Note: Descriptions are shown in the official language in which they were submitted.
2 0 1 1 1 9 7 ~
,.. ~.. ~, ,., ... - - 1 --
LACTAM DERIVATIVES
This invention relates to lactsm derivatives, to processes for
their preparation, to pharmaceutical compositions containing them and
to their medical use.
In particular the invention relates to compounds which are potent
and selective antagonists of 5-hydroxytryptamine (5-HT) at 5-HT
receptors of the type located on terminals of primary afferent nerves.
;; Receptors of this type are now designated as 5-HT3 receptors and are
also present in the central nervous system. 5-HT occurs widely in the
neuronal pathways in the central nervous system and disturbance of
these 5-HT containing pathways is known to alter behavioural syndromes
such as mood, psychomotor activity, appetite and memory.
Compounds having antagonist activity at 5-HT3 receptors have been
described previously.
Thus for example German Offenlegungsschrift No. 3740352 discloses
compounds which may be represented by the general formula:
~ \ /B\
;` A Im
20~ / \ / 2 n
wherein Im represents an imidazolyl group of the formuls:
, ~ ~
~, / R4
I _ I or
N /NR3 R3N\ //N - -~
R2 R2
Rl represents a hydrogen atom or a group selected from Cl_6alkyl,
~ C3_6alkenyl, C3_lOalkynyl, C3_7cycloalkyl, C3_7cycloalkylCl-4alkyl-,
; phenyl, phenylCl_3alkyl-, -CO2R5, -COR5, -CONR5R6 or -502R5 (wherein
R5 and R6, which may be the same or different, each represents a
hydrogen atom, a Cl_6alkyl or C3_7cycloalkyl group, or a phenyl or
: :
:
2 0 1 1 ~ 0 ~
~ ;, ,.,. , .,i- ,. . .
phenylCl-4alkyl- group, in which the phenyl group is optionally
substituted by one or more C1_4alkyl~ Cl-4alkoxy or hydroxy groups or
halogen atoms, with the proviso that R5 does not represent a hydrogen
stom when Rl represents a group -Co2R5 or -502R5);
one of the groups represented by R2, R3 snd R4 is a hydrogen atom or a
Cl-6alkyl, C3_7cycloalkyl, C3_6alkenyl, phenyl or phenylCl-3alkyl-
group, and each of the other two groups, which may be the same or
different, represents a hydrogen atom or a C1_6alkyl group;
~ Q represents a hydrogen or a halogen atom, or a hydroxy, Cl_4alkoxy,
: lO phenylCl_3alkoxy- or Cl_6alkyl group or a group -NR7R3 or -CûNR7R8
(wherein R7 and R8, which may be the same or different, each
represents a hydrogen atom or a Cl-4alkyl or C3_4alkenyl group, or
i~ together with the nitrogen atom to which they are attached form a
saturated 5 to 7 membered ring);
n represents 1, 2 or 3;
and A-B represents the group CH-CH2 or C=CH; and physiologically
:, acceptable salts and solvates thereof.
We have now found a novel group of compounds which differ in
structure from those described previously, and which are potent
20 antagonists of the effect of 5-HT at 5-HT3 receptors. ::
The present invention provides a tetracyclic lactam of the
, general formula (I):
,~ O :
~` 25 // \ / \ / \
i ~_-_- IN Im (I) 1
;\ / \N/ n
,J ;. ~ ",:
: :
wherein n represents 2 or 3;
Im represents an imidazolyl group of the formula:
R3 R3 ~ :~
' / / : :
N~ /NR2 or R2N\ /yN
- t t
Rl Rl
:- .' ' ' ':' ' `
~ 20~1107
. ~. , ,. -
wherein one of the groups represented by Rl, R2 and R3 is a hydrogen
atom or a Cl-6alkYl- C 3_ 7cycloalkyl~ C ~ 6alkenyl, phenyl or
phenylCl-3alkyl- group, nnd each of the other two groups, which may be
the same or different, represents a hydrogen atom or a Cl_6alkyl
group;
Y represents a group -(CH2)m-, wherein m represents 2, 3 or 4; or Y
represents a group -X(CH2)p-, wherein p represents 2 or 3, X
represents an oxygen or a sulphur atom or a group NR4, where R4 is a
Cl_6alkyl group, and X is attached to the benzene ring moiety of the
lo molecule;
and physiologically acceptable salts and solvates thereof.
