Note: Descriptions are shown in the official language in which they were submitted.
~ ~ p~ 9 l l o ~ s 9
B2981 1 1 ~3
Tetrahydrobenzothienopyridines and The1r Use As Pharmaceuticals
This invention relates to compounds having pharmacological
activity, to a process for their preparation, to
s compositions containing them and to their use in the
treatment of mammals.
EP-A-0 327 223 (Beecham Group plc~ discloses a class of
tetrahydrobenzothienopyridines which have anxiolytic and~or
o anti-depressant activity.
A class of compounds has now been discovered, which
compounds have been found to have CNS activity, in
: particular anxiolytic and/or anti-depressant activity.
Accordingly, the present invention provides a compound of
formula (I) or a pharmaceutically acceptable salt thereof:
R2
2; ~ ~ 2 4
R~
wherein:
30 R1 is hydrogen, Cl_6 alkyl, phenyl or phenyl Cl_4 alkyl
: wherein the phenyl moiety is optionally substituted by one
or more Cl_6 alkyl, Cl 6 alkoxy~ Cl_6 alkylthio~ hydroxy~
; C2_7 alkanoyl, halo, trifluoromethyl, nitro, amino
Unitec' ~ 10m IP,~ t,c~ SUBSTiTUTE SHEET
," -'
WO~1/17165 PCT~GB~1/00697
2~82392 -2-
optionally substituted by one or two C1_6 alkyl sroups o- by
C2_7 alkanoyl, cyano, carbamoyl or carboxy groups;
R2 anà R3 are inde?endently selected from hydrogen, Ci_~
5 alkyl, C3_7 cycloalkyl, C3_7 cycloalkyl-Cl_4 alkyl, C2_~
alkenyl, C1_7 alkanoyl, C1_6 alkylsulphonyl, di-(C1_6
alkyl~amino C1_6 alkyl, 3-oxobutyl, 3-hydroxybutyl, phenyl,
phenyl C1_4 alkyl, benzoyl, phenyl C2_7 alkanoyl or
benzenesulphonyl any of which phenyl moieties are optionally
o substituted by one or two halogen, C1_6 alkyl, C1_6 alkoxy,
CF3, amino or carboxy, or R2 and R3 together are C2_6
- polymethylene`optionally interrupted by oxygen or NR6
wAerein R6 is hydrogen ox C1_6 alkyl oDtionally substituted
Dy hydroxy;
R~ is hydrogen or C1_6 alkyl and R8 is hydrogen or R5 and R8
together form a C1_6 alkylidene group at the 8-position;
and
20 -CO2R4 is a pharmaceutically acceptable ester group.
Alkyl moieties within the variables R1 to R5 are prererably
C1 3 alkyl, such as methyl, ethyl and n- and iso-propyl.
:
25 Values for R1 incLude hydrogen, methyl, ethyl, n- and
lso-propyl, phenyl and benzyl. P-eferably, R1 is methyl.
t will be appreciated in selectlng variables R2 and R3 that
_he ni~rogen atom is not directly attached to unsat~-2led
30 alipnatic carbon.
Vaiues for R2 and R3 include hydrogen, methyl, e~hyl, n- and
so~propyl, n-, sec-, lso_ and ter.-butyl, n-, sec, ~so- and
neo-?en~yl, cyclopentyl, cyclohexy , cycloheptyl,
~5 cyclo?entyl-C1_4 alkyl, cyclohexyl-C1_4 alkyl and
. .
WO91/171~5 PCT/GB91/On697
_3_ 20~2392
cycloheptyl-Cl_4 alkyl, where values for Cl_4 alkyl include
methylene and ethylene, but-2-enyl, but-3-enyl,
l-methylprop-2-enyl, formyl, acetyl, propionyl,
methylsulphonyl, 3-dimethylaminobutyl, 3-oxobu~yl,
_ 3-hyàroxybutyl, phenyl, ben7yl, henzoyl, benzylcarbonyl and
benzenesulphonyl, or R2 and R3 together form
-(CH2)r-X-(CH2)s- wherein r and s are independently l, 2 or
3 and X is a bond, O or NR6, for example C4 or C5
polymethylene, -~C~2)2-O-(CH2)2- or -(CH2)2 NR6 (CH2)2
lO where R6 is preferably methyl.
- Preferably R2 is hydrogen and R3 is hydrogen or Cl_6 alkyl,
for example methyl.
5 Most preferably R2 and R3 are hydrogen.
Suitable examples of pharmaceutical esters of the compounds
of formula ~I) include Cl_6 alkyl esters wherein the alkyl
moiety is optionally substituted by up to three halo atoms
20 selected from chloro, fluoro and bromo, such as methyl,
ethyl, n- and iso-propyl, n-, sec- and tert-butyl and
2,2,2-trifluoroethyl esters, C2_6 alkenyl esters such as
vinyl, prop-l-enyl, prop-2-enyl, l-methylvinyl, but-l-enyl,
but-3-enyl, l-methylenepropyl and l-methylprop-2-enyl, (in
2s both their E and Z forms where stereoisomerism exists), C2_6
alkynyl esters such as prop-2-ynyl, but-2-ynyl and but-3-
ynyl, C3-6 cycloalkyl esters and C3-6 cycloalkyl-Cl_4 alkyl
esters such as cyclopropylmethyl. ~referably the
pharmaceutically acceptable ester is the methyl, ethyl,
30 2,2,2-trifluoroethyl, propyl, prop-2-enyl, prop-2-ynyl, but-
3-enyl, but-2-ynyl, but-3-ynyl or cyclopropylmethyl ester,
i.e. R4 is methyl, ethyl, 2,2,2-trifluoroethyl, propyl,
prop-2-enyl, prop-2-ynyl, but-3-enyl, but-2-ynyl, but-3-ynyl
or cy~lopropylmethyl.
