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Title:
BORANE DERIVATES OF ADENOSINE
Document Type and Number:
WIPO Patent Application WO/2010/090541
Kind Code:
A1
Abstract:
A purine nucleoside derivative comprising a boron cluster or its complex with a metal (metallocarborane) conjugated to at least one of: a nucleic base, sugar residue or sugar residue analogue.

Inventors:
Leśnikowski, Zbigniew (Beli Bartoka 27/12, Łódź, PL-92-546, PL)
Olejniczak, Agnieszka (Smocza 17/18, Łódź, PL-93-520, PL)
Sulowska, Zofia (Lorentza 1/8, Łódź, PL-91-083, PL)
Bednarska, Katarzyna (Marynarska 20/7, Łódź, PL-91-803, PL)
Application Number:
PL2010/050004
Publication Date:
August 12, 2010
Filing Date:
February 05, 2010
Export Citation:
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Assignee:
Instytut Biologii Medycznej Polskiej Akademii Nauk (Lodowa 106, Lodz, PL-93-232, PL)
Leśnikowski, Zbigniew (Beli Bartoka 27/12, Łódź, PL-92-546, PL)
Olejniczak, Agnieszka (Smocza 17/18, Łódź, PL-93-520, PL)
Sulowska, Zofia (Lorentza 1/8, Łódź, PL-91-083, PL)
Bednarska, Katarzyna (Marynarska 20/7, Łódź, PL-91-803, PL)
International Classes:
C07H23/00
Domestic Patent References:
WO1996014073A1
Foreign References:
EP1113020A2
US6838574B1
EP1364954A1
Other References:
AGNIESZKA B. OLEJNICZAK ET AL.: "DNA-Dinucleotides Bearing a 3',3'-Cobalt- or 3',3'-Iron-1,2,1',2'-dicarbollide Complex" ORGANOMETALLICS, vol. 26, no. 14, 26 May 2007 (2007-05-26), pages 3272-3274, XP002581214 DOI: 10.1021/om070102z
LESNIKOWSKI ET AL: "Nucleoside-boron cluster conjugates - Beyond pyrimidine nucleosides and carboranes" JOURNAL OF ORGANOMETALLIC CHEMISTRY, ELSEVIER-SEQUOIA S.A. LAUSANNE, CH LNKD- DOI:10.1016/J.JORGANCHEM.2008.12.061, vol. 694, no. 11, 3 January 2009 (2009-01-03), pages 1771-1775, XP026063046 ISSN: 0022-328X DOI: 10.1016/j.jorganchem.2008.12.061 [retrieved on 2009-01-03]
AGNIESZKA B. OLEJNICZAK ET AL.: "Nucleoside-Metallacarborane Conjugates for Base-Specific Metal Labeling of DNA" CHEMISTRY - A EUROPEAN JOURNAL, vol. 13, no. 1, 14 November 2006 (2006-11-14), - 2007 pages 311-318, XP002581215 DOI: 10.1002/chem.200600740
BLAZEJ A. WOJTCZAK ET AL.: "Highly Lipophilic p-Carborane-Modified Adenosine Phosphates" COLLECT. CZECH. CHEM. COMMUN., vol. 73, 24 February 2008 (2008-02-24), pages 175-186, XP002581216 DOI: 10.1135/cccc20080175
OLEJNICZAK AGNIESZKA ET AL.: "2'-Deoxyadenosine Bearing Hydrophobic Carborane Pharmacophore" NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS, vol. 26, no. 10-12, October 2007 (2007-10), pages 1611-1613, XP009133215 ISSN: 1525-7770 DOI: 10.1080/15257770701548733
Attorney, Agent or Firm:
Witek, Rafał (WTS Patent Attorneys, Witek Śnieżko & Partner, ul. Rudolfa Weigla Wrocław, PL-53-114, PL)
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Claims:
Claims

1. A purine nucleoside derivative comprising a boron cluster or its complex with a metal (metallocarborane) conjugated to at least one of: a nucleic base, sugar residue or sugar residue analogue.

2. A nucleoside derivative according to Claim 1, characterised in that the nucleic base is adenine.

A nucleoside derivative according to Claim 1, characterised in that the metallocarborane group contains a metal atom (Me) selected from among Sn, Mn, Tc, Re, Fe, Ru, Os, Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, Au, Sc, Cr, Mg, Zr, Mo, Sm, Yb, Hf, W, Hg, Gd, U and Y or a non-metal selected from among As, S, Si, Se, Te, P, Sb, Bi, Ge and N, or isotopes thereof.

