USE OF CERTAIN GLUTARIMIDE DERIVATIVES IN THE TREATMENT OF DEPRESSION AND MANIA

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

Description: USE OF CERTAIN GLUTARIMIDE DERIVATIVES IN THE TREATMENT OF DEPRESSION AND MANIA This invention relates to the manufacture of certain glutarimide derivatives for their use as medicaments in the treatment of depression and mania. More specifically, this invention relates to the use in the manufacture of a medicament for treating depression and mania utilizing a compound of the formula their geometric, stereo- or optical isomers, the mixtures thereof, and the pharmaceuticallyacceptableacid addition salts thereof, wherein X is selected from the group consisting of R χ is hydrogen, C 1 _ 4 alkyl, C 1 _ 4 alkoxy, halogeno, nitro, hydroxy, S0 3 H, S0 2 NK 2 , or S0 2 NH 2 -CH 2 -, R 2 is hydrogen, C 1 _ 4 -alkyl, C χ _ 4 alkoxy, halogeno, nitro or hydroxy, and R and R 2 , taken together with the carbon atoms to which they are attached, form a benzenoid moiety at the indicated 1,2- or 3,4-positions,R 3 is H or C 1 _ 4 alkyl, R_ and R 5 are H, C 1-4 alkyl or, when taken together with the carbon atom to which they are attached, form a C 3 _ 6 cycloalkyl moiety, n is an integer of 2 to 5 inclusive, A and B independently are oxygen, sulfur or NR 3 , their geometric, stereo- or optical isomers and the mixtures thereof, and the pharmaceutically acceptable 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 inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric and phosphoric acid and acid metal salts such as sodium πtonohydrogen 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, alonic, succinic, glutaric, fu aric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, p-hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic acids, and sulfonic 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 hydrated or a substantially anhydrous form. In general, the acid addition salts of these compounds are crystalline materials which are soluble in water 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, C 1 _ / . alkyl includes the straight and branched alkyl radicals having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl and the like. C 1 _ 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, bro o 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 designed to enrich the production of the desired isomers. However, mixtures may be resolved or isolated according to conventional and standard procedures well known in the art, e.g. chromatographic 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 (CH 2 ) π alkylene bridging moiety. Preferably n represents 2 o 5. Illustrative of the X moieties are: (2,3-dihydro-l, -benzodioxin-2-yl)methylamino, (2,3-dihydro-l,4-benzoxathiin-3-yl)methylamino, (2,3-dihydro-l,4-benzodithiin-2-yl)methylamino, (2,3-dihydro-l,4-benzoxazin-3-yl)methylamino, (2,3-dihydro-l,4-dihydroquinazolin-2-yl)methylamino, (2,3-dihydronaphtho[1,2-b] [1,4]dioxin-2-yl)methylamino, (2,3-dihydronaphtho[1,2-b] [1,4]dioxin-3-yl)methylamino, (indol-3-yl)ethylamino, (1,2,3,4-tetrahydro-β-carbolinyl) , and tetralin-2-amino and the R χ , R 2 and/or R 3 substituted analogs. Specific subclasses of compounds that fall within the the present invention are illustrated as follows: 8-[ω-[ (2,3-dihydro-l,4-benzodioxin-2-yl)methylamino]alkyl]' 8-azaspiro[4,5ldecane-7,9-diones, (1a) 8-[ω-[ (2,3-dihydro-l,4-benzoxathiin-3-yl)methylamino]alkyi; 8-azaspiro[4,5]decane-7,9-diones, (1b) g-[ω-[ (2,3-dihydro-l,4-benzodithiin-2-yl)methylamino]alkyl] 8-azasoiro[4,5]decane-7,9-diones, (1c) 8-[ω-[ (2,3-dihydro-l,4-benzoxazin-3-yl)methylamino]alkyl]-8- azaspiro [4,5] decane-7 , 9-diones , (1d) 8-[ω-[ (2,3-dihydroquinazolin-2-yl)methylamino]alkyl]-8- azaspiro[4,5]decane-7,9-diones, de) 8-[ω-[ (2,3-dihydronaphtho[l,2-b] [1,4]dioxin-2- yl)methylamino]-alkyl]-8-azaspiro[4,5]decane-7,9-diones Of ) (Compounds of this sub-class can be substituted either at the 2- or 3-position of the dioxin ring.) 8-[ω-[ (indol-3-yl)ethylamino]alkyl]-8-azaspiro[4, 5]decane- 7,9-diones, dg) 8-[ω-[l,2,3,4-tetrahydro-β-carbolinyl]alkyl]-8- azaspiro[ 4,5]-decane-7 ,9-diones, (1h) 8-[ω-[ (substituted)tetralin-2-amino]alkyl]-8-azaspiro[ 4,5] ■ decane-7,9-diones, di) Of course, in each of the illustrative structures (1a) to (1i), the compounds are depicted without the R χ , R 2 and R 3 substitutents (other than H) , but it is understood that the illustrative structures include those compounds bearing the defined R χ , R 2 and/or R 3 substituents. For convenience, the glutarimide moiety has been depicted as an 8-azaspiro[4,5]decane-7,9-dione but also included are the corresponding 4,4-dimethyl-2,6- piperidinedione derivatives. Obviously, also, the β-carbolinyl moiety of formula (1h) can also be named as [4- (l,2,3,4-tetrahydro-9H-pyrido[3,4-b]-indol-2-yl] . A preferred subclass of this invention consists of .those compounds of formula (1h) wherein the X moiety is an R 1 -substituted-l,2,3,4-tetrahydro-β-carboline ring system. Another preferred subclass of this invention relates to those compounds of formula (1f) wherein the X-moiety is a 2,3 dihydronaphtho[l,2-] [l,4]-dioxin-2-yl or 3-yl ring system. Another preferred class of compounds of this invention relates to those compounds of formula (1a) wherein the X-moiety is terminally substituted by the 2,3-dihydro-l,4- benzodioxin-2-yl ring system. The aromatic glutarimide derivatives of formula (1) can be prepared via a condensation of theappropriate nucleophilic a ine of formula (2) with an appropriate glutarimide substrate of formula (3) using processes and techniques analogously known in the art, such as that shown by the following reaction scheme. (2) (3) (1) wherein X, R 4 , R 5 and n are as defined in formula (1) and the symbol (L) represents a suitable leaving group, such as chlorine, bromine, iodine, a mesylate, tosylate or hydroxyl. Such a nucleophilic condensation is preferably conducted by reacting approximately equimolar amounts of the nucleophile (2) with the substrate (3), for a period of from about 1 hour to 24 hours depending upon the particular reactants employed. The reaction temperature can range from about 25°C to 150°C. Preferably the reaction is conducted at a temperature ranging from 60°Cto 150°C. Further details and specific exemplification for the nucleophilic condensation have been previously described in U.S. Patent 4,612,312, issued on September 16, 1986. The nucleophilic primary amines indicated by formula (2) are compounds which are either commercially available or which have been previouslydescribed in the literature. Generic teachings and the details and exemplifications for the preparation of the nucleophilic primary amines embraced by Formula (2) 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 essentially N-alkyl derivatives of glutarimide. The leaving groups (L) for compounds of formula (3) can represent any group known to those skilled in the art, such as a tosylate (OTS) or a mesylate (OMS), an iodide, bromide or chloride, or hydroxyl group. Generic teachings and the details and exemplifications for the preparation of the glutarimide 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-(l,4-benzodioxan-2-ylmethylamino)butyl]-8-azaspiro- [4,5] ecane-7,9-dione; 8-[4-(1,4-benzodioxan-2-ylmethyl-N-methylaιrtino)butyl]-8- azaspiro[4,5]decane-7,9-dione, hydrochloride salt; 8-[4-(1,4-benzodioxan-2-ylmethyl-N-ethylamino)butyl]-8- azaspiro[4,5]decane-7,9-dione, oxalate, 0.5 H 2 0; 8-[4-(1,4-benzodioxan-2-ylmethyl-N-n-propylamino)butyl]-8- azaspirof4,5]decane-7,9-dione, oxalate; 8-[4-(l,4-benzodio>:ar.