Pyrazolopyrimidine and Pyrimidinyl Bisphosphonic Esters As Anti

Europaisches Patentamt (19) European Patent Office Office europeenpeen des brevets EP 0 521 622 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) intci.6: C07F 9/6512, A61K31/675 of the grant of the patent: 13.08.1997 Bulletin 1997/33

(21) Application number: 92305207.0

(22) Date of filing: 08.06.1992

(54) Pyrazolopyrimidine and pyrimidinyl bisphosphonic esters as anti-inflammatories Pyrazolopyrimiden- und Pyrimidinylbisphosphonsaureester als entzundungshemmende Mittel Esters de I'acide pyrazolopyrimidine et pyrimidinyl bisphosphonique comme anti-inflammatoires

(84) Designated Contracting States: (74) Representative: Perry, Robert Edward et al PT GILL JENNINGS & EVERY Broadgate House (30) Priority: 03.07.1991 US 725046 7 Eldon Street 03.07.1991 US 725047 London EC2M 7LH (GB)

(43) Date of publication of application: (56) References cited: 07.01.1993 Bulletin 1993/01 EP-A- 0 274 158 DE-A-2 703 712

(73) Proprietor: PHARMACIA & UPJOHN COMPANY • CHEMICAL ABSTRACTS, vol. 112, no. 21, 21 May Kalamazoo, Michigan 49001 (US) 1990, Columbus, Ohio, US; abstract no. 191396, W.K. SIETSEMA ET AL: 'Antiresorptive (72) Inventors: dose-response relationship across three • Nugent, Richard Allen generations of bisphosphonates' page 19 Galesburg, Michigan 49053 (US) ;column 1 ; • Schlachter, Stephen Thomas Kalamazoo, Michigan 49009 (US)

DO CM CM CO

CM lO Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice the Patent Office of the Notice of shall be filed in o to European opposition to European patent granted. opposition a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. a. 99(1) European Patent Convention). LU

Printed by Jouve, 75001 PARIS (FR) 1 EP 0 521 622 B1 2

Description

Field of the Invention

The present invention relates to pyrazolopyrimidine 5 and pyrimidinyl bisphosphonic esters, acids, and their pharmaceutically-acceptable salts, which are useful as anti-inflammatory and anti-arthritic agents.

Background of the Invention 10 0 0 Typically, prostaglandin synthetase activity is inhib- FORMULA 1; ited by non-steroidal anti-inflammatory agents and many of their actions, including side-effects, have been attributed to this inhibition of prostaglandin synthesis. 15 US-A-4746654 discloses bisphosphonates useful as anti-inflammatory agents. AU-A-51 534/85 discloses bisphosphonates useful in treating abnormal calcium and phosphorus metabolism and in treating arthritis. 20 US-A-3638080 discloses polyphosphonates, in particular diphosphonates, useful in inhibiting anoma- lous deposition and mobilisation of calcium phosphate in animal tissue. DE-A-3719513 discloses diphosphonic acid deriv- 25 atives useful in treatment of disorders of calcium metabolism. The alkylation of 5,7-dimethylpyrazolo[1 ,5-a]pyrimidines was disclosed at the American Chemical Soci- FORMULA 2; ety Spring Meeting on June 9, 1 988 (PD 7244-88-021 ). 30 EP-A-0354806 discloses imidazo[1 ,2-a]pyridines and imidazo[1 ,2-a]imidazoles. wherein X is O or S; DE-A-3626058 discloses heteroaromatic diphosphonates bound to a diphosphonate. R-i is independently selected from the group con- EP-A-0274158 discloses heterocycle-substituted 35 sisting of H, C-,-C6 alkyl, CH2-phenyl and phenyl, or diphosphonates and their use in treating abnormal cal- both OR1 on the same P are taken together along cium and phosphorus metabolism. with CH2-CH2, CH2-CH2-CH2, or CH2-C(CH3)2- CH2 to form a heterocyclic ring having one P, two O Summary of the Invention and two or three carbon atoms; 40 R2 is hydrogen, C-,-C6 alkyl, benzoyloxy, benzyloxy, Novel compounds according to this invention are C-,-C6 alkoxy, C3-C7 cycloalkyl, phenyl (optionally pyrazolopyrimidine (Formula 1 ) and pyrimidinyl (Formu- substituted with 1 to 5 halo, CN, CF3 or C-,-C10 la 2) bisphosphonic esters, acids, and their pharmaceu- alkyl), 2-, 4- or 5-pyrimidyl, 2-, 3- or 4-pyridyl, or 1- tically-acceptable salts. The Formulae are or 2-naphthalenyl; 45 R3 is H, halo, N02, CN, CF3, CrC10 alkyl, C3-C7 cycloalkyl, or phenyl; R5 is H, C-,-C6 alkyl or C3-C7 cycloalkyl; R6 is H, halo, or C-,-C6 alkyl; R10 is H, C-|-C6 alkyl, C3-C7 cycloalkyl, or phenyl; so is H, CrC6 alkyl, C3-C7 cycloalkyl, allyl, CH2- phenyl, or phenyl (optionally substituted with 1 to 5 N02, halos, or C-1-C4 alkyl); and either R12 is H, C-,-C6 alkyl, or halo; and R13 is hydrogen, C-,-C6 alkyl, C3-C7 cycloalkyl, phe- 55 nyl (optionally substituted with 1 to 5 halos, CN, CF3, or C-|-C10 alkyl), 2-, 3- or 4-pyridyl, or 1- or 2-naphthalenyl; or R12and R13form a ring of 4 to 7 members having