~s
WO91/17165 PCT/CB91/~697
2082392
~Suitable values of R5 include hydrogen, methyl, ethyl and n
and iso propyl, preferably hydrogen. Alternatively, R5 and
~8 together may -epresent an 8-(i-methylethylidene) group.
s There is a prefe~red group o- compounds within formula (I)
of formula (II) or a pharmaceutically acceptable salt
thereof:
~` 1
N~R3
O ~ 2~4 (II
wherein R3l is hydrogen or Cl_6 alkyl and Rl and R4 are as
defined in formula (I).
- Preferred values for Rl and R31 are as described for the
corresponding variables in formula (I).
The compounds of the formula (I) can form acid addition
2s salts with acids, such as the conventional pharmaceutically
acceptable acids, for example, maleic, hydrochloric,
hydrobromic, phosphoric, acetic, fumaric, salicylic, citric,
lactic, mandelic, tartaric and methanesulphonic.
30 It will be appreciated tha~ the compounds of formula (I) in
which R2 or R3 is hydrogen may exist tautomerically in more
than one form. The invention extends to each of these forms
and to mixtures thereof.
3; Compounds of formula ( T ) may also form solvates such as
hydra~es, and the inver.~ion also e~tends to hese rorms.
WO91/17165 PCT/GB91/00697
~5~ 208239~
When referred to herein, it is understood that the term
''com?ound of formula (I)'' also includes solvates thereo .
.
It should be apprecia~ed that co~pounds o~ formula (I) n
, which R8 is hydrogen and R5 is other than hydroaen have a
chiral centre on the carbon atom adjacent to the R5 moiety.
In addition, compounds in which R5 and R8 represent an
alkylidene group may exist in E and Z forms, while
substituents Rl, R2, R3, R4, and R5 may contain asymmetric
lO carbon atoms. The present invention extends to any single
stereoisomers such as enantiomers, or mixtures thereof
including racemates, of compounds of formula ~I).
The invention also provides a process for the preparation o_
lS a compound of formula ~I), or a pharmaceutically acceptable
salt thereof which process comprises the cyclisation of a
compound of formula ~III):
R M
~ 1 R4
S ~ N Rl' ~III)
R8 R7
or imine tautomer thereof, wherein Rl' is Rl as defined in
formula ~I) or a sroup convertible thereto, R4f is -CO2R9 as
defined in formula (I) or an electron-withdrawing group
convertible to -CO2R4, R5 and R8 are as defined.as in
30 formula (I), R7 is hydrogen or an N-protecting group, J and
~ toaether represent a keto group or a group convertible
there~o, Y is a group CN or COLi, wherein Ll is a leaving
group and M is hydrogen, or Y is hydrogen and M is a grou?
. CN o- CvL2, wAerein L2 ls a leaving g;oup; and thereafte-,
WO 91/17165 PCI/GB9!/00697
2~g~`92
--6--
optionally or as necessary, and in any appropriate order,
converting R7 when hydrogen to an N-protecting g-oup, when Y
or M is a group COL1 or COL2, converting the resultins .
hydroxy group to a leaving group and reac~ing the latter
wi~h a compound HNR2'R3' wnerein R2' and R3' are R2 and R3
or N-protecting groups, removing any R7 N-protecting sroup,
converting any electron-withdrawing group R4' to CO2Rq~
converting Rl' when other than R1 to Rl, interconverting R2,
R3, R4, R5 and R8, converting J and K ~o a keto group,
10 separating any stereoisomers such as enantiomers and/or
forming a pharmaceutically acceptable salt of a compound of
formula (I).
. .
The cyclisation of the enamine of formula (III) or imine
5 tautomer thereof may be carried out under conventional
conditions, in the presence of a strong base such as an
alkali me~al alkoxide, for example sodium methoxide in a
; suitable solvent such as methanol, at elevated temperature,
or in the presence of a Lewis acid such as ZnC12, SnCl4 or
20 CuOCOCH3 in a suitable solvent such as n-butyl acetate at
elevated temperature.
.
Lewis acid catalysed cyclisation using copper (I) acetate or
tin (IV) chloride is preferred especially when cyclising tO.
25 give compounds of formula (I) directly i.e. where R4' is
C02R4.,
~referably J and K together represent a group convertible tO
a keto group such as a protected hydroxy group or a
30 protected keto group. A protected hydroxy such as
~rimethylsilyl or tetrahydropyranyl may be de-protected .
conventionally to give a hydroxy group which may be oxidised
conventionally for example using oxalylchloride/
-imetnylsulphoxide or ?yridinium chlorochromate to give ~he
ketone.
WO91/17165 PCT/GB91/~697
208~3g~
~rotected keto groups J and K a~e exemplified by compounds
of formula (III) wherein J is XR,3 and K is ZRl~, X and Z
are independently oxygen or sulphur and Rl3 and Rl~ are
independently Cl_6 aikyl or toge~her are C2_4 polymethylene
optionally substituted wirh one or more Cl_6 alkyl croups.
When X and Z are both oxygen, the group -X-Rl3 and -Z-Rl4
may be conventionally converted to a keto group for example
by treatment with aqueous hydrochloric acid.
