AU2001274763A1 - Novel compounds - Google Patents
Novel compoundsInfo
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- AU2001274763A1 AU2001274763A1 AU2001274763A AU2001274763A AU2001274763A1 AU 2001274763 A1 AU2001274763 A1 AU 2001274763A1 AU 2001274763 A AU2001274763 A AU 2001274763A AU 2001274763 A AU2001274763 A AU 2001274763A AU 2001274763 A1 AU2001274763 A1 AU 2001274763A1
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- phenyl
- acetamide
- amino
- piperidinyl
- hydroxy
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Description
NOVEL COMPOUNDS
The present invention relates to novel compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
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 kDa 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.
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).
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 lα and lβ (MlP-l and MlP-lβ).
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.
In accordance with the present invention, there is therefore provided a compound of general formula
wherein m is 0, 1, 2 or 3; each R independently represents halogen, cyano, nitro, carboxyl, hydroxyl,
C3-C6 cycloalkyl, CrC6 alkoxy, CrC6 alkoxycarbonyl, CrC6 haloalkyl, CrC6 haloalkoxy, -NR 9 R 10 , C3-C6 cycloalkylammo, CrC6 alkylthio,
C Cg alkylcarbonyl, Cj-C6 alkylcarbonylamino, sulphonamido (-SO2NH2),
CrC6 alkylsulphonyl, -C(O)NRUR12, -NR13C(O)-(NH)pR14, phenyl, or CrC6 alkyl optionally substituted by carboxyl or Ci -Cg alkoxycarbonyl; p is 0 or 1;
Z represents a bond or a group (CH2)q where q is 1 or 2;
2 1 2
Z represents a bond or a group CH2, with the proviso that Z and Z do not both simultaneously represent a bond;
Q represents an oxygen or sulphur atom or a group CH2 or NH;
R represents a group
n is 0, 1 or 2;
3 eac R independently represents a Cj-Cg alkyl, Ci-Cg alkoxycarbonyl, -CH2OH or carboxyl group;
R , R , R and R each independently represent a hydrogen atom or a Cj-06 alkyl group, or R , R , R and R together represent a C1-C4 alkylene chain linking the two
carbon atoms to which they are attached to form a 4- to 7-membered saturated carbocycle, or R , R and R each represent a hydrogen atom and R and R together with the carbon atoms to which they are attached form a 5- to 6-membered saturated carbocycle; R represents a hydrogen atom, a CrC6 alkyl group or is linked to R as defined 5 above;
9 10
R and R each independently represent a hydrogen atom or a C Cg alkyl group, or
9 10
R and R together with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocycle;
11 12
R and R each independently represent a hydrogen atom or a CrC6 alkyl group l o optionally substituted by C j -Cg alkoxycarbonyl;
13 R represents a hydrogen atom or a Cj-Cg alkyl group;
14
R represents a hydrogen atom, or a CrC6 alkyl group optionally substituted by carboxyl, CrC6 alkoxy or CrC6 alkoxycarbonyl;
R represents carboxyl, CrC6 alkoxy, CrC6 alkylcarbonyl, CrC6 alkoxycarbonyl, 15 CrC6 alkoxycarbonylCrC6 alkyl or a group -NR17R18, -NHSO2CH3, -C(O)NR17R18, -NHC(O)NR17R18, -OC(O)NR17R18, -OCH2C(O)NR17R18, -NHC(O)OR19 or -NHC(O)R20; t is 0, 1, 2 or 3; each R independently represents halogen, cyano, nitro, carboxyl, hydroxyl, 20 Cβ-Cg cycloalkyl, Cj-Cg alkoxy, Cj-Cg alkoxycarbonyl, Cj- haloalkyl,
21 22
Ci-Cg haloalkoxy, -NR R , C3-C6 cycloalkylamino, CrC6 alkylthio, Cj-Cg alkylcarbonyl, Cj-Cg alkylcarbonylamino, sulphonamido (-SO2NH2), CrC6 alkylsulphonyl, -C(O)NR23R24, -NR25C(O)(NH)vR26, phenyl, or CrC6 alkyl optionally substituted by carboxyl or CrC6 alkoxycarbonyl;
17 18
25 R and R each independently represent a hydrogen atom, or a Cj-Cg alkyl group
17 18 optionally substituted by carboxyl or Cj-Cg alkoxycarbonyl, or R and R together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle; R 19
R rreeppiresents a hydrogen atom, or a C Cg alkyl group optionally substituted by 0 carboxyl or Cj-Cg alkoxycarbonyl
20
R represents a group CrC6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, adamantyl, C5- cycloalkenyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one heteroatom selected from nitrogen, oxygen and sulphur, each of which may be optionally substituted by one or more substituents independently selected from nitro, hydroxyl, oxo, halogen, carboxyl, CrC6 alkyl,
CrC6 alkoxy, CrC6 alkylthio, CrC6 alkylcarbonyl, CrC6 alkoxycarbonyl, phenyl and -NHC(O)-R27;
21 22
R and R each independently represent a hydrogen atom or a Ci -C6 alkyl group, or
21 22
R and R together with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocycle;
23 24
R and R each independently represent a hydrogen atom or a Ci-Cg alkyl group optionally substituted by Cj-C6 alkoxycarbonyl; v is 0 or 1 ;
25
R represents a hydrogen atom or a Cj-C6 alkyl group; represents a hydrogen atom, or a Cj-Cg alkyl group optionally substituted by carboxyl, CJ-C6 alkoxy or C C6 alkoxycarbonyl; and
27 R represents a Cj-C6 alkyl, amino (-NH2) or ph< or a pharmaceutically acceptable salt or solvate thereof.
In the context of the present specification, an alkyl substituent group or an alkyl moiety in
9 10 17 18 21 a substituent group may be linear or branched. When R and R (or R and R , or R
22 and R ) represent a saturated heterocycle, it should be understood that the only heteroatom
9 10 17 18 21 22 present is the nitrogen atom to which R and R (or R and R , or R and R ) are
20 attached. In the definition of R , it should be noted that the saturated or unsaturated 5- to 10-membered heterocyclic ring system may be aliphatic or aromatic.
The integer m is preferably 1 or 2.
Each R independently represents halogen (e.g. chlorine, fluorine, bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C3-C6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl
or cyclohexyl), Ci-Cg, preferably C1-C4, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), Cj-Cg, preferably C1-C4, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), CrC6, preferably CrC , haloalkyl (e.g. trifluoromethyl), CrCg, preferably Cι-C4, haloalkoxy (e.g. trifluoromethoxy), -NR 9 R 10 , C3-C6 cycloalkylamino (e.g. cyclopropylamino, cyclobutylamino, cyclopentylamino or cyclohexylamino), Cι-C6, preferably C1-C4, alkylthio (e.g. methylthio or ethylthio),
Cj-Cg, preferably CrC , alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), Cι-C6, preferably C1-C4, alkylcarbonylamino (e.g. methylcarbonylamino or ethylcarbonylamino), sulphonamido,
Ci-Cg, preferably C C4, alkylsulphonyl (e.g. methylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl, n-butylsulphonyl, n-pentylsulphonyl or n-hexylsulphonyl), -C(O)NRUR12, -NR13C(O)-(NH)pR14, phenyl, or C Cg, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl or C^Cg, preferably CrC4, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl).
Most preferably, each R independently represents halogen (particularly chlorine or fluorine), cyano, nitro, Cι-C6 alkoxy (especially methoxy), Cj-Cg alkylcarbonyl (especially methylcarbonyl) or Cι-C6 alkylcarbonylamino (particularly methylcarbonylamino). Each R especially represents a halogen atom.
Q preferably represents an oxygen atom.
3 Each R independently represents a Cj-Cg, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), Cj-Cg, preferably
Cj-04, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), -CH2OH or carboxyl
3 3 g jrroouupp.. IItt iiss pprreeffeerrrreedd tthhaatt RR represents a methyl, methoxycarbonyl, ethoxycarbonyl,
CH2OH or carboxyl group.
R , R , R and R each independently represent a hydrogen atom or a Cj-Cg, preferably CJ-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), or R , R , R and R together represent a Ci -C 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
each represent a hydrogen
4 8 atom and R and R together with the carbon atoms to which they are attached form a 5- to
6-membered saturated carbocycle (preferably cyclopentyl).
R represents a hydrogen atom, a C Cg, preferably C Q^ alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) or is linked to R as defined above.
9 10
R and R each independently represent a hydrogen atom or a Cj-C6, preferably C1-C4, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,
9 10 n-pentyl or n-hexyl), or R and R together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle (preferably pyrrolidinyl or piperidinyl).
11 12
R and R each independently represent a hydrogen atom or a Cj-Cg, preferably C1-C4, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by a Cj-Cg, preferably Ci -C4, alkoxycarbonyl substituent group.
13
R represents a hydrogen atom or a Cj-Cg, preferably Cj^, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl).
R represents a hydrogen atom, or a C Cg, preferably Cj^, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl, C Cg, preferably C1-C4, alkoxy or Ci-Cg, preferably C1-C4, alkoxycarbonyl.
R represents carboxyl, CrC6, preferably CrC4, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), CrC6, preferably CrC4, alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), CrC6, preferably CrC4, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), CrC6 alkoxycarbonylCrC6 alkyl, preferably
CrC4 alkoxycarbonylCrC4 alkyl (e.g. methoxycarbonylmethyl or methoxycarbonylethyl), or a group -NR17R18, -NHSO2CH3, -C(O)NR17R18, -NHC(O)NR17R18, -OC(O)NR17R18, -OCH2C(O)NR17R18, -NHC(O)OR19 or -NHC(O)R20.
It is preferred that R represents CrC4 alkoxy (especially methoxy), C1-C4 alkylcarbonyl (especially methylcarbonyl or ethylcarbonyl), CrC4 alkoxycarbonylCrC4 alkyl
(particularly methoxycarbonylmethyl or methoxycarbonylethyl), -C(O)NR 17 R 18 , -NHSO2CH3, -NHC(O)NR17R18 or, especially, -NHC(O)R20.
Each R independently represents halogen (e.g. chlorine, fluorine, bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C3-C6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), CrC6, preferably CrC4, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), CrC6, preferably Cι-C , alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), CrC6, preferably CrC4, haloalkyl (e.g. trifluoromethyl),
21 22
CrC6, preferably CrC4, haloalkoxy (e.g. trifluoromethoxy), -NR R , C3-C6 cycloalkylamino (e.g. cyclopropylamino, cyclobutylamino, cyclopentylamino or cyclohexylamino), CrC6, preferably C1-C4, alkylthio (e.g. methylthio or ethylthio), Cj-Cβ, preferably C1-C4, alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), C Cg, preferably C1-C4, alkylcarbonylamino (e.g. methylcarbonylamino or ethylcarbonylamino), sulphonamido,
Cj-Cg, preferably Cj-04, alkylsulphonyl (e.g. methylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl, n-butylsulphonyl, n-pentylsulphonyl or n-hexylsulphonyl), -C(O)NR23R24, -NR25C(O)-(NH)vR26, phenyl, or
CrC6, preferably CrC4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl or Cj-Cg, preferably C1-C4, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl).
Preferably, each R independently represents halogen (particularly chlorine or fluorine), cyano, CrC alkoxy (especially methoxy), CrC4 alkoxycarbonyl (especially methoxycarbonyl), CrC4 haloalkyl (especially trifluoromethyl), CrC4 alkylcarbonyl (particularly methylcarbonyl), phenyl or CrC4 alkyl (e.g. methyl or tert-butyl).
17 18 R and R each independently represent a hydrogen atom or a Cj-Cg, preferably
CrC4, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl or, more preferably,
17 18
Cj-Cg, preferably Ci -C4, alkoxycarbonyl, especially methoxycarbonyl, or R and R together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle (preferably pyrrolidinyl or piperidinyl).
19
R represents a hydrogen atom or a CrC6, preferably C C4, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl or, more preferably, CrC6, preferably CrC , alkoxycarbonyl, especially methoxycarbonyl.
20
R represents a group Cj-Cg, preferably CrC5, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), C2-C6, preferably C2-C4, alkenyl, C3-Cg cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), adamantyl, C5-C6 cycloalkenyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one heteroatom (e.g. one, two, three or four heteroatoms) selected from nitrogen, oxygen and sulphur, each of which 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, Cj-06, preferably Ci -C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
tert-butyl, n-pentyl or n-hexyl), CrC6, preferably CrC4, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), CrC6, preferably
alkylthio (e.g. methylthio or ethylthio), CrC6, preferably
alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), CrC6, preferably CrC4, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), phenyl and -NHC(O)-R 27.
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, tetrazolyl and pyridinyl.
R 21 and R 22 each independently represent a hydrogen atom or a Ci -C6, preferably
Cι-C4, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,' n-pentyl or n-hexyl), or R 21 and R 22 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle (preferably pyrrolidinyl or piperidinyl).
R 23 and R 24 each independently represent a hydrogen atom or a C C6, preferably CJ-C4, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by a C Cg, preferably C1-C4, alkoxycarbonyl substituent group.
R 25 represents a hydrogen atom or a C Cg, preferably C!-C4, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl).
<-:
R represents a hydrogen atom, or a CrC6, preferably C C4, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally
substituted by carboxyl, CrC6, preferably CrC4, alkoxy or CrC6, preferably C1-C4, alkoxycarbonyl.
27
R represents a Cj-Cg, preferably C1-C4, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), amino or phenyl group.
