Patent Application
20050130983
1. Field of the Invention
The invention relates to a series of pyrrolopyrimidinone derivatives of the formula (1), processes for their preparation, intermediates in their preparation, their use as therapeutic agents, and pharmaceutical compositions containing them,
wherein
2. Description of the Prior Art
European patent applications EP-A-0463756 and EP-A-0526004 disclose certain pyrazolo[4,3-d]pyrimidin-7-ones as cGMP PDE inhibitors, useful in the treatment of cardiovascular disorders such as angina, hypertension and heart failure. International application WO 94/28902 discloses their use for the treatment of impotence.
The present inventors have recently disclosed a series of pyrazolo[4,3-d]pyrimidin-7-one derivatives (Appln. No. KR 98-60436 and KR 99-7580) and a series of pyrrolo[3,2-d]pyrimidin-4-one derivatives (PCT Appln. No. KR01/00227) as PDE V inhibitors. Herein a new series of pyrrolo[3,2-d]pyrimidin-4-one derivatives are prepared as PDE V inhibitors. However, none of the compounds of this invention are specifically disclosed.
The compounds (1) of this invention are potent and selective inhibitors of cyclic guanosine 3′,5′-monophosphate specific phosphodiesterase (cGMP specific PDE; PDE V) having utility in a variety of therapeutic areas where such inhibition is thought to be beneficial, including the treatment of impotence (male erectile dysfunction), sexual dysfunction in female, and various cardiovascular disorders such as angina, hypertension, heart failure and atherosclerosis.
As a consequence of the selective PDE V inhibition exhibited by compounds of this invention, cGMP levels are elevated, which in turn can give rise to beneficial vasodilatory, anti-vasospastic, anti-platelet, anti-neutrophil, natriuretic and diuretic activities as well as potentiation of the effects of endothelium-derived relaxing factor (EDRF), nitrovasodilators, atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP) and endothelium-dependent relaxing agents such as bradykinin, acetylcholine and 5-HT1.
The compounds of this invention therefore have utility in the treatment of a number of disorders, including impotence, sexual dysfunction in female, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, conditions of reduced blood vessel patency (e.g. post-percutaneous transluminal coronary angioplasty), peripheral vascular disease, vascular disorders such as Raynaud's disease, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma and diseases characterized by disorders of gut motility (e.g. irritable bowel syndrome).
Thus, according to a first aspect, this invention provides compounds of the formula (1) and pharmaceutically acceptable salts and solvates (e.g. hydrates) thereof,
wherein R1, R2, R3, R4, W, n and R5 are as previously defined.
Throughout this specification, the term aromatic heterocyclic group means a 5-6 membered aromatic ring containing one or more atoms selected from oxygen, sulfur and nitrogen atoms on the ring, said ring being optionally condensed with a carbon ring or other heterocyclic ring.
Examples include pyrrole, indole, carbazole, imidazole, pyrazole, benzimidazole, pyridine, naphthyridine, furopyridine, thienopyridine, pyrrolopyridine, oxazolopyridine, imidazolopyridine, thiazolopyridine, quinoline, isoquinoline, acridine, phenanthridine, pyridazine, pyrimidine, pyrazine, cinnoline, phthaladine, quinazoline, naphthylidine, quinoxaline, isoxazole, benzisoxazole, oxazole, benzoxazole, benzoxadiazole, isothiazole, benzisothiazole, thiazole, benzthiazole, benzthiadiazole, furan, benzofuran, thiophen, benzothiophen and the like.
As used herein, “1 to 4 carbons” means a carbon number per a single substituent; for example, for dialkyl substitution it means 2 to 8 carbons.
A halogen may be fluorine, chlorine, bromine or iodine.
A C1-C4 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
A C1-C4 alkoxy includes methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
A C1-C4 aminoalkyl includes aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl and the like.
A C1-C4 alkylamino includes N-methylamino, N,N-dimethylamino, N,N-diethylamino, N-methyl-N-ethylamino, N,N-diisopropylamino and the like.
A C1-C4 acyl includes acetyl, propanoyl, butanoyl and the like.
A C1-C4 acylamino includes acetylamino, propanoylamino, butanoylamino and the like.
A C1-C4 alkylthio includes methylthio, ethylthio, n-propylthio and the like.
