Benzo[C]-1,5-naphthyridines, a process and intermediates for their preparation and their use as medicaments

Abstract: The invention relates to novel compounds of the formula where X is H, halogen, loweralkyl, loweralkoxy, -CF₃, or -OH; R is H, loweralkyl, arylloweralkyl, diarylloweralkyl, loweralkanoyl, arylloweralkanoyl or diarylloweralkanoyl; and R₁ is H₂, O or -NR₂R₃, R₂ and R₃ being independently H or loweralkyl, or taken together with the nitrogen atom to which they are attached constitute , R₄ in turn being H, loweralkyl, hydroxyloweralkyl, aryl, arylloweralkyl or diarylloweralkyl or pharmaceutically acceptable acid addition salts thereof, which are useful for enchancing memory. The invention relates further to a process and intermediates for the preparation of the above compounds.

Description: This invention relates to novel compounds of the formula where X is H, halogen, loweralkyl, loweralkoxy, -CF₃, or -OH; R is H, loweralkyl, arylloweralkyl, diarylloweralkyl, loweralkanoyl, arylloweralkanoyl or diarylloweralkanoyl; and R₁ is H₂, O or -NR₂R₃, R₂ and R₃ being independently H or loweralkyl, or taken together with the nitrogen atom to which they are attached constitute in turn being H, loweralkyl, hydroxyloweralkyl, aryl, arylloweralkyl or diarylloweralkyl or pharmaceutically acceptable acid addition salts thereof, which are useful for enhancing memory, methods for synthesizing them, pharmaceutical compositions comprising an effective memory enhancing amount of such a compound and methods of treating a patient in need of memory enhancement by administering such a compound to the patient. This invention also relates to novel compounds of the formula where X is as defined above, which are useful as an intermediate for synthesizing compounds 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 general rules of terminology shall apply throughout the specification and the appended claims. Unless otherwise stated or indicated, the term loweralkyl denotes a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of said loweralkyl group include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl. Unless otherwise stated or indicated, the term loweralkoxy denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms. Examples of said loweralkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight- and branched-chain pentoxy and hexoxy. Unless otherwise stated or indicated, the term halogen shall mean fluorine, chlorine, bromine or iodine. Unless otherwise stated or indicated, the term aryl shall mean a phenyl group having Ø, 1, 2 or 3 substituents each of which being independently loweralkyl, loweralkoxy, halogen or CF₃, and the term diaryl shall mean two such aryl groups each of which being independent of the other. The term loweralkanoyl shall mean a group obtained by removing a hydroxy group from the carboxyl group of a loweralkanoic acid, and thus it includes for instance formyl, acetyl and the like. The term arylloweralkanoyl shall mean a loweralkanoyl group having an aryl substituent thereon, the terms loweralkanoyl and aryl having the respective meanings defined above. The compounds of this invention are prepared by following one or more of the steps described below. Throughout the description of the synthetic steps, the definitions of X, R and R₁ through R₄ are as given above unless otherwise stated or indicated, and R₅ appearing below shall mean loweralkyl, arylloweralkyl or diarylloweralkyl and R₆ appearing below shall mean H, loweralkyl, arylloweralkyl or diarylloweralkyl. STEP A This compound of formula III below is cyclized to afford compound of formula IV below. Said cyclization is typically conducted by refluxing an aqueous solution of compound III, followed by isolation and esterification with acidic methanol. STEP B Compound IV is reacted with a compound of formula V below in the presence of a strong base such as NaH to afford a compound of formula VI below. Said reaction is conveniently conducted in a suitable solvent such as an anhydrous aromatic compound, namely, toluene or the like at a temperature of about 8Ø-1ØØ°C. STEP C Compound VI is hydrolyzed to afford a compound of formula VII below. Said hydrolysis is conveniently conducted in an aqueous system containing compound VI and an alkaline substance such as sodium hydroxide and heating the system with a steam bath. STEP D The carboxyl group of compound VII is converted to its acid chloride with a suitable agent such as thionyl chloride and the resultant acid chloride compound is cyclized under a Friedel-Crafts condition to afford a compound of the formula VIII below. Said reaction is typically conducted by dissolving compound VII and thionyl chloride in a suitable solvent such as dichloromethane and reluxing the solution. The Friedel-Crafts reaction is typically conducted by adding AlCl₃ to the solution remaining after the acid chloride formation step and stirring the resultant mixture at or below the ambient temperature. STEP E Compound VIII is reacted with hydroxylamine to afford the aforementioned compound II. VIII + NH₂OH II Said oxime formation reaction is conveniently conducted, for instance, by preparing a suspension comprising compound VIII, hydroxylamine hydrochloride, water, ethanol and a weak base such as sodium acetate and refluxing the suspension. STEP F The oxime compound of the formula II is converted to a compound of the formula Ia below by heating it in a substantially anhydrous acidic medium. It is convenient to conduct the above reaction by adding compound II to a vigorously stirred large excess of polyphosphoric acid at a temperature of about 1ØØ-15Ø°C, but since this reaction may be considered a species of so-called Wolff-Semmler aromatization reaction (see for instance "Mechanisms of Molecular Migrations", Volume 4, edited by B. S. Thyagarajan, Wiley-Interscience, New York, 1971), other suitable reaction conditions used for Wolff-Semmler aromatization reactions may also be used to effect the above reaction step, including the use of so-called Beckmann's mixture which is a mixture of hydrogen chloride, acetic acid and acetic anhydride. STEP G Compound Ia is reacted with an amine of the formula NHR₂R₃ to afford a compound of the formula Ib below. Said reaction is typically conducted in the presence of TiCl₄ and a suitable solvent such as anhydrous tetrahydrofuran at a temperature of about Ø-4Ø°C. STEP H Compound Ia is reacted with a compound of the formula R₅-Hal where R₅ is as defined earlier and Hal is bromine, chlorine or