Note: Descriptions are shown in the official language in which they were submitted.
CA 02373855 2001-11-13
11V
1 International
r:lU~lA Application
l No
IVIrAL
~L'
Al(l.tl
l(LYVI(1
PCT/EP
00/03506
C.(Continuation)
DOCUMENTS
CONSIDERED
TO
BE
RELEVANT
CategoryCitation of document, with indication,where Relevant to
appropriate, of the relevant passages claim No.
X WO 97 17343 A (AMERICAN HOME PROD) 1,2
15 May 1997 (1997-05-15)
abstract
page 6, line 9 -page 8, line 27; claims
X WO 98 28293 A (BANG ANDERSEN BENNY 1,2
;DANCER
ROBERT (DK); MIKKELSEN I11AN (DK);
PEDE)
2 July 1998 (1998-07-02)
abstract
page 1, line 1 - line 35
page 3, line 30 - line 34
page 4, line 1 - line 9
page 6, line 7 - line 18
page 58, line 1 - line 19; claims
X EP 0 722 942 A (MERCK PATENT GMBH) 1,2
24 July 1996 (1996-07-24)
abstract
page 2, line 1 -page 3, line 9; claims;
examples
A DE 44 14 113 A (MERCK PATENT GMBH) 1,2
26 October 1995 (1995-10-26)
the whole document
A EP 0 830 864 A (LILLY CO ELI) 1,2
25 March 1998 (1998-03-25)
cited in the application
the whole document
A WO 92 12977 A (WARNER LAMBERT CO) 1-5
6 August 1992 (1992-08-06)
abstract
page 6, line 33 - line 35; claims 1-6;
example 16
A EP 0 560 669 A (SQUIBB BRISTOL MYERS 1-5
CO)
15 September 1993 (1993-09-15)
abstract
page 2, line 1 - line 8
page 4, line 47 - line 51
page 5, line 45 - line 56; claims;
examples 36-39
Form PCTIISA/210 (continuation of second sheet) (July 1992)
page 2 of 2
CA 02373855 2001-11-13
International application
No.
INTERNATIONAL SEARCH REPORT PCT/EP 00/03506
Box I Observations where certain claims were
found unsearchable (Continuation of item 1
of first sheet)
This International Search Report has not been
established in respect of certain claims under
Article 17(2)(a) for the following reasons:
1. ~ Claims Nos.:
because they relate to subject matter not required
to be searched by this Authority, namely:
2. ~ Claims Nos.:
because they relate to parts of the International
Application that do not comply with the prescribed
requirements to such
an extent that no meaningful International
Search can be carried out, specifically:
3. ~ Claims Nos.:
because they are dependent claims and are not
drafted in accordance with the second and
third sentences of Rule 6.4(a).
Box II Observations where unity of invention
is lacking (Continuation of item 2 of first
sheet)
This International Searching Authority found
multiple inventions in this international
application, as follows:
see additional sheet
1. ~ As all required additional search fees
were timely paid by the applicant, this International
Search Report covers all
searchable claims.
2. ~ As all searchable claims could be searched
without effort justifying an additional fee,
this Authority did not invite payment
of any additional fee.
3. ~ As only some of the required additional
search fees were timely paid by the applicant,
this International Search Report
covers only those claims for which fees were
paid, specifically claims Nos.:
4. ~ No required additional search fees were
timely paid by the applicant. Consequently,
this International Search Report is
restricted to the invention first mentioned
in the claims; it is covered by claims Nos.:
1-3 (partially), 4, 5 (partially)
Remark on Protest ~ The additional search fees
were accompanied by the applicant's protest.
No protest accompanied the payment of additional
search fees.
Form PCT/ISA/210 (continuation of first sheet (1 )) (July 1998)
CA 02373855 2001-11-13
International Application No. PCT/EP 00 /03506
FURTHER INFORMATION CONTINUED FROM PCTIISA/ ~ Leo I
Continuation of Box 3.
Present claims 1-2 relate to a compound defined by reference to a
desirable characteristic or property, namely "compound having combined
dopamine D2-antagonistic and serotonin reuptake inhibitory activity".
