U.S. patent application number 11/304110 was filed with the patent office on 2006-05-04 for 5-ht4 receptor antagonists.
This patent application is currently assigned to SMITHKLINE BEECHAM P.L.C.. Invention is credited to Laramie Mary Gaster, Francis David King, Keith Raymond Mulholland.
Application Number | 20060094702 11/304110 |
Document ID | / |
Family ID | 10735954 |
Filed Date | 2006-05-04 |
United States Patent
Application |
20060094702 |
Kind Code |
A1 |
King; Francis David ; et
al. |
May 4, 2006 |
5-HT4 receptor antagonists
Abstract
Compounds of formula (I) and pharmaceutically acceptable salts
thereof, and the use of a compound of formula (I) or a
pharmaceutically acceptable salt thereof: X--CO--CH.sub.2-Z wherein
X is a monocyclic or polycyclic aromatic group, Z is of sub-formula
(h), (j) or (k): ##STR1## wherein n.sup.1 is 1, 2, 3 or 4; n.sup.2
is 0, 1, 2, 3 or 4; n.sup.3is 2, 3, 4 or 5; q is 0, 1, 2 or 3; p is
0, 1 or 2; m is 0, 1 or 2; R.sub.5 is hydrogen, C.sub.1-2 alkyl,
aralkyl or R.sub.5 is (CH.sub.2).sub.z-R.sub.10 wherein z is 2 or 3
and R.sub.10 is selected from cyano, hydroxyl, C.sub.1-6 alkoxy,
phenoxy, C(O)C.sub.1-6 alkyl, COC.sub.6H.sub.5,
--CONR.sub.11R.sub.12, NR.sub.11COR.sub.12,
SO.sub.2NR.sub.11R.sub.12 or NR.sub.11SO.sub.2R.sub.12 wherein
R.sub.11 and R.sub.12 are hydrogen or C.sub.1-6 alkyl; or R.sub.5
is straight or branched chain alkylene of chain length 1-6 carbon
atoms terminally substituted by aryl, 3 to 8 membered cycloalkyl, 3
to 8 membered heterocyclyl, 5 or 6 membered monocyclic heteroaryl
or 9 or 10 membered fused bicyclic heteroaryl linked through
carbon, C.sub.2-7 alkoxycarbonyl, or secondary or tertiary hydroxy
substituted C.sub.1-6 alkyl; ; and R.sub.6, R.sub.7 and R.sub.8 are
independently hydrogen or C.sub.1-6 alkyl; and R.sub.9 is hydrogen
or C.sub.1-10alkyl; and their use as pharmaceuticals in the
treatment of gastrointestinal disorders, cardiovascular disorders
and CNS disorders.
Inventors: |
King; Francis David;
(Bishop's Stortford, GB) ; Gaster; Laramie Mary;
(Bishop's Stortford, GB) ; Mulholland; Keith Raymond;
(Harlow, GB) |
Correspondence
Address: |
GLAXOSMITHKLINE;Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
SMITHKLINE BEECHAM P.L.C.
|
Family ID: |
10735954 |
Appl. No.: |
11/304110 |
Filed: |
December 15, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10317159 |
Dec 11, 2002 |
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11304110 |
Dec 15, 2005 |
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09939914 |
Aug 27, 2001 |
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10317159 |
Dec 11, 2002 |
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09013135 |
Jan 26, 1998 |
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09939914 |
Aug 27, 2001 |
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08553390 |
Nov 22, 1995 |
5741801 |
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PCT/EP94/01583 |
May 16, 1994 |
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09013135 |
Jan 26, 1998 |
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Current U.S.
Class: |
514/183 ;
514/211.05; 514/222.8; 514/306; 514/321; 540/490; 544/105; 546/138;
546/198 |
Current CPC
Class: |
A61P 13/02 20180101;
A61P 43/00 20180101; A61P 9/06 20180101; C07D 401/06 20130101; A61P
1/00 20180101 |
Class at
Publication: |
514/183 ;
514/211.05; 514/222.8; 514/306; 514/321; 540/490; 544/105; 546/138;
546/198 |
International
Class: |
A61K 31/554 20060101
A61K031/554; A61K 31/553 20060101 A61K031/553; A61K 31/5415
20060101 A61K031/5415; A61K 31/538 20060101 A61K031/538; A61K
31/4745 20060101 A61K031/4745; C07D 417/02 20060101 C07D417/02;
C07D 413/02 20060101 C07D413/02; C07D 455/02 20060101
C07D455/02 |
Foreign Application Data
Date |
Code |
Application Number |
May 22, 1993 |
GB |
9310582.3 |
Claims
1. A compound of formula (I) or a pharmaceutically acceptable salt
thereof: X--CO--CH.sub.2-Z (I) wherein X is of formula (d):
##STR5## X.sub.1--(CH.sub.2).sub.x--X.sub.2 forms a 5-7 membered
ring wherein X.sub.1 is O or S; X.sub.2 is O, S, --CH.sub.2--, NR
or NRCO wherein R is hydrogen or C.sub.1-6 alkyl; and x is 1, 2 or
3; R.sub.1.sup.d is hydrogen, amino, halo, C.sub.1-6 alkyl, hydroxy
or C.sub.1-6 alkoxy; R.sub.2.sup.d is hydrogen, halo, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, nitro, amino or C.sub.1-6 alkylthio;
R.sub.3.sup.d is hydrogen, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy
or amino; R.sub.4.sup.d and R.sub.5.sup.d are independently
hydrogen or C.sub.1-6 alkyl; Z is of sub-formula (h), (j) or (k):
##STR6## wherein n.sup.1 is 1, 2, 3 or 4; n.sup.2is 0, 1, 2, 3 or
4; n.sup.3is 2, 3, 4 or 5; q is 0, 1, 2 or 3; p is 0, 1 or 2; m is
0, 1 or 2; R.sub.5 is hydrogen, C.sub.1-12 alkyl, aralkyl or
R.sub.5 is (CH.sub.2).sub.z--R.sub.10 wherein z is 2 or 3 and
R.sub.10 is selected from cyano, hydroxyl, C.sub.1-6 alkoxy,
phenoxy, C(O)C.sub.1-6 alkyl, COC.sub.6H.sub.5,
--CONR.sub.11R.sub.12, NR.sub.11COR.sub.12,
SO.sub.2NR.sub.11R.sub.12 or NR.sub.11SO.sub.2R.sub.12 wherein
R.sub.11 and R.sub.12 are hydrogen or C.sub.1-6 alkyl; or R.sub.5
is straight or branched chain alkylene of chain length 1-6 carbon
atoms terminally substituted by aryl, 3 to 8 membered cycloalkyl, 3
to 8 membered heterocyclyl, 5 or 6 membered monocyclic heteroaryl
or 9 or 10 membered fused bicyclic heteroaryl linked through
carbon, C.sub.2-7 alkoxycarbonyl, or secondary or tertiary hydroxy
substituted C.sub.1-6 alkyl; ; and R.sub.6, R.sub.7 and R.sub.8 are
independently hydrogen or C.sub.1-6 alkyl; and R.sub.9 is hydrogen
or C.sub.1-10 alkyl; having 5-HT.sub.4 receptor antagonist
activity.
