WO1993017025A1 - IMIDAZO(1,5-a)QUINOXALINES ET QUINAZOLINES SUBSTITUEES EN POSITION 3, ACTIVES PAR RAPPORT AU SYSTEME NERVEUX CENTRAL - Google Patents

IMIDAZO(1,5-a)QUINOXALINES ET QUINAZOLINES SUBSTITUEES EN POSITION 3, ACTIVES PAR RAPPORT AU SYSTEME NERVEUX CENTRAL Download PDF

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WO1993017025A1
WO1993017025A1 PCT/US1993/000291 US9300291W WO9317025A1 WO 1993017025 A1 WO1993017025 A1 WO 1993017025A1 US 9300291 W US9300291 W US 9300291W WO 9317025 A1 WO9317025 A1 WO 9317025A1
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alkyl
quinoxaline
oxoimidazo
cycloalkyl
isopropyl
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PCT/US1993/000291
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English (en)
Inventor
Ruth Elizabeth Ten Brink
Eric Jon Jacobsen
Jackson B. Hester, Jr.
Louis L. Skaletzky
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The Upjohn Company
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Priority to EP93903088A priority Critical patent/EP0626966A1/fr
Priority to JP5514826A priority patent/JPH07503970A/ja
Publication of WO1993017025A1 publication Critical patent/WO1993017025A1/fr

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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
    • 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
    • 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

Definitions

  • This invention is imidazo(l,5-a)quinoxalines and i ⁇ -idazo(1,5-a)quinazolines with aryl, heteroaryl, ketone and thioketone at position 3, which are uselful for treating anxiety, sleep disorders, panic disorders, convulsive disorders and/or depression.
  • European Patent 225,013 U.S. Patent 4,774,245; 4,771,051; 4,886,797; 4,880,799) disclose imidazo(1,5-a)quinoxaline and 4-oxoimidazo(1,5-a)quinoxalines compounds, useful as anxiolytic and hypnotic agents, having an ester or oxadiazole substituent at the 3-position.
  • European Patent 202,441-A discloses imidazo(1,5-a)quinazoline compounds useful as anxiolytic and hypnotic agents, containing an oxadiazole at the 3-position and halogen, nitrile, methyl and trifluoromethyl groups at the 6-position.
  • European Patent 320,136-A discloses 4-oxoimidazo(1,5-a)quinoxaline compounds useful as anxiolytic and hypnotic agents, containing oxadiazole or ester substituents at the 3-position and hydrogen or halogen substituents at the 6-position.
  • the ring atom at position 6 may be carbon or nitrogen.
  • European Patent 283,162 discloses 4-oxoimidazo(1,5- a)quinoxalines and 5-oxoimidazo(1,5-a)quinazolines having anticonvulsant and anxiolytic activity, with oxadiazoles, esters, and amides at position 3.
  • European Patent 368,652 discloses 4-oxoimidazoquinoxalines useful as anxiolytics and hypnotics with an oxadiazole at position 3 and tert-butyl at position 5.
  • European Patent Application 344,943A discloses imidazo[1,5- a]quinoxalin-4-ones with methyl at N 5 useful as anticonvulsants, anxiolytics and hypnotics.
  • Japanese Patent 89027074 discloses imidazobenzodiazepines useful as anticonvulsants and anxiolytics containing an oxadiazole at the 3-position.
  • U.S. Patent 4,440,929 discloses 4-thio, 4-imino, 4-hydroxyimino, 4-oxoimidazo(1,5- a)quinoxaline compounds containing nitrile, carboxaldehyde, carboxy ⁇ ic acid, ester, amide and methylalcohol substituents at the 3-posiuon and H, alkyl, alkenyl, alkynyl, aryl, aralkyl, hydroxy, and alkanoyl at the 5-position.
  • U.S. Patent 4,866,065 discloses imidazo(1,5-a)thieno(2,3-e)pyrimidines useful as anticonvulsant, hypnotics, etc. containing oxadiazoles and esters at position 3.
