U.S. patent application number 11/125335 was filed with the patent office on 2005-12-08 for novel piperidine and piperazine derivatives.
This patent application is currently assigned to ASTRAZENECA AB. Invention is credited to Bennion, Colin, Meghani, Premji.
Application Number | 20050272745 11/125335 |
Document ID | / |
Family ID | 20418266 |
Filed Date | 2005-12-08 |
United States Patent
Application |
20050272745 |
Kind Code |
A1 |
Meghani, Premji ; et
al. |
December 8, 2005 |
Novel piperidine and piperazine derivatives
Abstract
The invention provides piperidine and piperazine derivatives of
general formula (I), processes for their preparation,
pharmaceutical compositions containing them, a process for
preparing the pharmaceutical compositions, and their use in
therapy. 1
Inventors: |
Meghani, Premji;
(Loughborough, GB) ; Bennion, Colin;
(Loughborough, GB) |
Correspondence
Address: |
MORGAN LEWIS & BOCKIUS LLP
1111 PENNSYLVANIA AVENUE NW
WASHINGTON
DC
20004
US
|
Assignee: |
ASTRAZENECA AB
|
Family ID: |
20418266 |
Appl. No.: |
11/125335 |
Filed: |
May 10, 2005 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11125335 |
May 10, 2005 |
|
|
|
10168094 |
Jun 17, 2002 |
|
|
|
10168094 |
Jun 17, 2002 |
|
|
|
PCT/SE00/02580 |
Dec 18, 2000 |
|
|
|
Current U.S.
Class: |
514/255.02 ;
514/253.01; 514/317; 514/318; 544/360; 544/383; 546/194;
546/229 |
Current CPC
Class: |
C07D 261/10 20130101;
A61P 29/00 20180101; C07D 401/12 20130101; C07D 231/18 20130101;
C07D 513/04 20130101; A61P 31/00 20180101; C07D 211/58 20130101;
C07D 233/84 20130101; C07D 217/02 20130101; C07D 295/26 20130101;
C07D 495/04 20130101; A61P 37/06 20180101; C07D 239/94 20130101;
C07D 211/46 20130101; C07D 487/08 20130101; C07D 215/38 20130101;
C07D 473/34 20130101; A61P 19/02 20180101; C07D 295/15 20130101;
C07D 211/22 20130101; A61P 11/00 20180101; C07D 239/48
20130101 |
Class at
Publication: |
514/255.02 ;
514/317; 544/383; 546/229; 514/253.01; 544/360; 514/318;
546/194 |
International
Class: |
A61K 031/496; A61K
031/495; A61K 031/4545 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 22, 1999 |
SE |
9904738-3 |
Claims
1. A compound of general formula 125wherein, X represents a
nitrogen atom or a group C(R.sup.5); Y represents an oxygen or
sulphur atom or a group NR.sup.6; either R.sup.1 and R.sup.2 each
independently represent a hydrogen atom or a C.sub.1-C.sub.4 alkyl
group but do not both simultaneously represent a hydrogen atom; or
R.sup.1 and R.sup.2 together represent a group
--CH.sub.2ZCH.sub.2--; Z represents a bond, an oxygen or sulphur
atom or a group CH.sub.2 or NR.sup.7; m is 0 or 1; R.sup.3
represents a 5- to 10-membered unsaturated ring system which may
comprise from 1 to 4 ring heteroatoms independently selected from
nitrogen, oxygen and sulphur, the ring system being optionally
substituted by one or more substituents independently selected from
halogen, nitro, cyano, NR.sup.8R.sup.9, C.sub.1-C.sub.4 alkyl
C(O)NH--, NHR.sup.12C(O), C.sub.1-C.sub.4 alkyl-SO.sub.2--,
C.sub.1-C.sub.4 alkyl-SO.sub.2NH--,
C.sub.1-C.sub.4alkyl-NHSO.sub.2--, C.sub.1-C.sub.1 alkoxy, and
C.sub.1-C.sub.4 alkyl optionally substituted by one or more
fluorine atoms; R.sup.4 represents a phenyl or pyridinyl group,
each of which is substituted in an ortho position with a
substituent selected from halogen, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 alkylthio, and C.sub.1-C.sub.4 alkyl-optionally
substituted by one or more fluorine atoms, the phenyl or pyridinyl
group being optionally further substituted by one or more
substituents independently selected from halogen, cyano, hydroxyl,
C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4 alkyl-NH--,
NHR.sup.13-C.sub.1-C.sub.4 alkyl-, C.sub.1-C.sub.4
alkyl-SO.sub.2--, C.sub.1-C.sub.4 alkyl-SO.sub.2NH--,
C.sub.1-C.sub.4 alkyl-NHSO.sub.2--, C.sub.1-C.sub.4 alkyl-C(O)NH--,
C.sub.1-C.sub.4alkyl-NHC(O)--, -D-G, C.sub.1-C.sub.4 alkoxy
optionally substituted by --NR.sup.14R.sup.15 or by R.sup.16, and
C.sub.1-C.sub.4 alkyl optionally substituted by one or more
fluorine atoms or by one or more hydroxyl groups, or R.sup.4
represents a 9- or 10-membered unsaturated bicyclic ring system
which may comprise from 1 to 4 ring heteroatoms independently
selected from nitrogen, oxygen and sulphur, the bicyclic ring
system being optionally substituted by one or more substituents
independently selected from halogen, oxo, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkylthio and
--NR.sup.10R.sup.11; D represents an oxygen atom or a group
(CH.sub.2).sub.n, or CH.sub.2NH; n is 1, 2 or 3; G represents a
piperazinyl, morpholinyl or 2,5-diazabicyclo[2.2.1]heptyl group, or
G represents a piperidinyl group optionally substituted by amino;
R.sup.5 represents a hydrogen atom, or a hydroxyl or
C.sub.1-C.sub.4 alkoxy group; R.sup.6 represents a hydrogen atom,
or a cyano, nitro, hydroxyl C.sub.1-C.sub.4 alkyl or
C.sub.1-C.sub.4 alkoxy group; R.sup.7, R.sup.8 and R.sup.9 each
independently represent a hydrogen atom or a C.sub.1-C.sub.4 alkyl
group; R.sup.10 and R.sup.11 each independently represent a
hydrogen atom or a C.sub.1-C.sub.4 alkyl group, or R.sup.10 and
R.sup.11 together with the nitrogen atom to which they are attached
form a 5- or 6 membered saturated heterocyclic ring comprising one
or two ring nitrogen atoms; R.sup.12 represents a hydrogen atom, or
a C.sub.1-C.sub.4 alkyl group optionally substituted by amino;
R.sup.13 represents a hydrogen atom, or a C.sub.1-C.sub.4 alkyl
group optionally substituted by hydroxyl; R.sup.14 and R.sup.15
each independently represent a hydrogen atom or a C.sub.1-C.sub.4
alkyl group optionally substituted by hydroxyl, or R.sup.14 and
R.sup.15 together with the nitrogen atom to which they are attached
form a 5- or 6-membered saturated heterocyclic ring comprising one
or two ring nitrogen atoms; and R.sup.16 represents a
1-(C.sub.1-C.sub.4-alkyl)-piperidinyl group; with the proviso that
when m is 0, X is N and Y is O, then R.sup.4 does not represent
2-benzothiazolyl; or a pharmaceutically acceptable salt or solvate
thereof.
2. A compound according to claim 1, wherein X represents a nitrogen
atom.
3. A compound according to claim 1 or claim 2, wherein Y represents
an oxygen atom.
4. A compound according to any one of claims 1 to 3, wherein, in
R.sup.3, the 5- to 10 membered unsaturated ring system is selected
from phenyl, pyridinyl, pyrimidinyl naphthyl, furanyl, pyrryl,
thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl,
pyrazinyl, quinolinyl, isoquinolinyl, benzofuranyl,
isobenzofuranyl, benzothienyl, pyrazolyl, indolyl, isoindolyl,
purinyl, oxazolyl, isoxazolyl, thiazolyl, triazinyl benzothiazolyl,
benzooxazolyl, imidazopyrazinyl, triazolopyrazinyl, naphthyridinyl,
furopyridinyl, thiopyranopyrimidinyl, pyridazinyl, quinazolinyl
pteridinyl triazolopyrimidinyl, triazolopyrazinyl, thiapurinyl,
oxapurinyl, deazapurinyl, thiazolopyrimidinyl, indolinyl,
benzooxadiazolyl, benzothiadiazolyl, tetrahydroisoquinilinyl,
2-(isoxazol-3-yl)thienyl, and thienopyrimidinyl.
5. A compound according to any one of the preceding claims,
wherein, in R.sup.3, the ring system is optionally substituted by
one or more substituents independently selected from methyl, amino,
cyano, methoxy, chloro, nitro, NH.sub.2C(O), CH.sub.3C(O)NH--,
CH.sub.3SO.sub.2--, CH.sub.3SO.sub.2NH-- and
NH.sub.2CH.sub.2CH.sub.2NHC(O)--.
6. A compound according to any one of the preceding claims,
wherein, in R.sup.4, an ortho substituent in the phenyl or
pyridinyl group is halogen or C.sub.1-C.sub.4 alkyl optionally
substituted by one or more fluorine atoms.
7. A compound according to any one of claims 1 to 5, wherein,
R.sup.4, the 9- or 10-membered unsaturated bicyclic ring system is
selected from naphthyl, benzimidazolyl, quinolinyl, indolinyl,
isoquinolinyl, benzofuranyl, isobenzofuranyl, benzothienyl,
indolyl, isoindolyl, benzthiazolyl, benzoxazolyl and
quinazolinyl.
8. A compound of formula (I) or a pharmaceutically acceptable salt
or solvate thereof as defined in claim 1 which is selected from:
(.+-.)-N-(2,6-Dimethylphenyl)-2-(3-methyl-4-(thieno[2,3-d]pyrimidin-4-yl)-
piperazin-1-yl)acetamide,
cis-[2-(3,5-Dimethyl-4-(thieno[2,3-d]pyrimidinyl-
)piperazin-1-yl)]-N-(2,6-dimethylphenyl)acetamide,
(.+-.)-2-[3-Methyl-4-(4-
-methylphenyl)piperazin-1-yl]-N-(2,6-dimethylphenyl) acetamide,
cis-N-[3-Hydroxymethyl-2-methylphenyl]-2-(3,5-dimethyl-4-(thieno[2,3-d]py-
rimidin-4-yl)piperazin-1-yl)acetamide,
(R)-2-[4-(1-Methylimidazol-4-sulpho-
nyl-4-yl)-3-ethylpiperazin-1-yl]-N-quinolin-5-yl)acetamide,
cis-2-[3,5-Dimethyl-4-thieno[2,3-d]-pyrimidin-1-yl]-N-(2-methylphenyl)ace-
tamide, cis-N-(2
Chlorophenyl)-2-[3,5-dimethyl-4-(thieno[2,3-d]pyrimidin-4-
-yl-piperazin-1-yl]acetamide,
cis-N-(2-Chlorophenyl)-2-[3,5-dimethyl-4-(9--
methyl-9H-purin-6-yl)piperazin-1-yl]acetamide,
cis-2-3,5-Dimethyl-4-thieno-
[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-N-isoquinolin-5-yl)acetamide,
cis-2-(3,5-Dimethyl
thieno[2,3-d]pyrimidin-4-yl-N-quinolin-5-yl-[acetamid- e,
cis-2-(3,5-Dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-N-2--
methyl-5-methylsulphonamidophenyl)acetamide,
cis-2-(3,5-Dimethyl-4-(thieno-
[2,3-d]pyrimidin-4-yl)piperazin-1-yl]-N-(2-trifluoromethylphenyl)acetamide-
, cis-2-(3,5-Dimethyl-4-(thieno[2,3
d]pyrimidin-4-piperazin-1-yl)-N-(3-met- hylpyridin-2-yl)acetamide,
cis-2-3,5-Dimethyl-4-(thieno[2,3-d])pyrimidin-4-
-yl)piperazin-1-yl)-N-(isoquinolin-1-yl)acetamide,
cis-4-(4-Amino-5-cyanop-
yrimidin-2-yl)-3,5-dimethylpiperazin-1-yl)-N-(2-chlorophenyl)acetamide,
cis-2-(4-Benzenesulphonyl-3,5-dimethylpiperazin-1-yl)-N-(2
chloro-phenyl)acetamide,
(.+-.)-N-(2,6-Dimethylphenyl)-2-[(3,5-methyl-4-t-
hiazolo(5,4-d)pyrimidin-7-yl)piperazin-1-yl]acetamide,
cis-N-(2-Chlorophenyl)-2-[(3,5-dimethyl-quinazolin-4-yl)piperazin-1-yl]ac-
etamide,
N-(2-Chlorophenyl)-2-[(8-thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabi-
cyclo[3.2.1]oct-3-yl]acetamide,
N-(2-Methylphenyl)-2-[(8-(9-methyl-9H-puri- n-6-yl)-3,8
diazabicyclo[3.2.1]oct-3-yl]acetamide, 2-[8-(9-Methyl-9H-purin-
-6-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-(quinolin-5-yl)acetamide,
N-(Quinolin-5-yl)-2-[8-thiazolo[5,4-d]pyrimidin-7-yl)-3,8-diazabicyclo[3.-
2.1]oct-3-yl]acetamide,
N-(2-Methylphenyl)-2-[(8-thiazolo[5,4-pyrimidin-7--
yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]acetamide,
N-(2-Methyl-5-methylsulphon-
yl)amidophenyl)-2-(8-(9-methyl-9H-purin-6-yl)-3,8-diazabicyclo[3.2.1]oct-3-
-yl]acetamide,
N-[2-Methyl-5-methylsulphonyl)amidophenyl]-2-[(8-thiazolo[5-
,4-d]pyrimidin-7-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]acetamide,
N-[2-Methyl-5-methylsulphonyl)amidophenyl]-2-[4-thieno[2,3-pyrimidin-4-yl-
)-3,8-diazabicyclo[3.2.1]oct-3-yl]acetamide,
cis-2-3,5-Dimethyl-4-(thieno[-
2,3-d]pyrimidin-4-yl)piperazin-1-yl)-N-2-methyl-5-(1-piperazinylmethyl)phe-
nyl)acetamide, hydrochloride salt,
N-(2-Methylphenyl)-2-[(8-(thieno[2,3-d]-
pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]acetamide,
N-[5-(Methanesulphonylamido-2-methylphenyl)-2-[8-(thieno[2,3-d]pyrimidin--
4-yl)-8-azabicyclo[3.2.1]oct-3-yl]acetamide,
N-(2-Methyl-5-(1-piperazinylm-
ethyl)phenyl)-2-[(8-(thieno[2,34]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oc-
t-3-yl]acetamide,
cis-N-(5-(2-Aminoethoxy)-2-methyl-phenyl)-2-(3,5-ethyl(t-
hieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)acetamide, hydrochloride
salt,
cis-N-5-(2-(N-Methylamino)ethoxy)-2-methyl-phenyl)-2-3,5-dimethyl-4-(thie-
no[2,3 d]pyrimidin-4-yl)piperazin-1-yl)acetamide, hydrochloride
salt,
cis-N-(5-(2-Methylamino)ethoxy)-2-methyl-phenyl)-2-(4-benzenesulphonyl)-3-
,5-dimethyl)piperazin-1-yl)acetamide,
cis-N-[5(2-Aminoethoxy)-2-methyl-phe-
nyl)-2(4-benzenesulphonyl-3,5-dimethyl)piperazin-1-yl]acetamide,
hydrochloride salt, N-(2-Oxo-2,3
dihydro-1H-indol-4-yl)-2-(8-thieno[2,3-d-
]pyrimidin-4-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)acetamide,
N-3-Fluoro-2-methyl-phenyl)-2-((8
quinazolin-4-yl)-3,8-diazabicyclo[3.2.1- ]oct-3-yl)acetamide,
N-(2-Methylphenyl)-2-[8(benzenesulphonyl)-3,8-diazabi-
cyclo[3.2.1]oct-3-yl]acetamide,
N-(3-Fluoro-2-methylphenyl)-2-[8-(benzenes-
ulphonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]acetamide,
cis-N-(3-Fluoro-2-methyl-phenyl)-2-(4-benzenesulphonyl)-3,5-dimethyl)pipe-
razin-1-yl)acetamide,
N-(2-Methylphenyl)-2-[8-(3-cyanobenzenesulphonyl)-3,-
8-diazabicyclo[3.2.1]oct-3-yl]acetamide,
2-[8-(3-Methoxybenzenesulphonyl)--
3,8-diazabicyclo[3.2.1]oct-3-yl]-N-2-methylphenyl)acetamide,
2-[8-Benzo[1,2,5]oxadiazole-4-sulphonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-
-N-(2-methylphenyl)acetamide
2-[8-(Benzo[1,2,5]thiadiazole-4-sulphonyl)-3,-
8-diazabicyclo[3.2.1]oct-3-yl]-N-2-methylphenyl)acetamide,
2-[8-(5-Chlorthieno-2-yl)sulphonyl)-3,8-d]diazabicyclo[3.2.1]oct-3-yl]-N--
(2-methylphenyl)acetamide,
2-[8(2-Chlorobenzenesulphonyl)-3,8-diazabicyclo-
[3.2.1]oct-3-yl]-N-2-methylphenyl)acetamide,
2-[8-(5-Chloro-2-methoxybenze-
nesulphonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-(2-methylphenyl)acetamide,
(2-methylphenyl)acetamide,
N-(2-Methylphenyl)-2-[(8-(3-methylthieno[2,3-d-
]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]acetamide,
cis-2-(3,5-Dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-N-(1-m-
ethyl-1H-benzoimidazol-2-yl)acetamide,
cis-2-(3,5-Dimethyl(thieno[2,3-d]py-
rimidin-4-yl)piperazin-1-yl)-N-2-methyl-5-(4-piperidinyloxy)phenyl)acetami-
de, hydrochloride salt,
cis-2-(3,5-Dimethyl-4-benzenesulphonyl)piperazin-1-
-yl)-N-(2-methyl-5-(4-piperidinyloxy)phenyl)acetamide,
cis-2-3,5-Dimethyl(quinazolin-4-yl)piperazin-1-yl)-N-2-methyl-5-(4-piperi-
dinyloxy)phenyl)acetamide,
cis-2-3,5-Dimethyl-4-(4-quinazolinyl)piperazin--
1-yl)-N-2-methyl-5-(piperazin-4-yl-methyl)phenyl) acetamide,
cis-2-(3,5-Dimethyl-4-(quinazolinyl)piperazin-1-yl)-N-2-methyl-5-(2-(N-me-
thylamino)ethoxy)phenyl)acetamide, cis-2-043
Cyanobenzenesulphonyl)-3,5-di-
methylpiperazin-1-yl]-N-(2-methylphenyl)acetamide,
cis-N-2-Methylphenyl)-2-
-[4-(3-nitrobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-acetamide,
cis-2-[4-(3-Aminobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-methy-
lphenyl)acetamide
cis-2-(3,5-Dimethyl-4-(3-cyanobenzenesulphonyl-1-yl)pipe-
razin-1-yl)-N-quinolin-5-yl)acetamide,
cis-2-(3,5-Dimethyl-4-(4-cyanobenze-
nesulphonyl-1-yl)-N-quinolin-5-yl) acetamide,
cis-2-(4-(3-Cyanobenzenesulp-
honyl)-3,5-dimethylpiperazin-1-yl)-N-3-fluoro-2-methylphenyl)acetamide,
cis-2-(4-(4-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl)-N-3-fluoro-
-2-methylphenyl)acetamide,
cis-2-[4-(3-Acetylaminobenzenesulphonyl)-3,5-di-
methylpiperazin-1-yl]-N-2-methylphenyl)acetamide,
cis-2-[4-(3-Aminocarbony-
lbenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-methylphenyl)acetamide-
,
cis-2-[4-(3-Methanesulphonylalminobenzenesulphonyl)-3,5-dimethylpiperazi-
n-1-yl]-N-(2-methylphenyl)acetamide,
cis-2-[4-(2-Methanesulphonylbenzenesu-
lphonyl)-3,5-dimethylpiperazin-1-yl]-N-3-methoxy-2-methylphenyl)acetamide,
cis-2-[4-(2-Methanesulphonylbenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-
-N-3-fluoro-2-methylphenyl) acetamide,
cis-2-[4-(1-Methylimidazol-4-sulpho-
nyl-4-yl)-3,5-dimethylpiperazin-1-yl]-N-(quinolin-5-yl)acetamide,
cis-2-[4-(1-Methylimidazol-4-sulphonyl-4-yl)-3,5-dimethylpiperazin-1-yl]--
N-3-methoxy-2-methylphenyl)acetamide,
cis-2-[4-(1-Methylimidazol-4-sulphon-
yl-4-yl)-3,5-dimethylpiperazin-1-yl]-N-(3-fluoro-2-methylphenyl)acetamide,
trifluoromethylphenyl)acetamide,
cis-2-[4-2-Aminoethylaminocarbonylbenzen-
esulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-methylphenyl)acetamide,
cis-2-[4-(1,1,2,2-Tetrahydroisoquinilin-7-sulphonyl-7-yl)-3,5-dimethylpip-
erazin-1-yl]-N-2,6-dimethylphenyl)acetamide,
cis-2-[4-(3-Cyanobenzenesulph-
onyl)-3,5-dimethylpiperazin-1-yl]-N-(2,6-dimethylphenyl)acetamide,
cis-2-[4-(4-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-2-methyl-
phenyl)acetamide,
cis-2-[4-(2-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-
-1-yl]-N-(2,6 dimethylphenyl)acetamide, hydrochloride salt,
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-chlor-
ophenyl)acetamide,
2-[8(Isquinolin-1-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]--
N-2-methylphenyl)acetamide,
cis-2-[4-(4-Acetamidobenzenesulphonyl)-3,5-dim-
ethylpiperazin-1-yl-N-(2-methylphenyl)acetamide,
cis-2-[4-(3-Cyanobenzenes-
ulphonyl)-3,5-dimethylpiperazin-N-yl]-N-(2-trifluoromethylphenyl)acetamide-
,
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1]-yl]-N-2-meth-
yl-5-methanesulphonamidophenyl)acetamide,
2-[8-(4-Benzenesulphonyl)-3,8-di-
azabicyclo[3.2.1]oct-3-yl]-N-2-methylphenyl)acetamide,
2-[8-(2-Benzenesulphonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-2-methylphen-
yl)acetamide,
cis-2-[4-(1,2-Dimethylimidazol-4-sulphonyl-4-yl)-3,5-dimethy-
lpiperazin-1-yl]-N-(quinolin-5-yl)acetamide,
cis-2-[4-(5-Chloro-1,3-dimeth-
ylpyrazole-4-sulphonyl-4-yl)-3,5-dimethylpiperazin-1-yl]-N-(3-methoxy-2-me-
thylphenyl)acetamide,
2-[8-(2(Isoxazol-3-yl)thiophen-5-yl)-3,8-diazabicycl-
o[3.2.1]oct-3-yl]-N-(2-methylphenyl)acetamide,
2-[8-(1,1,2,2-Tetrahydroiso- quinilin-7-sulphonyl)-3,8
diazabicyclo[3.2.1]oct-3-yl]-N-(2-methylphenyl) acetamide,
cis-2-[4-(5-Chloro-1,3-dimethylpyrazole-4-yl)-3,5-dimethylpipe-
razin-1-yl]-N-(2-methylphenyl)acetamide,
cis-2-[4-3,5-Dimethylisoxazole-4--
sulphonyl-4-yl)-3,5-dimethylpiperazin-1-yl]-N-(2-methylphenyl)acetamide,
cis-2-[4-(2-Methanesulphonylbenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-
-N-2-methylphenyl)acetamide,
cis-2-[4-(3-Cyanobenzenesulphonyl)-N-(3,5-dim-
ethylpiperazin-1-yl]-N-3-methoxy-2-methylphenyl)acetamide,
cis-2-[4-Methanesulphonylbenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N--
(2-methylphenyl)acetamide,
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethyl-
piperazin-1-yl]-N-5-cyano-2-methylphenyl)acetamide,
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-5-acetam-
ido-2-methylphenyl)acetamide,
(R)-2-[4-(4-Cyanobenzenesulphonyl)3-methylpi-
perazin-1-yl]-N-quinolin-5-yl)acetamide,
(S)-2-[4-(4-Cyanobenzenesulphonyl-
)-3-methylpiperazin-1-yl]-N-quinolin-5-yl)acetamide,
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-2-methyl-
-5-methanesulphonylphenyl)acetamide,
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,-
5-dimethylpiperazin-1-yl]-N-(2-methyl-5-(4
amino-1-piperidinyl)methyl)phen- yl]acetamide,
(R)-2-[4-(Methanesulphonylbenzenesulphonyl)-3-methylpiperazi-
n-1-yl]-N-(quinolin-5-yl)acetamide,
(R)-2-[4-(4-Acetamidobenzenesulphonyl)-
-3-methylpiperazin-1-yl]-N-quinolin-5-yl)acetamide,
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl-]-N-2-methy-
l-5-piperazinymethyl)phenyl)acetamide,
cis-2-[4-(3-Cyanobenzenesulphonyl)--
3,5-dimethylpiperazin-1-yl]-N-2-methyl-5-(4-piperidinylamino)methyl)phenyl-
)acetamide,
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-
-N-2-methyl-5-morpholinyl)methyl)phenyl)acetamide,
cis-2-[4-(3-Cyanobenzen- esulphonyl)-3.5
methylpiperazin-1-yl]-N-2-methyl-5-(2-hydroxyethylamino)me-
thyl)phenyl)acetamide,
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpipe-
razin-1-yl]-N-2-methyl-5-(S,S)-(2,5
diazabicyclo[2,2,1]hept-2-yl)methyl)ph- enyl)acetamide,
(R)-2-[4-(2-Pyridinesulphonyl)-3-methylpiperazin-1-yl]-N-(-
quinolin-5-yl)acetamide,
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpi-
perazin-1-yl]-N-(2-methyl-3-(4-amino-1-piperidinyl)methyl)phenyl]acetamide-
,
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-2-methy-
l-3-(4-piperidinylamino)methyl)phenyl)acetamide,
cis-2-[4-(3-Cyanobenzenes-
ulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-methyl-3-(1-piperazinylmethyl)p-
henyl)acetamide,
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin--
1-yl]-N-2-methyl-3-(S,S-(2,5-diazabicyclo[2,2,1]hept-2-yl)methyl)phenylace-
tamide,
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(-
(2-methyl-3-(1-morpholinyl)methyl)phenyl)acetamide, cis-2-[4-(3
Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-((2-methyl-3-(2-(1-p-
yrrolidinyl)ethoxy)phenyl)acetamide,
(.+-.)cis-2-[4-(3-Cyanobenzenesulphon-
yl)-3,5-dimethylpiperazin-1-yl]-N-((2-methyl-3-(1-methylpiperidin-3-yl)met-
hoxy)phenyl)acetamide, cis-2-[4-(3
Cyanobenzenesulphonyl)-3,5-dimethylpipe-
razin-1-yl]-N-(2-methyl-4-(2-(1-pyrrolidinyl)ethoxy)phenyl)acetamide,
(.+-.) cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1
yl]-N-(2-methyl-4-(1-methylpiperidin-3-yl)methoxy)phenyl)acetamide,
(.+-.)
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(-
(2-methyl-5-(1-methylpiperidin-3-yl)methoxyphenyl)acetamide,
(.+-.)cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-((-
2-methyl-6-methylpiperidin-3-yl)methoxy)phenyl)acetamide, and
cis-2-[4-(1-Methylimidazol-4-sulphonyl
4-yl)-3,5-dimethylpiperazin-1-yl]--
N-((2-methyl-3(2-(1-pyrrolidinyl)ethoxyphenyl)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 126wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are
as defined in formula (I), with a compound of general formula
(III), R.sup.3--(SO.sub.2).sub.m-- -L.sup.1, wherein L.sup.1
represents a leaving group and m and R.sup.3 are as defined in
formula (1); or (b) when X represents a nitrogen atom and Y
represents an oxygen atom, reacting a compound of general formula
127wherein m, R.sup.1, R.sup.2 and R.sup.3 are as defined in
formula (I), with a compound of general formula 128wherein L.sup.2
represents a leaving group and R.sup.4 is as defined in formula
(I); or (c) reacting a compound of general formula 129wherein
L.sup.3 represents a leaving, group and m, X, Y, R.sup.1, R.sup.2
and R.sup.3 are as defined in formula (I), with a compound of
general formula (VII), H.sub.2N-R.sup.4 wherein R.sup.4 is as
defined in formula (I); and optionally after (a), (b) or (c)
converting the compound of formula (I) obtained to a
pharmaceutically acceptable salt or solvate thereof.
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
defined 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. 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 the treatment of rheumatoid arthritis.
14. 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 the treatment of chronic obstructive pulmonary disease.
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 therapy.
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 tang
rheumatoid arthritis.
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 beating
chronic obstructive pulmonary disease.
18. A method of effecting immunosuppression which comprises
administering 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 to a patient in need
thereof.
19. A method of treating rheumatoid arthritis which comprises
administering 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 to a patient in
need thereof.
20. A method of treating chronic obstructive pulmonary disease
which comprises administering 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 to a
patient in need thereof.
Description
[0001] The present invention relates to piperidine and piperazine
derivatives, processes for their preparation, pharmaceutical
compositions containing them, a process for preparing the
pharmaceutical compositions, and their use in therapy.
[0002] The P2X.sub.7 receptor (previously known as P2Z receptor),
which is a ligand-gated ion channel, is present on a variety of
cell types, largely those known to be involved in the
inflammatory/immune process, specifically, macrophages, mast cells
and lymphocytes (T and B). Activation of the P2X.sub.7 receptor by
extracellular nucleotides, in particular adenosine triphosphate,
leads to the release of interleukin-1.beta. (IL-1.beta.) and giant
cell formation (macrophages/microglial cells), degranulation (mast
cells) and L-selectin shedding (lymphocytes). P2X.sub.7 receptors
are also located on antigen-presenting cells (APC), keratinocytes,
salivary acinar cells (parotid cells), hepatocytes, erythrocytes,
erythroleukaemic cells, monocytes, fibroblasts, bone marrow cells,
neurones and renal mesangial cells.
[0003] It would be desirable to make compounds effective as
P2X.sub.7 receptor antagonists for use in the treatment of
inflammatory, immune or cardiovascular diseases, in the aetiologies
of which the P2X.sub.7 receptor may play a role.
[0004] In accordance with the present invention, there is therefore
provided a compound of general formula 2
[0005] wherein,
[0006] X represents a nitrogen atom or a group C(R.sup.5);
[0007] Y represents an oxygen or sulphur atom or a group NR.sup.6,
preferably an oxygen atom;
[0008] either R.sup.1 and R.sup.2 each independently represent a
hydrogen atom or a C.sub.1-C.sub.4 alkyl group but do not both
simultaneously represent a hydrogen atom, or R.sup.1 and R.sup.2
together represent a group C.sub.2ZCH.sub.2--;
[0009] Z represents a bond, an oxygen or sulphur atom or a group
CH.sub.2 or NR.sub.7, and is preferably a bond;
[0010] m is 0 or 1;
[0011] R.sup.3 represents a 5- to 10-membered unsaturated ring
system which may comprise from 1 to 4 ring heteroatoms
independently selected from nitrogen, oxygen and sulphur, the ring
system being optionally substituted by one or more substituents
independently selected from halogen, nitro, cyano, NR.sup.8R.sup.9,
C.sub.1-C.sub.4 alkyl-C(O)NH--, NR.sup.12C(O)--, C.sub.1-C.sub.4
alkyl-SO.sub.2--, C.sub.1-C.sub.4 alkyl-SO.sub.2NH--,
C.sub.1-C.sub.4alkyl-NHSO.sub.2--, C.sub.1-C.sub.4 alkoxy, and
C.sub.1-C.sub.4 alkyl optionally substituted by one or more
fluorine atoms;
[0012] R.sup.4 represents a phenyl or pyridinyl group, each of
which is substituted in an ortho position with a substituent
selected from halogen, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
alkylthio, and C.sub.1-C.sub.4 alkyl optionally substituted by one
or more fluorine atoms, the phenyl or pyridinyl group being
optionally further substituted by one or more substituents
independently selected from halogen, cyano, hydroxyl
C.sub.1-C.sub.4 alkylthio, C.sub.1-4 alkyl-NH--,
NHR.sup.13--C.sub.1-C.sub.4 alkyl-, C.sub.1-C.sub.4
alkyl-SO.sub.2--, C.sub.1-C.sub.4 alkyl-SO.sub.2NH--,
C.sub.1-C.sub.4 alkyl-NHSO.sub.2--, C.sub.1-C.sub.4 alkyl-C(O)NH--,
C.sub.1-C.sub.4 alkyl-NHC(O), -D-G, C.sub.1-C.sub.4 alkoxy
optionally substituted by NR.sup.14R.sup.15 or by R.sup.16 and
C.sub.1-C.sub.4 alkyl optionally substituted by one or more
fluorine atoms or by one or more hydroxyl groups,
[0013] or R.sup.4 represents a 9- or 10-membered unsaturated
bicyclic ring system which may comprise from 1 to 4 ring
heteroatoms independently selected from nitrogen, oxygen and
sulphur, the bicyclic ring system being optionally substituted by
one or more substituents independently selected from halogen, oxo,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
alkylthio and NR.sup.10R.sup.11;
[0014] D represents an oxygen atom or a group (CH.sub.2).sub.n or
CH.sub.2NH;
[0015] n is 1, 2 or 3;
[0016] G represents a piperazinyl, morpholinyl or
2,5-diazabicyclo[2.2.1]h- eptyl group, or G represents a
piperidinyl group optionally substituted by amino (--NH.sub.2);
[0017] R.sup.5 represents a hydrogen atom, or a hydroxyl or
C.sub.1-C.sub.4 alkoxy group;
[0018] R.sup.6 represents a hydrogen atom, or a cyano, nitro,
hydroxyl C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkoxy group;
[0019] R.sup.7, R.sup.8 and R.sup.9 each independently represent a
hydrogen atom or a C.sub.1-C.sub.4 alkyl group;
[0020] R.sup.10 and R.sup.11 each independently represent a
hydrogen atom or a C.sub.1-C.sub.4 alkyl group, or R.sup.10 and
R.sup.11 together with the nitrogen atom to which they are attached
form a 5- or 6-membered saturated heterocyclic ring comprising one
or two ring nitrogen atoms;
[0021] R.sup.12 represents a hydrogen atom, or a C.sub.1-C.sub.4
alkyl group optionally substituted by amino (--NH.sub.2);
[0022] R.sup.13 represents a hydrogen atom, or a C.sub.1-C.sub.4
alkyl group optionally substituted by hydroxyl;
[0023] R.sup.14 and R.sup.15 each independently represent a
hydrogen atom or a C.sub.1-C.sub.4 alkyl group R.sup.14, R.sup.15
each independently represent a hydrogen atom or a C.sub.1-C.sub.4
alkyl group optionally substituted by hydroxyl, or R and R together
with the nitrogen atom to which they are attached form a 5- or
6-membered saturated hetero cyclic ring comprising one or two ring
nitrogen atoms; and
[0024] R.sup.16 represents a 1-C.sub.1-C.sub.4-alkyl)-piperidinyl
group;
[0025] with the proviso that when m is 0, X is N and Y is O, then
R.sup.4 does not represent 2-benzothiazolyl;
[0026] or a pharmaceutically acceptable salt or solvate
thereof.