iodine to afford a compound of the formula Ic below. Said reaction is conducted typically in the presence of an acid scavenger such as KOH or the like in a suitable solvent such as dimethylsulfoxide at a temperature of about 2Ø-5Ø°C. STEP I Compound Ia is reduced to afford a compound of the formula Id below. Said reduction is conducted for instance by reacting compound Ia with diborane in a suitable solvent such as anhydrous tetrahydrofuran at the ambient temperature or in the vicinity thereof. STEP J Compound Id is reacted with a compound of the formula R₆COCl, where R₆ is as defined earlier except that it is not hydrogen, to afford a compound of formula Ie below. Said reaction is conveniently conducted in a suitable solvent such as pyridine or an excess of the acid chloride at a temperature of 2Ø-5Ø°C. When R₆ is hydrogen, compound Ie is prepared by reacting compound Id with formic-acetic anhydride. Typically, the reaction is conducted by first preparing formic-acetic anhydride from acetic anhydride and concentrated formic acid (95-99% for instance) at about 4Ø-6Ø°C and then adding compound Id to the resultant solution and heating the reaction mixture at about 8Ø-1ØØ°C. STEP K Compound Ie where R₆ is as defined earlier including R₆=H, is reduced to afford a compound of formula If below. Said reduction is conducted for instance by reacting compound Ie with diborane in a suitable solvent such as anhydrous tetrahydrofuran at the ambient temperature or in the vicinity thereof. The naphthyridine compounds of formula I of the present invention are useful in the treatment of various memory dysfunctions characterized by decreased cholinergic function, such as Alzheimer's disease. This utility is manifested by the ability of these compounds to inhibit the enzyme acetyl cholinesterase and thereby increase acetylcholine levels in the brain. Cholinesterase Inhibition Assay The ability to inhibit acetylcholinesterase was determined by the photometric method of Ellman et al., Biochem. Pharmacol. 7 , 88 (1961). This utility is further demonstrated by the ability of these compounds to restore cholinergically deficient memory in the Dark Avoidance Assay, where they are in general active over a broader dose range than heretofore known compounds, a distinct therapeutic advantage. 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 strong 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 agent 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 greater interval before re-entry into the dark compartment. The results for an active compound are expressed as the percent of a group of animals in which the effect of scopolamine is blocked, as manifested by an increased interval between being placed in the test chamber and re-entering 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 additon 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, malic, 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 Ø.5% of active compound, but may be varied depending upon the particular form and may conveniently be between 4% to about 7Ø% 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.Ø-3ØØ 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 contian, 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 purposes of parenteral therapeutic administration, the active compounds of the invention may be incorporated into a solution or suspension. These preparations should contain at least Ø.1% of active compound, but may be varied between Ø.5 and about 3Ø% 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 Ø.5 to 1ØØ 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 preparation can be enclosed in disposable syringes or multiple dose vials made of glass or plastic. Examples of the compounds of this invention (including intermediate compounds which are believed to be novel) include: (±)-1-[(3-Fluorophenyl)methyl]-5-methoxycarbonyl-2-­ pyrrolidinone; (±)-1-[(3-Chlorophenyl)methyl]-5-methoxycarbonyl-1-­ pyrrolidinone; (±)-1-[(4-Methoxyphenyl)methyl]-5-methoxycarbonyl-2-­ pyrrolidinone; (±)-1-[(3-Methylphenyl)methyl]-5-methoxycarbonyl-2-­ pyrrolidinone; (±)-1-[(3-Fluorophenyl)methyl]-5-oxo-2-pyrrolidinecarboxylic acid; (±)-1-[(3-Chlorophenyl)methyl]-5-oxo-2-pyrrolidinecarboxylic acid; (±)-1-[(4-Methoxyphenyl)methyl]-5-oxo-2-pyrrolidinecarboxylic acid; (±)-1-[(3-Methylphenyl)methyl]-5-oxo-2-pyrrolidinecarboxylic acid; 1,1Øa-Dihydropyrrolo[1,2-b)]isoquinoline-3,1Ø[2H,5H]-dione; 1,1Øa-Dihydro-7-fluoropyrrolo[1,2-b]isoquinoline-3,1Ø[2H,5H]-­ dione; 7-Chloro-1,1Øa-dihydropyrrolo[1,2-b]isoquinoline-3,1Ø[2H,5H]-­ dione; 1,1Øa-Dihydro-8-methoxypyrrolo[1,2-b]isoquinoline-­ 3,1Ø[2H,5H]-dione; 9-Chloro-1,1Øa-dihydropyrrolo[1,2-b]isoquinoline-3,1Ø[2H,5H]-­ dione; 1,1Øa-Dihydropyrrolo[1,2-b]isoquinoline-3,1Ø[2H,5H]-dione oxime; 7-Chloro-1,1Øa-dihydropyrrolo[1,2-b]isoquinoline-3,1Ø[2H,5H]-­ dione oxime; 8-Chloro-1,1Øa-dihydropyrrolo[1,2-b]isoquinoline-3,1Ø[2H,5H]-­ dione oxime; 9-Chloro-1,1Øa-dihydropyrrolo[1,2-b]isoquinoline-3,1Ø[2H,5H]-­ dione oxime; 1,1Øa-Dihydro-8-methoxypyrrolo[1,2-b]isoquinoline-­ 3,1Ø[2H,5H]-dione oxime; 1,1Øa-Dihydro-7-methylpyrrolo[1,2-b]isoquinoline-3,1Ø[2H,5H]-­ dione oxime; 1,4-Dihydrobenzo[c]-1,5-naphthyridin-2(3H)-one; 8-Chloro-1,4-dihydrobenzo[c]-1,5-naphthyridin-2(3H)-one; 9-Chloro-1,4-dihydrobenzo[c]-1,5-naphthyridin-2(3H)-one; 3,4-Dihydro-2-methylaminobenzo[c]-1,5-naphthyridine; 3,4-Dihydro-2-(4-methyl-1-piperzinyl)benzo[c]-1,5-­ naphthyridine hemihydrate; 1,4-Dihydro-1-phenylmethylbenzo[c]-1,5-naphthyridin-­ 2(3H)-one; 1,2,3,4-Tetrahydrobenzo[c]-1,5-naphthyridine; 8-Chloro-1,2,3,4-tetrahydrobenzo[c]-1,5-naphthyridine; 9-Chloro-1,2,3,4-tetrahydrobenzo[c]-1,5-naphthyridine; 8-Fluoro-1,2,3,4-tetrahydrobenzo[c]-1,5-naphthyridine; 9-Methoxy-1,2,3,4-tetrahydrobenzo[c]-1,5-naphthyridine; 1-Formyl-1,2,3,4-tetrahydrobenzo[c]-1,5-naphthyridine; 1-Benzoyl-1,2,3,4-tetrahydrobenzo[c]-1,5-naphthyridine; 1-(Phenylacetyl)-1,2,3,4-tetrahydrobenzo[c]-1,5-­ naphthyridine; 1-Methyl-1,2,3,4-tetrahydrobenzo[c]-1,5-naphthyridine dihydrochloride; 1-(2-Phenylethyl)-1,2,3,4-tetrahydrobenzo[c]-1,5-­ naphthyridine; and 1-phenylmethyl-1,2,3,4-tetrahydrobenzo[c]-1,5-naphthyridine. The following examples are shown for the purpose of illustrating the present invention. EXAMPLE 1 (±)-1-[(3-Fluorophenyl)methyl]-5-methoxycarbonyl-2-­ pyrrolidinone Sodium hydride (24.