Suitable physiologically acceptable salts of the compounds of
general formula (I) include acid addition salts formed with organic or
inorganic acids for example, hydrochlorides, hydrobromides, sulphates,
alkyl or aryl sulphonates (e.g. methanesulphonates or
p-toluenesulphonates), phosphates, citrates, succinates, tartrates,
acetates, fumarates and maleates. The solvates may, for example, be
` hydrates.
All optical isomers of compounds of general formula (I) and their
mixtures including the racemic mixtures thereof, and all the geometric
isomers of compounds of formula (I), are embraced by the invention.
Referring to the general formula (I), an alkyl group may be a
straight chain or branched chain alkyl group, for example, methyl,
ethyl, propyl, prop-2-yl, butyl, but-2-yl~ 2-methylprop-2-yl, pentyl,
pent-3-yl or hexyl. A C3_6alkenyl group may be, for example, a
propenyl or butenyl group. When R2 represents a C3_6alkenyl group,
the double bond may not be adjacent to the nitrogen atom. A
phenylCl_3alkyl- group may be, for example, a benzyl, phenethyl or
3-phenylpropyl group. A C3_7cycloalkyl group may be, for example, a
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.
A preferred class of compounds of formula (I) is that in which
Rl, R2 and R3 each independently represent a hydrogen atom or a
Cl_4alkyl (e.g. methyl) group. A further preferred class of compounds
~'
,. :
~.
, ~
- ~ 20~107
-- 4
is that wherein Rl and R2 each represent ~ hydrogen atorn, and R3 is a
~ Cl_3slkyl (e.g. methyl) group.
- Another preferred class of compounds of formula (I) is that in
which Y represents the group -(CH2)2-, -(CH2) ~ or -O(CH2)2-, more
preferably -(CH2) ~ or -(CH2) ~-
Preferred compounds according to the invention are:
5,6,9,1û-tetrahydro-10-[(5-methyl-lH-imidazol-4-yl)methyl]-4H-
pyrido[3',4':4,5] pyrrolo[3,2,1-ij]quinolin-11(8H)-one;
4,5,7,8-tetrahydro-9-[(5-methyl-lH-imidazol-4-yl)methyl~pyrido-
` 1 [4,3-b]pyrrolo[3,2,1-hi]indol- lO~9H)-one;
4,5,7,8,9,10-hexahydro-10-[(5-methyl-lH-imidazol-4-yl)methyl]-llH-
azepino[4,3-b]pyrrolo[3,2,1-hi]indol-11-one;
and their physiologically acceptable salts and solvates.
The potent and selective antagonism of 5-HT at 5-HT3 receptors by
1 the compounds of the invention may be demonstrated by their ability to ~ ~ -
inhibit 3-(5-rnethyl-lH-imidazol-4-yl)-l-[l-(methyl-t3)-lH-indol-
3-yl]-1-propanone binding in rat entorhinal cortex homogenates
(following the general procedure described by G. Kilpatrick et al. in
Nature, 1987, 330, 746), and/or by their ability to inhibit the
2 5-HT-induced depolarisation of the rat isolated vagus nerve
~ preparation.
,! Compounds of formula (I), which antagonise the effect of 5-HT at
5-HT3 receptors, are useful in the treatment of conditions such as
psychotic disorders (e.g. schizophrenia and mania); anxiety; and
nausea and vomiting, particularly that flssociated with cancer
chemotherapy and radiotherapy. Compounds of formula (I) are also
useful in the treatment of gastric stasis; symptoms of
gastrointestinal dysfunction such as occur with dyspepsia, peptic
ulcer, reflux oesophagitis, flatulence and irritable bowel syndrome;
` migraine; obesity and conditions such as bulimia; and pain. Compounds
of formula (I) may also be used in the treatment of dependency on
drugs and substances of abuse, depression, and dementia snd other
cogni'ive disorders.
According to another aspect, the invention provides a method of
treatment of a human or animal subject suffering from a psychotic
.
:~,
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,
, ~ ; .'
2 0 1 1 1 0 7
- 5
disorder such as schizophrenia or mania; or from anxiety; nausea or
vomiting; gastric stasis; symptoms of gastrointestinal dysfunction
such as dyspepsia, reflux oesophagitis, peptic ulcer, flatulence and
irritable bowel syndrome; migraine; obesity and conditions such as
bulimia; pain; dependency on drugs or substances of abuse;
depression; or dementia or another cognitive disorder, which comprises
administering an effective amount of a compound of formula (I) or a
physiologically acceptable salt or solvate thereof.
