JP2003514827A - New ribose compounds - Google Patents

Abstract

(57) Abstract The present invention provides novel ribose compounds of formula (I); their use as pharmaceuticals, compositions containing them, and methods for their preparation. Embedded image

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention provides novel ribose analogs, their use as pharmaceuticals, compositions containing them, and processes for their preparation.

[0002] adhesion and aggregation of the background art platelets are initial events in arterial thrombosis. The process of platelet attachment to the subendothelial surface may have an important role to play in the repair of damaged vessel walls, but the platelet aggregation triggered by this may lead to acute thrombotic occlusion of the live vascular bed. Can be deposited and lead to high prevalence events such as myocardial infarction and unstable angina. Successful interventions used to prevent or alleviate the above-mentioned conditions, such as thrombolysis and platelet-mediated occlusion or re-occlusion, also prevent angioplasty.

A number of convergent pathways lead to platelet aggregation. Whatever the initial stimulus, the final common event is the membrane-binding site glycoprotein IIb / IIIa (GPIIb /
IIIa) Crosslink formation of platelets by the binding of fibrinogen. GPI
The high antiplatelet effects of antibodies or antagonists to Ib / IIIa are explained by their interference with this final common event. However, this effect may also explain the bleeding problem that has been observed with this class of drugs. Although thrombin can produce platelet aggregation almost independently of other pathways, substantial amounts of thrombin may be present due to the preceding activation of platelets by other mechanisms.
Thrombin inhibitors such as hirudin are highly effective antithrombotic agents, but they can also produce excessive bleeding because they function as both antiplatelets and anticoagulants (The TIMI 9a Investigators (1994), Circulation 90,
pp. 1624-1630; "Using Global Strategies for Open Obstructive Coronary Arteries" (The Global Use
of Strategies to Open Occluded Coronary Arteries) (GUSTO) IIa Inv
estigators (1994) Circulation 90, pp. 1631-1637; Neuhaus KL et al. (1
994) Circulation 90 pp. 1638-1642).

ADP has been found to act as a major mediator of thrombosis.
ADP-induced platelet aggregation is mediated by _P2T receptor subtypes located on the membrane of platelets. The P _2T receptor (also known as P2Y _ADP or P2T _AC ) is
It is a G protein-coupled receptor mainly involved in platelet aggregation / activation. The pharmacological properties of this receptor are described, for example, in Humphries et al., Br. J. Pharmacology, (19
94), 113, 1057-1063 and Fagura et al., Br. J. Pharmacology (1998) 124, 15
7-164 in the literature. Recently, it has been shown that antagonists at this receptor provide significant improvement over other antithrombotic agents (J. Med. Chem. (1999) 42, 213.
checking). There is a need to find P _2T (P2Y _ADP or P2T _AC ) antagonists as antithrombotic agents.

[0005] In the description a first aspect of the invention, the invention of formula (I):

[0006]

[Chemical 9]

Wherein R ¹ is either alkyl C _1-6 or COR ⁴ substituted by OH; R ² is alkyl C _1-6 or haloalkyl C _1-6 ; R ³ Is cycloalkyl C _3-6 optionally substituted by R ⁵ ; R ⁴ is OR ⁶ or NHR ⁶ ; R ⁵ is 1 selected from alkyl C _1-6 , halogen and OR ^6. Phenyl optionally substituted by one or more groups; R ⁶ is H or alkyl C _1-6 ], or a pharmaceutically acceptable salt or solvate thereof, or such Solvates of various salts are provided.

[0008]   Preferably, the compound of formula (I) has the following stereochemistry:

[0009]

[Chemical 10]

Where R ¹ , R ² and R ³ are as defined above, and R ³ is:

[0011]

[Chemical 11]

Where R ⁵ is as defined above, this stereochemistry is preferably

[0013]

[Chemical 12]

It is Suitably R ¹ is CH ₂ OH, (CH ₂ ) ₂ OH, COOH or CONHEt.

Suitably R ² is alkyl C ₃ optionally substituted by 3 halogen atoms. Particularly preferred compounds of the invention include: (1R-trans) -N- (2-phenylcyclopropyl) -5- (propylthio) -3- (β-D-ribofuranosyl) -3H- [1,2,3]. − Triazolo [
4,5-d] pyrimidin-7-amine; (1R-trans) -N- [2- (4-chlorophenyl) cyclopropyl] -5.
-(Propylthio) -3- (β-D-ribofuranosyl) -3H- [1,2,3]
-Triazolo [4,5-d] pyrimidin-7-amine; (1R-trans) -N- [2- (3,4-difluorophenyl) cyclopropyl] -5- (propylthio) -3- (β-D -Ribofuranosyl) -3H- [1,
2,3] -Triazolo [4,5-d] pyrimidin-7-amine; (1R-trans) -N- [2- (4-methoxyphenyl) cyclopropyl]-
5- (propylthio) -3- (β-D-ribofuranosyl) -3H- [1,2,3
] -Triazolo [4,5-d] pyrimidin-7-amine; (1R-trans) -N- [2- (4-fluorophenyl) cyclopropyl]-
5- (propylthio) -3- (β-D-ribofuranosyl) -3H- [1,2,3
] -Triazolo [4,5-d] pyrimidin-7-amine; (1R-trans) -N- (2-phenylcyclopropyl) -5- (3,3,3)
-Trifluoropropylthio) -3- (β-D-ribofuranosyl) -3H- [1
, 2,3] -Triazolo [4,5-d] pyrimidin-7-amine; (1R-trans) -3- (5-deoxy-β-D-ribo-hexofuranosyl)
-N- (2-phenylcyclopropyl) -5- (propylthio) -3H- [1,
2,3] -Triazolo [4,5-d] pyrimidin-7-amine; (1R-trans) -1-deoxy-1- [7-[(2-phenylcyclopropyl) amino] -5- (propylthio) -3H- [1,2,3] -triazolo [4
, 5-d] Pyrimidin-3-yl] -β-D-ribofuranuronic acid; (1R-trans) -1-deoxy-N-ethyl-1- [7-[(2-phenylcyclopropyl) amino] -5 -(Propylthio) -3H- [1,2,3] -triazolo [4,5-d] pyrimidin-3-yl] -β-D-ribofuranuronamide; or a pharmaceutically acceptable salt or solvent thereof Solvates or solvates of such salts are included.