[0027] In the context of the present specification, unless
otherwise indicated, an alkyl substituent or alkyl moiety in a
substituent group may be linear or branched. In the present
invention, an alkyl group or moiety may contain up to 4 carbon
atoms, for example, methyl ethyl propyl isopropyl butyl isobutyl
and t-butyl.
[0028] When the substituent group is NHR.sup.13-C.sub.1-C.sub.4
alkyl-, it should be appreciated that the NHR.sup.13 moiety may be
attached to a terminal or intern carbon atom of the alkyl moiety
and when the substituent group is alkoxy substituted by
--NR.sup.14R.sup.15, the alkoxy group will contain at least 2
carbon atoms and the group --NR.sup.14R.sup.15 is not attached to
the same carbon atom to which the oxygen atom is attached.
[0029] R.sup.3 represents a 5- to 10-membered unsaturated ring
system which may comprise 1, 2, 3 or 4 ring heteroatoms
independently selected from nitrogen, oxygen and sulphur, the ring
system being optionally substituted by one or more (i.e. at least
one), e.g. one, two or three, substituents independently selected
from halogen (e.g. fluorine, chlorine, bromine or iodine), nitro,
cyano, NR.sup.8R.sup.9, C.sub.1-C.sub.4 allyl-C(O)NH-- (e.g.
CH.sub.3C(O)NH--), N.sup.12C(O)-- (e.g. NH.sub.2C(O)--,
NH(CH.sub.3)C(O)--, (CH.sub.3).sub.2NC(O)--NH.sub.2-
CH.sub.2CH.sub.2NHC(O)--), C.sub.1-C.sub.4 alkyl-SO.sub.2-- (e.g.
CH.sub.3SO.sub.2--), C.sub.1-C.sub.4 alkyl-SO.sub.2NH-- (e.g.
CH.sub.3SO.sub.2NH--), C.sub.1-C.sub.4 alkyl-NHSO.sub.2--(e.g.
CH.sub.3NHSO.sub.2--), C.sub.1-C.sub.4, preferably C.sub.1-C.sub.2,
alkoxy, and C.sub.1-C.sub.4, preferably C.sub.1-C.sub.2 alkyl
optionally substituted by one or more (i.e. at least one), e.g.
one, two, three or four, fluorine atoms (e.g. trifluoromethyl).
Specific substituents that may be mentioned include: methyl, amino
(--NH.sub.2), cyano, methoxy, chloro, nitro, NH.sub.2C(O)--,
CH.sub.3C(O)NH--, CH.sub.3SO.sub.2--, CH.sub.3SO.sub.2NH-- and
NH.sub.2CH.sub.2CH.sub.2NHC(O)--.
[0030] The ring system may be monocyclic or polycyclic. If
polycyclic, e.g. bicyclic, the two rings may be fused to one
another or may be joined by a bond. If the ring system is bicyclic,
it is preferred that the rings are fused to one another. Examples
of ring systems that may be used include phenyl, pyridinyl
pyrimidinyl naphthyl, furanyl, pyrryl, thienyl, isothiazolyl,
imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl
quinolinyl-isoquinolinyl, benzofuranyl, isobenzofuranyl,
benzothienyl, pyrazolyl indolyl isoindolyl, purinyl, oxazolyl,
isoxazolyl, thiazolyl, triazinyl benzothiazolyl, benzoxazolyl,
imidazopyrazinyl, triazolopyrazinyl, naphthyridinyl furopyridinyl,
thiopyranopyrimidinyl, pyridazinyl, quinazolinyl, pteridinyl,
triazolopyrimidinyl, triazolopyrazinyl, thiapurinyl, oxapurinyl,
deazapurinyl, thiazolopyrimidinyl, indolinyl, benzooxadiazolyl,
benzothiadiazolyl, tetrahydroisoquinilinyl,
2-(isoxazol-3-yl)thienyl, and thienopyrimidinyl. Preferred ring
systems are phenyl thienopyrimidinyl, purinyl pyrimidinyl
thiazolopyrimidinyl, quinazolinyl, benzooxadiazolyl,
benzothiadiazolyl, thienyl imidazolyl tetrahydroisoquinilinyl,
isoquinolinyl, pyrazolyl, isoxazolyl, 2-(isoxazol-3-yl)thienyl and
pyridinyl.
[0031] R.sup.4 may represent a phenyl or pyridinyl group comprising
at least one substituent selected from halogen (e.g. fluorine,
chlorine, bromine or iodine), C.sub.1-C.sub.4, preferably
C.sub.1-C.sub.2, alkoxy, C.sub.1-C.sub.4, preferably
C.sub.1-C.sub.2, alkylthio or C.sub.1-C.sub.4, preferably
C.sub.1-C.sub.2, alkyl optionally substituted by one or more (i.e.
at least one) fluorine atoms (e.g. trifluoromethyl), which
substituent is attached to the phenyl or pyridinyl group at a
position ortho (*) with respect to the point of attachment of
R.sup.4 to the rest of the molecule, for example as illustrated
below. Examples of preferred ortho substituents include chloro,
methyl and trifluoromethyl. 3
[0032] The phenyl or pyridinyl group may be optionally father
substituted by one or more (i.e. at least one) (e.g. one, two,
three or four) substituents independently selected from halogen
(e.g. fluorine, chlorine, bromine or iodine), cyano, hydroxyl
C.sub.1-C.sub.4 alkylthio (e.g. methylthio or ethylthio),
C.sub.1-C.sub.4 alkyl-NH-- (e.g. methylamino or ethylamino),
NHR.sup.13-C.sub.1-C.sub.4 alkyl-, C.sub.1-C.sub.4, preferably
C.sub.1-C.sub.2, alkyl-SO.sub.2--, C.sub.1-C.sub.4, preferably
C.sub.1-C.sub.4 alkyl-SO.sub.2NH--, C.sub.1-C.sub.4, preferably
C.sub.1-C.sub.2, alkyl-SO.sub.2--, C.sub.1-C.sub.4, preferably
C.sub.1-C.sub.2, alkyl-C(O)NH--, C.sub.1-C.sub.4, preferably
C.sub.1-C.sub.2, alkyl-NHC(O)--, -D-G, C.sub.1-C.sub.4 alkoxy
optionally substituted by --NR.sup.14R.sup.15 or by R.sup.16, and
C.sub.1-C.sub.4, preferably C.sub.1-C.sub.2, alkyl optionally
substituted by one or more (i.e. at least one) fluorine atoms (e.g.
trifluoromethyl) or by one or more (i.e. at least one) hydroxyl
groups (e.g. hydroxymethyl).
[0033] Alternatively, R.sup.4 may represent a 9- or 10-membered
unsaturated fused bicyclic ring system which may comprise 1, 2, 3
or 4 ring heteroatoms independently selected from nitrogen, oxygen
and sulphur, the ring system being optionally substituted by one or
more (i.e. at least one) (e.g. one, two, three or four)
substituents independently selected from halogen (e.g. fluorine,
chlorine, bromine or iodine), oxo, C.sub.1-C.sub.4 preferably
C.sub.1-C.sub.2, alkyl C.sub.1-C.sub.4, preferably C.sub.1-C.sub.2,
alkoxy, C.sub.1-C.sub.4, preferably C.sub.1-C.sub.2, alkylthio and
NR.sup.10R.sup.11. Examples of suitable bicyclic ring systems
include naphthyl benzimidazolyl, quinolinyl, indolinyl,
isoquinolinyl, benzofuranyl, isobenzofuranyl, benzothienyl,
indolyl, isoindolyl, benzthiazolyl, benzoxazolyl and quinazolinyl.
An example of an unsaturated fused bicyclic ring system substituted
by an oxo group is oxindolyl.
[0034] D represents an oxygen atom or a group (CH.sub.2).sub.n or
CH.sub.2NH (in that orientation), where n is 1, 2 or 3.
[0035] G represents a piperazinyl, morpholinyl or
2,5-diazabicyclo[2.2.1]h- eptyl group, or G represents a
piperidinyl group optionally substituted by at least one amino
group (e.g. 1-piperidinyl, 4-piperidinyl, 1-piperazinyl,
1-morpholinyl or amino-1-piperidinyl).
[0036] R.sup.5 represents a hydrogen atom, or a hydroxyl or
C.sub.1-C.sub.4 alkoxy group. In a preferred embodiment, R.sup.5
represents a hydrogen atom.
[0037] R.sup.6 represents a hydrogen atom, or a cyano, nitro,
hydroxyl C.sub.1-C.sub.4, preferably C.sub.1-C.sub.2, alkyl or
C.sub.1-C.sub.4, preferably C.sub.1-C.sub.2, alkoxy group.
[0038] R.sup.7, R.sup.8 and R.sup.9 each independently represent a
hydrogen atom or a C.sub.1-C.sub.4, preferably C.sub.1-C.sub.2,
alkyl group.
[0039] R.sup.10 and R.sup.11 each independently represent a
hydrogen atom or a C.sub.1-C.sub.4, preferably C.sub.1-C.sub.2,
alkyl group or R.sup.10 and R.sup.11 together with the nitrogen
atom to which they are attached form a 5- or 6-membered saturated
heterocyclic ring comprising one or two ring nitrogen atoms (e.g.
pyrrolidinyl, piperidinyl or piperazinyl).
[0040] R.sup.12 represents a hydrogen a or a C.sub.1-C.sub.4,
preferably C.sub.1, alkyl group optionally substituted by at least
one amino group (--NH.sub.2).
[0041] R.sup.13 represents a hydrogen atom, or a C.sub.1-C.sub.4,
preferably C.sub.11C.sub.2, alkyl group optionally substituted by
at least one hydroxyl group.
[0042] R.sup.14 and R.sup.15 each independently represent a
hydrogen atom or a C.sub.11, preferably C.sub.1-C.sub.2, alkyl
group optionally substitute by at least one hydroxyl group, or
R.sup.14 and R.sup.15 together with the nitrogen atom to which they
are attached form a 5- or 6-membered saturated heterocyclic ring
comprising one or two ring nitrogen atoms (e.g. pyrrolidinyl,
piperidinyl or piperazinyl).
[0043] R.sup.16 represents a 1-(C.sub.1-C.sub.4-alkyl)-piperidinyl
group, e.g. 1-methylpiperidinyl, specifically
1-methylpiperidin-3-yl.
[0044] Preferred compounds of the invention include:
[0045]
(.+-.)-N-(2,6-Dimethylphenyl)-2-(3-methyl(thieno[2,3-d]pyrimidin-4--
yl)piperazin-1-yl)acetamide,
[0046]
cis-[2-(3,5-Dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-
]-N-(2,6-dimethylphenyl)acetamide,
[0047]
(.+-.)-2-[3-Methyl-4-(4-methylphenyl)piperazin-1-yl]-N-2,6-dimethyl-
phenyl) acetamide,
[0048]
cis-N-[3-Hydroxymethyl-2-methylphenyl]-2-(3,5-dimethyl-4-(thieno[2,-
3-d]pyrimidin-4-yl)piperazin-1-yl)acetamide,
[0049]
(R)-2-[4-(1-Methylimidazol-4-sulphonyl-4-yl)-3-yl-piperazin-1-yl]-N-
-(quinolin-5-yl)acetamide,
[0050]
cis-2-[3,5-Dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl]--
N-2-methylphenyl)acetamide,
[0051]
cis-N-2-Chlorophenyl)-2-[3,5-dimethyl-4-(thieno[2,3-d]pyrimidinyl)p-
iperazin-1-cis-N-(2-Chlorophenyl)-2-[3,5-dimethyl-4-(9-methyl-9H-purin-6yl-
)piperazin-1-yl]acetamide,
[0052]
cis-2-3,5-Dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-N-
-(isoquinolin-5-yl)acetamide,
[0053]
cis-2-3,5-Dimethyl-4-thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-N--
quinolin-5-yl)acetamide,
[0054]
cis-2-(3,5-Dimethyl-4-thieno[2,3-d]pyrimidin-1-yl)-N-piperazin-1-yl-
)-N-(2-methyl-5-methylsulphonamidophenyl)acetamide,
[0055] cis-2-3,5-Dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl)piperazin
1-yl]-N-(2-trifluoromethylphenyl)acetamide,
[0056]
cis-2-(3,5-Dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl)-N-(3-methylpyri-
din-2-yl)acetamide,
[0057]
cis-2-3,5-Dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-N-
-(isoquinolin-1-yl)acetamide,
[0058]
cis-4-(4-Amino-5-cyanopyrimidin-2-yl)-3,5-dimethylpiperazin-1-yl)-N-
-(2-chlorophenyl)acetamide,
[0059] cis-2-(4-Benzenesulphonyl-3,5-dimethylpiperazin-1-yl)-N-2
chlorophenyl) acetamide,
[0060]
(.+-.)-N-(2,6-Dimethylphenyl)-2-[(3-methyl-4-thiazolo(5,4-d)pyrimid-
in-7-yl)piperazin-1-yl]acetamide,
[0061]
cis-N-(2-Chlorophenyl)-2-[(3,5-dimethyl-4-quinazolin-4-yl)piperazin-
-1-yl]acetamide,
[0062]
N-(2-Chlorophenyl)-2-[8-(thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicy-
clo[3.2.1]oct-3-yl]acetamide,
[0063]
N-(2-Methylphenyl)-2-[8-(9-methyl-9H-purin-6-yl)-3,8-diazabicyclo[3-
.2.1]oct-3-yl]acetamide,
[0064]
2-[8-(9-Methyl-9H-purin-6-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-(q-
uinolin-5-yl)acetamide,
[0065] N-(Quinolin-5-yl)-2-[8-thiazolo[5,4-d]pyrimidin-7-yl)
3,8-diazabicyclo[3.2.1]oct-3-yl]acetamide,
[0066] N-(2-Methylphenyl)-2-[(8-thiazolo[5,4-d]pyrimidin
7-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]acetamide,
[0067]
N-(2-Methyl-5-methylsulphonyl)amidophenyl)-2-[8-(9-methyl-9H-purin--
6-yl-3,8-diazabicyclo[3.2.1]oct-3-yl]acetamide,
[0068]
N-[2-Methyl-5-(methylsulphonyl)amidophenyl]-2-[(8-thiazolo[5,4-d]py-
rimidin-7-yl)-3,8 diazabicyclo[3.2.1]oct-3-yl]acetamide,
[0069]
N-[2-Methyl-methylsulphonyl)amidophenyl]-2-[4-thieno[2,3-d]pyrimidi-
nyl)-3,8 diazabicyclo[3.2.1]oct-3-yl]acetamide,
[0070] cis-2-(3,5-Dimethyl (thieno[2,3 d]pyrimidin
yl)piperazin-1-yl)-N-(2-
-methyl-5-(1-piperazinylmethyl)phenyl)acetamide, hydrochloride
salt,
[0071]
N-(2-Methylphenyl)-2-[(8-(thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabic-
yclo(3.2.1) oct-3-yl]acetamide,
[0072] N-[5-Methanesulphonylamido-2-methylphenyl)-2-[8-thieno
2,3]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct-3-yl-acetamide,
[0073]
N-(2-Methyl-5-(1-piperazinylmethyl)phenyl)-2-[(8-thieno[2,3-d]pyrim-
idin-4-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]acetamide,
[0074]
cis-N-5-(2-Aminoethoxy)-2-methyl-phenyl)-2-(3,5-dimethyl-4-thieno[2-
,3-d]pyrimidin-4-yl)piperazin-1-yl)acetamide, hydrochloride
salt,
[0075]
cis-N-(5-(2-N-Methylamino)ethoxy)-2-methyl-phenyl-2-3,5-dimethyl-(t-
hieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)acetamide, hydrochloride
salt,
[0076]
cis-N-(5--(N-Methylamino)ethoxy)-2-methyl-phenyl)-2-(4-benzenesulph-
onyl)-3,5--dimethyl)piperazin-1-yl)acetamide,
[0077]
cis-N-[5-(2-Aminoethoxy)-2-methyl-phenyl)-2-(benzenesulphonyl-3,5-d-
imethyl)piperazin-1-yl]acetamide, hydrochloride salt,
[0078]
N-(2-Oxo-2,3-dihydro-1H-indol-4-yl)-2-(8-thieno[2,3-d]pyrimidin
yl-3,8-diazabicyclo[3.2.1]oct-3-yl)acetamide
[0079] N-(3-Fluoro-2-methyl-phenyl-2-(8
quinazolin-4-yl)-3,8-diazabicyclo[- 3.2.1]oct-3-yl) acetamide,
[0080]
N-2-Methylphenyl)-2-[8-benzenesulphonyl)-3,8-diazabicyclo[3.2.1]oct-
-3-yl)acetamide,
[0081]
N-3-Fluoro-2-methylphenyl)-2-[8-(benzenesulphonyl)-3,8-diazabicyclo-
[3.2.1]oct-3-yl)acetamide,
[0082]
cis-N-(3-Fluoro-2-methylphenyl)-2-(4-benzenesulphonyl)-3,5-dimethyl-
)piperazin-1-yl) acetamide,
[0083] N-2-Methylphenyl)-2-[8-(3 benzenesulphonyl)-3,8
cyclo(3.2.1]oct-3-yl]acetamide,
[0084]
2-[8-(3-Methoxybenzenesulphonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-
-(2-methylphenyl)acetamide,
[0085]
2-[8-(Benzo[1,2,5]oxadiazole-4-sulphonyl)-3,8-diazabicyclo(3.2.1]oc-
t-3-yl]-N-(2-methylphenyl)acetamide,
[0086] 2-[8-(Benzo[1,2,5]thiadiazole-4-sulphonyl)-3,8
diazabicyclo[3.2.1]oct-3-yl]-N-(2-methylphenyl)acetamide,
[0087]
2-(8-(5-Chlorothieno-2-yl)sulphonyl)-3,8-diazabicyclo[3.2.1]oct-3-y-
l]-N-(2-methylphenyl)acetamide,
[0088]
2-[8-(2-Chlorobenzenesulphonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-N--
(2-methylphenyl)acetamide,
[0089] 2-[8-(5-Chloro-2-methoxybenzenesulphonyl)-3,8
diazabicyclo[3.2.1]oct-3-yl]-N-(2-methylphenyl)acetamide,
[0090]
2-[8-(4-Acetylaminomethoxybenzenesulphonyl)-3,8-diazabicyclo[3.2.1]-
oct-3-yl]-N-(2-methylphenyl)acetamide,
[0091]
N-(2-Methylphenyl-2-[(8-(3-methylthieno-[2,3-d]pyrimidin-4-yl)-3,8--
diazabicyclo[3.2.1]oct-3-yl-acetamide,
[0092]
cis-2-3,5-Dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-N-
-1-methyl-1H-benzoimidazol-2-yl)acetamide,
[0093]
cis-2-(3,5-Dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)--
N-(2-methyl-5-(4-piperidinyloxy)phenyl)acetamide, hydrochloride
salt,
[0094]
cis-2-(3,5-Dimethyl-4-benzenesulphonyl)piperazin-1-yl)-N-2-methyl-5-
-(4 piperidinyloxy)phenyl)acetamide,
[0095]
cis-2-3,5-Dimethyl-4-(4-quinazolin-4-yl)piperazin-1-yl)-N-(2-methyl-
-5-(4-piperidinyloxy)phenyl)acetamide,
[0096]
cis-2-(3,5-Dimethyl-4-(4-quinazolinyl)piperazin-1-yl)-N-2-methyl-5--
(piperazin-4-yl-methyl)phenyl)acetamide,
[0097]
cis-2-(3,5-Dimethyl-4-(quinazolinyl)piperazin-1-yl)-N-(2-methyl-5-(-
2-(N-methylamino)ethoxy)phenyl)acetamide,
[0098]
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-
-methylphenyl)acetamide,
[0099]
cis-N-(2-Methylphenyl)-2-[4-(3-nitrobenzenesulphonyl)-3,5-dimethylp-
iperazin-1-yl]-acetamide,
[0100]
cis-2-[4-(3-Aminobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-
-methylphenyl)acetamide,
[0101]
cis-2-(3,5-Dimethyl-4-(3-cyanobenzenesulphonyl)piperazin-1-yl)-N-(q-
uinolin-5-yl)acetamide,
[0102]
cis-2-(3,5-Dimethyl-4-(4-cyanobenzenesulphonyl)piperazin-1-yl)-N-qu-
inolin-5-yl)acetamide,
[0103]
cis-2-(4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl)-N-3--
fluoro-2-methylphenyl)acetamide,
[0104]
cis-2-(Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl)-N-3-fluor-
o-2-methylphenyl)acetamide,
[0105]
cis-2-[4-(3-Acetylaminobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl-
]-N-(2-methylphenyl)acetamide,
[0106]
cis-2-[4-(3-Aminocarbonylbenzenesulphonyl)-3,5-dimethylpiperazin-1--
yl]-N-(2-methylphenyl)acetamide,
[0107]
cis-2-[4-(3-Methanesulphonylaminobenzenesulphonyl-3,5-dimethylpiper-
azin-1-yl]-N-2-methylphenyl)acetamide,
[0108]
cis-2-(4-(2-Methanesulphonylbenzenesulphonyl)-3,5-dimethylpiperazin-
-1-yl]-N-3-methoxy-2-methylphenyl)acetamide,
[0109]
cis-2-[4-(2-Methanesulphonylbenzenesulphonyl)-3,5-dimethylpiperazin-
-1-yl]-N-(3-fluoro-2-methylphenyl)acetamide,
[0110] cis-2-[4-(1-Methylimidazol
4-sulphonyl-4-yl)-3,5-dimethylpiperazin--
1-yl)-N-(quinolin-5-yl)acetamide,
[0111]
cis-2-[4-(1-Methylimidazol-4-sulphonyl-4-yl)-3,5-dimethylpiperazin--
1-yl]-N-(3-methoxy-2-methylphenyl)acetamide,
[0112]
cis-2-[4-(1-Methylimidazol-4-sulphonyl-4-yl)-3,5-dimethylpiperazin--
1-yl]-N-(3-fluoro-2-methylphenyl) acetamide,
[0113]
cis-2-[4-(3-Methanesulphonylbenzenesulphonyl)-3,5-dimethylpiperazin-
-1-yl]-N-2-trifluoromethylphenyl)acetamide,
[0114]
cis-2-[4-(2-Aminoethylaminocarbonylbenzenesulphonyl)-3,5-dimethylpi-
perazin-1-yl]-N-2-methylphenyl)acetamide,
[0115]
cis-2-[4-1,1,2,2-Tetrahydroisoquinilin-7-sulphonyl-7-yl)-3,5-dimeth-
ylpiperazin-1-yl]-N-(2,6 dimethylphenyl)acetamide,
[0116]
cis-2-[(4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(-
2,6-dimethylphenyl)acetamide,
[0117]
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-
-dimethylphenyl)acetamide,
[0118]
cis-2-[4-(2-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-2,-
6 dimethylphenyl)acetamide, hydrochloride salt,
[0119]
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-
-chlorophenyl)acetamide,
[0120]
2-[8-(Isquinolin-1-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-2-methylp-
henyl)acetamide,
[0121]
cis-2-[4-(4-Acetamidobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]--
N-(2-methylphenyl)acetamide,
[0122]
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-2--
trifluoromethylphenyl)acetamide,
[0123]
cis-2-[4-(3-Cyanobenzenesulphonyl-3,5-dimethylpiperazin-1-yl]-N-(2--
methyl-5-methanesulphonamidophenyl)acetamide,
[0124]
2-[8-(4-Benzenesulphonyl-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-(2-meth-
ylphenyl)acetamide,
[0125]
2-[8-(2-Benzenesulphonyl-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-(2-meth-
ylphenyl)acetamide,
[0126]
cis-2-[4-(1,2-Dimethylimidazol-4-sulphonyl-4-yl)-3,5-dimethylpipera-
zin-1-yl]-N-(quinolin-5-yl) acetamide,
[0127] cis-2-[4-(5-Chloro-1,3
dimethylpyrazole-4-sulphonyl-4-yl)-3,5-dimet-
hylpiperazin-1-yl]-N-(3-methoxy-2-methylphenyl) emide,
[0128]
2-[8-(2-(Isoxazol-3-yl)thiophen-5-yl)-3,8-diazabicyclo[3.2.1]oct-3--
yl]-N-(2-methylphenyl)acetamide,
[0129] 2-[8-(1,1,2,2-Tetrahydroisoquinilin-7-sulphonyl)-3,8
diazabicyclo[3.2.1]oct-3-yl]-N-(2-methylphenyl)acetamide,
[0130] cis-2-[4-(5-Chloro
1,3-dimethylpyrazole-4-sulphonyl-4-yl)-3,5-dimet-
hylpiperazin-1-yl]-N-2-methylphenyl)acetamide,
[0131]
cis-2-(4-(3,5-Dimethylisoxazole-4-sulphonyl-4-yl)-3,5-dimethylpiper-
azin-1-yl]-N-2-methylphenyl)acetamide,
[0132]
cis-2-[4-(2-Methanesulphonylbenzenesulphonyl)-3,5-dimethylpiperazin-
-1-yl]-N-(2-methylphenyl)acetamide,
[0133]
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(3-
-methoxy-2-methylphenyl)acetamide,
[0134]
cis-2-[4-(4-Methanesulphonylbenzenesulphonyl)-3,5-dimethylpiperazin-
-1-yl]-N-(2-methylphenyl)acetamide,
[0135]
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(5
cyano-2-methylphenyl)acetamide,
[0136]
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(5-
-acetamido-2-methylphenyl)acetamide,
[0137]
(R)-2-[4-(4-Cyanobenzenesulphonyl)-3-methylpiperazin-1-yl]-N-(quino-
lin-5-yl)acetamide,
[0138]
(S)-2-[4-(4-Cyanobenzenesulphonyl)-3-methylpiperazin-1-yl]-N-quinol-
in-5-yl)acetamide,
[0139]
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-2--
methyl-5-methanesulphonylphenyl)acetamide,
[0140] cis-2-[4-(3
Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-
-methyl-5-(4-amino-1-piperidinyl)methyl)phenyl]acetamide,
[0141]
(R)-2-[4-(4-Methanesulphonylbenzenesulphonyl)-3-methylpiperazin-1-y-
l]-N-(quinolin-5-yl)acetamide,
[0142]
(R)-2-[4-(4-Acetamidobenzenesulphonyl)-3-methylpiperazin-1-yl]-N-(q-
uinolin-5-yl)acetamide,
[0143] cis-2-[4-(3
Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-2--
methyl-5-(1-piperazinylmethyl)phenyl)acetamide,
[0144] cis-2-[4-3
benzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-2-methyl-
-5-(4-piperidinylamino)methyl)phenyl)acetamide,
[0145]
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-
-methyl-5-(1-morpholinyl)methyl)phenyl)acetamide,
[0146]
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-2--
methyl-5-(2-hydroxyethylamino)methyl)phenyl)acetamide,
[0147]
cis-2-[4(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-2-m-
ethyl-5-(S,S)-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl)phenyl)acetamide,
[0148]
(R)-2-[4-(2-Pyridinesulphonyl)-3,5-methylpiperazin-1-yl]-N-(quinoli-
n-5-yl)acetamide,
[0149]
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-
-methyl-3-(4 amino-1-piperidinyl)methyl)phenyl]acetamide,
[0150]
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-
-methyl-3-(4 piperidinylamino)methyl)phenyl)acetamide,
[0151]
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-
-methyl-3-(1-piperazinylmethyl)phenyl)acetamide,
[0152]
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-
-methyl-3-(S,S)-(2,5
diazabicyclo[2.2.1]hept-2-yl)methyl)phenyl)acetamide,
[0153]
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-((-
2-methyl-3-(1-morpholinyl)methyl)phenyl)acetamide,
[0154]
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-((-
2-methyl-3-(2-(1-pyrrolidinyl)ethoxy)phenyl)acetamide,
[0155] (.+-.)
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-y-
l]-N-((2-methyl-3-(1-methylpiperidin-3-yl)methoxy)phenyl)acetamide,
[0156]
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-((-
2-methyl(2-(1-pyrrolidinyl)ethoxy)phenyl)acetamide,
[0157]
(.+-.)(cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-y-
l]-N-(2-methyl-4-(1-methylpiperidin-3-yl)methoxy)phenyl)acetamide,
[0158]
(.+-.)-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-
-(2-methyl-5-(1-methylpiperidin-3-yl)methoxy)phenyl)acetamide,
[0159] (.+-.)
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-y-
l]-N-(2-methyl-6-(1-methylpiperidin-3-yl)methoxy)phenyl) acetamide,
and
[0160]
cis-2-[4-(1-Methylimidazol-4-sulphonyl-4-yl)-3,5-dimethylpiperazin--
1-yl]-N-((2-methyl-3-(2-(1-pyrrolidinyl)ethoxyphenyl)acetamide,
[0161] and their pharmaceutically acceptable salts and
solvates.
[0162] The present invention further provides a process for the
preparation of a compound of formula (I) as defined above which
comprises:
[0163] (a) reacting a compound of general formula 4
[0164] wherein X, Y, R.sup.1, R.sup.2 and R.sup.4 are as defined in
formula (I), with a compound of general formula (III),
R.sup.3--(SO.sub.2m--L.sup.1, wherein L.sup.1 represents a leaving
group (e.g. a halogen atom or triflate) and m and R.sup.3 are as
defined in formula (I), or (b) when X represents a nitrogen atom
and Y-represents an oxygen atom, reacting a compound of general
formula: 5
[0165] wherein m, R.sup.1, R.sup.2 and R.sup.3 are as defined in
formula (I), with a compound of general formula 6
[0166] wherein L.sup.2 represents a leaving group such as a halogen
atom and R.sup.4 is as defined in formula (I); or
[0167] (c) reacting a compound of general formula 7
[0168] wherein L.sup.3 represents a leaving group such as a halogen
atom or hydroxyl group and m, X, Y, R.sup.1, R.sup.2 and R.sup.3
are as defined in formula (I), with a compound of general formula
(VII), H.sub.2N--R.sup.4, wherein R.sup.4 is as defied in formula
(I);
[0169] and optionally after (a), (b) or (c) converting the compound
of formula (I) obtained to a pharmaceutically acceptable salt or
solvate thereof.
[0170] Processes (a) and (b) are conveniently carried out in the
presence of a base, e.g. a metal carbonate such as potassium or
caesium carbonate or a trialkylamine such as triethylamine,
preferably N,N-diisopropylethylamine, and in the presence of a
polar solvent (e.g. 1-methyl-2-pyrrolidinone, dimethylformamide,
ethanol, tetrahydrofuran or 1,4-dioxane).
[0171] Process (c) is conveniently carried out in the presence of a
base and a polar solvent as described above for processes (a) and
(b). In addition, a coupling reagent is suitably used, for example,
1,1'-bonyldiimidazole, 1,3-dicyclohexylcarbodiimide or
bromo-tris-oxy-tripyrrolidinophosphonium hexaflurophosphate.
[0172] Compounds of formulae (II), (III), (IV), (V), (VI) and (VII)
are either commercially available, are well known in the literature
or may be prepared easily using known techniques.
[0173] It will be appreciated by those skilled in the art that in
the processes of the present invention certain functional groups
such as hydroxyl, carboxyl 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 a certain stage the removal of one or more protecting
groups.
[0174] 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).
[0175] It will be appreciated that certain compounds of formula (1)
may be converted to further compounds of formula (I) by techniques
known in the art such as alkylation, hydrolysis, amide bond
formation, esterification or reductive amination.
[0176] 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 p-toluenesulphonate, or an alkali metal salt
such as a sodium or potassium salt.
[0177] Certain compounds of formula (I) are capable of existing in
stereoisomeric forms. It will be understood that the invention
encompasses all geometric and optical isomers of the compounds of
formula (I) and mixture thereof including racemes. Tautomers and
mixtures thereof also form an aspect of the present invention. The
compounds of the present invention are advantageous in that they
possess pharmacological activity and have utility as modulators of
P2X.sub.7 receptor activity. They are therefore indicated as
pharmaceuticals for use in the treatment or prevention of
rheumatoid arthritis, osteoarthritis, psoriasis, allergic
dermatitis, ash hyperresponsiveness of the airway, chronic
obstructive pulmonary disease (COPD), bronchitis, septic shock,
glomerulonephritis, irritable bowel disease, Crohn's disease,
ulcerative colitis, atherosclerosis, growth and metastases of
malignant cells, myoblastic leukemia, diabetes, neurodegenerative
disease, Alzheimer's disease, meningitis, osteoporosis, burn
injury, ischaemic heart disease, stroke, peripheral vascular
disease and varicose veins.
[0178] Accordingly, the present invention provides a compound of
formula (I), or a pharmaceutically acceptable salt or solvate
thereof as hereinbefore defined for use in therapy.
[0179] In another aspect, the 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.
[0180] 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.
[0181] Prophylaxis is expected to be particularly relevant to the
treatment of persons who have suffered a previous episode of, or
are otherwise considered to be at increased risk of, the disease or
condition in question. Persons at risk of developing a particular
disease or condition generally include those having a family
history of the disease or condition, or those who have been
identified by genetic testing or screening to be particularly
susceptible to developing the disease or condition.
[0182] The invention further provides a method of effecting
immunosuppression (e.g. in the treatment of rheumatoid arthritis,
irritable bowel disease, atherosclerosis, psoriasis, pulmonary
disease, e.g. COPD or bronchitis, or diseases of the Cal nervous
system, e.g. Alzheimer's disease or stroke) which comprises
administering a therapeutically effective amount of a compound of
formula (I), or a pharmaceutically acceptable salt or solvate
thereof as hereinbefore defined to a patient.
[0183] 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 disease or
condition indicated For effecting immunosuppression, the daily
dosage of the compound of formula (I) will typically be in the
range from 0.001 mg/kg to 30 mg/kg.
[0184] 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 0.10 to 70% w, of active ingredient, and, from 1 to 99.95% w,
more preferably from 30 to 99.90% w, of a pharmaceutically
acceptable adjuvant, diluent or carrier, all percentages by weight
being based on total composition.
[0185] Thus, 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.
[0186] 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.
[0187] The pharmaceutical composition of the invention 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.
[0188] The present invention will now be further explained by
reference to the following illustrative examples.
EXAMPLE 1
(.+-.)-N-(2,6-Dimethylphenyl)-2-(3-methyl-4-thieno[2,3-d]pyrimidin-4-yl)pi-
perazin-1-yl)acetamide
[0189] 8
i) (.+-.)-1,1-Dimethylethyl,
3-methyl-4-thieno[2,3-d]pyrimidin-4-yl)pipera-
zine-1-carboxylate
[0190] A solution of 4-chloro-thieno[2,3-d]pyrimidine (0.2 g) and
(.+-.)-1,1-dimethyl 3-methylpiperazine-1-carboxylate (J. Med. Chem,
1993, 36,690-698) (0.23 g) in ethanol (50 ml) was heated under
reflux for 24 hours. The solvent was evaporated and the residue
purified by flash column chromatography eluting with ethyl
acetate/isohexane (3:7) to give the subtitle compound as a yellow
gum Yield 0.33 g.
