Substituted 9-Amino-Spiro [cycloalkyl[b]quinoline-2,1'cycloalkanes], a process and intermediates for their preparation and their use as medicaments

Abstract: There are disclosed compounds having the formula wherein m is 1 or 2; n is 1 or 2; p is 1-5; X is hydrogen, loweralkyl, cycloalkyl, loweralkoxy, halogen, hydroxy, nitro, trifluoromethyl, formyl, loweralkylcarbonyl, arylcarbonyl, -SH, loweralkylthio, -NHCOR₂ or -NR₃R₄ where R₂ is hydrogen or loweralkyl, and R₃ and R₄ are independently hydrogen, loweralkyl or cycloalkyl; R is hydrogen, loweralkyl or loweralkylcarbonyl; and R₁ is hydrogen, loweralkyl, loweralkylcarbonyl, aryl, diloweralkylaminoloweralkyl, arylloweralkyl, diarylloweralkyl, oxygen-bridged arylloweralkyl or oxygen-bridged diarylloweralkyl; stereo, optical and geometrical isomers thereof, and pharmaceutically acceptable acid addition salts thereof, which are useful for enhancing memory.

Description: This invention relates to compounds having the formula I wherein m is l or 2; n is 1 or 2; p is 1-5; X is hydrogen, C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₁-C₆-alkoxy, halogen, hydroxy, nitro, trifluoromethyl, formyl, C₁-C₆-alkylcarbonyl, phenylcarbonyl wherein the phenyl group may be substituted with 1, 2 or 3 substituents each of which being independently C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen, hydroxy, trifluoromethyl, phenoxy or benzyloxy; -SH, C₁-C₆-alkylthio, -NHCOR₂ or -NR₃R₄ where R₂ is hydrogen or C₁-C₆-alkyl, and R₃ and R₄ are independently hydrogen, C₁-C₆-alkyl or C₃-C₇-cycloalkyl; R is hydrogen, C₁-C₆-alkyl or C₁-C₆-alkylcarbonyl; and R₁ is hydrogen, C₁-C₆-alkyl, C₁-C₆-alkylcarbonyl, di-C₁-C₆-alkylamino-C₁-C₆-alkyl, phenyl, phenyl-C₁-C₆-alkyl, diphenyl-C₁-C₆-alkyl or phenoxy-C₁-C₆-alkyl wherein the phenyl group may be substituted as indicated above; stereo, optical and geometrical isomers thereof, which are useful for enhancing memory, methods for synthesizing them, and pharmaceutical compositions comprising an effective memory enhancing amount of such a compound. Preferred are compounds of the formula I where m is 1, n is 2 and p is 3. This invention also relates to compounds having the formulas wherein X, m, n, and p are as defined above, R₅ is hydrogen or C₁-C₆-alkyl, and Y is chloro, bromo, hydroxy or C₁-C₆-alkoxy, which are useful as intermediates for synthesizing the compounds of formula I. Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo, optical and geometrical isomers thereof where such isomers exist, as well as pharmaceutically acceptable acid addition salts thereof and solvates thereof such as for instance hydrates. The following definitions shall apply throughout the specification and the appended claims. Unless otherwise stated or indicated, the term C₁-C₆-alkyl denotes a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of said C₁-C₆-alkyl include methyl, ethyl, n-propyl, iso-butyl, pentyl, and hexyl. Unless otherwise stated or indicated, the term C₃-C₇-cycloalkyl denotes a saturated ring containing 3 to 7 carbon atoms. Examples of said C₃-C₇-cycloalkyl include cyclopropyl, cyclohexyl and cycloheptyl. Unless otherwise stated or indicated, the term C₁-C₆-alkoxy denotes a straight or branched alkoxy group having 1 to 6 carbon atoms. Examples of said C₁-C₆-alkoxy include methoxy, ethoxy, iso-propoxy, sec-butoxy, and straight and branched chain hexyloxy. Unless otherwise stated or indicated, the term halogen shall mean fluorine, chlorine, bromine or iodine. The compounds of this invention are prepared by utilizing one or more of the steps described below. Throughout the description of the synthetic steps, the definitions of X, Y, R and R₁ through R₅ are as given above unless otherwise stated or indicated. STEP A A compound of formula II can be prepared by reacting a compound of Formula IV with a compound of the