161
TABLE-US-00007 Preparation Name analogous to Characterising Data
159 N-{[(2S)-4-(3,4- Example LC-MS (System A):
dichlorobenzyl)morpholin-2- 158 Rt 2.66 mins.
yl]methyl}-2-(2-isopropyl- Mass Spectrum m/z 5-methyl-1,3- 440
[MH.sup.+]. oxazol-4-yl)acetamide 160 N-{[(2S)-4-(3,4- Example
LC-MS (System A): dichlorobenzyl)morpholin-2- 162 Rt 2.50 mins.
yl]methyl}-2-{4- Mass Spectrum m/z [(methylamino)sulfonyl]- 486
[MH.sup.+]. phenyl}acetamide 161 N-{[(2S)-4-(3,4- Example LC-MS
(System A): dichlorobenzyl)morpholin-2- 162 Rt 2.58 mins.
yl]methyl}-2-{4- Mass Spectrum m/z [(ethylamino)sulfonyl]- 500
[MH.sup.+]. phenyl}acetamide
Example 162
2-[3-(Aminosulfonyl)phenyl]-N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]-
methyl}acetamide
[0427] To a stirred solution of Intermediate 40 (0.021 g) in
N,N-dimethylformamide (1 ml) was added 1-hydroxybenzotriazole
(0.015 g), N,N-diisopropylethylamine (0.028 ml) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.025
g) followed by a solution of Intermediate 9 (0.023 g) in
N,N-dimethylformamide (1 ml). The mixture was stirred for 4 h at
22.degree. C., and applied to an ion exchange cartridge (2 g
Isolute SCX, pre-conditioned with methanol). Elution with methanol
(3 column volumes) followed 10% 0.880 ammonia in methanol (2 column
volumes) and evaporation of the first basic fraction in vacuo gave
a residue which was re-dissolved in dichloromethane and applied to
a silica gel cartridge (2 g Varian Bond Elut, pre-conditioned with
dichloromethane). Elution with dichloromethane, chloroform, ether,
ethyl acetate, acetone, acetonitrile and methanol (1 column volume
each), and evaporation of the product containing fractions in vacuo
gave the title compound as a yellow gum (0.026 g).
[0428] LCMS (System A) R.sub.t 2.38 min Mass Spectrum m/z 472
[MH.sup.+].
[0429] Chiral Analytical HPLC on Chiralcel OD-H column, detection
at 230 nm, eluent 25% EtOH/n-heptane, Rt 12.4 min.
Examples 162A-213
TABLE-US-00008 [0430] Preparation Name analogous to Characterising
Data 162 A 2-[3-(Aminosulfonyl)phenyl]-N-{[4- Example LC-MS (System
A): (3,4-dichlorobenzyl)morpholin-2- 162 (from Rt 2.36 mins.
yl]methyl}acetamide Intermediate Mass Spectrum m/z 1) 472
[MH.sup.+]. Chiral Analytical HPLC on Chiralcel OD-H column,
detection at 230 nm, eluent 25% EtOH/n-heptane, Rt 12.5 min and
10.3 min. 163 2-{3- Example LC-MS (System A):
[(cyclopropylamino)sulfonyl]phenyl}- 162 Rt 2.66 mins.
N-{[(2S)-4-(3,4- Mass Spectrum m/z dichlorobenzyl)morpholin-2- 512
[MH.sup.+]. yl]methyl}acetamide 164 N-{[(2S)-4-(3,4- Example LC-MS
(System A): dichlorobenzyl)morpholin-2- 162 Rt 2.62 mins.
yl]methyl}-2-{3- Mass Spectrum m/z
[(ethylamino)sulfonyl]phenyl}acetamide 500 [MH.sup.+]. 165
N-{[(2S)-4-(3,4- Example LC-MS (System A):
dichlorobenzyl)morpholin-2- 162 Rt 2.50 mins. yl]methyl}-2-{3- Mass
Spectrum m/z [(methylamino)sulfonyl]phenyl}acetamide 486
[MH.sup.+]. 166 N-{[(2S)-4-(3,4- Example 41 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.41 mins. yl]methyl}-2-(5-methyl-2-
Mass Spectrum m/z morpholin-4-yl-1,3-oxazol-4- 483 [MH.sup.+].