According to the present invention there is further provided a process for preparing a compound of formula (I), said process comprising:
Includes the following steps a-e: a. For compounds of formula (I) where R ¹ is CH ₂ OH, formula (II):

[0017]

[Chemical 13]

A compound of the formula: wherein R ² is defined above and P is a protecting group, preferably benzoyl, is treated with a dipolar aprotic solvent, preferably N, N-dimethylformamide, or an alcohol. Preferably about 1 in the presence of n-butanol.
Reacting with R ³ NH ₂ (where R ³ is defined above) and a base, preferably triethylamine or N, N-diisopropylethylamine, and optionally followed by protection at a temperature of 00 to about 150 ° C. Removing the group.

Protecting groups can be added and removed using known reaction conditions. For more information on the use of protecting groups, see Protective Groups in Organ.
ic Chemistry) J. WF McOmie, ed., Plenum Press (1973) and "Protective Groups in Organic Synthesis" 2nd edition, TW Gree.
Ne & PGM Wutz, Willy Interscience (1991).

R ³ is:

[0021]

[Chemical 14]

And when R ⁵ is phenyl, it is LA Mitscher et al, J. Med. C
hem., 1986, 29, 2044. R ⁵ is C _1-6 alkyl,
If is phenyl substituted by one or more groups selected from halogen and OR ^6, it can be prepared as described in International Patent Application No. WO9905143.

[0023]   The compound of formula (II) has the formula (III):

[0024]

[Chemical 15]

A compound of the formula: wherein R ² is defined above at a temperature of about 100 to about 150 ° C., and 1-O-acetyl-2,3,4-tri-O-benzoyl-β-. It can be prepared by reacting D-ribofuranose with an acid, preferably p-toluenesulfonic acid.

[0026]   The compound of formula (III) has the formula (IV):

[0027]

[Chemical 16]

A compound of the formula: wherein R ² is defined above, in the presence of an acid, preferably acetic acid,
Metal, preferably followed by reduction with iron powder, aprotic inert solvents amphoteric, preferably in the presence of acetonitrile, at a temperature of about 20 to about 100 ° C., nitrite C _1-6 alkyl, preferably nitrous It can be prepared by diazotization using isoamyl nitrate.

[0029]   The compound of formula (IV) has the formula (V):

[0030]

[Chemical 17]

A compound of the formula: wherein R ² is as defined above, in the presence of an inert ethereal solvent, preferably 1,4-dioxane, at a temperature of about 0 to about 50 ° C. It can be prepared by reacting with aqueous ammonia.

The compound of formula (V) may be prepared as described in International Patent Application WO9828300. b. For the preparation of compounds of formula (I) wherein R ¹ is CH ₂ OH, see formula (VI)
:

[0033]

[Chemical 18]

A compound of the formula: wherein R ² and R ³ are as defined above, i) sodium hydrosulfide (NaSH) and an amphoteric aprotic solvent, preferably N, N-dimethyl Reacting in the presence of formamide at a temperature of about 0 to about 50 ° C., and the product of this reaction is treated with an amphoteric aprotic solvent, preferably N,
Treating with an alkyl halide (R ^{2 ′} X) in the presence of N-dimethylformamide at a temperature of about 0 to about 50 ° C., or ii) sodium alkylthiolate (R ^{2 ′} SNa) and an amphoteric aprotic solvent. Interconverting R ² by reacting at a temperature of about 0 to about 50 ° C., preferably in the presence of N, N-dimethylformamide, wherein R ^{2 ′} is the interconverted R ² Is different).

[0035]   The compound of formula (VI) has the formula (VII):

[0036]

[Chemical 19]

A compound of the formula: wherein R ² and R ³ are as defined above, in the presence of a chlorocarbon solvent, preferably dichloromethane, at a temperature of about 0 to about 50 ° C. acid,
Preferably it can be synthesized by oxidation with m-chloroperoxybenzoic acid.

The preparation of compounds of formula (VII) was described in step a above. c. For compounds of formula (I) wherein R ¹ is (CH ₂ ) ₂ OH, see formula (VIII
):

[0039]

[Chemical 20]

A compound of the formula: wherein P and P ′ are protecting groups, preferably CMe ₂ , and R ² and R ³ are as defined above, in the presence of an inert solvent, preferably toluene. Reduction under a metal hydride, preferably di-isobutylaluminium hydride, at a temperature of about 0 to about 50 ° C., and optionally the subsequent removal of any protecting groups. Preferably, the protecting group is about 0.
It is removed by reaction with trifluoroacetic acid using water or aqueous acetonitrile as solvent at a temperature of ~ 100 ° C.

[0041]   The compound of formula (VIII) has the formula (IX):

[0042]

[Chemical 21]

Oxidation of a compound of the formula (where P, P ′, R ² and R ³ are as defined above) in the presence of an alcohol, preferably methanol, at a temperature of about 20 to about 80 ° C. Silver(
It can be synthesized by reacting with I).

[0044]   The compound of formula (IX) has the formula (X):

[0045]

[Chemical formula 22]

A compound of the formula: wherein P, P ′, R ² and R ³ are as defined above, in the presence of a base, preferably N-methylmorpholine, an alkyl chloroformate, preferably chloroformate. Following reaction with isobutyl acid, about -10 to about 20 in the presence of an ethereal solvent, preferably a mixture of tetrahydrofuran and diethyl ether.
It can be synthesized by reaction with diazomethane at a temperature of ° C.

[0047]   The compound of formula (X) has the formula (XI):

[0048]

[Chemical formula 23]

A compound of the formula (wherein P, P ′, R ² and R ³ are as defined above) in the presence of an amphoteric aprotic inert solvent, preferably N, N-dimethylformamide. , At temperatures of about 0 to about 50 ° C., preferably by oxidation with pyridinium dichromate.

The compound of formula (XI) is obtained by reacting the compound of formula (VII) at a temperature of about 0 to about 100 ° C. with a ketal or acetal, preferably 2,2-dimethoxypropane / acetone. )) with an acid, preferably p-toluenesulfonic acid.

D. For compounds of formula (I) where R ¹ is COOH, compounds of formula (X) are treated with an acid, preferably trifluoroacetic acid / an acid, at a temperature of about 0 to about 100 ° C.
Deprotection using preferably trifluoroacetic acid, in water) or aqueous acetonitrile.