formula V. Said reaction can be conducted in a suitable solvent such as benzene, toluene or xylene at a temperature of about 80-150°C in the presence of an acid catalyst such as p-toluene sulfonic acid, benzenesulfonic acid or methanesulfonic acid. STEP B A compound of formula III where Y is hydroxy or C₁-C₆-alkoxy can be prepared by reacting compound II with phosphorous pentoxide in the presence of a high boiling tertiary amine such as N,N-dimethylcyclohexylamine. Said reaction can be conducted without additional solvent at a temperature of about 170-220°C. STEP C A compound of the formula III where Y is chloro or bromo can be prepared by reacting compound III where Y is hydroxy with phosphorous oxychloride or -bromide and phosphorous pentachloride or -bromide, respectively. Said reaction can be conducted at a temperature of about 100-150°C. STEP D A compound of formula I can be prepared by reacting compound III wherein Y is chloro or bromo, with an amine of formula HNRR₁ (VI). Said reaction can be conducted at a temperature of 120-220°C in the presence of a hydroxylated aromatic compound such as or phenol or cresol. Steps A through D can be combined into a single step. Thus compound I can be obtained by heating together a mixture of phosphorous pentoxide, N,N-dimethylcyclohexylamine and the hydrochloride of amine VI and then adding compound IV followed by compound V. Said reaction can be carried out at a temperature of 150-250°C. STEP E A compound of formula I wherein R and R₁ are both hydrogen, can be prepared by reacting an anthranilonitrile of formula VII with compound V. Said reaction can be conducted in the presence of a Lewis acid such as zinc chloride, without solvent at a temperature of about 80-150°C or in a solvent such as 1,2-dichloroethane or nitrobenzene, again at a temperature of about 80-150°C. The compounds of formula I of the present invention can be used for the treatment of various memory dysfunctions characterized by decreased cholinergic function, such as Alzheimer's disease. This utility can be ascertained by determining the ability of these compounds to inhibit the activity of the enzyme acetylcholinesterase and thereby increase the acetylcholine levels in the brain. This utility can also be ascertained by determining the ability of these compounds to restore cholinergically deficient memory in the Dark Avoidance Assay. In this assay mice are tested for their ability to remember an unpleasant stimulus for a period of 24 hours. A mouse is placed in a chamber that contains a dark compartment; a srong incandescent light drives it to the dark compartment, where an electric shock is administered through metal plates on the floor. The animal is removed from the testing apparatus and tested again, 24 hours later, for the ability to remember the electric shock. If scopolamine, an anticholinergic that is known to cause memory impairment, is administered before an animal's initial exposure to the test chamber, the animal re-enters the dark compartment shortly after being placed in the test chamber 24 hours later. This effect of scopolamine is blocked by an active test compound, resulting in a greater interval before re-entry into the dark compartment. Effective quantities of the compounds of the invention may be administered to a patient by any of the various methods, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. The free base final products, while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable acid addition salts for purposes of stability, convenience of crystallization, increased solubility and the like. Acids useful for preparing the pharmaceutically acceptable acid addition salts of the invention include inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as well as organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric and oxalic acids. The