Note: Descriptions are shown in the official language in which they were submitted.
WO92/11011 - l - PCT/US91/08g35
, ~ .
USE OF CERTAIN GLUTARIMID~ DE:RIVATIVES IN THE TREATMENT OF
DEPRESSION AND MANIA
This invention relates to the manufacture o~ certain
glutarimide derivatives for thei- use as medicamen~s in the
treatment of depression and mania. .
More specificallv, t:nis invention relates to the use in
the manufactu~e of a medicament for trea~ing depression and
mania utilizing a compound of the formula
o ,~;.. ,
~\ ~. '
X (CH~)n
\---~/ Rs
O
. .:
their geometric, stereo- or optical isomers, the mi~tures ~
thereof, and the pharmaceuticallyacceptableacid addition .
salts thereof, wherein X is selected from the group
consisting of : :
',.'~ .
WO92/llOII PCT/US91/08935
-- 2 -- ~
~,~9~ G~
Rl 1 3
Rl ~A 1 ~ CH2CH2-N-
R2 B CH2-NH-, ~J~ N
H
R~ R
~ ~ ~\ ~ N- and ~ R3
Ei :
5 R is hydrogen, Cl 4 alkyl, Cl_4 2_'~0~:-i, hc loge-.s, -~ ro,
hydroxy, SO~H, S02N~.2, or S02N~2-CH2-,
R2 is hydrogen, Cl 4 alkyl, Cl 4 alkoxy, halogeno, ni-ro or
hydroxy, and
Rl and R2, taken together with the carbon atoms to which
20they are attached, form a benzenoid moiety a- the
indicated l,2- or 3,4-positions,R3is H or Cl 4 alkyl,
R4 and R5 are H, Cl 4 alkyl or, when taken toge her with the
carbon atom to which they are attached, form a C3 6
cycloalkyl moiety,
n is an integer of 2 to 5 inclusive,
A and B independently are oxygen, sul~ur or NR3, their
geometric, stereo- or optical isomers and the mixtures
thereof, and the pharmaceutically accepta;ble acid
addition salts thereof.
As used herein the term "pharmaceutically acceptable
acid addition salts" is intended to apply tO any non-toxic
-organic or inorganic acid addition salts of the base
compounds represented by Formula ~1). Illustrative ino.ganic
W092/11011 3 PCT/US91/OX935
acids which form suitable sal~s incQude hydrochloric,
hydrobromic, sulphuric and phosphoric acid and acid metal
salts such as sodium monohydrogen orthophosphate and
potassium hydrogen sulfate. Illustrative organic acids which
form suitable salts include the mono-, di- and tricarboxylic
acids. Illustrative of such acids are for example, acetic,
glycolic, lactic, pyruvic, ma].onic, succinic, glutaric,
` fumaric, malic, tartaric, citric, ascorbic, maleic,
hydroxymaleic, benzoic, ~-hydroxybenzoic, phenylacetic,
lO cinnamic, salicylic, 2-phenoxybenzoic acids, and sul~onic -
` acids such as methanesulfonic acid or 2-hydroxyethane-
sulfonic acid. Either the mono- or the di-acid salts can be
formed, and such salts can exist in either a hyd-ated or a
substantially anhydrous form. In general, the acid addition
salts o~ these co~.Dounds are crystalli.ne m~rerials which are
- soluble in wa.er and in various hydrophilic organic
solvents. Additionally, in comparison to their free base
. forms, such salts generally demonstrate higher melting
-/ points and an increased chemical stability.
As used herein, Cl_4 alkyl includes the straight and
branched alkyl radicals having l to 9 carbon.atoms such as
methyl, ethyl, n-propyl, isopropyl, n-bu~yl, t-butyl,
isobutyl and the like. Cl_4 alkoxy includes the straight and
branched alkoxy radicals such as methoxy, ethoxy, n-propoxy,
.~ isopropoxy, n-butoxy, t-butoxy, isobutoxy and the like.
Halogeno includes chloro, bromo and fluoro. The isomers
contemplated include the position isomers~ the stereoisomers
as well as the enantiomeric isomers, and the mixtures
thereof. The individual isomers of the compounds of formula
I may best be prepared by processes desiqned to enrich the
production of the desired isomers. ~owever, mixtures may be
resolved or lsolated according to conventional and standard
procedures well known in the art, e.g. chromatographic
WO92/llO~I _ 4 PCT/US91/08935
~,~9~Q~
separation, fractional crystallization, use of optically
active acids, enzymatic resolution and the like.
