WO1993013103A1 - Imidazoquinazoline compounds and their preparation and use - Google Patents

Imidazoquinazoline compounds and their preparation and use Download PDF

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Publication number
WO1993013103A1
WO1993013103A1 PCT/DK1992/000385 DK9200385W WO9313103A1 WO 1993013103 A1 WO1993013103 A1 WO 1993013103A1 DK 9200385 W DK9200385 W DK 9200385W WO 9313103 A1 WO9313103 A1 WO 9313103A1
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WIPO (PCT)
Prior art keywords
compound
cyclopropyl
quinazoline
imidazo
oxadiazol
Prior art date
Application number
PCT/DK1992/000385
Other languages
French (fr)
Inventor
Holger Claus Hansen
Marit Kristiansen
Original Assignee
Novo Nordisk A/S
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Filing date
Publication date
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to AU33448/93A priority Critical patent/AU673814B2/en
Priority to EP93902092A priority patent/EP0619820A1/en
Priority to JP5511363A priority patent/JPH07502278A/en
Publication of WO1993013103A1 publication Critical patent/WO1993013103A1/en
Priority to NO942301A priority patent/NO942301L/en
Priority to FI942963A priority patent/FI942963A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • the present invention relates to therapeutically active imidazoquinazoline compounds, a method of preparing the same, pharmaceutical compositions comprising the compounds, and to methods of treating therewith.
  • the novel compounds are useful in psychopharmaceutical applications, e.g. in the treatment of central nervous system ailments, for example as anticonvul- sants, anxiolytics, hypnotics, antipsychotics, antiemetics, in improving the cognitive function of the brain of mammals, or as benzodiazepine antagon- ists.
  • R 1 is hydrogen, straight or branched C ⁇ -alkyl, unsubstituted or C ⁇ -alkyl substituted G ⁇ -cycloalkyl, C ⁇ -alkoxy, C ⁇ -alkoxy-C ⁇ -alkyl or tri- fluoromethyl;
  • R 8 is straight or branched C 1-6 -alkyl;
  • R 2 and R 3 independently are hydrogen, C ⁇ -alkyl, optionally substituted with C ⁇ -cycIoalkyl, di-C ⁇ -alkylamino, phenyl or a p ⁇ peridinyl group optionally substituted with C ⁇ -alkyl, or R 2 and R 3 independently are C ⁇ -cycloalkyl,
  • R 4 , R 5 , R 6 and R 7 independently are hydrogen, hydroxy, CI, Br, F, I, triffuoro- methyl, nitro, amino, cyano, straight or branched C ⁇ -alkyl, C 2 ⁇ -alkenyl, C 2 ⁇ - alkynyl, C ⁇ -alkoxy, C ⁇ -alkoxy-C ⁇ -alkyl or C ⁇ -alkoxycarbonyl;
  • R 4 , R 5 , R 6 , R 7 at the same time cannot all be hydrogen when Q is
  • R 1' is H, C ⁇ -alkyl or unsubstituted C ⁇ -cycloalkyl
  • R 2 and R 3 independently are H, C ⁇ -alkoxy, C ⁇ -cycloalkyl or C ⁇ -alkyl or NR 2 R 3 forms an unsubstituted morpholino or thiomorpholino group
  • the compound of formula I is not ethyl 6-chloro-5-morpholino-imidazo[1 ,5-a]quinazoiine-3- carboxylate or 6-chloro-3-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-5-morpholino- imidazo[1 ,5-a]quinazoline.
  • the invention also relates to methods of preparing the above-mentioned compounds. These methods comprise:
  • R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above and wherein Y is a leaving group, with a compound having the formula III
  • R 1 is as defined above to form a compound of the general formula I wherein Q is
  • R 1 is as defined above, or
  • R 2 , R 3 , R 4 , R 5 , R 8 and R 7 have the meanings set forth above, with a dehydrating agent to form a compound of formula I, wherein R 2 , R 3 , R 4 , R 5 , R 6 and R 7 have the meanings set forth above and wherein Q is cyano, or
  • R 2 , R 3 , R 4 , R 5 , R 8 and R 7 have the meanings set forth above, with NH 2 OH to form a compound of formula VIII
  • R 2 , R 3 , R 4 , R 5 , R 8 and R 7 have the meanings set forth above, and reacting the compound of formula VIII with R 1 -COOEt or with (R 1 CO) 2 0, wherein R 1 is as defined above to form a compound of the general formula I wherein Q is
  • the leaving group, Y may be any suitable leaving group and, for example, those disclosed in U.S. Patents 4,031 ,079 or 4,359,420, for example, halogen, alkylthio, for example methylthio, ar alkylthio, N-nitrosoalkylamino, alkoxy, mercapto, -0P(0)(0R) 2 wherein R is lower-alkyl or -OP(0)(NR'R") 2 wherein R' and R" each represents lower-alkyl or phenyl, or together with the nitrogen atom to which they are attached represent a heterocyclic radical such as morpholino, pyrrolidino, piperidino, or methylpiperazinyl.
  • the reaction is preferably carried out under alkaline conditions, i.e., in the presence of a base, and among bases alkali metal (e.g., potassium or sodium) alkoxides or hydrides are preferred.
  • the reaction is preferably conducted in the presence of an organic solvent which is nonreactive with the reactants and products of reaction under the conditions of reaction, especially an anhydrous solvent and preferably and anhydrous aprotic solvent such as dimethylformamide (DMF), tetrahydrofuran (THF), or the like.
  • the temperature range employed may be any range suitable for the reaction to proceed at a reasonable rate and without undue delay or decomposition and a range from -40°C to about room temperature is accordingly usually particularly suitable.
  • the starting materials employed in the syntheses of the compounds of formula I are either known or may be prepared in conventional manner from commercially available materials, e.g. according to Karminski et al., J. Environ. Sci. Health, Part B, 1983 B 18 (4-5) 599.
  • the pharmaceutical properties of the compounds of the invention can be illustrated by determining their capability for displacing radioactive labelled flunitrazepam from benzodiazepine receptors.
  • the displacement activity of the compounds of the invention may be found by determining the ED ⁇ value.
  • the ED ⁇ value represents the dose (mg/kg) of a test substance which causes the specific binding of 3 H-flunitrazepam to benzodiazepine receptors in a living brain to be reduced to 50% of the control value.
  • the compounds of the invention together with a conventional adjuvant, carrier, or diluent, and if desired in the form of a pharmaceutically accept ⁇ able acid addition salt thereof, may be placed into the form of pharmaceuti- cal compositions and unit dosages thereof, and in such form may be em ⁇ ployed as solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including sub- cutaneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective central nervous system ailment alleviating amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the compounds of the invention can thus be used for the formulation of pharmaceutical preparations, e.g. for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy.
  • Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or oral application which do not deleteriously react with the active compound.
  • E ⁇ xamples of such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, mag ⁇ nesium stearate, talc, silicic acid, fatty acid monoglycerides and diglyce- rides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinyl- pyrrolidone.
  • the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compound.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compound.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Ampoules are convenient unit dosage forms.
  • tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch.
  • a syrup, elixir or the like can be used when a sweetened vehicle can be employed.
  • the compounds of the invention are dispensed in unit dosage form comprising 0.05-100 mg in a pharmaceuti ⁇ cally acceptable carrier per unit dosage.
  • a typical tablet which may be prepared by conventional tabletting tech- niques contains:
  • the compounds of the invention are extremely useful in the treatment of central nervous system ailments or disorders, when administered in an amount effective for the alleviation, amelioration, or elimination thereof.
  • the import ⁇ ant CNS activity of the compounds of the invention includes both anti- convulsant, anxiolytic, hypnotic, antipsychotic, and antiemetic activities and activity as to improvement of the cognitive function of the brain of mammals along with a low toxicity, together presenting a most favourable therapeutic index.
  • the compounds of the invention may accordingly be administered to a subject, e.g.
  • a living mammal body including a human, in need of the same for the treatment, alleviation, amelioration, or elimination of an indica- tion, associated with the central nervous system and the so-called benzo ⁇ diazepine receptors, which requires such psychopharmaceutical treatment, e.g. especially convulsion, insomnia, anxiety, psychosis, emesis, dementia states and/or as benzodiazepine antagonists, if desired in the form of a pharmaceutically acceptable acid addition salt thereof (such as the hydro- bromide, hydrochloride, tartrate or sulphate, in any event prepared in the usual or conventional manner, e.g.
  • a pharmaceutically acceptable acid addition salt thereof such as the hydro- bromide, hydrochloride, tartrate or sulphate, in any event prepared in the usual or conventional manner, e.g.
  • a pharmaceutically acceptable carrier or diluent especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective psychopharmaceutical central nervous system ailment alleviating amount, e.g. an anticonvulsant, anxiolytic, hypnotic and/or antipsychotic amount, and in any event an amount which is effective for the alleviation of such a central nervous system ailment due to their benzodiazepine receptor affinity.
