JP2000501095A - 2 '-[[4'-halo- [1,1'-biphenyl] -4-yl] methyl] -5'-methyl-spiro [cyclopentane-1,7' (8'H)-[3H] imidazo [2,1-b] purines] -4 '(5'H) -ones - Google Patents

Abstract

(57) Abstract: A compound of formula I that is hypotensive and bronchodilator, or a pharmaceutically acceptable salt thereof: Where X is fluoro, chloro or bromo.

Description

DETAILED DESCRIPTION OF THE INVENTION2 '-[[4'- Halo- [1,1'-biphenyl] -4-yl] methyl] -5'-methyl-spiro [cyclope 1,7 '(8'H)-[3H] imidazo [2,1-b] purine] -4'(5'H) -ones background   The present invention relates to 2 ′-[[4′-halo- [1,1′-biphenyl] -4-yl] methyl] -5′-methyl-spin B [Cyclopentane-1,7 '(8'H)-[3H] imidazo [2,1-b] purine] -4' (5'H) -one And their use in treating cardiovascular and lung diseases, and Pharmaceutical compositions having the same. The phosphodiesterase inhibitory compound of the present invention, In PCT Publication No.WO 91/19717 published December 26, 1991, Generally disclosed. A related compound was published on September 1, 1994 by the PCT It was generally and specifically disclosed in the publication WO 94/19351. The present inventors have When administered intravenously, subcutaneously or orally, the compounds of the present invention can It was found to show unexpectedly superior plasma concentrations compared to the original compound.Summary of the Invention   The present invention relates to a 2 ′-[[4′-halo- [1,1′-biphenyl] -4-yl] methyl] -5′-methyl of formula I Le-spiro [cyclopentane-1,7 '(8'H)-[3H] imidazo- [2,1-b] purine] -4' (5'H ) -Ons: Or for a pharmaceutically acceptable salt thereof, wherein:   X is fluoro, chloro, or bromo.   The compounds of formula I are useful as antihypertensives, bronchodilators, and platelet inhibitors. You. Compounds of the invention are useful in inhibiting phosphodiesterase enzymes; Vascular phosphodiesterase inhibition is associated with vasodilation and vasorelaxation, It is expected to induce antihypertensive and antianginal activities. Also, the compound of formula I , Can be useful as a smooth muscle relaxant and is therefore useful in the treatment of bronchoconstriction. Ma In addition, such compounds inhibit smooth muscle proliferation, vascular growth, and platelet function. Disease, such as restenosis, atherosclerosis, and post-angioplasty, and Inhibition of platelet function is useful in treating diseases where beneficial. The above physiological mechanism Through one or more of the compounds of formula I, ischemic diseases and peripheral vascular disorders (peri It is also effective in the treatment of peripheral vascular disease).   Compared with known phosphodiesterase inhibitors of similar structure, the compounds of the invention It is not easily metabolized. They maintain high blood levels and have antiplatelet activity Showing sexual and vasodilatory activity and at the same time, phosphodiesterase isozyme Shows good selectivity for inhibition of group I and type V.   The invention also provides a phosphodiesterase enzyme, smooth muscle proliferation, vascular growth, or An effective amount of a compound of formula I for inhibiting platelet function or for relaxing smooth muscle. It relates to a pharmaceutical composition containing the compound. The present invention also provides anti-hypertension, anti-angina, Compositions containing an effective amount of a compound of formula I for inhibiting bronchodilation or platelets About adult.   