In essence, the compounds of formula (1) contain a
glutarimide moiety joined to the defined X moieties by a
(CH2)n alkylene bridging moiety. Preferably n represents 2 or
5. Illustrative of the X moieties are:
(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino,
(2,3-dihydro-1,4-benzoxathiin-3-yl)methylamino,
(2,3-dihydro-1,4-benzodithiin-2-yl)methylamino,
~2,3-dihydro-1,4-benzoxazin-3-yl)methylamino,
~2,3-dihydro-1,4-dihydroquinazolin-2-yl)methylamino,
(2,3-dihydronaphtho[1,2-b][1,4]dioxin-2-yi)methylamino,
(2,3-dihydronaphtho[1,2-b][1,4]dioxin-3-yl)methylamino,
(indol-3-yl)ethylamino,
(1,2,3,4-tetrahydro-B-carbolinyl), and
tetralin-2-amino and the Rl, R2 and/or R3 substituted
analogs.
Specific subclasses of compounds that fall within the
scope of the present invention are illustrated as follows:
WO 92/110ll PCr/VS91/08935
: r 2~7~07
8-[~-[(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]alkyl]-
8-azaspiro[4,5~decane-7,9-diones,
S [~ o l C~-NH- ~ CS ~ - N~
O
(1a)
8-[~-[(2,3-dihydro-1,4-benzoxathiin-3-yl)methylamino)alkyl]-
8-azaspiro[4,5]decane-7,9-diones, ;
:.2-N~-(Ca~)n- N
O
: (1b)
~ .
8-[~-[(2,3-dihydro-1,4-benzodithiin-2-yl)methylamino]alkyl]-
8-azasplro[4,5]decane-7,9-diones,
S 1 C~z-NH-(Ca~)A- N X ]
O
(1c)
;.
W092/llOII 2 0 9 ~ v ~ ~ - 6 - PCT/US91/~8935
8-[w-[(2,3-dihydro-1,4-benzoxazin-3-yl)methylamino]alkyl]-8-
azaspiro[4,5]decane-7,9-diones,
e~NlCH2-NH-(CH~)n- N ~>~
H O
(1d)
8-[~-[(2,3-dihydroquina201in-2-yl)methylamino]alkyl]-8-
azasplro[4,5]decan~-7,9-diones,
~ ~ 1 _E2-N~-(C ,) _ ~ ~ =
r: O
(1e) :
8-[~-[(2,3-dihydrona~htho[1,2-b][1,4]dioxin-2-
yl)methylamino]-ailcyl]-8-azasDiro[4,5]decane-7,9-dior.es,
~ ~o1CH2-NH-(CH~)n N X
. .
(1f)
(Compounds of this sub-class can be substituted either at
the 2- or 3-position of the dioxin rin~.)
WO92/11011 P~TIUS~ 935
~ 2~7607
; 8-[w-[(indol-3-yl)ethylamino]alkyl]-8-azaspiro[4,5]decane-
7,9-diones,
O
~~ ~~ CH2CHZ-N-(CH2~ - N ~ \
(19)
'.
8-[w-[l,2,3,4-tetrahydro-3-carbolinyl]alkyl]-8-
azaspiro[4,5]-decane-7,9-diones, ::
~ ~N-(CaZ'~
H O
(1h)
8-[~-[(substituted)tetralin-2-amino]alkyl]-8-azaspiro[4,5]-
decane-7,9-diones,
.. l
~ N~(CH2)n~ N
,
(1i)
:~
- .
..... .. . ..
:;" ,~",:, ,. ..i"", ",, "", .~
WO92/11011 PCT/US91/08935
9~6~ 8 - ~
Of course, in each of the illustrative structures (1a) to
~1i), the compounds are depicted without the Rl, R2 and R3
substitutents (other than H), but it is understood that the
illustrative structures include those compounds bearing the
defined Rl, R2 and/or R3 substituents.
~ or convenience, the glutarimide moiety has been
depicted as an 8-azaspiro[4,5]decane-7,9-dione but aiso
included are the corresponding 4,4-dimethyl-2,6-
piperidinedione derivatives. Obviously, also, tAe3-carbolinyl moiety of formula (1h) can also be named as [4-
(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]-indol-2-yl].
A preferred subclass of this invention consists of ~hose
com?ounds of formula (lh) where1n the X ~oiety is a.^
Rl-substituted-l,2,3,4-tetrahydro-3-carboline ring system.
Another preferred subclass of this invention relates to
those compounds of fo~mula (1f) wherein the X-moiety is a 2,3-
dihydronaphtho[l,2-][1,4]-dioxin-2-yl or 3-yl ring sys~em.