  • an effective psychopharmaceutical central nervous system ailment alleviating amount e.g. an anticonvulsant, anxiolytic, hypnotic and/or antipsychotic amount, and in any event an amount which is effective for the alleviation of such a central nervous system ailment due to their benzodiazepine receptor affinity.
  • Suitable dosage ranges are 1-200 milligrams daily, 1-100 milligrams daily, and especially 1-30 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
  • 6-Chloro-3-(3-cyclopro ⁇ yl-1 ,2,4-oxadiazol-5-yl)-5-morpholi ⁇ o-imidazo[1,5-a]- quiriazoline (1.45 g) in 25 ml of 6 M aqueous hydrochloric acid was stirred at 100°C for 45 min. Then the mixture was cooled to 0°C and the precipi ⁇ tated crystals were filtered off, rinsed on the filter with 25 ml of water, then with 5 x 1 ml of ethyl acetate, and finally with 10 ml of diethyl ether. The beige crystals were dried, yielding 0.85 g of the title compound, m.p. 270- 272°C (decomp.).
  • Trifluoroacet ⁇ c anhydride (0.15 ml) was added dropwise to a suspension of 5-morpholino-imidazo[1,5-a]quinazoline-3-carboxamide oxime in 4 ml of dry tetrahydrofuran. After stirring for 3 hours at room temperature the reaction mixture was evaporated in vacuo. The residue was dissolved in a mixture of water and ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulphate, and evaporated to dryness. The crystals were rinsed by stirring with isopropanol (3 ml) to give yellow crystals of the title compound, m.p. 182-186°C. Yield 0.06 g.
  • Glacial acetic acid (2 mi) and dichloromethane (50 ml) were added, and after the precipitated product had dissolved the sieves were removed by filtration through celite. The filtrate was evaporated and the residue was triturated with 100 ml of water. The undissolved material was collected by filtration, dried and treated with 25 ml of acetone. Yellow crystals precipi ⁇ tated and were filtered off and dried. Yield 0.47 g, m.p. 262-264°C.

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Abstract

Imidazoquinazoline compounds having formula (I), wherein Q is (a), (b), (c), or (d) -COOR8 or -CN; wherein R1 is H, alkyl, unsubstituted or substituted cycloalkyl, alkoxy, alkoxyalkyl or CF¿3; R?8 is alkyl; R?2 and R3¿ independently are H, alkyl optionally substituted, cycloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, formylalkyl, or an acetal thereof, or R?2 and R3¿ together with the N-atom form a 4-6 membered cyclic amino group in which ring system one or more of the carbon atoms may be exchanged with N,O or S, sulphinyl, sulphonyl or carbonyl or an acetal thereof, each of these ring systems optionally being substituted; R?4, R5, R6 and R7¿ independently are H, OH, halogen, CF¿3? NO2, NH2, CN, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl or alkoxycarbonyl. The compounds are useful in psychopharmaceutical preparations as anticonvulsants, anxiolytics, hypnotics, antipsychotics, antiemetics, in improving the cognitive function of the brain of mammals, or as benzodiazepine antagonists.

Description

Tmidazoαuinazoline compounds and Their Preparation and Use.
The present invention relates to therapeutically active imidazoquinazoline compounds, a method of preparing the same, pharmaceutical compositions comprising the compounds, and to methods of treating therewith. The novel compounds are useful in psychopharmaceutical applications, e.g. in the treatment of central nervous system ailments, for example as anticonvul- sants, anxiolytics, hypnotics, antipsychotics, antiemetics, in improving the cognitive function of the brain of mammals, or as benzodiazepine antagon- ists.
It is well known (Squires, R.F. and Braestrup, C. in Nature (London) 266 (1977) 732-734) that specific sites in the central nervous systems of verte¬ brates exhibit a high specific affinity for binding 1,4- and 1 ,5-benzodiaze- pines. These sites are called benzodiazepine receptors.
It has now been found that members of a novel group of imidazoquinazo¬ line compounds have strong affinity for the benzodiazepine receptors which make them useful in psychopharmaceutical preparations.
Accordingly, it is an object of the invention to provide such novel imidazo¬ quinazoline compounds.
The compounds of the invention have the general formula I
(I)
Figure imgf000003_0001
and pharmaceutically acceptable acid addition salts or hydrates thereof, wherein Q is
Figure imgf000004_0001
-COOR8 or -CN;
wherein R1 is hydrogen, straight or branched C^-alkyl, unsubstituted or C^-alkyl substituted G^-cycloalkyl, C^-alkoxy, C^-alkoxy-C^-alkyl or tri- fluoromethyl; R8 is straight or branched C1-6-alkyl;
R2 and R3 independently are hydrogen, C^-alkyl, optionally substituted with C^-cycIoalkyl, di-C^-alkylamino, phenyl or a pϊperidinyl group optionally substituted with C^-alkyl, or R2 and R3 independently are C^-cycloalkyl,
C1-6-hydroxyalkyl, C^-alkoxy, C^-alkoxy-C^-alkyl, C^-alkoxycarbonyl-C^- alkyl, formyl-C^-alkyl or a cyclic or non-cyclic acetal thereof, or R2 and R3 together with the nitrogen atom form a 4-6 membered cyclic amino group in which ring system one or more of the carbon atoms may be exchanged with nitrogen, oxygen, sulphur, sulphinyl, sulphonyf or carboπyl or a hydrate, an acyclic or a cyclic acetal thereof, each of these ring systems optionally being substituted with one or more of C1α3-alkyl, C^-alkoxy- methyl, hydroxy, C^-hydroxyalkyl or phenyl;
R4, R5, R6 and R7 independently are hydrogen, hydroxy, CI, Br, F, I, triffuoro- methyl, nitro, amino, cyano, straight or branched C^-alkyl, C2^-alkenyl, C2^- alkynyl, C^-alkoxy, C^-alkoxy-C^-alkyl or C^-alkoxycarbonyl;
provided that R4, R5, R6, R7 at the same time cannot all be hydrogen when Q is
O — N N -0 wherein R1' is H, C^-alkyl or unsubstituted C^-cycloalkyl; R2 and R3 independently are H, C^-alkoxy, C^-cycloalkyl or C^-alkyl or NR2R3 forms an unsubstituted morpholino or thiomorpholino group; and the compound of formula I is not ethyl 6-chloro-5-morpholino-imidazo[1 ,5-a]quinazoiine-3- carboxylate or 6-chloro-3-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-5-morpholino- imidazo[1 ,5-a]quinazoline.
The invention also relates to methods of preparing the above-mentioned compounds. These methods comprise:
a) reacting a compound of formula II
Figure imgf000005_0001
wherein R2, R3, R4, R5, R6 and R7 are as defined above and wherein Y is a leaving group, with a compound having the formula III
CN - CH, - Q (III)
wherein Q is as defined above, to form a compound of the general formula I, or
b) reacting a reactive derivative of a compound having the general formula IV
Figure imgf000006_0001
wherein R2, R3, R4, R5, R6 and R7 are as defined above with a compound having the general formula V
R1-C(=NOH)NH, (V)
wherein R1 is as defined above to form a compound of the general formula I wherein Q is
O-N
X±..' *-
wherein R1 is as defined above, or
c) reacting a compound of the general formula VI
Figure imgf000006_0002
wherein R2, R3, R4, R5, R8 and R7 have the meanings set forth above, with a dehydrating agent to form a compound of formula I, wherein R2, R3, R4, R5, R6 and R7 have the meanings set forth above and wherein Q is cyano, or
d) reacting a compound of formula VII
Figure imgf000007_0001
wherein R2, R3, R4, R5, R8 and R7 have the meanings set forth above, with NH2OH to form a compound of formula VIII
Figure imgf000007_0002
wherein R2, R3, R4, R5, R8 and R7 have the meanings set forth above, and reacting the compound of formula VIII with R1-COOEt or with (R1CO)20, wherein R1 is as defined above to form a compound of the general formula I wherein Q is
N-0
X .-X R '
wherein R1 is as defined above, or e) hydrolysis of a compound of the general formula I to form a compound of the general formula IX
Figure imgf000008_0001
wherein Q, R4, R5, R8 and R7 have the meanings set forth above, and reacting the compound of formula IX with POCI3 to form a compound of formula X
Figure imgf000008_0002
which is reacted with a compound of formula XI
NHR2R3 (XI)
wherein R2 and R3 have the meanings set forth above, to form a compound of the general formula I.