Preferred compounds of the invention include:
N-[2-(3-{[l-(3,4-dichlorobenzylpiperidinyl]aminohydroxypropoxy)phenyl]acetamide, N- [5 -chloro-2-(3 - { [ 1 -(3 ,4-dichlorobenzyl)-4-piperidinyl] amino } -2- hydroxypropoxy)phenyl]acetamide,
N-[2-(3-{[l-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-5- methylphenyl] acetamide,
N-[4-(3 - { [ 1 -(3 ,4-dichlorobenzyl)-4-piperidinyl] amino} -2-hydroxypropoxy) [ 1 , 1'- biphenyl]-3-yl]acetamide, N-[3-acetyl-2-(3-{[l-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-
5 -methylpheny 1] acetamide,
N-[2-(3 - { [ 1 -(3 ,4-dichlorobenzyl)-4-piperidinyl] amino} -2-hydroxypropoxy)-4- fluorophenyl] acetamide,
N-[2-(3- { [ 1 -(3,4-dichlorobenzyl)-4-piperidinyl]amino} -2-hydroxypropoxy)-5- fluorophenyljacetamide,
N- [2-(3 - { [ 1 -(3 ,4-dichlorobenzyl)-4-piperidinyl] amino } -2-hydroxypropoxy)-5 - cyanophenyl] acetamide,
N-[2-(3-{[l-(4-chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)phenyl]- acetamide, N-[2-(3-{[l-(4-chlorobenzyl)-4-piperidinyl]amin0}-hydroxypropoxy)phenyl]- isobutyramide,
N-[2-(3-{[l-(4-chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)phenyl]-2-2- dimethyl-propiomanide,
N-[5-chloro-2-(3-{[l-(4-chlorobenzyl)-4-piperidinyl]amino}-2- hydroxypropoxy)phenyl]acetamide,
N- [2-(3 - { [ 1 -(4-chlorobenzyl)-4-piperidinyl] amino } -2-hydroxypropoxy)-5 - methylphenyl] acetamide,
N-[2-(3- { [ 1 -(4-chlorobenzyl)-4-piperidinyl] amino } -2-hy droxypropoxy)-4- methylphenyl] acetamide, N-[2-(3-{[l-(4-chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-4- fluorophenyl] acetamide,
N- [2-(3 - { [ 1 -(4-chlorobenzyl)-4-piperidinyl] amino } -2-hy droxypropoxy)-5 - cy anophenyl] acetamide,
Ν-(2-{[(2S)-3-({-[(4-Chlorophenyl)methyl]-4-piperidinyl}amino)-2- hydroxypropyl]oxy}phenyl)acetamide bi(trifluoroacetate),
N-(2-{(2R)-3-[l-(4-Chloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl- propoxy } -phenyl)-acetamide,
N-(2-{[3-({l-[(4-Chlorophenyl)methyl]-4-piperidinyl}amino)-2-hydroxy-2- methylpropyl]oxy}phenyl)acetamide, N-(2- {(2S)-3-[l -(4-Chloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl- propoxy } -phenyl)-acetamide,
N- {2-[((2S)-3- { [1 -(4-Fluorobenzyl)-4-piperidinyl]amino} -2- hydroxypropyl)oxy]phenyl}acetamide,
N-{2-[((2S)-3-{[l-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropyl)oxy]-4- fluorophenyl} acetamide,
N-{4-fluoro-2-[((2S)-3-{[l-(4-fluorobenzyl)-4-piperidinyl]amino}-2- hydroxypropyl)oxy]phenyl} acetamide,
N-{2-[((2S)-3-{[(3S)-l-(4-Chlorobenzyl)pyrrolidinyl]amino}-2-hydroxypropyl)oxy]- 4-fluorophenyl } acetamide, N-{2-[((2S)-3-{[(3R)-l-(4-Chlorobenzyl)pyrrolidinyl]amino}-2-hydroxypropyl)oxy]-
4-fluorophenyl} acetamide,
N- [2-(3 - { [ 1 -(4-Fluorobenzyl)-4-piperidinyl] amino } -2-hydroxy-2- methylpropoxy)phenyl] acetamide,
N-[2-(3-{[l-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxy-2-methylpropoxy)-4- fluorophenyl] acetamide,
N-[4-Fluoro-2-(3-{[l-(4-fluorobenzyl)-4-piperidinyl]amino}-2-hydroxy-2- methy lpropoxy)phenyl] acetamide,
N-[2-(3 - { [ 1 -(4-Chlorobenzyl)-4-piperidinyl] amino } -2-hydroxypropoxy)-4- methylphenyl] acetamide, N-[2-(3- { [ 1 -(4-Fluorobenzyl)-4-piperidinyl]amino} -2-hydroxypropoxy)-4- methylphenyl] acetamide,
N-[2-(3-{[l-(4-Chlorobenzyl)-4-piperidinyl]amino}-2- hydroxypropoxy)phenyl]benzamide,
N-[2-(3- {[1 -(4-Fluorobenzyl)-4-piperidinyl]arnino}-2- hydroxypropoxy)phenyl]benzamide,
N-[2-(3-{[(3S)-l-(4-Chlorobenzyl)pyrrolidinyl]amino}-2- hydroxypropoxy)phenyl]benzamide,
N-[2-(3- { [(3R)- 1 -(4-Chlorobenzyl)pyrrolidinyl]amino} -2- hydroxypropoxy)phenyl]benzamide, N-[2-(3-{[l -(4-Bromobenzyl)-4-piperidinyl] amino } -2- hydroxypropoxy)phenyl]benzamide,
N-[2-(3-{[l-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxy-2- methylpropoxy)phenyl]benzamide,
N-[2-(3-{[l-(4-Fluorobenzyl)-4-piperidinyl]amino}-2-hydroxy-2- methylpropoxy)phenyl]benzamide,
N-[2-(3- { [(3R)- 1 -(4-Chlorobenzyl)pyrrolidinyl]amino} -2-hydroxy-2- methylpropoxy)phenyl]benzamide,
N-[2-(3-{[l-(4-Bromobenzyl)-4-piperidinyl]amino}-2-hydroxy-2- methylpropoxy)phenyl]benzamide, N-[2-(3-{[l-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-4- methoxyphenyl] acetamide,
N-[2-(3-{[l-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-6- fluorophenyl]acetamide,
N-[2-Fluoro-6-(3- {[l-(4-fluorobenzyl)-4-piperidinyl]amino} -2- hydroxypropoxy)phenyl]acetamide,
2-(3-{[l-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxy-2-methylpropoxy)-N- methylbenzamide,
N-(2-{3-[l-(3,4-Dichloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-phenyl)- benzamide, N-(2-{3-[l-(3-Chloro-4-fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}- phenyl)-benzamide,
N-(2-{3-[l-(3,4-Difluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-phenyl)- benzamide,
N-(2- { 3 -[ 1 -(3 ,4-Dichloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy } -6- methyl-phenyl)-acetamide,
N-(2-{3-[l-(4-Fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-6-methyl- phenyl)-acetamide,
N-(2- {3-[ 1 -(4-Bromo-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl-propoxy} - phenyl)-acetamide, N-(2-{3-[l-(3,4-Dichloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl- propoxy } -phenyl)-acetamide,
N-(2-{3-[l-(3-Chloro-4-fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl- propoxy } -phenyl)-acetamide,
N-(2- { 3 - [ 1 -(3 ,4-Difluoro-benzyl)-piperidin-4-ylamino] -2-hydroxy-2-methyl- propoxy}-phenyl)-acetamide,
2-{3-[l-(4-Bromo-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-N-methyl- benzamide,
2-{3-[l-(3,4-Dichloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-N-methyl- benzamide, 2-{3-[l-(4-Chloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-N-methyl- benzamide,
2-{3-[l-(4-Fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-N-methyl- benzamide,
3,5-Dimethyl-lH-pyrrole-2-carboxylic acid (2-{3-[l-(4-bromo-benzyl)-piperidin-4- ylamino]-2-hydroxy-propoxy } -phenyl)-amide,
3 , 5-Dimethyl- 1 H-pyrrole-2-carboxylic acid (2- { 3 - [ 1 -(3 -chloro-benzyl)-piperidin-4- ylamino]-2-hydroxy-propoxy}-phenyl)-amide,
3,5-Dimethyl-lH-pyrrole-2-carboxylic acid (2- {3-[l-(3-fluoro-benzyl)-piperidin-4- ylamino]-2-hydroxy-propoxy}-phenyl)-amide, N-(2- {3-[ 1 -(4-Bromo-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy} -phenyl)- acetamide,
N-(2-{3-[l-(3-Chloro-4-fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}- phenyl)-acetamide,
N-(2-{3-[l-(3,4-Difluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-phenyl)- acetamide, and
N-(2-{3-[l-(4-Fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-phenyl)- acetamide.
The present invention further provides a process for the preparation of a compound of formula (I) as defined above which comprises (a) reacting a compound of general formula
1 2 1 3 wherein m, n, Z , Z , R and R are as defined in formula (I), with a compound of general formula
wherein Q,
are as defined in formula (I); or
(b) reacting a compound of general formula
wherein m, n, Z ,Z ,R,R,R,R,R,R and R are as defined in formula (I), with a compound of general formula
L^Q-R2 (N) wherein L represents a hydrogen atom or a leaving group (e.g. Li when Q is CH2) and Q
2 and R are as defined in formula (I); or
(c) reacting a compound of general formula
wherein m, n, Z 1 , Z2 , R 1 and R 3 are as defined in formula (I), with a compound of general formula
9 A ( 1 R wherein Q, R , R , R , R , R and R are as defined in formula (I);
and optionally after (a), (b) or (c) converting the compound of formula (I) to a further compound of formula (I) and/or forming a pharmaceutically acceptable salt or solvate of the compound of formula (I).
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) or acetonitrile at a temperature of, for example, 15°C or above such as a temperature in the range from 20 to 120°C.
Compounds of formulae (II), (III), (IN), (N), (NI) and (Nil) are either commercially available, are well known in the literature or may be prepared easily using known techniques.
Compounds of formula (I) can be converted into further compounds of formula (I) using standard procedures. For example, a compound of formula (I) in which R represents -ΝHC(O)CH3 can be converted to a further compound of formula (I) in which R represents -NH2 by a hydrolysis reaction in the presence of hydrochloric acid.
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 starting 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.
The protection and deprotection of functional groups is described 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).
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 or -toluenesulphonate.
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. Preferred . . optical isomers are the (S)-enantiomers.
The compounds of formula (I) have activity as pharmaceuticals, in particular as modulators of chemokine receptor (especially MlP-lα chemokine receptor) activity, and may be used in the treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically-mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).
Examples of these conditions are:
(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 asthma (e.g. late asthma and airways hyper-responsiveness); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis 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;
(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;
(3) (skin) psoriasis, atopical dermatitis, contact dermatitis and other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus,
Epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia areata and vernal conjunctivitis;
(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;
(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;
(6) (allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease;
(7) cancers, especially non-small cell lung cancer (NSCLC) and squamous sarcoma;
(8) diseases in which angiogenesis is associated with raised chemokine levels (e.g. NSCLC); and
(9) cystic fibrosis, stroke, re-perfusion injury in the heart, brain, peripheral limbs and sepsis.
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.
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.
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.
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.
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 therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary 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.
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.
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.
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.
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 administration or by rectal administration in the form of suppositories or transdermally.
The invention will now be further explained by reference to the following illustrative examples, in which !H NMR spectra were recorded on Narian Unity Inova 400. The central solvent peak of chloroform- (δH 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 ACD/IUPAC Name Pro.
Examples 1-16
Starting material: l-(3,4-Dichlorobenzyl)-4-piperidinylamine
i) tert-Butyl 4-piperidinylcarbamate
Di-tert-butyl-dicarbonate (11.6g, 53.16mmol) was added to a solution of l-benzyl-4- piperidinamine (13.10g, 68.84mmol) in dichloromethane (100ml) and triemylamine (2ml) and the solution was stirred at room temperature for 2 hrs. Water was added to the solution and the organic layer was separated, dried over natrium sulphate, filtered and concentrated. The resulting residue was taken up into ethanol. Palladium hydroxide 20% (500mg) was added to the solution and the mixture was hydrogenated (parr apparatus) over 50psig hydrogen for 48 hrs. The mixture was filtered over a pad of celite. The solid was washed with two portions of hot ethanol and concentrated in vacuo to give 8.85g product.
APCI-MS: m z 201[MH+]
1HNMR (400MHz, CD3OD) δ 2.97-3.39(lH, m), 3 (2H, m), 2.55-2.62 (2H, m), 1.8-1,84
(2H,dd), 1.42 (9H, s), 1.27-1.37 (2H,m)
ii) l-(3,4-DichIorobenzyl)-4-piperidinyIamine l,2-dichloro-4-(chloromethyl)benzene (390mg, 1.99mmol) ) was added to a solution of tert-butyl 4-piperidinylcarbamate (400mg, 2.0mmol) in DMF (25ml) and triethylamine (2ml). The solution was stirred at room temperature for 3hrs and then concentrated in vacuo. To the solution of the solid in dichloromethane was added (30ml) trifluoroacetic acid (6ml) was added and stirred at room temperature for 2hrs. The solution was diluted with dichloromethane and washed with two portions of water. The combined water washings were treated with 2M NaOH to pH 10 and extracted with ether. The ether was dried (Na2SO ), filtered and evaporated to leave a yellow residue (300mg, 1.16mmol).