Accordingly, the invention also provides a pharmaceutical
composition which comprises at least one compound selected from
compounds of the general formula (I), and their physiologically
acceptable salts and solvates (e.g. hydrates), for use in human or
veterinary medicine, and formulated for administration by any
convenient route.
1, Such compositions may be formulated in conventional manner using
one or more physiologically acceptable carriers and/or excipients.
Thus the compounds according to the invention may be formulated
for oral, buccal, parenteral or rectal administration or in a form
suitable for administration by inhalation or insufflation (either
D through the mouth or nose).
For oral administration, the pharmaceutical compositions may take
the form of, for example, tablets or capsules prepared by conventional ~
means with pharmaceutically acceptable excipients such as binding ~ -
, agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or
! 25 hydroxylpropyl methylcellulose); fillers (e.g. lactose,
microcrystalline cellulose or calcium hydrogen phosphate); lubricants
(e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato
starch or sodium starch glycollate); or wetting agents (e.g. sodium
` lauryl sulphate). The tablets may be coated by methods well known in
3 the art. liquid preparations for oral administration may take the
form of, for example, solutions, syrups or suspensions, or they may be
presented as a dry product for constitution with water or other
suitable vehicle before use. Such liquid preparations may be prepared
by conventional means with pharmaceutically acceptable additives such
as suspending agents (e.g. sorbitol syrup, cellulose derivatives or
hydrogenated edible fats); emulsifying agents (e.g. lecithin or
. ~:
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2011~ 07
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-- 6
acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl
alcohol or fractionated vegetable oils); and preservatives (e.g.
methyl or propyl-~-hydroxybenzoates or sorbic acid). The preparations
may also contain buffer salts, flavouring, colouring and sweetening
agents as appropriate.
Preparations for oral administration may be suitably formulated
to give controlled release of the active compound.
For buccal administration the compositions may take the form of
tablets or lozenges formulated in conventional manner. -
The compounds of the invention may be formulated for parenteral
administration by bolus injection or continuous infusion.
Formulations for injection may be presented in unit dosage form e.g.
in ampoules or in multi-dose containers, with an added preservative~
The compositions may take such forms as suspensions, solutions or
~5 emulsions in oily or aqueous vehicles, and may contain formulatory
agents such as suspending, stabilising and/or dispersing agents.
Alternatively~ the active ingredient may be in powder form for
constitution with a suitable vehicle, e.g. sterile pyrogen-free water,
before use.
; 20 The compounds of the invention may also be formulated in rectal; compositions such as suppositories or retention enemas, e.g.
containing conventional suppository bases such as cocoa butter or
other glycerides.
In addition to the formulations described previously, the
compounds of the invention may also be formulated as depot
preparations. Such long acting formulations may be administered by
` implantation tfor example subcutaneously or intramuscularly) or by
intramuscular injection. Thus, for example, the compounds of the
invention may be formulated with suitable polymeric or hydrophobic
materials (for example as an emulsion in an acceptable oil) or ion
exchange resins, or as sparingly soluble derivatives, for example, as
" a sparingly soluble salt.
For administration by inhalation the compounds according to the ;~
~ invention are conveniently delivered in the form of an aerosol spray
''J 35 presentation from pressurised packs or a nebuliser, with the use of a
~..
~i suitable propellant, e.g. dichlorodifluoromethane,
:
:
.La..,
~- ` 2 o 1 1 1 0 7 ~
-- 7
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or
; other suitable gas. In the case of a pressurised aerosol the dosage
unit may be determined by providing a valve to deliver 8 metered
amount. Capsules and cartridges of e.g. gelatin for use in an inhaler
or insufflator may be formulated containing a powder mix of a compound
of the invention and a suitable powder base such as lactose or
starch.
For intranasal administration, the compounds according to the
invention may be formulated as solutions for administration via a
suitable metered or unit dose device or alternatively as a powder mix
with a suitable carrier for administration using a suitable delivery
- device.
; The compounds of formula (I) may also be administered in
combination with other therapeutic agents. Thus, for example, in the
treatment of gastric stasis, symptoms of gastrointestinal dysfunction
and nausea and vomiting, the compounds of formula (I) may be
1 administered in combination with antisecretory agents such as
; histamine H2-receptor antagonists (e.g. ranitidine, sufotidine,
cimetidine, famotidine, nizatidine or roxatidine) or H+K+ATPase
inhibitors (e.g. omeprazole). In the treatment of nausea and vomiting,
compounds of formula (I) may also be administered in combination with
dexamethasone or a cyclo-oxygenase inhibitor such as piroxicam.