A C1-C4 perfluoroalkyl includes trifluoromethyl, pentafluoroethyl and the like.
A C1-C4 perfluoroalkoxy includes trifluoromethoxy, pentafluoroethoxy and the like.
A C1-C4 alkoxycarbonyl includes methoxycarbonyl, ethoxycarbonyl and the like.
Compounds of the formula (1) may contain one or more asymmetric centers and thus can exist as enantiomers or diastereomers. It is to be understood that the invention includes both mixtures and separate individual isomers of compounds of the formula (1). Furthermore certain compounds of the formula (1) which contain alkenyl groups may exist as cis- or trans-isomers. In each instance, the invention includes both mixtures and separate individual isomers.
Compounds of the formula (1) may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers thereof.
Also included in the invention are radiolabelled derivatives of compounds of formula (1) which are suitable for biological studies.
Compounds of the formula (1) wherein one or more basic nitrogen atoms are present may form pharmaceutically acceptable salts with acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, citric, fumaric, lactic, maleic, succinic and tartaric acids.
Compounds of the formula (1) may form pharmaceutically acceptable salts with metal ions, such as alkali metals for example sodium and potassium, or with an ammonium ion.
A preferred group of compounds of the formula (1) is that wherein
A particularly preferred group of compounds of the formula (1) is that wherein
Especially preferred individual compounds of the invention include:
In another aspect, this invention provides processes for the preparation of compounds of the formula (1) or pharmaceutically acceptable salts thereof.
Compounds of the general formula (1) may be prepared by the reaction of compounds of the general formula (2) which are disclosed in the PCT application (KR01/00227):
(wherein R1, R2, R3 and R4 are as previously defined in the general formula (1), and X represents a halogen atom, preferably a chlorine atom) with a compound of the general formula (3):
wherein W, n and R5 are as previously defined in the general formula (1). The coupling reaction is generally carried out at from 0° C. to room temperature for 1-24 hours in a suitable solvent such as a C1-C3 alkanol, dichloromethane, N,N-dimethylformamide (DMF) or water using an excess amount of (3) or in the presence of an organic tertiary amine such as triethylamine to scavenge the acid by-product.
Compounds of the general formula (1) may be also prepared by the esterification reaction of compounds of the general formula (4) which are disclosed in the PCT application (KR01/00227):
(wherein R1, R2, R3, R4, W and n are as previously defined in the general formula (1)) with a compound of the general formula (5), (6) or (7):
wherein R6 is as previously defined, and Y represents a hydroxyl group or a halogen atom, preferably a chlorine atom. Z in the general formula (7) represents a halogen atom or a phenoxy group optionally substituted with one or more NO2 groups. The reaction of (4) with (5), (6) (wherein Y represents a halogen atom) or (7) is generally carried out at from 0° C. to room temperature for 1-24 hours in a suitable solvent such as dichloromethane or DMF in the presence of an organic tertiary amine such as triethylamine to scavenge the acid by-product, optionally in the presence of a catalyst such as 4-dimethylaminopyridine (DMAP). For convenience, pyridine may be also used as a solvent. Alternatively, compounds of the general formula (1) may be obtained by the treatment of (4) with (6) (wherein Y represents a hydroxyl group) using an appropriate coupling reagent such as 1,3-dicyclohexylcarbodiimide (DCC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) in the presence of an excess of 1-hydroxybenzotriazole, optionally in the presence of a catalyst such as DMAP in an inert solvent such as dichloromethane or DMF at from 0° C. to room temperature for 1-24 hours.
Compounds of the general formula (4) may be prepared from compounds of the general formula (8):
wherein R1, R2, R3, R4, W and n are as previously defined in the general formula (1). The cyclization reaction is generally carried out by heating at an elevated temperature, for example 50-150° C., in the presence of an acid or a base in a suitable solvent such as an aqueous C1-C4 alkanol, water, a halogenated hydrocarbon or acetonitrile. Thus, for example, the cyclization may be affected by treatment of a compound of the formula (8) with a base such as sodium hydroxide, potassium carbonate or potassium tert-butoxide in an aqueous alcoholic medium.