APCI-MS: m/z 259[MH+] HNMR (400MHz, CD3OD) δ 7.41(1H, d), 7.36 (1H, br d), 7.13 (1H, dd), 3.42 (2H, s),
2.97-3.01 (1H, m), 3 (2H, m), 2.55-2.62 (2H, m), 1.41-1.55 (2H,dd), 1.31-1.54 (2H,m)
Example 1 N-[2-(3-{[l-(3,4-dichlorobenzylpiperidinyl]aminohydroxypropoxy)phenyl]acetamide
The mixture of N-Acetyl-2-(2,3-epoxypropoxy)aniline (120mg, 0,58mmol) and the above starting material (150mg, 0,58mmol) in ethanol (10ml 99.5%) was refluxed for 3hrs. The solvent distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluant: dichloromethane/methanol 15:1) to give 108mg of the title compound as a gum. Addition of 1.0M ethereal HCI solution gave a white solid product.
APCI-MS :m/z 466[MH+] . 'HNMR (400MHz, CD3OD) δ 8.0 (IH, dd,), 7.5 (IH, d), 7.45 (IH d), 7.23 (IH, dd), 6.89- 7.08 (4H, m), 4.15 (IH, m), 3.9-4.1 (2H, m), 3.40 (2H, S), 2.97-3.11 (IH, m), 3 (2H, m), 2.55-2.68 (2H, m), 1.39-1.55 (2H,dd), 1.31-1.44 (2H,m), 2.17 (3H, s).
The following compounds were synthesised by methods analogous to the method described in Example 1.
Example 2
N-[5-chloro-2-(3-{[l-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-2- hydroxypropoxy)phenyl] acetamide
APCI-MS: m/z 500[MH+]
Example 3
N-[2-(3-{[l-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-5- methylphenyl] acetamide
APCI-MS: m z 480[MH+]
Example 4
N-[4-(3-{[l-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)[l,l'- biphenyl]-3-yl] acetamide
APCI-MS: m/z 542[MH+]
Example 5
N-[3-acetyl-2-(3-{[l-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-5- methylphenyl] acetamide
APCI-MS: m/z 522[MH+]
Example 6
N-[2-(3-{[l-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-4- fluorophenyl] acetamide
APCI-MS: m/z 484[MH+]
Example 7
N-[2-(3-{[l-(3,4-dichIorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-5- fluorophenyl] acetamide
APCI-MS: m/z 484[MH+]
Example 8 N-[2-(3-{[l-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-5- cyanophenyl] acetamide
APCI-MS: m z 491 [MH+]
Example 9
N-[2-(3-{[l-(4-chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)phenyl]- acetamide
APCI-MS: m/z 432[MH+]
Example 10
N-[2-(3-{[l-(4-chlorobenzyl)-4-piperidinyl]amin0}-hydroxypropoxy)phenyl]- isobutyramide
APCI-MS: m/z 460[MH+]
Example 11
N-[2-(3-{[l-(4-chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)phenyl]-2-2- dimethyl-propiomanide
APCI-MS: m/z 474[MH+]
Example 12
N-[5-chloro-2-(3-{[l-(4-chlorobenzyI)-4-piperidinyl]amino}-2- hydroxypropoxy)phenyl] acetamide
APCI-MS: m/z 466[MH+]
Example 13 N-[2-(3-{[l-(4-chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-5- methylphenyl] acetamide
APCI-MS: m/z 446[MH+]
Example 14
N-[2-(3-{[l-(4-chlorobenzyl)-4-piperidinyl]ammo}-2-hydroxypropoxy)-4- methylphenyl] acetamide
APCI-MS: m/z 446[MH+]
Example 15
N-[2-(3-{[l-(4-chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-4- fluorophenyl] acetamide
APCI-MS: m/z 450[MH+]
Example 16
N-[2-(3-{[l-(4-chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-5- cyanophenyl] acetamide
APCI-MS: m/z 457[MH+]
Starting Materials for Examples 17 to 63.
Epoxide: A
N-{2-[(2S)Oxiranylmethoxy]phenyl} acetamide
(2S)-2-[(2-nitrophenoxy)methyl]oxirane (1.17 g, 6 mmol) was dissolved in ethyl acetate (50 ml). Platinum on charcoal (0.50 g) was added, and the mixture was stirred in the atmosphere of hydrogen for 3 h at room temperature and atmospheric pressure. The catalyst was filtered and washed on the filter with ethyl acetate (10 ml). Acetic anhydride (1.23g, 1.13.ml, 12 mmol) and ethyldi(f-propyl)amine (1.55 g, 2.05 ml, 12 mmol) were added to the solution. The reaction mixture was stirred at room temperature for 3 h, then washed with 1M NaOH (2 x 50 ml) and brine (2 x 50 ml), and dried with Na^O^ Evaporation of the solvent and flash chromatography on silica gel with n-heptane/ethyl
acetate (from 25 to 75 %) afforded the title compound (0.74 g, 3.57 mmol, 60 %) as colourless crystals.
'H-NMR (400MHz, CDC13): δ 8.36 (m, IH), 7.89 (br. S, IH), 6.8 - 7.0 (m, 3H), 4.35 (dd, IH, J = 2.5, J = 11.3), 3.95 (dd, IH, J = 5.9, J = 11.3), 3.39 (m, IH), 2.95 (t, IH, J = 4.8), 2.78 (dd, IH, J = 2.7, J = 4.8), 2.22 (s, 3H). APCI-MS: m/z 208 [MH+]
Epoxide: B i) [(2R)-2-Methyloxiranyl]methyl-4-methylbenzenesulfonate
(S)-2-methyl-glycidol (0,10g, 1.13mmol), dimethylaminopyridine (0.5mg, 3.8μmol) in triethylamine (2ml) was cooled on an ice bath and tosyl chloride (0.217g, 1.14mmol) was added in portions during 10 min. The flask was sealed and kept at -10°C over night. The reaction mixture was evaporated and the residue was stirred with dry diethylether (3.5ml). The solid was filtered off and washed with diethylether ( 3 x 1ml). The filtrate was dried and concentrated in vacuo. The crude product was purified on silica (Heptane/EtOAc 1:2) to give 145mg (53%) of the subtitle compound.
'H-NMR (400MHz, CDC13): δ 7.80 (2H, d, J8.4Hz), 7.36 (2H, d, J8.1Hz), 4.04 (IH, d, J10.7Hz), 3.95 (IH, d, J10.7Hz), 2.70 (IH, d, J4.7Hz), 2.64 (IH, d, J4.6Hz), 2.46 (3H, s), 1.36 (3H, s).
ii) N-(2-{[(2R)-2-Methyloxiranyl]methoxy}phenyl)acetamide
To 2-acetamidophenol (90.5mg, 0.598mmol) and cesium carbonate( 234mg, 0.718mmol) was added [(2R)-2-methyloxiranyl]methyl 4-methylbenzene-sulfonate (145mg,
0.598mmol) dissolved in DMF (1ml). The mixture was stirred at room temperature for four hours and then partitioned between ethyl-acetate and water. After extraction the combined organic phases were dried and concentrated in vacuo. The residue was purified on silica (Heptane/EtOAc 3:1 - 2:1) to give 63mg (48%) of the title compound.
Η-NMR (400MHz, CDC13): δ 8.38-8.31 (IH, m), 8.02 (IH, bs), 7.04-6.97 (2H, m), 6.93- 6.86 (IH, m), 4.11 (IH, d, J10.9Hz), 4.01 (IH, d, J10.9Hz), 2.95 (IH, d, J4.7Hz), 2.78 (IH, d, J4.7Hz), 2.21 (3H, s), 1.48 (3H, s).
Epoxide: C i) [(2-S)-2-Methyloxiranyl]methyl-3-nitrobenzenesulfonate
To an oven-dried 1000 ml three-necked flask was added powdered activated molecular sieves (8.0 g, 4A) and CH2C12 (440 ml, dried over molecular sieves). D-(-)-Diisopropyl tartrate (3.0 ml, 14.2 mmol) and 2-methyl-2-propan-l-ol (20 ml, 240 mmol) was added and the mixture was cooled to -20°C. Titanium tetraisopropoxide (3.5 ml, 11.9 mmol) was added with a few ml of CH2C12 and the mixture was stirred at -20°C for 30 minutes. Cumene hydroperoxide (75 ml, approx. 430 mmol) was added dropwise over 1.5 hours maintaining the temperature at -20°C. The mixture was stirred at this temperature over night. Trimethylphosphite (40 ml, 340 mmol)was added dropwise over 5 hours maintaining the temperature at -20°C. Triethylamine (50 ml, 360 mmol) and DMAP (3.48 g, 28.5 mmol) was added followed by a solution of 3-nitrobenzenesulphonyl chloride (47 g, 212 mmol) in CH2C12 (400 ml). The temperature was raised to -10°Cand the mixture was stirred at this temperature over night. After removing the external cooling, the reaction mixture was filtered through celite®. The organic phase was washed with 10%> tartaric acid (500 ml), saturated NaHCO3 (300 ml) and brine (300 ml). The organic phase was dried (MgSO4) and evaporated to give ca 150 g of a yellow oil. The crude material was chromatographed (1 kg silica, Heptane/EtOAc 100:0 to 50:50 gradually increased polarity) to give 48.8 g (84%) of the sub-title compound as a yellow oil. The compound was pure enough to use further without any additional purification.
'H-NMR (400 MHz, CDC13): D 8.79-8.75 (IH, m); 8.52 (IH, ddd, J 1.1 2.3 8.3 Hz); 8.25 (IH, ddd, J 1.1 1.8 7.8 Hz); 7.81 (IH, t, J8.5 Hz); 4.28 (IH, d, J 11.3 Hz); 4.05 (IH, d, J 11.3 Hz); 2.73 (IH, d, J4.4 Hz); 2.67 (IH, d, J4.4 Hz); 1.56 (3H, s)
ii) N-(2-{[(2-S -2-Methyloxiranyl]methoxy}phenyl)acetamide
In a flask was added the compound obtained in a) (24.57 g, 90 mmol), 2-acetamido-phenol (13.59 g, 90 mmol), Cs2CO3 (35.1 g, 108 mmol, powdered anhydrous) and DMF (90 ml). The flask was sealed and the mixture was stirred with a magnetic stirrer at room temperature for 2 hours. A heavy precipitate was formed, and the starting materials were converted in 2 hours. The mixture was partitioned between EtOAc/water (400 + 400 ml). The organic phase was collected and the aqueous phase was washed with EtO Ac (2 x 200 ml). The combined organic phases were washed with water (200 ml), 1M NaOH (2 x 200 ml) and brine (150 ml). The organic solution was dried over N-^S ,, and concentrated in vacuo after filtration. The crude material was purified on silica (Heptane/EtOAc 5:1 to 1:1, gradually increasing the polarity), eluting 18.5 g (92%>) of the sub-title compound. The optical purity was 97.4 %, according to chiral HPLC (Chiralpak ™, iso-hexane/iso- propanol 95:5).
Η-NMR (400 MHz, CDC13): D 8.39-8.32 (IH, m); 8.00 (IH, bs); 7.05-6.97 (2H, m); 6.95- 6.88 (IH, m) 4.12 (IH, d, AB, J l l.O Hz); 4.02 (IH, d, AB, J 11.0 Hz); 2.96 (IH, d, J 4.6 Hz); 2.79 (IH, d, J4.8 Hz); 2.22 (3H, s); 1.49 (3H, s)
Epoxide: D N-{4-Fluoro-2-[(2S)oxiranyImethoxy]phenyl} acetamide was prepared from (2S)-2-[(5-fluoro-2-nitrophenoxy)methyl]oxirane according to the method described for Epoxide: A.
APCI-MS: m/z 226 [MH+]
'H-NMR (400MHz, CDC13): δ 8.30 (dd, IH, J = 5.2, J = 9.0), 7.71 (br. S, IH), 8.6 - 8.8 (m, 2H), 4.36 (dd, IH, J = 2.3, J = 11.3), 3.90 (dd, IH, J = 6.3, J = 11.3), 3.40 (m, IH), 2.97 (t, IH, J = 4.4), 2.78 (dd, IH, J = 2.7, J = 4.8), 2.21 (s, 3H).
Epoxide: E N-{2-[(2-Methyl-2-oxiranyl)methoxy]phenyl}benzamide
A mixture of N-(2-hydroxyphenyl)benzamide (159 mg, 0.75 mmol), 2-(chloromethyl)-2- methyloxirane (1.60 g, 15 mmol), and benzyltriethylammonium chloride (27 mg, 0.12 mmol) was stirred at 70 - 75 °C for 6 h. After cooling to room temperature, water (2 ml) was added and the mixture was vigorously shaken. It was extracted with dichloromethane (2 x 5 ml), and the combined organic extracts were washed with aq. ΝaOH (2M, 5 ml) and water (10 ml). Drying with ΝajSO,,, evaporation of the solvent and flash chromatography on silica gel with n-heptane/ethyl acetate (ethyl acetate from 25 to 50 %>) afforded title compound as yellowish solid (131 mg, 0.46 mmol, 62 %).
APCI-MS: m/z 284 [MH+]
Η-ΝMR (400MHz, CDC13): δ 8.68 (br. S, IH), 8.54 (m, IH), 7.94 (m, 2H), 7.4 - 7.6 (m, 3H), 7.07 (m, 2H), 6.92 (m, IH), 4.19 (d, IH, J = 10.7), 4.06 (d, IH, J 10.7), 2.92 (d, IH, J = 4.6), 2.7S (d, m, J = 4.6).
Epoxide: F
N-Methyl-2-[(2-methyl-2-oxiranyl)methoxy]benzamide was prepared from 2-hydroxy-N-methylbenzamide (prepared according to Cohen et al, J. Am. Chem. Soc, 1998, 20, 6277 - 6286.) according to the method described for N-{2-[(2- methyl-2-oxiranyl)methoxy]phenyl}benzamide.
