EP0487673A1 - Nouveaux derives de xanthine - Google Patents

Nouveaux derives de xanthine

Info

Publication number
EP0487673A1
EP0487673A1 EP91910772A EP91910772A EP0487673A1 EP 0487673 A1 EP0487673 A1 EP 0487673A1 EP 91910772 A EP91910772 A EP 91910772A EP 91910772 A EP91910772 A EP 91910772A EP 0487673 A1 EP0487673 A1 EP 0487673A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
optionally substituted
general formula
group
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP91910772A
Other languages
German (de)
English (en)
Inventor
Ulrike Küfner-Mühl
Werner Stransky
Karl-Heinz Weber
Helmut Ensinger
Franz Josef Kuhn
Günter Schingnitz
Erich Lehr
Gerhard Walther
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim GmbH filed Critical Boehringer Ingelheim International GmbH
Publication of EP0487673A1 publication Critical patent/EP0487673A1/fr
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/01—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products based on oxide ceramics
    • C04B35/10—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products based on oxide ceramics based on aluminium oxide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • 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
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/01—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products based on oxide ceramics
    • C04B35/46—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products based on oxide ceramics based on titanium oxides or titanates
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F05—INDEXING SCHEMES RELATING TO ENGINES OR PUMPS IN VARIOUS SUBCLASSES OF CLASSES F01-F04
    • F05C—INDEXING SCHEME RELATING TO MATERIALS, MATERIAL PROPERTIES OR MATERIAL CHARACTERISTICS FOR MACHINES, ENGINES OR PUMPS OTHER THAN NON-POSITIVE-DISPLACEMENT MACHINES OR ENGINES
    • F05C2201/00—Metals
    • F05C2201/02—Light metals
    • F05C2201/021—Aluminium

