WO1992003463A1 - Nouveaux derives de l'adenosine, preparation et utilisation - Google Patents

Nouveaux derives de l'adenosine, preparation et utilisation Download PDF

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Publication number
WO1992003463A1
WO1992003463A1 PCT/CH1991/000170 CH9100170W WO9203463A1 WO 1992003463 A1 WO1992003463 A1 WO 1992003463A1 CH 9100170 W CH9100170 W CH 9100170W WO 9203463 A1 WO9203463 A1 WO 9203463A1
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WO
WIPO (PCT)
Prior art keywords
carbonate
purinyl
deoxy
ethylamide
adenosine
Prior art date
Application number
PCT/CH1991/000170
Other languages
German (de)
English (en)
Inventor
Fulvio Gadient
Original Assignee
Sandoz Ltd.
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 Sandoz Ltd. filed Critical Sandoz Ltd.
Priority to KR1019920700868A priority Critical patent/KR920702369A/ko
Priority to TW080109279A priority patent/TW197448B/zh
Publication of WO1992003463A1 publication Critical patent/WO1992003463A1/fr
Priority to CS92978A priority patent/CS97892A3/cs
Priority to FI921691A priority patent/FI921691A0/fi

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61P9/12—Antihypertensives
    • 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
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the invention relates to new adenosine-2 ', 3'-carbonates, processes for their preparation and their use and others. to treat high blood pressure.
  • the invention particularly relates to compounds of the formula
  • R 1 is (C 1-6 ) alkyl, (C 3-8 ) cycloalkyl, phenyl or phenyl (C 1-6 ) alkyl, where the phenyl rings are each optionally independently of one another by halogen with an atomic number of 9 to 35, (C 1- 4 ) alkyl, (C 1-4 ) alkoxy and / or.
  • CF 3 can be mono- or disubstituted and in the case of phenylalkyl the alkylene chain is straight or branched.
  • R 2 represents hydrogen, (C 1-4 ) alkyl, halogen with an atomic number of 9 to 35 or (C 3-8 ) cycloalkyl
  • R 3 represents groups of the formulas -CH 2 OH or -CONHR 4 in which R 4 represents hydrogen, (C 1-6 ) alkyl or (C 3-8 ) cycloalkyl and X represents 0 or S.
  • R 2 is hydrogen or halogen with an atomic number of 9 to 35
  • R 3 is the group of the formula -CONH (C 1-6 ) alkyl
  • R 1 a p-methoxyphenyl, p-chlorophenyl,
  • R 2 a is hydrogen or methyl
  • X stands for 0 or S.
  • halogen with an atomic number of 9-35 represents fluorine, chlorine or bromine, preferably fluorine or chlorine
  • a (C 1-4 ) alkyl group represents methyl, ethyl, n-propyl, i-propyl, n-butyl , i-butyl, tert-butyl and if the alkyl group has up to 6 carbon atoms also for n-pentyl, i-pentyl, 3-pentyl, n-hexyl, i-hexyl, etc.
  • (C 3-8 ) cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, especially cyclopentyl or cyclohexyl.
  • the phenyl ring can be substituted in the o-, m- or p-position, the substituents preferably being in the m- and p- positions and, in the case of monsubstitution in the m- or p-position, but preferably in the p-position.
  • phenylalkyl the alkylene chain and phenyl substitution are as discussed above.
  • Adenosine carbonates are known from US Pat. No. 4,167,565, from which the present application is delimited.
  • the known adenosine carbonates serve a different purpose than the compounds of the present invention - they are used to control unwanted animals such as rodents, coyotes and birds.
  • R 1 , R 2 and X have the above meaning 4,4'-dimethoxytrityl protecting group is tet.
  • R 1 , R 2 and R 4 have the above meaning.
  • Group in compounds of the formula III is advantageously carried out by reacting them with, for example, 1,1'-carbonyl- or 1,1'-thiocarbonyl-diimidazole in a solvent such as dimethylformamide with stirring for 5 hours at room temperature.
  • the compound of formula III are known for example from DE-OS 3810551.
  • the compounds of the formula II can be prepared, for example, by using compounds of the formula
  • R 2 and DMT have the above meaning with a compound of the formula R 1 -NH 2 in which R 1 has the above meaning in a solvent such as dioxane at the boiling point of the reaction mixture and in the compounds of the formula formed thereby
  • 1,1'-thiocarbonyl-diimidazole in a solvent such as dimethylformamide with stirring for 5 hours at room temperature.
  • the product is eluted on silica gel with a mixture of ethyl acetate / n-hexane 8: 2.
  • the 6-cyclohexyl-5 '- (4,4'-dimethoxytrityl) adenosine-2', 3'-carbonate used as the starting material can e.g. are prepared as follows: a) A solution of 14 g of 4,4'-dimethoxytrityl- chloride in 96 ml of dimethylformamide and the mixture is stirred for 1 hour at room temperature. The solvent is then distilled off in a high vacuum at 35 ° and the residue is partitioned between ethyl acetate and ice water. The organic extracts are dried over sodium sulfate and concentrated, and the residue is eluted on silica gel with a mixture of ethyl acetate / hexane 8: 2.
  • the purified 6-chloro-5 '- (4,4'-dimethoxytrityl) adenosine is obtained as a foam and has an Rf value of 0.6 in ethyl acetate.
  • b) 5 g of 6-chloro-5 '- (4,4'-dimethoxytrityl) adenosine and 2.95 ml of cyclohexylamine in 30 ml of dioxane are stirred in an oil bath at 105 ° for 2 hours. It is then cooled, filtered and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and extracted with cold 0.1 N hydrochloric acid.
