JPH09504010A - Pyrimidinone as an anti-arthritic and anti-inflammatory agent - Google Patents

Abstract

(57) [Summary] Formula I: [Wherein R ² is a) (CH ₂ ) _n —Yi) When n is 1, Y is C ₁ -C ₆ alkoxy, morpholinyl, piperidinyl, pyrrolidinyl, phenoxy, phenylthio, phenylsulfonyl, phenylsulfinyl,- NHC (O) -C ₁ -C ₆ carboxylic acid, N ₃ , NH ₂ , diethylamino, hydrogen (provided that R ⁴ is benzyloxy), halogen (provided that R ³ is C ₁ -C ₆ alkyl) or CH (“ EWG ") ₂ , where" EWG "is each independently an electron withdrawing group selected from the group consisting of CO ₂ R ⁶ and PO (OR ⁷ ) ₂ or ii) 'n is 2. In some cases, Y is CH (“EWG”) ₂ or b) i) aryl or heteroaryl ii) hydroxy and C ₁ -C ₆ alkyl, phenyl or (CH ₂ ) _m —CO ₂ where m is 1-3. terminal olefins substituted with R ⁶ or c, (Optionally _{halogen, (PO (OC 2 H 5} ) 2) 2 or may be substituted by CN) C ₃ -C ₆ cycloalkyl; R ³ is hydrogen or C ₁ -C ₆ alkyl; R ⁴ is Hydrogen, hydroxyl, C ₁ -C ₆ alkyl, alkoxy, benzyloxy or phenoxy; R ⁵ is hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, phenoxy, C ₁ -C ₆ alkylthio, thiphenyl, NH ₂ , aryl (provided that R ⁴ and Y are both hydrogen, except when R ⁵ is other than phenyl) or heteroaryl; R ⁶ is H, C ₁ -C ₆ alkyl, benzyl, phenyl, 1-5 F, Cl, Br, I, NO 2, OCH 3 or C ₁ -C ₄ phenyl substituted by alkyl; and R ⁷ is H, C ₁ -C ₆ alkyl, benzyl, phenyl, 1 5 F, Cl, Br, I, NO ₂ , O CH ₃ or C ₁ -C ₄ alkyl-substituted phenyl, or both R ⁷ are joined together to form CH ₂ —CH ₂ , CH ₂ —CH ₂ —CH ₂ or CH ₂ —C (CH ₃ ) Forming a _2- CH _{2 and} thereby forming a heterocycle containing a bonded P atom and two O atoms] or structurally represented as a pharmaceutically acceptable salt thereof, useful in the treatment of inflammation Compound.

Description

Detailed Description of the Invention                Pyrimidinone as an anti-arthritic and anti-inflammatory agentBackground of the Invention   The present invention is characterized by (Formula I), which is useful as an anti-inflammatory and anti-arthritic agent. Directed to pyrimidinone and its pharmaceutically acceptable salts.   The compounds of the present invention are useful in humans and as a safe and effective treatment for acute inflammatory diseases. Useful for lower animals. These diseases include periodontal disease, rheumatoid arthritis, Osteoarthritis, neuritis, synovial cystitis, pneumoconiosis, Crohn's disease, chronic inflammatory bowel disease Patient, chronic asthma, atherosclerosis, multiple sclerosis and sarcoidosis It is.Description of related technology   For the purpose of state-of-the-art statement, US Pat. And useful bisphosphonates; Australian Patent No. A-515 34/85 is useful for treating abnormal calcium and phosphorus metabolism and Discloses bisphosphonates useful in the treatment of arthritis; and US Pat. No. 3, 683,080 shows abnormal deposition and movement of calcium phosphate in animal tissues. Disclosing Polyphosphonates Useful For Inhibiting Membership; Especially Diphosphonates .   European patent application 0 168 262 has a corresponding R₂Is hydrogen or lower alk Intermediate of Formula VIIa, which is similar to the subject compound except that only Disclosed are gin compounds. The compounds are useful for treating hypertension and cerebrovascular disease Is described.Summary of the invention   In one aspect, the invention features the formula I: [Where R²Is     a) (CH₂)_n-Y           i) when n is 1, Y is C₁-C₆Alkoxy, morpholinyl, pi Peridinyl, pyrrolidinyl, phenoxy, phenylthio, phenylsulfonyl, Phenylsulfinyl, -NHC (O) -C₁-C₆Carboxylic acid, N_Three, NH₂, Jiechi Lumino, hydrogen (however, R^FourIs benzyloxy), halogen (provided that R^ThreeIs C₁-C₆A Rukiru) or CH (“EWG”)₂And here, "EWG" is independent of each other. CO₂R⁶And PO (OR⁷)₂An electron-withdrawing group selected from the group consisting of: Is           ii) When n is 2, Y is CH (“EWG”)₂, Or     b) i) aryl or heteroaryl,           ii) hydroxyl and C₁-C₆Alkyl, phenyl or m 1-3 (CH₂) m-CO₂R⁶ A terminal olefin substituted with, or     c) (optionally halogen, (PO (OC₂H_Five)₂)₂Or replaced by CN May be) C_Three-C₆Cycloalkyl;   R^ThreeIs hydrogen or C₁-C₆Alkyl;   R^FourIs hydrogen, hydroxyl, C₁-C₆Alkyl, alkoxy, benzyloxy Or phenoxy;   R^FiveIs hydrogen, halogen, C₁-C₆Alkyl, C₁-C₆Alkoxy, phenoxy, C₁-C₆Alkylthio, thiophenyl, NH₂, Aryl (provided that R^FourAnd Y are both R is hydrogen when^FiveExcept when phenyl is other than phenyl) or heteroaryl Le;   R⁶Is H, C₁-C₆Alkyl, benzyl, phenyl, 1 to 5 F, Cl, Br , I, NO₂, OCH_ThreeOr C₁-C_FourPhenyl substituted with alkyl; and   R⁷Is H, C₁-C₆Alkyl, benzyl, phenyl, 1 to 5 F, Cl, Br , I, NO₂, OCH_ThreeOr C₁-C_FourPhenyl substituted with alkyl, or Both R⁷CH together when₂-CH₂, CH₂-CH₂-CH₂Or CH₂- C (CH_Three)₂-CH₂To thereby form a bonded P atom and two O atoms Form a heterocycle containing Is pyrimidinone or a pharmaceutically acceptable salt thereof.   