ØØ g as a 5Ø% dispersion in mineral oil) was washed with sieve dried toluene (3 × 1ØØ ml). Sieve dried toluene (5ØØ ml) was then added to the NaH and the stirred suspension was treated dropwise over 45 minutes with a solution of (±)-methyl pyroglutamate (71.58 g) in sieve dried toluene (5Ø ml). The flask was immersed during this time in an oil bath which served as a heat sink. After the addition of the (±)-methyl pyroglutamate solution was complete, the internal temperature of the flask was raised to 65°C and maintained there for 3Ø minutes. The flask was then cooled to the ambient temperature and the solution was treated dropwise over 1Ø minutes with a solution of 3-fluorobenzyl bromide (1ØØ g) in sieve dried toluene (5Ø ml). After the addition was complete, the internal temperature of the flask was raised to 9Ø°C and maintained there until a thin layer chromatographic analysis (TLC analysis hereafter) using silica gel and ethyl acetate indicated the absence of the starting material. While still hot, the suspension was vacuum filtered through a Celite pad and concentrated to an oil (9Ø g) which solidified on standing. The solid was recrystallized from hexane (1ØØ ml) to afford 78.69 g of nearly pure crystals, m.p. 46-51°C. A 6 g sample was recrystallized from hexane (3Ø ml) to give 5.31 g of crystals, m.p. 52-55°C. ANALYSIS: EXAMPLE 2 (±)-1-[(3-Chlorophenyl)methyl]-5-methoxycarbonyl-2-­ pyrrolidinone Sodium hydride (23.38 g of a 5Ø% dispersion in mineral oil) was washed with sieve dried toluene. Sieve dried toluene (1ØØØ ml) was then added to the NaH and the stirred suspension was treated dropwise over 45 minutes with a solution of (±)-methyl pyroglutamate (63.Ø g) in sieve dried toluene (75 ml). The flask was immersed during this time in an oil bath which served as a heat sink. After the addition of the (±)-methyl pyroglutamate solution was complete, the bath temperature was raised to 65°C. After heating for 3Ø minutes, the oil bath was removed and the solution was treated dropwise over 1 minutes with a solution of 3-chloro­ benzyl bromide (1ØØ g) in sieve dried toluene (5Ø ml). After the addition was complete, the oil bath was replaced and the solution was heated for 2 hours at 1ØØ°C. Celite was then added to the mixture and while still hot, the mixture was vacuum filtered through a Celite pad. The filtrate was concentrated to an oil which was stored in a refrigerator under nitrogen. Purification of 11.2Ø g of the oil by high performance liquid chromatography (HPLC, hereafter) using silica gel column and methanol gave 8.1Ø g of an oil. The sample was dried in an Abderhalden pistol over toluene. ANALYSIS: EXAMPLE 3 (±)-1-[(4-Methoxyphenyl)methyl]-5-methoxycarbonyl-2-­ pyrrolidinone Sodium hydride (27.84 g of a 5Ø% dispersion in mineral oil) was washed with sieve dried toluene (3 × 1ØØ ml). Sieve dried toluene (5ØØ ml) was then added to the NaH and the stirred suspension was treated dropwise over 45 minutes with a solution of (±)methyl pyroglutamate (83.Ø3 g) in sieve dried toluene (5Ø ml). The flask was immersed during this time in an oil bath which served as a heat sink. After the addition of the (±)methyl pyroglutamate solution was complete, the bath temperature was raised to 8Ø°C (internal temperature 65°C). After heating for 3Ø minutes, the flask was cooled to room temperature and the solution was treated dropwise over 1Ø minutes with a solution of 4-methoxybenzyl chloride (1ØØ g) in sieve dried toluene (5Ø ml). After the addition was complete, the mixture was heated to 85°C (internal temperature). While still hot, the mixture was vacuum filtered and the filtrate was concentrated to an oil. Purification of 1Ø g of the oil was accomplished by HPLC (silica gel column, eluted with ethyl acetate) to give 4.85 g of an oil. The sample was dried in an Abderhalden pistol over toluene. ANALYSIS: EXAMPLE 4 (±)-1-[(3-Fluorophenyl)methyl]-5-oxo-2-pyrrolidinecarboxylic acid A solution of 19.ØØ g of sodium hydroxide pellets in 225 ml of water was treated with 115.52 g of (±)-1-[(3-­ fluorophenyl)methyl]-5-methoxycarbonyl-2-pyrrolidinone and the mixture was heated for four hours (steam bath). The solution was cooled to the ambient temperature and extracted with diethyl ether (3 × 25Ø ml). The aqueous phase was acidified with concentrated hydrochloric acid to about pH=1. The aqueous phase was extracted with dichloromethane (2 × 3ØØ ml) and the combined organic phase was dried over Na₂SO₄. The solution was vacuum filtered and the filtrate was concentrated to an oil which solidified on standing. The solid was recrystallized from 3ØØ ml of toluene to yield 72.16 g of crystals, m.p. 114-116.5°C. ANALYSIS: EXAMPLE 5 (±)-1-[(3-Chlorophenyl)methyl]-5-oxo-2-pyrrolidinecarboxylic acid A solution of 16.ØØ g of sodium hydroxide pellets in 165 ml of water was treated with 99.Ø1 g of (±)-1-[(3-­ chlorophenyl)methyl]-5-methoxycarbonyl-2-pyrrolidinone and was heated for two hours with a steam bath. The solution was cooled to room temperature and extracted with diethyl ether (2 × 3ØØ ml). The aqueous phase was acidified with 45 ml of concentrated hydrochloric acid and extracted with dichloromethane (3 × 2ØØ ml). Crystals precipitated out of the dichloromethane. The crystals (8Ø.21 g, damp with solvent) were dried overnight at 65°C under vacuum. The solid was recrystallized from 8ØØ ml of toluene to give 54.72 g of crystals m.p. 144-146°C. The crystals were dried overnight at 85°C under vacuum. ANALYSIS: EXAMPLE 6 (±)-1-[(4-Methoxyphenyl)methyl]-5-oxo-2-pyrrolidinecarboxylic acid A solution of 16.8Ø g of sodium hydroxide pellets in 175 ml of water was treated with 75 g of (±)-1-[(4-methoxy­ phenyl)methyl]-5-methoxycarbonyl-2-pyrrolidinone and the mixture was heated for two hours with a steam bath. The solution was cooled to room temperature and extracted with diethyl ether (2 × 3ØØ ml). The aqueous phase was acidified to about pH = 1 with 5Ø ml of concentrated hydrochloric acid and extracted with dichloromethane (3 × 25Ø ml). The dried (Na₂SO₄) organic phase was vacuum filtered and concentrated to an oil which solidified on standing (8Ø g). The solid was recrystallized from toluene (3ØØ ml) to give 34.18 g of crystals, m.p. 1Ø3-1Ø4.5°C. ANALYSIS: EXAMPLE 7 1,1Øa-Dihydropyrrolo[1,2-b]isoquinoline-3,1Ø[2H,5H]-dione To a solution prepared from 11.68 g of (±)-N-­ benzylpyroglutamic acid (See E. Campaigne and D.P. Matthews, J. Het. Chem., 12 , 391 (1975)), 1ØØ ml of CH₂Cl₂ and a drop of dimethylformamide (DMF), 7.57 g of SOCl₂ was added dropwise. The mixture was refluxed for five hours and allowed to stand overnight at ambient temperature. The reaction mixture was cooled in an ice-salt bath. Aluminum chloride (22.6 g) was added in portions with exclusion of moisture and vigorous stirring. The temperature did not exceed 1Ø°C during the addition. The mixture was stirred 1.5 hours and then ice was added gradually. The mixture was partitioned between water and CH₂Cl₂. The CH₂Cl₂ phase was washed with water, dried (Na₂SO₄), filtered and evaporated to give 1Ø g of a crude product. Recrystallization from toluene gave 7.45 g of crystals, m.p. 1Ø3-1Ø5°C. ANALYSIS: EXAMPLE 8 1,1Øa-Dihydro-7-fluoropyrrolo[1,2-b]isoquinoline-3,1Ø[2H,5H]-­ dione To a solution of 5Ø.