  • U.S. Patent 5,034,530 discloses imidazo(1,5-a)quinoxalines useful as anxiolytics and hypnotics with oxadiazoles at position 3 and no substitution at position 5 (imino) or 5 N-oxide ⁇
  • U.S. Patent 4,939,139 discloses imidazo(1,5-a)benzodiazepines useful as anxiolytics containing an oxadiazole at position 3.
  • WO 91/07408 discloses 4-oxo ⁇ midazoquinoxalines useful as anxiolytics and hypnotics with ketones at position 3.
  • J. Med. Chem (1991) 34, 281-290 discloses 5-oxo(1,2,4)triazolo(1,5-c)quinazoIines with affinity for the benzodiazepine receptor, with phenyl, pyridinyl, CF 3 , ester, furanyl, thienyl, tetrahydrofuranyl at position 2.
  • J. Med. Chem. (1988) 31 1098-1115 discloses 4-oxoimidazo(1,5-a)quinoxaIines with an ester at position 3.
  • the subject of the paper is antiallergy agents.
  • the subject invention is directed toward 4-oxoimidazo(1,5-a)quinoxalines of Formula (I)
  • R 5 is C 1-8 alkyl, C 3-7 cycloalkyl, C 1-4 alkyl-C 3-7 cycloalkyl, C 2-6 alkenyl (optionally substituted with C 1-3 alkyl), (CH 2 ) n -Aryl, (CH 2 ) m N(R 12 ) 2 , or (CH 2 ) m OR 11 and n is 0-4 and m is 2-4;
  • R 6 and R 7 are independently H, F, Cl, Br, I, C 1 -C 4 alkyl, C ⁇ N, NO 2 ,
  • R 8 is O, S, NH, NCH 3 , N(CH 2 ) n -C 3-7 cycloalkyl, -C(R 9 ) 2 or NCHO;
  • R 9 is H, C 1-4 alkyl, phenyl (except that only one R 9 can be phenyl or t-butyl at the same time);
  • R 11 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-4 alkyl-C 3-7 cycloalkyl, or -(CH 2 ) n -Aryl;
  • R 12 is independentiy H, C 1-6 alkyl, C 3 -C 7 cycloalkyl, -C 1-4 alkyI-C 3-7 cycloalkyl, phenyl, or taken together with the attached nitrogen atom to form a heterocyclic ring - N*(CH 2 ) p R 13 (CH 2 ) o * where the * indicates the atoms bonded to each other to form said heterocyclic ring, where p is 2-5 and o is 0-3;
  • R 13 is O, S, CO, CH 2 , NR 16 ;
  • R 14 is independently H, F, Cl, Br, I, CN, NO 2 , OCOR 11 , (CH 2 ) n CF 3 , C 1-6 alkyl, C 3 -C 7 cycloalkyl, C 1-4 alkyl-C 3-7 cycloalkyl, (CH 2 ) n N(R 12 ) 2 , (CH 2 ) n OR 11 , N(R 12 )COR 11 , (CH 2 ) n CO 2 R 11 , (CH 2 ) n SR H , SO 2 N(R 12 ) 2 , COR 11 , phenyl (optionally substituted with F, Cl, Br, OCH 3 , CH 3 or CF 3 ); and
  • R 16 is H, C 1-4 alkyl, C 3 -C 7 cycloalkyl, CHO, C 1-4 alkyl-C 3-7 cycloalkyl, CO-R 11 .
  • the subject invention is directed toward 5-oxoimidazo(1,5-a)quinazoline of foraiula (II)
  • the R-groups are as defined above.
  • the subject invention is directed toward a diimidazoquinazoline of formula (III)
  • R 4 is a H or C 1-6 alkyl; and the remaining R-groups are as defined above except that R 5 includes a H.
  • R 3 is selected from the group consisting of benzoxazoI-2-yl, oxazolin-2-yI, thiazol-2-yI, 1,2,4-triazol-3-yI and a phenyl optionally substituted with one -CH 3 , -OCH 3 or -F. More preferred is where R 3 is selected from the group consisting of 4-fluorophenyl, thiazol-2-yl and benzoxazoI-2-yl.