Compounds of the general formula (8) may be prepared from compounds of the general formula (9) and (10):
wherein R1, R2, R3, R4, W and n are as previously defined in the general formula (1), and R8 is H or C1-C4 alkyl. The reaction is generally carried out by first converting a carboxylic acid ester of the formula (9) to the corresponding carboxylic acid using an excess amount of a well-known reagent in the literature, preferably lithium hydroxide or sodium hydroxide, in a solvent such as tetrahydrofuran-water or ethanol-water at room temperature to reflux temperature. The following coupling reaction of (9) (wherein R8 is H) with a compound of the formula (10) is generally effected by using an excess amount of a well-known reagent in the literature, preferably DCC or EDC, in the presence of an excess amount of 1-hydroxybenzotriazole, optionally in the presence of a catalyst such as DMAP in an inert solvent such as dichloromethane or DMF, at from 0° C. to room temperature for 1-24 hours. For convenience, pyridine may be also used as a solvent.
Compounds of the general formula (9) may be prepared from compounds of the general formula (11):
wherein R8, W and n are as previously defined in the general formula (9). The O-alkylation may be effected under a standard condition using an appropriate alkyl halide in the presence of a base such as potassium carbonate in a suitable solvent such as DMF at room temperature to 100° C. for 1-24 hours.
Compounds of the general formula (11) may be prepared by the reaction of compounds of the general formula (12) with a compound of the general formula (13):
wherein R8 and X are as previously defined in the general formulas (9) and (2),
wherein W and n are as previously defined. The coupling reaction is generally carried out at from 0° C. to room temperature for 1-24 hours in a suitable solvent such as a C1-C3 alkanol, dichloromethane, DMF or water using an excess amount of (13) or in the presence of an organic tertiary amine such as triethylamine or an inorganic base such as potassium carbonate, to scavenge the acid by-product.
Compounds of the general formula (12) may be prepared from compounds of the general formula (14):
(wherein R8 is as previously defined) by using a known method for the introduction of a sulfonyl halide group into an aromatic ring, for example, when halide represents a chlorine atom, by the reaction of chlorosulfonic acid at 0° C. to room temperature for 1-24 hours with or without thionyl chloride.
Compounds of formulas (3), (5), (6), (7), (10), (13) and (14), when not commercially available, can be obtained by conventional procedures, in accordance with literature precedent, from readily accessible starting materials using standard reagents and conditions.
The resulting compounds of this invention represented by the formulas (1)-(4) and (8)-(12) can be separated and purified by appropriate conventional methods such as column chromatography and recrystallization.
The pharmaceutically acceptable acid addition salts of compounds of the general formula (1) which contain a basic center may be prepared in a conventional manner. For example, a solution of the free base is treated with an appropriate acid, either neat or in a suitable solvent, and the resulting salts are isolated either by filtration or by evaporation under vacuum of the reaction solvent.
Compounds of the invention may be administered by any suitable route, for example by oral, buccal, sub-lingual, rectal, vaginal, nasal, topical or parenteral (including intravenous, intramuscular, subcutaneous and intracoronary) administration.
For administration to man in the curative or prophylactic treatment of the disorders identified above, oral, buccal or sub-lingual dosages of a compound of the formula (1) will generally be in the range of from 0.1-400 mg daily for an average adult patient (70 Kg). Thus for a typical adult patient, individual tablets or capsules contain from 0.05-200 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier, for administration in single or multiple doses, once or several times per day. Dosages for parenteral administration will typically be within the range of from 0.01-100 mg per single dose as required. In practice the physician will determine the actual dosing regimen which will be most suitable for an individual patient, and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case but there can be individual instances in which higher or lower dosage ranges may be merited, and such are within the scope of this invention.
For human use, a compound of the formula (1) can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, the compound may be administered orally, buccally or sublingually, in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. Such liquid preparations may be prepared with pharmaceutically acceptable additives such as suspending agent (e.g. methylcellulose, a semi-synthetic glyceride such as witepsol or mixtures of glycerides such as a mixture of apricot kernel oil and PEG-6 esters or mixtures of PEG-8 and caprylic/capric glycerides). A compound may also be injected parenterally, for example intravenously, intramuscularly, subcutaneously or intracoronarily. For parenteral administration, the compound is best used in the form of a sterile aqueous solution which may contain other substances, for example salts, or monosaccharides such as mannitol or glucose, to make the solution isotonic with blood.
Thus, the invention provides in a further aspect a pharmaceutical composition comprising a compound of the formula (1), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier therefor.