ØØ g of (±)-1-[(3-fluorophenyl)-­ methyl]-5-oxo-2-pyrrolidine carboxylic acid in sieve dried dichloromethane (45Ø ml), 27.48 g of thionyl chloride was added, and the resultant solution was stirred and refluxed for 5 hours. An infrared spectrum of the solution indicated the presence of the acid chloride. After standing overnight at ambient temperature, the solution was chilled to 5°C and 84 g of aluminum chloride was added in portions with vigorous stirring. The reaction was exothermic and there was a slow evolution of gas. The mixture was stirred at ambient temperature for 3 hours. The reaction was quenched by the addition of ice chips and water. The two phases of the mixture were separated and the aqueous phase was extracted with dichloromethane (4 × 15Ø ml). The combined organic phase was dried (Na₂SO₄) and concentrated to a solid (69.73 g). The solid was purified by HPLC (silica gel, eluted with ethyl acetate) to give 37.23 g of the 7-fluoro isomer and 4 g of the 9-fluoro isomer. The 7-fluoro isomer was recrystallized from ethyl acetate (4ØØ ml) to afford 28.63 g of crystals, m.p. 16Ø-163°C. ANALYSIS: EXAMPLE 9 7-Chloro-1,1Øa-dihydropyrrolo[1,2-b]isoquinoline-­ 3,1Ø[2H,5H]-dione To a solution of 25.37 g of (±)-1-[(3-chlorophenyl)-­ methyl]-5-oxo-2-pyrrolidinecarboxylic acid in sieve dried dichloromethane (2Ø ml), 13.Ø9 g of thionyl chloride was added, and the resultant solution was stirred and refluxed with the exclusion of moisture for 6 hours. An infrared spectrum of the solution indicated the presence of the acid chloride. After standing overnight at ambient temperature, the solution was chilled to 5°C and 4Ø g of aluminum chloride was added in portions with exclusion of moisture and vigorous stirring. The reaction was slightly exothermic and a solid began to precipitate. The flask was heated intermittently with a steam bath to increase the rate of the reaction. After each heating, the gas evolution was allowed to subside. When heating did not produce gas evolution, ice chips were added to quench the reaction. Water was then added to the mixture and the phases were separated. The aqueous phase was extracted with dichloromethane and the combined organic phase was dried (Na₂SO₄). The mixture was vacuum filtered and concentrated to a solid to which ethyl acetate was added and the resultant mixture was vacuum filtered to give 11.56 g of a solid. The solid was dried overnight under vacuum. The ethyl acetate washings were concentrated to 1Ø.3Ø g of a solid. A TLC analysis (silica, ethyl acetate) showed that the compositions of the two crops of solid were the same. The combined solid was purified by HPLC (silica gel, eluted with ethyl acetate) to give 16.35 g of a solid which was recrystallized from ethyl acetate (25Ø ml) to yield 12.Ø g of a solid, m.p. 15Ø.5-154°C. ANALYSIS: EXAMPLE 1Ø 9-Chloro-1,1Øa-dihydropyrrolo[1,2-b]isoquinoline-­ 3,1Ø[2H,5H]-dione 9-Chloro-1,1Øa-dihydropyrrolo[1,2-b]isoquinoline-­ 3,1Ø[2H,5H]-dione was isolated by HPLC (silica gel, ethyl acetate) as the minor product from the reaction which afforded 7-chloro-1,1Øa-dihydropyrrolo[1,2-b]isoquinoline-­ 3,1Ø[2H,5H]-dione. From two runs of the reaction, a total of 3.55 g of the 9-chloro isomer was obtained and recrystallized from 1ØØ ml of ethyl acetate to afford 2.Ø3 g of crystals, m.p. 198-2Ø2°C. ANALYSIS: EXAMPLE 11 1,1Øa-Dihydropyrrolo[1,2-b]isoquinoline-3,1Ø[2H,5H]-dione oxime A mixture consisting of 2.5 g of 1,1Øa-dihydropyrrolo-­ [1,2-b]isoquinoline-3,1Ø[2H,5H]-dione in 2Ø ml of 95% ethanol (EtOH), 1.72 g of hydroxylamine hydrochloride in 1Ø ml of water and 3.7 g of sodium acetate trihydrate in 1Ø ml of water was refluxed for 7 hours and thereafter allowed to stand overnight at ambient temperature. The product crystallized from the reaction mixture to give 2.2 g of crystals. Recrystallization from 95% EtOH gave 1.4 g of crystals, m.p. 2Ø6-2Ø9°C. ANALYSIS: EXAMPLE 12 7-Chloro-1,1Øa-dihydropyrrolo[1,2-b]isoquinoline-­ 3,1Ø[2H,5H]-dione oxime A suspension of 9.ØØ g of 7-chloro-1,1Øa-dihydro­ pyrrolo[1,2-b]isoquinoline-3,1Ø[2H,5H]-dione in 95% ethanol (65 ml) was treated with a premixed solution prepared from 1Ø.4Ø g of sodium acetate trihydrate in water (35 ml) and 5.31 g of hydroxylamine hydrochloride in water (35 ml). The suspension was heated to reflux and after 1Ø minutes a solution formed. After 1 hour of refluxing, a precipitate began to form and heating was continued for another 1.5 hours, after which time the mixture was allowed to cool to ambient temperature. The precipitate was isolated by vacuum filtration and dried under vacuum at 4Ø°C. The solid was recrystallized form n-propanol (3ØØ ml) to give 6.45 g of crystals, m.p. 249-252°C. ANALYSIS: EXAMPLE 13 8-Chloro-1,1Øa-dihydropyrrolo[1,2-b]isoquinoline-­ 3,1Ø[2H,5H]-dione oxime A stirred suspension of 12.65 g of 8-chloro-1,1Øa-­ dihydropyrrolo[1,2-b]isoquinoline-3,1Ø[2H,5H]-dione (prepared in substantially the same manner as the 7-chloro compound in Example 12, m.p. 13Ø-136°C) in 95% ethanol (85 ml) was treated with a premixed solution prepared from sodium acetate trihydrate (14.56 g) in water (48 ml) and hydroxylamine hydrochloride (7.44 g) in water (48 ml). The stirred suspension was heated to reflux, during which a solution formed followed by separation of a crystalline precipitate. After 2 hours of refluxing, the mixture was cooled and the precipitate was collected and washed twice with 5Ø% aqueous ethanol. Drying at 4Ø°C overnight in vacuo gave 1Ø.95 g of a solid, m.p. 227.5-23Ø.5°C. Recrystallization of the solid from n-propanol (3ØØ ml) afforded 8.56 g of crystals, m.p. 229-235°C. ANALYSIS: EXAMPLE 14 9-Chloro-1,1Øa-dihydropyrrolo[1,2-b]isoquinoline-­ 3,1Ø[2H,5H]-dione oxime A suspension of 1.