U.S. patent application number 11/157742 was filed with the patent office on 2005-10-27 for novel compounds.
Invention is credited to Eriksson, Tomas, Henriksson, Krister.
Application Number | 20050239801 11/157742 |
Document ID | / |
Family ID | 29273460 |
Filed Date | 2005-10-27 |
United States Patent
Application |
20050239801 |
Kind Code |
A1 |
Eriksson, Tomas ; et
al. |
October 27, 2005 |
Novel compounds
Abstract
The invention provides compounds of general formula (I) wherein
m, n, Z.sup.1, Z.sup.2, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as defined in the
specification, process for their preparation, pharmaceutical
compositions containing them and their use in therapy.
Inventors: |
Eriksson, Tomas; (Lund,
SE) ; Henriksson, Krister; (Lund, SE) |
Correspondence
Address: |
FISH & RICHARDSON P.C.
225 FRANKLIN STREET
BOSTON
MA
02110
US
|
Family ID: |
29273460 |
Appl. No.: |
11/157742 |
Filed: |
June 21, 2005 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11157742 |
Jun 21, 2005 |
|
|
|
10311667 |
Dec 17, 2002 |
|
|
|
10311667 |
Dec 17, 2002 |
|
|
|
PCT/SE01/01378 |
Jun 14, 2001 |
|
|
|
Current U.S.
Class: |
514/255.05 ;
514/408; 514/422; 544/405; 548/527; 548/571 |
Current CPC
Class: |
C07D 409/12 20130101;
C07D 207/416 20130101; C07D 405/12 20130101; C07D 211/58 20130101;
C07D 211/46 20130101; C07D 403/12 20130101; C07D 413/12 20130101;
C07D 401/12 20130101; C07D 417/12 20130101; C07D 207/12
20130101 |
Class at
Publication: |
514/255.05 ;
514/422; 514/408; 544/405; 548/527; 548/571 |
International
Class: |
A61K 031/497; A61K
031/4025; A61K 031/40 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 20, 2000 |
SE |
0002330-9 |
Oct 31, 2000 |
SE |
0003980-0 |
Claims
1. A compound of general formula 4wherein: m is 0, 1, 2 or 3; each
R.sup.1 independently represents halogen, cyano, nitro, carboxyl,
hydroxyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkoxy, --NR.sup.9R.sup.10, C.sub.3-C.sub.6
cycloalkylamino, C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6
alkylcarbonyl, C.sub.1-C.sub.6 alkylcarbonylamino, sulphonamido,
C.sub.1-C.sub.6 alkylsulphonyl, --C(O)NR.sup.11R.sup.12,
--NR.sup.13C(O)--(NH).sub.PR.sup.14, phenyl, or C.sub.1-C.sub.6
alkyl optionally substituted by carboxyl or C.sub.1-C.sub.6
alkoxycarbonyl; p is 0 or 1; X represents an oxygen atom or a
CH.sub.2, OCH.sub.2, CH.sub.2O, CH.sub.2NH, NH, carbonyl or
sulphonyl group and Y represents a nitrogen atom or a CH or C(OH)
group, provided that when X represents an oxygen atom or a
CH.sub.2O, CH.sub.2NH or NH group, then Y represents a CH group;
Z.sup.1 represents a group (CH.sub.2).sub.q where q is 1 or 2;
Z.sup.2 represents a bond or a group CH.sub.2, with the proviso
that when Z.sup.1 is CH.sub.2, Z.sup.2 is CH.sub.2, and when
Z.sup.1 is (CH.sub.2).sub.2. Z.sup.2 is a bond; Q represents an
oxygen or sulphur atom or a group CH.sub.2 or NH; R represents a
group 5n is 0, 1 or 2; each R.sup.3 independently represents a
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl, --CH.sub.2OH
or carboxyl group; R.sup.4, R.sup.5, R.sup.6 and R.sup.7 each
independently represent a hydrogen atom or a C.sub.1-C.sub.6 alkyl
group, or R.sup.4, R.sup.5, R.sup.6 and R.sup.7 together represent
a C.sub.1-C.sub.4 alkylene chain linking the two carbon atoms to
which they are attached to form a 4- to 7-membered saturated
carbocycle, or R.sup.5, R.sup.6 and R.sup.7 each represent a
hydrogen atom and R.sup.4 and R.sup.8 together with the carbon
atoms to which they are attached form a 5- to 6-membered saturated
carbocycle; R.sup.8 represents a hydrogen atom, a C.sub.1-C.sub.6
alkyl group or is linked to R.sup.4 as defined above; R.sup.9 and
R.sup.10 each independently represent a hydrogen atom or a
C.sub.1-C.sub.6 alkyl group, or R.sup.9 and R.sup.10 together with
the nitrogen atom to which they are attached form a 4- to
7-membered saturated heterocycle; R.sup.11 and R.sup.12 each
independently represent a hydrogen atom or a C.sub.1-C.sub.6 alkyl
group optionally substituted by C.sub.1-C.sub.6 alkoxycarbonyl;
R.sup.13 represents a hydrogen atom or a C.sub.1-C.sub.6 alkyl
group; R.sup.14 represents a hydrogen atom, or a C.sub.1-C.sub.6
alkyl group optionally substituted by carboxyl, C.sub.1-C.sub.6
alkoxy or C.sub.1-C.sub.6 alkoxycarbonyl; R.sup.15 represents a
group C.sub.2-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.3-C.sub.6 cycloalkyl, C.sub.5-C.sub.6 cycloalkenyl,
adamantyl, phenyl or a saturated or unsaturated 5- to 10-membered
heterocyclic ring system comprising at least one heteroatom
selected from nitrogen, oxygen and sulphur, wherein each group may
be optionally substituted by one or more substituents independently
selected from nitro, hydroxyl, oxo, halogen, carboxyl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkylthio, C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6
alkoxycarbonyl, phenyl and --NHC(O)--R.sup.17, with the proviso
that R.sup.15 does not represent an unsubstituted 1-pyrrolidinyl,
an unsubstituted 1-piperidinyl or an unsubstituted
1-hexamethyleneiminyl group; t is 0, 1, 2 or 3; each R.sup.16
independently represents halogen, cyano, nitro, carboxyl, hydroxyl,
C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkoxycarbonyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
haloalkoxy, --NR.sup.18R.sup.19, C.sub.3-C.sub.6 cycloalkylamino,
C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 alkylcarbonyl,
C.sub.1-C.sub.6 alkylcarbonylamino, sulphonamido
(--SO.sub.2NH.sub.2), C.sub.1-C.sub.6 alkylsulphonyl,
--C(O)NR.sup.20R.sup.21, --NR.sup.22C(O)(NH).sub.vR.sup.23, phenyl,
or C.sub.1-C.sub.6 alkyl optionally substituted by carboxyl or
C.sub.1-C.sub.6 alkoxycarbonyl; R.sup.17 represents a
C.sub.1-C.sub.6 alkyl, amino or phenyl group; R.sup.18 and R.sup.19
each independently represent a hydrogen atom or a C.sub.1-C.sub.6
alkyl group, or R.sup.18 and R.sup.19 together with the nitrogen
atom to which they are attached form a 4- to 7-membered saturated
heterocycle; R.sup.20 and R.sup.21 each independently represent a
hydrogen atom or a C.sub.1-C.sub.6 alkyl group optionally
substituted by C.sub.1-C.sub.6 alkoxycarbonyl; v is 0 or 1;
R.sup.22 represents a hydrogen atom or a C.sub.1-C.sub.6 alkyl
group; and R.sup.23 represents a hydrogen atom, or a
C.sub.1-C.sub.6 alkyl group optionally substituted by carboxyl,
C.sub.1-C.sub.6 alkoxy or C.sub.1-C.sub.6 alkoxycarbonyl; or a
pharmaceutically acceptable salt or solvate thereof.
2. A compound according to claim 1, wherein X represents an oxygen
atom or a CH.sub.2 or NH group.
3. A compound according to claim 1, wherein Y represents a CH
group.
4. A compound according to claim 1, wherein Q represents an oxygen
atom.
5. A compound according to claim 1, wherein R.sup.15 represents a
group C.sub.2-C.sub.5 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.3-C.sub.6 cycloalkyl, C.sub.5-C.sub.6 cycloalkenyl,
adamantyl, phenyl or a saturated or unsaturated 5- to 10-membered
heterocyclic ring system comprising at least one heteroatom
selected from nitrogen, oxygen and sulphur, wherein each group may
be optionally substituted by one, two or three substituents
independently selected from hydroxyl, oxo, halogen, carboxyl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkylthio, C.sub.1-C.sub.6 alkylcarbonyl, Cl-C.sub.6
alkoxycarbonyl, phenyl and --NHC(O)--R.sup.17.
6. A compound according to claim 5, wherein the saturated or
unsaturated 5- to 10-membered heterocyclic ring system comprising
at least one heteroatom selected from nitrogen, oxygen and sulphur,
is pyrrolidinyl, piperidinyl, pyrazolyl, thiazolidinyl, thienyl,
thiadiazolyl, isoxazolyl, pyrrolyl, furanyl, thiazolyl, indolyl,
quinolinyl, benzimidazolyl, triazolyl, tetrazolyl or pyridinyl.
7. A compound according to claim 1, wherein each R.sup.16
independently represents halogen, cyano, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 alkoxycarbonyl, C.sub.1-C.sub.4haloalkyl,
C.sub.1-C.sub.4 alkylcarbonyl, phenyl or C.sub.1-C.sub.4 alkyl.
8. A compound of formula (I), or a pharmaceutically acceptable salt
or solvate thereof, as defined in claim 1 being selected from:
Thiophene-2-carboxylic acid
(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-y-
l]-2-hydroxy-propoxy}-phenyl)-amide,
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-pip-
eridin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide,
N-(2-{3-[4-(3,4-Dichlor-
o-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-nicotinamide,
Pyridine-2-carboxylic acid
(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl-
]-2-hydroxy-propoxy}-phenyl)-amide,
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-pipe-
ridin-1-yl]-2-hydroxy-propoxy}-phenyl)-isonicotinamide,
Cyclohexanecarboxylic acid
(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl-
]-2-hydroxy-propoxy}-phenyl)-amide,
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-pipe-
ridin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide,
5-Methyl-thiophene-2-carboxylic acid
(2-{3-[4-(3,4-dichloro-phenoxy)-pipe-
ridin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide, Cyclobutanecarboxylic
acid
(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl-
)-amide,
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propo-
xy}-phenyl)-propionamide, Pentanoic acid
(2-{3-[4-(3,4-dichloro-phenoxy)-p-
iperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide, Pent-4-enoic acid
(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl-
)-amide, Cyclopentanecarboxylic acid
(2-{3-[4-(3,4-dichloro-phenoxy)-piper-
idin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
N-(2-{3-[4-(3,4-Dichloro-phen-
oxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide,
4-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phen-
ylcarbamoyl)-3-methyl-butyric acid,
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-pipe-
ridin-1-yl]-2-hydroxy-propoxy}-phenyl)-succinamic acid,
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-2-methyl-prop-
oxy}-phenyl)-benzamide,
N-(2-{3-[4-(3,4-Dichloro-phenylamino)-piperidin-1--
yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide.
