IL27396A - Imidazo(1,5-a)quinolin-1-one (or thione) derivatives and process for their preparation - Google Patents

Imidazo(1,5-a)quinolin-1-one (or thione) derivatives and process for their preparation

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IL27396A
IL27396A IL2739667A IL2739667A IL27396A IL 27396 A IL27396 A IL 27396A IL 2739667 A IL2739667 A IL 2739667A IL 2739667 A IL2739667 A IL 2739667A IL 27396 A IL27396 A IL 27396A
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lower alkyl
piperazinyl
pyrrolidinyl
quinolin
tetrahydro
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IL2739667A
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American Cyanamid Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
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  • Nitrogen Condensed Heterocyclic Rings (AREA)
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Description

PATENTS FORM NO.
PATENTS AND DESIGNS ORDINANCE SPECIFICATION IMIDAZOjl 5-a QUINOLIN-l-0NE (ORjTHIONE) DERIVATIVES AND PROCESS FOR THEIR PREPARATION (ΐΐ'ηγκ) ' i 3»ip j.-5tlj in'«t *?v nn^in We, AMERICAN CYANAMID COMPANY, a corporation organized and existing under the laws of the State of Maine, United States of America, and having its executive offices at Wayne, New Jersey, United States of America DO HEREBY DECLARE the nature of this invention and in what manner the same is to be performed, to be particularly described and ascertained in and by the 'following statement :- i · 1 l This invention relates to new organic compounds and processes for preparing the same . More particularly the invention relates to novel derivatives of imidazo- [l,5-a]quinolin-l-one or thione, intermediates and addition salts thereof and their preparation.
The novel compounds of this invention may be illustrated by the following general formula: h rein R and R are h dro en halo en lower alk l 1 · lower alkoxy or trifluoromethyl; R2 is hydrogen, lower alkyl or halogen Y is oxygen or sulfur; n is an integer 1, 2, 3, or 4; and R3 and R4 are hydrogen, lower alkyl, lower alkenyl; methyl and - R3R4, when taken together is 1-pyrrolidinyl, lower alkyl-l-pyrrolidinyl, piperidino, lower alkyl-piperidino, morpholino, lower alkylmorpholino, hexa-methyleneimino, 1-piperazinyl, 1- (lower alkyl) -4-piperazinyl, 1-(hydroxy lower alkyl ) -4-piperazinyl, 1- (lower alkanoyloxyalkyl) -4-piperazinyl, l-phenyl-4-piperazinyl, l-( lower alkoxyphenyl ) -4-piperazinyl, 1-trifluoromethylphenyl-4-piperazinyl, l-(lower alkyl-phenyl) -4-piperazinyl, l-halophenyl-4-piperazinyl, 4-phenyl-l, 2,5* 6-tetrahydro-l-pyridinyl, 4-alkylphenyl-1, 2,5* 6-tetrahydro-l-pyridinyl, 4-halophenyl-l, 2,5*6-tetrahydro-l-pyridinyl, 4-lower alkoxyphenyl-1, 2,5* 6-tetrahydro-l-pyridinyl, 4-trifluoromethylphenyl-l, 2,5* 6-tetrahydro-l-pyridinyl or azabicyclo[3.2.2]nonan-3-yl; and -CnH2nNR3R4, when taken together, is (2-pyrrolidinyl)-lower alkyl, (3-pyrrolidinyl) lower alkyl, (1-lower alkyl-pyrrolidinyl) lower alkyl, (1-benzylpyrrolidinyl)lower alkyl, [l-(halobenzyl)pyrrolidinyl]lower alkyl, [1-(lower alkoxybenzyl)pyrrolidinyl]lower alkyl, [l-(lower alkylbenzyl)pyrrolidinyl]lower alkyl, (piperidinyl)lower alkyl, (1-lower alkylpiperidinyl)lower alkyl, (1-benzyl-piperidinyl)lower alkyl, [l-(halobenzyl)piperidinyl]lower alkyl, [l-(lower alkoxybenzyl)piperidinyl]lower alkyl, or [1-(lower alkylbenzyl)piperidinyl]lower alkyl; and pharmaceutically acceptable acid addition salts thereof .
The free bases of this invention, in general, may be either liquids or solids at room temperature .
The free bases are, in general, relatively insoluble in water, but soluble in most organic solvents such as lower alkyl alcohols and esters, acetone, or chloroform. These compounds form acid addition salts with strong acids, such as hydrochloric acid, sulfuric acid, or perchloric acid. The compounds also form salts with organic acids, as for example, fumaric and maleic acid. Such salts, in general, are soluble in water, methanol and ethanol, but relatively insoluble in benzene, ether, or petroleum ether .
The compounds of the present invention possess central nervous system (CNS) activity at non-toxic doses and, as such, are useful as highly active tranquilizers . The compounds have been tested pharmacologically and found to have tranquilizing properties which show a desirable wide spread between doses producing sedative actions and toxic symptoms such as paralysis or lethality.
A useful test for tranquilizer activity con-sists or measuring the reduction of spontaneoux motor activity in animals by means of an actophotometer (a photoelectric device for quantitatively measuring locomotor activity) . Graded doses of the active compounds prepared by the process of this invention are adminis-tered to groups of mice, and the effective dosage range for a significant reduction of motor activity (a measure of tranquilization) compared to control groups is established .