ØØ g of 9-chloro-1,1Øa-dihydro­ pyrrolo[1,2-b]isoquinoline-3,1Ø[2H,5H]-dione in 95% ethanol (1Ø ml) was treated with a premixed solution prepared from 1.17 g of sodium acetate trihydrate in water (5 ml) and Ø.6Ø g of hydroxylamine hydrochloride in water (5 ml). The suspension was heated to reflux and after 15 minutes a solution formed. After 1 hour of reflux, a precipitate began to form. Heating was continued for another 1.5 hours, after which time the mixture was allowed to cool to ambient temperature. The precipitate was isolated by vacuum filtration and dried under vacuum at 4Ø°C. The solid (Ø.75 g) was combined with Ø.92 g of a material obtained in similar manner and recrystallized from 95% ethanol (1ØØ ml) to afford 1.25 g of crystals, m.p. 26Ø-265°C. ANALYSIS: EXAMPLE 15 1,4-Dihydrobenzo[c]-1,5-naphthyridin-2(3H)-one To 3ØØ g of vigorously stirred polyphosphoric acid warmed to 115°C, 1Ø g of 1,1Øa-dihydropyrrolo[1,2-b]-­ isoquinoline-3,1Ø[2H,5H]-dione oxime was added. The mixture was held at this bath temperature for 1Ø minutes. The internal temperature rose to 135-14Ø°C. The mixture was then poured into 15ØØ ml of ice water, and the mixture was basified with 5Ø% NaOH to about pH=8 and the resultant crystalline precipitate was collected to give 7.14 g of crude product. Chromatography on a silica gel column, using ethyl acetate gave 4.8 g of pure product, m.p. 225°C. ANALYSIS: EXAMPLE 16 8-Chloro-1,4-dihydrobenzo[c]-1,5-naphthyridin-2(3H)-one To 11Ø g of vigorously stirred polyphosphoric acid, which had been heated to 1Ø5°C, 1Ø.21 g of 7-chloro-1,1Øa-­ dihydropyrrolo[1,2-b]isoquinoline-3,1Ø[2H,5H]-dione oxime was added. The bath temperature was held at 1Ø5°C for 25 minutes. On addition of the oxime, however, the internal temperature rose to 145°C. The reaction was quenched by pouring the mixture into 8ØØ ml of water and subsequently another 3ØØ ml of water was added to the mixture. The mixture was basified to about pH-11 with 5Ø% sodium hydroxide at which point precipitate began to separate from the mixture. Due to a large amount of inorganic phosphate salts formed, the mixture was diluted with water to approximately 2Ø liters. The precipitate was collected by vacuum filtration and dried overnight under vacuum at 6Ø°C. The solid was recrystallized from 12ØØ ml of n-propanol to afford 6.1 g of crystals, m.p. 281-284°C. The crystals were dried under vacuum overnight at 5Ø°C. ANALYSIS: EXAMPLE 17 9-Chloro-1,4-dihydrobenzo[c]-1,5-naphthyridin-2(3H)-one To stirred hot (1ØØ°C) polyphosphoric acid (7Ø g) was added finely powdered 8-chloro-1,1Øa-dihydropyrrolo[1,2-b]-­ isoquinoline-3,1Ø[2H,5H]-dione oxime (5.Ø1 g) in one portion. An exothermic reaction initiated and quickly subsided. Fourteen minutes after the addition of the oxime, the reaction mixture was decanted into water (25Ø ml). The suspension was diluted with water to approximately 4ØØ ml of total volume and basified with 5Ø% sodium hydroxide solution with cooling. The mixture was extracted with CH₂Cl₂ (2ØØØ ml), dried (Na₂SO₄), filtered and concentrated to give 5.3 g of a solid. The material was purified by HPLC (silica gel, eluted with ethyl acetate) to give 4.5 g of a solid. Recrystallization from n-propanol gave 2.92 g of crystals, m.p. 285-286°C ANALYSIS: EXAMPLE 18 3,4-Dihydro-2-methylaminobenzo[c]-1,5-naphthyridine A solution of anhydrous methylamine (3Ø ml), 1,4-­ dihydrobenzo[c]-1,5-naphthyridin-2(3H)-one (5.46 g) and sieve dried tetrahydrofuran (45Ø ml) was stirred and chilled with ice water, and was treated dropwise over 3Ø minutes with a preformed complex of titanium tetrachloride (3.Ø ml, 5.2 g) and sieve dried tetrahydrofuran (22Ø ml). The resultant mixture was stirred with cooling for 1 hour, followed by stirring for 3.5 hours at ambient temperature. After standing overnight at ambient temperature the reaction was quenched with water (1ØØ ml) and 1Ø% NaOH solution (3Ø ml). The suspension was filtered and concentrated to give a biphasic residue (pH 1Ø). The mixture was extracted with dichloromethane (2 × 2ØØ ml) dried (Na₂SO₄), filtered and evaporated to dryness (residue wt: 7.66 g). The residue was purified by HPLC (silica gel, eluted with 1Ø% (v/v) methanol in ethyl acetate). The appropriate fractions were concentrated to give 5.1 g of pure product which was recrystallized from toluene (35 ml) to afford 3.56 g of crystals, m.p. 144-145°C. ANALYSIS: EXAMPLE 19 3,4-Dihydro-2-(4-methyl-1-piperazinyl)benzo[c]-1,5-­ naphthyridine hemihydrate A complex of TiCl₄ and tetrahydrofuran was prepared by dropwise treatment via syringe of tetrahydrofuran (2ØØ ml) with TiCl₄ (2.8 ml,4.84 g) with stirring and ice water chilling (exclusion of moisture). The resultant suspension was treated with tetrahydrofuran (5Ø ml) to give a solution of the complex which was transferred to a dropping funnel (without side arm). A stirred, ice water chilled solution of 1,4-dihydrobenzo[c]-1,5-naphthyridine-2(3H)-one (3.39 g), tetrahydrofuran (275 ml) and 1-methylpiperazine (34 ml) was treated dropwise over 35 minutes with the TiCl₄-­ tetrahydrofuran complex with exclusion of moisture. The mixture was then stirred overnight at ambient temperature. The reaction was quenched by addition of water (1ØØ ml) over approximately one minute. The resultant mixture was filtered through coarse-grade fluted filter paper and the filtrate was concentrated to remove the tetrahydrofuran. After basification with 1Ø% NaOH and extraction with CH₂Cl₂ (2 x 25Ø ml), the dried (Na₂SO₄) organic phase was filtered and evaporated to afford an oil (5.17 g) which contained several components by TLC (silica gel, methanol) analysis. The oil was purified by HPLC (silica gel, eluted with methanol) to give 3.93 g of a viscous oil which appeared pure by TLC (silica gel, methanol). This sample and another sample prepared in a similar manner were combined and repurified by HPLC as described above to give 4.48 g of an oil which appeared pure by TLC (silica gel, methanol). ANALYSIS: EXAMPLE 2Ø 1,4-Dihydro-1-phenylmethylbenzo[c]1,5-naphthyridin-2(3H)-one A stirred solution of 1,4-dihydrobenzo[c]-1,5-­ naphthyridin-2(3H)-one (3.97 g) in dimethylsulfoxide (sieve dried, 8Ø ml) was treated sequentially with powdered potassium hydroxide (2.64 g of 85% KOH) and benzyl bromide (3.76 g). The solution was stirred for 1.5 hours at ambient temperature, transferred to a separatory funnel, diluted with water (4ØØ ml) and extracted with ethyl acetate (2 × 25Ø ml). The organic phase was washed with water (2 × 2ØØ ml), dried (Na₂SO₄), filtered and evaporated to give a solid (4.9 g). Recrystallization from 95% ethanol (32 ml) gave 3.35 g of crystals, m.p. 153.5-155.5°C. ANALYSIS: EXAMPLE 21 1,2,3,4-Tetrahydrobenzo[c]-1,5-naphthyridine A stirred solution of 1,4-dihydrobenzo[c]-1,5-­ naphthyridin-2(3H)-one (4.