2 3 EP 0 521 622 B1 4

4 to 7 carbons, 1 to 3 nitrogens, 0 to 2 oxygens, and The pyrazolopyrimidine bisphosphonic esters, ac- 0 to 2 sulfurs. ids and derivatives (Formula 1 ) useful as antiinflamma- tories and antiarthritics are prepared as shown in Exam- The novel compound possess anti-inflammatory re- ples 1-13. The general pyrazolopyrimidine heterocyclic sponse without suppressing the production of prostag- 5 ring structure can be prepared by procedures well landin. This can be an advantage because it is known known in the art. For example, the synthesis of pyrazolo that, at high concentrations, prostaglandins are consid- [1 ,5-a]pyrimidines is described by M.H. Elnagdi, G.E.H. ered anti-inflammatory. The subject compounds are al- Elgemeie, and M.R.H. Elmoghayar in Advances in Het- so useful for treating arthritis and its related symptoms erocyclic Chemistry, Vol. 41 , pg 319; M.R.H. Elmoghay- such as inflammation and prevention of excessive bone 10 ar et al., Pyrimidine Derivatives and Related Com- regrowth and remodelling. pounds, Arch. Pharm. (Weinheim), 316, pp 697-702 The novel compounds may be used in humans and (1983); and T. Novinson et al., 3-Substituted lower animals as a safe and effective treatment of dis- 5,7-Dimethylpyrazolo(1 ,5-a)pyrimidines, J. Med. eases characterised by abnormal phosphate and calci- Chem., 17, pp 645-48 (1974). um metabolism, and as a treatment of inflammation. is One procedure for synthesizing the Formula 1 com- These diseases include osteoporosis, Paget's disease, pounds of this invention is by dissolving the pyrazolopy- periodontal disease, rheumatoid arthritis, osteoarthritis, rimidine in a suitable solvent (THF, pyridine or a combi- neuritis, bursitis, soft tissue mineralisation disorders, nation of the two). This liquid is added dropwise to a ankylosing spondylitis, atherosclerosis, multiple myelo- -78°C THF solution, although this can also be done at ma of bone, metastic bone disease, and mitral valve cal- 20 0°C, of a strong kinetic base (lithium hexamethyldis- cification. The compounds do not inhibit cyclooxygen- ilazide or lithium diisopropyl amide) and the resulting so- ase or lipoxygenase metabolism of arachidonic acid. lution is stirred for about 30 minutes at -78°C, although Routes of administration of the compounds include this can also be done at 0°C. Vinylidene diphosphonate oral, intramuscular, intravenous, transdermal, intra-ar- is added either neat or in THF solution to the cold reac- ticular, subcutaneous and intraperitoneal. An amount is 25ts tion, whereupon the reaction is allowed to warm to am- administered such that the symptoms of inflammation bient temperature. Specific workup conditions are de- or arthritis such as pain and discomfort are relieved or scribed in the examples. reduced, or mobility of the affected area is increased. A The synthesis of the corresponding Formula 1 acid typical dosage is 0.001 mg to 1 .0 g, the dose being de- is accomplished by either of two procedures, both of termined by the particular mode of administration, use 30 which are well known to those skilled in the art. The first and frequency of administration. is to reflux the tetraester in concentrated hydrochloric acid for 12 hours and concentrate the solution, and is Detailed Description of the Invention illustrated by the synthesis of Compound "b" from "a" of Example 1, below. Alternatively, one can treat the The carbon content of various hydrocarbon contain- 35 tetraester with trimethylsilyl bromide followed by aque- ing moieties is indicated by a prefix designating the min- ous workup to isolate the acid. imum and maximum number of carbon atoms in the moi- The Formula 1 compounds of this group are fluo- ety, i.e. the prefix C-, -Cj defines the number of carbon rescent and as such allow for the tracing of the com- atoms present from the integer "i" to the integer "j" in- pound through biological tissue. clusive. 40 The pyrimidinyl bisphosphonic esters, acids and Thus, (VC3 alkyl refers to alkyl of 1-3 carbon at- derivatives (Formula 2) useful as an anti-inflammatory oms, inclusive, or methyl, ethyl, propyl, and isopropyl. and anti-arthritic are prepared as shown in Examples 1 4 With respect to the above, C-,-C6 alkyl is methyl, and 15 (Compounds p-x). The synthesis of 4-pyrimidi- ethyl, propyl, butyl, pentyl, hexyl, and isomeric forms nones is well known to those skilled in the art. Briefly, a thereof. C3-C7 cycloalkyl is cyclopropane, cyclobutane, 45 p-keto ester is treated with acetamidine hydrochloride cyclopentane, cyclohexane, cycloheptane and isomeric in the presence of base to form the parent heterocyclic. forms thereof. The base can be sodium hydroxide, potassium carbon- The term "halo" includes fluoro, chloro, bromo and ate, sodium methoxide or sodium ethoxide. The reaction iodo. can be run neat or the solvent can be ethanol or meth- C-|-C8 alkoxy is methoxy, ethoxy, propoxy, butoxy, 50 anol. N-alkylated derivatives are synthesised by treat- pentoxy, hexoxy, heptoxy, octooxy, and isomeric forms ment of the parent compound with a nucleophile in the thereof. presence of base, such as potassium carbonate, sodi- Pharmaceutical^ acceptable salts means salts um hydride or potassium fluoride. useful for administering the compounds of this invention In one procedure, the Formula 2 compounds can and include hydrochloride, hydrobromide, hydroiodide, 55 be synthesised by reacting the alkylated pyrimidinones sulfate, phosphate, acetate, propionate, lactate, me- with a strong base, such as lithium hexamethyl dis- sylate, maleate, malonate, succinate, tartrate, citric acid ilazide or lithium diisopropyl amide, then treatment with and the like. These salts may be in hydrated form. a diphosphonate vinylidene such as ethenylidenebis-

