WO1998016539A1 - Novel therapeutically active adenosine derivatives - Google Patents

Novel therapeutically active adenosine derivatives

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Publication number
WO1998016539A1
WO1998016539A1 PCT/DK1997/000423 DK9700423W WO9816539A1 WO 1998016539 A1 WO1998016539 A1 WO 1998016539A1 DK 9700423 W DK9700423 W DK 9700423W WO 9816539 A1 WO9816539 A1 WO 9816539A1
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WO
WIPO (PCT)
Prior art keywords
adenosine
thio
pyridyl
piperidinyl
deoxy
Prior art date
Application number
PCT/DK1997/000423
Other languages
French (fr)
Inventor
Lars Knutsen
Original Assignee
Novo Nordisk A/S
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Publication date
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to AU43773/97A priority Critical patent/AU4377397A/en
Publication of WO1998016539A1 publication Critical patent/WO1998016539A1/en

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    • 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

Definitions

  • the present invention relates to therapeutically active ⁇ /-substituted adenosine and 5'- deoxyadenosine derivatives, further substituted at the ribose 5'- and purine 2- and 6- positions and pharmaceutically acceptable addition salts thereof, and their pharmaceutical compositions as well as methods for using the compounds in the treatment of myocardial and cerebral ischaemia and epilepsy.
  • Adenosine is a naturally occurring purine nucleoside, from which is derived a range of agonists at adenosine receptors having considerable potential in the treatment of human disease (Life Sciences, 1991 , 49, 1435-1453; Journal of Medicinal Chemistry, 1992, 35, 407-422; Annual Reports in Medicinal Chemistry, 1993, 28, 295-304).
  • Adenosine has been shown to have a number of significant effects on the mammalian central nervous system (CNS) (Annual Reports in Medicinal Chemistry, 1988, 23, 39-48; Adenosine in the Nervous System, T.W. Stone, Ed., Academic Press Ltd., London 1991 ) especially under conditions of neuronal stress where the compound appears to act as an endogenous neuroprotectant (Progress in Neurobiology, 1988, 31, 85-108, Trends in Pharmacological Sciences, 1992, 11, 439-445). For example, the concentration of adenosine has been demonstrated to rise greatly in certain brain regions following epileptic seizures or conditions of neuronal ischaemia/anoxia (Brain Research, 1990, 516, 248-256).
  • adenosine receptor agonists or compounds which increase extracellular adenosine levels can exhibit what is termed neuromodulator activity (Trends in Neurosciences, 1984, 164-168).
  • Such substances influence the release of neurotransmitters in regions of the central nervous system (Annual Review of Neuroscience, 1985, 8, 103-124; Trends in Neurosciences, 1984, 164-168), with particular inhibitory effects on the release of the excitatory amino acid glutamic acid (glutamate) in the CNS (Nature, 1985, 316, 148-150) especially under ischaemic conditions (Journal of Neurochemistry, 1992, 58, 1683-1690).
  • Adenosine receptors represent a subclass (Pj) of the group of purine nucleotide and nucleoside receptors known as purinoreceptors. This subclass has been further classified into distinct receptor types which have become known as A 1 t A 2 and A 3 . Extensive research has been carried out in a quest to identify selective ligands at these sites. Selective ligands exist for A 1 t A 2 and A 3 adenosine receptors and the structure-activity relationships of the various reference ligands have been reviewed (Comprehensive Medicinal Chemistry, Volume 3, (Hansch, C, Sammes, P.G.
  • adenosine receptor agonists most selective for the A., receptor over the A 2 receptor are the examples where the adenine nucleus is substituted with a cycloalkyl group on the amino function, for example ⁇ /-cyclopentyladenosine (CPA) and N- cyclohexyladenosine (CHA) (Journal of Medicinal Chemistry, 1985, 28, 1383-1384) or 2- chloro- ⁇ /-cyclopentyladenosine (CCPA) (Naunyn-Schmiedeberg's Arch. Pharmacol. 1988, 337, 687-689).
  • CPA ⁇ /-cyclopentyladenosine
  • CHCA N- cyclohexyladenosine
  • CCPA 2- chloro- ⁇ /-cyclopentyladenosine
  • Adenosine receptors there is evidence for further subdivision of adenosine receptors into the subtypes A 2a , A 2b (of high and low affinity) A 3 and A 4 .
  • the latest status of these subtypes has been reviewed (Drug Development Research, 1993, 28, 207-213; Trends in Pharmacological Sciences 1993, 290-291 ; Pharmacological Reviews, 1994, 46, 143-156).
  • the A 3 receptor (Proceedings of the National Academy of Sciences of the USA, 1992, 89, 7432-7436; Trends in Pharmacological Sciences, 1994, 15, 298-306) appears to be responsible for some of the cardiovascular effects of reference ligands (British Journal of Pharmacology, 1993, 709, 3-5).
  • N 6 - substituted adenosine derivatives compounds substituted on adenosine's 6-amino position are referred to as N- substituted adenosine derivatives.
  • Derivatives of adenosine with the heteroatoms sulphur, oxygen or nitrogen bonded directly to the 6-amino substituent are not common in the chemical literature, but those cases known are summarised below.
  • Derivatives with hydrogen at the purine 2-position include ⁇ /-aminoadenosine, N-[(N- methyl- ⁇ /-phenyl)amino]adenosine, ⁇ /-hydroxyadenosine, ⁇ /-methoxyadenosine and N- benzyloxyadenosine (Journal of Medicinal Chemistry, 1985, 28, 1636-1643); N- ethoxyadenosine (Chemical and Pharmaceutical Bulletin, 1973, 21, 1676-1682; ibid., 1973, 21, 1835-1838); /V-(methylamino) adenosine and ⁇ /-[( ⁇ /-hydroxy- ⁇ /-methyl)- aminojadenosine (Journal of Medicinal Chemistry, 1968, 11, 521-523).
  • EP 181 ,128 and EP 181 ,129 disclose 5'-deoxy adenosine derivatives containing 5'- hydrogen, 5'-halogen and 5'-methylthio, which are claimed to have desirable antiinflam- matory, analgesic as well as CNS and antihypertensive properties respectively.
  • EP 232,813 discloses ⁇ /-substituted adenosines including a larger range of 5'-modified compounds which are also claimed to have desirable CNS and antihypertensive properties.
  • WO 94/02497 reveals certain sulphohydrocarbon derivatives of adenosine, where the possibilty exists for substitution at the 5'-position of the ribose moiety.
  • WO 88/03147 5'- substituted adenosine derivatives with selectivity for the adenosine A 2 receptor are disclosed.
  • adenosine analogues with hydrazone derivatives on the 6- amino function are disclosed as hypotensive agents.
  • adenosine and 2- aminoadenosine derivatives having a -NH-R 2 group joined to the 6-amino function are disclosed as coronary dilators and platelet aggregation inhibitors.
  • a series of 2-, 6- and 8- substituted adenosine derivatives are described having activity as anti- allergy agents.
  • adenosine and 2-haloadenosine analogues having an alkyl, cycloalkyl or an aralkyl group attached to the 6-amino function are described with activity as antidementia agents.
  • EP 402,752 derivatives of adenosine unsubstituted in the 2-position are described which have a substituted heteroaromatic 1-pyrrolyl moiety attached to the 6-amino group.
  • WO 91/04032 methods of preventing neural tissue damage in neurodegenerative diseases by increasing extracellular concentrations of adenosine are described. Examples are given of prodrug esters of AICA riboside which are claimed to be centrally acting neuroprotective agents.
  • analogues of AICA riboside are described which increase extracellular adenosine levels with beneficial effects claimed in peripheral and CNS ischaemia.
  • WO 90/055266 2-(alkylalkynyl)adenosine derivatives are described for treatment of ischaemic disease of the heart and brain.
  • EP 423 777 a method for treating gastrointestinal motility disorders using N(6) (substituted aminoalkyl) adenosine deriva- fives is disclosed.
  • EP 490 818 describes a new use of 2'-0-methyl adenosine derivatives for a range of ailments including neurodegenerative disorders.
  • the present invention relates to new adenosine analogues with ribose moieties optionally modified at C-5 which show potent binding in vitro to the adenosine A ⁇ receptor, and which also display selectivity for A receptor binding in vitro over that to the A 2 receptor subtype.