Definitions

  • the invention relates to new xanthine derivatives, processes for their preparation and their use as
  • the new compounds correspond to the general formula I.
  • NC 1 -C 4 alkyl may contain, the
  • Heterocycle can carry one of the following radicals, C 1 to C 6 , preferably C 1 -C 4 alkyl,
  • OR 4 , OR 7 ; O, - (CH 2 ) 1-4 OR 4 ,
  • R 3 is a monosaccharide, preferably a radical of
  • R H, alkyl, OR 4 , OR 7 , CH 2 OR 4 ,
  • R 3 is an optionally substituted C 4 -C 8 , preferably C 5 or C 6 cycloalkane,
  • C 1 - C 6 - preferably C 1 - C 4 alkyl
  • Phenyl optionally substituted aralkyl, NR 5 R 6 , COO R 4 , CON R 5 R 6 , OR 4 , SR 4 ,
  • R 3 is a ketal of the general formula
  • A oxygen or sulfur
  • m + n 2, 3, 4, 5 or 6,
  • R a C 1 - C 4 alkyl
  • R b can be C 1 -C 4 alkyl, or R a and R b together form a C 2 or
  • C 3 alkylene bridge which may be mono- or disubstituted by C 1 - C 5 alkyl, C 1 - C 5 alkyloxycarbonyl or Hydroxy-C 1 -C 4 alkyl, preferably hydroxymethyl, is substituted, the carbocyclic ring of the ketal may be substituted by one or more of the following radicals: C 1 - C 6 -, preferably C 1 - C 4 alkyl, C 3 - C 6 -, preferably C 3 - or C 4 -alkenyl, C 3 - C 6 -, preferably C 3 - or C 4 -alkynyl, C 1 - C 4 -alkylidene, phenyl, substituted phenyl, optionally substituted aralkyl, NR 5 R 6 ,
  • R 3 is a radical of the general formula
  • substituted C 3 -C 6 cycloalkyl may be substituted
  • R 3 is a radical of the general formula
  • A O, CH 2 , -CH 2 -CH 2 -, wherein the ring system is optionally substituted by one or more C 1 -C 6 - preferred
  • OR 4 , OR 7 , SR 4 , O, CH 2 OR 4 , CH 2 OR 7 ,
  • R 3 preferably a radical of the general formula
  • R 4 is hydrogen, C 1 - C 8 -, preferably C 1 -
  • C 4 alkyl optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 1 - C 4 alkylphenyl, C 3 - C 8 -, preferably C 3 or C 4 alkenyl, optionally
  • R 5 is hydrogen, C 1 -C 6 -, preferred
  • R 6 is hydrogen, an alkyl group with 1 to 6, preferably 1 to 4, carbon atoms,
  • Heteroatom from the group oxygen, sulfur or nitrogen can contain, which
  • Nitrogen atom can be substituted by the radical R 4 ;
  • R 7 is linked via the carbonyl function
  • R 8 is hydrogen, O, -Cg-, preferred
  • R 9 is hydrogen, C 1 -C 6 -, preferred
  • 5- or 6-membered carbocyclic ring can mean as a racemate, as an optically active compound, as pure diastereomers or as
  • Diastereomer mixture as well as, where appropriate, their pharmacologically acceptable
  • Preferred compounds of general formula I are those in which
  • R 1 is an alkyl group having 3 to 4 carbon atoms, a propenyl group or a propargyl group;
  • R 2 is an alkyl group having 3 to 4 carbon atoms, a propenyl group or a propargyl group;
  • R 3 is an N-linked saturated 5- or
  • 6-membered ring which may optionally contain oxygen or sulfur as a further heteroatom - preferably selected from the group pyrrolidine, piperidine, horpholine,
  • R 3 is a 2,3,4-trihydroxy-tetrahydrofuran-5-yl, a 2,3,4,5-tetrahydroxy-tetrahydropyran-6-yl, a 2-hydroxymethyl-3,4,5-trihydroxy-tetrahydropyran-6 -yl,
  • R 3 is a cyclopentane or cyclohexane or
  • Cyclohexanones which are substituted one or more times by C 1 - C 4 alkyl, C 3 - or C 4 alkenyl, C 3 - or
  • R 4 can be hydrogen, methyl, ethyl or propyl
  • R 3 is a bicyclo [3.3.0] octane or oxa- or
  • OR 4 O, OR 7 ;
  • R 4 is hydrogen, an alkyl group with 1 to 3
  • R 5 is hydrogen, an alkyl group with 1 to 3
  • R 6 is hydrogen, methyl, ethyl, propyl,
  • R 7 prolinoyl, CO- (CH 2 ) 0-3 -CH 3 , benzoyl
  • optically active compounds can mean, and optionally their optically active compounds as well as their
  • Alkyl, alkenyl or alkynyl groups can be branched or unbranched. As alkyl groups
  • decanyl examples of longer-chain alkyl radicals called decanyl, ündecanyl, dodecanyl and tridecanyl and their isomers.
  • alkenyl residues are allyl (provided they do not form enamines), propenyl,
  • Suitable substituents are, for example, hydroxy, halogen (fluorine, chlorine, bromine or iodine), nitro, cyano, amino, C 1 -C 4 -alkyl or. C 1 - C 4 dialkylamino, SH, SC 1 -C 4 alkyl
  • substituted alkyl groups include CF 3 , hydroxymethyl, hydroxyethyl,