APCI-MS: m/z 284 [MH+]
'H-ΝMR (400MHz, CDC13): δ 8.68 (br. S, IH), 8.54 (m, IH), 7.94 (m, 2H), 7.4 - 7.6 (m, 3H), 7.07 (m, 2H), 6.92 (m, IH), 4.19 (d, IH, J = 10.7), 4.06 (d, IH, J 10.7), 2.92 (d, IH, J = 4.6), 2.78 (d, 1U, J = 4.6), 1.51 (s, 3H).
Epoxide: G
N- [4-Methyl-2-(2-oxiranylmethoxy)phenyl] acetamide
A mixture of N-(2-hydroxy-4-methylphenyl)acetamide (10 g, 60 mmol), 2- (bromomethyl)oxirane (9.86 g, 72 mmol, 6.0 ml) and potassium carbonate (16.8 g, 120 mmol) in DMF (100 ml) was heated at 55 °C for 2 h. Then the reaction mixture was diluted
with ethyl acetate and washed with aq. HCI (1.5 %), aq. sat. NaHCO3, and brine. Evaporation of the solvent and flash chromatography on silica gel with n-heptane/ethyl acetate (ethyl acetate from 35 to 70 %) afforded the title compound (5.65 g, 25 mmol, 43 %).
APCI-MS: m/z 222 [MH+]
Η-NMR (400MHz, CDC13): δ 8.20 (d, IH, J = 8.2), 7.78 (br. s, IH), 6.79 (d, IH, J = 8.2), 6.70 (s, IH), 4.32 (dd, 1H, J = 2.5, J = 11.4), 3.93 (dd, 1H, J= 5.9, J = 11.4), 3.38 (m, IH), 2.94 (t, IH, J = 4.8), 2.77 (dd, IH, J = 2.7, J = 4.8), 2.29 (s, 3H), 2.19 (s, 3H).
Epoxide: H N-[4-Methoxy-2-(2-oxiranylmethoxy)phenyl]acetamide
Was prepared from N-(2-hydroxy-4-methoxyphenyι)acetamide according to the method described for N-[4-methyl-2-(2-oxiranylmethoxy)phenyl] acetamide using cesium carbonate instead of potassium carbonate.
APCI-MS: m/z 238 [MH+]
'H-ΝMR (400MHz, CDC13): δ 8.20 (d, IH, J = 8.8), 7.62 (br. s, IH), 6.4 - 6.6 (m, 2H), 6.70 (s, IH), 4.32 (dd, 1H, J= 2.5, J= 11.3), 3.91 (dd, 1H, J= 6.1, J = 11.3), 3.77 (s, 3H), 3.37 (m, IH), 2.94 (t, IH, J = 4.8), 2.76 (dd, IH, J = 2.7, J = 4.8), 2.18 (s, 3H).
Epoxide: I i) 2-Amino-3-fluorophenol
To a stirred solution of 2,6-difluoronitrobenzene (11 OO g, 6.9mmol) in dry methanol (20ml) was added a solution of sodium (180mg, 7.8mmol) in dry methanol ( 8 ml). The solution was stirred overnight. After concentration, water was added and the solution was extracted with ether, dried over MgSO4, filtered and concentrated to a yellow residue (870mg.5.08 mmol). To the solution of the yellow residue in dichloromethane (10 ml) boron tribromide (1M in dichloromethane, 10 ml) was added and stirred at room temperature overnight. Water was then added and the solution stirred for further 60 min.
The organic phase was separated and the water phase was extracted with ether. The combined organic phase were dried over MgSO4, filtered and concentrated in vacuo to give a brownish residue. The residue was taken up into ether and washed with 2M sodium hydroxide and water. The water and sodium hydroxide washings were combined and neutralised with 6M HCI and extracted with ether, dried over MgSO4 and evaporated to give a yellow residue which was purified by flash chromatography on silica gel with EtOAc:Heptane: 1:3 as eluant to give the product ( 720mg, 4.6mmol) which was directly suspended with palladium-charcoal (140mg) in water-ethanol (30ml). Sodium borohydride (530mg) was added over a period of 5 min and the suspension was stirred at room temperature (Ih). The catalyst was removed by filtration through a Celite pad. The filtrate was acidified with 6M hydrochloric acid to destroy any residual borohydride, neutralised with 2 M sodium hydroxide, and then extracted with ether. The ethereal extracts were dried over MgSO4 and evaporated.
APCI-MS: m/z 128.2 [MH+]
ii) N-[2-Fluoro-6-(2-oxiranylmethoxy)phenyl]acetamide
To a stirred solution of 2-amino-3-fluorophenol (300 mg, 2.36 mmol) in water-methanol (10 ml) acetic acid anhydride was added until all 2-amino-3-fluorophenol was consumed. The solution was concentrated to a residue of N-(2-fluoro-6-hydroxyphenyl) acetamide. To a mixture of N-(2-fluoro-6-hydroxyphenyl)acetamide (399mg, 2.36mmol) and potassium carbonate (652mg, 4.72mmol) in DMF (5 ml) epibromohydrin (388 mg, 2.8mmol) was added and the mixture was stirred at 70°C for 3hr. Water and ethyl acetate were added, the organic phase separated, dried and concentrated. The resulting residue was purified by RP- HPLC (10- 40 % CH3CN) to give the desired product as a solid (242 mg,1.08mmol).
APCI-MS: m/z 226 [MH+]
'H-NMR (400MHz, CDC13): D 7.15 (m, IH), 6.87 (br. s, IH), 6.6 - 6.8 (m, 2H), 4.30 (dd, IH, J = 2.3, J = 11.3), 3.93 (dd, IH, J = 5.7, J = 11.3), 3.34 (m, IH), 2.91 (t, IH, J = 4.4), 2.75 (dd, IH, J = 2.8, J = 4.8), 2.20 (br. s, 3H).
Epoxide: J
N-(2-Oxiranylmethoxy-phenyl)-benzamide
To a stirred solution of Ν-(2-Hydroxy-phenyl)-benzamide (0.81g, 3.80 mmol), and cesium carbonate (1.61g, 4.94 mmol) in acetonitrile was added epibromohydrin (0.63 ml, 7.60 mmol). After 4 hours the reaction mixture was partitioned between dichloromethane and water. After evaporation of the organic solvent the residue was crystallised from petroleum ether and diethyl ether yielding (0.741g, 73%).
APCI-MS: m z 227[MH+]
Η -NMR (400 MHz, CDC13): δ 8.65 (bs, IH), 8.55 (bs, IH), 7.94 (d, 2H), 7.53 (m, 3H), 7.08 (bs, 2H), 6.96 (bs, IH), 4.42 (d, IH), 4.02, (m, IH), 3.41 (bs, IH), 2.96 (s, IH), 2.80 (s, IH).
Epoxide: K N-MethyI-2-oxiranylmethoxy-benzamide To a solution of 2-Hydroxy-N-methyl-benzamide (0.5g, 3.31 mmol prepared according to Cohen, Seth M et al j. Am. Chem. Soc, (1998), 120(25), 6277-6286.) and cesium carbonate (2.16g, 6.62mmol) in acetonitrile was added epibromohydrin (0.274ml, 3.31mmol). The mixture was heated at 50°C for 2 hours and then after cooling to room temperature partitioned between water(50 ml)and dichloromethane (100ml). The dichloromethane was dried and evaporated . Chromatography (EtOAc) gave 0.43g (64%) of the product as a solid.
APCI-MS: m/z 208[MH+]
Η -NMR (400 MHz, CDC13): δ 8.20 (dd, IH), 7.85 (bs, IH), 7.42 (m, IH), 7.11 (m, IH), 6.95 (dd, IH), 4.46 (dd, IH), 4.11 (dd, IH), 3.41 (m, IH), 3.02 (d, 3H), 2.97 (t, IH), 2.84 (dd, IH).
Epoxide: L
N-(2-Methyl-6-oxiranylmethoxy-phenyl)-acetamide
A mixture of 3-methyl-2-acetamidophenol (0.165g, 1 mmol), and epichlorohydrin (1.84g, 20mmol) was stirred at 70°C to afford a clear solution. Triethylbenzylammonium chloride (0.15g, 1 mmol) was then added and stirring was continued at 125°C for 15 minutes. After cooling to room temperature IM ΝaOH solution was added and the solution was extracted with dichloromethane. The organic extract was washed with water and dried. After evaporation of the dichloromethane the resulting brownish oil was purified through silica chromatography 50-70%) EtOAc in heptane yielding the product as a colourless oil (0.12g, 0.54mmol).
APCI-MS: m/z 208 [MH+]
Epoxide: M
3,5 Dimethyl-l-H-pyrrole-2-carboxylic acid (2-oxiranylmethoxy-phenyl)-acetamide The compound was prepared from 3,5 Dimethyl- l-H-pyrrole-2-carboxylic acid-(2-phenyl)- acetamide (300 mg, 1.3 mmol) analogously to that described for Epoxide: L.
APCI-MS: m/z 287 [MΗ+]
Η-ΝMR (400 MHz, CDC13): δ 8.46 (m,lH), 8.31 (m,lH), 6.99 (m,2H), 6.87 (m,lH), 5.85(m,lH), 4.34(m;lH), 3.92 (m, IH), 3.36 (m,lH), 2.91 (m,2H), 2.71 (m,lH), 2.47 (m, 3H), 2.25 (m,3H).
(i) 3,5 Dimethyl-l-H-pyrrole-2-carboxylic acid (2-phenyl)-acetamide
2-Aminofenol ( 545mg, 5 mmol), 3,5 dimethyl- l-H-pyrrole-2-carboxylic acid (ii) (695mg, 5 mmol) and HATU (1900ήιg, 5 mmol) were stirred in DMF (20 ml).
Diisopropylethylarnine was added to pH 8. The mixture was stirred overnight and then concentrated. The residue was purified on C18 ( acetonitrile/water 10/90 to 40/60 with 0.5% trifluoroacetic acid ) to give the title compound ( 550 mg, 48% ).
APCI-MS: m/z 231 [MH+]
'H-NMR (400MHz, CDC13): δ 9.22 (s,lH), 7.63 (s, IH), 7.1 l(m, 2H), 7.03 (m, IH), 6.88 (m,lH), 5.88 (s, IH), 2.44 (s,lH), 2.24 (s,lH).
(ii) 3,5 Dimethyl-l-H-pyrrole-2-carboxylic acid To a solution of ethyl 3,5-dimethyl-2-pyrrolecarboxylate (Aldrich ) (504mg, 3 mmol ) in THF/H20/MeOH (5:1:1, 30ml ) was added NaOH ( 480 mg, 12 mmol ) in H20 ( 12 ml ). The mixture was stirred at 75° C overnight. The homogeneous mixture was washed with ether. To the aqueous layer was added a saturated aqueous KHSO4 solution until the pH was about 3. The solution was then extracted with dichloromethane. The extracts were dried over MgSO4 and evaporated. The residue was purified on silica (ethylacetate /methanol 90/10) to give the title compound ( 375 mg, 90 % ).
Η-NMR (400MHz, CDC13): δ 8.75(s,lH), 5.83(s,lH), 2.25(s,lH), 2.38 (s,lH).
Amine: N l-(4-Chlorobenzyl)-piperidineamine l-Chloro-4-(chloromethyl)benzene (1.61 g, 10 mmol) was added to a stirred solution of tert-butyl 4-piperidinylcarbamate (2.02 g. 10.1 mmol) and triethylamme (10 ml) in dry DMF (100 ml). The solution was stirred at room temperature overnight and then the solvent was removed in vacuo. The residue was taken in dichloromethane (150 ml) and trifluoroacetic acid (30 ml) was added. After stirring at room temperature for 3 h, the solution was diluted with dichloromethane (150 ml), and extracted with water (2 x 150 ml). The pH of the combined aqueous extracts was adjusted to 10 by addition of 2 M NaOH. The solution was extracted with ether (3 x 100 ml). Drying with sodium sulfate and
evaporation of the solvent afforded the title compound as yellowish oil (1.91 g, 8.5 mmol, 85 %).
Η-NMR (400MHz, CDC13): δ 7.2 -7.3 (m, 4H), 3.41 (s, 2H), 2.76 (m, 2H), 2.63 (m, IH), 1.98 (m, 2H), 1.76 (m, 2H), 1.3 - 1.6 (m, 4H). APCI-MS: m/z 225 [MH+]
Amine: O (3S)-l-(4-Chlorobenzyl)-3-pyrrolidinamine was prepared according the method described for Amine: N from tert-butyl (3S)pyrrolidinylcarbamate.
APCI-MS: m/z 211 [MH+]
'H-NMR (400MHz, CDC13): δ 7.2 - 7.3 (m, 4H), 5.55 (d, 2H), 3.49 (m, IH), 2.66 (m, 2H),
2.41 (m, IH), 2.29 (dd, IH), 2.18 (m, IH), 1.68 (br. s, 2H), 1.48 (m, IH).
Amine: P (3R)-l-(4-Chlorobenzyι)-3-pyrrolidinamine
Was prepared according the method described for Amine: N from tert-butyl (3R)pyrrolidinylcarbamate.
APCI-MS: m/z 211 [MH+]
'H-NMR (400MHz, CDC13): δ 7.2 - 7.3 (m, 4H), 5.55 (d, 2H), 3.49 (m, IH), 2.66 (m, 2H),
2.41 (m, IH), 2.29 (dd, IH), 2.18 (m, IH), 1.68 (br. s, 2H), 1.48 (m, IH).