In another aspect, the present invention provides a safe and effective treatment for chronic inflammatory diseases. Thus consisting of the use of these compounds in humans and lower animals. this These diseases include periodontal disease, rheumatoid arthritis, osteoarthritis, pneumoconiosis, Croh n) Disease, chronic inflammatory bowel disease, chronic asthma, atherosclerosis, multiple sclerosis And sarcoidosis are included.   In yet another embodiment, the invention provides a patient (human) in need of treatment for inflammation. (Comprising animals) by administering an anti-inflammatory effective amount of a compound of formula I It is a method of performing light treatment. The routes of administration include oral, intramuscular, intravenous, transdermal, and joint. It includes internal, subcutaneous or intraperitoneal. An effective amount is that which causes pain and Symptoms of inflammation or arthritis such as relief are alleviated or diminished, or the affected area is mobile. This is the amount that improves the sex. A typical dosage will depend on the particular mode of administration, use of administration and Approximately 0.001 mg to 1.0 g, depending on dose determined by frequency.Detailed description of the invention   The present invention is characterized by (formula I above) useful as anti-inflammatory and anti-arthritic agents. Consists of pyrimidinone and its pharmaceutically acceptable salts. these The compounds are particularly useful for arthritis and inflammation and excessive bone growth or remodeling. It is useful in treating the symptoms associated with it. In Equation I, the variable design is as follows. Further defined.   The carbon content of various hydrocarbon-containing groups depends on the minimum and maximum number of carbon atoms in the group. Indicated by the prefix shown, ie the prefix C_i-C_jIs an integer “i” to an integer “j Defines the number of carbon atoms present. Therefore, C₁-C_ThreeAlkyl is 1-3 Represents an alkyl of 4 carbon atoms, methyl, ethyl, propyl and isopropyl But Included.   In connection with the above, C₁-C₆Alkyl means methyl, ethyl, propyl, butyl , Pentyl, hexyl and their isomers. "Aryl" means phenyl Le or naphthyl. "Heteroaryl" means morpholinyl, piperazinyl. , Piperidinyl, imidazolidinyl, pyrazolidinyl, isoxazolyl, pyro Ril, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl or Means pyridazinyl. The term "halogen" includes fluoro, chloro, bromo. And iodine are included. "Terminal olefin" means -CH = CH₂Means It can be replaced as shown on one or both sides of the terminal hydrogen.   A pharmaceutically acceptable salt is a salt useful for administering the compounds of the invention, or Useful compounds that can be taken in vitro or in vivo Meaning the form, potassium salt, sodium salt, hydrochloride, hydrobromide, hydrogen iodide Acid salt, sulfate, phosphate, acetate, propionate, lactate, mesylate, male Included are inates, malonates, succinates, tartrates, citrates and others. This These salts may also exist in hydrated form.   Pyrimidinone and its derivatives useful as anti-inflammatory and anti-arthritic agents (formula I) is prepared as shown in Examples 1-35 and Table 1 below.   The compounds of formula I according to the invention are used in the delayed inflammation hypersensitivity granuloma assay (DTH GRA). ) Tested with model. This assay is based on Dunn, CJ et al. Of a delayed hypersensitivity granuloma model in mice for experimental immune-mediated inflammatory disease Development of a delayed-type hypersensitivity granuloma model in t he mouse for the study of chronic immune-mediated inflammatory disease.) '' Agents and Actions Vol. 27, 3/4 ( 1989) and "Murine Delayed-Type Hy. persensitivity Granuloma) "International Journal of Imnov Pharmacology (Int. J. Immunopharmc.) Volume 12, 8: 899-904 (19 90 years).   Briefly, implant the mBSA-immersion filter subcutaneously after 9 days. And mBSA-sensitized mice with DTH granuloma (DTH GRA) lesions Was induced. Administer compounds to mice and measure their effect on lesions . Results are recorded as% inhibition. The greater the inhibition, the higher the effect of the compound. 