EP0654033A1 - Xanthine substituee asymetriquement ayant des proprietes antagonistes de l'adenosine - Google Patents

Xanthine substituee asymetriquement ayant des proprietes antagonistes de l'adenosine

Info

Publication number
EP0654033A1
EP0654033A1 EP93917743A EP93917743A EP0654033A1 EP 0654033 A1 EP0654033 A1 EP 0654033A1 EP 93917743 A EP93917743 A EP 93917743A EP 93917743 A EP93917743 A EP 93917743A EP 0654033 A1 EP0654033 A1 EP 0654033A1
Authority
EP
European Patent Office
Prior art keywords
och
conr
substituted
general formula
coor
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.)
Withdrawn
Application number
EP93917743A
Other languages
German (de)
English (en)
Inventor
Ulrike Küfner-Mühl
Helmut Ensinger
Joachim Mierau
Franz Josef Kuhn
Erich Lehr
Enzio MÜLLER
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 EP0654033A1 publication Critical patent/EP0654033A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications

Definitions

  • the present invention relates to new xanthine derivatives, processes for their preparation and their use as medicaments and their use as intermediates.
  • R 1 cannot have the meaning of R 2 at the same time and how
  • R 1 is hydrogen, R 1 -C 6 -alkyl, preferably methyl, ethyl, n-butyl, or allyl, particularly preferably n-propyl,
  • R 2 is hydrogen, an R 1 -C 8 alkyl
  • -CH CH-R 10 , -OCONR 6 R 7 , -CH 2 -O-CONR 6 R 7 ,
  • R 2 is a radical of the formula
  • AC 1 -C 6 alkenylene or AC 1 -C 6 alkynylene, where A is a C- or N-linked 5- or 6-membered heterocyclic ring which contains nitrogen or sulfur as heteroatoms and
  • R 3 C 3 -C 7 cycloalkyl, preferably cyclopentyl, which is optionally substituted by O, -OH, -OR 8 , OCOR 8 or
  • R 3 is phenyl, optionally substituted by -OH, halogen, -OR 8 , C 1 -C 4 alkyl, -CH 3 -, -NH 2 , -COOH, -SO 3 H, -COOR 8 , -OCH 2 COOR 8 , -CN, -OCH 2 CONR 6 R 7 is substituted or
  • R 3 is a norbornane, norbornene, a C 3 -C 6 dicycloalkylmethyl
  • R 3 -CH CH-phenyl, with the phenyl ring one or more times
  • R 3 is a [3,3,0] bicyclooctane; preferably a [3,3,0] bicyclooctan-2-yl;
  • R 3 is a C-linked piperidine or furan
  • R 4 is hydrogen, methyl or benzyl where the benzyl group can be substituted by 1-3 methoxy groups
  • R 5 C 1 - C 4 alkyl which is optionally substituted by OH, OCOR 8 , NH 2 , NR 6 R 7 or NHCOR 8 , preferably -CH 2 -CH 2 -OH, -CH 2 CH 2 OCOR 8 , - CH 2 -CH 2 -CH 2 -OH; -CH 2 -CH 2 CH 2 OCOR 8 ;
  • R 6 is hydrogen, an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, a branched or unbranched alkyl,
  • C 1 to C 4 alkoxy can preferably be substituted
  • R 7 is hydrogen, an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, a branched or unbranched alkyl,
  • C 1 to C 4 alkoxy may be substituted, - (CH 2 ) m -NHCOOR 8 with m 1, 2, 3 or 4;
  • R 6 and R 7 together with the nitrogen atom form a saturated or unsaturated 5- or 6-ring which may contain nitrogen, oxygen or sulfur as heteroatoms, the heterocycle being represented by a branched or unbranched alkyl group having 1 to 4
  • R 8 is hydrogen, C 1 -C 4 alkyl
  • R 9 C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, if appropriate
  • R 10 -COOR 8 , -CH 2 OR 8 , -CONR 6 R 7 , hydrogen, C 1 -C 3 alkyl,
  • R 11 is hydrogen phenyl, substituted phenyl, -CH 3 ; optionally in the form of their racemates, their enantiomers, their
  • Preferred compounds of general formula I are those in which
  • R 1 methyl, ethyl, n-butyl, allyl, n-propyl is particularly preferred;
  • R 2 is a C 2 - or an unbranched C 3 alkyl radical, which by
  • R 2 is a benzyl or phenethyl or phenylpropyl radical which is replaced by one of the following radicals
  • phenyester can also be substituted three times; a C 3 -, C 4 -, C 5 - or
  • R 2 is a radical of the formula
  • A-CO-NH-CH 2 - A-CO-NH-CH 2 -CH 2 -, or
  • A is a C- or N-linked 5- or 6-membered heterocyclic
  • Ring which contains nitrogen or sulfur as heteroatoms and optionally one or more times by C 1 -C 4 alkyl, O, OH,
  • R 2 an unbranched C 2 -C 5 alkyl radical which is replaced by -CN, -OH, SO 2 -R 5 ,
  • radicals R 2 of the general formulas I and Ia are:
  • radicals are particularly preferred
  • R 3 is a residue from the group
  • alkyl groups (also insofar as they are part of other radicals) are meant branched and unbranched alkyl groups with ibis 10 carbon atoms, preferably 1-4 carbon atoms, for example the following are mentioned: methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec Butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl and octyl.
  • alkenyl groups branched and unbranched alkenyl groups with 2 to 10 carbon atoms, preferably 2 to 3 carbon atoms, are mentioned, provided that they have at least one double bond, for example also alkyl groups mentioned above, if they have at least one double bond, such as vinyl (provided that no unstable enamines or Enol ether are formed), propenyl, iso-propenyl, butenyl, pentenyl, hexenyl.
  • Alkynyl groups with 2 to 10 carbon atoms are designated as alkynyl groups insofar as they have at least one triple bond,