  • the compounds contained in this invention have a relatively high lipophilicity, especially when compared to adenosine analogues which are not substituted on the 6-amino group or the purine 2-position. This latter property makes these compounds suitable for passage across the blood brain barrier.
  • the compounds are also substrates for nucleoside-specific active transport systems into the CNS across the blood barrier. These useful properties support the notion that the compounds are candidate drugs for treatment of the CNS ailments mentioned within this invention in humans as well as cardiovascular disorders such as myocardial ischaemia.
  • WO 95/07921 Novartis A/S, we have revealed a series of compounds which are modified at the ribose C-5, but contain for example a pyrrolidine or piperidine group which may be optionally substituted with one or two C 1-6 -alkyl groups, C 2 .
  • novel compounds having a heteroaryloxy or heteroarylthio substitution on the pyrrolidine or piperidine nucleus described within this present application have improved aqueous solubility, which renders them suitable for formulation for human use. Furthermore, the compounds described herein, such as the examples containing a pyridylthio- functionality show superior potency to other adenosine agonists tested in the gerbil model of severe temporary forebrain ischaemia.
  • the compounds of the invention are purine derivatives of formula I, or a pharmaceutically acceptable salt thereof:
  • •O is the residue of a 4- to 7-membered heterocycle containing at least one nitrogen heteroatom, said heterocycle being substituted with the group -Y-Z;
  • X is halogen, amino, C 1-6 -alkoxy, C 1-6 -alkylthio or C 1-e -alkylamino; A is hydroxymethyl or haiomethyl;
  • Y is oxygen, sulphur, sulphinyl or sulphonyl
  • Z is a five- or six-membered heterocycle, optionally substituted by C 1-6 -alkyl, C ⁇ -alkoxy, C 1-6 -alkylthio or C 1-6 -alkylamino.
  • the 6-amino substituent can contain one or more asymmetric carbon atoms in addition to those asymmetric centres already present in the molecule. In examples where this is the case, this invention includes all resulting diastereoisomers and mixtures thereof.
  • the 4- to 7-membered heterocycle is preferably a five- or six-membered heterocycle, more preferably piperidinyl or pyrrolidinyl, still more preferably piperidinyl;
  • X is preferably halogen
  • Y is preferably oxygen or sulphur, more preferably sulphur
  • Z is preferably thiazole, 1 ,2,4-triazole, imidazole or pyridyl, more preferably pyridyl;
  • A is preferably haiomethyl, more preferably chloromethyl.
  • the present invention furthermore relates to a method of treating myocardial or cerebral ischaemia (disorders where the blood flow to the brain is interrupted) and epilepsy, comprising administering to a subject in need thereof a compound of formula (I) and the use of a compound of formula (I) for the preparation of a medicament for treating epilepsy or ischaemia.
  • salts of compounds of formula (I) can be prepared which is physiologically acceptable. These include addition salts derived from inorganic or organic acids, for example, acetates, fumarates, glutarates, glutaconates, lactates, maleates, methanesul- phonates, phosphates, salicylates, succinates, sulphates, sulphamates, tartrates and paratoluenesulphonat.es. In some cases, solvates of either the free nucleosides or the acid addition salts can be isolated and these solvates may, for example, be hydrates or alcoholates.
  • Compounds of formula (I), which act as adenosine receptor agonists, are furthermore useful in the treatment of central nervous system conditions such as anxiety, neuronal ischaemia/anoxia, convulsive disorders and neurodegeneration (including Parkinson's disease) in humans. This includes treating disorders where the blood flow to the brain is interrupted, for example during traumatic head injury, cardiac arrest and stroke. Further, the compounds of formula (I) are useful as analgesic agents, in lowering plasma free fatty acid (FFA) levels or as cardiovascular agents.
  • FFA plasma free fatty acid
  • the compounds according to the invention possess desirable central nervous system properties. For example, they act as anticonvulsant agents, are effective in animal models of pain, and show cerebroprotective effects in laboratory test animals subjected to simulated cerebral ischaemia. In addition, the compounds may have efficacy as neuroprotective agents in cases of cerebral oedema and traumatic head injury.
  • the affinity of the novel compounds described in this invention for the adenosine Aj receptor was determined essentially as described in the literature using [ 3 H]-R-PIA as a radioligand (Naunyn-Schmiedeberg's Archives of pharmacology, 1980, 313, 179-187). Affinity for the A ⁇ receptor was measured using the radioligand [ 3 H]-CGS 21680 (European Journal of Pharmacology, 1989, 168, 243-246), and the values for representa- tive compounds is given in the table below.
  • the compounds of the invention together with a conventional adjuvant, carrier or diluent, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets of filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral use (including subcutaneous administration and infusion).
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the adenosine receptor agonist commensurate with the intended daily dosage range to be employed.
  • the compounds of this invention can thus be used for the formulation of pharmaceutical preparation, e.g. for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy.
  • excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or enteral application which do not deleteriously react with the active compounds.
  • Such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Ampoules are convenient unit dosage forms.
  • a syrup, elixir or the like can be used in cases where a sweetened vehicle can be employed.
  • the compounds of this invention are dispensed in unit form comprising 0.05-100 mg in a pharmaceutically acceptable carrier per unit dosage.
  • the dosage of the compounds according to this invention is 0.1-300 mg/day, preferably 10-100 mg/day, when administered to patients, e.g. humans, as a drug.
  • a typical tablet which may be prepared by conventional tabletting techniques contains:
  • the compounds of the invention may be administered to a subject, e.g., a living animal body, including a human, in need of adenosine receptor agonist, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof (such as the hydrobromide, hydrochloride, or sulphate, in any event prepared in the usual or conventional manner, e.g., evaporation to dryness of the free base in solution together with the acid), ordinarily concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective amount of adenosine receptor agonist, and in any event an amount which is effective for the treatment of the disease.
  • a pharmaceutically acceptable acid addition salt thereof such as the hydrobromide, hydrochloride, or sulphate, in any event prepared in the usual or conventional manner, e.g., evaporation to
  • Suitable dosage ranges are 1-200 milligrams daily, 10-100 milligrams daily, and especially 30-70 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
  • TLC thin layer chromatography
  • THF tetrahydrofuran
  • TFA trifluoracetic acid
  • mp melting point. Where melting points are given, these are uncorrected.
  • Compounds used as starting materials are either known compounds or compounds which can be prepared by methods known per se. on a Merck Hitachi model L6200A Intelligent chroma- tograph interfaced to a Merck Hitachi L4000A UV detector to a LiChrospher 100 reversed phase C 18 column (5mm, 250 x 4 mm, 5mm, 10 ⁇ A; eluent flow rate 1 mlJmin). Retention times are given in minutes.
  • This compound was prepared from 4-(4-pyridylthio)piperidine (1.78 g, 6.7 mmol) by the method described in Example 4, via the intermediate 2 ' 3 ' 5 ' -tri-0-acetyl-2-chloro- ⁇ /-[4-(4- pyridylthio)-1-piperidinyl]adenosine (0.61 g), which was deacylated to provide the title compound (0.43 g) as a foam; ⁇ NMR (400MHz, DMSO-d 6 ) d 3.52 - 3.58 (1 H, m, H-5' a ), 3.62 -3.69 (1 H, m, H-5' b ), 3.94 (1 H, q, H-4'), 4.13 (1 H, q, H-3'), 4.51 (1H, q, H-2'), 5.06 (1 H, t, 5'-0H), 5.21 (1 H, d, 3'-OH), 5.48 (1H, d, 2'
  • This compound was prepared from 1-amino-4-(2-pyridylthio)pipehdine (prepared by the method described in Example 4) (0.78 g, 3.71 mmol) was reacted with 2-fluoro-9-(2 ' 3 ' 5 ' - tri-0-acetyl-b-D-ribofuranosyl)-6-chloro-9H-purine (see WO 93/08206; Bioorganic and Medicinal Chemistry Letters, 1993, 3, 2661-2666) ( 3.20 g, 7.42 mmol) in the presence of triethylamine, followed by deacylation as described above, to provide the title compound 2-fluoro- ⁇ /-[4-(2-pyridyl)thio-1-piperidinyl]adenosine (0.37g, 21 %) as a foam; 1 H NMR (300MHz, DMSO-d 6 ) d 3.56 (1 H, m, H-5' a ), 3.64 (1 H, m, H

Abstract

Novel therapeutically active adenosine derivatives of general formula (I) wherein (a) is the residue of a 4- to 7-membered heterocycle containing at least one nitrogen heteroatom, said heterocycle being substituted with the group -Y-Z; X is halogen, amino, C1-6-alkoxy, C1-6-alkylthio or C1-6-alkylamino; A is hydroxymethyl or halomethyl; Y is oxygen, sulphur, sulphinyl or sulphonyl; and Z is a five- or six-membered heterocycle, optionally substituted by C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio or C1-6-alkylamino; and pharmaceutically acceptable addition salts thereof, and their pharmaceutical compositions as well as methods for using the compounds in the treatment of myocardial and cerebral ischaemia and epilepsy.