yl)acetamide 167 2-[4-(aminosulfonyl)phenyl]-N-{[4- Example LC-MS
(System A): (3,4-dichlorobenzyl)morpholin-2- 162 Rt 2.34 mins.
yl]methyl}acetamide Mass Spectrum m/z 472 [MH.sup.+]. 168 2-{4-
Example LC-MS (System A): [(cyclopropylamino)sulfonyl]phenyl}- 162
Rt 2.65 mins. N-{[4-(3,4- Mass Spectrum m/z
dichlorobenzyl)morpholin-2- 512 [MH.sup.+]. yl]methyl}acetamide 169
methyl 2-[2-({[4-(3,4- Example 86 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.76 mins.
yl]methyl}amino)-2-oxoethyl]-2H- Mass Spectrum m/z
1,2,3-benzotriazole-5-carboxylate 492 [MH.sup.+]. 170 N-{[4-(3,4-
Example 86 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.59
mins. yl]methyl}-2-(1H-pyrrolo[2,3- Mass Spectrum m/z
b]pyridin-1-yl)acetamide 433 [MH.sup.+]. 171 N-{[4-(3,4- Example 86
LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.48 mins.
yl]methyl}-2-(5-pyridin-2-yl-2H- Mass Spectrum m/z
tetraazol-2-yl)acetamide 462 [MH.sup.+]. 172 N-{[4-(3,4- Example 86
LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.45 mins.
yl]methyl}-2-(5-pyridin-3-yl-2H- Mass Spectrum m/z
tetraazol-2-yl)acetamide 462 [MH.sup.+]. 173 N-{[4-(3,4- Example 86
LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.77 mins.
yl]methyl}-2-[5-(3-formylphenyl)- Mass Spectrum m/z
2H-tetraazol-2-yl]acetamide 489 [MH.sup.+]. 174 methyl
1-[2-({[4-(3,4- Example 86 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.66 mins.
yl]methyl}amino)-2-oxoethyl]-1H- Mass Spectrum m/z
1,2,3-benzotriazole-5-carboxylate, 492 [MH.sup.+]. compound with
methyl 1-[2-({[4- (3,4-dichlorobenzyl)morpholin-2-
yl]methyl}amino)-2-oxoethyl]-1H- 1,2,3-benzotriazole-6-carboxylate
(1:1) 175 N-{[(2S)-4-(3,4- Example 41 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.65 mins.
yl]methyl}-2-[2-(2-furyl)-5-methyl- Mass Spectrum m/z
1,3-oxazol-4-yl]acetamide 464 [MH.sup.+]. 176 N-{[(2S)-4-(3,4-
Example 41 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.80
mins. yl]methyl}-2-(5-methyl-2-thien-2-yl- Mass Spectrum m/z
1,3-oxazol-4-yl)acetamide 478 [MH.sup.+]. 177
N-({(2S)-4-[(5-chlorothien-2- Example 41 LC-MS (System A):
yl)methyl]morpholin-2-yl}methyl)-2- Rt 2.75 mins.
(5-methyl-2-phenyl-1,3-oxazol-4- Mass Spectrum m/z yl)acetamide 446
[MH.sup.+]. 178 N-{[(2S)-4-(2,3- Example 41 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.97 mins.
yl]methyl}-2-(5-methyl-2-phenyl- Mass Spectrum m/z
1,3-oxazol-4-yl)acetamide 474 [MH.sup.+]. 179
N-({(2S)-4-[(5-chlorothien-2- Example 41 LC-MS (System A):
yl)methyl]morpholin-2-yl}methyl)-2- Rt 2.82 mins.