I The preferred method of preparing the compounds of the present invention can be illustrated as follows: wherein R, Ri, R2J R3, R4 and n are as defined hereinbefore and X is halogen, lower alkylsulfonyloxy or arylsulfonyloxy group. The imidazo[l,5-a]quinolin-l- one is dissolved in an inert solvent, as for example, diethyleneglycol dimethyl ether (diglyme) and reacted with a condensing agent such as sodium hydride and then with an appropriate aminoalkyl derivative. The reaction may be best carried out at temperatures within the range of about j50°-200°C. for a period of from 30 minutes to 4 hours . The product can be recovered by methods well known in the art and described hereinafter in the examples » A further method of preparing the present compounds can be illustrated by the following procedure: wherein R, Rx, Ra, R3, R4, and n are as defined above and X is a halogen, alkylsulfonyloxy, or arylsulfonyl- oxy radical. The reaction takes place when the reagents are contacted in an inert solvent such as ether, tetra- hydrofuran, toluene, or benzene, and the reagent mixture is maintained within the temperature of from about 50° to 150°C. for a period of 10 minutes to several hours.
The novel compounds of the present invention may also be prepared by a method wherein a triamine , is reacted with a cyclizing ®¾· agent, as for example, phosgene, ethyl chloroformate, or N, -carbonyl diimidazole to produce compounds having an oxygen in the 1-position. By using thiophosgene the corresponding compounds are produced wherein sulfur is present in the 1-position. These reactions may be illustrated as follows : wherein R, Ri, R2, R4, Y, and n are as defined hereinbefore. The reaction takes place when the reagents are mixed in an inert solvent such as ether, tetrahydrofuran, benzene, or toluene, and the mixture is gradually heated to a temperature within the range of 50°-200°C. for a period of time sufficient to complete the reaction.
Additionally, if desired, the imidazo[l,5-a]- quinolin-l-ones of this invention may be converted to the corresponding imidazo[l,5-a]quinolin-l-thiones by heating with phosphorus pentasulfide in an inert solvent . The preferred temperature range is from about 50°C. to 150°C. Suitable solvents include benzene, toluene, pyridine and the like .
The products of the present invention as tranquilizers can be incorporated in yarious pharmaceut- ical forms such as tablets, capsules, pills, for immediate or sustained release, by combining with carriers well known in the compounding arts. They may be in the form of dosage units for a single therapeutic dose or in small units for multiple dosages or in larger units for division into single doses. Obviously, in addition to the therapeutic tranquilizing compound there may be present excipients, binders, fillers, and other therapeutically inert ingredients necessary in the formulation of the desired pharmaceutical preparation.
The following specific examples illustrate the preparation of representative imidazo[l, 5-a]-q.uinolin-1-one or thione derivatives, intermediates and acid addition salts of the present invention. Parts are by weight unless otherwise indicated.
EXAMPLE 1 Preparation of 2- Γ2- ) 1-Pyrrolidinyl)ethyl ] -3 , 3a, , 5 -tetrahydroimidazo .1 , 5-a quinolin-l-(2H)-one fumarate A mixture of 1.6 parts of 50$ sodium hydride (in mineral oil) and 5-6 parts of 3, 3a, 4 , 5-tetrahydro-imidazo[l, 5-a]quinolin-l-(2H)-one in 150 parts of diglyme is stirred while 4.6 parts of 2-(l-pyrrolidinyl)ethyl chloride in 50 parts of dry ether are added. The reaction mixture is stirred for 30 minutes and then gradually heated for hours as the ether is distilled off. The solid is filtered off and discarded and the mother liquor is concentrated to removed the solvent. Ether and 50 parts of 1 N hydrochloric acid are added to the residue. The mixture is shaken and the layers are separated. The aqueous layer is made alkaline with 5 ·^ sodium hydroxide and the product is extracted into ether or benzene . The organic layer is mixed with a solution of 2.5 parts of fumaric acid in ethanol and a precipitate is formed. The precipitate is separated by filtration and recrystallized from ethanol. Pure 2-[2- (1-pyrrolidinyl)ethyl]3, 5a,k,5-tetrahydroimidazo-[l, 5-a]quinolin-l-(2H)-one fumarate melts at 163°-165°C. This compound is highly active as a CNS depressant.
EXAMPLE 2 Preparation of 2-(2-Dimethylajninoethyl)-3,5a- ,5-tetra- h droimidazo[l,5-a]quinolin-l-(2H)^-one fumarate The above compound, melting point 151-152°C, is obtained when 2-dimethylaminoethyl chloride is substituted for 2- (1-pyrrolidinyl) ethyl chloride in the procedure of Example 1 . This compound is active as a CNS depressant.
EXAMPLE 5 Preparation of 2-[2( 2-Methyl-l-pyrrolidinyl)ethyl 1- 3 j 5a,4 5-tetrahydroimidazoL 1, ¾-*alauinolin-li- 2H) -one The above compound is obtained when 2-(2-methyl-l-pyrrolidinyl)ethyl chloride is substituted for 2- (1-pyrrolidinyl) ethyl chloride in the procedure of Example 1.