Amine: Q
3-(4-Chlorophenoxy)piperidine tert-Butyl 3-hydroxy-l-piperidinecarboxylate (1.85 g, 9.18 mmol, prepared according to Costa et al., J. Med. Chem. 1992, 35, 4334 - 4343) (1.85 g, 9.18 mmol) and triphenyl phosphine (2.41 g, 9.18 mmol) were dissolved in dry THF (25 ml) under nitrogen. The solution was cooled to 0 °C and a solution of 4-chlorophenol (1.18 g, 9.18 mmol) in dry
THF (10 ml) was added followed by diethyl azodicarboxylate (1.60 g, 9.18 mmol, 1.45 ml). After 15 minutes the reaction mixture was allowed to warm to room temperature and stirred overnight. The solvent was removed in vacuo, the residue stirred with ether/n- heptane (1 : 2, 50 ml) mixture. The solid triphenyl phosphine oxide was filtered off, the solution washed with aq. NaOH (IM, 3 x 75 ml). Evaporation of the solvent and flash chromatography on silica gel with ethyl acetate/n-heptane (ethyl acetate from 5 to 25 %>) afforded the BOC-protected subtitle compound, which was dissolved in dichloromethane (20ml). Trifluoroacetic acid (10 ml) was added, and the reaction mixture was stirred overnight at room temperature. The solution was concentrated in vacuo and the product was purified by flash chromatography on silica gel (MeOH/CHCl3/NH3, 100 : 100 : 1) to afford colourless oil (0.23 g, 12%).
APCI-MS : m/z 212 [MH+]
'H-NMR (400MHz, CDC13): δ 7.19 (m, 2H), 6.84 (m, 2H), 4.25 (m, IH), 3.17 (m, IH), 2.7 - 2.9 (m, 4H), 1.97 (m, IH), 1.7 - 1.9 (m, 2H), 1.53 (m, IH).
Amine: R l-(4-Bromobenzyl)-4-piperidinylamine
To a solution of 4-bromo benzylbromide (l.Og, 4.1mmol) in dichloromethane (20ml) and diisopropyletylamine (1ml) was added tert-butyl 4-piperidinylcarbamate (l.Og, 5.0mmol). The solution was then stirred at room temperature over night. The solvent was evaporated and 25 ml of 50% TFA in dichloromethane was added to the resulting white solid. The mixture was then stirred at room temperature for 2h and then evaporated to dryness. The resulting solid was dissolved in water and extracted with toluene. After removal of the toluene the water phase was made basic with IM NaOH giving a pH of 13. The water phase was then extracted with dichloromethane 3 times and the combined extracts were dried and then evaporated to give the pure product as a slightly yellow oil (0.96g, 3.6mmol)
APCI-MS: m/z 269[M+]
H-NMR (400 MHz, CDC13): δ 7.42 (d, 2H), 7.18 (d, 2H), 3.43 (s, 2H), 2.78 (m, 3H), 2.43 (bs, 2H), 2.10 (t, 2H), 1.82 (m, 2H), 1.44 (m, 2H).
The following Amines (S, T, U) were synthesised by methods analogous to the method described for Amine R.
Amine: S l-(3,4-Difluorobenzyl)-4-piperidinylamine
APCI-MS: m/z 227[MH+]
Amine: T l-(3-Chloro-4-fluorobenzyl)-4-piperidinyIamine
APCI-MS: m/z 243[MH+]
Amine: U l-(4-Fluorobenzyl)-4-piperidinylamine
APCI-MS: m/z 209[Mff]
Example 17
N-(2-{[(2S)-3-({-[(4-Chlorophenyl)methyl]-4-piperidinyl}amino)-2- hydroxypropyl]oxy}phenyl)acetamide bi(trifluoroacetate)
A solution of l-(4-chlorobenzyl)-piperidine amine (0.80 g, 3.57 mmol) andN-{2- [(2S)oxiranylmethoxy]phenyl}acetamide (0.74 g, 3.57 mmol) in ethanol (50 ml, 99.5 %>) was refluxed for 4h. The solvent was distilled off under reduced pressure. The residue was purified by preparative HPLC (Kromasil C18 column; eluant: [acetonitrile + 0.1 % TF A/water + 0.1 % TFA]) to afford colourless solid (1.158 g, 1.75 mmol, 49 %).
APCI-MS: m/z 432 [MH+]
Example 18
N-(2-{(2R)-3-[l-(4-Chloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl- propoxy}-phenyl)-acetamide
l-(4-chlorobenzyl)-4-piperidinamine (62mg, 0.276mmol) andN-(2-{[(2R)-2- methyloxiranyl]methoxy}phenyl)acetamide (61mg, 0.276mmol) in ethanol (1.5ml) was stirred in a sealed vial at 80°C for 4 hours. The reaction mixture was diluted with water and purified by reversed phase HPLC to give 130mg (70%o) of the title compound as a ditrifluoroacetate after lyophilisation. The optical purity was determined to 86% ee, by chiral HPLC on a Chiralpak AD-column.
APCI-MS: m/z446.1 [M+]
Example 19
Ν-(2-{[3-({l-[(4-Chlorophenyl)methyl]-4-piperidinyl}amino)-2-hydroxy-2- methylpr opyl] oxy}phenyl) acetamide
Prepared by analogy to the method described in Example 18 from racemic epoxide.
APCI-MS : m/z 446.1 [M+]
Example 20 N-(2-{(2S)-3-[l-(4-Chloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl- propoxy}-phenyI)-acetamide
Prepared according to the method described in Example 18 from N-(2-(((2S)-2- methyloxiranyl)methoxy)phenyl)acetamide, >98% yield was obtained.
APCI-MS: m/z 446.1 [M+]
General Procedure (Examples 21-43)
To a solution of the amine in EtOH (0.1 M, 0.2 ml) a solution of the epoxide in DMSO (0.1 M, 0.2 ml) was added. The reaction mixture was heated at 80 °C for 24 h.
Example 21
N-{2-[((2S)-3-{[l-(4-Fluorobenzyl)-4-piperidinyl]amino}-2- hydroxypropyl)oxy]phenyl}acetamide
APCI-MS: m/z 416 [MH+]
Example 22 N-{2-[((2S)-3-{[l-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropyl)oxy]-4- fluorophenyl} acetamide
APCI-MS: m/z 450 [MH+]
Example 23
N-{4-fluoro-2-[((2S)-3-{[l-(4-fluorobenzyl)-4-piperidinyl]amino}-2- hydroxypropyl)oxy]phenyl}acetamide
APCI-MS: m/z 434[MH+]
Example 24
N-{2-[((2S)-3-{[(3S)-l-(4-Chlorobenzyl)pyrrolidinyl]amino}-2-hydroxypropyl)oxy]-4- fluorophenyl} acetamide
APCI-MS: m/z 436 [MH+]
Example 25
N-{2-[((2S)-3-{[(3R)-l-(4-Chlorobenzyl)pyrrolidinyl]amino}-2-hydroxypropyl)oxy]-4- fluorophenyl}acetamide
APCI-MS: m/z 436 [MH+]
Example 26
N-[2-(3-{[l-(4-Fluorobenzyl)-4-piperidinyl]amino}-2-hydroxy-2- methylpropoxy)phenyl] acetamide
APCI-MS: m/z 430 [MH+]
Example 27 N-[2-(3-{[l-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxy-2-methylpropoxy)-4- fluorophenyl] acetamide
APCI-MS: m z 464 [MH+]
Example 28
N-[4-Fluoro-2-(3-{[l-(4-fluorobenzyl)-4-piperidinyl]amino}-2-hydroxy-2- methylpropoxy)phenyl] acetamide
APCI-MS: m/z 448 [MH+]
Example 29
N-[2-(3-{[l-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-4- methylphenyl] acetamide
APCI-MS: m/z 446 [MH+]
Example 30
N-[2-(3-{[l-(4-Fluorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-4- methylphenyl] acetamide
APCI-MS: m/z 430 [MH+]
Example 31
N-[2-(3-{[l-(4-Chlorobenzyl)-4-piperidinyI]amino}-2- hydroxypropoxy)phenyl]benzamide
APCI-MS: m/z 494 [MH+]
Example 32 N-[2-(3-{[l-(4-Fluorobenzyl)-4-piperidinyl]amino}-2- hy dr oxyprop oxy)phenyl] b enzamide
APCI-MS: m/z 478 [MH+]
Example 33
N-[2-(3-{[(3S)-l-(4-Chlorobenzyl)pyrrolidinyl]amino}-2- hydroxypropoxy)phenyl]benzamide
APCI-MS: m/z 480 [MH+]
Example 34
N-[2-(3-{[(3R)-l-(4-Chlorobenzyl)pyrrolidinyl]amino}-2- hydroxypropoxy)phenyl]benzamide
APCI-MS: m/z 480 [MH+]
Example 35
N-[2-(3-{[l-(4-Bromobenzyl)-4-piperidinyl]amino}-2- hydroxypropoxy)phenyl]benzamide
APCI-MS: m/z 540 [MH+]
Example 36
N-[2-(3-{[l-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxy-2- methylpropoxy)phenyl]benzamide
APCI-MS: m/z 508 [MH+]
Example 37 N-[2-(3-{[l-(4-FIuorobenzyl)-4-piperidinyι]amino}-2-hydroxy-2- methylpropoxy)phenyl]benzamide
APCI-MS: m/z 492 [MH+]
Example 38
N-[2-(3-{[(3R)-l-(4-Chlorobenzyl)pyrrolidinyl]amino}-2-hydroxy-2- methylpropoxy)phenyl]benzamide
APCI-MS: m/z 494 [MH+]
Example 39
N-[2-(3-{[l-(4-Bromobenzyl)-4-piperidinyl]amino}-2-hydroxy-2- methylpropoxy)phenyl]benzamide
APCI-MS: m/z 554 [MH+]
Example 40
N-[2-(3-{[l-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-4- methoxyphenyl] acetamide
APCI-MS: m/z 462 [MH+]
Example 41
N-[2-(3-{[l-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-6- fluorophenyl] acetamide
APCI-MS: m/z 450 [MH+]
Example 42 N-[2-Fmoro-6-(3-{[l-(4-fluorobenzyl)-4-piperidinyl]amino}-2- hydroxypropoxy)phenyl] acetamide
APCI-MS: m/z 434 [MH+]
Example 43
2-(3-{[l-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxy-2-methylpropoxy)-N- methylbenzamide
APCI-MS: m/z 446 [MH+]
Example 44
N-(2- {3- [l-(3 ,4-DichIoro-b enzyl)-pip eridin-4-yIamino]-2-hydroxy-p rop oxy}-phenyl)- benzamide
To a solution of N-(2-Oxiranylmethoxy-phenyl)-benzamide (0.2ml, 0.1M in DMSO) was added (0.2ml, 0.1M in EtOH) of l-(3,4-Dichloro-benzyl)-piperidin-4-ylamine. The resulting mixture was heated at 75-80°C for 24hours. The ethanol was removed and the product was purified with preparative LC/MS .
APCI-MS: m/z 529[MH+]
The following Examples 45-63 were synthesised by methods analogous to the method described in Example 44.
Example 45
Ν-(2-{3-[l-(3-Chloro-4-fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}- phenyl)-benzamide
APCI-MS : m/z 513 [MH+]
Example 46
N-(2-{3-[l-(3,4-Difluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-phenyl)- benzamide.
APCI-MS:. m/z 496[MH+]
Example 47
N-(2-{3-[l-(3,4-Dichloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-6-methyl- phenyι)-acetamide
APCI-MS: m/z 481[MH+]
Example 48
N-(2-{3-[l-(4-Fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-6-methyl- phenyl)-acetamide
APCI-MS: m/z 430[MH+]
Example 49
N-(2-{3-[l-(4-Bromo-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl-propoxy}- phenyl)-acetamide
APCI-MS: m/z 490[M+]
Example 50
N-(2-{3-[l-(3,4-Dichloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl-propoxy}- phenyl)-acetamide
APCI-MS: m/z 481[MH+]
Example 51
N-(2-{3-[l-(3-Chloro-4-fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl- propoxy}-phenyl)-acetamide
APCI-MS: m/z 464[MH+]
Example 52 N-(2-{3-[l-(3,4-Difluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl-propoxy}- phenyl)-acetamide
APCI-MS: m/z 448[MH+]
Example 53
2-{3-[l-(4-Bromo-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-N-methyl- benzamide
APCI-MS: m/z 476[M+]
Example 54
2-{3-[l-(3,4-Dichloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-N-methyl- benzamide
APCI-MS: m/z 467[M+]
Example 55
2-{3-[l-(4-Chloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-N-methyl- benzamide
APCI-MS: m/z 432[MH+]
Example 56
2-{3-[l-(4-Fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-N-methyl- benzamide
APCI-MS: m/z 416[MH+]
Example 57 3,5-Dimethyl-lH-pyrrole-2-carboxylic acid (2-{3-[l-(4-bromo-benzyl)-piperidin-4- ylamino]-2-hydroxy-propoxy}-phenyl)-amide
APCI-MS: m/z 456[MH+]
Example 58
3,5-Dimethyl-lH-pyrrole-2-carboxylic acid (2-{3-[l-(3-chloro-benzyl)-piperidin-4- ylamino]-2-hydroxy-propoxy}-phenyl)-amide
APCI-MS: m/z 512[MH+]
Example 59
3,5-Dimethyl-lH-pyrrole-2-carboxylic acid (2-{3-[l-(3-fluoro-benzyl)-piperidin-4- ylamino]-2-hydroxy-propoxy}-phenyl)-amide
APCI-MS: m/z 495[MH+]
Example 60
N-(2-{3-[l-(4-Bromo-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-phenyl)- acetamide
APCI-MS: m/z 476[M+]
Example 61
N-(2-{3-[l-(3-Chloro-4-fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}- phenyl)-acetamide
APCI-MS: m z 450[MH+]
Example 62 N-(2-{3-[l-(3,4-Difluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-phenyl)- acetamide
APCI-MS: m/z 434[MH+]
Example 63
N-(2-{3-[l-(4-Fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-phenyl)- acetamide
APCI-MS: m/z 416[MH+]
THP-1 Chemotaxis Assay
Introduction
The assay measured the chemotactic response elicited by MlP-lα chemokine in the human monocytic cell line THP-1. The compounds of the Examples were evaluated by their ability to depress the chemotactic response to a standard concentration of MlP-lα chemokine.