3 5 EP 0 521 622 B1 6 tetraethyl ester phosphonic acid or 2,2'-ethenylidene- 107°C (methyl t-butyl ether). bis(5,5-dimethyl-2,2'-dioxide-1 ,3,2-dioxaophos- porinane). Compounds are purified either by chroma- Example 3: (3-(3-Bromo-2,5-dimethyl-pyrazolo(1 ,5-a) tography or crystallisation. pyrimidin-7-yl)-propane-1 ,1 -diyl)bisphosphonic acid Compounds of this invention have been tested in a 5 tetraethyl ester (d) Delayed Type Hypersensitivity Granuloma Assay (DTH GRA) model for inflammation. This assay is described 3-Bromo-2,5,7-trimethyl-pyrazolo(1 ,5-a)pyrimi- by Dunn et al, Agents and Actions, 27:3/4 (1989), and dine (460 mg, 1 .92 mmol) was dissolved in THF (10 mL) Int. J. Immunopharmac.,12(8):899-904 (1990). at 0°C and treated with LiHMDS (2.0 mL, 2.0 mmol). Briefly, mBSA-sensitised mice have a DTH granu- 10 After stirring for 30 min., ETE phosphonic acid (576 mg, loma (DTH GRA) lesion induced by subcutaneously im- 1 .92 mmol) in THF (1 mL) was added. After stirring for planting a mBSA-soaked filter which is excised after 1 hour at 22°C, the reaction was poured onto 10% HCI. nine days. Compounds are administered to the mice to The organics were extracted with methylene chloride, determine their effect on the lesions. The results are re- then washed once each with 1N HCI, sodium bicarbo- corded as percent inhibition. The larger the inhibition, 15 nate, and brine, then dried with MgS04, and stripped. the more effective the compounds. Inhibition of 10 to The sample was purified by chromatography (ethyl ac- 20% is considered to indicate anti-granuloma activity. etate, ethyl acetate/acetone 7:4): 527 mg (0.975 mmol, Greater than 30% inhibition is good activity. 51%), an oil. The DTH GRA data obtained for compounds a, c, d, e, f, g, h, i, j, m, n, o, p, r, s, t, v, w and x are, respec- 20 Example 4: (3-(3-Nitro-2,5-dimethyl-pyrazolo(1 ,5-a) tively, 46, 26, 44, 41 , 41 , 44, 49, 47, 53, 41 , 45, 53, 60, pyrimidin-7-yl)-propane-1 ,1 -diyl)bisphosphonic acid 1 7, 32, 7, 40, 1 3 and 6% (1 0 MPK, PO), for compounds tetraethyl ester (e) k and 1 are respectively 31 and 23% (50 MPK), and for compound q is 57% (1 MPK, PO). 2,5,7-Trimethyl-3-nitro-pyrazolo(1 ,5-a)pyrimidine 25 (900 mg, 4.36 mmol) was dissolved in pyridine (10 mL) Example 1 : (3-(3-Cyano-2,5-dimethyl-pyrazolo(1 ,5-a) at 0°C, then treated with LiHMDS (4.5 mL, 4.5 mmol). pyrimidin-7-yl)-propane-1 , 1 -diyl)bisphosphonic acid After stirring for 30 min., ETE phosphonic acid (1 .31 g, tetraethyl ester (a) 4.36 mmol) in THF (1 mL) was added. After stirring for 1 hour at 22°C, the reaction was poured onto 10% HCI. Pyrazolo(1 ,5-a)pyrimidine (3.02 g, 16.2 mmol) was 30 The organics were extracted with methylene chloride, suspended in pyridine (40 ml) at 0°C and treated with a then washed once each with 1N HCI, sodium bicarbo- solution of LiHMDS (1M in THF, 18 mL, 18 mmol). After nate, and brine, then dried with MgS04, and stripped. stirring at 0°C for 30 min. ethenylidenebis-tetraethyl es- The sample was purified by chromatography (ethyl ac- ter phosphonic acid (hereinafter, ETE phosphonic acid) etate, ethyl acetate/acetone 7:4): 1.374 g (2.71 mmol, (4.86 g, 1 6.2 mmol) was added, the reaction warmed to 35 62%), an oil. 22°C, and stirred for 1 hour. It was then poured onto 10% HCI, extracted thrice with methylene chloride, dried Example 5: (3-(2-Benzoyloxy-5-methyl-pyrazolo(1 ,5-a) with magnesium sulfate and stripped. The sample was pyrimidin-7-yl)-propane-1 ,1 -diyl)bisphosphonic acid purified by chromatography (ethyl acetate, ethyl ace- tetraethyl ester (f) tate/acetone 3:1, 2:1, 1:1): 3.97 g (8.16 mmol, 50%) 40 Sample solidified upon standing, m.p. 49-50°C. A) Cyanoacetohydrazide (9.91 g, 0.10 mmol) and 2,4 pentanedione (10.5 mL, 0.10 mol) were heated Example 2: (3-(3-Cyano-5-methyl-2-phenyl-pyrazolo for 30 min. in ethanol (20 mL) and acetic acid (0.5 (1 ,5-a)pyrimidin-7-yl)-propane-1 , 1 -diyl)bisphosphonic mL). The reaction was cooled to 22°C, then treated acid tetraethyl ester (c) 45 with 1 N sodium hydroxide (1 20 mL) and refluxed for 15 min. The stirred hot flask was titrated to neutrality 5,7-dimethyl-2-phenyl-pyrazolo(1 ,5-a)pyrimidine- with 12N HCI, then cooled overnight at 0°C. The 3-carbonitrile (621 mg, 2.50 mmol) in pyridine (5.0 mL) solid was collected and recrystallized from ethanol: at 0°C was treated with LiHMDS (2.6 mL, 2.6 mmol) and 8.565 g (0.0525 mol, 53%). stirred for 30 min. The deep red solution was treated 50so 5,7-Dimethyl-pyrazolo[1 ,5-a]pyrimidine-2-ol with ETE phosphonic acid (750 mg, 2.50 mmol) in THF (3.26 g, 20 mmol) in pyridine (60 mL) at 0°C was (.5 mL). After stirring for 1 hour at 22°C, the reaction treated with LiHMDS (42 mL, 42 mmol) and stirred was poured onto 1 0% HCI. The organics were extracted for 30 min. ETE phosphonic acid (6.30 g, 21 mmol) with methylene chloride, then washed once each with in THF (1 0 mL) was added and the reaction warmed 1 N HCI, sodium bicarbonate, and brine, then dried with 55 to 22°C for 1 hour. The reaction was extracted thrice MgS04, and stripped. The sample was purified by chro- with 1 N sodium hydroxide (20 mL) and these were matography (methylene chloride, methylene chloride/ washed thrice with ethyl acetate. The aqueous frac- acetone 9:1, then 1:9): 600 mg (1.09 mmol, 49%), m.p. tion was brought to neutrality with 1 2N HCI , extract -

4 7 EP 0 521 622 B1 8

ed thrice with ethyl acetate, washed with brine, The crude ether (1 .876 g, 7.6 mmol) was dissolved dried with magnesium sulfate, and stripped. The in THF (5 mL), cooled to -78°C, and treated with LiH- material was used without further purification in the MDS (7.6 mL, 7.6 mmol). After stirring for 30 min., ETE next reaction. phosphonic acid (2.27 g, 7.6 mmol) in a trace of THF B) The crude pyrazolo[1 ,5-a]pyrimidine-2-ol (475 5 was added and the reaction was stirred at 22°C for 1 mg, 1 .02 mmol) in methylene chloride (5 mL) at 0°C hour. The organics were poured onto 10% HCI, extract- was treated with benzoyl chloride (0.12 mL, 1.02 ed thrice with ethyl acetate, washed with sodium bicar- mmol) and triethyl amine (0. 1 7 mL, 1 .2 mmol). After bonate and brine, dried with magnesium sulfate, and stirring for 1 hour, the reaction was quenched with stripped. The product was purified by chromatography 1N HCI, extracted thrice with ethyl acetate, then 10 (ethyl acetate, ethyl acetate/acetone 1:1): 1 .632 g (2.98 washed with sodium bicarbonate, brine, dried with mmol, 39%). magnesium sulfate, and stripped. The sample was chromatographed (ethyl acetate, ethyl acetate/ac- Example 8: (3-(5-Methyl-2-phenyl-pyrazolo(1 ,5-a) etone 1:1) and the semi-pure product crystallized pyrimidin-7-yl)-propane-1 ,1 -diyl)bisphosphonic acid upon standing. It was recrystallized with ether/hex- is tetraethyl ester (i) ane: 97 mg (0.17 mmol, 17%), m.p. 56-57°C. Pyrazolopyrimidine (1.00 g, 4.5 mmol) dissolved in Example 6: (3-(2-Benzyloxy-5-methyl-pyrazolo(1 ,5-a) pyridine (9 mL) was cooled to 0°C and treated with LiH- pyrimidin-7-yl)-propane-1 , 1 -diyl)bisphosphonic acid MDS (4.9 mL, 4.9 mmol) and stirred for 30 min. A solu- tetraethyl ester (g) 20 tion of ETE phosphonic acid (1 .28 g, 4.2 mmol) in THF (4 mL) was added and the solution was stirred for an 5,7-Dimethyl-pyrazolo[1 ,5-a]pyrimidine-2-ol (1 .63 additional 30 minutes. The reaction mixture was poured g, 10 mmol), potassium carbonate (690 mg, 5 mmol), into cold 1 0% HCI and washed three times with methyl- and DMF (6 mL) were heated to 115-120°C for 5 min., ene chloride. The combined organic layers were then treated with benzyl chloride (1.2 mL, 1 0 mmol). The 25 washed with 10% HCI, H20, NaHC03, NaCI, dried with reaction was stirred for 20 min. at 120°C, then poured MgS04 and stripped. Chromatographed with ethyl ace- onto excess 1N NaOH. The organics were extracted tate followed by 10% acetone/ethyl acetate. The result- twice with ethyl acetate, then washed with sodium bi- ant material solidified on standing. The solid was dis- carbonate and brine, dried with magnesium sulfate, and solved in ether and precipitated with hexane, m.p. stripped. The product crystallized when stripped from 30 51 -52°C. Recovered 0.824 g (1 .57 mmol, 37%). hexane, then was recrystallized from hexane with Dar- co: 539 mg. From the mother liquors an additional 248 Example 9: (3-(3-lodo-5-methyl-2-phenyl-pyrazolo mg were recovered: 787 mg (3.10 mmol, 31%). (1 ,5-a)pyrimidin-7-yl)-propane-1 ,1-diyl)bisphosphonic The benzyl ether (539 mg, 2.1 mmol) in THF (2 mL) acid tetraethyl ester (j) at -78°C was treated with LiHMDS (2.2 mL, 2.2 mmol) 35 and stirred for 30 min. ETE phosphonic acid (630 mg, Compound "i" from Example 8 (0.786 g, 1 .5 mmol) 2.1 mmol) in THF (1 mL) was added and stirred at 22°C dissolved in chloroform (4.8 mL) was treated with N-lo- for 1 hour. The organics were poured onto 10% HCI, dosuccinimide (0.345 g, 1 .54 mmol) and refluxed for 20 extracted thrice with ethyl acetate, washed with sodium min. The solution was cooled and poured onto 2N KOH bicarbonate and brine, dried with magnesium sulfate, 40 (6.7 mL). The layers were separated and the chloroform and stripped. The product was isolated by chromatog- was washed with water, dried with MgS04 and stripped. raphy (ethyl acetate, ethyl acetate/acetone 1:1): 547 mg Purified by chromatography on silica gel with 2% etha- (0.988 mmol, 47%), an oil. nol/ethyl acetate. The material solidified upon standing, m.p. 81-82°C. Recovered 0.741 g (1 .14 mmol, 76%). Example 7: (3-(2-Hexyloxy-5-methyl-pyrazolo(1 ,5-a) 45 pyrimidin-7-yl)-propane-1 , 1 -diyl)bisphosphonic acid Example 10: (3-(3-Chloro-5-methyl-2-phenyl-pyrazolo tetraethyl ester (h) (1 ,5-a)pyrimidin-7-yl)-propane-1 ,1-diyl)bisphosphonic acid tetraethyl ester (k) 5,7-Dimethyl-pyrazolo[1 ,5-a]pyrimidine-2-ol (1 .63 g, 10 mmol), potassium carbonate (690 mg, 5 mmol), 50 Compound "i" from Example 8 (1 .490 g, 2.8 mmol) and DMF (6 mL) were heated to 115-120°C for 5 min., in chloroform (1 0 mL) was treated with N-Chlorosuccin- then treated with hexyl bromide (1.5 mL, 10.7 mmol). imide (0.418 g, 3.1 mmol) and refluxed for 30 min. The The reaction was stirred for 20 min. at 120°C, then solution was cooled and poured onto cold 2N KOH (13 poured onto excess 1N NaOH. The organics were ex- mL). Separated and washed the organic layer twice with tracted twice with ethyl acetate, then washed with 1 N 55 water and NaCI. Dried with MgS04 and stripped then HCI and brine, dried with magnesium sulfate, and chromatographed with 2% ethanol/ethyl acetate. Prod- stripped. The product refused to crystallize: 1 .876 g (7.6 uct solidified upon standing, m.p. 66-68°C. Recovered mmol, 76%). 0.763 g (1.37 mmol, 49%).