EXAMPLE Preparation of 2- (4-Piperidinobutyl) -3, 3a, 4, 5-tetra- hydroimidazo 1 , -aJquinolin- 1- (2HJ -one When 4-piperidinobutyl chloride is substituted dinyl Λ , . for 2-(l-pyrroli¾^^¾ik)ethyl chloride in the method of ( ^ Example 1, the above compound is obtained.
EXAMPLE 5 Preparation of 2- [ 2- ( -Methyl^iperidino)ethyll-5, 3a, , 5- ;etrahydroimidazoLl, 5-a]quinolin-l-(2H)-one This compound is obtained when 2- (4-methyl-piperidino)ethyl chloride is used in place of 2-(l-pyrrolidinyl)ethyl chloride in the procedure of Example 1 .
EXAMPLE 6 The above compound, melting point 134-135°C, is obtained when 2-diethylaminoethyl chloride is substituted for 2-(l-pyrrolidinyl)ethyl chloride in the procedure of Example 1 .
EXAMPLE 7 Preparatio o 8-Chloro-2-[2-(l-pyrrolidinyl)ethyl]- j 3a> ^j 5-tetrahydroimid zo[l,5-a]quinolin-1-(2Hj -one When 8-chloro-3 , 3a, , 5-tetrahydro[l, 5-a]-quinolin-l-(2H)-one is substituted for 3, 3a, , 5-tetra-hydro[lJ 5-a]quinolin-l-(2H)-one in the procedure of Example 1, this compound is obtained.
EXAMPLE 8 Preparation of 7-Bromo-2-r2-(l-pyrrolidinyl)ethyl]- ¾*5~Ά> ^> 5-tetrahydroimidazo[ 1 , 5-a]quinolin-1-( 2H)-one The above compound is obtained when 7-bromo- 33a, } 5-tetrah droimidazo[ 1 , 5-a]quinolin-1- ( H) -one is substituted for 3, 3a,4, 5-tetrahydroimidazo[l,5-a]-quinolin-l-(2H)-one in the procedure of Example 1..
EXAMPLE Preparation of 2- ( 2-Dimethylaminoethyl) -7-methoxy-- j5, 3a,4, 5-tetranydroimidazo[ 1, 5-aJquinolin-l-( 2ΤΓ) -one When 2-dimethylaminoethyl chloride is reacted with 7-methoxy-3, 3a, , 5-tetrahydroimidazo[l, 5-a]-quinolin-l-(2H)-one using the procedure of Example 1, the above compound is obtained.
EXAMPLE 10 Preparation of 2-(2-Morpholinoetlyl) -7-tr^ 3, 3a,4, 5-tetrahydroimidazo[l,5-a] uinolin-l-(2H)-one This compound is obtained when 2-morpholino-ethyl chloride is reacted with 7-trifuoromethyl- 3 } 3aj 4j 5-tetrahydroimidazo[1, 5-a]quinolin-l- (2H) -one using the method of Example 1.
EXAMPLE 11 Preparation of 9-Ghloro-2-(2-dimethylaminoethyl) -7--methyl-^, ^a, , - etrahydroxmidazo 1, 5-a]quinolin-I^" ( gH j_ong When 9-chloro-7-methyl-3i 3a, 4, 5-tetrahydroimidazo[1, 5-a]-quinolin-l-(2H) -one is treated with 2-dimethylaminoethyl chloride, using the procedure of Example 1, this compound is obtained.
EXAMPLE 12 Preparation of 2- [2- (2, 6-Dimethylmorpholino)ethyl) -7-fluoro-3 , 3a, 4, - 1etrahydroimidazo[1, - ]-quinolin-1- (2H)-one If 2- ( 2,6-dimethylmorpholino)ethyl chloride is reacted with 7-fluoro-3, a, 4, 5-tetrahydroimidazo-[l,5-a]-quinolin-l-(2H)-one using the procedure of Example 1, the above compound is obtained.
EXAMPLE 13 Preparation of 2- ( 2-Hexamethyleniminoethyl) -3, 3 , , 5- tetrahydroimidazotl , 5-a]quinolin-l-(2H)-one When 2-hexamethyleniminoethyl chloride is substituted for 2-(l-pyrrolidinyl)ethyl chloride in the procedure of Example 1, this compound is obtained.
EXAMPLE 14 Preparation of 2- [2- ( 3-Azabicyclo[3.2.2] nonan-3-yl)- This compound is obtained when 2- (3-azabicycl [3.2.2]nonan-3-yl)ethyl chloride is substituted for 2-(l-pyrrolidinyl)ethyl chloride in the procedure of Example 1.
EXAMPLE 15 Preparation of 2-(2^ethy¾henethylaminoethyl-3,3a, ,5- ft* tetrahydroimidazo[l,5a]quinolin-l-(2H)-one If 2¾thyl¾henethylaminoethyl chloride is f)^ substituted for 2-(l-pyrrolidinyl)ethyl chloride in the procedure of Example 1, this compound is obtained.