4. A nucleoside derivative to any of Claims 1-3 as well as formulae from 1 to 6, characterised in that a boron cluster is conjugated with the molecule either directly or via a bridge, preferably with the formula -[(CH2)n-(W)m]k(CH2)h, where f is 0 or 1, g is 0 or 1, h is from 0 to 5, k is from 0 to 6, m is 0 or 1, n is from 0 do 5, p is from 0 to 5, r is 0 or 1, s is from 0 to 5, t is from 0 to 6, u is from 0 to 2 whereas W is O, S, C(O), S(O), S(O)2, Se, NR (where R = an H, alkyl, haloalkyl, alkoxyalkyl or aryl), X-P(Z)(Y)O (where X = O, S, Se; Z = O, S, Se; Y = OH, SH, SeH or alkyl, haloalkyl, alkoxyalkyl, aryl or halogen, in particular fluorine), as well as CH=CH, CC, N=N, CHOH and CHN3.

5. A nucleoside derivative according to Claim 4, characterised in that the boron cluster is a 1,2-dicarba-closo-dodecaborane (ortho-carborane) group, 1,7-dicarba- closo-dodecaborane (meta-carborane), 1,12-dicarba-closo-dodecaborane (para- carborane), 7,8-dicarba-nido-undecaboranewa^ (nido-carborane), closo- dodecaborane or derivatives thereof substituted on a carbon or boron atom.

6. A nucleoside derivative according to Claim 4, characterised in that the metallocarborane group is a -{8-[(l,2-dicarba-closo-undecaborane)-3,3'-Me-(l',2'- dicarba-closo-undecaborane)] } or -{ 8-[(l,2-dicarba-closo-undecaborane)-3-Me- cyclopentadienyl] } group.

7. A nucleoside derivative according to Claim 6, characterised in that the metallocarborane group is a -{8-[(l,2-dicarba-closo-undecaborane)-3,3'-cobalt- (l',2'-dicarba-closo-undecaborane)] } or -{8-[(l,2-dicarba-closo-undecaborane)-3- kobalt-cyclopentadienyl] } group.

8. A nucleoside derivative according to Claim 4, characterised in that at least one of the hydroxyl groups (-OH) of the sugar residue or its analogue has been replaced with a group with the structure -OP(Z)(Y)X (Z = O, S, Se; Y = OH, SH, SeH or alkyl, haloalkyl, alkoxyalkyl, aryl or halogen; X = OH, SH, SeH or alkyl, haloalkyl, alkoxyalkyl, aryl or halogen) or -OP(Y)X [Y = alkyl, haloalkyl, alkoxyalkyl (-Oalkyl), aryl, aryloxyl (-Oaryl), NR2 or halogen; X =alkyl, haloalkyl, alkoxyalkyl (-Oalkyl), aryl, aryloxy (-Oaryl), NR2 or halogen]

9. A nucleoside derivative according to any of the preceding Claims, characterised in that it is a nucleotide of, preferably, mono-, di- or triphosphate nucleosides.

Description:
Borane derivatives of adenosine

The subject of the present invention are derivatives of adenosine for use in medicine in the design of drugs or as drugs.