  • Cycloalkyl radicals are, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, which can be substituted by alkyl having 1 to 4 carbon atoms or halogen.
  • aryl stands for an aromatic ring system with up to 10, preferably 6-10, carbon atoms, which may be used as
  • C 1 - C 4 alkyl can contain and is optionally substituted by C 1 - C 4 alkyl, halogen, hydroxy, nitro, C 1 -C 4 alkoxy,
  • Amino, C 1 -C 4 alkylamino and / or C 1 -C 4 dialkylamino may be substituted, the preferred aryl radical is phenyl.
  • Phenyl groups can be preferred one or more times by alkyl having 1 to 4 carbon atoms - preferably methyl, by alkoxy having 1 to 4 carbon atoms
  • Methoxy, hydroxy, and / or halogen - such as fluorine, chlorine or bromine - trifluoromethyl, halogen - preferably chlorine or bromine, CN, NO 2 , cyano, COH, COOH, COOC 1 -C 4 alkyl, CONH 2 , CON (C 1 -C 4 alkyl) 2 ,
  • Aralkyl stands for a linked by C 1 -C 6
  • Aryl group preferably phenyl.
  • substituted phenyl are: 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl,
  • Formula NR R may be mentioned: pyrrole, pyrroline,
  • heterocyclic radicals which can be linked via a carbon atom are examples of heterocyclic radicals which can be linked via a carbon atom.
  • heterocyclic residues which have an N atom
  • pyrrolidine may be linked and contain a nitrogen atom
  • pyrrolidine may be linked and contain a nitrogen atom
  • piperidine may be linked and contain a nitrogen atom
  • morpholine may be linked and contain a nitrogen atom
  • thiomorpholine may be linked and contain a nitrogen atom
  • heterocycles mentioned also being C 1 -C 4 -alkyl
  • Naturally occurring amino acids include, for example, alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, histidine, arginine, lysine.
  • the definition - (CH 2 ) 1-4 also includes branched
  • Bridge elements such as -CH 2 -CH (CH 3 ) -CH 2 -,
  • O means an oxygen atom linked via a double bond.
  • Patent application 374 808 are more similar to xanthines
  • Adenosine antagonists in particular, they have high affinity for the A. receptor and high selectivity for this receptor subtype.
  • Such substances are for the symptomatic
  • the high receptor affinity should allow therapy with low doses, so that hardly with
  • Blockage of adenosine receptors can be attributed. Likewise, due to the high
  • adenosine antagonists described could be useful for the treatment of cardiovascular diseases.
  • Parkinson's traumatic CNS damage, post stroke neurological deficit, respiratory depression
  • the compounds of the invention can be prepared by analogy methods known per se.
  • Tetrahydrofurans or tetrahydropyrans substituted several times with hydroxyl, alkoxy or acyloxy groups
  • Carboxylic acid which can be used in the xanthine synthesis according to the general regulations. If benzyl groups are chosen for the alkylation, these can be removed hydrogenolytically from the finished xanthine and the free hydroxyl functions can be acylated.
  • Carrying acyloxymethylene residues is obtained from suitably protected halogenoses in which the halogen atom is substituted in the 1-position by cyanide and this is then converted into a dithioacetate via the thioimidate.
  • halogenoses in which the halogen atom is substituted in the 1-position by cyanide and this is then converted into a dithioacetate via the thioimidate.
  • Such compounds directly yield xanthines in the reaction with 5.6-diamino-1,3-dialkyluracilene (see, for example, Carbohydrate Research 153, 271-283 (1986)), in which, after the protective groups have been split off, the
  • Hydroxy groups can be acylated in the usual way.
  • Heterocyclic radicals R 3 which are linked to the xanthine via a nitrogen atom, are obtained by using the corresponding N-formyl heterocycles
  • N-formyl compounds can be purchased or can be obtained from commercially available free bases
  • Formic acid and acetic anhydride can be produced (see e.g. Organic Synthesis III, 813).
  • A O, S, CH 2 , NC 1 -C 6 alkyl
  • Xanthine derivatives are based on 2- or
  • 3-Oxocycloalkan-1-carboxylic acid esters prepared by protecting the keto function as ethylene ketal, saponifying the ester and reacting the resulting carboxylic acid according to the general procedure.