2. A compound according to claim 1 wherein:
X.sub.1--(CH.sub.2).sub.x--X.sub.2 is O--(CH.sub.2).sub.2--O,
O--(CH.sub.2).sub.3--O, O--CH.sub.2--O, O--(CH.sub.2).sub.2--NR,
O--(CH.sub.2).sub.2--S, O--CH.sub.2--CONR,
O--(CH.sub.2).sub.2--CH.sub.2, O--(CH.sub.2).sub.3--CH.sub.2, or
O--CH.sub.2--CH.sub.2, wherein any of the methylene linkages are
optionally mono- or di- substituted by C.sub.1-6 alkyl groups;
R.sub.1.sup.d is hydrogen or amino; R.sub.2.sup.d is hydrogen or
halo; R.sub.3.sup.d is hydrogen or halo.
3. A pharmaceutical composition comprising a compound according to
claim 1, and a pharmaceutically acceptable carrier.
4. A method of treating a gastrointestinal disorder selected from
the group consisting of irritable bowel syndrome, emesis, urinary
incontinence associated with irritable bowel syndrome, dyspepsia
and gastro-oesophageal reflux disease which comprises administering
a compound according to claim 1.
5. A method of treating atrial arrhythmia or stroke which comprises
administering a compound according to claim 1.
6. A method of treating a CNS disorder selected from the group
consisting of migraine, schizophrenia, Parkinson's disease,
Huntingdon's chorea and anxiety which comprises administering a
compound according to claim 1.
Description
[0001] This is a continuation of application Ser. No. 10/317,159
filed Dec. 11, 2002 (pending) which is a continuation of
application Ser. No. 09/939,914 filed Aug. 27, 2001(abandoned),
application Ser. No. 09/013,135 filed Jan. 26, 1998 (abandoned),
which is a continued prosecution application of Application Ser.
No. 09/013,135 filed Dec. 1, 2000, which is a continued prosecution
application of application Ser. No. 09/013,135 filed Feb. 24, 2000,
which is a divisional application of application Ser. No.
08/553,390 filed Nov. 22, 1995 U.S. Pat. No. 5,741,801, which is a
371 of International Application No. PCT/EP94/01583 filed May 16,
1994, which claims benefit from foreign application GB 9310582.3
filed May 22, 1993.
[0002] This invention relates to novel compounds having
pharmacological activity, to a process for their preparation and to
their use as pharmaceuticals.
[0003] European Journal of Pharmacology 146 (1988), 187-188, and
Naunyn-Schmiedeberg's Arch. Pharmacol. (1989) 340:403-410, describe
a non classical 5-hydroxytryptamine receptor, now designated the
5-HT.sub.4 receptor, and that ICS 205-930, which is also a
5-HT.sub.3 receptor antagonist, acts as an antagonist at this
receptor.
[0004] WO 91/16045 (SmithKline and French Laboratories Limited)
describes the use of cardiac 5-HT.sub.4 receptor antagonists in the
treatment of atrial arrhythmias and stroke.
[0005] EP-A-501322 (Glaxo Group Limited), WO 93/02677, WO 93/03725,
WO 93/05038, WO 93/05040, WO 93/18036, PCT/EP93/03054,
PCT/GB93/01895, PCT/GB93/02028, PCT/EP93/02808, PCT/EP93/02775,
PCT/EP93/02809, PCT/GB93/02130, PCT/EP93/003054, PCT/GB94/000172
(SmithKline Beecham plc) describe compounds having 5-HT.sub.4
receptor antagonist activity.
[0006] It has now been discovered that certain novel compounds also
have 5-HT.sub.4 receptor antagonist properties.
[0007] Accordingly, the present invention provides a compounds of
formula (I) and pharmaceutically acceptable salts thereof, and the
use of a compound of formula (1) or a pharmaceutically acceptable
salt thereof: X--CO--CH.sub.2-Z (I) [0008] X is a monocyclic or
polycyclic aromatic group, such as a group of formula (a), (b),
##STR2## wherein [0009] L is N or CR.sub.S wherein R.sub.S is
hydrogen, C.sub.1-6 alkoxy, halogen, C.sub.1-4 alkyl or cyano;
[0010] Q is NR.sub.1.sup.a, CH.sub.2, O or S; [0011] W is CH or N;
[0012] X.sub.1--(CH.sub.2).sub.x--X.sub.2 forms a 5-7 membered ring
wherein X.sub.1 is O or S; X.sub.2 is O, S, --CH.sub.2--, NR or
NRCO wherein R is hydrogen or C.sub.1-6 alkyl; and [0013] x is 1, 2
or 3; [0014] one of X.sub.3 and X.sub.4 is N and the other is C;
and [0015] X.sub.5 is N or CR.sup.1 wherein R.sup.1 is hydrogen,
C.sub.1-6 alkoxy, halo, C.sub.1-6 alkyl or cyano; [0016]
R.sub.1.sup.a is hydrogen, C.sub.1-10 alkyl, C.sub.2-6 alkenyl,
aralkyl, C.sub.2-6 alkanoyl or C.sub.2-6 alkanoyl C.sub.1-3 alkyl;
[0017] R.sub.3.sup.a is hydrogen, halo, C.sub.1-6 alkyl, amino,
nitro or C.sub.1-6 alkoxy; [0018] R.sub.4.sup.a is hydrogen, halo,
C.sub.1-6 alkyl or C.sub.1-6 alkoxy; [0019] R.sub.1.sup.b is
C.sub.1-6 alkoxy; and [0020] R.sub.2.sup.b is hydrogen, chloro or
fluoro; [0021] R.sub.3.sup.b is hydrogen, C.sub.1-6 alkyl, amino
optionally substituted by a C.sub.1-6 alkyl group, halo, hydroxy or