In the immune system, the nucleoside adenosine is an endogenous factor which regulates the activity of leukocytes. In the nervous system, it is a neurotransmitter and in the blood coagulation system, it counteracts platelet aggregation. Adenosine is an internal purine nucleoside which diffuses through the cell membrane into surrounding cells where it binds with surface receptors, following its release from cells or through extracellular production. Important cells which produce extracellular adenosine are mesothelium cells and neutrophiles. Adenosine is constitutively present in the extracellular space at low concentrations, but its level significantly rises at sites of metabolic stress such as hypoxia, coronary hypoxia, inflammation or infection. It's believed that the concentration of extracellular adenosine in healthy tissue are below 1 μM, whereas a sites of inflammation or infection the concentration may approach 100 μM. Adenosine is characterized by a short half- life in the serum. The physiological activity of adenosine is a combination of an appropriate receptor on the cell surface and induction of intracellular pathways. Four types of receptors, belonging to the G. protein receptor family, are known: A 1 , A 2A -, A 2B , and A 3 . The interaction of adenosine with receptors A 2A . and A 2B on immune cells constitutes a strong, endogenous immunosuppressive mechanism which regulates an excessive response to external negative stimuli. When acting through the A 1 and A 3 receptors, adenosine exhibits inflammation- promoting and immunostimulant activity. Adenosine inhibits platelet activation through receptor A 2A , present on their surface. These receptors are important targets in the search for new drugs. Adenosine is modified in order to increase its metabolic stability and to obtain a high selectivity in relation to adenosine receptors, as well as a high affinity for them. EP 1113020 discloses the use of nucleosides and oligonucleotides in borane-neutron therapy (BNCT) and other therapeutic and diagnostic uses. Nucleosides and oligonucleotides according to that invention are conjugated with one or more boron clusters through alkyl groups connected to carbon atoms of an appropriate nucleic base (i.e. adenine), or through phosphate or sugar residues. WO 96/14073 discloses methods and composithions for the treatment of urogenital cancer, particularly prostate, bladder and kidney cancer using boron- neutron therapy. Compounds according to said invention used in the above-mentioned therapy are nucleosides and oligonucleotides containing carborane groups conjugated with an appropriate nucleic base through phosphate, thiophosphate or selenophosphate residues. These compounds are characteristic in that they are more lipophilic. Another patent, US 6,838,574, discloses a drug having as its active substance a dicarba-closo-dodecaborane derivative or its pharmacologically permissible salt. The borane group is conjugated with an aromatic ring either directly or through a connecting group. Compounds according to the invention exhibit an affinity for RAR and RXR retinoic acid receptors, and can be used as agonists or antagonists of these receptors. EP 1364954 describes a compound being a dicarba- closo-dodecaborane derivative or its pharmacologically permissible salt, which is useful as an agent modulating vitamin D activityor as an agent augmenting vitamin D activity. The compound according to the cited invention may be described with the formula R1-X-R2, where X denotes a dicarba-closo-dodecaboranedyl group, whereas Rl and R2 are hydroxyl derivatives of alkyl, aryl, etc. groups. Both antagonists and agonists of adenosine receptors are useful in primary research as well as being used as anticoagulants, vasodilators and antiinflammatories. They are also being tested for anticancer, anti-neurodegeneration and antiviral activity. However, the often short half-life of adenosine and its derivatives in the blood limits the possibilities of making use of the benefits of this class of compounds. Thus, there exists a need to formulate a compound, a derivative of adenosine, for the above mentioned uses which would have a longer a dentist seen half-life than the extant compounds.

The present invention relates to derivatives of adenosine, having the formula: g-[(CH 2 )n(W)m]k(CH 2 )hR 2

(D and also:

(2) as well as:

(3)

and also:

(4) as well as:

(5) and:

(6) Where: R 1 = HO-, CH 3 (CH 2 )n0-, CH 3 (CH 2 )nC(O)O-, H 2 N-, H 2 N(CH 2 )nNH-,

R 3 = OH-, H-

And 1 represents a carbon atom or a CH group and m represents a boron atom or a BH group.

Preferably, a compound according to the present invention has the following formula:

(7)

Equally preferably, the compound according to the present invention has the following formula:

(8)

In the next equally preferable embodiment of the present invention, the compound has the following formula:

(9 )

Equally preferably, the compound according to the present invention has the following formula:

(10)

In the next equally preferable embodiment of the present invention, the compound has the following formula:

(H)

Boron clusters constitute a novel type of pharmacophore used in the design of various types of drugs. The advantage of boron clusters in this area is their structure in the form of a regular dodecahedron which is similar in volume to a rotating benzene ring, their highly lipophilic character, and orthogonality which entails stability under physiological conditions and resistance to catabolism. Derivatives of adenosine modified with boron clusters have thus far not been available due to the lack of a method of synthesis. These derivatives have been used as in vitro modulators of human blood platelet functions: aggregation, secretion of granular proteins and the expression of selectin P on the platelet surface.