  • the ketal function can then be split acidic.
  • the released ketone can - e.g. with complex hydrides - reduced to alcohol and this can be acylated according to the respective requirements.
  • the OH group can be configured by Mitsunobu reaction with benzoic acid and hydrolysis or reductive cleavage of the benzoate
  • the keto function can then, as under 4.
  • n 1, 2, 3, 4, 5
  • R alkyl
  • Double bond and / or obtained by the method described in 4. Double bond and / or obtained by the method described in 4..
  • Carboxylic acids in protected form. After acidic cleavage of the protective group, the hydroxy function is blocked with the t-butyldimethylsilyl protective group and then the xanthine is built up using the general method. Desilylation with fluoride leads to alcohol, which can be alkylated, acylated or oxidized to ketone. This can be followed by further subsequent reactions as described under 4.
  • Cyclopentane or cyclohexane units functionalized multiple times with hydroxyl, alkoxy or acyloxy groups and optionally with additional C substituents can be prepared from carbohydrates in a variety of ways. As an example here is J. Org. Chem. 54.
  • aldehydes which are analogous to Tetrahedron Lett. 30, 2465 (1989) from the t-leucine t-butyl ester imines of
  • n 2, 3, 4, 5, 6
  • R alkyl, alkenyl, aryl
  • R ' alkyl, alkenyl, benzyl 10)
  • Xanthine derivative in which the double bond can be cis-hydroxylated by oxidation with N-methylmorpholine-N-oxide / osmium tetroxide or converted to trans-diol by epoxidation with peracids and hydrolysis of the epoxide.
  • the hydroxy groups can then be acylated; in the implementation with
  • n-Dicarboxylic acid chlorides form cyclic diesters, with ketones cyclic ketanes are obtained.
  • R, R ' H, alkyl, cycloalkyl or R 8 , R 9 together form
  • the ketal carbon atom has a 5- or 6-ring 11
  • Cycloalkenones are obtained by DIBAH reduction of the ketone to alcohol and subsequent ones
  • Pulegonic acid (5-methyl-2- (2-propylidene) -1-cyclopentanecarboxylic acid) can be obtained by
  • 1-Alkyl or 1-arylcycloalkane carboxylic acids can be purchased commercially or according to regulations known in the literature, e.g. according to Liebigs Ann. Chem.,
  • the monothioketal is synthesized with 1,2-dimercaptoethane.
  • the second keto function is converted to the carboxylic acid, which reacts to the xanthine according to the general instructions.
  • Follow-up reactions on the keto group can be carried out as described under 4. The separation of isomers is achieved by chromatography.
  • Keto group with 1,2-dimercaptoethane to form the dithioketal after analogous xanthine synthesis, the two ketal protective groups can be split off independently of one another (the ketal with acid, the thioketal by treatment with mercury salts) and the free keto group in each case - as described under 4
  • Double bond and saponification of the esters give rise to further bicyclic carboxylic acid units which can be converted to xanthines according to the general instructions. Splitting off the protective groups by customary methods allows the alcohol functions to be released.
  • Regulation Xanthine can be synthesized.
  • the double bond can then, as under 19.
  • Alcohol which can subsequently be alkylated or acylated.
  • a solution of 8.0 g (0.020 mol) of 7-benzyl-8- (3-oxocyclopentyl) -1.3-dipropylpurine-2,6-dione in 70 ml of absolute tetrahydrofuran is then added dropwise at the same temperature. It is stirred for 2 hours at -70 ° C and then for 2 hours at -30 ° C, then carefully mixed with water at -30 ° C.
  • tert-butanol added.
  • the mixture is stirred at 0 ° C. for 2 hours, then allowed to warm to room temperature over a period of 4 hours, 150 mg of sodium bisulfite, about 5 g of diatomaceous earth and 15 ml of water are added in succession and the mixture is stirred at room temperature for 1 hour.
  • the solids are filtered off and the acetone is distilled off.
  • Ratio 90 10 chromatographed on silica gel and the product triturated with ether and then recrystallized from ethanol.
  • Trifluoroacetic acid added. The mixture is stirred at 40 ° C. for 6 hours, then a further 0.43 g are added
  • Ratio 95: 5 can be cleaned. The two isomers can be separated.