10-2 It is considered that 0% inhibition shows anti-granulomatous activity. Also, inhibition greater than 30% is Good activity. The DTH GRA data obtained from the compound of formula I is Is shown in Table 2. Compounds have 30% anti-inflammatory activity with 10-20% inhibition. Greater inhibition is recorded as having good activity.   "Compound name" corresponds to the display in the examples. The specific compounds shown are Is as follows: Example 1: 4 (3H) -pyrimidinone, 2- (chloromethyl) -3-methyl-6-phenyl-Step A:   4 (3H) -pyrimidinone, 2,3-dimethyl-6-phenyl (1 in THF (55 ml) 1.0 g, 54.9 mmol) was added to LiHMDS (60 mmol, 1M in THF, 60 ml) at -78 ° C solution was added slowly. After stirring for 45 minutes, then this This was mixed with hexachloroethane (13.64g, 57.6g) in THF (50ml). (40 mmol) solution at −40 ° C. for 45 minutes. This reactant Warmed to room temperature for 1 hour, then NH 3_FourQuench with Cl and extract 3 times with ethyl acetate And saturated NaHCO_ThreeAnd washed with brine, MgSO_FourDried in vacuum and concentrated under vacuum. Shrunk. The product was recrystallized from methyl t-butyl ether (6.555 g , 27.9 mmol, 51%). Melting point 121-122 ° C Example 2: 4 (3H) -pyrimidinone, 3-methyl-2- (phenoxymethyl) -6-phen Nil-Process B:   Sodium hydride (0.191 g, 3.98 mmol) in toluene (9 ml) at 0 ° C. To the suspension was added phenol (0.34 g, 3.61 mmol). 15 minutes later, 2- (chloromethyl) -3-methyl-6-phenyl-4 (3H) -pyrimidinone (0.775 g, 3.2 mmol) was added and the reaction was heated to reflux for 2.5 hours. Cooled Later, the reaction mixture was diluted with methylene chloride and then saturated NaHCO 3._Three3 times Wash, MgSO_FourDried in vacuo and concentrated under vacuum (57%). Melting point 104-105 ℃   Examples 3-6 were carried out by the same method as described in Example 2, and the compounds thereof were Was identified as Example 3: 4 (3H) -pyrimidinone, 3-methyl-6-phenyl-2-[(phenylthio) Methyl]-   R^ThreeIs methyl; R^FourIs hydrogen; R^FiveIs phenyl; R²Is -CH₂-S-phenyl A compound of formula I Melting point 94-95 ℃ Example 4: Phosphonic acid, [2- (1,6-dihydro-1-methyl-6-oxo-4-phenyl- 2-pyrimidinyl) ethylidene] bis-, tetraethyl ester   R^ThreeIs methyl; R^FourIs hydrogen; R^FiveIs phenyl; R²Is -CH₂-CH- (PO (O Et)₂)₂A compound of formula I Melting point 86-88 ℃ Example 5 Malonic acid, [(1,6-dihydro-1-methyl-6-oxo-4-phenyl-2- Pyrimidinyl) methyl]-, diethyl ester   R^ThreeIs methyl; R^FourIs hydrogen; R^FiveIs phenyl; R²Is -CH₂-CH- (CO₂ Et)₂A compound of formula I Melting point 102-103 ° C Example 6: 2-Pyrimidinepropanoic acid, .alpha .- (diethoxyphosphinyl) -1 , 6-Dihydro-1-methyl-6-oxo-4-phenyl-, ethyl ester   R^ThreeIs methyl; R^FourIs hydrogen; R^FiveIs phenyl; R²Is -CH₂-CH (CO₂ Et) (PO (OEt)₂) A compound of formula I Melting point 119 ° C Example 7: 4 (3H) -pyrimidinone, 3-methyl-2- (4-morpholinylmethyl)- 6-phenyl-Step C:   2- (Chloromethyl) -3-methyl-6-phenyl-4 (3H) -pi in THF (12 ml) Limidinone (0.507 g, 2.2 mmol) was added to morpholine (0.40 ml, 4.5 mm). Mol) and then heated at reflux for 1.5 hours. The reaction mixture is cooled and Filter through an Ito pad and concentrate under vacuum. The residue in methylene chloride It was dissolved and filtered twice. The organic layer was concentrated under vacuum to give a light yellow solid. The crude material was purified by recrystallisation from ethyl acetate (27%). Melting point 135-136 ° C Example 8: 4 (3H) -Pyrimidinone, 3-Methyl-6-phenyl-2-piperidinyl-   The title compound was prepared in the same manner as in Example 7. Melting point 133-134 ° C Example 9: 4 (3H) -Pyrimidinone, 3-methyl-6-phenyl-2-pyrrolidinyl-   The title compound was prepared in the same manner as in Example 7. Melting point 112-113 ° C Example 10: 4 (3H) -Pyrimidinone, 2-dimethylamino-3-methyl-6-phenyl Le-   The title compound was prepared in the same manner as in Example 7. Melting point 84-85 ° C Example 11: 4 (3H) -Pyrimidinone, 2-methoxy-3-methyl-6-phenyl-   The title compound was prepared in the same manner as in Example 7. Melting point 86-87 ℃ Example 12: 4 (3H) -Pyrimidinone, 2- (aziodomethyl) -3-methyl-6-fu Phenyl-   4 (3H) -pyrimidinone, 2- (iodomethyl) -3-methyl-6-phenyl- (4.06 g, 12.4 mmol) with sodium azide (1.62 g, 24.9 mmol) and And acetonitrile (25 ml), stirred at 22 ° C. for 60 hours, then vacuum Concentrated below. The residue was dissolved in methylene chloride and saturated NaHCO_Three3 x 1M NaHSO_Three, Washed with saturated NaCl, MgSO_FourAnd then concentrated under vacuum ( 40%). Melting point 111-112 ° C Example 13: 4 (3H) -Pyrimidinone, 2- (iodomethyl) -3-methyl-6-phenyl Le-   2- (chloromethyl) -3-methyl-6-phenyl-4 (3H) -pyrimidinone (0.98 g, 4.16 mmol) and sodium iodide (0.654 g, 4.37 