Example embodiments of the present invention are shown in the attached figure (Fig.l) which shows the effect of adenosine (10 μM) and its derivatives: 2'-0-methyl-0-propyl-/?αra- carborane-1 -adenosine (compound 11; 0.1 μM) as well as 6-iV-{5-[3-cobartbis(l,2- dicarbollide)-8-yl]-3-oxa-pentoxy}-2'-deoxyadenosine (compound 10; 0.1 μM) on the expression of selectin P (CD62P) in blood platelets stimulated with adenosine-5' -diphosphate (ADP, 3μM). Average values ±SEM are shown from experiments on 6 donors.

Example 1

Modification of 2'-deoxyadenosine with a /?αra-carborane cluster at position 8 using a cross- coupling reaction.

(7)

The substrate nucleoside, 8-bromo-deoxyadenosine, was lyophilised from water (0.5 rnL). A round-bottomed flask, 25 ml, heated with a burner flame and cooled over hydrophilic gel, was loaded with 2-ethinyl-/?αra-carborane (90.5 mg, 0.144 mmol), copper iodide (1.37 mg, 0.0072 mmol) as well as tetrakistriphenylphosphinopalladium (4.2 mg, 0.0036 mmol). Next, DMF (1.35 mL) and TEA (980 μL) were added (in argon). The reaction was performed in an argon atmosphere, on a magnetic stirrer, at a temperature of 80°C. After a half-hour, the reaction was stopped and the solvent was evaporated until dry under reduced pressure. The remainder was topped off with methylene chloride (10 mL) and extracted with distilled water (2x5 mL). The organic phases were collected and extracted with 0.5% EDTA (2x5 mL). The organic phases were separated and dried over anhydrous magnesium (VI) sulphate. The drying agent was additionally rinsed with methylene chloride. The solvent was evaporated off under reduced pressure. The raw product was purified using column chromatography on a silica gel (4 g, 230-400 mesh). The eluent used was a methanol gradient in methylene chloride (0-14%). Efficiency: 200 mg (80%). TLC (CH 2 C1 2 /CH 3 OH 1:9, v/v): R/=0,46; UV (95% C 2 H 5 OH): ^=250 nm, ^ ax =236, 301 nm; δ 1 H-NMR (CD 3 OD): 0-4 (HH, BH-carborane), 2,2-2,4 (m, IH, 2'-H), 3,03-3,09 (m, IH,

2"-H), 3,62-3,69 (m, 2H, 5'-H,5"-H), 3,85-3,88 (m, IH, 4'-H), 4,43-4,45 (m, IH, 3'-H), 6,39 (t, IH, l'-H, J 3 rra =7,78, J 3 r2 < b =6,62), 8,15 (s, IH, 2-H); δ 13 C-NMR (CD 3 OD): 40,31 (C-2'), 64,16 (C-5'), 65,45, 67,90 (CH - carborane), 73,60 (C-3'), 88,12 (C-I'), 90,34 (C-4'), 120,77 (C-5), 134,90 (C-8), 149,45 (C-4), 154,31 (C- 2), 157,45 (C-6); δ 11 B-NMR (CD 3 OD): -12,99 (9H, BH); FAB-MS (+VE): 419,3 [M+l] + .

Example 2 Modification of 2'-deoxyadenosine at position 8 with a nido-carborane cluster, using a "click chemistry" reaction.

(8)

8-Ethinyl-2'-deoxyadenosine (53 mg, 0.19 mmol) as well as radocarborane (50 mg, 0.19 mmol) were dissolved in an aqueous solution of tert-butanol (1 mL 1:1, v/v). Next, copper

(VI) sulphate was added (2.3 mg, 0.0094 mmol), water (150 μL), tert-butanol (150 μL) and potassium ascorbinate (1.65 mg, 0.0094 mmol). The reaction was performed in room temperature on a magnetic stirrer for 18 hours. The progress of the reaction was monitored with TLC tests in a CH3OH/CH2CI2 system (2:8, v/v). The solvent was evaporated under a vacuum produced by an oil vacuum pump. The product was purified using column chromatography on a silica gel (3 g, 230 - 400 mesh) using a linear gradient of methanol in methylene chloride (0-20%) as the eluent. The fractions containing the desired product were pooled, and the solvent was evaporated off under reduced pressure and dried under an oil pump vacuum. Efficiency: 17,87 mg (35%). TLC (CH 2 Cl 2 ZCH 3 OH 2:8, v/v): Ry=O, 16;