, A proposed dose of the compounds of the invention for
'~ 25 administration to man (of approximately 70kg body weight) is O.OOl to
lOOmg, preferably O.Ol to 50mg, of the active ingredient per unit dose
expressed as the weight of free base, which could be administered, for
example, l to 4 times per day. It will be appreciated that it may be
necessary to make routine variations to the dosage, depending on the
~i age and condition of the patient. The dosage will also depend on the
route of administration.
Compounds of general formula (I) and physiologically acceptable
~! 35 salts or solvates thereof may be prepared by the general methods
outlined hereinafter. In the following description, the groups pl to
, R3, n, Y and Im are as defined for compounds of general formula (I)
- unless otherwise stated.
~,
2 0 1 1 1 0 7
, . ,.. . . .. . .. . . .. . ... . . ........ .. .... .... , .. ,, .. , ., , . .. , .. , , , ~ .~ . ..... .. .
8 -
According to 8 first general process (A) a compound of general
, formula (I) may be prepared by alkylating a compound of formulH (II):
1l
., . . -.
N (II) ~ ~
~yJ .:
with a compound of formula (III):
j LCH2-Im (III)
or a protected derivative thereof, wherein L represents a leaving atom
or group, such as a halogen atom (e.g. chlorine, bromine or iodine),
or an acyloxy group (e.g. trifluoroacetyloxy or acetoxy), or a
15 sulphonyloxy group (e.g. trifluoromethanesulphonyloxy,
~, p-toluenesulphonyloxy or methanesulphonyloxy); followed where
necessary by removal of any protecting groups. L is preferably a
halogen atom (e.g. a chlorine atom).
The reaction may be carried out in an inert solvent such as an
J 20 ether (e.g. dimethoxyethane, diglyme or tetrahydrofuran), a
substituted amide (e.g. dimethylformamide or N-methylpyrrolidone), an
aromatic hydrocarbon (e.g. toluene), a ketone (e.g. acetone), or
dimethyl sulphoxide, at a temperature between ambient and lOûC, in
J the presence of a base. Suitable bases include alkali metal hydrides
-'~ 25 (e.g. sodium hydride), alkali metal carbonates (e.g. sodium
carbonate), alkali metal amides (e.g. sodium amide), alkali metal
~ alkoxides (e.g. potassium t-butoxide) or alkali metal hydroxides (e.g. ~;~
`~l sodium or potassium hydroxide).
According to another general process (B), a compound of general
3 formula (I) may be converted into another compound of formula (I)
¦ using conventional techniques. Such conventional techniques include
.l, hydrogenation and alkylation using protection and deprotection where
necessary.
Thus, according to one embodiment of the interconversion process
(B), hydrogenation may be used to convert an alkenyl substituent into
an alkyl substituent. Hydrogenation according to general process (B)
~, :
i
.
.
,~ ~.,.. , ~ . . -
201~1 07
. ~ 9
may be effected using conventional procedures, for example, using
hydrogen in the presence of a catalyst, as described in published
[uropean Patent specification No. 242973.
The term 'alkylation' according to general process (B) includes
the introduction of groups such as cycloalkyl, alkenyl or phenalkyl
groups.
Thus, for example, a compound of formula (I) in which
R2 represents a Cl_6alkyl, C ~ ~ycloalkyl, C ~ 6alkenyl or
~ phenylCl-3alkyl- group may be prepared by alkylating the corresponding
; 10 compound of formula (I) in which R2 represents a hydrogen atom, using
` conventional procedures, for example as described in published
European Patent specification No. 242973. Thus the reactions may be
effected using an appropriate alkylating agent of formula R5Z (where
Rs is the group to be introduced and Z is a leaving atom or group),
` 15 preferably in the presence of a base.
It should be appreciated that in the above transformations it may
be necessary or desirable to protect any sensitive groups in the
molecule of the compound in question to avoid undesirable side
reactions. For example, it may be necessary to protect the imidazole
nitrogen atom, for example with an arylmethyl (e.g. trityl), alkyl
(e.g. t-butyl), alkoxymethyl (e.g. methoxymethyl), acyl (e.g.
benzyloxycarbonyl) or a sulphonyl (e.g. N,N-dimethylaminosulphonyl or
~` p-toluenesulphonyl) group.
Thus according to another general process (C), a compound of
general formula (I) may be prepared by the removal of any protecting
groups from a protected form of a compound of formula (I).