Another preferred class of compounds o this invention
relates to those compounds of formula ~1a) whereir. the
X-moiety is terminally substituted by the 2,3-dihvdro-l,4-
benzodioxin-2-yl ring system.
'.
The aromatic glutarimide derivatives of formula (1) can
be prepar-ed via a condensation of theappropriate
nucleophilic amine of formula (2) with an appropriate
glutarimide substrate of formula (3) using processes and
techniques analogously known in the art, such as tha' shown
by the following reaction scheme.
.
WO92/11011 9 PCT/US91/08935
20976Q7
`.
X-H + ~-(C~2)n N ~ R4 ______~_ X-(C32)n~ N ~ R5
(2) t3~
wherein X, ~4, R5 and n are as defined ir. formula (1) and the
symbol (L) represents a suitable leaving group, such as
chlorine, bromine, iodine, a mesylate, tosylate or hydroxyl.
Such a nucleophilic condensa'ion is ?referab'y conduc~ed
by reac~ing appro~i~,ately eq mo;ar amount-i of the
nucleopnile (2) with the substrate (3), for a period of -ro~
about l hour to 24 hours depending upo~ the partic~l2r
reactants e~ployed. The reaction temperature can range from
about 25C to 150C. Preferably the reaction is conducted at
a temperature ranging from 60Cto 150C.Fu ther details and
specific exemplification for the nucleophilic condensa.ion
have been previously described in U.S. Paterlt 4,6l2,3'2,
j issued on September 16, 1986.
The nucleoph lic primary amines incicated by formul2 (2)
are comDounds which are either commercially available or
which have been previouslydescribed inthe literature.
Generic teachings and the details and exemplifications for
the preparation of the nucleophilic primary amines embraced
by Formula t2) of this invention may readily be obtained from
issued U.S. Patent 4,612,312 and U.S. Patent 4,748,182
issued May 31, 1988.
The compounds of formula (3) are esse~tially N-alkyl
derivatives of glutarimide. The leaving groups (L) for
compounds oE formul3 (3) can represent any qroup known to
'.~.', . '
~' .
WO92~1101l 2097~7 - 10 - PCT/US~l/08935
those skilled in the art, such as a tosylate (0~S) or a
mesylate (OMS), an iodide, bromide or chloride, or hydroxyl
group. ~eneric teachings and the details and
exemplifications for the preparation of the glutarimide
-~ 5 reactants of Formula (3) (and the precursors therefor) are
readily obtained from issued U.S. Patent 4,612,312.
Illustrative of the preferred compounds of this
invention are:
8-[4-(1,4-benzodioxan-2-ylmethylamino)butyl~-8-azaspiro-
[4,5]decane-7,9-dione;
.
8-[4-(1,4-benzodioxan-2-ylmethyl-N-methyl2mino)DU~yl]-8.-
azaspiro[4,5~decane- " 9-dione, hydrochloride sa: ;
-:
. 8-[4-(1,4-benzodioxan-2-ylmethyl-N-ethylamino)buty ]-8-
azaspiro[4,5]decane-7,9-dione, oxalate, 0.5 H20;
8-[4-(1,4-benzodioxan-2-ylmethyl-N-n-pro~ylamino)butyl]-8-
azaspiro[4,5]decane-7,9-dione, oxalate;
8-[4-(1,4-benzodioxan-2-ylmethvl-N-isopropylamino)butyl]-8- ~: .
azaspiro[4,5]decane-7,9-dione, oxalate;
8-[4-(1,4-benzoxazine-2-ylmethylamino)butyl]-8-azaspiro-.
[4,5]decane-7,9-dione
N-[4-(1,4-benzodioxan-2-ylmethylamino)butyl]-3,3-dimethyl~
glutarimide, hydrochloride,
-.
(-)8-[4-(1,4-benzodioxan~2-ylmethylamino)butyl~-8~azaspiro-
[4,5]decane-7,9-dionei
;:
' ..