C.sub.1-6 alkoxy; [0022] R.sub.4.sup.b is hydrogen, halo, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, nitro, amino or C.sub.1-6 alkylthio; and
[0023] R.sub.5.sup.b is hydrogen, halo, C.sub.1-6 alkyl, C.sub.1-6
alkoxy or amino; [0024] R.sub.c is hydrogen, C.sub.1-6 alkoxy, halo
or C.sub.1-6 alkyl; [0025] R.sub.1.sup.d is hydrogen, amino, halo,
C.sub.1-6 alkyl, hydroxy or C.sub.1-6 alkoxy; [0026] R.sub.2d is
hydrogen, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, nitro, amino or
C.sub.1-6 alkylthio; [0027] R.sub.3.sup.d is hydrogen, halo,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy or amino; [0028] R.sub.4.sup.d
and R.sub.5.sup.d are independently hydrogen or C.sub.1-6 alkyl;
[0029] R.sub.1.sup.e is hydrogen, halogen, CF.sub.3, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, C.sub.1-6
alkylsulphonyl, C.sub.1-6 alkylsulphinyl, C.sub.1-7 acyl, cyano,
C.sub.1-6 alkoxycarbonyl, C.sub.1-7 acylamino, hydroxy, nitro or
amino, aminocarbonyl, or aminosulphonyl, optionally N-substituted
by one or two groups selected from C.sub.1-6 alkyl, C.sub.3-8
cycloalkyl, and C.sub.3-8 cycloalkyl C.sub.1-4 alkyl or
disubstituted by C.sub.4 or C.sub.5 polymethylene; phenyl or phenyl
C.sub.1-4 alkyl group optionally substituted in the phenyl ring by
one or two of halogen, C.sub.1-6 alkoxy or C.sub.1-6 alkyl groups;
[0030] R.sub.3.sup.e is hydrogen, halo, C.sub.1-6 alkyl, amino,
nitro or C.sub.1-6 alkyl; [0031] R.sub.4.sup.e is hydrogen, halo,
C.sub.1-6 alkyl or C.sub.1-6 alkoxy; [0032] X.sub.6-X.sub.7 is
NR.sub.z--CO or
CR.sub.1.sup.fR.sub.2.sup.f--CR.sub.3.sup.fR.sub.4.sup.f where
[0033] R.sub.z and R.sub.1.sup.f to R.sub.4.sup.f are independently
hydrogen or C.sub.1-6 alkyl; and/or [0034]
R.sub.1.sup.f/R.sub.2.sup.f and R.sub.3.sup.f/R.sub.4.sup.f
together are a bond and/or
R.sub.1.sup.f/R.sub.2.sup.f/R.sub.3.sup.f/R.sub.4.sup.f are joined
to form C.sub.3-6 polymethylene; [0035] R.sub.a.sup.f is hydrogen,
halo, C.sub.1-6 alkyl, amino, nitro or C.sub.1-6 alkyl; [0036]
R.sub.b.sup.f is hydrogen, halo, C.sub.1-6 alkyl or C.sub.1-6
alkoxy; [0037] X.sup.g is O, S, SO, SO.sub.2, CH.sub.2, CH, N or NR
wherein R is hydrogen or C.sub.1-6 alkyl; [0038] A is a saturated
or unsaturated polymethylene chain of 2-4 carbon atoms; [0039]
R.sub.1.sup.g and R.sub.2.sup.g are hydrogen or C.sub.1-6 alkyl;
[0040] R.sub.3.sup.g is hydrogen, halo, C.sub.1-6 alkyl, amino,
nitro or C.sub.1-6 alkoxy; [0041] R.sub.4.sup.g is hydrogen, halo,
C.sub.1-6 alkyl or C.sub.1-6 alkoxy; [0042] Z is of sub-formula
(h), (j) or (k): ##STR3## wherein [0043] n.sup.1 is 1, 2, 3 or 4;
n.sup.2 is 0, 1, 2, 3 or 4; n.sup.3 is 2, 3, 4 or 5; [0044] q is 0,
1, 2 or 3; p is 0, 1 or 2; m is 0, 1 or 2; [0045] R.sub.5 is
hydrogen, C.sub.1-12 alkyl, aralkyl or R.sub.5 is
(CH.sub.2).sub.z-R.sub.10 wherein z is 2 or 3 and R.sub.10 is
selected from cyano, hydroxyl, C.sub.1-6 alkoxy, phenoxy,
C(O)C.sub.1-6 alkyl, COC.sub.6H.sub.5, --CONR.sub.11R.sub.12,
NR.sub.11COR.sub.12, SO.sub.2NR.sub.11R.sub.12 or
NR.sub.11SO.sub.2R.sub.12 wherein R.sub.11 and R.sub.12 are
hydrogen or C.sub.1-6 alkyl; or R.sub.5 is straight or branched
chain alkylene of chain length 1-6 carbon atoms terminally
substituted by aryl, 3 to 8 membered cycloalkyl, 3 to 8 membered
heterocyclyl, 5 or 6 membered monocyclic heteroaryl or 9 or 10
membered fused bicyclic heteroaryl linked through carbon, C.sub.2-7
alkoxycarbonyl, or secondary or tertiary hydroxy substituted
C.sub.1-6 alkyl; ; and [0046] R.sub.6, R.sub.7 and R.sub.8 are
independently hydrogen or C.sub.1-6 alkyl; and [0047] R.sub.9 is
hydrogen or C.sub.1-10 alkyl; having 5-HT.sub.4 receptor antagonist
activity.
[0048] Examples of alkyl or alkyl containing groups include
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7,
C.sub.8, C.sub.9, C.sub.10, C .sub.11 or C.sub.12 branched,
straight chained or cyclic alkyl, as appropriate. C.sub.1-4 alkyl
groups include methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and
tert-butyl. Cyclic alkyl includes cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl optionally
substituted by one of more alkyl groups of up to 4 carbon
atoms.
[0049] Aryl includes phenyl and naphthyl optionally substituted by
one or more substituents selected from halo, C.sub.1-6 alkyl and
C.sub.1-6 alkoxy.
[0050] Values for monocyclic heteroaryl include pyridyl, pyrimidyl,
pyrazinyl, pyrryl, imidazolyl, thienyl, furanyl, oxazole or
thiazole (all possible isomers). Bicyclic heteroaryl include
benzofuranyl, benzothiophenyl, indolyl and indazolyl, quinolyl and
isoquinolyl (all possible isomers).