Deprotection may be effected using conventional techniques such as
those described in 'Protective Groups in Organic Synthesis' by
T. W. Greene (Oohn Wiley and Sons, 1981).
` For example, a trityl group may be cleaved by acid hydrolysis(e.g. using dilute hydrochloric or acetic acid). An alkoxyalkyl group
may be removed using a mineral acid (e.g. dilute hydrochloric acid). -~
An acyl group may be removed by hydrolysis under acidic or basic
conditions (e.g. using hydrogen bromide or sodium hydroxide). A
sulphonyl group may be removed by alkaline hydrolysis.
!
. .
~,
~` 2 0 1 1 1 0 7
I' '- '- " " ~
Compounds of formula (II) may be prepared, for example, by
, cyclising a compound of formula (IV):
.,, o
j . -
! . . NH
-(cH2) (IV)
N _ N
i Y H
or a salt thereof. The cyclisation may be carried out in aqueous or
-Yl non-aqueous media, optionally in the presence of an acid catalyst.
When an acid catalyst is used, this may be, for example, an inorganic
i acid such as concentrated sulphuric or hydrochloric acid. The acid
catalyst may also act as the reaction solvent. In an anhydrous
reaction medium, the acid catalyst may alternatively be a Lewis acid
such as zinc chloride. The cyclisation reaction may conveniently be
carried out at a temperature in the range of 20 to 200C. When no acid
, catalyst is used, the cyclisation may be effected thermally, by
`1 heating in a high boiling organic solvent, such as diethylene glycol,
conveniently at a temperature in the range 100 to 20ûC.
Compounds of formula (IV) may be prepared, for example, by the
~ reaction of a compound of formula (V):
`I // \
:i . . .
`~ 25 l 11 (V)
:~ ;\ / \
.,~. y
, or a salt thereof, with a compound of formula (VI):
; 30 0 -
~ 35 Jy~ 2)n (Vl)
~ .
.
~'
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201~07
or a protected derivative thereof, in a suitable solvent such as an
alcohol (e.g. ethanol), and at a temperature of, for example, frorn 2n
to lûûC.
Alternatively, compounds of formula (II) may be prepared directly
by the reaction of a compound of formula (V), or a salt thereof, with
a compound of formula (VI), or a protected derivative thereof, using
the appropriate conditions QS described above. Compounds of formula
(IV) may be isolated as intermediates in the above reaction.
Compounds of formula (III) and protected derivatives thereof, are
eitner known, or may be prepared, for example, by the methods
described in German Offenlegungsschrift No. 3740352.
Compounds of formulae (V) and (VI) are either known, or may be
prepared from known compounds by conventional procedures.
Where it is desired to isolate a compound of the invention as a
salt, for example a physiologically acceptable salt, this may be
achieved by reacting the compound of formula (I) in the form of the
free base with an appropriate acid, preferably with an equivalent
amount, in a suitable solvent such as an alcohol (e.g. ethanol or
methanol), an aqueous alcohol (e.g. aqueous ethanol), a halogenated
hydrocarbon (e.g. dichloromethane), an ester (e.g. ethyl acetate) or
an ether (e.g. tetrahydrofuran).
Physiologically acceptable salts may also be prepared from other
salts, including other physiologically acceptable salts, of the
compound of formula (I) using conventional methods.
Individual enantiomers of the compounds of the invention may be
~` obtained by resolution of a mixture of enantiomers using conventional
; means, such as an optically active resolving acid; see for example,1 'Stereochemistry of Carbon Compounds' by E.L.Eliel (McGraw Hill, 1962)
and 'Tables of Resolving Agents' by S. H. Wilen.
The methods described above for preparing the compounds of the
invention may be used for the introduction of the desired groups at
; any stage in the stepwise formation of the required compounds, and it
!~'`', 35 will be appreciated that these methods can be combined in differentways in such multi-stage processes. The sequence of the reactions in
- multi-stage processes should of course be chosen so that the reaction
conditions used do not affect groups in the molecule which are desired
in the final product.
-: .
r
~~ 20 1 ~L107
- 12 -
The invention is further illustrated by the following
Intermediates and Examples. All temperatures are in C. Thin layer
chromatography (t.l.c.) was carried out on silica, and flash column
chromatography (FCC) was carried out on silica (Merck 9385). Solvent
System A as used for chromatography denotes
dichloromethane:ethanol:O.88 ammonia solution. Organic extracts were
dried, where indicated, over magnesium sulphate.