When one of X or Z is an oxygen atom and the other is a
sulphur atom, the group -X-Rl3 and -Z-Rl4 may be
conventionally converted to a keto group, for example by
treatment with aqueous hydrochloric acid or quaternisation
l5 of the sulphur atom followed by hydrolysis, for exàmple
using an alkylhalide followed by water.
When X and Z are both sulphur the group -X-Rl3 and -Z-Rl4
may be conventionally converted to a keto group by reacting
0 one of the sulphur atoms with;
(i) a heavy metal cation such as silver
tii) a quaternising agent such as an alkylhalide or
(iii) an oxidising agen. such as a peracetic acid
and thereafter, hydrolysing off the protecting group to
afford a keto group, for example using aqueous acetone or
30 aqueous acetonitrile.
~rererably X and Z are oxygen.
R5 and R8 hydrogen may ~e conver~eA to an alkylidene grcup
3s in the 8-position by an aldol condensation with an
,: ' '
WO91/1716~ PCT/GB91/00697
2~3`~3~ -8- ~
appropriate aldehyde or ketone, such as acetone. The
alkylidene group may then be hydrogenated to the
correspondins ~S al~yl c-oup conventionally usi-.g, Lor
example, a pal'adlum ~n charcoal catalyst.
_xamples of R7 N-protecting groups include trimethylsilyi
and 2-(trimethylsilyl)ethoxymethyl, which may be removed
conventionally, for example using tetra-n-butylammonium
fluoride.
Preferably R7 is hydrogen. ;
Sui.able examples of groups R4' include the groups
- hereinbefore described for -CO2R4, CORa where Ra is
15 hydrogen, Cl_6 alkyl, C3_7 cycloalkyl C1_4 alkyl or C3_7
cycloalkyl, CH=NOH, CO2H, CO2O where Q is a protecting group
such as benzyl wherein the benzyl moiety is optionally
substitu~ed in the phenyl ring by one or two of halogen,
CF3, Cl 6 alkoxy, Cl_6 alkyl or nitro, cyano and -CONRgRlo
20 where Rg and R1o are independently selected from hydrogen,
C1_6 al~yl, C1_6 alkoxy and phenyl or phenyl C1_4 alkyl
optionally substituted as described above for optional
substituents in the phenyl ring of a benzyl ester, or
together form a C2_6 polymethylene-chain optionally
; 25 interrupted by oxygen or NR11 wherein Rll is hydrogen or
C1_6 alkyl, e.g. morpholino or piperazino.
protecting group Q may be removed by conventional
hycrolysis or hydrogenolysis to yield the free acid which
3~ can then be esterified under conventional condi~ions by
reaction with the appropria~e alcohol R40H, optionally with
?rior conversion Oc the acid to the acid chloride by
reac~ion with a suitable chlorinating agent such as thionyl
c:-lo-ide, or witn an alkylating agent R~X where X is a
39 ieaving group suc~ ~s cnloro, broma or iodo, ln the pres-nce
:
WO 91/17165 PCI`/GB91/00697
9 2082392 - -
of a suitable base such as potassium ca_bonate in an iner_
solvent such as dimetAylformamide.
~n ir.termediate amide may be hydrolysed to the f-ee aci~
- which can then be esteri~ied as described above.
An R4' cyano group may be converted under anhydrous acidic
conditions to an imino ester by reaction with the
appropriate alcohol R40H and then hydrolysed to the group
10 -C02R4 .
An R4' CH=NOH group may be converted to cyano by dehydration
with a suitable dehydrating agent such as formic acid at
elevated temperature, and the resulting cyano group
5 converted to C02R4 as just described. Alternatively ~he
CH=NOH group may be converted to formyl by hydrolysis,
oxidised to the free acid using a suitable oxidising agent
such as CrO3 and esterified as above.
o R4' CORa groups may be converted to C02R4 via the acid by a
haloform reaction and esterification.
Suitable examples of a leaving groups L~ and L2 when v or M
is COL1 or COL2 include hydroxy and, more preferably, alkoxy
25 such as C1_6 alkoxy, for example ethoxy or methoxy. The
- cyclisa~ion of the compound or formula (III) or imine
tautomer thereof gives a resulting compound having an
hydroxy group in the 4-position of the pyridine ring. The
hydroxy group may be converted to a leaving group such as
30 those defined below for L, preferably halo such as chloro,
~y reaction with a halogenating agent such as phosphorus
oxycr.loride or phosphorus oxybromide. The leaving group may
.e displaced by the compound HNR2'R3' under conventional
-o..d-_lons fo- nucleophil c aromati_ cisplacements, a~
'a elevated temperatures n an inert solvent sucr. as toluene,
~et-.anol, etAanol, - : ne, dimet-yi ormami~e c- d oxar..
.
~ . ,
WO91/17165 PCT/GB91/0~97
2082392
--10--
Alternatively, the reaction may be carried out in neat
HNR2'R3' which funct~ons as the solvent.
~ n R2' or R3' pro~ec~ing srou? such as p-methoxybenzyl may
5 be removed conventionally.
Conversion of R2 and R3 hydrogen to other R2/R3 may be
carried out in accordance with conventional procedures for
the alkylation or acylation of a primary amine. Acylation
lO may be carried out by reaction with the appropriate acyl
halide. However, R2/R3 other tban hydrogen or acyl groups
are preferably introduced via the route in which Y or M is
COLl or COL2 in the compound of formula (III), by
displacement of the leaving group with the compound HNR2'R3'
lS as discussed above.