Description

NOVEL THERAPEUTICALLY ACTIVE ADENOSINE DERIVATIVES
FIELD OF THE INVENTION
The present invention relates to therapeutically active Λ/-substituted adenosine and 5'- deoxyadenosine derivatives, further substituted at the ribose 5'- and purine 2- and 6- positions and pharmaceutically acceptable addition salts thereof, and their pharmaceutical compositions as well as methods for using the compounds in the treatment of myocardial and cerebral ischaemia and epilepsy.
BACKGROUND OF THE INVENTION
Adenosine is a naturally occurring purine nucleoside, from which is derived a range of agonists at adenosine receptors having considerable potential in the treatment of human disease (Life Sciences, 1991 , 49, 1435-1453; Journal of Medicinal Chemistry, 1992, 35, 407-422; Annual Reports in Medicinal Chemistry, 1993, 28, 295-304).
Adenosine has been shown to have a number of significant effects on the mammalian central nervous system (CNS) (Annual Reports in Medicinal Chemistry, 1988, 23, 39-48; Adenosine in the Nervous System, T.W. Stone, Ed., Academic Press Ltd., London 1991 ) especially under conditions of neuronal stress where the compound appears to act as an endogenous neuroprotectant (Progress in Neurobiology, 1988, 31, 85-108, Trends in Pharmacological Sciences, 1992, 11, 439-445). For example, the concentration of adenosine has been demonstrated to rise greatly in certain brain regions following epileptic seizures or conditions of neuronal ischaemia/anoxia (Brain Research, 1990, 516, 248-256).
It has been established for some years now that centrally acting adenosine receptor agonists or compounds which increase extracellular adenosine levels can exhibit what is termed neuromodulator activity (Trends in Neurosciences, 1984, 164-168). Such substances influence the release of neurotransmitters in regions of the central nervous system (Annual Review of Neuroscience, 1985, 8, 103-124; Trends in Neurosciences, 1984, 164-168), with particular inhibitory effects on the release of the excitatory amino acid glutamic acid (glutamate) in the CNS (Nature, 1985, 316, 148-150) especially under ischaemic conditions (Journal of Neurochemistry, 1992, 58, 1683-1690).
There are several CNS ailments for which this adenosine receptor mediated neuromodulator activity is accepted by persons skilled in the art as being of clear therapeutic benefit including the treatment of convulsive disorders (European Journal of Pharmacology, 1991 , 195, 261-265; Journal of Pharmacology and Experimental Therapeutics, 1982, 220, 70-76; European Journal of Pharmacology, 1993, 242, 221-228), prevention of neuro- degeneration under conditions of brain anoxia/ischaemia (Neuroscience Letters, 1987, 83, 287-293; Stroke, 1988, 19, 1133-1 139; Neuroscience, 1989, 30, 451-462; Pharmacology of Cerebral Ischaemia 1990, (Kriegelstein, J. and Oberpichler, H., Eds., Wissenschaftliche Verlagsgesellschaft mbH: Stuttgart, 1990, pp 439-448; Trends in Pharmacological Sciences 1992, 11, 439-445) or the use of a purinergic agent in the treatment of pain (European Journal of Pharmacology, 1989, 162, 365-369; Neuroscience Letters, 1991 , 121, 267-270).
Adenosine receptors represent a subclass (Pj) of the group of purine nucleotide and nucleoside receptors known as purinoreceptors. This subclass has been further classified into distinct receptor types which have become known as A1 t A2 and A3. Extensive research has been carried out in a quest to identify selective ligands at these sites. Selective ligands exist for A1 t A2 and A3 adenosine receptors and the structure-activity relationships of the various reference ligands have been reviewed (Comprehensive Medicinal Chemistry, Volume 3, (Hansch, C, Sammes, P.G. and Taylor, J.B., Eds., Pergamon Press PLC: 1990, pp 601-642, Journal of Medicinal Chemistry, 1994, 37, 636 - 646). Among the known adenosine receptor agonists most selective for the A., receptor over the A2 receptor are the examples where the adenine nucleus is substituted with a cycloalkyl group on the amino function, for example Λ/-cyclopentyladenosine (CPA) and N- cyclohexyladenosine (CHA) (Journal of Medicinal Chemistry, 1985, 28, 1383-1384) or 2- chloro-Λ/-cyclopentyladenosine (CCPA) (Naunyn-Schmiedeberg's Arch. Pharmacol. 1988, 337, 687-689).
There is evidence for further subdivision of adenosine receptors into the subtypes A2a, A2b (of high and low affinity) A3 and A4. The latest status of these subtypes has been reviewed (Drug Development Research, 1993, 28, 207-213; Trends in Pharmacological Sciences 1993, 290-291 ; Pharmacological Reviews, 1994, 46, 143-156). The A3 receptor (Proceedings of the National Academy of Sciences of the USA, 1992, 89, 7432-7436; Trends in Pharmacological Sciences, 1994, 15, 298-306) appears to be responsible for some of the cardiovascular effects of reference ligands (British Journal of Pharmacology, 1993, 709, 3-5).
Various examples of Λ/-heteroarylalkyl substituted A^ selective adenosine analogues have been reported in the literature. It should be noted that some of these are named as N6- substituted adenosine derivatives, but this is equivalent to ACS-approved nomenclature where compounds substituted on adenosine's 6-amino position are referred to as N- substituted adenosine derivatives. Derivatives of adenosine with the heteroatoms sulphur, oxygen or nitrogen bonded directly to the 6-amino substituent are not common in the chemical literature, but those cases known are summarised below.
Derivatives with hydrogen at the purine 2-position include Λ/-aminoadenosine, N-[(N- methyl-Λ/-phenyl)amino]adenosine, Λ/-hydroxyadenosine, Λ/-methoxyadenosine and N- benzyloxyadenosine (Journal of Medicinal Chemistry, 1985, 28, 1636-1643); N- ethoxyadenosine (Chemical and Pharmaceutical Bulletin, 1973, 21, 1676-1682; ibid., 1973, 21, 1835-1838); /V-(methylamino) adenosine and Λ/-[(Λ/-hydroxy-Λ/-methyl)- aminojadenosine (Journal of Medicinal Chemistry, 1968, 11, 521-523). A range of compounds which have no further substitution on the ribose moiety have been been published by Novo Nordisk (Bioorganic and Medicinal Chemistry Letters, 1993, 3, 2661-2666). There are also very few examples of compounds designed as adenosine receptor agonists where the ribose moiety in adenosine is chemically modified, and many of those known have poor affinity for the adenosine receptor (Journal of Medicinal Chemistry, 1986, 29, 346-353). However, minor modifications at the 3'- and 5'-positions appear to be allowed and amongst these the 5'-chloro-5'-deoxy adenosines show particularly good receptor affinity (Journal of Medicinal Chemistry, 1989, 32, 8-11 ). Other scientific articles also describe 5'-modifications of adenosine derivatives (Journal of Medicinal Chemistry, 1986, 29, 1683-1689).