E. For compounds of formula (I) wherein R ¹ is CONHR ⁶ , the carboxylic acid group of the compound of formula (X) is converted into a suitable activating reagent, preferably benzotriazolyl-1-yloxytris (hexafluorophosphate). R ⁶ at the temperature of about 0 to about 50 ° C. in the presence of a base (preferably N, N-diisopropylethylamine) / inert ethereal solvent (preferably tetrahydrofuran) activated with dimethylamino) phosphonium.
NH ₂ (where R ⁶ is as defined above) is reacted with, and optionally, removing any protecting groups afterwards. Preferably the protecting group is from about 0.
It is removed using trifluoroacetic acid in water or aqueous acetonitrile at a temperature of about 100 ° C.

The compounds of formula (II), (VI), (VII), (VIII) and (X) form a further aspect of the invention. Salts of compounds of formula (I) include free bases, or salts or derivatives thereof, with one or more equivalents of a suitable acid (eg, halohydrogenic acid (especially HCl), sulfuric acid,
Oxalic acid or phosphoric acid). This reaction is carried out in a solvent or medium in which the salt is insoluble, or a solvent in which the salt is soluble, such as water, ethanol,
It can be carried out in tetrahydrofuran or diethyl ether, but these can be removed in vacuo or by freeze-drying. This reaction can also be a metathesis method or it can be carried out in an ion exchange resin. Non-toxic, physiologically acceptable salts are preferred, but other salts may be useful, for example when isolating or purifying the product.

The compounds of the present invention act as P _2T (P2Y _ADP or P2T _AC ) receptor antagonists. Accordingly, the compounds of the present invention are useful in treatments, including combination therapies, particularly where they are inhibitors of platelet activation, aggregation and degranulation, promoters of platelet segregation,
As an antithrombin agent: or atherosclerosis such as unstable angina, coronary revascularization including angioplasty (PTCA), myocardial infarction, perithrombolysis, thrombotic or embolic stroke. Primary arterial thrombotic complications, transient ischemic attacks, peripheral vascular disease, myocardial infarction with or without thrombolysis, angioplasty,
Of arterial complications due to intervention in atherosclerosis such as endarterectomy, stent placement, coronary or other vascular graft surgery, tissue salvage after accidental or surgical trauma Thrombotic complications of surgical or mechanical injury, regenerative surgery involving skin and muscle flaps, pathologies with dispersive thrombus / platelet consuming components, such as disseminated intravascular coagulation, thrombotic thrombocytopenia Purpura,
Venous, such as hemolytic uremic syndrome, thrombotic complications of sepsis, adult respiratory distress syndrome, antiphospholipid syndrome, heparin-induced thrombocytopenia and preeclampsia / eclampsia, or deep vein thrombosis Thrombosis, venous occlusive disease, myeloproliferative diseases including thrombocythemia, treatment or prevention of hematological conditions such as sickle cell disease; or cardiopulmonary bypass and extracorporeal membrane oxygenation (prevention of microthromboembolism) In vivo platelet activation, such as in the storage of blood products such as platelet concentrates, or renal dialysis and plasmapheresis.
shunt obstruction, vasculitis, arteritis, glomerulonephritis,
Thrombosis secondary to vascular injury / inflammation such as inflammatory bowel disease and organ transplant rejection, pathologies such as migraine, Raynaud's phenomenon, atherosclerotic plaque formation / progression, stenosis / restenosis, vascular wall Applicable for the use in the prevention of other inflammatory conditions such as asthma, where platelets may be the cause of the underlying inflammatory disease process, and where platelets and platelet-inducing factors are involved in the immunological disease process. To be done. Further indications include treatment of CNS disorders and prevention of tumor growth and spread.

The invention further provides the use of a compound according to the invention as an active ingredient in the manufacture of a medicament for use in the treatment or prevention of the disorders mentioned above. In particular, the compounds of the present invention are useful for treating myocardial infarction, thrombotic stroke, transient ischemic attacks, peripheral vascular disorders, and unstable or stable angina, especially unstable angina. . The present invention also provides a method for treating or preventing the above disorders, said method comprising:
Administering to a human suffering from or susceptible to such a disorder a therapeutically effective amount of a compound according to the invention.

The compounds of the invention may be applied topically, eg in the form of solutions, suspensions, HFA aerosols and dry powders, to the lungs and / or respiratory tract; or, for example, tablets, pills, capsules, syrups, Oral administration in the form of powder or granules, parenteral administration in the form of sterile parenteral solution or suspension, subcutaneous administration, rectal administration in the form of suppository, or systemic administration by transdermal administration Can be done.

The compounds of the invention may be administered on their own or as a pharmaceutical composition comprising a compound of the invention together with a pharmaceutically acceptable diluent, adjuvant or carrier. Especially preferred are compositions that do not contain substances that can cause adverse reactions, eg allergic reactions.

Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation. For inhalation, the compounds of the invention are desirably finely divided. The compounds of this invention may also be administered by a dry powder inhaler. The inhaler may be a single dose or a multi dose inhaler, and may be a breath actuated dry powder inhaler.

One possibility is to mix the finely divided compound with a carrier material, for example a mono-, di- or polysaccharide, sugar alcohols or other polyols. Suitable carriers include sugar and starch. Alternatively, the finely divided compound may be coated with other materials. The powder mixture can also be formulated into hard gelatin capsules, each containing the desired dose of the active compound.

Another possibility is to process the finely divided powder into spheres which decompose during the inhalation method. This spheronized powder can be used in multi-dose inhalers (eg Turbuha
(known as ler®) drug reservoirs. Here, the dosage unit controls the desired dose inhaled by the patient. This system delivers the active compound, with or without a carrier substance, to the patient.

Pharmaceutical compositions comprising the compounds of the invention are conveniently tablets, pills, capsules, syrups, powders or granules for oral administration; sterile parenteral or parenteral for parenteral administration or It can be a subcutaneous solution or a suppository for rectal administration.

For oral administration, the active compound is administered as an adjuvant or carrier, for example a starch such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch or amylopectin, a cellulose derivative, a binder such as gelatin or polyvinylpyrrolidone, and It may be mixed with a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, etc. and then compressed into tablets. If a coated tablet is desired, the core, prepared as described above, may be coated with a concentrated sugar solution (which may contain gum arabic, gelatin, talc, titanium dioxide, etc.). Alternatively, suitable polymers dissolved in either readily volatile organic or aqueous solvents may be used to coat tablets.

For the production of soft gelatin capsules, the compounds according to the invention can be mixed with, for example, vegetable oils or polyethylene glycol. Hard gelatin capsules are the above excipients for tablets,
For example, lactose, saccharose, sorbitol, mannitol, starch,
Either cellulose derivatives or gelatin may be used to contain granules of the compound. Also, liquid or semi-solid formulations of the drug may be filled into hard gelatin capsules.

Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing the compound of the invention with the remainder being a mixture of sugar with ethanol, water, glycerol and polyethylene glycol. If desired, such a liquid preparation may be
Colorants, fragrances, saccharin and carboxymethyl cellulose as thickeners,
Or it may contain other excipients known to those skilled in the art.

[0065]

【Example】

The present invention is illustrated by the following non-limiting examples. In the examples, NMR spectra were taken from Varian Unity Inova 3
00 or 400 spectrometer and MS spectra were measured as follows: EI
Spectra are VG70-250S or Finnigan Mat Incos.
Obtained by -XL spectrometer, FAB spectrum was obtained by VG70-250 SEQ spectrometer, ESI and APCI spectra were obtained by Finnigan Mat S.
Obtained by SQ7000 or Micromass Platform spectrometer. In general, preparative HPLC separations were performed on a Novc packed with BDSC-18 reverse phase silica, Nov.
apak (registered trademark), Bondapak (registered trademark) or Hypersil (
Performed using a registered trademark column. Flash chromatography (shown as (SiO ₂ ) in the examples) was performed using Fisher Matrix silica,
Performed using 35-70 μm. The proton NMR spectrum shows the rotamer (
In the examples showing the presence of rotamers) only the chemical shifts of the major rotamers are cited.

[0066]

Example 1 (1R-trans) -N- (2-phenylcyclopropyl) -5- (propylthio) -3- (β-D-ribofuranosyl) -3H- [1,2,3] -triazolo [
4,5-d] Pyrimidin-7-amine a) 6-chloro-5-nitro-2- (propylthio) pyrimidin-4-amine 4,6-dichloro-5-nitro-2- (propylthio) pyrimidine (WO98
A solution of (prepared as described in 28300) (2.6 g) in 1,4-dioxane (50 ml) was treated with concentrated ammonia solution (1 ml) at room temperature for 24 hours. The reaction mixture was concentrated in vacuo and the residue triturated with hexane to give the subtitle compound (2
． 2 g) was obtained. MS (APCI) 247/9 (M-H ⁺ , 100%) b) 7-chloro-5- (propylthio) -3H- [1,2,3] triazolo [
4,5-d] Pyrimidine Iron powder (5 g) was added portionwise over 2 hours to a solution of the product from step a) (5 g) in acetic acid (200 ml) and the suspension was stirred for a further 2 hours. The reaction mixture was neutralized with sodium bicarbonate solution and extracted with dichloromethane. The organic extracts dried (MgSO ₄₎ and concentrated in vacuo. The resulting oil was dissolved in acetonitrile (25 ml), isoamyl nitrite (7.5 ml) was added, and this solution was added to 6 ml.
The mixture was stirred at 5 ° C for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography (SiO ₂ , dichloromethane as eluent followed by ethyl acetate) to give the subtitle compound (5g). MS (APCI) 228/30 (M + H ⁺ , 100%).

C) 2,3,5-Tri-O-benzoyl-1-deoxy-1- [7-chloro-
5- (Propylthio) -3H- [1,2,3] triazolo [4,5-d] pyrimidin-3-yl] -β-D-ribofuranose (2,3,5-tri-O-benzoyl-1) -Deoxy-1- [7-chloro-5- (propylthio) -3H- [1,2
, 3] Triazolo [4,5-d] pyrimidin-2-yl] -β-D-ribofuranose and 2,3,5-tri-O-benzoyl-1-deoxy-1- [7-chloro-
5- (Propylthio) -3H- [1,2,3] triazolo [4,5-d] pyrimidin-1-yl] -β-D-ribofuranose is included) The product from step b) (8 g), 1-O-acetyl-2,3,4-tri-O-
A mixture of benzoyl-β-D-ribofuranose (16g) and p-toluenesulfonic acid was heated together in vacuum at 120 ° C for 30 minutes. Chromatography of the cooled reaction mixture (SiO ₂ , dichloromethane: ethyl acetate = eluent =
9: 1) and the subtitle compound (15g) as the major fraction of the mixture of isomers.
Was obtained (used without further purification).

D) (1R-trans) -N- (2-phenylcyclopropyl) -5- (propylthio) -3- (2,3,5-tri-O-benzoyl-β-D-ribofuranosyl) -3H -[1,2,3] -Triazolo [4,5-d] pyrimidin-7-amine The product from step c) (3.37 g), (1R-trans) -2-phenylcyclopropylamine [R- (R ^* , R ^* )]-2,3-dihydroxybutanedioate (1: 1) (prepared as described by LA Mitscher et al, J. Med. Chem., 1986, 29, 2044) (1. 5 g) and diisopropylethylamine (3 ml)
A mixture of dichloromethane (60 ml) was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography (SiO ₂ , ethyl acetate: isohexane = 1: 4 as eluent) to give the subtitle compound (3.4g).
MS (APCI) 771 (M + H ⁺ , 100%).

E) (1R-trans) -N- (2-phenylcyclopropyl) -5- (propylthio) -3- (β-D-ribofuranosyl) -3H- [1,2,3] -triazolo [4 , 5-d] Pyrimidin-7-amine A mixture of the product from step a) (3 g) and sodium methoxide (1 g) in methanol (20 ml) was stirred at 25 ° C. for 2 hours. The reaction mixture is concentrated in vacuo and the residue is chromatographed (SiO ₂ , dichloromethane as eluent, then,
Purification by methanol: dichloromethane = 1: 9) gave the title compound (1 g).

[0070]

[Chemical formula 24]

[0071]

Example 2 (1R-trans) -N- [2- (4-chlorophenyl) cyclopropyl] -5
-(Propylthio) -3- (β-D-ribofuranosyl) -3H- [1,2,3]
-Triazolo [4,5-d] pyrimidin-7-amine a) (1R-trans) -N- [2- (4-chlorophenyl) cyclopropyl] -5- (propylthio) -3- (2,3,5 -Tri-O-benzoyl-β-D
-Ribofuranosyl) -3H- [1,2,3] -triazolo [4,5-d] pyrimidin-7-amine (1R-trans) -2- (4-chlorophenyl) cyclopropylamine (in International Patent Application WO9905143). Prepared as described in Example 1,
The subtitle compound was prepared by the method of step d). MS (APCI) 805 (M + H ⁺ , 100%).

B) (1R-trans) -N- [2- (4-chlorophenyl) cyclopropyl] -5- (propylthio) -3- (β-D-ribofuranosyl) -3H- [1,2
, 3] -Triazolo [4,5-d] pyrimidin-7-amine The product from step a) was used to prepare the title compound by the method of Example 1, step e).