The leaving group, Y, may be any suitable leaving group and, for example, those disclosed in U.S. Patents 4,031 ,079 or 4,359,420, for example, halogen, alkylthio, for example methylthio, ar alkylthio, N-nitrosoalkylamino, alkoxy, mercapto, -0P(0)(0R)2 wherein R is lower-alkyl or -OP(0)(NR'R")2 wherein R' and R" each represents lower-alkyl or phenyl, or together with the nitrogen atom to which they are attached represent a heterocyclic radical such as morpholino, pyrrolidino, piperidino, or methylpiperazinyl. The reaction is preferably carried out under alkaline conditions, i.e., in the presence of a base, and among bases alkali metal (e.g., potassium or sodium) alkoxides or hydrides are preferred. The reaction is preferably conducted in the presence of an organic solvent which is nonreactive with the reactants and products of reaction under the conditions of reaction, especially an anhydrous solvent and preferably and anhydrous aprotic solvent such as dimethylformamide (DMF), tetrahydrofuran (THF), or the like. The temperature range employed may be any range suitable for the reaction to proceed at a reasonable rate and without undue delay or decomposition and a range from -40°C to about room temperature is accordingly usually particularly suitable.
The starting materials employed in the syntheses of the compounds of formula I are either known or may be prepared in conventional manner from commercially available materials, e.g. according to Karminski et al., J. Environ. Sci. Health, Part B, 1983 B 18 (4-5) 599.
The pharmaceutical properties of the compounds of the invention can be illustrated by determining their capability for displacing radioactive labelled flunitrazepam from benzodiazepine receptors.
The displacement activity of the compounds of the invention may be found by determining the ED^ value. The ED^ value represents the dose (mg/kg) of a test substance which causes the specific binding of 3H-flunitrazepam to benzodiazepine receptors in a living brain to be reduced to 50% of the control value.
Such an jn vivo test is carried out as described in US 4,774,245. Test results obtained by testing some compounds of the invention will appear from the following table I.
TABLE I
Figure imgf000010_0001
The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, and if desired in the form of a pharmaceutically accept¬ able acid addition salt thereof, may be placed into the form of pharmaceuti- cal compositions and unit dosages thereof, and in such form may be em¬ ployed as solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including sub- cutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective central nervous system ailment alleviating amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing 0.1-100 mg of active ingredient or, more specified, 1.0-50 mg per tablet, are accord¬ ingly suitable representative unit dosage forms.
The compounds of the invention can thus be used for the formulation of pharmaceutical preparations, e.g. for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy. Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or oral application which do not deleteriously react with the active compound.
EΞxamples of such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, mag¬ nesium stearate, talc, silicic acid, fatty acid monoglycerides and diglyce- rides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinyl- pyrrolidone.
The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compound.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
Ampoules are convenient unit dosage forms.
For oral application, particularly suitable are tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch. A syrup, elixir or the like can be used when a sweetened vehicle can be employed. Generally, as to broader ranges, the compounds of the invention are dispensed in unit dosage form comprising 0.05-100 mg in a pharmaceuti¬ cally acceptable carrier per unit dosage.
A typical tablet which may be prepared by conventional tabletting tech- niques contains:
Active compound 1.0 mg
Lactosum 67.8 mg Ph.Eur. Avicelβ 31.4 mg
Amberliteβ IRP 88 1.0 mg
Magnesii stearas 0.25 mg Ph.Eur.
Due to their high degree of affinity for the benzodiazepine receptors, the compounds of the invention are extremely useful in the treatment of central nervous system ailments or disorders, when administered in an amount effective for the alleviation, amelioration, or elimination thereof. The import¬ ant CNS activity of the compounds of the invention includes both anti- convulsant, anxiolytic, hypnotic, antipsychotic, and antiemetic activities and activity as to improvement of the cognitive function of the brain of mammals along with a low toxicity, together presenting a most favourable therapeutic index. The compounds of the invention may accordingly be administered to a subject, e.g. a living mammal body, including a human, in need of the same for the treatment, alleviation, amelioration, or elimination of an indica- tion, associated with the central nervous system and the so-called benzo¬ diazepine receptors, which requires such psychopharmaceutical treatment, e.g. especially convulsion, insomnia, anxiety, psychosis, emesis, dementia states and/or as benzodiazepine antagonists, if desired in the form of a pharmaceutically acceptable acid addition salt thereof (such as the hydro- bromide, hydrochloride, tartrate or sulphate, in any event prepared in the usual or conventional manner, e.g. evaporation to dryness of the free base in solution together with the acid), ordinarily concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective psychopharmaceutical central nervous system ailment alleviating amount, e.g. an anticonvulsant, anxiolytic, hypnotic and/or antipsychotic amount, and in any event an amount which is effective for the alleviation of such a central nervous system ailment due to their benzodiazepine receptor affinity. Suitable dosage ranges are 1-200 milligrams daily, 1-100 milligrams daily, and especially 1-30 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
The invention will now be described in further detail with reference to the following examples, which may not be construed as limiting:
EXAMPLE 1
3-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-5-morpholino-6-trifluoromethyl-imi- dazo[1,5-a]quinazoline (Compound 1)
To a stirred solution of 2-chloro-4-morpholino-5-trifiuoromethyl-quinazoline (600 mg, 1.9 mmol) and 3-cyclopropyl-5-isocyanomethyl-1 ,2,4-oxadiazole (440 mg, 2.9 mmol) in dry DMF (15 ml) under nitrogen at 5-10°C was added solid potassium t-butoxide (330 mg, 2.9 mmol). The mixture was stirred at 5-10°C for 0.5 h and triturated with water (20 ml). The crystals were filtered off and washed with water (10 ml) and ethyl acetate. A final purification was done by stirring the crystals in acetone (10 ml) to give 330 mg of the title compound, m.p. 197-199°C.
1H-nmr (CDCI3) δ: 8.4 (s, 1H, imidazo-), 8.2-7.9 (m, 3H, benzo-), 4.0-3.2 (m, 8H, morpholino-), 2.2 (m, 1H, CH), 1.3-1.0 (m, 4H, CH2). EXAMPLE 2
3-(3-Cyclopropyl-1,2r4-oxadiazol-5-yl)-6-methyl-5-morpholino-imidazo[1,5-a]- quϊnazoline (Compound 2)
A mixture of 2-chloro-5-methyl-4-morpholino-quinazoline (1.68 g, 6.4 mmol) and 3-cyclopropyl-5-isocyanomethyl-1,2,4-oxadiazole (1.9 g) in 15 ml of dry dimethylformamide was cooled to 0°C. Solid potassium tert-butoxide (1.4 g, 12.5 mmol) was added gradually during 5 min. to the stirred mixture, the temperature being kept below 10°C. The mixture was stirred at ambient temperature for two hors, and then cooled to 0°C. The precipitated crystals were collected by filtration, rinsed on the filter with ethyl acetate and water, and dried to give the title compound as light yellow crystals, m.p. 262- 266°C. Yield 1.29 g.
1H-nmr (CDCy δ: 8.30 (s, 1H, imidazo-), 7.85-7.35 (m, 3H, benzo-), 4.05-3.8 (m, 4H, N-CH2), 3.75-3.30 (m, 4H, 0-CH2), 2.88 (s, 3H, CHg), 2.30-2.12 (m, 1H, CH), 1.3-1.0 (m, 4H, CH2).