-2-ylmethyl-N-isopropylamino)butyl]-8- azaspiro[4,5]decane-7,9-dione, oxalate; 8-[4-(1,4-benzoxazine-2-ylmethylamino)butyl]-8-azaspiro- [4,5] ecane-7, -dione; N-[4-(1,4-benzodioxan-2-ylmethylamino)butyl]-3,3-dimethyl- glutarimide, hydrochloride; (-)8-[4-(l,4-benzodioxan-2-ylmethylamino)butyl]-8-azaspiro- [4,5]άecane-7,9-dione; 8-[2-(1,4-benzodioxan-2-ylmethylamino)ethyl]-8-azaspiro- [4,5]-decane-7,9-dione; 8-[2-(l,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[l,2,b]dioxin-2- ylmethylamino)butyl]-8-azaspiro[4,5]decane-7,9-dione; 8-[4-(2,3-dihydronaphtho[1,2,b]dio in-2-ylmethyl- amino)butyl]-8-azaspiro[4,5]decane-7,9-dione; 8-[4-(5,6-dimethy1-1,4-benzodioxan-2-yl)methyl(n- methylamino)-butyl]-8-azaspiro[4,5]decane-7,9-dione; 8-[3-(5,7-di-n-butyl-l,4-benzodioxan-2-yl)methyl(n-n-propyl- amino)propyl]-8-azaspiro[4,5]decane-7,9-dione; 9-[2-(5,8-dihydroxy-l,4-benzodioxan-2-yl)methyl(n- ethylamino)-ethyl]-9-azaspiro[5,5]undecane-8,10-dione; 9-[2-(5,8-dimethoxy-l,4-benzodioxan-2-yl)methyl(n-2-hydroxy- ethylamino)ethyl]-9-azaspiro[5,5]undecane-8,10-dione; 9-[2-(5,8-di-n-butoxy-l,4-benzodioxan-2-y1)methyl(n-2- hydroxyethylamino)ethyl]-9-azaspi o[5,5]undecane-8,10-dione; 8-[2-(5-chloro-l,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; 8-[2-(5-nitro-1,4-benzodioxan-2-y1-methylamino)ethyl]-8- azaspiro[4,5] ecane-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-l,4-benzodioxan-2-y1-methylamino)ethyl]-8- azaspiro[4,5]decane-7,9-dione; 8-[4-[ (1,2,3 ,4-tetrahydro-8-methoxy-2-naphthalenyl)amino]- butyl]-8-azaspiro[4,5]decane-7,9-dione, hydrochloride; 8-[4-(l,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2-yl)butyl]- 8-azaspiro[4,5]decane-7,9-dione, hydrochloride; ,4-άimethyl-l-[4-(1,2,3,4-tetrahydro-9E-pyrido-[3,4- b]indol-2-yl)butyl]-2,6-piperidinedione, hydrochloride; 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, hydrochlo ide; 8-[4-[ (3,4-dihydro-2H-l,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-l,4-benzodioxin-2-yl)ethyl]-8-azaspiro- [4,5]decane-7,9-dione, hydrochloride; 8-[2-[(2,3-dihydro-8-methoxy-l,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; 2-[4-[ (2,3-dihydro-l,4-benzodioxin-2-yl)methylamino]butyl]- lH-isoindole-l,3(2H)-dione, methanesulfonate (salt), hemihydrate; 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-l,4-benzodioxin-2-yl)methyl]- butyl]-lH-isoindole-l,3(2H)-dione, monohydrochloride; 8-[4-[ (2,3-dihydro-8-methoxy-l,4-benzodio in-2-yl)methyl]- butyl]-8-azaspiro[4,5]decane-7,9-dione, ethanedioate salt. U.S. Patent 4,612,312 teaches that certain compounds of this invention have properties which are useful for the treatment of hypertension and for treating anxiety. It recently has been found that the compounds possess properties which also will render them useful in the treatment of affective disorders, i.e., the compounds will be useful in the pharmacological treatment of depression and mania. In general, the compounds of the prior art which have been found to be successful in the treatment of affective disorders have also been characterized as "mood elevators" and in recent years a plethora of the tricyclic-type 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 butriptyline. 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 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 that the compounds of this invention are effective 5HT 1A agonists capable of exerting a pharmacological effect useful for the treatment of depression and mania in the general range of 0.005 to 10 mg/kg of patient body weight, but preferably in the range of 0.05 to 5 mg/kg of patient body weight per day. The compounds of this invention can be administered either orally, subcutaneously, intravenously, intramuscularly, intraperitoneally or rectally. The preferred route of administration is oral. The amount of compound to be administered can be any effective amount, and will vary depending upon the patient, the mode of administration and the severity of the anxiety to be treated. Repetitive daily administration of the compounds may be desirable, and