UV (95% C 2 H 5 OH): λ min =246 ran, λ max =284 nm; δ 1 H-NMR (CD 3 OD): 0-2 (m, 10 H, BH), 2,14-2,49 (m, IH, 2'-H), 3,29-3,30 (m, IH, T- H), 3,61-3,63 (m, 4H, OCH 2 CH 2 O), 3,60-3,89 (m, 2H, 5'-H, 5"-H), 3,89 (m, IH, 4'-H), 4,09-4,1 (m, 4H, OCH 2 CH 2 N), 4,44-4,46 (m, IH, 3'-H), 7,18-7,24 (m, IH, l'-H), 8,15 (s, IH, 2-H), 8,67 (s, IH, CH- triazole ring); δ 13 C-NMR (CD 3 OD): 40,75 (C-2'), 51,86 (CH 2 - linker), 64,24 (C-5'), 70,10 (CH 2 - linker), 70,42 (CH 2 - linker), 72,63 (CH 2 - linker), 73,74 (C-3'), 88,59 (C-I'), 90,21 (C-4'), 121,65 (C-5), 128,58 (C-5 triazole ring), 139,6 (C-8), 143,74 (C-4 triazole ring), 150,95

(C-4), 152,97 (C-2), 157,53 (C-6); δ 11 B-NMR ((CDs) 2 CO): -9,67 (B- 10), -11, 37-(-13,08) (B-9, 11), -16,43-(-18,06) (B-5,

6), -22,91-(-24,94) (B-2, 4), -26,067 (B-3), -39,52-(-40,78) (B-I);

IR (KBr) 3439 cm "1 (v O-H), 2954 cm "1 (v aliphatic C-H), 2918, 2526 cm "1 (v B-H), 1640 cm "1 (v N-H), 1472, 1463 cm "1 (v N=N);

FAB-MS (-VE): 538,4 [M-I] " .

Example 3

Modification of adenosine with a /?αra-carborane cluster at position 2, using a cross-coupling reaction.

(12)

A round-bottomed flask, 25 ml, heated with a burner flame and cooled over hydrophilic gel, was loaded with 2-ethinyl-/?αra-carborane (23.56 mg, 0.140 mmol), copper iodide (3.06 mg, 0.0016 mmol) as well as tetrakistriphenylphosphinopalladium (6.3 mg, 0.0055 mmol) as well as 2-iodoadenosine (50 mg, 0.127 mmol). Next, DMF (0.9 mL mL) and TEA (0.3mL) were added (in argon). The reaction was performed in an argon atmosphere, on a magnetic stirrer, at room temperature. After an hour, the reaction was stopped and the solvent was evaporated until dry under reduced pressure. The raw product was purified using column chromatography on a silica gel (4 g, 230-400 mesh). The eluent used was a methanol gradient in methylene chloride (2-10%). Efficiency: 37.69 mg (68%). TLC (CH 2 Cl 2 ICH 3 OH): Rf=O 5 I l;

UV (95% C2H5OH): A 01111 =251 ran, 280 nm, ^=239 nm, 270 nm, 300 nm; δ 1 H-NMR ((CDs) 2 CO): 1,00-3,50 (m, 9H, BH-carborane), 3,51 (bs, IH, IH-CH- carborane), 3,71-3,84 (m, 3H, 2H-5',5", lH-CH-carborane), 4,14-4,16 (m, IH, 1H-4'), 4,37-4,39 (m, 2H, 1H-3', IH-OH), 4,73-4,82 (m, 2H, 1H-2', IH-OH), 5,05-5,10 (m, IH, IH-OH), 5,97 (d, IH, IH-I', J r2 =7,50), 6,81 (bs, 2H, 2H-NH 2 ), 8,31 (s, IH, 1H-8);

δ 13 C-NMR ((CDs) 2 CO): 63,20 (C-5'), 64,90 (CH-carborane), 67,53 (CH-carborane), 72,38 (C-3'), 75,17 (C-2'), 87,81 (C-4'), 90,38 (C-I'), 121,00 (C-5), 142,15 (C-8), 146,21 (C-4), 150,00 (C-2), 157,02 (C-6);

δ 11 B-NMR ((CDs) 2 CO): -12,18 (2B), -13,90 (4B), -15,90 (4B);

FAB-MS (gly): 435,4 [M+2].