In a similar way the following compounds were prepared:
6-Bromo-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-morpholino-imidazo[1,5-a]- quinazoline (Compound 3), m.p. 275-277°C, from 2-chloro-5-bromo-4- morpholino-quinazoline and 3-cyclopropyl-5-isocyanomethyl-1 ,2,4-oxadia- zole;
tert-Butyl 6-methyl-5-thiomorpholino-imidazo[1,5-a]quinazoIine-3-carboxylate (Compound 4), m.p. 164-166°C, from 2-chloro-5-methyl-4-thiomorpholino- quinazoline and tert-butyl isocyanoacetate;
6-Bromo-3-(3-cyciopropyi-1,2,4-oxadiazol-5-yl)-5-(N-(2,2-dimethoxyethyl)-N- methylamino)-imidazo[1,5-a]quinazoline (Compound 5), m.p. 170-171°C, from 2-chloro-5-bromo-4-(N-(2,2-dimethoxyethyl)-N-methylamino)quinazoline and 3-cyclopropyl-5-isocyanomethyl-1 ,2,4-oxadiazole;
3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-6-methyl-5-thiomorpholino-imidazo-
[1 ,5-a]quinazoline (Compound 6), m.p. 205-206°C, from 2-chloro-5-methyl-4- thiomorpholino-quinazoline and 5-cyclopropyl-3-isocyanomethyi-1 ,2,4- oxadiazole;
6-Bromo-3-(3-cyclopropyi-1 ,2,4-oxadiazol-5-yl)-5-(N-ethoxycarbonylmethyl-N- methylamino)-imidazo[1,5-a]quinazoline (Compound 7), m.p. 189-191 °C, from 2-chloro-5-bromo-4-(N-ethoxycarbonylmethyl-N-methylamino)quinazo- line and 3-cyclopropyl-5-isocyanomethyl-1 ,2,4-oxadiazole;
7-Chloro-3-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-5-(N,N-bis(2-methoxyethyl)- amino)-imidazo[1,5-a]quinazoline (Compound 8), m.p. 212-215°C, from 2,6- dichloro-4-(N,N-bis(2-methoxyethyl)amino)quinazoline and 3-cyclopropyl-5- isocyanomethyl-1 ,2,4-oxadiazole;
7-Chloro-3-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-5-(N-(1 ,3-dioxoian-2-yl)- methyl-N-methylamino)-imidazo[1,5-a]quinazoline (Compound 9), m.p. 223- 226°C, from 2,6-dichloro-4-(N-(1 ,3-dioxolan-2-yl)methyl-N-methylamino)- quinazoline and 3-cyclopropyl-5-isocyanomethyl-1 ,2,4-oxadiazole;
3-(3-Cyclopropyl-1 ,2,4-oxadiazol-5-yl)-7-fluoro-5-morpholino-imidazo[1 ,5-a]- quinazoiine (Compound 10), m.p. 243-245°C, from 2-chloro-6-fluoro-4- morpholino-quinazoline and 3-cyclopropyl-5-isocyanomethyl-1 ,2,4-oxa- diazole;
Ethyl 7-fluoro-5-morpholino-imidazo[1,5-a]quinazoline-3-carboxylate (Com¬ pound 11), m.p. 238-239°C, from 2-chloro-6-fluoro-4-morpholino-quinazoline and ethyl isocyanoacetate;
Isopropyl 7-chloro-5-(N-(1,3-dioxolan-2-yl)methyl-N-methylamino)imidazo- [1,5-ajquinazoline-3-carboxylate (Compound 12), m.p. 135-137°C, from 2,6- dichloro-4-(N-(1 ,3-dioxolan-2-yl)-methyl-N-methylamino)quinazoline and isopropyl isocyanoacetate;
9-Chloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-morpholino-imidazo[1,5-a]- quiπazoline (Compound 13), m.p. 121-124°C, from 2,8-dichloro-4-morpho- lino-quinazoline and 3-cyclopropyl-5-isocyanomethyl-1,2,4-oxadiazole;
9-Chloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-(4-methyl-1-piperazinyl)- imidazo[1,5-a]quinazoline (Compound 14), m.p. 199-201 °C, from 2,8- dichioro-4-(4-methyl-1 -piperazinyl)quinazoline and 3-cyclopropyl-5-isocyano- methyl-1,2,4-oxadiazole;
6,9-Dichloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-morpholino-imidazo[1,5- ajquinazoline (Compound 15), m.p. 184-186°C, from 2,5,8-trichloro-4- morpholino-quinazoiine and 3-cyclopropyl-5-isocyanomethyl-1 ,2,4-oxadia- zole;
7-Chloro-3-(5-methoxymethyl-1,2,4-oxadiazol-3-yl)-5-(N-ethyl-N-methyl- amino)imidazo[1,5-a]quinazoline (Compound 16), m.p. 169-172°C, from 2,6- dichloro-4-(N-methyl-N-ethylamino)quiπazoline and 3-isocyanomethyl-5- methoxymethyl-1,2,4-oxadiazole;
3-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-5-thiomorpholiπo-6-trifIuoromethyl- imidazo[1,5-a]quinazoline (Compound 17), m.p. 162-165°C, from 2-chloro-4- thiomorpholino-5-trifluoromethyI-quinazoline and 3-cyclopropyl-5-isocyano- methyl-1 ,2,4-oxadiazole; 3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-5-thiomorpholino-6-trifiuoromethyl- imidazo[1 ,5-a]quinazoline (Compound 18), m.p. 155-158°C, from 2-chloro-4- thiomorpholino-5-trifluoromethyl-quinazoline and 5-cyclopropyl-3-isocyano- methyl-1 ,2,4-oxadiazole;
6-Cyano-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-morpholino-imidazo[1,5-a]- quinazoiine (Compound 19), m.p. 184-187°C, from 2-chloro-5-cyano-4- morpholino-quinazoline and 5-cyclopropyl-3-isocyanomethyl-1 ,2,4-oxadia- zole;
3-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-6-fluoro-5-morpholino-imidazo[1 ,5-a]- quinazoline (Compound 20), m.p. 216-218°C, from 2-chloro-5-fluoro-4- morpholino-quinazoline and 3-cyclopropyl-5-isocyanomethyl-1 ,2,4-oxadia- zole;
3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-6-fluoro-5-morpholino-imidazo[1,5-a]- quinazoline (Compound 21), m.p. 204-207°C, from 2-chloro-5-fluoro-4- morpholino-quinazoline and 5-cyclopropyl-3-isocyanomethyl-1 ,2,4-oxadia- zole;
3-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-6-fluoro-5-(cis-2,6-dimethylmorpho- lino)-imidazo[1,5-a]quinazoiine (Compound 22), m.p. 187-188°C, from 2- chloro-5-fluoro-4-(cis-2,6-dimethylmorpholino)-quinazoline and 3-cyclopro- ρyl-5-isocyanomethyl-1 ,2,4-oxadiazole;
3-(3-Cyclopropyl-1 ,2,4-oxadiazol-5-yl)-6-fluoro-5-thiomorpholino-imidazo- [1f5-a]quinazoline (Compound 23), m.p. 252-253°C, from 2-chloro-5-fluoro- 4-thiomorpholino-quinazoline and 3-cyciopropyl-5-isocyanomethyl-1 ,2,4- oxadiazole;
3-(3-Cyclopropyl-1 ,2,4-oxadiazol-5-yl)-6-fluoro-5-(4-methyl-1 -piperazinyl)- imidazo[1,5-a]quinazoline (Compound 24), m.p. 258-260°C, from 2-chloro-5- f Iuoro-4-(4-methyl-1 -piperaziny l)-quinazoline and 3-cyclopropy l-5-isocyano- methyl-1 ,2,4-oxadiazole;
3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(trans-2,5-dimethylmoφholino)-6- fluoro-imidazo[1,5-a]quinazoiine (Compound 25), m.p. 208-210°C, from 2- chloro-5-fluoro-4-(2,5-dimethylmoφholino)-quinazoline and 5-cyclopropyl-3- isocyanomethyl-1 ,2,4-oxadiazole. Compound 25 was separated from com¬ pound 26 by column chromatography (eluent: ethyl acetate:acetone (2:1));
3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(cis-2,5-dimethylmorpholino)-6- fluoro-imidazo[1,5-a]quiπazoline (Compound 26), m.p. 186-189°C, from 2- chloro-5-fluoro-4-(2,5-dimethylmorpholino)-quinazoline and 5-cyclopropyl-3- isocyanomethyl-1 ,2,4-oxadiazole. Compound 26 was separated from com- pound 25 by column chromatography (eluent: ethyl acetate-.acetone (2:1));
3-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-8-fluoro-5-morpholino-imidazo[1,5-a]- quinazolϊrie (Compound 27), m.p. 276-278°C, from 2-chloro-7-fiuoro-4- morpholiπo-quinazoiine and 3-cyclopropyl-5-isocyanomethyl-1 ,2,4-oxadia- zole;
3-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-5-(3,3-dimethylmorpholino)-7-fluoro- imidazo[1,5-a]quinazoline (Compound 28), m.p. 259°C, from 2-chloro-6- fluoro-4-(3,3-dimethylmorpholiπo)-quinazoline and 3-cyclopropyl-5-isocyano- methyl-1,2,4-oxadiazole;
3-(3-Cyciopropyl-5-isoxazolyl)-6-fluoro-5-morpholino-imidazo[1,5-a]quina- zoline (Compound 29), m.p. 208-210°C, from 2-chloro-5-fluoro-4-morpho- lino-quinazoline and 3-cyclopropyl-5-isocyanomethyl-isoxazole; 3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(3,3-dimethylmorpholino)-7-fluoro- imidazo[1 ,5-a]quinazoline (Compound 30), m.p. 251-254°C, from 2-chloro-6- fluoro-4-(3,3-dimethylmorpholino)-quinazoline and 5-cyclopropyl-3-isocyano- methyl-1 ,2,4-oxadiazole;
tert-Butyl 6-fluoro-5-morpholino-imidazo[1,5-a]quinazoline-3-carboxylate (Compound 31), m.p. 191-193°C, from 2-chloro-5-fluoro-4-morpholino- quinazoline and t-butyl isocyanoacetate;
3-(5-Cyclopropyl-1 ,2,4-oxadiazol-3-yl)-7-fluoro-5-(4-methyl-1 -piperazinyl)- imidazo[1,5-a]quiπazoline (Compound 32), m.p. 202-204°C, from 2-chloro-6- fluoro-4-(4-methyl-1 -piperazinyl)-quinazoline and 5-cyclopropyl-3-isocyano- methyl-1 ,2,4-oxadiazole;
3-(3-Cyclopropyl-1 ,2,4-oxadiazol-5-yl)-5-(N-(1 ,3-dioxolan-2-yl)methyl-N- methylamino)-6-fluoro-imidazo[1 ,5-a]quinazoline (Compound 33), m.p. 209- 211°C, from 2-chloro-4-(N-(1 ,3-dioxolan-2-yl)methyl-N-methylamino)-5-fluoro- quinazoline and 3-cyclopropyl-5-isocyanomethyl-1 ,2,4-oxadiazole;
3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(3,3-dimethylmorpholino)-6-fluoro- imidazo[1 ,5-a]quinazoline (Compound 34), m.p. 210-212°C, from 2-chioro-4- (3,3-dimethylmorpholino)-5-fluoro-quinazoline and 5-cyclopropyl-3-isocyano- methyl-1 ,2,4-oxadiazole;
3-(5-Cyclopropyl-1 ,2,4-oxadiazol-3-yl)-5-(cis-2,6-dimethyl-1 -piperidinyl)-6- fluoro-imidazo[1,5-a]quinazoline (Compound 35), m.p. 163-164°C, from 2- chloro-4-(cis-2,6-dimethyl-1 -piperidinyl)-5-fluoro-quinazoiine and 5-cyclopro- pyl-3-isocyanomethyl-1,2,4-oxadiazole;
3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-7-fluoro-5-thiomorpholino-imidazo-
[1,5-ajquinazoline (Compound 36), m.p. 233-235°C, from 2-chloro-6-fluoro- 4-thiomorpholino-quinazoline and 5-cyclopropyl-3-isocyanomethyi-1 ,2,4- oxadiazole;
3-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-5-(4-methyl-1-piperazinyl)-6-trifluoro- methyl-ϊmidazo[1,5-a]quinazoiine, hydrochloride (Compound 37), m.p. decomp. at 300°C, from 2-chloro-4-(4-methyl-1-piperazinyl)-5-trifluoromethyl- quinazoline and 3-cyclopropyl-5-isocyanomethyl-1 ,2,4-oxadiazole. The hydrochloride was formed by dissolving the base in methylene chloride and adding hydrogen chloride.