The invention also relates to hypertension, angina, bronchoconstriction, angioplasty in mammals. Later restenosis, atherosclerosis, ischemia, peripheral vasculopathy, or platelet inhibition A method for treating a beneficial disease. This method is suitable for feeding mammals in need of such treatment. The animal is administered an effective amount of a compound of formula I for treating any of the above diseases. Step. Further, the present invention relates to a guanosine 3 ′, 5′-cyclic monophospho An effective amount of a compound of Formula I to maintain or increase glucose (cGMP) levels. Providing a method of maintaining cGMP levels in a mammal by administering the same.Detailed description of the invention   The compounds of the present invention have a moiety that contains a basic nitrogen and include organic and inorganic acids. Can be used to form pharmaceutically acceptable salts. Acids suitable for the formation of such salts Examples of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicyl Acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, methanesulfur Fonic acid, and other inorganic and carboxylic acids well known to those skilled in the art. This salt In a conventional manner, the free base form of the compound is converted to a desired amount of a salt sufficient to form a salt. Is prepared by contact with an acid.   The compounds of the present invention are of the route described in WO 91/19717 and WO 94/19351 And can be prepared by several routes. The following example is a representative procedure However, those skilled in the art will recognize that the preparation of these compounds is not limited to these procedures. You. In the following examples, Me represents methyl, Bn represents benzyl, and Ph represents phenyl. And SEM stands for trimethylsilylethoxymethyl.                                 Example 1 Step 1:   CH of 4-chlorobiphenyl (115g, 0.61mol)_TwoCl_Two(L 200 ml) A lCl_Three(97.5 g, 0.73 mol) are added in portions over 0.5 hour. Acetyl chloride (4 8 ml, 0.68 mol) were added dropwise over 0.75 h and the resulting red reaction mixture was added to 0 Stir at ５5 ° C. After 3.5 hours, the reaction mixture was warmed to 10 ° C. and then vigorously While stirring, pour onto a slurry of ice / 1M HCl (1000 ml). Let this mixture stand overnight And then wash the organic layer with saturated NaCl solution, dry (MgSO_Four), Filter, and To give a pale yellow solid. The solid is triturated with ether and collected. To give ketone 1 (122 g, 87%).¹H NMR CDCl_Threeδ8.01m, 2H; 7.62m, 2H; 7.53m, 2H ; 7.41m, 2H; 2.62s, 3H.Step 2 :  Ketone 1 (60 g, 0.26 mol), sulfur (12.5 g, 0.39 mol), and morpholine ( 38 ml, 0.43 mol) is heated under reflux. After 28 hours, the resulting brown solid was filtered with N Add aOH (240 g) in water (1200 ml) solution. Reflux the mixture for 24 hours and allow to cool And collect the precipitate, wash with water and air dry. Hot water (2000ml) And acidified to pH 2 with about 200 ml of 1M HCl. Cool this mixture, Collect the solid, wash with water and air dry. This solid was extracted with EtOAc (1000 ml) And washed with saturated NaCl solution, dried (MgSO_Four), Filter and dry. To afford acid 2 (54.9 g, 86%) as a brown solid.¹H NMR CDCl_Threeδ7 .52m, 4H; 7.40m, 4H; 3.72s, 2H.Step 3 :   Diaminouracil 3 (33.3 g, 0.21 mol), acid 2 (58.0 g, 0.24 mol) and 4- To a stirred solution of dimethylaminopyridine (2.6 g, 0.021 mol) in DMF (1000 ml) was added 1- (3 -Dimethylaminopropyl) -3-ethylcarbodiimide methiodide (76 g, 0.26 mol ). Stir at room temperature overnight, then add the reaction mixture to an ice water slurry (3000 p.m.). Collect the solid, wash with water and ethanol, and dry in vacuo. Dry to obtain amide 4 (69.9 g, 87%). This amide was used without further purification. To use.¹H NMR DMSO-d6δ 10.51s, 1H; 8.64s, 1H; 7.70-7.40m, 8H; 6.01s, 2H; 3.65s, 2H; 3.02s, 3H.Step 4 :  Amide 4 (45.0 g, 0.117 mole) POCl_Three(1500 ml) Stir the suspension at 90-95 ° C for 43 Heat at 100 ° C. for 16 hours, then at 110 ° C. for 8 hours. Steaming under reduced pressure POCl_ThreeAnd the resulting oil is cooled in an ice bath. Saturated NaHCO_Three Carefully add any residual POCl_ThreeAnd the resulting solid is collected by filtration and washed several times with water And air dried, then dried at 50 ° C. in vacuo. This solid (53g) is CH_TwoCl_Two/ CH_ThreeOH (9: 1) (1000 ml) and collected, then CH with gentle heating_ThreeOH / CH_TwoCl_Two Further crush with (1: 1). The filtrate is concentrated in vacuo and chromatographed as a brown solid. Lopulin 5 (25.6 g) is obtained. CH_TwoCl_Two/ CH_ThreeConcentrate the filtrate from the OH (9: 1) trituration in vacuo Shrink, and the smallest capacity CH_TwoCl_Two/ CH_ThreeAbsorb OH (about 4: 1). The solid begins to separate Hexane is added to the resulting solution until complete. Collect the brown solid, CH_TwoCl_TwoCleaning with To give additional chloropurine 5 (6.0 g). This chloropurine (dried in vacuum The subsequent total yield of 31.0 g, 69%) is used in the next step without further purification.