Methods Culture of THP-1 cells
Cells were thawed rapidly at 37°C from frozen aliquots and resuspended in a 25 cm flask containing 5 ml of RPMI- 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.
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 4x10+5 cells/ml.
Chemotaxis assay
Cells were removed from the flask and washed by centrifugation in RPMI+10%HIFCS+glutamax. The cells were then resuspended at 2x10+7 cells/ml in fresh medium (RPMI+10%HIFCS+glutamax) to which was added calcein-AM (5 μl of stock solution to 1 ml to give a final concentration of 5x10" M). After gentle mixing the
cells were incubated at 37°C in a CO2 incubator for 30 minutes. The cells were then diluted to 50 ml with medium and washed twice by centrifugation at 400xg. Labelled cells were then resuspended at a cell concentration of 1x10+7 cells/ml and incubated with an eeqquuaall vvoolluummee ooff MMllPP--llαα aannttaaggoonniisstt ((11(0" 10, M , t ,o , 10 Λ-"6 M, final concentration) for 30 minutes at 37°C in a humidified CO2 incubator.
Chemotaxis was performed using Neuroprobe 96-well chemotaxis plates employing 8 μm filters (cat no. 101-8). Thirty microlitres of chemoattractant supplemented with 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 25μl 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°C in a humidified CO2 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.
Claims (20)
1. A compound of general formula
wherein m is 0, 1, 2 or 3; each R independently represents halogen, cyano, nitro, carboxyl, hydroxyl,
C3-C6 cycloalkyl, Cj-C6 alkoxy, Cj-Cg alkoxycarbonyl, Cj-Cg haloalkyl, CrC6 haloalkoxy, -NR 9 R 10 , C3-C6 cycloalkylamino, CrC6 alkylthio,
C^Cg alkylcarbonyl, Cj-C6 alkylcarbonylamino, sulphonamido, Cj-Cg alkylsulphonyl,
-C(O)NRπR12, -NR13C(O)-(NH)pR14, phenyl, or CrC6 alkyl optionally substituted by carboxyl or Cj-C6 alkoxycarbonyl; p is 0 or 1 ; Z represents a bond or a group (CH2)q where q is 1 or 2;
2 1 2
Z represents a bond or a group CH2, with the proviso that Z and Z do not both simultaneously represent a bond;
Q represents an oxygen or sulphur atom or a group CH2 or NH;
R represents a group
n is 0, 1 or 2;
3 eeaacchh RR iinnddependently represents a Cj-Cg alkyl, C]-C6 alkoxycarbonyl, -CH2OH or carboxyl group; R , R , R and R each independently represent a hydrogen atom or a CrC6 alkyl group, or R , R , R and R together represent a CrC4 alkylene chain linking the two carbon atoms to which they are attached to form a 4- to 7-membered saturated carbocycle, or R , R and R each represent a hydrogen atom and R and R together with the carbon atoms to which they are attached form a 5- to 6-membered saturated carbocycle;
8 4
R represents a hydrogen atom, a Cj-Cg alkyl group or is linked to R as defined above;
9 10
R and R each independently represent a hydrogen atom or a Cj-Cg alkyl group, or
9 10
R and R together with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocycle;
11 12
R and R each independently represent a hydrogen atom or a CrC6 alkyl group optionally substituted by C Cg alkoxycarbonyl;
13
R represents a hydrogen atom or a Cj-Cg alkyl group;
14
R represents a hydrogen atom, or a Cj-Cg alkyl group optionally substituted by carboxyl, C Cg alkoxy or C Cg alkoxycarbonyl;
R represents carboxyl, Cj-Cg alkoxy, Cj-C6 alkylcarbonyl, Cj-Cg alkoxycarbonyl, CrC6 alkoxycarbonylCrC6 alkyl or a group -NR17R18, -NHSO2CH3, -C(O)NR17R18, -NHC(O)NR17R18, -OC(O)NR17R18, -OCH2C(O)NR17R18, -NHC(O)OR19 or -NHC(O)R20; t is 0, 1, 2 or 3; each R independently represents halogen, cyano, nitro, carboxyl, hydroxyl, C3-Cg cycloalkyl, C Cg alkoxy, C C6 alkoxycarbonyl, C]-C6 haloalkyl,
21 22
CrC6 haloalkoxy, -NR R , C3-C6 cycloalkylamino, C^Cg alkylthio, CrC6 alkylcarbonyl, Cj-Cg alkylcarbonylamino, sulphonamido, C^-Cg alkylsulphonyl, -C(O)NR23R24, -NR25C(O)(NH)vR26, phenyl, or CrC6 alkyl optionally substituted by carboxyl or Cj-Cg alkoxycarbonyl;
17 18
R and R each independently represent a hydrogen atom, or a C Cg alkyl group
17 18 optionally substituted by carboxyl or CrC6 alkoxycarbonyl, or R and R together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle; 19
R represents a hydrogen atom, or a CrC6 alkyl group optionally substituted by carboxyl or Cj-Cg alkoxycarbonyl;
20
R represents a group CrC6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, adamantyl, C5- cycloalkenyl, phenyl or a saturated or unsaturated 5- to 10-membered heterocyclic ring system comprising at least one heteroatom selected from nitrogen, oxygen and sulphur, each of which may be optionally substituted by one or more substituents independently selected from nitro, hydroxyl, oxo, halogen, carboxyl, CrC6 alkyl, CrC6 alkoxy, CrC6 alkylthio, CrC6 alkylcarbonyl, C C6 alkoxycarbonyl, phenyl and
-NHC(O)-R27;
21 22 R and R each independently represent a hydrogen atom or a Cj-Cg alkyl group, or
21 22
R and R together with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocycle;
23 24
R and R each independently represent a hydrogen atom or a Cj- alkyl group optionally substituted by C C6 alkoxycarbonyl; v is O or l;
25 R represents a hydrogen atom or a Cj-Cg alkyl group; alkyl group optionally substituted by carboxyl, Cj-Cg alkoxy or Cj-Cg alkoxycarbonyl; and
27 R represents a Cj-Cg alkyl, amino (-NH2) or phenyl group; or a pharmaceutically acceptable salt or solvate thereof.
2. A compound according to claim 1, wherein m is 1 or 2.
3. A compound according to claim 2, wherein each R represents a halogen atom.
4. A compound according to any one of claims 1 to 3, wherein Q represents an oxygen atom.
A compound according to any one of claims 1 to 4, wherein R represents a group -NHC(O)R20. 20
6. A compound according to claim 5, wherein, in R , the saturated or unsaturated 5- to
10-membered heterocyclic ring system comprising at least one heteroatom selected from nitrogen, oxygen and sulphur, is pynolidinyl, piperidinyl, pyrazolyl, thiazolidinyl, thienyl, isoxazolyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, indolyl, quinolinyl, benzimidazolyl, triazolyl, tetrazolyl or pyridinyl.
7. A compound according to any one of claims 1 to 6, wherein each R independently represents halogen, cyano, C1-C4 alkoxy, C C4 alkoxycarbonyl, C1-C4 haloalkyl, CrC4 alkylcarbonyl, phenyl or CrC alkyl.
8. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined in claim 1 being selected from:
N- [2-(3 - { [ 1 -(3 ,4-dichlorobenzylpiperidinyl] aminohydroxypropoxy)phenyl] acetamide, N-[5-chloro-2-(3-{[l-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-2- hydroxypropoxy)phenyl]acetamide,
N-[2-(3- { [ 1 -(3 ,4-dichlorobenzyl)-4-piperidinyl]amino } -2-hydroxypropoxy)-5- methylphenyl] acetamide,
N-[4-(3-{[l-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)[l,r- biphenyl]-3-yl]acetamide,
N-[3-acetyl-2-(3-{[l-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)- 5-methylphenyl]acetamide,
N-[2-(3-{[l-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-4- fluorophenyl] acetamide, N- [2-(3 - { [ 1 -(3 ,4-dichlorobenzyl)-4-piperidinyl] amino } -2-hy droxypropoxy)-5 - fluorophenyl]acetamide,
N- [2-(3 - { [ 1 -(3 ,4-dichlorobenzyl)-4-piperidinyl] amino } -2-hy droxypropoxy)-5- cyanophenyl] acetamide,
N-[2-(3-{[l-(4-chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)phenyl]- acetamide, N-[2-(3 - { [ 1 -(4-chlorobenzyl)-4-piperidinyl] aminO } -hydroxypropoxy)phenyl]- isobutyramide,
N-[2-(3-{[l-(4-chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)phenyl]-2-2- dimethyl-propiomanide, N- [5 -chloro-2-(3 - { [ 1 -(4-chlorobenzy l)-4-piperidinyl] amino } -2- hydroxypropoxy)phenyl] acetamide,
N- [2-(3 - { [ 1 -(4-chlorobenzy l)-4-piperidinyl] amino } -2-hydroxypropoxy)-5 - methylphenyl] acetamide,
N-[2-(3-{[l-(4-chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-4- methylphenyl] acetamide,
N- [2-(3 - { [ 1 -(4-chlorobenzyl)-4-piperidinyl] amino } -2-hy droxypropoxy)-4- fluoropheny 1] acetamide,
N-[2-(3- {[1 -(4-chlorobenzyl)-4-piperidinyl]amino} -2-hydroxypropoxy)-5- cyanophenyl]acetamide, Ν-(2- {[(2S)-3-({-[(4-Chlorophenyl)methyl]-4-piperidinyl} amino)-2- hydroxypropyl]oxy}phenyl)acetamide bi(trifluoroacetate),
N-(2- {(2R)-3-[ 1 -(4-Chloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl- propoxy } -phenyι)-acetamide,
N-(2- { [3 -( { 1 -[(4-Chlorophenyl)methyl]-4-piperidinyl} amino)-2-hydroxy-2- methylpropyl] oxy } pheny l)acetamide,
N-(2-{(2S)-3-[l-(4-Chloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl- propoxy } -phenyl)-acetamide,
N- {2-[((2S)-3- {[ 1 -(4-Fluorobenzyl)-4-piperidinyl]amino} -2- hydroxypropyl)oxy]phenyl}acetamide, N-{2-[((2S)-3-{[l-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropyl)oxy]-4- fluorophenyl} acetamide,
N-{4-fluoro-2-[((2S)-3-{[l-(4-fluorobenzyl)-4-piperidinyl]amino}-2- hydroxypropyl)oxy]phenyl}acetamide,
N- {2-[((2S)-3- { [(3S)- 1 -(4-Chlorobenzyl)pyrrolidinyl]amino} -2-hydroxypropyl)oxy]- 4-fluorophenyl} acetamide, N- {2-[((2S)-3- {[(3R)- 1 -(4-Chlorobenzyl)pynolidinyl]amino} -2-hydroxypropyl)oxy]- 4-fluorophenyl} acetamide,
N-[2-(3-{[l-(4-Fluorobenzyl)-4-piperidinyl]amino}-2-hydroxy-2- methylpropoxy)phenyl]acetamide, N-[2-(3-{[l-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxy-2-methylpropoxy)-4- fluorophenyl]acetamide,
N-[4-Fluoro-2-(3-{[l-(4-fluorobenzyl)-4-piperidinyl]amino}-2-hydroxy-2- methylpropoxy)phenyl]acetamide,
N- [2-(3 - { [ 1 -(4-Chlorobenzyl)-4-piperidinyl] amino } -2-hy droxypropoxy)-4- methylphenyl] acetamide,
N-[2-(3-{[l-(4-Fluorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-4- methylphenyl] acetamide,
N-[2-(3 - { [ 1 -(4-Chlorobenzyl)-4-piperidinyl] amino} -2- hydroxypropoxy)phenyl]benzamide, N- [2-(3 - { [ 1 -(4-Fluorobenzyl)-4-piperidinyl] amino } -2- hydroxypropoxy)phenyl]benzarnide,
N-[2-(3-{[(3S)-l-(4-Chlorobenzyl)pynolidinyl]amino}-2- hydroxypropoxy)phenyl]benzarnide,
N-[2-(3- { [(3R)- 1 -(4-Chlorobenzyl)pyrrolidinyl]amino} -2- hydroxypropoxy)phenyl]benzamide,
N- [2-(3 - { [ 1 -(4-Bromobenzyl)-4-piperidinyl] amino } -2- hydroxypropoxy)phenyl]benzamide,
N-[2-(3 - { [ 1 -(4-Chlorobenzyl)-4-piperidinyl]amino } -2-hydroxy-2- methylpropoxy)phenyl]benzamide, N-[2-(3- { [ 1 -(4-Fluorobenzyl)-4-piperidinyl]amino} -2-hydroxy-2- methylpropoxy)phenyl]benzamide,
N-[2-(3- { [(3R)- 1 -(4-Chlorobenzyl)pyrrolidinyl]amino} -2-hydroxy-2- methylpropoxy)phenyl]benzamide,
N- [2-(3 - { [ 1 -(4-Bromobenzyl)-4-piperidinyl] amino } -2-hydroxy-2- methylpropoxy)phenyl]benzamide, N-[2-(3-{[l-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-4- methoxyphenyl] acetamide,
N-[2-(3-{[l-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-6- fluorophenyljacetamide, N-[2-Fluoro-6-(3-{[l-(4-fluorobenzyl)-4-piperidinyl]amino}-2- hydroxypropoxy)phenyl] acetamide,
2-(3-{[l-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxy-2-methylpropoxy)-N- methylbenzamide,
N-(2-{3-[l-(3,4-Dichloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-phenyl)- benzamide,
N-(2-{3-[l-(3-Chloro-4-fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}- phenyl)-benzamide,
N-(2-{3-[l-(3,4-Difluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-phenyl)- benzamide, N-(2-{3-[l-(3,4-Dichloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-6- methyl-phenyl)-acetamide,
N-(2-{3-[l-(4-Fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-6-methyl- phenyl)-acetamide,
N-(2-{3-[l-(4-Bromo-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl-propoxy}- phenyl)-acetamide,
N-(2-{3-[l-(3,4-Dichloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl- propoxy } -phenyl)-acetamide,
N-(2-{3-[l-(3-Chloro-4-fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl- propoxy } -phenyl)-acetamide, N-(2-{3-[l-(3,4-Difluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-2-methyl- propoxy } -phenyl)-acetamide,
2-{3-[l-(4-Bromo-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-N-methyl- benzamide,
2-{3-[l-(3,4-Dichloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-N-methyl- benzamide, 2- {3-[l -(4-Chloro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy} -N-methyl- benzamide,
2-{3-[l-(4-Fluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-N-methyl- benzamide, 3,5-Dimethyl-lH-pynole-2-carboxylic acid (2-{3-[l-(4-bromo-benzyl)-piperidin-4- ylamino]-2-hydroxy-propoxy}-phenyl)-amide,
3,5-Dimethyl-lH-pyrrole-2-carboxylic acid (2-{3-[l-(3-chloro-benzyl)-piperidin-4- ylamino]-2-hydroxy-propoxy}-phenyl)-amide,
3,5-Dimethyl-lH-pynole-2-carboxylic acid (2-{3-[l-(3-fluoro-benzyl)-piperidin-4- ylamino]-2-hydroxy-propoxy} -phenyl)-amide,
N-(2- {3-[l -(4-Bromo-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy} -phenyl)- acetamide,
N-(2- { 3 - [ 1 -(3 -Chloro-4-fluoro-benzyl)-piperidin-4-ylamino] -2-hy droxy-propoxy } - phenyl)-acetamide, N-(2-{3-[l-(3,4-Difluoro-benzyl)-piperidin-4-ylamino]-2-hydroxy-propoxy}-phenyl)- acetamide, and
N-(2- { 3 -[ 1 -(4-Fluoro-benzyl)-piperidin-4-ylamino] -2 -hy droxy-propoxy } -phenyl)- acetamide.