[0073]

[Chemical 25]

[0074]

Example 3 (1R-trans) -N- [2- (3,4-difluorophenyl) cyclopropyl] -5- (propylthio) -3- (β-D-ribofuranosyl) -3H- [1,
2,3] -Triazolo [4,5-d] pyrimidin-7-amine a) (1R-trans) -N- [2- (3,4-difluorophenyl) cyclopropyl] -5- (propylthio) -3 -(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl) -3H- [1,2,3] -triazolo [4,5-d
] Pyrimidin-7-amine (1R-trans) -2- (3,4-difluorophenyl) cyclopropylamine [R- (R ^* , R ^* )]-2,3-dihydroxybutanedioate (1: 1) (
Example 1 using (as prepared in International Patent Application WO9905143)
The subtitle compound was prepared by the method of Step d). MS (APCI) 806 (M + H ⁺ , 100%).

B) (1R-trans) -N- [2- (3,4-difluorophenyl) cyclopropyl] -5- (propylthio) -3- (β-D-ribofuranosyl) -3H-
[1,2,3] -Triazolo [4,5-d] pyrimidin-7-amine The product from step a) was used to prepare the title compound by the method of Example 1, step e).

[0076]

[Chemical formula 26]

[0077]

Example 4 (1R-trans) -N- [2- (4-methoxyphenyl) cyclopropyl]-
5- (propylthio) -3- (β-D-ribofuranosyl) -3H- [1,2,3
] -Triazolo [4,5-d] pyrimidin-7-amine a) (1R-trans) -N- [2- (4-methoxyphenyl) cyclopropyl] -5- (propylthio) -3- (2,3 , 5-tri-O-benzoyl-β-
D-ribofuranosyl) -3H- [1,2,3] -triazolo [4,5-d] pyrimidin-7-amine (1R-trans) -2- (4-methoxyphenyl) cyclopropylamine [
R- (R ^* , R ^* )]-2,3-dihydroxybutanedioate (1: 1) (prepared as described in International Patent Application WO9905143) was used to prepare Example 1, step d). The subtitle compound was prepared by the method. MS (APCI) 801 (M + H ⁺ , 100%).

B) (1R-trans) -N- [2- (4-methoxyphenyl) cyclopropyl] -5- (propylthio) -3- (β-D-ribofuranosyl) -3H- [1,
The title compound was prepared by the method of Example 1, step e), using the product from step a), 2,3] -triazolo [4,5-d] pyrimidin-7-amine.

[0079]

[Chemical 27]

[0080]

Example 5 (1R-trans) -N- [2- (4-fluorophenyl) cyclopropyl]-
5- (propylthio) -3- (β-D-ribofuranosyl) -3H- [1,2,3
] -Triazolo [4,5-d] pyrimidin-7-amine a) (1R-trans) -N- [2- (4-fluorophenyl) cyclopropyl] -5- (propylthio) -3- (2,3 , 5-tri-O-benzoyl-β-
D-ribofuranosyl) -3H- [1,2,3] -triazolo [4,5-d] pyrimidin-7-amine (1R-trans) -2- (4-fluorophenyl) cyclopropylamine (
Example 1 using (as prepared in International Patent Application WO9905143)
The subtitle compound was prepared by the method of Step d). MS (APCI) 789 (M + H ⁺ , 100%).

B) (1R-trans) -N- [2- (4-fluorophenyl) cyclopropyl] -5- (propylthio) -3- (β-D-ribofuranosyl) -3H- [1,
The title compound was prepared by the method of Example 1, step e), using the product from step a), 2,3] -triazolo [4,5-d] pyrimidin-7-amine.

[0082]

[Chemical 28]

[0083]

Example 6 (1R-trans) -N- (2-phenylcyclopropyl) -5- (3,3,3)
-Trifluoropropylthio) -3- (β-D-ribofuranosyl) -3H- [1
, 2,3] -Triazolo [4,5-d] pyrimidin-7-amine a) (1R-trans) -N- (2-phenylcyclopropyl) -5- (propylsulfonyl) -3- (β-D -Ribofuranosyl) -3H- [1,2,3]-
Triazolo [4,5-d] pyrimidin-7-amine A mixture of the product from Example 1 (0.6 g) and m-chloroperbenzoic acid (0.9 g) was stirred in a dichloromethane (20 ml) solution for 1 hour. . The reaction mixture was washed with aqueous sodium bicarbonate solution and the organic phase was concentrated in vacuo. The residue was purified by chromatography (SiO ₂ , ethyl acetate: isohexane = 1: 4 as eluent) to give the subtitle compound (0.6 g). MS (APCI) 491 (M + H ⁺ , 100%).

B) (1R-trans) -N- (2-phenylcyclopropyl) -5- (3,
3,3-trifluoropropylthio) -3- (β-D-ribofuranosyl) -3H
-[1,2,3] -Triazolo [4,5-d] pyrimidin-7-amine To a solution of the product from step a) (0.5 g) in dimethylformamide (5 ml), sodium hydrosulfide (0.2 g). ) Was added over 15 minutes. 1-Bromo-3,3,3-trifluoropropane (1 ml) was added and the mixture was heated to 25 ° C.
And stirred for 4 hours. Water was added and the product was extracted into ethyl acetate. The organic phase was concentrated in vacuo and the residue was purified by chromatography (SiO ₂ , ethyl acetate: isohexane = 1: 4 as eluent) to give the title compound (0.1g).

[0085]

[Chemical 29]

[0086]

Example 7 (1R-trans) -3- (5-deoxy-β-D-ribo-hexofuranosyl)
-N- (2-phenylcyclopropyl) -5- (propylthio) -3H- [1,
2,3] -Triazolo [4,5-d] pyrimidin-7-amine a) (1R-trans) -3- [2,3-O- (1-methylethylidene) -β
-D-ribofuranosyl] -N- (2-phenylcyclopropyl) -5- (propylthio) -3H- [1,2,3] -triazolo [4,5-d] pyrimidine-7-
Amine (1R-trans) -N- (2-phenylcyclopropyl) -5- (propylthio) -3- (β-D-ribofuranosyl) -3H- [1,2,3] -triazolo [4,5-d ] Pyrimidin-7-amine (prepared as described in Example 1) (3.
To a solution of 1 g) in dry acetone was added 2,2-dimethoxypropane (8 ml) followed by p-toluenesulfonic acid (1.6 g). The mixture was stirred for 1 hour, neutralized by addition of triethylamine and the mixture was evaporated. The residue is washed with water (50
ml) and dichloromethane (50 ml). The organic extract was concentrated in vacuo and the residue was purified by chromatography (SiO ₂ , ethyl acetate: isohexane = 1: 2 as eluent) to give the subtitle compound (3.0g). MS (APCI) 500 (M + H ⁺ , 100%).