EP 181 ,128 and EP 181 ,129 disclose 5'-deoxy adenosine derivatives containing 5'- hydrogen, 5'-halogen and 5'-methylthio, which are claimed to have desirable antiinflam- matory, analgesic as well as CNS and antihypertensive properties respectively. EP 232,813 discloses Λ/-substituted adenosines including a larger range of 5'-modified compounds which are also claimed to have desirable CNS and antihypertensive properties. WO 94/02497 reveals certain sulphohydrocarbon derivatives of adenosine, where the possibilty exists for substitution at the 5'-position of the ribose moiety. In WO 88/03147 5'- substituted adenosine derivatives with selectivity for the adenosine A2 receptor are disclosed.
in US 4,962,194 methods for preparing 5', Λ/-disubstituted adenosine derivatives are revealed. GB 1 ,101 ,108 discloses 5', Λ/-disubstituted adenosine analogues which possess cardiovascular activity. US 3,910,885 reveals 4'-alkoxy and 4'-haloalkoxy nucleosides. WO 94/06348 discloses a number of pyrrolo[3,4-d]pyrimidine structures which are formally isosteric with adenosine and which are modified with substituents at the sugar 5'-position. US 5308837 covers the use of 5'-amine substituted adenosine analogues as immuno- suppressants.
In US 3,819,613, substituted adenosine analogues with hydrazone derivatives on the 6- amino function are disclosed as hypotensive agents. In GB 1 ,351 ,501 , adenosine and 2- aminoadenosine derivatives having a -NH-R2 group joined to the 6-amino function are disclosed as coronary dilators and platelet aggregation inhibitors. In EP 152,944, a series of 2-, 6- and 8- substituted adenosine derivatives are described having activity as anti- allergy agents. In EP 253,962, adenosine and 2-haloadenosine analogues having an alkyl, cycloalkyl or an aralkyl group attached to the 6-amino function are described with activity as antidementia agents.
In EP 402,752, derivatives of adenosine unsubstituted in the 2-position are described which have a substituted heteroaromatic 1-pyrrolyl moiety attached to the 6-amino group. In WO 91/04032, methods of preventing neural tissue damage in neurodegenerative diseases by increasing extracellular concentrations of adenosine are described. Examples are given of prodrug esters of AICA riboside which are claimed to be centrally acting neuroprotective agents. In WO 92/02214, analogues of AICA riboside are described which increase extracellular adenosine levels with beneficial effects claimed in peripheral and CNS ischaemia. In WO 90/05526, 2-(alkylalkynyl)adenosine derivatives are described for treatment of ischaemic disease of the heart and brain. In EP 423 777 a method for treating gastrointestinal motility disorders using N(6) (substituted aminoalkyl) adenosine deriva- fives is disclosed. EP 490 818 describes a new use of 2'-0-methyl adenosine derivatives for a range of ailments including neurodegenerative disorders.
The present invention relates to new adenosine analogues with ribose moieties optionally modified at C-5 which show potent binding in vitro to the adenosine A^ receptor, and which also display selectivity for A receptor binding in vitro over that to the A2 receptor subtype. In addition, the compounds contained in this invention have a relatively high lipophilicity, especially when compared to adenosine analogues which are not substituted on the 6-amino group or the purine 2-position. This latter property makes these compounds suitable for passage across the blood brain barrier.
The compounds are also substrates for nucleoside-specific active transport systems into the CNS across the blood barrier. These useful properties support the notion that the compounds are candidate drugs for treatment of the CNS ailments mentioned within this invention in humans as well as cardiovascular disorders such as myocardial ischaemia. In WO 95/07921 (Novo Nordisk A/S, we have revealed a series of compounds which are modified at the ribose C-5, but contain for example a pyrrolidine or piperidine group which may be optionally substituted with one or two C1-6-alkyl groups, C2.6-alkenyl, C2-6-alkynyl, phenoxy, phenylsulphonyl, phenylsulphinyl, phenylthio, hydroxy, phenyl, C1-6-alkoxy or C,. e-alkoxy-C^e-alkyl, phenylthioalkyl.
The novel compounds having a heteroaryloxy or heteroarylthio substitution on the pyrrolidine or piperidine nucleus described within this present application have improved aqueous solubility, which renders them suitable for formulation for human use. Furthermore, the compounds described herein, such as the examples containing a pyridylthio- functionality show superior potency to other adenosine agonists tested in the gerbil model of severe temporary forebrain ischaemia.
The compounds of the invention are purine derivatives of formula I, or a pharmaceutically acceptable salt thereof:
Figure imgf000008_0001
wherein
Y-
•O is the residue of a 4- to 7-membered heterocycle containing at least one nitrogen heteroatom, said heterocycle being substituted with the group -Y-Z;
X is halogen, amino, C1-6-alkoxy, C1-6-alkylthio or C1-e-alkylamino; A is hydroxymethyl or haiomethyl;
Y is oxygen, sulphur, sulphinyl or sulphonyl; and
Z is a five- or six-membered heterocycle, optionally substituted by C1-6-alkyl, C^-alkoxy, C1-6-alkylthio or C1-6-alkylamino.
In certain examples, the 6-amino substituent can contain one or more asymmetric carbon atoms in addition to those asymmetric centres already present in the molecule. In examples where this is the case, this invention includes all resulting diastereoisomers and mixtures thereof.
In the compounds of formula (I), the following structural features are particularly advanta- geous:
The 4- to 7-membered heterocycle is preferably a five- or six-membered heterocycle, more preferably piperidinyl or pyrrolidinyl, still more preferably piperidinyl;
X is preferably halogen;
Y is preferably oxygen or sulphur, more preferably sulphur;
Z is preferably thiazole, 1 ,2,4-triazole, imidazole or pyridyl, more preferably pyridyl;
A is preferably haiomethyl, more preferably chloromethyl.
The most preferred compounds of formula (I) are the following:
2-Chloro-Λ/-[4-(2-thiazolyl)thio-1-piperidinyl]adenosine 2-Chloro-Λ/-[4-(4-methyl-1 ,2,4-triazol-2-yl)thio-1-piperidinyl]adenosine 2,5'-Dichloro-5'-deoxy-Λ/-[4-(4-methyl-1 ,2,4-triazol-2-yl)thio-1-piperidinyl]adenosine
2-Chloro-Λ/-[4-(2-pyridylthio)-1-piperidinyl]adenosine 2-Chloro-Λ/-[4-(4-pyridylthio)-1-piperidinyl]adenosine 2,5'-Dichioro-5,-deoxy-W-[4-(2-pyridyl)thio-1-piperidinyl]adenosine
2,5'-Dichloro-5'-deoxy-Λ/-[4-(4-pyridyl)thio-1-piperidinyl]adenosine
2,5'-Dichloro-5'-deoxy-Λ/-[4-(2-thiazoly)thio-1-piperidinyl]adenosine
2-Bromo-A/-[4-(2-pyridyl)thio-1-piperidinyl]adenosine
2-Bromo-5'-chloro-5'-deoxy-Λ/-[4-(2-pyridyl)thio-1-piperidinyl]adenosine
2-Fluoro-/V-[4-(2-pyhdyl)thio-1-piperidinyl]adenosine
5'-Chloro-5'-deoxy-2-fluoro-Λ/-[4-(2-pyridyl)thio-1-piperidinyi]adenosine
2-Chloro-Λ/-[4-(1-methylimidazol-2-yl)thio-1-piperidinyl]adenosine
2,5'-Dichloro-5'-deoxy-Λ/-[4-(1-methylimidazol-2-yl)thio-1-piperidinyl]adenosine
with
2,5,-Dichloro-5,-deoxy-Λ/-[4-(2-pyridyl)thio-1-pipehdinyl]adenosine and 2,5'-Dichloro-5'-deoxy-/\/-[4-(4-pyridyl)thio-1-piperidinyl]adenosine
being the most preferred.
The present invention furthermore relates to a method of treating myocardial or cerebral ischaemia (disorders where the blood flow to the brain is interrupted) and epilepsy, comprising administering to a subject in need thereof a compound of formula (I) and the use of a compound of formula (I) for the preparation of a medicament for treating epilepsy or ischaemia.
Various salts of compounds of formula (I) can be prepared which is physiologically acceptable. These include addition salts derived from inorganic or organic acids, for example, acetates, fumarates, glutarates, glutaconates, lactates, maleates, methanesul- phonates, phosphates, salicylates, succinates, sulphates, sulphamates, tartrates and paratoluenesulphonat.es. In some cases, solvates of either the free nucleosides or the acid addition salts can be isolated and these solvates may, for example, be hydrates or alcoholates.
Compounds of formula (I), which act as adenosine receptor agonists, are furthermore useful in the treatment of central nervous system conditions such as anxiety, neuronal ischaemia/anoxia, convulsive disorders and neurodegeneration (including Parkinson's disease) in humans. This includes treating disorders where the blood flow to the brain is interrupted, for example during traumatic head injury, cardiac arrest and stroke. Further, the compounds of formula (I) are useful as analgesic agents, in lowering plasma free fatty acid (FFA) levels or as cardiovascular agents.