[2-(4-fluorophenyl)-5-methyl-1,3- Mass Spectrum m/z
oxazol-4-yl]acetamide 464 [MH.sup.+]. 180 N-{[(2S)-4-(4- Example 41
LC-MS (System A): fluorobenzyl)morpholin-2- Rt 2.54 mins.
yl]methyl}-2-[2-(4-fluorophenyl)-5- Mass Spectrum m/z
methyl-1,3-oxazol-4-yl]acetamide 442 [MH.sup.+]. 181
N-{[(2S)-4-(2,3- Example 54 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.97 mins.
yl]methyl}-2-[2-(4-fluorophenyl)-5- Mass Spectrum m/z
methyl-1,3-oxazol-4-yl]acetamide 492 [MH.sup.+]. 182
N-({(2S)-4-[(5-chlorothien-2- Example 41 LC-MS (System A):
yl)methyl]morpholin-2-yl}methyl)-2- Rt 2.64 mins.
(2-phenyl-1,3-oxazol-4- Mass Spectrum m/z yl)acetamide 432
[MH.sup.+]. 183 N-{[(2S)-4-(4- Example 41 LC-MS (System A):
fluorobenzyl)morpholin-2- Rt 2.39 mins.
yl]methyl}-2-(2-phenyl-1,3-oxazol- Mass Spectrum m/z 4-yl)acetamide
410 [MH.sup.+]. 184 N-{[(2S)-4-(2,3- Example 41 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.86 mins.
yl]methyl}-2-(2-phenyl-1,3-oxazol- Mass Spectrum m/z 4-yl)acetamide
460 [MH.sup.+]. 185 N-{[(2S)-4-(3,4- Example 41 LC-MS (System A):
difluorobenzyl)morpholin-2- Rt 2.59 mins.
yl]methyl}-2-(5-methyl-2-phenyl- Mass Spectrum m/z
1,3-oxazol-4-yl)acetamide 442 [MH.sup.+]. 186 N-{[(2S)-4-(3-
Example 41 LC-MS (System A): chlorobenzyl)morpholin-2- Rt 2.63
mins. yl]methyl}-2-(5-methyl-2-phenyl- Mass Spectrum m/z
1,3-oxazol-4-yl)acetamide 440 [MH.sup.+]. 187 N-{[(2S)-4-(3,4-
Example 41 LC-MS (System A): difluorobenzyl)morpholin-2- Rt 2.64
mins. yl]methyl}-2-[2-(4-fluorophenyl)-5- Mass Spectrum m/z
methyl-1,3-oxazol-4-yl]acetamide 460 [MH.sup.+]. 188 N-{[(2S)-4-(3-
Example 41 LC-MS (System A): chlorobenzyl)morpholin-2- Rt 2.68
mins. yl]methyl}-2-[2-(4-fluorophenyl)-5- Mass Spectrum m/z
methyl-1,3-oxazol-4-yl]acetamide 458 [MH.sup.+]. 189
N-{[(2S)-4-(3,4- Example 41 LC-MS (System A):
difluorobenzyl)morpholin-2- Rt 2.50 mins.
yl]methyl}-2-(2-phenyl-1,3-oxazol- Mass Spectrum m/z 4-yl)acetamide
428 [MH.sup.+]. 190 N-{[(2S)-4-(3- Example 41 LC-MS (System A):
chlorobenzyl)morpholin-2- Rt 2.54 mins.
yl]methyl}-2-(2-phenyl-1,3-oxazol- Mass Spectrum m/z 4-yl)acetamide
426 [MH.sup.+]. 191 N-{[(2S)-4-(3,4- Example 54 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.90 mins.
yl]methyl}-2-[2-(4-fluorophenyl)-5- Mass Spectrum m/z
methyl-1,3-oxazol-4-yl]acetamide 492 [MH.sup.+]. 192
N-{[(2S)-4-(3,4- Example 41 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.81 mins.