Pharmaceutically acceptable salts may be prepared
conventionally by reactioh with the appropriate acid or
derivative.
Compounds of formula ~III) may be prepared by the reaction
of a compound of formula ~IV):
a~
2s ~ / Y
J ~ ~ S ~
K ¦ N~R7
R8
~ IV)
with a compound of formula (v):
WO91/17165 PCT/GB91/00697
2082392
--11--
M / R4f
- / R
L~ 1
:: (V)
lO wherein Rl', R4', ~5, R7, R8, Y, J, and K are as defined as
in formula (III), L is a leaYing~group and M is as defined
~ in formula (III) or L and M together represent a bond.
-- ` : ~ :
Intermediates of formula (III) and (IV) are novel and form a
i 15 further aspect to the present invention.
Suitable examples of the leaving group L include:halogens,
such as chloro and bromo, hydroxy, Cl_6 acyloxy such as
acetoxy, Cl 6 aLkoxy,~such as methoxy or ethoxy, preferably
20 methoxy or~;NRa~ where Ra and Rb are independently hydrogen
or Cl_4 alkyl or together form~a C2_6 polymethylene chain
optionally interrupted by oxygen or NRC where Rc is hydrogen
;~ ~ or Cl_6 alkyl optionally subst~ituted by hydroxy. When L is
hydroxy, it wl1l be~appreciated that the compound o~ formula
25 (V) exists in~more than one tautomeric form.
The ~reaction of a~compound of ,~ormula~(IV) with a compound
of formula (V)~may be carried out under conditions
conventional for condensation reac~ions, at elevated
- ~30 temperatures~in an inert solvent such as toluene, benzene,
ethanol,~ pyridine, dimethylformamide or dioxan, optiona}ly
in the presence of a cat~alyst such as para-toluene sulphon c
acid~or lO-camphorsulphonic acid, with water separation i.
appropriate. ~ ~ ~
:: :
i r
.~ I
.
'
'
' .
'
WO91/17165 PCT/GB91/0~97
2082392 ` -12-
For the preparation of compounds of formula (I) in which R.
is hydrogen, ~he compound o-^ formula (V) ma~ be used in
which:
(i) L and M together represent a bond or L is hydroxy and M
is hydrogen, and Rl' is a Cl_6 alkoxycarbonyl group. The
reaction with the compound of formula (IV) may then be
followed by a decarboxylation step to give Rl hydrogen;
(ii) L is a leaving group and Ri' is hydroxy. In the
resulting compound, the Rl' hydroxy may be converted to
hydrogen by first replacing~it by chloro by conventional
chlorination with a chlorinating agent such as phosphorus
5 oxychloride followed by reductive dehalogenation under
conventional conditions, for example zinc in acetic acid.
The conversion to Rl hydrogen may be carried out before or,
- more preferably, after cyclisation of the compound of
formula (III);
(iii) L is a leaving group, M and R4' are both Cl_6
alkoxycarbonyl, and Rl' is hydrogen.
Compounds of formula (IV) are prepared analogously to the
~s methods described in K. Gewald et al, Chem. Ber. 94 (1966)
by reacting compounds of formula (VI):
R5
R8 J~
.
(VI)
WO91/17165 PCT/GB91/00697
-13- 2 082 3 9 2
wherein R5, R8, J and ~ are as defined in formula (III),
with NCC~2Y and sulphur in the presence of a base such as
diethylamine in an iner- solvent such as methanol or
ethanol.
Compounds of formula (VI) are either known compounds o- car.
be prepared analogously to known compounds.
Compounds of formula ~V) are known compounds or can be
0 prepared analogously to known compounds. For example,
compounds of formula (V) wherein M is hydrogen, L is OH and
Rl is CH3 may be prepared by reacting diketene with the
appropriate alcohol R40H using a method similar to that c
R.J. Clemens and J.A. Hyatt, J. Org. Chem., 1985 50 2431.
The compound of formula (V) in which Rl' is phenyl, M is
hydrogen, L is ethoxy and R4' is ethoxycarbonyl is described
by V.L. Leighton, Amer. Chem. Journal ~1898), 20, 133.
A class of intermediates comprises compounds of formula
20 ~VII) or a salt ester or amide thereof:
~ r
R~ j
~VII)
30 wherein R4'' is R4' as defined in formula (III) or a grou?
convertible to CO2R4, X is NR2'R3', OH or chloro, Rl', R2',
R3', J and K are as defined in formula ~III) and R4, R5 and
R8 are as defined in formula (I), provided that when X is
NR2R3, J and K togethe_ represent a keto group and R,' is
~5 Rl, R4'' is other than CO2R4. Novel compounds of formula
.
;'
`
WO91/17165 PCT/GB91/00697
2082392 -14- -:~
~V_I) also form par~ o the invention. ',
_xamples of R4'' when other than CO2R4 include CO2H.
; In a ;^urther aspect, the invention also provides a process
for the preparation of a compound of formula (I) or a
pharmaceutically acceptable salt thereof which process
comprises deprotecting a compound of formula ~VII) in which
~ is NR2R3, R4'' is C02R4 and Rl is Rl, and J
l0 together represent a group convertible to a keto group and
,hereafter optionally separating any stereoisomers such as
enantiomers and/or forming a pharmaceutically acceptable
salt of a compound of formul;a (I).
lS The present invention also provides a pharmaceutical
composition, which comprises a compound of formula (I) or a
pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.