5 9 EP 0 521 622 B1 10

Example 11 : (3-(3-Bromo-5-methyl-2-phenyl-pyrazolo sulfate, and stripped. The material was recrystallized (1 ,5-a)pyrimidin-7-yl)-propane-1 , 1 -diyl)bisphosphonic from methyl t-butyl ether: 20.61 g (41 .2 mmol, 63%), m. acid tetraethyl ester (I) p. 83-84°C. Additional compounds were obtained by following this same general procedure for the following Compound "i" from Example 8 (1 .488 g, 2.8 mmol) 5 compounds. in chloroform (10 mL) was treated with N-Bromosuccin- imide (0.52 g, 2.9 mmol) and the solution was refluxed (r) (3-(2-(3-Benzyl-4-oxo-6-phenyl-4(3H)-pyrimidi- for 25 min. Cooled and poured onto cold 2N KOH (13 nyl))-propane-1,1-diyl)bisphosphonic acid tetrae- mL) and separated. Washed organic layer twice with thyl ester, m.p. 72-74°C; water and with brine. Dried with MgS04 and stripped 10 then chromatographed with 2% ethanol/ethyl acetate. (s) (3-(2-(3-Methyl-4-oxo-6-(3-fluoro-phenyl)-4 Product solidified upon standing, m.p. 46-48°C. Recov- (3H)-pyrimidinyl))-propane-1 , 1 -diyl)bisphosphonic ered 1 .47 g (2.44 mmol, 87%). acid tetraethyl ester, m.p. 93.5-95. 5°C;

Example 12: (3-(3-Cyano-2,5-dimethyl-pyrazolo(1 ,5-a) is (t) (3-(2-(3-Allyl-4-oxo-6-phenyl-4(3H)-pyrimidi- pyrimidin-7-yl)-propane-1 , 1 -diyl)bisphosphonic acid nyl))-propane-1,1-diyl)bisphosphonic acid tetrae- tetramethyl ester (m) thyl ester, m.p. 53-55°C;

Pyrazolo (1 ,5-a)pyrimidine (1.25 g, 6.71 mmol) in (u) (3-(2-(5-Bromo-3-methyl-4-oxo-6-phenyl-4 pyridine (15 mL) at 0°C was treated with LiHMDS (8.1 20 (3H)-pyrimidinyl))propane-1 ,1-diyl)bisphosphonic mL, 8.1 mmol) and stirred for 30 min. Ethenylidene bis- acid tetraethyl ester, oil, m/e 580, 578 (m+), 443, tetramethyl ester phosphonic acid (1.64 g, 6.71 mmol) 441, 293, 291, 288; was added, the reaction warmed to 22°C and stirred for 1 hour. The solution was poured onto 10% HCI, extract- (v) (3-(2-(3-Methyl-4-oxo-6-(3-methyl-phenyl)-4 ed thrice with methylene chloride, dried with magnesium 25 (3H)-pyrimidinyl))-propane-1 , 1 -diyl)bisphosphonic sulfate and stripped. The product was recrystallized acid tetraethyl ester, m.p. 90-91 °C; from ethyl acetate: 1.152 g (2.68 mmol, 40%), m.p. 100-1 01 °C. (w) (3-(2-(3-Methyl-4-oxo-6-(3-methoxy-phenyl)-4 (3H)-pyrimidinyl))-propane-1 , 1 -diyl)bisphosphonic Example 13: (3-(3-Cyano-2,5-dimethyl-pyrazolo(1 ,5-a) 30 acid tetraethyl ester, m.p. 65-66°C; pyrimidin-7-yl)-propane-1 , 1 -diyl)bis(5,5-dimethyl-2,2'- dioxide-1 ,3,2-dioxaphosphorinane) (n) (x) (3-(2-(3-Methyl-4-oxo-6-(3-trifluoromethyl-phenyl)-4(3H)-pyrimidinyl))-propane-1 , 1 -diyl)bisphos- Pyrazolo (1 ,5-a)pyrimidine (1.30 g, 6.98 mmol) in phonic acid tetraethyl ester, m.p. 77-79°C. pyridine (15 mL) at 0°C was treated with LiHMDS (7.1 35 mL, 7. 1 mmol) and stirred for 30 min. Solid 1 , 1 '-ethenyli- Example 15: (3-(2-(3-Methyl-4-oxo-6-phenyl-4(3H)- dene-bis-(5,5-dimethyl-2,2'-dioxide-1 .3,2-dioxaphos- pyrimidinyl))-propane-1 , 1 -diyl)bisphosphonic acid phorinane) phosphonic acid (2.26 g, 6.98 mmol) was disodium salt (q) added, the reaction warmed to 22°C, and stirred for 30 min. The reaction was poured onto 10% HCI, extracted 40 (3-(2-(3-Methyl-4-oxo-6-phenyl-4(3H)-pyrimidi- thrice with methylene chloride, dried with magnesium nyl))-propane-1 , 1 -diyl)bisphosphonic acid tetraethyl es- sulfate and stripped. The sample was recrystallized ter (2.29 g, 4.58 mmol) was heated in concentrated hy- from methylene chloride/hexane: 1.743 g (3.41 mmol, drochloric acid (20 ml) at reflux for 24 hours, then the 49%), m.p. 258-259°C. solution was stripped to dryness. The residue was sus- 45 pended in water and the pH was adjusted to 7 with so- Example 14: (3-(2-(3-Methyl-4-oxo-6-phenyl-4(3H)- dium hydroxide. The product was precipitated from the pyrimidinyl))-propane-1 ,1-diyl)bisphosphonic acid solution with methanol, filtered and air dried: 940 mg tetraethyl ester (p) (2.17 mmol, 47%), m.p. > 300°C.