  • the polar isomer has a melting point of 230-232 ° C.
  • the non-polar isomer melts at 177 - 179 ° C.
  • the diastereomers of 8- (7-oxo-cis-bicyclo [3.3.0] octan-3-yl) -1,3-dipropyl-7H-purine-2,6-dione prepared according to Example 14 can be reduced separately.
  • the ketone with mp. 162 - 163 ° C then leads to the alcohol with mp. 177 - 179 ° C
  • the ketone with mp. 206 ° gives the alcohol with mp. 230 - 232 ° C.
  • Lithium aluminum hydride in ether gives the isomeric product with an inverted alcohol configuration from the polar alcohol with mp 230-232 ° C
  • Tetrahydrofuran is added dropwise at -72 ° C to 9.49 ml
  • Tetrahydrofuran too.
  • the mixture is stirred 2.5 hours at -70 ° C, 1 hour at -70 to -60 ° C, 1.5 hours at -30 ⁇ C and 30 minutes at -30 to -10 ° C after.
  • Tetrahydrofuran dissolved and mixed with 35 ml of water. The mixture is heated to 50 ° C. and 2.34 g are added
  • the ethanol is distilled off at a bath temperature of 30 ° C. and the aqueous solution is extracted with ethyl acetate.
  • the aqueous phase is acidified to a pH of 6 with ice cooling and extracted with dichloromethane, which combined
  • the title compound is obtained in accordance with the general instructions and purified by recrystallization from ethanol.
  • the title compound is obtained in the form of colorless crystals in a yield of 17% of theory. Th. Of mp. 215-216 ° C.
  • the title compound is prepared according to the general procedure and purified by chromatography on silica gel with a mixture of dichloromethane and methanol in a ratio of 99: 1.
  • the carboxylic acid comes with eguimolar amounts
  • Ice cooling is acidified and shaken out with dichloromethane. The neutral washed, combined organic extracts are dried and concentrated and the product by chromatography or
  • Active ingredients optionally also in combination with other pharmacologically active ingredients
  • Suitable forms of use are, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders.
  • Corresponding tablets can be made, for example, by mixing the active ingredient or ingredients with known ones
  • Diluents such as calcium carbonate
  • Disintegrants such as corn starch or alginic acid
  • Binders such as starch or gelatin, lubricants, such as magnesium stearate or talc, and / or agents for achieving the depot effect, such as
  • Carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate can be obtained.
  • the tablets can also consist of several layers.
  • coated tablets can be coated by coating cores produced analogously to the tablets with agents commonly used in coated tablet coatings, for example collidone or shellac, gum arabic, talc,
  • Titanium dioxide or sugar.
  • Drage cover to achieve a depot effect consist of several layers, the above in the
  • Sweeteners such as saccharin, cyclamate, glycerin or Sugar and a taste-improving agent, for example flavorings such as vanillin or orange extract,
  • suspending agents or thickeners such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
  • Injection solutions are made in the usual way, e.g. with the addition of preservatives, such as
  • the one or more active ingredients respectively
  • Capsules containing active ingredient combinations can be produced, for example, by the
  • Suitable suppositories can be produced, for example, by mixing them with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.
  • the finely ground active ingredient, milk sugar and part of the corn starch are mixed together.
  • the finely ground active ingredient part of the corn starch, milk sugar, microcrystalline cellulose and
  • Polyvinylpyrrolidone are mixed together, the mixture is sieved and processed with the rest of the corn starch and water to form a granulate which
  • Sodium carboxymethyl starch and the magnesium stearate mix and compress the mixture into tablets of a suitable size.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Ceramic Engineering (AREA)
  • Health & Medical Sciences (AREA)
  • Manufacturing & Machinery (AREA)
  • Materials Engineering (AREA)
  • Structural Engineering (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Neurosurgery (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Compositions Of Oxide Ceramics (AREA)