  • R 5 is preferably a C 1 -C 4 alkyl and R 6 and R 7 are independently -H, -F, -Cl, -CF 3 or -CH 3 .
  • the preferred compounds of 4-oxoimidazo(1,5-a)quinoxaline (I) are exemplified in Examples 1-16.
  • R 3 is selected from the group consisting of substituted phenyl, benzoxazol-2-yl, thiazol-2-yl, oxazolin-2-yl and 1,2,4-triazol-3-yl, more preferably where R 3 is selected from the group consisting of 4-fluorophenyl, thiazoI-2-yl and benzoxazol-2-yl.
  • R 5 is a C 1-4 alkyl and R 6 and R 7 are independently -H, -F, -Cl, -CF 3 or -CH 3 .
  • R 3 is selected from the group consisting of substituted phenyl, thiazoI-3-yl, benzoxazol-2-yl, oxazoIin-2-yl and 1,2,4-triazol-3-yI, more preferably where, R 3 is selected from the group consisting of 4-fluorophenyl, thiazol-2-yl and benzoxazol-2-yl.
  • R 5 is a C 1 -C 4 alkyl and R 6 and R 7 are independently -H, -F, -Cl, -CF 3 or -CH 3 .
  • the subject invention is directed toward a method for treating central nervous system disorders associated with benzodiazepine receptors in a subject or patient in need of such treatment comprising administering to the patient a therapeutically-effective amount of a Formula I, II or m compound for alleviation of such disorder.
  • a pharmaceutical composition comprising a pharmaceutically-acceptable carrier or diluent.
  • the subject invention is directed toward a pharmaceutical composition for treating central nervous system disorders associated with the benzodiazepine receptors comprising an effective amount of a compound of Formula I, II, or III with a pharmaceutically-acceptable carrier or diluent DETAILED DESCRIPTION OF THE INVENTION
  • the 4-oxoimidazo(1,5-a)quinoxalines (I) of the present invention are named and numbered following the Chemical Abstracts ring system nomenclature system, see Ring Systems Handbook, Chemical Abstracts Service, Ring Systems File I, see RF 23543, 1988 Edition.
  • V diketoquinoxalines
  • the isocyanides (VI) are either known to those skilled in the art or can be readily be prepared by known methods from compounds known to those skilled in the art. A general review of synthesis of isocyanides (also known as isonitriles) is found in Angew. Chem.
  • One method involves starting with primary amines of the formula NH 2 -CH 2 -R 3 , which are known to those skilled in the art. These primary amines are then reacted with a reagent such as methyl or ethylformate (or their equivalent) by known means at about 20-25° to provide the corresponding formamide, CHO-NH-CH 2 -R 3 . The formamides are then transformed to the isocyanides (VI) by exposure to phosphorous oxychloride in a solvent such as methylene chloride in the presence of a base such as triethylamine by known means (preferred for higher molecular weight isocyanides).
  • isocyanides For low molecular weight isocyanides, the method of J. Chem. Soc. (Lon.) 4280 (1963), using p-toluenesulfonyl chloride and quinoline is useful.
  • the isocyanides (VI) can be prepared directly from the primary amine by treatment with chloroform and a base, see Tetrahedron Letters, 1637 (1972) or Angew. Chem. Int. Ed. Engl., 11, 530 (1972).
  • This may be accomplished with standard protecting groups such as acetate, benzyl, tert-butyl, and tert-butyloxycarbonyl.
  • the protecting group may be removed by standard procedures at the completion of the isocyanide synthesis, or at the completion of the synthesis of the final product 4-oxoimidazo(1,5-a)quinoxalines (I).
  • These amines are then formylated to give the CHO-NH-CH 2 -X 3 as discussed above.
  • the formyl amines are then converted to isocyanides (CN-CH 2 -X 3 ),as discussed above.