EXAMPLE 16 Preparation of 2-(3-Diraethylaiainopropy: -3,3a,4,5-tetrahydroimldazo[l,5-a]quinolin-l-( 2HJ-one fumarate This compound is obtained when 3-dimethylamino propyl chloride is reacted with 3* 3a, 4,5-tetrahydro-imidazo[l,5-a]quinolin-l-(2H)-one by the procedure of Example 1. The melting point is 147-149°C.
EXAMPLE 17 Preparation of 2-[2(4-Phenyl-l-piperazinyl)ethyl-3, , 4,5-tetrahydroimidazo[l,5-ajquinolin-l-( 2H)-one hydrochloride The above compound, melting point 251-252°C, is obtained when 2-(4-phenyl-l-piperazinyl)ethyl chloride is reacted with 3,3a,4,5-tetrahydroimidazo[l,5-a]-quinolin-l-(2H)-one by the procedure of Example 1.
EXAMPLE 18 Preparation of 2-[3-( -Phenyl-l-piperazinyl)propyl]- , a, 4, -tetrahydroimidazo[l,5-ajquinolin-l- (2H)-one A mixture of 5.6 parts of 3,3a,4,5-tetra-hydroimidazo[i,5-a]quinolin-l-(2H)-one and 1.6 parts of 50 sodium hydride (in mineral oil) in 100 parts of diglyme is stirred and a solution of 12 parts of 1,3-dibromopropane is added. The reaction mixture is stirred for hours the reci itated salt is filtered off and the mother liquor is concentrated to remove the diglyme and excess 1,3-dibromopropane .
The crude 2-(3-bromopropyl)-3,3a,4,5-tetra-hydroimidazo[l,5-a]quinolin-l-(2H)-one is mixed with parts of 1-phenylpiperazine and 200 parts of benzene and heated at re lux temperature for 8 hours . The reaction mixture is extracted twice with aqueous sodium hydroxide solution and then with water. The aqueous layers are discarded. The reaction product is shaken with dilute hydrochloric acid and the benzene layer is discarded. Dilute sodium hydroxide is added and the product is dissolved in benzene or chloroform. On concentration, crude 2-[3-(4-phenyl-l-piperazinyl)-propyl]-J>,3a,4,5-tetrahydroimidazo[1,5-a]quinolin-1-(2H)-one is obtained. It is further purified by partition chromatography. The dihydrochloride salt melts at 230-232°C. after recrystallization from ethanol .
In the above procedure by substituting l-(p_-chlorophenyl)piperazine, 1-(m-trifluorometh l phenyl)-piperazine, l-(m-bromophenyl)piperazine, l-(p-tolyl)-piperazine, l-(o-fluorophenyl)piperazine and l-(m-methoxyphenyl)piperazine for the phenylpiperazine the following compounds are respectively obtained: 2-[3-(4-p-chlorophenyl-l-piperazinyl)propyl]-3,3a,4,5-tetrahydroimidazo[l,5-a]quinolin-l-(2H)-one 2-[3- ( -m-trifluoromethylphenyl-l-piperazinyl)propyl]3,3a,-4,5-tetrahydroimidazo[l,5- ]quinolin-l-(2H) -onej 2-[3-(4-m-bromophenyl-l-piperazinyl)propyl]-3,3a,4,5-tetrahydro- . imidazo[1,5-a3quinolin-l-(2H)-onej 2-[3-(4-£-tolyl-l-piperazinyl)propyl]-3, a,4, -tetrahydroimidazo[1,5-a]- I 1 quinolin-1-(2H)-one ; 2- [3- ( 4-o-fluorophenyl-l-pipera- zinyljpropylj-^^a^^-tetrahydroimidazofl^-ajquinolin- 1-(2H) -one; 2- [ 3 - ( 4-m-methoxypheny 1 -1-piperazinyl)propyl) - 3 , 3a, 4, 5-tetrahydroimidazo[ 1 , 5-a] uinolin-1- (2H)-one .