[0051] Values for 3 to 8 membered heterocyclyl, include cyclic
polymethylene interrupted by one or two of N, O or S, linked
through C or N, for example N-linked piperidinyl or pyrrolidinyl.
[0052] Halo includes fluoro, chloro, bromo and iodo, preferably
chloro. [0053] L in formula (a) is favourably C--H, C--CH.sub.3,
C--Cl or C--OCH.sub.3. [0054] Q in formula (a) is favourably
NR.sub.1.sup.a. [0055] R.sub.1.sup.a is preferably hydrogen or a
methyl or ethyl group. [0056] R.sub.1.sup.b is preferably methoxy.
[0057] R.sub.3.sup.b is preferably amino. [0058] R.sub.4.sup.b is
preferably halo. [0059] R.sub.5.sup.b is preferably hydrogen.
[0060] A substituent when halo is selected from fluoro, chloro,
bromo and iodo. R.sub.4.sup.a when halo is preferably iodo
[0061] Suitable examples of the X.sub.1--(CH.sub.2).sub.x--X.sub.2
moiety include O--(CH.sub.2).sub.2--O, O--(CH.sub.2).sub.3--O,
O--CH.sub.2--O, O--(CH.sub.2).sub.2--NR, O--(CH.sub.2).sub.2--S or
O--CH.sub.2--CONR, wherein any of the methylene linkages are
optionally mono- or di- substituted by C.sub.1-6 alkyl groups, such
as methyl. Preferably X.sub.1--(CH.sub.2).sub.2--X.sub.2 is
O--(CH.sub.2).sub.2--O.
[0062] Further suitable examples of
X.sub.1--(CH.sub.2).sub.x--X.sub.2 include
O--(CH.sub.2).sub.2--CH.sub.2, O--(CH.sub.2).sub.3--CH.sub.2,
O--CH.sub.2--CH.sub.2, or corresponding values wherein
X.sub.1.dbd.X.sub.2.dbd.CH.sub.2, wherein any of the methylene
linkages are optionally mono- or di-substituted by C.sub.1-6 alkyl
groups, such as methyl. Preferably such
X.sub.1--(CH.sub.2).sub.2--X.sub.2 is
O--(CH.sub.2).sub.2--CH.sub.2. [0063] R.sub.1.sup.d is preferably
hydrogen or amino. [0064] R.sub.2.sup.d is preferably hydrogen or
halo. [0065] R.sub.3.sup.d is preferably hydrogen or halo. [0066]
R.sub.4.sup.d and R.sub.5.sup.d are often hydrogen. When
R.sub.4.sup.d or R.sub.5.sup.d is C.sub.1-6 alkyl, it is often
methyl. [0067] R.sub.1.sup.e is preferably CF.sub.3 or an ethyl
group. [0068] X.sub.5 is preferably N, C--H or C--OCH.sub.3; [0069]
R.sub.3.sup.e is preferably hydrogen. [0070] R.sub.4.sup.e is
preferably hydrogen or halo, such as iodo.
[0071] Suitable examples of X.sub.6-X.sub.7 when
CR.sub.1.sup.fR.sub.2.sup.f--CR.sub.3.sup.fR.sub.4.sup.f include
CH.sub.2--CH.sub.2 and CH.dbd.CH. X.sub.6--X.sub.7 is preferably
NR.sub.z--CO, however, such as NH--CO or NEt-CO. [0072]
R.sub.a.sup.f is preferably hydrogen. [0073] R.sub.b.sup.f is
preferably hydrogen or halo, such as iodo.
[0074] Values for A include
--CH.sub.2--(CH.sub.2).sub.r--CH.sub.2-- wherein r is 0, 1 or 2;
--CH.sub.2--CH.dbd.CH--; --C(CH.sub.3).dbd.CH-- or when Xg is CH or
N, A may be --(CH.sub.2).sub.2--CH.dbd.or --CH.dbd.CH--CH.dbd..
Other examples of A are as described in the aforementioned patent
publications.
[0075] R.sub.1.sup.g and R.sub.2.sup.g are often hydrogen or
R.sub.1.sup.g and R.sub.2.sup.9 are gem-dimethyl. r is often 1.
[0076] R.sub.3.sup.g is preferably hydrogen.
[0077] R.sub.4.sup.g is preferably hydrogen or halo, such as
fluoro.
[0078] Other suitable values of X are as described in
PCT/GB93/020208, PCT/EP93/02808, PCT/EP93/02775, PCT/EP93/02809,
PCT/GB93/02130, PCT/GB94/00172 (all in the name of SmithKline
Beecham plc).
[0079] When Z is of sub-formula (h), n.sup.1 is preferably 2, 3 or
4 when the azacycle is attached at the nitrogen atom and n1 is
preferably 1 when the azacycle is attached at a carbon atom, such
as the 4-position when q is 2.
[0080] When Z is of sub-formula (j), n.sup.2 is preferably such
that the number of carbon atoms between the ester or amide linkage
is from 2 to 4 carbon atoms.
[0081] Suitable values for p and m include p=m=1; p=0, m=1, p=1,
m=2 p=2, m=1.
[0082] When Z is of sub-formula (k), n.sup.3 is preferably 2, 3 or
4.
[0083] R.sub.8 and R.sub.9 are preferably both alkyl, especially
one of R.sub.8 and R.sub.9 is C.sub.4 larger alkyl.
[0084] Specific values of Z of particular interest are as follows:
##STR4##
[0085] The invention also provides novel compounds within formula
(I) with side chains (i), (ii), (iii), (iv), (v), (vi) or (vii). In
a further aspect, the piperidine ring in (i), (ii) or (iii) may be
replaced by pyrrolidinyl or azetidinyl, and/or the N-substituent in
(i) or (ii) may be replaced by C.sub.3 or larger alkyl or
optionally substituted benzyl.
[0086] In an alternative aspect, the N-substituent in formula (i)
or (ii) may be replaced by (CH.sub.2).sub.nR.sub.4 as defined in
formula (I) of EPA 501322 and in relation to the specific examples
of EP-A-501322, or it may be replaced by a substituent as as
defined in formula (I) and in relation to the specific examples of
in PCT/EP93/03054 (SmithKline Beecham plc).
[0087] The pharmaceutically acceptable salts of the compounds of
the formula (I) include acid addition salts with conventional acids
such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric
acids and pharmaceutically acceptable organic acids such as acetic,
tartaric, maleic, citric, succinic, benzoic, ascorbic,
methanesulphonic, a-keto glutaric, a-glycerophosphoric, and
glucose-1-phosphoric acids.