The claims cover all compounds having this characteristic or property,
whereas the appl i cati on p~cides-suppor-t--wi-tf~i~n-the-me?arri~ng-of Arfi
cTe ~
and cTisclosure within the meaning of Article 5 PCT for only a very
limited number of such compounds. In the present case, the claims so lack
support, and the application so lacks disclosure, that a meaningful
search over the whole of the claimed scope is impossible. Independent of
the above reasoning, the claims also lack clarity (Article 6 PCT). An
attempt is made to define the compound by its pharmacological profile.
Again, this lack of clarity in the present case is such as to render a
meaningful search over the whole of the claimed scope impossible.
Consequently, the search for the first subject has been carried out for
those parts of the claims which appear to be clear, supported and
disclosed, namely those parts relating to the compounds structurally
identified on page 2 and 3 in the description and in claims 3-4, with due
regard to the general idea underlying the present invention.
Claims searched completely: 3-5
Claims searched incompletely: 1-2
The applicant's attention is drawn to the fact that claims, or parts of
claims, relating to inventions in respect of which no international
search report has been established need not be the subject of an
international preliminary examination (Rule 66.1(e) PCT). The applicant
is advised that the EPO policy when acting as an International
Preliminary Examining Authority is normally not to carry out a
preliminary examination on matter which has not been searched. This is
the case irrespective of whether or not the claims are amended following
receipt of the search report or during any Chapter II procedure.
CA 02373855 2001-11-13
International Application No.. PCT/EP 00 /03506
FURTHER INFORMATION CONTINUED FROM PCT/ISA/ 2I,O I
This International Searching Authority found multiple (groups of)
inventions in this international application, as follows:
1. Claims: 1-3 (partially),4,5 (partially)
Compounds having formula (Ia) and their use in the treatment
of psychotic disorders such as schizophrenia
2. Claims: 1-3,5 all partially)
Compounds having formula (Ib) and their use in the treatment
of psychotic disorders such as schizophrenia
CA 02373855 2001-11-13
INTERNATIONAL SEARCH REPORT
International Application No
reformation on patent family members pCT/EP 00/03506
Patent document Publication Patent family Publication
cited in search report date members) date
WO 0023441 A 27-04-2000 AU 6474199 A 08-05-2000
WO 9717343 A 15-05-1997 AU 704216 B 15-04-1999
AU 7524596 A 29-05-1997
BR 9611406 A 05-O1-1999
CA 2236678 A 15-05-1997
EP 0861248 A 02-09-1998
HU 9902091 A 28-02-2000
JP 2000500136T 11-O1-2000
NZ 321821 A 29-07-1999
US 5750724 A 12-05-1998
WO 9828293 A 02-07-1998 AU 5310998 A 17-07-1998
BG 103561 A 30-06-2000
BR 9714039 A 09-05-2000
CN 1246117 A O1-03-2000
CZ 9902227 A 15-12-1999
EP 0946542 A 06-10-1999
JP 2000513731T 17-10-2000
NO 992895 A 13-08-1999
PL 334011 A 31-O1-2000
SK 81399 A 10-12-1999
TR 9901407 T 23-08-1999
ZA 9711376 A 21-07-1998
EP 0722942 A 24-07-1996 DE 19500689 A 18-07-1996
AU 704484 B 22-04-1999
AU 4086296 A 18-07-1996
CA 2166958 A 13-07-1996
CN 1133840 A 23-10-1996
CZ 9600093 A 17-07-1996
HU 9600071 A 28-09-1998
JP 8253474 A O1-10-1996
NO 960125 A 15-07-1996
PL 312270 A 22-07-1996
SK 4396 A 06-11-1996
US 5670511 A 23-09-1997
ZA 9600228 A 26-07-1996
DE 4414113 A 26-10-1995 AT 172730 T 15-11-1998
AU 697749 B 15-10-1998
AU 1648895 A 02-11-1995
CA 2147451 A 23-10-1995
CN 1114651 A,B 10-O1-1996
CZ 9501035 A 13-12-1995
DE 59504032 D 03-12-1998