EXAMPLE 19 Preparation of 2-[3-(4-Phenyl-l,2,5, 6-tetrahydro-l- pyrldinyl)propyl] -3 ,3a,4, 5-te rahydroimidazo[ 1 , -a]- quinolin-1-( 2H) -ones When the procedure of Example 18 is used and the phenyl piperazine is replaced by 4-phenyl-l, 2,5, 6- 10 tetrahydropyridine, 4-(m-trifluoromethylphenyl)-l, 2,5,6- tetrahydropyridine, 4-(o-fluorophenyl) -1, 2, 5, 6-tetrahydropyridine, -(_-chlorophenyl) -1 , 2 , 5, 6-tetrahydropyridine, 4-(m-bromophenyl) -1, 2, 5, 6-tetrahydropyridine, 4-(p_-tolyl)-l, 2,5, 6-tetrahydropyridine and 4-(m- 15 methoxyphenyl)-l, 2,5, 6-tetrahydropyridine, the following compounds are respectively obtained: 2-[3-(4-phenyl- 1, 2,5, 6-tetrahydro-l-pyridinyl)propyl] -3,3a, 4,5-tetra- hydroimidazo[ 1,5-a]quinolin-1-(2H)-one, 2-[3-(4-m- trifluoromethylphenyl) -1, 2, 5, 6-tetrahydro-l-pyridinyl)- 20 propyl] -3, 3a, , 5-tetrahydroimidazo [1, 5-a]quinolin-l- (2H)-one, 2-[3-(4-o-fluorophenyl-l, 2, 5, 6-tetrahydro-l- pyridinyl)propyl] -3, 3a, 4, -tetrahydroimidazo[ 1, 5-a]- quinolin-1- (2H) -one, 2- [3- (4-p_-chlorophenyl-l, 2, , 6- tetrahydro-l-pyridinyl)propyl]-3,3a,4,5-tetrahydro- 25 imidazo[l,5-a]quiholin-l-(2H)-one, 2-[3-(4-m-bromophenyl- 1,2,5» 6-tetrahydro-l-pyridinyl)propyl] -3, 3a, 4, 5-tetra- hydroimidazo[l, -a]quinolin-1-(2H) -one, 2-[3-(4-p_-tolyl- 1,2,5, 6-tetrahydro-l-pyridinyl)propyl-3 , 3a, , -tetra- hydroimidazo[l,5-a]quinolin-l-(2H)-one and 2-[3-(4-m- 30 methoxyphenyl-1 , 2,5, 6-tetrahydro-l-pyridinyl)propyl]- 3j3a,4,5-tetrahydroimidazo[l,5-a]quinolin-l-(2H)-one EXAMPLE 20 Preparation of 2-[ (-L-Benzyl-3-pyrrolidinyl)methyl]- 3,3a,4,5-tetrahydroimidazo[1,5-a]quinolin-1-( 2HJ-one fumarate A slurry of 5.6 parts of 3,3a, 4,5-tetrahydro- imidazo[1, -a]quinolin-1-(2H) -one in 100 parts of diglyme is added to a suspension of 1.6 parts of 50 sodium hydride (in mineral oil) in 10 parts of diglyme and the mixture is stirred until liberation of hydrogen is com- plete . A solution of 7 parts of l-benzyl-3-chloromethyl- pyrrolidine in 20 parts of diglyme is added and the mixture is heated at reflux temperature for 4 hours and filtered hot . The filtrate is concentrated to remove the solvent. The residue is dissolved in dilute hydro- chloric acid and extracted with benzene to remove impurities. The aqueous layer is made alkaline and extracted with benzene . The benzene layer is concentrated and the residue is warmed with 4 parts of fumaric acid and enough ethanol to cause solution to occur. Ether is added until crystallization occurs . The product is filtered off and recrystallized twice from ethanol .
The 2-[ (l-benzyl-3-pyrrolidinyl)methyl]-3,3a, ,5-tetra- hydroimidazo[l,5-a]quinolin-l-(2H)-one fumarate melts at 166-168°C.
When 1-(m-bromobenzyl) -3-chloromethylpyrrol- idine is substituted for l-benzyl-3-chloromethylpyrrol- idine in the procedure of Example 20, this compound is obtained .
EXAMPLE ggx 22 J^ Preparation of 2-[Q-Benzyl~3-piperidinyl)methyl] -3, 3aJ - , 5-tetrahydroimidazo[ 1, 5-ajquinolin-1- ( 2H) -one If l-benzyl-3-chloromethylpiperidine is substituted for l-benzyl-3-chloromethylpyrrolidine in the procedure of Example 20, the above compound is obtained .
EXAMPLE 2k 23 ψ^" Preparation of 2- [ (l-Benzyl-2-pyrrolidinyl) ethyl ] - J 3a- 4, -1etrahydroimida o[ 1 , -aJquinolin-1-( 2Hj -one This compound is obtained when 2-(l-benzyl-2- pyrrolidinyl)ethyl chloride is substituted for 1-benzyl- 3-chloromethylpyrrolidine in the procedure of Example .
EXAMPLE g¾ 24 Preparation of 2- [ (l-Methyl-3-pyrrolidinyl)methyl]- 3, a, 4, 5-tetrahydroimidazo [1,5-a]quinolin-1- ( 2H) -one When 3-chloromethyl-l-methylpyrrolidine is substituted for l-benzyl-3-chloromethylpyrrolidine in the procedure of Example 20, this compound is obtained.
The fumarate salt melts at 176-178°C.
This compound is obtained when 2-allylmethyl- aminoethyl chloride is substituted for 2-(l-pyrrolidinyl)- ethyl chloride in the procedure of Example 1.
EXAMPLE ¾¾ 26 j^j!fl Prepa ation of 2-[2-(N-Cyclopropylmethyl-N-methylamino) -ethyl]- , a, 4, 5-tetrahydroimidazo[1,5-a]quinolin-l~ (2H)-one" When 2-(N-cyclopropylmethyl-N-methylamino)-ethyl chloride is substituted for 2-(l-pyrrolidinyl)-ethyl chloride in the procedure of Example 1, this compound is obtained.
EXAMPLE A 27 Preparation of 2-[2-(l-Methyl-4-piperazinyl ethyl]-^,3aJ - ,5-tetrahydroimidazo[1,5-ajquinolin-1-( 2H) -one If 2-(l-pyrrolidinyl)ethyl chloride is replaced by 2-(l-methyl- -piperazinyl)ethyl chloride in the procedure of Example 1, the above compound is obtained .