[0088] Examples of pharmaceutically acceptable salts include
quaternary derivatives of the compounds of formula (I) such as the
compounds quaternised by compounds R.sub.x-T wherein R.sub.x is
C.sub.1-6 alkyl, phenyl-C.sub.1-6 alkyl or C.sub.5-7 cycloalkyl,
and T is a radical corresponding to an anion of an acid. Suitable
examples of R.sub.x include methyl, ethyl and n- and iso-propyl;
and benzyl and phenethyl. Suitable examples of T include halide
such as chloride, bromide and iodide.
[0089] Examples of pharmaceutically acceptable salts also include
internal salts such as N-oxides.
[0090] The compounds of the formula (I), their pharmaceutically
acceptable salts, (including quaternary derivatives and N-oxides)
may also form pharmaceutically acceptable solvates, such as
hydrates, which are included wherever a compound of formula (I) or
a salt thereof is herein referred to.
[0091] The compounds of formula (I) may be prepared by conventional
methods for forming ketones, such as those described in EP-A-242973
(Glaxo Group Limited) and EP-A-387431 (Beecham Group plc).
[0092] Reference is made to the aforemetioned patent publications
in the name of Beecham Group plc in respect of intermediates
containing X and Z moieties.
[0093] The compounds of the present invention are 5-HT.sub.4
receptor antagonists and it is thus believed may generally be used
in the treatment or prophylaxis of gastrointestinal disorders,
cardiovascular disorders and CNS disorders.
[0094] They are of potential interest in the treatment of irritable
bowel syndrome (IBS), in particular the diarrhoea aspects of IBS,
i.e., these compounds block the ability of 5-HT to stimulate gut
motility via activation of enteric neurones. In animal models of
IBS, this can be conveniently measured as a reduction of the rate
of defaecation. They are also of potential use in the treatment of
urinary incontinence which is often associated with IBS.
[0095] They may also be of potential use in other gastrointestinal
disorders, such as those associated with upper gut motility, and as
antiemetics. In particular, they are of potential use in the
treatment of the nausea and gastric symptoms of gastro-esophageal
reflux disease and dyspepsia. Antiemetic activity is determined in
known animal models of cytotoxic-agent/radiation induced
emesis.
[0096] Specific cardiac 5-HT.sub.4 receptor antagonists which
prevent atrial fibrillation and other atrial arrhythmias associated
with 5-HT, would also be expected to reduce occurrence of stroke
(see A. J. Kaumann 1990, Naumyn-Schmiedeberg's Arch. Pharmacol.
342, 619-622, for appropriate animal test method).
[0097] Anxiolytic activity is likely to be effected via the
hippocampus (Dumuis et al 1988, Mol Pharmacol., 34, 880-887).
Activity can be demonstrated in standard animal models, the social
interaction test and the X-maze test.
[0098] Migraine sufferers often undergo situations of anxiety and
emotional stress that precede the appearance of headache (Sachs,
1985, Migraine, Pan Books, London). It has also been observed that
during and within 48 hours of a migraine attack, cyclic AMP levels
are considerably increased in the cerebrospinal fluid (Welch et
al., 1976, Headache 16, 160-167). It is believed that a migraine,
including the prodomal phase and the associated increased levels of
cyclic AMP are related to stimulation of 5-HT.sub.4 receptors, and
hence that administration of a 5-HT.sub.4 antagonist is of
potential benefit in relieving a migraine attack.
[0099] Other CNS disorders of interest include schizophrenia,
Parkinson's disease and Huntingdon's chorea.
[0100] The invention also provides a pharmaceutical composition
comprising a compound of formula (I), or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable
carrier.
[0101] Such compositions are prepared by admixture and are usually
adapted for enteral such as oral, nasal or rectal, or parenteral
administration, and as such may be in the form of tablets,
capsules, oral liquid preparations, powders, granules, lozenges,
reconstitutable powders, nasal sprays, suppositories, injectable
and infusable solutions or suspensions. Orally administrable
compositions are preferred, since they are more convenient for
general use.
[0102] Tablets and capsules for oral administration are usually
presented in a unit dose, and contain conventional excipients such
as binding agents, fillers, diluents, tabletting agents,
lubricants, disintegrants, colourants, flavourings, and wetting
agents. The tablets may be coated according to well known methods
in the art, for example with an enteric coating.
[0103] Suitable fillers for use include cellulose, mannitol,
lactose and other similar agents. Suitable disintegrants include
starch, polyvinylpolypyrrolidone and starch derivatives such as
sodium starch glycollate. Suitable lubricants include, for example,
magnesium stearate.
[0104] Suitable pharmaceutically acceptable wetting agents include
sodium lauryl sulphate. Oral liquid preparations may be in the form
of, for example, aqueous or oily suspensions, solutions, emulsions,
syrups, or elixirs, or may be presented as a dry product for
reconstitution with water or other suitable vehicle before use.
Such liquid preparations may contain conventional additives such as
suspending agents, for example sorbitol, syrup, methyl cellulose,
gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium
stearate gel or hydrogenated edible fats, emulsifying agents, for
example lecithin, sorbitan monooleate, or acacia; non-aqueous
vehicles (which may include edible oils), for example, almond oil,
fractionated coconut oil, oily esters such as esters of glycerine,
propylene glycol, or ethyl alcohol; preservatives, for example
methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired
conventional flavouring or colouring agents.
[0105] Oral liquid preparations are usually in the form of aqueous
or oily suspensions, solutions, emulsions, syrups, or elixirs or
are presented as a dry product for reconstitution with water or
other suitable vehicle before use. Such liquid preparations may
contain conventional additives such as suspending agents,
emulsifying agents, non-aqueous vehicles (which may include edible
oils), preservatives, and flavouring or colouring agents.
[0106] The oral compositions may be prepared by conventional
methods of blending, filling or tabletting. Repeated blending
operations may be used to distribute the active agent throughout
those compositions employing large quantities of fillers. Such
operations are, of course, conventional in the art.
[0107] For parenteral administration, fluid unit dose forms are
prepared containing a compound of the present invention and a
sterile vehicle. The compound, depending on the vehicle and the
concentration, can be either suspended or dissolved. Parenteral
solutions are normally prepared by dissolving the compound in a
vehicle and filter sterilising before filling into a suitable vial
or ampoule and sealing. Advantageously, adjuvants such as a local
anaesthetic, preservatives and buffering agents are also dissolved
in the vehicle. To enhance the stability, the composition can be
frozen after filling into the vial and the water removed under
vacuum.