The invention also provides a compound of the formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, for use in the treatment of impotence, sexual dysfunction in female, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, conditions of reduced blood vessel patency (e.g. post-percutaneous transluminal coronary angioplasty), peripheral vascular disease, vascular disorders such as Raynaud's disease, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma and diseases characterized by disorders of gut motility (e.g. irritable bowel syndrome).
The invention further provides the use of a compound of the formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, for the manufacture of a medicament for the treatment of impotence, sexual dysfunction in female, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, conditions of reduced blood vessel patency (e.g. post-percutaneous transluminal coronary angioplasty), peripheral vascular disease, vascular disorders such as Raynaud's disease, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma and diseases characterized by disorders of gut motility (e.g. irritable bowel syndrome).
In a further aspect, the invention provides a method of treating or preventing impotence, sexual dysfunction in female, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, conditions of reduced blood vessel patency (e.g. post-percutaneous transluminal coronary angioplasty), peripheral vascular disease, vascular disorders such as Raynaud's disease, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma and diseases characterized by disorders of gut motility (e.g. irritable bowel syndrome), in a mammal (including a human being), which comprises administering to said mammal a therapeutically effective amount of a compound of formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity.
The present invention is further illustrated in the following Examples, which should not be taken to limit the scope of the invention.
To a cooled solution of SOCl2 (156 g, 1.31 mol) and ClSO3H (460 g, 3.94 mol) at 0° C. was added slowly methyl salicylate (200 g, 1.31 mol) for 30 minutes, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was poured slowly into the ice (2 kg) and H2O (3 L) mixture, and the resulting white precipitates were collected by filtration. The filtered solid was washed with H2O (3 L), air-dried for 2 days and then dried under vacuum at 40° C. for 2 days to afford the titled product (232 g, 93%) as a white solid.
mp 76.5-77.5° C. (toluene/hexanes);
IR (neat) 1699 (C═O) cm−1;
1H NMR (CDCl3/TMS) δ 3.90 (s, 3H, OCH3), 6.93 (d, J=8.7 Hz, 1H, H-3), 7.70 (dd, J=8.7 Hz, 2.4 Hz, 1H, H-4), 8.03 (d, J=2.4 Hz, 1H, H-6).
To a mixture of 1-(2-hydroxyethyl)piperazine (27 mg, 0.21 mmol) and K2CO3 (33 mg, 0.24 mmol) in DMF (5 mL) was added methyl 3-chlorosulfonyl-6-hydroxybenzoate (50 mg, 0.20 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with H2O (10 mL), and the aqueous layer was further extracted with 5% MeOH in CH2Cl2 (20 mL). The combined organic layer was dried (MgSO4), filtered, and the filtrate was evaporated to dryness under reduced pressure. The crude residue was purified by MPLC on silica gel (5% MeOH in CH2Cl2) to afford the titled compound (59 mg, 86%) as white solid.
mp 152° C. (dec) (CH2Cl2/ether);
IR (neat) 1685 (C═O) cm−1;
1H NMR (CDCl3/TMS) δ 2.30 (br s, 1H, CH2OH), 2.63 (t, J=5.4 Hz, 2H, NCH2CH2O), 2.70 (m, 4H, 2 NCH2), 3.12 (m, 4H, 2 SO2NCH2), 3.64 (t, J=5.4 Hz, 2H, NCH2CH2O), 4.01 (s, 3H, OCH3), 7.12 (d, J=8.7 Hz, 1H, H-3), 7.81 (dd, J=8.7 Hz, 2.4 Hz, 1H, H-4), 8.26 (d, J=2.4 Hz, 1H, H-6), 11.26 (br s, 1H, OH);
MS (FAB) m/z 345 (MH+).