¹H NM R CDCl_Threeδ 7.53-7.46m, 4H; 7.41-7.37m, 4H; 4.31s, 2H; 3.75s, 3H.Step 5 :   Chloropurine 5 (11.7 g, 0.030 mole), 1-amino-1-cyclopentanemethanol (7.1 g, 0.06 mole) and N, N-diisopropylethylamine (13.2 ml, 0.076 m ole) in NMP (25 ml) is heated at 120 ° C. in argon gas for 30 hours. This anti The reaction mixture is cooled and then poured into a stirred ice / water slurry (1000 ml). Times the sediment Collect, wash with water, air dry, and dry at 50 ° C. in vacuo. The solid (13.3g ), Warm CH_TwoCl_Two/ CH_ThreeTriturate with OH (1: 1) then filter. The filtrate is silica gel (75 g) and flash chromatography (CH_TwoCl_Two/ CH_ThreeOH (24: 1), Then when the product began to elute CH_TwoCl_Two/ CH_ThreeOH (19: 1)) Alcohol 6 (7.5 g, 53%) is obtained as a body. C_{twenty five}H₂₆N_FiveO_TwoCl ・ 0.75H_TwoO Theoretical value: C , 62.11; H, 5.73; N, 14.49. Found: C, 62.38; H, 5.59; N, 14.30%. MS (FAB) m / z 466.1. , 464.1 (M + H)⁺.Step 6 :   CH of alcohol 6 (12.1 g, 0.026 mol)_TwoCl_Two(750ml) Stir the suspension with SOCl_Two(5.7 ml, 0.078 mol) is quickly added dropwise. The reaction mixture is stirred well for 3 hours and then And evaporate under vacuum. CH the residue_ThreeDissolve in OH (100 ml), filter and Filtrate 10% NaHCO_ThreePour into rapidly stirring solution. Collect the precipitate, water (1000 ml) and CH_Three Wash with OH (150 ml) and then dry. CH_ThreeOH / CH_TwoCl_TwoRecrystallized from gray-white To give the product 7 as a powder (10.30 g, 88%). C_{twenty five}H_{twenty four}N_FiveOCl theoretical: C, 67.33; H , 5.42; N, 15.70; Cl, 7.95 Found: C, 67.41; H, 5.66; N, 15.41; Cl, 8.24%. MS (FAB) m / z448.3,446.3 (M + H)⁺.Step 7 :   Tetracyclic guanine 7 heated in a steam bath (10.30 g, 0.023 mol To a suspension of) in EtOH (125 ml) is added concentrated HCl (1.9 ml, 0.023 mol). Turbidity The mixture obtained is filtered and the filter pad is washed with warm EtOH (75 ml). Filtration Hot water (100 ml) is added to the combined solution and washing solution, and the solution is allowed to stand. Recover the crystalline mass and add EtOH / H_TwoWash with O (1: 1), air dry and in vacuo at 50 ° C. To give hydrochloride 8 (7.0 g, 63%). Secondary recovery of product 8 (second c rop) (3.0 g, 27%) is obtained from the mother liquor. Combine the two harvests and in vacuo, 5 P at 0 ° C_TwoO_FiveDry with. C_{twenty five}H_{twenty five}N_FiveOCl_Two・ 1.75H_TwoO Theoretical: C, 58.43; H, 5.59; N, 13.63 Cl, 13.80 Found: C, 58.45; H, 5.24; N, 13.45; Cl, 13.70%.¹H NMR CD_ThreeODδ7.58-7 .56m, 4H; 7.43-7.37m, 4H; 4.38s, 2H; 4.19s, 2H; 3.46s, 3H; 2.10-1.79m, 8H.                                 Example 2 Step 1:   Using the procedure of Step 1 of Example 1, bromobiphenyl (51.36 g, 0.22 mol) was added. To give ketone 9 (50.94 g, 84%) as a light yellow solid.¹H NMR CDC l_Threeδ 8.03dd (J = 6.6 and 2.2Hz), 2H; 7.65dd (J = 6.6 and 2.2Hz), 2H; 7.55dd ( J = 6.6 and 2.2 Hz), 2H; 7.49dd (J = 6.6 and 2.2 Hz), 2H; 2.64s, 3H.Step 2 :   Heat with sulfur and morpholine for 4 hours using the procedure of Step 2 of Example 1 Then, ketone 9 (50.93 g, 0.19 mol) was converted to acid 10 (51.3 g, 95%) as a white solid. Invert.¹1 H NMR DMSO-d6δ7.65-7.59, m, 6H; 7.35d (J = 8.2Hz), 2H; 3.60s, 2H.Step 3 :  Treat acid 10 (51.3 g, 0.18 mol) using the procedure of Step 3 of Example 1 to give a yellow This gives amide 12 (61.2 g, 82%) as a solid.