WO1988002370A1 - 2-substituted-e-fused-[1,2,4]triazolo[1,5-c]pyrimidines pharmaceutical compositions and uses thereof - Google Patents

2-substituted-e-fused-[1,2,4]triazolo[1,5-c]pyrimidines pharmaceutical compositions and uses thereof Download PDF

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Publication number
WO1988002370A1
WO1988002370A1 PCT/EP1987/000547 EP8700547W WO8802370A1 WO 1988002370 A1 WO1988002370 A1 WO 1988002370A1 EP 8700547 W EP8700547 W EP 8700547W WO 8802370 A1 WO8802370 A1 WO 8802370A1
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compound
tautomer
ring
lower alkyl
triazolo
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PCT/EP1987/000547
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English (en)
French (fr)
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John E. Francis
Karl O. Gelotte
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Ciba-Geigy Ag
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Priority claimed from US07/020,055 external-priority patent/US4831013A/en
Application filed by Ciba-Geigy Ag filed Critical Ciba-Geigy Ag
Priority to JP62505839A priority Critical patent/JPH06104666B2/ja
Publication of WO1988002370A1 publication Critical patent/WO1988002370A1/en
Priority to FI882081A priority patent/FI86727C/fi
Priority to DK289888A priority patent/DK289888A/da

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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
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • 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
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms

Definitions

  • the invention relates to new e-fused-[1,2,4]triazolo[1,5-c]pyrimidines. More particularly, the inventive compounds have the formula
  • X is O, NR, or S;
  • R is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl;
  • R 1 is optionally substituted phenyl, pyridyl, thienyl, furyl, pyrrolyl, thiazolyl or ribofuranosyl; the R 1 optional substituents being lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl, hydroxy-lower alkyl, or amino; and ring A, inclusive of the two atoms it shares with the pyrimdine ring, is optionally substituted and selected from:
  • n and m are each independently one to three ; and C) a heterocyclic ring selected from 2,5-dihydropyrrole, pyrrole, furan, oxazole, thiophene, piperidine, pyridine, pyrazine, pyrimidine, pyrazole, and imidazole;
  • the ring A optional substituents being selected from lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl, nitro, araino, carbamoyl, carbamoyl-lower alkyl, carboxy-lower alkyl, lower alkoxy-carbonyl, lower alkoxy carbonyl-lower alkyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, aryl, aryl lower alkyl, aryl lower alkoxy, aryl sulfonyl and tetrazolylalkyl;
  • the aryl group as a separate group or as part of a larger group being (i) phenyl, hydroxy phenyl, lower alkyl phenyl, lower alkoxy phenyl or halophenyl; or (ii) pyridyl, thienyl, or furanyl, each of which is unsubstituted or further substituted by lower alkyl or halogen.
  • Triazolo[1,5-c]pyrimidines have been described in a number of references.
  • US Patents 3,045,015 and 3,053,844 disclose primarily bicyclic compounds having an unsubstituted amino group in the two-position of the triazolo pyrimidine ring.
  • some tricyclic rings are generically set forth such as those have a cyclohex-1- ene ring fused to the [e] face of the pyrimidine ring.
  • These compounds are claimed as bronchodilators, respiratory stimulants, and antiarthritic agents.
  • antibacterial, sedative, and hypotensive properties are disclosed.
  • Novinson concludes that the compounds in US Patent 3,045,015 are active because they inhibit CAMP phosphodiesterase.
  • Triazolopyrimidines having a phenyl ring fused at the [e] face, instead of the present invention ring A are mentioned in US Patents 4,463,007 and 4,053,600.
  • Analogous pyrazolo pyrimidines are mentioned in US Patents 4,112,096; 4,112,098; 4,128,644; and 4,164,578.
  • US Patent 4,585,772 discloses imidazopyrimidines or tetrahydropyrimidopyrimidines having a phenyl ring or a 6-membered heterocyclic having 5 carbons and nitrogen or 4 carbons and 2 nitrogens fused thereto.
  • US Patents 4,087,423 and 4,124,764 disclose pyrazolotriazolo[4,3-c]pyrimidines.
  • US Patents 4,479,955; 4,560,689; and 4,602,014 relate to pyrazolo pyridines having a partially saturated carbocyclic or heterocyclic ring fused to the pyridine ring.
  • the new, useful compounds of the invention affect benzodiazepine receptors, and, particularly when X is NR, affect adenosine receptors.
  • Those compounds wherein X is S are primarily intermediates in the production of the compounds when X is oxygen or NR.
  • BR benzodiazepine receptor
  • CNS depressants find utility as anxiolytics, CNS depressants, and anticonvulsants.
  • BR inverse agonists (previously included with antagonists) elicit a response from the receptor, but opposite that which would result from an agonist, and as such find utility as anorectics, CNS stimulating agents, agents to increase cognitive ability, and to counteract the effects of benzodiazepines.
  • True benzodiazepine antagonists merely block the receptor from benzodiazepines without eliciting a response therefrom. They are primarily useful in countering the effects of benzodiazepine.
  • the BR agonists elicit less of a response than benzodiazepines, they can also be used to counteract the effects of a benzodiazepine; however, due to the eliciting of an agonistic response from the receptor, it will necessarily be less efficacious than a similarly bound antagonist.
  • Adenosine agonists are primarily useful as antihypertensives.