Intermediate 1
10 5,6,9,10-Tetrahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]-
quinolin-11(8H)-one
A solution of 2-amino-1,2,3,4-tetrahydroquinoline hemisulphate (500mg)
and 2,4-dioxopiperidine (287mg) in absolute ethanol (20ml) was kept
~ under nitrogen for 20h. The solvent was removed in vacuo to leave a
`~ 15 gum (700mg) which was treated with concentrated sulphuric acid (7ml)
for 15 min. The resulting solution was neutralised with 8~ sodium
bicarbonate solution (200ml) and extracted with dichloromethane
" (3xlOOml). The combined, dried organic extracts were evaporated to
give a solid (470mg) which was purified by FCC eluting with System A
;:~ 20 (4nO:10:1) to give the title compound (230mg) as a solid, m.p.
~ 254-256.
:~.
- Intermediate 2
4,5,7,8-Tetrahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indol-10(9H)-one
25 A solution of l-amino-indoline hydrochloride (1.09) and
2,4-dioxopiperidine (663mg) in absolute ethanol (4ûm~) was stirred
under nitrogen for 48h. The solvent was removed in vacuo and the
residue was dissolved in diethylene glycol (30mQ) and heated at 200
for 2h. The solution was allowed to cool, poured into water (2ûOm~)
i~- 30 and extracted with dichloromethane (3xlOOm~). The combined, dried
ii organic extracts were evaporated to give an oil (ca.2.5g) which was
- purified by short path column chromatography on silica gel (Merck
7729) eluting with System A (4ûO:10:1) to give the title compound
(330mg) as a solid, m.p. 265-267.
. ~:
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:. ::: : :.: : , .: :
~ 2011107
.
- 13
Intermediate 3
~,4-Dihydro-2H-1,4-benzoxazin-4-amine
A cold (0) solution of sodium nitrite (2.69) in water (12.5mQ) was
added dropwise to a cold (0) stirred solution of 3,4-dihydro-2H-1,4-
benzoxazine (4.99) in water (27.5mQ) and concentrated hydrochloric
acid (9.5mQ). The mixture was stirred at 0-5 for 1.5h, then
extracted with ether (3x60mQ). The combined, dried organic extracts
were evaporated to give a solid which was dissolved in a mixture of
acetic acid (llmQ), water (llmR) and ethanol (17mQ) and added dropwise
to a vigorously stirred suspension of zinc powder (259) in ethanol
(32mQ) at 40-50. After 30min the mixture was cooled and filtered,
and the filtrate was evaporated to dryness. The residue was treated
with 5N sodium hydroxide solution (300mQ) and extracted with ether
(3xlOOmQ). The combined, dried organic extracts were evaporated to
give an oil (ca.5.3g) which was purified by FCC eluting with
hexane:ethyl acetate (4:1) to give the title compound (3.29) as an
oil, t.l.c. (hexane:ethyl acetate, 4:1) Rf 0.25.
~`
Intermediate 4
1,2,9,10-Tetrahydropyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzoxazin-
; 7(8H)-one
'~ A solution of 4-amino-3,4-dihydro-2H-1,4-benzoxazine (1.09) and 2,4-
` dioxopiperidine (753mg) in absolute ethanol (40mQ) was stirred under
nitrogen for 1.5h. Tne solvent was removed in vacuo and the residue
was dissolved in diethylene glycol (30mQ) and heated at 100 for lh,
then at 150 for 2h. The solution was allowed to cool, poured into
~ wster (200m~) and extracted with dichloromethane (3xlOOmQ). The
j combined, dried organic extracts were evaporated to give a semi-solid~ (ca.3g) which was purified by FCC eluting with System A (400:10:1) to!~ 30 give the title compound (740mg) as a solid, m.p. 298-300. ;~
` . .:
^ 2011107
. .
- 14
Intermediste 5
3-(2,3-Dihydro-lH-indol-l-yl)-2-cyclohexen-1-one
A mixture of indoline (5.399) and cyclohexane-1,3-dione (5.079) was
heated at ca. 150 for 7h. After cooling, the mixture was purified by
FCC eluting with ethyl acetate: methanol (10:1) to give a solid
(7.309) which was recrystallised from ethyl acetate: ether (ca. 4:1)
to give the title compound (5.089), m.p. 85-86.
.
Intermediate 6
4~5~8~9-Tetrahydropyrrolo[3~2Jl-jk]cQrbazol-lo(7H)-one
A mixture of 3-(2,3-dihydro-lH-indol-l-yl)-2-cyclohexen-1-one
(2.5159), cupric acetate (4.719) and palladium (II) acetate (0.209) in i~
dry dimethylformamide (40ml) was heated at 135 under nitrogen for 4h.