EXAMPLE 29 28 Preparation of 2-( 2¾enzy-¾ethylaminoethyl)- 3& J s - tetrahydroimiaazoLljS-a-J uinolin-l-t 2Hj-one hydrochloride The above compound, melting point 198-200°C. is obtained when ^-benzy¾ethylaminoethyl chloride is substituted for 2-(l-pyrrolidinyl)ethyl chloride in the procedure of Example 1.
EXAMPLE 29 Preparation of 2-[3-(1-piperazinyl) ropyl ]-3, 3a,4,5- tetrahydroimidazo[1,5-aJquinolin-1-( 2H)-one When piperazine is substituted for 1-phenyl-piperazine in the procedure of Example 18, this compound is obtained.
EXAMPLE $Zx 30 Preparation of 2-(2-Methylaminoethyl)-3,3a, ,5-tetra-hydroimidazoLl>5- ]quinolin-1-( 2H) -one hydrochloride tf A mixture of parts of 2-(a'-benzyimethyl- aminoethyl) -3 * 3a, 4, 5-tetrahydroimidazo[ 1 , 5-a]quinolin-l-(2H)-one hydrochloride (Example 29 ) , 200 parts of 90$ ethanol and 1 .0 part of 10$ palladium-on-carbon catalyst is shaken in a Parr hydrogenated under about 3 atmospheres of hydrogen pressure until hydrogen uptake is complete.
The catalyst is filtered off, the solvent is distilled off and the 2- ( 2-methylaminoethyl)3, 3a, , 5-tetrahydro-imidazo[l,5-a]quinolin-l-(2H)-one hydrochloride, is thus obtained .
EXAMPLE 31 Preparation of 2- [ (l-m-Methylbenzyl-3-piperidinyl)methyl]- * ?a-> , 5-tetrahydroimidazo[l, 5-aJquinolin-1- ( 2H) -one The above compound is obtained when l-(m-methylbenzyl) -3-chloromethylpiperidine is substituted for l-benzyl-3-chlormethylpyrrolidine in the procedure of Example 20.
EXAMPLE g¾x 32 vO^ Preparation of 2-Γ (l-p-Methoxybenzyl-2-piperidinyl)-methy 1 ] -3 , 3a, , 51-tetrahydroimidazo[ 1 , 5-a]quinolin-1- ^2H)_one When l-benzyl-3-chloromethylpyrrolidine is replaced by l-(p-methoxybenzyl) -2-chloromethylpiperidine in the procedure of Example 20, the above compound is obtained .
EXAMPLE ¾k 33 (^A* Preparation of 2- [l-p-Fluorobenzyl-2-piperidinyl)methyl ]-3, a, , 5-tetrahyd oimidazo[ 1, 5-a]quinolin-l- ( 2H) -one The above compound is obtained when 1-benzyl- 3-chloromethylpyrrolidine is replaced by l-(p-fluoro-benzyl) -2-chloromethylpiperidine in the procedure of Example 20.
EXAMPLE ¾ξ> 34 Preparation of 2- [ (l-p-(¾lorobenzyl-3-piperidinyl) me¾hyl]-5, 5a, 4,5-tetr EXAMPLE 35 0ψ^> Preparation of 2-[ (l-m-Bromobenzyl-2-pi^eridinyl)methyl]-3, 3a, ,5-tetrahydroimidazo[lJ5-a]quinolin-l-(2H)-one When 1-(m-bromobenz 1) -2-chlorometh lpiperi-dine is substituted for 1-benzy1-5-chloromethylpyrrol-idine in the procedure of Example 20, this compound is prepared .
EXAMPLE 36 /\ ^° Preparation o 5j7-Dimethyl-2-(2-dimethylaminoethyl)-5,5a,4, -tetrahydroimidazo[l,5-a]quinolin-l-(2H)-one This compound is obtained when * 7-limethyl-5,5a, ,5-tetrah droimidazo[l, -a]quinolin-l-(2H)-one is reacted with 2-dimethylaminoethyl chloride by the procedure of Example 1.
EXAMPLE g¾.37 Preparation of 5, 8-Dichloro- -( 2-dimethylaminoethyl)- 5j5a, 4, 5-tetrahydroimidazo[1, -ajquinolin-1-(2H)-one If 5> 8-dichloro-5, 5a, ,5-tetrahydroimidazo- [l,5-a]quinolin-l-(2H)-one is reacted with 2-dimethyl-aminoethyl chloride by the procedure of Example 1, this compound is obtained .
EXAMPLE ¾k 38 Preparation of 2-[2-(N-Cyclohexyl- -methylamino)ethyl]- 5, a, , 5-tetrah droimidazo[1, -a]quinolin-1-(2H)-one The above compound is obtained when 2-(N- cyclohexyl-N-methylamino)ethyl chloride is substituted for 2-(l-pyrrolidinyl)ethyl chloride in the procedure of Example 1.
EXAMPLE ¾fl 39 (^ Preparation of 2-[3-(4-Aceto^ethyl-l-piperazinyl propyl j 3*3a, 4, 5-1etranydroimidazo[1, 5-aj uiriolin-1-(2H) -one This compound is obtained when the 1-phenyl-piperazine is replaced by l-(acetoxyethyl)piperazine in the procedure of Example 18.