¹H NMR DMSO-d6δ 10.52s, 1H; 8.6 6s, 1H; 7.66-7.59m, 6H; 7.43d (J = 8.2Hz), 2H; 6.01s, 2H; 3.61s, 2H; 3.04s, 3H.Step 4 :   Amide 12 (40.0 g, 0.093 mole) POCl_Three(2100 ml) stirred suspension at 90-100 ° C Heat for 6 days. POCl by rotovaporation under reduced pressure (below 45 ° C)_Three And remove the resulting oil with a minimum amount of CH_TwoCl_Two(~ 400ml). This CH_TwoCl_TwoThe solution was washed with cold saturated NaHCO_Three(2200ml) carefully for one hour More residual POCl_ThreeNeutralize. The mixture was stirred overnight at room temperature and formed by filtration. The solid collected is collected, washed several times with water, air-dried and dried at 60 ° C. under vacuum. This (28.47 g, 71%) of chloropurine 13 and xanthine 14 : 1 mixture (¹1 H NMR analysis).¹H NMR CDCl_Threeδ7.64-7.58m, 6H; 7.38d (J = 8.2 Hz), 2H; 4.13s, 2H; 3.61s, 3H.Step 5 :  Chloropurine 13 (28.57 g, 0.066 mole), 1-amino-1-cyclopentanemethanol (19.77 g, 0.17 mole) and N, N-diisopropylethylamine (30 ml, 0.17 mole) le) A suspension of NMP (96 ml) is heated at 120 ° C. in argon for 18 hours. This reaction mixture The mixture is cooled then poured onto a stirred ice / brine slurry (1000 ml). Settling Collect, wash with water, air dry, and dry at 50 ° C. in vacuo. This solid ( 42.36g) CH_TwoCl_Two-CH_ThreeTriturate with OH (4: 1), then filter to give alcohol 15 and 17.48 g of a solid consisting of xanthine 14 are obtained. The filtrate is adsorbed on silica gel. And flash chromatography [Gradient CH_TwoCl_Two/ CH_ThreeOH = 32: 1-19 : 1 (product starts eluting) ~ 11.5: 1] and alcohol 1 as off-white solid 5 (7.4 g, 22%) is obtained, and impurity 15 containing xanthine 14 (5.79 g) is obtained.¹H NMR  CDCl_Threeδ7.64-7.58m, 6H; 7.37m, 2H: 5.76-5.63m, 1H; 5.09,4.89t, t (J = 5.8Hz), 1H; 4. 02,3.97s, s, 2H; 3.64d (J = 5.8Hz), 2H; 3.36s, 3H; 2.05m, 2H; 1.72m, 4H; 1.53m, 2H.Step 6 :   Treat alcohol 15 (10.1 g, 0.020 mol) according to the procedure of Step 6 of Example 1. To give tetracyclic guanine 16 (9.6 g, 95%) as a white solid.¹H N MR DMSO-d6δ7.65-7.58, m, 6H; 7.37, d (J = 8.2Hz), 2H; 4.02s, 2H; 4.80s, 2H; 3.18s, 3H; 1.75-1.62m, 8H.Step 7 :  CH_ThreeExample 1 except for recrystallization twice from OH and then twice from ethanol-water Amine 16 (11.7 g, 0.024 mol) was treated using a procedure similar to Step 7 of The hydrochloride salt 17 (10.22 g, 81%) is obtained as a colored solid. C_{twenty five}H_{twenty five}N_FiveOBrCl ・ 3H_TwoO theoretical value: C, 51.69; H, 5.39; N, 12.06; Br, 13.75; Cl, 6.10 Found: C, 51.58; H, 5.63; N, 11.84; Br , 13.55; Cl, 5.77%. MS (FAB) m / z 490.1, 491.1 (M + H).¹H NMR DMSO-d6 + D_TwoOδ7 .63-7.56, m, 6H; 7.37, d (J = 8.2Hz), 2H; 4.28s, 2H; 4.12s, 2H; 3.31s, 3H; 1.98-1.87m , 4H; 1.79-1.61m, 4H.                                 Example 3 Step 1:   Pd (OH)_Two(5g) CH_ThreeHNH to OH suspension_FourCO_Two(14 g, 223 mmol) and then 5'- Methyl-3 '-(phenylmethyl) -spiro [cyclopentane-1,7' (8'H)-[3'H] -i Midazo [2,1-b] purine] -4 ′ (5′H) -one (15 g, 44.7 mmol) CH_ThreeOH solution at room temperature Add (total volume 1000 ml). The mixture was heated at reflux for 6 hours, filtered and the Concentrate the liquid to give a white solid. This catalyst is heated to 10% CH_ThreeOH / CH_TwoCl_TwoStir in Filter and concentrate. Combine the concentrated filtrates and add 10-% CH_ThreeOH / CH_TwoCl_Two(400ml) Dissolved in NaHCO_ThreeWash with water. This aqueous solution is_ThreeOH / CH_TwoCl_Two(200m 1 × 2) and extract the combined extracts with MgSO_Four, Filtered, and concentrated, Compound 18 (9.7 g, 88.5%) is obtained as a white solid.