To a solution of lithium hexamethyldisilazide (1 .0 M 50 in THF, 72 ml, 72 mmol) at -78°C was added dropwise Claims to a solution of 2,3-dimethyl-6-phenyl-pyrimidin-4(3H) one (1 3.064 g, 65. 1 6 mmol) in THF (50 ml). After stirring 1 . A compound of Formula 1 or 2 or a pharmaceutical- for 30 min. at -78°C, the vinylidene diphosphonate (21 .6 ly-acceptable salt thereof g, 72 mmol) was added and the reaction warmed to 55 22°C for 1 hour. The reaction was quenched with satu- rated ammonium chloride, extracted thrice with ethyl acetate, washed twice with brine, dried with magnesium

6 11 EP 0 521 622 B1 12

or R12 and R13 form a ring of 4 to 7 members having 4 to 7 carbons, 1 to 3 nitrogens, 0 to 2 oxygens, and 0 to 2 sulfurs.

5 2. The compound of claim 1 , wherein R1 is ethyl.

3. The compound of claim 1 , wherein R2 is methyl, hydrogen or phenyl.

0 0 4. The compound of claim 1 , wherein R3 isCN, phenyl, N02, hydrogen or halo. FORMULA 1; 5. The compound of claim 1 , wherein R5 is methyl.

6. The compound of claim 1 , wherein R6 is hydrogen. I 7. The compound of claim 1 , of Formula 1 , which is:

a) (3-(3-cyano-2,5-dimethylpyrazolo(1 ,5-a)py- 20 rimidin-7-yl)propane-1 , 1 -diyl)bisphosphonic acid tetraethyl ester,

b) (3-(3-cyano-2,5-dimethylpyrazolo(1 ,5-a)pyrimidin-7-yl)propane-1 , 1 -diyl)bisphosphonic acid, dipotassium salt, 0 0 c) (3-(3-cyano-5-methyl-2-phenylpyrazolo FORMULA 2; (1 ,5-a)pyrimidin-7-yl)propane-1 ,1 -diyl)bisphosphonic acid tetraethyl ester, 30 wherein X is O or S; d) (3-(3-bromo-2,5-dimethylpyrazolo(1 ,5-a)pyrimidin-7-yl)propane-1 , 1 -diyl)bisphosphonic R-i is independently selected from the group acid tetraethyl ester, consisting of H, 0,-C6 alkyl, CH2-phenyl and phenyl, or both OR1 on the same P are taken 35 e) (3-(3-nitro-2,5-dimethylpyrazolo(1 ,5-a)pyri- together along with CH2-CH2, CH2-CH2-CH2, midin-7-yl)propane-1 ,1-diyl)bisphosphonic ac- or CH2-C(CH3)2-CH2 to form a heterocyclic ring id tetraethyl ester, having one P, two O and two or three carbon atoms; f) (3-(2-benzoyloxy-5-methylpyrazolo(1 ,5-a) R2 is hydrogen, 0,-C6 alkyl, benzoyloxy, ben- 40 pyrimidin-7-yl)propane-1 , 1 -diyl)bisphosphon- zyloxy, C-,-C6 alkoxy, C3-C7 cycloalkyl, phenyl ic acid tetraethyl ester, (optionally substituted with 1 to 5 halo, CN, CF3 or C-|-C10 alkyl), 2-, 4- or 5-pyrimidyl, 2-, 3- or g) (3-(2-benzyloxy-5-methylpyrazolo(1 ,5-a)py- 4-pyridyl, or 1- or 2-naphthalenyl; rimidin-7-yl)propane-1 , 1 -diyl)bisphosphonic R3 is H, halo, N02, CN, CF3, CrC10 alkyl, C3- 45 acid tetraethyl ester, C7 cycloalkyl, or phenyl; R5 is H, C-,-C6 alkyl or C3-C7 cycloalkyl; h) (3-(2-hexyloxy-5-methylpyrazolo(1 ,5-a)pyri- R6 is H, halo, or 0,-C6 alkyl; midin-7-yl)propane-1 ,1-diyl)bisphosphonic ac- R10 is H, C-|-C6 alkyl, C3-C7 cycloalkyl, or phe- id tetraethyl ester, nyl; so R11 is H, C-|-C6 alkyl, C3-C7 cycloalkyl, allyl, i) (3-(5-methyl-2-phenylpyrazolo(1 ,5-a)pyrimi- CH2-phenyl, or phenyl (optionally substituted din-7-yl)propane-1 ,1 -diyl)bisphosphonic acid with 1 to 5 N02, halos, or C1-C4 alkyl); and tetraethyl ester, either R12 is H, 0,-C6 alkyl or halo; and R13 is hydrogen, 0,-C6 alkyl, C3-C7 cycloalkyl, 55 j) (3-(3-iodo-5-methyl-2-phenylpyrazolo phenyl (optionally substituted with 1 to 5 halos, (1 ,5-a)-pyrimidin-7-yl)propane-1 ,1-diyl)bi- CN, CF3, or 0,-0,0 alkyl), 2-, 3- or 4-pyridyl, or sphosphonic acid tetraethyl ester, 1- or 2-naphthalenyl;

7 13 EP 0 521 622 B1 14

k) (3-(3-chloro-5-methyl-2-phenylpyrazolo v) (3-(2-(3-methyl-4-oxo-6-(3-methylphenyl-4 (1 ,5-a)pyrimidin-7-yl)propane-1 , 1 -diyl)bi- (3H)-pyrimidinyl)propane-1 ,1 -diyl))bisphos- sphosphonic acid tetraethyl ester, phonic acid tetraethyl ester,