  • Cycloalkyl radicals with 3 to 6 carbon atoms are, for example
  • Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl which can also be substituted by branched or unbranched alkyl having 1 to 4 carbon atoms, hydroxy, and / or halogen or as previously defined.
  • Halogen is generally referred to as fluorine, chlorine, bromine or iodine.
  • cyclic radicals of the general formula NR 6 R 7 are: pyrrole, pyrroline, pyrrolidine, 2-methylpyrrolidine, 3-methylpyrrolidine, piperidine, piperazine, N-methylpiperazine, N-ethylpiperazine, N- (n-propyl) piperazine , N-benzylpiperazine, morpholine, thiomorpholine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine - wherein the heterocycles mentioned can be substituted by alkyl having 1 to 4 carbon atoms - preferably methyl - or carry one of the following radicals
  • C-linked 5- or 6-membered heterocyclic rings which can contain nitrogen, oxygen or sulfur as heteroatoms, for example tetrahydrofuran, 2-methyltetrahydrofuran, 2-hydroxymethylfuran,
  • Xanthine derivatives with high adenosine A 1 affinity promote neurotransmission in the brain and can, for example, be regarded as functional cholinomimetics.
  • Such substances are of great interest for the symptomatic therapy of degenerative diseases of the central nervous system, such as dementia senilis and Alzheimer's disease.
  • the high receptor affinity should make it possible to treat with low doses, so that side effects that are not attributable to the blocking of adenosine receptors can hardly be expected.
  • adenosine antagomsten could be useful for the treatment of cardiovascular diseases and in the treatment of respiratory diseases - in particular bronchial asthma.
  • xanthines of the general formula I show diuretic properties and are therefore for the treatment of
  • Kidney diseases and due to diuresis also of interest for the treatment of high blood pressure.
  • a 1 antagonists increase the efflux of chloride ions, for example in CF PAC cells.
  • the cells originate from a pancreatic adenocarcinoma cell line which was isolated from patients suffering from cystic fibrosis (CF). The action could be blocked by agonists such as 2-chloroadenosine. Interestingly, an increase in efflux was only observed in cells that came from sick patients or that had the corresponding gene defect.
  • Adenosine antagomes can be used to treat lung diseases, in particular asthma, allergic lung diseases and chronic obstructive lung diseases. It is to be expected that the compounds according to the invention, due to their high potency, are also suitable for the inhalative treatment of lung diseases.
  • the receptor binding values were determined in analogy to Ensinger et al. in "Cloning and functional characterization of human A 1 adenosine Receptor - Biochemical and Biophysical Communications, Vol 187, No. 2, 919-926, 1992".
  • locomotor activity in mice adenosine antagonism:
  • Subcutaneous administration of an adenosine agonist can induce locomotor inhibition in mice in the hour following application. It is examined how a test substance influences this hypomotility.
  • the measurements for this experiment record the number of light barrier interruptions in motility chambers. Registration begins immediately after administration of the substance by computer. It is only evaluated the first hour after application, since the adenosine agonist's effects occur during this period.
  • mice which are both the adenosine agonists and the
  • the compounds of the invention can be prepared according to known methods
  • Analogy processes can be produced, such as in the
  • Synthesis schemes I, II and III is shown.
  • the synthesis of xanthines is well known to the person skilled in the art, but will be explained again in detail in the following experimental section on the basis of important key compounds.
  • a characteristic feature of the synthesis shown in synthesis plan I is that R 2 'has already been introduced at the stage of the diaminouracil (III).
  • R 2 ' is a functional radical selected from the group of definitions of R 2 with the proviso that R 2 ' does not interfere with the structure of the xanthine and before or after
  • R 4 preferably benzyi
  • formula VIII can be converted into the desired R 2 'of the general formula I.
  • a preferred radical R 2 ' is, for example, a methoxybenzyl group.
  • R 3 is introduced by aminoacylation and subsequent ring closure to form xanthine.
  • R 1 is now introduced into the protected xanthine VI by N-alkylation.
  • R 4 Conversion of R 4 into hydrogen. If R 2 'does not yet have the desired meaning R 2 of the end compound I, R 2 ' can now be converted into R 2 . (Formula VIa) and, if not already done, the protective group is then split off. Examples of this are described in the general work instructions under points 12 and 14 to 23.
  • R 2 'into R 2 can be prepared in a simple manner compounds of the general formula I.
  • the invention thus also relates to a simple - generally applicable manufacturing process for the synthesis of substituted in the 1- and 3-position