Methods for assessing adenosine receptor binding in vitro have been reviewed [Adenosine Receptors, Cooper, D.M.F. and Londos, C, Eds., Alan R. Liss, Inc.: New York, 1988, 43-62].
Evaluation of these compounds in established animal models has indicated that the compounds according to the invention possess desirable central nervous system properties. For example, they act as anticonvulsant agents, are effective in animal models of pain, and show cerebroprotective effects in laboratory test animals subjected to simulated cerebral ischaemia. In addition, the compounds may have efficacy as neuroprotective agents in cases of cerebral oedema and traumatic head injury.
Evaluation of in vitro binding to adenosine Aj and A2A receptors:
The affinity of the novel compounds described in this invention for the adenosine Aj receptor was determined essentially as described in the literature using [3H]-R-PIA as a radioligand (Naunyn-Schmiedeberg's Archives of pharmacology, 1980, 313, 179-187). Affinity for the A^ receptor was measured using the radioligand [3H]-CGS 21680 (European Journal of Pharmacology, 1989, 168, 243-246), and the values for representa- tive compounds is given in the table below. In vitro receptor binding values obtained for the reference standards CPA [Λ/-(cyclopentyl)adenosine] and R-PIA [(R)-Λ/-(1-phenyl-2- propyl)adenosine]) are included for comparison. The methods both for the above in vitro examination of the compounds are summarized in the European Journal of Pharmacology, 1993, 224, 221-228.
The results obtained by testing selected compounds disclosed in the present invention are shown in the table I.
TABLE
Figure imgf000012_0001
The compounds of the invention, together with a conventional adjuvant, carrier or diluent, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets of filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral use (including subcutaneous administration and infusion). Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the adenosine receptor agonist commensurate with the intended daily dosage range to be employed. Tablets containing ten (10) milligrams of active ingredient or, more broadly, ten (10) to hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
The compounds of this invention can thus be used for the formulation of pharmaceutical preparation, e.g. for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy.
Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or enteral application which do not deleteriously react with the active compounds.
Examples of such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
Ampoules are convenient unit dosage forms.
Tablets, dragees, or capsules having talc and/or carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch, are particularly suitable for oral application. A syrup, elixir or the like can be used in cases where a sweetened vehicle can be employed.
Generally, the compounds of this invention are dispensed in unit form comprising 0.05-100 mg in a pharmaceutically acceptable carrier per unit dosage. The dosage of the compounds according to this invention is 0.1-300 mg/day, preferably 10-100 mg/day, when administered to patients, e.g. humans, as a drug.
A typical tablet which may be prepared by conventional tabletting techniques contains:
Active compound 5.0 mg Lactosum 67.0 mg Ph.Eur.
Avicel™ 31.4 mg
Amberlite™IRP 88 1.0 mg
Magnesii stearas 0.25 mg Ph.Eur.
The compounds of the invention may be administered to a subject, e.g., a living animal body, including a human, in need of adenosine receptor agonist, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof (such as the hydrobromide, hydrochloride, or sulphate, in any event prepared in the usual or conventional manner, e.g., evaporation to dryness of the free base in solution together with the acid), ordinarily concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective amount of adenosine receptor agonist, and in any event an amount which is effective for the treatment of the disease. Suitable dosage ranges are 1-200 milligrams daily, 10-100 milligrams daily, and especially 30-70 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
The preparation of compounds of formula (I) is further illustrated in the following examples.
Hereinafter, TLC is thin layer chromatography, THF is tetrahydrofuran, TFA is trifluoracetic acid and mp is melting point. Where melting points are given, these are uncorrected. The structures of the compounds are confirmed by assignment of NMR spectra (from which representative peaks are quoted) and by microanalysis where appropriate. Compounds used as starting materials are either known compounds or compounds which can be prepared by methods known per se. on a Merck Hitachi model L6200A Intelligent chroma- tograph interfaced to a Merck Hitachi L4000A UV detector to a LiChrospher 100 reversed phase C18 column (5mm, 250 x 4 mm, 5mm, 10θA; eluent flow rate 1 mlJmin). Retention times are given in minutes.
Example 1
2-Chloro- /-[4-(2-thiazolyl)thio-1-piperidinyl]adenosine
2 '3 '5 '-Tri-0-acetyl-2-chloro-N-(4-hydroxypiperidinyl)adenosine
9-(2'3'5'-Tri-0-acetyl-b-D-hbofuranosyl)-2,6-dichloro-9H-puhne (5.5 g, 12.3 mmol), 1- amino-4-hydroxypiperidine (Knutsen, L.J.S., Lau, J., Sheardown, M.J. and Thomsen, C. The synthesis and biochemical evaluation of new A., selective adenosine receptor agonists containing a 6-hydrazinopurine moiety. BioMed. Chem. Lett. 1993, 3, 2661-2666) (2.86 g, 24.6 mmol) and triethylamine (4.3 ml, 3.14 g, 30.8 mmol) were dissolved in dioxan (30 ml) and the solution was stirred at ambient temperature for 18 h. The reaction mixture was filtered and evaporated to a residue which was purified by flash column chromatography. Elution with EtOAc provided the title compound as a foam (2.20 g, 34%); 1H NMR (400MHz, DMSO-d6) d 2.03, 2.06, 2.12 (9H,3s, 2', 3' & 5'-0-acetyl), 4.26 (1 H, dd, H-5'a), 4.38 (1 H, dd, H-5'b), 4.62 (1 H, d, H-4'), 5.57(1 H, t, H-3'), 5.87 (1 H, t, H-4'), 6.15 (1 H, d, H- 1'), 8.39 (1 H, s, H-8).
2-chloro-N-[4-(2-thiazolyl)thio-1-piperidinyl]adenosine
2'3'5'-Tri-0-acetyl-2-chloro-Λ/-(4-hydroxypiperidinyl)adenosine (0.75 g, was dissolved in THF (15 ml). Ph3P (0.41 g, 1.57 mmol) and diethylazodicarboxylate (0.25 ml, 0.276 g, 1.57 mmol) were introduced, followed by a solution of 2-mercaptothiazole (0.18 g, 1.57 mmol) in THF (5 ml) which was added dropwise over 0.5 h. The reaction mixture as stirred at ambient temperature for 2 h, filtered and evaporated to a residue which was purified by flash column chromatography. Elution with EtOAc provided 2',3',5'-tri-0-acetyl- b-D-ribofuranosyl-2-chioro-Λ/-[4-(2-thiazolyl)thio-1-piperidinyl]adenosine as a foam (0.14 g, 16%) which was deacylated using methanolic ammonia to afford the title compound (0.065 g, 58%) as a foam; 1H NMR (400MHz, DMSO-d6) d 3.52 - 3.58 (1 H, m, H-5'a), 3.62 -3.68 (1 H, m, H-5'b), 3.93 (1 H, q, H-4'), 4.12 (1 H, q, H-3'), 4.50 (1 H, q, H-2'), 5.05 (1 H, t, 5'-0H), 5.21 , 5.50 (2H, 2d, 2'-and 3'-OH), 5.82 (1H, d, H-1"), 7-72, 7.80 (2H, 2d, thiazole C-H), 8.41 (1 H, s, H-8).
