CA2097607A1 - Use of certain glutarimide derivatives in the treatment of depression and mania - Google Patents

Use of certain glutarimide derivatives in the treatment of depression and mania

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Publication number
CA2097607A1
CA2097607A1 CA002097607A CA2097607A CA2097607A1 CA 2097607 A1 CA2097607 A1 CA 2097607A1 CA 002097607 A CA002097607 A CA 002097607A CA 2097607 A CA2097607 A CA 2097607A CA 2097607 A1 CA2097607 A1 CA 2097607A1
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Prior art keywords
alkyl
azaspiro
decane
dione
moiety
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CA002097607A
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French (fr)
Inventor
Marcel Hibert
Maurice W. Gittos
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Sanofi Aventis France
Aventis Pharmaceuticals Inc
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Individual
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

This invention relates to the manufacture of certain glutarimide derivatives for their use as medicaments in the treatment of depression and mania.

Description

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 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"", ",, "", .~

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.
.

`.

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~
;, ~ . _ 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;

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.

Claims (10)

WHAT IS CLAIMED IS:
1. A process for treating affective disorders which comprises administering to a patient in need thereof a therapeutically amount of a compound of the formula their geometric, stereo- or optical isomers, the mixtures thereof, and the pharmaceutically acceptable acid addition salts thereof, wherein X is selected from the group consisting of , , and R1 is hydrogen, C1-4 alkyl, C1-4 alkoxy, halogeno, nitro, hydroxy, SO3H, SO2NH2, or SO2NH2-CH2-R2 is hydrogen, C1-4 alkyl, C1-4 alkoxy, halogeno, nitro or hydroxy, and and R2, taken together with the carbon atoms to which they are attached, form a benzenoid moiety at the indicated 1,2- or 3,4-positions, R3 is H or C1-4 alkyl, R4 and R5 are H, C1-4 alkyl or, when taken together 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, sulfur or NR3.
2. A process according to Claim 1 wherein X is a moiety having the structure and R4 and R5, together with the carbon atom to which they are attached, form a cyclopentyl moiety.
3. A process according to Claim 1 wherein the compounds are 8-(2-(2,3-dihydro-1,4-benzodioxin-2-ylmethylamino) ethyl]-8-azaspiro[4,5]decane-7,9-dione,methylsulfonate and 8-[4-[(2,3-dihydronaphtho[1,2-b]-1,4-dioxin-2-yl)methyl-amino]butyl]-8-azaspiro[4,5]decane-7,9-dione,hydrochloride.
4. A process according to Claim 3 wherein the affective disorder is depression.
5. A process according to Claim 3 wherein the affective disorder is mania.

METHOD-OF-USE CLAIMS
6. The use in the manufacture of a medicament for the treatment of depression and mania of compounds of the formula their geometric, stereo- or optical isomers, the mixtures thereof, and the pharmaceutically acceptable acid addition salts thereof, wherein X is selected from the group consisting of , , and R1 is hydrogen, C1-4 alkyl, C1-4 alkoxy, halogeno, nitro, hydroxy, SO3H, SO2NH2, or SO2NH2-CH2-R2 is hydrogen, C1-4 alkyl, C1-4 alkoxy, halogeno, nitro or hydroxy, and R1 and R2, taken together with the carbon atoms to which they are attached, form a benzenoid moiety at the indicated 1,2 or 3,4-positions, R3 is H or C1-4 alkyl, R4 and R5 are H, C1-4 alkyl or, when taken together 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, sulfur or NR3.
7. The use in the manufacture of a medicament wherein X
is a moiety having the structure and R4 and R5, together with the carbon atom to which they are attached, form a cyclopentyl moiety.
8. The use in the manufacture of a medicament according to claim 6 wherein the compounds are 8-[2-(2,3-dihydro-1,4-benzodioxin-2-ylmethylamino)ethyl]-8-azaspiro[4,5]decane-7,9-dione,methylsulfonate and 8-[4-[(2,3 dihydronaphtho[1,2-b]-1,4-dioxin-2-yl)methylamino]butyl]-8-azaspiro[4,5]decane-7,9-dione,hydrochloride.
9. The use in the manufacture according to Claim 8 wherein the affective disorder is depression.
10. The use in the manufacture of a medicament according to claim 6 wherein the affective disorder is mania.
CA002097607A 1990-12-24 1991-12-02 Use of certain glutarimide derivatives in the treatment of depression and mania Abandoned CA2097607A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
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EP90403757 1990-12-24

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US4361565A (en) * 1981-12-28 1982-11-30 Mead Johnson & Company 2-[4-[(4,4-Dialkyl-2,6-piperidinedion-1-yl)butyl]-1-piperazinyl]pyridines
ZA855563B (en) * 1984-07-30 1986-05-28 Merrell Dow Pharma Glutarimide antianxiety and antihypertensive agents
AU583343B2 (en) * 1985-01-23 1989-04-27 Glaxo Group Limited Heterocyclic compounds
US4748182A (en) * 1986-03-05 1988-05-31 Merrell Dow Pharmaceuticals Inc. Aromatic 2-aminoalkyl-1,2-benzoisothiazol-3(2H)one-1,1-dioxide derivatives and their use as anti-hypertensive and anxiolytic agents
US4788290A (en) * 1987-12-11 1988-11-29 American Home Products Corporation Serotonergic pyrazine derivatives
DE3831888A1 (en) * 1988-09-20 1990-03-29 Troponwerke Gmbh & Co Kg MEDICINES FOR TREATING APOPLEXIA CEREBRI
EP0375819A1 (en) * 1988-12-20 1990-07-04 Merrell Dow Pharmaceuticals Inc. Novel derivatives of 1,7'-[imidazo-[1,2-a]pyridine]5'-(6'H)ones

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AU9134191A (en) 1992-07-22
HU9301856D0 (en) 1993-09-28

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