EP0056057A1 - Derives substitues de l'adenosine-3',5'phosphobenzyl-triester, procede de leur preparation et remedes contenant de tels composes - Google Patents

Derives substitues de l'adenosine-3',5'phosphobenzyl-triester, procede de leur preparation et remedes contenant de tels composes

Info

Publication number
EP0056057A1
EP0056057A1 EP19810902302 EP81902302A EP0056057A1 EP 0056057 A1 EP0056057 A1 EP 0056057A1 EP 19810902302 EP19810902302 EP 19810902302 EP 81902302 A EP81902302 A EP 81902302A EP 0056057 A1 EP0056057 A1 EP 0056057A1
Authority
EP
European Patent Office
Prior art keywords
substituted
methyl
halogen
phenyl
adenosine
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Withdrawn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
EP19810902302
Other languages
German (de)
English (en)
Inventor
Joachim Department of Chemistry ENGELS
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.)
Takeda GmbH
Original Assignee
Byk Gulden Lomberg Chemische Fabrik 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 Byk Gulden Lomberg Chemische Fabrik GmbH filed Critical Byk Gulden Lomberg Chemische Fabrik GmbH
Publication of EP0056057A1 publication Critical patent/EP0056057A1/fr
Withdrawn legal-status Critical Current

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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
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • the invention relates to substituted adenosine-3 ', 5'-phosphoric acid benzyl triester, a process for their preparation and medicaments containing these compounds.
  • Adenosine-3 ', 5'-phosphoric acid benzyl ester (cAMP-benzyl ester, Naunyn-Schmiedeberg's Arch. Pharmacol. 310, 103-111 [1979]) and 8-sub-substituted cAMP derivatives (J.Med.Chem. 1980, 23 242-251).
  • cAMP-benzyl ester Naunyn-Schmiedeberg's Arch. Pharmacol. 310, 103-111 [1979]
  • 8-sub-substituted cAMP derivatives J.Med.Chem. 1980, 23 242-251.
  • Their positive inotropic effects on isolated guinea pig myocardium are also known. However, these compounds have been shown to show their effects only at relatively high concentrations, i.e. in the millimolar range, which is often already of no interest for systemic use. In some cases, negative side effects were also shown, for example with dibutyryl-cAMP, negative inotropic effects were initially found.
  • the object of the invention is therefore to find new substances which show the desired effect in a lower concentration and which are as free as possible from side effects.
  • the invention relates to substituted adenosine-3 ', 5'-phosphoric acid benzyl triesters of the general formula
  • R 1 is halogen, SR 3 , wherein R 3 is a straight-chain or branched C 1 C 5 alkyl or C 2 -C 5 alkenyl radical, which is substituted by hydroxy or phenyl, with halogen, methyl, ethyl, methoxy, ethoxy or Nitro may be substituted, may be a C 4 -C 7 cycloalkyl, phenyl or naphthyl, which may be ring-substituted with halogen, methyl, ethyl, methoxy or ethoxy, means SeR 4 , wherein R 4 is a straight-chain or branched C 1 C 5 alkyl radical, or
  • Is benzyl which may be ring substituted with halogen, methyl, ethyl, methoxy, ethoxy or nitro, or NR 5 R 6 , wherein R 5 and R 6 , which are the same or different, are hydrogen or R 3 , or together with that Nitrogen atom represent a piperidino or morpholino radical, and R 2 is phenyl, which is electron-donating or electro Groups can be substituted.
  • a preferred subject of the invention are substituted adenosine-3 ', 5'-phosphoric acid benzyl triester of the general formula I'
  • R 1 ' is chlorine, bromine, iodine, methylthio, ethylthio, t-butylthio, cyclohexylthio, benzylthio, where the phenyl group can be monosubstituted by halogen, methyl or ethyl, phenylthio, where the phenyl group can be monosubstituted by halogen, methyl or ethyl may, benzyl be eno, where the phenyl group may be monosubstituted by halogen, methyl or ethyl, NR 5 ' R 6' , where R 5 ' , R 6' are the same or different and are hydrogen, methyl, ethyl or benzyl, and R 2 ' the meaning phenyl, the phenyl group being halogen, methyl to have .
  • a particularly preferred object of the invention are substituted adenosine-3 ', 5'-phosphoric acid benzyl triesters of the general formula I "