  • Adenosine antagonists find their primary utility as anti-asthmatic agents and in the treatment of bradyarrhythmias associated with clinical conditions such as myocardiac infarction and sleep apnea.
  • the compounds of the invention are of the formula
  • X is oxygen, NR, or S; R being hydrogen, lower alkyl, lower alkenyl, or lower alkynyl;
  • R 1 is a) phenyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen, or trifluoromethyl; b) furyl, thienyl, pyridyl, pyrrolyl, or thiazolyl, each of which is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, hydroxy-lower alkyl, halogen, or amino; or c) ⁇ -D-ribofuranosyl; ring A is a) a 5-8 membered cycloalkene; b) a bridged ring of the formula
  • n and m are each independently one or two or three; or c) a heterocycle selected from 2,5-dihydropyrrole, pyrrole, furan, oxazole, thiophene, piperidine, pyridine, pyrazine, pyrimidine, pyrazole, and imidazole;
  • each ring A being unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, trifluoromethyl, nitro. amino, carbamoyl, carbamoyl lower alkyl, carboxy lower alkyl, lower alkoxy carbonyl, lower alkoxy carbonyl-lower alkyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, aryl, aryl-lower alkyl, aryl carbonyl, aryl lower alkoxy, or aryl sulfonyl; wherein aryl portion of the ring A substituent is selected from a) phenyl, hydroxyphenyl, lower alkyl phenyl, lower alkoxyphenyl, and halophenyl; and b) pyridyl, thienyl, and furyl, each of which is unsubstituted or substituted by lower alkyl or halogen
  • “Lower alkyl” means C 1 -C 7 , preferably C 1 -C 5 , more preferably C 1 -C 4 , alkyl.
  • “Lower alkenyl” means C 2 -C 7 , preferably C 2 -C 5 , more preferably C 2 -C 4 alkenyl.
  • “Lower alkynyl” means C 2 -C 7 , preferably C 2 -C 5 , more preferably C 2 -C 4 alkynyl.
  • “Lower alkoxy” means C 1 -C 7 , preferably C 2 -C 5 , more preferably C 2 -C 4 alkoxy.
  • Halogen and halo means fluorine, chlorine, and bromine. Unless apparent otherwise, reference made to “compounds” will also include the tautomers thereof. For purposes of consistency, when referring to the triazolopyrimidine bicyclic structure, the numbering system shown in structure la above will be used. Preferred compounds for affecting the BR are those in which X is oxygen. For affecting the adenosine receptor (AR), the compounds wherein X is NR, more preferably NH or N-lower alkyl, are preferred.
  • R 1 is preferably a) phenyl which is unsubstituted or substituted by one to three, preferably one, groups selected from lower alkyl (preferably methyl or ethyl), lower alkoxy (preferably methoxy or ethoxy), halogen (preferably fluorine or chlorine), hydroxy, and trifluoromethyl; or b) furyl, pyridyl, pyrrolyl, or thiazolyl, more preferably furyl, pyridyl, or pyrrolyl, most preferably furyl or pyrrolyl, each of which is unsubstituted or mono or di-substituted (preferably ur.substituted or mono substituted) by lower alkyl (preferably methyl or ethyl), by lower alkoxy (preferably methoxy or ethoxy), by hydroxy, by hydroxy-lower alkyl (preferably hydroxy methoxy or hydroxy ethoxy), halogen (preferably fluorine or chlorine), or amino;
  • R 1 groups phenyl, furyl, pyrrolyl and pyridyl, either unsubstituted or substituted by fluorine or chlorine are more preferred.
  • R 1 phenyl groups are most advantageously ortho or meta, preferably ortho, substituted by fluorine or chlorine, preferably fluorine.
  • Ring A is cyclopentene, cyclohexene, cycloheptene cyclooctene; a ring of the formula
  • n and m are each independently one, two or three; or a heterocycle selected from 2,5-dihydropyrrole, pyrrole, furan, oxazole, thiophene, piperideine, pyridine, pyrazine, pyrimidine, pyrazole, and imidazole, each ring A being optionally substituted.
  • n is one where n is three, or m and n are both two.
  • the heterocyclic ring A is 2 ,5-dihydropyrrole, piperideine or pyridine.
  • the piperideine ring is ⁇ 1 , ⁇ 2 , ⁇ 3 , or ⁇ 4 piperideine, preferably ⁇ 3 piperideine.
  • the pyridine ring is preferably fused at the [c] or [d] side thereof to the pyrimidine ring in formula la.
  • the piperideine ring is preferably unsubstituted or substituted as below, preferably N-substituted.
  • the ring A substituents are lower alkyl (preferably methyl or ethyl), lower alkoxy (preferably methoxy or ethoxy), hydroxy, trifluoromethyl, nitro, amino, carbamoyl, carbamoyl-lower alkyl (preferably carbamoyl methyl or carbamoyl ethyl), carboxy lower alkyl (preferably carboxy methyl or carboxy ethyl), lower alkoxy carbonyl (preferably methoxy- or ethoxy-carbonyl), lower alkoxy-carbonyl lower alkyl (preferably methoxy-or ethoxy-carbonyl methyl or ethyl), lower alkylthio (preferably methylthio or ethylthio), lower alkylsulfinyl (preferably methyl or ethyl sulfinyl), lower alkyl sulfonyl (preferably methyl or ethyl sulfonyl), aryl, ary
  • ring A substituent is selected from lower alkoxy carbonyl lower alkyl, carbamoyl lower alkyl, carboxy lower alkyl, carbamoyl, aryl, aryl lower alkyl, aryl lower alkoxy, and aryl sulfonyl (preferences within each group and the definition of aryl being a in the preceding paragraph).