  • the synthesis may begin with halo-CH 2 -R 3 or HO-CH 2 -R 3 (which itself may be converted halo-CH 2 -R 3 or the hydroxy group may be converted to a leaving group such as p-toluenesulfonate or memanesulfonate57whieh-are then converted to NH 2 -CH 2 -R 3 by standard routes such as displacement with azide and reduction of azide to amine.
  • the NH 2 -CH 2 -R 3 are then converted to the isocyanides (VI) using the procedures mentioned above.
  • halo group of halo-CH 2 -R 3 may be directly displaced with the anion formed from formamide and a strong base such as sodium hydride to produce directly the CHO-NH-CH 2 -R 3 precursor to the isocyanides (VI).
  • a strong base such as sodium hydride
  • halo-CH 2 -R 3 or HO-CH 2 -R 3 are not commercially available and must be prepared. This can be accomplished using several methods. One method begins with 2-halo acetyl halide, which is reacted with o-hydroxy, o-thiol, or o-aminoanilines (aryl or heteroaryl) to form an amide or ester.
  • anilino group or the o-hydroxy, thiol, or amino group may be preferable to protect either the anilino group or the o-hydroxy, thiol, or amino group during the addition to the acid halide.
  • the protecting group is removed and the resulting amide or ester is subjected to dehydrating and cyclizing conditions such as methanesulfonic acid saturated with phosphorous pentoxide. This then gives the desired halo-CH 2 -R 3 , which are then taken on to the isocyanides (VI) by the procedures mentioned above.
  • Still another method is to add 2-haloacetyl halide to an ortho-halo aniline using refluxing trimethyl polyphosphate, a variation of the method of EP 419 348.
  • protection of groups on the aryl or heteroaryl portion of R 3 is through standard methods such as acetate, tert-butyl, tert-butyloxycarbonyl, benzyl, and others.
  • the desired diketoquinoxalines (V) are contacted with the isocyanides (VI) to produce the desired 4-oxo ⁇ midazo(1,5-a)quinoxalines (I) as is known in the art. More particularly, the diketoquinoxalines (V) are cooled and contacted with a small excess of strong base, preferably potassium tert-butoxide or its equivalent After stirring, diethyl chlorophosphate is added. After further stirring, isocyanide (VI) is added with potassium tert-butoxide. After stirring for 1-4 hours the mixture is allowed to return to ambient temperature. The mixture is then partitioned between the ethyl acetate or methylene chloride and aqueous sodium bicarbonate or water and purified.
  • strong base preferably potassium tert-butoxide or its equivalent
  • isocyanide (VI) is added with potassium tert-butoxide. After stirring for 1-4 hours the mixture is allowed to return to ambient temperature. The mixture is then partitioned between the
  • an appropriate amine to an already constructed 3-substituted-4-oxoimidazo(1,5-a)quinoxaline or imidazoquinoxaline-carboxylate (IX), produced from reaction of diketoquinoxalines (V) with isocyanides (XII), to form an amide (IX), which is then cyclized with loss of water or with loss of some leaving group such as halo or mesylate or tosylate to form the desired 4-oxoimidazo(1,5-a)quinoxalines (I). Additional routes to the construction of R3 groups are given in J. Med. Chem.
  • the 5-oxolrrIidazo(1-5-a)quinazolines (II) are prepared as set forth in CHART B by known means, see J8 9027 074B and US Patent 4,774,245.
  • the dioxoquinazolines (VII) starting materials are known to those skilled in the art and are reacted with the isocyanides (VI) as discussed above.
  • the R 3 group may be added following formation of an X 3 substituted-5-oxoimidazo(l,5-a)quinazoline (X), more particularly an imidazoquinazolinecarboxylate (X) as discussed above.
  • the 3-substituted-5-oxoimidazo(1,5-a)quinazoIines (X) are then converted to 5-oxoimidazo(1,5-a)quinazolines (II) by known means.
  • the d ⁇ midazoquinazolines (III) are prepared as set forth in CHART C by known means, see European Patent Application No. EP 417027A1 assigned to Ferrosan.