Example 2
2-Chloro-Λ/-[4-(4-methyl-1,2,4-triazole-2-yl)thio-1-piperidinyl]adenosine
4-[(4-Methyl-1 ,2,4-triazole-2-yl)thio]piperidine (prepared by the method used for the synthesis of 1-amino-4-(phenylthio)pipehdine, as described in Knutsen, L.J.S., Lau, J., Sheardown, M.J. and Thomsen, C. The synthesis and biochemical evaluation of new A., selective adenosine receptor agonists containing a 6-hydrazinopurine moiety. BioMed. Chem. Lett. 1993, 3, 2661-2666) (2.0 g, 8.5 mmol) and KOH (1.91 g, 3.4 mmol) were taken up in water (10 ml). This mixture was heated to 50°C and hydroxylamine O-sulphonic acid (1.45 g, 12.8 mmol) in water (3.8 ml) was introduced dropwise, and the mixture was heated at 50°C for a further 1 h. The reaction mixture was extracted with EtOAc (30 ml) and the organic phase was separated and washed with water (10 ml), and combined with the filtered aqueous reaction mixture. Extraction with dichloromethane (8 x 50 ml), drying (MgS04) and evaporation provided crude 1-amino-4-[(4-methyl-1 ,2,4-triazole-2- yl)thio]piperidine (1.0 g) which was dissolved in dioxan (30 ml). Triethylamine (1.37 ml, 9.9 mmol) and 9-(2'3'5'-tri-0-acetyl-b-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.21 g, 4.9 mmol) were added, and the remainder of the synthesis proceeded as described for Example 1 , to provide the title compound (0.32 g) as a solid, mp 175-179°C; Η NMR (400MHz, DMSO-d6) d 3.49 (3H, s, -CH3), 3.52 - 3.58 (1 H, m, H-5'a), 3.62 -3.68 (1 H, m, H-5'b), 3.92 (1 H, q, H-4'), 4.13 (1 H, q, H-3'), 4.51 (1H, q, H-2'), 5.07 (1 H, t, 5'-0H), 5.21 , 5.49 (2H, 2d, 2'-and 3'-OH), 5.84 (1 H, d, H-1'), 8.43 (1 H, s, H-8), 8.55 (1 H, s, triazole C-H). HPLC retention time 8.27 min (gradient elution over 30 min.; 20-80% acetonithle/0.1% TFA in water, 99.9% purity at 250 nm).
Example 3
2,5'-Dichloro-5"-deoxy-/V-[4-(4-methyl-1 ,2,4-triazol-2-yl)thio-1 -piperidinyljadenosine
2-Chloro-A/-[4-(4-methyl-1 ,2,4-triazole-2-yl)thio-1-piperidinyl]adenosine (Example 2) (0.27 g, 0.54 mmol) was dissolved in acetonitrile (3 ml) and cooled on an ice-water bath. Under a nitrogen atmosphere, thionyl chloride (0.25 g, 0.15 ml, 1.62 mmol) (see Borchardt, R.T., Huber, J.A. and Wu, Y.S., J. Org. Chem., 1976, 41, 565-567) was added. Pyridine (0.087 ml, 0.085 g, 1.08 mmol) was introduced gradually, the reaction mixture became yellow in colour and was allowed to reach room temperature gradually. After stirring the mixture overnight, ice was added and the reaction mixture was basified with aqueous sodium bicarbonate (resulting in hydrolysis of the 2',3'-0-sulphinyl function) prior to extraction with ethyl acetate (2 x 15 ml). The combined organic extracts were dried (MgS04) and evaporated to provide a residue which was purified by flash chromatography on silica gel eluting with a mixture of dichloromethane and 10% ammonia in ethanol (19/1 to 9/1 ), to provide the title 2,5'-dichloro-5'-deoxy-Λ/-[4-(4-methyl-1 ,2,4-triazol-2-yl)thio-1- pipehdinyljadenosine (0.13 g, 47%) as a solid foam; Η-NMR (400MHz, DMSO-d6) d 3.50 (3H, s, -CH3), 3.86 (1 H, dd, H-5"a), 3.94 (1 H, m, H-5'b), 4.12 (1 H, q, H-4'), 4.19 (1H, q, H-3'), 5.51 , 5.65 (2H, 2d, 2'-and 3'-OH), 5.90 (1 H, d, H-1'), 8.42 (1H, s, H-8), 8.56 (1 H, s, triazole C-H). HPLC retention time 27.38 min (gradient elution over 30 min.; 20-80% acetoni- trile/0.1% TFA in water, 99.2% purity at 250 nm).
Example 4
2-Chloro-Λ/-[4-(2-pyridylthio)-1-piperidinyl]adenosine
4-(2-pyridylthio)piperidine (prepared by the method described in Example 2) (0.92 g, 3.44 mmol) was reacted with hydroxylamine O-sulphonic acid (2.32 g, 20.5 mmol) in the presence of KOH as described in Example 2. The crude 1-amino-4-(2- pyridylthio)piperidine was likewise reacted with 9-(2'3'5'-tri-0-acetyl-b-D-ribofuranosyl)- 2,6-dichioro-9H-purine (2.21 g, 4.9 mmol) in the presence of triethylamine, followed by deacylation as described above, to provide the title compound (0.16 g) as a foam; H NMR (400MHz, DMSO-d6) d 3.52 - 3.58 (1 H, m, H-5'a), 3.62 -3.68 (1 H, m, H-5'b), 3.93 (1 H, q, H-4'), 4.13 (1 H, q, H-3'), 4.51 (1 H, q, H-2'), 5.06 (1 H, t, 5'-0H), 5.21 (1 H, d, 3'-OH), 5.48 (1 H, d, 2'-OH), 5.84 (1 H, d, H-1"), 7.11 (1 H, dd, pyridyl H-5), 7.29 (1 H, d, pyridyl H-3), 7.64 (1 H, dd, pyridyl H-4), 8.42 (1 H, s, H-8), 8.46 (1H, d, pyridyl H-6). HPLC retention time 7.88 min (gradient elution over 30 min.; 20-80% acetonitrile/0.1 % TFA in water, 98.29% purity at 250 nm).
Example 5
2-Chloro-Λ/-[4-(4-pyridylthio)-1-piperidinyl]adenosine
This compound was prepared from 4-(4-pyridylthio)piperidine (1.78 g, 6.7 mmol) by the method described in Example 4, via the intermediate 2'3'5'-tri-0-acetyl-2-chloro-Λ/-[4-(4- pyridylthio)-1-piperidinyl]adenosine (0.61 g), which was deacylated to provide the title compound (0.43 g) as a foam; Η NMR (400MHz, DMSO-d6) d 3.52 - 3.58 (1 H, m, H-5'a), 3.62 -3.69 (1 H, m, H-5'b), 3.94 (1 H, q, H-4'), 4.13 (1 H, q, H-3'), 4.51 (1H, q, H-2'), 5.06 (1 H, t, 5'-0H), 5.21 (1 H, d, 3'-OH), 5.48 (1H, d, 2'-OH), 5.83 (1 H, d, H-1'), 7.33 (2H, dd, pyridyl H-3 & H-5), 8.38 (2H, dd, pyridyl H-2 & H-6), 8.41 (1H, s, H-8), 9.51 (1H, s, -NH). HPLC retention time 11.66 min (gradient elution over 30 min.; 20-80% acetonitrile/0.1% TFA in water, 98.46% purity at 250 nm). Example 6
2,5,-Dichloro-5"-deoxy-W-[4-(2-pyridyl)thio-1-piperidinyl]adenosine
2-Chloro-Λ/-[4-(2-pyridylthio)-1-piperidinyl]adenosine (Example 4) (1.75 g, 3.54 mmol) was dissolved in acetonitrile (75 ml) and reacted with thionyl chloride (1.44 g, 0.86 ml, 10.6 mmol) using the method described in Example 3. Once the crude 5'-chloro-2',3'-0- sulphinyl derivative had been identified, it was treated with methanol (50 ml) and 25% NH4OH solution (1.75 ml), and after 1.5 h at ambient temperature the reaction mixture was evaporated. Purification of the resultant residue by flash chromatography on silica gel, eluting with a mixture of dichloromethane and 10% ammonia in ethanol (50/1 ), provided the title compound (1.20 g, 66%) as a solid foam; H-NMR (400MHz, DMSO-d6) d 3.85 (1 H, dd, H-5'a), 3.93 (1 H, m, H-5'b), 4.10 (1 H, q, H-4'), 4.17 (1 H, q, H-3'), 4.64 (1 H, dt, H-2'), 5.49 (1 H, d, 3'-OH), 5.62 (1H, d, 2'-OH), 5.87 (1 H, d, H-1'), 7.11 (1 H, dd, pyridyl H-5), 7.28 (1 H, d, pyridyl H-3), 7.64 (1 H, dt, pyridyl H-4), 8.41 (1 H, s, H-8), 8.47 (1H, d, pyridyl H-6).