[0191] MS: APCI(+ve) 335(M+1,100%)
ii) (.+-.)-2-Methyl-1-(thieno[2,3-d]pyrimidine-4-yl)piperazine,
Trifluoroacetic Acid Salt
[0192] A mixture of the product from step (i) (0.33 g) and
trifluoroacetic acid (4 ml) in dichloromethane (5 ml) was stirred
at room temperate for 2 hours. The solvent was evaporated under
reduced pressure. Toluene (20 ml) was added to the residue and then
evaporated under reduced pressure to give the crude subtitle
compound as a gum. The product was used without further
purification in the next step.
[0193] MS: APCI(+ve) 235(M+1,100%)
iii)
(.+-.)-N-(2,6-Dimethylphenyl)-2-(3-methyl(thieno[2,3-d]pyrimidin-4-yl-
)piperazin-1-yl)acetamide
[0194] A mixture of the product from step (ii) (0.23 g),
N,N-diisopropylethylamine (0.65 g) and
2-chloro-N-2,6-dimethylphenyl)acet- amide (0.2 g) in
dimethylformamide (4 ml) was heated at 80.degree. C. for 18 hours.
The reaction mixture was cooled and diluted with ethyl acetate. The
organic solution was washed with a small volume of water and the
solvent evaporated under reduced pressure. The residue was purified
by flash chromatography eluting with ethyl acetate/isohexane (6:4)
to give the product as a gum. The gum was further purified by
reverse phase high pressure liquid chromatography (methanol/0.1%
aqueous ammonium acetate, gradient elution 15% to 85% organic
phase) to give the title product, after freeze drying, as a beige
solid. Yield 0.095 g.
[0195] MS: APCI(+ve) 396(M+1,100%)
[0196] .sup.1H NMR .delta. (CDCl.sub.3) 8.5(2H, s); 732(2H, q);
7.13(3H, m); 4.98(1H, bs); 4.60(1H, bd); 3.59(1H, dt); 3.25(2H, q);
3.12(1H, bd); 2.98(1H, d); 2.72(1H, dd); 2.55(1H, dt); 2.28(6H, s);
1.53(3H, d).
[0197] MP: 184-185.degree. C.
EXAMPLE 2
cis-[2-(3,5-Dimethyl-4-thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl]-N-(2,6--
dimethylphenyl)acetamide
[0198] 9
i)
cis-1,1-Dimethylethyl-3,5-dimethyl-4-(thieno[2,3-pyrimidine-4-yl)pipera-
zin-1-carboxylate
[0199] A solution of 4-chloro-thieno[2,3-pyrimidine (4.0 g),
cis-1,1-dimethylethyl, 3,5-dimethylpiperazine-1-carboxylate (J.
Med. Chem., 1999, 4(7), 1123-1114) (12 g) and
N,N-diisopropylethylamine (10 ml) in 1-methyl-2-pyrolidinone (30
ml) was heated at 120.degree. C. for 5 days under nitrogen. The
reaction mixture was cooled and diluted with ethyl acetate. The
organic solution was washed with water, dried (MgSO.sub.4) and the
solvent evaporated under reduced pressure. The residue was purified
by flash column chromatography eluting with ethyl acetate/isohexane
(2:8) to give the subtitle compound as a beige solid. Yield 5.5
g.
[0200] MS: APCI(+ve) 349(M+1,100%.
ii) cis-2,6-Dimethyl-1-(thieno[2,3-d]pyrimidinyl)piperazine,
Trifluoroacetic Acid Salt
[0201] The subtitle compound was prepared from the product of step
(i) (0.15 g) by the method of Example 1 step (ii) as a gum. This
was used without purification in the next step. MS: APCI(+ve)
249(M+1,100%).
iii)
cis-[2(3,5-Dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl-piperazin-1-yl]-N--
(2,6-dimethylphenyl)acetamide
[0202] A mixture of the product from step (ii),
N,N-diisopropylethylamine (0.37 ml) and 2
chloro-N-(2,6-dimethylphenyl)acetamide (0.08 g) in
1-methyl-2-pyrrolidinone (5 ml) was heated at 100.degree. C. for 24
hours. The reaction mixture was cooled and diluted with ethyl
acetate. The organic solution was washed with a small volume of
water, dried (MgSO.sub.4) and the solvent evaporated under reduced
pressure. The residual red oil was purified by reverse phase high
pressure liquid chromatography (acetontrile/0.1% aqueous ammonium
acetate, gradient elution 20% to 80% organic phase) to give the
title product, after freeze drying, as a cream solid. Yield 0.05
g.
[0203] MS: APCI(+ve) 410(M+1,100%)
[0204] .sup.1H NMR: .delta. (CDCl.sub.3) 8.5(2H, s); 7.38(1H, d);
7.26(1H, d); 7.14(3H, m); 5.10(2H, bs); 3.29(2H, s); 3.01(2H, d);
2.65(2H, dd); 2.30(6H, s); 1.56(6H, d).
[0205] MP:186-189.degree. C.
EXAMPLE 3
(.+-.)-2-[3-Methyl(methylphenyl)piperazin-1-yl]-N-2,6
dimethylphenyl) acetamide
[0206] 10
[0207] The title compound was prepared from (.+-.)-3-methyl
4-(4-methylphenyl)piperazine (0.1 g) and 2 chloro-N-2,6
dimethylphenyl)acetamide (0.1 g) by the method of Example 1 step
(iii) as a white solid. Yield 0.056 g.
[0208] MS: APCI(+ve) 352(M+1,100%).
[0209] .sup.1H NMR: .delta. (CDCl.sub.3) 8.63(1H, s); 7.09(5H, m);
6.87(2H, d); 3.78(1H, bm); 3.24(2H, d); 3.17(2H, m); 2.95(1H, m);
2.88(1H, dd); 2.72(2H, m); 2.29(3H, s); 2.26(6H, s); 1.08(3H,
d).
EXAMPLE 4
cis-N-[3-Hydroxymethyl-2-methylphenyl]-2-(3,5-dimethyl-4-(thieno[2,3-d]-py-
rimidin-4-yl)piperazin-1-yl)acetamide
[0210] 11
i)
cis-N-[3-((1,1-Dimethyl)-1-dimethylethyl)silyloxymethyl-2-methylphenyl]-
-2-(3,5
dimethyl-4-thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)acetamide
[0211] The subtitle compound was prepared from
N-(3-((1,1-dimethyl-1-dimet-
hylethyl)silyloxymethyl)-2-methylphenyl)-2-chloroacetamide (Chem.
Abs, 1997, 765311) (0.1 g) and the product from Example 2 step (ii)
(0.1 g) by the method of Example 2 step (iii) as a red oil. This
was used directly in the next step without further
purification.
ii)
cis-N-[3-Hydroxymethyl-2-methylphenyl]-2-(3,5-dimethyl-4-(thieno[2,3-d-
]pyrimidin-4-yl)piperazin-1-yl)acetamide
[0212] The subtitle product from step (i) (0.15 g) in anhydrous
tetrahydrofuran was treated with a 1M solution of tetrabutyl
ammonium fluoride in tetrahydrofuran (0.31 ml) and the mixture
stirred at room temperature for 1 hour. The solvent was removed
under reduced pressure and the residue purified by high pressure
liquid chromatography (acetonitrile/0.1% aqueous ammonium acetate,
gradient elution 20% to 80% organic phase) to give the title
compound as a white solid. Yield 0.025 g.
[0213] MS: APCI(+ve) 426(M+1,100%)
[0214] .sup.1H NMR: .delta. (CDCl.sub.3/DMSO) 8.97(1H, s), 8.49(1H,
s), 7.89(1H, d), 7.32(1H, d), 7.26(3H, m), 5.09(2H, bs), 4.74(2H,
s), 3.27(2H, s), 2.96(2H, d), 2.63(2H, dd), 2.36(3H, s), 1.58(6H,
bs)
[0215] MP: 203-204.degree. C.
EXAMPLE 5
(R)-2-[4-Methylimidazol-4-sulphonyl-4-yl)-3-ethylpiperazin-1-yl]-N-(quinol-
in-5-yl)acetamide
[0216] 12
i) (R)-3-Ethyl-1-(phenylmethyl)-2,5-piperazinedione
[0217] To a stirred Solution of (R)-N-BOC-2-aminobutyric acid (3.36
g) and ethyl N-benzylglycine (4.52 g) in dichloromethane (50 ml) at
15.degree. C. was added dicyclohexylcarbodiimide (3.59 g). The
temperature was maintained at 10-15.degree. C. for a further 2 h
and then allowed to stir at ambient temperature for a further 16 h.
The mixture was filtered and the mother liquor collected and
solvent evaporated under reduced pressure. The residue was
redissolved in dichloromethane (20 ml) and hydrogen chloride gas
passed through the mixture for 20 minutes. The mixture was quenched
with aq. saturated sodium bicarbonate solution and extracted with
ethyl acetate, collected, dried (MgSO.sub.4) and solvent evaporated
under reduced pressure to leave a colourless oil. This was purified
by crystallisation from ether/iso-hexane mixtures to give the
subtitle compound as a white solid Yield: 135 g
[0218] .sup.1H NMR (DMSO) 8.30(s, 1H), 7.24-7.39(m, 5H), 4.60(d,
1H), 4.44(d, 1H), 3.92(t, 1H), 3.78(d, 3H, 1.75(m, 2H), 0.84(t,
3H)
ii) (R)-3-Ethyl-1-phenylmethylpiperazine
[0219] A stirred solution of the product from step (i) (6.0 g) in
tetrahydrofuran (250 ml) at 0.degree. C. was treated with lithium
aluminium hydride (3.44 g). The mixture was allowed to stir at
ambient temperature for 24 h and then set at reflux for 4 h. The
mixture was carefully quenched with 10% aq. sodium hydroxide
solution (10 ml). After siring for 30 minutes the mixture was
filtered and the mother liquor partitioned between ethyl acetate
and brine. The organic layer collected, dried (MgSO.sub.4) and
solvent evaporated under reduced pressure to give the subtitle
compound as a pale yellow oil. Yield: 5.8 g
[0220] .sup.1H NMR .delta. (CDCl.sub.3) 732(s, 5H), 3.50(dd, 2H),
2.62-3.0(m, 5H), 2.00(m, 1H), 1.70(t, 1H), 1.57(s, 1H), 1.27(m,
2H), 090(t, 3H)
iii) (R)-1-(1-Methylimidazol-4-sulphonyl
4-yl)-2-ethyl-4-phenylmethyl)pipe- razine
[0221] The subtitle compound was prepared from the product of step
(ii) (0.5 g) and 1-methylimidazole-4-sulphonyl chloride (0.5 g) by
the method of Example 80 step (i) as a pale yellow solid. Yield:
0.53 g
[0222] .sup.1H NMR .delta. (CDCl.sub.3) 7.46(s, 1H), 7.38(s, 1H),
7.29(m, 5H), 3.80(s, 2H), 3.47(d, 1H), 3.3(d+m, 2H), 2.64(d, 2H,
2.08(m, 2H), 1.79(m, 2H), 0.82(t, 3H)
iv) (1-(1-Methylimidazol-4-sulphonyl-4-yl) 2-ethyl)piperazine
[0223] The subtitle compound was prepared from the product of step
(iii) (0.49 g) by the method of Example 80 step (ii) as a pale
yellow solid. Yield: 0.32 g
[0224] .sup.1H NMR .delta. (CDCl.sub.3) 7.6(d, 2H), 7.5(m, 4H),
4.05(s, 1H), 3.73(s, 3H), 3.42(d, 1H), 3.04(d, 2H), 2.87(m, 1H),
232(m, 1H), 1.87(m, 2H), 0.91(t, 3H).
[0225] v)
(R)-2-[4-(1-Methylimidazol-4-sulphonyl-4-yl)-3-ethylpiperazin-1--
yl]-N-(quinolin-5-yl)acetamide
[0226] The title compound was prepared from the product of step
(iv) (0.23 g) and 2-chloro-N-(quinolin-5-yl)acetamide (0.21 g)) (J.
Indian Chem Soc, 1940, 17, 619-621) by the method of Example 80
step (iii) as a cream solid. Yield: 21 mg
[0227] MS: APCI (+ve) 443(M+1)
[0228] .sup.1H NMR .delta. (CD.sub.3OD) 9.16(d, 1H), 9.07(d, 1H),
8.10(s, 3H), 7.97(t, 1H), 7.81(d, 1H), 7.70(t, 1H), 7.50(dd, 1H),
4.29(m, 2H), 4.10(m, 2H), 3.81(s, 3H), 3.69(m, 2H), 3.32(m, 2H),
3.15(m, 2H), 1.84(m, 2H), 0.99(t, 3H)
EXAMPLE 6
cis-2-[3,5-Dimethyl-4-thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl]-N-(2-met-
hylphenyl)acetamide
[0229] 13
[0230] The title compound was prepared from the product of Example
9 step (ii)-(0.316 g) and 2-methylaniline (0.09 g) by the method of
Example 8 step (v) as a white solid.
[0231] Yield 0.202 g
[0232] MS: APCI(+ve) 396(M+1, 100%)
[0233] .sup.1H NMR; .delta. (DMSO) 925(1H, s), 8.40(1H, d),
7.60-7.67(3H, m), 7.26(2H, m), 7.10(1H, m), 5.01(2H, bs), 3.23(2H,
s), 2.96(2H, d), 2.45(2H, m), 2.29(3H, s), 1.50(6H, m) MP:
174-175.degree. C.
EXAMPLE 7
cis-N-(2-Chlorophenyl)-2-[3,5-dimethyl-4-thieno[2,3-d]pyrimidin-4-yl)piper-
azin-1-yl]acetamide
[0234] 14
[0235] The title compound was prepared from the product of Example
8 step (ii) (0.316 g) and 2 chloroaniline (0.107 g) by the method
of Example 1 step (iii) as a white solid.
[0236] Yield 0.119 g.
[0237] MS: APCI(+ve) .sup.416(M+1, 100%)
[0238] .sup.1H NM (DMSO) 9.70(1H, s), 8.55(1H, d), 7.27-7.42(3H,
m), 7.26(2H, s), 7.08(1H, t), 5.08(2H, bs), 3.26(2H, s), 2.94(2H,
d), 2.60(2H, m), 1.63(6H, d)
[0239] MP: 206-207.degree. C.
EXAMPLE 8
cis-N-(2-Chlorophenyl-2-[3,5-dimethyl-4-(9-methyl-9H-purin-6yl)piperazin-1-
-yl]acetamide
[0240] 15
i) cis-1,1-Dimethylethyl,
3,5-dimethyl-4-(9-methyl-9H-purin-6-yl)piperazin-
e-1-carboxylate
[0241] The subtitle compound was prepared from
6-chloro-9-methyl-9H-purine (J. Org. Chem., 1983, 48(6), 850-5) (2
g) and cis-1,1-dimethylethyl, 3,5-dimethylpiperazine-1-carboxylate
(2.74 g) by the method of Example 2 step (i) as beige solid Yield
0.2 g.
[0242] .sup.1H NMR: .delta. (CDCl.sub.3) 8.40(1H, S), 7.73(1H, S),
4.20-4.00(3H, BRM), 3.30-3.00(3H, BRM), 1.5(9H, S), 1.40(6H, D)
ii) cis-2,6-Dimethyl-1-(9-methyl-9H-purin-6-yl)piperazine,
Trifluoroacetic Acid Salt
[0243] The subtitle compound was prepared from the product of step
(i) (0.2 g) by the method of Example 1 step (ii) as a red gum This
was used directly in the next step.
[0244] MS: APCI(+ve) 247(M+1,100%)
iii) cis-1,1-Dimethylethyl,
2-(3,5-dimethyl-4-(9-methyl-9H-purin-6-yl)pipe-
razine-1-yl)acetate
[0245] A mixture of the product from step (ii) (0.34 g), tert-butyl
bromoacetate (0.13 g) and sodium bicarbonate (0.8 g) in acetone was
heated at 45.degree. C. for 18 hours. The reaction mixture was
filtered and the file evaporated under reduced pressure. The
residual brown gum was purified by flash chromatography eluting
with ethyl acetate/isohexane/triethylamine (7:2.5;0.5) to give the
subtitle compound as a pale yellow gum Yield 0.12 g
[0246] MS: APCI(+ve) 361(M+1,100%)
iv)
cis-2-(3,5-Dimethyl-4(9-methyl-9H-purin-yl)piperazin-4-yl)acetic
Acid, Hydrochloride Salt
[0247] The product from step (iii) (0.12 g) in dichloromethane was
treated with 1M hydrogen chloride in diethyl ether (12 ml). The
mixture was stirred at room temperature for 18 hours. The solvent
was evaporated under reduced pressure to give the subtitle product
as a pale yellow solid. Yield 0.15 g.
[0248] MS: APCI(+ve) 305(M+1,100%)
v)
cis-N-(2-Chlorophenyl)-2-[3,5-dimethyl-(9-methyl-9H-purin-6yl)piperazin-
-1-yl]acetamide
[0249] Bromo-tris-oxy-tripyrrolidinophosphonium hexafluorophosphate
(known as PyBroP) (0.18 g) was added to a stirred solution of the
product from step (iv) (0.14 g), 2 chloroaniline (0.05 g) and
N,N-diisopropylethylamin- e (0.3 g) in anhydrous dimethylformamide
(6 ml). After stirring for 4 hours a further aliquot of
2-chloroaniline (0.1 ml) and PyBroP (0.18 g) were added and the m
further stirred at room temperature for four days. Water was added
and the precipitate filtered to give the crude product as a brown
solid (0.07 g). This was purified by high pressure liquid
chromatography (acetonitrile/0.1% aqueous ammonium acetate,
gradient elution 25% to 75% organic phase) to give the title
product as a white solid Yield 0.04 g.
[0250] MS: APCI(+ve) 414/416(M+1, 100%)
[0251] .sup.1H NMR: .delta.(CDCl.sub.3/DMSO) 9.76(1H, s), 8.52(1,
dd), 8.39(1H, s), 7.78(1H, s), 7.40(1H, dd), 7.31(1H, dt), 7.07(1H,
dt), 5.50(2H, bs), 3.83(3H, s), 3.26(2H, s), 2.94(2H, d), 2.59(2H,
m), 1.58(6H, d)
[0252] MP: 221-222.degree. C.
EXAMPLE 9
cis-2-(3,5-Dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-N-(isoq-
uinolin-5-yl)acetamide
[0253] 16
[0254] i) cis-1,1-Dimethylethyl, 2-(3
dimethyl-4-(thieno[2,3-d-]pyrimidin--
4-yl)piperazin-1-yl)acetate
[0255] The subtitle compound was prepared from the product of
Example 2 step (ii) (3.0 g) and tert-butyl bromoacetate (1.15 g) by
the method of Example 8 step (iii) as a white solid.
[0256] Yield 1.0 g.
[0257] MS: APCI(+ve) 363(+1,100%) ii)
cis-2-(3,5-Dimethyl-4-(thieno[2,3-d]-
pyrimidin-4-yl)piperazin-1-yl)acetic acid, hydrochloride salt
[0258] The product from step (i) (1.0 g) in 1,4-dioxane was treated
with 4M hydrogen chloride in 1,4 dioxane (40 ml). The mixture was
sired at room temperate for 18 hours. The solvent was evaporated
under reduced pressure to give the subtitle compound as a white
solid. Yield 1.9 g.
[0259] MS: APCI(+ve) 307(M+100%)
iii)
cis-2-(3,5-Dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-N--
(isoquinolin-5-yl)acetamide
[0260] The title product was prepared from the product of step (ii)
(0.2 g) and 5-aminoisoquinoline (0.084 g) by the method of Example
8 step (v) as a white solid. Yield 0.11 g.
[0261] MS: APCI(+ve) 433(M+1,100%)
[0262] .sup.1H NMR: .delta.(CDCl.sub.3) 9.62(1H, bs), 9.30(1H, s),
8.59(1H, d), 8.51(1H, s), 8.46(1H, d), 7.85(1H, d), 7.68(2H, m),
7.38(1H, d), 7.28(1H, m), 5.13(2H, bs), 3.38(2H, s), 3.03(2H, d),
2.70(2 dd), 1.65(6H, d)
[0263] MP: 213-216.degree. C.
EXAMPLE 10
cis-2-(3,5-Dimethyl
4-thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-N-(quino-
lin-5-yl)acetamide
[0264] 17
[0265] The title compound was prepared from the product of Example
9 step (ii) (0.207 g) and 5-aminoquinoline (0.072 g) by the method
of Example 8 step (v) as a white solid.
[0266] Yield 0.11 g.
[0267] MS: APCI(+ve) 433(M+1, 100%) .sup.1H NMR:
.delta.(CDCl.sub.3) 9.53(1H, s), 8.97(1H s), 8.51(1H, s); 8.28(1H,
s), 8.00(1H, s), 7.77(1H, t), 7.47(1H, m), 7.42(1H, d), 7.37(1H,
d), 5.13(2H, s), 3.38(2H, s), 3.03(2H, d), 2.71(2H, d), 2.29(3H,
s), 1.63(6H, d)
[0268] MP: 194-195.degree. C.
EXAMPLE 11
cis-2-(3,5-Dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-N-(2-me-
thyl-5 methylsulphonamidophenyl)acetamide
[0269] 18
i) 2-Methyl-5-bis(methylsulphonyl)amido-1-nitrobenzene
[0270] To a mixture of 5-nitro-4-methylamine (3.04 g) and
N,N-diisopropylethylamine (5.2 ml) in dichloromethane (40 ml) was
added dropwise a solution of methanesulphonyl chloride (2.29 g) in
dichloromethane (10 ml) over 40 mins. After string for 16 hours the
mixture was poured into 2% aq. HCl. The organic phase collected and
further washed with brine, dried (Na.sub.2SO.sub.4) and solvent
evaporated under reduced pressure to leave the crude product. This
was purified by silica-gel chromatography eluting with
dichloromethane to give the subtitle compound as a pale yellow
solid. Yield 4.46 g. This was used directly in the next
ii) 2-Methyl-5-bis(methylsulphonyl)amido-1-aniline
[0271] A mixture of the product from step (i) (3.8 g), ammonium
chloride (3.8 g), reduced iron powder (3.8 g) in ethanol (30 ml)
and water (10 ml) were stirred at 80.degree. C. for 5 minutes. The
mixture was filtered through Celite and further washed with ethanol
and dichloromethane. The filtrate was concentrated to a quarter of
the volume and then water added to give a brown precipitate. This
was filtered to give the subtitle compound as a brown solid. Yield
1.25 g. The mother liquor was further partitioned between water and
ethyl acetate. The organic phase collected, dried
(Na.sub.2SO.sub.4) and evaporated to give a second batch of the
subtitle compound as an orange solid Yield 1.1 g.
[0272] .sup.1H NMR: .delta.(DMSO) 6.98(1H, d), 6.65(1H, s),
6.56(1H, d), 2.50(6H, s), 2.06(3H, s)
iii)
cis-2-(3,5-Dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-N--
(2-methyl-5-bis(methylsulphonyl)amidophenyl)acetamide
[0273] The subtitle product was prepared from the product of
Example 9 step (ii) (0.318 g) and the product of step (ii) (0.172
g) by the method of Example 8 step (v) as a white solid. Yield 0.21
g. This product was used directly in the nest step without further
purification.
iv)
cis-2-(3,5-Dimethyl-4-(thieno[2,3-d)pyrimidin-4-yl)piperazin-1-yl)-N-2-
-methyl-5-methylsulphonamidophenyl)acetamide
[0274] A mixture of the product from step (iii) (0.21 g) and
potassium carbonate (0.5 g) was stirred in methanol (20 ml) and
water (10 ml) over 24 hours at room temperature. The solid product
was filtered and purified by reverse phase HPLC to give the title
compound as white solid. Yield 0.058 g.
[0275] MS: APCI(+ve) 489(M+1, 100%)
[0276] .sup.1H NMR: .delta. (DMSO) 9.66(1H, s), 9.23(1H, s),
8.40(1H, s), 7.60(3H, s), 7.17(1H, d), 6.94(1H, d),4.50(2H,
bs),3.22(2H, s),2.93(2H, s),2.43(2H, m),2.22(3H, s), 1.49(6H,
d)
EXAMPLE 12
cis-2-(3,5-Dimethyl-4-(thieno[2,3-d]piperazin-1-yl]N--N(2-trifluoromethylp-
henyl)acetamide
[0277] 19
[0278] i)
cis-2-(3,5-Dimethyl-4-thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl-
)acetyl chloride, hydrochloride Salt
[0279] A mixture of the product from Example 9 step (ii) (1.15 g)
and oxalyl chloride (1.2 ml) in dichloromethane (100 ml) was
treated with 2 drops of dimethylformamide. After 24 hours at room
temperature a further aliquot of oxalyl chloride (3.6 ml) was added
and the mixture heated under reflux for 48 hours. The solvent was
evaporated under reduced pressure. Toluene was added to the residue
and then evaporated under reduced pressure to give the subtitle
product as a yellow oil (0.95 g).
[0280] MS: (methanol added to give the methyl ester):APCI(+ve)
320(M(methyl ester)+1,100%)
ii)
cis-2-(3,5-Dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl]-N-(-
2-trifluoromethylphenyl)acetamide
[0281] A mixture of the product from step (i) (0.2 g),
2-trifluoromethylaniline (0.11 g) and N,N-diisopropylethylamine in
1,4 dioxane(5 ml) was heated at 80.degree. C. for 18 hours. LC mass
spectrum analysis showed
cis-3,5-dimethyl-4-(thieno[2,3-d]pyrimidinyl)piperazin-1--
yl]acetic acid present. PyBroP (0.18 g) and 4-dimethylaminopyridine
(0.05 g) were added and the mixture further sired at room
temperature for 18 hours. The solvent was evaporated under reduced
pressure and the residue purified by high pressure liquid
chromatography (acetonitrile/0.1% aqueous ammonium acetate,
gradient elution 25% to 75% organic phase) to give the title
product as a white solid. Yield 0.08 g.
[0282] MS: APCI(+ve) 450(M+1,100%)
[0283] .sup.1H NMR: .delta. (CDCl.sub.3) 9.41(1H, bs), 8.49(1H, s),
8.34(1H, d), 7.65(1H, d), 7.60(1H, t), 7.37(1H, d), 7.27(2H, m),
5.06(2H, bs), 3.24(2H, s), 2.92(2H, d), 2.59(2H, dd), 1.55(6H,
d)
[0284] MP: 154-155.degree. C.
EXAMPLE 13
cis-2-(3,5-Dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-N-(3-me-
thylpyridin-2-yl)acetamide
[0285] 20
[0286] The title compound was prepared by from the product of
Example 12 step (i) (0.2 g) and 2-amino-3-methylpyridine (0.076 g)
by the method of Example 12 step (ii) as a cream solid.
[0287] Yield 0.025 g.
[0288] MS: APCI(+ve) 397(M+1,100%)
[0289] .sup.1HNMR: .delta.(CDCl.sub.3) 9.13(1H, s), 8.47(1H s),
8.31(1H, d), 7.60(1H, d), 7.40(1H, m), 7.27(1H, d), 7.13(1H, m),
5.09(2H, bs), 3.28(2H, s), 2.91(2H, d), 2.61(2H, m), 2.3(3H, s),
1.60(6H, d)
[0290] MP: 157-159.degree. C.
EXAMPLE 14
cis-2-(3,5-Dimethyl-4(thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-N-(isoqu-
inolin-1-yl)acetamide
[0291] 21
[0292] The title product was prepared by from the product of
Example 12 step (i) (0.2 g) and isoquinolin-1-ylamine (0.1 g) by
the method of Example 12 step (ii) as a cream solid Yield 0.055
g.
[0293] MS: APCI(+ve) 433(M+1,100%)
[0294] .sup.1H NMR: .delta. (CDCl.sub.3) 9.65(1H, bs); 8.49(1H, s);
8.37(1H, bs); 8.05(1H, bd); 7.72(1H, t); 7.60(2H, t); 7.39(1H, d);
7.26(1H, m); 5.12(2H, bs); 3.39(2H, s); 3.07(2H, d); 2.67(2H, dd);
1.63(6H, d).
[0295] MP: 206-207.degree. C.
EXAMPLE 15
cis-2-(4-(4-Amino-5-cyanopyrimidin-2-yl)-3,5-dimethyl-piperazin-1-yl)-N-(2-
-chlorophenyl)acetamide
[0296] 22
i) 2-Chloro-N-(2-chlorophenyl)acetamide
[0297] 2-Chloroaniline (5 g) was dissolved in dichloromethane (10
ml) and chloroacetyl chloride (3.11 ml) and
N,N-diisopropylethylamine (13.65 ml) were added at 0.degree. C.
under a nitrogen atmosphere. The mixture was stirred for 1 hour at
0.degree. C. and 12 hours at room temperature, then quenched with
water. The product was extracted with dichloromethane. The organic
layer was washed with water, brine, dried (MgSO.sub.4) and
concentrated under reduced pressure to leave the subtitle product
as a beige solid. Yield 7.5 g. This was used in the next step
without further purification.
[0298] MS: ES(-ve) 203(M-1, 100%)
ii)
cis-N-(2-Chlorophenyl)-2-(3,5-dimethylpiperazin-1-yl)acetamide
[0299] The product of step (i) (5.9 g) was dissolved in ethanol (50
ml) and cis-2,6-dimethylpiperazine (3 g) and sodium
hydrogencarbonate (6.63 g) were added at room temperature under a
nitrogen atmosphere. The mixture was heated under reflux for 24
hours and the cooled solution was filtered and the filtrate was
evaporated under reduced pressure. The residue was dissolved in 1M
HCl (22 ml) and washed with dichloromethane. The aqueous solution
was then basified to pH13 with a solution of sodium hydroxide and
the product was extracted with dichloromethane. The organic layer
was washed with water, brine, collected, dried (MgSO.sub.4) and
concentrated under reduced pressure to give the subtitle compound
as a beige solid. Yield 4 g.
[0300] MS: ES(+ve) 282(M+1,100%)
iii)
cis-2-(4-(4-Amino-5-cyanopyrimidin-2-yl)-3,5-dimethylpiperazin-1-yl)--
N-(2-chlorophenyl)acetamide
[0301] A mixture of the product from step (ii) (0.5 g),
4-amino-2-chloro-5-cyanopyrimidine (0.275 g) and
N,N-diisopropylethylamin- e (1.55 ml) in 1-methyl-2-pyrrolidinone
(5 ml) was heated under nitrogen at 120.degree. C. for 3 days. The
cooled mixture was partioned between ethyl acetate and water. The
organic phase collected was dried (MgSO.sub.4) and the solvent
evaporated. The crude product purified by silica-gel chromatography
eluting with 2% ethyl acetate in isohexane to give the title
compound as white solid. Yield 0.1 g.
[0302] MS: APCI (+ve) 400(M+1, 100%)
[0303] .sup.1H NMR: .delta. (DMSO) 9.67(1H, s), 832(1H, dd),
8.29(1H, s), 7.53(1H, dd), 7.37(1H, t), 7.23(2H, brs), 7.15(1H, t),
4.76-4.72(2H, m), 3.23(2H, s), 2.86(2H, d), 2.38(2H, dd), 1.36(6H
d)
EXAMPLE 16
cis-2-(4-Benzenesulphonyl-3,5-dimethylpiperazin-1-yl)-N-(2-chloro-phenyl)a-
cetamide
[0304] 23
[0305] Benzenesulphonyl chloride (0.124 g) was added to a solution
of the product from Example 15 step (ii) (0.2 g) in pyridine (2
ml). The mixture was stirred at room temperature for 16 hours and
then the solvent was evaporated under reduced pressure. The residue
was purified by flash silica-gel chromatography eluting with 1%
EtoH, 1% Et.sub.3N, 98% CH.sub.2Cl.sub.2 followed by trituration
with ethyl acetate to give the title compound. Yield 0.03 g.
[0306] MS: APCI(+ve) 422(M+1,100%)
[0307] .sup.1H NMR: .delta. (CDCl.sub.3) 9.49(brs, 1H), 8.48(dd,
1H), 7.82(d), 7.60-750(m, 3H), 7.37 (dd, 1H), 7.30(m, 1H), 7.05(dt,
1H), 4.17(quin, 2H), 3.07(s, 2H, 2.65(d, 2H), 2.15(dd, 2H), 1.55(s,
6H).
[0308] M.P: 182-3.degree. C.
EXAMPLE 17
(.+-.)-N-(2,6-Dimethylphenyl)-2-[(3-methyl-4-thiazolo(5,4-d)pyrimidin-7-yl-
)piperazin-1-yl]acetamide
[0309] 24
i)
(.+-.)-N-(2,6-Dimethylphenyl-2-(3-methylpiperazin-1-yl)acetamide
[0310] The subtitle compound was prepared from
2-chloro-N-(2,6-dimethylphe- nyl)acetamide (7 g) and
(+)-2-methyl-piperazine (3.55 g) by the method of Example 15 step
(ii) as a white solid.
[0311] Yield 7 g.
[0312] MS: ES(+ve) 262(M+1,100%)
ii)
(.+-.)-N-(2,6-Dimethylphenyl)-2-[(3-methyl-4-thiazolo(5,4-d)pyrimidin--
7-yl)piperazin-1-yl]acetamide
[0313] The title compound was prepared from the product of step (i)
(0.381 g) and 7-chloro-thiazolo[5,4-d]pyrimidine (Chem. Pharm.
Bull. 1968, (16(4), 750-755) (0.25 g) by the method of Example 15
step (iii) as a beige solid. Yield 0.01 g.
[0314] MS: ES(+ve) 397(+1,100%)
[0315] .sup.1H NMR: .delta. (CDCl.sub.3) 8.84(1H, s), 8.77(1H, s),
8.48(1H, s) 7.18-7.06(3H, m) 3.14(2H, s), 3.88-2.68(7H, brm),
2.26(6H, s), 1.25(3H, m)
EXAMPLE 18
cis-N-(2-Chlorophenyl)-2-[(3,5-dimethyl-4-quinazolin-4-yl)piperazin-1-yl]a-
cetamide
[0316] 25
[0317] A mixture of the product from Example 15 step (ii) (2.1 g),
4-chloroquinazoline (1.23 g) (J. Chem. Soc., 1944, 619-623) and
N,N-diisopropylethylamine (6.15 ml) in 1-methyl-2pyrrolidinone(14
ml) under nitrogen was heated at 120.degree. C. for 4 days. The
cooled mixture was partitioned between ethyl acetate and water. The
organic layer was further washed with water, brine, dried
(MgSO.sub.4) and concentrated under reduced pressure. The residue
was purified by silica-gel chromatography eluting with ethyl
acetate/isohexane (4:6) to give the title compound as a white
solid. Yield 0.08 g.