20 A pharmaceutical composition of the invention, which may be
?repared by admixture, suitably at ambient temperature and
atmospheric pressure, is usually adapted for oral or
?arenteral administration and, as such, may be in the form
o- ~ablets, capsules, oral liquid preparations, powders,
2s granules, lozenges, reconstitutable powders, or injectable
o- infusable solutions or suspensions. Orally administrable
compositions are generally preferred.
~ablets and capsules for oral administration may be in unit
30 dose form, and may contain conventional excipients, such as
binding agents, fillers, tabletting lubricants,
-isintegrants and acceptable wetting agents. The tablets
may be coated according to methods well known in normal
^harmaceutical practice.
's
-al llquid preparations may be in the form of, for example,
aqueous or oily suspension, solutions, emulsions, syrups o-
.
WO 91/17165 PC[/~1191/On697
2082392
-15-
elixirs, or may be in the rorm of a dry product for
-econstitution with wate- or other suitable vehicle before
use. Such liquid preparations may contain conventional
additives such 2S suspending agents, emulsi~ying agen~s,
non-aqueous vehi_les (which may include edible oils),
preservatives, and, if desired, conventional flavourings o-
colourants.
!
For parenteral administration, fluid unit dosage forms are
prepared utilising a compound of the invention or
pharmaceutically acceptable salt thereof and a sterile
vehicle. The compound, depending on the vehicle and
_oncentration used, can be either suspended or dissolved in
the vehicle. In preparing solutions, the compound can be
dissolved for injection and filter sterilised before filling
into a suitable vial or ampoule and sealing.
Advantageously, adjuvants such as a local anaestheti¢,
preservatives and buffering agents are dissolved in the
vehicle. To enhance the stability, the composition can be
frozen after filling into the vial and the water removed
under vacuum. Parenteral suspensions are prepared in
substantially the same manner, except that the compound is
suspended in the vehicle instead or being dissolved, and
sterilization cannot be accomplished by filtration. The
compound can be sterilised by exposure to ethylene oxide
before suspension in a sterile vehicle. Advantageously, a
surfactant or wetting agent is included in the composition
~o facilitate uniform distribution of the compound.
The composition may contain from 0.1% to 99% by weight,
?referably from 10 to 60% by weight, of the active material,
depending on the method of administration.
.
~he dose O r the compound used in the treat~ent of C~S
~_ disorders, such as anxiety or depression will vary in the
usual ay wit:l the seriousness cr ~:~e disoraers, the we c^.~
;
~ ~ .
WO 91/17165 PCI'/GB9.1/00697
2~82392 - - -16-
of the sufferer, and other similar factors. However, as a
genèral guide suitable unit doses may be 0.05 to 1000 mg,
more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and
such unit doses may be administered more than once a day,
5 for example two or three a day, so that the total daily
dosage is in the range of about 0.01 to 100 mg/kg; and such
therapy may extend for a number of weeks or months.
The invention further provides a pharmaceutical composition
o for use in the treatment of CNS disorders, in particular
anxiety or depression which composition comprises an
effective, non-toxic amount of compound of formula (I) or a
pharmaceut~calli accrptable salt thereof, and a
pharmaceutically acceptab'le carrier.
The invention further provides a method for the treatment
and/or prophylaxis of CNS disordexs, in particular anxiety
or depression in mammals, including humans, which comprises
administering to the sufferer an effective, non-toxic amount
20 of a compound of formula (I) or a pharmaceutically
acceptable salt thereof.
The invention also provides a compound of formula (I), or a
pharmaceutically acceptable salt thereof for the use in the
s treatment and/or prophylaxis of CNS disorders, in particular
anxiety or depression.
The invention yet further provides the use of a compound of
formula (I), or a pharmaceutically acceptable salt thereof,
~; 30 in the manufacture of a medicament for treatment and~or
prophylaxis of CNS disorders, in particular anxiety or
depression.
The following examples illustrate the preparation of
35 compounds of the invention.
WO9l/17165 PCT/GB91/00697
-17- 2082392
Description l
2-Amino-6,6-ethvlenedioxy-4,5,6,7-tetrahydrobenzo~bL
thio~hene-3-carbonitrile (D1)
(D1)
The title compound was prepared from 1,4-cyclohexandione
mono-ethylene ketal using a procedure similar to that o_ K.
5 Gewald et al., Chem. Ber. 1966, 94 (49% yield).
NMR (CDCl3) S:
1.95 (2H, t), 2.72 (4H, m), 4.02 (4H, s), 4.72 (2H,
bs).
20 Description 2
N-3-(2-(3-Cyano-6,6-ethvlenedioxy-4~,6,7-~etrahydrobenzo
~blthienyl)amino)-2-butenoic acid, ethvl es~er (32?
\\ ~ ~ ~ _
(D2 ~
.
::
WO91/17165 PCT/GB91/00697
.
2 o823 9 2 -18-
A mixture of aminonitrile (D1) (13.16g; 55.7mmol) and etAy:
~-ethoxycrotonate (26g; 164mmol) in mesitylene (400ml) was
heated at reflux for l.Sh then evaporated to dryness. ~he
residue was chromatographed on Kieselgel 60 eluting with a
0-2~ methanol in dichloromethane gradient. Trituration of
the product with petrol (bpt:40 - 60C) and filtration
afforded the title compound as a yellow solid (11.9g, 61%)
0 m.p. 115-I18C.
.
NMR ~CDC13) ~:
1.30 ~3H, t), 1.95 ~2H, t), 2.10 ~3H, s), 2.85 (4H,
m), 4.02 (4H, s), 4.20 (2H, q), 4.90 (lH, s).