I) (3-(3-bromo-5-methyl-2-phenylpyrazolo w) (3-(2-(3-methyl-4-oxo-6-(3-methoxyphenyl- (1 ,5-a)-pyrimidin-7-yl)propane-1 , 1 -diyl)bi- 4(3H)-pyrimidinyl)propane-1 , 1 -diyl))bisphos- sphosphonic acid tetraethyl ester, phonic acid tetraethyl ester,

m) (3-(3-cyano-2,5-dimethylpyrazolo(1 ,5-a)py- x) (3-(2-(3-methyl-4-oxo-6-(3-trifluoromethyl- rimidin-7-yl)propane-1 ,1-diyl)bisphosphonic 10 phenyl-4(3H)-pyrimidinyl)propane-1 ,1-diyl))bi- acid tetraethyl ester, sphosphonic acid tetraethyl ester, or

n) (3-(3-cyano-2,5-dimethylpyrazolo(1 ,5-a)py- y) (3-(2-(3-methyl-4-oxo-6-phenyl-4(3H)-pyri- rimidin-7-yl)propane-1 , 1 -diyl)bis(5,5-dimethyl- midinyl)propane-1 , 1 -diyl))bisphosphonic acid 2,2'-dioxide-1 ,3,2-dioxaphosphorinane), or 15 tetraethyl ester.

o) (3-(6-chloro-3-cyano-2,5-dimethylpyrazolo 14. Use of a compound of claim 1 , for the preparation (1 ,5-a)pyrimidin-7-yl)propane-1 , 1 -diyl)bi- of a medicament for treatment of inflammation. sphosphonic acid tetraethyl ester. 20 15. The use of claim 14, wherein the medicament pro- 8. The compound of claim 1 , wherein X is oxygen. vides 0.001 mg to 1.0 g of the compound and is adapted for administration orally, intramuscularly, 9. The compound of claim 1 , wherein R10 is hydrogen. intravenously, transdermally, intra-articularly, subcutaneously or intraperitoneal^. 10. The compound of claim 1, wherein R11 is C-1-C3 25 alkyl. Patentanspriiche 11. The compound of claim 1 , wherein R-, 3 is phenyl. 1. Verbindung der Formel 1 oder 2 oder ein pharma- 12. The compound of claim 1, wherein R13 is phenyl 30 zeutisch akzeptables Salz hiervon substituted with a halo, methyl or CF3.

13. The compound of claim 1 , of Formula 2, which is:

p) (3-(2-(3-methyl-4-oxo-6-phenyl-4(3H)-pyri- 35 midinyl)propane-1 ,1-diyl))bisphosphonic acid tetraethyl ester,

q) (3-(2-(3-methyl-4-oxo-6-phenyl-4(3H)-pyrimidinyl))propane-1,1-diyl)bisphosphonic acid 40 disodium salt, 0 0

r) (3-(2-(3-benzyl-4-oxo-6-phenyl-4(3H)-pyri- FORMEL 1 midinyl)propane-1 ,1-diyl))bisphosphonic acid tetraethyl ester, 45

s) (3-(2-(3-methyl-4-oxo-6-(3-fluorophenyl-4 (3H)-pyrimidinyl))propane-1 , 1 -diyl)bisphosphonic acid disodium salt, 50 t) (3-(2-(3-allyl-4-oxo-6-phenyl-4(3H)-pyrimidinyl)propane-1 , 1 -diyl))bisphosphonic acid tetraethyl ester,

u) (3-(2-(5-bromo-3-methyl-4-oxo-6-phenyl-4 55 (3H)-pyrimidinyl)propane-1 , 1 -diyl))bisphosphonic acid tetraethyl ester,

8 15 EP 0 521 622 B1 16

4. Verbindung nach Anspruch 1 , worin R3furCN, Phe- nyl, N02, Wasserstoff oder Halogen steht. ■11 5. Verbindung nach Anspruch 1, worin R5 fur Methyl 5 steht.

6. Verbindung nach Anspruch 1 , worin R6 fur Wasser- stoff steht.

10 7. Verbindung nach Anspruch 1 der Formel 1, nam- II lich: 0 a) (3-(3-Cyano-2,5-dimethylpyrazolo(1 ,5-a)py- FORMEL 2 rimidin-7-yl)-propan-1 , 1 -diyl)-bisphosphon- 15 sauretetraethylester, b) (3-(3-Cyano-2,5-dimethylpyrazolo(1 ,5-a)py- worin bedeuten: rimidin-7-yl)-propan-1 , 1 -diyl)-bisphosphonsaure-dikaliumsalz, XOoderS; c) (3-(3-Cyano-5-methyl-2-phenylpyrazolo R-, alleine jeweils H, C1-C6-Alkyl, CH2-Phenyl 20 (1 ,5-a)pyrimidin-7-yl)-propan-1 , 1 -diyl)-bis- oder Phenyl oder beide Reste OR-, am selben phosphonsauretetraethylester, P zusammen mit CH2-CH2, CH2-CH2-CH2 oder d) (3-(3-Brom-2,5-dimethylpyrazolo(1 ,5-a)pyri- CH2-C(CH3)2-CH2 einen heterocyclischen midin-7-yl)-propan-1 , 1 -diyl)-bisphosphonsau- Ring mit einem P, zwei O und zwei oder drei retetraethylester, Koh lenstoff atomen ; 25 e) (3-(3-Nitro-2,5-dimethylpyrazolo(1,5-a)pyri- R2 Wasserstoff, C1-C6-Alkyl, Benzoyloxy, Ben- midin-7-yl)-propan-1 , 1 -diyl)-bisphosphonsau- zyloxy, C-|-C6-Alkoxy C3-C7-Cycloalkyl, (gege- retetraethylester, benenfalls 1- bis 5fach halogen-, CN-, CF3- f) (3-(2-Benzyloxy-5-methylpyrazolo(1 ,5-a)py- oder C-|-C10-alkyl-substituiertes) Phenyl, 2-, 4- rimidin-7-yl)-propan-1 , 1 -diyl)-bisphosphon- oder 5-Pyrimidyl, 2-, 3- oder 4-Pyridyl oder 1- 30 sauretetraethylester, oder 2-Naphthalinyl; g) (3-(2-Benzoyloxy-5-methylpyrazolo(1 ,5-a) R3 H, Halogen, N02, CN, CF3, CrC10-Alkyl, pyrimidin-7-yl)-propan-1 , 1 -diyl)-bisphosphon- C3-C7-Cycloalkyl oder Phenyl; sauretetraethylester, R5 H, CrC6-Alkyl oder C3-C7-Cycloalkyl; h) (3-(2-Hexyloxy-5-methylpyrazolo(1 ,5-a)py- R6 H, Halogen oder C1-C6-Alkyl; 35 rimidin-7-yl)-propan-1 , 1 -diyl)-bisphosphon- R10H, C-,-C6-Alkyl, C3-C7-Cycloalkyl oder Phe- sauretetraethylester, nyl; i) (3-(5-Methyl-2-phenylpyrazolo(1 ,5-a)pyrimi- R-,-, H, CrC6-Alkyl, C3-C7-Cycloalkyl, Allyl, din-7-yl)-propan-1 , 1 -diyl)-bisphosphonsaure- CH2-Phenyl oder (gegebenenfalls 1- bis 5fach tetraethylester, N02-, halogen- oder C-|-C4-alkyl-substituier- 40 j) (3-(3-Jod-5-methyl-2-phenylpyrazolo(1,5-a) tes) Phenyl und pyrimidin-7-yl)-propan-1 , 1 -diyl)-bisphosphon- entweder R12 H, C-,-C6-Alkyl oder Halogen und sauretetraethylester, R13 Wasserstoff, CrC6-Alkyl, C3-C7-Cycloal- k) (3-(3-Chlor-5-methyl-2-phenylpyrazolo kyl, (gegebenenfalls 1- bis 5fach halogen-, (1 ,5-a)pyrimidin-7-yl)-propan-1 , 1 -diyl)-bis- CN-, CF3- oder CrC10-alkyl-substituiertes) 45 phosphonsauretetraethylester, Phenyl, 2-, 3- oder 4-Pyridyl oder 1- oder I) (3-(3-Brom-5-methyl-2-phenylpyrazolo 2-Naphthalinyl; (1 ,5-a)pyrimidin-7-yl)-propan-1 , 1 -diyl)-bis- oder R12 und R13 (zusammen) einen 4- bis phosphonsauretetraethylester, 7-gliedrigen Ring mit 4 bis 7 Kohlenstoffato- m) (3-(3-Cyano-2,5-dimethylpyrazolo(1 ,5-a) men, 1 bis 3 Stickstoffatom(en), 0 bis 2 Sauer- so50 pyrimidin-7-yl)-propan-1 , 1 -diyl)-bisphosphon- stoffatom(en) und 0 bis 2 Schwefelatom(en). sauretetraethylester, n) (3-(3-Cyano-2,5-dimethylpyrazolo(1 ,5-a)py- 2. Verbindung nach Anspruch 1, worin R1 fur Ethyl rimidin-7-yl)-propan-1 ,1-diyl)-bis-(5,5-dime- steht. thyl-2,2'-dioxid-1 ,3,2-dioxaphosphorinan) oder 55 o) (3-(6-Chlor-3-cyano-2,5-dimethylpyrazolo 3. Verbindung nach Anspruch 1, worin R2 fur Methyl, (1 ,5-a)-pyrimidin-7-yl)-propan-1 , 1 -diyl)-bis- Wasserstoff oder Phenyl steht. phosponsauretetraethylester.