  • 6-cyclohexyl-5 '- (4,4'-dimethoxytrityl) adenosine is a foam and has an Rf value of 0.5 in ethyl acetate.
  • the solvent is then distilled off at 35 ° in a high vacuum and the residue is partitioned between ethyl acetate and ice water.
  • the aqueous phase is extracted three more times with ethyl acetate and the organic extracts are dried over sodium sulfate.
  • the residue is chromatographed on silica gel with a mixture of ethyl acetate / hexane 8: 2.
  • the 6-cyclohexyl-5 '- (4,4'-dimethoxytrityl) adenosine-2', 3'-carbonate is a foam and has an Rf value of 0.8 in ethyl acetate.
  • the compounds according to the invention are distinguished by interesting pharmacological properties. They can therefore be used as medicines.
  • the compounds according to the invention have an antihypertensive effect, as can be seen from the results of the following tests:
  • Noradrenaline from nerve endings as well as direct vasodilation are involved. It follows from this that the compounds according to the invention are not only usable as antihypertensives, but also have a protective effect in the case of heart failure. They reduce the workload on the heart by inhibiting renin secretion and neurotransmitters Release, reduce the afterload. Coronary vasodilation also improves the metabolism of the heart. Both the quality and the duration of life are considered
  • peripheral vasodilators As peripheral vasodilators, they expand the blood vessels directly, increase blood circulation and thus the oxygen supply to the tissues. Above all, this increase in nutritional blood flow affects the ischemic skeletal muscle. For the compounds of the invention, this results in a potential for the treatment of peripheral vascular diseases such as intermittent claudication and Raynaud's disease. Furthermore, coronary vasodilation leads to the suppression or improvement of myocardial ischemia and thus angina pectoris.
  • the compounds according to the invention also act on
  • arrhythmias As adenosine AI receptor agonists, they lead to normal sinus rhythm in supraventricular and ß-adrenergically stimulated ventricular tachycardias.
  • the compounds according to the invention also have a neuroprotective effect. They can therefore also be used for the prophylaxis of peripheral vascular diseases that are associated with neuronal degeneration. They also reduce thrombus formation by inhibiting platelet aggregation and protect the vascular endothelium by preventing the
  • the compounds according to the invention lower the plasma insulin without affecting the glucose tolerance. They potentiate glucose uptake in adipose tissue. This insulin-saving effect can be used for the treatment of type II diabetes. They also lower blood lipids, an effect that favorably affects arteriosclerosis, the cause of many cardiovascular diseases flows.
  • the dose to be used varies depending on the substance used, the mode of administration and the desired treatment. In general, however, satisfactory results are achieved with a daily dose of approximately 0.01 to approximately 10 mg per kg body weight; if necessary, it can be administered in 2 to 4 portions or as a slow-release form.
  • the daily dose ranges from about 1 to about 500 mg; suitable dosage forms for e.g. Oral or non-oral administration generally contain from about 5 to about 250 mg of a compound of formula I in addition to solid or liquid carriers.
  • the compounds according to the invention can be administered alone or in a suitable dosage form.
  • the dosage forms e.g. a solution or a tablet can be prepared analogously to known methods.
  • the invention therefore also relates to medicaments which contain the compounds according to the invention in free form or in the form of their physiologically tolerable salts, and also the

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

On revendique des adénosines-2',3'-carbonates de formule (I) dans laquelle R1-R3 et X possèdent la notation indiquée dans la revendication (1), des procédés pour leur préparation et leur utilisation pour le traitement des élévations de la pression artérielle, la protection contre les insuffisances cardiaques, la vasodilatation périphérique et coronaire, la réduction de la formation de thrombi, la protection de l'endothélium vasculaire, l'abaissement de la proportion de lipides dans le sang, l'amélioration de la tolérance au glucose et l'abaissement du taux de plasma-insuline, comme anti-arythmiques dans les tachycardies supraventriculaires, ainsi que pour le traitement de la claudication intermittente et de la maladie de Reynaud.
PCT/CH1991/000170 1990-08-16 1991-08-13 Nouveaux derives de l'adenosine, preparation et utilisation WO1992003463A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
KR1019920700868A KR920702369A (ko) 1990-08-16 1991-08-13 신규 아데노신 유도체, 그것의 제조방법 및 사용방법
TW080109279A TW197448B (fr) 1990-08-16 1991-11-26
CS92978A CS97892A3 (en) 1990-08-16 1992-04-01 Adenosine derivatives, process of their preparation and therapeuticalcompositions comprising said derivatives
FI921691A FI921691A0 (fi) 1990-08-16 1992-04-15 Nya adenosinderivat, deras framstaellning och anvaendning.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4025879A DE4025879A1 (de) 1990-08-16 1990-08-16 Neue adenosin derivate, deren herstellung und verwendung
DEP4025879.3 1990-08-16