B) (1R-trans) -1-deoxy-2,3-O- (1-methylethylidene) -1- [7- (2-phenylcyclopropylamino) -5- (propylthio) -3H- [1,2,3] -Triazolo [4,5-d] pyrimidin-3-yl]
-Β-D-ribofuranuronic acid A mixture of the product from step a) (3.0 g) and pyridinium dichromate (30 g) in dry dimethylformamide (30 ml) was stirred for 48 hours. The mixture was poured into water (500 ml), extracted with ethyl acetate and washed with 10% sodium metabisulfite solution. The organic layer is dried, concentrated in vacuo and the residue is purified by reverse phase HPLC (Novapak C ₁₈ , acetonitrile: 0.1% aqueous ammonium acetate = 35: 65 as eluent) to give the subtitle compound (
2.1 g) was obtained. MS (APCI) 513 (M + H ⁺ , 100%).

C) [3aR- [3aα, 4α, 6α (1R ^* , 2S ^* ), 6aα]]-2-diazo-1- [2,2-dimethyl-6- [7- (2-phenylcyclopropyl) Amino) -5- (propylthio) -3H- [1,2,3] -triazolo [4,5-d
] Pyrimidin-3-yl] tetrahydrofuro [3,4-d] [1,3] dioxol-4-yl] ethanone Product from step b) (300 mg) and N-methylmorpholine (0.059 m
Isobutyl chloroformate (0.076 ml) was added dropwise to the dry tetrahydrofuran (10 ml) ice-cooled mixture of l). The mixture was allowed to reach room temperature and stirred for a further 30 minutes. This mixture was then slowly added to an ethereal solution of diazomethane (3.0g). After 1 hour, the mixture was concentrated in vacuo and the residue was purified by chromatography (SiO ₂ , dichloromethane as eluent) to give the subtitle compound (0.3g). ^{MS (APCI) 509 (M +} H + -N 2, 100%).

D) (1R-trans) -1,5-dideoxy-2,3-O- (1-methylethylidene) -1- [7- (2-phenylcyclopropyl) amino-5- (propylthio)- 3H- [1,2,3] -triazolo [4,5-d] pyrimidine-3-
Il] -β-D-ribo-hexofuranuronic acid, methyl ester The product from step c) (0.3 g), methanol (50 ml) and silver oxide (I
) (0.3 g) was heated under reflux for 8 hours. This reaction mixture was added to Celi
It was filtered through te and the filtrate was concentrated in vacuo. The residue was subjected to reverse phase HPLC (Novap
akC ₁₈ , acetonitrile as eluent: 0.1% ammonium acetate aqueous solution = 6
(0:40) to give the subtitle compound (0.18 g). MS (APCI) 541 (M + H ⁺ , 100%).

E) (1R-trans) -3- [5-deoxy-2,3-O- (1-methylethylidene) -β-D-ribo-hexofuranosyl] -N- (2-phenylcyclopropyl) -5- (Propylthio) -3H- [1,2,3] -triazolo [4,5]
-D] Pyrimidin-7-amine To a solution of the product from step d) (0.18g) in ice cold toluene (10ml) was added diisobutylaluminum hydride (1.5M / toluene, 2.2ml). The mixture was stirred for 30 minutes, cooled with water (1 ml), concentrated in vacuo and the residue was purified by chromatography (SiO ₂ , dichloromethane as eluent) to give the subtitle compound (0.085g). MS (APCI) 513 (M + H ⁺ , 100%).

F) (1R-trans) -3- (5-deoxy-β-D-ribo-hexofuranosyl) -N- (2-phenylcyclopropyl) -5- (propylthio) -3H-
[1,2,3] -Triazolo [4,5-d] pyrimidin-7-amine A mixture of the product from step e) (85 mg), trifluoroacetic acid (0.1 ml) and water (0.01 ml) was added. Stir for 15 minutes. The reaction mixture was concentrated in vacuo,
The residue was purified by chromatography (SiO ₂ , diethyl ether as the eluent) to give the title compound (0.035g).

[0092]

[Chemical 30]

[0093]

Example 8 (1R-trans) -1-deoxy-1- [7-[(2-phenylcyclopropyl) amino] -5- (propylthio) -3H- [1,2,3] -triazolo [4
, 5-d] Pyrimidin-3-yl] -β-D-ribofuranuronic acid The product from Example 7, step b) (0.41 g) of trifluoroacetic acid (3.6
ml) solution was treated with water (0.4 ml) and left at room temperature for 30 minutes. The mixture was diluted with ethyl acetate (300 ml) and the solution was stirred with a slight excess of cold aqueous sodium bicarbonate solution. The mixture was acidified by the addition of a slight excess of acetic acid, the ethyl acetate layer was separated, dried and concentrated in vacuo. The residue was chromatographed (SiO ₂ , acetic acid: methanol: chloroform = 1: 6 as eluent).
: 93) to give the title compound (0.29 g).

[0094]

[Chemical 31]

[0095]

Example 9 (1R-trans) -1-deoxy-N-ethyl-1- [7-[(2-phenylcyclopropyl) amino] -5- (propylthio) -3H- [1,2,3] -Triazolo [4,5-d] pyrimidin-3-yl] -β-D-ribofuranuronamide a) (1R-trans) -1-deoxy-N-ethyl-2,3-O- (1-methyl Ethylidene) -1- [7-[(2-phenylcyclopropyl) amino] -5
-(Propylthio) -3H- [1,2,3] -triazolo [4,5-d] pyrimidin-3-yl] -β-D-ribofuranuronamide The product from Example 7, step b) ( 0.41 g) of anhydrous tetrahydrofuran (
Benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (0.39 g) and then N, N-diisopropylethylamine (0.11 g) was added to the solution at room temperature. Stir for 40 minutes. The reaction mixture was then treated with a 70% aqueous solution of ethylamine (0.5 ml) and stirring was continued for another hour at room temperature. The mixture was neutralized by addition of acetic acid, then ethyl acetate (200 ml) and saturated aqueous sodium bicarbonate solution (200 ml).
Fractionated between. The ethyl acetate layer was washed with brine (3x200ml) and concentrated in vacuo. The residue was purified by chromatography (SiO ₂ , ethyl acetate: isohexane = 2: 3 as an eluent) to give the subtitle compound (0.39 g). MS (APCI) 540 (M + H ⁺ , 100%).