Example 4

Modification of adenosine modyfikowanej cluster nido-carborane w pozycji 6N, w oparciu o reakcJQ otwierania pierscienia dioxanylwego wobec zasady nieorganicznej.

(9)

2',3',5'-O,O,O-tri-(?er?-butyldimethylsilyl)-adenosine (100 mg, 0.16 mmol) as well as dioxane-nido-carborane (72.28 mg, 0.33 mmol) was dried under an oil vacuum pump over 24 hours, and then transferred into a 10 ml round-bottomed flask heated over a gas burner and cooled in an exsicator with a dessicating gel. The contents of the flask were evaporated off with anhydrous toluene (3 x 3 mL), and the atmosphere was replaced with argon. Sodium hydride was added (60% suspension in mineral oil, 13.11 mg). The dry substrate mixture was dissolved in anhydrous toluene (2.5 mL) and the entirety heated to 70°C for 5 godzin on an oil bath. Next, the reaction mixture was cooled to room temperature and the solvent was evaporated off. The raw product was purified using column chromatography on a silica gel (12 g, 230-400 mesh). The eluent used was a methanol gradient in methylene chloride (0- 20%). Efficiency: 52 mg (38%).

A flask containing a solution of 2',3',5'-O,O,O-tri-(?er?-butyldimethylsilyl)-6N-dietylenoksy - nido-C2B9H 11 -adenosine (80 mg, 0.10 mmol) in THF (1.5 mL) was placed in an ice bath. TBAF (0.615 mL, IM solution in THF) was added after cooling to 0°C. The reaction was performed over 1.5 hours at room temperature. The reaction mixture was supplemented with 15 mL ethyl acetate, and then extracted with water (3 x 10 mL) and saturated sodium chloride (10 mL). The organic phase was separated and dried using magnesium sulphate. Next, the drying agent was filtered off and the phase was rinsed with ethyl acetate (2.5 mL). The solvent was evaporated using a venturi pump. The raw product was purified using column chromatography on a silica gel (5 g, 230-400 mesh). The eluent used was a methanol gradient in methylene chloride (10-40%). Efficiency: 62%.

δ 1 H-NMR(CD 3 OD): 0,88-2,00 (m, 9H, BH-carborane), 3,49 (m, 4H, 2 x CH 2 -bridge), 3,69- 3,79 (m, 4H, 2H-5',5", CH 2 -bridge), 4,03 (m, IH, 1H-4'), 4,23 (m, IH, 1H-3'), 4,42-4,52 (m, 5H, 1H-2', CH 2 -bridge, 2 x CH-carborane), 5,97 (d, IH, IH-I'), 8,40 (s, IH-, 1H-2), 8,49 (s, IH, 1H-8);

δ 13 C-NMR(CD 3 OD): 52,26 (CH 2 -bridge), 62,50 (C-5'), 68,83 (CH 2 -bridge), 70,23 (CH 2 - bridge), 71,63 (C-3'), 73,12 (CH 2 -bridge), 76,49 (C-2'), 87,22 (C-4'), 90,74 (C-I'), 121,31 (C-5), 144,14 (C-8), 148,18 (C-4), 149,15 (C-2), 152,54 (C-6);

δ 11 B-NMR { IH BB } (CD 3 OD): 9B: -40,79 (s), -23,80 (s), -17,37 (s), -12,44 (s), -10,13 (s);

FAB-MS (gly): 487,6 [M+l].

Example 5

Modification of 2'-deoxyadenosine modified with a metallocarborane cluster (with various metal ions) at position 6N of the nucleic base using a dioxane ring decyclization reaction by an inorganic base. The protocol uses a metallocarborane derivative containing a cobalt ion in its structure.

(10)