mmol) Were combined in acetone (10 ml) and heated to reflux for 30 minutes. The reaction mixture Cooled, filtered and concentrated under vacuum. The resulting solid is dried under high vacuum, A light yellow solid was collected. Example 14: 4 (3H) -Pyrimidinone, 2- (aminomethyl) -3-methyl-6-phen Nil-   2- (chloromethyl) -3-methyl-6-phenyl-4 (3H) -pyrimidinone (3.98) g, 17.0 mmol) and sodium azide (2.21 g, 34 mmol). Combined in cetonitrile (25 ml) and gently heated to reflux for 1 hour. Cool to room temperature After that, the solvent was removed under vacuum. Dilute the residue with methylene chloride to 6% NaHCO_Three, H₂Wash with O and brine, treat with charcoal, MgSO 4._FourThe Pa Tsu Filtered through a bed. After concentrating under vacuum, the crude product was treated with 5% carbon palladium. Resuspend in an ethanol mixture (80 ml) containing sodium (0.4 g), and add 2 to 2 in a hydrogen atmosphere. Hydrogenated for hours. The reaction mixture was filtered through Celite and concentrated under vacuum did. The product was recrystallized from ethyl acetate / hexane (0.80 g, 3.7 mm). Mol, 22%). Melting point 90-92 ℃ Example 15: Butyric acid, 4-[[(1,6-dihydro-1-methyl-6-oxo-4-phenyl-2 -Pyrimidinyl) methyl] amino] -4-oxo-   4 (3H) -Pyrimidinone, 2- (aminomethyl) -dissolved in chloroform (5 ml) 3-Methyl-6-phenyl- (304 mg, 1.41 mmol) was added to succinic anhydride (1 41 mg, 1.41 mmol) and then heated to reflux for 1 hour. Obtained solid The product was filtered, washed with chloroform and dried (0.377g, 1.20mM). 85%). Melting point 200-201 ℃ Example 16: Pentanoic acid, 5-[[(1,6-dihydro-1-methyl-6-oxo-4-phene) Nyl-2-pyrimidinyl) methyl] amino] -5-oxo-   The title compound was prepared from glutaric anhydride in a similar manner to that of Example 15. 62%). Melting point 181-182 ° C Example 17: 4 (3H) -Pyrimidinone, 3-methyl-6-phenyl-2-[(phenyls Rufonyl) -methyl]-   Toluene the sodium salt of benzenesulfinic acid (0.346 g, 2.1 mmol) Slurried in methanol (5 ml), then 4 (3H) -pyrimidinone, 2- (iodomethyi) ) -3-Methyl-6-phenyl (0.517 g, 1.6 mmol) at 70 ° C. It was heated for 20 hours. Cool the reaction to room temperature and remove most of the solvent under vacuum. Removed. The residue was dissolved in methylene chloride and saturated NaHCO 3._ThreeAnd 1M Na HSO_ThreeWashed 3 times with MgSO 4._FourDried in vacuo and concentrated in vacuo. The product is Purified by chromatography on lica gel (226 mg, 0.66 mm Mol, 41%). Melting point 174-175 ° C Example 18: 4 (3H) -Pyrimidinone, 3-methyl-6-phenyl-2-[(phenyls Rufinyl) -methyl]-   4 (3H) -pyrimidinone, 3-methyl-dissolved in methanol (10 ml) at 0 ° C 6-phenyl-2-[(phenylthio) methyl]-(0.589 g, 1.91 mmol) Treated with an aqueous solution of oxone (7.23 g, 5.7 mmol) in water (21 ml). The reaction mixture was stirred at 0 ° C. for 5 hours, then the sample was heated to 40 ° C. while heating 1 M NaHSO_ThreeAnd concentrated in vacuo. Separated by adding methylene chloride The organic layer with 1M NaHSO._Three3 times with saturated NaHCO_ThreeWashed once with Purified, MgSO_FourDried in vacuo and concentrated in vacuo. The sample should be a Purified by chromatography (217 mg, 0.67 mmol, 35%). Melting point 158-159 ° C Example 19: 4-Pentenoic acid, 5- (1,6-dihydro-1-methyl-6-oxo-4-phene Nyl-2-pyrimidinyl) -4-hydroxy-, (Z)-   4 (3H) -pyrimidinone, 2,3-dimethyl-6-phenyl (5.45 g, 27.2 mi Limol) was dissolved in THF (25 ml), cooled to -20 ° C, and LiHMDS (60 mm). Mol, 1M in THF, 60 ml). After stirring for 30 minutes, Silicic acid (3.0 g, 30.0 mmol) was added and the reaction was warmed to room temperature for 2 hours. Was. It was quenched with water, extracted twice with ethyl acetate, and the aqueous solution was treated with 1N H 2 Acidified with Cl, then filtered. The product was recrystallized from iPrOH (4. 30 g, 14.3 mmol, 53%). Melting point 232-233 ° C Example 20: 5-Hexenoic acid, 6- (1,6-dihydro-1-methyl-6-oxo-4-furf Phenyl-2-pyrimidinyl) -5-hydroxy-, (Z)-   The title compound was prepared from glutaric anhydride by a method similar to that of Example 19 (26 %). Melting point 170-171 ° C Example 21: 4-Pentenoic acid, 5- (1,6-dihydro-1-methyl-6-oxo-4-phene Nyl-2-pyrimidinyl) -4-hydroxy-, methyl ester, (Z)-   Methanol (25 ml) and H₂SO_Four4-pentanoic acid, 5- (1,6-dihi) in (1 drop) Doro-1-methyl-6-oxo-4-phenyl-2-pyrimidinyl) -4-hydroxy-, (Z) -(693 mg, 2.31 mmol) was heated to reflux for 3 hours. Under vacuum, most of the After removing the tanol, the crystals were filtered and washed with ether (646 mg, 2.06 mmol, 89%). Melting point 153 ° C Example 22: Phosphonic acid, [(1,6-dihydro-1-methyl-6-oxo-4-phenyl- 2-pyrimidinyl) cyclopropylidene] bis-, tetraethyl ester   4 (3H) -pyrimidinone, 2- (chloromethyl) -3-methyl-6-phenyl- (705 mg, 3.0 mmol), ethenylidene bis (phosphonic acid), tetraethyl ester ( 900 mg, 3.0 mmol) and DBU (0.5 ml, 3.3 mmol) in THF ( 5 ml) and stirred at room temperature for 24 hours. NH the reaction product_FourQuench with Cl, vinegar Extract 3 times with ethyl acetate and MgSO 4._FourDried in and stripped. The crude Was purified by silica gel chromatography (471 mg, 0.95 mm Mol, 32%).   