9. A process for the preparation of a compound of formula (I) as
defined in claim 1 which comprises reacting a compound of general
formula 6or a salt thereof, wherein m, n, t, R.sup.1, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.16, Q, Z.sup.1
and Z.sup.2 are as defined in formula (I), with a compound of
general formula R.sup.15--CO.sub.2H (III) or chemically equivalent
derivative thereof, wherein R.sup.15 is as defined in formula (I);
and optionally thereafter forming a pharmaceutically acceptable
salt or solvate of the compound of formula (I) obtained.
10. A pharmaceutical composition comprising a compound of formula
(I), or a pharmaceutically acceptable salt or solvate thereof, as
claimed in any one of claim 1 in association with a
pharmaceutically acceptable adjuvant, diluent or carrier.
11. A process for the preparation of a pharmaceutical composition
as claimed in claim 10 which comprises mixing a compound of formula
(I), or a pharmaceutically acceptable salt or solvate thereof, as
claimed in claim 1 with a pharmaceutically acceptable adjuvant,
diluent or carrier.
12-18. (canceled)
19. A method of treating an inflammatory disease in a patient
suffering from, or at risk of, said disease, which comprises
administering to the patient a therapeutically effective amount of
a compound of formula (I), or a pharmaceutically acceptable salt or
solvate thereof, as claimed in claim 1.
20. A method of treating an airways disease in a patient suffering
from, or at risk of, said disease, which comprises administering to
the patient a therapeutically effective amount of a compound of
formula (I), or a pharmaceutically acceptable salt or solvate
thereof, as claimed in claim 1.
21. A method of treating a human disease or condition in which
modulation of chemokine receptor activity is beneficial, in a
patient suffering from, or at risk of, said disease or condition,
which comprises administering to the patient a therapeutically
effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt or solvate thereof, as claimed in
claim 1.
22. A method of treating rheumatoid arthritis in a patient
suffering from, or at risk of, rheumatoid arthritis, which
comprises administering to the patient a therapeutically effective
amount of a compound of formula (I), or a pharmaceutically
acceptable salt or solvate thereof, as claimed in claim 1.
23. A method of treating chronic obstructive pulmonary disease in a
patient suffering from, or at risk of, said disease, which
comprises administering to the patient a therapeutically effective
amount of a compound of formula (I), or a pharmaceutically
acceptable salt or solvate thereof, as claimed in claim 1.
24. A method of treating asthma, in a patient suffering from, or at
risk of, asthma, which comprises administering to the patient a
therapeutically effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt or solvate thereof, as claimed in
claim 1.
25. A method of treating multiple sclerosis in a patient suffering
from, or at risk of, multiple sclerosis, which comprises
administering to the patient a therapeutically effective amount of
a compound of formula (I), or a pharmaceutically acceptable salt or
solvate thereof, as claimed in claim 1.
Description
[0001] The present invention relates to novel compounds, processes
for their preparation, pharmaceutical compositions containing them
and their use in therapy.
[0002] Chemokines play an important role in immune and inflammatory
responses in various diseases and disorders, including asthma and
allergic diseases, as well as autoimmune pathologies. such as
rheumatoid arthritis and atherosclerosis. These small secreted
molecules are a growing superfamily of 8-14 ka proteins
characterised by a conserved four cysteine motif. The chemokine
superfamily can be divided into two main groups exhibiting
characteristic structural motifs, the Cys-X-Cys (C-X-C) and
Cys-Cys.(C-C) families. These are distinguished on the basis of a
single amino acid insertion between the NH-proximal pair of
cysteine residues and sequence similarity.
[0003] The C-X-C chemokines include several potent chemoattractants
and activators of neutrophils such as interleukin-8 (IL-8) and
neutrophil-activating peptide 2 (NAP-2).
[0004] The C-C chemokines include potent chemoattractants of
monocytes and lymphocytes but not neutrophils such as human
monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES
(Regulated on Activation, Normal T Expressed and Secreted), eotaxin
and the macrophage inflammatory proteins 1.alpha. and 1.beta.
(MIP-1.alpha. and MP-1.beta..
[0005] Studies have demonstrated that the actions of the chemokines
are mediated by subfamilies of G protein-coupled receptors, among
which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3,
CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and
CXCR4. These receptors represent good targets for drug development
since agents which modulate these receptors would be useful in the
treatment of disorders and diseases such as those mentioned
above.
[0006] In accordance with the present invention, there is therefore
provided a compound of general formula 1
[0007] wherein:
[0008] m is 0, 1, 2 or 3;
[0009] each R.sup.1 independently represents halogen, cyano, nitro,
carboxyl, hydroxyl, C.sub.3-C.sub.6 cycloakl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkoxy, --NR.sup.9R.sup.10, C.sub.3-C.sub.6
cycloalkylano, C.sub.1pk -C.sub.6 alkylthio, C.sub.1-C.sub.6
akylcarbonyl, C.sub.1-C.sub.6 allcarbonylamio, sulphonamido
(--SO.sub.2NH.sub.2), C.sub.1-C.sub.6 alkylsuiphonyl,
--C(O)NR.sup.11R, --NR.sup.13 C(O)--.sub.pR.sup.14, phenyl, or
C.sub.1-C.sub.6 alkyl optionally substituted by carboxyl or
C.sub.1-C.sub.6 alkoxycarbonyl;
[0010] p is 0 or 1;
[0011] X represents an oxygen atom or a CH.sub.2, OCH.sub.2,
CH.sub.2O, CH.sub.2NH, NH, carbonyl or sulphonyl group and Y
represents a nitrogen atom or a CH or C(OH) group, provided that
when X represents an oxygen atom or a CH.sub.2O, CH.sub.2NH or NH
group, then Y represents a CH group;
[0012] Z.sup.1 represents a bond or a group (CH.sub.2).sub.q where
q is 1 or 2;
[0013] Z.sup.2 represents a bond or a group CH.sub.2, with the
proviso that Z.sup.1 and Z.sup.1 do not both simultaneously
represent a bond;
[0014] Q represents an oxygen or sulphur atom or a group CH.sub.2
or NH;
[0015] R.sup.2 represents a group 2
[0016] n is 0, 1 or 2;
[0017] each R.sup.3 independently represents a C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxycarbonyl, --CH.sub.2OH or carboxyl
group;
[0018] R.sup.4, R.sup.5, R.sup.6 and R.sup.7 each independently
represent a hydrogen atom or a C.sub.1-C.sub.6 alkyl group, or
R.sup.4, R.sup.5, R.sup.6 and R.sup.7 together represent a
C.sub.1-C.sub.4 alkylene chain linking the two carbon atoms to
which they are attached to form a 4 to 7-membered satrn carbocycle,
or R.sup.5, R.sup.6 and R.sup.7 each represent a hydrogen atom and
R.sup.4 and R.sup.8 together with the carbon atoms to which they
are attached form a 5- to 6-membered saturated carbocycle;
[0019] R.sup.8represents a hydrogen atom, a C.sub.1-C.sub.6 alkyl
group or is linked to R.sup.4 as defined above;
[0020] R.sup.9 and R.sup.10 each independently represent a hydrogen
atom or a C.sub.1-C.sub.6 alkyl group, or R.sup.9 and R.sup.10
together with the nitrogen atom to which they are attached form a 4
to 7-membered saturated heterocycle;
[0021] R.sup.11 and R.sup.12 each independently represent a
hydrogen atom or a C.sub.1-C.sub.6 alkyl group optionally
substituted by C.sub.1-C.sub.6 alkoxycarbonyl;
[0022] R.sup.13represents a hydrogen atom or a C.sub.1-C.sub.6
alkyl group;
[0023] R.sup.14 represents a hydrogen atom, or a C.sub.1-C.sub.6
alkyl group optionally substituted by carboxyl, C.sub.1-C.sub.6
alkoxy or C.sub.1-C.sub.6 alkoxycarbonyl;
[0024] R.sup.15 represents a group C.sub.2-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.5-C.sub.6 cycloalkenyl, adamantyl, phenyl or a saturated or
unsaturated 5- to 10-membered heterocyclic ring system comprising
at least one heteroatom selected from nitrogen, oxygen and sulphur,
wherein each group may be optionally substituted by one or more
substituents independently selected from nitro, hydroxyl, oxo,
halogen, carboxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 alkylcarbonyl,
C.sub.1-C.sub.6 alkoxycarbonyl, phenyl and --NHC(O)--R.sup.17 with
the proviso that R.sup.15 does not represent an unsubstituted
1-pyrrolidinyl, an unsubstituted 1-piperidinyl or an unsubstituted
1-hexamethyleneiminyl (1-homopiperidinyl) group;
[0025] t is 0, 1, 2 or 3;
[0026] each R.sup.16 independently represents halogen, cyano,
nitro, carboxyl, hydroxyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy,
--NR.sup.18R.sup.19, C.sub.3-C.sub.6 cycloalkylammo,
C.sub.1-C.sub.6allylthio, C.sub.1-C.sub.6 alkylcarbonyl,
C.sub.1-C.sub.6 alkylcarbonylamino, sulphonamido
(--SO.sub.2NH.sub.2), C.sub.1-C.sub.6 alkylsuphonyl,
--C(O)NR.sup.20R.sup.21, --NR.sup.22C(O)(NH).sub.vR.sup.23, phenyl,
or C.sub.1-C.sub.6 alkyl optionally substituted by carboxyl or
C.sub.1-C.sub.6 alkoxycarbonyl;
[0027] R.sup.17 represents a C.sub.1-C.sub.6 alkyl, amino
(--NH.sub.2) or phenyl group;
[0028] R.sup.18 and R.sup.19 each independently represent a
hydrogen atom or a C.sub.1-C.sub.6 alkyl group, or R.sup.18 and
R.sup.19 together with the nitrogen atom to which they are attached
form a 4- to 7-membered saturated heterocycle;
[0029] R.sup.20 and R.sup.21 each independently represent a
hydrogen atom or a C.sub.1-C.sub.6 alkyl group optionally
substituted by C.sub.1-C.sub.6 alkoxycarbonyl;
[0030] v is 0 or 1;
[0031] R.sup.22 represents a hydrogen atom or a C.sub.1-C.sub.6
alkyl group; and
[0032] R.sup.23 represents a hydrogen atom, or a C.sub.1-C.sub.6
alkyl group optionally substituted by carboxyl, C.sub.1-C.sub.6
alkoxy or C.sub.1-C.sub.6 alkoxycarbonyl;
[0033] or a pharmaceutically acceptable salt or solvate
thereof.