To a mixture of methyl 2-hydroxy-5-(4-(2-hydroxyethyl)piperazin-1-ylsulfonyl)benzoate (800 mg, 2.32 mmol) and K2CO3 (482 mg, 3.49 mmol) in DMF (5 mL) was added 1-bromopropane (253 μL, 2.79 mmol), and the mixture was stirred at 60° C. overnight. The reaction mixture was evaporated to dryness under reduced pressure, washed with H2O (10 mL), and the aqueous layer was further extracted with CH2Cl2 (50 mL×2). The combined organic layer was dried (MgSO4), filtered, and the filtrate was evaporated to dryness under reduced pressure. The crude residue was purified by MPLC on silica gel (3% MeOH in CHCl3) to afford the titled compound (309 mg, 80%) as a white solid.
mp 88-89° C. (EtOAc/hexanes);
IR (neat) 3242 (OH), 1741 (C═O) cm−1;
1H NMR (CDCl3/TMS) δ 1.09 (t, J=7.5 Hz, 3H, OCH2CH2CH3), 1.84-1.95 (m, 2H, OCH2CH2CH3), 2.23 (br s, 1H, CH2OH), 2.54 (t, J=5.4 Hz, 2H, NCH2CH2O), 2.60 (m, 4H, 2 NCH2), 3.04 (m, 4H, 2 SO2NCH2), 3.58 (t, J=5.4 Hz, 2H, NCH2CH2O), 3.91 (s, 3H, OCH3), 4.08 (t, J=6.6 Hz, 2H, OCH2CH2CH3), 7.07 (d, J=9.0 Hz, 1H, H-3), 7.82 (dd,J=9.0 Hz, 2.4 Hz, 1H, H-4), 8.15 (d, J=2.4 Hz, 1H, H-6);
MS (FAB) m/z 387 (MH+).
To a cooled solution of 2-{2-ethoxy-5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]phenyl}-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (100 mg, 0.20 mmol) and DMAP (12 mg, 0.10 mmol) in anhydrous pyridine (4 mL) in an ice bath was added slowly acetic anhydride (93 μL, 0.99 mmol), and the mixture was stirred for 20 minutes. The reaction mixture was evaporated to dryness under reduced pressure, and the resulting residue was diluted with aqueous NaHCO3 (20 mL), and was extracted with CH2Cl2 (30 mL×2). Combined organic layer was dried (MgSO4) and filtered, and the filtrate was evaporated to dryness under reduced pressure. The crude product was purified by MPLC on silica gel (1.5% MeOH in CHCl3) to afford the titled compound (101 mg, 93%) as white solid.
mp 191.5-192.5° C. (CHCl3/ether/hexanes);
IR (neat) 3322 (NH), 1739 (C═O), 1685 (C═O) cm−1;
1H NMR (CDCl3/TMS) δ 0.99 (t, J=7.2 Hz, 3H, CH2CH2CH3), 1.64 (t, J=6.9 Hz, 3H, OCH2CH3), 1.67-1.79 (m, 2H, CH2CH2CH3), 2.01 (s, 3H, O2CCH3), 2.60 (m, 4H, 2 NCH2), 2.62 (t, J=5.7 Hz, 2H, NCH2CH2O), 2.71 (t, J=7.5 Hz, 2H, CH2CH2CH3), 3.11 (m, 4H, 2 SO2NCH2), 4.08 (s, 3H, NCH3), 4.12 (t, J=5.7 Hz, 2H, NCH2CH2O), 4.35 (q, J=6.9 Hz, 2H, OCH2CH3), 6.89 (s, 1H, H-2), 7.12 (d, J=8.7 Hz, 1H, H-3′), 7.80 (dd, J=8.7 Hz, 2.4 Hz, 1H, H-4′), 8.86 (d, J=2.4 Hz, 1H, H-6′), 10.62 (br s, 1H, NH);
MS (FAB) m/z 547 (MH+).
To a solution of 2-{5-[4-(2-Acetoxyethyl)piperazin-1-ylsulfonyl]-2-ethoxyphenyl}-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (62 mg, 0.11 mmol) in anhydrous CH2Cl2 (4 mL) was added 10% H2SO4 in THF (70 μL, 0.13 mmol) at room temperature under nitrogen atmosphere, and the solution was stirred for about 30 minutes. The reaction mixture was poured slowly into anhydrous ether (20 mL), and the resulting white precipitates were collected by filtration. The filtered solid was dissolved in H2O (30 mL), filtered through a membrane filter (0.45 μm), and the filtrate was freeze-dried to afford the titled compound (70 mg, 96%) as a white solid.