9 17 EP 0 521 622 B1 18

8. Verbindung nach Anspruch 1 , worin XfurSauerstoff Revendications steht. 1 . Compose de formule 1 ou 2 ou un de ses sels phar- 9. Verbindung nach Anspruch 1, worin R10 fur Was- maceutiquement acceptables serstoff steht. 5

10. Verbindung nach Anspruch 1 , worin R11 fur C-|-C3- Alkyl steht.

11. Verbindung nach Anspruch 1 , worin R-, 3 fur Phenyl 10 steht.

12. Verbindung nach Anspruch 1, worin R13 fur halogen-, methyl- oder CF3-substituiertes Phenyl steht. 15 0 0 13. Verbindung nach Anspruch 1 der Formel 2, nam- lich: FORMULE. 1;

p) (3-(2-(3-Methyl-4-oxo-6-phenyl-4(3H)-pyrimidinyl)-propan-1 , 1 -diyl))-bisphosphonsaure- 20 tetraethylester, q) (3-(2-(3-Methyl-4-oxo-6-phenyl-4(3H)-pyri- I midinyl)-propan-1 , 1 -diyl))-bisphosphonsaure- dinatriumsalz, r) (3-(2-(3-Benzyl-4-oxo-6-phenyl-4(3H)-pyri- 25 midinyl)-propan-1 , 1 -diyl))-bisphosphonsaure- tetraethylester, s) (3-(2-(3-Methyl-4-oxo-6-(3-fluorphenyl-4 (3H)-pyrimidinyl)-propan-1 , 1 -diyl))-bisphosphonsaure-dinatriumsalz, 30 t) (3-(2-(3-Allyl-4-oxo-6-phenyl-4(3H)-pyrimidi- (R^P P(0Rl)2 nyl)-propan-1 ,1 -diyl))-bisphosphonsaurete- 0 0 traethylester, u) (3-(2-(5-Brom-3-methyl-4-oxo-6-phenyl-4 FORMULA 2; (3H)-pyrimidinyl)-propan-1 , 1 -diyl))-bisphos- 35 phonsauretetraethylester, v) (3-(2-(3-Methyl-4-oxo-6-(3-methylphenyl-4 dans laquelle X represente O ou S ; (3H)-pyrimidinyl)-propan-1 , 1 -diyl))-bisphos- phonsauretetraethylester, Fti est choisi, independamment, dans le groupe w) (3-(2-(3-Methyl-4-oxo-6-(3-methoxyphenyl- 40 consistant en H, radicaux alkyle en C-, a C6, 4(3H)-pyrimidinyl)-propan-1 , 1 -diyl))-bisphos- CH2-phenyle et phenyle, ou bien les deux grou- phonsauretetraethylester, pes OR1 sur le meme atome de P sont pris con- x) (3-(2-(3-Methyl-4-oxo-6-(3-trifluormethyl- jointement avec un groupe CH2-CH2, CH2- phenyl-4(3H)-pyrimidinyl)-propan-1 ,1-diyl))-bi- CH2-CH2 ou CH2-C(CH3)2-CH2 en formant un sphosphonsauretetraethylester oder 45 noyau heterocyclique ayant un atome de P, y) (3-(2-(3-Methyl-4-oxo-6-phenyl-4(3H)-pyri- deux atomes de O et deux ou trois atomes de midinyl)-propan-1 , 1 -diyl))-bisphosphonsaure- carbon e ; tetraethylester. R2 represente I'hydrogene, un groupe alkyle en C-, a C6, benzoyloxy, benzyloxy, alkoxy en C-, 14. Verwendung einer Verbindung nach Anspruch 1 zur so a C6, cycloalkyle en C3 a C7, phenyle (faculta- Herstellung eines Medikaments zur Behandlung tivement substitue avec 1 a 5 groupes haloge- von Entzundungen. no, CN, CF3 ou alkyle en C-, a C10), 2-, 4- ou 5-pyrimidyle, 2-, 3- ou 4-pyridyle, ou 1- ou 15. Verwendung nach Anspruch 14, wobei das Medika- 2-naphtalenyle ; ment 0,001 mg bis 1 ,0 g der Verbindung bereitstellt 55 R3 represente H, un groupe halogeno, N02, und fur eine orale, intramuskulare, intravenose, CN, CF3, alkyle en C-, a C10, cycloalkyle en C3 transdermale, intraartikulare, subkutane oder intra- a C7 ou phenyle ; peritoneale Verabreichung ausgelegt ist. R5 represente H, un groupe alkyle en C-, a C6