DK 683166 T 12-07-1999
EP 0683166 A 22-11-1995
ES 2125508 T O1-03-1999
HU 74096 A 28-11-1996
JP 7291969 A 07-11-1995
NO 951529 A 23-10-1995
PL 308287 A 30-10-1995
SK 50895 A 08-11-1995
US 5693655 A 02-12-1997
ZA 9503260 A 09-O1-1996
EP 0830864 A 25-03-1998 AU 719033 B 04-05-2000
Form PCT/ISA/210 (patent family annex) (July 1992)
page 1 of 2
CA 02373855 2001-11-13
INTERNATIONAL SEARCH REPORT
Internanonal Application No
reformation on patent family members pCT/ EP 00/03506
Patent document Publication Patent family Publication
cited in search report date members) date
EP 0830864 A AU 4411297 A 14-04-1998
BR 9711530 A 24-08-1999
CN 1230886 A 06-10-1999
CZ 9900987 A 15-12-1999
NU 9903905 A 28-10-2000
NO 991381 A 22-03-1999
PL 332481 A 13-09-1999
WO 9811897 A 26-03-1998
US 6147072 A 14-11-2000
ZA 9707967 A 04-03-1999
WO 9212977 A 06-08-1992 US 5124332 A 23-06-1992
EP 0560669 A 15-09-1993 AT 123774 T 15-06-1995
CA 2091204 A,C 12-09-1993
DE 69300192D 20-07-1995
DK 560669 T 02-10-1995
ES 2076051 T 16-10-1995
GR 3017368 T 31-12-1995
HK 1005030 A 18-12-1998
JP 2101094 C 22-10-1996
JP 6080655 A 22-03-1994
JP 7110857 B 29-11-1995
US 5352678 A 04-10-1994
US 6153611 A 28-11-2000
US 5595993 A 21-O1-1997
Form PCT/ISA/210 (patent family annex) (July 1992)
page 2 of 2
CA 02373855 2001-11-13
WO 00/69424 PCT/EP00/03506
Method of treating,.ps~rchotic disorders
The invention relates to the use of compounds having combined dopamine DZ-
antagonistic activity and serotonin reuptake inhibitory activity for the
preparation of
pharmaceutical compositions for the treatment of psychotic disorders such as
schizophrenia.
It is described in J. Clin, Psychopharmacol, (1998) vol 18, no.l, p. 2-9 and
(1998), vol.
18, no.3, p.208-211 that there is considerable evidence that adding selective
serotonin
reuptake inhibitor (SSRI) to antipsychotic treatment improves negative
symptoms of
schizophrenia.
EP 0830864 describes a method for treating a patient suffering from or
susceptible to
psychosis, acute mania, mild anxiety states, or depression in combination with
psychotic episodes by administering to said patient an effective amount of a
first
component which is an atypical antipsychotic, in combination with an effective
amount
of a second component which is a serotonin reuptake inhibitor.
It has now been found that compounds having affinity for both the dopamine DZ
receptor
and the serotonin reuptake site are particularly useful for the treatment of
psychotic
disorders such as schizophrenia. Such compounds allow for a more complete
treatment
of all disease symptoms (e.g. positive symptoms and negative symptoms). Such
compounds can be used also in patients suffering from mania, anxiety or
depression in
combination with psychotic episodes.
Such compounds show activity as antagonists at dopamine DZ receptors as they
potentially antagonize apomorphine-induced climbing behaviour in mice. The
compounds
also show activity as inhibitors of serotonin reuptake, as they potentiate 5-
HTP induced
behaviour in mice.
Preferably used compounds have K;-values of less than 10 nanomolair in the
receptor
binding assays for DZ antagonistic activity and serotonin reuptake inhibitory
activity.
These compounds are active in therapeutic models sensitive to clinically
relevant
antipsychotics (e.g. the conditioned avoidance response; Van der Heijden &
Bradford,
CONFIRMATION COPY
CA 02373855 2001-11-13
WO 00/69424 PCT/EP00/03506
2
Behav. Brain Res., 1988, 31:61-67) and antidepressants or anxiolytics (e.g.
suppression
of stress-induced vocalization; van der Poel et al., Psychopharmacology, 1989,
97: 147-
148).