[0034] In the context of the present specification, an alkyl or
alkenyl substituent group or an alkyl or alkenyl moiety in a
substituent group may be linear or branched. In the definition of
R.sup.15, it should be noted that the unsaturated 5- to 10-membered
heterocyclic ring system may be aliphatic or aromatic.
[0035] The integer m is preferably 1 or 2.
[0036] Each R.sup.1 independently represents halogen (e.g.
chlorine, fluorine, bromine or iodine), cyano, nitro, carboxyl,
hydroxyl, C.sub.3-C.sub.6 cycloalkyl (cyclopropyl,
cyclobutyl,cyclopentyl or cyclohexyl), C.sub.1-C.sub.6, preferably
C.sub.1-C.sub.4, alkoxy (e.g. methoxy, ethoxy, n-propoxy or
n-butoxy), C.sub.1-C.sub.6, preferably C.sub.1-C.sub.4,
alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl),
C.sub.1-C.sub.6, preferably C.sub.1-C.sub.4, haloalkyl (e.g.
trifluoromethyl), C.sub.1-C.sub.6, preferably C.sub.1-C.sub.4,
haloalkoxy (e.g. trifluoromethoxy), --NR.sup.9R.sup.10,
C.sub.3-C.sub.6 cycloalkylamino (e.g. cyclopropylarnio,
cyclobutylamino, cyclopentylamino or cyclohexylamino),
C.sub.1-C.sub.6, preferably C.sub.1-C.sub.4, alkylthio (e.g.
methylthio or ethylthio), C.sub.1-C.sub.6, preferably
C.sub.1-C.sub.4, alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl,
n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl,
n-pentylcarbonyl or n-hexylcarbonyl), C.sub.1-C.sub.6, preferably
C.sub.1-C.sub.4, alkylcarbonylanino (e.g. methylcarbonylamino or
ethylcarbonylamino), sulphonauido, C.sub.1-C.sub.6, preferably
C.sub.1-C.sub.4, alkylsulphonyl (e.g. methylsulphonyl
ethylsulphonyl, n-propylsulphonyl isopropylsulphonyl,
n-butylsulphonyl, n-pentylsulphonyl or n-hexylsulphonyl),
--C(O)NR.sup.11R.sup.12, --NR.sup.13C(O)--(NH).sub.pR.- sup.14,
phenyl or C.sub.1-C.sub.6, preferably C.sub.1-C.sub.4, alkyl (e.g.
methyl, ethyl, n-propyl, isopropyl, n-butyl isobutyl, tert-butyl,
n-pentyl or n-hexyl) optionally substituted by carboxyl or
C.sub.1-C.sub.6, preferably C.sub.1-C.sub.4, alkoxycarbonyl (e.g.
methoxycarbonyl or ethoxycarbonyl).
[0037] Most preferably, each R.sup.1 independently represents
halogen (particularly chlorine or fluorine), cyano, nitro,
C.sub.1-C.sub.6 alkoxy (especially methoxy), C.sub.1-C.sub.6
alkylcarbonyl (especially methylcarbonyl) or C.sub.1-C.sub.6
alkylcarbonylamino (particularly methylcarbonylamino). Each R.sup.1
especially represents halogen or cyano
[0038] Preferably X represents an oxygen atom or a CH.sub.2 or NH
group.
[0039] Preferred combinations of Y, Z.sup.1 and Z.sup.2
include:
1 Y Z.sup.1 Z.sup.2 CH CH.sub.2 bond CH bond CH.sub.2 CH CH.sub.2
CH.sub.2 CH (CH.sub.2).sub.2 bond N CH.sub.2 CH.sub.2
[0040] Q preferably represents an oxygen atom.
[0041] Each R.sup.3 independently represents a C.sub.1-C.sub.6,
preferably C.sub.1-C.sub.4, alkyl (e.g. methyl, ethyl n-propyl,
isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hecyl),
C.sub.1-C.sub.6, preferably C.sub.1-C.sub.4, alkoxycarbonyl (e.g.
methoxycarbonyl or ethoxycarbonyl), --CH.sub.2OH or carboxyl group.
It is preferred that R.sup.3 represents a methyl, methoxycarbonyl,
ethoxycarbonyl --CH.sub.2OH or carboxyl group.
[0042] R.sup.4, R.sup.5, R.sup.6 and R.sup.7 each independently
represent a hydrogen atom or a C.sub.1-C.sub.6, preferably
C.sub.1-C.sub.4, alkyl (e.g. methyl ethyl, n-propyl, isopropyl,
n-butyl, isobutyl tert-butyl, n-pentyl or n-hexyl), or R.sup.4,
R.sup.5, R.sup.6 and R.sup.7 together represent a C.sub.1-C.sub.4
alkylene chain linking the two carbon atoms to which they are
attached to form a 4 to 7-membered saturated carbocycle (e.g.
cyclohexyl or preferably cyclopentyl), or R.sup.5, R.sup.6 and
R.sup.7 each represent a hydrogen atom and R.sup.4 and R.sup.8
together with the carbon atoms to which they are attached form a 5-
to 6-membered saturated carbocycle (preferably cyclopentyl).
[0043] R.sup.8 represents a hydrogen atom, a C.sub.1-C.sub.6,
preferably C.sub.1-C.sub.4, alkyl group (e.g. methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or
n-hexyl) or is linked to R.sup.4 as defined above.
[0044] R.sup.9 and R.sup.10 each independently represent a hydrogen
atom or a C.sub.1-C.sub.6, preferably C.sub.1-C.sub.4, alkyl group
(e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
teit-butyl, n-pentyl or n-hexyl), or R.sup.9 and R.sup.10 together
with the nitrogen atom towhich they are attached form a 4- to
7-membered saturated heterocycle.
[0045] R.sup.11 and R.sup.12 each independently represent a
hydrogen atom or a C.sub.1-C.sub.6, preferably C.sub.1-C.sub.4,
alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted
by a C.sub.1-C.sub.6, preferably C.sub.1-C.sub.4, alkoxycarbonyl
substituent group.
[0046] R.sup.13 represents a hydrogen atom or a C.sub.1-C.sub.6,
preferably C.sub.1-C.sub.4, alkyl group (e.g. methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or
n-hexyl).
[0047] R.sup.14 represents a hydrogen atom, or a C.sub.1-C.sub.6,
preferably C.sub.1-C.sub.4, alkyl group (e.g. methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or
n-hexyl) optionally substituted by carboxyl C.sub.1-C.sub.6,
preferably C.sub.1-C.sub.4, alkoxy or C.sub.1-C.sub.6, preferably
C.sub.1-C.sub.4, alkoxycarbonyl.
[0048] R.sup.15 represents a group C.sub.2-C.sub.6, preferably
C.sub.2-C.sub.4, alyl group (e.g. ethyl n-propyl, isopropyl,
n-butyl, isobutyl tert-butyl or n-pentyl), C.sub.2-C.sub.6,
preferably C.sub.2-C.sub.4, alkenyl C.sub.3-C.sub.6 cycloalkyl
(e.g. cyclobutyl or cyclopentyl), C.sub.5-C.sub.6 cycloalkenyl,
amntyl, phenyl or a saturated or unsaturated 5- to 10-membered
heterocyclic ring system comprising at least one heteroatom
selected. from nitrogen, oxygen and sulphur, wherein each group may
be optionally substituted by one or more (e.g. one, two, three or
four) substituents independently selected from nitro, hydroxyl,
oxo, halogen (e.g: fluorine, chlorine, bromine or iodine),
carboxyl, C.sub.1-C.sub.6, preferably C.sub.1-C.sub.4, alkyl (e.g.
methyl ethyl, n-propyl, isopropyl, n-butyl isobutyl, tert-butyl,
n-pentyl or n-hexyl), C.sub.1-C.sub.6, preferably C.sub.1-C.sub.4,
alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy),
C.sub.1-C.sub.6, preferably C.sub.1-C.sub.4, alkylthio (e.g.
methylthio or ethylthio), C.sub.1-C.sub.6, preferably
C.sub.1-C.sub.4, alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl,
n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl,
n-pentylcarbonyl or n-hexylcarbonyl), C.sub.1-C.sub.6, preferably
C.sub.1-C.sub.4, alkoxycarbonyl (e.g. methoxycarbonyl or
ethoxycarbonyl), phenyl and --NHC(O)--R.sup.17.
[0049] The saturated or unsaturated 5- to 10-membered heterocyclic
ring system may be monocyclic or polycyclic (e.g. bicyclic) and may
comprise up to four heteroatoms independently selected from
nitrogen, oxygen and sulphur. Examples of ring systems that may be
used include pyrrolidinyl, piperidinyl, pyrazolyl, thiazolidinyl,
thienyl, isoxazolyl thiadiazolyl, pyrrolyl, furanyl, thiazolyl,
indolyl, quinolinyl, benzimidazolyl, triazolyl, tetraaolyl and
pyridinyl.
[0050] Each R.sup.16 independently represents halogen (e.g.
chlorine, fluorine, bromine or iodine), cyano, nitro, carboxyl,
hydroxyl, C.sub.3-C.sub.6 cycloalkyl (cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl), C.sub.1-C.sub.6, preferably
C.sub.1-C.sub.4, alkoxy (e.g. methoxy, ethoxy, n-propoxy or
n-butoxy), C.sub.1-C.sub.6, preferably C.sub.1-C.sub.4,
alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl),
C.sub.1-C.sub.6, preferably C.sub.1-C.sub.4, haloalkyl (e.g.
trifluoromethyl), C.sub.1-C.sub.6, preferably C.sub.1-C.sub.4,
haloalkoxy(e.g. trifluoromethoxy), --NR.sup.18R.sup.19,
C.sub.3-C.sub.6 cycloalylamino (e.g. cyclopropylamino,
cyclobutylamino., cyclopentylamino or cyclohexylamno),
C.sub.1-C.sub.6, preferably C.sub.1-C.sub.4, alkylthio (e.g.
methylthio orethylthio), C.sub.1-C.sub.6, preferably
C.sub.1-C.sub.4, alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl
n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl,
n-pentylcarbonyl or n-hexylcarbonyl), C.sub.1-C.sub.6, preferably
C.sub.1-C.sub.4, alkylcarbonylamino (e.g. methylcarbonylamino or
ethylcarbonylamino), sulphonamido, C.sub.1-C.sub.6, preferably
C.sub.1-C.sub.4, alkylsulphonyl (e.g. methylsulphonyl,
ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl,
n-butylsulphonyl, n-pentylsulphonyl or n-hexylsulphonyl),
--C(O)NR.sup.21R.sup.22, --NR.sup.23C(O)--(NM).sub.vR.- sup.24,
phenyl, or C.sub.1-C.sub.6, preferably C.sub.1-C.sub.4, alkyl (e.g.
methyl, ethyl, n-propyl, isopropyl, n-butyl isobutyl, tert-butyl
n-pentyl or n-hexyl) optionally substituted by carboxyl or
C.sub.1-C.sub.6, preferably C.sub.1-C.sub.4, alkoxycarbonyl (e.g.
methoxycarbonyl or ethoxycarbonyl).