[0318] MS: ES(+ve) 410(M+1,100%), ES(-ve) 408(M-1,100%)
[0319] .sup.1H NMR: .delta. (DMSO) 9.81(1H, s), 8.82(1H, brs),
8.30(1H, dd), 8.18(1H, d), 7.87(2H, d), 7.63-7.58(1H, m), 7.55(1H,
dd), 7.38(1H, t), 7.17(1H, t), 4.38(2H, brs), 3.26(2H, s), 2.69(4H,
brs), 1.30-1.15(6H, m)
EXAMPLE 19
N-(2-Chlorophenyl)-2-[(8-(thieno[2,3-d]pyrimidinyl)-3,8-diazabicyclo[3.2.1-
]oct-3-yl]acetamide
[0320] 26
i) 1,1-Dimethylethyl,
3-[(2-chlorophenylcarbamoyl)methyl]-3,8-diaza-bicycl-
o[3.2.1]octane-8-carboxylate
[0321] A mixture of 1,1-dimethylethyl,
3,8-diaza-bicyclo[3.2.1]octane-8-ca- rboxylate (0.048 g) (J. Med.
Chem., 1998, 41(5), 674-681), sodium bicarbonate (0.058 g),
potassium iodide (0.003 g) and the product of Example 15 step (i)
(0.051 g) in ethanol (05 ml) was heated at 70.degree. C. for
3-hours. The cooled mixture was partitioned between ethyl acetate
and water and the organic phase was washed with water and brine,
dried (MgSO.sub.4) and the solvent evaporated under reduced
pressure. Purification was by flash silica-gel chromatography
eluting with 2% EtoH, 1% Et.sub.3N, 97% CH.sub.2Cl.sub.2. Yield
0.068 g.
[0322] MS: ES(+ve) 380(M+1,100%)
ii) N-(2-Chlorophenyl)-2-(3,8-diaza-bicyclo[3.2.1]oct-3
yl)acetamide Trifluoroacetic Acid Salt
[0323] The subtitle compound was prepared from the product of step
(i) (0.068 g) by the method of Example 1 step (ii) as a white
solid. Yield 0.061 g.
[0324] MS: ES(+ve) 280(M+1,100%)
iii)
N-(2-Chlorophenyl)-2-[(8-(thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyc-
lo[3.2.1]oct-3-yl]acetamide
[0325] The title compound was prepared from the product of step
(ii) (0.061 g) by the method of Example 15 step (iii), with heating
for 1 hour only, as a white solid. Yield 0.04 g.
[0326] MS: APCI(+ve) 414(M+1,100%)
[0327] .sup.1HNMR: .delta.(CDCl.sub.3) 9.65(s, 1H), 8.53(dd, 1H),
8.49(s, 1H), 7.41(dd, 1H), 7.33-7.28 (m, 3H), 7.07(t, 1H),
5.02(brs, 1H), 3.18(s, 2H), 2.95(d, 2H, 2.77(d, 2H, 2.32(m, 2H),
2.12(m, 2H).
[0328] MP: 164.degree. C.
EXAMPLE 20
N-(2-Methylphenyl)-2-[8-(9-methyl-9H-purin-6-yl)-3,8-diazabicyclo[3.2.1]oc-
t-3-yl]acetamide
[0329] 27
i) 1,1-Dimethylethyl,
3-phenylmethyl-3,8-diazabicyclo[3.2.1]oct-8-carboxyl- ate
[0330] 3-Phenylmethyl-3,8-diazabicyclo[3.2.1]octane hydrochloride
salt (1.5 g) was dissolved in dichloromethane (16 ml) and water (16
ml) and sodium hydrogencarbonate (1.61 g) were added. The mixture
was stirred rapidly for 10 minutes at room temperature and then
di-tert-butyl dicarbonate (1.15 g) was added in portions. The
mixture was stirred rapidly for an additional 2 hours. The organic
layer was separated, dried over magnesium sulphate, filtered and
concentrated to afford a white crystalline solid Yield 1.45 g.
[0331] MS: ES(+ve) 303(M+1,100%)
ii) 1,1-Dimethylethyl, 3,8-diazabicyclo[3.2.1]oct-8-carboxylate
Hydrochloride Salt
[0332] A solution of the product from step (i) (1.45 g) was
dissolved in ethyl acetate (12 ml) and cooled at -10.degree. C.
under a nitrogen atmosphere. 1M HC in diethyl ether (4.81 ml) was
added dropwise, causing the salt to precipitate out of solution The
mix was stirred an additional 1 hour and the crystalline product
was collected by filtration and dried in a vacuum oven. This white
solid was dissolved in methanol (18 ml) and 10% palladium on carbon
(0.1 g) added under a nitrogen atmosphere. The mixture was then
stirred vigorously under an hydrogen atmosphere for 12 hours. After
completion of the reaction, the mixture was filtered through Celite
and the mother liquor concentrated to afford the subtitle compound
as a white crystalline solid. Yield 1.18 g
[0333] .sup.1H NMR: .delta. (CDCl.sub.3) 4.34(2H, brs), 3.16(4H,
brs), 2.27-2.09(4H, m), 1.47(9H, s)
iii) 1,1-Dimethylethyl, 3[(2-methylphenylcarbamoyl)methyl]-3,8
diaza-bicyclo[3.2.1]octane-8-carboxylate
[0334] A mixture of the product from step (ii) (0.16 g),
2-chloro-N-(2-methyl)acetamide (Synthesis, 1982, (9), 795-796)
(0.13 g), sodium hydrogencarbonate (0.16 g), and potassium iodide
(8 mg) in ethanol (2 ml) under a nitrogen atmosphere was heated at
70.degree. C. for 4 hours. The reaction mixture was partitioned
between ethyl acetate and water. The organic layer was washed with
water, brine, dried (MgSO.sub.4) and concentrated under reduced
pressure. The residue was purified by silica-gel chromatography
eluting with 2% ethanol 1% triethylamine in dichloromethane to give
the subtitle compound as beige solid. Yield 0.23 g.
[0335] MS: ES(+ve) 360(M+1,100%)
iv)
N-(2-Methylphenyl)-2-[3,8-diazabicyclo[3.2.1]oct-3-yl]acetamide,
Trifluoroacetic Acid Salt
[0336] A mixture of the product from step (iii) (0.23 g) in
dichloromethane (30 ml) and trifluoroacetic acid (1.80 ml) under a
nitrogen at room temperature was stirred for 24 hours. The mixture
was concentrated under reduced pressure to leave brown gum. This
was used in the next step without further purification.
[0337] MS: ES(+ve) 260(M+1,100%)
v)
N-(2-Methylphenyl-2-[8-(9-methyl-9H-purin-6-yl)-3,8-diazabicyclo[3.2.1]-
oct-3-yl]acetamide
[0338] A mixture of the product from step (iv) (0.12 g),
6-chloro-9-methylpurine (0.06 g) (J. Org. Chem, 1983, 48(6),
850-855), and N,N-disopropylethylamine (1 ml) in 1,4-dioxane (5 ml)
were heated together at reflux for 5 hours. The volatiles were
removed under reduced pressure and the residue purified by reverse
phase HPLC eluting with a gradient from 5% acetonitrile in aqueous
1% ammonium acetate to 75% over 7 min. The title product was on
obtained, by freeze drying, as a white solid Yield: 0.027 g.
[0339] MS: APCI(+ve) 392(M+1,100%)
[0340] .sup.1HNMR .delta. (DMSO); 9.16(s, 1H), 8.27(s, 1H), 8.15(s,
1H), 7.75(d, 1H), 7.10(t, 1H), 7.08(t, 1H), 3.74(s, 3H), 5.70(bs,
1H), 5.00(bs, 1H), 3.74(s, 3H), 3.07(, 2H), 2.90(m, 2H),
2.50-1.80(m, 6H), 2.30(s, 3H)
EXAMPLE 21
2-[4-(9-Methyl-9H-purin-6-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-(quinolin-
-5-yl)acetamide
[0341] 28
i) 1,1-Dimethylethyl,
3-[(quinolin-5-ylcarbamoyl)methyl]-3,8-diazabicyclo[-
3.2.1]octane-8-carboxylate
[0342] The subtitle compound was prepared from the product of
Example 20 step (ii) (0.24 g) and
2-chloro-N-(quinolin-5-yl)acetamide (J. Indian Chem Soc, 1940, 17,
619-621) (0.234 g) by the method of Example 20 step (iii) as a pale
yellow solid Yield 0.38 g.
[0343] MS: ES(+ve) 397(M+1,100%)
ii) 2-(3,8-Diazabicyclo[3.2.1]oct-3-yl)-N-(quinolin-5-yl)acetamide,
Trifluroacetic Acid Salt
[0344] The subtitle compound was prepared from the product of step
(i) (0.38 g) by the method Example 20 step of step (iv) as a pale
yellow gum. This was used directly in the next step.
[0345] MS: ES(+ve) 297(M+1,100%)
iii) 2-[8-(Methyl-9H-purin-yl)-3,8
diazobicyclo[3.2.1]oct-3-yl]-N-(quinoli- n-5-yl)acetamide
[0346] A mixture of the product from step (ii) (0.20 g),
6-chloro-9-methylpurine (0.1 g) (J. Org. Chem., 1983, 48(6),
850-855), and N,N-disopropylethylamine (1 ml) in 1,4-dioxane (5 ml)
were heated together at reflux for 4 hours. The volatiles were
removed under reduced press and the residue purified by reverse
phase HPLC eluting with a gradient from 5% acetonitrile in aqueous
1% ammonium acetate to 75% over 7 min. The title product was
obtained, by freeze drying, as a white solid. Y-eld: 0.047 g.
[0347] MS: APCI(+ve) 429(M+100%), APCI(-ve) 427(M-1,100%)
[0348] .sup.1H NMR: .delta.(DMSO); 9.9(bs, 1H), 8.90(m, 1H),
8.40(d, 1H), 8.30(s, 1H), 8.18(s, 1H), 7.90(d, 1H), 7.80(d, 1H),
7.75(t, 1H), 7.60(m, 1H), 5.78(bs, 1H), 5.00(bs, 1H), 3.78(s, 3H),
3.30(s, 2H, 2.90(m, 2H), 2.70-1.80(m, 6H).
EXAMPLE 22
N-(Quinolin-5-yl)-2-[8-thiazolo[5,4-d]pyrimidin-7-yl)-3,8-diazabicyclo[3.2-
.1]oct-3-yl]acetamide
[0349] 29
[0350] The title compound was prepared from the product Example 21
step (ii) (0.1 g) and 7-chlorothiazolo[5,4-d]pyrimidine (Chem.
Pharm. Bull, 1968, 16(4), 750-755) (0.06 g) by the method of
Example 21 step (iii) as a pale yellow solid. Yield 0.1 g.
[0351] MS: ES(+ve) 432(M+1,100%)
[0352] .sup.1H NMR: .delta. (CDCl.sub.3) 9.62(1H, s), 8.99-8.98(1H,
m), 8.77(1H, s), 8.50(1H, s), 8.26(1H, d), 8.16(1H, d), 7.99(1H,
d), 7.75(1H, t), 7.52-7.49(1H, m), 6.04(1H, brs), 529(1H, brs),
3.27(2H, s), 3.03(2H, d), 2.83(2H--, bs), 2.22(2H, brs), 1.70(1H,
brs), 1.45(1H, dd),
EXAMPLE 23
N-(2-Methylphenyl)-2-[(8-thiazolo[5,4-d]pyrimidin-7-yl)-3,8-diazabicyclo[3-
.2.1]oct-3-yl]acetamide
[0353] 30
[0354] The title compound was prepared from the product of Example
20 step (iv) (0.1 g) and 7-chlorothiazolo[5,4-d]pyrimidine (Chem.
Pharm. Bull, 1968, 16(4), 750-755) (0.06 g) by the method of
Example 21 step (iii) as a white solid. Yield 0.06 g.
[0355] MS: ES(+ve) 395(M+1,100%)
[0356] .sup.1HNMR .delta. (CDCl.sub.3) 8.99(1H, s), 8.75(1H, s),
8.48(1H, s), 8.08(1H, d), 727-7.21(2H, m), 7.08(1H, t), 6.00(1H,
brs), 5.29(1H, brs), 3.15(2H, s), 2.95(2H, d), 2.74(2H, brs),
2.38(3H, s), 227-2.07(1H, m)
EXAMPLE 24
N-(2-Methyl-5(methylsulphonyl)amidophenyl)-2-[8-(9-methyl-9H-purin-6-yl)-3-
,8-diazabicyclo[3.2.1]oct-3-yl]acetamide
[0357] 31
i)
2-Chloro-N-(5-bis(methylsulphonyl)amido-2-methylphenyl)acetamide
[0358] A mixture of the product from step (ii) (0.62 g) and
N,N-diisopropylethylamine (1.04 ml) in dichloromethane (40 ml) at
10.degree. C. was treated with chloroacetyl chloride (0.19 ml)
dropwise. After stirring for 4 hours the mixture was poured into
saturated sodium bicarbonate solution and the organic phase
collected and further washed with brine, collected, dried
(CaCl.sub.2) and solvent evaporated under reduced pressure to leave
a yellow gum. This was purified by silica-gel chromatography
eluting with 10% diethyl ether in dichloromethane to give the
subtitle product as a white solid. Yield 0.71 g.
[0359] MS: APCI (-ve) 353(M-1, 100%)
ii) 1,1-Dimethylethyl, 3-[(5-bis(methylsulphonyl)amido-2-methyl
phenylcarbamoyl)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
[0360] The subtitle compound was prepared from the product of step
(i) (0.266 g) and the product from Example 20 step (ii) (0.2 g) by
the method of Example 20 step (iii) as a white solid.
[0361] Yield 0.45 g.
[0362] MS: ES(+ve) 531(M+1,100%)
iii)
2-(3,8-Diazabicyclo[3.2.1]oct-3-yl-(N-[5-bis(methylsulphonyl)amido-2--
methylphenyl]acetamide, Trifluoroacetic Acid Salt
[0363] The subtitle compound was prepared from the product of step
(ii) (0.45 g) by the method of Example 20 step (iv) as a white
solid. Yield 0.42 g.
[0364] MS: ES(+ve) 431(M+1,110%)
iv)
N-[5-Bis(methylsulphonyl)amido-2-methylphenyl]-2-[8-(9-methyl-9H-purin-
-6-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]acetamide
[0365] The subtitle compound was prepared from the product of step
(iii) (0.2 g) and 6-chloro-9-methylpurine (J. Org. Chem., 1983,
48(6), 850-855) (0.1 g) by the method of Example 20 step (v) as
white solid. Yield 0.1 g.
[0366] MS: ES(+ve) 563(M+1,100%)
v)
N-(2-Methyl-5-(methylsulphonyl)amidophenyl)-2-[8-(9-methyl-9H-purin-6-y-
l)-3,8-diazabicyclo[3.2.1]oct-3-yl]acetamide
[0367] A mixture of the product from step (iv) (0.1 g) and sodium
bicarbonate (0.05 g) in wet ethanol (2 ml) was heated at reflux for
1.5 hours, cooled and filtered. Purification was by flash
silica-gel chromatography eluting with 2.5% EtOH, 1% aq. NH.sub.3,
96.5% CH.sub.2Cl.sub.2 followed by trituration with ethyl acetate
to give the title product as a white solid. Yield 0.066 g.
[0368] MS: AP(+ve) 485(M+1,100%)
[0369] .sup.1H NMR: .delta. (CDCl.sub.3): 9.19 (s, 1H), 8.40 (s,
1H), 8.14 (d, 1H), 7.74 (s, 1H), 7.20 (d, 1H), 7.12 (dd, 1H), 7.08
(s, 1H), 3.84 (s, 3H), 3.17 (s, 2H), 2.97 (s, 3H), 2.90 (d,2H),
2.75 (d, 2H), 2.37 (s, 3H), 2.15 (brm, 4H).
[0370] MP: 216-217.degree. C.
EXAMPLE 25
N-[2-Methyl-5(methylsulphonyl)amidophenyl]-2-[(8-thiazolo[5,4-d]pyrimidin--
7-yl) 3,8 diazabicyclo[3.2.1]oct-3-yl]acetamide
[0371] 32
i)
N-[5-Bis(methylsulphonyl)amido-2-methylphenyl]-2-[(8-thiazolo[5,4-d]pyr-
imidin-7-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]acetamide
[0372] The subtitle compound was pared from the product of Example
24 step (iii) (0.21 g) and 7-chloro-thiazolo[5,4-d]pyrimidine
(Chem. Pharm. Bull 1968, 16(4), 750-755) (0.069 g) by the method of
Example 20 step (v) as a white solid. Yield 0.1113 g.
[0373] MS: APCI(+ve) 566(M+1,100%)
ii)
N-[2-Methyl-5-(methylsulphonyl)amidophenyl]-2-[(8-thiazolo[5,4-d]pyrim-
idin-7-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]acetamide
[0374] The title compound was prepared from the product of step (i)
(0.113 g) by the method of Example 24 step (v) as a white solid
Yield 0.085 g.
[0375] MS: APCI(+ve) 488(M+1,100%)
[0376] .sup.1HNMR: .delta. (CDCl.sub.3) 9.18 (s, 1H), 8.76 (s, 1H),
8.48 (s, 1H), 8.17 (d, 1H), 7.31 (s, 1H), 7.20 (d, 1H), 7.13 (dd,
1H), 3.21 (s, 2H), 295 (s, 3H), 2.92(m, 2H), 2.76 (mM), 2.38 (s,
3H), 2.17 (brm, 4H).
[0377] MP: 145-187.degree. C.
EXAMPLE 26
N-[2-Methyl-5-(methylsulphonyl)amidophenyl]-2-[4-(thieno[2,3-d]pyrimidin-4-
-yl)-3,8 diazabicyclo[3.2.1]oct-3-yl]acetamide
[0378] 33
i)
N-[(5-Bis(methylsulphonyl)amido-2-methylphenyl]-2-[4-(thieno[2,3-d]pyri-
midin-4-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]acetamide
[0379] The subtitle compound was prepared from the product of
Example 24 step (iii) (0.216 g) and 4-chlorothieno[2,3-d]pyrimidine
(0.056 g) by the method of Example 20 step (v) as a white solid.
Yield 0.13 g.
[0380] MS: ESI (+ve) 565(M+1,100%)
ii)
N-[2-Methyl-5-(methylsulphonyl)amidophenyl]-2-[4-(thieno[2,3-d]pyrimid-
in-4-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]acetamide
[0381] The title compound was prepared from the product of step (i)
(0.130 g) by the method of Example 24 step (v) as a white solid.
Yield 0.025 g.
[0382] MS: APCI(+ve) 487(M+1, 100%)
[0383] .sup.1H NMR: .delta. (DMSO) 9.18(1H, s), 8.38(1H, s),
7.71-7.62(31 m), 7.17(1H, d), 6.93(1H, dd), 5.04(2H, brs), 3.12(2H,
s), 2.93(3H, s), 2.90(2H, d), 2.58(2H, d), 2.23(3H, s), 2.13(2H,
d), 1.98-1.95(2H, m)
EXAMPLE 27
Cis-2-(3,5-Dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-N-(2-me-
thyl-5-(1 piperazinylmethyl)phenyl)acetamide, Hydrochloride
Salt
[0384] 34
i) 1,1-Dimethylethyl,
4-((4-methyl-3-nitrophenyl)methylpiperazine-1-carbox- ylate
[0385] A mixture of 4-methyl-3-nitrobenzyl chloride (5.55 g),
1,1-dimethylethyl piperazine-1-carboxylate (5.6 g),
N,N-diisopropylethylamine (5 ml) in N,N-dimethylformamide (25 ml)
were heated at 110.degree. C. for 3 h. After cooling to ambient
temperature the mixture was partitioned between dichloromethane and
water. The organic phase collected, dried (MgSO.sub.4) and solvent
evaporated under reduced pressure to leave the subtitle compound as
a pale yellow oil. Yield: 9.6 g
[0386] MS: APCI(+ve) 336(M+1)
ii) 1,1-Dimethylethyl,
4-((3-amino-4-methylphenyl)methyl)piperazine-1-carb- oxylate
[0387] The product form step (i) (9.6 g), 10% palladium on charcoal
(100 mg) in ethanol (100 ml) was stirred under an atmosphere of
hydrogen gas for 24 h. The catalyst was filtered through celite and
the mother liquor collected and solvent evaporated under reduced
pressure to give the subtitle compound as a pale yellow oil. Yield:
9 g
[0388] MS: APCI(+ve) 322(M+1)
iii)
cis-2-(3,5-Dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl-N-(-
2-methyl-5-((4-(1,1-dimethylethyloxycarbonyl)piperazin-1-yl)methyl)phenyla-
cetamide
[0389] The product from Example 9 step (ii) (0.21 g), the product
from step (ii) (0.15 g),
benzotriazol-1-yl-oxy-tripyrrolidinophosphonium hexfluorophosphate
(PyBrop) (0.24 g), N,N-diisopropylethylamine (0.36 ml) in dry
N,N-dimethylformamide were stirred together under nitrogen for 20
h. The mixture was poured into water and the resulting precipitate
filtered as an off white solid. Purification was by silica gel
chromatography eluting with ethyl acetate to give the subtitle
compound as a white solid Yield: 0.21 g
[0390] MS: APCI (+ve) 594(M+1)
iv)
Cis-2-(3,5-Dimethyl-4-(thieno[2,3-d]pyrimidinyl)piperazin-1-yl)-N(2-me-
thyl-5-(1-piperazinylmethyl)phenyl)acetamide, Hydrochloride
Salt
[0391] The product from step (iii) (0.17 mg) was dissolved in 4M
hydrogen chloride in 1,4 dioxane (2 ml). After 48 h the solvents
were evaporated under reduced pressure to leave the title compound
as a white solid. Yield: 0.16 g
[0392] MS: APCI (+ve) 494(M+1)
[0393] .sup.1H NMR: .delta. (DMSO) 8.50(s, 1H), 7.78(s, 1H),
7.65(d, 1H), 7.58(d, 1H), 7.39(d, 1H), 7.31(d, 1H), 5.25(m, 1H),
5.05(bs, 2H), 4.23(s, 2H), 3.77(bs, 2H, 3.43(s, 4H), 3.18(m, 6H),
3.04(m, 2H), 2.71(s, 1H), 2.30(s, 30, 1.47(d, 6H)
EXAMPLE 28
N-(2-Methylphenyl)-2-[(8-(thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.-
2.1]oct-3-yl]acetamide
[0394] 35
[0395] The title compound was prepared from the product of Example
20 step (iv) (0.45 g) and 4-chloro-thieno[2,3-d]pyrimidine by the
method of Example 1 step (i). Yield: 0.22 g.
[0396] MS: APCI(+ve) 394(M+1)
[0397] .sup.1H NMR: .delta. (DMSO) 9.17 (1H, brs), 8.39 (1H, s),
7.73-7.62 (3H, m), 7.25-7.15 (2H, m), 7.07 (1H, m), 5.05 (2H, brs),
3.12 (2H, s), 2.92 (2H, d), 2.58 (2H, d), 2.28 (3H, s), 2.15 (2H,
m), 1.97 (2H, m).
EXAMPLE 29
N-[5-(Methanesulphonylamido-2-methylphenyl)-2-[8-(thieno[2,3-d]pyrimidin-4-
-yl)-8-azabicyclo[3.2.1]oct-3-yl]acetamide
[0398] 36
i) Ethyl,
2-(8-(thieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct-3-yl)e-
thanoate
[0399] Ethyl, 2-(8-azabicyclo[3.2.1]oct-3-yl)ethanoate (0.64 g)
(Arch. Pharm., 1976, 309(6), 447. Arch. Pharm., 1975, 308(5), 365),
4-chlorothieno[2,3-d]4-pyrimidine (0.55 g),
N,N-diisopropylethylamine (1.7 ml) in 1,4-dioxane (10 ml) were
heated at 105.degree. C. for 4 h. The precipitate was filtered and
the mother liquor collected, the solvent evaporated under reduced
pressure to leave a brown oil. Purification was by silica gel
chromatography eluting with ethyl acetate/iso-hexane (3:7) to give
the subtitle compound as a colourless oil. Yield: 0.35 g.
[0400] MS: APCI(+ve) 332(M+1)
ii)
2-(8(Thieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct-3-yl)ethanoic
Acid
[0401] The product from step (i) (0.14 g) in ethanol (0.3 ml) was
treated with 1N sodium hydroxide (0.6 ml) at ambient temperature
for 48 h. The mixture was acidified to pH4 with 2N hydrochloric
acid and the solvents evaporated under reduced pressure. The
residue was treated with ethanol (5 ml) and inorganic salts
filtered. The mother liquor collected and solvent evaporated under
reduced pressure to leave a gummy residue. Purification was by
trituration with diethyl ether. Yield: 0.097 g
[0402] MS: APCI(+ve) 304(M+1)
iii)
N-[5-bis((Methanesulphonyl)amido-2-methylphenyl)-2-[S-(thieno[2,3-d]p-
yrimidin-azabicyclo[3.2.1]oct-3-yl]acetamide
[0403] The product from step (ii) (0.097 g), the product from
Example 11 step (ii) (0.089 g),
benzotriazol-1-yl-oxy-tripyrrolidinophosphonium hexfluorophosphate
(PyBrop) (0.16 g), 4N,N-dimethylaminopyridine (0.04 g),
N,N-diisopropylethylamine (0.28 ml) in dichloromethane (10 ml) were
stirred at ambient temperature for 48. The mixture was partitioned
between water and dichloromethane. The organic phase collected,
dried (MgSO.sub.4 and solvent evaporated under reduced pressure.
Purification was by reverse phase HPLC eluting with 1% aq. ammonium
acetate/acetonitrile (90% to 50%) to give the subtitle compound as
a white solid Yield: 0.1 g
[0404] MS: APCI(+ve) 564(M+1)
iv)
N-[5-(Methanesulphonylamido-2-methylphenyl)-2-[8-(thieno[2,3-d]pyrimid-
in-4-yl)-8-azabicyclo[3.2.1]oct-3-yl]acetamide
[0405] The product from step (iii) (0.1 g), potassium carbonate
(0.14 g), water (5 ml) and 1,4-dioxane (5 ml) were heated at
110.degree. C. for 1 h. The mire was treated with acetic acid (2
ml) and solvents evaporated under reduced pressure. Purification
was by silica gel chromatography eluting with ethyl acetate to give
the title compound as a white solid.
[0406] Yield: 0.011 g
[0407] MS: APCI (+ve) 486(M+1)
[0408] .sup.1H NMR: .delta. (DMSO) 9.33(bs, 1H), 9.16(bs, 1H),
8.38(2xs, 1H), 7.6(m, 3H), 7.30(m, 1H), 7.15(t, 1H), 6.90(m, 1H),
5.0(bm, 2H),2.90 (s, 3H), 2.30-1.89(bm, 4H), 2.10(s, 3H),
1.5-0.9(bm, 2H)
EXAMPLE 30
N-(2-Methyl-5-(1-piperazinylmethyl)phenyl)-2-[(8-(thieno[2,3-d]pyrimidin-4-
-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]acetamide
[0409] 37
i) Methyl,
2-(8-(1,1-dimethylethyloxycarbonyl)-3,8-diazabicyclo[3.2.1]oct--
3-yl)acetate
[0410] A mixture of 1,1-dimethylethyl,
3,8-diazabicyclo[3.2.1]oct-8-carbox- ylate (0.35 g), sodium
bicarbonate (84 mg), potassium iodide (20 mg) and methyl
bromoacetate (355 mg) in ethanol (5 ml) were heated at 70.degree.
C. for 6 h. The reaction mixture was partitioned between eth
acetate and water. The organic phase collected, dried (MgSO.sub.4)
and the solvent evaporated under reduced pressure to leave the
subtitle compound as a pale yellow solid.
[0411] Yield: 380 mg
[0412] .sup.1H NMR: .delta. (DMSO) 4.01 (bs, 2H, 3.58 (s, 2H), 3.29
(s, 3H), 2.62-2.49 (m, 4H), 1.82-1.64 (m, 4H), 1.40 (s, 9H)
ii) Methyl, 2-(3,8 diazabicyclo[3.2.1]oct-3-ylacetate,
Trifluoroacetic Acid Salt
[0413] The subtitle compound was prepared from the product of step
(i) (380 mg) by the method of Example 1 step (ii). The product was
used without further purification directly in next step.
iii) Methyl,
2-(8-(thieno[2,3-d]pyrimidin-4-yl)-(3,8-diazabicyclo[3.2.1]oc-
t-3-yl)acetate
[0414] The subtitle compound was prepared from the product of step
(ii) (400 mg) and 4-chloro-thieno[2,3]pyrimidine (288 mg),
N,N-diisopropylethylamine (232 ul) in 1,4-dioxane at 100.degree. C.
for 48 h. Solvent was evaporated under reduced pressure.
Purification was by silica gel chromatography eluting with 2%
ethanol in dichloromethane to give the subtitle compound as a beige
solid. Yield: 170 mg.
[0415] MS: APCI (+ve) 319(M+1, 100%)
iv)
2-(8-(Thieno[2,3-d]pyrimidin-4-yl)-(3,8-diazabicyclo[3.2.1]oct-3-yl)ac-
etic Acid
[0416] The product from step (iii) (170 mg) was dissolved in
ethanol (1 ml) and treated with 1N sodium hydroxide solution (0.8
ml) at room ambient temperature. After 3 h the mixture was
acidified with 2M hydrochloric acid to pH4. The solvents were then
evaporated under reduced pressure and the residue treated with
ethanol and filtered to remove inorganic salts. The mother liquor
was collected and evaporated under reduced pressure to leave the
subtitle compound as a white solid. Yield: 160 mg.
[0417] MS: APCI(+ve) 305(M+1)
v)
N-(5-(4-(1,1-Dimethylethyloxycarbonyl)piperazin-1-ylmethyl).sub.2-methy-
l)phenyl)-2-[(8-(thieno[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-3-
-yl]acetamide
[0418] The product of step (iv) (83 mg), the product of Example 27
step (ii) (92 mg), benzotriazol-1-yl-oxy-tripyrrolidinophosphonium
hexafluorophosphate (PyBrop) (153 mg) and N,N-diisopropylethylamine
(95 ul) were sired in N,N-dimethylformamide (5 ml) at ambient
temperature for 12. The solvents were evaporated under reduced
pressure and purification was by silica gel chromatography eluting
with iso-hexane/acetone (7:3) containing 1% triethylamine to give
the subtitle compound as a white solid. Yield: 40 mg.
[0419] .sup.1H NMR .delta. (DMSO) 9.15(s, 1H), 8.38(s, 1H),
7.67-7.66(m, 2H), 7.17(d, 1H), 7.00(d, 1H), 5.04(bs, 2H), 3.41(s,
2H), 3.29(s, 4H), 3.11(s, 2H), 2.90(d, 2H), 2.29(t, 4H), 2.24(s,
3H), 2.14(d, 2H), 2.00-1.93(m, 2H), 1.38(s, 9H)
vi)
N-(2-Methyl-(1-piperazinylmethyl)phenyl)-2-[(8-(thieno[2,3-d]pyrimidin-
-4-yl)-3,8 diazabicyclo[3.2.1]oct-3-yl]acetamide
[0420] The title compound was prepared from the product of step (v)
(35 mg) by the method of Example 8 step (iv) as a white solid
Yield: 35 mg
[0421] MS: APCI(+ve) 492(M+1)
[0422] .sup.1H NMR .delta.(DMSO) 9.66(bs, 1H), 8.53(s, 1H), 7.75(s,
2H), 7.63(bs, 1H), 7.42(d, 1H), 7.33(d, 1H), 5.21(bs, 2H), 4.33(bs,
2H), 3.79-3.13(bm, 10H), 2.40-2.26(bm, 4H), 2.23(s, 3H),
2.20-2.10(bm, 4H).