Abstract

Nouveaux dérivés de xanthine ayant la formule (I), leur procédé de production et leur utilisation comme médicaments.
EP91910772A 1990-06-22 1991-06-19 Nouveaux derives de xanthine Ceased EP0487673A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4019892 1990-06-22
DE4019892A DE4019892A1 (de) 1990-06-22 1990-06-22 Neue xanthinderivate

Publications (1)

Publication Number Publication Date
EP0487673A1 true EP0487673A1 (fr) 1992-06-03

Family

ID=6408865

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91910772A Ceased EP0487673A1 (fr) 1990-06-22 1991-06-19 Nouveaux derives de xanthine

Country Status (7)

Country Link
US (1) US5641784A (fr)
EP (1) EP0487673A1 (fr)
JP (1) JPH05501265A (fr)
KR (1) KR0186008B1 (fr)
CA (1) CA2064742A1 (fr)
DE (1) DE4019892A1 (fr)
WO (1) WO1992000297A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994026743A1 (fr) * 1993-05-18 1994-11-24 Boehringer Ingelheim Kg Procede ameliore de preparation de derives de xanthine, notamment de 1,3-dipropyl-8-(3-oxocyclopentyl)-xanthine

Families Citing this family (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5565566A (en) * 1987-04-24 1996-10-15 Discovery Therapeutics, Inc. N6 -substituted 9-methyladenines: a new class of adenosine receptor antagonists
US5290782A (en) * 1989-09-01 1994-03-01 Kyowa Hakko Kogyo Co., Ltd. Xanthine derivatives
CA2061544A1 (fr) * 1991-02-25 1992-08-26 Fumio Suzuki Composes de la xanthine
EP0541120B1 (fr) * 1991-11-08 1999-05-26 Kyowa Hakko Kogyo Co., Ltd. Dérivés de Xanthine pour le traitement de la démence
IT1260444B (it) * 1992-01-24 1996-04-09 Mario Brufani Derivati della 8-(1-amminocicloalchil)1,3-dialchilxantina, procedimenbto di preparazione e loro composizioni farmaceutiche antidepressive, nootropiche e psicostimolanti
EP0556778A3 (en) * 1992-02-17 1993-11-24 Kyowa Hakko Kogyo Kk Xanthine derivatives
US5484920A (en) * 1992-04-08 1996-01-16 Kyowa Hakko Kogyo Co., Ltd. Therapeutic agent for Parkinson's disease
CA2093403C (fr) * 1992-04-08 1999-08-10 Fumio Suzuki Agent de traitement de la maladie de parkinson
WO1994003173A1 (fr) * 1992-08-01 1994-02-17 Boehringer Ingelheim Kg Utilisation de 8-(3-oxocyclopentyle)-1,3-dipropyle-7h-purine-2,6-dione pour le traitement symptomatique de la fibrose cystique
TW252044B (fr) * 1992-08-10 1995-07-21 Boehringer Ingelheim Kg
DE4236331A1 (de) * 1992-10-28 1994-05-05 Boehringer Ingelheim Kg Synergistische Kombination
CN1041418C (zh) * 1993-02-26 1998-12-30 默里尔多药物公司 用作腺苷a1受体拮抗剂的黄嘌呤衍生物
NZ265790A (en) * 1993-05-06 1996-10-28 Merrell Dow Pharma 8-tetrahydronaphthyl or 2-phenyl-pentyl or -hexyl substituted xanthine derivatives and pharmaceutical compositions
US5446046A (en) * 1993-10-28 1995-08-29 University Of Florida Research Foundation A1 adenosine receptor agonists and antagonists as diuretics
US5736528A (en) * 1993-10-28 1998-04-07 University Of Florida Research Foundation, Inc. N6 -(epoxynorborn-2-yl) adenosines as A1 adenosine receptor agonists
US5789416B1 (en) * 1996-08-27 1999-10-05 Cv Therapeutics Inc N6 mono heterocyclic substituted adenosine derivatives
US5834458A (en) * 1996-10-09 1998-11-10 Eli Lilly And Company Heterocyclic compounds and their use
DE19816857A1 (de) * 1998-04-16 1999-10-21 Boehringer Ingelheim Pharma Neue unsymmetrisch substituierte Xanthin-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
US6576619B2 (en) 1999-05-24 2003-06-10 Cv Therapeutics, Inc. Orally active A1 adenosine receptor agonists
USRE47351E1 (en) 1999-06-22 2019-04-16 Gilead Sciences, Inc. 2-(N-pyrazolo)adenosines with application as adenosine A2A receptor agonists
US6403567B1 (en) * 1999-06-22 2002-06-11 Cv Therapeutics, Inc. N-pyrazole A2A adenosine receptor agonists
US6815446B1 (en) 1999-08-31 2004-11-09 Vanderbilt University Selective antagonists of A2B adenosine receptors
TR200201132T2 (tr) * 1999-08-31 2002-08-21 Vanderbilt University A2B adenosin reseptörlerinin seçici antagonistleri.
UA77391C2 (en) * 1999-11-12 2006-12-15 Biogen Inc Polycycloalkylpurines as antagonists of adenosine receptors
SK6622002A3 (en) * 1999-11-12 2003-02-04 Biogen Inc Adenosine receptor antagonists and methods of making and using the same
KR100335393B1 (ko) * 2000-02-09 2002-05-06 한상목 알루미늄 티타네이트와 점토의 복합체를 이용한 적외선 방사체의 제조방법
US20020012946A1 (en) 2000-02-23 2002-01-31 Luiz Belardinelli Method of identifying partial agonists of the A2A receptor
US7125993B2 (en) * 2001-11-09 2006-10-24 Cv Therapeutics, Inc. A2B adenosine receptor antagonists
US6977300B2 (en) * 2001-11-09 2005-12-20 Cv Therapeutics, Inc. A2B adenosine receptor antagonists