  • Xanthine derivatives in which R 1 and R 2 can represent any radicals, provided that they can be introduced by an electrophilic reaction.
  • acylation position (5- or 6-position) is irrelevant for the subsequent reaction and has not been determined.
  • acylation position (5- or 6-position) is irrelevant for the subsequent reaction and has not been determined.
  • methyl ether derivative 0.5 mmol methyl ether derivative are dissolved in 5 ml absolute acetonitrile. 300 mg (40 mmol) of sodium iodide are added and then 0.39 ml (3.0 mmol)
  • Washed sodium thiosulfate solution knocked over sodium sulfate and concentrated to dryness. If necessary, the product is purified by crystallization or chromatography.
  • N-benzyl compound 0.01 mol are hydrogenated together with 0.5 g of palladium on activated carbon or Pearlman catalyst in methanol, tetrahydrofuran or in glacial acetic acid under pressure and, if necessary, with heating until the
  • N-benzyl compound 3.3 mmol of N-benzyl compound are dissolved in 70 ml of absolute methylene chloride. 3.36 g (52.8 mmol) of ammonium formate and 1.32 g of Pearlman catalyst are added and the suspension is stirred at the reflux temperature for 2 hours. After cooling, filter through diatomaceous earth and concentrate the filtrate to dryness. If necessary, the residue is purified by crystallization or chromatography.
  • Toothed hydrogenolysis was carried out according to this method, among others one obtains: a) from
  • nitrile derivative 3.3 mmol are dissolved in 40 ml of methanol and 10.5 ml of 25% aqueous ammonia solution and hydrogenated under pressure in the presence of Raney nickel, if necessary with heating, until the starting compound is completely reacted.
  • Output connection is fully implemented. It is extracted with dist. Water and dilute hydrochloric acid, the organic phase dries over sodium sulfate and evaporates it to dryness. The residue is purified by crystallization or by chromatography.
  • R 1 n-propyl
  • R 3 cyclopentyl
  • R 4 hydrogen
  • Suitable forms of use are, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders.
  • Corresponding tablets can be mixed, for example, by mixing the active substance or substances with known auxiliary substances, for example inert diluents, such as
  • Calcium carbonate calcium phosphate or milk sugar
  • 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 produced by coating cores produced analogously to the tablets with agents commonly used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • agents commonly used in tablet coatings for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the core can also consist of several layers.
  • the coated tablet can also be used to achieve a
  • Combinations of materials can additionally contain a sweetener, such as
  • Saccharin, cyclamate, glycerin or sugar as well as a taste-improving agent, e.g. Flavorings, such as vanillin or orange extract, contain.
  • Flavorings such as vanillin or orange extract. You can also use suspending aids or thickeners, such as
  • Preservatives such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediamine tetraacetic acid, and prepared in
  • Bottled injection bottles or ampoules The capsules containing one or more tools or combinations of tools can be produced, for example, by mixing the tools with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatin capsules.
  • inert carriers such as lactose or sorbitol
  • Suitable suppositories can be produced, for example, by mixing them with carriers, such as new fats or polyethylene glycol or its derivatives.
  • a therapeutically effective daily dose is between 1 and 800 mg, preferably 10-300 mg per adult.
  • the finely ground active ingredient, milk sugar and part of the corn starch are mixed together.
  • the mixture is sieved, whereupon it is moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried.
  • the granules, the rest of the corn starch and the magnesium stearate are sieved and mixed together.
  • the mixture is compressed into tablets of a suitable shape and size.
  • 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 is kneaded and sieved.
  • the sodium carboxymethyl starch and the magnesium stearate are added, and the mixture is mixed and pressed into tablets of a suitable size.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Neurology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Cardiology (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux dérivés de xanthine, leur procédé de fabrication et leur utilisation comme médicaments, ainsi que leur utilisation comme composés intermédiaires.
EP93917743A 1992-08-10 1993-08-05 Xanthine substituee asymetriquement ayant des proprietes antagonistes de l'adenosine Withdrawn EP0654033A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE4226371 1992-08-10
DE4226371 1992-08-10
DE4238423 1992-11-13
DE4238423 1992-11-13
PCT/EP1993/002077 WO1994003456A1 (fr) 1992-08-10 1993-08-05 Xanthine substituee asymetriquement ayant des proprietes antagonistes de l'adenosine