WO9~/l1011 - 11 - PC~IUS9l/0~935
2~76~7
8-[2-(1,4-benzodioxan-2-ylmethylamino)ethyl]-8-azaspiro-
[4,5]-decane-7,9-dione;
8-[2-(1,4-benzodioxan-2-ylmethylamino)ethyl]-8-azaspiro-
[4,5]-decane-7,9-dione;
8-[5-(1,4-benzodioxan-2-ylmethylamino)n-pentyl]-8-azaspiro-
~4,5]decane-7,9-dione;
8-[4-(2,3-dihydronaphtho[1,2,b]dioxin-2-
ylmethylamino)butyl]-8-azaspiro[4,5]decane-7,9-dione;
8-[4-(2,3-dihydronaphtho[1,2,b]dioxin-2-ylmethyl-
amino)butyl]-8-azaspiro[4,5]aecane-7,9-aione;
8-[4-(5,6-d-methyl-~,4-be-.zcdioxan-2-vl)ma~h~yl(~.-
methylamino)-butyl]-8-azaspiro[4,5]decane-7,9-dione;
8-[3-(5~7-di-n-buty~ 4-benzodioxan-2-yl)methyl(n-n-~r
amino)propyl]-8-azaspiro[4,5]decane-7,9-dione;
9-[2-(5,8-dihydroxy-1,4-benzodioxan-2-yl)methyl(n-
ethylamino)-ethyl]-9-azasp1ro[5,5]undecane-8,10-dione;
9-[2-~5,8-dimethoxy-1,4-benzodioxar.-2-yl)methyl(n-2-hydroxy-
ethylamino)ethyl]-9-azaspiro[5,5]undecane-8,10-dione;
9-[2 (5,8-di-n-bu'oxy-1,4-benzodioxan-2-yl)methyl(n-2-
hydroxyethylamino)ethyl]-9-azaspiro[5,5]undecane-8,10-dione;
30 8-[2-(5-chloro-1,4-benzodioxan-2-yl)methyl(n- -
ethylamino)ethyl]-8-azaspiro[4,5]decane-7,9 dione;
8-[2-(5-fluoro-1,4-benzodioxan-2-yl-methylamino)ethyl]-8-
azaspiro[4,5]decane-7,9-dione;
~5
WO92/1101l ~ ~ 9~ 12 - PCT/US91/08935
8-[2-(5-nitro-1,4-benzodioxan 2-yl-methylamino)ethyl~-8-
azaspiro~4,5]decane-7,9-dione;
8-[2-~5-aminosulfonyl-1,4-benzodioxan-2-yl-
methylamino)ethyl]-8-azaspiro[4,5]decane-7,9-dione;
8-[2-(5-sulfo-1,4-benzodioxan-2-yl-methylamino)ethyl]-8-
azaspiro[4,5]decane-7,9-dione;
'~
8-[4-[(1,2,3,4-tetrahydro-8-methoxy-2-naphthalenyl)amino~-
; 10 butyl~-8-azaspiro[4,5]decane-7,9-dione, hydrochloride;
8-[4-(1,2,3,4-tetrahydro-9~-pyrido[3,4-b]indol-2-yl)butv'j-
8-azaspiro[4,5]decane-7,9-cione, hydroch:oriàe;
1~ 4,4-cimethyl-1-~ ',2,3,4-te~-ahvdro-9u-pyrid^-[3,~-
b]indol-2-yl)bu-yl]-2,6-piperidinedione, hydrochlo~ide;
6-methoxy-8-[4-(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2-
yl)-butyl]-8-azaspiro~4,5]decane-7,9-dione, hydrochloride;
' ``
8-[4-[(3,4-dihydro-2~:-1,4-benzoxazin-3-
yl)methylamino]butyl]-8-azaspiro[4,5]decane-7,9-dione,
oxalate;
8-[5-[2-(5-methoxy-3-indolyl)ethylamino]butyl]-8-
azaspiro[4,5]-decane-7,9-dione, oxalate; ~;
3-dihydro-5-methoxy-1,4-benzodioxin-2-yl)ethyl]-8-azaspiro-
[4,5]decane-7,9-dione, hydrochloride;
8-[2-[(2,3-dihydro-8-methoxy-1,4-benzodioxin-2-yl)ethyl]-8-
azaspiro[4,5]decane-7,9-dione, hydrochloride;
8-[4[(1,4-benzodioxin-2-yl)methylamino]butyl]~8 azaspiro- --
[4,5]decane-7,9-dione, hydrochloride;
''. '
,
i~
;,
W092/11011 - 13 PCT/US91/08935
~ . _
20976~7
; 2-[4-[(2,3-dihydro-1,4-benzodioxin-2-yl)methylamlno]butyl]-
lH-isoindole-1,3(2H)-dione, methanesulfonate (salt),
~ hemihydrate;
- 5 8-[4-[(2~3-dihydro-5-methoxy-l~4~benzodioxin-2-yl)methyl]
butyl]-8-azaspiro[4,5~decane-7,9-dione, monohydrochloride;
. . .
2-[4-[(2,3-dihydro-8 methoxy-1,4-benzodioxin-2-yl)methyl]-
butyl]-lH-isoindole-1,3(2H)-dione, monohyarochloride;
- 10
8-[4-[(2,3-dihydro-8-methoxy-1,4-benzodioxin-2-yl)methyl]-
butyl]-3-2zaspi !0[ ~, 5]decane-7,9-dione, ethanedioate salt.