IR (neat) 3330 (NH), 1739 (C═O), 1685 (C═O) cm−1;
1H NMR (DMSO-d6) δ 0.93 (t, J=7.2 Hz, 3H, CH2CH2CH3), 1.37 (t, J=6.9 Hz, 3H, OCH2CH3), 1.58-1.70 (m, 2H, CH2CH2CH3), 2.03 (s, 3H, O2CCH3), 2.58 (t, J=7.5 Hz, 2H, CH2CH2CH3), 2.57-2.78 (m, 2H, 2 SO2NCHax), 3.13-4.18 (m, 8H, 2 SO2NCHeq, 2H+NCHax, 2H+NCHeq, and NCH2CH2O), 3.99 (s, 3H, NCH3), 4.24 (q, J 6.9 Hz, 2H, OCH2CH3), 4.19-4.32 (m, 2H, NCH2CH2O), 7.24 (s, 1H, H-2), 7.43 (d, J=8.7 Hz, 1H, H-3′), 7.87 (dd, J=8.7 Hz, 2.4 Hz, 1H, H-4′), 7.96 (d, J=2.4 Hz, 1H, H-6′).
The titled compound was prepared as described in Example 4 by using 2-{2-ethoxy-5-[4-(3-hydroxypropyl)piperazin-1-ylsulfonyl]phenyl}-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one in place of 2-{2-ethoxy-5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]phenyl}-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one.
yield: 90%
mp 157-158.5° C. (CH2Cl2/EtOAc/hexanes);
IR (neat) 3334 (NH), 1737 (C═O), 1677 (C═O) cm−1;
1H NMR (CDCl3/TMS) δ 0.99 (t, J=7.5 Hz, 3H, CH2CH2CH3), 1.64 (t, J=6.9 Hz, 3H, OCH2CH3), 1.66-1.80 (m, 4H, CH2CH2CH3 and CH2CH2CH2O), 2.00 (s, 3H, O2CCH3), 2.40 (t, J=6.9 Hz, 2H, NCH2CH2CH2), 2.52 (m, 4H, 2 NCH2), 2.71 (t, J=7.5 Hz, 2H, CH2CH2CH3), 3.09 (m, 4H, 2 SO2NCH2), 4.04 (t, J=6.6 Hz, 2H, CH2CH2CH2O), 4.08 (s, 3H, NCH3), 4.36 (q, J=6.9 Hz, 2H, OCH2CH3), 6.88 (s, 1H, H-2), 7.13 (d, J=8.7 Hz, 1H, H-3′), 7.80 (dd, J=8.7 Hz, 2.4 Hz, 1H, H-4′), 8.87 (d, J=2.4 Hz, 1H, H-6′), 10.63 (br s, 1H, NH);
MS (FAB) m/z 560 (MH+).
(Method A)
A mixture of 2-(5-chlorosulfonyl-2-n-propoxyphenyl)-5-ethyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrinmidin-4-one (100 mg, 0.24 mmol) and 1-(2-acetoxyethyl)piperazine dihydrochloride (72 mg, 0.29 mmol) in EtOH (5 mL) was added Et3N (204 μL, 1.46 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness under reduced pressure, and the resulting residue was purified by MPLC on silica gel (2% MeOH in CH2Cl2) to afford the titled compound (114 mg, 86%).
mp 139-140° C. (EtOAc/hexanes);
IR (neat) 3323 (NH), 1737 (C═O), 1686 (C═O) cm−1;
1H NMR (CDCl3/TMS) δ 1.00 (t, J=7.5 Hz, 3H, CH2CH2CH3), 1.19 (t, J=7.5 Hz, 3H, OCH2CH2CH3), 1.48 (t, J=7.2 Hz, 3H, NCH2CH3), 1.68-1.81 (m, 2H, CH2CH2CH3), 1.99-2.10 (m, 2H, OCH2CH2CH3), 2.01 (s, 3H, O2CCH3), 2.60 (m, 4H, 2 NCH2), 2.62 (t, J=5.7 Hz, 2H, NCH2CH2O), 2.72 (t, J=7.5 Hz, 2H, CH2CH2CH3), 3.11 (m, 4H, 2 SO2NCH2), 4.12 (t, J=5.7 Hz, 2H, NCH2CH2O), 4.24 (t, J=6.3 Hz, 2H, OCH2CH2CH3), 4.45 (q, J=7.2 Hz, 2H, NCH2CH3), 6.97 (s, 1H, H-2), 7.13 (d, J=8.7 Hz, 1H, H-3′), 7.80 (dd, J=8.7 Hz, 2.4 Hz, 1H, H-4′), 8.89 (d, J=2.4 Hz, 1H, H-6′), 10.69 (br s, 1H, NH);
MS (FAB) m/z 574 (MH+).