10 19 EP 0 521 622 B1 20

ou cycloalkyle en C3 a C7 ; loxy-5-methylpyrazolo(1 ,5-a)pyrimidine-7-yl) R6 represente H, un groupe halogeno ou alkyle propane-1 , 1 -diyl)bisphosphonique, en C-, a C6 ; g) Tester tetra-ethylique d'acide (3-(2-benzy- R10 represente H, un groupe alkyle en C-, a C6, loxy-5-methylpyrazolo(1 ,5-a)pyrimidine-7-yl) cycloalkyle en C3 a C7 ou phenyle ; s propane-1 , 1 -diyl)bisphosphonique, R-,-, represente H, un groupe alkyle en C1 a C6, h) Testertetra-ethylique d'acide (3-(2-hexyloxy- cycloalkyle en C3 a C7, allyle, CH2-phenyle ou 5-methylpyrazolo(1 ,5-a)pyrimidine-7-yl)propa- phenyle (facultativement substitue avec 1 a 5 ne-1 ,1-diyl)bisphosphonique, groupes N02, halogeno ou alkyle en C-, a C4) ; i) Tester tetra-ethylique d'acide (3-(5-methyl- et 10 2- phenylpyrazolo(1 ,5-a)pyrimidine-7-yl)propa- R12 represente H, un groupe alkyle en C1 a C6 ne-1 ,1-diyl)bisphosphonique, ou halogeno ; et j) Tester tetra-ethylique d'acide (3-(3-iodo- R13 represente I'hydrogene, un groupe alkyle 5-methyl-2-phenylpyrazolo(1 ,5-a)pyrimidine- en C-, a C6, cycloalkyle en C3 a C7, phenyle (fa- 7-yl)propane-1 , 1 -diyl)bisphosphonique, cultativement substitue avec 1 a 5 groupes is k) Tester tetra-ethylique d'acide (3-(3-chloro- halogeno, CN, CF3 ou alkyle en C-, a C10), 2-, 5-methyl-2-phenylpyrazolo(1 ,5-a)pyrimidine- 3- ou 4-pyridyle, ou 1- ou 2-naphtalenyle ; 7-yl)propane-1 , 1 -diyl)bisphosphonique, ou bien R12 et R13 torment un noyau tetra- a I) Tester tetra-ethylique d'acide (3-(3-bromo- heptagonal comprenant 4 a 7 atomes de car- 5-methyl-2-phenylpyrazolo(1 ,5-a)pyrimidine- bone, 1 a 3 atomes d'azote, 0 a 2 atomes d'oxy- 20 7-yl)propane-1 , 1 -diyl)bisphosphonique, gene et 0 a 2 atomes de soufre. m) Tester tetra-ethylique d'acide (3-(3-cyano- 2,5-dimethylpyrazolo(1 ,5-a)pyrimidine-7-yl) 2. Compose suivant la revendication 1 , dans lequel R1 propane-1 , 1 -diyl)bisphosphonique, represente un groupe ethyle. n) le (3-(3-cyano-2,5-dimethylpyrazolo(1 ,5-a)- 25 pyrimidine-7-yl)propane-1 , 1 -diyl)bis(5,5-dime- 3. Compose suivant la revendication 1 , dans lequel R2 thyl-2,2'-dioxyde-1 ,3,2-dioxaphosphorinane), represente un groupe methyle, I'hydrogene ou un ou groupe phenyle. o) Tester tetra-ethylique d'acide (3-(6-chloro- 3- cyano-2,5-dimethylpyrazolo(1 ,5-a)pyrimidi- 4. Compose suivant la revendication 1 , dans lequel R3 30 ne-7-yl)propane-1 , 1 -diyl)bisphosphonique. represente un groupe CN, phenyle, N02, I'hydrogene ou un groupe halogeno. 8. Compose suivant la revendication 1 , dans lequel X represente Toxygene. 5. Compose suivant la revendication 1 , dans lequel R5 represente un groupe methyle. 35 9. Compose suivant la revendication 1, dans lequel R10 represente I'hydrogene. 6. Compose suivant la revendication 1 , dans lequel R6 represente I'hydrogene. 10. Compose suivant la revendication 1, dans lequel R11 represente un groupe alkyle en C-, a C3. 7. Compose suivant la revendication 1 , repondant a la 40 formule 1 , qui est : 11. Compose suivant la revendication 1, dans lequel R13 represente un groupe phenyle. a) Tester tetra-ethylique d'acide (3-(3-cyano- 2,5-dimethylpyrazolo(1 ,5-a)pyrimidine-7-yl) 12. Compose suivant la revendication 1, dans lequel propane-1 ,1 -diyl)bisphosphonique, 45 R13 represente un groupe phenyle substitue avec b) le sel dipotassique d'acide (3-(3-cyano- un groupe halogeno, methyle ou CF3. 2,5-dimethylpyrazolo(1 ,5-a)pyrimidine-7-yl) propane-1 ,1 -diyl)bisphosphonique, 1 3. Compose suivant la revendication 1 , repondant a la c) Tester tetra-ethylique d'acide (3-(3-cyano- formule 2, qui est : 5-methyl-2-phenylpyrazolo(1 ,5-a)pyrimidine- so 7-yl)propane-1 , 1 -diyl)bisphosphonique, p) Tester tetra-ethylique d'acide (3-(2-(3-me- d) Tester tetra-ethylique d'acide (3-(3-bromo- thyl-4-oxo-6-phenyl-4(3H)-pyrimidinyl)propa- 2,5-dimethylpyrazolo(1 ,5-a)pyrimidine-7-yl) ne-1 ,1-diyl))bisphosphonique, propane-1 ,1 -diyl)bisphosphonique, q) le sel disodique d'acide (3-(2-(3-methyl- e) Tester tetra-ethylique d'acide (3-(3-nitro- 55 4- oxo-6-phenyl-4(3H)-pyrimidinyl))propane- 2,5-dimethylpyrazolo(1 ,5-a)pyrimidine-7-yl) 1 ,1-diyl)bisphosphonique, propane-1 ,1 -diyl)bisphosphonique, r) Tester tetra-ethylique d'acide (3-(2-(3-benzyl- f) Tester tetra-ethylique d'acide (3-(2-benzoy- 4-oxo-6-phenyl-4(3H)-pyrimidinyl)propane-

11 21 EP 0 521 622 B1 22

1 , 1 -diyl))bisphosphonique, si le sel disodique d'acide (3-(2-(3-methyl- 4-oxo-6-(3-fluorophenyl-4(3H)-pyrimidinyl)) propane-1 ,1 -diyl)bisphosphonique, t) Tester tetra-ethylique d'acide (3-(2-(3-allyl- s 4-oxo-6-phenyl-4(3H)-pyrimidinyl)propane- 1 , 1 -diyl))bisphosphonique, u) Tester tetra-ethylique d'acide (3-(2-(5-bromo-3-methyl-4-oxo-6-phenyl-4(3H)-pyrimidinyl)propane-1 , 1 -diyl))bisphosphonique, 10 v) Tester tetra-ethylique d'acide (3-(2-(3-methyl-4-oxo-6-(3-methylphenyl-4(3H)-pyrimidinyl)propane-1 , 1 -diyl))bisphosphonique, w) Tester tetra-ethylique d'acide (3-(2-(3-methyl-4-oxo-6-(3-methoxyphenyl-4(3H)-pyrimi- 15 dinyl)propane-1 ,1-diyl))bisphosphonique, x) Tester tetra-ethylique d'acide (3-(2-(3-methyl)-4-oxo-6-(3-trifluoromethylphenyl-4(3H)- pyrimidinyl)propane-1 ,1 -diyl))bisphosphonique, ou 20 y) Tester tetra-ethylique d'acide (3-(2-(3-methyl-4-oxo-6-phenyl-4(3H)-pyrimidinyl)propane-1 , 1 -diyl))-bisphosphonique.

14. Utilisation d'un compose suivant la revendication 1 , 25 pour la preparation d'un medicament destine au traitement de Tinflammation.

15. Utilisation suivant la revendication 14, dans lequel le medicament fournit 0,001 mg a 1 ,0 g du compose 30 et est apte a Tadministration par la voie orale, intra- musculaire, Intraveineuse, transcutanee, intra-arti- culaire, sous-cutanee ou intraperitoneale.