EXAMPLE 31
Cis-N-(5-(2-Aminoethoxy)-2-methyl-phenyl)-2-(3,5-dimethyl-4(thieno[2,3-d]p-
yrimidin yl)piperazin-1-yl)acetamide, Hydrochloride Salt
[0423] 38
i) 1,1-Dimethylethyl,
2-(4-methyl-3-nitro-phenoxy)ethylamino-1-carboxylate
[0424] The subtitle compound was prepared from
4-methyl-3-nitrophenol(2 g) and 1,1-dimethylethyl
2-hydroxyethylamino-1-carboxylate (2.5 g) by the method of Example
50 step (i) as a beige solid. Yield: 3 g
[0425] .sup.1H NMR .delta. (CDCl.sub.3) 7.50(s, 1H), 7.22(d, 1H),
7.05(dd, 1H), 4.96(bs, 1H), 4.07(t, 2H), 3.56(q, 2H), 2.52(s, 3H),
1.46(s, 9H)
ii) 1,1-Dimethylethyl,
2-(3-aminomethyl-Phenoxy)ethylamino-1-carboxylate
[0426] The subtitle compound was prepared from the product of step
(i) (1 g) by the method of Example 50 step (ii) as an off white
solid. Yield: 0.9 g
[0427] MS: APCI (+ve) 267(M+1)
[0428] iii)
cis-N--(S-(2-(1,1-Dimethylethyloxycarbonylaminoethoxy))-2-meth-
yl-phenyl)-Z-3,5
dimethyl-4-(thieno[2,3-d]pyrimidinyl-4-yl)piperazin-1-yl)-
acetamide
[0429] The product of Example 9 step (ii) (0.54 g), the product
from step (ii) (0.35 g),
benzotriazol-1-yl-oxy-tripyrrolidinophosphonium hexafluorophosphate
PyBrop) (0.59 g), N,N-diisopropylethylamine (0.8 ml) in dry
N,N-dimethylformamide (15 ml) were stirred together under nitrogen
for 24 h. The mixture was poured onto water (50 ml) and the
resulting precipitate filtered as a pale yellow solid. Purification
was by silica gel chromatography eluting with diethyl ether/ethyl
acetate (9:1) as eluant to give the subtitle compound as a white
solid. Yield: 0.51 g MS: APCI(+ve) 555(M+1)
iv)
Cis-N-(5-(2-Aminoethoxy)-2-methyl-phenyl)-2-(3,5-dimethyl-4-(thieno[2,-
3-d]pyrimidin-4-yl)piperazin-1-yl)acetamide, Hydrochloride Salt
[0430] The title compound was prepared from the product of step
(iii) (0.42 g) according to the method of Example 27 step (iv) as a
white sold. Yield: 0.36 g
[0431] MS: APCI(+ve) 455 (M+1)
[0432] .sup.1HNMR .delta.(DMSO) 9.57(bs, 1H), 8.50(s, 1H), 8.15(bs,
2H), 7.65(d, 1H), 7.57(d, 1H), 7.37(s, 1H), 7.15(d, 1H), 6.75(dd,
1H), 5.05(bs, 21, 4.17(t, 2H), 3.77(bs, 2H), 3.27(d, 2H), 3.19(d,
2H), 3.00(bs, 2H), 2.22(s, 3H), 1.48(d, 61)
EXAMPLE 32
Cis-N-(5-(2-(N-Methylamino)ethoxy)-2-methyl-phenyl)-2-(3,5-dimethyl-4-(thi-
eno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)acetamide, Hydrochloride
Salt
[0433] 39
i) 1,1-Dimethylethyl
2-(4-methyl-3-nitro-phenoxy)ethyl(N-methylamino)-1-ca-
rboxylate
[0434] The subtitle compound was prepared from
4-methyl-3-nitrophenol (0.5 g) and 1,1-dimethylethyl
2-hydroxyethyl-(N-methylamino)-1-carboxylate (0.69 g) by the method
of Example 50 step (i) as a beige solid. Yield: 0.67 g
[0435] .sup.1H NMR .delta. (CDCl.sub.3) 7.5(s, 1H), 7.24(d, 1H),
7.61(dd, 1H), 4.12(bs, 2H), 3.64(t, 2H), 2.98(s, 3H), 2.53(s, 3H),
1.46(s, 9H)
ii) 1,1-Dimethylethyl,
2-(3-amino-4-methyl-phenoxy)ethyl(N-methylamino)-1--
carboxylate
[0436] The subtitle compound was prepared from the product of step
(i) (1 g) by the method of Example 50 step (ii) as an off white
solid. Yield: 0.95 g MS: APCI (+ve) 281(M+1)
iii)
N-(5-(2-(1,1-Dimethylethoxycarbonyl(N-methylamino)ethoxy))-2-methyl-p-
henyl)-2-(3,5-dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)aceta-
mide
[0437] The subtitle compound was prepared from the product of
Example 9 step (ii) (0.26 g), the product of step (ii) (0.175 g) by
the method of Example 31 step (iii). Purification was by silica gel
chromatography eluting with diethyl ether/ethyl acetate (9:1) as
eluant to give the subtitle compound as a white solid. Yield: 0.25
g
[0438] MS: APCI(+ve) 569(M+1)
[0439] iv)
cis-N-5-(2N-Methylamino)ethoxy)-2-methyl-phenyl)-2-(3,5-dimethy-
l-4-(thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)acetamide,
hydrochloride salt
[0440] The title compound was prepared from the product of step
(iii) (0.189 g) by the method of Example 27 step (iv) as a white
solid. Yield: 0.077 g
[0441] MS: APCI(+ve) 469(M+1)
[0442] .sup.1HNMR .delta. (DMSO) 9.50(bs, 1H), 9.00(bs, 1H),
8.49(s, 1H), 7.64(d, 1H), 7.57(d, 1H), 7.39(s, 1H), 7.17(d, 1H),
6.76(d, 1H), 5.05(bs, 2H), 4.24(s, 2H), 3.22-3.30(m, 4H), 2.95(bs,
2H), 2.62(s, 2H), 2.22(s, 3H), 1.48(d,
EXAMPLE 33
Cis-N-(5-(2-(N-Methylamino)ethoxy)-2-methyl-phenyl)-2-(4-benzenesulphonyl)-
-3,5-dimethyl)piperazin-1-yl)acetamide
[0443] 40
i) cis-1,1-Dimethylethyl,
(4-benzenesulphonyl-3,5-dimethyl)piperazine-1-ca- rboxylate
[0444] A solution of cis-1,1-dimethyl,
3,5-dimethylpiperazine-1-carboxylat- e (5 g) in pyridine (60 ml)
was treated with benzene sulphonyl chloride (3 ml). After 48 h the
solvent was evaporated under reduced pressure and purification of
the residue was by silica gel chromatography eluting with ethyl
acetate containing 1% triethylamine to give the subtitle compound
as a yellow solid. Yield: 5 g
[0445] MS: APCI(+ve) 255(M-99)
ii)cis-1-Benzenesulphonyl-3,5-dimethylpiperazine, Trifluoroacetic
Acid Salt
[0446] The subtitle compound was prepared from the product of step
(i) (5 g) by the method Example 1 step (ii). Purification was by
recrystallisation from ethanol. Yield: 2 g
[0447] MS: APCI(+ve) 255(M+1)
iii)
Cis-2-chloro-N-[5-(2-(1,1-dimethylethoxycarbonyl)-N-methylamino)ethox-
y)-2-methyl-phenyl]acetamide
[0448] A solution of the product from Example 32 step (ii) (0.65
g), N,N-diisopropylethylamine (1 ml) in dichloromethane (30 ml) at
0.degree. C. under nitrogen was treated with chloroacetyl chloride
(202 ul). After 2 h the mixture was partitioned with water and the
product extracted into dichloromethane. The organic phase
collected, dried (MgSO.sub.4) and solvent removed under reduced
pressure to give the subtitle compound as a beige foam. Yield: 0.9
g
[0449] MS: APCI (-ve) 355(M-1)
iv)
Cis-N-(5-(2-((1,1-dimethylethoxycarbonyl)-N-methylamino)ethoxy)-2-meth-
yl-phenyl)-2-(4-benzenesulphonyl)-3,5-dimethyl)piperazin-1-yl)acetamide
[0450] The product of step (ii) (100 mg), sodium bicarbonate (99
mg), potassium iodide (5 mg) in ethanol (6 ml) was treated with the
product of step (iii) at 70.degree. C. for 12 h. The mixture was
partitioned between ethyl acetate and water. The organic phase
collected, dried (MgSO.sub.4) and solvent evaporated under reduced
pressure. Purification was by silica gel chromatography eluting
with iso-hexane/acetone (7:3) containing 1% triethylamine to give
the subtitle compound as a white solid. Yield: 126 mg
[0451] MS: APCI(+ve) 575(M+1), APCI(-ve) 573(M-1)
v)
Cis-N-(5-(2-(N-Methylamino)ethoxy)-2-methyl-phenyl)-2-(4-benzenesulphon-
yl)-3,5-dimethyl)piperazin-1-yl)acetamide, Hydrochloride Salt
[0452] The title compound was prepared from the product of step
(iv) (120 mg) by the method of Example 27 step (ii) as a white
solid. Yield: 107 mg
[0453] MS: APCI(+ve) 475(M+1), APCI (-ve) 473(M-1)
[0454] .sup.1H NMR .delta. (DMSO) 9.01(bs, 2H), 7.85(d, 2H),
7.69(t, 1H), 7.62(t, 2H), 7.30(bs, 1H), 7.15(d, 1H), 6.74(dd, 1H),
4.18(t, 4H), 4.01(bs, 2H), 3.56(s, 2H), 3.31-3.25(m, 2H),
2.61-2.58(m, 3H), 2.50(m, 2H), 2.15(s, 3H), 1.44(d, 6H)
EXAMPLE 34
Cis-N-[5-(2-Aminoethoxy)-2-methyl-phenyl)-2-(4-benzenesulphonyl-3,5-dimeth-
yl)piperazin-1-yl]acetamide, Hydrochloride Salt
[0455] 41
i)
Cis-2-chloro-N-[5-(2-(1,1-dimethylethyloxycarbonyl)amino)ethoxy-2-methy-
l-phenyl]acetamide
[0456] The subtitle compound is prepared from the product of
Example 31 step (ii) (650 mg) and chloroacetyl chloride (213 ul) by
the method of Example 33 step (iii) as a beige foam.
[0457] Yield: 900 mg
[0458] MS: APCI(-ve) 341(M-1)
ii)
Cis-N-[5-(2-(1,1-Dimethylethoxycarbonyl)amino)ethoxy-2-methyl-phenyl)--
2-(4-benzenesulphonyl-3,5-dimethyl)piperazin-1-yl]acetamide
[0459] The subtitle compound was prepared from the product of step
(i) (148 mg) and the product of Example 33 step (ii) by the method
of Example 33 step (iv) as a pale yellow solid Yield: 150 mg.
[0460] MS: APCI(+ve) 561(M+1), APCI (-ve) 559(M-1)
iii)
Cis-N-[5-(2-(Aminoethoxy)-2-methyl-phenyl)-2-(4-benzenesulphonyl-3,5--
dimethyl)piperazin-1-yl]acetamide, Hydrochloride Salt
[0461] The title compound was prepared from the product of step
(ii) (150 mg) by the method Example 27 step (iv) as a white solid.
Yield: 150 mg
[0462] MS: APCI (+ve) 461(M+1), APCI (-ve) 459(M-1)
[0463] .sup.1H NMR .delta. (DMSO) 8.13(bs, 2H), 7.85(d, 2H),
7.70-7.59(m, 3H), 7.32(bs, 1H), 7.14(d, 1H), 6.73(dd, 1H), 4.16(bs,
2H), 4.10(t, 2H), 3.56(s, 2H), 3.19(d, 2H), 3.10-3.03(m, 2H),
2.50(m, 2H), 2.15(s, 3H), 1.43(d, 6H)
EXAMPLE 35
N-(2-Oxo-2,3-dihydro-1H-indol-4-yl)-2-(8-thieno[2,3-d]pyrimidin-4-yl-3,8-d-
iazabicyclo[3.2.1]oct-3-yl)acetamide
[0464] 42
i) 2-Chloro-N-(2-oxo-2,3-dihydro-1H-indol-4-yl)acetamide
[0465] The subtitle compound was prepared from 4-amino-oxindole
(0.19 g) (J. Org Chem., 1983, 48(15), 2468-72) and chloroacetyl
chloride (0.1 ml) by the method of Example 15 step (i).
[0466] Yield: 0.25 g
[0467] MS: ES(-ve) 223(M-1)
ii)
3-[(2-Oxo-2,3-dihydro-1H-indol-4ylcarbamoyl)-methyl]-3,8-diazabicyclo[-
3.2.1]octan-8-carboxylic acid, 1,1-dimethylethyl Ester
[0468] The subtitle compound was prepared from the product of step
(i) (0.24 g) and 1,1 dimethyl
3,8-diaza-bicyclo[3.2.1]octane-8-carboxylate (0.26 g) by the method
of Example 19 step (i)
[0469] Yield: 0.8 g
[0470] .sup.1H NMR (DMSO) 10.45(1H, s), 9.26(1H, s), 7.39(1H, d),
7.15(1H, t), 6.62(1H, d), 4.06 (2H, brs), 3.45(2H, s), 3.10(2H, s),
2.72(2H, d), 2.38(2H, d), 1.95(2H, d), 1.79(2H, m), 1.41 (9H,
s).
iii)
2-(3,8-Diazabicyclo[3.2.1]oct-3-yl)-N-(2-oxo-2,3-dihydro-1H-indol-4-y-
l)acetamide Hydrochloride Salt
[0471] The product of step (ii) (0.8 g) was dissolved in 2M
hydrogen chloride in 1,4-dioxime (10 ml), 1,4-dioxane (10 ml),
methanol (10 ml) and the reaction mixture was s at ambient
temperature for 2 hours. The solvents evaporated under reduced
pressure to dryness. Yield: 0.8 g
[0472] MS: ES(+ve) 301(M+1)
iv)
N-(2-Oxo-2,3-dihydro-1H-indol-4-yl)-2-(8-thieno[2,3-d]pyrimidin-4-yl-3-
,8-diazabicyclo[3.2.1]oct-3-yl)acetamide
[0473] The title compound was prepared from the product of step
(iii) (0.8 g) by the method of Example 1 step (i). Yield: 0.1 g
[0474] MS ES(+ve) 435(M+1)
[0475] .sup.1H NMR: .delta. (DMSO) 10.43 (1H, s), 9.27 (1H, s),
8.39 (1H, s), 7.66 (1H, d), 7.62 (1H, d), 7,40 (1H, d), 7.15 (1H,
t), 6.62 (1H, d), 5.04 (2H, brs), 3.47 (2H, s), 3.12 (2H, s), 2.87
(2H, d), 2.57 (2H, d), 2.15 (2H, m), 1.97 (2H, m).
[0476] M.P. 265.degree. C. decomp.
EXAMPLE 36
N-(3-Fluoro-2-methyl-phenyl)-2-((8-quinazolin-4-yl)-3,8-diazabicyclo[3.2.1-
]oct-3-yl)acetamide
[0477] 43
i) 2-Chloro-N-(3-fluoro-2-methyl-phenyl)acetamide
[0478] The subtitle compound was prepared from
3-fluoro-2-methylaniline (0.232 g) and chloroacetyl chloride (0.164
ml) by the method of Example 33 step (iii) as a beige solid
[0479] Yield: 0.3 g
[0480] MS: APCI(-ve) 200(M-1)
ii)
N-(3-Fluoro-2-methyl-phenyl)-2-(1,1-dimethylethyloxycarbonyl)-3,8-diaz-
abicyclo[3.2.1]oct-3-yl]acetamide
[0481] The subtitle compound was prepared from the product of step
(i) (179 mg) and
1,1-dimethyl-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylate (0.2 g)
by the method of Example 33 step (iv) as a white solid. Yield: 305
mg
[0482] MS: APCI (+ve) 378(v+1)
iii)
N-(3-Fluoro-2-methyl-phenyl)-2-(3,8-diazabicyclo[3.2.1]oct-3-yl)aceta-
mide Hydrochloride Salt
[0483] The subtitle compound was prepared from the product of step
(ii) (303 mg) by the method of Example 27 step (iv) as a white
solid Yield: 305 mg
[0484] MS: APCI(+ve) 278(M+I), APCI (-ve) 276(M-1)
iv)
N-(3-Fluoro-2-methyl-phenyl)-2-((8-quinazolin-4-yl)-3,8-diazabicyclo[3-
.2.1]oct-3-yl)acetamide
[0485] The title compound was preapred from the product of step
(iii) (223 mg) and 4 chloroquinazoline (133 mg) by the method of
Example 2 step (i) as a white solid
[0486] Yield: 120 mg
[0487] MS: APCI(+ve) 406(+1)
[0488] .sup.1H NMR .delta. (DMSO) 9.34(s, 1H), 8.57(s, 1H), 8.09(d,
1H), 7.84-7.77(m, 2H), 7.60-7.53(m, 2H), 7.22(q, 1H), 6.99(t, 1H),
4.87(bs, 2H), 324(s, 2H), 2.97(dd, 2H), 2.77(dd, 2H), 2.17(s, 3H),
2.12-2.04(m, 2H), 1.91-1.85(m, 2H)
EXAMPLE 37
N-(2-Methylphenyl)-2-[8-(benzenesulphonyl)-3,8
diazabicyclo[3.2.1]oct-3-yl- ]acetamide
[0489] 44
[0490] The trifluoroacetate salt of Example 20 step (iv) was
converted to the free base by use of aqueous 2N NaOH solution
followed by extraction with ethyl acetate. The extracts were dried
(MgSO.sub.4), filtered and evaporated to dryness, leaving an oil
which crystallised on standing.
[0491] MS: ES(+ve) 260(M+1,100%)
[0492] The amine free base (0.075 g) was stirred in acetone (15 ml)
and a solution of K.sub.2CO.sub.3 (0.08 g) in water (0.5 ml) was
added, followed by benzenesulphonyl chloride (0.047 g) dissolved in
acetone (5.0 ml). The solution was stirred for 1 hour, quenched
with water and the white solid was collected by filtration, washed
with water and dried in vacuo, to give the title compound. Yield
0.037 g.
[0493] MS: APCI(+ve) 487(M+1, 100%)
[0494] .sup.1H NMR: .delta. (CDCl.sub.3) 1.55 (s, H.sub.2O), 1.70
(2H, m), 1.85(2H, m), 2.26(3H, s), 2.67(2H, m), 2.85(2H, d of d),
3.18(2H, s), 7.05(2H--, m), 7.2(2H, m), 7.52(2H, m), 7.6(1H, m),
7.9(2H, d)
[0495] MP: 169-170.degree. C.
EXAMPLE 38
N-(3-Fluoro-2-methylphenyl)-2-[8-(benzenesulphonyl)-3,8-diazabicyclo[3.2.1-
]oct-3-yl]acetamide
[0496] 45
i) Methyl, (3,8-Diazabicyclo[3.2.1]oct-3-yl)acetate, Hydrochloride
Salt
[0497] A mixture of the product from Example 30 step (i), 2M HCl in
1,4-dioxane (10 ml) and methanol (10 ml) was stirred at ambient
temperature for 2 hours and evaporated to dryness. Yield 0.54 g.
Used directly in the next step.
ii) Methyl
(8-benzenesulphonyl-3,8-diazabicyclo[3.2.1]oct-3-yl)acetate
[0498] A mixture of the product of step (i) (0.53 g), potassium
carbonate (0.66 g) and benzenesulphonyl chloride (0.32 ml) in
acetone (10 ml) and 1,4-dioxane (10 ml) was stirred at ambient
temperature for 4 hours. The mixture was partitioned between ethyl
acetate and water. The organic phase was washed with water,
saturated sodium bicarbonate and brine, dried (MgSO.sub.4) and
evaporated. The product was purified by silica gel chromatography
eluting with 0.5% ethanol in dichloromethane. Yield 0.29 g.
[0499] .sup.1H NMR: .delta.(DMSO) 7.86 (2H, d), 7.69 (1H, m), 7.59
(2H, m), 4.13 (2H, brs), 3.59 (3H, s), 3.29 (2H, s), 2.67 (2H, dd),
2.57 (2H, d), 1.59 (2H, m), 1.13 (2H, m).
iii) (8-Benzenesulphonyl-3,8 diazabicyclo[3.2.1]oct-3-yl)acetic
Acid
[0500] A solution of the product of step (ii) (029 g) in ethanol (5
ml) was treated with 1 ml of 1N sodium hydroxide solution. After 1
hour at ambient temperature the reaction mixture was acidified with
2N hydrochloric acid to pH4 and evaporated to dryness to give a
white solid. This was dried at 40.degree. C. in vacuo over
phosphorous pentoxide for 2 hours and used directly in the next
step.
iv)
N-(3-Fluoro-2-methylphenyl)-2-[(benzenesulphonyl)-3,8-diazabicyclo[3.2-
.1]oct-3-yl]acetamide
[0501] A mixture of the product of step (iii) (0.45 mmol),
2-fluoro-2-methylaniline (60 .mu.l), PyBroP (0.25 g),
N,N-dimethylaminopyridine (54 mg) and N,N-diisopropylethylamine
(0.23 ml) in N,N-dimethylformamide (5 ml) was stirred at ambient
temperature for 16 hours. The reaction mixture was partitioned
between ethyl acetate and water. The organic phase was washed with
water and brine, dried (MgSO.sub.4) and evaporated. The residue was
purified by is flash chromatography eluting with 1% ethanol in
dichloromethane followed by further chromatography with 20% ethyl
acetate/iso-hexane to give the title compound as a white solid
Yield: 30 mg.
[0502] MS: AP (+ve) 418(+1)
[0503] .sup.1H NMR: .delta. (DMSO) 9.20 (1H, s), 7.88 (2H, d), 7.70
(1H, m), 7.60 (2H, m), 7.49 (1H, d), 7.20 (1H, q), 6.97 (1H, t),
4.17 (2H, brs), 3.17 (2 h, s), 2.81 (2H, dd), 2.50(2H, d), 2.09(3H,
s), 1.78 (2H, m), 1.20(2H, m).
[0504] M.P. 168-9.degree. C.
EXAMPLE 39
Cis-N-(3-Fluoro-2-methyl-phenyl)-2-(4-benzenesulphonyl)-3,5-dimethyl)piper-
azin-1-yl)acetamide
[0505] 46
i)
Cis-N-(3-Fluoro-2-methyl))phenyl)-2-(4-benzenesulphonyl)-3,5-dimethyl)p-
iperazin-1-yl)acetamide
[0506] The title compound was prepared from the product of Example
33 step (i) (152 mg) and the product of Example 36 step (i) (132
mg) by the method of Example 33 step (iv) as a white solid
Purification was by silica gel chromatography eluting with
iso-hexane/acetone (7:3). Yield: 58 mg.
[0507] MS: APCI(+ve) 420(M+1)
[0508] .sup.1H NMR .delta. (DMSO) 9.23(s, 1H), 7.83(d, 2H),
7.69-7.58(m, 3H), 7.34(d, 1H), 7.20(q, 1H), 6.99(t, 1H),
4.06-3.99(m, 2H), 3.03(s, 2H), 2.64(d, 2H), 2.08(s, 3H), 1.90(dd,
2H), 1.42(d,
EXAMPLE 40
N-(2-Methylphenyl)-2-[8-(3-cyanobenzenesulphonyl)-3,8-diazabicyclo[3.2.1]o-
ct-3-yl]acetamide
[0509] 47
[0510] The title compound was prepared from the product of Example
20 step (iv) and 3-cyanobenzenesulphonyl chloride by the method of
Example 37 as a white solid. Yield 0.101 g.
[0511] MS: APCI(+ve) 425(M+1, 100%)
[0512] .sup.1H NMR: .delta. (CDCl.sub.3) 1.76(2 m) 1.92(2H, m),
227(3H, s), 2.64(2H, d), 2.85(2 H, m), 3.20(2H, s), 4.26(2H, s),
7.06(1H, m), 7.20(2H, m), 7.68(1H, m), 7.87(1H, m), 8.02(1H, d),
8.13(1H, m), 8.18(1H, s), 8.68(1H, s)
[0513] MP: 166-8.degree. C.
EXAMPLE 41
2-[8-(3-Methoxybenzenesulphonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-(2-met-
hylphenyl)acetamide
[0514] 48
[0515] The tilde compound was prepared from the product of Example
20 step (iv) and 3-methoxybenzenesulphonyl chloride by the method
of Example 37 as a white solid
[0516] Yield 0.095 g.
[0517] MS: APCI(+ve) 430(M+1, 100%)
[0518] .sup.1H NMR: .delta. (CDCl.sub.3) 1.75(21H m), 1.82(2H, m),
2.26(3H, s), 2.65(2H, d), 2.82(2H, d of d), 3.18(2H, s), 3.86(3H,
s), 4.25(2H, br s), 7.02-7.25(4H, m), 7.40-7.50(3H, m), 8.02(1H,
d), 8.75(1H, br s)
[0519] MP: 163-5.degree. C.
EXAMPLE 42
2-[8(Benzo[1,2,5]oxadiazole-4-sulphonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl-N-
-(2-methylphenylacetamide
[0520] 49
[0521] The title compound was prepared from the product of Example
20 step (iv) by the method of Example 37 as a white solid. Yield:
0.088 g.
[0522] MS: APCI(+ve) 442(M+1, 100%)
[0523] .sup.1H NMR: .delta.(CDCl.sub.3) 1.90-2.02(4H, m), 2.28(3H
s), 2.65(2H, m), 2.90(2H, m), 3.16(2H, s), 4.55(2H, s), 7.06(1H,
m), 7.19(2H, m), 7.54(1H, m), 8.08(3H, d), 8.75(1H, br s)
[0524] MP: 167-8.degree. C.
EXAMPLE 43
2-[8-(Benzo[1,2,5]thiadiazole-4-sulphonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl-
]-N-(2-methylphenyl)acetamide
[0525] 50
[0526] The title compound was prepared from the product of Example
20 step (iv) by the method of Example 37 as a white solid. Yield
0.108 g.
[0527] MS: APCI(+ve) 458(+1, 100%)
[0528] .sup.1H NMR: .delta.(CDCl.sub.3) 1.75(2H, m), 1.93(2H, m),
2.27(3H, s), 2.62(2H, m), 2.85(2H, d of d), 3.14(2H, s), 4.61(2H,
br s), 7.05(1H, m), 7.20(2H, m), 7.70(1H, m), 8.02(1H, d), 8.26(2H,
d of d), 8.77(1H, br s)
[0529] MP: 169-70.degree. C.
EXAMPLE 44
2-[8-(5-Chlorothieno-2-yl)sulphonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-(2-
-methylphenyl)acetamide
[0530] 51
[0531] The title compound was prepared from the product of Example
20 step (iv) and 2-chloro-5-chlorosulphonyl-thiophene by the method
of Example 37 as a white solid. Yield 0.108 g.
[0532] MS: APCI(+ve) 440(M+1, 100%)
[0533] .sup.1H NMR: .delta.(CDCl.sub.3) 1.90(41H, m), 2.28(3H, s),
2.70(2H, d), 2.86(2H m), 3-21(2H, s), 4.27(2H, br s), 6.94(1H, d),
7.05(1H, m), 7.20(2H, m), 7.42(1H, d), 8.04(1H, d), 8.73(1H, br
s)
[0534] MP: 150-2.degree. C.
EXAMPLE 45
2-[8-(2-Chlorobenzenesulphonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-(2-meth-
ylphenyl)acetamide
[0535] 52
[0536] The title compound was prepared from the product of Example
20 step (iv) and 2-chlorobenzenesulphonyl chloride by the method of
Example 37 as a white solid.
[0537] Yield 0.085 g.
[0538] MS: APCI(+ve) 434(M+1, 100%)
[0539] .sup.1H NMR: .delta. (CDCl.sub.3) 2.07(4H, m), 2.31(3H, s),
2.66(2.times., d), 2.82(2H, m), 3.18(2H, s), 4.31(2H), br s),
7.05(1H, m), 722(2H, m), 7.40(1H, m), 7.53(2H, m), 8.05(1H, d),
8.12(1H, d of d), 8.80(1H, br s)
[0540] MP: 170-1.degree. C.
EXAMPLE 46
2-[8-(5-Chloro-2-methoxybenzenesulphonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-
-N-(2-methylphenyl)acetamide
[0541] 53
[0542] The title compound was prepared from the product of Example
20 step (iv) and 3-chloro-6-methoxybenzenesulphonyl chloride by the
method of Example 37 as a white solid
[0543] Yield 0.105 g.
[0544] MS: APCI(+ve) 464(M+1, 100%).
[0545] .sup.1H NMR: (CDCl.sub.3) 1.93(4H, m), 2.30(3H, s), 2.62(2H,
m), 2.85(2H, m), 3.17(2H, s), 3.95(3H, s), 4.35(2H, br s), 6.95(1H,
d), 7.05(1H, m), 7.20(2H, m), 7.46(1H, d of d), 7.91(1H, d),
8.05(1H, d), 8.80(1H, br s)
[0546] MP: 180-1.degree. C.
EXAMPLE 47
2-[8-(4-Acetylaminomethoxybenzenesulphonyl)-3,8-diazabicyclo[3.2.1]oct-3-y-
l]-N-(2-methylphenyl)acetamide
[0547] 54
[0548] The title compound was prepared from the product of Example
20 step (iv) and 4 acetylamidobenzenesulphonyl chloride by the
method of Example 37 as a white solid.
[0549] Yield 0.108 g.
[0550] MS: APCI(+ve) 457(M+1, 100%)
[0551] .sup.1H NMR: .delta.(CDCl.sub.3) 1.60(2H, m), 1.82(2H, m),
2.18(3H, s), 226(3H, s), 2.65(2H, d), 2.80(2H, d of d), 3.18(2H,
s), 4.20(2H, br s), 7.05(1H, m), 7.18(2H, m), 7.78(4H, s), 8.00(1H,
d), 8.77(1H br s), 9.64(1H, s)
[0552] MP: 205-6.degree. C.
EXAMPLE 48
N-(2-Methylphenyl)-2-[(8-(3-methylthieno[2,3-d]pyrimidin-4-yl)-3,8-diazabi-
cyclo[3.2.1]oct-3-yl]acetamide
[0553] 55
[0554] The trifluoroacetate salt of Example 20 step (iv) was
converted to the free base by use of aqueous 2N NaOH solution
followed by extraction with ethyl acetate. The extracts were dried
(MgSO.sub.4, filtered and evaporated to dryness, leaving an oil
which crystallised on standing
[0555] MS: ES(+ve) 260(M+1,100%)
[0556] A mixture of the amine free base (0.13 g),
N,N-disopropylethylamine (0.5 ml), s dimethylaminopyrimidine (0.06
g) and 4-chloro-3-methylthieno[- 2,3-d]pyrimidine was heated in
N-methylpyrrolidin-2-one (5.0 ml) at 100.degree. C. for 5 hours.
The solvent was evaporated under high vacuum and the residue was
slurried with water, filtered and dried. Purification was by
chromatography on silica gel eluting with dichloromethane
containing ethanol (1%) to give the title compound as a white
solid. Yield (0.053 g).
[0557] MS: APCI(+ve) 408(M+1, 100%)
[0558] .sup.1H NMR: .delta. (CDCl.sub.3) 1.98(4H, m), 2.35(3H, s),
2.62(3H, s), 2.95(4H, m), 3.26(2H, s), 4.46(2H, br s), 7.00(1H, s),
7.10(1H, m), 7.20(2H, m), 8.10(1H, d), 8.53(1H, s), 8.96(1H, br
s)
[0559] MP: 199-200.degree. C.
EXAMPLE 49
cis-2-(3,5-Dimethyl-4-(thieno[2,3-d]pyridinyl)piperazin-1-yl)-N-(1-methyl--
1H-benzoimidazol-2-yl)acetamide
[0560] 56
[0561] The title compound was prepared from the product of Example
9 step (ii) (0.2 g) and 2-amino-1-methyl-benzimidazole (0.14 g) by
the method of Example 38 step (iv). Purification was by silica gel
chromatography followed by recrystallisation from methanol. Yield
45 mg.
[0562] MS: APCI (+ve) 436(M+1)
[0563] .sup.1H NMR: .delta. (CDCl.sub.3) 8.47(1H, s), 7.41(1H, d),
7.26(3H, m), 5.01(2H, brs), 3.68(3H, s), 3.40(2H, s), 3.05(2H, d),
2.50(2H, d), 1.61(6H, s).
[0564] M.P. 200.degree. C.
EXAMPLE 50
Cis-2-(3,5-Dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-N-(2-me-
thyl-5-(4-piperidinyloxy)phenyl)acetamide, Hydrochloride Salt
[0565] 57
i) 1,1-Dimethylethyl,
4-(4-methyl-3-nitro)phenoxypiperidine-1-carboxylate
[0566] A solution of 4-methyl-3-nitrophenol (2 g), 1,1
dimethylethyl, 4-hydroxypiperidine-1-carboxylate (2.6 g),
triphenylphosphine (4.11 g) in tetrahydrofuran (40 ml) under
nitrogen at 0.degree. C. was treated with diethylazidodicarboxylate
(2.3 ml) over 1 minute. The cooling bath was removed and the
mixture allowed to stir at ambient temperature for 48 h. The
solvent was evaporate under reduced pressure. The residue was
purified by silica gel chromatography eluting with dichloromethane
containing 1% triethylamine to give the subtitle product as a pale
yellow oil Yield: 3.46 g
[0567] .sup.1H NMR .delta. (CDCl.sub.3) 7.52(dd, 1H), 7.21(dd, 1H),
7.08(dd, 1H), 4.50(m, 1H), 3.70(m, 2H), 3.55(m, 2H), 2.50(s, 3H),
2.0-1.6(m, 4H), 1.5(s, 9H)
ii) 1,1-Dimethylethyl,
4-(3-amino-4-methyl)phenoxypiperidine-1-carboxylate
[0568] A solution of the product from step (i) (2 g), 10% Palladium
on charcoal (300 mg) were stirred under a 1 bar atmosphere of
hydrogen at ambient temperature. The mixture was filtered through
celite and solvent removed under reduced press to leave the
subtitle product as a beige solid. Yield: 1.88 g
[0569] .sup.1H NMR .delta. (CDCl.sub.3) 6.9(d, 1H), 6.3(m, 2H),
4.4(m, 1H), 3.7(m, 2H), 3.6(bs, 2H), 3.3(m, 2H), 2.10(s, 3H),
1.9-1.6(m, 4H), 1.50(s, 9H)
iii)
2-Chloro-N-5-(1-(1,1-dimethylethoxycarbonyl)-4-piperdinyloxy)methyl-5
nitro)acetamide
[0570] A solution of the product from step (ii) (1.4 g),
N,N-diisopropylethylamine (2 ml) in dichloromethane(30 ml) under
nitrogen at 0.degree. C. was treated with chloroacetylchloride (0.4
ml). After 4 h the reaction mixture was partitioned between water
and dichloromethane. The organic phase collected, dried
(MgSO.sub.4) and solvent reduced under reduced pressure to leave
the subtitle compound as a brown oil. Yield: 1.8 g This was used d
y in the next step.
iv)
Cis-2-(3,5-Dimethiyl-4-thieno[2,3-d]pyrimidinyl)piperazin-1-yl)-N-(2-m-
ethyl-5-(1-(1,1-dimethylethoxycarbonyl)-4-piperidinyloxy)phenyl)acetamide
[0571] The subtitle compound was prepared from the product of
Example 2 step (ii) (0.4 g) and the product of step (iii) (0.56 g)
by the method of Example 33 step (iv) as a pale yellow gum.
[0572] Yield: 0.25 g
[0573] MS: APCI(+ve) 595(M+i), APCI(-ve) 593(M-1)
v)
Cis-2-(3,5-Dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl-piperazin-1-yl)-N-(2-
-methyl-5-(4-piperidinyloxy)phenyl)acetamide, Hydrochloride
Salt
[0574] The title compound was prepared from the product of step
(iv) (0.24 g) by the method of Example 27 step (iv) as a white
solid. Purification was by reverse phase HPLC eluting with aq. 1%
ammonium acetate/acetonitrile (95% to 60%). Yield: 80 mg
[0575] MS: APCI(+ve) 495(M+1), APCI(-ve) 493(M-1)
[0576] .sup.1HNMR .delta. (DMSO) 8.97(bs, 1H), 8.52(s, 1H), 7.7(d,
1H), 7.62(d, 1M), 7.26(s, 1H), 7.18(d, 1H), 6.84(d, 1H), 5.30(bs,
2H), 4.60(bs, 1H), 330-3.00(2xbs, 4H), 2.20(s, 3H), 2.15-1.80(m,
4H), 1.60(d, 6H)
EXAMPLE 51
Cis-2-(3,5-Dimethyl-4-benzenesulphonyl)piperazin-1-yl)-N-(2-methyl-5-(4-pi-
peridinyloxy)phenyl)acetamide
[0577] 58
i)
Cis-2-(3,5-Dimethyl-4-benzenesulphonyl)piperazin-1-yl)-N-(2-methyl-5-(1-
-(1,1-dimethylethoxycarbonyl)4-piperidinyloxy)phenyl)acetamide
[0578] The subtitle compound was prepared from the product of
Example 33 step (ii) (0.42 g) and the product of Example 50 step
(iii) (0.55 g) by the method of Example 33 step (iv). Purification
was by silica gel chromatography eluting with dichloromethane/ethyl
acetate (95:5) to give the subtitle compound as colourles gum.
Yield: 0.23 g
[0579] MS: APCI(+ve) 601(M+1), APCI(-ve) 599(M-1)
ii)
Cis-2-(3,5-Dimethyl-4-benzenesulphonyl)piperazin-1-yl)-N-(2-methyl-5-(-
4-piperidinyloxy)phenyl)acetamide
[0580] The title compound was prepared from the product of step (i)
(0.2 g) by the method of Example 27 step (iv) as a white solid
after purification by reverse phase HPLC eluting with is 1% aq.
ammonium acetate/acetonitrile (95% to 60%). Yield: 50 mg
[0581] MS: APCI(+ve) 501(M+1), APCI(-ve) 499(M-1)
[0582] .sup.1HNMR .delta. (DMSO) 8.8(bs, 1H), 7.8(d, 2H), 7.7(m,
3H), 7.25(s, 1H), 7.15(d, 1H), 6.75(d, 1H), 4.60(m, 1H),
4.2-4.0(bs, 2H), 3.3-3.0(2xm, 4H), 2.2(s, 3H), 2.15-1.70(m, 4H),
1.5(d, 6H.