(Method B)
The titled compound was prepared as described in Example 4 by using 5-ethyl-2-{5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]-2-n-propoxyphenyl}-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one in place of 2-{2-ethoxy-5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]phenyl}-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one.
yield: 72%
The titled compound was prepared as described in Example 5 by using 2-{5-[4-(2-acetoxyethyl)piperazin-1-ylsulfonyl]-2-n-propoxyphenyl}-5-ethyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one and 10% H2SO4 in EtOH in place of 2-{5-[4-(2-acetoxyethyl)piperazin-1-ylsulfonyl]-2-ethoxyphenyl}-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one and 10% H2SO4 in THF.
yield: 99%
IR (neat) 1716 (C═O), 1645 (C═O) cm−1;
1H NMR (DMSO-d6) δ 0.93 (t, J=7.2 Hz, 3H, CH2CH2CH3), 0.97 (t, J=7.5 Hz, 3H, OCH2CH2CH3), 1.37 (t, J=7.2 Hz, 3H, NCH2CH3), 1.58-1.82 (m, 4H, CH2CH2CH3 and OCH2CH2CH3), 2.04 (s, 3H, O2CCH3), 2.58 (t, J=7.5 Hz, 2H, CH2CH2CH3), 2.62-2.82 (m, 2H, 2 SO2NCHax), 3.15-3.88 (m, 8H, NCH2CH2O, 2 SO2NCHeq, 2H+NCHax, and 2H+NCHeq), 4.15 (t, J=6.3 Hz, 2H, OCH2CH2CH3), 4.29 (br t, J=4.8 Hz, 2H, NCH2CH2O), 4.38 (q, J=7.2 Hz, 2H, NCH2CH3), 7.36 (s, 1H, H-2), 7.44 (d, J=8.7 Hz, 1H, H-3), 7.88 (dd, J=8.7 Hz, 2.4 Hz, 1H, H-4′), 7.98 (d, J=2.4 Hz, 1H, H-6′).
The titled compound was prepared as described in Example 5 by using 2-{5-[4-(2-acetoxyethyl)piperazin-1-ylsulfonyl]-2-n-propoxyphenyl}-5-ethyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one and 1M HCl in ether in place of 2-{5-[4-(2-acetoxyethyl)piperazin-1-ylsulfonyl]-2-ethoxyphenyl}-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one and 10% H2SO4 in THF.
yield: 95%
IR (neat) 1738 (C═O), 1683 (C═O) cm−1;
1H NMR (DMSO-d6) δ 0.93 (t, J=7.2 Hz, 3H, CH2CH2CH3), 0.96 (t, J=7.5 Hz, 3H, OCH2CH2CH3), 1.36 (t, J 7.2 Hz, 3H, NCH2CH3), 1.57-1.81 (m, 4H, CH2CH2CH3 and OCH2CH2CH3), 2.04 (s, 3H, O2CCH3), 2.59 (t, J 7.5 Hz, 2H, CH2CH2CH3), 2.82-2.96 (m, 2H, 2 SO2NCHax), 3.14-3.31 (m, 2H, 2 SO2NCHeq), 3.36-3.47 (m, 2H, NCH2CH2O), 3.49-3.63 (m, 2H, 2H+NCHax), 3.73-3.85 (m, 2H, 2H+NCHeq), 4.15 (t, J=6.3 Hz, 2H, OCH2CH2CH3), 4.32-4.40 (m, 2H, NCH2CH2O), 4.38 (q, J=7.2 Hz, 2H, NCH2CH3), 7.36 (s, 1H, H-2), 7.44 (d, J=8.7 Hz, 1H, H-3′), 7.88 (dd, J=8.7 Hz, 2.4 Hz, 1H, H-4′), 8.01 (d, J=2.4 Hz, 1H, H-6′).