Example 7
2,5'-Dichloro-5'-deoxy-Λ/-[4-(4-pyridyl)thio-1-piperidinyl]adenosine
2-Chloro-Λ/-[4-(2-pyridylthio)-1-piperidinyl]adenosine (Example 5) (0.35 g, 0.7 mmol) was dissolved in acetonitrile (7 ml) and reacted with thionyl chloride (0.16 g, 0.1 ml, 0.6 mmol) using the method described in Example 3. Once the crude 5'-chloro-2',3'-0-sulphinyl derivative had been prepared, it was treated with methanol (5 ml) and 25% NH4OH solution (0.35 ml), and after 1 h at ambient temperature the reaction mixture was evaporated. Purification of the resultant residue by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (9/1 to 4/1 ), provided the title compound (0.12 g, 33%) as a solid foam; Η-NMR (400MHz, DMSO-dβ) d 3.84 (1 H, dd, H-5"a), 3.94 (1 H, m, H-5'b), 4.11 (1H, q, H-4"), 4.18 (1H, q, H-31), 4.64 (1H, dt, H-2'), 5.50 (1 H, d, 3'-OH), 5.63 (1 H, d, 2'-OH), 5.88 (1 H, d, H-1"), 7.33 (2H, dd, pyridyl H-3 & H-5), 8.38 (2H, dd, pyridyl H-2 & H-6), 8.40 (1 H, s, H-8), 9.56 (1 H, s, -NH). HPLC retention time 19.34 min (gradient elution over 30 min.; 20-80% acetonitrile/0.1 % TFA in water, 98.1% purity at 250 nm). The hydrochloride salt was prepared by dissolving this foam in methanol (10 ml) and adding a mixture of chlorotrimethylsilane (0.06 ml) in methanol (1 ml), and evaporating the solvent to give a solid (0.125 g).
Example 8
2,5'-Dichloro-5'-deoxy-Λ/-[4-(2-thiazoly)thio-1-piperidinyl]adenosine
2-Chloro-Λ/-[4-(2-thiazolyl)thio-1-pipehdinyl]adenosine (Example 1 ) (0.80 g, 1.6 mmol) was dissolved in acetonitrile (30 ml) and thionyl chloride (0.65g, 0.4 ml, 4.8mmol) was introduced and under a nitrogen atmosphere. After stirring for 3 h, pyridine (0.25 g, 0.26 ml, 3.2 mmol) was gradually introduced. The mixture was stirred overnight, ice was added and reaction mixture extracted with ethyl acetate (3 x 50 ml). The combined organic extracts were dried (MgS04) and evaporated to a residue which was purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and 10% ammonia in ethanol (25/1 ), to give the title compound 2,5'-dichloro-5'-deoxy-Λ/-[4-(2- thiazoly)thio-1-piperidinyl]adenosine (0.177 g, 21 %) as a solid foam; 1H-NMR (300MHz,
DMSO-d6) d 3.85 (1 H, dd, H-5'a), 3.91 (1H, m, H-5'b), 4.10 (1 H, q, H-4'), 4.18 (1 H, q, H-3'),
4.65 (1 H, dt, H-2'), 5.48 (1 H, d, 3'-OH), 5.61 (1H, d, 2'-OH), 5.88 (1 H, d, H-1'), 7.70, 7,79 (2H, 2d, thiazole C-H), 8,39 (1 H, s, H-8), 9.45 (1 H, s, -NH). HPLC retention time 3.72 min
(gradient elution over 30 min.; 20-80% acetonitrile/0.1% TFA in water, 97.75% purity at 250 nm).
Example 9
2-Bromo-Λ/-[4-(2-pyridyl)thio-1-piperidinyl]adenosine
This example was prepared from 1-amino-4-(2-pyhdylthio)piperidine (prepared by the method described in Example 4) (0.47g, 2.23mmol) reacted with 2-bromo-9-(2'3'5'-tri-0- acetyl-b-D-ribofuranosyl)-6-chloro-9H-purine (see WO 93/08206; Bioorganic and Medicinal Chemistry Letters, 1993, 3, 2661-2666) (2.2 g, 4.46 mmol) in the presence of triethy- lamine, followed by deacylation as described above, to provide the title compound 2- bromo-Λ/-[4-(2-pyridyl)thio-1-piperidinyl]adenosine (0.37g, 31 %) as a foam; 1H NMR (300 MHz, DMSO-d6) d 3.55 (1 H, m, H-5'a), 3.65 (1 H, m, H-5'b), 3.93 (1 H, q, H-4'), 4.12 (1 H, q, H-3'), 4.50 (1 H, q, H-2'), 5.04 (1 H, t, 5'-0H), 5.20 (1 H, d, 3'-OH), 5.48 (1 H, d, 2'-OH), 5.83 (1 H, d, H-1'), 7.10 (1 H, dd, pyridyl H-5), 7.28 (1 H, d, pyridyl H-3), 7.64 (1 H, dd, pyridyl H-4), 8.40 (1 H, s, H-8), 8.45 (1H, d, pyridyl H-6), (9.45, s, -NH). Mass m/z 538 (m+).
Example 10
2-Bromo-5'-chloro-5"-deoxy-Λ/-[4-(2-pyridyl)thio-1 -piperidinyljadenosine
2-Bromo-Λ/-[4-(2-pyridylthio)-1-piperidinyl]adenosine (Example 9) (0.37 g, 0.69 mmol) was dissolved in acetonitrile (20 ml) and reacted with thionyl chloride (0.28 g, 0.17 ml, 2.06 mmol) using the method described in Example 8. Purification of the resultant residue by flash chromatography on silica gel, eluting with a mixture of dichloromethane and 10% ammonia in ethanol (25/1 ), provided the title compound 2-bromo-5'-chloro-5'-deoxy-Λ/-[4- (2-pyridyl)thio-1-piperidinyl]adenosine (0.03g, 8%) as a solid foam; 1H-NMR (400MHz, DMSO-dβ) d 3.85 (1 H, dd, H-5'a), 3.92 (1 H, m, H-5'b), 4.09 (1 H, q, H-4'), 4.17 (1 H, q, H-3'), 4.64 (1 H, dt, H-2'), 5.50 (1H, d, 3'-OH), 5.62 (1 H, d, 2'-OH), 5.88 (1 H, d, H-1'), 7.12 (1 H, dd, pyridyl H-5), 7.30 (1 H, d, pyridyl H-3), 7.65 (1 H, dt, pyridyl H-4), 8.40 (1H, s, H-8), 8.48 (1 H, d, pyridyl H-6), 9.50 (1 H, s, -NH). Mass m/z 558 (m+). Example 11
2-Fluoro-Λ/-[4-(2-pyridyl)thio-1-piperidinyl]adenosine
This compound was prepared from 1-amino-4-(2-pyridylthio)pipehdine (prepared by the method described in Example 4) (0.78 g, 3.71 mmol) was reacted with 2-fluoro-9-(2'3'5'- tri-0-acetyl-b-D-ribofuranosyl)-6-chloro-9H-purine (see WO 93/08206; Bioorganic and Medicinal Chemistry Letters, 1993, 3, 2661-2666) ( 3.20 g, 7.42 mmol) in the presence of triethylamine, followed by deacylation as described above, to provide the title compound 2-fluoro-Λ/-[4-(2-pyridyl)thio-1-piperidinyl]adenosine (0.37g, 21 %) as a foam; 1H NMR (300MHz, DMSO-d6) d 3.56 (1 H, m, H-5'a), 3.64 (1 H, m, H-5'b), 3.93 (1 H, q, H-4'), 4.12 (1 H, q, H-3"), 4.51 (1 H, q, H-2"), 5.05 (1 H, t, 5'-0H), 5.20 (1 H, d, 3'-OH), 5.49 (1 H, d, 2'-OH), 5.83 (1H, d, H-1'), 7.11 (1H, dd, pyridyl H-5), 7.28 (1H, d, pyridyl H-3), 7.65 (1H, dd, pyridyl H-4), 8.41 (1 H, s, H-8), 8.46 (1 H, d, pyridyl H-6), (9.43, s, -NH). Mass m/z 478 (m+).