Ethyl 6-fluoro-5-morpholino-imidazo[1 ,5-a]quinazoline-3-carboxylate (Com¬ pound 38), m.p. 196-198°C, from 2-chloro-5-fluoro-4-morpholino-quinazoline and ethyl isocyanoacetate;
3-(5-Cyclopropyl-1 ,2,4-oxadiazol-3-yl)-5-(4-methyl-1 -piperazinyl)-6-trifluoro- methyl-imidazo[1,5-a]quinazoline, hydrochloride (Compound 39), m.p. decomp. at 200°C, from 2-chloro-4-(4-methyl-1-piperazinyl)-5-trifluoromethyl- quinazoline and 5-cyclopropyl-3-isocyanomethyl-1 ,2,4-oxadiazole. The hydrochloride was formed by dissolving the base in methylene chloride and adding hydrogen chloride.
3-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-5-(trans-2,5-dimethylmorpholino)-6- fluoro-ϊmidazo[1,5-a]quinazoline (Compound 40), m.p. 211-214°C, from 2- chloro-5-fluoro-4-(2,5-dimethylmorpholino)-quinazoline and 3-cyclopropyl-5- isocyaπomethyl-1,2,4-oxadiazole. Compound 40 was separated from com¬ pound 41 by column chromatography (eluent: methylene chloride:ethyl acetate (1:1));
3-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-5-(cis-2,5-dimethylmorpholino)-6- fiuoro-imidazo[1,5-a]quinazoline (Compound 41), m.p. 169-171 °C, from 2- chloro-5-fluoro-4-(2,5-dimethylmorpholino)-quinazoline and 3-cycloproρyl-5- isocyanomethyl-1 ,2,4-oxadiazole. Compound 41 was separated from com¬ pound 40 by column chromatography (eluent: methylene chloride:ethyl acetate (1:1));
3-(5-Cyclopropyl-1 ,2,4-oxadiazol-3-yl)-5-(N-(1 ,3-dioxolan-2-yl)methyl-N- methylamino)-6-fluoro-imidazo[1,5-a]quinazoline (Compound 42), m.p. 184- 186°C, from 2-chloro-4-(N-(1 ,3-dioxolan-2-yl)methyl-N-methylamino)-5-fluoro- quinazoline and 5-cyclopropyl-3-isocyanomethyl-1 ,2,4-oxadiazole;
3-(3-Cyclopropyl-1 ,2,4-oxadiazol-5-yl)-5-(cis-2,6-dimethyl-1 -piperidinyl)-6- fiuoro-imidazo[1,5-a]quinazoline (Compound 43), m.p. 132-134°C, from 2- chloro-4-(cis-2,6-dimethyl-1 -piperidinyl)-5-fluoro-quinazoline and 3-cyclopro- pyl-5-isocyanomethyl- 1 ,2,4-oxadiazole;
3-(3-Cyclopropyl-1 ,2,4-oxadiazol-5-yl)-5-(3,3-dimethylmorpholino)-6-fluoro- imidazo[1 ,5-a]quinazoline (Compound 44), m.p. 244-246°C, from 2-chloro-4- (3,3-dimethylmorpholino)-5-fluoro-quinazoline and 3-cyclopropyl-5-isocyano- methyl-1 ,2,4-oxadiazole;
3-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-5-(N-(2-dimethylaminoethyl)-N-ethyl- amino)-7-fluoro-imidazo[1,5-a]quinazoline (Compound 45), m.p. 170-172°C, from 2-chloro-6-fluoro-4-(N-(2-dimethylaminoethyl)-N-ethylamino)-quinazoline and 3-cyclopropyl-5-isocyanomethyl-1 ,2,4-oxadiazole.
EXAMPLE 3
6-Chloro-3-(3-cyciopropyl-1,2,4-oxadiazol-5-yl)-4,5-dihydro-5-oxo-imidazo- [1,5-a]quinazoline
6-Chloro-3-(3-cycloproρyl-1 ,2,4-oxadiazol-5-yl)-5-morpholiπo-imidazo[1,5-a]- quiriazoline (1.45 g) in 25 ml of 6 M aqueous hydrochloric acid was stirred at 100°C for 45 min. Then the mixture was cooled to 0°C and the precipi¬ tated crystals were filtered off, rinsed on the filter with 25 ml of water, then with 5 x 1 ml of ethyl acetate, and finally with 10 ml of diethyl ether. The beige crystals were dried, yielding 0.85 g of the title compound, m.p. 270- 272°C (decomp.).
In a similar way the following compounds were prepared:
3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-6-fluoro-4,5-dihydro-5-oxo-imidazo- [1,5-a]quinazoline, m.p. 260-264°C (decomp.), by hydrolysis of 3-(5-cyclo- propyl-1,2,4-oxadiazol-3-yl)-6-fluoro-5-(3,5-dimethylmorpholino)-imidazo- [1,5-ajquinazoline;
3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-7-fiuoro-4,5-dihydro-5-oxo-imidazo- [1,5-a]quinazoline, m.p. 254-255°C, by hydrolysis of 3-(5-cyclopropyl-1 ,2,4- oxadiazol-3-yl)-7-fluoro-5-(3,3-dimethylmoφholino)-imidazo[1,5-a]quinazo- line.
E≡XAMPLE 4
5,6-Dichloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-imidazo[1,5-a]quinazoline
A stirred mixture of 6-chloro-3-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-4,5- dihydro-5-oxo-ϊmidazo[1,5-a]quinazoline (1.0 g), tripropylamine (0.5 ml) and phosphorus oxychloride (5 ml) was heated at 140-150°C. After 1 hour, more POCI3 (5 ml) and tripropylamine (0.5 ml) was added, and heating was continued for 1 V_ hours. Then the warm mixture was poured into 200 ml of ice water with vigorous stirring. After 15 min. 100 ml of dichloromethane was added. Undissolved material was collected by filtration, rinsed with diethyl ether and dried to give the title compound as tan crystals, m.p. 238- 240°C. Yield 0.47 g.
In a similar way the following compounds were prepared:
5-Chloro-3-(5-cyclopropyl-1 ,2,4-oxadiazol-3-yl)-6-fluoro-imidazo[1 ,5-a]- quinazoline, from 3-(5-cyclopropyl-1 ,2,4-oxadiazol-3-yl)-6-fluoro-4,5-dihydro- 5-oxo-imidazo[1 ,5-a]quinazoline;
5-Chloro-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-7-fluoro-imidazo[1,5-a]- quinazoline, m.p. 249-251°C, from 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-7- fiuoro-4,5-dihydro-5-oxo-imidazo[1,5-a] quinazoline.