US7317017B2 (en) * 2002-11-08 2008-01-08 Cv Therapeutics, Inc. A2B adenosine receptor antagonists
PL370207A1 (en) 2001-11-09 2005-05-16 Cv Therapeutics, Inc. A2b adenosine receptor antagonists
US20080318983A1 (en) * 2001-11-09 2008-12-25 Rao Kalla A2b adenosine receptor antagonists
US7495004B2 (en) * 2002-06-17 2009-02-24 Glaxo Group Limited Purine derivatives as liver X receptor agonists
KR20050026546A (ko) 2002-07-29 2005-03-15 씨브이 쎄러퓨틱스, 인코포레이티드 Ａ2ａ 수용체 작용제를 이용한 심근 관류 조영
US8470801B2 (en) 2002-07-29 2013-06-25 Gilead Sciences, Inc. Myocardial perfusion imaging methods and compositions
US20050020915A1 (en) 2002-07-29 2005-01-27 Cv Therapeutics, Inc. Myocardial perfusion imaging methods and compositions
US20040229901A1 (en) * 2003-02-24 2004-11-18 Lauren Otsuki Method of treatment of disease using an adenosine A1 receptor antagonist
US20060293312A1 (en) * 2003-04-25 2006-12-28 Howard Dittrich Method of improved diuresis in individuals with impaired renal function
EP1620107A1 (fr) * 2003-04-25 2006-02-01 Novacardia, Inc. Methode pour ameliorer la diurese chez des personnes a fonction renale alteree
EP1755594A1 (fr) * 2004-04-16 2007-02-28 Novacardia, Inc. Therapie combinee impliquant un antagoniste de recepteur d'adenosine a1 et un inhibiteur d'aldosterone
NZ553487A (en) * 2004-09-01 2010-09-30 Gilead Palo Alto Inc Method of wound healing using A2B adenosine receptor antagonists
WO2006044856A2 (fr) 2004-10-20 2006-04-27 Cv Therapeuitics, Inc. Utilisation d'agonistes du recepteur de l'adenosine a2a
KR101494125B1 (ko) 2006-02-03 2015-02-16 길리애드 사이언시즈, 인코포레이티드 Ａ2ａ-아데노신 수용체 효능제 및 이의 다형체의 제조 방법
JP2009540003A (ja) * 2006-06-16 2009-11-19 ノヴァカーディア，インク． Ａａ１ｒａの低頻度投与を含む腎機能の長期間にわたる改善
US20090081120A1 (en) * 2006-09-01 2009-03-26 Cv Therapeutics, Inc. Methods and Compositions for Increasing Patient Tolerability During Myocardial Imaging Methods
US20080213165A1 (en) * 2006-09-01 2008-09-04 Cv Therapeutics, Inc. Methods and Compositions for Increasing Patent Tolerability During Myocardial Imaging Methods
US20080170990A1 (en) * 2006-09-29 2008-07-17 Cv Therapeutics, Inc. Methods for Myocardial Imaging in Patients Having a History of Pulmonary Disease
CA2673653A1 (fr) * 2007-01-03 2008-07-17 Cv Therapeutics, Inc. Imagerie de perfusion myocardique
US20080242684A1 (en) * 2007-03-29 2008-10-02 Howard Dittrich Methods of administration of adenosine a1 receptor antagonists
US20090197900A1 (en) * 2007-03-29 2009-08-06 Howard Dittrich Methods of treating heart failure and renal dysfunction in individuals with an adenosine a1 receptor antagonist
BRPI0918962A2 (pt) * 2008-09-29 2015-12-01 Gilead Sciences Inc combinações de um agente de controle de taxa e um antagonista do receptor a-2-alfa para utilização em métodos tomografia computadorizada de multidetectores
KR101110368B1 (ko) * 2010-04-30 2012-02-15 한국세라믹기술원 내열 충격저항성 산화물 소결체 및 그 제조방법
LT2794627T (lt) 2011-12-22 2019-01-10 Alios Biopharma, Inc. Pakeistieji nukleozidai, nukleotidai ir jų analogai
USRE48171E1 (en) 2012-03-21 2020-08-25 Janssen Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US9441007B2 (en) 2012-03-21 2016-09-13 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3624215A (en) * 1970-06-25 1971-11-30 Abbott Lab 8-substituted theophyllines as anti-anxiety agents
US4061753A (en) * 1976-02-06 1977-12-06 Interx Research Corporation Treating psoriasis with transient pro-drug forms of xanthine derivatives
FR2531085A1 (fr) * 1982-07-28 1984-02-03 Adir Nouveaux derives de la xanthine, leur procede de preparation et les compositions pharmaceutiques les renfermant
US4612315A (en) * 1984-10-26 1986-09-16 The United States Of America As Represented By The Department Of Health And Human Services Biologically-active 1,3-dipropyl-8-phenylxanthine derivatives
DE3525801A1 (de) * 1985-07-19 1987-01-22 Hoechst Ag Tertiaere hydroxyalkylxanthine, verfahren zu ihrer herstellung, die sie enthaltenden arzneimittel und ihre verwendung
US4755517A (en) * 1986-07-31 1988-07-05 Warner-Lambert Company Derivatives of xanthine, pharmaceutical compositions and methods of use therefor
DE8817122U1 (fr) * 1988-12-22 1993-02-04 Boehringer Ingelheim Kg, 6507 Ingelheim, De
JP2843634B2 (ja) * 1989-03-06 1999-01-06 協和醗酵工業株式会社 キサンチン誘導体
JPH06102662B2 (ja) * 1989-09-01 1994-12-14 協和醗酵工業株式会社 キサンチン誘導体
US5290782A (en) * 1989-09-01 1994-03-01 Kyowa Hakko Kogyo Co., Ltd. Xanthine derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9200297A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994026743A1 (fr) * 1993-05-18 1994-11-24 Boehringer Ingelheim Kg Procede ameliore de preparation de derives de xanthine, notamment de 1,3-dipropyl-8-(3-oxocyclopentyl)-xanthine