yl]methyl}-2-(2-phenyl-1,3-oxazol- Mass Spectrum m/z 4-yl)acetamide
460 [MH.sup.+]. 193 N-cyclopropyl-3-[2-({[(2S)-4-(2,3- Example 41
LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.45 mins.
yl]methyl}amino)-2- Mass Spectrum m/z oxoethyl]benzamide 476
[MH.sup.+]. 194 3-{2-[({(2S)-4-[(5-chlorothien-2- Example 41 LC-MS
(System A): yl)methyl]morpholin-2- Rt 2.28 mins.
yl}methyl)amino]-2-oxoethyl}-N- Mass Spectrum m/z
cyclopropylbenzamide 447 [MH.sup.+]. 195
N-cyclopropyl-3-[2-({[(2S)-4-(4- Example 41 LC-MS (System A):
fluorobenzyl)morpholin-2- Rt 2.11 mins. yl]methyl}amino)-2- Mass
Spectrum m/z oxoethyl]benzamide 425 [MH.sup.+]. 196
3-[2-({[(2S)-4-(3- Example 41 LC-MS (System A):
chlorobenzyl)morpholin-2- Rt 2.24 mins.
yl]methyl}amino)-2-oxoethyl]-N- Mass Spectrum m/z
cyclopropylbenzamide 442 [MH.sup.+]. 197
N-cyclopropyl-3-[2-({[(2S)-4-(3,4- Example 41 LC-MS (System A):
difluorobenzyl)morpholin-2- Rt 2.12 mins. yl]methyl}amino)-2- Mass
Spectrum m/z oxoethyl]benzamide 444 [MH.sup.+]. 198
N-cyclopropyl-3-[2-({[(2S)-4-(3,4- Example 41 LC-MS(System A):
dichlorobenzyl)morpholin-2- Rt 2.46 mins. yl]methyl}amino)-2- Mass
Spectrum m/z oxoethyl]benzamide 476 [MH.sup.+]. 199
N-{[(2S)-4-(2,3- Example 41 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.90 mins.
yl]methyl}-2-(5-phenyl-2H- Mass Spectrum m/z
tetraazol-2-yl)acetamide 461 [MH.sup.+]. 200 N-{[(2S)-4-(4- Example
41 LC-MS (System A): fluorobenzyl)morpholin-2- Rt 2.42 mins.
yl]methyl}-2-(5-phenyl-2H- Mass Spectrum m/z
tetraazol-2-yl)acetamide 410 [MH.sup.+]. 201 N-{[(2S)-4-(3- Example
41 LC-MS (System A): chlorobenzyl)morpholin-2- Rt 2.57 mins.
yl]methyl}-2-(5-phenyl-2H- Mass Spectrum m/z
tetraazol-2-yl)acetamide 427 [MH.sup.+]. 202 N-{[(2S)-4-(3,4-
Example 41 LC-MS (System A): difluorobenzyl)morpholin-2- Rt 2.53
mins. yl]methyl}-2-(5-phenyl-2H- Mass Spectrum m/z
tetraazol-2-yl)acetamide 429 [MH.sup.+]. 203 N-{[(2S)-4-(3,4-
Example 41 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.95
mins. yl]methyl}-2-[5-methyl-2-(3- Mass Spectrum m/z
methylthien-2-yl)-1,3-oxazol-4- 494 [MH.sup.+]. yl]acetamide 204
N-{[(2S)-4-(3,4- Example 41 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.63 mins.
yl]methyl}-2-[2-(1,3-dimethyl-1H- Mass Spectrum m/z
pyrazol-5-yl)-5-methyl-1,3-oxazol- 492 [MH.sup.+]. 4-yl]acetamide
205 2-[2-(3-chlorothien-2-yl)-5-methyl- Example 41 LC-MS (System
A): 1,3-oxazol-4-yl]-N-{[(2S)-4-(3,4- Rt 2.93 mins.
dichlorobenzyl)morpholin-2- Mass Spectrum m/z yl]methyl}acetamide
514, 516 [MH.sup.+]. 206 N-({(2S)-4-[(5-chlorothien-2- Example 41
LC-MS (System A): yl)methyl]morpholin-2-yl}methyl)-2- Rt 2.69 mins.