NMR: δ (CDCl_Three) 7.97 (m, 2H), 7.44 (m, 3H), 6.84 (s, 1H) , 4.39 (m, 4H), 4.1-3.8 (m, 4H), 3.75 (s, 3H), 2.99 (m, 1H), 2.56 (m, 1H), 1.95 (m, 1H), 1.402 (t, J = 7.2, 3H), 1.39 ( t, J = 7.2,3H), 1.19 (t, J = 7.2,3H), 1.08 (t, J = 7.2,3H) Example 23: Cyclopropanecarbonitrile, 2- (1,6-dihydro-1-methyl-6- Oxo-4-phenyl-2-pyrimidinyl)-, trans-   The title compound was prepared by the same method as in Example 22. Melting point 166-167 ° C Example 24: Cyclopropanecarbonitrile, 2- (1,6-dihydro-1-methyl-6- Oxo-4-phenyl-2-pyrimidinyl)-, cis-   The title compound was prepared by the same method as in Example 22. Melting point 195-196 ° C Example 25: Malonic acid, [2- (1,6-dihydro-1-methyl-6-oxo-4-phenyl- 2-Pyrimidinyl) ethyl]-, bis (1,1-dimethylethyl) ester   4 (3H) -pyrimidinone, 2,3-dimethyl-6-phenyl (0.744 g, 3.72 Mmol) in THF (37 ml), cooled to -78 ° C, then charged with lithium Treatment with su (trimethylsilyl) amide (4.1 ml, 4.1 mmol). To -78 ° C After stirring for 30 minutes at room temperature, 2-tert-butylcarboxy-2-propyl in THF (10 ml) was added. A solution of ropenoic acid t-butyl ester (0.424 g, 1.86 mmol) was added to It was added slowly with a pump for about 1 hour. The reaction product was 4.1M NH_FourQuench immediately with Cl (1 ml, 4.1 mmol) then warm to 22 ° C. Was. The reaction mixture was concentrated under vacuum and dissolved in ethyl acetate. The organic layer 3 times with 1N HCl, H₂O once, NaHCO_Three3 times and once with saline Wash, then MgSO_FourDried in vacuo and concentrated in vacuo. The crude mixture Chromatography on silica gel (0.317 g, 0.74 mmol, 40%). Melting point 94-95 ℃ Example 26: 4 (3H) -Pyrimidinone, 2,3-Dimethyl-6-phenyl-5- (phenyl Lumethoxy)-   Sodium hydride (19.2 g, 0.40 mol, 50% in oil) was added to toluene (20 0 ml), then benzyl alcohol (43.2 g, 0.40 mol) was added dropwise. did. After stirring for 45 minutes, the gray foam was washed with chloroacetic acid in toluene (100 ml). It was treated slowly with a solution of acid (18.8 g, 0.20 mol) then heated to reflux. Two o'clock After refluxing for a while, the reaction was cooled to room temperature and poured into water (100 ml). That The organic layer was separated and toluene was extracted twice with water. The aqueous layer is methyl t-butyl Wash with ether and discard organics. After adjusting the pH to 2 with concentrated HCl, The fractions are extracted 3 times with methylene chloride and MgSO 4._FourAnd then concentrated under vacuum (2 9.50g). This crude material, ethanol (40 ml), toluene (50 ml) and concentrated H₂SO_Four(3 ml) was heated to reflux overnight. After cooling it with water, NaHCO._Threeso Wash, MgSO_FourDried in vacuo and concentrated in vacuo. The product is distilled Isolated (24.38 g, 0.126 mol, 63%). Bp_0.155-60 ℃ This synthesis is based on the Australian Journal of Chemistry (Aust.J.Che). m.) Substantially the same as described in 1976, 29, 1335-1339. Is the same as   The ester (22.10 g, 0.113 mol) was dissolved in THF (5 ml) and LiH Slowly add to a -78 ° C solution of MDS (0.230 mol, 1M in THF, 230 ml). Added. After stirring for 45 minutes, benzoyl chloride (13.1 ml, 0.113 mol) Was added and the reaction was warmed to room temperature for 45 minutes. Quench it with 1N HCl And extracted three times with methyl t-butyl ether, MgSO 4._FourDried in stripy (45.68 g, 0.153 mol). Crude material, acetamide hydrochloride (28.9 5 g, 0.306 mol) and 25% sodium methoxide / methanol (77 ml) , 0.336 mol) and heated under reflux for 36 hours. Cool it, dilute with water The pH was adjusted to 7 with concentrated HCl. The precipitate is collected, washed with cold ether and air dried. (20.45 g, 70.00 mmol, 62%). Melting point 168 ° C   Pyrimidinone (5.84 g, 20.0 mmol), K₂CO_Three(3.20g, 23mm Mol) and methyl iodide (3.7 ml, 60 mmol) in refluxing methanol (50 ml). Heated in overnight. The reaction was cooled and seeded. Collect the precipitate and wash with water And dried in oven (5.052 g, 16.49 mmol, 82%) Melting point 118-119 ° C Example 27: Phosphonic