¹H NMR CDCl_Threeδ7.62, s, 1H; 3.95, s, 2H; 3.40, s, 3H; 1.8-2.0, m, br, 4H; 1.6-1.8, m, br, 4H.Step 2 :   At room temperature NaH (3.16 g, 60%, 79 mmol) was added to 18 (9.7 g, 39.5 mmol) in THF (400 ml). Add to the mixture. Stir at room temperature for 1.5 hours, and trimethylsilylethoxymethyl chloride A ride (9.88 g, 59.25 mmol) is added and stirred at room temperature for 1.5 hours. The resulting yellow The color mixture is quenched with ice, extracted with EtOAc (200 ml × 2), and the combined EtOAc extracts are combined. And washed with brine, MgSO_Four, Filter, and concentrate. This crude The product is SiO_TwoFlash chromatography (1% to 10% CH)_ThreeOH / CH_TwoCl_Two) Compound 19 (11.4 g), 20 (2.37 g), and a mixture of 19 and 20 (1.1 g) (98%). 19 of¹H NMR CDCl_Threeδ7.61, s, 1H; 5.65, s, 2H; 3.91, s, 2H; 3.62, t, 2 H; 3.38, s, 3H; 1.8-2.0, m, 4H; 1.6-1.8, m, 4H; 0.95, t, 3H; 0.00, s, 9H. 20 of¹H NMR CD Cl_Threeδ7.26, s, 1H; 5.32, s, 2H; 4.00, s, 2H; 3.53, t, 2H; 3.40, s, 3H; 1.8-2.0, m, 4H; 1.6- 1.8, br, 4H; 0.92, t, 2H; 0.00, s, 9H.Step 3 :   Pd (PPh_Three)_Four(1.5 g, 1.3 mmol) in toluene (52 ml) mixture, p-bromobenz Aldehyde (4.8 g, 25.98 mmol), Na_TwoCO_ThreeWater (26 ml, 2.0 M, 52 mmol), and p -Fluorophenylboronic acid (4 g, 28.58 mmol) in EtOH (13 ml) and CH_ThreeOH (2 ml) Add the solution. The mixture was heated at reflux for 6 hours, cooled to room temperature and NaHCO_Three Poured into water, extracted with EtOAc (200 ml × 3),_Four, Filter, and concentrate To obtain a darkened thick oil. This crude product is converted to SiO_TwoFlash column Purify by chromatography (1: 9, 1: 7 EtOAc / hexane) to give compound 21 (4 .88 g, 93.8%).¹H NMR CDCl_Threeδ10.06, s, 1H; 7.96, d, 2H; 7.72, d, 2H; 7.62, dd, 2H; 7.18, t, 2H.Step 4 :   n-BuLi (6.65 ml, 2.5 M, 16.62 mmol) was added to diisopropylamine (1.68 g, 16.6 g). (2 mmol) in THF (30 ml) at 0 ° C. Stir at 0 ° C for 1 hour and cool to -70 ° C Cool and add dropwise a solution of compound 19 (4.8 g, 12.78 mmol) in THF (60 ml). this After the addition is complete, the mixture is stirred at -70 ° C for 1 hour and then pre-cooled A solution of 21 (3.85 g, 19.17 mmol) in THF (15 ml) is added. At 70 ° C Stir for 3 h, quench with AcOH (4 mL), warm to 0 ° C. and_FourCl water (30m Process in l). The mixture was extracted with EtOAc (200 ml × 3), NaHCO 3_ThreeWater and water Wash with line, dry (MgSO 4_Four) And concentrate. This crude product is converted to SiO_TwoNo Rush column chromatography (0% to 2% CH_ThreeOH / EtOAc) Compound 22 (5.34 g, 72.6%) is obtained.¹H NMR CDCl_Threeδ7.55, m, 4H; 7.54,2H; 7.15, t, 2H; 6.05, d, br, 1H; 5.56, ABq, 2H; 3.97, s, 2H; 3.60, t, 2H; 3.38, s, 3H; 1.8-2.0, m, 4H; 1 .6-1.8, m, 4H; 0.90, m, 2H; 0.00, s, 9H.Step 5 :  EtSiH (5.34 g, 45.4 mmol) was added to a solution of 22 (5.23 g, 9.08 mmol) in TFA (24 ml). Add warm. The reaction mixture was stirred at room temperature overnight and NaHCO_ThreeCarefully neutralize with water, 10% CH_ThreeOH / CH_TwoCl_TwoExtracted with MgSO_Four, Filter, and concentrate. This coarse The product is SiO_TwoColumn chromatography (3% to 10% CH)_ThreeOH / CH_TwoCl_Two ) To give compound 24 (3.35 g).¹H NMR CDCl_Threeδ7.51, m, 4H; 7.49, d , 2H; 7.11, t, 2H; 4.18, s, 2H; 3.92, s, 2H; 3.39, s, 3H; 1.8-2.0, m, 4H: 1.6-1.8, m, 4H.Step 6 :   Using compound 20 (8 g, 21.7 mmol) in the procedure of step 4 of example 3, compound 23 (4.6 g, 37%).¹H NMR CDCl_Threeδ7.50, m, 6H; 7.10, t, 2H; 6.18, s, 1H; 5. 21, s, 2H; 3.99, ABq, 2H; 3.39, s, 3H; 3.10, m, 2H; 1.8-2.0, m, 4H; 1.6-1.8, m, 4H; 0.65, t , 2H; -0.10, s, 9H.Step 7 :   Compound 23 is treated according to the procedure of Step 5 of Example 3 to give compound 24.¹H N MR CDCl_Threeδ7.51, m, 4H; 7.49, d, 2H; 7.11, t, 2H; 4.18, s, 2H; 3.92, s, 2H; 3.39, s, 3H; 1. 8-2.0, m, 4H; 1.6-1.8, m, 4H.Step 8 :   Concentrated HCl (5.1 ml, 61.2 mmol) was added dropwise to a hot EtOH suspension of 24 (17.5 g, 40.74 mmol). To obtain a clear solution. The solution was stirred at room temperature for 30 minutes and the EtOH was evaporated to give a white A solid is obtained, which solid is dried in vacuo at 50 ° C._TwoO_FiveDry with. C_{twenty five}H_{twenty four}N_FiveOF.1.05HCl.0 .75H_TwoO Theory: C, 62.39; H, 5.56; N, 14.55; Cl, 7.73, F, 3.95 Found: C, 62.44; H, 5.71 ; N, 14.38; Cl, 7.80; F, 4.00%.