active compounds of the present invention may be orally administered, for example, with an inert diluent or with an edible carrier, or they may be enclosed in gelatin capsules, or they may be compressed into tablets. For the purpose of oral therapeutic administration, the active compounds of the invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum and the like. These preparations should contain at least 0.5% of active compound, but may be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 1.0-300 milligrams of active compound. The tablets, pills, capsules, troches and the like may also contain the following ingredients: a binder such as micro-crystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, cornstarch and the like; a lubricant such as magnesium stearate or Sterotex; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes, coloring and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used. For the purpose of parenteral therapeutic administration, the active compounds of the invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1% of active compound, but may be varied between 0.5 and about 30% of the weight thereof. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.5 to 100 milligrams of active compound. The solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparations can be enclosed in disposable syringes or multiple dose vials made of glass or plastic. Examples of the compounds of this invention include: 9-amino-3,4-dihydrospiro[acridine-2(1H),1′-cyclopropane]; 9-amino-3,4-dihydro-6-trifluoromethylspiro[acridine-2(1H),1′-cyclopropane]; 3,4-dihydro-9-methylaminospiro[acridine-2(1H),1′-cyclopropane]; 9-benzylamino-3,4-dihydrospiro[acridine-2(1H),1′-cyclopropane]; 9-benzylamino-7-chloro-3,4-dihydrospiro[acridine-2(1H),1′-cyclopropane]; 9-anilino-3,4-dihydrospiro[acridine-2(1H),1′-cyclopropane]; 9-amino-3,4-dihydrospiro[acridine-2(1H),1′-cyclopentane]; 9-amino-6-chloro-3,4-dihydrospiro[acridine-2(1H),1′-cyclopentane]; 9-amino-3,4-dihydro-6-methoxyspiro[acridine-2(1H),1′-cyclopentane]; 3,4-dihydro-9-methylaminospiro[acridine-2(1H),1′-cyclopentane]; 3,4-dihydro-6-fluoro-9-methylaminospiro[acridine-2(1H),1′-cyclopentane]; 9-(4-chlorobenzylamino)-3,4-dihydrospiro[acridine-2(1H),1′-cyclopentane]; 9-anilino-3,4-dihydrospiro[acridine-2(1H),1′-cyclopentane]; 3,4-dihydro-9-(2-fluoroanilino)spiro[acridine-2(1H),1′-cyclopentane]; 9-amino-3,4-dihydrospiro[acridine-2(1H),1′-cyclohexane]; 7-acetamido-9-amino-3,4-dihydrospiro[acridine-2(1H),1′-cyclohexane]; 9-amino-3,4-dihydro-7-methoxyspo[acridine-2(1H),1′-cyclohexane]; 7-chloro-3,4-dihydro-9-methylaminospiro[acridine-2(1H),1′-cyclohexane]; 3,4-dihydro-9-(3-fluorobenzylamino)spiro[acridine-2(1H),1′-cyclohexane]; 3,4-dihydro-9-(3-methoxybenzylamino)spiro[acridine-2(1H),1′-cyclohexane]; 3,4-dihydro-9-(4-methoxyanilino)spiro[acridine-2(1H),1′-cyclohexane]; 9-amino-1,3-dihydrospiro[cyclopenta[b]quinoline-2,1′-cyclopentane]; 9-amino-1,3-dihydro-6-fluorospiro[cyclopenta[b]quinoline-2,1′-cyclopentane]; 9-amino-1,3-dihydro-7-methoxyspiro[cyclopenta[b]quinoline-2,1′-cyclopentane]; 7-acetamido-9-amino-1,3-dihydrospiro[cyclopenta[b]quinoline-2,1′-cyclopentane]; 1,3-dihydro-9-methylaminospiro[cyclopenta[b]quinoline-2,1′-cyclopentane]; 1,3-dihydro-9-propylaminospiro[cyclopenta[b]quinoline-2,1′-cyclopentane]; 1,3-dihydro-9-(4-methylbenzylamino)spiro[cyclopenta[b]quinoline-2,1′-cyclopentane]; 9-(3,4-dichlorobenzylamino)-1,3-dihydrospiro[cyclopenta[b]quinoline-2,1′-cyclopentane]; 9-(3,4-dichloroanilino)-1,3-dihydrospiro[cyclopenta[b]quinoline-2,1′-cyclopentane]; 9-amino-1,3-dihydrospiro[cyclopenta[b]quinoline-2,1′-cyclohexane]; 1,3-dihydro-9-ethylaminospiro[cyclopenta[b]quinoline-2,1′-cyclohexane]; 9-benzylamino-1,3-dihydrospiro[cyclopenta[b]quinoline-2,1′-cyclohexane]; and 9-anilino-1,3-dihydrospiro[cyclopenta[b]quinoline-2,1′-cyclohexane].