  • R 1 have the meaning bromomethylthio, t-butylthio, cyclohexylthio, benzylthio, p-chlorophenylthio, benzylseleno, benzylamino, benzylmethylamino
  • R 2 have the meaning phenyl, p-cyanophenyl and p-methylphenyl.
  • the compounds according to the invention are prepared by the corresponding adenosine-3 ', 5'-monophosphoric acids substituted in the 8-position according to the method described in J.Med.Chem. 1977, 20, 907-911 specified methods are v ⁇ restert with the corresponding diazomethanes.
  • adenosine-3 ', 5'-monophosphoric acids substituted in the 8-position are converted by halogenation, preferably bromination, of adenosine-3', 5'-monophosphoric acid to 8-halo, preferably 8-bromo-adenosine-3 ', 5' -monophosphoric acid produced and optionally converted into the compounds according to the invention by nucleophilic substitution of the halogen atom analogously to the process given in Biochemistry 10, 2390 (1971).
  • the invention further relates to a process for the preparation of the compounds according to the invention, which is characterized in that a compound of the general formula 8-R 1 -cAMP, 8-R 1 ' -cAMP or
  • the compounds according to the invention are obtained as mixtures, the two components of which differ in that the ester group in the dioxaphosphorinane ring is aligned once axially and once equatorially.
  • the bond between the phosphorus atom and the oxygen atom of the benzyloxy group is shown as a wavy line in the general formulas I, I 'and I ".
  • the separation of the diasterecmeres is readily possible by a chromatographic route. Since the diastereomers are pharmacologically active If there is no noticeable difference, a separation for use as a medicine is not necessary.
  • the invention relates to medicaments which are distinguished by a content of one or more of the compounds according to the invention and the use of the compounds according to the invention in the treatment of diseases of the heart and / or the respiratory tract.
  • which also contain a phosphodiesterase inhibiting substance show a potentiated effect which is about 30 to 40 times that of the medicinal products without this additional substance.
  • 1-Methyl-3-isobutylxanthine, theophylline and / or papaverine is preferably used as such substance.
  • the invention therefore furthermore relates to medicaments which, in addition to one or more compounds according to the invention, contain a substance which takes the phosphodiesterase, preferably 1-methyl -3-isobutylxanthine, theophylline and / or papaverine.
  • a substance which takes the phosphodiesterase preferably 1-methyl -3-isobutylxanthine, theophylline and / or papaverine.
  • the medicaments are produced by methods known per se, the new compounds or their combinations with phosphodi esterase inhibitors being used as such or, if appropriate, in combination with suitable pharmaceutical carriers. If the new active pharmaceutical ingredients contain pharmaceutical excipients, the active ingredient content of these mixtures is 0.5 to 95, preferably 15 to 75 percent by weight of the total mixture.
  • the active ingredients are used in any suitable formulation, provided that the training bm. Maintaining sufficient drug levels is guaranteed. This can be done, for example, through oral, rectal or parenteral.
  • a unit dose can be, for example, a tablet, a dragee, a capsule, a suppository or a measured volume of a powder, a granulate, a solution, an emulsion or a suspension.
  • unit dose is understood to mean a physically determined unit which contains an individual amount of the active ingredient in combination with a pharmaceutical carrier, the active ingredient content of which corresponds to a fraction or a multiple of a single therapeutic dose.
  • a single dose contains preference as the amount of active ingredient that is administered in one application and usually corresponds to a whole, a half, a third or a quarter of a daily dose. If only a fraction, such as half or a quarter, of the unit dose is required for a single therapeutic administration, the unit dose is advantageously divisible, for example in the form of a tablet with a notch.