(5-phenyl-2H-tetraazol-2- Mass Spectrum m/z yl)acetamide 433
[MH.sup.+]. 207 N-{[(2S)-4-(3- Example 54 LC-MS (System A):
cyanobenzyl)morpholin-2- Rt 2.55 mins.
yl]methyl}-2-[2-(4-fluorophenyl)-5- Mass Spectrum m/z
methyl-1,3-oxazol-4-yl]acetamide 449 [MH.sup.+]. 208
N-{[(2S)-4-(2,1,3-benzoxadiazol-5- Example 54 LC-MS (System A):
ylmethyl)morpholin-2-yl]methyl}-2- Rt 2.80 mins.
[2-(4-fluorophenyl)-5-methyl-1,3- Mass Spectrum m/z
oxazol-4-yl]acetamide 466 [MH.sup.+]. 209
2-[2-(4-fluorophenyl)-5-methyl-1,3- Example 54 LC-MS (System A):
oxazol-4-yl]-N-{[(2S)-4-(2,3,4- Rt 2.78 mins.
trifluorobenzyl)morpholin-2- Mass Spectrum m/z yl]methyl}acetamide
478 [MH.sup.+]. 210 2-[2-(4-fluorophenyl)-5-methyl-1,3- Example 54
LC-MS (System A): oxazol-4-yl]-N-({(2S)-4-[4-fluoro-3- Rt 2.89
mins. (trifluoromethyl)benzyl]morpholin- Mass Spectrum m/z
2-yl}methyl)acetamide 510 [MH.sup.+]. 211 N-{[(2S)-4-(3,4- Example
56 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.62 mins.
yl]methyl}-2-{5-methyl-2-[4- Mass Spectrum m/z
(methylsulfonyl)phenyl]-1,3-oxazol- 552 [MH.sup.+]. 4-yl}acetamide
212 N-{[(2S)-4-(3,4- Example 41 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.97 mins.
yl]methyl}-2-(5-methyl-2-phenyl- Mass Spectrum m/z
1,3-thiazol-4-yl)acetamide 490 [MH.sup.+]. 213 N-{[(2S)-4-(3,4-
Example 41 LC-MS (System A): dichlorobenzyl)morpholin-2- Rt 2.51
mins. yl]methyl}-2-(5-methyl-2-pyrazin-2- Mass Spectrum m/z
yl-1,3-thiazol-4-yl)acetamide 492 [MH.sup.+].
Example 214
N-({(2S)-4-[3-(4-chlorophenyl)propyl]morpholin-2-yl}methyl)-2-[2-(4-fluoro-
phenyl)-5-methyl-1,3-oxazol-4-yl]acetamide
[0431] A mixture of Intermediate 28 (0.04 g),
3-(4-chlorophenyl)propanal (0.026 g) and acetic acid (0.02 ml) in
dichloromethane (4 ml) was treated with sodium
triacetoxyborohydride (0.080 g). The mixture was stirred at
20.degree. C. for 72 h. The mixture was partitioned between
chloroform (6 ml) and saturated aqueous sodium hydrogen carbonate
(6 ml). The phases were separated and the organic phase applied to
an ion exchange cartridge (2 g Isolute SCX, prewashed with
methanol). The SCX cartridge was eluted with methanol (10 ml)
followed by 10% 0.880 ammonia in methanol (10 ml) and the
appropriate fractions were concentrated in vacuo to give the title
compound as a colourless gum (0.055 g).
[0432] LCMS (system A) R.sub.t 2.65 min Mass Spectrum m/z 486
[MH.sup.+].