Publications (1)

Publication Number Publication Date
EP0654033A1 true EP0654033A1 (fr) 1995-05-24

Family

ID=25917371

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93917743A Withdrawn EP0654033A1 (fr) 1992-08-10 1993-08-05 Xanthine substituee asymetriquement ayant des proprietes antagonistes de l'adenosine

Country Status (21)

Country Link
US (1) US5719279A (fr)
EP (1) EP0654033A1 (fr)
JP (1) JPH08500344A (fr)
KR (1) KR950702988A (fr)
CN (1) CN1043348C (fr)
AU (1) AU681348B2 (fr)
BG (1) BG62618B1 (fr)
CA (1) CA2140883A1 (fr)
CZ (1) CZ286459B6 (fr)
FI (1) FI950542A0 (fr)
HU (1) HUT65734A (fr)
IL (1) IL106624A (fr)
MX (1) MX9304819A (fr)
NZ (1) NZ254804A (fr)
PL (1) PL176389B1 (fr)
RU (1) RU2138500C1 (fr)
SG (1) SG55038A1 (fr)
SK (1) SK18595A3 (fr)
TW (1) TW252044B (fr)
UA (1) UA46697C2 (fr)
WO (1) WO1994003456A1 (fr)

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PL307397A1 (en) 1995-05-15
AU681348B2 (en) 1997-08-28
CA2140883A1 (fr) 1994-02-17
AU4707193A (en) 1994-03-03
FI950542A (fi) 1995-02-08
SK18595A3 (en) 1995-07-11
RU95109100A (ru) 1996-12-27
IL106624A0 (en) 1993-12-08
IL106624A (en) 1999-01-26
PL176389B1 (pl) 1999-05-31
MX9304819A (es) 1994-02-28
WO1994003456A1 (fr) 1994-02-17
BG62618B1 (bg) 2000-03-31
UA46697C2 (uk) 2002-06-17
JPH08500344A (ja) 1996-01-16
US5719279A (en) 1998-02-17
NZ254804A (en) 1997-01-29
CN1043348C (zh) 1999-05-12
BG99489A (bg) 1996-01-31
RU2138500C1 (ru) 1999-09-27
SG55038A1 (en) 1998-12-21
HU9302302D0 (en) 1993-10-28
CZ286459B6 (en) 2000-04-12
FI950542A0 (fi) 1995-02-08
CZ34895A3 (en) 1995-10-18
KR950702988A (ko) 1995-08-23
HUT65734A (en) 1994-07-28
CN1086818A (zh) 1994-05-18

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