In contrast to clinically relevant dopamine DZ receptor antagonists these
compounds
have a low propensity to induce catalepsy in rodents and as such are likely to
induce less
extrapyramidal side effects than existing antipsychotic agents.
The inhibitory activity of serotonin reuptake inherent in these compounds may
be
responsible for the therapeutic effects observed in behavioural models
sensitive to either
antidepressants or anxiolytics.
The combination of two desired types of activity into one molecule has a
number of
advantages in view of combining two different active components in a
composition:
1. constant ratio of both activities due to one kinetic behaviour
2. less burden for the body of the patient with chemical compounds
3. less possibilities for undesired side-effects
4. no interaction between active components.
The invention is illustrated by means of a group of 3-tetrahydropyridin 4-yl
indoles having
a combination of a high affinity for the dopamine D2 receptor and the
serotonin reuptake
site, but is not restricted to the use of these compounds.
The group of 3-tetrahydropyridin-4-yl indole derivatives of the formula (I):
0
\N-(CFIZ)~-[~ I / ~Ra~P
~Rt~m
N O
wherein:
- R, is halogen, CF3, alkyl (1-3C), alkoxy (1-3C), CN or SCH3
- m the value 0, 1 or 2
- RZ is H or alkyl (1-3C)
- n has the value 3, 4, 5 or 6
CA 02373855 2001-11-13
WO 00/69424 PCT/EP00/03506
3
- R3 is halogen, alkyl (1-4C) or alkoxy (1-4C)
- p has the value 0, 1, or 2
and salts thereof, show high affinity both for the dopamine DZ-receptor and
the
serotonin reuptake site. This group of compounds is described in patent
application no.
WO 99/EP/07912.
Preferred compounds of the invention are compounds having formula (I) wherein
R,
hydrogen (i.e. m=0) or F, CI, CH3 or CN, and m=1, RZ is H or CH3, n=4, R3 is
hydrogen
(i.e. p=0), or F or alkyl (1-4C), p=1, and the salts thereof.
The invention is further illustrated by means of a group of novel compounds
having the
general formula
~Rt~m ~ ~ ~ / (CH2~q O (~a)
'N~
I
wherein (R,)m and RZ have the above meanings, q has the value 2-4, and Q is a
group of
the formula
NR4 CO
(a)
(Rs~c
wherein R4 represents H, C,.~-alkyl, C,_3 alkoxy or CN, R5 is H, halogen, C,~-
alkyl,
C,_3-alkoxy, CN, NH2, SOZ-alkyl (1-3C), NOZ or SOZNH2, and t has the value 1-
3, or Q is a
group of the formula ii-vi
0 0 0 ~ o
/ N~O / N~Re / N_ / N O N-
I~ N I I I N I
R~ ~ O
II III IV V VI
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WO 00/69424 PCT/EP00/03506
4
wherein Rs is H or C,_3-alkyl, and R, is H or OH, or the general formula (1b)
(~,)m w I I / (CHZ)2 c~,
o~ (Ib)
wherein (R,)m has the above meanings and Q, represents a group of the formula
(i)
0
N~~ RB
~~N
and salts thereof.
A preferred compound of this group of novel compounds is the compound of
formula (la)
wherein (R,)m 5-F, RZ=H, q=4 and Q is the group of the formula (iii), and the
salts
thereof.
Pharmacologically acceptable acids with which the compounds of the invention
can form
suitable acid addition salts are for example hydrochloric acid, sulphuric
acid, phosphoric
acid, nitric acid, and organic acids such as citric acid, fumaric acid,
malefic acid, tartaric
acid, acetic acid, benzoic acid, p-toluene sulphonic acid, methanesulphonic
acid and
naphthalene sulphonic acid.
The compounds are their acid addition salts can be brought into forms suitable
for
administration by means of suitable processes using auxiliary substances such
as
liquid and solid carrier materials.