Example 12
5'-Chloro-5'-deoxy-2-fluoro-Λ/-[4-(2-pyridyl)thio-1-piperidinyl]adenosine
2-Fluoro-Λ/-[4-(2-pyridylthio)-1-piperidinyl]adenosine (Example 11 ) (0.37 g, 0.77 mmol) was dissolved in acetonitrile (20 ml) and reacted with thionyl chloride (0.31 g, 0.19 ml, 2.31 mmol) using the method described in Example 8. Purification of the resultant residue by flash chromatography on silica gel, eluting with ethyl acetate, provided the title compound 5,-chloro-5'-deoxy-2-fluoro-Λ/-[4-(2-pyhdyl)thio-1-piperidinyl]adenosine (0.14g, 36%) as a solid foam; Η-NMR (400 MHz, DMSO-d6) d 3.85 (1H, dd, H-5'a), 3.93 (1H, m, H-5'b), 4.10 (1 H, q, H-4'), 4.18 (1 H, q, H-3'), 4.64 (1 H, dt, H-2'), 5.49 (1H, d, 3'-OH), 5.62 (1H, d, 2"-OH), 5.86 (1H, d, H-1'), 7.11 (1H, dd, pyridyl H-5), 7.28 (1 H, d, pyridyl H-3), 7.64 (1 H, dt, pyridyl H-4), 8.35 (1 H, s, H-8), 8.47 (1 H, d, pyridyl H-6), 9.56 (1H, s, -NH). Mass m/z 496 (m+). Example 13
2-Chloro-Λ/-[4-(1-methylimidazol-2-yl)thio-1-piperidinyl]adenosine
4-[2-(1-methylimidazole)thio]piperidine (prepared by the method used for the synthesis of 1-amino-4-(phenylthio)piperidine, as described in Knutsen, L.J.S., Lau, J., Sheardown, M.J. and Thomsen, C. The synthesis and biochemical evaluation of new A^ selective adenosine receptor agonists containing a 6-hydrazinopurine moiety. BioMed. Chem. Lett. 1993, 3, 2661-2666) was converted to 1-amino-4-[2-(1-methylimidazole)thio]piperidine by the method described in Example 2. This 1-amino-4-[2-(1-methylimidazole)thio]pipehdine (0.68 g) was dissolved in dioxan (50 ml), triethylamine (1.34 ml, 9.6 mmol) and 9-(2'3'5'- tri-0-acetyl-b-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.87 g, 6.4 mmol) were added, and the remainder of the synthesis proceeded as described for Example 1 , to provide the title compound 2-chloro-Λ/-[4-(1-methylimidazol-2-yl)thio-1-piperidinyl]adenosine (0.57 g, 35%) as a foam; 1H NMR (200MHz, DMSO-d6) d 3.41 (1 H, m, H-5'a), 3.46 (1 H, m, H-5'b), 3.62 (3H, s, -CH3), 4.20 (1 H, q, H-4'), 4.38 (1 H, q, H-3'), 4.56 (1 H, q, H-2'), 5.39, 5.59 (2H, 2d, 2'- and 3'-OH), 5.84 (1 H, d, H-1'), 6.97, 7.29 (2H, 2d, imidazole C-H), 8.36 (1 H, s, H-8), 9.40 (1 H, s, -NH). Mass m/z 497 (m+).
Example 14
2,5,-Dichloro-5,-deoxy-Λ/-[4-(1-methylimidazol-2-yl)thio-1-piperidinyl]adenosine
2-Chloro-A/-{4-[2-(1-methylimidazole)thio]-1-piperidinyl}adenosine (Example 13) (0.57g, 1.15mmol) was dissolved in acetonitrile (25 ml) and reacted at room temperature and under a nitrogen atmosphere with thionyl chloride (0.46g, 0.29ml, 3.5mmol). After stirring for 3h, pyridine (0.18g, 0.19ml, 2.3mmol) was gradually introduced. After stirring the mixture overnight, ice was added and reaction mixture extracted with ethyl acetate (3 x 50ml). The combined organic extracts were dried (MgS04) and evaporated to a residue which was purified by flash chromatography on silica gel eluting with a mixture of dichloromethane and 10% ammonia in ethanol (50/1 ), to afford the title compound 2,5'- dichloro-5,-deoxy-Λ/-[4-(1-methylimidazol-2-yl)thio-1-piperidinyl]adenosine (0.01 g) as a solid foam; 1H-NMR (400 MHz, DMSO-d6) d 3.42, (1H, m, H-5'a), 3.45, (1H, m, H-5'b), 3.63, (3H, s, -CH3), 4.20 (1 H, q, H-4'), 4.36, (1 H, q, H-3'), 4.56 (1 H, q, H-2'), 5.46, 5.62 (2H, 2d, 2'- and 3'-OH), 5.88 (1 H, d, H-1'), 6.97, 7.28 (2H, 2d, imidazole C-H), 8.39 (1 H, s, H-8). Mass m/z 515 (m+).

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof
Figure imgf000025_0001
HO OH
wherein
Y — z
•O is the residue of a 4- to 7-membered heterocycle containing at least one nitrogen heteroatom, said heterocycle being substituted with the group -Y-Z;
X is halogen, amino, Cj.β-alkoxy, C1-β-alkylthio or C^-alkylamino;
A is hydroxymethyl or haiomethyl;
Y is oxygen, sulphur, sulphinyl or sulphonyl; and
Z is a five- or six-membered heterocycle, optionally substituted by C1-6-alkyl, C^-alkoxy, C^-alkylthio or C^-alkylamino.
2. A compound according to claim 1 , wherein the 4- to 7-membered heterocycle is a five- or six-membered heterocycle, preferably piperidinyl or pyrrolidinyl, more preferably piperidinyl.
3. A compound according to claim 1 or 2, wherein X is halogen.
4. A compound according to any one of the preceding claims, wherein Y is oxygen or sulphur, preferably sulphur.
5. A compound according to any one of the preceding claims, wherein Z is thiazole, 1 ,2,4-triazole, imidazole or pyridyl, preferably pyridyl.
6. A compound according to any one of the preceding claims, wherein A is haiomethyl, preferably chloromethyl.
7. A compound according to claim 1 selected from the following list of compounds:
2-Chloro-Λ/-[4-(2-thiazolyl)thio-1-pipehdinyl]adenosine 2-Chloro-Λ/-[4-(4-methyl-1 ,2,4-triazol-2-yl)thio-1-piperidinyl]adenosine
2,5'-Dichloro-5'-deoxy-Λ/-[4-(4-methyl-1 ,2,4-triazol-2-yl)thio-1-piperidinyl]adenosine
2-Chloro-Λ/-[4-(2-pyridylthio)-1-piperidinyl]adenosine
2-Chloro-Λ/-[4-(4-pyridylthio)-1-piperidinyl]adenosine
2,5'-Dichloro-5'-deoxy-Λ/-[4-(2-pyhdyl)thio-1-pipehdinyl]adenosine 2,5'-Dichloro-5'-deoxy-Λ/-[4-(4-pyridyl)thio-1 -piperidinyljadenosine
2,5'-Dichloro-5'-deoxy-A/-[4-(2-thiazoly)thio-1-piperidinyl]adenosine
2-Bromo-Λ/-[4-(2-pyridyl)thio-1 -piperidinyljadenosine
2-Bromo-5'-chloro-5'-deoxy-Λ/-[4-(2-pyridyl)thio-1 -piperidinyljadenosine
2-Fluoro-Λ/-[4-(2-pyridyl)thio-1 -piperidinyljadenosine 5'-Chioro-5'-deoxy-2-fluoro-Λ/-[4-(2-pyridyl)thio-1 -piperidinyljadenosine
2-Chloro-Λ/-[4-(1-methylimidazol-2-yl)thio-1 -piperidinyljadenosine
2,5'-Dichloro-5'-deoxy-Λ/-[4-(1-methylimidazol-2-yl)thio-1 -piperidinyljadenosine
8. 2,5'-Dichloro-5'-deoxy-Λ/-[4-(2-pyridyl)thio-1 -piperidinyljadenosine.
9. 2,5'-Dichloro-5'-deoxy-Λ/-[4-(4-pyridyl)thio-1 -piperidinyljadenosine.
10. A compound according to any one of the preceding claims for use in the treatment of myocardial or cerebral ischaemia or epilepsy.
11. A method of treating myocardial or cerebral ischaemia or epilepsy, comprising administering to a subject in need thereof a compound according to any one of claims 1 to 9.
12. The use of a compound according to any one of the claims 1 to 9 for the preparation of a medicament for treating myocardial or cerebral ischaemia or epilepsy.
PCT/DK1997/000423 1996-10-14 1997-10-02 Novel therapeutically active adenosine derivatives WO1998016539A1 (en)

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