[0108] Parenteral suspensions are prepared in substantially the
same manner except that the compound is suspended in the vehicle
instead of being dissolved and sterilised by exposure of ethylene
oxide before suspending in the sterile vehicle. Advantageously, a
surfactant or wetting agent is included in the composition to
facilitate uniform distribution of the compound of the
invention.
[0109] The invention further provides a method of treatment or
prophylaxis of irritable bowel syndrome, dyspepsia, atrial
arrhythmias and stroke, anxiety and/or migraine in mammals, such as
humans, which comprises the administration of an effective amount
of a compound of the formula (I) or a pharmaceutically acceptable
salt thereof.
[0110] An amount effective to treat the disorders hereinbefore
described depends on the relative efficacies of the compounds of
the invention, the nature and severity of the disorder being
treated and the weight of the mammal. However, a unit dose for a 70
kg adult will normally contain 0.05 to 1000 mg for example 0.5 to
500 mg, of the compound of the invention. Unit doses may be
administered once or more than once a day, for example, 2, 3 or 4
times a day, more usually 1 to 3 times a day, that is in the range
of approximately 0.0001 to 50 mg/kg/day, more usually 0.0002 to 25
mg/kg/day.
[0111] No adverse toxicological effects are indicated within the
aforementioned dosage ranges.
[0112] The invention also provides a compound of formula (1) or a
pharmaceutically acceptable salt thereof for use as an active
therapeutic substance, in particular for use in the treatment of
irritable bowel syndrome, gastro-oesophageal reflux disease,
dyspepsia, atrial arrhythmias and stroke, anxiety and/or
migraine.
[0113] The following Examples illustrates the preparation of
compounds of formula (I), and the following Descriptions relate to
the preparation of intermediates.
[0114] A preferred compound corresponds to any example, but wherein
there is an amino substituent in the 4-position and a chloro
substituent in the 5-position of the benzoic acid nucleus depicted
in formula (I).
EXAMPLE 1
[X=a), L=CH, Q=NCH.sub.3, R.sub.3.sup.a and R.sub.4.sup.a=H,Z=]
a) 1-(1-Methyl-1H-indol-3-yl)-3-(4-pyridyl)-propan-1-one
[0115] The product from Description 1, (0.190 g, 0.540 mmol) was
dissolved in trifluoroacetic acid (7 ml), and heated to reflux with
stirring. After 4 h, the reaction mixture was allowed to cool, was
diluted with water and treated with aq. potassium carbonate until
basic. The aqueous suspension was then extracted with CHCl.sub.3
(2.times.). The combined organic layers were then dried
(Na.sub.2SO.sub.4), and evaporated under reduced pressure to give
an orange solid, which was dried in vacuo (0.101 g). The solid was
then dissolved in EtOH (15 ml), treated with 10% PdC, and
hydrogenated at atmospheric pressure. After 16 h, the reaction
mixture was filtered through kieselguhr, evaporated under reduced
pressure, and dried in vacuo to give the title compound as a
colourless oil (0.100 g, 69%).
[0116] .sup.1H NMR (250 MHz, CDCl.sub.3), .delta. 8.50 (d, 2H),
8.35 (m, 1H), 7.70 (s, 1H), 7.40-7.10 (m, 5H), 3.84 (s, 3H), 3.15
(m, 4H).
b)
1-(1-Methyl-1H-indol-3-yl)-3-(1-butylpiperidin-4-yl)propan-1-one
[0117] The product from a) above (0.100 g, 0.379 mmol) was
dissolved in acetone (4 ml), and treated with 1-bromobutane (0.122
ml, 1.137 mmol) and the mixture was heated to reflux with stirring.
After 3 h, a further amount of 1-bromobutane (0.122 ml, 1.137 mmol)
was added and reflux continued overnight. More 1-bromobutane was
then added (0.244 ml, 2.274 mmol), and reflux continued for a
further 8 h. The reaction mixture was then evaporated under reduced
pressure and the residue dissolved in ethanol (10 ml) and acetic
acid (0.5 ml). Platinum (IV) oxide (0.03 g) was then added and the
mixture hydrogenated at atmospheric pressure. After 16 h, the
reaction mixture was filtered through kieselguhr and the filtrate
evaporated under reduced pressure and dried in vacuo. The product
was then purified by silica-gel chromatography
(CH.sub.2Cl.sub.2/10% MeOH as eluant) to give the title compound as
a pale yellow oil (0.052 g, 43%) which was converted to its oxalate
salt m.pt 124-126 .degree.C. (oxalate salt)
[0118] .sup.1 H NMR (200 MHz, CDCl.sub.3)-free base-.delta. 8.38
(m, 14H), 7.80 (s, 1H), 7.32 (m, 3H), 3.90 (s, 3H), 3.20 (d, 2H),
2.90 (t, 2H), 2.58 (t, 2H), 2.28 (t, 2H), 1.90-1.50 (m, 8H), 1.35
(m, 3H), 0.95 (t, 3H).
EXAMPLE 2
[X=(g), X.sup.g.dbd.O, A=(CH.sub.2).sub.3, R.sub.1.sup.g,
R.sub.2.sup.g, R.sub.3.sup.g, R.sub.4.sup.g.dbd.H; Z=(i)]
a)
1-(3,4-Dihydro-2H-[-1,3]oxazino[3,2a]indol-10-yl)-3-hydroxy-3-(4-pyri-
dyl)propan-1-one
[0119] 1.6M n-Butyllithium (1.67 ml, 2.67 mmol) was added to dry
THF (12 ml), containing diisopropylamine (0.374 ml, 2.67 mmol)
under argon at 0.degree. C. with stirring. After 15 minutes, the
mixture was cooled to -78.degree. C., and the product from
Description 2 (0.420 g, 2.43 mmol) in dry THF (8 ml) was added
slowly. The resulting mixture was then left at -78.degree. C. for 1
h, before pyridine-4-carboxaldehyde (0.232 ml, 2.43 mmol) was
added. After a further 1 h, at -78.degree. C., the reaction mixture
was allowed to warm to room temperature, whereupon the reaction
mixture was quenched with aq. ammonium chloride. The reaction
mixture was then partitioned between ethyl acetate and water. The
aqueous layer was then extracted with ethyl acetate (1.times.), and
the combined organic layers were dried (Na.sub.2SO.sub.4), and
evaporated under reduced pressure to give a pale brown solid, which
was purified by silica-gel chromatography (CH.sub.2Cl.sub.2/5%MeOH
as eluant) to give the title compound as an off white solid (0.246
g, 31%).