Examples 215-219
TABLE-US-00009 [0433] Preparation Name analogous to Characterising
Data 215 2-(2-cyclopropyl-5-methyl- Example LC-MS (System A):
1,3-oxazol-4-yl)-N-{[(2S)-4- 158 Rt 2.48 mins. (3,4- Mass Spectrum
m/z dichlorobenzyl)morpholin- 438 [MH.sup.+]. 2-yl]methyl}acetamide
216 N-{[(2S)-4-(3,4- Example LC-MS (System A):
dichlorobenzyl)morpholin-2- 158 Rt 2.70 mins.
yl]methyl}-2-(2-isobutyl-5- Mass Spectrum m/z methyl-1,3-oxazol-4-
454 [MH.sup.+]. yl)acetamide 217 N-{[(2S)-4-(3,4- Example LC-MS
(System A): dichlorobenzyl)morpholin-2- 158 Rt 2.71 mins.
yl]methyl}-2-[5-methyl-2-(2- Mass Spectrum m/z
methylprop-1-enyl)-1,3- 452 [MH.sup.+]. oxazol-4-yl]acetamide 218
N-{[(2S)-4-(3,4- Example LC-MS (System A):
dichlorobenzyl)morpholin-2- 158 Rt 2.38 mins.
yl]methyl}-2-(5-methyl-2- Mass Spectrum m/z pyridin-2-yl-1,3- 475
[MH.sup.+]. oxazol-4-yl)acetamide compound with formic acid (1:1)
219 N-{[(2S)-4-(3,4- Example 41 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.85 mins. yl]methyl}-2-[5-(4- Mass
Spectrum m/z fluorophenyl)-2H-tetraazol-2- 479 [MH.sup.+].
yl]acetamide
Example 220
N-{[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-[5-(4-fluorophenyl-
)-1, 2,4-oxadiazol-3-yl]acetamide
[0434] A mixture of Intermediate 38 (0.024 g), Intermediate 9
(0.025 g), and 1-methyl-2-pyrrolidinone (1 drop) was subjected was
subjected to irradiation in a 600 W microwave oven on full power
for 4 mins. The reaction mixture was dissolved in methanol and
applied to an ion exchange cartridge (2 g Isolute SCX,
pre-conditioned with methanol). Elution with methanol (3 column
volumes) followed 10% 0.880 ammonia in methanol (2 column volumes)
and evaporation of the first basic fraction in vacuo gave the crude
product. Purification by Biotage flash column chromatography on
silica gel (8 g cartridge), eluting with 100:8:1
dichloromethane/ethanol/0.880 ammonia, gave the title compound as a
white solid (0.025 g).
[0435] LCMS (System A) R.sub.t 2.85 min Mass Spectrum m/z 479, 481
[MH.sup.+]
Examples 221-224
TABLE-US-00010 [0436] Preparation Name analogous to Characterising
Data 221 N-{[(2S)-4-(2,1,3- Example 54 LC-MS (System A):
benzothiadiazol-5- Rt 2.51 mins. ylmethyl)morpholin-2- Mass
Spectrum m/z yl]methyl}-2-[2-(4- 482 [MH.sup.+].
fluorophenyl)-5-methyl-1,3- oxazol-4-yl]acetamide 222
4-{4-[2-({[(2S)-4-(3,4- Example 56 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 2.50 mins. yl]methyl}amino)-2- Mass
Spectrum m/z oxoethyl]-5-methyl- 545 [MH.sup.+].
1,3-oxazol-2-yl}-N,N- dimethylbenzamide 223 2-{2-[4- Example 56
LC-MS (System A): (acetylamino)phenyl]-5- Rt 2.54 mins.