U.S. Petent ~,612,312 teaches th2t certa~n com30unds 0c
'his inver.'ion heve p~o?erties wh~ch ere ~se^ul -~ e
treatment of hvpertension and for trea.ing anxie~y. It
recently has been found that the compounds possess
properties which also willrender them useful in the
treatmentof affective disoraers, i.e., the compounds wi'1 be
useful in the pharmacoloqical treatment of depression and
mania.
. .
In general, the com30unas of the p.ior a~t which have
; been found to be successful in the treatmen. of af ective
disorders have also been characterized as "mood elevators"
and in recent years a plethora of the tricyclic-tyDe of
compounds have been found to be mood elevators having anti-
depressant effects in endogenous and involutional
depression. Illustrative of such successful tricyclic
compounds are amitriphyline, desipramine, imipramine,
nortriptyline, opipranol, depepin and butripty~ine. Of
course, many other tricyclic compounds are known but listing
, all such compounds is unnecessary here as they may be
readily ascertained from standard works well known in the
.
WO92/11011 PCT/US91~0B935
~ - 14 -
art. It is to the end-use application of these compounds to
which the compounds of this invention will be useful.
Based upon standard laboratory assays as well as by
comparison with compounds known to be useful in treating
depression and mania, it is to be found Ihat the compounds
of this invention are effective 5HTl~ agonists capable of
exerting a pharmacological effect useful for the treatment
of depression and mania in the genera' range of 0.005 to
lO mg/kg of patient body weiqht, but preferably in the range
of 0.05 to 5 mg/kg of patient body weight per day.
The compounds o~ this in~ention c2n be ad~inis.erec
either or2l~y, subcutaneously, intravenously,
intramuscuiarly, in raDeritonea'ly c- rec~all~
preferred route of administration is oral. The amount G~-
compound to be administered can be any e~fective amoun., and
will vary depending upon the patien', the mode of
administration and the severity of the an~iety to be
treated. Repetitive daily administra.ion or the compounds
may be desirable, and will vary depencing upon the patient's
condition and the mode of administration.
.:
For oral administra.ion, an anti-de?ressant ef^ective
amount of a formula (1) compound can range from 0.005 to
l0 mg/kg of patient body weight per dayj preferably from -
0.05 to 5 mgjkg of patient body weight per day. The
preferred dose of the compounds of formula (1) is about
0.l mg/kg of patient body weight per day. Pharmaceutical
compositions in unit dose form can contain from l to 50 mg
of active ingredient and can be taken one or more times per
day.
... ....
~or parenteral administration, an anti-depressant
effective amount of a formula (1) compound can range from
~092/l101~ ~ PCT/U~1/08935
2 ~ ~7 6 0 ~
0.005 to 10 mg/kg of patient body weight per day, preferably
from 0.05 to 5 mg/kg of patient body weight per day. A
parenteral composition in unit dose form can contain from
0.1 g to 10 mg of active ingredient and can be taken one or
more times daily.
For oral administration the compounds can b~ formulated
into solid or liquid preparations such as capsules, ~ills,
tablets, lozenges, melts, powders, solutions, suspensions or
` 10 emulsions. Solid dosage unit forms generally employed
include capsules or tablets. Capsules can be of the ordinary
gelatin type which contain additional excipients such as
surfactants, lubricants and iner. fillers such as iac~ose,
sucrose and corns.arch. Additionally, the compounas o
-ormula (1) can be tabletec witr. conver.; ona t2~1e- bases
such as lactose, sucrose, and cornstarch in combina'ion with
binders, such as acacia, cornstarch or gelatin,
disintegrating agents such as potato starch or alginic acid,
and lubricants such as stearic acid or magnesium stearate.
For parenteral administration the compounas may be
administered as injectable dosages of a solution or a
suspension Oc the compound in a physiologically acceptable
diluent with or without a pharmaceutical car-ier. Suitable
diluents or carriers include sterile liquids such as water
or oils, with or without the addition of surfactants or
other pharmaceutically acceptable adjuvants.Illustrativeof
various oils that can be employed in the practice oE this
invention are those of petroleum, animal, vegetable, or
synthetic origin, for example, peanut oil, soybean oil, and
mineral oil. In gneral, water, saline, aqueous dextrose and
related sugar solutions, ethanol and glycols such as
propylene glycol or polyethylene glycol are preferredliquid
carriers, particularly for injectable solutions.