[0120] .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 8.54 (d, 2H), 8.27
(d, 1H), 7.40-7.00 (m, 5H), 5.30 (dd, 1H), 4.88 (s, 1H), 4.50 (t,
2H), 4.10 (t, 2H), 3.30 (dd, 1H), 3.05 (dd, 1H), 2.33 (m, 2H).
b)
E-1-(3,4-Dihydro-2H-[1,3]oxazino[3,2a]indol-3-yl)-3(4-pyridyl)-prop-2-
-en-1-one
[0121] The product from a) (0.220 g, 6.83 mmol) was dissolved in
trifluoroacetic acid (20 ml), and heated to reflux with stirring.
After 4 h, the reaction mixture was allowed to cool and was
evaporated under reduced pressure. The residue was then treated
with aq. sodium bicarbonate and the resultant yellow suspension was
extracted with CHCl.sub.3 (3.times.). The combined organic layers
were then dried (Na.sub.2SO.sub.4), and evaporated under reduced
pressure to give a yellow solid. The solid was purified by
silica-gel chromatography (CH.sub.2Cl.sub.2/5% MeOH as eluant) to
give the title compound as a yellow solid (0.190 g, 92%).
[0122] .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 8.60 (d, 2H), 8.45
(d, 1H), 7.80 (d, 1H), 7.62 (d, 1H), 7.40 (d, 2H), 7.35-7.00 (m,
3H), 4.60 (t, 2H), 4.03 (t, 2H), 2.48-2.30 (m, 2H).
c)
1-(3,4-Dihydro-2H-[1,3]oxazino[3,2a]indol-10-yl)-3(4-pyridyl)propan-1-
-one
[0123] The product from b) (0.190 g, 0.625 mmol) was dissolved in
ethanol (40 ml) and hydrogenated at atmospheric pressure in the
presence of 10% PdC (0.05 g). After 17 h, the reaction mixture was
filtered through kieselguhr, and the filtrate evaporated under
reduced pressure and dried in vacuo to give a colourless oil, which
was purified by silica-gel chromatography (CH.sub.2Cl.sub.2/5% MeOH
as eluant) to give the title compound as a pale yellow solid (0.130
g, 68%).
[0124] .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 8.48 (d, 2H), 8.32
(d, 1H), 7.32-7.05 (m, 5H), 4.50 (t, 2H), 4.08 (t, 2H), 3.20-2.95
(m, 4H), 2.35 (m, 2H).
d) 1-(3,4-Dihydro-2H[1,3]oxazino[3,2a]indol-10-yl)-3
(1-butyl-4-piperidinyl)propan-1-one
[0125] The product from c) (0.120 g, 0.392 mmol) was dissolved in
acetone (4 ml), and treated with 1-bromobutane (0.127 ml, 1.18
mmol) and heated to reflux with stirring. After 2 h, and 5 h,
further amounts of 1-bromobutane were added, (0.127 ml, 1.18 mmol)
and (0.254 ml, 2.36 mmol) respectively. Reflux was continued for a
further 15 h. The reaction mixture was then evaporated under
reduced pressure, and dried in vacuo. The off white solid obtained
was then redissolved in ethanol (20 ml) containing acetic acid (0.5
ml); platinum (IV) oxide (0.03 g) was then added and the mixture
was hydrogenated at atmospheric pressure. After 24 h, the reaction
mixture was filtered through kieselguhr, and the filtrate
evaporated under reduced pressure and dried in vacuo. The reaction
mixture was then purified by silica-gel chromatography
(CH.sub.2Cl.sub.2/10% MeOH as eluant) to give the title compound as
an off white solid (0.053 g, 37%), which was converted to its
oxalate salt. m.pt 156-159.degree. C. (oxalate salt)
[0126] .sup.1H NMR (200 MHz, CDCl.sub.3)-free base-.delta. 8.32 (d,
1H), 7.30-7.05 (m, 3H), 4.55 (t, 2H), 4.12 (t, 2H), 3.20 (d, 2H),
2.88 (t, 2H), 2.60 (t, 2H), 2.45-2.18 (m, 4H), 1.95-1.50 (m, 9H),
1.35 (m, 2H), 0.97 (t, 3H).
Description 1 (Intermediate for Example 1)
a) 3-Acetyl-1-methyl-1H-indole
[0127] 3-Acetyl-1H-indole (4.00 g, 0.025 mol) was dissolved in dry
THF (100 ml), and treated with 80% sodium hydride (0.794 g, 0.0263
mol) with stirring under Ar. After 0.5h, methyl iodide (2.36 ml,
0.038 mol) was added. After 20h, the reaction mixture was
evaporated under reduced pressure and the residue partitioned
between ethyl acetate and water. The organic layer was then dried
(Na.sub.2SO.sub.4), and evaporated under reduced pressure to give
the title compound as a pale brown oil which crystallised on
standing (4.20 g, 97%).
[0128] .sup.1H NMR (250 MHz, CDCl.sub.3), .delta. 8.40 (m, 1H),
7.70 (s, 1H), 7.30 (m, 3H), 3.85 (s, 3H), 2.52 (s, 3H).
b)
1-(1-Methyl-1H-indol-3-yl)-3-(4-pyridyl)-3-trimethylsilyloxypropan-1--
one
[0129] 1.6M n-Butyllithium (1.19 ml, 1.90 mmol) was added to dry
THF (10 ml) containing diisopropylamine (0.266 ml, 1.90 mmol) under
Ar at 0.degree. C. After 15 mins, the mixture was cooled to
-78.degree. C., and 3-acetyl-1-methyl-1H-indole (0.300 g, 1.73
mmol) in dry THF (5 ml) was added slowly. The resulting mixture was
left at -78.degree. C. for 1h, before pyridine-4-carboxaldehyde
(0.165 ml, 1.73 mmol) was added. The reaction mixture was then left
at -78.degree. C. for 1h, before being allowed to warm to 0.degree.
C., whereupon chlorotrimethylsilane (0.439 ml, 3.46 mmol) was
added. The mixture was then allowed to warm to room temp and
stirred for 1 h, before being evaporated under reduced pressure and
partitioned between dichloromethane and water. The organic layer
was then dried (Na.sub.2SO.sub.4) and evaporated under reduced
pressure to give a pale yellow solid which was purified by
silica-gel chromatography (EtOAc as eluant) to give the title
compound as a yellow solid (0.300 g, 51%).