methyl-1,3-oxazol-4-yl}-N- Mass Spectrum m/z {[(2S)-4-(3,4- 531
[MH.sup.+]. dichlorobenzyl)morpholin- 2-yl]methyl}acetamide 224
N-{[(2S)-4-(1,2,3- Example LC-MS (System A): benzothiadiazol-6- 214
Rt 2.59 mins. ylmethyl)morpholin-2- Mass Spectrum m/z
yl]methyl}-2-[2-(4- 482 [MH.sup.+]. fluorophenyl)-5-methyl-1,3-
oxazol-4-yl]acetamide
Example 225
N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}pentanamide
[0437] A solution of Intermediate 9 (0.028 g) in dichloromethane (2
ml) containing a suspension of polyvinyl pyridine (0.1 g) was
treated with valeryl chloride (0.018 ml), and the mixture was
shaken at 20.degree. C. for 16 h. Tris (2-aminoethyl)amine
polystyrene scavenger resin (Argonaut Technologies, 4.46 mmol/g;
0.067 g) was added, and the mixture was shaken at 20.degree. C. for
2 h. The mixture was filtered and the filtrate applied directly to
a silica gel cartridge (1 g Varian Bond Elut). Elution with
chloroform, ether, and ethyl acetate gave the title compound
(0.0225 g).
[0438] LC-MS (System A) Rt 2.43 mins. Mass Spectrum m/z 359
[MH.sup.+].
Examples 226-238
TABLE-US-00011 [0439] Preparation Name analogous to Characterising
Data 226 N-{[(2S)-4-(3,4- Example LC-MS (System A):
dichlorobenzyl)morpholin-2- 225 Rt 2.58 mins.
yl]methyl}-4-methylpentanamide Mass Spectrum m/z 373 [MH.sup.+].
227 N-({4-[3- Example 1 LC-MS (System A):
(3,4-dichlorophenyl)propyl]morpholin-2- Rt 2.76 mins.
yl}methyl)-2-phenoxyacetamide Mass Spectrum m/z 437 [MH.sup.+]. 228
2-cyclohexyl- Example 1 LC-MS (System A):
N-{[4-(3,4-dichlorobenzyl)morpholin-2- Rt 2.81 mins.
yl]methyl}acetamide Mass Spectrum m/z trifluoroacetate 399
[MH.sup.+]. 229 2-(4-chlorophenyl)-N-{[4-(3,4- Example 1 LC-MS
(System A): dichlorobenzyl)morpholin-2- Rt 3.00 mins.
yl]methyl}propanamide Mass Spectrum m/z 443 [MH.sup.+]. 230
N-{[4-(3,4- Example 1 LC-MS (System A): dichlorobenzyl)morpholin-2-
Rt 2.39 mins. yl]methyl}-2-(1,1- Mass Spectrum m/z
dioxidothiomorpholin-4- 450 [MH.sup.+]. yl)acetamide 231
2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4 Example 54 LC-MS
(System A): -yl]-N-({(2S)-4-[2-(4- Rt 2.58 mins. fluorophenyl)-2-
Mass Spectrum m/z oxoethyl]morpholin-2- 470 [MH.sup.+].
yl}methyl)acetamide 232 N-({(2S)-4-[(3-chloro-1-benzothien- Example
54 LC-MS (System A): 2-yl)methyl]morpholin-2-yl}methyl)- Rt 3.46
mins. 2-[2-(4-fluorophenyl)-5-methyl-1,3- Mass Spectrum m/z
oxazol-4-yl]acetamide 514 [MH.sup.+]. 233
2-[2-(4-fluorophenyl)-5-methyl-1,3- Example 54 LC-MS (System A):
oxazol-4-yl]-N-{[(2S)-4-(2- Rt 2.37 mins.
methylprop-2-enyl)morpholin-2- Mass Spectrum m/z
yl]methyl}acetamide 488 [MH.sup.+]. 234
2-[2-(4-fluorophenyl)-5-methyl-1,3- Example 54 LC-MS (System A):
oxazol-4-yl]-N-{[(2S)-4-(1- Rt 2.48 mins. phenylethyl)morpholin-2-
Mass Spectrum m/z yl]methyl}acetamide 438 [MH.sup.+]. 235
N-{[(2S)-4-(3-cyano-4- Example 54 LC-MS (System A):
fluorobenzyl)morpholin-2- Rt 2.59 mins.