  • the pharmaceutical preparations according to the invention when in unit doses and used for app ration, e.g. are determined on human vision, contain about 10 to 500 mg, advantageously 50 to 300 mg and in particular 100 to 300 mg of active ingredient.
  • Parenteral preparations can be about 2 to 40 mg, advantageously 4 to. Contain 30 mg and in particular 10 to 25 mg of active ingredient.
  • the active ingredients are administered orally in a daily dose of 0.05 to 5, preferably 0.5 to 5, in particular 1 to 3 mg / kg body weight, optionally in the form of several, preferably 1 to 3 single doses to achieve the desired results.
  • a single dose contains the active ingredient (s) in amounts of 0.05 to 3, preferably 0.1 to 3, in particular 0.5 to 2 mg / kg body weight.
  • the active ingredient (s) in a daily dose of 0.5 to 10 mg, preferably 1 to 8 mg, in particular 2 to 5 mg, optionally in the form of several, preferably 1 to 3, single doses administer.
  • Preparations for intravenous administration are particularly useful for emergency treatment.
  • the therapeutic administration of the pharmaceutical preparation can take place 1 to 4 times a day at fixed or varying times, for example before meals and / or in the evening. However, it may be necessary to deviate from the doses mentioned, depending on the type, body weight and age of the individual to be treated, the type and severity of the disease, the type of preparation and administration of the drug, and the period or Interval within which the administration takes place. So it can be in be sufficient in some cases with less than the above amount of active ingredient, while in other cases the above-mentioned amount of active ingredient must be exceeded. In acute cases, a higher dose is given at the start of treatment. After the desired effect occurs, the dose is reduced to a lower dose.
  • the pharmaceutical preparations generally consist of the active compounds according to the invention, if desired in combination with phosphodiesterase inhibitors, and non-toxic, pharmaceutically acceptable medicament carriers which are used as admixtures or diluents in solid, semi-solid or liquid form or as protective agents, for example in a capsule or a tablet coating , a bag or another container for which the therapeutically active ingredient is used.
  • a carrier can e.g. serve as a mediator for the absorption of medicinal products by the body, as a formulation aid, as a sweetener as a taste corrector, as a color or as a preservative.
  • Tablets, dragees, hard and soft capsules e.g. come from gelatin, dispersible powders, granules, aqueous and oily suspensions, emulsions, solutions or syrups.
  • Tablets can contain inert diluents, for example calcium carbonate, calcium phosphate, sodium phosphate or lactose; Granulating and distributing agents, for example corn starch or alginates; Binders, for example starch, gelatin or acacia; and lubricants, for example aluminum or magnesium stearate, talc or silicone oil. They can also be provided with a coating, which can also be such that it causes a delayed dissolution and absorption of the drug in the gastrointestinal tract, so that, for example, better tolerance, protracting or retardation is achieved.
  • Gelatin capsules can contain the drug mixed with a solid, for example calcium carbonate or kaolin, or an oily, for example olive, peanut or paraffin oil, diluent.
  • Aqueous suspensions which may be prepared at short notice, may include suspending agents, for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium alginate, polyvinyl pyrrolidone tragacanth or acacia; Dispersing and wetting agents, for example polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate or lecithin; Preservatives, for example methyl or propyl hydroxybenzate; Flavoring agents; Sweeteners, for example sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup, contain.
  • suspending agents for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium alginate, polyvinyl pyrrolidone tragacanth or acacia
  • Dispersing and wetting agents for example polyoxyethylene stearate,