¹H NMR DMSO-d6δ 10.65, d, br, 1H; 7.7, m, 2H; 7.65, d , 2H; 7.40, d, 2H; 7.26, t, 2H; 4.32s, 2H; 4.19s, 2H; 3.39s, 3H; 1.6-2.1m, 8H.Pharmaceutical preparation   The compound of formula I can be combined with a suitable pharmaceutical carrier and administered parenterally or orally. A pharmaceutical composition suitable for administration is prepared. Such pharmaceutical compositions may be of mammalian type. Useful for the treatment of cardiovascular and pulmonary diseases such as hypertension and bronchoconstriction You.   The effective daily dose (ED₅₀) Is typically 1 It is in the range of about 1 to about 100 mg per kg and is administered in single or divided doses. The exact dose to be administered can be determined by your clinician and It will depend on the particular compound falling within the range, as well as the age, weight and condition of the individual.   In general, for the treatment of people who need treatment for hypertension or bronchoconstriction Wherein the compound is administered daily at a dosage ranging from about 10 to about 500 mg per patient. It can be administered many times, providing a total daily dosage of about 10 to about 2000 mg per day.   The composition of the present invention can be administered orally or parenterally. Typical injectable Suitable formulations include solutions and suspensions. Typical oral formulations include tablets , Capsules, syrups, suspensions and elixirs. Also mechanical Various delivery systems (eg, transdermal dosage forms) are also contemplated.   Representative pharmaceutically acceptable carriers for use in the above formulations Is a sugar (eg, lactose, sucrose, mannitol and sorbitol) , Starch (eg, corn starch, tapioca starch and potatoes) Cellulose and derivatives (eg, carboxymethylcellulose) Sodium, sodium ethylcellulose and sodium methylcellulose) Calcium phosphates (eg, dicalcium phosphate and tricalcium phosphate); Sodium sulfate; calcium sulfate; polyvinylpyrrolidone, polyvinyla Alcohol; stearic acid; stearates of alkaline earth metals (eg, stearic acid) Magnesium phosphate and calcium stearate), stearic acid, vegetable oils ( For example, peanut oil, cottonseed oil, sesame oil, olive oil and corn oil); On, cationic and anionic surfactants; ethylene glycol polymers; β-cyclodextrin; hydrolyzed solids of fatty alcohols and grains (hydrol yzed cereal solids); and other non-toxic and compatible excipients, binders, Breakers, buffers, preservatives, antioxidants, lubricants, flavoring agents, and Illustrated by analogs commonly used in pharmaceutical formulations.   The following are representative examples of oral and parenteral formulations. Here, the term “Yes "Active ingredient" refers to a compound of Formula I.               capsule Amount (mg)               Active ingredient 250.0 125.0               Lactose 173.0 86.5               Corn starch 75.0 37.5               Magnesium stearate 2.0 1.0               Total amount 500.0 250.0   Formulate this active ingredient, lactose and corn starch until uniform Then the resulting powder is formulated with magnesium stearate. This mixture In a hard two-piece gelatin capsule of appropriate size.       tablet Amount (mg)       Active ingredient 250.0 125.0       Lactose 161.0 80.5       Corn starch 12.0 6.0       Water (per 1000 tablets) 120ml 60ml                                       (Evaporated) (evaporated)       Corn starch 75.0 37.5       Magnesium stearate 2.0 1.0       Total amount 500.0 250.0   This active ingredient is compounded with lactose until uniform. Smaller amount of corn Mix the corn starch with water, add the resulting corn starch paste, Then mix until a uniform wet mass is formed. The remaining corn starch Add to the wet mass and mix until uniform granules are obtained. 