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A compound of the formula wherein m is 1 or 2; n is 1 or 2; p is 1-5; X is hydrogen, C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₁-C₆-alkoxy, halogen, hydroxy, nitro, trifluoromethyl, formyl, C₁-C₆-alkylcarbonyl, phenylcarbonyl wherein the phenyl group may be substituted with 1, 2 or 3 substituents each of which being independently C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen, hydroxy, trifluoromethyl, phenoxy or benzyloxy; -SH, C₁-C₆-alkylthio, -NHCOR₂ or -NR₃R₄ where R₂ is hydrogen or C₁-C₆-alkyl, and R₃ and R₄ are independently hydrogen, C₁-C₆-alkyl or C₃-C₇-cycloalkyl; R is hydrogen, C₁-C₆-alkyl or C₁-C₆-alkylcarbonyl; and R₁ is hydrogen, C₁-C₆-alkyl, C₁-C₆-alkylcarbonyl, di-C₁-C₆-alkylamino-C₁-C₆-alkyl, phenyl-C₁-C₆-alkyl, phenyl, diphenyl-C₁-C₆-alkyl or phenoxy-C₁-C₆-alkyl wherein the phenyl group may be substituted as indicated above; a stereo, optical or geometrical isomer thereof, or a pharmaceutically acceptable acid addition salt thereof. The compound as defined in Claim 1, where m is 1, n is 2 and p is 3. The compound as defined in Claim 2, where R is hydrogen and R₁ is hydrogen or phenyl-C₁-C₆-alkyl, wherein the phenyl group may be substituted as indicated in claim 1. The compound as defined in Claim 3, where X is hydrogen, C₁-C₆-alkyl or trifluoromethyl. A process for the preparation of a compound as defined in claim 1, which comprises a) reacting a compound of the formula IIIa wherein X, m, n and p are as defined in claim 1, with an amine of the formula HNRR₁, where R and R₁ are as defined in claim 1, or b₁) reacting a compound of the formula II wherein X, m, n and p are as defined in claim 1 and R₅ is hydrogen or C₁-C₆-alkyl, with phosphorous pentoxide in the presence of N,N-dimethylcyclohexylamine to form a compound of the formula III wherein X, m, n and p are as defined in claim 1 and Y is hydroxy or C₁-C₆-alkoxy, b₂) reacting a compound of the formula III wherein Y is hydroxy, with phosphorous oxychloride or -bromide and phosphorous pentachloride or -bromide respectively to form a compound of the formula III wherein Y is chloro or bromo, and reacting the compound of the formula III as indicated in step a) above, or c) reacting a compound of the formula IV where R₅ is hydrogen or C₁-C₆-alkyl and X is as defined in claim 1 with a mixture of phosphorous pentoxide, N,N-dimethylcyclohexylamine and the hydrochloride of the amine of the formula HNRR₁, and then adding a compound of the formula wherein m, n and p are as defined in claim 1, or d) reacting an anthraniionitrile of the formula VII wherein X is as defined in claim 1, with a compound of the formula wherein m, n and p are as defined in claim 1, to afford a compound of the formula I, where R and R₁ are both hydrogen, and optionally preparing in a conventional manner a pharmacologically acceptable acid addition salt thereof. A compound of the formula II where R₅ is hydrogen or C₁-C₆-alkyl, and X, m, n and p are as defined in claim 1. A compound of the formula III where X, m, n and p are as defined in claim 1 and Y is chloro, bromo, hydroxy or C₁-C₆-alkoxy. A pharmaceutical composition which comprises an effective amount of a compound as defined in claim 1 and a suitable carrier therefor. Use of a compound as defined in claim 1 for the preparation of a medicament having the ability of increasing the cholinergic function in a mammal. Claims for the following Contracting States : ES, GR A process for the preparation of the compound of the formula I wherein m is 1; n is 2; p is 3; X is