yl]methyl}-2-[2-(4-fluorophenyl)-5- Mass Spectrum m/z
methyl-1,3-oxazol-4-yl]acetamide 467 [MH.sup.+]. 236
N-{[(2S)-4-(3,4- Example 41 LC-MS (System A):
dichlorobenzyl)morpholin-2- Rt 3.16 mins.
yl]methyl}-2-[2-(4-fluorophenyl)-5- Mass Spectrum m/z
isopropyl-1,3-oxazol-4- 520 [MH.sup.+]. yl]acetamide 237
N-{[(2S)-4-(3,4- Example LC-MS (System A):
dichlorobenzyl)morpholin-2- 225 Rt 2.22 mins.
yl]methyl}cyclopropane Mass Spectrum m/z carboxamide 343
[MH.sup.+]. 238 N-({(2S)-4-[2-(3- Example 54 LC-MS (System A):
chlorophenoxy)ethyl]morpholin-2- Rt 2.72 mins.
yl}methyl)-2-[2-(4-fluorophenyl)-5- Mass Spectrum m/z
methyl-1,3-oxazol-4-yl]acetamide 488 [MH.sup.+].
Example 239
N-{[(2S)-4-(3,4-dichlorobenzoyl)morpholin-2-yl]methyl}-2-[2-(4-fluoropheny-
l)-5-methyl-1,3-oxazol-4-yl]acetamide
[0440] A mixture of Intermediate 12 (0.015 g),
1-hydroxybenzotriazole (0.0097 g),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.012
g) and N,N-diisopropylethylamine (0.027 ml) in
N,N-dimethylformamide (2 ml) was stirred at 20.degree. C. for 10
min. The mixture was treated with Intermediate 31 (0.023 g) and
stirred at 20.degree. C. for 96 h. The mixture was applied
sequentially to a sulphonic acid ion exchange cartridge (1 g SCX,
prewashed with methanol) and Isolute.sup.R aminopropyl solid phase
extraction cartridge (1 g), eluting both cartridges with methanol
(5 ml). The solvent was removed in vacuo to give the title compound
as a yellow gum (0.032 g).
[0441] LCMS (system A) R.sub.t 3.3 min Mass Spectrum m/z 506
[MH.sup.+]
Example 240
tert-butyl
4-[3-({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-
-3-oxopropyl]piperidine-1-carboxylate
[0442] Example 240 was prepared in an analogous manner to Example
44 from 3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoic
acid.
[0443] LC-MS (System A) Rt 2.89 mins Mass Spectrum m/z 514
[MH.sup.+]
Biological Data
[0444] The compounds of the Examples were tested in the CCR-3
binding and/or eosinophil chemotaxis assays (assays (a) and (b))
and results were obtained as follows:
TABLE-US-00012 CCR-3 Eosinophil CCR-3 Binding Chemotaxis Example
Assay (pIC50) Assay (fpKi) 2 6.51 3 7.15 5 7.11 6 6.86 7 7.82 8
6.84 10 6.80 12 6.82 13 6.62 14 6.47 17 6.24 19 6.08 22 6.96 25
7.22 27 7.39 31 6.29 32 7.32 35 6.81 37 7.97 38 7.00 39 8.31 41
7.99 42 9.32 44 8.17 45 7.88 46 7.14 49 8.07 53 8.39 54 7.62 7.96
55 6.40 162 7.9 8.2
[0445] Compounds of Examples 1, 4, 9, 11, 15-16, 18, 20-21, 23-24,
26, 28-30, 33-34, 36, 40, 43, 47-48, 50-52, 56-161 and 163-240 were
also tested in CCR-3 binding assay (assay (a)) and achieved a plC50
value greater than 5.0.
[0446] Throughout the specification and the claims which follow,
unless the context requires otherwise, the word `comprise`, and
variations such as `comprises` and `comprising`, will be understood
to imply the inclusion of a stated integer or step or group of
integers but not to the exclusion of any other integer or step or
group of integers or steps.
* * * * *