EXAMPLE fct 40 ^j Preparation of 2-[^-( -Hydroxyethyl-l-piperazinyl)propyl] 3 3 , 4,5-tetrahydroimidazo 1^5- jquinolin-1- 2H)-one When l-(hydroxyethyl)piperazine is used in place of 1-phenylpiperazine in the procedure of Example 18, this compound is obtained.
The above compound is obtained when l-(p-methoxybenzyl)-3-chloromethylpyrrolidine is substituted for l-benzyl-3-chloromethylpyrrolidine in the procedure of Example 20.
EXAMPLE ¾x 42 Preparation of 2-[(l-Fluorobenzyl-2-pyrrolidinyl)methyl]- 3j3a^j5-^e¾r^ydroi^dazoL1^"a ¾^nolin~1" 2H)-one This compound is obtained when l-(p-fluoro-benzyl)-2-chloromethylpyrrolidine is substituted for 1-benzyl-3-chloromethylpyrrolidine in the procedure of Example 20.
EXAMPLE ¾¼x 43 Preparation of 2- [ (l-Benzyl-3-pyrrolidinyljmethyl -8- - - - ' [l,5-a]quinolin-l-(2H)-one is substituted for 3j3a,5*5-tetrahydroimidazo[l,5-a]quinolin-l-(2H)-one in the procedure of Example 20, this compound is obtained.
EXAMPLE ¾¾ 44 (^JU> Preparation of 2-[ (l-Benzyl-3-pyrrolid^nyl) ethyl]-^ 7-bΓomo-3,3 ,4, -tetrahydroimidazo[l,5-a]quinolin^ (2Hj_ong If the 5>3a,4,5-tetrahydroimidazo[l,5-a]-quinolin-l-(2H)-one is replaced by 7-bromo-3,5 , 4,5-tetrahydroimidazo-[l,5-a]quinolin-l-(2H)-one in the procedure of Example 20, this compound is obtained.
EXAMPLE kSx 45 Preparation of 2- [2-(1-Pyrrolldinyl)ethyl ]-3,3a, 4,5- tetrahydroimidazo[1, -ajquinolin-1-( 2H)-thione A mixture of 10 parts of 2-[2-(l-pyrrolidinyl)-ethyl ]-5, 3a,4, -tetrahydroimidazo[1, - ]quinolin-1-(2H)-one, 100 parts of xylene, and 10 parts of phosphorous pentasulfide is heated with stirring in an oil bath at 155-160°C. for 48 hours. The reaction mixture is cooled and 175 ml. of 2N sodium hydroxide and 100 ml. of benzene are added. The mixture is stirred until the glassy layer is dissolved and the layers are separated. The aqueous layer is extracted with benzene . The organic layers are combined, washed with water, dried over magnesium sulfate and concentrated to remove solvent . The residue contains 2-[2-(l-pyrrolidinyl)ethyl]-3,3a,4,5-tetrahydroimidazo[l,5-a]quinolin-l-(2H)-thione and is further purified by partition chromatography.
EXAMPLE 46 \M**- Preparation of 2-(4-Phenyl-l-piperazinylmethyl)-5, a,4,5- tetrahydroimidazo[1, -ajquinolin-1-( H) -one A mixture of 1.86 parts of 3,3a,4,5-tetra- hydroimidazo[l, 5-a]quinolin-l-(2H)-one, 1.62 parts of 1-phenylpiperazine, 30 parts of ethanol and 0.8 parts of 37 formaldehyde is heated at reflux temperature for 90 minutes and concentrated. The residue is triturated with ether and the insoluble portion, 0.2 parts, is filtered off and discarded . The mother liquor is concentrated to remove the ether, and the residue is dissolved in benzene. This solution is again concentrated. The glassy residue is triturated with ether and crystal-lization occurs. The 2- ( 4-phenyl -1-piperazinylmeth 1) -3, 3a, , 5-tetrah dro[l, 5-a]quinolin-l-(2H)-one is filtered off and melts at 111-113°C.