9. A process for the preparation of a compound of formula (I) as defined in claim 1 which comprises, (a) reacting a compound of general formula
1 2 1 3 wherein m, n, Z , Z , R and R are as defined in formula (I), with a compound of general formula £ Q wherein Q, R , R , R , R , R and R are as defined in formula (I); or
(b) reacting a compound of general formula
wherein m, n, Z ,Z ,R,R,R,R,R,R and R are as defined in formula (I), with a compound of general formula
L!-Q-R2 (N) wherein L 1 repr eesseennttss aa hhyyddrrooggeenn aattom or a leaving group and Q and R 2 are as defined in formula (I); or
(c) reacting a compound of general formula
wherein m, n, Z 1 , Z2 , R 1 and R 3 are as defined in formula (I), with a compound of general formula
wherein Q, are as defined in formula (I);
and optionally after (a), (b) or (c) converting the compound of formula (I) to a further compound of formula (I) and/or forming a pharmaceutically acceptable salt or solvate of the compound of formula (I).
10. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 8 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 any one of claims 1 to 8 with a pharmaceutically acceptable adjuvant, diluent or carrier.
12. A compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as claimed in any one of claims 1 to 8 for use in therapy.
13. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 8 in the manufacture of a medicament for use in therapy.
14. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 8 in the manufacture of a medicament for the treatment of human diseases or conditions in which modulation of chemokine receptor activity is beneficial.
15. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 8 in the manufacture of a medicament for use in treating rheumatoid arthritis.
16. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 8 in the manufacture of a medicament for use in treating chronic obstructive pulmonary disease.
17. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 8 in the manufacture of a medicament for use in treating asthma.
18. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 8 in the manufacture of a medicament for use in treating multiple sclerosis.
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 any one of claims 1 to 8.
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 any one of claims 1 to 8.
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Families Citing this family (43)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CO5300399A1 (en) | 2000-02-25 | 2003-07-31 | Astrazeneca Ab | HETEROCICLIOCS CONTAINING NITROGEN, PROCESS FOR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
AR028948A1 (en) * | 2000-06-20 | 2003-05-28 | Astrazeneca Ab | NEW COMPOUNDS |
US7005439B2 (en) * | 2000-06-20 | 2006-02-28 | Astrazeneca Ab | Compounds |
AR035230A1 (en) * | 2001-03-19 | 2004-05-05 | Astrazeneca Ab | BENCIMIDAZOL COMPOUNDS, PROCESS FOR PREPARATION, PHARMACEUTICAL COMPOSITION, PROCESS FOR THE PREPARATION OF SUCH PHARMACEUTICAL COMPOSITION, AND USES OF THESE COMPOUNDS FOR THE PREPARATION OF MEDICINES |
SE0202133D0 (en) | 2002-07-08 | 2002-07-08 | Astrazeneca Ab | Novel compounds |
RU2330842C2 (en) * | 2003-02-17 | 2008-08-10 | Ф.Хоффманн-Ля Рош Аг | Piperidinbenzolsulfamide derivatives |
US8017762B2 (en) | 2003-04-17 | 2011-09-13 | Alnylam Pharmaceuticals, Inc. | Modified iRNA agents |
EP2664672A1 (en) | 2003-04-17 | 2013-11-20 | Alnylam Pharmaceuticals Inc. | Modified iRNA agents |
US8796436B2 (en) | 2003-04-17 | 2014-08-05 | Alnylam Pharmaceuticals, Inc. | Modified iRNA agents |
US7851615B2 (en) | 2003-04-17 | 2010-12-14 | Alnylam Pharmaceuticals, Inc. | Lipophilic conjugated iRNA agents |
US7723509B2 (en) | 2003-04-17 | 2010-05-25 | Alnylam Pharmaceuticals | IRNA agents with biocleavable tethers |
US7732442B2 (en) | 2003-09-05 | 2010-06-08 | Ono Pharmaceutical Co., Ltd. | Chemokine receptor antagonist and medical use thereof |
SE0303090D0 (en) | 2003-11-20 | 2003-11-20 | Astrazeneca Ab | Novel compounds |
SE0303541D0 (en) | 2003-12-22 | 2003-12-22 | Astrazeneca Ab | New compounds |
EP1912942A1 (en) * | 2005-08-01 | 2008-04-23 | AstraZeneca AB | Novel piperidine derivatives as chemokine receptor modulators useful for the treatment of respiratory diseases. |
TW200738634A (en) * | 2005-08-02 | 2007-10-16 | Astrazeneca Ab | New salt |
TW200734305A (en) * | 2005-08-02 | 2007-09-16 | Astrazeneca Ab | New salt III |
TW200738635A (en) * | 2005-08-02 | 2007-10-16 | Astrazeneca Ab | New salt |
TW200744612A (en) * | 2005-08-26 | 2007-12-16 | Astrazeneca Ab | New combination |
JO2769B1 (en) | 2005-10-26 | 2014-03-15 | جانسين فارماسوتيكا ان. في | Fast Dissociting Dopamine 2 Receptor Antagonists |
TW200800895A (en) * | 2005-11-02 | 2008-01-01 | Astrazeneca Ab | Novel compounds |
WO2007102767A1 (en) * | 2006-03-07 | 2007-09-13 | Astrazeneca Ab | Piperidine derivatives, their process for preparation, their use as therapeutic agents and pharmaceutical compositions containing them |
CN101437797A (en) * | 2006-03-07 | 2009-05-20 | 阿斯利康(瑞典)有限公司 | Piperidine derivatives, their process for preparation, their use as therapeutic agents and pharmaceutical compositions containing them |
US20080064884A1 (en) * | 2006-05-10 | 2008-03-13 | Astrazeneca Ab | Novel Process 1 |
US20100041905A1 (en) * | 2006-07-18 | 2010-02-18 | Astrazeneca Ab | Process for the Preparation of Substituted 2-Acetylamino-Alkoxyphenyl |
JO2642B1 (en) | 2006-12-08 | 2012-06-17 | جانسين فارماسوتيكا ان. في | Fast Dissociating Dopamine 2 Receptor Antagonists |
GB0702456D0 (en) | 2007-02-08 | 2007-03-21 | Astrazeneca Ab | New combination |
JO2849B1 (en) | 2007-02-13 | 2015-03-15 | جانسين فارماسوتيكا ان. في | Fast -Dissociating Dopamine 2 Receptor Antagonists |
US20110136843A1 (en) * | 2007-02-23 | 2011-06-09 | Tomas Eriksson | Novel Combination of Compounds to be Used in the Treatment of Airway Diseases, Especially Chronic Obstructive Pulmonary Disease (COPD) and Asthma |
WO2008121065A1 (en) * | 2007-03-30 | 2008-10-09 | Astrazeneca Ab | Novel pyrrolidine derivatives as antagonists of the chemokine receptor |
KR101506156B1 (en) | 2007-04-23 | 2015-03-26 | 얀센 파마슈티카 엔.브이. | Thia(dia)zoles as fast dissociating dopamine 2 receptor antagonists |
CN101663292A (en) | 2007-04-23 | 2010-03-03 | 詹森药业有限公司 | 4-alkoxypyridazine derivatives as quick dissociated dopamine 2 receptor antagonists |
CA2729313C (en) | 2008-07-03 | 2016-08-30 | Janssen Pharmaceutica Nv | Substituted 6-(1-piperazinyl)-pyridazines as 5-ht6 receptor antagonists |
EA019048B1 (en) | 2008-07-31 | 2013-12-30 | Янссен Фармацевтика Нв | Piperazin-1-yl-trifluoromethyl-substituted pyridines as fast dissociating dopamine 2 receptor antagonists |
GB0913345D0 (en) | 2009-07-31 | 2009-09-16 | Astrazeneca Ab | New combination 802 |
WO2011061527A1 (en) | 2009-11-17 | 2011-05-26 | Astrazeneca Ab | Combinations comprising a glucocorticoid receptor modulator for the treatment of respiratory diseases |
WO2011073662A1 (en) | 2009-12-17 | 2011-06-23 | Astrazeneca Ab | Combination of a benzoxazinone and a further agent for treating respiratory diseases |
GB201021979D0 (en) | 2010-12-23 | 2011-02-02 | Astrazeneca Ab | New compound |
GB201021992D0 (en) | 2010-12-23 | 2011-02-02 | Astrazeneca Ab | Compound |
WO2012163848A1 (en) | 2011-05-27 | 2012-12-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of crohn's disease |
EP3083609B1 (en) * | 2013-12-19 | 2018-08-15 | Merck Sharp & Dohme Corp. | Hiv protease inhibitors |
EP3962903A1 (en) * | 2019-05-01 | 2022-03-09 | Boehringer Ingelheim International GmbH | (r)-(2-methyloxiran-2-yl)methyl 4-bromobenzenesulfonate |
EP4115885A1 (en) | 2021-07-05 | 2023-01-11 | Charité - Universitätsmedizin Berlin | A pharmaceutical composition comprising bay 86-5277 and salts thereof for use in the treatment of viral infections and hyperinflammation |
Family Cites Families (97)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1220440B (en) | 1962-02-14 | 1966-07-07 | Sanol Arznei Schwarz Gmbh | Process for the preparation of derivatives of 1- (o-bromophenoxy) -2-hydroxy-3-aminopropane and their acid addition salts |
US3577432A (en) * | 1968-12-23 | 1971-05-04 | Robins Co Inc A H | 1-substituted-3-phenoxypyrrolidines |
US4029801A (en) | 1970-09-03 | 1977-06-14 | John Wyeth & Brother Limited | Pharmaceutical compositions and methods of treating hypertension |
JPS5511670B1 (en) | 1971-07-13 | 1980-03-26 | ||
US4080328A (en) * | 1971-07-13 | 1978-03-21 | Sumitomo Chemical Company, Limited | N-substituted heterocyclic derivatives and preparation thereof |
US3994974A (en) * | 1972-02-05 | 1976-11-30 | Yamanouchi Pharmaceutical Co., Ltd. | α-Aminomethylbenzyl alcohol derivatives |
US3755584A (en) * | 1972-04-03 | 1973-08-28 | Abbott Lab | Tranquilizers |
SE378109B (en) | 1972-05-19 | 1975-08-18 | Bofors Ab | |
FR2190430A1 (en) | 1972-06-29 | 1974-02-01 | Ferlux | N-aminomethylhydroxamic acids - with antiinflammatory activity pre-pared by Mannich reaction |
US3894030A (en) | 1973-01-04 | 1975-07-08 | Janssen Pharmaceutica Nv | 1-{8 1-(2-Hydroxy-3-aryloxypropyl)-4-piperidyl{9 -2-benzimidazolinones and related compounds |
US3818017A (en) | 1973-01-04 | 1974-06-18 | Janssen Pharmaceutica Nv | 1-{8 1-(2-hydroxy-3-aryloxypropyl)-4-piperidyl{9 -2-benzimidazolinones and related compounds |
US4166119A (en) * | 1978-04-14 | 1979-08-28 | American Hoechst Corporation | Analgesic and tranquilizing spiro[dihydrobenzofuran]piperidines and pyrrolidines |
WO1980000152A1 (en) * | 1978-07-03 | 1980-02-07 | Sandoz Ag | 3-aminopropoxy-aryl derivates,preparation and use thereof |
US4264613A (en) | 1979-08-01 | 1981-04-28 | Science Union Et Cie, Societe Francaise De Recherche Medicale | Piperidylbenzimidazolinone compounds |
FR2469411A1 (en) | 1979-11-15 | 1981-05-22 | Science Union & Cie | NOVEL PIPERIDYLBENZIMIDAZOLINONE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