Ø g) in sieve dried tetrahydrofuran (4ØØ ml) was treated over a few minutes with Ø.98 M borane in tetrahydrofuran (62 ml) under a dry nitrogen atmosphere. The resultant suspension was stirred for 5 hours at ambient temperature during which time a solution formed. After standing overnight at ambient temperature the solution was treated with glacial acetic acid (16 ml) followed by stirring for several minutes. The solution was then treated with 1Ø% sodium hydroxide solution (18Ø ml) to give a biphasic system. Concentration on a rotary evaporator to remove the tetrahydrofuan gave a suspension of a solid which was extracted with CH₂Cl₂ (2 × 8ØØ ml). The combined, dried (Na₂SO₄) organic phase was concentrated to afford a solid (5.18 g, tentatively identified as a borane complex). A suspension of the solid in glacial acetic acid (15 ml) was treated gradually with concentrated HCl (5Ø ml). When the gas evolution ceased, the mixture was warmed for a few minutes and then stirred for Ø.5 hour at ambient temperature. The solution was strained through glass wool, and the filtrate was diluted with ice (3ØØ ml) and water (1ØØ ml) and then made alkaline with 5Ø% sodium hydroxide solution. The mixture was extracted with CH₂Cl₂, dried (Na₂SO₄), filtered and concentrated to dryness (3.7 g). Recrystallization from acetonitrile (2Ø ml) gave 1.97 g of a crystalline material which was combined with 2.Ø1 g of a similarly prepared product. The material was purified by HPLC (silica gel, eluted with 5% methanol in ethyl acetate) to give 3.72 g of a solid. Recrystallization from acetonitrile (2Ø ml) afforded 3.Ø1 g of crystals, m.p. 124.5-127.5°C. ANALYSIS: EXAMPLE 22 9-Chloro-1,2,3,4-tetrahydrobenzo[c]-1,5-naphthyridine A stirred suspension of 9-chloro-1,4-dihydrobenzo[c]-­ 1,5-naphthyridin-2(3H)-one (5.82 g) in sieve dried tetrahydrofuran (6ØØ ml) was treated rapidly with 1 M borane in tetrahydrofuran (15Ø ml) and the resultant solution was stirred 48 hours at ambient temperature. The solution was treated dropwise with 1Ø% sodium hydroxide solution (125 ml) (gas evolution noted), concentrated to remove the tetrahydrofuran and the residual suspension was filtered. The filter cake (a borane complex of the product) was suspended in glacial acetic acid (4Ø ml) and was treated under nitrogen with concentrated hydrochloric acid (35 ml, gas evolution noted). After stirring for 1 hour at ambient temperature the solution was decanted over crushed ice (5ØØ ml), diluted with water (1ØØ ml) and basified with 5Ø% sodium hydroxide solution. The resultant suspension was extracted with dichloromethane (2 × 35Ø ml) and the combined dried (Na₂SO₄) organic phase was evaporated to afford a solid (5.84 g). A TLC analysis (silica gel, ethyl acetate) indicated the presence of a major product and three impurities. The material was purified by HPLC (silica gel, eluted with ethyl acetate) to afford 4.64 g of a purified material. Recrystallization from acetonitrile (125 ml) gave 3.54 g of needles, m.p. 185-186°C. ANALYSIS: EXAMPLE 23 1-Formyl-1,2,3,4-tetrahydrobenzo[c]-1,5-naphthyridine Formic-acetic anhydride was prepared by treating 3Ø ml of acetic anhydride with 13.5 ml of 95-97% formic acid and stirring the resultant solution at 5Ø°C for 4Ø minutes. 1,2,3,4-Tetrahydrobenzo[c]-1,5-naphthyridine (5.Ø g) was added to the solution in one portion followed by heating at 86°C for 3.5 hours. A vigorous gas evolution was noted during the first hour of heating. A TLC analysis (silica gel, 1Ø% methanol in ethyl acetate) suggested the presence of the starting material and the solution was held at 1ØØ°C overnight. The cooled reaction solution was decanted into 3ØØ ml of ice water and basified with 5Ø% NaOH solution. After CH₂Cl₂ extraction (2 × 15Ø ml), the combined and dried (Na₂SO₄) organic phase was filtered and concentrated to an oil which still contained the starting material by TLC analysis. The mixed anhydride prepared from acetic anhydride (6Ø ml) and 95-97% formic acid (27 ml) was added to the oil and the solution was stirred at 58°C. Again gas evolution was noted. The solution was stirred for 2 hours at 85°C (gas evolution subsided) and then quenched as described above. A TLC analysis indicated the absence of the starting material. Recrystallization of the crude product (5.2 g) from hot toluene (1Ø ml) by diluting the filtered solution gradually with cyclohexane (45 ml) and seeding gave 3.Ø2 g of crystals, m.p. 85-88°C. ANALYSIS: EXAMPLE 24 1-Benzoyl-1,2,3,4-tetrahydrobenzo[c]-1,5-naphthyridine A stirred solution of 1,2,3,4-tetrahydrobenzo[c]-1,5-­ naphthyridine (4.6 g) and KOH-dried pyridine (5Ø ml) was treated dropwise over one minute with benzoyl chloride (8.4 g). A crystalline precipitate formed. The stirred suspension was heated (steam bath) for 1.25 hours and the resultant solution was then stirred overnight at ambient temperature during which a crystalline precipitate formed. The mixture was decanted into water (2ØØ ml), basified with 1Ø% sodium hydroxide solution and extracted with dichloromethane. The dried (Na₂SO₄) organic phase was filtered and evaporated to dryness (7.47 g of crystalline solid). Recrystallization from toluene afforded 6.25 g of crystals, m.p. 2Ø8.5-21Ø.5°C. An aliquot of the material (4.81 g) was further purified by preparative HPLC (silica gel, eluted with ethyl acetate). The appropriate fractions were concentrated and the residue was recrystallized from toluene (1ØØ ml) to give 4.14 g of crystals, m.p. 2Ø8-21Ø°C. ANALYSIS: EXAMPLE 25 1-(Phenylacetyl)-1,2,3,4-tetrahydrobenzo[c]-1,5-naphthyridine 1,2,3,4-Tetrahydrobenzo[c]-1,5-naphthyridine (3.22 g) was treated with cold phenylacetyl chloride (35 ml). Most of the material dissolved and then a precipitate separated. The mixture was diluted with ether (5Ø ml), and the precipitate was isolated by vacuum filtration and washed twice with ether. The filter cake was dissolved in water (1ØØ ml), and the solution was basified with 1Ø% sodium hydroxide solution and extracted with dichloromethane (2 × 1ØØ ml). The combined and dried (Na₂SO₄) organic phase was filtered and concentrated to an oil (5.4 g), which was purified by HPLC (silica gel, eluted with ethyl acetate). The appropriate fractions were combined and concentrated to an oil (4.76 g). Trituration with ether and seeding (seed crystals formed on the neck of the flask which contained the oil) gave 2.68 g of crystals, m.p. 88.5-89.5°C. ANALYSIS: EXAMPLE 26 1-Methyl-1,2,3,4-tetrahydrobenzo[c]-1,5-naphthyridine dihydrochloride