EXAMPLE 5
(R)-6-chloro-3-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-5-(2-hydroxymethyl-1 - pyrrolidinyl)-imidazo[1 ,5-a]quinazoline (Compound 46)
A mixture of (R)-2-hydroxymethylpyrrolidine (70 mg) and triethylamine (90 mg) dissolved in dry DMF (1 ml) was added dropwise to a stirred suspen¬ sion of 5,6-dichloro-3-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-imidazo[1 ,5-a]- quinazoline (0.20 g) in dry DMF (5 ml) at 0°C. After 20 min. the reaction mixture was filtered. The filtrate was diluted with 15 ml of water and stirred at 0°C for 10 min. The crystals which had formed were filtered off, rinsed with water, and dried to give the title compound as yellow crystals, m.p. 220-221°C. Yield 0.15 g.
In the same way the following compounds were prepared:
6-Chloro-3-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-5-thiomorpholino-imidazo[1 ,5- a]quinazoline (Compound 47), m.p. 240-241 °C, from 5,6-dichloro-3-(3- cyclopropyl-1 ,2,4-oxadiazol-5-yl)-imidazo[1 ,5-a]quinazoline and thiomorpho- line;
6-ChIoro-3-(3-cyclopropyi-1,2,4-oxadiazol-5-yl)-5-(cis-2,6-dimethylmorpho- l.no)-ϊmϊdazo[1,5-a]quinazoline (Compound 48), m.p. 236-238°C, from 5,6- dichloro-3-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-imidazo[1 ,5-a] quinazoline and cϊs-2,6-dimethylmorpholine;
(S)-6-Chloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-(2-methoxymethyl-1- pyrrol-dinyl)-imidazo[1,5-a]quinazoline (Compound 49), m.p. 266-269°C, from 5,6-dichloro-3-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-imidazo[1 ,5-a]- quinazoline and (S)-2-methoxymethyIpyrrolidine;
(S)-6-ChIoro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-(2-hydroxymethyl-1- pyrrolidinyl)-imidazo[1 ,5-a] quinazoline (Compound 50), m.p. 230-232°C, from 5,6-dichloro- 3-(3-cyclopr opyl-1 ,2,4-oxadiazol-5-yl)-imidazo[1 ,5-a]- quinazoline and (S)-2-hydroxymethylpyrrolidine;
6-Chforo-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-(3-hydroxy-1-piperidinyl)- imidazo[1,5-a3quinazoliπe (Compound 51), m.p. 258-261°C, from 5,6-di- chloro-3-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-imidazo[1 ,5-a]quinazoline and 3-hydroxypiperidine;
6-Chloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-(4-phenyl-1-piperazinyl)- imidazo[1,5-a]quinazoiine (Compound 52), m.p. 255-257°C, from 5,6-di- chloro-3-(3-cycIopropyl-1 ,2,4-oxadiazol-5-yl) -imidazo [1 ,5-a]quinazoline and 1 -phenyipiperazine;
6-Chloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-(4-methyl-1-piperazinyl)- imidazo[1,5-a]quinazoline (Compound 53), m.p. 273-275°C, from 5,6-di- chloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-imidazo[1 ,5-a] quinazoline and -methylpiperazine; 6-Chloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-(4-(2-hydroxyethyl)-1- piperazinyl)-imidazo[1,5-a]quinazoline (Compound 54), m.p. 252-254°C, from 5,6-dichloro-3-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-imidazo[1 ,5-a]- quinazoline and 1-(2-hydroxyethyl)piperazine;
5-Amino-6-chloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-imidazo[1,5-a]- quinazoiine (Compound 55), m.p. 343°C, from 5,6-dichloro-3-(3-cyclopropyl- 1,2,4-oxadiazol-5-yl)-imidazo[1,5-a]quinazoline and aqueous ammonia;
6-Chlor o-3-(3-cyclopr opyl-1 ,2,4-oxadiazol-5-yl)-5-(4-propyl-1 -piperazinyl)- imidazo[1 ,5-a] quinazoline (Compound 56), m.p. 186-188°C, from 5,6-di- chloro-3-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-imidazo[1 ,5-a] quinazoline and 1-propylpiperazine;
3-(5-Cyclopropyl-1 ,2,4-oxadiazol-3-yl)-6-fluoro-5-morpholino-imidazo[1 ,5-a]- quinazoline (Compound 21), m.p. 204-206°C, from 5-chloro-3-(5-cyclopro- pyl-1 ,2,4-oxadiazol-3-yl)-6-fluoro-imidazo[1 ,5-a]quinazoline and morpholine;
5-(N-Cyclopropylmethyl-N-methylamino)-3-(5-cyclopropyl-1,2,4-oxadiazol-3- yl)-7-fluoro-imidazo[1 ,5-a] quinazoline (Compound 57), m.p. 176-177°C, from 5-chloro-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-7-fluoro-imidazo[1,5-a]quin- azoline and (N-methylaminomethyl)cyclopropane;
3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-7-fluoro-5-(3-thiazolidinyl)-imidazo- [1,5-a]quinazoline (Compound 58), m.p. 240-242°C, from 5-chloro-3-(5- cyclopropyl-1 ,2,4-oxadiazol-3-yl)-7-fluoro-imidazo[1 ,5-a] quinazoline and thia- zoiidine;
3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-7-fluoro-5-morpholino-imidazo[1,5-a]- quinazoline (Compound 59), m.p. 213-214°C, from 7-fluoro-3-(5-cyclopropyl- 1,2,4-oxadiazol-3-yl)-5-chloro-imidazo[1,5-a]quinazoline and morpholine; 3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(1,3-dioxolane-2-spiro-4'-piperidino)- 7-fluoro-.midazo[1,5-a]quinazoline (Compound 60), m.p. 245-246°C, from 5- chloro-3-(5-cyclopropyl-1 ,2,4-oxadiazol-3-yl)-7-fluoro-imidazo[1 ,5-a]quiπ- azoline and 1,3-dioxolane-2-spiro-4'-piperidine;
3-(5-CycIopropyl-1,2,4-oxadiazol-3-yl)-5-(N-(2-dimethylaminoethyl)-N-methyl- amino)-7-fluoro-imidazo[1 ,5-a] quinazoline (Compound 61), m.p. 148-150°C, from 5-chloro-3-(5-cyclopropyl-1 ,2,4-oxadiazol-3-yl)-7-fluoro-imidazo[1 ,5-a]- quinazoiine and N.N.N'-trimethylethylenediamine;
3-(5-Cycloproρyl-1,2,4-oxadiazol-3-yl)-6-fluoro-5-(4-methyl-1-piperazinyl)- imidazo[1,5-a]quinazoline (Compound 62), m.p. 274-276°C, from 5-chloro-3- (5-cyclopropyl-1 ,2,4-oxadiazol-3-yl)-6-fluoro-imidazo[1 ,5-a] quinazoline and 1 - methylpiperazine;
3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-6-fluoro-5-(4-(2-hydroxyethyl)-1-pipera- zinyl)-imidazo[1,5-a]quinazoliπe (Compound 63), m.p. 228-23Q°C, from 5- chloro-3-(5-cyclopropyl-1 ,2,4-oxadiazol-3-yl)-6-fluoro-imidazo [1 ,5-a] quin¬ azoline and 1-(2-hydroxyethyl)piperazine;
3-(5-Cyclopropyf-1,2,4-oxadiazol-3-yl)-7-fiuoro-5-(N-(2-hydroxyethyl)-N- methyiamino)-.midazo[1,5-a]quinazoline (Compound 64), m.p. 161-163°C, from 5-chloro-3-(5-cyclopropyl-1 ,2,4-oxadiazoI-3-yl)-7-fluoro-imidazo[1 ,5-a]- quϊnazoline and 2-(N-methylamino)ethanol;
3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-7-fluoro-5-(4-oxopiperidino)-imidazo- [1 ,5-a] quinazoline (Compound 65), m.p. 234-236°C (dec), from 5-chloro-3- (5-cyclopropyI-1 ,2,4-oxadiazol-3-yl)-7-fluoro-imidazo[1 ,5-a] quinazoline and 4- piperidone;
3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-7-fluoro-5-(N-methyl-N-(1-methyl-4- piperidinyi)amino)-imidazo[1 ,5-a]quinazoline (Compound 66), m.p. 204- 207°C, from 5-chloro-3-(5-cycloρropyl-1 ,2,4-oxadiazol-3-yl)-7-fiuoro-imidazo- [1 ,5-a] quinazoline and 1-methyl-4-(methylamino)piperidine.
EXAMPLE 6
5-Morpholino-imidazo[1,5-a]quinazoline-3-carboxamide
A stirred mixture of ethyl 5-morpholino-imidazo[1 ,5-a]quinazoline-3-car- boxylate (2.0 g) and acetamide (1.2 g) in 20 ml of dry dimethylformamide was heated to 80°C. 30% sodium methoxide in methanol (1 ml) was added and the mixture was stirred at 100°C for 2 hours, cooled to room tempera¬ ture and diluted with isopropanol (20 ml). Crystals were filtered off, washed with isopropanol (15 ml), water (20 ml) and diethyl ether (10 ml), and dried to give the title compound as yellow crystals, m.p. >300°C. Yield 1.3 g.