The solvent was then removed under reduced pressure and the residue
was suspended in methanol and then filtered. The filtrate was
evaporated under reduced pressure and the resultant residue was
purified by FCC eluting with ethyl acetate to give the title compound
(0.36y) as a solid. A sample (20mg) was recrystallised from ethyl
acetate to give the title compound (15mg), m.p. 208-210.
Intermediate 7
4,5,8,9-Tetrahydropyrrolo[3,2,1-jk]carbazol-10(7H)-one oxime
A mixture of 4,5,8,9-tetrahydropyrrolo[3,2,1-jk]carbazol-10(7H)-one
(364mg) snd hydroxylamine hydrochloride (479mg) in pyridine (50ml) was
heated to 50 for 60h, and was then poured into 2N hydrochloric acid
(lOOml). The resultant precipitate was filtered off, washed with
water (50ml), and dried in vacuo at 50 for 6h to give the title
compound (140mg). Filtration of the precipitate that formed
. ~
subsequently in the filtrate gave a further crop of the title compound
(104mg), m.p. 271-272.
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- 15
Intermediate 8
4,5,7,8,9,10-Hexahydro-llH-azepino[4,3-b]pyrrolo[3~2,1- hi]indol-
ll-one
4,5,8,9-Tetrahydropyrrolo[3,2,1-jk]carbazol-10(7H)-one oxime (244mg)
was added to polyphosphoric acid (20ml) at 120, and the mixture was
stirred at 120 for lh. After cooling, the mixture was poured into
water (150ml) and extracted with dichloromethane: ethanol (10:1; 4 x
lOOml). The combined, dried organic extracts were evaporated under
reduced pressure to give a solid (150mg) which was purified by FCC
eluting with System A (100:10:1) to give the title compound (92mg),
t.l.c. (System A, lûO:10:1) Rf 0.47.
i``
; Example 1
5,6,9,10-Tetrahydro-10-[(5-methyl-lH-imidazol-4-yl)methyl]-4H-
~~ 15 pyrido[3'~4':4,5]pyrrolo[3,2~1-ij]quinolin-11(8H)-one maleate
`- Sodium hydride (60~ dispersion in oil; 57mg) was added to a stirred
suspension of 5,6,9,10-tetrahydro-4H-pyrido[3',4':4,5]pyrrolo-
[3,2,1-ij]quinolin-11(8H)-one (270mg) in dimethoxyethane (15ml) and
the mixture was heated at 50 for 6h. The mixture was then treated
with 4-(chloromethyl)-5-methyl-1-(triphenylmethyl)-lH-imidazole
(522mg) and stirring was continued at 50 for 18h. Water (3ml) and
acetic acid (3ml) were added and the solution was heated at reflux for
`~! 3h. The mixture was poured into 8~ sodiu~ bicarbonate solution (60ml)
;1 25 and extracted with dichloromethane (3x30ml). The combined, dried
organic extracts were evaporated to give a solid (810mg) which was
~ purified by FCC eluting with System A (200:10:1) to give a solid
i (324mg). This material was dissolved in dichloromethane/absolute
ethanol (3ml) and treated with a solution of maleic acid (117mg) in -~
absolute ethanol (lml). The solvent was removed in vacuo and the
~ residue was triturated with dry ether (3x5ml) to give the title
¦ compound (415mg), m.p. 146-14B.
¦ Water Analysis Found 0.56~ w/w - 0.13mol H20.
~, Analysis Found: C,62.8; H,5.5; N,12.55;
Cl~ 20N40.C4H404Ø13H20 requires C,62.9; H,5.5; N,12.8~.
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- 16 -
Example 2
4,5,7,8-Tetrahydro-9-[(5-methyl-lH-imida~ol-4-yl)methyl]pyrido-
t4,3-b]pyrrolo[3,2,1-hi]indol-10(9H)-one maleate
Sodium hydride (60~ dispersion in oil; 68mg) was added to a stirred
solution of 4,5,7,8-tetrahydropyrido[4,3-b]pyrrolo[3,2,1-hi]-
indol-10(9H)-one (300mg) in dry dimethoxyethane (15mR) under nitrogen,
and the mixture was heated at 60 for 6h. The mixture was then treated
with 4-(chloromethyl)-5-methyl-1-ttriphenylmethyl)-lH-imidazole
(634mg) and stirring was continued for 20h. Water (3mQ) and acetic
; 10 acid (3mR) were added and the solution was heated at reflux for 4h.