  • substituents of ring A are aryl lower alkyl (most preferably 2-picolyl, 4-picolyl, benzyl, 1-phenethyl), methoxy carbonyl methyl, carbamoyl methyl, phenyl sulfonyl, carbamoyl, and carboxy methyl.
  • phenyl is preferably unsubstituted or substituted by hydroxy (preferably 2- or 4-hydroxy) or by lower alkoxy (preferably 2- or 4-methoxy or ethoxy), while pyridyl, thienyl or furyl are preferably unsubstituted.
  • Especially preferred compounds of formula la are :
  • the invention also relates to compounds of formula la wherein X is oxygen, NR, or S, with R being hydrogen or lower alkyl; R 1 being phenyl which is unsubstituted or substituted by one to three groups selected from lower alkyl, lower alkoxy, hydroxy, halogen, and trifluoromethyl; or furyl, thienyl, pyridyl, pyrrolyl, or thiazolyl, each optionally substituted by hydroxy, lower alkyl or halogen; and ring A is unsubstituted or substituted by one to three substituents selected from lower alkyl, lower alkoxy, aryl lower alkoxy, hydroxy, halogen, and trifluoromethyl, the "aryl" group being selected from unsubstituted or lower alkyl or halogen substituted phenyl , pyridyl , thienyl , and furyl and further selected from hydroxy phenyl and lower alkoxy phenyl
  • Another preferred grouping are the compounds wherein X is oxygen and R 1 is optionally substituted phenyl, especially o- or m-halophenyl.
  • An additional preferred class of compounds are those wherein R 1 is other than optionally substituted phenyl and X is NR; more preferably when R 1 is 2-furyl and X is NH.
  • Especially preferred compounds are those mentioned in the Examples.
  • Some of the compounds of the present invention can form acid addition salts, preferably pharmaceutically acceptable salts. Salts which are not pharmaceutically acceptable are suitable as intermediates for the preparation of the pharmaceutically acceptable salts or in the process of converting one compound of formula la into another of formula la.
  • the acid addition salts are inorganic, exemplified by halide salts (such as chlorides), and sulfates, or organic which are typically exemplified by sulfonated or carboxylated lower alkyl or aryl groups.
  • Some suitable organic salts include acetate, raethanesulfonate, toluenesulfonate, fumarate, cinnamate, and benzoate.
  • the compounds of formula la wherein X is oxygen affect primarily the BR, while those wherein X is NR primarily influence the adenosine receptor.
  • the imino compounds (X is NR) are adenosine antagonists and consequently are primarily useful as antiasthmatic agents and central nervous system stimulating agents (they enhance cognitive ability).
  • the compounds of the invention, especially those wherein X is oxygen are useful in the treatment of nervous system disorders such as anxiety, convulsive conditions (i.e. epilepsy) and other disorders responsive to BR agonists or mixed agonist/antagonists.
  • the above effects are demonstrable in in vitro and in vivo tests using mammals, e.g. mice, rats, or monkeys, as test objects.
  • the compounds can be administered enterally or parenterally, advantageously orally, subcutaneously, intravenously, or intraperitoneally in these tests, for example, in gelatin capsules or as aqueous solutions or suspensions.
  • the dosage range for these tests is between about 0.1 and about 100 mg/kg/day, preferably between about 0.5 and about 50 mg/kg/day, advantageously between about 1 and 25 mg/kg/day.
  • the applied dose range is between about 10 -5 and about 10 -10 M concentration, preferably between about 10 -7 and about 10 -9 M.
  • the compounds are administered orally, intraperitoneally, or by inhalation in doses in the range of 0.01 mg/kg to 500 mg/kg, preferably 0.1 mg/kg to 100 mg/kg, and most preferably about 10 mg/kg to about 30 mg/kg, body weight.
  • the benzodiazepine receptor binding properties indicative of the nervous system regulatory activity of said new compounds are determined in the receptor binding assay in vitro, e.g. similarly to that in Nature 266, 732 (1977) or Proc. Nat. Acad. Sci. USA 74, 3805 (1977).
  • tritiated flunitrazepam When tritiated flunitrazepam is used, the interaction of other drugs with said receptor can be readily assessed thus: Synaptosomal membranes from rat fore-brain are incubated at 0-5° for 30 minutes with 0.5 nM tritiated flunitrazepam and various concentrations of the test substance in a buffer medium maintained at pH 7.5.
  • Solutions of the various concentrations of test substance are prepared by dilution of a 4.2 mM stock solution in dimethylacetamide-ethanol (1:10) with 50 mM pH 7.5 Tris-HCl buffer.
  • the membranes, containing the receptors with various amounts of tritiated flunitrazepam, are filtered onto glass fiber filters, which are then analyzed in a liquid scintillation counter.
  • the concentration of the compounds of this invention, required to inhibit the specific binding of 0.5 nM of tritiated flunitrazepam by 50%, i.e. the IC 50 is determined graphically.
  • Test compounds in a corn starch vehicle are administered orally or intraperitoneally to mice or rats.