[0051] Preferably, each R.sup.16 independently represents halogen
(particularly chlorine or fluorine), cyano, C.sub.1-C.sub.4 alkoxy
(especially methoxy), C.sub.1-C.sub.4 alkoxycarbonyl (especially
methoxycarbonyl), C.sub.1-C.sub.4 haloalkyl (especially
trifluoromethyl), C.sub.1-C.sub.4 akylcarbonyl (particularly
methylcarbonyl), phenyl or C.sub.1-C.sub.4 alkyl (e.g. methyl or
tert-butyl). Each R.sup.16 is especially a halogen atom or methyl
group.
[0052] R.sup.17 represents a C.sub.1-C.sub.6, preferably
C.sub.1-C.sub.4, all group (e.g. methyl, ethyl n-propyl, isopropyl,
n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), amino or
phenyl group.
[0053] R.sup.18 and R.sup.19 each independently represent a
hydrogen atom or a C.sub.1-C.sub.6, preferably C.sub.1-C.sub.4,
alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl n-butyl,
isobutyl, tert-butyl, n-pentyl or n-hexyl), or R.sup.19 and
R.sup.20 together with the nitrogen atom to which they are attached
form a 4 to 7-membered saturated heterocycle. R.sup.20 and R.sup.21
each independently represent a hydrogen atom or a C.sub.1-C.sub.6,
preferably C.sub.1-C.sub.4, alkyl group (e.g. methyl ethyl,
n-propyl, isopropyl, n-butyl isobutyl tert-butyl n-pentyl or
n-hexyl) optionally substituted by a C.sub.1-C.sub.6, preferably
C.sub.1-C.sub.4, alkoxyCarbonyl substituent group.
[0054] R.sup.22 represents a hydrogen atom or a C.sub.1-C.sub.6,
preferably C.sub.1-C.sub.4, alkyl group (e.g. methyl ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or
n-hexyl).
[0055] R.sup.23 represents a hydrogen atom, or a C.sub.1-C.sub.6,
preferably C.sub.1-C.sub.4, alkyl group (e.g. methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or
n-hexyl) optionally substituted by carboxyl, C.sub.1-C.sub.6,
preferably C.sub.1-C.sub.4, alkoxy or C.sub.1-C.sub.6, preferably
C.sub.1-C.sub.4, alkoxycarbonyl.
[0056] Preferred compounds of the invention include:
[0057]
N-(5-Chloro-2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-pr-
opoxy})-phenyl)-isobutramide,
[0058] Thiophene-2-carboxylic acid
(2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-
-yl]-2-hydroxy-propoxy}-phenyl)-amide,
[0059]
N-[(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-p-
henylcarbamoyl)methyl]-benzamide,
[0060] Pyrazine-2-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-
-yl]-2-hydroxy-propoxy}-phenyl)-amide,
[0061] Cyclohexanecarboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-
-yl]-2-hydroxy-propoxy}-phenyl)-amide,
[0062]
N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-ph-
enyl)-phthalamic acid methyl ester,
[0063]
N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-ph-
enyl)-3-hydrpxy-butyramide,
[0064]
N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-p-
henyl)-2-ureido-acetamide,
[0065]
4-Acetylamino-N-(2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydro-
xy-propoxy}-phenyl)-butyramide,
[0066] 1-Acetyl-piperidine-4-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-p-
yrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
[0067]
N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-p-
henyl)-3-methoxy-benzamide,
[0068]
2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydr-
oxy-propoxy}-phenyl)-3-methyl-butyramide,
[0069]
2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydr-
oxy-propoxy}-phenyl)-3-hydroxy-butyramide,
[0070] Adamantane-1-carboxylic acid
(2-{3-[34-chloro-phenoxy)-pyrrolidin-1-
-yl]-2-hydroxy-propoxy}-phenyl)-amide,
[0071]
2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydr-
oxy-propoxy}-phenyl)-3-phenyl-propionamide,
[0072]
N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-p-
henyl)-2-methoxy-benzamide,
[0073] 5-Methyl-thiophene-2-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-py-
rrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
[0074] 1-Acetyl-pyrrolidine-2-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)--
pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
[0075] 1,5-Dimethyl-1H-pyrazole-3-carboxylic acid
(2-{3-[3-(4chloro-phenox-
y)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
[0076] 5-Oxo-pyrrolidine-2-carboxylic acid
(2-{3-[3-(4chloro-phenoxy)-pyrr-
olidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
[0077] 1H-Indole-6-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin--
1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
[0078] Cyclobutanecarboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-
-yl]-2-hydroxy-propoxy}-phenyl)-amide,
[0079]
N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-p-
henyl)-propionamide,
[0080] Pentanoic acid
(2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydrox-
y-propoxy}-phenyl)-amide,
[0081] Pent-4-enoic acid
(2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hyd-
roxy-propoxy}-phenyl)-amide,
[0082] Cyclopentanecarboxylic acid
(2-{3-[3(4-chloro-phenoxy)-pyrrolidin-1-
-yl]-2-hydroxy-propoxy}-phenyl)-amide,
[0083] Cyclopropanecarboxylic acid
(2-{3-[3-(chloro-phenoxy)-pyrrolidin-1--
yl]-2-hydroxy-propoxy}-phenyl)-amide,
[0084]
N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-ph-
enyl)-isobutyramide,
[0085]
N2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phen-
yl)-2-methylsulfinyl-acetamide,
[0086]
2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydr-
oxy-propoxy}-phenyl)-propionamide,
[0087]
N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-ph-
enyl)-butyramide,
[0088]
N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-p-
henyl)-3-methyl-butyramide,
[0089]
N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-p-
henyl)-2-methoxy-acetamide,
[0090]
N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-p-
henyl)-2,2-dimethyl-propionamide,
[0091] 5-Oxo-hexanoic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2--
hydroxy-propoxy}-phenyl)-amide,
[0092] Hexanoic acid
(2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-
-propoxy}-phenyl)-amide,
[0093]
2-Chloro-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-p-
ropoxy}-phenyl)-benzamide,
[0094]
3-Chloro-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-p-
ropoxy}-phenyl)-benzamide,
[0095]
(4R)-N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-
phenyl)-1,3-thiazlidine-carboxamide ditrifluoroacetate,
[0096] Thiophene-2-carboxylic acid
(2-{3-[4-(3,4dichloro-phenoxy)-piperidi-
n-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
[0097]
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy-
}-phenyl)-benzamide,
[0098]
N-(2-{3-[4(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-
-phenyl)-nicotinamide,
[0099] Pyridine-2-carboxylic acid
(2-{3-[4-(3,4dichloro-phenoxypiperidin-1-
-yl]-2-hydroxy-propoxy}-phenyl)-amide,
[0100]
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy-
}-phenyl)-isonicotinamide,
[0101] Cyclohexanecarboxylic acid
(2-{3-[4-(3,4-dichloro-phenoxy)-piperidi-
n-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
[0102]
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy-
}-phenyl)-3-hydroxy-butyramide,
[0103] 5-Methyl-thiophene-2-carboxylic acid
(2-{3-[4-(3,4-dichloro-phenoxy-
)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
[0104] Cyclobutanecarboxylic acid
(2-{3-[4-(3,4-dichloro-phenoxy)-piperidi-
n-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
[0105]
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy-
}-phenyl)-propionamide,
[0106] Pentanoic acid
(2-{3-[4-(3,4dichloro-phenoxy)-piperidin-1-yl]-2-hyd-
roxy-propoxy}-phenyl)-amide,
[0107] Pentenoic acid
(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hy-
droxy-propoxy}-phenyl)-amide,
[0108] Cyclopentanecarboxylic acid (2-{3-[4-(3
,4dichloro-phenoxy)-piperid-
in-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,
[0109]
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy-
}-phenyl)-3-methyl-butyramide,
[0110]
N2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-
-2,2,2-trifluoroacetamide hydrochloride,
[0111]
4-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy-
}-phenylcarbamoyl)3-methyl-butyric acid,
[0112]
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy-
}-phenyl)-succinamic acid,
[0113] Furan-2-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl-
]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0114] 1H-Pyrrole-2-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-
-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0115] Thiophene-2-carboxylic acid
(2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-
-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0116] Cyclopentanecarboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin--
1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0117] 5-Methyl-thiophene-2-carboxylic acid
(2-{3-[3-(4chloro-phenoxy)-pyr-
rolidin-1-yl]-2-hydroxy-propoxy}-4methyl-phenyl)-amide,
[0118] 3-Chloro-thiophene-2-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-py-
rrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0119] 5-Methyl-isoxazole-4-carboxylic acid
(2-{3-[3-(4chloro-phenoxy)-pyr-
rolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0120] [1,2,3]Thiadiazole-4-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-py-
rrolidn-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0121] 3-Methyl-furan-2-carboxylic acid
(2-{3-[3-(4chloro-phenoxy)-pyrroli-
din-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0122] Cyclopent-1-enecarboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolid-
in-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0123] 2-Methyl-furan-3-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrol-
idin-1-yl]-2-hydroxy-propoxy}-methyl-phenyl)-amide,
[0124] 3-Methyl-thiophene-2-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-py-
rrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0125] 5-Nitro-1H-pyrazole-3-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-p-
yrrolidin-1-yl]-2-hydroxy-propoxy}4-methyl-phenyl)-amide,
[0126] Thiophene-3-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin--
1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0127] Cyclobutanecarboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-
-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0128] Furan-2-carboxylic acid
(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl-
]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0129] 1H-Pyrrole-2-carboxylic acid
(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-
-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0130] Thiophene-2-carboxylic acid
(2-{3-[3-(4fluoro-phenoxy)-pyrrolidin-1-
-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0131] 3-Chloro-thiophene-2-carboxylic acid
(2-{3-[3-(4-fluoro-phenoxy)-py-
rrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0132] 5-Methyl-isoxazole-4-carboxylic acid
(2-{3-[3-(4-fuoro-phenoxy)-pyr-
rolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0133] 3-Methyl-furan-2-carboxylic acid
(2-{3-[3-(4-fluoro-phenoxy)-pyrrol-
idin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0134] Cyclopent-1-enecarboxylic acid
(2-{3-[3-(4fluoro-phenoxy)-pyrrolidi-
n-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0135] 2-Methyl-furan-3-carboxylic acid
(2-{3-[3-(4-fluoro-phenoxy)-pyrrol-
idin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0136] 3-Methyl-thiophene-2-carboxylic acid
(2-{3-[3-(4fluoro-phenoxy)-pyr-
rolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0137] 5-Chloro-thiophene-2-carboxylic acid
(2-{3-[3-(4fluoro-phenoxy)-pyr-
rolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0138] Thiophene-3-carboxylic acid
(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin--
1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0139] 2,5-Dimethyl-furan-3-carboxylic acid
(2-{3-[3-(4-fluoro-phenoxy)-py-
rrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0140] Cyclobutanecarboxylic acid
(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-
-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0141] Furan-3-carboxylic acid
(2-{3-[3-(4fluoro-phenoxy)-pyrrolidin-1-yl]-
-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,
[0142]
N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)o-
xy]-4-methylphenyl}-1H-pyrrole-2-carboxamide,
[0143]
N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)o-
xy]-4-methylphenyl}-3-thiophenecarboxamide,
[0144]
N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-2-methy-
lpropyl)oxy]phenyl}-2-thiophenecarboxamide, compound with
trifluoroacetic acid,
[0145]
N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)o-
xy]-4-methylphenyl}-2-thiophenecarboxamide,
[0146]
N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)o-
xy]phenyl}-2-furancarboxamide,
[0147]
N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)o-
xy]phenyl}-1-pyrrole-2-carboxamide,
[0148]
N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)o-
xy]-4-methylphenyl}-1H-pyrrole-3-carboxamide,
[0149]
N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)o-
xy]-4-methylphenyl}-2-furancarboxamide,
[0150]
N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-2-methy-
lpropyl)oxy]phenyl}cyclopentanecarboxamide, compound with
trifluoracetic acid,
[0151]
N-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-p-
ropoxy}-phenyl)-benzamide,
[0152]
N-(2-{3-[3-(4-Cyano-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-pr-
opoxy}-phenyl)-benzamide,
[0153]
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-2-methy-
l-propoxy}-phenyl)-benzamide,
[0154]
N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-p-
ropoxy}-phenyl)-benzamide, and
[0155]
N-(2-{3-[4-(3,4-Dichloro-phenylamino)-piperidin-1-yl]-2-hydroxy-2-m-
ethyl-propoxy}-phenyl)-benzamide.