EXAMPLE 52
Cis-2-(Dimethyl-4-quinazolin-4-yl)piperazin-1-yl-N-(2-methyl-5-(4-piperidi-
nyloxy)phenyl)acetamide
[0583] 59
i) 1,1-Dimethylethyl, 4-(4
quinazolinyl)-3,5-dimethylpiperazine-1-carboxyl- ate
[0584] 4-Chloroquinazoline(6 g), cis-1,1-diethylethyl,
3,5-dimethylpiperazine-1-carboxylate (7.8 g),
N,N-diisopropylethylamine (32 ml) in 1-methyl-2-pyrrolidinone (70
ml) were heated at 120.degree. C. for 6 days under nitrogen. The
mixture was partitioned between ethyl acetate and brine. The
organic phase collected and further washed with brine (.times.2),
collected, dried (MgSO.sub.4) and solvent evaporated under reduced
pressure to leave a pale brown solid. Purification was by silica
gel chromatograpy eluting with ethyl acetate/iso-hexane (3:7) to
give the subtitle compound as a pale yellow oil. Yield: 1.1 g
[0585] MS: APCI(+ve) 343(M+1)
ii) cis-4(4-Quinazolinyl)-2,6-dimethylpiperazine, Hydrochloride
Salt
[0586] The subtitle compound was prepared from the product of step
(i) (1 g) by the method of Example 27 step (iv) as cream solid.
Yield: 1.8 g
[0587] MS: APCI(+ve) 243(M+1)
ii)
Cis-2-(3,5-Dimethyl-4-(4-quinazolinyl)piperazin-1-yl)-N-(2-methyl-5(1--
(1,1-dimethylethoxycarbonyl)4-piperidinyloxy)phenyl)acetamide
[0588] The subtitle compound was prepared from the product of step
(ii) (0.56 g) and the product of Example 50 step (iii) (0.37 g) by
the method of Example 33 step (iv). Purification was by silica gel
chromatography eluting with ethyl acetate/iso-hexane (9:1) to give
the subtitle compound as a white solid Yield: 0.18 g
[0589] MS: APCI(+ve)589(M+1)
[0590] iv)
Cis-2-(3,5-Dimethyl-4-(quinazolin-4-yl)piperazin-1-yl)-N-(2-met-
hyl-5-(4-piperadinyloxy)phenyl)acetamide
[0591] The title compound was prepared from the product of step
(iii) (0.18 g) by the method of Example 27 step (iv). Purification
was by reverse phase HPLC eluting qith 1% aq. ammonium
acetate/acetonitrile (99% to 50%) to give the title compound as a
white solid.
[0592] Yield: 0.079 g
[0593] MS: APCI(+ve) 489(M+1)
[0594] .sup.1H NMR .delta. (CDCl.sub.3) 9.26(bs, 1H), 9.08(bs, 1H),
8.35(d, 1H), 8.00(d, 1H), 7.95(s, 1H, 7.90(t, 1H), 7.60(t, 1H),
7.10(d, 1H), 6.61(d, 1H), 4.57(m, 1H), 3.25(m+s, 4H), 3.05(m, 2H),
2.90(d, 2H), 2.60(m, 2H), 2.30(s, 3H), 2.10(m, 2H), 2.0(m, 2H),
1.0(d, 6H)
EXAMPLE 53
Cis-2-(3,5-Dimethyl-4-(4-quinazolinyl)piperazin-1-yl)-N-(2-methyl-5-(piper-
azin-4-yl-methyl)phenyl)acetamide
[0595] 60
i)
2-Chloro-N-5-((1-(1,1-dimethylethyloxycarbonyl)piperazin-4-yl-methyl)ph-
enyl-2-methyl)acetamide
[0596] The subtitle compound was prepared from the product of
Example 27 step (ii) (0.1 g) by the method of Example 33 step (iii)
as a beige foam Yield: 0.15 g
[0597] MS: APCI(+ve) 382(M+1)
ii)
Cis-2-(3,5-Dimethyl-4-(4-quinazolinyl)piperazin-1-yl)-N-(2-methyl-5-(1-
-(1,1-dimethylethyloxycarbonyl)piperazin-4-yl-methyl)phenyl)acetamide
[0598] The subtitle compound was prepared from the product of
Example 52 step (ii) (0.2 g) and the product of step (i) (0.21 g)
by the method of Example 33 step (iv). Purification was by silica
gel chromatography eluting with ethyl acetate/iso-hexane (9:1) to
give the subtitle compound as a white solid Yield 0.068 g
[0599] MS: APCI(+ve) 588(M+1)
iii)
Cis-2-(3,5-Dimethyl-4-(4-quinazolinyl)piperazin-1-yl)-N-2-methyl-5-(p-
iperazin-4-yl-methyl)phenyl)acetamide
[0600] The title compound was prepared from the product of step
(ii) (0.069 g) by the method of Example 27 step (iv). Purification
was by reverse phase HPLC eluting with 1% aq. ammonium
acetate/acetonitrile (99% to 50%) to give the title compound as a
white solid
[0601] Yield: 0.072 g
[0602] MS: APCI(+ve) 488(M+1)
[0603] .sup.1H NMR .delta. (CDCl.sub.3) 8.58(bs, 1H), 8.25(bs, 1H),
7.63(d, 1H), 7.20(m, 2H), 6.95(t, 1H), 6.50(d, 1H), 6.35(d, 1H),
3.60(bs, 2H), 2.80(s, 1H), 2.60(s, 1H), 230(bs, 3H), 2.20(d, 1H),
2.0(m, 1H), 1.90(bs, 2H), 1.70(s, 2H), 1.30(bd, 6H)
EXAMPLE 54
Cis-2-(3,5-Dimethyl-4-(4-quinazolinyl)piperazin-1-yl)-N-(2-methyl-5-(2-(N--
methylamino)ethoxy)phenyl)acetamide
[0604] 61
Cis-2-(3,5-Dimethyl-4-(4-quinazolinyl)piperazin-1-yl)-N-(2-methyl-5-(2-(1,-
1-dimethylethyloxycarbonyl-N-methylaminoethoxy)phenyl)acetamide
[0605] The subtitle compound was prepared from the product of
Example 52 step (ii) (0.64 g) and the product from Example 33 step
(iii) (0.59 g) by the method of Example 33 step (iv).
[0606] Yield: 0.45 g
[0607] MS: APCI(+ve) 563(M+1), APCI(-ve) 561(M-1)
ii)
Cis-2-(3,5-Dimethyl-4-(4-quinazolinyl-1-piperazin-1-yl)-N-(2-methyl-5--
(2(N-methylamino)ethoxy)phenyl)acetamide
[0608] The title compound was prepared from the product of step (i)
(0.4 g) by the method of Example 27 step (iv). Purification was by
reverse phase HPLC eluting with 1% aq. ammonium
acetate/acetonitrile (99% to 50%) to give the title compound as a
white solid.
[0609] Yield: 0.25 g
[0610] MS: APCI(+ve) 463(M+1)
[0611] .sup.1H NMR .delta. (CDCl.sub.3) 9.30(bs, 1H), 9.12(bs, 1H),
8.39(1H), 8.05(d, 1H), 7.95(m, 2H), 7.60(t, 1H), 7.10(d, 1H),
6.70(d, 1), 4.20(m, 2H), 4.0(bs, 2H), 3.30(s, 2H), 3.20(m, 2H),
2.90(m, 2H), 2.60(m+s, 5H), 2.35(s, 3H), 1.0(bs, 6H)
EXAMPLE 55
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-methyl-
phenyl)acetamide
[0612] 62
i)
cis-2-(3,5-Dimethylpiperazin-1-yl-N-(2-methylphenyl)acetamide
[0613] A mixture of 2-chloro-N-(2-methylphenyl)acetamide (1.83 g),
N,N-disopropylethylamine (5.0 ml), sodium iodide (0.020 g) and
cis-2,6-dimethylpiperazine 1.14 g) in ethanol (50 ml) was heated at
reflux for 2.5 hours. The solvent was removed and the residue was
crystallised from ethanol as white needles. It was dissolved in
water and the solution was made basic with 2N aqueous NaOH,
extracted with dichloromethane and the extracts were dried
(MgSO.sub.4), filtered and evaporated to dryness, leaving an oil
which crystallised on standing. Yield 1.1 g.
[0614] .sup.1H NMR: .delta.(CDCl.sub.3) 1.08(6H, d), 1.40(1H br s)
1.94(2H, t), 2.27(3H, s), 2.83(2H, m), 2.98(2H, m) 3.14(2H, s),
7.03(1H, m), 7.20(2H, m), 8.18(1H, d), 9.32(1H, br s) MP:
105-6.degree. C.
ii)
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-me-
thylphenyl)acetamide
[0615] The product of step (i) (0.60 g), 4-dimethylaminopyridine
(0.14 g) in pyridine (2.0 ml) was stirred while
3-cyanobenzenesulphonyl chloride (0.46 g) was added. The mixture
was stirred for 10 minutes after which it solidified. After 1 hour
the solid was triturated with water and filtered off. It was
purified by chromatography on silica eluting with ethyl
acetate/iso-hexane (1:1) to give the title compound as a pale
yellow solid. Yield: 0.22 g.
[0616] MS: APCI(+ve) 427(M+1, 100%)
[0617] .sup.1H NMR: .delta.(CDCl.sub.3) 1.55(6H, d), 2.17(2H, d of
d), 2.32(3H, s), 2.73(2H, d), 3.10(2H, s), 4.13(2H, m), 7.10(1H,
m), 7.20(2H, m), 7.67(1H, m), 7.85(1H, m), 7.95(1H, m), 8.05(1H,
m), 8.12(1H, m), 8.67(1H, br s).
[0618] MP: 152-3.degree. C.
EXAMPLE 56
Cis-N-(2-Methylphenyl)-2-[4-(3-nitrobenzenesulphonyl)-3,5-dimethylpiperazi-
n-1-yl]-acetamide
[0619] 63
[0620] The title compound was prepared from the product of Example
55 step (i) and 3-nitrobenzenesulphonyl chloride by the method of
Example 55 step (ii) as an off white solid.
[0621] Yield: 3.06 g
[0622] MS: APCI(+ve) 447(M+1,100%)
[0623] .sup.1H NMR: .delta.(CDCl.sub.3) 1.59(6H, d), 2.20(2H, d of
d), 2.30(3H s), 2.74(2H, d), 3.10(2H, s), 4.16(2H, m), 7.05(1H, m),
7.20(2H, m), 7.75(1H, t), 7.96(1H, d), 8.16(1H, d of d), 8.43(1H, d
of d), 8.67(2H, br s). MP: 163-4.degree. C.
EXAMPLE 57
cis-2-[4-(3-Aminobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-methyl-
phenyl)acetamide
[0624] 64
[0625] To a stirred solution of the product of Example 56(3.0 g) in
ethanol (1500 ml) was added 5%; palladium on charcoal (1.5 g)
followed by dropwise addition of hydrazine hydrate (20 ml). The
mixture was stirred for 1 hour, filtered through `hyflo` and the
filtrate was evaporated to dryness. The solid residue was
crystallised from ethanol to give the title compound as a white
solid. Yield 1.6 g.
[0626] MS: APCI(+ve)417(M+1, 100%)
[0627] .sup.1H NMR: .delta. (CDCl.sub.3) 1.54(6H, d), 2.18(2H, d of
d), 2.30(3H, s), 2.65(2H, d), 3.07(2H, s), 3.90(2H, s), 4.15(2H,
m), 6.82(1H, d of d), 7.05-7.20(6H, m), 7.99(1H, d), 8.75(1H,
s).
[0628] MP: 202-3.degree. C.
EXAMPLE 58
Cis-2-(3,5-Dimethyl-4-(3-cyanobenzenesulphonyl)piperazin-1-yl)-N-(quinolin-
-5-yl)acetamide
[0629] 65
i)
Cis-2-(3,5-Dimethyl-piperazin-1-yl)-N-(quinolin-5-yl)acetamide
[0630] A mixture of 2-chloro-N-(quinolin-5-yl)acetamide (7.76 g)
(J. Indian Chem Soc, 1940, 17, 619-621), cis-2,6-dimethylpiperazine
(4.42 g), sodium bicarbonate (8.9 g) in ethanol (100 ml) was heated
at reflux for 4 h. The solvent was removed under reduced pressure.
The residue was partitioned between chloroform and brine. The
organic phase collected and the aqeuous phase fiber extracted
(.times.6) with chloroform. The combined extracts dried
(MgSO.sub.4) and solvent removed under reduced pressure. Yield: 6.8
g
[0631] MS: APCI(+ve) 299(M+1)
ii)
Cis-2-(3,5-Dimethyl-4-(3-cyanobenzenesulphonyl)piperazin-1-yl)-N-(quin-
olin-5-yl)acetamide
[0632] The product from step (i) (150 mg), 4N,N-dimethylnopyridine
(31 mg) in pyridine (0.5 ml) was treated in one portion with
3-cyanobenzenesuphonyl chloride (1 eq) and then immediately heated
for 30 minutes. The mixture was partitioned between dichloromethane
and water. The organic phase collected, dried (MgSO.sub.4) and
solvent removed under reduced pressure. The reisdue was purified by
reverse phase HPLC eluting with 0.1% aq. ammonium
acetate/acetontrile (95% to 50%) as eluant to give the title
compound as a white solid. Yield: 8 mg
[0633] MS: APCI(+ve) 464(M+1)
[0634] .sup.1HNMR .delta.(CD.sub.3OD) 9.87(d, 1H), 8.4(d, 1H),
8.3(d, 1H), 82(m, 2H), 8.0(m 2H, 7.78(m, 2H), 7.6(m, 1H), 4.2(m,
2H, 3.24(s, 2H), 2.82(d, 2H), 2.1(dd, 2H), 1.57(d, 6H)
EXAMPLE 59
Cis-2-(3,5-Dimethyl-4(4-cyanobenzenesulphonyl)piperazin-1-yl)-N-quinolin-5-
-yl)acetamide
[0635] 66
[0636] The title compound was prepared from the product of Example
58 step (i) (0.503 mmol) and 4-cyanobenzenesulphonyl chloride
(0.503 mmol) by the method of Example 58 step (ii) as a white solid
Yield: 4 mg
[0637] MS: APCI(+ve) 464(M+1)
[0638] .sup.1HNMR .delta.(CD.sub.3OD) 8.9(d, 1H), 8.4(d, 1H),
8.1(d, 2H), 7.93-7.96(m, 2), 7.8(m, 2H), 7.6(m, 1H), 4.2(m, 2H),
3.24(s, 2H), 2.81(d, 2H), 2.1(dd, 2H), 1.57(d, 6H)
EXAMPLE 60
Cis-2-(4-(3-cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl)-N-(3-fluoro-
-2-methylphenyl)acetamide
[0639] 67
i)
cis-(3,5-Dimethylpiperazin-1-yl)-N-(2-methyl-3-fluorophenyl)acetamide
[0640] The subtitle compound was prepared from the product of
Example 36 step (i) (14.5 g) and cis-2,6-dimethylpiperazine (9.0 g)
by the method of Example 58 step (i) as cream solid.
[0641] Yield: 11.48 g
[0642] MS: APCI(+ve) 280(M+1)
ii)
Cis-2-(4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl)-N-(3-fl-
uoro-2-methylphenyl)acetamide
[0643] The title compound was prepared from the product of step (i)
(0.503 mmol) and 3-cyanobenzenesulphonyl chloride (0.503 mmol) by
the method of Example 58 step (ii) as a white solid. Yield: 44
mg
[0644] MS: APCI(+ve) 445(M+1)
[0645] .sup.1HNMR .delta. (CD.sub.3OD) 8.24(d, 1H), 8.14(d, 1H),
7.98(d, 1H), 7.76(t, 1H), 7.36(d, 1H), 7.1(q, 1H), 6.93(t, 1H),
4.14-4.16(m, 2H), 3.10(s, 2H), 2.73(d, 2H), 2.16(d, 3H), 2.04(dd,
2H), 1.53(d, 6H)
EXAMPLE 61
Cis-2-(4-(4-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl)-N-(3-fluoro-
-2-methylphenyl)acetamide
[0646] 68
[0647] The title compound was prepared from the product of Example
60 step (i) (0.503 mmol) and 4-cyanobenzenesulphonyl chloride
(0.503 mmol) by the method of Example 58 step (ii) as a white sold.
Yield: 4 mg
[0648] MS: APCI(+ve) 445(M+1)
[0649] .sup.1H NNMR .delta. (CD.sub.3OD) 8.24(d, 1H), 8.14(d, 1H),
7.98(d, 1H), 7.76(t, 1H), 736(d, 1H), 7.1(q, 1H), 6.93(t, 1H),
4.14-4.16(m, 2H, 3.10(s, 2H), 2.73(d, 2H), 2.16(d, 3H), 2.04(dd,
2H), 1.53(d, 6H)
EXAMPLE 62
cis-2-[4-(3-Acetylaminobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-2-m-
ethylphenyl)acetamide
[0650] 69
[0651] A solution of the product from Example 57(0.2 g) and
N,N-diisopropylethylamine (0.3 ml) in dichloromethane (10 ml) was
rapidly stirred whilst a solution of acetyl chloride (0.055 g) in
dichloromethane (2.0 ml) was added. After 3 hours a further amount
of acetyl chloride (0.022 g) was added, the mixture was stirred 3
hours more then evaporated to dryness. The residue was triturated
with water, filtered and dried in vacuo, to give the title compound
as a white solid. Yield 0.17 g.
[0652] MS: APCI(+ve) 459(M+1, 100%)
[0653] .sup.1HNMR: .delta. (CDCl.sub.3+DMSO) 1.53(6H, d), 2.17(3H,
s), 2.26(2H, m), 2.30(3H, s), 2.66(2H, d), 3.08(2H, s), 4.14(2H,
m), 7.07(1H, m), 7.20(2H, m), 7.42(1H, m), 7.48(1H, m), 7.82(1H,
d), 7.95(1H, d), 8.16(1H, s), 8.77(1H, s), 9.49(H, s)
[0654] MP: 236-8.degree. C.
EXAMPLE 63
cis-2-[4-(3-Aminocarbonylbenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(-
2-methylphenyl)acetamide
[0655] 70
[0656] Hydrgen chloride gas was bubbled through a solution of the
product of Example 55 step (ii) (0.21 g), in methanol (50 ml) at
0.degree. C. for 4 hours. The mixture was evaporated to dryness,
the residue was dissolved in methanol and ethylenediamine (0.18 g)
was added. After 3 hours LC/MS indicated mainly amide. After 18
hours the mixture was evaporated to dryness, the residue was
triturated with ether/ethanol, filtered and the solid was purified
by chromatography oh silica gel eluting with dichloromethane
containing ethanol (2.5-5%) to give the title compound as a white
sold. Yield 0.08 g.
[0657] MS: APCI(+ve) 445(M+1, 100%)
[0658] .sup.1H NMR: .delta. (CDCl.sub.3+DMSO) 1.54(6H, d), 2.13(2H,
m), 2.29(3H, s), 2.70(2H, d), 3.06(2H, s), 4.14(2H, m), 6.24(1H, br
s), 7.07(1H, m), 7.21(2H, m), 7.60(1H, t), 7.68(1H, br s), 7.93(2H,
d), 8.15(1H, d), 8.41(1H, s), 8.74(1H, s)
[0659] MP: 124-5.degree. C.
EXAMPLE 64
cis-2-[4-(3-Methanesulphonylaminobenzenesulphonyl)-3,5-dimethylpiperazin-1-
-yl]-N-(2-methylphenyl)acetamide
[0660] 71
[0661] The title compound was prepared from the product of Example
57 and methane sulphonyl chloride by the method of Example 62. The
solid obtained at the end of the reaction was suspended in ethanol
(50 ml) to which a solution of K.sub.2CO.sub.3(0.2 g) in water (10
ml) was added, and stirred for 18 hours, in order to hydrolyse any
bis-sulphonamide. The ethanol was removed, water (50 ml) was added
and the pH was adjusted to 5.0. The solid was filtered of, washed
with water and ether and dried in vacuo to give the title compound
as a white solid. Yield 0.13 g.
[0662] MS: APCI(+ve) 495(M+1, 100%)
[0663] .sup.1H NMR: .delta.(CDCl.sub.3) 1.54(6H, d), 2.20(2H, m),
2.30(3H, s), 2.68(2H, d), 3.06(3H, s), 3.09(2H, s), 4.13(2H, m),
7.07(1H, m), 7.20(2H, m), 7.25(1H, s), 7.40(1H, d of d), 7.48(1H,
t), 7.60(1H, d), 7.68(1H, m), 7.95(1H, d), 8.73(1H, s)
[0664] MP: 102-3.degree. C.
EXAMPLE 65
cis-2-[4-(2-Methanesulphonylbenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]--
N-(3-methoxy-2-methylphenyl)acetamide
[0665] 72
i)
cis-[3,5-Dimethylpiperazin-1-yl]-N-(3-methoxy-2-methylphenyl)acetamide
[0666] The subtitle compound was prepared from
2-chloro-N-(3-methoxy-2-met- hylphenyl)acetamide (10.72 g) and
cis-2,6 dimethylpiperazine (6.29 g) by the method of Example 58
step (i) as a tan solid. Yield: 13.13 g
[0667] .sup.1H NMR .delta. (CDCl.sub.3) 9.32(bs, 1H), 7.79(d, 1H,
7.18(t, 1H), 6.68(d, 1H), 3.83(s, 3H), 3.14(s, 2H), 2.93-3.04(m,
2H), 2.81-2.85(m, 2H), 2.14(s, 3H), 1.92(t, 2H), 1.10(d, 6H)
ii)
cis-2-[4-(2-Methanesulphonylbenzenesulphonyl)-3,5-dimethylpiperazine-1-
-yl]-N-(3 methoxy-2-methylphenyl)acetamide
[0668] The title compound was prepared from the product of step (i)
(0.503 mmol) and 2-methanesulphonylbenzenesulphonyl chloride (0.503
mmol) by the method of Example 58 step (ii) as a white solid.
Yield: 6 mg
[0669] MS: APCI(+ve) 510(M+1)
[0670] .sup.1HNMR .delta.(CD.sub.3OD) 8.4(m, 1H), 8.3(m, 1H),
7.91-7.89(m, 2H), 7.16-7.18(m, 2H), 6.8(t, 1H), 4.2(m, 2H), 3.84(s,
3H), 3.43(s, 3H), 3.14(s, 2H), 2.74(d, 2H), 2.33(dd, 2H), 2.14(s,
3H), 1.61(d, 6H)
EXAMPLE 66
cis-2-[4-(2-Methanesulphonylbenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]--
N-(3 fluoro-2-methylphenyl)acetamide
[0671] 73
[0672] The title compound was prepared from the product of Example
60 step (i) (0.503 mmol) and 2-methanesulphonylbenzenesulphonyl
chloride (0.503 mmol) by the method of Example 58 step (ii) as a
white solid. Yield: 17 mg
[0673] MS: APCI(+ve) 498(M+1)
[0674] .sup.1H NMR .delta. (CD.sub.3OD) 8.4(m, 1H), 8.3(m, 1H),
7.89-7.91(m, 2H), 7.4(d, 1H), 7.1(q, 1H), 6.9(t, 1H), 4.2(m, 2H),
3.44(s, 3H), 3.16(s, 2H), 2.74(d, 2H), 2.3(dd, 1H), 2.20(d, 2H),
1.62(d, 6H)
EXAMPLE 67
cis-2-[4-(1-Methylimidazol-4-sulphonyl-4-yl)-3,5-dimethylpiperazin-1-yl]-N-
-(quinolin-5-yl)acetamide
[0675] 74
[0676] The title compound was prepared from the product of Example
58 step (i) (0.503 mmol) and 1-methylimidazole-4-sulphonyl chloride
(0.503 mmol) by the method of Example 58 step (ii) as a white
solid. Yield: 16 mg
[0677] MS: APCI(+ve) 443(M+1)
[0678] .sup.1H NMR .delta. (CD.sub.3OD) 8.90(d, 1H), 4.45(d, 1H),
7.97(t, 1H), 7.82(s, 1H), 7.80(d, 1H), 7.68(s, 1H), 7.58-7.63(m,
1H), 4.17-2.21(m, 2H), 3.79(s, 3H), 3.26(s, 2H), 2.80(d, 2),
2.25(dd, 2H, 1.58(d, 6H)
EXAMPLE 68
cis-2-[4-(1-Methylimidazol-4-sulphonyl-4-yl)-3,5-dimethylpiperazine-1-yl]--
N-(3-methoxy-2-methylphenyl)acetamide
[0679] 75
[0680] The title compound was prepared from the product of Example
65 step (i) (0.503 mmol) and 1-methylimidazol-4-sulphonyl chloride
(0.503 mmol) by the method of Example 58 step (ii) as a white
solid. Yield: 31 mg
[0681] MS APCI(+e) 436(M+1)
[0682] .sup.1H NMR .delta. (CD.sub.3OD) 7.77(s, 1H), 7.67(s, 1H),
7.16-7.18(m, 2H), 6.82-6.85(m, 1H), 4.14-4.18(m, 2H), 3.84(s, 3H),
3.79(s, 3H), 3.10(s, 2H), 2.72(d, 2H), 2.20(dd, 2H), 2.13(s, 3H),
1.53(d, 6H)
EXAMPLE 69
cis-2-[4-(1-Methylimidazol-4-sulphonyl-4-yl)-3,5-dimethylpiperazin-1-yl-]--
N-3-fluoro-2-methylphenyl)acetamide
[0683] 76
[0684] The title compound was prepared from the product of Example
60 step (i) (0.503 mmol) and 1-methylimidazol sulphonyl chloride
(0.503 mmol) by the method of Example 58 step (ii) as a white
solid. Yield: 21 mg
[0685] MS: APCI(+ve) 424(M+1)
[0686] .sup.1H NMR .delta.(CD.sub.3OD) 7.77(s, 1H), 7.67(s, 1H),
7.43(d, 1H), 7.20(q, 1H), 6.95(t, 1H), 4.12-4.20(m, 2H), 3.79(s,
3H), 3.12(s, 2H), 2.72(d, 2H), 2.17-2.23(m, 5H), 1.54(d, 6H)
EXAMPLE 70
cis-2-[4-(3-Methanesulphonylbenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]--
N-(2-trifluoromethylphenyl)acetamide
[0687] 77
i) 2-Chloro-N-(2-trifluoromethylphenyl) acetamide
[0688] The subtitle compound was prepared from
2-trifluoromethylaniline(10- .5 g) and chloroacetyl chloride (6.8
ml) by the method of Example 33 step (iii) as a white solid.
[0689] Yield: 13.7 g
[0690] MS: APCI(-ve) 236(M-1)
ii)
cis-3,5-Dimethylpiperazin-1-yl]-N-(2-trifluoromethylphenyl)acetamide
[0691] The subtitle compound was prepared from the product of step
(i) (7.6 g) and cis-2,& dimethylpiperazine (3.53 g) by the
method of Example 58 Step (i) as a white solid. Yield: 8.57 g
[0692] MS: APCI(+ve) 316(M+1)
iii)
cis-2-[4-(3-Methanesulphonylbenzenesulphonyl)-3,5-dimethylpiperazin-1-
-yl-N-(2-trifluoromethylphenyl)acetamide
[0693] The product of step (iii) (0.25 g) and
3-methanesulphonylbenzenesul- phonyl chloride (0.606 g), potassium
carbonate (0.275 g) in 2,6-lutidine(0.5 ml) were heated in a 100
Watt microwave oven at 120.degree. C. for 10 min. The mixture was
then partitioned between dichloromethane and water. The organic
phase collected, dried (MgSO.sub.4), and the solvent evaporated
under reduced pressure. Purification was by revese phase HPLC
eluing with 1% q. ammonium acetate/acetonitrile (95% to 60%) to
give the title compound as a white solid. Yield: 0.1 g
[0694] MS: APCI(+ve) 534(M+1)
[0695] .sup.1H NMR .delta. (CDCl.sub.3) 9.16(bs, 1H), 8.41(s, 1H),
8.30(d, 1H), 8.20(d, 1H), 7.58(t, 1H), 7.26(d, 1H), 4.15(m, 2H)
EXAMPLE 71
cis-2-[4-(2-Aminoethylaminocarbonylbenzenesulphonyl)-3,5-dimethylpiperazin-
-1-yl-N-(2-methylphenyl)acetamide
[0696] 78
[0697] The title compound was prepared from the product of Example
55 by the method of Example 63 followed by addition of
ethylenediamine, the mixture was heated at reflux for 5 hours,
evaporated to dryness and the residue was crystallised from ethanol
to give the title compound as a white solid. Yield 0.15 g
[0698] MS: APCI(+ve) 488(M+1, 100%)
[0699] .sup.1H NMR: .delta. (CDCl.sub.3) 1.56(8H, m), 2.17(2H, m),
2.29(3H, s), 2.68(2H, d), 2.98(2H, t), 3.06(2H, s), 3.51(2H m),
4.14(2H, m), 6.97(1H, br t), 7.07(1H, m), 7.20(2H, m), 7.60(1H, t),
7.9(3H, m), 8.25(1H, m), 8.71(1H, br s)
[0700] MP: 90-2.degree. C.
EXAMPLE 72
cis-2-[4-(1,1,2,2-Tetrahydroisoquinilin-7-sulphonyl-7-yl)-3,5-dimethylpipe-
razin-1-yl]-N-(2,6 dimethylphenyl)acetamide
[0701] 79
i)
cis-3,5-Dimethylpiperazin-1-yl]-N-(2,6-dimethylphenyl)acetamide
[0702] The subtitle compound was prepared from
2-chloro-N-(2,6-dimethylphe- nyl)acetamide (6.54 g)- and
cis-2,6-dimethylpiperazine(3.78) by the method of Example 58 step
(i) as a white solid. Yield:7.85 g
[0703] MS: APCI(+ve): 276(M+1)
ii)
cis-2-[4-(N-Trifluoroacetyl(1,1,2,2-tetrahydroisoquinilin)-7-sulphonyl-
-7-yl)-3,5-dimethylpiperazin-1-yl]-N-(2,6
dimethylphenyl)acetamide
[0704] The subtitle compound was prepared from the product of step
(i) (0.165 g) and
N-trifluoroacetyl(1,1,2,2]-tetrahydroisoquinolin)-7-sulphon- yl
chloride (0.39 g) by the method of Example 58 step (ii) as a white
solid Yield: 96 mg
[0705] MS: APCI(+ve) 567(M+1)
iii)
cis-2-[4-<1,1,2,2-Tetrahydroisoquinilin-7-sulphonyl-7-yl)-3,5-dime-
thylpiperazin-1-yl]-N-(2,6-dimethylphenyl)acetamide
[0706] The product from step (ii) (90 mg), potassium carbonate (200
mg) in water (10 ml) and methanol (15 ml) were heated at reflux for
2 h Water (50 ml) was added and the mixture extracted with ethyl
acetate. The organic phase collected, dried (MgSO.sub.4) and
solvent evaporated under reduced pressure to give the title
compound as a white solid. Yield: 55 mg
[0707] MS: APCI(+ve) 471(M+1)
[0708] .sup.1H NMR .delta. (CDCl.sub.3) 8.29(s, 1H), 7.55(d, 1H),
7.50(s, 1H), 7.17(d, 1H), 7.11(m, 3H), 4.14(m, 2H), 4.06(s, 2H),
3.48(q, 1H), 3.17(t, 1H), 3.12(s, 2H), 2.87(t, 2H), 2.72(d, 2H),
2.25(d, 1H), 2.22(s, 6H), 2.05(s, 1H), 1.69(bs, 1H), 1.51(d, 6H),
1.19-1.28(m, 4H)
EXAMPLE 73
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2,6-dime-
thylphenyl)acetamide
[0709] 80
[0710] The title compound was prepared from the product of Example
72 step (i) (0.165 g) and 3-cyanobenzenesulphonyl chloride (0.15 g)
by the method of Example 58 step (ii) as a white solid. Yield: 40
mg
[0711] MS: APCI(+ve) 441(M+1)
[0712] .sup.1HNMR .delta. (CDCl.sub.3) 8.22(s, 1H), 8.13(s, 1H),
8.05(d, 1H), 7.86(d, 1H), 7.67(t, 1H), 7.12(m, 3H), 4.15(m, 2H),
3.14(s, 2H), 2.78(d, 2H), 2.22(s, 8H), 1.54(d, 6H)
EXAMPLE 74
cis-2-[4-(4-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-2-methylp-
henyl)acetamide
[0713] 81
[0714] 4-Cyanobenzenesulphonyl chloride (0.36 g) was added to a s
mixture of the product of Example 55 step (i) (0.5 g) and potassium
carbonate (0.62 g) in 1-methyl-2-pyrrolidinone (3 ml). A 20 min the
reaction mixture was partitioned between ethyl acetate and water.
The organic phase was washed with water and brine, dried
(MgSO.sub.4) and evaporated under reduced pressure. Purification
was by flash chromatography eluting with 1% ethanol in
dichloromethane followed by trituration with methanol to give the
title compound as a white crystalline solid. Yield 55 mg.
[0715] MS: ES (+ve) 427(M+1)
[0716] .sup.1H NMR: .delta. (CDCl.sub.3) 8.67(1H, brs),
7.99-7.93(3H, m), 7.83(2H, d), 7.21(2H, m), 7.08 (1H, m), 4.14(2H,
m), 3.10(2H, s), 2.73(2H, d), 2.30(3H, s), 2.18(2H, dd), 1.57(3H,
s), 1.54 (3H, s).
EXAMPLE 75
cis-2-[4-(2-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2,6-dime-
thylphenyl)acetamide, Hydrochloride Salt
[0717] 82
[0718] The free base of the title compound was prepared from the
product of Example 72 step (i) (0.165 g) and
2-cyanobenzenesulphonyl chloride (0.15 g) by the method of Example
58 step (ii). The title compound was prepared by adding 1M hydrogen
chloride in diethyl ether to a solution of the free base to produce
a white precipitate. This was filtered and further washed with
diethyl ether to give the title compound as a white solid. Yield:
20 mg
[0719] MS: APCI(+ve) 441(M+1)
[0720] .sup.1H NMR .delta. (CDCl.sub.3) 8.19(bs, 1H), 7.91(bs, 1H),
7.78(bs, 2H), 7.10(m, 3H), 4.40(bs, 2H, 4.20(bs, 2H), 3.50(m, 3H),
2.20(s, 6H), 2.00-1.40(m, 6H)
EXAMPLE 76
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2
chlorophenyl)acetamide
[0721] 83
[0722] The title compound was prepared from the product of Example
15 step (ii) (0.2 g) and 3-cyanobenzenesulphonyl chloride (0.28 g)
by the method of Example 74 as a white solid.