  • the tricyclic amide (VIII) starting materials are known to those skilled in the art and are reacted with the isocyanides (VI) as discussed above.
  • the R 3 group may be added following formation of a X 3 substituted-diimidazoquinazolines (XI), more particularly an
  • R 3 be benzoxazol-2-yl, oxazolin-2-yl, thiazol-2-yl, 1,2,4-triazol-3-yl and phenyl optionally substituted with a -CH 3 , -OCH 3 or -F; it is more preferred that R 3 be 4-fluorophenyl, thiazol-2-yl or benzoxazol-2-yl. It is preferred that R 5 be C 1-4 alkyl; it is more preferred that R 5 be C 3 alkyl and it is even more preferred that R 5 be isopropyl.
  • R 6 and R 7 are H, F, Cl, CF 3 or CH 3 , more preferrably that R 6 is -H, -CH 3 or -Cl and more preferrably that R 7 is -H, -Cl or -F. It is preferred that the 4-oxoimidazo(1,5-a)quinoxalines (I) be the compounds of EXAMPLES 1-12.
  • R 3 is an aryl such as phenyl, included substituted phenyls, Aryl-I to III (shown in Chart D) and heteroaryls Aryl-IV through Aryl-LXIV (shown in Chart D).
  • the imidazo(1,5-a)quinoxalines (IV) are amines, and as such may form acid addition salts when reacted with acids of sufficient strength.
  • Pharmaceutically acceptable salts include salts of both inorganic and organic acids. The pharmaceutically acceptable salts are preferred over the corresponding free amines since they produce compounds which are more water soluble and more crystalline.
  • the preferred pharmaceutically acceptable salts include salts of the following acids methanesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric, maleic, CH 3 -(CH 2 ) n -COOH where n is 0 thru 4, HOOC-(CH 2 )n-COOH where n is as defined above.
  • the imidazo(1,5-a)quinoxalines (IV) of the present invention have relatively more anxiolytic and less sedative activity than other known anxiolytic compounds such as diazepam and therefore are useful as anxiolytic agents at lower doses and as sedatives at higher doses.
  • the imidazo(1,5-a)quinoxalines (IV) are active orally or parenterally. Orally the imidazo(1,5-a)quinoxalines (IV) can be given in solid dosage forms as tablets or capsules, or can be given in liquid dosage forms such as elixirs, syrups or suspensions as is known to those skilled in the art. It is preferred that the 4-oxoimidazo(1,5-a)quinoxalines (IV) be given in solid dosage form and that it be a tablet or capsule.
  • the imidazo(1,5-a)quinoxalines (IV) should be administered in a therapeutically effective amount to a subject or patient in an amount of about 0.25 mg to about 100 mg/person, one to three times a day. Preferably, about 1 to about 50 mg/day in divided doses.
  • the imidazo(1,5-a)quinoxalines (IV) should be administered in a therapeut ⁇ cally effective amount to a subject or patient in an amount of about 0.25 mg to about 100 mg/person, preferrably at bedtime or when sedation is needed. It is preferred the sedative/hypnotic dose be from about 1 to about 50 mg/person.
  • the imidazo(1,5-a)quinoxalines (IV) should be administered in a therapeutically effective amount to a subject or patient in an amount of about 1 mg to about 100 mg/person. It is preferred the dose be from about 1 to about 50 mg/person.
  • the imidazo(1,5-a)quinoxalines (IV) should be administered in a therapeutically effective amount to a subject or patient in an amount of about 1 mg to about 100 mg/person. It is preferred the anti-convulsive dose be from about 1 to about 50 mg/person.
  • the imidazo(1,5-a)quinoxalines (IV) should be administered in a therapeutically effective amount to a subject or patient in an amount of about 1 mg to about 100 mg/person- It is preferred the anti-depressant dose be from about I to about 50 mg/person.
  • the exact dosage and frequency of administration depends on the particular imidazo(1,5-a)quinoxalines (IV) used, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the imidazo(1,5-a)quinoxalines (IV) in the patient's blood and/or the patient's response to the particular condition being treated.
  • variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in parenthesis.
  • each of the consecutive variable substituents is bonded to the immediately preceding atom to the left which is not enclosed in parentheses.
  • R i and R j are bonded to the preceding carbon atom.
  • C i is the integer corresponding to the carbon atom number.
  • C 6 represents the 6 position or carbon atom number in the steroid nucleus as traditionally designated by those skilled in the art of steroid chemistry.
  • R 6 represents a variable substituent (either monovalent or bivalent) at the C 6 position.
  • variable substituents The carbon atom content of variable substituents is indicated in one of two ways.
  • the forms are either “C 1-4 " or “C 1 -C 4 " where both “1” and “4" are integers representing the minimum and maximum number of carbon atoms in the variable.
  • C 1 -C 4 alkyl represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given).
  • this single prefix indicates the entire carbon atom content of the variable being defined.
  • C 2 -C 4 alkoxycarbonyl describes a group CH 3 -(CH 2 ) n -O-CO- where n is zero, one or two.
  • C 2 -C 6 alkoxyalkyl and (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms
  • the two definitions differ since the former definition allows either the alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits either of these groups to 3 carbon atoms.
  • Aryl is defined as those compounds (structures) shown in Chart D.
  • Chart D shows the compounds identified by the "Aryl Roman numeral" designation as all of which can be optionally substituted with the R14 or R 16 group as defined above.
  • (M + H) + refers to the positive ion of a parent plus a hydrogen atom.
  • EI refers to electron impact.
  • CI refers to chemical ionization.
  • FAB refers to fast atom bombardment.
  • Ether refers to diethyl ether.
  • Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a
  • An analytical sample is prepared by recrystallization from ethyl acetate/hexane, mp 223-224°; IR (mineral oil) 3094, 2955, 2925, 2855, 1657, 1598, 1520, 1361, 1291, 1218, 1095, 752 cm -1 ; NMR (CDCl 3 ) 8.40, 8.16, 7.77, 7.3-7.5, 7.2-7.3, 6.9-7.0, 5.1-5.5, 1.66 ⁇ ; MS (EI) m/e 321, 279.
  • EXAMPLE 11 4,5-Dihydro-5-isopropyl-3-(oxazolin-2-yl)-4-oxoimidazo(1,5-a)quinoxaline (I) Following the the general procedure of EXAMPLES 1-3 and making non-critical variations but using 1,2,3,4-tetrahydro-1-isopropyl-2,3-dioxoquinoxaline (V, 1.108 g) and tert-butyl isocyanoacetate (XII, 0.918 g) are converted to tert-butyl 4,5-dihydro-5-isopropyl-4-oxoimidazo(1,5-a)quinoxaline-3-carboxylate (IX). After crystallization from
  • a stirred mixture of the product from Step 1 (0.66 g), acetic acid (6.5ml) and hydrazine hydrate (0.11 ml) is warmed under nitrogen from 45° to 98° during 50 min and kept at 97-98° for 4 hr.
  • TLC with methanol/chloroform (10/90) the mixture still contained starting material; it is cooled, treated with one drop of hydrazine hydrate and warmed at 97° for an additional 1 hr 25min.
  • the mixture is then concentrated under a stream of nitrogen to one half of its original volume and mixed with ice water.
  • a stirred mixture of 2-methyl-3-thiosemicarbazide (2.8 g) in pyridine is cooled to -20°, under nitrogen, and treated portionwise during 20 min with the acid chloride prepared in Step 1.
  • the mixture is kept at -30° to -20° for 1 hr, at -20° to -10° for 30 min and at 20-25° for 18 hr. It is then concentrated under reduced pressure.
  • the residue is mixed with toluene twice with concentration after each addition. This residue is mixed with water (150 ml) and ether (20 ml) and stirred for 30 min.