The compounds having formula (I) can be obtained as follows:
a) by reaction of a compound of formula (II)
(R.~)rt, ~ I I / \NH (II)
'N-
I
Rz
CA 02373855 2001-11-13
WO 00/69424 PCT/EP00/03506
with a compound of the formula (III)
0
L-ECHZ)~ N;~(R3)P (III)
5 0
wherein the symbols have the above meanings and L is a so-called leaving
group, for
example bromo.
This reaction is carried out in a solvent such as acetonitrile in the presence
of
triethylamine or K2C03 and KI at reflux temperature, or
b) by (i) reduction of the cyano group in a compound of formula (IV)
N-A (I~
(R1)m ~ I (
N
t
Rz
wherein A represents the group -(CHZ)~_,-CN, to the corresponding group -
(CHZ)"NH2;
and
(ii) reacting the obtained amine with an optionally substituted phthalic
anhydride of the
formula (V)
0
o I i (~)p M
0
in which formula the symbols have the meanings give above.
Reaction step b (i) can be carried out for example with LiAIH4 in an organic
solvent
such as tetrahydrofuran at reflux temperature.
Reaction step b (ii) can be carried out for example in organic solvents such
as
tetrahydrofuran and toluene at reflux temperature.
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6
The starting compounds as used in method a) of the formula (II) can be
obtained in a
manner known per se by reacting an optionally substituted indole derivate with
4-
piperidone.
The starting compounds used in method b) having formula (IV) can be obtained
by
reaction of a compound having formula (II) with a bromoalkyl nitrite of the
formula
Br-(CHZ)~_,-CN in a manner known per se.
The compounds having formula (la) wherein Q is the group of formula (a) can be
obtained by reacting an amine obtainable according to the above method b (i)
with the
appropriate benzoyl chloride.
The compounds having formula (la) wherein Q represents a group of the formula
i-vi
can be prepared according to the above method a), i.e. reaction of a compound
having
formula (II) with a compound of the formula
L-(CH2)q Q.
The preparation of the compounds having formula (I) and (la) will now be
described in
more detail in the following Examples.
Example I
Preparation of 1-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)indole.
To a solution of 4-piperidone.H20.HC1 (50 g , 0.32 mot) in 100 ml of acetic
acid and
150 ml of trifluoroacetic acid was added dropwise a solution of 1-methylindole
(11.5 ml,
0.09 mot) in 100 ml of acetic acid at room temperature. After stirring for 1 h
the reaction
mixture was concentrated (in vacuum , temp. ca. 30°C), water was added
, the
mixture was made basic with potassium carbonate and extracted with ethyl
acetate.
The organic layer was separated, dried and purified by silica gel column
chromatography (dichloromethane/methanol/ammonium hydroxide = 84/15/1 ) to
give
9 g (47%) of the title compound.
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WO 00/69424 PCT/EP00/03506
7
xam I 2
Preparation of 5-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)indole.
To a solution of sodium (60 g , 2.6 mol) in 1000 ml of methanol was added 5-
fluoroindole (49 g, 0.36 mol) and 4-piperidone.HzO.HCI (170 g , 1.11 mol). The
mixture
was heated under reflux for 18h , then concentrated , water was added and
extracted
with ethyl acetate. The combined organic layer was dried over sodium sulfate
and then
concentrated. The resulting solid was dissolved in methanol (about 200 ml) and
then
diluted with water (about 1000-1500 ml). The precipitate was collected, washed
with
water and petroleum ether and then dried in a vacuum oven at 60°C.
Yield 74 g (95%)
of a yellow solid.
Example 3
Preparation of N-[4-[4-[(5-fluoro-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-
yl]butyl]-
phthalimide.HCl (compound 1).