[0723] Yield 8 mg.
[0724] MS: APCI (+ve) 447(M+1)
[0725] .sup.1HNMR: .delta. (CDCl.sub.3) 9.45(1H, brs), 8.49(1H,
dd), 8.13(1H, s), 8.05(1H, d), 7.87(1H, d), 7.68(1H, t), 7.38(1H,
d), 7.29(1H, m), 7.06(1H, t), 4.14(2H, m), 3.11(2H, s), 2.72(2H,
d), 2.18(1H, dd), 1.60(3H, s), 1.58(3H, s).
EXAMPLE 77
2-[8-(Isquinolin-1-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-(2-methylphenyl)-
acetamide
[0726] 84
[0727] The title compound was prepared form the product Example 20
step (iv) (0.32 g) and 1-chloroisoquinoline (0.14 g) by the method
of Example 52 step (i) as a beige solid Yield: 40 mg
[0728] MS: ESI(+ve) 387(M+1)
[0729] .sup.1H NMR .delta. (DMSO) 9.21(bs, 1H), 8.20(d, 1H),
8.00(d, 1H), 7.93(d, 2H), 7.70(t, 1H), 7.60(t, 1H), 7.35(d, 1H),
7.20(m, 2H), 7.06(t, 1H), 4.40(bs, 2H), 2.98(d, 2H, 2.85(d, 2H),
2.30(s, 3H), 2.00(d, 2H), 1.90(m, 2H)
EXAMPLE 78
cis-2-[4-(4-Acetamidobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-me-
thylphenyl)acetamide
[0730] 85
[0731] 2,6-Lutidine (0.3 ml) was added to a mixture of
4-acetamidobenzenesulphonyl chloride (0.25 g), potassium carbonate
(0.18 g) and the product of Example 55 step (i) (0.14 g). The
reaction mixture was heated at 100.degree. C. for 5 minutes in a
100 Watt microwave oven, allowed to cool and partitioned between
dichloromethane and water. The organic phase was washed with brine,
dried (MgSO.sub.4) and evaporated under reduced pressure.
Purification was by reverse phase HPLC (acetonitrile/1% aq.ammonium
acetate). Yield 15 mg.
[0732] MS: AP (+ve) 459(M+1)
[0733] .sup.1HNMR: .delta. (DMSO) 10.35 (1H, s), 7.76 (4H, q), 7.55
(1H, d), 7.22-7.14(2H, m), 7.07(1H, m), 4.00(2H, m), 3.02(2H, s),
2.64(2H, d), 2.20(3H, s), 2.09(3H, s), 1.92(2H, dd), 1.42(3H, s),
1.40(3H, s)
EXAMPLE 79
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-triflu-
oromethylphenyl)acetamide
[0734] 86
[0735] The title compound was prepared from the product of Example
70 step (i) (0.189 g) and 3-cyanobenzenesulphonyl chloride (0.15 g)
by the method of Example 58 step (ii) as a white solid. Yield: 17
mg
[0736] MS: APCI(+ve) 481(M+1)
[0737] .sup.1H NM .delta.(DMSO) 8.98(bs, 1H), 8.11(m, 2H), 7.93(m,
2H), 7.05(m, 4H), 4.10(m, 2H), 3.30(s, 2H), 2.90(d, 2H), 2.40(bd,
2H), 1.50(d, 6H)
EXAMPLE 80
cis-2-[4-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-methyl-5--
methanesulphonamidophenyl)acetamide
[0738] 87
i)
cis-1-(3-Cyanobenzenesulphonyl-2,6-dimethyl-4-phenylmethylpiperazine
[0739] A solution of cis-4-benzyl-2,6-dimethylpiperazine (1 g),
4-N,N-dimethylaminopyridine(0.54 g), 3-cyanobenzenesulphonyl
chloride (2.13 g) in pyridine (3 ml) were stirred at ambient
temperate. After 1 h the mixture was partitioned between
dichloromethane and water. The organic phase ether washed with
brine, collected, dried, (MgSO.sub.4) and solvent evaporated under
reduced pressure to leave the subtitle compound as an orange gum.
Yield: 1 g
[0740] MS: APCI(+ve) 370(M+1)
ii) cis-1-(3-Cyanobenzenesulphonyl)-2,6-dimethylpiperazine
[0741] A solution of the product from step (i) (1 g) in
1,2-dichloroethane (10 ml) was treated with 1-chloroethyl
chloroformate (0.44 ml). The mixture was heated at 80.degree. C.
for 16 h. The solvents were then evaporated under reduced pressure
and the residue dissolved in methanol (50 ml). The mixture then
heated at 50.degree. C. for 1 h. The solvents were then evaporated
under reduced pressure. Purification was by trituration with ethyl
acetate and filtration to give the subtitle compound as a white
solid Yield: 0.85 g
[0742] MS: APCI(+ve) 279(M+1)
iii)
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl-]-N-(2--
methyl-5-bis(methanesulphonyl)amidophenyl)acetamide
[0743] A solution of the product from step (ii) (0.5 g) and the
product of Example 24 step (i) (0.8 g), N,N-diisopropylethylamine
(0.6 ml), potassium iodide (2 mg) in 1-methyl-2-pyrrolidinone (10
ml) were heated at 90.degree. C. for 3 h. The mixture was then
partitioned dichloromethane and water. The organic phase collected,
further washed with brine, dried (MgSO.sub.4) and solvent
evaporated under reduced pressure to give the subtitle compound as
a brown foam.
[0744] Yield: 1.04 g
[0745] MS: APCI(+ve) 597(M+1)
[0746] iv)
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]--
N-(2-methyl-5-methanesulphonamidophenyl)acetamide
[0747] The product from step (iii) (1 g), potassium carbonate (1
g), water (10 ml) and tetrahydrofuran (20 ml) were stirred at
ambient temperature for 16 h then heated at 90.degree. C. for 6 h.
The mixture partitioned between dichloromethane and water. The
organic phase collected, dried (MgSO.sub.4) and solvent evaporated
under reduced pressure. Purification was by silica gel
chromatography eluting with iso-hexane ethyl ate (1:9) to give the
title compound as a white solid. Yield: 0.5 g
[0748] MS: APCI(+ve) 520(M+1), APCI(-ve) 518(M-1)
[0749] .sup.1HNMR .delta. (CDCl.sub.3) 8.9(bs, 1H), 8.13(2xs, 2H),
8.05(d, 1H), 7.90(d, 1H), 7.70(t 1H), 7.40(bs, 1H), 7.10(m, 2H),
4.10(m, 2H), 3.10(s, 2H), 2.95(s, 3H), 2.70(d, 2H), 2.30(s, 3H),
2.20(m, 2H), 1.60(d, 6H)
EXAMPLE 81
2-[8-(4-Benzenesulphonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-(2-methylphen-
yl)acetamide
[0750] 88
[0751] The title compound was prepared from the product of Example
20 step (iv) (0.34 mmol) and 4-cyanobenzenesulphonyl chloride (0.34
mmol) by the method of Example 58 step (ii) as a white solid Yield:
10 mg
[0752] MS: ESI(+ve) 425(M+1)
[0753] .sup.1H NMR .delta. (CDCl.sub.3) 8.68(bs, 1H), 8.05(m, 3H),
7.83(d, 2H), 7.23-7.17(m, 2H), 7.07(m, 1H), 4.26(m, 2H), 3.19(s,
2H), 2.86(dd, 2H), 2.65(d, 2H), 2.27(s, 3H), 1.94(m, 2H), 1.74(m,
2H)
EXAMPLE 82
2-[8-(2-Benzenesulphonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-2-methylpheny-
l)acetamide
[0754] 89
[0755] The title compound was prepared from the product of Example
20 step (iv) (0.34 mmol) and 2-cyanobenzenesulphonyl chloride (0.34
mmol) by the method of Example 58 step (ii) as a white solid Yield:
8 mg
[0756] MS: APCI(+ve) 425(M+1)
[0757] .sup.1H NMR .delta. (CDCl.sub.3) 8.77(bs, 1H), 8.15(dd, 1H),
8.03(d, 1H), 7.88(ss, 1H), 7.78-7.69(m, 2H), 7.25-7.18(m, 2H),
7.07(t, 1H), 4.36(m, 2H), 3.20(s, 3H), 2.85(dd, 1H), 2.74(d, 1H),
2.30(s, 3H, 2.07-1.99(m, 4H)
EXAMPLE 83
cis-2-[4-(1,2-Dimethylimidazol-4-sulphonyl-4-yl)-3,5-dimethylpiperazin-1-y-
l]-N-(quinolin-5-yl)acetamide
[0758] 90
[0759] The title compound was prepared from the product of Example
58 step (i) (0.503 mmol) and 1,2-dimethylimidazole-4-sulphonyl
chloride (0.503 mmol) by the method of Example 58 step (ii) as a
white solid. Yield: 20 mg
[0760] MS: APCI(+ve) 457(M+1)
[0761] .sup.1H NMR .delta. (CD.sub.3OD) 8.88-8.89(m, 1H), 8.44(d,
1H), 7.97-7.94(m 1, 7.76-7.81(m, 2H), 7.56-7.60(m, 2H),
4.19-4.13(m, 2H, 3.65(s, 3H)-3.25(s, 2H), 2.79(d, 2H), 2.38(s, 3H),
2.54(dd, 2H), 1.55(d, 6H)
EXAMPLE 84
cis-2-[4-(5-Chloro-1,3
dimethylpyrazole-4-sulphonyl-4-yl)-3,5-dimethylpipe-
razin-1-yl]-N-(3-methoxy-2-methylphenyl)acetamide
[0762] 91
[0763] The title compound was prepared from the product of Example
65 step (i) (0.503 mmol) and 5-chloro-1,3-dimethyl-4-sulphonyl
chloride (0.503 mmol) by the method of Example 58 step (ii) as a
white solid. Yield: 6 mg
[0764] MS: APCI(+ve) 485(M+1)
[0765] .sup.1HNMR .delta.(CD.sub.3OD) 7.15-7.16(m, 2H),
6.81-6.84(m, 1H), 4.07-4.10(m, 2H), 3.83(s, 3H), 3.82(s, 3H),
3.15(s, 2H), 2.79(d, 2H), 2.37(s, 3H), 2.56(dd, 2H), 2.12(s, 3H),
1.54(d, 6H)
EXAMPLE 85
2-[8-(2-Isoxazol-3-yl)thiophen-5-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-(2-
-methylphenyl)acetamide
[0766] 92
[0767] The title compound was prepared from the product of Example
20 step (iv) (0.34 mmol) and 2-(isoxazol-3-yl)thiophenesulphonyl
chloride (0.34 mmol) as a white solid. Yield: 10 mg
[0768] MS: ESI(+ve) 473(M+1)
[0769] .sup.1H NMR .delta. (CDCl.sub.3) 8.72(bs, 1H), 8.05(d, 1H),
7.61(d, 1H), 7.46(d, 1H), 7.23(d, 2H), 7.06(t, 1H), 6.53(d, 1H),
4.33(m, 2, 3.22(s, 2H), 2.89(dd, 2H), 2.73(d, 2H), 2.28(s, 3H),
1.94(m, 2H), 1.87(m, 2H)
EXAMPLE 86
2-[8-(1,1,2,2-Tetrahydroisoquinilin-7-sulphonyl)-3,8-diazabicyclo[3.2.1]oc-
t-3-yl]-N-(2-methylphenyl)acetamide
[0770] 93
[0771] The title compound was prepared from the product of Example
20 step (iv) (0.34 mmol) and
N-trifluoroacetyl-1,2,1,2-tetrahydroisoquinoline-7-s- ulphonyl
chloride (0.34 mmol) by the method of Example 58 step (ii) followed
by the method of Example 72 step (iii) as a white solid. Yield: 26
mg
[0772] MS: ESI(+ve) 551(M+1)
[0773] .sup.1H NMR .delta. (CDCl.sub.3) 8.73(bs, 1H), 8.04(d, 1H),
7.77-7.68(m, 2H, 7.33(t, 1H), 7.25-7.17(m, 2H), 7.06(t, 1H),
4.83(d, 2H), 4.24(m, 2H), 3.92(dt, 2H), 3.19(s, 2H), 3.05(m, 2H),
2.85(dd, 2H), 2.66(d, 2H), 2.27(s, 3H), 1.90(m, 2H), 1.76(d,
2H)
EXAMPLE 87
cis-2-[4-(5-chloro-1,3-dimethylpyrazole-4-sulphonyl-yl-3,5-dimethylpiperaz-
in-1-yl]-N-(2-methylphenyl)acetamide
[0774] 94
[0775] The title compound was prepared from the product of Example
20 step (iv) (0.34 mmol) and
5-chloro-1,3-dimethylpyrazole-4-sulphonyl chloride (0.34 mmol) by
the method of Example 58 step (ii) as a white solid Yield: 12
mg
[0776] MS: ESI (+ve) 452(M+1)
[0777] .sup.1H NMR .delta.(CDCl.sub.3) 8.77(bs, 1H), 8.04(d, 1H),
7.23-7.18(m, 2H), 7.07(t, 1H), 4.25(m, 2H), 3.83(s, 3H), 3.19(s,
2H), 2.85(dd, 2H), 2.65(d, 2H), 2.43(s, 3H), 2.30(s, 3H), 1.95(s,
4H)
EXAMPLE 88
cis-2-[4-(3,5-Dimethylisoxazole-4-sulphonyl-4-yl)-3,5-dimethylpiperazin-1--
yl]-N-2-methylphenyl)acetamide
[0778] 95
[0779] The title compound was prepared from the product of Example
20 step (iv) (0.34 mmol) and 3,5-dimethylisoxazol-4-sulphonyl
chloride (0.34 mmol) by the method of Example 58 is step (ii) as a
white solid. Yield: 5.6 mg
[0780] MS ESI (+ve) 419(M+1)
[0781] .sup.1H NMR .delta. (CDCl.sub.3) 8.72(bs, 1H), 8.04(d, 1H),
7.21(t, 2H), 7.08(t, 1H), 4.18(m, 2H), 3.20(s, 2H), 2.88(dd, 2H),
2.66(s, 3H), 2.61(d, 2H), 2.44(s, 3H), 2.31(s, 3H), 2.03(m, 4H)
EXAMPLE 89
cis-2-[4-(2-Methanesalphonylbenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]--
N-(2 methylphenyl) acetamide
[0782] 96
[0783] The title compound was prepared from the product of Example
20 step (iv) (0.34 mmol) and 2-methanesulphonylbenzenesulphonyl
chloride (0.34 mmol) by the method of Example 58 step (ii) as a
white solid. Yield: 13 mg
[0784] MS: ESI (+ve) 478(M+1)
[0785] .sup.1HNMR .delta. (CDCl.sub.3) 8.81(bs, 1H), 8.40(m, 1H),
8.28(m, 1H), 8.03(d, 1H), 7.80(m, 2H), 7.25-7.17(m, 2H), 7.06(t,
1-H), 4.48(m, 2H), 3.46(s, 3H), 3.16(s, 2H), 2.82(dd, 2H), 2.68(d,
2H), 2.29(s, 3H), 1.95(d, 4H)
EXAMPLE 90
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(3-methox-
y-2-methylphenyl)acetamide
[0786] 97
[0787] The title compound was prepared from the product of Example
65 step (i) (0.503 mmol) and 3-cyanobenzenesulphonyl chloride
(0.503 mmol) by the method of Example 58 step (ii) as a white
solid. Yield 21 mg
[0788] MS: ESI (+ve) 424(M+1)
[0789] .sup.1H NMR .delta.(CD.sub.3OD) 7.77(s, H), 7.67(s, 1H))
7.43(d, H), 7.20(q, 1, 695(t 1H), 4.12-4.20(m, 2H), 3.78(s, 3H),
3.12(s, 2H), 2.72(d, 2H), 2.17-2.23(m, 5H), 1.54(d, 6H)
EXAMPLE 91
cis-2-[4-(4-Methanesulphonylbenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]--
N-(2-methylphenyl)acetamide
[0790] 98
[0791] The title compound was prepared from the product of Example
20 step (iv) (0.34 mmol) and 4-methanesulphonylbenzenesulphonyl
chloride (0.34 mmol) by the method of Example 58 step (ii) as a
white solid. Yield: 25 mg
[0792] MS: ESI (+ve) 478(M+1)
[0793] .sup.1H NMR .delta. (CDCl.sub.3) 8.69(bs, 1H), 8.10(q, 4H),
8.04(d, 1H), 725-7.17(m, 2H), 7.07(t, 1H), 4.28(m, 2H), 320(s, 2H),
3.11(s, 3H), 2.87(dd, 2H), 2.67(d, 2H), 227(s, 3H), 1.93(m, 2H),
1.74(m, 2H)
EXAMPLE 92
cis-2-[4-(3-Cyanobenzenesulphonyl-3,5-dimethylpiperazin-yl-]-N-(5-cyano-2--
methylphenyl)acetamide
[0794] 99
i) 2-Chloro-N-(5-cyano-2-methylphenyl)acetamide
[0795] The subtitle compound was prepared from
5-cyano-2-methylaniline (1.6 g) and chloroacetyl chloride (1.1 ml)
by the method of Example 33 step (iii) as a white solid. Yield:
1.85 g
[0796] MS: APCI (-ve) 207(M-1)
ii)
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(5-cy-
ano-2-methylphenyl)acetamide
[0797] The title compound was prepared from the product of step (i)
(0.19 g) and the product from Example 80 step (ii) (0.2 g) by the
method of Example 80 step (iii) as a white solid. Yield: 0.25 g
[0798] MS: APCI(+ve) 452(M+1)
[0799] .sup.1H NMR .delta. (CDCl.sub.3) 8.81(bs, 1H), 8.49(s, 1H),
8.13(s, 1H), 8.05(d, 1H), 7.90(d, 1H), 7.70(t, 1H), 7.29(d, 1H),
7.27(d, 1H), 4.20(m, 2H), 3.10(s, 2H), 2.70(d, 2H), 2.36(s, 3H),
2;20(m, 2H), 1.60(d, 6H)
EXAMPLE 93
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(5-acetam-
ido-2-methylphenyl)acetamide
[0800] 100
i) cis-2-Chloro-N-(5-acetamido-2-methylphenyl)acetamide
[0801] The subtitle compound was prepared from
5-acetamido-2-methylaniline (0.5 g) and chloroacetyl chloride (0.27
ml) by the method of Example 33 step (iii) as a beige solid.
[0802] Yield: 0.55 g
[0803] MS: APCI(+ve) 241(M+1)
ii)
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-methylpiperazin-1-yl-N-(5-aceta-
mido-2 methylphenyl)acetamide
[0804] The title compound was prepared from the product of step (i)
(0.22 g) and the product of Example 80 step (ii) (0.2 g) by the
method of Example 80 step (iii) as a white solid.
[0805] Yield: 0.11 g
[0806] MS: APCI(+ve) 468(M+1)
[0807] .sup.1H NMR .delta. (CDCl.sub.3) 9.60(bs, 1H), 8.78(bs, 1H),
8.19(s, 1H), 8.17(d, 1H), 8.05(s, 1H), 7.98(d, 1H), 8.77(t, 1H),
7.75(s, 1H), 7.50(d, 1H), 7.10(d, 1H), 4.10(m, 2H), 2.75(d, 2H),
2.25(s, 3H), 2.16(m, 2H), 2.10(s, 3H), 1.50(d, 6H)
EXAMPLE 94
(R)-2-[4-(4-Cyanobenzenesulphonyl)-3-methylpiperazin-1-yl-N-(quinolin-5-yl-
)acetamide
[0808] 101
i) R)-2-(3-Methylpiperazin-1-yl)-N-<quinolin-5-yl)acetamide
[0809] The subtitle compound was prepared from
2-chloro-N-quinolin-5-yl)ac- etamide (1 g) (J Indian Chem Soc,
1940, 17, 619-621) and (R)-2-methylpiperazine (0.5 g) by the method
of Example 58 step (i) as a white solid. Yield: 1.4 g
[0810] MS: APCI(+ve) 285(M+1)
ii)(R)-2-[4-(4-Cyanobenzenesulphonyl-3-methylpiperazin
1-yl]-N-quinolin-5-yl)acetamide
[0811] The title compound was prepared from the product of step (i)
(1.4 g) and 4-cyanobenzenesulphonyl chloride (1 g) by the method of
Example 58 step (ii) as a white solid. Yield: 0.41 g
[0812] MS: APCI(+ve) 450(M+1)
[0813] .sup.1H NMR .delta. (CDCl.sub.3) 9.30(s, 1H), 8.95(d, 1H),
8.09(m, 2H), 7.99-7.94(m, 3H), 7.86-7.82(d, 2H), 7.73(m, 1H),
7.43(m, 1H), 4.27(m, 1H), 3.78(d, 1H), 3.42(m, 1H), 3.26(q, 2H),
2.98(d, 1H), 2.82(d, 1H), 2.55(dd, 1H), 2.39(m, 1H), 135(d, 3H)
EXAMPLE 95
(S)-2-[4-(4-Cyanobenzenesulphonyl)-3-methylpiperazin-1-yl]-N-(quinolin-5-y-
l)acetamide
[0814] 102
i) (S)-2-(3-Methylpiperazin-1-yl)-N-(quinolin-5-yl)acetamide
[0815] The subtitle compound was prepared from
2-chloro-N-(quinolin-5-yl) acetamide (1 g) (J Indian Chem Soc,
1940, 17, 619-621) and (S)-2-methylpiperazine (0.5 g) by the method
of Example 58 step (i) as a white solid. Yield: 1.4 g
[0816] MS: APCI(+ve) 285(M+1)
ii)
(S)-2-[4-(4-Cyanobenzenesulphonyl)-3-methylpiperazin-1-yl]-N-(quinolin-
-5-yl)acetamide
[0817] The title compound was prepared from the product of step (i)
(1.4 g) and 4-cyanobenzenesulphonyl chloride (1 g) by the method of
Example 58 step (ii) as a white solid. Yield: 0.53 g
[0818] MS: APCI(+ve) 450(M+1)
[0819] .sup.1H NMR .delta. (CDCl.sub.3) 9.30(s, 1H), 8.95(d, 1H),
8.09(m, 2H), 7.99-7.94(m, 3H), 7.86-7.82(d, 2H), 7.73(m, 1H),
7.43(m, 1H), 427(m, 1H), 3.78(d, 1H), 3.42(m, 1), 3.26(q, 21),
2.98(d, 1H), 2.82(d, 1H), 2.55(dd, III), 2.39(m, 1H), 135(d,
3H)
EXAMPLE 96
cis-2-[4-(3-Cyanobenzenesulphonyl-3,5-dimethylpiperazin-1-yl]-N-(2-methyl--
5-methanesulphonylphenyl)acetamide
[0820] 103
i) 2-Chloro-N-(2-methyl-5-methanesulphonylphenyl)acetamide
[0821] The subtitle compound was prepared from
5-methanesulphonyl-2-methyl- aniline (0.82 g) and chloroacetyl
chloride (0.72 ml) by the method of Example 33 step (iii) as a
beige solid.
[0822] Yield: 0.61 g
[0823] MS: APCI -ve) 260(M-1)
ii)
cis-2-[4-(3-Cyanobenzenesulphonyl)-3-dimethylpiperazin-1-yl-N-2-methyl-
-5-methanesulphonylphenyl)acetamide
[0824] The title compound was prepared from the product of step (i)
(0.14 g) and the product of Example 80 step (ii) by the method of
Example 80 step (iii) as a white solid. Yield: 0.03 g
[0825] MS: APCI(+ve) 505(M+1)
[0826] .sup.1HNMR .delta. (CDCl.sub.3) 8.84(bs, 1H), 8.63(s, 1H),
8.10(s, 1H), 8.06(d, 1H), 7.90(d, 1H), 7.65(d, 1H), 7.64(d, 1H),
7.40(d, 1 Hz, 4.25(m, 2H), 3.14(s, 2H), 3.07(s, 3H), 2.74(d, 2H)S
2.40(s, 3H), 2.20(m, 2H), 1.60(d, 6H)
EXAMPLE 97
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl-N(2-methyl-5-
-(4-amino-1-piperidinyl)methyl)phenyl]acetamide
[0827] 104
i)
2-Methyl-5-((1,1-dimethyl)-1-dimethylethyl)silyloxymethyl-aniline
[0828] A mixture of 2-methyl-5-hydoxymethylaniline (10 g),
tert-butyldimethylsilyl chloride (10.84 g), imidazole (12.24 g) in
dry N,N-dimethylformamide (80 ml) were stirred at ambient
temperature for 18 h. The mixture was partitioned between ethyl
acetate and saturated brine. The organic phase washed with water,
collected, dried (MgSO.sub.4) and solvent evaporated under reduced
pressure to leave a brown gum which slowly crystalised on standing.
Yield: 19.2 g
[0829] MS:APCI(+ve) 252(M+1)
ii)
cis-2-Chloro-N-(2-methyl-5-((1,1-dimethylethyl)silyloxymethyl)acetamid-
e
[0830] The subtitle compound was prepared from the product of step
(i) (18.3 g) and chloroacetyl chloride (17.5 ml) by the method of
Example 33 step (iii) as a beige solid. Yield: 23 g
[0831] MS: APCI(-ve) 326(M-1)
iii)
2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl-N-(2-methyl-
-5 ((1,1-dimethyl)-1-dimethyl)silyloxymethyl)phenyl]acetamide,
[0832] The subtitle compound was prepared from the product of step
(ii) (125 g) and the product of Example 80 step (ii) (1 g) by the
method of Example 80 step (iii) as a beige foam
[0833] Yield: 1.3 g
[0834] MS: APCI(+ve) 571(M+1)
iv)
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-me-
thyl-S hydroxymethyl)phenyl]acetamide
[0835] A solution of the product of step (iii) (1.3 g) in
tetrahydrofuran (9 ml) was treated with 1M tetrabutylammonium
fluoride in tetrahydrofuran (2.6 ml) at ambient temperature. After
stirring for 1.5 h the solvent was evaporated under reduced
pressure to leave a brown gum Purification was by silica gel
chromatography eluting with ethyl acetate/iso-hexane (9:1) to give
the subtitle compound as a white solid. Yield: 0.93 g
[0836] MS: APCI(+ve) 457(M+I).
v)
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-2-meth-
yl-5-iodomethyl)phenyl]acetamide
[0837] The product from step (iv) (0.1 g) in tetrahydrofuran (2
ml), N,N-diisopropylethylamine (0.15 ml), potassium iodide (2 mg)
was treated with methanesulphonyl chloride (0.34 ml). After
stirring at ambient temperature for 40 h The solvent was evaporated
under reduced pressure to leave a beige gum This was used directly
in the next step.
vi)
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl-N-2-meth-
yl-5-(4-amino-1-piperidinyl)methyl)phenyl]acetamide
[0838] The crude product from step (v) (0.2 g) was treated with
1,1-dimethylethyl, 4-amino-piperidin-yl-carboxylate (0.13 g) in
tetrahydrofuran (2 ml) at 55.degree. C. for 24 h. The solvent was
evaporated under reduced pressure. The residue was then treated
with 4M hydrogen chloride in 1,4-dioxane (3 ml) for 5 h. The
solvents were then evaporated under reduced pressure. Purification
was by reverse phase HPLC to give the title compound as a white
solid. Yield 0.1 g
[0839] MS: APCI(+ve) 539(M+1)
[0840] .sup.1H NMR .delta. (DMSO) 9.84(bs, 1H), 9.19(s, 1H),
8.33(s, 1H), 8.16(m, 4H), 7.82(t, 1H), 7.76(s, 1H), 7.32(d, 1H),
7.19(d, 1H), 422(s, 2H), 4.11(m, 2H), 3.41(d, 2H), 3.25(bs, 2H),
3.10(s, 2H), 3.01(m, 2H, 2.70(d 2H, 2.40(m, 2H), 2.34(s, 3H),
2.08(d, 2H), 1.96(dd, 1.75(q, 2H), 1.45(d, 6H
EXAMPLE 98
(R)-2-[4-(4-Methanesulphonylbenzenesulphonyl)-3-methylpiperazin-1-yl-]-N-(-
quinolin-5-yl)acetamide
[0841] 105
i) (R)-1,1-Dimethylethyl,
(4-Methanesulphonylbenzenesulphonyl-3-methylpipe-
razin-1-yl-carboxylate
[0842] The subtitle compound was prepared from
(R)-1,1-dimethylethyl, 3-methylpiperazin-1-yl-1-carboxylate (0.75
g) (J. Med. Chem, 1993, 36(6), 690)and
4-methanesulphonyl-benzenesulphonyl chloride (0.96 g) by the method
of Example 58 step (ii) as white solid.
[0843] Yield: 0.9 g
[0844] .sup.1H NMR .delta.(DMSO) 8.15(d, 2H), 8.07(d, 2H), 4.08(bs,
1H), 3.85(bs, 1H), 3.65(bs, 1H), 3.33(s, 2H), 3.32(s, 3H), 3.09(t,
1H), 1.36(s, 9H), 0.93(d, 3H)
ii) (R)-1-(4-Methanesulphonylbenzenesulphonyl-3-methylpiperazine,
Hydrochloride Salt
[0845] The subtitle compound was prepared from the product of step
(i) (0.209 g by the method of Example 27 step (iv) as a white solid
Yield: 0.15 g
[0846] MS:APCI(+ve) 319(M+1)
iii)
(R)-2-[4-(4-Methanesulphonylbenzenesulphonyl)-3-methylpiperazin-1-yl]-
-N-(quinolin-5-yl)acetamide
[0847] The title compound was prepared from the product of step
(ii) (0.14 g) and 2-chloro-N-(quinolin-5-yl)acetamide (0.97 g) (J
Indian Chem Soc, 1940, 17, 619-621) by the method of Example 33
step (iv) as a white solid. Yield: 0.135 g
[0848] MS: APCI(+ve) 503(M+1)
[0849] .sup.1HNMR .delta. (DMSO) 9.88(s, 1H), 8.91(d, 1H), 8.32(d,
1H), 8.16(d, 2H), 8.09(d, 2H), 7.88(dd, 1H), 7.73(m, 2H), 7.55(q,
1H), 4.09(d, 1H), 3.66(d, 1H), 3.38(d, 1H), 3.31(s, 3H), 3.22(s,
2H), 2.91(d, 1H), 2.73(d, 1H), 2.31(m, 2H, 2.15(t, 1H), 1.21(d,
3H)
EXAMPLE 99
(R)-2-[4-(4-Acetamidobenzenesulphonyl)-3-methylpiperazin-1-yl]-N-(quinolin-
-5-yl)acetamide
[0850] 106
i) (1,1-Dimethylethyl,
(4-Acetamidobenzenesulphonyl-3-methylpiperazin-1-yl-
-1-carboxylate
[0851] The subtitle compound was prepared from
(R)-1,1-dimethylethyl, 3-methylpiperazin-1-yl-1-carboxylate (4 g)
(J. Med. Chem, 1993, 36(6), 690) and 4 acetamidobenzenesulphonyl
chloride (4.68 g) by the method of Example 58 step (ii) as white
solid. Yield: 4.9 g
[0852] MS: APCI(+ve) 398(M+1)
ii)(R)-1-(4-Acetamidobenzenesuphonyl)-3-methylpiperazine,
Hydrochloride Salt
[0853] The subtitle compound was prepared from the product of step
(i) (4.9 g) by the method of Example 27 step (iv) as a white solid.