  • 3 H-flunitrazepam (2 nmoles/Kg in saline) is injected into the tail vein, and the animals are sacrificed 20 minutes after injection of the flunitrazepam. The brains are then assayed by determining radioactivity in a liquid scintillation counter for binding of the radioligand to the receptors. A decrease in the binding of 3 H-flunitrazepam in the drug-treated animals (as compared with the binding observed in animals treated with vehicle alone) is indicative of benzodiazepine receptor binding by the test compound.
  • Anxiolytic effects are observed, for example, according to the Cook-Davidson conflict procedure, using male Wistar rats which are maintained at 80% of normal body weight by dietary-, but not water-restriction. They are trained to press a lever within a conditioning chamber, also containing a liquid dipper, a house light, a speaker and a grid-floor. The grids are connected to an electrical shock source and the chamber is situated in a sound-attenuated room in which a white noise-source is activated during testing, in order to mask any extraneous auditory cues. Each session of 47 minutes duration consists of two alternating schedules.
  • the first is a Variable Interval (VI) schedule of 30 seconds, lasting for 5 minutes, during which a sweetened, condensed milk reinforcement is delivered following the first lever-press after an average of 30 seconds have elapsed, and a drug-induced decrement of this performance is taken as an indication of a neurological deficit.
  • Vl-schedule both a 1000 Hz tone and a light-cue are activated, indicating the commencement of the second Fixed Ratio (FR) schedule, lasting for 2 minutes, wherein the milk reinforcement is delivered concomitant with an electric foot shock immediately following the tenth response, thereby establishing a conflict situation.
  • FR Fixed Ratio
  • the intensity of said shock ranges between 1.0-2.5 mA, varying with each animal, in order to adjust them to about 25-100 responses during this schedule over the entire session.
  • a drug-induced enhancement of performance during the FR-schedule is taken as indication of antianxiety effects. This increased performance is measured by the increased number of electric foot shocks taken during six FR sessions lasting 2 minutes each. Anticonvulsant effects are observed, for example in the standard Metrazole (pentylenetetrazole) and maximal electroshock tests for assessing anticonvulsant activity, e.g. orally in the rat.
  • Male Wister rats (130-175 g) are fasted for 18 hours but allowed water as desired prior to testing.
  • the test compound is administered in a cornstarch vehicle by oral intubation in a volume of 10 ml/Kg of body weight.
  • One hour after administration of the test compound the animals are administered intravenously (caudal vein) a dose of 24 mg/Kg of Metrazole in water in a volume of 2.5 ml/Kg of body weight.
  • the rats are immediately placed in plexiglass cylinders and observed for clqnic seizures of at least 5 seconds duration during the next 60 seconds.
  • the ED 50 is the dose at which half the animals are protected from Metrazole induced clonic seizures during the observation periods.
  • Compounds which are preferred benzodiazepine agonists include, among others, those of formula la wherein X is oxygen, R 1 is 2-furanyl or optionally substituted phenyl and A completes a heptene ring or an optionally substituted, preferably N-benzyl substituted, 1,2,5,6-tetrahydro pyridine ring.
  • Specific benzodiazepine agonists include the compounds of Examples 8, 10, 11, 12, and 25.
  • a preferred mixed benzodiazepine agonist/antagonist of the invention is, inter alia, 2(2-fluorophenyl)- 7,8,9,10-tetrahydro-[1,2,4] triazolo [1,5-c] quinazoline-5- (6-H) one, set forth in Example 2.
  • the compounds of the invention act as adenosine antagonists.
  • Adenosine antagonism is assessed by determination of inhibition of adenosine activation of adenylate cyclase in vesicular preparations from guinea pig brains essentially as described in J. Neurochem. 22, 1031 (1974) and J. Neurochem. 38, 1437 (1982).
  • adenosine antagonists of the invention are 5-amino-2-(2-furyl)-7,8,9,10-tetrahydro- (1,2,4]triazolo[1,5-c]quinazoline methanesulfonate and 5,6-dihydro-2-(2-fufyl)-5-iminopyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine methanesulfonate.
  • the compounds of formula la are formulated into pharmaceutical compositions comprising an effective amount of the triazolopyrimidine compounds of formula la or a pharmaceutically acceptable salt thereof in combination with conventional excipients or carriers suitable for either enteral or parenteral, such as oral, bronchial, rectal or intravenous, administration.
  • conventional excipients or carriers suitable for either enteral or parenteral, such as oral, bronchial, rectal or intravenous, administration.
  • binders e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired, d) disintegrants, e.g. starches, agar, alginic acid or its sodium salt, or effervescent mixtures and/or, e) absorbents, colorants, flavors and sweeteners.
  • Dragee or tablet cores may be provided with suitable coatings, which may be resistant to gastric juices.
  • Coating solutions are, for example, concentrated aqueous sugar solutions, which may contain gum arabic, polyvinylpyrrolidone, polyethylene glycol, talcum and/or titanium dioxide. Resistant coatings are obtained with lacquer solutions in organic solvents, such as shellac, acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate in ethanol and the like. Dyestuffs or pigments may be added for identification of brand name and dose.
  • Capsules are either made from hard gelatin, or they are soft, closed capsules made from gelatin and a softener, e.g., glycerin or sorbitol. The hard capsules contain either uncompressed powder mixtures, e.g.