[0156] The present invention further provides a process for the
preparation of a compound of formula (I) as defined above which
comprises reacting a compound of general formula 3
[0157] or a salt thereof (e.g. an acid addition salt such as a
hydrochloride salt), wherein m, n, t, R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.16, Q, Z.sup.1 and
Z.sup.2 are as defined in formula (I), with a compound of general
formula
R.sup.15--CO.sub.2H (III)
[0158] or chemically equivalent derivative thereof (e.g. acyl
halide or anhydride derivative) wherein R.sup.15 is as defined in
formula (I);
[0159] and optionally thereafter forming a pharmaceutically
acceptable salt or solvate of the compound of formula (I)
obtained.
[0160] The process of the invention may conveniently be carried out
in a solvent, e.g. an organic solvent such as an alcohol (e.g.
methanol or ethanol), a hydrocarbon (e.g. toluene), an amine (e.g.
triethylamine or diisopropylethylamine) or acetonitrile at a
temperature ot, for example, 15.degree. C. or above, such as a
temperature in the range from 20 to 120.degree. C.
[0161] Compounds of formulae (II) and (III) are either commercially
available, are well known in the literature or may be prepared
easily using known techniques.
[0162] It will be appreciated by those skilled in the art that in
the process of the present invention certain functional groups such
as hydroxyl or amino groups in the staring reagents or intermediate
compounds may need to be protected by protecting groups. Thus, the
preparation of the compounds of formula (I) may involve, at an
appropriate stage, the removal of one or more protecting
groups.
[0163] The protection and deprotection of functional groups is
descnbed in `Protective Groups in Organic Chemistry`, edited by J.
W. F. McOmie, Plenum Press (1973) and `Protective Groups in Organic
Synthesis`, 2nd edition, T. W. Greene and P. G. M. Wuts,
Wiley-Interscience (1991).
[0164] The compounds of formula (I) above may be converted to a
pharmaceutically acceptable salt or solvate thereof, preferably an
acid addition salt such as a hydrochloride, hydrobromide,
phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate,
methanesulphonate orptolienesulphonate.
[0165] Compounds of formula (I) are capable of existing in
stereoisomeric forms. It will be understood that the invention
encompasses the use of all geometric and optical isomers of the
compounds of formula (I) and mixtures thereof including racemates.
The use of tautomers and mixtures thereof also form an aspect of
the present invention.
[0166] The compounds of formula (I) have activity as
pharmaceuticals, in particular as modulators of chemokine receptor
(especially MIP-1.alpha. chemokine receptor) activity, and may be
used in the treatment of autoimmune, inflammatory, proliferative
and hyperproliferative diseases and immunologically-mediated
diseases including rejection of taplanted organs or tissues and
Acquired Ilununodeficiency Syndrome (AIDS).
[0167] Examples of these conditions are:
[0168] (1) (the respiratory tract) airways diseases including
chronic obstructive pulmonary disease (COPD) such as irreversible
COPD; asthma, such as bronchial, allergic, intrinsic, extrinsic and
dust asthma, particularly chronic or inveterate asthmn (e.g. late
asthma and airways hyper-responsiveness); bronchitis; acute,
allergic, atrophic rhinitis and chronic rhinitis including rhinitis
caseosa, hypertrophic rhinitis, iinitis purulenta, rhinitis sicca
and rhinitis medicamentosa; membranous rhinitis including croupous,
fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis;
seasonal rhinitis including rhinitis nervosa (hay fever) and
vasomotor rhinitis; sarcoidosis, farmer's lung and related
diseases, fibroid lung and idiopathic interstitial pneumonia;
[0169] (2) (bone and joints) rheumatoid arthritis, seronegative
spondyloarthropathies (including ankylosing spondylitis, psoriatic
arthritis and Reiter's disease), Behcet's disease, Sjogren's
syndrome and systemic sclerosis;
[0170] (3) (skin) psoriasis, atopical dermatitis, contact
dermatitis and other eczmatous dermitides, seborrhoetic dermatitis,
Lichen planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa,
urticaria, angiodermas, vasculitides, eiydiemas, cutaneous
eosinophilias, uveitis, Alopecia areata and vernal
conjunctivitis;
[0171] (4) (gastrointestinal tract) Coeliac disease, proctitis,
eosinopilic gastro-enteritis, mastocytosis, Crohn's disease,
ulcerative colitis, food-related allergies which have effects
remote from the gut, e.g., migraine, rhinitis and eczema;
[0172] (5) (other tissues and systemic disease) multiple sclerosis,
atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), lupus
erythematosus, systemic lupus, erythematosus, Hashimoto's
thyroiditis, myasthenia gravis, type I diabetes, nephrotic
syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous
leprosy, sezary syndrome and idiopathic thrombocytopenia
pupura;
[0173] (6) (allograft rejection) acute and chronic following, for
example, tnsplantation of kidney, heart, liver, lung, bone marrow,
skin and cornea; and chronic graft versus host disease;
[0174] (7) cancers, especially non-sraill cell lung cancer (NSCLC)
and squamous sarcoma;
[0175] (8) diseases in which angiogenesis is associated with raised
chemokine levels (e.g. NSCLC); and
[0176] (9) cystic fibrosis, stroke, re-perfusion injury in the
heart, brain, peripheral limbs and sepsis.
[0177] Thus, the present invention provides a compound of formula
(I), or a pharmaceutically-acceptable salt or solvate thereof, as
hereinbefore defined for use in therapy.
[0178] In a further aspect, the present invention provides the use
of a compound of formula (I), or a pharmaceutically acceptable salt
or solvate thereof as hereinbefore defined in the manufacture of a
medicament for use in therapy.
[0179] In the context of the present specification, the term
"therapy" also includes "prophylaxis" unless there are specific
indications to the contrary. The terms "therapeutic" and
"therapeutically" should be construed accordingly.
[0180] The invention also provides a method of treating an
inflammatory disease in a patient suffering from, or at risk of,
said disease, which comprises administering to the patient a
therapeutically effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt or solvate thereof, as
hereinbefore defined.
[0181] The invention still further provides a method of treating an
airways disease in a patient suffering from, or at risk of, said
disease, which comprises administering to the patient a
therapeuticallyeffective amount of a compound of formula (I), or a
pharmaceutically acceptable salt or solvate thereof, as
hereinbefore defined.
[0182] For the above-mentioned therapeutic uses the dosage
administered will, of course, vary s with the compound employed,
the mode of administration, the treatment desired and the disorder
indicated. The daily dosage of the compound of formula (I) may be
in the range from 0.001 mg/kg to 30 mg/kg.
[0183] The compounds of formula (I) and pharmaceutically acceptable
salts and solvates thereof may be used on their own but will
generally be administered in the form of a pharmaceutical
composition in which the formula (I) compound/salt/solvate (active
ingredient) is in association with a pharmaceutically acceptable
adjuvant, diluent or carrier. Depending on the mode of
administration, the pharmaceutical composition will preferably
comprise from 0.05 to 99% w (per cent by weight), more preferably
from 0.05 to 80% w, still more preferably from 0.10 to 70% w, and
even more preferably from 0.10 to 50% w, of active ingredient, all
percentages by weight being based on total composition.
[0184] The present invention also provides a pharmaceutical
composition comprising a compound of formula (I), or a
pharmaceutically acceptable salt or solvate thereof, as
hereinbefore defined, in association with a pharmaceutically
acceptable adjuvant, diluent or carrier.
[0185] The invention further provides a process for the preparation
of a pharmaceutical composition of the invention which comprises
mixing a compound of formula (I), or a pharmaceutically acceptable
salt or solvate thereof, as hereinbefore defined,,with a
pharmaceutically acceptable adjuvant, diluent or carrier.
[0186] The pharmaceutical compositions may be administered
topically (e.g. to the lung and/or airways or to the skin) in the
form of solutions, suspensions, heptafluoroalkane aerosols and dry
powder formulations; or systemically, e.g. by oral administration
in the form of tablets, capsules, syrups, powders or granules, or
by parenteral administration in the form of solutions or
suspensions, or by subcutaneous ad i:stion or by rectal
administration in the form of suppositories or transdermally.