Claims (6)

Having now particularly described and ascertained the nature of our said invention and in what manner the same is to be performed, we declare that what we claim is:
1. A method of preparing compounds of the formula: wherein R and Ri are hydrogen, halogen, lower alkyl, lower alkoxy or trifluoromethyl; R2 is hydrogen, lower alkyl or halogen; Y is oxygen or sulfur n is an integer from 1 to k; and R3 and R4 are hydrogen, lower alkyl, lower alkenyl, cycloalkyl, aralkyl, or lower (cycloalkyl)-methyl, and -NR3R4, when taken together is 1-pyrro-lidinyl, lower alkyl~l-pyrrolidinyl, piperidino, lower alkylpiperidino, morpholino, lower alkylmorpholino, hexamethyleneimino, 1-piperazinyl, 1- (lower alkyl) -4-piperazinyl, 1-(hydroxy lower alkyl) - -piperazinyl, 1-(lower alkanoyloxyalkyl)- -piperazinyl, l-phenyl- -piperazinyl, l-(lower alkoxyphenyl)- -piperazinyl, 1-trifluoromethylphenyl- -piperazinyl, l-(lower alkylphenyl) -piperazinyl, l-halophenyl- -piperazinyl, -phenyl-1, 2,4,5-tetrahydro-l-pyridinyl, -alkylphenyl-l, 2,5, 6-tetrahydro-l-pyridinyl, . -halophenyl-l, 2,5,6-tetranydro-1-pyridinyl, -lower alkoxyphenyl-1, 2,5, 6-tetrahydro-1-pyridinyl, -trifluoromethylphenyl-1, 2,5, 6-tetrahydro-1-pyridinyl or azabicyclo [3.2.2]nonan-3-yl; and -CnH2n R3R4, when taken together, is (2-pyrrolidinyl) -lower alkyl, (3-pyrrolidinyl)lower alkyl, (1-lower alkyl-pyrrolidinyl) -lower alkyl, (1-benzylpyrrolidinyl)lower * alkylbenzyl)pyrrolidinyl] -lower alkyl, (piperidinyl)-lower alkyl, (1-lower alkylpiperidinyl)lower alkyl, (1-benzylpiperidinyl)lower alkyl, [l-(halobenzyl)-piperidinyl]lower alkyl, [1- (lower alkoxybenzyl)piperi-dinyl]-lower alkyl or [l-(lower alkylbenzyl)plperidinyl ] lower alkyl; and pharmaceutically acceptable acid addition salts thereof characterized by: (a) heating a compound of the formula: wherein R, i and R2 are as hereinbefore defined and Z is hydrogen or CnH2nX,whe ein X is halogen, lower alkyl-sulfonyloxy, or arylsulfonyloxy, and n is as hereinbefore definedj (l) with a compound of the formula: X-CnH2n-NR3R4 when Z is hydrogen, wherein R3, R4, X and n are as defined above; or (2) with a compound of the formula: when Z is CnH2nX, wherein R3, R4, X, and n are as hereinbefore defined; (b) and, if desired, doing one or more of the following: (1) when the 1-position is oxygen, treating it with P2Sg to convert oxygen to sulfur, and 2 forming the therapeutically useful salts of ;
2. A process for the preparation of the Formula I in compounds of/ Claim 1 which comprises reacting a compound of the formula: wherein R, Ri, R2, R3, R4, and n are as hereinbefore defined.,, „ ¾56s&K3K&ax with a cyclizing agent .
3. The process according to Claim 2 wherein the cyclizing agent is phosgene, thiophosgene, ethyl chloroformate, or N, N' -carbonyl diimidazole.
4. An imidazo[l,5-a]quinoline of the formula: wherein R and i are hydrogen, halogen, lower alkyl, lower alkoxy or trifluoromethyl; R2 is hydrogen, lower alkyl or halogen; Y is oxygen or sulfur; n is an integer from 1 to 4; and R3 and R4 are hydrogen, lower alkyl, lower alkenyl, cycloalkyl, aralkyl, or lower (cyclo-alkyl)methyl and -NR3R4, when taken together, is 1-pyrrolidinyl, lower alkyl-l-pyrrolidinyl, piperidino, lower alkylpiperidino, morpholino, lower alkylmorpholino, hexamethyleneimino, 1-piperazinyl, l-(loweralkyl)-4-piperazinyl, l-(hydroxy lower alkyl) -4-piperazinyl, 1- (lower aJLkanoyloxyalkyl) -4-piperazinyl, l-phenyl-4- I* 2,5,6-tetrahydro-l-pyridinyl, ½-halophenyl-l, 2, ,6- tetrahydro-l-pyridinyl, 4-lower alkoxyphenyl-1,2,5, 6- tetrahydro-l-pyridinyl, -trifluoromethylphenyl-1, 2,5, 6- tetra ydro-l-pyridinyl or azabicyclo [J .2.2]nonan-3-yl; and -CnH2nNR3R4, when taken together, is (2-pyrroli- dinyl)lower alkyl, (3-P3rrrolidinyl)lower alkyl, (1-lower alkylpyrrolidinyl) lower alkyl, (1-benzylpyrrolidinyl)- lower alkyl, [l-(halobenzyl)pyrrolidinyl]lower alkyl, [l-( lower alkoxybenzyl)pyrrolidlnyl]lower alkyl, 1- (lower alkylbenzyl)pyrrolldinyl]lower alkyl, (piperidinyl) lower alkyl, (1-lower alkylpiperidinyl)lower alkyl, (1- benzylpiperidinyl)lower alkyl, [l-(halobenzyl)piperi- dinyl] lower alkyl, [l-(lower alkoxybenzyl)piperidinyl ]- lower alkyl, or [l-( lower alkylbenzyl)piperidinyl]lower alkyl; and pharmaceutically acceptable acid addition salts thereof.
5. The imidazo[l,5-a]quinoline according to 4 Claim ¾, 2-(2-dimethylaminoethyl)-3,3a,4,5-tetrahydro- imidazo[l,5-a]quinolin-l-(2H)-one .
6. ¾ The imidazo[l,5-a]quinoline according to 4 - N- Claim ±, 2-(y-benzyl ethylaminoethyl)-3,3a, ,5-tetra- hydroimidazo[1, - ]quinolin-l- (2H) -one . DATED the 5th day of February, 1967
IL2739667A 1966-02-18 1967-02-06 Imidazo(1,5-a)quinolin-1-one (or thione) derivatives and process for their preparation IL27396A (en)

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