[0130] .sup.1 H NMR (270 MHz, CDCl.sub.3) .delta. 8.54 (d, 2H),
8.40 (m, 1H), 7.63 (s, 1H), 7.38 (d, 2H), 7.30 (m, 3H), 5.45 (dd,
1H), 3.80 (s, 3H), 3.30 (dd, 1H), 2.92 (dd, 1H), 0.0 (s, 9H).
Description 2 (Intermediate for Example 2)
[0131] a) N-Methoxy-N-methyl-(1H-indol-3-yl)-carboxamide
Indole-3-carboxylic acid (2.50 g, 0.0155 mol) was suspended in
dichloromethane (60 ml) and treated with oxalyl chloride (1.62 ml,
0.0186 mol), followed by a drop of dry DMF. The reaction mixture
was then stirred at room temperature overnight, before being
evaporated under reduced pressure and dried in vacuo. The product
was then redissolved in dichloromethane (50 ml) and added slowly to
a solution of N,O-dimethylhydroxylamine hydrochloride (1.59 g,
0.0163 mol) in dichloromethane (50 ml) containing triethylamine
(4.53 ml, 0.0326 mol) under argon. The resultant mixture was then
stirred at room temperature for 2 h, before being washed with
water, followed by aq. NaHCO.sub.3. The organic layer was then
dried (Na.sub.2SO.sub.4), evaporated under reduced pressure and
dried in vacuo to yield the title compound as white solid (2.46 g,
78%).
[0132] .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 9.00 (s, 1H), 8.40
(m, 1H), 7.90 (d, 1H), 7.40 (m, 1H), 7.25 (m, 2H), 3.70 (s, 3H),
3.40 (s, 3H).
b)
N-Methoxy-N-Methyl-(3,4-dihydro-2H[1,3oxazino[3,2a]indol-10-yl]carbox-
amide
[0133] The product from a) (2.42 g, 0.0119 mol) was suspended in
chloroform (95 ml), with stirring, and treated with triethylamine
(1.65 ml, 0.0119 mol) and 3-bromopropanol (2.15 ml, 0.0238 mol),
followed by N-chlorosuccinimide (1.85 g, 0.0139 mol). The mixture
was then stirred at room temperature for 1.5 h. 1M HCl in diethyl
ether (0.333 ml, 0.333 mmol), was then added. After 5 minutes, and
10 minutes, further quantities of 1M HCl (0.333 ml) were added.
Upon addition of the last quantity of HCl, the temperature was
observed to rise to 34.degree. C. After a further 0.5 h, the
reaction mixture was washed with 10% Na.sub.2CO.sub.3. The organic
layer was then dried (Na.sub.2SO.sub.4), evaporated under reduced
pressure and dried in vacuo, before being redissolved in acetone
(70 ml) and treated with anhydrous K.sub.2CO.sub.3 (3.07 g, 0.0222
mol) with stirring. The reaction mixture was then stirred
overnight, filtered, and the filtrate evaporated under reduced
pressure to give a brown oil, which was dried in vacuo, and then
purified by silica-gel chromatography (EtOAc as eluant) to give the
title compound as a colourless oil which crystallised on standing
(2.60 g, 84%).
[0134] .sup.1 H NMR (200 MHz, CDCl.sub.3) .delta. 7.75 (m, 1H),
7.25-7.10 (m, 3H), 4.50 (t, 2H), 4.12 (t, 2H), 3.70 (s, 3H), 3.32
(s, 3H), 2.35 (m, 2H).
c) 10-Acetyl-3,4-dihydro-2H-[1,3]oxazino[3,2]indole
[0135] The product from b) (0.99 g, 3.81 mmol) was dissolved in dry
THF, cooled to 0.degree. C., and treated with 3.0M methylmagnesium
bromide in diethyl ether (1.41 ml, 4.24 mmol) under argon, with
stirring. After 20 minutes at 0.degree. C., the reaction mixture
was allowed to warm to room temperature, and after 2 h, a further
quantity of 3.0M methylmagnesium bromide (1.41 ml, 4.24 mmol) was
added. The reaction mixture was then stirred for a further 2 h,
before aq. ammonium chloride was added. The reaction mixture was
then partitioned between EtOAc and water. The aqueous layer was
then extracted with EtOAc, and the combined organic layers were
dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure to
give a red solid. Recrystalisation of the solid from EtOAc gave the
title compound as a pale pink solid (0.275 g, 34%). A further
quantity of the title compound was obtained by silica-gel
chromatography (pentane:EtOAc, 1:2 as eluant) of the filtrate from
the recrystallisation, to give the title compound as a cream solid
(0.152 g, 18%).
[0136] 1 H NMR (250 MHz, CDCl.sub.3) .delta. 8.32 (d, 1H),
7.30-7.00 (m, 3H), 4.52 (t, 2H), 4.05 (t, 2H), 2.50 (s, 3H), 2.35
(m, 2H).
5-HT.sub.4 Receptor Antagonist Activity
1) Guinea Pig Colon
[0137] Male guinea-pigs, weighing 250-400 g are used. Longitudinal
muscle-myenteric plexus preparations, approximately 3 cm long, are
obtained from the distal colon region. These are suspended under a
0.5 g load in isolated tissue baths containing Krebs solution
bubbled with 5% CO.sub.2 in O.sub.2 and maintained at 37.degree. C.
In all experiments, the Krebs solution also contains methiothepin
10-7M and granisetron 10-6M to block effects at 5-HT.sub.1,
5-HT.sub.2 and 5-HT.sub.3 receptors.
[0138] After construction of a simple concentration-response curve
with 5-HT, using 30 s contact times and a 15 min dosing cycle, a
concentration of 5-HT is selected so as to obtain a contraction of
the muscle approximately 40-70% maximum(10-9M approx). The tissue
is then alternately dosed every 15 min with this concentration of
5-HT and then with an approximately equi-effective concentration of
the nicotine receptor stimulant, dimethylphenylpiperazinium (DMPP).
After obtaining consistent responses to both 5-HT and DMPP,
increasing concentrations of a putative 5-HT.sub.4 receptor
antagonist are then added to the bathing solution. The effects of
this compound are then determined as a percentage reduction of the
contractions evoked by 5-HT or by DMPP. From this data, pIC.sub.50
values are determined, being defined as the -log concentration of
antagonist which reduces the contraction by 50%. A compound which
reduces the response to 5-HT but not to DMPP is believed to act as
a 5-HT.sub.4 receptor antagonist.
[0139] The compound of Example 1 had a pIC.sub.50 of 6.8.
* * * * *