  • said active ingredients are preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffins or polyethylene glycols.
  • suitable liquids such as fatty oils, paraffins or polyethylene glycols.
  • Suppositories are advantageously solid, fatty emulsions or suspensions, containing the active ingredient, for example, in natural or synthetic triglycerides, paraffins, waxes and/or polyethylene glycols.
  • compositions for parenteral administration are preferably aqueous solutions or suspensions of said active substances, but also oily solutions or suspensions of said active substances, but also oily solutions or suspensions thereof, e.g., in natural or synthetic fatty oils, such as sesame oil or ethyl oleate, in suitable ampules.
  • Bronchial compositions are preferably aerosol sprays and may be administered from a dispenser such as is described in U.S. Patents 4,292,966, 4,174,712, and 4,137,914.
  • the active ingredient is mixed with a propellant such as a hydrocarbon, chlorofluorocarbon mixture, or carbon dioxide.
  • compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. They may also contain other therapeutically valuable substances, and are prepared according to conventional mixing, granulating or coating methods respectively. They may contain from about 10 to 95%, preferably from about 20 to 70% of the active ingredient. Individual unit dosages thereof for a mammal of about 50-70 Kg weight may contain preferably between about 10 and 200 mg., advantageously about 20 to 100 mg of said active ingredients.
  • adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. They may also contain other therapeutically valuable substances, and are prepared according to conventional mixing, granulating or coating methods respectively. They may contain from about 10 to 95%, preferably from about 20 to 70% of the active ingredient. Individual unit dosages thereof for a ma
  • Benzodiazepine antagonism is measured by the antagonism of the diazepam-induced rotorod deficit in the rat. Diazepam (30 mg/kg/ip) and test compound are administered 30 minutes and 1 hour, respectively, before the test.
  • seizures are induced by applying 150 mA of electric current for 0.2 seconds through corneal electrodes two hours after oral administration of test compound.
  • the ED 50 is the dose at which half the animals are protected from electroshock induced seizures during a 5 second observation period.
  • the pharmacological benzodiazepine agonist and/or antagonist profile of the compounds of the invention can also be determined by measuring their effect in a rat brain membrane preparation on the displacement of 3H-flunitrazepam in the presence or absence of gamma-aminobutyric acid (GABA), or on the enhancement of 3 H-muscimol binding by etazolate, or on the binding by etazolate, or on the binding of 35 S-butyl bicyclophosphorothionate (TBPS).
  • GABA gamma-aminobutyric acid
  • the compounds of the present invention can be prepared by methods known in the art. In addition, they can be prepared by the following methods.
  • the compounds of formula la wherein X is oxygen can be prepared by a) reacting a compound of the formula
  • a reactive derivative of carbonic acid which includes esters , amides , and anhydrides of carbonic acid . Included here are phosgene, diethylcarbonate , ethylcarbamate and trichloromethyl chloro formate .
  • the compounds of formula III can be prepared by treating a reactive intermediate of an alpha, beta-cyclicbeta-amino acrylic acid , such as tetrahydro isatoic anhydride, with a compound of the formula
  • alpha,beta-cyclic-beta-amino acrylic acid intermediates may also be of the formula
  • Compounds of formula III can also be obtained by hydrolyzing the compounds of formula la by treatment thereof with alkali metal hydroxide.
  • the compounds of formula III can further be prepared by selective ring closure in a compound of the formula
  • W 1 and W 2 are oxygen and the other is NH or wherein W 1 and W 2 are both NH.
  • W 1 and W 2 are as defined in process (a) , by treatment thereof with a base , preferably a tertiary amine such as triethylamine or piperidine .
  • a base preferably a tertiary amine such as triethylamine or piperidine .
  • the compound of formula IX is prepared by selective ring closure of a compound of formula VIII (defined above) .
  • Z is isocyanato, -N -lower alkyl, or -N N(lower alkyl) 2 with a hydrazide of the formula
  • B is halo or alkoxy
  • oxo oxygen
  • process c and d Where isocyanates are indicated for the oxo compound synthesis isothiocyates will yield the corresponding thiono compounds.
  • Compounds of formula la wherein X is NR can be prepared by i) reacting a compound of formula III, as defined in process (a) above, with cyanogen halide followed by cyclization or reacting a compound of formula III with cyanamide or a reactive imino carbonyl derivative.
  • W 1 and W 2 are oxygen and the other NH, or W 1 and W 2 are both NH, instead of the compound of formula IX, preferably by treatment thereof with ammonia.
  • the compound of formula XIV is prepared by selectively cyclizing a compound of the formula
  • the compounds of formula XV are prepared from those of formula XVI.
  • the reaction of compounds of formula XVI to compounds of Formula XIV requires the presence of a reactive imino carbonic acid derivative, a cyanogen halide or cyanamide.
  • the compounds of formula XVII are prepared from the reaction of a compound of the formula
  • the compounds of formula XIX are obtained by reacting the corresponding thiono compounds with cyanogen halide in the presence of base. o ) reacting a compound of the formula
  • a compound of formula VIII is converted to a compound of formula III by reaction thereof with a base, preferably a tertiary amine or ammonia.
  • a compound of formula VIII is converted to a compound of formula IX by reaction thereof with a reactive derivative of carbonic acid as that term is defined in process a.
  • a reactive derivative of carbonic acid as that term is defined in process a.