  • a stream of nitrogen is then bubbled through the mixture to remove the ether; the mixture is cooled and the solid is collected by filtration and dried under reduced pressure to give the product
  • Step 3 The product of Step 3 (1.3 g) is added portionwise during 10 min to nitric acid (20%, 4.2 ml) that had been warmed on a steam bath. The resulting suspension is warmed for an additional 25 min and kept at 20-25° for 1 hr. It is then cooled in an ice bath, treated with cold dilute ammonium hydroxide until the pH is 9-10 and extracted with chloroform. The extracts are washed with water and saline, dried over magnesium sulfate and concentrated. The residue is chromatographed under pressure on silica gel (200 ml) to give the product which is crystallized from methylene chloride/hexane to give the title compound, mp 243-244°.
  • the analytical sample is recrystallized from isopropanol, mp 243-246°; MS (m/z) 308 (M+), 293), 266), 238; IR 3106, 3072, 1655, 1616, 1586 cm -1 ; NMR (CDCl 3 ) 1.66, 4.05, 5.52, 7.27, 7.41, 7.59, 7.84, 8.21, 8.50 ⁇ .
  • the residue is chromatographed on silica gel using a gradient solvent system of 4% to 10% methanol--dichloromethane.
  • the fractions containmg 4,5-dmydro-5-isopropyl-4-oxoimidazo(1,5-a)quinoxalme-3-thiocarboxamide are rechromatographed on silica gel using 4% methanol ⁇ 96% dichloromethane containing about 0.1% of ammonium hydroxide to give 2.25 g of 4,5-dihydro-5-isopropyl-4-oxoimidazo(1,5-a)quinoxaIine-3-thiocarboxamide.
  • reaction mixture is then poured onto ice/water and extracted with dichloromethane.
  • organic layers are backwashed with aq. sodium bicarbonate and then dried over sodium sulfate and concentrated.
  • the residue is chromatographed on silica gel using 4% methanol-- 96% dichloromethane as eluent to give 0.589 g of product, which was crystallized from

Abstract

4-oxoimidazo(1,5-a)quinoxaline de la formule (I), 5-oxoimidazo(1,5-a)quinoxaline de la formule (II), diimidazoquinazoline de la formule (III), ou sel pharmaceutiquement acceptable de ces composés, R3 représentant (a), (b), (c), (d). Les groupes R et 'Aryle' sont tels que définis dans le descriptif. Ces composés peuvent être utilisés pour le traitement d'affections du système nerveux central associées aux récepteurs de benzodiazépine chez un patient, le traitement consistant à administrer au patient une dose thérapeutique efficace d'un composé de la formule (I), (II) ou (III) permettant d'en soulager les symptômes. Généralement, le composé de la formule (I), (II) ou (III) est administré sous la forme d'une composition pharmaceutique comprenant un diluant ou un excipient pharmaceutiquement acceptables.
PCT/US1993/000291 1992-02-19 1993-01-25 IMIDAZO(1,5-a)QUINOXALINES ET QUINAZOLINES SUBSTITUEES EN POSITION 3, ACTIVES PAR RAPPORT AU SYSTEME NERVEUX CENTRAL WO1993017025A1 (fr)

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EP93903088A EP0626966A1 (fr) 1992-02-19 1993-01-25 IMIDAZO(1,5-a)QUINOXALINES ET QUINAZOLINES SUBSTITUEES EN POSITION 3, ACTIVES PAR RAPPORT AU SYSTEME NERVEUX CENTRAL
JP5514826A JPH07503970A (ja) 1992-02-19 1993-01-25 ＣＮＳ活性を有する３−置換イミダゾ（１，５−ａ）−キノキサリン類およびキナゾリン類

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US07/838,519 1992-02-19

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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
US5792766A (en) * 1996-03-13 1998-08-11 Neurogen Corporation Imidazo 1,5-c! quinazolines; 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