3',5'-O,O-di-(?er?-butyldimethylsilyl)-2'-deoxyadenosine (100 mg, 0.2 mmol) as well as 8- dioxanyl-[bis(l,2-dicarba-c/øsO-undekaborane)-cømmc>-3, 3'-cobartate (III)(-1)] (129.2 mg, 0.3 mmol) was dried under an oil vacuum pump for 24 hours, whereafter it was transfereed into a 50 mL round-bottomed flask that had been heated over a gas burner and cooled in an exicator with a dessicating gel. The contents of the flask were evaporated off with anhydrous toluene (3 x ImL), displacing the air in the dessicator with argon. Next, sodium hydride was added (60% suspension in oil, 12.6 mg, 0.5 mmol). The dry substrate mixture was dissolved in anhydrous toluene (2.57 mL) and the entirety heated to 70°C for 6 hours on an oil bath. Next, the reaction mixture was cooled to room temperature and the solvent was evaporated off. The raw product (ca. 243 mg) was purified using column chromatography on a silica gel (1O g, 230-400 mesh). A linear acetonitrile gradient in methylene chloride (0-6%) was used as the eluent. Efficiency: 104.2 mg (56%). A flask containing a solution of 3',5'-O,O-di-(tert-butyldimethylsilyl)-6-N-{5-{ [bis(l,2- dicarba-c/o5'o-undecaborane)-commc>-3,3'-cobaltate(III)(- l)]-8-yl}-3-oxa-pentoxy}-2'- deoxyadenosine (390.9 mg, 0.4 mmol) in THF (6 mL) was placed in an ice bath. TBAF (IM solution in THF, 1.6 mL, 1.6 mmol) was added after cooling to 0°C. The reaction was carried out over 1.5 hours at room temperature. The reaction mixture was supplemented with 30 mL of ethyl acetate, and then extracted with water (3 x 20 mL) and saturated sodium chloride (20 mL). The organic phase was separated and dried out with magnesium sulphate. Next, the drying agent was filtered off and washed with ethyl acetate (5 mL). The solvent was evaporated off using a water venturi pump. The raw product (ca. 460 mg) was purified using column chromatography on a silica gel (6g, 230-400 mesh). The elution system used comprised a linear methanol gradient in methylene chloride (2-10%). Efficiency: 210.5 mg, (72%).

TLC (CH 3 OH/CH 2 C1 2 , 2:8 v/v): R/=0,5; UV (C 2 H 5 OH) λ min =234 nm, 294 nm, λ max =260 nm, 313 nm;

5 1 H-NMR (CD 3 OD): 1,00-2,50 (m, 17H, BH-metallocarborane), 2,55-2,77 (m, 2H, 2H-2 1 ), 3,61 (s, 4H, 2 x CH 2 -linker), 3,75-3,80 (m, 2H, 2H-5 1 , 5"), 3,89-3,97 (m, 6H, 2H-CH 2 -linker, 4 x CH-metallocarborane), 4,03 (m, IH, 1H-4 1 ), 4,48 (m, 2H, 2H-CH 2 -linker), 4,57 (m, IH, 1H-3 1 ), 6,47 (t, IH, IH-I 1 J r2 <=6,52), 8,46 (s, IH, 1H-2), 8,55 (s, IH, 1H-8); 5 13 C-NMR (CD 3 OD): 41,9 (C-2 1 ), 48,0 (CH-metallocarborane), 52,0 (CH 2 -linker), 54,1 (CH- metallocarborane), 63,0 (C-5 1 ), 68,8 (CH 2 -linker), 69,8 (CH 2 -linker), 72,3 (C-3 1 ), 73,6 (CH 2 - linker), 86,5 (C-I 1 ), 89,6 (C-4 1 ), 121,1 (C-5), 143,8 (C-8), 147,8 (C-2), 149 (C-4), 152,4 (C-6); 5 11 B-NMR (CD 3 OD): 24,11 (B-8), 6,16 (B-8 1 ), -5,90 (B- 10, 4, 7, 9, 12, 10', 4', 7, 9', 12'), - 18,11 (B- 5, 11, 6, 5', 11', 6'); FAB-MS (-VE): 660,4 [M].

Example 6

Modification of adenosine at position 2' with a para-carborane group using the methyl-thio- methyl method.