[0187] The invention will now be further explained by reference to
the following illustrative examples, in which .sup.1H NMR spectra
were recorded on Varian Unity Inova 400. The central solvent peak
of chloroform-d (.delta..sub.H 7.27 ppm) were used as internal
standard Low resolution mass spectra and accurate mass
determination were recorded on a Hewlett-Packard 1100 LC-MS system
equipped with APCI/ESI ionisation chambers. All solvents and
commercial reagents were laboratory grade and used as received. The
nomenclature used for the compounds was generated with ACDUAC Name
Pro. The following abbreviations are used in the examples:
[0188] NMP: 1-Methyl-2-pyrrolidinone
[0189] DIMA: N,N-Diisopropylethylanine
[0190] HBTU: 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate
[0191] HoBT: 1-Hydroxybenzotriazole
[0192] THF: Tetrahydrofuran
EXAMPLE 1
N-(5-Chloro-2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-
-phenyl)-isobutyramide
[0193] a) N-(5-Chloro-2-hydroxy-phenyl)-isobutyramide
[0194] In a flask was added 4-chloro-2-aminophenol (1.2 g, 8.39
mmole) and water (25 ml). The suspension was vigorously stirred and
isobutyric anhydride (1.6 ml, 10.5 inmole) was added. The mixture
was heated to 60.degree. C. for 30 minutes under vigorous stirring.
The emulsion was cooled, and a precipitate was formed, which was
collected through filtration. The solid was washed twice with water
on the filter and was finally dried to give 1.4 g (78%) of the
sub-title compound as a white solid.
[0195] .sup.1H-NMR (400 MHz DMSO-d.sub.6) .delta.: 10.11 (1H, s);
9.12 (1H, s); 7.94 (1H, d, J2.5 Hz); 6.95 (1H, dd, J 8.7 2.6 Hz);
6.84 (1H, d, J8.5 Hz); 2.79 (1H, p, J6.7 Hz); 1.08 (6H, d, J6.8
Hz)
[0196] b) N-(5-Chloro-2-oxiranylmethoxy-phenyl)-isobutyramide
[0197] In a vial was added the compound obtained in a) (0.4 g, 1.87
mmole), epibromohydrin (0.28 g, 2.06 mmole), K.sub.2CO.sub.3 (0.5
g, 3.7 mnmole) and DMF (2 ml). The vial was sealed and heated with
stirrng (2 hours, 60.degree. C.). The mixture was then partitioned
between EtOAc and water, and the organic phase was washed twice
with water and once with brine, and was finally evaporated to give
a brown solid. The crude epoxide was purified on silica, to give
0.22 g (44%) of the sub-title compound as a white solid.
[0198] c) In a vial was added the compound obtained in b) (0.026 g,
0.13 mmole), 3-(4-chlorophenoxy)-pyrrolidine (0.035 g, 0.13 mmole)
in ethanol (2 ml). The vial was sealed and heated with stirring at
75.degree. C. for 3 hours. The solution was allowed to cool, and
the solvent was evaporated. The crude product was purified on
silica, and the pure fractions were collected. The title compound
was lyophilized as the hydrochloride, giving 0.055 g (84%) as a
white solid. The compound was a mixture of four stereoisomers,
which had an effect on the NMR-spectra.
[0199] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 10.84-10.34
(1H, m); 9.12 (1H, s); 8.09 (1H, s); 7.36 (2H, dd, J 9.2 1.3 Hz);
7.11-7.00 (3H, m); 7.00 (211 d, J 8.8 Hz); 6.22-6.06 (1H, m);
5.22-5.10 (1H, m); 4.34 (1H, bs); 4.08-3.96 (1.5H, m); 3.95-3.87
(1H, m); 3.83-3.66 (1.5H m); 3.61-3.23 (3H, m); 2.86 (1H, sept,
J6.6 Hz); 2.64-2.51 (1/2H, m); 2.36-2.14 (1H, m); 2.14-2.00 (1/2H,
m); 1.08 (6H, d, J 6.7 Hz) APCI-MS: m/z 467.2 [MH+]
[0200] Aniline Intermediate 1
[0201]
1-(2-aminophenoxy)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-prop-
anol dihydrochloride
[0202]
N-(2-{3-[4-(3,4-chlorophenoxy)-1-piperidinyl]-2-hydroxypropoxy}phen-
yl)-acetamide (1.418 g, 3.13 mmol, prepared by analogy to Example
1) was dissolved in 50 ml HCl (35%/aq, puriss) and refluxed
overnight. The product precipitated and was filtered and dried to
give 0.835 g (65%) of the title compound.
[0203] APCI-MS m/z: 411, 413 [MH.sup.+].sup.1H NMR (400 Mz,
CDCl.sub.3): .delta. 8.39-3.31 (m, 2H), 7.31(d, 1H), 7.01-6.98(m,
3E), 6.94-6.91(m, 1H), 6.75(dd, 1H), 4.31(m, 1), 4.12-4.02 (m, 2H),
3.92(dd, 1H), 2.90(m, 1H), 2.69(m, 1H), 2.62-2.51(m, 2H), 2.46(dd,
1H), 2.34(m, 1H), 2.18(s, 3H), 2.04-1.93(m, 2H), 1.89-1.77(m,
2H).
[0204] Aniline Intermediate 2
[0205]
1-[(2-aminophenyl)oxy]-3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-
-propanol dihydrochloride
[0206] Prepared according to the method described in Aniline
Intermediate 1.
[0207] APCI-MS m/z: 363, 365 [MH.sup.+]
[0208] The intermediate anilines 1 and 2 described above were used
in the following examples.
EXAMPLE 2
Thiophene-2-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-
-hydroxy-propoxy}-phenyl)-amide
[0209] To a solution of 80 uL 0.2M 2-thiophenecarboxylic acid in N
were IBTU (80uL, 0.2M/NMP) ,HoBT (80 uL, 0.2M/NMP), DIEA (30 uL,
0.5M/NMP) and pyridine (30 uL, 0.5M/NMP) added and stirred for 30
minutes before 1-[(2-aminophenyl)oxy]-3-{3-[(4-
chlorophenyl)oxy]-1-pyrrolidinyl}-2-prop- anol (75 uL, 0.2 M/NMP)
was added. The mixture was stirred overnight at room temperature
before it was concentrated under reduced pressure to dryness. The
product was diluted with 1000 uL dichloromethane and washed with
with sat. NaHCO.sub.3/aq (800 uL), 1.8% HCl/aq(800 uL) and sat
NaC])aq.
[0210] The organic layer was concentrated under reduced pressure to
dryness and used without further purification Yield 3.6 mg, 51%
[0211] APCI-MS m/z: 473.2 [MH.sup.+].sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 7.88-7.85 (d, 1H), 7.74-7.65 (m, 2H),
7.34-7.28 (m, 2H), 7.27-7.21 (m, 1H), 7.20-7.15 (m, 1H), 7.14-7.09
(dd, 1H), 7.06-7.00 (m, 1H), 6.96-6.91 (m, 2H), 5.18-5.12 (m, 1H),
4.39-4.30 (m, 1H), 4.19-3.24 (m, 9H), 2.66-2.11 (m, 3H)
[0212] The following Examples 3 to 53 were prepared by methods
analogous to the method descnbed in Example 2.
EXAMPLE 3
N-[(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenylc-
arbamoyl)-methyl]-benzamide
[0213] APCI-MS m/z: 524.3 [MH.sup.+]
EXAMPLE 4
Pyrazine-2-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2--
hydroxy-propoxy}phenyl)-amide
[0214] APCI-MS m/z: 469.2 [MH.sup.+]
EXAMPLE 5
Cyclohexanecarboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2--
hydroxy-propoxy}-phenyl)-amide
[0215] APCI-MS m/z: 473.3 [MH.sup.+]
EXAMPLE 6
N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-p-
hthalamic acid methyl ester
[0216] APCI-MS m/z: 525.2 [MH.sup.+]
EXAMPLE 7
N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-
-hydroxy-butyramide
[0217] APCI-MS m/z: 449.2 [MH.sup.+]
EXAMPLE 8
N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-
-ureido-acetamide
[0218] APCI-MS m/z: 463.2 [MH.sup.+]
EXAMPLE 9
4-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-pro-
poxy}-phenyl)-butyramide
[0219] APCI-MS m/z: 490.3 [MH.sup.+]
EXAMPLE 10
1-Acetyl-piperidine-4-carboxylic acid
(2-{3-[3-(4chloro-phenoxy)-pyrrolidi-
n-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
[0220] APCI-MS m/z: 516.3 [MH.sup.+]
EXAMPLE 11
N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)--
3-methoxy-benzamide
[0221] APCI-MS m/z: 497.2 [MH.sup.+]
EXAMPLE 12
2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-pro-
poxy}-phenyl)-3-methyl-butyramide
[0222] APCI-MS m/z: 504.3 [MH.sup.+]
EXAMPLE 13
2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-pro-
poxy}-phenyl)-3-hydroxy-butyramide
[0223] APCI-MS m/z: 506.2 [MH.sup.+]
EXAMPLE 14
Adamantane-1-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]--
2-hydroxy-propoxy}-phenyl)-amide
[0224] APCI-MS m/z: 525.3 [MH.sup.+]
EXAMPLE 15
2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-pro-
poxy}-phenyl)-3-phenyl-propionamide
[0225] APCI-MS m/z: 552.3 [MH.sup.+]
EXAMPLE 16
N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)--
2-methoxy-benzamide
[0226] APCI-MS m/z: 497.2
EXAMPLE 17
5-Methyl-thiophene-2-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidi-
n-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
[0227] APCI-MS m/z: 487.2 [MH.sup.+]
EXAMPLE 18
1-Acetyl-pyrrolidine-2-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrroli-