Publications (1)

Publication Number Publication Date
WO1992003463A1 true WO1992003463A1 (fr) 1992-03-05

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CH1991/000170 WO1992003463A1 (fr) 1990-08-16 1991-08-13 Nouveaux derives de l'adenosine, preparation et utilisation

Country Status (11)

Country Link
EP (1) EP0496852A1 (fr)
JP (1) JPH05502889A (fr)
AU (1) AU638600B2 (fr)
CA (1) CA2064869A1 (fr)
CS (1) CS97892A3 (fr)
DE (1) DE4025879A1 (fr)
FI (1) FI921691A0 (fr)
HU (1) HUT60504A (fr)
PL (1) PL294368A1 (fr)
TW (1) TW197448B (fr)
WO (1) WO1992003463A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994007904A1 (fr) * 1992-10-01 1994-04-14 Mcneilab, Inc. Derives de guanosines a disubstitution en positions 7,8
WO1994017090A1 (fr) * 1993-01-20 1994-08-04 Glaxo Group Limited Derives de la 2,6-diaminopurine

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114437159B (zh) * 2022-04-11 2022-06-28 佛山市晨康生物科技有限公司 一种环状碳酸酯核苷类化合物及其应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4167565A (en) * 1976-11-08 1979-09-11 Abbott Laboratories Adenosine-5'-carboxamides and method of use
US4514405A (en) * 1981-09-17 1985-04-30 Merck Patent Gesellschaft Mit Beschrankter Haftung Use of adenosine derivatives as anticonvulsants
EP0152944A2 (fr) * 1984-02-23 1985-08-28 Roche Diagnostics GmbH Utilisation de dérivés d'adénosine comme produit anti-allergique, et médicaments les contenant
EP0179667A2 (fr) * 1984-10-26 1986-04-30 Warner-Lambert Company Adénosines N6-substituées

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4167565A (en) * 1976-11-08 1979-09-11 Abbott Laboratories Adenosine-5'-carboxamides and method of use
US4514405A (en) * 1981-09-17 1985-04-30 Merck Patent Gesellschaft Mit Beschrankter Haftung Use of adenosine derivatives as anticonvulsants
EP0152944A2 (fr) * 1984-02-23 1985-08-28 Roche Diagnostics GmbH Utilisation de dérivés d'adénosine comme produit anti-allergique, et médicaments les contenant
EP0179667A2 (fr) * 1984-10-26 1986-04-30 Warner-Lambert Company Adénosines N6-substituées

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Carbohydrate Research, Band 109, 1982, Elsevier Scientific Publishing Company, (Amsterdam, NL), Ichiro Hirao et al.:" Bis(tributylin) oxide-phenyl isocyanate system for regioselective(phenylcarbamoyl)ation of purine and pyrimidine ribonucleosides", Seiten 181-205, siehe Seite 182, Verbindung 2 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994007904A1 (fr) * 1992-10-01 1994-04-14 Mcneilab, Inc. Derives de guanosines a disubstitution en positions 7,8
WO1994017090A1 (fr) * 1993-01-20 1994-08-04 Glaxo Group Limited Derives de la 2,6-diaminopurine
AU679714B2 (en) * 1993-01-20 1997-07-10 Glaxo Group Limited 2,6-diaminopurine derivatives
US5889178A (en) * 1993-01-20 1999-03-30 Glaxo Group Limited 2-6-diaminopurine precursors
US5925624A (en) * 1993-01-20 1999-07-20 Glaxo Group Limited 2,6-Di (substitutedamino) purine ribonucleoside analogues and administration to treat respiratory inflammation

Also Published As

Publication number Publication date
TW197448B (fr) 1993-01-01
EP0496852A1 (fr) 1992-08-05
CS97892A3 (en) 1992-08-12
AU8303291A (en) 1992-03-17
JPH05502889A (ja) 1993-05-20
PL294368A1 (en) 1993-06-28
CA2064869A1 (fr) 1992-02-17
HUT60504A (en) 1992-09-28
FI921691A0 (fi) 1992-04-15
AU638600B2 (en) 1993-07-01
HU9201080D0 (en) 1992-06-29
DE4025879A1 (de) 1992-02-20

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