acid, [3- [1,6-dihydro-1-methyl-6-oxo-4-phenyl] L-5- (phenylmethoxy) -2-pyrimidinyl] propylidene] bis-, tetraethyl ester   To a -78 ° C solution of LiHMDS (8.4 mmol, 1M in THF, 8.4 ml), 4 (3H) -pyrimidinone, 2,3-dimethyl- in THF / pyridine (1: 1, 4 ml) Add a solution of 6-phenyl-5- (phenylmethoxy)-(1.23 g, 4.0 mmol). did. After stirring for 30 minutes, ethenylidene bis (phosphonic acid) in THF (5 ml) ), Tetraethyl ester (2.52 g, 8.4 mmol) was added and the reaction was allowed to come to room temperature. It was warmed for 30 minutes. It was quenched with water, extracted 3 times with ethyl acetate and extracted with 1N HCl, NaHCO_ThreeAnd washed once with brine, then MgSO_FourDried in Tripped. The sample was purified by silica gel chromatography (1.937 g, 3.19 mmol, 80%).   NMR: δ (CDCl_Three) 8.04 (m, 2H), 7.38 (m, 3H), 7.31 (m, 2H) , 7.25 (m, 3H), 5.08 (s, 2H), 4.17 (m, 8H), 3.60 (s, 3H), 3. 13 (t, J = 7.2,2H), 2.79 (tt, J_t1= 6.6, J_t2= 23.7, 1H), 2. 46 (m, 2H), 1.32 (m, 12H) Example 28: Phosphonic acid, [3- (1,6-dihydro-5-hydroxy-1-methyl-6-o Xo-4-phenyl-2-pyrimidinyl) propylidene] bis-, tetraethyl ester   Phosphonic acid in ethanol (50 ml), [3- [1,6-dihydro-1-methyl-6-o] Xo-4-phenyl-5- (phenylmethoxy) -2-pyrimidinyl] propylidene] bis -, Tetraethyl ester (1.60 g, 2.64 mmol) was added to 10% Pd / C (32 0 mg) and ammonium formate (4.00 g), then heated at reflux for 2 hours. did. The catalyst was removed by filtration through Celite and stripped. That Dissolve the residue in methylene chloride, filter through a short pad of silica gel and wash the pad. The pad was thoroughly washed with acetone. After concentration, the crude material is treated with methyl t-butyl ether. Recrystallized from ether (884 mg, 1.71 mmol, 65%). Melting point 138-139 ° C Example 29: 4 (3H) -pyrimidinone, 6-chloro-2,3-dimethyl-   Hydrogen chloride gas (2.0 g, 55 mmol) was gradually added to acetonitrile (7.5 ml). I bubbled. Phosgene (4.9 g, 50 ml) in acetonitrile (7.5 ml) A second solution containing (mol) was prepared in a pressure bottle and dissolved in that pressure bottle. The liquid was added. Close the mixture tightly and heat at 60-65 ° C for 64 hours Was. The solution was cooled to −78 ° C., filtered, then the solids were washed with a small amount of acetonitrile. Wash with nitrile followed by hexane (4.06 g, 22.4 mmol, 45%).   6-Chloro-2-methyl-4-pyrimidinone.HCl (3.95 g, 21.7 mmol) And potassium carbonate (8.98 g, 65 mmol) in acetone (90 ml). Iodomethane (3.4 ml, 54.2 mmol) was added and the solution was diluted to 2 ml. Refluxed for hours. The reaction mixture was cooled and concentrated under vacuum. The residue is salted Dissolved in methylene chloride, saturated NH_FourWash with Cl, MgSO_FourAnd dry under vacuum Concentrated. (3.3 g, 20.8 mmol, 96%). Melting point 85-86 ℃ Example 30: 4 (3H) -pyrimidinone, 2,3-dimethyl-6-methoxy-   Diethyl malonate (28.6 g, 0.178 mmol) was added to methanol (180 ml). Dissolved in and added acetamidine.HCl. The suspension in methanol Treat with 25% sodium methoxide (86 ml, 0.375 mol) and add for 3.5 hours. Heat to reflux and then cool to a sufficient amount of H₂Dilute with O to dissolve the solid. The solution was cooled to 0 ° C. and neutralized with concentrated HCl to pH 6.5-6.0. Thick solid Was filtered and dried on the filter to give 14.1 g of crude material which was Used directly. The compound is Collect.Czech.Communi (Collect.Czech.Ch em.Commun.) 32: 1298-304 (1967).   Intermediate 6-Hydroxy-2-methyl-4-pyrimidinone.HCl (14.1 g, 0.1 Slurry) in methanol (160 ml) and potassium carbonate (46.3 g, 0 .33 mol) and iodomethane (28 ml, 0.45 mol), then 45 Heated to reflux for an hour. After cooling and concentrating under vacuum, the residue was₂Melted in O It was thawed and washed 6 times with methylene chloride. Concentrate the combined organics under vacuum and let stand The yellow oily substance was solidified. Recrystallize from toluene / cyclohexane, A whitish solid that appeared to be slightly hygroscopic was collected (12.1 g, 67 mm Mol, 37%). Melting point 66-68 ° C Example 31: 4 (3H) -pyrimidinone, 2,3-dimethyl-6-phenylthio-   Sodium hydride (0.3 mL) slurried in dimethylformamide (25 mL) 6 g, 7.5 mmol) with thiophenol (0.73 ml, 7.12 mmol) and 6-chloro-2,3-dimethyl-4 (3H) -pyrimidinone (1.13 g, 7.13 millimolar ). The mixture was stirred at 22 ° C. for 24 hours, then H 2₂O (70 ml ). The aqueous solution was washed with ethyl acetate (50 ml) and after separation, Hexane (50 ml) was added to the organic layer. The combined organic matter is H₂O and salt Wash 5 times with water, MgSO_FourDried in vacuo and then concentrated under vacuum. Pale yellow solid