Description 3
4-Amino-7,7-ethvlenedioxy-2-methvl-5,6,7,8-tetrahvdro-
benzo~blthieno~2,3-blPyridine-3-carboxvlic acid, ethvl
20 ester ~D3)
~2 il
~,fqf--C2H5
< ~ ~ S ~ N~ ~ C~
~ O
~D3)
~ solution of enaminoester D2 (11.7g, 33.6 mmol) in ~oluene
30 (400ml) was treated with a 1~ solution of sodium ethoxide in
ethanol (90ml) and heated to reflux for 2.5h. The reaction
mixture was cooled and added to ethyl acetate and
.
.
WO91/1716S PCT/GB91/00697
-19- 20823~2
half-sa~urated aqueous ammonium chloride. The mixture was
filtered, the organic phase separated, dried (Na2S04) and
evaporation n vacuo gave a brown oil. Chromatography c-
TLC alumina, eluting with a 0-2~ methanol in dichloromethane
, gradient, af-orded the title compound as a yellow gum (7g,
60%).
NMR (CDCl3) ~:
1.40 (3H, t), 2.05 (2H, t), 2.70 ~3H, s), 3.00
~2H, s), 3.23 ~2H, t), 4.05 (4H, s), 4.38 ~2H, q),
6.60 ~2H, bs).
N~2
COOR4
Exam~le 1
4-Amino-2-methyl-7-oxo-5,6,7,8-tetrahYdrobenzo~bl
thieno~2,3-blPYridine-3-carboxYlic acid, ethvl ester
(El, R4 = C2H5~
2s A solution of ketal D3 ~4.62g, 13.3mmol) in acetone ~200ml)
was treated with water ~lOml) and concentrated hydrochloric
acid ~2ml) then heated to reflux under nitrogen for 24h.
~- Additional concentrated hydrochloric acid ~2ml) was added,
and the mixture heated to reflux for 8h, then stored at c~ -
30 5C for 12h. Filtration afforded a white crystalline solid
~3.5g) which was partitioned between ethyl acetate and
saturated aqueous sodium bicarbonate solution. The organ.c
~ phase was separated, dried (Na2SO4) and concentrated ln
: ~ .
.
.
. . .
..
WO 91/17165 . PCI/GB9t/00697
2082392 -20-
- vacuo whereupon crystallisation occured. After storing at
ca. 5C for 12h, filtration affoxded the title compound as a
white crystalline solid (2.37g, 59%).
m.p. 159-161C
Found: C, 59.32; H, 5.19; N, 9.17
C15H16N2O3S requires C, 59.19; H, 5.30; N, 9.20
NMR (CDCl3) S:
o 1.42 (3H, t), 2.71 (3H, s), 2.80 (2H, t), 3.45
(2H, t), 3.78 (2H, s), 4.40 (2H, q), 6.55 (2H, bs).
Example 2
4-Amin ~ trahvdrobenzo~blthieno
~2,3-bLeYridine-3-carboxylic acid, cyclopropvlmethvl ester
(E2, R4 = CH2 c C3H5)
The title compound was prepared from Dl and 3-oxo-butyric
20 acid, cyclopropylmethyl ester via the intermediate
~ 4-amino-7,7-ethylenedioxy-2-me~thyl-5,6,7,8-tetrahydro-
-- benzoEb]thieno[2,3-b]pyridine-3-carboxylic acid,
cyclopropylmethyl ester using a procedure similar to that
described in Description 2, Description 3 and Example 1.
~5
m.p. 168 (from ethyl acetate)
:
Found: C, 61.89; H, 5.51; N, 8.53
C17H18N2O3S requires C, 61.80; H, 5.49, N, 8.48%
; 30
:
.
WO91/17165 PCT/GB9!/00697 .
-21- 2082392
- Exam~le 3
4-.~r.ino-2-meth~l-?-oxo-5, 6, 7, 8-tetrahydroben70 fbl thien:~
'2,3-bl~yridine-3-ca~boxyllc_acid, methyl es_e- (E3,
5 ~4 = CH3~
The title compound was prepared from D1 and methyl
acetoacetate via the intermediate 4-amino-
7,7-ethylenedioxy-2-methyl-5,6,7,8-tetrahydro- .
lo benzo[b]thieno[2,3-b]pyridine-3-carboxylic acid, methyl
ester using a procedure similar to that of Example 2.
m.p. 202-6 (from ethyl acetate)
5 Found: C, 57.95; H, 4.86; N, 9.65
C14H14N2O3S requires C, 57.92; H, 4.86; N, 9.65%.
.
~ Exam~le 4
- 20 4-Amino-2-methYl-7-oxo-5,6,7,8-tetrahYdrobenzo~b]thieno
~2,3-blpvridine-3-carboxvlic acid, Pro~yl ester
~E4, R4 - CH2CH2CH3)
.. '~
~he title-compound was prepared in 11% overall yield f-om
25 D1 and 3-oxo-butyric acid, propyl ester via the intermediate
:: 4-amino-7,7-ethylenedioxy-2-methyl-5,6,7,8-tetrahydro-
benzo[b]~hieno~2,3-b]py~idine-3-carboxylic acid, propyl
- ester using a procedure similar to that or Example 2.
0 m.p. 141-2 ~from ethyl acetate f 60:80 petroleum ether)
. ' . .
:~ .
:.' -". . ~ '. .