  • oily suspensions can e.g. Peanut, olive, sesame, coconut or paraffin oil and thickeners such as e.g. Beeswax, hard paraffin or cetyl alcohol; also sweeteners, flavoring agents and antioxidants.
  • the drugs can be mixed with dispersing, wetting and suspending agents, e.g. contain the above, as well as with sweeteners, flavoring agents and colorings.
  • Erieticsfonen can e.g. Olive, peanut or paraffin oil in addition to emulsifying agents, e.g. Acacia, tragacanth, phosphatides, sorbitan mncooleate, polyoxyethylene sorbitan monooleate, and sweetening and flavoring agents.
  • emulsifying agents e.g. Acacia, tragacanth, phosphatides, sorbitan mncooleate, polyoxyethylene sorbitan monooleate, and sweetening and flavoring agents.
  • Suppositories are used for rectal application of the medicinal products, which are produced with the aid of binders melting at rectal temperature, for example cocoa butter or polyethylene glycol.
  • sterile injectable if necessary short-term, aqueous suspensions, isotonic salt solutions or other solutions, the dispersing or wetting agents and / or pharmacologically acceptable diluents, e.g. Propylene or butylene glycol.
  • the inhalative application of the compounds according to the invention is also preferred. These are administered either directly as a powder or by atomizing solutions or suspensions containing the compounds according to the invention.
  • the nebulization can take place in a conventional manner, for example by compressed air nebulizers or ultrasound nebulizers. Administration from spray cans, in particular those with a conventional metering valve (metering aerosols), is particularly advantageous. Dosing aerosols make it possible to provide a defined amount of active ingredient per spray. So-called synchronous inhalers are particularly advantageous here, with which the release of active substance can take place synchronously with inhalation. Suitable synchronous inhalation devices are disclosed, for example, in DE-PS 1945257, DE-PS 19 17911 and DE-OS 20 55 734.
  • the active ingredients are preferably used in a micronized form, particle sizes of less than 10 .mu.m being advantageous.
  • the active ingredients are dispersed in customary blowing agents, preferably with the aid of a dispersant.
  • Mixtures of trichlorofluoromethane (Frigen ® 11) and dichlorodifluoromethane (Frigen ® 12) are particularly suitable as blowing agents, trichlorofluoromethane being able to be replaced in whole or in part by 1, 1, 2-trichlorotrifluoromethane (Frigen ® 113).
  • Particularly suitable dispersants are the sorbitan esters (Spane ® from Atlas GmbH) and lecithin which are customary for this purpose.
  • the dispersant is dissolved in the less volatile propellant component, which is refrigerated.
  • the micronized active ingredient or the micronized active ingredients are stirred into the solution.
  • the dispersion is filled into spray cans. After crimping, the more volatile blowing agent component is pressed on.
  • the active ingredient (s) can, if appropriate, also be formulated in microencapsulated form with one or more of the stated carriers or additives.
  • the compounds according to the invention showed positive inotropic activity on the isolated guinea pig myocardium in the absence of a positive chronotropic or even negative chronotropic effect; both are desirable for a substance that selectively increases the cardiac strength. It was also observed that after administration of the compounds according to the invention there was a relaxation of the smooth muscles of the respiratory tract, which is desirable for substances for the treatment of asthma attacks. Finally, the effect of the compound according to the invention on the smooth muscles of the blood vessels makes it suitable for regulating blood pressure.
  • Tablets with 100 mg of 8- (4-chlorophenylthio) -3 ', 5'-monophosphoric acid benzyl triester, 40,000 kg of active ingredient, 24,000 kg of dairy farmer and 16,000 kg of corn starch are granulated with 4,000 kg of polyvinylpyrrolidone (MW 25,000) in approximately 5.5 liters of water and pressed through a sieve of 1.25 mm mesh size. After drying, 10,000 kg of carboxymethyl cellulose, 4,000 kg of talc and 2,000 kg of magnesium stearate are added. The granules are pressed on an eccentric machine into tablets of 9 mm in diameter, 250 mg in weight and a hardness of 4 to 5 kg.