B) (1R-trans) -1-deoxy-N-ethyl-1- [7-[(2-phenylcyclopropyl) amino] -5- (propylthio) -3H- [1,2,3
] -Triazolo [4,5-d] pyrimidin-3-yl] -β-D-ribofuranuronamide A solution of the product from step b) (0.38 g) in trifluoroacetic acid (3.6 ml) in water ( 0.4 ml) and left at room temperature for 30 minutes. The mixture was diluted with ethyl acetate (300 ml) and the resulting solution washed with a slight excess of cold saturated aqueous sodium bicarbonate solution. The ethyl acetate layer was dried and concentrated in vacuo. The residue was chromatographed (SiO ₂ , methanol: chloroform = 4: 9 as eluent).
Purification by 6) gave the title compound (0.21 g).

[0097]

[Chemical 32]

[0098]

[Pharmacological data]

P _2T (P2Y _ADP or P in washed human platelets for compounds of the invention)
Preparation of an assay for 2T _AC ) receptor agonist / antagonist activity was performed as follows.

Human venous blood (100 ml) was evenly divided into 3 tubes each containing 3.2% trisodium citrate (4 ml) as anticoagulant. This tube is 240G
Platelet-rich plasma (PRP) was obtained by centrifugation for 15 minutes at 300 μg / ml prostacyclin to stabilize the platelets during the washing process. Erythrocyte-free PRP was obtained by centrifugation at 125 G for 10 minutes followed by further centrifugation at 640 G for 15 minutes. The supernatant is discarded, and the platelet pellets are modified calcium-free Tyrode's solution (10 ml) (Calcium Fr
ee Tyrode solution: CFT) [Composition: NaCl 137 mM, NaHCO ₃
11.9 mM, NaH ₂ PO ₄ 0.4 mM, KCl 2.7 mM, MgCl ₂
1.1 mM, dextrose 5.6 mM] and resuspended, 95% O ₂ /5%
It was filled with CO ₂ gas and maintained at 37 ° C. After adding another 300 ng / ml of PGI ₂ , the pooled suspension was centrifuged once again at 640 G for 15 minutes. The supernatant was discarded, the platelets were first resuspended in 10 ml of CFT, and CFT was further added to adjust the final platelet count to 2 × 10 ⁵ cells / ml. This final suspension was stored at 3 ° C. in a degassed 60 ml syringe. PGI ₂ normal function - to enable recovery from inhibition, platelets were used in aggregation studies from the final resuspension after 2 h.

In all tests, a 3 ml aliquot of the platelet suspension was treated with CaCl ₂ solution (50
60 μl of mM solution, final concentration 1 mM) was added to the test tube. Human fibrinogen (Sigma, F4883) and 8-sulfophenyltheophylline (8-S
PT; used to block the P ₁ -agonist activity of the compound) at a final concentration of 0.2 mg / ml (10 mg clottable protein / 1 ml saline, 6 respectively)
0 μl) and 300 nM (10 μl of 15 mM solution / 6% glucose). Platelets or appropriate buffer (platelet) into individual wells of a 96-well plate
s or buffer as appropriate) was added in a volume of 150 μl. All measurements were performed on the same 3 samples of platelets from each donor.

Agonist / antagonist potency was assessed as follows: Aggregation in 96-well plates was measured using the change in absorbance at 660 nm as indicated by a plate reader. . As a plate reader, Bio-Tec Ceres 900C or Dynatech MRX was used.

The absorbance of each well in the plate was read at 660 nm to establish a baseline image. Saline or an appropriate solution of test compound was added to each well in a volume of 10 μl to give a final concentration of 0, 0.01, 0.1, 1, 10 or 100 mM. The plate is then placed on an orbital shaker scale 10
It was vibrated for 5 minutes at (setting 10) and the absorbance was read at 660 nm. Aggregation at this point indicated agonistic activity of the test compound. Saline or ADP (30 mM; 450 mM, 10 μl) was then added to each well, the plate was shaken for an additional 5 minutes, and then the absorbance at 660 nm was read again.

The antagonistic strength was evaluated as the inhibition rate (%) of the control ADP reaction, and IC ₅₀ was obtained. Various compounds of the Examples have a higher than 5.0 pIC ₅₀ values.

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE, TR), OA (BF , BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, G M, KE, LS, MW, MZ, SD, SL, SZ, TZ , UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, B Z, CA, CH, CN, CR, CU, CZ, DE, DK , DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, J P, KE, KG, KP, KR, KZ, LC, LK, LR , LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, R O, RU, SD, SE, SG, SI, SK, SL, TJ , TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Ingirl, Anthony             United Kingdom Leicestershire Elly 11.             5 Rh, Loughvalo, Bakewe             Le Road, AstraZeneca Earl A             Nde Dee Cornwood (72) Inventor Willis, Paul             United Kingdom Leicestershire Elly 11.             5 Rh, Loughvalo, Bakewe             Le Road, AstraZeneca Earl A             Nde Dee Cornwood F-term (reference) 4C057 BB02 DD01 LL03                 4C086 AA01 AA02 AA03 AA04 EA16                       MA01 MA04 NA14 ZA36 ZA40                       ZA54

Claims (23)