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Λ^-benzoyl-3 ' ,5 ' -O-(tetraisopropyldisiloxa- 1 ,3-diyl)-2' -O-methylthiomethyl-adenosine (50 mg, 0.07 mmol), tert-butyl bromide (26 mg, 0,08 mmol) and l-(pαra-carborane)-3- hydroxypropane (37 mg, 0,19 mmol) dissolved in 1,2-dichloroethane (2 mL). The reaction mixture was left protected from moisture for 24 at room temperature, with agitation on a magnetic mixture. Copper bromide (II) (18 mg, 0.08 mmol) was then added. The reaction was performed at room temperature for a further 26 hours. The progress of the reaction was controlled using chromatography in a CH 2 Cl 2 ZMeOH (9:1) development system. Next, the reaction mixture was diluted 1,2-dichloroethane (3 mL) and rinsed with water (3 x 3 mL). The organic fraction was separated and dried with anhydrous magnesium sulphate. The magnesium sulphate was filtered off, and the fraction was washed with methylene chloride, whereafter the solvent was evaporated off yielding ca. 120 mg (efficiency: 60%) of the raw intermediate product, Λ^-benzoyl-3',5'-O-(tetraisopropyldisiloxa-l,3-diyl)-2'-O-( p-carborane- l-yl)propyladenosine. This product, without purification, was dissolved in dry tetrahydrofuran (1,5 mL), te^ra-butylammonium flouride was added (ImL, 3.5 mmol) and the entirety was left protected from moisture at room temperature. After 15 minutes, a piridine/methanol/water mixture was added (3:1:1), and then the ion exchange resin Dowex 50WX8 (piridinyl form). The entirety was left at room temperature with agitation on a magnetic stirrer. After 30 minutes, the ion exchanger was filtered off and the remainder was rinsed with the solvent mixture given above (3 x 5 mL). The filtrates were pooled and the solvents were evaporated off with an addition of toluene at the end of the evaporation (3 mL). The raw product was purified using column chromatography on a silica gel (5g, 230-400 mesh) using a methanol gradient in methylene chloride (0-5%). The fractions containing the product were pooled and the solvents were evaporated off. Efficiency: 30%.

TLC (CH 2 Cl 2 MeOH, 9:1): R/= 0,59; UV (96% C 2 H 5 OH): l min = 257,34 nm, l max = 281,15 nm; d 1 H-NMR (CDCl 3 ): 1,34-1,48 (m, 2H, 2H-a-CH 2 ), 1,66-1,78 (m, 2H, 2H-b-CH 2 ), 2,64 (bs, IH, lH-C-carborane), 3,5 (t, 2H, 2H-α-CH2), 3,63-4,63 (m, 5H, 1H-2', 1H-3', 1H-4', 2H-5'), 4,96 (m, 2H, OCH 2 ), 6,0 (s, IH, IH-I'), 7,51-7,73 (m, 5H, benzoyl group), 8,05 (s, IH, IH- 2), 8,8 (s, IH, 1H-8); d 13 C-NMR (CDCl 3 ): 29,63 (C-a-CH 2 ), 32,21 (C-b -CH 2 ), 35,26 (C-^-CH 2 ), 58, 06 (OCH 2 ), 61,82 (C-5'), 63,17 (C-3'), 67,65 (C-4'), 68,11 (C-2'), 71,73 (C-I'), 77,15 (C-carborane), 127,91 (C-5), 128,26 (C-2, C-6 benzoyl group), 128,74 (C-3, C-5 benzoyl group), 132,40 (C- 1 benzoyl group), 140,8 (C-8), 167,69 (CO benzoyl group); d 11 B-NMR (CDCl 3 ): -13,86 (t, 10B); d 11 B-NMR (with decoupled H) (CDCl 3 ): -13,86 (d, 10B).

Example 7 During initial research, we obtained, among others, adenosine derivatives containing a para- carborane-1-yl group attached to position 2' of the adenosine (compound 11) or C8 T- deoxyadenosine (compound 7), 50-100 times more active as platelet aggregation inhibitors than unmodified adenosine. In the abovementioned research, we used blood platelets as model cells which lack any adenosin receptor other than A2. This research has shown that adenosine modified with a boron cluster at positions 2' and 2, acting via the A2A receptor, is a stronger inhibitor of blood platelet activity in vitro than adenosine. The results of platelet activation (i.e. using the agonist ADP) include an increase in the expression of selectin P (Schematic 1). As is shown in Fig. 1, at micromolar concentrations, adenosine inhibits platelet activation. Derivative 11 already inhibits platelet activation at nanomolar concentration. The presence of A2A on neutrophiles suggests that such a modified adenosine can also significantly affect neutrophiles via this receptor, at the site of an inflammation reaction and regulate this process in said fashion. Moreover, derivatives of adenosine resulting from the directed synthesis of compounds with a long half-life in serum, low cytotoxicity, being more lipophilic, as well as capable of inhibiting proinflammatory neutrophile activity can be considered as potential drugs in the future.