  • Papillary muscles from the right ventricle of the guinea pig heart were used to determine positive inotropic effects.
  • the adrenergic nerve endings were free of noradrenaline (catecholamine storage by intraperitoneal injection of 5 mg / kg reserpine 24 hours before preparation of the animals).
  • the muscles were suspended on an inductive force transducer in a physiological nutrient solution saturated with oxygen (volume 50 ml). The force registration was carried out isometrically, contraction curves were recorded using an ink pen and then analyzed. Before adding the test substance, the muscles were equilibrated with constant irritation (frequency 0.2 Hz, stimulus duration 1 ms) until the force in the nutrient solution had reached a steady state. The concentration of the test substance was increased if the force did not increase within 10 minutes.
  • the following table II shows the concentrations of the individual test substances at which the positive inotropic effect was just noticeable (concentration of the swelling) or reached 50% of the maximum increase in strength (EC 50 ). These values were compared in the lower part of the table with those of known test substances. Furthermore, threshold concentrations and EC 50 values for the test substances listed are given in the presence of the phosphodiesterase inhibitor 1-methyl-3-isobutylxanthirt (IBMX) (2 ⁇ 10 mol / 1). This results in a shift to 30- to 40-fold lower concentrations compared to the values without phophodiesterase inhibitor. A similar synergism was also observed with papaverine (1 x 10 -5 mol / 1) and with theophylline (3 x 10 -4 mol / 1).
  • a relaxation can be brought about, whereby after each single dose of the test substance a constant relaxation response is waited for before the next higher concentration is applied a complete dose-response curve of the test substance is thus obtained up to 30 minutes.
  • the respective relaxation is expressed as a percentage of the maximum relaxation that can be achieved by adding (-) isoprenaline (10 -6 mol / 1).
  • Table IV shows the ED 50 (dose of the half-maximum relaxation possible) and the relative potency compared to theophylline for compounds according to the invention.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Derives substitues de l'adenosine-3',5'-phosphobenzyl-triester de formule generale I (FORMULE) dans laquelle R1 signifie soit halogene, soit SR3, ou R3 designe un reste en chaine droite ou ramifiee alkyle C1-C5 ou alkanyle C2-C5, qui peuvent etre substitues par hydroxy ou un reste phenyle, qui lui peut porter les substituants halogene, methyle, ethyle, methoxy, ethoxy ou nitro, R3 peut signifier egalement un reste cyclo-alkyle C4-C7, phenyle ou naphthyle, ces derniers restes peuvent etre substitues dans le cycle par halogene, methyle, ethyle, methoxy ou ethoxy, soit SeR4, ou R4 signifie un reste en chaine droite ou ramifiee alkyle C1-C5 ou un reste benzyle, ce dernier pouvant etre substitue dans le cycle par halogene, methyle, ethyle, methoxy, ethoxy ou nitro, soit NR5R6, ou R5 et R6, qui sont egaux ou differents, signifient l'hydrogene ou le reste R3, ou alors qui constituent ensemble en commun avec l'atome d'azote un reste cyclique piperidino ou morpholino; dans laquelle R2 signifie un reste phenyle, qui lui peut etre substitue par des groupements livrant des electrons ou enlevant des electrons. Ces composes sont nouveaux et presentent des activites pharmacologiques interessantes, comme par exemple une activite inotrope, une activite relaxante sur le tractus respiratoire et les vaisseaux sanguins. L'on decrit la preparation de ces composes et leur formulation en remedes.
EP19810902302 1980-07-18 1981-07-15 Derives substitues de l'adenosine-3',5'phosphobenzyl-triester, procede de leur preparation et remedes contenant de tels composes Withdrawn EP0056057A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3027279 1980-07-18
DE19803027279 DE3027279A1 (de) 1980-07-18 1980-07-18 Substituierte adenosin-3',5'-phosphorsaeurebenzyltriester, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel

Publications (1)

Publication Number Publication Date
EP0056057A1 true EP0056057A1 (fr) 1982-07-21

Family

ID=6107538

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Application Number Title Priority Date Filing Date
EP19810902302 Withdrawn EP0056057A1 (fr) 1980-07-18 1981-07-15 Derives substitues de l'adenosine-3',5'phosphobenzyl-triester, procede de leur preparation et remedes contenant de tels composes
EP81105575A Withdrawn EP0044527A1 (fr) 1980-07-18 1981-07-15 Dérivés de benzyl triesters de l'adénosine 3',5'-monophosphate cyclique, méthode pour leur préparation et compositions pharmaceutiques les contenant

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP81105575A Withdrawn EP0044527A1 (fr) 1980-07-18 1981-07-15 Dérivés de benzyl triesters de l'adénosine 3',5'-monophosphate cyclique, méthode pour leur préparation et compositions pharmaceutiques les contenant

Country Status (3)

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EP (2) EP0056057A1 (fr)
DE (1) DE3027279A1 (fr)
WO (1) WO1982000293A1 (fr)

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1196261B (it) * 1984-09-20 1988-11-16 Pierrel Spa Derivati nucleosidici e purinici 8-sostituiti
WO1989007102A1 (fr) * 1988-02-08 1989-08-10 Schering Corporation Composes du type nucleoside utilises comme inhibiteurs de phosphodiesterase
US5091431A (en) * 1988-02-08 1992-02-25 Schering Corporation Phosphodiesterase inhibitors
US5559102A (en) * 1988-08-16 1996-09-24 Nippon Shinyaku Company, Limited Adenosine and guanosine-3'-5'-cyclic methylphosphonate derivatives
EP0355899B1 (fr) * 1988-08-16 1994-11-02 Nippon Shinyaku Company, Limited Dérivés de nucléotides
US4971972A (en) * 1989-03-23 1990-11-20 Schering Corporation Phosphodiesterase inhibitors having an optionally substituted purine derivative portion and a benzo- or cyclopenta-furan portion
US5688778A (en) * 1989-05-15 1997-11-18 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Nucleoside analogs
CA2297294C (fr) * 1989-05-15 2005-11-08 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Derives de phosphonomethoxymethylpurine/pyrimidine
DE19529025A1 (de) * 1995-07-28 1997-01-30 Forschungsverbund Berlin Ev Neue 8-bromsubstituierte cyclische Nucleotidester, Verfahren zu ihrer Herstellung und ihre Verwendung
AU3307999A (en) 1998-02-23 1999-09-06 Icos Corporation Phosphodiesterase 10
KR102708995B1 (ko) 2018-01-10 2024-09-23 누코리온 파마슈티컬스, 인코포레이티드. 포스포르(포스포론)아미다타세탈 및 포스프(온)아탈세탈 화합물
US11427550B2 (en) 2018-01-19 2022-08-30 Nucorion Pharmaceuticals, Inc. 5-fluorouracil compounds
MX2021012894A (es) * 2019-04-22 2021-11-17 Ligand Pharm Inc Compuestos ciclicos de fosfato.
MX2022000573A (es) 2019-07-17 2022-02-10 Nucorion Pharmaceuticals Inc Compuestos ciclicos de desoxirribonucleotido.
JP2023523415A (ja) 2020-04-21 2023-06-05 リガンド・ファーマシューティカルズ・インコーポレイテッド ヌクレオチドプロドラッグ化合物
WO2021216431A1 (fr) 2020-04-21 2021-10-28 Ligand Pharmaceuticals, Inc. Composés de benzyloxy phosph(on)ate
EP4232456A4 (fr) * 2020-10-21 2026-04-01 Ligand Pharm Inc Composés de promédicaments antiviraux

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US3712885A (en) * 1968-09-10 1973-01-23 G Weimann Purine-ribofuranoside-3',5'-cyclophosphates and process for their preparation

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Also Published As

Publication number Publication date
WO1982000293A1 (fr) 1982-02-04
DE3027279A1 (de) 1982-05-06
EP0044527A1 (fr) 1982-01-27

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