The mixture was poured into 8~ sodium bicarbonate solution (60mR) and
; extracted with dichloromethane (3x30mQ). The combined, dried organic
extracts were evaporated to give a solid (935mg) which was purified by
FCC eluting with System A (200:10:1) to give a solid (310mg). This
material was dissolved in absolute ethanol (5mR) and treated with a
solution of maleic acid (118mg) in absolute ethanol (2mR). The
solvent was removed in vacuo and the residue was triturated with dry
ether (3xlOmR) to give the title compound (413mg), m.p.l25-128.
~ater Analysis Found: 1.79~w/w --0.43mol H20.
Analysis Found: C,61.3; H,5.4; N,12.9;
i Cl8Hl8N4U C4H44 43H2 requires C,61-4; H,5.4; N,13.0~.
!, Example 3
1,2,9,10-Tetrahydro-8-~(5-methyl-lH-irnidazol-4-yl)methyl]pyrido-
[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzoxazin-7(8H)-one maleate
1,2,9,10-tetrahydropyrido[3',4':4,5]pyrrolo[1,2,3-de][1,4]benzoxazin-
7(8H)-one (350mg) and 4-(chloromethyl)-5-methyl-1-(triphenylmethyl)-
lH-imidazole (686mg) were treated according to the method of Example 2
to give the title compound (565mg) as a solid, m.p. 149-151.
Analysis Found: C,60.0; H,5.1; N,12.6;
Cl8Hl8N4o2-c4H4o4 requires C,60.3; H,5.1; N,12.9~.
2 0 ~ 7
-- 17
Example 4
4,5,7,8,9,10-Hexahydro-10-[(5-methyl-lH-imidazol-4-yl)methyl]-
llH-azepino[4,~-b]pyrrolo[3,2,1-hi]indol-11-one maleate
4,5,7,8,9,10-Hexahydro-llH-azepino[4,3-b]pyrrolo[3,2,1-hi]indol-
5 ll-one (43mg) and 4-(chloromethyl)-5-methyl-1-(triphenylmethyl)-lH-
imidazole (159mg) were treated according to the method of Example 2,
except that the FCC eluant was System A (100:15:1), to give the title
compound (57mg) as a solid, m.p. 173-176.
Analysis Found: C,63.4; H,5.8; N,12.8;
10 C23H24N405 requires C,63.3; H,5.5; N,12.8'.
The following examples illustrate pharmaceutical formulations
according to the invention. The term "active ingredient" is used
` herein to represent a compound of formula (I).
TABLETS FOR ORAL ADMINISTRATION
Tablets may be prepared by the normal methods such as direct
compression or wet granulation.
The tablets may be film coated with suitable film forming
20 materials, such as hydroxypropyl methylcellulose, using standard
techniques. Alternatively the tablets may be sugar coated.
~ Tablets of other strengths may be prepared by altering the ratio
`l of active ingredient to excipients or the compression weight and using punches to suit.
i Direct Compression Tablet
mq/tablet
Active Ingredient 0.50
Calcium Hydrogen Phosphate BP*87.25
Croscarmellose Sodium NF 1.80
11agnesium Stearate BP 0.45
.. ~' ;
Compression weight 90.00
-~ 35
-~ * of a grade suitable for direct compression.
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- 18
:
- The active ingredient is passed through a 60 mesh sieve, blended
with the calcium hydrogen phosphate~ croscarmellose sodium and
- magnesium stearate. The resultant mix is compressed into tablets
using a Manesty F3 tablet machine fitted with 5.5mm, flat bevelled
edge punches.
IN~ECTION FûR INTRAVENOUS ADMINISTRATIûN
mg/m~
~3 10
,` Active ingredient 0.05 1.0
Sodium Chloride BP as required as required
Water for Injection BP to l.Om~ l.ûm~
f 15 Sodium chloride may be added to adjust the tonicity of the
solution and the pH may be adjusted, using acid or alkali, to that of
optimum stability and/or facilitate solution of the active ingredient.
` Alternatively, suitable buffer salts may be used.
The solution is prepared, clarified and filled into appropriate
size ampoules sealed by fusion of the glass. The injection is
sterilised by heating in an autoclave using one of the acceptable
cycles. Alternatively, the solution may be sterilised by filtration
and filled into sterile ampoules under aseptic conditions. The
solution may be packed under an inert atmosphere of nitrogen or other
suitable gas.
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