din-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
[0228] APCI-MS m/z: 502.3 [MH.sup.+]
EXAMPLE 19
1,5-Dimethyl-1H-pyrazole-3-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyr-
rolIdin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
[0229] APCI-MS m/z: 485.3 [MH.sup.+]
EXAMPLE 20
5-Oxo-pyrrolidine-2-carboxylic acid
(2-{3-[3-(4-chlorophenoxy)-pyrrolidin--
1-yl]-2-hydroxy-propoxy}-phenyl)-amide
[0230] APCI-MS m/z: 474.2 [MH.sup.+]
EXAMPLE 21
1H-Indole-6-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-
-hydroxy-propoxy}-phenyl)-amide
[0231] APCI-MS m/z: 506.2 [MH.sup.+]
EXAMPLE 22
Cyclobutanecarboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2--
hydroxy-propoxy}-phenyl)-amide
[0232] APCI-MS m/z: 445.3 [MH.sup.+]
EXAMPLE 23
N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-p-
ropionamide
[0233] APCI-MS m/z: 419.2 [MH.sup.+]
EXAMPLE 24
Pentanoic acid
(2-{3-[3-(4chloro-phenoxy)-pyrrolldin-1-yl]-2-hydroxy-propo-
xy}-phenyl)-amide
[0234] APCI-MS m/z: 447.3 [MH.sup.+]
EXAMPLE 25
Pent-4-enoic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolIdin-1-yl]-2-hydroxy-p-
ropoxy}-phenyl)-amide
[0235] APCI-MS m/z: 445.3 [MH.sup.+]
EXAMPLE 26
Cyclopentanecarboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-
-hydroxy-propoxy}-phenyl)-amide
[0236] APCI-MS m/z: 459.3 [MH.sup.+]
EXAMPLE 27
Cyclopropanecarboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-
-hydroxy-propoxy}-phenyl)-amide
[0237] APCI-MS m/z: 431.2 [MH.sup.+]
EXAMPLE 28
N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)--
isobutyramide
[0238] APCI-MS m/z: 433.3 [MH.sup.+]
EXAMPLE 29
N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)--
2-methylsulfanyl-acetamide
[0239] APCI-MS m/z: 451.2 [MH.sup.+]
EXAMPLE 30
2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-pro-
poxy}-phenyl)-propionamide
[0240] APCI-MS m/z: 476.2 [MH.sup.+]
EXAMPLE 31
N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroy-propoxy}phenyl)-bu-
tyramide
[0241] APCI-MS m/z: 433.3 [MH.sup.+]
EXAMPLE 32
N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)--
3-methyl-butyramide
[0242] APCI-MS m/z: 447.3 [MH.sup.+]
EXAMPLE 33
N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)--
2-methoxy-acetamide
[0243] APCI-MS m/z: 435.2 [MH.sup.+]
EXAMPLE 34
N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)--
2,2-dimethyl-propionamide
[0244] APCI-MS m/z: 447.2 [MH.sup.+]
EXAMPLE 35
5-Oxo-hexanoic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-
-propoxy}-phenyl)-amide
[0245] APCI-MS m/z: 475.3 [MH.sup.+]
EXAMPLE 36
Hexanoic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propo-
xy}-phenyl)-amide
[0246] APCI-MS m/z: 461.3 [MH.sup.+]
EXAMPLE 37
2-Chloro-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-
-phenyl)-benzamide
[0247] APCI-MS m/z: 501.2, 503.2 [MH.sup.+]
EXAMPLE 38
3-Chloro-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-
-phenyl)-benzamide
[0248] APCI-MS m/z: 501.2, 503.2 [MH.sup.+]
EXAMPLE 39
(4R)-N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-
-1,3-thiazolidine-4-carboxamide ditrifluoroacetate
[0249] APCI-MS m/z: 478.2 [MH.sup.+]
EXAMPLE 40
Thiophene-2-carboxylic acid
(2-{3-[4-(3,4dichloro-phenoxy)-piperidin-1-yl]-
-2-hydroxy-propoxy}-phenyl)-amide
[0250] APCI-MS m/z: 521.0, 523.0 [MH.sup.+]
EXAMPLE 41
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperdin-1-yl]-2-hydroxy-propoxy}-phenyl-
)-benzamide
[0251] APCI-MS m/z: 515.2, 517.2[MH.sup.+]
EXAMPLE 42
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperdin-1-yl]-2-hydroxy-propoxy}-phenyl-
)-nicotinamide
[0252] APCI-MS m/z: 516.2, 518.2 [MH.sup.+]
EXAMPLE 43
Pyridine-2-carboxylic acid
(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]- -2-hydroxy-
propoxy}-phenyl)-amide
[0253] APCI-MS m/z: 516.2, 518.2 [MH.sup.+]
EXAMPLE 44
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-pheny-
l)-isonicotinamide
[0254] APCI-MS m/z: 516.2, 518.2 [MH.sup.+]
EXAMPLE 45
Cyclohexanecarboxylic acid
(2-{3-[4-(3,4-chloro-phenoxy)-piperldin-1-yl]-2-
-hydroxy-propoxy}-phenyl)-amide
[0255] APCI-MS m/z: 521.3, 523.3 [MH.sup.+]
EXAMPLE 46
N-(2-{3-[4-(3,4-Dichlorophenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}phenyl)-
-3-hydroxy-butyramide
[0256] APCI-MS m/z: 497.2, 499.3 [MH.sup.+]
EXAMPLE 47
5-Methyl-thiophene-2-carboxylic acid
(2-{3-[4-(3,4-dichloro-phenoxy)-piper-
din-1-yl]-2-hydroxy-propoxy}-phenyl)-amide
[0257] APCI-MS m/z: 535.2, 537.2 [MH.sup.+]
EXAMPLE 48
Cyclobutanecarboxylic acid
(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-
-2-hydroxy-propoxy}-phenyl)-amide
[0258] APCI-MS m/z: 493.3, 495.2 [MH.sup.+]
EXAMPLE 49
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-pheny-
l)-propionamide
[0259] APCI-MS m/z: 467.2, 469.2 [MH.sup.+]
EXAMPLE 50
Pentanoic acid
(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-p-
ropoxy}-phenyl)-amide
[0260] APCI-MS m/z: 495.3,497.3 [MH.sup.+]
EXAMPLE 51
Pent-4-enoic acid
(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydrox-
y-propoxy}-phenyl)-amide
[0261] APCI-MS m/z: 493.3 ,495.2[MH.sup.+]
EXAMPLE 52
Cyclopentanecarboxylic acid
(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl-
]-2-hydroxy-propoxy}-phenyl)-amide
[0262] APCI-MS m/z: 507.3, 509.3 [MH.sup.+]
EXAMPLE 53
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-pheny-
l)-3-methyl-butyramide
[0263] APCI-MS m/z: 495.3,497.3 [MH.sup.+]
EXAMPLE 54
N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-2,2,-
2-trifluoroacetamide hydrochloride
[0264] A mixture of
1-(2-aminophenoxy)-3-[3-(4-chlorophenoxy)-1-pyrrolidin-
yl]-2-propanol (10 mg, 0.022 mmol), dichloromethane (3 ml) and
Triethyl amine was cooled in an ice bath A solution of Trifluoro
acetic anhydride (3.5 .mu.l, 0.025 mmol) in dichloromethane (2 ml)
was then added and the mixture stirred at 0.degree. C. until
reaction completion. The mixture was diluted with dichloromethane,
washed with 1M H.sub.2SO.sub.4, water, dried over natrium sulphate
and concentrated to give an oil. The oil was treated with 1.0M
ethereal HCl solution to give the product as solid (9 mg).
[0265] APCI-MS: m/z 459,460 [MH.sup.+]
EXAMPLE 55
4-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-pheny-
lcarbamoyl)-3-methyl-butyric acid
[0266]
1-(2-aminophenoxy)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-prop-
anol (75 uL, 0.2M/NMP) was mixed with 3-methyl glutaric anhydride
(3 eq, 225 uL 0.2 M/NMP) to get a product containing both esther
and amide. After evaporation of the mixture it was treated with 3
eq 0.5M LiOH in (TF/water 1:4) for two hours at 80.degree. C. to
hydrolyse the esther. The reaction mixture was diluted with more
water (2 mL) and the desired product was extracted with 5.times.500
uL EtOAc which was evaporated to dryness.
[0267] APCI-MS m/z: 539.2, 541.2 [MH.sup.+]
EXAMPLE 56
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-pheny-
l)-succinamic acid
[0268] Prepared according to the method described in Example
55.
[0269] APCI-MS m/z: 511.2, 513.2 [MH.sup.+]
[0270] Aniline Intermediate 3
[0271]
1-(2-amino-5-methylphenoxy)-3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]--
2-propanol
[0272] APCI-MS m/z: 377.2, 379.1 [MH.sup.+]
[0273] .sup.1H NMR (400 MHz, CDCl3): .delta. 7.26-7.21 (m, 2H),
6.79-6.74 (m, 2H), 6.67-6.62 (m, 3H), 4.83-4.76 (m, 1H), 4.15-4.06
(m, 1H), 4.04-4.00 (d, 2H), 3.73-3.64 (s, 2H), 3.47-3.35 (s, 1H),
3.14-2.56 (m, 6H), 2.36-2.22(m, 4H), 2.05-1.95(m, 1H)
[0274] Aniline Intermediate 4
[0275]
1-(2-amino-5-methylphenoxy)-3-[3-(4-fluorophenoxy)-1-pyrrolidinyl]--
2-propanol
[0276] APCI-MS m/z: 361.1 [MH.sup.+]
[0277] .sup.1H NMR (400 MHz, CDCl3): .delta. 7.00-6.94 (m, 2H),
6.81-6.76 (m, 2H), 6.67-6.62(m, 3H), 4.81-4.74 (m, 1H), 4.15-4.06
(m, 1H), 4.03-3.99 (m, 2H), 3.88-3.36 (m, 3H), 3.12-2.56 (m, 6H),
2.33-2.23(m, 4H), 2.05-1.96(m, 1H)
[0278] The compounds of Examples 57 to 85 were prepared using one
of the Aniline Intermediates 3 and 4.