  • Use of the corresponding reactive derivative of thiocarbonic acid will yield the corresponding thiono compound and use of the corresponding reactive derivative of imino carbonic acid (which includes cyanamide) will result in the corresponding imino compound of formula XIV.
  • the reactive derivative of carbonic acid and the base are preferably those in variants a and b.
  • the reaction takes place preferably in a solvent, such as an ether solvent, for example dioxane, or an alcohol solvent, for example 2-methoxyethanol, or a liquid amide such as dimethylacetamide.
  • a solvent such as an ether solvent, for example dioxane, or an alcohol solvent, for example 2-methoxyethanol, or a liquid amide such as dimethylacetamide.
  • the reaction is conducted in the presence of a base such as a tertiary amine, for example N-methylmorpholine, triethylamine, and, especially, tripropylamine.
  • a base such as a tertiary amine, for example N-methylmorpholine, triethylamine, and, especially, tripropylamine.
  • Lower alkyl is preferably methyl or ethyl.
  • the preferred solvents when Z represents isocyanato are ether solvents, especially dioxane.
  • a preferred solvent in either case is a liquid amide, such as dimethyl acetamide.
  • the reaction is preferably conducted at temperatures of 0 to 250 °C, preferably 20 to 150°C.
  • A is a bridged group of formula II
  • A is a bridged group of formula II
  • a typical reaction scheme is
  • the oxidizing agent may be , or example , lead tetraacetate or a hypohalite .
  • the hypohalite is preferably an alkali metal hypohalite such as sodium hypochlorite or sodium hypobromite.
  • the amide function is believed to undergo the first stage of the Hofmann reaction (Ber. 14, 2725 (1881), forming the isocyanate which then reacts with the free NH of the triazole.
  • a 5-halo, lower alkoxy or aryl lower alkoxy substituted e-fused [1,2,4]triazolo[1,5-c]-pyrimidine is hydrolyzed.
  • the hydrolysis is preferably carried out with aqueous alkali.
  • the 5-halo compounds may be prepared be reacting a compound of formula la wherein X represents 0 with a reactive halide such as phosphoryl chloride or phosphorous pentachloride, most preferably phenylphosphonic dichloride, with or without an inert solvent.
  • a reactive halide such as phosphoryl chloride or phosphorous pentachloride, most preferably phenylphosphonic dichloride, with or without an inert solvent.
  • the 5-lower alkoxy or 5-aryl-alkoxy compounds may be prepared from the 5-halo compounds by treatment with the appropriate alcohol in the presence of a base, preferably a tertiaryamine.
  • hypohalite salt is preferably the same as that in process variant e.
  • the cyanogen halide is preferably cyanogen chloride or cyanogen bromide, more preferably cyanogen bromide.
  • the hydrohalide formed in the reaction may be neutralized with base, suitably triethylamine, pyridine, sodium hydride.
  • the cyclization step is catalyzed by mineral acids or by bases, such as hydrohalides or trialkylamines, respectively.
  • process variant j procedures analogous to those in variant a are used.
  • the related o-cyanimidobenzonitriles, which replace instant ring A with a benzene ring are described by Wentrup in Tetrahedron, 27., 367 (1971) and by Bedford in J. Chem. Soc. 1633 (1959).
  • the compound of formula Xa can also be converted directly into a compound of formula la by the described reaction, structure XVII being an intermediate therein, as in process variant f.
  • the reaction is carried out in an aprotic solvent, preferably at or near room temperature.
  • the compounds of Formula XIX can be prepared from the corresponding thiono compounds of Formula la by treatment thereof with cyanogen halide, preferably cyanogen bromide, in the presence of base, such as sodium hydride.
  • the starting material is prepared in the following way:
  • the ethyl carbamate is prepared in the following way:
  • the methanesulphonate salt of 2-(2-methylaminophenyl)-7,8,9,10-tetrahydro-[1,2,4]triazolo[1,5- c]quinazolin-5(6H)one crystallizes, m.p. 257-260°, in 36% yield.
  • the above ethyl carbamate derivative is prepared by the method described in Example 2 from N-benzyl-3-cyano-4-amino- ⁇ 3 -piperideine (Taylor et al. Tetrahedron 23, 855-890 (1967)) and is obtained as an oil in 94% yield.
  • the bis-urethane starting material is prepared in the following way: To a solution of sodium ethoxide in ethanol, prepared from 40.2 g of sodium dissolved in 500 ml of absolute ehtanol, is added 3-cyano-4-amino- ⁇ 3 -piperidiene (26.9 g, prepared as described by Bachmann and Barker, J. Amer. Chem. Soc. 69, 1535 1-1947)) and the whole refluxed 1 hour under nitrogen. Diethyl carbonate (205 ml) is added and the whole stirred at reflux for 2 hours under nitrogen, cooled to room temperature and glacial acetic acid (20 ml) followed by water (1.31) is added cautiously.
  • the salt is suspended in 2-methoxyethanol, filtered and converted back to the free base in dilute ammonium hydroxide, in 42% yield.
  • the pure 9-benzyl-2-(4-fluorophenyl)-7,8,9,10-tetrahydropyrido- [3,4-e] [1,2,4]triazolo[1,5-c]pyrimidin-5(6H)one melts in the range 252 to 256°.