A solution of 1-formyl-1,2,3,4-tetrahydrobenzo[c]-­ 1,5-naphthyridine (9.6 g) in sieve dried tetrahydrofuran (1ØØØ ml) was treated under nitrogen over 6Ø seconds with excess 1M borane-tetrahydrofuran complex (175 ml). After stirring for 48 hours at ambient temperature, the solution was treated dropwise with 1Ø% sodium hydroxide solution (vigorous gas evolution during initial addition of NaOH) to give a biphasic liquid which was concentrated to remove the tetrahydrofuran. The residual oil-water mixture was extracted with CH₂Cl₂ (2 × 3ØØ ml) and the combined and dried (Na₂SO₄) organic phase was filtered and concentrated to an oil (a borane complex). A solution of the oil in glacial acetic acid (25 ml) was treated gradually with concentrated hydrochloric acid (35 ml) under N₂ purge. After stirring for Ø.5 hours at ambient temperature, the solution was decanted onto ice chips (5ØØ ml), diluted with water (3ØØ ml) and made alkaline with 5Ø% sodium hydroxide solution. Extraction with CH₂Cl₂ (2 × 3ØØ ml) and concentration of the dried (Na₂SO₄) organic phase gave a mobile oil (7.59 g). The oil contained three significant impurities and the desired product according to a TLC analysis (silica gel, ethyl acetate). Initial purification was conducted by HPLC (silica gel, eluted with ethyl acetate) to give 1.85 g of a two component oil (1,2,3,4-tetrahydrobenzo[c]-1,5-naphthyridine and the desired product). A further HPLC purification in a similar manner utilizing the recycle technique to optimize the separation gave 1.66 g of the product as an oil. The product was combined with 1.38 g of a similarily prepared material, and a methanol solution of the oils was treated with excess ethereal hydrogen chloride. Concentration of the resultant solution gave 3.44 g of a crude material which was recrystallized from absolute ethanol (15Ø ml) to give Ø.82 g of crystals. Concentration of the mother liquor and recrystallization of the residue from absolute ethanol (1ØØ ml) give 1.43 g of crystals. The two lots of the material were combined, after a TLC analysis (silica gel, methanol) had confirmed the identity, to give 2.25 g of crystals, m.p. 2Ø6-2Ø9°C (transition with gas evolution), 261-274°C. ANALYSIS: EXAMPLE 27 1-(2-Phenylethyl)-1,2,3,4-tetrahydrobenzo[c]-1,5-­ naphthyridine A stirred solution of 1-(phenylacetyl)-1,2,3,4-­ tetrahydrobenzo[c]-1,5-naphthyridine (5.11 g) in sieve dried tetrahydrofuran (3ØØ ml) was treated rapidly with 1 M borane in tetrahydrofuran (68 ml). The resultant solution was stirred overnight under a nitrogen atmosphere with exclusion of moisture and thereafter allowed to stand 24 hours. The reaction was quenched by dropwise addition of 1Ø% sodium hydroxide solution (6Ø ml) and then concentrated to remove the tetrahydrofuran. The oil-aqueous phase mixture was further diluted with water (1ØØ ml) and extracted with dichloromethane (2 × 2ØØ ml). The combined and dried (Na₂SO₄) organic phase was filtered and concentrated to a viscous oil (a borane complex of the product). A solution of the oil in glacial acetic acid (3Ø ml) was cautiously treated with concentrated hydrochloric acid (15 ml) under nitrogen (vigorous gas evolution noted). After stirring for 1 hour at ambient temperature the solution was decanted over crushed ice (5ØØ ml), diluted with water (2ØØ ml) and basified with 5Ø% sodium hydroxide solution. The mixture was extracted with CH₂Cl₂ (2 × 25Ø ml) and the combined and dried (Na₂SO₄) organic phase was filtered and concentrated to an oil (4.72 g). A TLC analysis (silica gel, ethyl acetate) indicated the oil was a mixture of the desired product and 1,2,3,4-tetra­ hydrobenzo[c]-1,5-naphthyridine. The mixture was separated by preparative HPLC (silica gel, eluted with ethyl acetate, overlap fractions repurified using new columns) to give 1.92 g of the product as a viscous oil which was combined with a similarly prepared material to give 2.52 g of pure product. ANALYSIS:

Claims: 1. A compound having the formula I where X is H, halogen, loweralkyl, loweralkoxy, -CF₃ or -OH, R is H, loweralkyl, arylloweralkyl, diarylloweralkyl, loweralkanoyl, arylloweralkanoyl, diarylloweralkyl, loweralkanoyl, arylloweralkanoyl or diarylloweralkanoyl; and R₁ is H₂, O or -NR₂R₃, R₂ and R₃ being independently H or loweralkyl, or taken together with the nitrogen atom to which they are attached constitute , R₄ in turn being H, loweralkyl, hydroxyloweralkyl, aryl, arylloweralkyl or diarylloweralkyl or pharmaceutically acceptable acid addition salts thereof. 2. A compound as defined in claim 1 where R is hydro­ gen, X is hydrogen or halogen and R₁ is oxygen. 3. The compound as defined in claim 2 which is 1,4-di­ hydrobenzo[c]-1,5-naphthyridin-2(3H)-one. 4. A compound as defined in claim 1 where R is hydro­ gen, X is hydrogen or halogen and R₁ is H₂ or, -NR₂R₃, R₂ and R₃ being independently H or lower alkyl, or taken together with the nitrogen atom to which they are attached constitute , R₄ in turn being hydrogen or lower­ alkyl. 5. The compound as defined in claim 4 which is 1,2,3,4-­ Tetrahydrobenzo[c]-1,5-naphthyridine. 6. The compound as defined in claim 4 which is 3,4-Di­ hydro-2-(4-methyl-1-piperazinyl)benzo[c]-1,5-naphthyridine. 7. A compound as defined in claim 4 wherein R is lower­ alkanoyl or arylloweralkanoyl. 8. The compound as defined in claim 7 which is 1-­ (Phenacetyl)-1,2,3,4-tetrahydrobenzo[c]-1,5-naphthyridine. 9. A pharmaceutical composition which comprises as ac­ tive ingredient a compound as defined in claim 1 in asso­ ciation with a pharmaceutically acceptable carrier. 10. Use of a compound as defined in claim 1 for the preparation of a medicament being useful in the treatment of memory dysfunctions characterized by decreased choli­ nergic function. 