hydrogen, C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₁-C₆-alkoxy, halogen, hydroxy, nitro, trifluoromethyl, formyl, C₁-C₆-alkylcarbonyl, phenylcarbonyl wherein the phenyl group may be substituted with 1, 2 or 3 substituents each of which being independently C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen, hydroxy, trifluoromethyl, phenoxy or benzyloxy; -SH, C₁-C₆-alkylthio, -NHCOR₂ or -NR₃R₄ where R₂ is hydrogen or C₁-C₆-alkyl, and R₃ and R₄ are independently hydrogen, C₁-C₆-alkyl or C₃-C₇-cycloalkyl; R is hydrogen, C₁-C₆-alkyl or C₁-C₆-alkylcarbonyl; and R₁ is hydrogen, C₁-C₆-alkyl, C₁-C₆-alkylcarbonyl, di-C₁-C₆-alkylamino-C₁-C₆-alkyl, phenyl, phenyl-C₁-C₆-alkyl, diphenyl-C₁-C₆-alkyl or phenoxy-C₁-C₆-alkyl wherein the phenyl group may be substituted as indicated above; a stereo, optical or geometrical isomer thereof, or a pharmaceutically acceptable acid addition salt thereof, which comprises a) reacting a compound of the formula III wherein Y is chloro or bromo X, m, n and p are as defined, with an amine of the formula HNRR₁, where R and R₁ are as defined, or b₁) reacting a compound of the formula II wherein X, m, n and p are as defined in claim 1 and R₅ is hydrogen or C₁-C₆-alkyl, with phosphorous, pentoxide in the presence of N,N-dimethylcyclohexylamine to form a compound of the formula III wherein X, m, n and p are as defined in claim 1 and Y is hydroxy or C₁-C₆-alkoxy, b₂) reacting a compound of the formula III wherein Y is hydroxy, with phosphorous oxychloride or -bromide and phosphorous pentachloride or -bromide respectively to form a compound of the formula III wherein Y is chloro or bromo, and reacting the compound of the formula III as indicated in step a) above, or c) reacting a compound of the formula IV where R₅ is hydrogen or C₁-C₆-alkyl and X is as defined, with a mixture of phosphorous pentoxide, N,N-dimethylcyclohexylamine and the hydrochloride of the amine for the formula HNRR₁, and then adding a compound of the formula wherein m, n and p are as defined, or d) reacting an anthranilonitrile of the formula VII wherein X is as defined above, with a compound of the formula wherein m, n and p are as defined in claim 1, to afford a compound of the formula I, where R and R₁ are both hydrogen, and optionally preparing in a conventional manner a pharmacologically acceptable acid addition salt thereof. A process as defined in claim 1 where R is hydrogen and R₁ is hydrogen or phenyl-C₁-C₆-alkyl, wherein the phenyl group may be substituted as defined in claim 1. A process as defined in claim 2 where X is hydrogen, C₁-C₆-alkyl or trifluoromethyl. A process as defined in claims 1-3 wherein the reaction according to step a) is carried out at a temperature of 120 - 220 °C in the presence of a hydroxylated aromatic compound. A process as defined in claims 1-3 wherein the reaction according to step c) is carried out at a temperature of 150 - 250°C. A process as defined in claims 1-3 wherein the reaction according to step d) is carried out in the presence of a Lewis acid at a temperature of 80 - 150°C. A compound of the formula II where R₅ is hydrogen or C₁-C₆-alkyl, and X, m, n and p are as defined in claim 1. A compound of the formula III where X, m, n and p are as defined in claim 1 and Y is chloro, bromo, hydroxy or C₁-C₆-alkoxy. Use of a compound as defined in claim 1 for the preparation of a medicament having the ability of increasing the cholinergic function in a mammal.

Inventors: SHUTSKE GREGORY MICHAEL, SHUTSKE, GREGORY MICHAEL
Applicants: HOECHST ROUSSEL PHARMA, HOECHST-ROUSSEL PHARMACEUTICALS INCORPORATED
Application year: 1988
Main classification: C07D221
IPC codes: C07D221