  • the solid is taken up in methanol, treated with an equimolar quantity of methanesulphonic acid and the resulting salt collected and dried in vacuo to afford pure 2-(2-fluorophenyl)-9-methyl-7,8,9,10-tetrahydropyrido- [3,4-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)one methanesulphorate, m.p. 285-287° in 41% yield.
  • the starting carbamate is prepared by the method described in Example 2 from N-methyl-3-cyano-4-amino- ⁇ 3 - piperideine, prepared as described by Cologne et al. Bull, Soc. Chim. France, 1963, 2264-2270, in 86% yield.
  • the ethyl carbamate is prepared by the method described in Example 2 from N-ethyl-3-cyano-4-amino- ⁇ 3 - piperideine, prepared as described by Cologne et al, Bull. Soc. Chim. France, 1963, 2264-2270, in 81% yield.
  • the ethyl carbamate used as starting material is prepared from N-isopropyl-3-cyano-4-amino- ⁇ 3 -piperideine as described in Example 2.
  • This amino compound is prepared from N-isopropyl bis( ⁇ -cyanoethyl)amine as described by Cologne et al. Bull. Soc. Chim. France, 1963, 2264-2270.
  • the amine is prepared by reaction of isopropylamine in water with two moles of acrylonitrile at ambient temperature over 4 days in almost quantitative yield. The material is extracted with ether, the ether solution dried over magnesium sulphate and concentrated to a heavy oil. All intermediates are oils and require no further purification.
  • the ethyl carbamate starting material was prepared in the same manner as the ethyl carbamate in Example 22, except that
  • the ethyl carbamate intermediate is prepared from 3-amino-1-benzyl-4-cyano-2-methyl- ⁇ 3 -pyrroline (Cavalla, J. Chem. Soc. 1962, 4664) as described in Example 2.
  • Example 25 3-amino-1-benzyl-4-cyano-2-methyl- ⁇ 3 -pyrroline (Cavalla, J. Chem. Soc. 1962, 4664) as described in Example 2.
  • the starting ethyl carbamate is prepared from 1-amino-2-cyanocyclohept-1-ene (Krtiger, J. Organometal. Chem. 9, 125 (1967)) as described in Example 2.
  • the starting ethyl carbamate is prepared in the following way: To a heterogeneous mixture of 4-amino-3-cyano ⁇ pyridine (1.2 g), sodium bicarbonate (1.9 g) and methyl ethyl ketone (30 ml) is added under nitrogen and stirring ethyl chloroformate (1.9 ml). It is refluxed under nitrogen for 20 hours, filtered free of inorganic solid and the filtrate concentrated at reduced pressure. The residual solid is recrystallized from chlorobenzene-cyclohexane to give the desired carbamate, melting in the range 108-120°. This is suitable for the next step.
  • the combined material is recrystallized from 2-methoxyethanol and dried 20 hours at 100°/0.01 mm to afford 2-(2- fluorophenyl)-8,9,10,11-tetrahydro[1]benzothieno[3,2-e]- [1,2,4]triazolo[1,5-c]pyrimidin-1(6H)one, which decomposes above 316°.
  • the yield is 50%.
  • the starting carbamate is prepared in the following way:
  • the starting methyl carbamate is obtained from the aminonitrile (prepared by the method of Gewald et al, loc. cit.) as described in Example 27, m.p. 155-157° after recrystallization.
  • the pure 5-amino-2(2-furyl)-7,8,9,10-tetrahydro[1,2,4]triazolo-[1,5-c]quinazoline methanesulphonate melts in the range 269 to 271°. It is obtained in 38% yield.
  • the starting chloro compound is prepared as follows:
  • the starting triazole is prepared in the following manner: To a suspension of sodium ethoxide, prepared from sodium (460 mg), in dry ethanol (20 ml) is added 2-furylcarboxamidine hydrochloride (2.9 g) in ethanol (20 ml) under nitrogen and after 5 min. stirring it is filtered and the filtrate added to a mixture of 2-aminopyrazine3-carbohydrazide (3.1 g), ethanol (10 ml) and chlorobenzene (40 ml). It is heated under nitrogen in an apparatus with a solvent separator at 120° until no more solvent distills, then heated 18 hours at reflux. The mixture is cooled, filtered and the solid washed with methanol (3X30 ml) and recrystallized from 2-methoxyethanol to afford the pure triazole m.p. 247-250°.
  • the starting hydrazide is prepared by reaction of methyl-2-aminopyrazine-3-carboxylate with hydrazine hydrate at 80° for 1 hours.
  • the methyl ester is prepared by reaction of 2-aminopyrazine-3-carboxylic acid with methanol containing concentrated sulphuric acid over 3 days, m.p. 167-170°.
  • the starting material is prepared in the following way: 9.6 g tert-butyl carbamate of 2-aminopyridine is treated dropwise under nitrogen in 980 ml ether at -78° with tert-butyl lithium in pentane (1.55 molar, 70.19 ml). It is stirred at room temperature for 2 hours, recoo ⁇ ed to -78° and a solution of 9.84g p-toluenesulphonyl cyanide in 98 ml ether added dropwise under nitrogen. The mixture is stirred at room temperature over 18 hours, treated with 400 ml brine and extracted with ether. The ether extract is dried over magnesium sulphate, concentrated to dryness at reduced pressure and the residual solid is recrystallized from 1:1 ether-petroleum-ether to afford the desired carbamate ester.