,
WO91~17165 PCT/GB91/00697
20823~2 -22-
NMR (d6 DMSO) ~: 0.95 (3H, t, J=7Hz), 1.75 (2H, sx, J=7H~),
2.55 (3H, s), 2.70 (2H, t, J=6Hz), 3.40 (2H, ~,
J=6Hz), 3.70 (2H, s), 4.25 (2H, t, J=7Hz), o.75 ~2~:,
bs).
.
Exam~le 5
4-Amino-2-methvl-?-oxo-5,6,7.8=tetrahydrobenzo~b1
thieno~2L3-blpvridine-3-carboxvlic acid, Prop-2-enyl
o ester (E5, R4 - CH2CH=CH2L
. . , ~ . .
The title compound was prepared in 8% overall yield from D1
and 3-oxo-butyric acid, p,rop-2-enyl ester via the
intermediate 4-amino-7,7-ethylenedloxy-2-methyl-5,6,7,8-
15 tetrahydrobenzo[b]thieno~2,3-b]pyrldine-3-carboxylic acid,
prop-2-enyl ester using a procedure similar to that
described in Example 2.
m.p. 148-150 (from ethyl acetateJ.
- 20
NMR (CDC13) ~: 2.74 (3H,s), 2.80 (2H, t, J=8.5Hz), 3.4â
(2H, mj), 3.70 (2H, s), 4.85 (2H, m), 5.30 - 5.50
(2H, bm), 5.95-6.18 (lH, bmj, 6.60 (2H, broad).
:`
~ s Example 6
. . .
9-Amino-2-methvl-;7-oxo-~,6,7,8-tetrahvdrobenzo[b ! thieno
r2,3-1 pyrldine-3-carboxv~ ut-2-vnvl es~er (E6,
R4 C~2C=CC~3)
; The title compound was prepared in 5% overall yield f-om
Dl and 3-oxo-butyric acid, 2-but-2-ynyl ester via the
.~ ; . .
WO9t/17165 PCT/GB91/00697
2082392
-23-
intermediate 4-amino-7,7-ethylenedioxy-2-me~hyl-5,~,7,8-
tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxyli~ acid,
but-2-ynyl es~er using a ~rocedure similar ~o that desc-~bec
_n ~xample 2.
m.p. 190-2 tfrom ethyl acetate).
NMR (CDC13) ~:~.90 (3H, t, J=3HZ), 2.74 (3H, s), 2.80
(2H, t, J=8Hz), 3.4S (2H, m~, 3.70 (2H, s), 4.90
o (2H, q, J=3Hz), 6.55 (2H, broad s).
~xamPle 7
.~ ..
4-Amino-2-methvl-7-oxo-5,6,7,8-tetrahvdrobenzo[blthieno
S ~2,3-blpyridine-3-carboxvlic acid, 2,2,2-trifluoroethyl
ester (E7, R4 = C~2CF3)
The title compound was prepared in 1% overall yield from
2,2,2-trifluoroethyl acetoacetate and D1 via the
20 intermediate 4-amino-7,7-ethylenedioxy-2-methyl-5,6,7,8-
tetrahydrobenzo~b]thieno~2,3-b]pyridine-3-carboxylic acid,
2,2,2-trirluoroethyl ester using a procedure similar to that
oî r xample 2.
~5 ~.p. 140-6
' '
~MR (CDC13) ~: 2.55(3H, s), 2.80 (2H, t, J=6Hzj, 3.40
(2H, t, J=6Hz), 3.65 (2H, s), 4.70 (2H, q, J=8Hz),
5.70 (2H, broad s).
m/~ = 358 (M+).
.
WO 91/17165 PCI/GB91/00697
. . , _.
~082392 -24-
Exam~le 8
4-Amino-2-methvl-7-oxo-5,6,7,9-tetrahYdrobenzo[blthieno
s ~2,3-blpYridine-3-carboxvlic acid, but-3-envl ese~- (E8,
R4 = ~CH2L2 CH=CH2)
The title compound was prepared from Dl and 3-oxo-butyric
acid, but-3-enyl ester via the intermediate 4-amino-
o 7,7-ethylenedioxy-2-methyl-5,6, 7,8-tetrahydrobenzo-
[b]thieno[2,3-b]pyridine-3-carboxylic acid, but-3-enyl ester
using copper ~I) acetate following a procedure similar to
that of Example 2. ~
- 15 m.p. 130-2 (from ethyl acetate~.
NMR ~CDC13) ~: 2.5S (2H, m), 2.70 (3H, s), 2.85 (~H, t,
J=8.5 Hz), 3.45 (2H, t, J=8.S Hz), 3.70 (2H, s), 4.45
(2H, t, J=8.5 Hz), 5.10-5.25 (2H, br, m), 5.80-5.95
~lH, br, m), 6.60 (2H, br, s~.
Example 9
:
4-Amino-2-methvl-7-oxo-5;617,8-tetrahydrobenzorblthieno
-- 2s t2,3-blpvridine-3-carboxYlic acid, but-3-vnvl ester (E9,
~ R4 = (CH2)2c--cH).
.
The title compound was prepared in 5~ overall yield from Dl
and 3-oxo-butyric acid, but-3-ynyl ester via the
30 intermediate 4-amino-7,7-ethylenedioxy-2-methyl-5,6,
7,8-tetrahydrobenzo[b]thieno~2,3-b]pyridine-
3-carboxylic acid, but-3-ynyl ester using a procedure
similar to that of Example 2, but in which the cycllsatlon
WO91/17165 PCT/~B91/00697
-25- 2~82392
step was carried out in n-butyl acetate using SnCl~.