EXAMPLE 57
Furan-2-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hyd-
roxy-propoxy}-4-methyl-phenyl)-amide
[0279] APCI-MS m/z: 471.5, 473.5 [MH.sup.+]
EXAMPLE 58
1H-Pyrrole-2-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]--
2-hydroxy-propoxy}-4-methyl-phenyl)-amide
[0280] APCI-MS m/z: 470.5, 472.5 [MH.sup.+]
EXAMPLE 59
Thiophene-2-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-
-hydroxy-propoxy}-4-methyl-phenyl)-amide
[0281] APCI-MS m/z: 487.5, 489.5 [MH.sup.+]
EXAMPLE 60
Cyclopentanecarboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrilidin-1-yl]-2-
-hydroxy-propoxy}-4-methyl-phenyl)-amide
[0282] APCI-MS m/z: 473.6, 475.5 [MH.sup.+]
EXAMPLE 61
5-Methyl-thiophene-2-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolldi-
n-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
[0283] APCI-MS m/z: 501.5, 503.5 [MH.sup.+]
EXAMPLE 62
3-Chloro-thiophene-2-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidi-
n-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
[0284] APCI-MS m/z: 521.5, 532.5 [MH.sup.+]
EXAMPLE 63
5-Methyl-isoxazole-4-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidi-
n-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
[0285] APCI-MS m/z: 486.5, 488.6 [MH.sup.+]
EXAMPLE 64
[1,2,3]Thiadiazole-4-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrroldin-
-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
[0286] APCI-MS m/z: 489.5, 491.5[MH.sup.+]
EXAMPLE 65
3-Methyl-furan-2-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1--
yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
[0287] APCI-MS m/z: 485.5, 487.6 [MH.sup.+]
EXAMPLE 66
Cyclopent-1-enecarboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl-
]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
[0288] APCI-MS m/z: 471.6, 473.6 [MH.sup.+]
EXAMPLE 67
2-Methyl-furan-3-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrroldin-1-y-
l]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
[0289] APCI-MS m/z: 485.6, 487.6 [MH.sup.+]
EXAMPLE 68
3-Methyl-thiophene-2-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidi-
n-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
[0290] APCI-MS m/z: 501.6, 503.5 [MH.sup.+]
EXAMPLE 69
5-Nitro-1H-pyrazole-3-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolid-
in-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
[0291] APCI-MS m/z: 516.5, 518.5 [MH+]
EXAMPLE 70
Thiophene-3-carboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-
-hydroxy-propoxy}-4-methyl-phenyl)-amide
[0292] APCI-MS m/z: 487.5, 489.5 [MH+]
EXAMPLE 71
Cyclobutanecarboxylic acid
(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2--
hydroxy-propoxy}-4-methyl-phenyl)-amide
[0293] APCI-MS m/z: 459.5, 461.5 [MH+]
EXAMPLE 72
Furan-2-carboxylic acid
(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hyd-
roxy-propoxy}-4-methyl-phenyl)-amide
[0294] APCI-MS m/z: 455.5 [MH+]
EXAMPLE 73
1H-Pyrrole-2-carboxylic acid
(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]--
2-hydroxy-propoxy}-4-methyl-phenyl)-amide
[0295] APCI-MS m/z: 454.6 [MH+]
EXAMPLE 74
Thiophene-2-carboxylic acid
(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-
-hydroxy-propoxy}-4-methyl-phenyl)-amide
[0296] APCI-MS m/z: 471.5 [MH.sup.+]
EXAMPLE 75
3-Chloro-thiophene-2-carboxylic acid
(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidi-
n-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
[0297] APCI-MS m/z: 505.5, 507.5 [MH+]
EXAMPLE 76
5-Methyl-isoxazole-4-carboxylic acid
(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidi-
n-1-yl]-2-hydroxy-propoxy}-4-methyl-phenylamide
[0298] APCI-MS m/z: 470.5 [MH+]
EXAMPLE 77
3-Methyl-furan-2-carboxylic acid
(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1--
yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
[0299] APCI-MS m/z: 469.6 [MH+]
EXAMPLE 78
Cyclopent-1-enecarboxylic acid
(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl-
]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
[0300] APCI-MS m/z: 455.6 [MH+]
EXAMPLE 79
2-Methyl-furan-3-carboxylic acid
(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1--
yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
[0301] APCI-MS m/z: 469.6 [MH+]
EXAMPLE 80
3-Methyl-thiophene-2-carboxylic acid
(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidi-
n-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
[0302] APCI-MS m/z: 485.5 [MH+]
EXAMPLE 81
5-Chloro-thiophene-2-carboxylic acid
(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidi-
n-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
[0303] APCI-MS m/z: 505.5, 507.5 [MH+]
EXAMPLE 82
Thiophene-3-carboxylic acid
(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-
-hydroxy-propoxy}-4-methyl-phenyl)-amide
[0304] APCI-MS m/z: 471.5 [MH+]
EXAMPLE 83
2,5-Dimethyl-furan-3-carboxylic acid
(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidi-
n-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide
[0305] APCI-MS m/z: 483.6 [MH+]
EXAMPLE 84
Cyclobutanecarboxylic acid
(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2--
hydroxy-propoxy}-4-methyl-phenyl)-amide
[0306] APCI-MS m/z: 443.6 [MH+]
EXAMPLE 85
Furan-3-carboxylic acid
(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hyd-
roxy-propoxy}-4-methyl-phenyl)-amide
[0307] APCI-MS m/z: 455.5 [M+H.sup.+]
EXAMPLE 86
N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-m-
ethylphenyl}-1H-pyrrole-2-carboxamlde
[0308] APCI-MS: m/z 454.1 [M+H.sup.+]
EXAMPLE 87
N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-m-
ethylphenyl}-3-thiophenecarboxamide
[0309] APCI-MS: m/z 471.1 [M+H.sup.+]
EXAMPLE 88
N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-2-methylpropyl-
)oxy]phenyl}-2-thiophenecarboxamide, compound with trifluoroacetic
acid
[0310] Aniline intermediate 3 (60 mg, 0.159 mmol),
2-thiophenecarboxylic acid (20.4 mg, 0.159 mmol) and HATU (72 mg,
0.191 mmol) were stirred in dichloromethane (2 ml).
[0311] Diisopropylethylamine was added to pH 8. The mixture was
stirred overnight and then concentrated. The residue was purified
on silica (dichloromethane/methanol 98/2) followed by purificaton
on C18 (2 g Isolute, acetonitfile/water 20/80 to 35/65 with 0.5%
trifluoroacetic acid) to give the title compound (75 mg, 79%).
[0312] .sup.1H-NMR (400 MHz, MeOD): .delta. 7.86 (m, 1H), 7.72 (m,
1H), 7.50 (m, 1H), 7.29 (m, 3H), 7.16 (m, 2H), 7.07 (m, 1H), 6.91
(m, 2H), 5.10 (m, 1H), 3.82-4.17 (m, 4H), 3.24-3.69 (m, 4H),
2.13-2.64 (m, 2H), 1.38 (m, 3H). MS-APCI+: m/z 487 [MH.sup.+]
EXAMPLE 89
N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-m-
ethylphenyl}-2-thiophenecarboxamiide
[0313] APCI MS APCI-MS: m/z 471.1 [M+H.sup.+]
EXAMPLE 90
N-{2-[(3-{3-[(4-chlorophenyl)oxyl-1-pyrroldinyl}-2-hydroxpropyl)oxy]phenyl-
}-2-furancarboxamide
[0314] APCI-MS: m/z 456.9 [M+H.sup.+]
EXAMPLE 91
N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]phen-
yl}-1-pyrrole-2-carboxamide
[0315] APCI-MS: m/z 456.1 [M+H.sup.+]
EXAMPLE 92
N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-m-
ethylphenyl}-1H-pyrrole-3-carboxamide
[0316] APCI-MS: m/z 470.0 [M+H.sup.+]
EXAMPLE 93
N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-m-
ethylphenyl}-2-furancarboxamide
[0317] APCI-MS: m/z 4551 M+H.sup.+]
EXAMPLE 94
N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-2-methylpropyl-
)oxy]phenyl}cyclopentanecarboxamide, compound with trinfluoracetic
acid
[0318] The compound (80 mg, 86%) was prepared from aniline
intermediate 3 (60 mg, 0.159 mmol) and cyclopentanecarboxylic acid
(18 .mu.l, 0.159 mmol) as descnbed in Example 88.
[0319] .sup.1H-NMR (400 MHz, MeOD): .delta. 7.59 (m, 1H), 7.29 (m,
2H), 7.19 (m, 1H), 7.09 (m, 1H), 6.97 (m, 3H), 5.17 (m, 1H),
3.86-4.23 (m, 4H), 3.35-3.73 (m, 4H), 2.86 (m, 1H), 1.45 (bs,
3H).
[0320] MS-APCI+: m/z 473 [MH.sup.+]
EXAMPLE 95
N-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-
-phenyl)-benzamide
[0321] The compound was prepared using an analogous method as in
Example 88.
[0322] APCI-MS: m/z 465 [MH.sup.+]
EXAMPLE 96
N-(2-{3-[3-(4-Cyano-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}--
phenyl)-benzamide
[0323] The compound was prepared using an analogous method as in
Example 88.
[0324] APCI-MS: m/z 472 [MH.sup.+]
EXAMPLE 97
N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-2-methyl-propo-
xy}-phenyl)-benzamide
[0325] The compound was prepared using an analogous method as in
Example 88.
[0326] APCI-MS: m/z 529 [MH.sup.+]
EXAMPLE 98
N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-
-phenyl)-benzamide
[0327] The compound was prepared using an analogous method as in
Example 88.
[0328] APCI-MS: m/z 481 [MH.sup.+]
EXAMPLE 99
N-(2-{3-[4-(3,4-Dichloro-phenylamino)-piperidin-1-yl]-2-hydroxy-2-methyl-p-
ropoxy}-phenyl)-benzamide
[0329] The compound was prepared using an analogous method as in
Example 88.
[0330] APCI-MS: m/z 528 [MH.sup.+]
[0331] THP-1 Chemotaxis Assay
[0332] Introduction
[0333] The assay measured the chemotactic response elicited by
MIP-1.alpha. chemokine in the human monocytic cell line TBP-1. The
compounds of the Examples were evaluated by their ability to
depress the chemotactic response to a standard concentration of
MP-lx chemokine.
[0334] Methods
[0335] Culture of THP-1 cells
[0336] Cells were thawed rapidly at 37.degree. C. from frozen
aliquots and resuspended in a 25 cm flask containing 5 ml of
RPI-1640 medium supplemented with Glutamax and 10% heat inactivated
fetal calf serum without antibiotics (RPMI+10%HIFCS). At day 3 the
medium is discarded and replaced with fresh medium
[0337] THP-1 cells are routinely cultured in RPMI-1640 medium
supplemented with 10% heat inactivated fetal calf serum and
glutamax but without antibiotics. Optimal growth of the cells
requires that they are passaged every 3 days and that the minimum
subculture density is 4.times.10+5 cells/ml.
[0338] Chemotaxis Assay
[0339] Cells were removed from the flask and washed by centrigation
in RPMI+10%HEFCS+glutamax. The cells were then resuspended at
2.times.10+7 cells/mi in fresh medium (RPMI+10%HIFCS+glutamax) to
which was added calcein-AM (5 .mu.l of stock solution to 1 ml to
give a final concentration of 5.times.10.sup.-6 M). After gentle
mixing the cells were incubated at 37.degree. C. in a CO.sub.2
incubator for 30 minutes. The cells were th diluted to 50 ml with
medium and washed twice by centrifigation at 400 .times.g. Labelled
cells were then resuspended at a cell concentration of 1.times.10+7
cells/ml and incubated with an equal volume of MIP-1.alpha.
antagonist (10.sup.-10M to 10.sup.-6M final concentration) for 30
minutes at 37.degree. C. in a humidified CO.sub.2 incubator.
[0340] Chemotaxis was performed using Neuroprobe 96-well chemotaxis
plates employing 8 .mu.M (filters (cat no. 101-8). Thirty
microlitres of chemoattractant supplemented withy various
concentrations of antagonists or vehicle were added to the lower
wells of the plate in triplicate. The filter was then carefully
positioned on top and then 25 .mu.l of cells preincubated with the
corresponding concentration of antagonist or vehicle were added to
the surface of the filter. The plate was then incubated for 2 hours
at 37.degree. C. in a humidified CO.sub.2 incubator. The cells
remaining on the surface were then removed by adsorption and the
whole plate was centrifuged at 2000 rpm for 10 minutes. The filter
was then removed and the cells that had migrated to the lower wells
were quantified by the fluorescence of cell associated calcein-AM.
Cell migration was then expressed in fluorescence units after
subtraction of the reagent blank and values were standardized to %
migration by comparing the fluorescence values with that of a known
number of labelled cells. The effect of antagonists was calculated
as % inhibition when the number of migrated cells were compared
with vehicle.
* * * * *