  • the tert-butyl carbamate of 2-aminopyridine is prepared by reaction of equimolar quantities of 2-aminopyridine and di- tert-butyl carbonate at reflux for 2 hours and at ambient temperature for 18 hours. The mixture is filtered to remove white solid and the filtrate evaporated to dryness at reduced pressure, taken up in hot ethanol, diluted with water and cooled whereupon the carbamate crystallizes at 93-94°.
  • the triazole starting material is prepared in the following way:
  • the tert-butylcarbamate of 3-amino-4-cyanopyridine, mp. 100-103° is obtained from the tert-butyl carbamate of 3-aminopyridine , mp . 105-109 ° , as described in Example 37.
  • the tert-butyl carbamate of 4-amino-3-cyanopyridine is prepared from the carbamate of 4-aminopyridine (Fishwick et al, J.C.S. Chem. Comm. 1984, 1304) in 42% yield as described in Example 37.
  • the starting material is obtained in 66% yield from the compound of Example 40 as described in Example 38.
  • Example 15 By a method similar to that described in Example 43 , the product from Example 15 is reacted with benzene sulphonyl chloride to give 2-( 2-fluorophenyl ) -9-phenylsulphonyl- 7 , 8 , 9 , 10-tetrahydropyrido [3 , 4-e ] [1 , 2 , 4] triazolo [1 , 5-c] -pyrimidin-5 ( 6H)one .

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PCT/EP1987/000547 1986-09-30 1987-09-25 2-substituted-e-fused-[1,2,4]triazolo[1,5-c]pyrimidines pharmaceutical compositions and uses thereof WO1988002370A1 (en)

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US5173492A (en) * 1989-09-14 1992-12-22 Kyowa Hakko Kogyo Co., Ltd. s-Triazolo(3,4-I)purine derivatives
WO2014101113A1 (en) * 2012-12-28 2014-07-03 Merck Sharp & Dohme Corp. Piperazine-substituted 7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine compounds with a2a antagonist properties
WO2022029063A1 (en) 2020-08-04 2022-02-10 Bayer Aktiengesellschaft Pyrido[1,2,4]triazolo[1,5-c]pyrimidin-5-amines
US12351583B2 (en) 2019-04-03 2025-07-08 Chemiteras, Inc. Triazolopyrimidines based on thymine nucleobase and methods for producing them

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US5095015A (en) * 1990-07-24 1992-03-10 Neurogen Corporation Certain azacycloalkyl imidazopyrimidines; a new class of gaba brain receptor ligands
US5185446A (en) * 1990-09-04 1993-02-09 Neurogen Corporation Certain cycloalkyl imidazopyrimidines; a new class of gaba brainreceptor ligands
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IT1264901B1 (it) * 1993-06-29 1996-10-17 Schering Plough S P A Analoghi eterociclici di 1,2,4-triazolo(15-c)pirimidine ad attivita' antagonista per il recettore a2 dell'adenosina
WO1995003806A1 (fr) * 1993-07-27 1995-02-09 Kyowa Hakko Kogyo Co., Ltd. Remede contre la maladie de parkinson
US5677309A (en) * 1996-03-22 1997-10-14 Neurogen Corporation 1,2,4-triazolo 4,3-c! quinazolin-3-ones and 1,2,4-triazolo 4,3-c!quinazolin-3-thiones; a new class of GABA brain receptor ligands
US5955465A (en) * 1996-03-22 1999-09-21 Neurogen Corporation 1,2,4-triazolo 4,3-c!quinazolin-3-ones and 1,2,4-triazolo 4,3-c!quinazolin-3-thiones
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JP4077155B2 (ja) * 1998-04-03 2008-04-16 株式会社大塚製薬工場 トリアゾロプリン誘導体、該誘導体を含有する医薬組成物、アデノシンａ３受容体親和剤および喘息治療剤
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US6448253B1 (en) * 1998-09-16 2002-09-10 King Pharmaceuticals Research And Development, Inc. Adenosine A3 receptor modulators
JP4077198B2 (ja) 1999-09-28 2008-04-16 株式会社大塚製薬工場 トリアゾロプリン誘導体、該誘導体を含有する医薬組成物およびアデノシンａ３受容体親和剤
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US7196106B2 (en) 2002-11-05 2007-03-27 Merck & Co., Inc Cyanothiophene derivatives, compositions containing such compounds and methods of use
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EP0217748A2 (en) * 1985-09-30 1987-04-08 Ciba-Geigy Ag 2-Substituted-e-fused-[1,2,4,]triazolo-[1,5-c]pyrimidines pharmaceutical compositions and uses thereof

Cited By (4)

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Publication number Priority date Publication date Assignee Title
US5173492A (en) * 1989-09-14 1992-12-22 Kyowa Hakko Kogyo Co., Ltd. s-Triazolo(3,4-I)purine derivatives
WO2014101113A1 (en) * 2012-12-28 2014-07-03 Merck Sharp & Dohme Corp. Piperazine-substituted 7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine compounds with a2a antagonist properties
US12351583B2 (en) 2019-04-03 2025-07-08 Chemiteras, Inc. Triazolopyrimidines based on thymine nucleobase and methods for producing them
WO2022029063A1 (en) 2020-08-04 2022-02-10 Bayer Aktiengesellschaft Pyrido[1,2,4]triazolo[1,5-c]pyrimidin-5-amines

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