US6080873A (en) * 1996-01-19 2000-06-27 Neurogen Corporation Fused pyrrolecarboxamides; a new class of GABA brain receptor ligands
US6211365B1 (en) 1996-01-19 2001-04-03 Neurogen Corporation Fused pyrrolecarboxamides; a new class of GABA brain receptor ligands
WO2002076963A1 (fr) 2001-03-21 2002-10-03 Merck Patent Gmbh Derives bicycliques de guanidine et leurs utilisations therapeutiques
US6720339B2 (en) 1996-03-22 2004-04-13 Neurogen Corporation Certain fused pyrrolecarboxamides; a new class of GABA brain receptor ligands
US7109351B1 (en) 1999-08-31 2006-09-19 Neurogen Corporation Fused pyrrolecarboxamides; GABA brain receptor ligands
WO2010101230A1 (fr) 2009-03-05 2010-09-10 アステラス製薬株式会社 Composés de quinoxaline
WO2012033101A1 (fr) 2010-09-07 2012-03-15 アステラス製薬株式会社 Composé quinoxaline
GB2574862A (en) * 2018-06-21 2019-12-25 Curadev Pharma Ltd Azaheterocyclic small molecule modulators of human STING

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EP0417027A1 (fr) * 1989-09-08 1991-03-13 Novo Nordisk A/S Dérivés tétracycliques d'imidazoquinazoline, leur procédé de prÀ©paration et compositions pharmaceutiques les contenant
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EP0283162A2 (fr) * 1987-03-18 1988-09-21 Novo Nordisk A/S Composés hétérocycliques, leur préparation et utilisation
EP0417027A1 (fr) * 1989-09-08 1991-03-13 Novo Nordisk A/S Dérivés tétracycliques d'imidazoquinazoline, leur procédé de prÀ©paration et compositions pharmaceutiques les contenant
WO1991007407A1 (fr) * 1989-11-22 1991-05-30 Novo Nordisk A/S Composes d'imidazoquinoxaline, leur preparation et emploi

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6080873A (en) * 1996-01-19 2000-06-27 Neurogen Corporation Fused pyrrolecarboxamides; a new class of GABA brain receptor ligands
US6211365B1 (en) 1996-01-19 2001-04-03 Neurogen Corporation Fused pyrrolecarboxamides; a new class of GABA brain receptor ligands
US5792766A (en) * 1996-03-13 1998-08-11 Neurogen Corporation Imidazo 1,5-c! quinazolines; a new class of GABA brain receptor ligands
US6297252B1 (en) 1996-03-13 2001-10-02 Neurogen Corporation Imidazo[1,5-c]quinazolines; 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
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
US6720339B2 (en) 1996-03-22 2004-04-13 Neurogen Corporation Certain fused pyrrolecarboxamides; a new class of GABA brain receptor ligands
US7109351B1 (en) 1999-08-31 2006-09-19 Neurogen Corporation Fused pyrrolecarboxamides; GABA brain receptor ligands
WO2002076963A1 (fr) 2001-03-21 2002-10-03 Merck Patent Gmbh Derives bicycliques de guanidine et leurs utilisations therapeutiques
WO2010101230A1 (fr) 2009-03-05 2010-09-10 アステラス製薬株式会社 Composés de quinoxaline
US8357688B2 (en) 2009-03-05 2013-01-22 Astellas Pharma Inc. Substituted imidazo[1,5-a]quinoxalin-4(5H)-ones as PDE9 inhibitors
US8674096B2 (en) 2009-03-05 2014-03-18 Astellas Pharma Inc. Substituted imidazo[1,5-a]quinoxalin-4-ones as phosphodiesterase 9 inhibitors
WO2012033101A1 (fr) 2010-09-07 2012-03-15 アステラス製薬株式会社 Composé quinoxaline
US8901126B2 (en) 2010-09-07 2014-12-02 Astellas Pharma Inc. Substituted imidazo[1,5-A]quinoxalin-4-ones are useful for preventing or treating storage dysfunction, voiding dysfunction and bladder/urethral diseases
GB2574862A (en) * 2018-06-21 2019-12-25 Curadev Pharma Ltd Azaheterocyclic small molecule modulators of human STING

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JPH07503970A (ja) 1995-04-27
AU3443493A (en) 1993-09-13
EP0626966A1 (fr) 1994-12-07

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