3/4 inch stainless steel The granules are sieved through a suitable milling machine using a stainless steel sieve. The milled granules are placed in a suitable drying oven until the desired moisture content is obtained. dry. Dry the granules using a 16 mesh stainless steel sieve. Mill through a milling machine. Mix magnesium stearate and mix The compound is compressed into tablets of desired shape, thickness, hardness and disintegration.       Injectable solution mg / ml       Active ingredient 5.00       Methyl parahydroxybenzoate 0.80       Propyl parahydroxybenzoate 0.10       Disodium edetate 0.10       Citric acid monohydrate 0.08       Dextrose 40.0       Water for injection (qs.ad.) 1.0ml   At a temperature between 60 ° C and 70 ° C, these p-hydroxybenzoic acids are converted into a portion of the water for injection. And cool the solution to 20-30 ° C. All other excipients and The active ingredient is charged and dissolved. Bring this solution to final volume and pass through sterile membrane. And filtered and filled into sterile containers.2 '-[[4'- Halo- [1,1'-biphenyl] -4-yl] methyl] -5'-methyl-spiro [cyclope Biology of tan-1,7 '(8'H)-[3H] imidazo [2,1-b] purine] -4'(5'H) -ones Activity   The compound is a phosphodiesterase enzyme (particularly a phosphodiesterase isozyme) It is useful for inhibiting type I and type V) of the These phosphodiesters Lase enzymes are known to hydrolyze cGMP in smooth muscle. High level CGMP is involved in the relaxation of vascular smooth muscle, with a consequent decrease in blood pressure. Follow Therefore, inhibition of these phosphodiesterase enzymes maintains cGMP levels in muscle. Is either retained or increased, with a subsequent decrease in blood pressure Can be considered. In vivo antihypertensive activity in spontaneously hypertensive rats (SHR) Orally measuredIn vitro phosphodiesterase inhibition   Hydrolyzes compounds to cyclic guanosine monophosphate (cGMP) Evaluate for inhibition of two phosphodiesterase enzymes. The first enzyme, calci Um-calmodulin-dependent phosphodiesterase (CaM-PDE) DEAE-cellulose and calmodulin-affinity Partially pure enzyme purified by tea chromatography. This yeast Is activated several times by Ca-calmodulin and is selective for cGMP However, cAMP also hydrolyzes. A second enzyme, cGMP phosphodiesterase (cGMP -PDE) is obtained from bovine lung and is subjected to ion exchange chromatography, gel filtration, And a homogeneous enzyme purified by sucrose gradient centrifugation. cGMP-PDE, cGMP High selectivity for Bovine aortic homogenate and bovine aortic endothelium Primary cultures of cells and vascular smooth muscle have properties very similar to lung isozymes. Including enzymes.   This enzyme assay is performed using the Biomek Automated Pipetting Station. You. Compounds are dissolved in distilled water or DMSO and diluted with 10% DMSO. Compound With several concentrations at logarithmic intervals (typically 0.1, 1.0, 10 and 100 μM final concentrations) ).           The assay contains the following components:                 1 μM substrate^ThreeH-cGMP                 50 mM Tris-HCl (pH 7.5), 5 mM MgCl_Two                 0.5mg / ml snake venom alkaline phosphatase                 0.1 μM calmodulin and 1 mM CaCl_Two(Only for CaM-PDE)   The assay is started by the addition of the enzyme and 10 mM isobutylmethylxanthine (one The addition is stopped by the addition of a general phosphodiesterase inhibitor). Assay takes 25 minutes The reaction is carried out at room temperature for between 5 and 10% of the hydrolysis of the substrate is achieved. Then negatively charged Substrate is bound to an anion exchange resin (AG1-X8) and centrifuged or filtered. Guanosine. The product is then converted to the remaining soluble By counting the counts per minute (cpm) by scintillation Weigh. The percent inhibition is calculated as follows:   % Inhibition = 100-[(compound-blank cpm) / (control-blank cpm) x 100] Activity is IC₅₀Value (ie, the concentration required to inhibit enzyme activity by 50 percent) Degree).Antihypertensive activity in rats   The ability of the compounds of the present invention to lower blood pressure was demonstrated in conscious, spontaneously hypertensive rats (SH R) can be evaluated in vivo. Male of SHR is Taconic Farms, Germantown New  About 16-18 weeks old when purchased from York and anesthetized with ether. Baum, T et al J Cardiovasc. Pharmacol. 