11. Process for the preparation of a compound of the formula I where X is H, halogen, loweralkyl, loweralkoxy, -CF₃ or -OH, R is H, loweralkyl, arylloweralkyl, diarylloweralkyl, loweralkanoyl, arylloweralkanoyl, diarylloweralkyl, loweralkanoyl, arylloweralkanoyl or diarylloweralkanoyl; and R₁ is H₂, O or -NR₂R₃, R₂ and R₃ being independently H or loweralkyl, or taken together with the nitrogen atom to which they are attached constitute , R₄ in turn being H, loweralkyl, hydroxyloweralkyl, aryl, arylloweralkyl or diarylloweralkyl or pharmaceutically acceptable acid addition salts thereof, which comprises a) heating a compound of the formula II in a substantially anhydrous acidic medium to afford a compound of the formula I, where R is hydrogen, R₁ is oxygen and X is as defined, b) optionally reacting the compound obtained with an amine of the formula NHR₂R₃ where R₂ and R₃ are as defined above to afford a compound of the formula I where R is hydrogen, R₁ is -NR₂R₃ and X is as defined, c) optionally reacting a compound of the formula I where R is hydrogen, R₁ is oxygen and X is as defined, with a compound of the formula R₅-Hal, where R₅ is loweralkyl, arylloweralkyl or diarylloweralkyl and Hal is bromine, chlorine or iodine, to afford a compound of the formu­ la I wherein R₁ and X are as defined above and R is loweralkyl, arylloweralkyl or diarylloweralkyl, d) optionally reducing a compound of the formula I where R₁ is oxygen, R is loweralkyl, arylloweralkyl or di­ arylloweralkyl and X is as defined above, to afford a compound of the formula I wherein R₁ is H₂, R is hydro­ gen and X is as defined, e) optionally reacting a compound of the formula I, where R₁ is H₂, R is hydrogen and X is as defined, with a compound of the formula R₆COCl where R₆ is loweralkyl, arylloweralkyl or diarylloweralkyl to afford a compound of the formula I where R₁ is H₂, X is as defined and R is , where R₆ is as defined, or f) optionally reacting a compound of the formula I where R₁ is H₂, R is hydrogen and X is as defined, with formic-acetic anhydride to afford a compound of the formula I where R₁ is H₂, X is as defined and R is , g) optionally reducing a compound of the formula I where R₁ is H₂, X is as defined and R is the radical , where R₆ is hydrogen, loweralkyl, arylloweralkyl or diarylloweralkyl, to afford a compound of the formula I where R₁) is H₂, X is as defined and R is -CH₂-R₆, R₆ being as defined, h) and optionally preparing the pharmaceutically accept­ able acid addition salts thereof. 12. A compound having the formula II wherein X is H, halogen, loweralkyl, loweralkoxy, -CF₃ or -OH. 13. A process for the preparation of a compound of the formula II, which comprises cyclizing a compound of the formula VII a where X is as defined above, under Friedel-Crafts-condi­ tions to afford a compound of the formula and reacting the compound obtained with hydroxylamine. Claims for Austria: 1. Process for the preparation of a compound of the formula I where X is H, halogen, loweralkyl, loweralkoxy, -CF₃ or -OH, R is H, loweralkyl, arylloweralkyl, diarylloweralkyl, loweralkanoyl, arylloweralkanoyl, diarylloweralkyl, loweralkanoyl, arylloweralkanoyl or diarylloweralkanoyl; and R₁ is H₂, O or -NR₂R₃, R₂ and R₃ being independently H or loweralkyl, or taken together with the nitrogen atom to which they are attached constitute , R₄ in turn being H, loweralkyl, hydroxyloweralkyl, aryl, arylloweralkyl or diarylloweralkyl or pharmaceutically acceptable acid addition salts thereof. which comprises a) heating a compound of the formula II in a substantially anhydrous acidic medium to afford a compound of the formula I, where R is hydrogen, R₁ is oxygen and X is as defined, b) optionally reacting the compound obtained with an amine of the formula NHR₂R₃ where R₂ and R₃ are as defined above to afford a compound of the formula I where R is hydrogen, R₁ is -NR₂R₃ and X is as defined, c)optionally reacting a compound of the formula I where R is hydogen. R₁ is oxygen and X is as defined, with a compound of the formula R₅-Hal, where R₅ is loweralkyl, arylloweralkyl or diarylloweralkyl and Hal is bromine, chlorine or iodine, to afford a compound of the formu­ la I wherein R₁ and X are as defined above and R is loweralkyl, arylloweralkyl or diarylloweralkyl, d) optionally reducing a compound of the formula I where R₁ is oxygen, R is loweralkyl, arylloweralkyl or di­ arylloweralkyl and X is as defined above, to afford a compound of the formula I wherein R₁ is H₂, R is hydro­ gen and X is as defined, e) optionally reacting a compound of the formula I, where R₁ is H₂, R is hydrogen and X is as defined, with a compound of the formula R₆COCl where R₆ is loweralkyl, arylloweralkyl or diarylloweralkyl to afford a compound of the formula I where R₁ is H₂, X is as defined and R is ,where R₆ is as defined, or f) optionally reacting a compound of the formula I where R₁ is H₂, R is hydrogen and X is as defined, with formic-acetic anhydride to afford a compound of the 0 formula I where R₁ is H₂, X is as defined and R is -CH, g) optionally reducing a compound of the formula I where R₁ is H₂, X is as defined and R is the radical , where R₆ is hydrogen, loweralkyl, arylloweralkyl or diarylloweralkyl, to afford a compound of the formula I where R₁) is H₂, X is as defined and R is-CH₂-R₆, R₆ being as defined, h) and optionally preparing the pharmaceutically accept­ able acid addition salts thereof. 2. The process as defined in claim 1 wherein the con­ verting reaction of a compound of the formula II is con­ ducted in the presence of an excess of polyphosphoric acid or a mixture of hydrogen chloride, acetic acid and acetic anhydride and at a temperature of 100 - 150°C. 3. The process as defined in claims 1 or 2 wherein a compound of the formula I is prepared, where R is hydrogen, X is hydrogen or halogen and R₁ is oxygen. 4. The process as defined in claims 1 or 2, wherein a compound of the formula I is prepared, where R is hydrogen, X is hydrogen or halogen and R₁ is H₂ or -NR₂R₃ R₂ and R₃ being independently H or loweralkyl or taken together with the nitrogen atom to which they are attached constitute the radical where R₄ is hydrogen or loweralkyl. 5. The process as defined in claim 3 wherein 1,4-Di­ hydrobenzo[c]-1,5-naphthyridine-2(3H)-one is prepared. 6. The process as defined in claim 4 wherein 1,2,3,4-­ Tetrahydrobenzo-[c]-1,5-naphthyridine is prepared. 7. The process as defined in claim 4 wherein 3,4-Di­ hydro-2-(4-methyl-1-piperazinyl)benzo-[c]-1,5-naphthyridine is prepared. 8. The process as defined in claims 1 or 2 wherein 1-(Phenyacetyl)-1,2,3,4-tetrahydrobenzo-[c]-1,5-naphthyri­ dine is prepared. 9. A process for the preparation of a compound of the formula II, which comprises cyclizing a compound of the formula VII a where X is as defined above, under Friedel-Crafts-condi­ tions to afford a compound of the formula and reacting the compound obtained with hydroxylamine. 10. The process as defined in claim 9 wherein the Friedel-Crafts-reactions is conducted in the presence of AlCl₃ and at ambient temperature.

Inventors: MARTIN, LAWRENCE L., SCOTT, SUSAN J., SETESCAK, LINDA L.
Applicants: HOECHST-ROUSSEL PHARMACEUTICALS INCORPORATED
Application year: 1986
Main classification: C07D471
IPC codes: A61P25, A61P21, A61K31, C07D471, C07D207