A solution of 5-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)indole (7.5 g , 34.7
mmol) , N-
(4-bromobutyl)phthalimide (10.8 g, 38.3 mmol) , triethylamine (4.5 ml) and
potassium
iodide (5.5 g) in 150 ml of acetonitrile was heated under reflux for 18h. The
reaction
mixture was concentrated and purified by silica gel column chromatografy
(dichloromethane/methanol /ammonium hydroxide= 92/7.5/0.5) to give 8.3 g of
the title
compound as a free base. Mp. 186°C. The hydrochloride was prepared by
dissolving
the above mentioned free base in 20 ml of 1 M HCI in ethanol. The solution was
concentrated and the resulting solid was washed with ether. Yield 8.4 g (54%)
of
compound 1, mp. 224°C (dec.).
xam
Preparation of 5-fluoro-3-[1-(3-cyanopropyl)-1,2,3,6-tetrahydropyridin-4-
yl]indole.
A solution of 5-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)indole (10 g , 46
mmol) , 4-
bromobutyronitrile(5.6 ml , 56 mmol) , potassium carbonate (6.3 g) and
potassium
iodide (7.6 g) in 100 ml of acetonitrile was heated under reflux for 18h. The
mixture
was filtered and the residue on the filter was washed with
CA 02373855 2001-11-13
WO 00/69424 PCT/EP00/03506
8
dichloromethane/methanol/ammonium hydroxide = 84/15/1. The organic layer was
concentrated to give 10.9 g (83%) of the title compound. M.p 152°C.
Example 5
Preparation of 5-fluoro-3-[1-(4-aminobutyl)-1,2,3,6-tetrahydropyridin-4-
yl]indo1e.
To a solution of 5-fluoro-3-[1-(3-cyanopropyl)-1,2,3,6-tetrahydropyridin-4-
yl]indole (10
g, 35 mmol) in 300 ml of dry THF was added slowly LiAIH4 (2.0 g ). The mixture
was
stirred and heated to reflux for 2h. Then the reaction mixture was cooled and
water
(1.9 ml) in THF (10 ml) was added slowly, followed by 2N sodium hydroxide (1.9
ml) .
This mixture was heated to reflux for 0.25h , filtered over hyflo and
concentrated to
give 8.76 g (88%) of the title compound.
Example 6
Preparation of N-[4-[4-(5-fluoro-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-
yl]butyl]-4-
fluorophthalimide (compound 19).
To a solution of 5-fluoro-3-[1-(4-aminobutyl)-1,2,3,6-tetrahydropyridin-4-
yl]indo1e (1.46
g, 5 mmol) in 20 ml of THF was added 4-fluorophthalic anhydride and 50 ml of
toluene.
The THF was removed by distillation and the resulting mixture was heated to
reflux for
18h, with azeotropic removal of water (Dean and Stark apparatus). The reaction
mixture was concentrated and purified by silica gel column chromatografy
(dichloromethane/methanol/ammonium hydroxide =92/7.5/0.5) to give 1.52 g (69%)
of
the title compound 19. M.p. 197-199°C.
According to method a) as illustrated in Examples 1-3, or method b) as
illustrated in
Examples 4-6 the compounds listed in the following Table 1 have been prepared:
CA 02373855 2001-11-13
WO 00/69424 PCT/EP00/03506
Table 1
Comp.No (R,)m Rz n (R3) Salt/baseMelt. Point
C
1 5-F H 4 H HCI 224(decomp.)
2 H H 4 H Base 193-4
3 H H 3 H Base 190-2
4 H CH3 4 H HCI 230
7-CH3 H 4 H Base 175-8
6 5-F H 3 H Base 174-6
7 H H 4 3-F Base 173-4.
8 H H 4 3-CH3 Base 184-5
9 H H 4 4-CH3 Base 195-8
5-CN H 3 H Base amorph.
11 5-CN H 4 H Base amorph.
12 5-CI H 4 H Base amorph.