Compound 4 (3H) -pyrimidinone, 2,3-dimethyl-6-phenylthio-methyl t-butyl Recrystallized from ether (0.87 g, 3.7 mmol, 53%). Melting point 105-106 ℃ Example 32: 4 (3H) -Pyrimidinone, 2,3-Dimethyl-6-piperidinyl   4 (3H) -pyrimidinone, 6-chloro-2,3-dimethyl- (0.778 g, 4.90 mi Limol) was slurried in piperidine (15 ml) and the solution was heated to reflux for 1 hour. Then, it was heated at 60 ° C. for 18 hours. The reaction mixture is filtered through Celite. And concentrated in vacuo. The residue was dissolved in methylene chloride and 6% NaHC O_ThreeOnce, H₂Wash twice with O, then MgSO_FourDried in. Vacuum the solvent Concentrate under and elute the orange oil with 10: 1 ethyl acetate / methanol SiO₂It was subjected to the above chromatography. Material recovered from column 4 (3H)- Is pyrimidinone, 2,3-dimethyl-6-piperidinyl-methyl t-butyl ether? It was recrystallized to give light brown crystals (0.64 g, 3.1 mmol, 63%). Melting point 97-98 ° C Example 33: 3- (1,6-Dihydro-4-chloro-1-methyl-6-oxo-2-pyrimidi Nyl) -propylidene bisphosphonic acid, tetraethyl ester   4 (3H) -pyrimidinone, 6-chloro-2,3-dimethyl, dissolved in THF (40 ml) -(3.25g, 20.5mmol) was cooled to -78 ° C and LiHMDS (21.5ml). , 21.5 mmol) and stirred for 1 hour. Ethenili in THF (10 ml) Denbis (phosphonic acid), tetraethyl ester (5.84 g, 19.5 mmol) The solution is added slowly and after 30 minutes at -78 ° C the reaction mixture is allowed to reach 0 ° C for 1 hour. Heated. The reaction is saturated with NH_FourQuench with Cl and concentrate under vacuum. That The residue was dissolved in ethyl acetate and saturated NH_Four3 times with Cl, saturated NaHCO_ThreeThree times and Food Wash three times with brine, then MgSO_FourAnd dried in vacuo and concentrated in vacuo. Crude material 3- (1,6 -Dihydro-4-chloro-1-methyl-6-oxo-2-pyrimidinyl) -propylidenebi Sphosphonic acid, tetraethyl ester can be chromatographed on silica gel. Thus purified (7.1 g, 15.5 mmol, 79%).   NMR: δ (CDCl_Three) 6.35 (s, 1H), 4.20-4.04 (m, 8H), 3.47 ( s, 3H), 3.08 (t, J = 7.3,2H), 2.62 (tt, J_t1= 6.6, J_t2= 23. 8,1H), 2.43-2.25 (m, 2H), 1.29 (t, J = 7.0,12H) Example 34: 3- (1,6-Dihydro-1-methyl-6-oxo-4-phenylthio-2-pi (Limidinyl) -propylidene bisphosphonic acid, tetraethyl ester   The title compound was treated with 4 (3H) -pyrimidinone, 2,3-dimethyl-6-phenyl by the same method. Prepared from phenylthio- (88%).   NMR: δ (CDCl_Three) 7.58-7.55 (m, 2H), 7.48-7.43 (m, 3H), 5.67 (s, 1H), 4.28-4.16 (dq, 8H), 3.47 (s, 3H), 3.10 (t, J = 7.3,2H), 2.72 (tt, J_t1= 6.4, J_t2= 24,1H), 2.47-2.3 3 (m, 2H), 1.37 (t, J = 7.0, 12H) Example 35: 3- (1,6-Dihydro-1-methyl-6-oxo-4-piperidinyl-2-pi (Limidinyl) -propylidene bisphosphonic acid, tetraethyl ester 3- (1,6-dihydro-4-chloro-1-methyl-6-oxo-2- (from Example 33) Pyrimidinyl) -propylidene bisphosphonic acid, tetraethyl ester (1.17 g 2.56 mmol) was added to piperidine (8 ml) and the solution was added to 55-60 ° C. Heated gently for hours. The solution was cooled, filtered through Celite and under vacuum. Concentrated. The obtained oily substance is SiO₂Subjected to chromatography above (0.83) g, 1.63 mmol, 64%).   NMR: δ (CDCl_Three) 5.40 (s, 1H), 4.24-4.14 (m, 8H), 3.53- 3.50 (m, 4H), 3.44 (s, 3H), 3.00 (t, J = 7.3, 2H), 2.72 (t t, J_t1= 6.7, J_t2= 24,1H), 2.49-2.34 (m, 2H), 1.68-1.57 (m, 6H), 1.34 (m, 12H)

────────────────────────────────────────────────── ─── Continuation of front page    (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, M C, NL, PT, SE), OA (BF, BJ, CF, CG , CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, MW, SD, SZ), AM, AT, AU, BB, BG, BR, BY, CA, CH, C N, CZ, DE, DK, EE, ES, FI, GB, GE , HU, JP, KE, KG, KP, KR, KZ, LK, LR, LT, LU, LV, MD, MG, MN, MW, N L, NO, NZ, PL, PT, RO, RU, SD, SE , SI, SK, TJ, TT, UA, US, UZ, VN

Claims (1)

[Claims]   1. Formula I: [Where R²Is   a) (CH₂)_n-Y     i) when n is 1, Y is C₁-C₆Alkoxy, morpholinyl, piperidi Nyl, pyrrolidinyl, phenoxy, phenylthio, phenylsulfonyl, phenyl Rusulfinyl, -NHC (O) -C₁-C₆Carboxylic acid, N_Three, NH₂, Diethylamino , Hydrogen (however, R^FourIs benzyloxy), halogen (provided that R^ThreeIs C₁-C₆Alkyl) Or CH (“EWG”)₂And here, "EWG" is independent of CO₂R⁶Oh And PO (OR⁷)₂An electron-withdrawing group selected from the group consisting of, or     ii) When n is 2, Y is CH (“EWG”)₂Or   b)     i) aryl or heteroaryl     ii) hydroxy and C₁-C₆Alkyl, phenyl or m of 1 to 3 ( CH₂)_m-CO₂R⁶ A terminal olefin substituted with, or   c) (optionally halogen, (PO (OC₂H_Five)₂)₂Or replaced by CN May be) C_Three-C₆Cycloalkyl;   R^ThreeIs hydrogen or C₁-C₆Alkyl;   R^FourIs hydrogen, hydroxyl, C₁-C₆Alkyl, alkoxy, benzyloxy Or phenoxy;   R^FiveIs hydrogen, halogen, C₁-C₆Alkyl, C₁-C₆Alkoxy, phenoxy, C₁-C₆Alkylthio, thiphenyl, NH₂, Aryl (provided that R^FourAnd Y together R when hydrogen^FiveIs other than phenyl) or heteroaryl;   R⁶Is H, C₁-C₆Alkyl, benzyl, phenyl, 1-5 F, Cl, B r, I, NO₂, OCH_ThreeOr C₁-C_FourPhenyl substituted with alkyl; and   R⁷Is H, C₁-C₆Alkyl, benzyl, phenyl, 1 to 5 F, Cl, Br , I, NO₂, OCH_ThreeOr C₁-C_FourPhenyl substituted with alkyl, or , Both R⁷Are bound together CH₂-CH₂, CH₂-CH₂-CH₂Or CH₂-C (CH_Three)₂-CH₂To form a bonded P atom and two bonded P atoms Form heterocycle containing O atom] Or a pharmaceutically acceptable salt thereof.   