Also Published As

Publication number Publication date
DE4019892A1 (de) 1992-01-02
KR920000662A (ko) 1992-01-29
US5641784A (en) 1997-06-24
CA2064742A1 (fr) 1991-12-23
WO1992000297A1 (fr) 1992-01-09
JPH05501265A (ja) 1993-03-11
KR0186008B1 (ko) 1999-04-15

Similar Documents

Publication Publication Date Title
WO1992000297A1 (fr) Nouveaux derives de xanthine
EP0374808B1 (fr) Dérivés de xanthine à activité antagoniste d'adénosine
EP0287907B1 (fr) Pyrazolo[3,4-d]pyrimidines, procédé pour leur préparation et leur utilisation comme médicaments
DE60016566T2 (de) Triazolopyridazinderivate als liganden für gaba-rezeptoren
EP0194416B1 (fr) Thiéno-triazolo-1,4-diazépino-2-carboxamides, leur procédé de préparation et composition pharmaceutique
EP0458214A1 (fr) Aza-1 bicyclo-alcanes
DE10327439A1 (de) Neue Imidazopyridazinon- und Imidazopyridonderivate, deren Herstellung und deren Verwendung als Arzneimittel
DE3724164A1 (de) Neue 1,4-benzodiazepine, ihre herstellung und verwendung
EP0240899A2 (fr) 1,4-Diazépines
DE69907675T2 (de) Ein substituiertes triazolo-pyridazin-derivat, davon hergestellte arzneimittel
EP0222693A2 (fr) Dérivés de 3-oxadiazolyl et 3-acide carboxylique bêta-carboline, leur préparation et leur utilisation comme médicament
EP0214592B1 (fr) Pyrrolobenzimidazoles, procédé pour leur préparation et médicaments contenant ces composés
DE4116582A1 (de) Bicyclische 1-aza-cycloalkane
EP0255028A2 (fr) 1,4-Benzodiazépines, leur préparation et utilisation comme antagonistes PAF
DE2330990A1 (de) Vincaminderivate, verfahren zur herstellung von vincamin und dessen derivaten, sowie diese vincaminderivate als wirkstoff enthaltende arzneimittel
EP0880524A1 (fr) Nouvelles triazolopurines, procede pour les preparer et leur utilisation comme medicaments
DE3721223C2 (fr)
EP0621037A1 (fr) Composés pyrido-pyrimidinediones, leur préparation et leur utilisation pharmaceutique
EP0290003A2 (fr) Imidazoles
EP0812844A2 (fr) Utilisation de dérivés dt théophylline pour la prophylaxie et le traitement des conditions de choc, nouveaux composés à base de xanthine et leurs procédés de préparation
DE3217236C2 (de) 5,6-Dihydro-11H-dibenzo [b,e]- azepin-6-one, sowie diese enthaltende pharmazeutische Zusammensetzungen
DE2530005C3 (de) 6,11-Dihydrodibenzo [b,e] thiepin-Derivate und deren Salze, Verfahren zu ihrer Herstellung und diese Substanzen enthaltende pharmazeutische Zubereitungen
DE3151597A1 (de) (1,2)-anellierte 1,4-benzodiazepin-verbindungen sowie verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
CH626373A5 (fr)
EP0357043A2 (fr) Dérivés d'imidazodiazépine

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19920123

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

17Q First examination report despatched

Effective date: 19970418

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BOEHRINGER INGELHEIM INTERNATIONAL GMBH

Owner name: BOEHRINGER INGELHEIM PHARMA KG

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

RTI1 Title (correction)

Free format text: XANTHINE DERIVATIVES WITH ADENOSINE ANTAGONISTIC ACTIVTY

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED

18R Application refused

Effective date: 20000207