[Claims] 1. Formula (I): Wherein: R ¹ is either alkyl C _1-6 or COR ⁴ substituted by OH; R ² is alkyl C _1-6 or haloalkyl C _1-6 ; R ³ is R Cycloalkyl C _3-6 optionally substituted by ⁵ ; R ⁴ is OR ⁶ or NHR ⁶ ; R ⁵ is one or selected from alkyl C _1-6 , halogen and OR ^6. R ⁶ is H or alkyl C _1-6 ], or a pharmaceutically acceptable salt or solvate thereof, or a phenyl optionally substituted by the above groups. Solvates. 2. R ¹ , R ² and R ³ are as defined in claim 1, embedded image The compound of claim 1, which is 3. R ³ is: The compound of claim 2, wherein R ⁵ is as defined in claim 1. 4. R ¹ is CH ₂ OH, (CH ₂ ) ₂ OH, COOH or CONHE.
The compound according to any one of claims 1 to 3, which is t. 5. A compound according to any one of claims 1 to 4, wherein R ² is alkyl C ₃ optionally substituted with 3 halogen atoms. 6. (1R-trans) -N- (2-phenylcyclopropyl)
-5- (Propylthio) -3- (β-D-ribofuranosyl) -3H- [1,2,
3] -Triazolo [4,5-d] pyrimidin-7-amine; (1R-trans) -N- [2- (4-chlorophenyl) cyclopropyl] -5
-(Propylthio) -3- (β-D-ribofuranosyl) -3H- [1,2,3]
-Triazolo [4,5-d] pyrimidin-7-amine; (1R-trans) -N- [2- (3,4-difluorophenyl) cyclopropyl] -5- (propylthio) -3- (β-D -Ribofuranosyl) -3H- [1,
2,3] -Triazolo [4,5-d] pyrimidin-7-amine; (1R-trans) -N- [2- (4-methoxyphenyl) cyclopropyl]-
5- (propylthio) -3- (β-D-ribofuranosyl) -3H- [1,2,3
] -Triazolo [4,5-d] pyrimidin-7-amine; (1R-trans) -N- [2- (4-fluorophenyl) cyclopropyl]-
5- (propylthio) -3- (β-D-ribofuranosyl) -3H- [1,2,3
] -Triazolo [4,5-d] pyrimidin-7-amine; (1R-trans) -N- (2-phenylcyclopropyl) -5- (3,3,3)
-Trifluoropropylthio) -3- (β-D-ribofuranosyl) -3H- [1
, 2,3] -Triazolo [4,5-d] pyrimidin-7-amine; (1R-trans) -3- (5-deoxy-β-D-ribo-hexofuranosyl)
-N- (2-phenylcyclopropyl) -5- (propylthio) -3H- [1,
2,3] -Triazolo [4,5-d] pyrimidin-7-amine; (1R-trans) -1-deoxy-1- [7-[(2-phenylcyclopropyl) amino] -5- (propylthio) -3H- [1,2,3] -triazolo [4
, 5-d] Pyrimidin-3-yl] -β-D-ribofuranuronic acid; (1R-trans) -1-deoxy-N-ethyl-1- [7-[(2-phenylcyclopropyl) amino] -5 -(Propylthio) -3H- [1,2,3] -triazolo [4,5-d] pyrimidin-3-yl] -β-D-ribofuranuronamide; Or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt. 7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 together with a pharmaceutically acceptable diluent, adjuvant or carrier. 8. Use for the treatment or prevention of myocardial infarction, thrombotic stroke, transient ischemic attack, and / or peripheral vascular injury, comprising the compound according to any one of claims 1-6. Pharmaceutical composition. 9. A pharmaceutical composition for use in the treatment or prevention of unstable or stable angina, which comprises a compound according to any one of claims 1-6. 10. A compound according to any one of claims 1 to 6 for use in therapy. 11. A compound according to any one of claims 1 to 6 for use in the treatment or prevention of myocardial infarction, thrombotic stroke, transient ischemic stroke, and / or peripheral vascular injury. 12. A compound according to any one of claims 1 to 6 for use in the treatment or prevention of unstable or stable angina. 13. The method according to claim 1, which is used in the manufacture of a medicament for treating or preventing myocardial infarction, thrombotic stroke, transient ischemic attack, and / or peripheral vascular disorder.
Use of the compound according to any one of 1. as an active ingredient. 14. Use of the compound according to any one of claims 1 to 6 as an active ingredient in the manufacture of a medicament for use in the treatment or prevention of unstable or stable angina. 15. A method of treating or preventing a platelet aggregation disorder, which comprises treating a human suffering from or susceptible to such a disorder with the compound of any one of claims 1-6. Such a method comprising administering an effective amount. 16. A method for treating or preventing myocardial infarction, thrombotic stroke, transient ischemic attack, and / or peripheral vascular disorder, which is for a human suffering from or susceptible to such a condition. 7. The method, comprising administering a therapeutically effective amount of a compound of any one of claims 1-6. 17. A method for the treatment or prevention of unstable or stable angina, which comprises the steps of: providing a human suffering from or susceptible to such a pathological condition.
7. A method as described above comprising administering a therapeutically effective amount of a compound according to any one of to 6. 18. A process for preparing a compound of formula (I) wherein R ¹ is CH ₂ OH, comprising formula (II): A compound of the formula: wherein R ² is defined in claim 1 and P is a protecting group, in the presence of an amphoteric aprotic solvent or alcohol at a temperature of about 100 to about 150 ° C. R ³ NH ₂ ( R ³ is as defined in claim 1) and reacting with a base,
And optionally removing the protecting group thereafter. 19. A process for preparing a compound of formula (I) wherein R ¹ is CH ₂ OH, comprising formula (VI): A compound of the formula: wherein R ² and R ³ are as defined in claim 1, i) sodium hydrosulfide (NaSH) and about 0 to about 50 in the presence of an amphoteric aprotic solvent. Reacting at a temperature of 0 ° C. and treating the product of this reaction with an alkyl halide (R ^{2 ′} X) at a temperature of about 0 to about 50 ° C. in the presence of an amphoteric aprotic solvent, or ii) Interconverting R ² by reacting with sodium alkyl thiolate (R ^{2 ′} SNa) in the presence of an amphoteric aprotic solvent at a temperature of about 0 to about 50 ° C., where R ^{2 ′} Is different from R ² which is interconverted). 20. A process for the preparation of a compound of formula (I) wherein R ¹ is (CH ₂ ) ₂ OH, which comprises formula (VIII): (Wherein P and P ′ are protecting groups and R ² and R ³ are as defined in claim 1) at a temperature of about 0 to about 50 ° C. in the presence of an inert solvent. And the optional removal of protecting groups. 21. A process for the preparation of compounds of formula (I) wherein R ¹ is COOH, comprising formula (X): (Wherein P and P ′ are protecting groups and R ² and R ³ are as defined in claim 1) at a temperature of about 0 to about 100 ° C. in an acid / water or aqueous solution. Deprotection using acetonitrile, said method. 22. A process for the preparation of a compound of formula (I) wherein R ¹ is CONHR ^{6 wherein} the carboxyl group of the compound of formula (X) as defined in claim 21 is activated with a suitable activating reagent. The resulting compound in the presence of a base / inert ethereal solvent to about 0.
R ⁶ NH ₂ at a temperature of about 50 ° C., where R ⁶ is as defined in claim 1.
Said method comprising reacting with, and optionally subsequently removing the protecting groups. 23. Formulas (II), (VI), (VII), (VIII) and (
X): (Wherein P and P ′ are protecting groups and R ² and R ³ are as defined in claim 1).