2. R²Is -CH₂-CH (CO₂-C₁-C₆Alkyl)₂, -CH₂-CH [PO (O-C₁- C₆Alkyl)₂]₂(C-C_ThreeH_Three)-(PO (OC₂H_Five)₂)₂Or -CH₂-With morpholinyl A compound according to claim 1.   3. C₁-C₆The compound of claim 2 wherein the alkyl is ethyl.   4. R²Is hydroxyl and (CH₂)_m-CO₂R⁶Terminal olefins substituted with The compound according to claim 1, which is   5. R^ThreeThe compound of claim 1, wherein is methyl.   6. R^Four2. The compound according to claim 1, wherein is hydrogen, benzyloxy or hydroxyl. Compound.   7. R^FiveIs Cl, methoxy, phenyl, thiophenyl or piperidinyl A compound according to claim 1.   8. R^ThreeIs methyl, R^FourIs hydrogen and R^FiveIs phenyl. Compound.   9. a) 4 (3H) -pyrimidinone, 2- (chloromethyl) -3-methyl-6-phenyl- ;   b) 4 (3H) -pyrimidinone, 3-methyl-2- (phenoxymethyl) -6-phenyl- ;   c) 4 (3H) -pyrimidinone, 3-methyl-6-phenyl-2-[(phenylthio) methyi Le]-；   d) Phosphonic acid, [2- (1,6-dihydro-1-methyl-6-oxo-4-phenyl-2- Pyrimidinyl) -ethylidene] bis-, tetraethyl ester;   e) Malonic acid, [(1,6-dihydro-1-methyl-6-oxo-4-phenyl-2-pipet Linidinyl) -methyl]-, diethyl ester;   f) 2-pyrimidinepropanoic acid, alpha .- (diethoxyphosphinyl) -1,6- Dihydro-1-methyl-6-oxo-4-phenyl-, ethyl ester;   g) 4 (3H) -pyrimidinone, 3-methyl-2- (4-morpholinylmethyl) -6-phen Nil-;   h) 4 (3H) -pyrimidinone, 3-methyl-6-phenyl-2-piperidinyl-;   i) 4 (3H) -pyrimidinone, 3-methyl-6-phenyl-2-pyrrolidinyl-;   j) 4 (3H) -pyrimidinone, 2-dimethylamino-3-methyl-6-phenyl-;   k) 4 (3H) -pyrimidinone, 2-methoxy-3-methyl-6-phenyl-;   l) 4 (3H) -pyrimidinone, 2- (aziodomethyl) -3-methyl-6-phenyl-;   m) 4 (3H) -pyrimidinone, 2- (iodomethyl) -3-methyl-6-phenyl-;   n) 4 (3H) -pyrimidinone, 2- (aminomethyl) -3-methyl-6-phenyl-;   o) Butyric acid, 4-[[(1,6-dihydro-1-methyl-6-oxo-4-phenyl-2-pyridyl Midinyl) methyl] amino] -4-oxo-;   p) pentanoic acid, 5-[[(1,6-dihydro-1-methyl-6-oxo-4-phenyl-2 -Pyrimidinyl) methyl] amino] -5-oxo-;   q) 4 (3H) -pyrimidinone, 3-methyl-6-phenyl-2-[(phenylsulfoni Le) methyl]-;   r) 4 (3H) -pyrimidinone, 3-methyl-6-phenyl-2-[(phenylsulfi Nyl) methyl]-;   s) 4-Pentenoic acid, 5- (1,6-dihydro-1-methyl-6-oxo-4-phenyl- 2-pyrimidinyl) -4-hydroxy-, (Z)-;   t) 5-hexenoic acid, 6- (1,6-dihydro-1-methyl-6-oxo-4-phenyl- 2-pyrimidinyl) -5-hydroxy-, (Z)-;   u) 4-pentenoic acid, 5- (1,6-dihydro-1-methyl-6-oxo-4-phenyl- 2-pyrimidinyl) -4-hydroxy-, methyl ester, (Z)-;   v) Phosphonic acid, [(1,6-dihydro-1-methyl-6-oxo-4-phenyl-2-pi- Rimidinyl) cyclopropylidene] bis-, tetraethyl ester;   w) cyclopropanecarbonitrile, 2- (1,6-dihydro-1-methyl-6-oxy So-4-phenyl-2-pyrimidinyl)-, trans-;   x) cyclopropanecarbonitrile, 2- (1,6-dihydro-1-methyl-6-oxy) So-4-phenyl-2-pyrimidinyl)-, cis-; or   y) Malonic acid, [2- (1,6-dihydro-1-methyl-6-oxo-4-phenyl-2- Pyrimidinyl) -ethyl]-, bis (1,1-dimethylethyl) ester 9. The compound according to claim 8, which is 10.   a) 4 (3H) -pyrimidinone, 2,3-dimethyl-6-phenyl-5- (phenylmeth Xi)-;   b) Phosphonic acid, [3- [1,6-dihydro-1-methyl-6-oxo-4-phenyl-5- ( Phenylmethoxy) -2-pyrimidinyl] propylidene] bis-, tetraethyl ester Le;   c) Phosphonic acid, [3- (1,6-dihydro-5-hydroxy-1-methyl-6-oxo- 4-phenyl-2-pyrimidinyl) propylidene] bis-, tetraethyl ester;   d) 3- (1,6-dihydro-4-chloro-1-methyl-6-oxo-2-pyrimidinyl)- Propylidene bisphosphonic acid, tetraethyl ester;   e) 3- (1,6-dihydro-1-methyl-6-oxo-4-phenylthio-2-pyrimidi Nyl) -pyrrolidene bisphosphonic acid, tetraethyl ester; or   f) 3- (1,6-dihydro-1-methyl-6-oxo-4-piperidinyl-2-pyrimidi Nyl) -propylidene bisphosphonic acid, tetraethyl ester The compound according to claim 1, which is 11. A compound of formula I for use in treating inflammation. 12. For patients in need of the compound, an anti-inflammatory effective amount of 0.001 mg to 1.0 g Administer the compound orally, intramuscularly, intravenously, transdermally, intraarticularly, subcutaneously or intraperitoneally Use according to claim 11, wherein