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 ts25 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.

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