EP0095454A3 (en) | 1982-05-13 | 1985-04-03 | Gerot-Pharmazeutika Gesellschaft m.b.H. | Nuclens-substituted pyrogallol derivatives |
JPS59222484A (en) | 1983-06-02 | 1984-12-14 | Kowa Co | Tetrahydronaphthylcarboxylic acid phenyl ester derivative |
GB8334494D0 (en) * | 1983-12-24 | 1984-02-01 | Tanabe Seiyaku Co | Carbostyril derivatives |
US5614533A (en) * | 1987-03-13 | 1997-03-25 | Bio-Mega/Boehringer Ingelheim Research, Inc. | Substituted pipecolinic acid derivatives as HIV protease inhibitors |
DE3723568C2 (en) | 1987-07-16 | 1994-01-27 | Siemens Ag | Residual current circuit breaker |
DE3723648A1 (en) | 1987-07-17 | 1989-01-26 | Sandoz Ag | Indole derivatives, their preparation and medicaments containing them |
WO1990003358A1 (en) * | 1988-09-30 | 1990-04-05 | Mallinckrodt, Inc. | A process for the production of granular metal soaps |
GR1001529B (en) | 1990-09-07 | 1994-03-31 | Elmuquimica Farm Sl | Process for the obtainment of a new pregna-1,4-diene-3,20-dione -16-17-acetal-21 esters |
SE9003057D0 (en) | 1990-09-26 | 1990-09-26 | Astra Ab | NEW PROCESS |
ES2027897A6 (en) | 1991-01-24 | 1992-06-16 | Espanola Prod Quimicos | Diphenylmethylpiperazine derivatives. |
IL105716A0 (en) | 1992-06-08 | 1993-09-22 | Richter Gedeon Vegyeszet | Aminopropanol derivatives,their preparation and pharmaceutical compositions containing them |
AU662434B2 (en) | 1992-08-07 | 1995-08-31 | Sankyo Company Limited | Peptides capable of inhibiting the activity of HIV protease, their preparation and their use |
US5614523A (en) * | 1995-01-17 | 1997-03-25 | Eli Lilly And Company | Compounds having effects on serotonin-related systems |
US5627196A (en) * | 1995-01-17 | 1997-05-06 | Eli Lilly And Company | Compounds having effects on serotonin-related systems |
US5789402A (en) * | 1995-01-17 | 1998-08-04 | Eli Lilly Company | Compounds having effects on serotonin-related systems |
US5741789A (en) * | 1995-01-17 | 1998-04-21 | Eli Lilly And Company | Compounds having effects on serotonin-related systems |
US5576321A (en) * | 1995-01-17 | 1996-11-19 | Eli Lilly And Company | Compounds having effects on serotonin-related systems |
GB9624482D0 (en) | 1995-12-18 | 1997-01-15 | Zeneca Phaema S A | Chemical compounds |
ZA9610738B (en) | 1995-12-22 | 1997-06-24 | Warner Lambert Co | Subtype selective nmda receptor ligands and the use thereof |
BR9707495A (en) | 1996-02-13 | 1999-07-27 | Zeneca Ltd | Quinazoline derivative process for the preparation of the same pharmaceutical composition and process for the production of an antiangiogenic effect and / or reduction of vascular permeability in a warm-blooded animal |
KR100489174B1 (en) | 1996-03-05 | 2005-09-30 | 제네카-파마 소시에떼아노님 | 4-anilinoquinazoline derivatives |
GB9718972D0 (en) | 1996-09-25 | 1997-11-12 | Zeneca Ltd | Chemical compounds |
DE19703131A1 (en) | 1997-01-29 | 1998-07-30 | Bayer Ag | Use of quinoxaline in a combination of three with protease inhibitors and reverse transcriptase inhibitors as medicaments for the treatment of AIDS and / or HIV infections |
GB9714249D0 (en) | 1997-07-08 | 1997-09-10 | Angiogene Pharm Ltd | Vascular damaging agents |
IL125658A0 (en) | 1997-08-18 | 1999-04-11 | Hoffmann La Roche | Ccr-3 receptor antagonists |
WO1999025686A1 (en) | 1997-11-18 | 1999-05-27 | Teijin Limited | Cyclic amine derivatives and their use as drugs |
DE19755268A1 (en) | 1997-12-12 | 1999-06-17 | Merck Patent Gmbh | Benzamidine derivatives |
FR2780057B1 (en) | 1998-06-18 | 2002-09-13 | Sanofi Sa | PHENOXYPROPANOLAMINES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
DE69938193D1 (en) | 1998-11-20 | 2008-04-03 | Hoffmann La Roche | PIPERIDINE CCR-3 RECEPTOR HEMMER |
CA2350730A1 (en) | 1998-12-18 | 2000-06-22 | George V. Delucca | N-ureidoalkyl-piperidines as modulators of chemokine receptor activity |
EP1156807A4 (en) | 1998-12-18 | 2002-04-03 | Du Pont Pharm Co | N-ureidoalkyl-piperidines as modulators of chemokine receptor activity |
GB9900334D0 (en) | 1999-01-07 | 1999-02-24 | Angiogene Pharm Ltd | Tricylic vascular damaging agents |
GB9900752D0 (en) | 1999-01-15 | 1999-03-03 | Angiogene Pharm Ltd | Benzimidazole vascular damaging agents |
SE9900833D0 (en) | 1999-03-09 | 1999-03-09 | Astra Ab | Novel combination |
AU2942000A (en) | 1999-03-11 | 2000-09-28 | Banyu Pharmaceutical Co., Ltd. | Novel piperidine derivatives |
KR20010108394A (en) | 1999-03-26 | 2001-12-07 | 다비드 에 질레스 | Novel Compounds |
JP3495955B2 (en) * | 1999-03-26 | 2004-02-09 | シャープ株式会社 | Semiconductor memory device and method of manufacturing the same |
GB9913083D0 (en) | 1999-06-04 | 1999-08-04 | Novartis Ag | Organic compounds |
DE60014361T2 (en) | 1999-05-14 | 2006-02-02 | Bristol-Myers Squibb Pharma Research Labs, Inc. | CYCLIC AMINE DERIVATIVES AND ITS USE |
ES2165768B1 (en) * | 1999-07-14 | 2003-04-01 | Almirall Prodesfarma Sa | NEW DERIVATIVES OF QUINUCLIDINE AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM. |
AUPQ165599A0 (en) | 1999-07-15 | 1999-08-05 | University Of Sydney, The | Optical processing method and apparatus and products thereof |
SE9902987D0 (en) | 1999-08-24 | 1999-08-24 | Astra Pharma Prod | Novel compounds |
US6867220B2 (en) | 1999-12-17 | 2005-03-15 | Sanofi-Synthelabo | Phenoxypropanolamines, method for producing them and pharmaceutical compositions containing them |
FR2802533B1 (en) | 1999-12-17 | 2002-02-15 | Sanofi Synthelabo | PHENOXYPROPANOLAMINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
CO5300399A1 (en) | 2000-02-25 | 2003-07-31 | Astrazeneca Ab | HETEROCICLIOCS CONTAINING NITROGEN, PROCESS FOR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
GB0011838D0 (en) | 2000-05-17 | 2000-07-05 | Astrazeneca Ab | Chemical compounds |
GB0012260D0 (en) | 2000-05-19 | 2000-07-12 | Astrazeneca Ab | Novel composition |
IL152682A0 (en) | 2000-05-31 | 2003-06-24 | Astrazeneca Ab | Indole derivatives with vascular damaging activity |
US7005439B2 (en) * | 2000-06-20 | 2006-02-28 | Astrazeneca Ab | Compounds |
AR028948A1 (en) | 2000-06-20 | 2003-05-28 | Astrazeneca Ab | NEW COMPOUNDS |
AR028947A1 (en) | 2000-06-20 | 2003-05-28 | Astrazeneca Ab | NEW COMPOUNDS |
JP2004516238A (en) | 2000-06-21 | 2004-06-03 | ブリストル−マイヤーズ・スクイブ・ファーマ・カンパニー | N-ureidoalkyl-piperidines as modulators of chemokine receptor activity |
GB0015876D0 (en) | 2000-06-28 | 2000-08-23 | Novartis Ag | Organic compounds |
KR20030022264A (en) | 2000-07-07 | 2003-03-15 | 앤지오젠 파마슈티칼스 리미티드 | Colchinol derivatives as angiogenesis inhibitors |
US20050277627A1 (en) | 2000-07-07 | 2005-12-15 | Arnould Jean C | Colchinol derivatives as vascular damaging agents |
IL154175A0 (en) | 2000-08-05 | 2003-07-31 | Glaxo Group Ltd | 17. beta.-carbothioate 17. alpha-arylcarbonyloxyloxy androstane derivatives as anti-inflammatory agents |
GB0021670D0 (en) | 2000-09-04 | 2000-10-18 | Astrazeneca Ab | Chemical compounds |
GB0029562D0 (en) | 2000-12-04 | 2001-01-17 | Novartis Ag | Organic compounds |
GB2373186A (en) | 2001-02-23 | 2002-09-18 | Astrazeneca Ab | Pharmaceutical combinations of a CCR3 antagonist and a compound which is usefulreatment of asthma, allergic disease or inflammation |
AR035230A1 (en) * | 2001-03-19 | 2004-05-05 | Astrazeneca Ab | BENCIMIDAZOL COMPOUNDS, PROCESS FOR PREPARATION, PHARMACEUTICAL COMPOSITION, PROCESS FOR THE PREPARATION OF SUCH PHARMACEUTICAL COMPOSITION, AND USES OF THESE COMPOUNDS FOR THE PREPARATION OF MEDICINES |
GB0107228D0 (en) | 2001-03-22 | 2001-05-16 | Astrazeneca Ab | Chemical compounds |
WO2002076933A1 (en) | 2001-03-22 | 2002-10-03 | Glaxo Group Limited | Formailide derivatives as beta2-adrenoreceptor agonists |
SE0101038D0 (en) * | 2001-03-23 | 2001-03-23 | Astrazeneca Ab | Novel compounds |
KR100406536B1 (en) * | 2001-03-28 | 2003-11-20 | 주식회사 하이닉스반도체 | FeRAM having aluminum oxide layer as oxygen diffusion barrier and method for forming the same |
GB0108046D0 (en) | 2001-03-30 | 2001-05-23 | Astrazeneca Ab | Chemical compounds |
CA2445348A1 (en) | 2001-04-27 | 2002-11-07 | Mitsubishi Pharma Corporation | Novel benzylpiperidine compound |
AU2002253342B2 (en) | 2001-04-30 | 2007-01-04 | Glaxo Group Limited | Novel anti-inflammatory androstane derivatives |
CN1290194C (en) * | 2001-06-25 | 2006-12-13 | 松下电器产业株式会社 | Capacitance element, semiconductor storage and preparing method thereof |
US6818935B2 (en) * | 2001-09-12 | 2004-11-16 | Hynix Semiconductor Inc. | Semiconductor device and method for fabricating the same |
TWI249515B (en) | 2001-11-13 | 2006-02-21 | Theravance Inc | Aryl aniline beta2 adrenergic receptor agonists |
GB0127547D0 (en) | 2001-11-16 | 2002-01-09 | Astrazeneca Ab | Chemical compounds |
SE0104251D0 (en) | 2001-12-14 | 2001-12-14 | Astrazeneca Ab | Novel compounds |
TW200303304A (en) | 2002-02-18 | 2003-09-01 | Astrazeneca Ab | Chemical compounds |
SE0200919D0 (en) | 2002-03-25 | 2002-03-25 | Astrazeneca Ab | Chemical compounds |
GB0207436D0 (en) | 2002-03-28 | 2002-05-08 | Glaxo Group Ltd | Novel compounds |
US6583507B1 (en) * | 2002-04-26 | 2003-06-24 | Bum Ki Moon | Barrier for capacitor over plug structures |
MXPA05003866A (en) | 2002-10-11 | 2005-06-22 | Pfizer | Indole derivatives as beta-2 agonists. |
KR100578212B1 (en) * | 2003-06-30 | 2006-05-11 | 주식회사 하이닉스반도체 | Capacitor with merged top electrode plate line structure and method for fabricating the same |
US7180141B2 (en) * | 2004-12-03 | 2007-02-20 | Texas Instruments Incorporated | Ferroelectric capacitor with parallel resistance for ferroelectric memory |
EP1912942A1 (en) * | 2005-08-01 | 2008-04-23 | AstraZeneca AB | Novel piperidine derivatives as chemokine receptor modulators useful for the treatment of respiratory diseases. |
TW200734305A (en) * | 2005-08-02 | 2007-09-16 | Astrazeneca Ab | New salt III |
TW200738634A (en) * | 2005-08-02 | 2007-10-16 | Astrazeneca Ab | New salt |
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