13 H H 4 4-F Base 197-8
14 H H 4 4-t.C,H9Fumarate243-5
5-F H 4 4-t.C4H9Fumarate193-5
16 5-F H 4 3-CH3 Base 167-8
17 5-F H 4 4-CH3 Base 199-200
18 5-F H 4 3-F Base 188-190
19 5-F H 4 4-F Base 197-9
H H 6 H Base 196-7
21 5-F H 6 H Base 170-2
22 5-F H 4 4,5-diClBase 216-8
23 H H 4 4,5-diClBase 217-8
24 5-F H 5 H Base 194-8
5-F H 4 4-CI Base 186-8
26 H H ~-4I 4-CI I Base I 209-215
-- - -
CA 02373855 2001-11-13
WO 00/69424 PCT/EP00/03506
Example 7
N-[2-(4-((7-methyl-1 H-indol-3-yl)-1,2,3,6-tetrahydropyridi n-1-yl]ethyl]-4-
chlorobenzamid (compound 34)
5 To a stirred solution of 7-methyl-3-[1-(2-aminoethyl)-1,2,3,6-
tetrahydropyridin-4-yl]
indole (1.5g, 6 mmol) in 30 ml THF was added potassium carbonate (0.8g) and
para-
chloro-benzoyl chloride (0.8 ml). After stirring was continued for 30 minutes,
dichloromethane (100 ml) and water (50 ml) were added. The organic layer was
washed with water, dried and concentrated in vacuo to give the title compound
as a
10 yellow powder (1.3g, 56%). M.p. 176-181°C
Exam Ip a 8
a) 4-chlorobutyl-N-4-(3H)-quinazolinon
A mixture of isatoicacid anhydride (5g, 31 mmol), 4-hydroxy-butylamine (2.7g)
and
triethylformiate (5.6 ml) was heated at 130°C for 1 hour. The mixture
was concentrated
in vacuo to a dark brown oil, which could be used in the next step without
further
purification. The oil was dissolved in anhydrous acetonitril (50 ml) and to
this solution
was added thionylchloride (4.5m1, 61 mmol). The reaction mixture was heated at
80°C
for two hours giving a light brown precipitate. The mixture was cooled to room
temperature and the title compound was isolated by filtration in a yield of
6.3 g, 80%;
m. p. 162°C
b) 3-[4-[4-(5-fluoro-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-yl]-butyl]-4-
(3H)-
quinazolinon (compound 38)
To a stirring solution of 5-fluoro-3-[1,2,3,6-tetrahydropyridin]-indole (1.5g,
7 mmol) in
acetonitril (50 ml) was added potassium carbonate (1.0g), potassium iodide
(1.2 g) and
4-chloro-butyl-4-(3H)-quinazolinon (1.8g, 7.6 mmol). The mixture was refluxed
for 60
hours, after which time TLC showed complete conversion. The solution was
concentrated in vacuo on silica gel and the title compound was obtained as a
yellow
solid after flash chromatography. Yield: 1.6g, 55%; m.p. 168-170°C.
The compounds 27 to 44 indicated in tables 2 and 3 were prepared in a similar
manner:
CA 02373855 2001-11-13
WO 00/69424 PCT/EP00/03506
11
Table 2 yormula la)
Comp. (R,)m RZ q R, O (R5)t R6 R, Salt/baseM.p. C
No
27 H H 2 H a 4-F - - base 210-211
28 H H 2 H a 2-OMe, - - base 232-234
4-
NH2,
5-CI
29 5-F H 2 H a 4-F - - 1.HCI foam
salt
30 5-F H 2 H a 4-CN - - base 168-171
31 H H 2 H a 4-Me - - base 196-197
32 H H 2 H a 4-CN - - base foam
33 5-F H 2 H a 4-Me - - base foam
34 7-Me H 2 H a 4-CI - - base 176-181
35 H H 2 H a 2,4-F - - base foam
36 H H 4 H a 4-F - - base foam
37 5-F H 4 - ii - - - base 238-241
38 5-F H 4 - iii - H - base 168-170
39 5-F H 4 - iv - - H base 195-197
40 5-F H 4 - iv - - OH base 212-216
41 5-F H 4 - v - - - base 218-220
42 5-F H 4 - vi - - - base 200
43 5-F H 4 - iii - Me - base 176-177
Table 3 yformula lbllbl
~ Comp. No. ~ (R,)m ~ O, ~ R6 ~ Salt/base ~ M.p. °C- ~
44 H i Me 1.HCI foam
15