EXAMPLE 7
3-Cyano-5-morpholino-imidazo[1 ,5-a]quinazoline (Compound 67)
Bromine (0.15 ml) was added dropwise to a solution of triphenylphosphine (0.8 g) in 15 ml of methylene chloride at 5 °C. 5-morpholino-imidazo[1 ,5- a]quinazoline-3-carboxamide (0.5 g) and triethylamine (0.83 ml) were added to the solution. The resulting reaction mixture was stirred at room tempera¬ ture for 3 hours and evaporated in vacuo. Ethyl acetate (10 ml) was added to the residue and crude crystals of the title compound were isolated by filtration. The dried crystals were dissolved in acetone (30 ml) and an excess of hydrogen chloride in diethyl ether was added separating the hydrochloride of the title compound as beige crystals. M.p. 225-228°C. Yield 0.3 g. ln the same way the following compound was prepared:
3-Cyano-6-methoxy-5-morphoiino-imidazo[1 ,5-a]quinazoline (Compound 68), m.p. 283-284°C, from 6-methoxy-5-morpholino-imidazo[1,5-a]quiπazo- line-3-carboxamide.
EXAMPLE 8
5-Mθφholino-imidazo[1 ,5-a]quiπazoline-3-carboxamide oxime
A mixture of sodium hydroxide (0.06 g), hydroxylamine hydrochloride (0.10 g) and methanol (3 ml) was stirred for 1 hour at room temperature. The hydroxylamine was isolated as a methanol solution by filtration and washing of the filter cake with methanol (7 ml). This hydroxylamine solution was added to a suspension of 3-cyano-5-morpholiπo-imidazo[1 ,5-a] quinazoline (0.16 g) in 5 ml of methanol. The reaction mixture was refluxed for 4 hours, cooled to room temperature and filtered. The crystals were washed with methanol and dried to give the title compound as yellow crystals, m.p. 212- 213°C. Yield 0.17 g.
EXAMPLE 9
5-Morpholino-3-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-imidazo[1,5-a]quinazo- line (Compound 69)
Trifluoroacetϊc anhydride (0.15 ml) was added dropwise to a suspension of 5-morpholino-imidazo[1,5-a]quinazoline-3-carboxamide oxime in 4 ml of dry tetrahydrofuran. After stirring for 3 hours at room temperature the reaction mixture was evaporated in vacuo. The residue was dissolved in a mixture of water and ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulphate, and evaporated to dryness. The crystals were rinsed by stirring with isopropanol (3 ml) to give yellow crystals of the title compound, m.p. 182-186°C. Yield 0.06 g.
EXAMPLE 10
3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-6-methoxy-5-morpholino-imidazo- [1 ,5-a] quinazoline (Compound 70)
A mixture of 6-methoxy-5-morpholino-imidazo[1 ,5-a]quinazoiine-3-carboxa- mide oxime (0.9 g), ethyl cyclopropylcarboxylate (1.7 g), molecular sieves (3 g), and 80% sodium hydride (0.1 g) in 20 ml of dry DMF was heated for Vh hours at 120°C. The mixture was cooled to room temperature, diluted with acetic acid (0.5 ml) and methylene chloride (20 ml) and filtered. The filtered mixture was evaporated and the residue was purified by column chroma¬ tography (HPLC) (eluent: methylene chloride:acetone (2:1)) to give yellow crystals of the title compound, m.p. 227-228°C. Yield 0.38 g.
In the same manner the following compound was prepared:
3-(5-(1 -Methylcyclopropyl)-1 ,2,4-oxadiazol-3-yl)-5-morpholino-imidazo[1 ,5-a]- quinazoline (Compound 71), m.p. 232-236°C, from 5-morρhoiino-imidazo- [1,5-a]quinazoline-3-carboxamide oxime and ethyl 1-methylcyclopropyl carboxylate.
.EXAMPLE 11
3-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-5-(1-oxo-thiomorpholino)-imidazo- [1 ,5-a]quinazoline (Compound 72) and
3-(3-Cyclopropyl-1 ,2,4-oxadiazol-5-yl)-5-(1 ,1 -dioxo-thiomorpholino)-imidazo- [1 ,5-a]quinazoline (Compound 73) A solution of 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-thiomorpholino-imi- dazo[1,5-a]quiπazoline (0.5 g) and 30% aqueous hydrogen peroxide (0.2 ml) in 15 ml of acetic acid was refluxed for 40 minutes. After cooling to room temperature the crude crystals of 3-(3-cyclopropyl-1 ,2,4-oxadiazol-5- yl)-5-(1,1-d.oxo-thiomorpholino)-imidazo[1,5-a]quinazoline were isolated by filtration. Recrystallization from DMF gave the analytically pure compound. M.p. 328-335°C. Yield 64 mg.
The filtered acetic acid was evaporated in vacuo. The residue was stirred with water (10 ml) and filtered to give crude crystals of 3-(3-cyclopropyl- 1 ,2,4-oxadiazol-5-yl)-5-(1 -oxo-thiomorpho!ino)-imidazo[1 ,5-a] quinazoline. Recrystallization from DMF gave the analytically pure compound. M.p. 293- 294°C. Yield 0.2 g.
EXAMPLE 12
7-Fluoro-3-(3-ϊsopropyl-1,2,4-oxadiazol-5-yl)-5-morpholino-imidazo[1,5-a]- quinazoline (Compound 74)
A mixture of ethyl 7-fluoro-5-morpholino-imidazo[1,5-a]quinazoline-3-car- boxylate (1.6 g), 2-methyl-1-propanecarboxamide oxime (2.4 g), crushed 4 A molecular sieves (3.5 g), and sodium hydride (0.14 g, 80% in mineral oil) in 20 ml of dry DMF was stirred at ambient temperature. After 1 hour an additional amount of the carboxamide oxime (2.4 g) and sodium hydride suspension (0.14 g) was added, and the mixture was stirred for one more hour. Glacial acetic acid (2 mi) and dichloromethane (50 ml) were added, and after the precipitated product had dissolved the sieves were removed by filtration through celite. The filtrate was evaporated and the residue was triturated with 100 ml of water. The undissolved material was collected by filtration, dried and treated with 25 ml of acetone. Yellow crystals precipi¬ tated and were filtered off and dried. Yield 0.47 g, m.p. 262-264°C.

Claims

t. Imidazoquinazoline compounds having the general formula I
Figure imgf000031_0001
and pharmaceutically acceptable acid addition salts or hydrates thereof, wherein Q is
Figure imgf000031_0002
-COOR8 or -CN;
wherein R1 is hydrogen, straight or branched C^-alkyl, unsubstituted or C^-alkyl substituted C3_7-cycloalkyl, C^-alkoxy, C^-alkoxy-C^-alkyl or tri- fluoromethyl; R8 is straight or branched C1-β-ai_ yl;
R2 and R3 independently are hydrogen, C1-€-alkyl, optionally substituted with C^-cycloalkyl, di-C^-alkylamino, phenyl or a piperidinyl group optionally substituted with C^-alkyl, or R2 and R3 independently are C^-cycloalkyl,
C^-hydroxyalkyl, C^-alkoxy, C^-alkoxy-C^-alkyl, C^-alkoxycarbonyl-C,^- alkyl, formyl-C^-alkyl or a cyclic or non-cyclic acetal thereof, or R2 and R3 together with the nitrogen atom form a 4-6 membered cyclic amino group in which ring system one or more of the carbon atoms may be exchanged with nitrogen, oxygen, sulphur, sulphinyl, sulphonyl or carbonyl or a hydrate, an acyclic or a cyclic acetal thereof, each of these ring systems optionally being substituted with one or more of C^-alkyl, C^-alkoxy- methyl, hydroxy, C^-hydroxyalkyl or phenyl;
R4, R5, R6 and R7 independently are hydrogen, hydroxy, Cl, Br, F, I, trifluoro- 5 methyl, nitro, amino, cyano, straight or branched C^-alkyl, C^-alkenyl, C2^- alkynyl, C^-alkoxy, C^-alkoxy-C^-alkyl or C^-alkoxycarbonyl;
provided that R4, R5, R8, R7 at the same time cannot all be hydrogen when
Figure imgf000032_0001
wherein R1' is H, C^-alkyl or unsubstituted C^-cycloalkyl; R2 and R3 independently are H, C^-alkoxy, C-3_7-cycloalkyl or C^-alkyl or NR2R3 forms an unsubstituted morpholino or thiomorpholino group; and the compound 5 of formula I is not ethyl 6-chIoro-5-morpholino-imidazo[1 ,5-a]quinazoline-3- carboxylate or 6-chloro-3-(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)-5-morpholiπo- imidazo[1 ,5-a] quinazoline.