5, 655-667, (1983) Cannulate the caudal (ventral tail) artery using a polyethylene tube (PE50) Record blood pressure and heart rate. Rat in plastic cylinder cage Place and let the rat immediately regain consciousness. About 90 minutes before compound administration Leave to stabilize blood pressure and heart rate. The compound is fed into a feeding needle. le) via an aqueous solution or suspension of a 0.4% water-soluble methylcellulose vehicle Oral administration. Add this compound or 0.4% water-soluble methylcellulose vehicle Feed overnight fasted SHR at 4 ml / kg. Activity is measured in millimeters of mercury (mm  Hg), expressed as a decrease in mean blood pressure (MBP). Changes caused by compounds Is compared to the change in the appropriate placebo group.Plasma concentration :   The test compound is administered orally to the SHR at 10 mpk, followed by 0.5, 1, 2, 3 and And plasma concentrations were measured at 4 hour intervals. The plasma concentration (μ g / ml) and the area under the curve (AUC, μghr / ml) was calculated.   The results of the following test show that the known compound, 2 '-[[(4'-methoxy-1,1'-biphenyl Nyl) -4-yl] methyl] -5'-methyl-spiro [cyclopentane-1,7 '(8'H)-[3H] i Compared to midazo- [2,1-b] purine] -4 ′ (5′H) -one (reference compound).                                   Activity

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 7/02 A61K 31/00 607A 11/08 611D 43/00 643D A61K 31/522 31/52 601 (81 ) Designated country EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG) , CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, LS, MW, SD, SZ, UG), UA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AU, AZ, BA, BB, BG, BR, BY, CA, CN, CZ, EE, GE, HU, IL, IS JP, KG, KR, KZ, LC, LK, LR, LT, LV, MD, MG, MK, MN, MX, NO, NZ, PL, RO, RU, SG, SI, SK, TJ, TM, TR , TT, UA, UZ, VN (54) [Title of the Invention] 2 '-[[4'-Halo- [1,1'-biphenyl] -4-yl] methyl] -5'-methyl-spiro [ Cyclopentane-1,7 '(8'H)-[3H] imidazo [2,1-b] purine] -4'(5'H) -ones

Claims (1)

[Claims] 1. A compound having the formula: or a pharmaceutically acceptable salt thereof: Here, X is chloro, fluoro or bromo. 2. 2. A compound according to claim 1 selected from: 2 '-[[4'-fluoro- [1,1'-biphenyl] -4-yl] methyl] -5'-methyl-spiro [cyclopentane-1. , 7 '(8'H)-[3H] imidazo [2,1-b] purine] -4'(5'H)-one; 2 '-[[4'-chloro- [1,1'-biphenyl ] -4-yl] methyl] -5'-methyl-spiro [cyclopentane-1,7 '(8'H)-[3H] imidazo [2,1-b] purine] -4'(5'H)-One; and 2 '-[[4'-bromo- [1,1'-biphenyl] -4-yl] methyl] -5'-methyl-spiro [cyclopentane-1,7'(8'H)- [3H] imidazo [2,1-b] purine] -4 '(5'H) -one. 3. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 or 2 in a pharmaceutically acceptable carrier. 4. 4. A method for preparing a pharmaceutical composition according to claim 3, comprising mixing the compound according to claim 1 or 2 with a pharmaceutically acceptable carrier. 5. Drugs to treat hypertension, angina, bronchoconstriction, restenosis after angioplasty, atherosclerosis, ischemia, peripheral vascular disorders, or diseases where platelet inhibition is beneficial, or guanosine 3 ', 5 Use of a compound according to claim 1 or claim 2 for preparing a medicament that maintains' -cyclic monophosphate (cGMP) levels. 6. How to treat hypertension, angina, bronchoconstriction, restenosis after angioplasty, atherosclerosis, ischemia, peripheral vascular disorders, or diseases where platelet inhibition is beneficial or guanosine 3 ', 5'- A method of maintaining cyclic monophosphate (cGMP) levels, comprising administering an effective amount of a compound of claim 1 or claim 2 to a mammal in need of such treatment. Method.