Yield: 4.38 g
[0854] .sup.1H NMR .delta. (DMSO) 10.60(s, 1H), 8.92(bs, 1H),
8.91(d, 2H), 8.04(t, 1H), 7.85(d, 2H), 7.78(d, 2H), 7.45(d, 1H),
6.66(d, 1H), 3.27(t, 2H), 3.06(m, 2H), 2.87(m, 2H), 2.73(m, 3H),
2.10(s, 3H), 1.30(d, 2H), 1.16(d, 3H)
iii)
(R)-2-[4-(4-Acetylaminobenzenesulphonyl-3-methylpiperazin-1-yl]-N-(qu-
inolin-5-yl)acetamide
[0855] The title compound was prepared from the product of step
(ii) (0.65 g) and 2-chloro-N-(quinolin-5-yl)acetamide (0.39 g) (a
Indian Chem Soc, 1940, 17, 619-621) by the method of Example 33
step (iv) as a white solid. Yield: 0.064 g
[0856] MS: APCI(+ve) 439(M42(+H,-Ac))
[0857] .sup.1HNMR .delta. (DMSO) 9.89(s, 1H), 8.91(s, 1H), 8.31(d,
1H), 7.87(m, 1H, 7.75(s, 2H, 7.50(m, 1H), 7.43(d, 2H), 6.63(d, 2),
6.01(s, 2H), 3:90(s, 1H), 3.42(d, 1H), 3.42(d, 1H), 3.24(s, 1H),
3.20(d, 2H), 2.86(d, 1H), 2.68(d, 1H), 2.31(d, 1H), 2.18(t, 1),
1.18(d, 3H)
EXAMPLE 100
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-methyl-
-5-(1-piperazinylmethyl)phenyl)acetamide
[0858] 107
[0859] The title compound was prepared from the product of Example
97 step (v) (0.2 g) and 1,1-dimethylethyl, piperazine-1-carboxylate
(0.12 g) by the method of Example 97 step (vi) to give the title
compound as a white solid. Yield 74 mg
[0860] MS: APCI(+ve) 525 I+1)
[0861] .sup.1H NMR .delta. (DMSO) 9.21(s, 1H), 9.0(bs, 2H), 8.33(s,
1H), 8.17(d, 2H), 7.82(t, 1H), 7.69(s, 1H), 7.28(d, 1H), 7.16(d,
1H), 4.14(m, 2H), 3.27(bs, 4H), 3.15(s, 2H), 3.05(bs, 2H), 2.69(d,
2H), 2.21(s, 3H), 2.0(d, 2H, 1.44(d, 6H)
EXAMPLE 101
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-2-methyl--
5(4-piperidinylamino)methyl)phenyl)acetamide
[0862] 108
[0863] The title compound was prepared from the product of Example
97 step (v) (0.2 g) and 1,1-dimethylethyl,
4-aminopiperidinyl-1-carboxylate (0.12 g) by the method of Example
97 step (vi) as a white solid. Yield: 34 mg
[0864] MS: APCI(+ve) 539(M+1)
[0865] .sup.1H NMR .delta. (DMSO) 9.18(s, 1H), 9.09(s, 2H), 8.81(m,
1H), 8.60(m, 1H), 8.33(s, 1H), 8.15(d, 2H), 7.82(t, 1H), 7.75(s,
1H), 7.30(d, 1H), 7.21(d, 1H), 4.10(m, 4H), 3.40(d, 21), 3.32(s,
2H), 2.92(q, 2H), 2.68(d, 2H), 2.23(s, 3H), 1.94(dd, 2H), 1.73(q,
2H), 1.43(d, 6H)
EXAMPLE 102
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl-N-(2-methyl--
51--morpholinyl)methyl)phenyl)acetamide
[0866] 109
[0867] The title compound was prepared from the product of Example
97 step (v) (0.2 g) and morpholine (0.058 g) by the method of
Example 97 step (vi). The solvents evaporated under reduced
pressure and the residue purified by reverse phase HPLC to give the
title compound as a white solid. Yield: 97 mg
[0868] MS: APCI(+ve) 526(M+1)
[0869] .sup.1H NMR .delta. (DMSO) 10.11(bs, 1H), 9.22(s, 1H),
8.34(s, 1H), 8.16(d, 2H, 7.83(d, 1H), 7.78(d, 1H), 7.33(d, 1H),
7.21(d, 1H), 4.31(s, 2H), 4.12(t, 4H), 3.63(m, 2H), 3.3(m, 4H),
2.70(d, 2H), 2.23(s, 3H), 1.97(dd, 2H), 1.43(d, 6H)
EXAMPLE 103
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-methyl-
-5-(2-hydroxyethylamino)methyl)phenyl)acetamide
[0870] 110
[0871] The title compound was prepared from the product of Example
97 step (v) (0.2 g) and ethanolamine (0.041 g) by the method of
Example 97 step (vi). The solvents evaporated under reduced
pressure and the residue purified by reverse phase HPLC to give the
title compound as a white solid. Yield: 37 mg
[0872] MS: APCI(+ve) 500(M+1)
[0873] .sup.1HNMR .delta. (DMSO) 8.27(s, 1H), 8.18(d, 1H), 8.02(d,
1H), 7.74-7.82(m, 3H), 7.35(d, 2H), 7.25(d, 1H), 4.27(t, 2H),
4.20(s, 2H), 3.83(t, 2H), 3.40(s, 2H), 3.25(s, 1H), 3.14(t, 2H),
2.97(d, 2H), 2.33(s, 5H), 1.56(d, 6H)
EXAMPLE 104
cis-2-[4-(3-Cyanobenzenesulphonyl-3,5-dimethylpiperazin-1-yl]-N-(2-methyl--
5-(S,S)-(2,5-diazabicyclo[2,2,1]hept-2-yl)methyl)phenyl)acetamide
[0874] 111
[0875] The title compound was prepared from the product of Example
97 step (v) (0.2 g) and 1,1-dimethylethyl,
(S,S)-2,5-diazabicyclo[2,2,1]heptane-5- -=carboxylate (0.13 g) by
the method of Example 97 step (vi) as a white solid. Yield: 107
mg
[0876] MS: APCI(+ve) 537(M+I)
[0877] .sup.1H NMR .delta. (DMSO) 9.2(s, 1H), 8.34(s, 1H), 8.16(d,
2H), 7.83(d, 1H), 7.79(s, 1H), 7.31(d, 1H), 7.24(d, 1H), 4.46(s,
1H), 4.32(m, 2]), 4.12(s, 2H), 3.35(d, 2H), 3.11(s, 2H), 2.68(d,
2H), 2.23(s, 3H), 1.98(t, 3H), 1.44(d, 6H)
EXAMPLE 105
(R)-2-[4-(2-Pyridinesulphonyl)-3-methylpiperazin-1-yl]-N-(quinolin-5-yl)ac-
etamide
[0878] 112
i) (R)-1,1-Dimethylethyl,
(2-Pyridinesulphonyl-3-methylpiperazin-1-yl-1-ca- rboxylate
[0879] A solution of 1,1-dimethylethyl,
3-(R)-methylpiperazine-1-carboxyla- te (2 g) (J. Med. Chem,
1993,36(6), 690), 4-N,N'-dimethylaminopyridine (1.22 g) in pyridine
(10 ml) was treated with 2-pyridinesulphonyl chloride (2.7 g) at
0.degree. C. The ice bath was removed and the mixture further
stirred for 1 h at ambient temperature. The mixture was partitioned
between dichloromethane and water. The organic phase further washed
with brine, collected, dried (MgSO.sub.4) and solvent evaporated
under reduced pressure. Purification was by silica gel
chromatography eluting with ethyl acetate/dichloromethane mixtures
to give the subtitle compound as white solid. Yield: 3.3 g
[0880] MS: ESI(+ve) 342(M+I)
ii) (R)-1-(2-Pyridinesulphonyl-3-methylpiperazine, hydrochloride
salt
[0881] The subtitle compound was prepared from the product of step
(i) (2.5 g) by the method of Example 27 step (iv) as a white solid
Yield: 2.5 g
[0882] MS: ESI(+ve) 242(M+1)
iii)
(R)-2-[4-(2-Pyridinesulphonyl)-3-methylpiperazin-1-yl]-N-quinolin-5-y-
l)acetamide
[0883] The title compound was prepared from the product of step
(ii) (0.6 g) and 2-chloro-N-(quinolin-5-yl)acetamide (0.39 g) (I
Indian Chem Soc, 1940, 17, 619621) by the method of Example 80 step
(iii). Purification was by silica gel chromatography eluting with
ethyl acetate to give a white solid Yield: 0.41 g
[0884] MS: ESI(+ve) 424(M+1)
[0885] .sup.1HNMR .delta.(DMSO) 8.8(d, 1H), 8.35(d, 1H), 8.10(t,
1H), 7.97(d, 1H), 7.90(d, 1H), 7.7(m, 3H), 7.55(m, 1H), 4.10(m,
1H), 3.7(m, 1H) 3.5(t, 1H), 3.3(m, 2H), 3.2(m, 1H), 2.95(d, 1H),
2.7(d, 1H), 2.4-2.1(m, 2H), 1.2(d, 3H)
EXAMPLE 106
cis-2-[4-(3-Cyanobenzenesulphonyl).sub.3,
dimethylpiperazin-1-yl]-N-(2-met-
hyl-3-(4-amino-1-piperidinyl)methyl)phenyl)acetamide
[0886] 113
i)
2-Methyl-3-((1,1-dimethyl)-1-dimethylethyl)silyloxymethylaniline
[0887] The subtitle compound was prepared from
2-methyl-3-hydoxymethylanil- ine (5 g) and tert-butyldimethylsilyl
chloride (5.42 g) by the method of Example 97 step (i) as an oil
which crystalised on standing. Yield: 9.12 g
[0888] MS: APCI(+ve) 252(M+1)
ii)
2-Chloro-N-(2-methyl-3-((1,1-dimethyl)-1-dimethylethyl)silyloxymethyl)-
acetamide
[0889] The subtitle compound was prepared from the product of step
(i) (4.13 g) and chloroacetyl chloride (1.5 ml) by the method of
Example 33 step (iii) as a beige solid. Yield: 3.12 g
[0890] MS:APCI(+ve) 328(M+1)
iii)
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-m-
ethyl-5-((1,1-dimethyl)-1-dimethylethyl)silyloxymethyl)phenyl]acetamide
[0891] The subtitle compound was prepared from the product of step
(ii) (1.25 g) and the product of Example 80 step (ii) (1 g) by the
method of Example 80 step (iii) as a cream solid
[0892] Yield: 1.5 g
[0893] MS: APCI(+ve) 571(M+1)
iv)
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-me-
thyl-5-hydroxymethyl)phenyl]acetamide
[0894] The subtitle compound was prepared from the product of step
(iii) (1.4 g) and 1M tetrabutylammonium fluoride in tetrahydrofuran
(2.7 ml) by the method of Example 97 step (iv) as a white solid.
Yield: 1 g
[0895] MS:APCI(+ve) 457(M+1)
v)
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-met-
hyl-3-iodomethyl)phenyl]acetamide
[0896] The product from step (iv) (0.1 g) in tetrahydrofuran (2
ml), N,N-diisopropylethylamine (0.15 ml), potassium iodide (2 mg)
was treated with methanesulphonyl chloride (0.34 ml). After
stirring at ambient temperature for 40 h. The solvent was
evaporated under reduced pressure to leave a beige gum. This was
used directly in the next step.
vi)
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-me-
thyl-5-(4-amino-1-piperidinyl)methyl)phenyl]acetamide
[0897] The crude product from step (v) (0.2 g) was treated with
1,1-dimethylethyl, 4-aminopiperidinyl-4-carboxylate (0.13 g) in
tetrahydrofuran (2 ml) at 55.degree. C. for 24 h The to solvent was
evaporated under reduced pressure. The residue was then treated
with 4M hydrogen chloride in 1,4-dioxane (3 ml) for 5 h The
solvents were then evaporated under reduced pressure. Purification
was by reverse phase HPLC to give the title compound as a white
solid. Yield 0.068 g
[0898] MS: APCI(+ve) 539(M+1)
[0899] .sup.1H NMR .delta. (CDCl.sub.3/DMSO) 8.87(bs, 1H), 8.67(bs,
1H), 8.14(s, 1H), 8.10(d, 1H), 7.95(d, 1H), 7.80(d, 1H), 7.75(t,
1H), 7.30(m, 2H), 4.30(bs, 1H), 4.20(m, 2H), 3.10(s, 2H), 2.80(d,
2H), 2.30(s, 3H), 2.20(m, 4H), 1.60(d, 6H)
EXAMPLE 107
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-methyl-
-3-(4-piperidinylamino)methyl)phenyl)acetamide
[0900] 114
[0901] The title compound was prepared from the product of Example
106 step (v) (0.2 g) and 1,1-dimethylethyl
4-aminopiperidinyl-carboxylate (0.12 g) by the method of Example
106 step (vi) as a white solid. Yield: 38 mg
[0902] MS: APCI(+ve) 539(M+1)
[0903] .sup.1H NMR .delta. (DMSO) 9.33(bs, 1H), 9.10(bs, 1H),
8.8(bd, 1H), 8.60(bd, 1H), 8.37(s, 1H), 8.20(m, 1H), 7.90(t, 1H),
7.40(d, 1H), 7.30(m, 2M, 4.20(bs, 21). 4.10(m, 2H), 3.10(s, 2H),
3.00(m, 2H), 2.7(m, 2H), 2.30(m, 2H), 2.20(s, 3H), 2.00-1.80(m,
4H), 1.40(s, 6H)
EXAMPLE 108
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-methyl-
-3-(1-piperazinylmethyl)phenyl)acetamide
[0904] 115
[0905] The title compound was prepared from the product of Example
106 step (v) (0.2 g) and 1,1-dimethylethyl,
piperazine-1-carboxylate (0.12 g) by the method of Example 106 step
(vi) as a white solid. Yield: 74 mg
[0906] MS: APCI(+ve) 525(M+1)
[0907] .sup.1H NMR .delta. (DMSO) 8.34(s, 1H), 8.20(m, 2H), 7.80(t,
1H), 7.40(t, 1H), 720(2xd, 2H), 4.20(m, 2H), 3.90(bs, 2H), 3.20(m,
6H), 3.00-2.60(m, 6H), 2.20(s, 3H), 2.00(m, 2H), 1.50(d, 6H)
EXAMPLE 109
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-methyl-
-3-(S,S)-(2,5-diazabicyclo[2,2,1]hept-2-yl)methyl)phenyl)acetamide
[0908] 116
[0909] The title compound was prepared from the product of Example
106 step (v) (0.2 g) and 1,1-dimethylethyl,
(S,S)-2,5-diazabicyclo[2.2.1]hept- ane-5-carboxylate (0.13 g) by
the method of Example 106 step (vi) as a white solid. Yield: 82
mg
[0910] MS: APCI(+ve) 537(M+1)
[0911] .sup.1H NMR .delta. (DMSO) 8.38(s, 1H), 8.20(m, 2H), 7.80(t,
1H), 7.50(d, 1H), 7.30(m, 2H), 4.40(s, 1H), 4.30(m, 2H), 4.10(m,
2H), 3.30(m, 2H), 3.10(s, 2H), 2.80(m, 2H), 2.22(s, 3H), 2.00(m,
4H), 1.50(d, 6H)
EXAMPLE 110
cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-methyl-
-3-(1-morpholinyl)methyl)phenyl)acetamide
[0912] 117
[0913] The title compound was prepared from the product of Example
106 step (v) (0.2 g) and morpholine (0.058 g) by the method of
Example 106 step (vi) as a white solid. Yield: 69 mg
[0914] MS: APCI(+ve) 526(M+1)
[0915] .sup.1H NMR .delta. (DMSO) 8.34(s, 1H), 820(m, 2H), 7.80(t,
1H), 7.60(d, 1H), 7.40(m, 2H), 4.40(s, 2H), 4.20(m, 2H), 4.00(bs,
2H), 3.70(bs, 2H), 3.30(bs+s, 6H), 2.80(d, 2H), 2.30(s, 3H),
2.00(m, 2H), 1.50(d, 6H)
EXAMPLE 111
Cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-((2-methy-
l-3-(2-(1-pyrrolidinyl)ethoxy)phenyl)acetamide
[0916] 118
i) 2-Methyl-3-((1,1-dimethyl)-1-dimethylethyl)silyloxyaniline
[0917] The subtitle compound was prepared from
3-amino-2-methylphenol (10 g) and tert-butyldimethylsilyl
chloride(12.22 g) by the method of Example 97 step (i) as a brown
oil.
[0918] Yield: 15 g
[0919] .sup.1H NMR .delta. (CDCl.sub.3) 6.86(t, 1H), 6.33(d, 1H),
6.27(d, 1H), 3.58(bs, 2H, 2.04(s, 3H), 1.01(s, 9H), 0.20(s, 6H)
ii)
2-Chloro-N-(2-methyl-3-((1,1-dimethyl)-1-dimethylethyl)silyloxy)phenyl-
)acetamide
[0920] The product from step (i) (5 g), PyBrop (9.82 g),
chloroacetic acid (1.99 g), N,N-diisopropylethylamine (11 ml) in
dichloromethane (100 ml) were stirred at ambient temperature for 16
h. The mixture was partitioned between water and dichloromethane,
the organic phase collected, dried (MgSO.sub.4) and solvent
evaporated under reduced pressure. Purification was by silica gel
chromatography eluting with 10% diethyl ether in iso-hexane
containing 1% triethylamine to give the subtitle compound as a pale
yellow oil. Yield: 3.5 g
[0921] .sup.1H NMR .delta. (CDCl.sub.3) 8.21(bs, 1H), 7.48(d, 1H),
7.09(t, 1H), 6.68(d, 1H), 4.23(s, 2H), 2.16(s, 3H), 1.02(s, 9H),
0.22(s, 6H)
iii)
Cis-2-[4-(3-Cyanobenzenesulphonyl-3,5-dimethylpiperazin-1-yl]-N-((2-m-
ethyl-3-((1,1-dimethyl)-1-dimethylethyl)silyloxy)phenyl)acetamide
[0922] The subtitle compound was prepared from the product of step
(ii) (1 g) and the product of Example 80 step (ii) (0.89 g) by the
method of Example 80 step (iii) as a beige solid. Yield: 1.6 g.
[0923] .sup.1H NMR .delta.(CDCl.sub.3) 8.67(s, 1H), 8.12(s, 1H),
8.03(d, 1H), 7.85(d, 1H), 7.67(t, 1H), 7.59(d, 1H), 7.07(t, 1H),
6.64(d, 11, 4.05-4.10(m, 2H), 3.10(s, 2H), 2.73(d, 2H), 2.19(d,
2H), 2.10(s, 3H), 1.54(s, 6H), 1.01(s, 9H), 0.22(s, 6H)
iv)
Cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-me-
thyl-3-hydroxy)phenyl)acetamide
[0924] The subtitle compound was prepared from the product of step
(iii) (1.6 g) and tetrabutylammonium fluoride (3.18 ml) by the
method of Example 97 step (iv) as a white solid
[0925] Yield: 0.5 g
[0926] MS APCI(+ve) 443(M+1)
v)
Cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-((2-me-
thyl-3-(2(1-pyrrolidinyl)ethoxy)phenyl)acetamide
[0927] The product from step (iv) (0.1 g),
1-(2-chloroethyl)pyrrolidine hydrochloride (76 mg), ceasium
carbonate (0.36 g) in 1-methyl-2-pyrrolidinone (2 ml) were sired at
70.degree. C. for 16 h The mixture was partitioned between ethyl
acetate and water, the organic phase collected, dried (MgSO.sub.4)
and solvent evaporated under reduced pressure. Purification was by
reverse phase HPLC eluting with 5 to 90% methanol in 0.1% aqueous
trifluoroacetic acid to give the the title compound as a white
solid. Yield: 7 mg
[0928] MS: APCI(+ve) 540(M+1)
[0929] .sup.1H NMR .delta.(CD.sub.3OD) 8.15(s, 1H), 8.05(d, 1H),
7.89(d, 1H), 7.67(t, 1H), 7.06(s, 1H), 7.04(s, 1H), 6.74(t 1H),
4.01-4.09(m, 4H), 2.99(s, 2H), 2.88(t, 2H), 2.61-2.66(m, 6H),
2.05(s, 3H), 1.95(dd, 2H), 1.71-1.77(m, 4H), 1.44(d, 6H)
EXAMPLE 112
(.+-.)
Cis-2-[4-(3-Cyanobenzenesulphonyl-3,5-dimethylpiperazin-1-yl]-N-((2-
-methyl-3-(1-methylpiperidin-3-yl)methoxy)phenyl)acetamide
[0930] 119
[0931] The title compound was prepared from the product of Example
111 step (iv) (0.1 g) and (.+-.) 1-methyl-3-chloromethylpiperidine
(83 mg) by the method of Example 111 step (v) as a white solid.
Yield 19 mg
[0932] MS: APCI(+ve) 554(M+1)
[0933] .sup.1HNMR .delta. (CD.sub.3OD) 8.24(s, 1H), 8.14(d, 1H),
7.98(d, 1H), 7.77(t, 1H), 7.10-7.15(m, 2H), 6.78-6.81(m, 1H),
4.12-4.18(m, 2H), 3.80-3.92(m, 2H), 3.09(s, 3H), 2.75-2.85(m, 1H),
2.74(d, 2H), 2.31(s, 3H), 2.12(s, 3H), 1.64-2.17(m 8H), 1.53(d,
6H), 1.15-1.19(m, 2H)
EXAMPLE 113
Cis-2-[4-(3-Cyanobenzenesulphonyl-3,5-dimethylpiperazin-1-yl]-N-((2-methyl-
-4-(2-(1-pyrrolidinyl)ethoxy)phenyl)acetamide
[0934] 120
i) 2-Methyl-4-((1,1-dimethyl)-1-dimethylethyl)silyloxyaniline
[0935] The subtitle compound was prepared from 4
amino-3-methylphenol (10 g) and tert-butyldimethylsilyl
chloride(12.22 g) by the method of Example 97 step (i) as a brown
oil.
[0936] Yield: 14 g
[0937] .sup.1H NMR .delta. (CDCl.sub.3) 6.53-6.58(m, 3), 3.33(bs,
2H), 2.12(s, 3H), 0.98(s, 91), 0.15(s, 61)
ii) 2-Chloro-N-2-methyl-3((1,1-methyl)-1-dimethylethyl)
silyloxy)phenyl)acetamide
[0938] The subtitle compound was prepared from the product of step
(i) (5 g) by the method of Example 111 step (ii) as pale yellow
oil. Yield: 5 g
[0939] .sup.1H NMR .delta.(CDCl.sub.3) 8.06(bs, 1H), 7.57-7.60(m,
1H), 6.53-6.58(m, 3H), 3.33(bs, 2H), 2.12(s, 3H), 0.98(s, 9H),
0.15(s, 6H)
iii)
Cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-((2--
methyl-4
((1,1-dimethyl)-1-dimethylethyl)silyloxy)phenyl)phenyl)acetamide
[0940] The subtitle compound was prepared from the product of step
(ii) (1 g) and the product of Example 80 step (ii) (0.89 g) by the
method of Example 80 step (iii) as a white solid. Yield: 1.6 g
[0941] .sup.1H NMR .delta.(CDCl.sub.3) 8.48(s, 1H), 8.12(s, 1H),
8.04(d, 1H), 7.86(d, 1H), 7.64-7.70(m, 2H), 6.67-6.70(m, 2H),
4.11-4.15(m, 2H), 3.08(s, 2H), 2.73(d, 2H), 2.22(s, 3H), 2.16(dd,
2H), 1.55(d, 6H), 0.97(s, 9H), 0.18(s, 6H)
iv)
Cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-((2-m-
ethyl-4-hydroxy)phenyl)acetamide
[0942] The subtitle compound was prepared from the product of step
(iii) (1.6 g) and tetrabutylammonium fluoride (3.21 ml) by the
method of Example 97 step (iv) as a white solid Yield: 0.4 g
[0943] MS APCI(+ve) 443(M+1)
v)
Cis-2-[Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-methyl-4-
-(2-(1-pyrrolidinyl)ethoxy)phenyl)acetamide
[0944] The title compound was prepared from the product of step
(iv) (0.1 g) and 1-(2-chloroethyl)pyrrolidine hydrochloride (76 mg)
by the method of Example 111 step (v) as a white solid. Yield: 10
mg
[0945] MS: APCI(+ve) 540(M+1)
[0946] .sup.1H NMR .delta. (CD.sub.3OD) 8.24(s, 1H), 8.15(d, 1H),
7.98(d, 1H), 7.77(t, 1H), 730(d, 1H), 6.83(d, 1H), 6.77(dd, 1H),
4.13-4.18(m, 2H), 4.10(t, 2H), 3.07(s, 2H), 2.91(t, 2H), 2.73(d,
2H), 2.65-2.69(m, 4H), 2.25(s, 3H), 2.04(dd, 2H), 1.79-1.86(m, 4H),
1.53-1.54(d, 6H),
EXAMPLE 114
(.+-.)
Cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-((-
2-methyl-4-(1-methylpiperidin-3-yl)methoxy)phenyl)acetamide
[0947] 121
[0948] The title compound was prepared from the product of Example
113 step (iv) (0.1 g) and (.+-.) 1-methyl-3-chloromethylpiperidine
(83 mg) by the method of Example 111 step (v) as a white solid
Yield: 19 mg
[0949] MS: APCI(+ve) 554(M+1)
[0950] .sup.1H NMR .delta.(CD.sub.3OD) 8.24(s, 1H), 8.15(d, 1H),
7.98(d, 1H), 7.77(t, 1H), 729(d, 1H), 6.79(d, 1H), 6.74(dd, 1H),
4.13-4.16(m, 2H), 3.75-3.88(m, 2H), 3.08(s 2H), 3.02-3.04(m, 1H),
2.82-2.85(m, 1H), 2.73(d, 2H), 2.29(s, 3H), 2.21(s, 3H),
1.62-2.10(m, 8H), 1.53(d, 6H), 1.09-1.13(m, 1H),
EXAMPLE 115
(.+-.)
Cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-((-
2-methyl-5-(1-methylpiperidin-3-yl)methoxy)phenyl)acetamide
[0951] 122
i) 2-Methyl-5-((1,1-dimethyl)-1-dimethylethyl)silyloxyaniline
[0952] The subtitle compound was prepared from
3-amino-4-methylphenol (10 g) and tert-butyldimethylsilyl
chloride(12.22 g) by the method of Example 97 step (i) as a brown
oil.
[0953] Yield: 15 g
[0954] .sup.1H NMR .delta. (CDCl.sub.3) 6.84-6.88(m, 1H),
6.18-6.22(m, 2H), 3.52(bs, 2H), 2.08(s, 3H), 0.97(s, 9H), 0.17(s,
6H)
ii)
2-Chloro-N-(2-methyl-5((1,1-dimethyl)-1-dimethylethyl)silyloxy)phenyl)-
acetamide
[0955] The subtitle compound was prepared from the product of step
(i) (5 g) by the method of Example 111 step (ii) as pale yellow
oil. Yield: 5.3 g
[0956] .sup.1H NMR .delta. (CDCl.sub.3) 8.19(bs, 1H), 7.57(d, 1H),
7.03(d, 1H), 6.61(dd, 1H), 4.22(s, 2H), 2.23(s, 3H), 0.98(s, 9H),
0.21(s, 6H)
iii)
Cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-((2--
methyl-5-((1,1-dimethyl)-1-dimethylethyl)silyloxy)phenyl)phenyl)acetamide
[0957] The subtitle compound was prepared form the product of step
(ii) (1 g) and the product of Example 80 step (ii) (0.89 g) by the
method of Example 80 step (iii) as a white solid. Yield: 1.8 g
[0958] .sup.1H NMR .delta. (CDCl.sub.3) 8.64(s, 1H), 8.12(s, 1H),
8.04(d, 1H), 7.87(d, 1H), 7.68-7.70(m, 2H), 7.01(d, 1H), 6.56(dd,
1H), 4.09-4.16(m, 2H), 3.08(s, 2H), 2.72(d, 2H), 2.22(s, 3H),
2.16(dd, 2H), 1.55(d, 6H), 0.97(s, 9H), 0.19(s, 6H)
iv)
Cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(2-me-
thyl-5-hydroxy)phenyl)acetamide
[0959] The subtitle compound was prepared from the product of step
(iii) (1.81 g) and tetrabutylammonium fluoride (3.24 ml) by the
method of Example 97 step (iv) as a white solid
[0960] Yield: 0.8 g
[0961] MS APCI(+ve) 443(M+1)
v) (.+-.)
Cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-
-((2-methyl-5-(1-methylpiperidin-3-yl)methoxy)phenyl)acetamide
[0962] The title compound was prepared from the product of step
(iv) (0.1 g) and (.+-.) 1-methyl-3-chloromethylpiperidine (76 mg)
by the method of Example 111 step (v) as a white solid
[0963] Yield: 5 mg
[0964] MS: APCI(+ve) 540(M+1)
[0965] .sup.1HNMR .delta.(CD.sub.3OD) 8.24(s, 1H), 8.14(d, 1H),
7.98(d, 1H), 7.77(t, 1H), 7.32(d, 1H), 7.10(d, 1H), 6.67(dd, 1H),
4.12-4.18(m, 2H), 3.73-3.86(m, 2H), 3.09(s, 2H), 3.02-3.05(m, 1H),
2.83-2.86(m, 1H), 2.74(d, 2H), 2.29(s, 3H), 2.24(s, 3H),
1.58-2.11(m, 9H), 1.54(d, 6H, 1.09-1.13(m, 1H),
EXAMPLE 116
(.+-.) Cis-2-[4-(3-Cyanobenzenesulphonyl).sub.3,
dimethylpiperazin-1-yl]-N- -((2-methyl-&
(1-methylpiperidin-3-yl)methoxy)phenyl)acetamide
[0966] 123
i) 2-Methyl(1,1-dimethyl)-1-dimethylethyl)silyloxyaniline
[0967] The subtitle compound was prepared from
2-amino-3-methylphenol (10 g) and tert-butyldimethylsilyl
chloride(12.22 g) by the method of Example 97 step (i) as a brown
oil
[0968] Yield: 14 g
[0969] .sup.1H NMR .delta.(CDCl.sub.3) 6.53-6.70(m, 3H), 3.66(bs,
2H, 2.17(s, 3H), 1.02(s, 9H), 0.24(s, 6H)
ii)
2-Chloro-N-(2-methyl-6-((1,1-dimethyl)-1-dimethylethyl)silyloxy)phenyl-
)acetamide
[0970] The subtitle compound was prepared from the product of step
(i) (5 g) by the method of Example 111 step (ii) as pale yellow
oil. Yield: 4.6 g
[0971] .sup.1H NMR .delta. (CDCl.sub.3) 7.97(bs, 1H), 7.07(t, 1H),
6.86(d, 1H), 6.72(d, 1H), 4.22(s, 2H), 2.23(s, 3H), 1.00(s, 9H),
0.22(s, 6H)
iii)
Cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-((2--
methyl-6-((1,1-dimethyl)-1-dimethylethyl)silyloxy)phenyl)acetamide
[0972] The subtitle compound was prepared from the product of step
(ii) (1 g) and the product of Example 80 step (ii) (0.89 g) by the
method of Example 80 step (iii) as a white solid. This product was
used directly in the next step
iv)
Cis-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-((2-m-
ethyl-6-hydroxy)phenyl)acetamide
[0973] The subtitle compound was prepared from the product of step
(iii) (2 g) and tetra-butylammonium fluoride (3.18 ml) by the
method of Example 97 step (iv) as a white solid
[0974] Yield: 0.8 g
[0975] MS APCI(+ve) 441(M-1)
v) (.+-.)
C-2-[4-(3-Cyanobenzenesulphonyl)-3,5-dimethylpiperazin-1-yl]-N-(-
(2-methyl-6-(1-methylpiperidin-3-yl)methoxy)phenyl)acetamide
[0976] The title compound was prepared from the product of step
(iv) (0.1 g) and (I) 1-methyl-3-chloromethylpiperidine (76 mg) by
the method of Example 111 step (v) as a white solid.
[0977] Yield: 26 mg
[0978] MS: APCI(+ve) 540(M+1)
[0979] .sup.1H NMR .delta. (CD.sub.3OD) 8.29(s, 1H), 8.17(d, 1H),
7.98(d, 1H), 7.78(t, 1H), 7.17(t, 1H), 6.87(s, 1H), 6.84(s, 1H),
4.19-4.20(m, 2H), 3.83-3.88(m, 2H), 3.12(s, 2H), 2.80-3.0(m, 3H),
2.28(s, 3H), 2.20(s, 3H), 1.6-2.1(m, 9H, 1.55(d, 6H, 1.0-1.2(m,
1H)
EXAMPLE 117
Cis-2-[4-(1-Methylimidazol-4-sulphonyl
4-yl)-3,5-dimethylpiperazin-1-yl]-N-
-((2-methyl-3-(2-(1-pyrrolidinyl)ethoxy)phenyl)acetamide
[0980] 124
i) Cis-1-(1-Methylimidazol 4-sulphonyl 4-yl)-2,
ethyl-4-phenylmethylpipera- zine
[0981] 1-methylimidazol-4-sulphonyl chloride (19.45 g) was added in
small portions to a solution of cis-4-benzyl-2,6 dimethylpiperazine
(20 g) in pyridine (53 ml) at 120.degree. C. After heating for a
further 10 min at reflux the solvent was evaporated under reduced
pressure. The mixture was partitioned between dichloromethane and
dilute sodium hydroxide solution The organic phase collected, dried
(MgSO.sub.4) and solvent evaporated under reduced pressure.
Purification was by silica gel chromatography eluting with 0 to 5%
methanol in dichloromethane to give the subtitle compound as pale
yellow solid. Yield: 14.2 g
[0982] .sup.1H NMR .delta. (CDCl.sub.3) 7.22-7.46(m, 7H),
4.07-4.15(m, 2H), 3.73(s, 3H), 3.42(d, 2H), 2.53(d, 2H), 2.08(dd,
2H), 1.46(d, 6H)
ii)
Cis-1-(1-Methylimidazol-4-sulphonyl-4-yl-2,6-dimethylpiperazine
[0983] The subtitle compound was prepared from the product of step
(i) (14.07 g) by the method of Example 80 step (ii) as tan solid.
Yield: 12.16 g
[0984] MS: APCI (+ve) 259(M+1)
iii)
Cis-2-[4-Methylimidazol-4-sulphonyl-4-yl)-3,5-dimethylpiperazin)-1-yl-
]-N-((2-methyl-3-(1(1-dimethyl)-1-dimethylethyl)silyloxy)phenyl)acetamide
[0985] The subtitle compound was prepared from the product of step
(ii) (0.82 g) and the product of Example 111 step (ii) (1 g) by the
method of Example 80 step (iii) as a white solid.
[0986] Yield: 1.6 g
[0987] .sup.1H NMR .delta. (CDCl.sub.3) 8.83(s, 1H), 7.61(d, 1H),
7.47(s, 1H), 7.40(s, 1H), 7.07(t, 1H), 6.63(d, 1H), 4.21-4.24(m,
2H), 3.75(s, 3H), 3.10(s, 2H), 2.65(d, 2H), 2.17(s, 3H), 1.56(d,
6H), 1.02(s, 9H), 0.22(s, 6H)
iv)
Cis-2-[4-(1-Methylimidazol-4-sulphonyl-4-yl)-3,5-dimethylpiperazin-1-y-
l]-N-((2-methyl-3-hydroxy)phenyl)acetamide
[0988] The subtitle compound was prepared from the product of step
(iii) (1.51 g) by the method of Example 111 step (iv) as a white
solid. Yield: 0.4 g
[0989] MS APCI(+ve) 422(+1)
v)
Cis-2-[4-(1-Methylimidazol-4-sulphonyl-4-yl)-3,5-dimethylpiperazin-1-yl-
]-N-((2-methyl-3-(2-(1-pyrrolidyl)ethoxy)phenyl)acetamide
[0990] The title compound was prepared from the product of step
(iv) (95 mg) and 1-(2-chloroethyl)pyrrolidine (83 mg) by the method
of Example 111 step (v) as a white solid.
[0991] Yield: 19 mg
[0992] MS: APCI(+ve) 519(M+1)
[0993] .sup.1H NMR .delta. (CD.sub.3OD) 7.76(s, 1H), 7.67(s, 1H),
7.13-7.24(m, 2), 6.84(d, 1H), 4.12-4.19(m, 4H), 3.78(s, 3H),
3.11(s, 2H), 3.01(t, 2H), 2.67-2.76(m, 6H), 2.18-2.28(m, 5H),
1.54(d, 6H)
[0994] Pharmacological Analysis
[0995] Certain compounds such as benzoylbenzoyl adenosine
triphosphate (bbATP) are known to be agonists of the P2X.sub.7
receptor, effecting the formation of pores in the plasma membrane
(Drug Development Research (1996), 37(3), p. 126). Consequently,
when the receptor is activated using bbATP in the presence of
ethidium bromide (a fluorescent DNA probe), an increase in the
fluorescence of intracellular DNA-bound ethidium bromide is
observed The increase in fluorescence can be used as a measure of
P2X.sub.7 receptor activation and therefore to quantify the effect
of a compound on the P2X.sub.7 receptor.
[0996] In this manner, each of the title compounds of the Examples
was tested for antagonist is activity at the P2X.sub.7 receptor.
Thus, the test was performed in 96-well flat bottomed microtitre
plates, the wells being filled with 250 .mu.l of test solution
comprising 200 .mu.l of a suspension of THP-1 cells
(2.5.times.10.sup.6 cells/ml) containing 10.sup.-4 ethidium
bromide, 25 .mu.l of a high potassium buffer solution containing
10.sup.-5 M bbATIP, and 25 .mu.l of the high potassium buffer
solution containing 3.times.10.sup.-5M test compound The plate was
covered with a plastics sheet and incubated at 37.degree. C. for
one hour. The plate was then read in a Perkin-Elmer fluorescent
plate reader, excitation 520 nm, emission 595 nm, slit widths: Ex
15 nm, Em 20 nm. For the purposes of comparison, bbATP (a P2X.sub.7
receptor agonist) and pyridoxal 5-phosphate (a P2X.sub.7
antagonist) were used separately in the test as controls. From the
readings obtained, a pIC.sub.50 figure was calculated for each test
compound, this figure being the negative logarithm of the
concentration of test compound necessary to reduce the bbATP
agonist activity by 50%. Each of the compounds of the Examples
demonstrated antagonist activity, having a pIC.sub.50 figure
>5.0.
* * * * *