2. Compounds according to claim 1 , wherein Q is 0
Figure imgf000032_0002
-COOR8 or CN, R1 is cyclopropyl, methylcyclopropyl, isopropyl, methoxy- 5 methyl or trifluoromethyl, R8 is ethyl, isopropyl or tert-butyl, and pharma¬ ceutically acceptable acid addition salts or hydrates thereof.
3. Compounds according to claims 1 - 2 wherein R2 and R3 independently are hydrogen, methyl, ethyl, hydroxyethyl, methoxyethyl, 2,2-dimethoxyethyl, 0 dimethyiaminoethyl, cyclopropylmethyl, ethoxycarbonylmethyl, N-methyl- piperidinyl or (1 ,3-dioxolan-2-yl)-methyl, or R2 and R3 together with the nitrogen atom form a morpholino, thiomorpholino, oxo- or dioxo-thiomor- pholino, pyrrolidinyl, piperidino, oxopiperidino or a hydrate, or an acyclic or a cyclic acetal thereof, a piperazinyl or thiazolidinyl group, each of these ring systems optionally being substituted with methyl, propyl, phenyl, hydroxy, hydroxymethyl, hydroxyethyl or methoxymethyl, and pharmaceutic¬ ally acceptable acid addition salts or hydrates thereof.
4. Compounds according to claims 1-3 wherein R4, R5, R6 and R7 inde¬ pendently are hydrogen, Cl, Br, F, OCH3, CN, trifluoromethyl or methyl, and pharmaceutically acceptable acid addition salts or hydrates thereof.
5. Compounds of claim 1 selected from:
3-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-7-fluoro-5-morpholino-imidazo[1,5- a] quinazoline,
3-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-5-morpholino-6-trifluoromethyl-imi- dazo[1 ,5-a] quinazoline,
3-(3-Cyclopropyl-1 ,2,4-oxadiazol-5-yl)-6-fluoro-5-morpholino-imidazo[1 ,5- a] quinazoline,
3-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-6-fluoro-5-(cis-2,6-dimethylmorpho- lino)-imidazo[1 ,5-a] quinazoline,
3-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-6-fluoro-5-thiomorpholino-imidazo[1,5- ajquinazoline,
3-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-6-fluoro-5-(4-methyl-1-piperazinyl)-imi- dazo[1 ,5-a] quinazoline, 3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(trans-2,5-dimethylmorpholino)-6- fluoro-imidazo[1,5-a]quinazoline,
3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(cis-2,5-dimethylmorpholino)-6- fiuoro-imidazo [1 ,5-a] quinazoline,
3-(3-Cyclopropyl-5-isoxazoiyl)-6-fluoro-5-morpholino-imidazo [1 ,5-a] quinazo¬ line,
3-(3-Cyclopropyl-1 ,2,4-oxadiazoi-5-yl)-5-(N-(1 , 3-dioxolan-2-yl) methyl-N- methylamino)-6-fluoro-imidazo [1 ,5-a] quinazoline,
3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(2f6-dimethyl-1-piperidinyl)-6-fluoro- imidazo[1 ,5-a]quinazoline.
6. A pharmaceutical composition comprising as active component a com¬ pound according to claims 1-5 or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent.
7. A pharmaceutical composition suitable for use in the treatment of a central nervous system ailment comprising an amount of a compound of claims 1-5 which is effective for the alleviation of such disorder together with a pharmaceutically acceptable carrier or diluent.
8j. A pharmaceutical composition according to claim 6 or 7 wherein it is in the form of an oral dosage unit containing 0.1-100 mg of the active com¬ pound.
9. Use of a compound according to claims 1-5 for producing a pharma- ceutical composition for the treatment of an indication related to a central nervous system ailment.
10. Use according to claim 9 wherein the indication is related to convulsion, anxiety or insomnia.
11. A method of treating a central nervous system ailment in a subject in need of such treatment comprising the step of administering to said subject an amount of a compound of claims 1-5 which is effective for the alleviation of such ailment.
12. A method of treating a central nervous system ailment in a subject in need of such treatment comprising the step of administering to said subject an amount of a compound of claims 1-5 which is effective for the alleviation of such ailment in the form of a pharmaceutical composition thereof, in which it is present together with a pharmaceutically acceptable carrier or diluent.
13. A method of preparing a compound according to claims 1-5, character¬ ized in
a) reacting a compound of formula II
Figure imgf000035_0001
wherein R2, R3, R4, R5, R6 and R7 are as defined above and wherein Y is a leaving group, with a compound having the formula III CN - CH2 - Q (III)
wherein Q is as defined above, to form a compound of the general formula I, or
b) reacting a reactive derivative of a compound having the general formula IV
Figure imgf000036_0001
wherein R2, R3, R4, R5, R8 and R7 are as defined above with a compound having the general formula V
R1-C(=N0H)NH2 (V)
wherein R1 is as defined above to form a compound of the general formula I wherein Q is
O-N
•R
wherein R1 is as defined above, or c) reacting a compound of the general formula VI
Figure imgf000037_0001
wherein R2, R3, R4, R5, R8 and R7 have the meanings set forth above, with a dehydrating agent to form a compound of formula I, wherein R2, R3, R4, R5, R8 and R7 have the meanings set forth above and wherein Q is cyano, or
d) reacting a compound of formula VII
Figure imgf000037_0002
wherein R2, R3, R4, R5, R8 and R7 have the meaning set forth above, with NH2OH to form a compound of formula VIII
Figure imgf000037_0003
wherein R2, R3, R4, R5, R8 and R7 have the meanings set forth above, and reacting the compound of formula VIII with R1-COOEt or with (R1CO)20, wherein R1 is as defined above to form a compound of the general formula I wherein Q is
N-0
Xl..X-,ι
wherein R1 is as defined above, or
e) hydrolysis of a compound of the general formula I to form a compound of the general formula IX
Figure imgf000038_0001
wherein Q, R4, R5, R6 and R7 have the meanings set forth above, and reacting the compound of formula IX with POCI3 to form a compound of formula X
Figure imgf000038_0002
which is reacted with a compound of formula XI
(XI) wherein R2 and R3 have the meanings set forth above, to form a compound of the general formula I.
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KR100864364B1 (en) 2005-12-13 2008-10-17 주식회사 엘지화학 Novel imidazoquinazoline derivative, process for preparing the same, and organic electronic device using the same
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CN1052724C (en) * 1996-07-01 2000-05-24 瑞安大药厂股份有限公司 Optical active 2, 3-dihydro-imidazole and [1, 2-c] quinazoline derivative, preparation method and use thereof
KR100864364B1 (en) 2005-12-13 2008-10-17 주식회사 엘지화학 Novel imidazoquinazoline derivative, process for preparing the same, and organic electronic device using the same
US8835426B2 (en) 2007-02-26 2014-09-16 Vitae Pharmaceuticals, Inc. Cyclic urea and carbamate inhibitors of 11β-hydroxysteroid dehydrogenase 1
US9079861B2 (en) 2007-11-07 2015-07-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8748444B2 (en) 2007-12-11 2014-06-10 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8846668B2 (en) 2008-07-25 2014-09-30 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8754076B2 (en) 2008-07-25 2014-06-17 Vitae Pharmaceuticals, Inc./Boehringer-Ingelheim Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8637505B2 (en) 2009-02-04 2014-01-28 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8680093B2 (en) 2009-04-30 2014-03-25 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8927539B2 (en) 2009-06-11 2015-01-06 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 based on the 1,3-oxazinan-2-one structure
US8883778B2 (en) 2009-07-01 2014-11-11 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11 beta-hydroxysteroid dehydrogenase 1
US8933072B2 (en) 2010-06-16 2015-01-13 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US9090605B2 (en) 2010-06-16 2015-07-28 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US8765744B2 (en) 2010-06-25 2014-07-01 Boehringer Ingelheim International Gmbh Azaspirohexanones
US8846613B2 (en) 2010-11-02 2014-09-30 Boehringer Ingelheim International Gmbh Pharmaceutical combinations for the treatment of metabolic disorders

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AU673814B2 (en) 1996-11-28
CA2125854A1 (en) 1993-07-08
JPH07502278A (en) 1995-03-09
ZA929770B (en) 1994-06-17
FI942963A0 (en) 1994-06-20
TW211568B (en) 1993-08-21
DK204291D0 (en) 1991-12-20
FI942963A (en) 1994-06-20
NO942301D0 (en) 1994-06-17
NZ246558A (en) 1995-07-26
IL104099A0 (en) 1993-05-13
EP0619820A1 (en) 1994-10-19
NO942301L (en) 1994-08-19
AU3344893A (en) 1993-07-28

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