will vary depending upon the patient's condition and the mode of administration. For oral administration, an anti-depressant effective amount of a formula (1) compound can range from 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. The preferred dose of the compounds of formula (1) is about 0.1 mg/kg of patient body weight per day. Pharmaceutical compositions in unit dose form can contain from 1 to 50 mg of active ingredient and can be taken one or more times per day. For parenteral administration, an anti-depressant effective amount of a formula (1) compound can range from 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 be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, solutions, suspensions or 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 inert fillers such as lactose, sucrose and cornstarch. Additionally, the compounds of formula (1) can be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination 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 compounds may be administered as injectable dosages of a solution or a suspension of the compound in a physiologically acceptable diluent with or without a pharmaceutical carrier. Suitable diluents or carriers include sterile liquids such as water or oils, with or without the addition of surfactants or other pharmaceutically acceptable adjuvants. Illustrative of various oils that can be employed in the practice of 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 preferred liquid carriers, particularly for injectable solutions.

Claims: 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 pharmaceuticallyacceptableacid addition sales thereof, wherein X is selected from the group consisting of _ χ is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halogeno, nitro, hydroxy, S0 3 H, S0 2 NK 2 , or S0 2 NH 2 -CH 2 - R 2 is hydrogen, C 1 _. alkyl, C 1-4 alkoxy, halogeno, nitro or hydroxy, and R χ and R 2 , taken together with the carbon atoms to which they are attached, form a benzenoid moiety at the indicated 1,2- or 3,4-positions, R 3 is H or C 1-4 alkyl, R 4 and R 5 are H, C 1-4 alkyl or, when taken together with the carbon atom to which they are attached, form a C 3 _ 6 cycloalkyl moiety, n is an integer of 2 to 5 inclusive, A and B independently are oxygen, sulfur or NR 3 . 2. A process according to Claim 1 wherein X is a moiety having the structure R 4 and R 5 , 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-l,4-benzodioxin-2-ylmethylamino) ethyl]-8-azaspiro[4,5]decane-7,9-dione,methylsulfonate and 8-[4-[ (2,3-dihydronaphtho[l,2-b]-l,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 pharmaceuticallyacceptable acid addition salts thereof, wherein X is selected from the group consisting of \ γ is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halogeno, nitro, hydroxy, S0 3 H, S0 2 NH 2 , or S0 2 NH 2 -CH 2 - R 2 is hydrogen, C 1 _ 4 alkyl, C 1-4 alkoxy, halogeno, nitro or hydroxy, and R χ and R 2 , taken together with the carbon atoms to which they are attached, form a benzenoid moiety at the indicated 1,2- or 3,4-positions, R 3 is H or C 1-4 alkyl, R 4 and R 5 are H, C λ _. alkyl or, when taken together with the carbon atom to which they are attached, form a C 3 _ 6 cycloalkyl moiety, n is an integer of 2 to 5 inclusive, A and B independently are oxygen, sulfur or NR 3 . 7. The use in the manufacture of a medicament wherein X is a moiety having the structure R 4 and R 5 , 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-l,4- benzodioxin-2-ylmethylamino)ethyl]-8-azaspiro[4,5]decane- 7,9-dione,methylsulfonate and 8-[4-[ (2,3-dihydronaphtho[1,2- b]-l,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.

Inventors: GITTOS MAURICE W, HIBERT MARCEL, GITTOS, MAURICE, W., HIBERT, MARCEL
Applicants: MERRELL DOW PHARMA, MERRELL DOW PHARMACEUTICALS INC.
Application year: 1991
Main classification: A61K31
IPC codes: A61K31, A61P25