.p. 167-8C
NMR (CDCl3) ~: 2.05 (lH, t, J = 2.8Hz), 2.,0 (2:i, d_,
J = 2.8, 8.5 Hz), 2.75 (3H, s), 2.80 (2~
8.5Hz), 3-45 (2H, m), 3.70 (2H, s), 4.45 (2U., _, J =
8.5 Hz), 6.60 (2H, broad s).
lO ExamPle 10
4-Amino-2-methyl-8-(l-methyl-I-ethylidene)-7-oxo-5,6,7,8-
~etrahvdrobenzo~blthieno~2,3-b1pvridine-3-carboxvl c acid,
but-3-envl ester ~ElO)
NH2
2 ( C~2 ) ~C~=C~2
~3C C~3
(ElO)
The amine D1 and 3-oxobutyrlc acid, but-3-enyl es~er were
;--onverted into the cyclised product using copper(I) acetate
; ~s in 39% yield by the method of Description 2 and Descr-ption
3. Treatment with aqueous hydrochloric acid/ace~one a~
reflux for 48h, similar to the method of Example l, ga~e a
crude product~in 93% yleld. Chromatography on silica, usi~
30% ethyl acetate/n-pentane, afforded a pure sample o the
JO title compound which was recrystallised from ethyl acetate
~ as yellow crystals.
.
......
.
.
WO91il7165 PCT/CBgl/On697
2082392 -26-
m.p. 136-8
NMR (CDC13) ~: 2.25 (3H, s), 2.27 (3H, s), 2.S5 (2H, m),
2.74 (3H, s), 2.80 (2H, t, J = 8.SHz), 3.40 (2H, _,
J=8.SHz), 4.42 (2H, t, J=8.5Hz), S.10-S.2S ~2H,
broad m), 5.7S-S.98 (lH, broad m), 6.70 (2H, broad s).
~ .
,~ .
~ .
.'~ .
.
W091/17165 PCT/GB91t~697
-27- 20~23~2
Dharmacoloqical Data
'. Geller-Seifter ~-ocedure
20tential anxiolyt c properties have been evaluated usi.
the Geller-Seifter procedure based on that originally
described by Geller and Seifter, (1960) Psychopharmacologia,
l, 482-492. This procedure has been shown to be selective
for drugs with anxiolytic properties (Cook and Sepinwall,
lO tl975) ''Mechanism of Action of Benzodiazepines'' ed. Costa,
E. and Greengard, ~., Raven Press, New York, pp. 1-28).
~ .
Rats are trained on a variable interval 30 sec schedule
(VI30) to press a lever in order to obtain food reward. The
~s 5 min sessions of the VI30 schedule alternate with 2-5 min
of a schedule (FR5) in which every 5th lever press is
followed by presentation of a food pellet paired with a 005
sec mild footshock. The total study lasts approximately 30
~- mins. Rats typically respond with high rates of lever
20 ?ressing under the VI30 schedule and low response rates
under the FR5 'conflict' session. Anxiolytic drugs increase
the suppressed response rates of rats in 'conflict' session.
Drugs are administered intraperitoneally or orally to groups
25 of 3-8 rats 30 min before testing.
.
- The results are expressed as the percentage increase in
square root of the total number of lever presses in the FR5
'conflict' session. Square root transformation is necessary
30 to normalise the data for statistical analysis using
?arametriC methods (ANOVA).
,
,~ .
,'.
,
.
WO9t/1716~ PCT/GB91/~697
2~82392 - -28-
2. ~35Sl-TBPS bindin~ to rat cerebral cortex membranes
in vitro
s ~ooled rat cerebral cortices are homogenised in 20 ~o'umes
of 0.32M sucrose and centrifuged at lOOOg for 20 minutes
(4C). The supernatant is removed and recentrifuged at
50,000g (4C, 20 mins). The P2 pellet is then suspended in
20 volumes of Tris citrate buffer (pH 7.l) and centrifuged
O at 50,000g (4C, 20 mins). This washing step is repeated
three times and the pellet finally resuspended in 20 volumes
of buffer and stored at~-~70C prior to use.
The tissue suspension (50~1) is incubated (25C, 120 mins)
15 with [35S]-TBPS (2nM) in Tris citrate buffer (pH 7.l)
- containing 0.2M NaCl and 5 x lO 6M GABA. Non-specific
binding is measured in the presence of I0-4M picrotoxin.
Varying concentrations of test dru~s (lO 7, lO 6, lO 5 and
lO 4M final concentration) are added in a volume of 50~
20 The total assay volume is 500~1. Incubation is stopped by
rapid filtration using a Skatron cell harvester and
radioactivity measured by liquid scintillation spectrometry.
IC50's are calculated as the concentration of test drug tO
inhibit 50~ of specific binding.
2s
~ ~Testinq Results
: i :
1. Geller-Seifter procedure
Compound Dose Increase in responding
(mg/kg) in the 'conflict' session
Example l 20 p.o. + 52%
~ .
.
:
~ .
" ~ `
WO 91/17165 PCr/GB91/00697
2~23~2-
Compound E2 also showed a significant increase in
-esponding in the `conflict' session at a dose o-
2Omg/kg p.o.
2. ~35Sl-TBPS bindin~ procedure
Compound IC50
0 Example 1 13~M, 17~m (2 determinations)
Compounds of Examples 2, 6, 7 and 1O showed an IC50 f
less than 20~M.