The titled compound was prepared as described in Example 4 by using 5-ethyl-2-{5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]-2-n-propoxyphenyl}-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one and propionic anhydride in place of 2-{2-ethoxy-5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]phenyl}-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one and acetic anhydride.
yield: 96%
mp 126.5-127.5° C. (EtOAc/hexanes);
IR (neat) 3324 (NH), 1733 (C═O), 1686 (C═O) cm−1;
1H NMR (CDCl3/TMS) δ 1.00 (t, J=7.5 Hz, 3H, CH2CH2CH3), 1.09 (t, J=7.5 Hz, 3H, O2CCH2CH3), 1.19 (t, J=7.5 Hz, 3H, OCH2CH2CH3), 1.48 (t, J=7.2 Hz, 3H, NCH2CH3), 1.68-1.81 (m, 2H, CH2CH2CH3), 1.99-2.10 (m, 2H, OCH2CH2CH3), 2.28 (q, J=7.2 Hz, 2H, O2CCH2), 2.60 (m, 4H, 2 NCH2), 2.62 (t, J=5.7 Hz, 2H, NCH2CH2O), 2.72 (t, J=7.5 Hz, 2H, CH2CH2CH3), 3.10 (m, 4H, 2 SO2NCH2), 4.13 (t, J=5.7 Hz, 2H, NCH2CH2O), 4.24 (t, J=6.3 Hz, 2H, OCH2CH2CH3), 4.45 (q, J=7.2 Hz, 2H, NCH2CH3), 6.97 (s, 1H, H-2), 7.13 (d, J=8.7 Hz, 1H, H-3′), 7.80 (dd, J=8.7 Hz, 2.4 Hz, 1H, H-4′), 8.89 (d, J=2.4 Hz, 1H, H-6′), 10.69 (br s, 1H, NH);
MS (FAB) m/z 588 (MH+).
The titled compound was prepared as described in Example 5 by using 5-ethyl-2-{5-[4-(2-propionyloxyethyl)piperazin-1-ylsulfonyl]-2-n-propoxyphenyl}-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one and 10% H2SO4 in EtOH in place of 2-{5-[4-(2-acetoxyethyl)piperazin-1-ylsulfonyl]-2-ethoxyphenyl}-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one and 10% H2SO4 in THF.
yield: 97%
IR (neat) 1707 (C═O), 1641 (C═O) cm−1;
1H NMR (DMSO-d6) δ 0.93 (t, J=7.2 Hz, 3H, CH2CH2CH3), 0.96 (t, J=7.5 Hz, 3H, OCH2CH2CH3), 1.02 (t, J=7.5 Hz, 3H, O2CCH2CH3), 1.37 (t, J=7.2 Hz, 3H, NCH2CH3), 1.57-1.81 (m, 4H, CH2CH2CH3 and OCH2CH2CH3), 2.34 (q, J=7.5 Hz, 2H, O2CCH2CH3), 2.58 (t, J=7.5 Hz, 2H, CH2CH2CH3), 2.62-2.78 (m, 2H, 2 SO2NCHax), 3.18-3.35 (m, 2H, 2 SO2NCHeq), 3.42-3.50 (m, 2H, NCH2CH2O), 3.52-3.86 (m, 4H, 2H+NCHax and 2H+NCHeq), 4.15 (t, J=6.3 Hz, 2H, OCH2CH2CH3), 4.31 (m, 2H, NCH2CH2O), 4.38 (q, J=7.2 Hz, 2H, NCH2CH3), 7.38 (s, 1H, H-2), 7.46 (d, J=8.7 Hz, 1H, H-3′), 7.90 (dd, J=8.7 Hz, 2.4 Hz, 1H, H-4′), 8.00 (d, J=2.4 Hz, 1H, H-6′).
The titled compound was prepared as described in Example 4 by using 5-ethyl-2-{5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]-2-n-propoxyphenyl}-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one and butyric anhydride in place of 2-{2-ethoxy-5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]phenyl}-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one and acetic anhydride.
yield: 91%
mp 71.5-73° C. (ether/hexanes);
IR (neat) 3324 (NH), 1737 (C═O), 1673 (C═O) cm−1;
1H NMR (CDCl3/TMS) δ 0.89 (t, J=7.5 Hz, 3H, O2CCH2CH2CH3), 1.00 (t, J=7.5 Hz, 3H, CH2CH2CH3), 1.19 (t, J=7.5 Hz, 3H, OCH2CH2CH3), 1.48 (t, J=7.2 Hz, 3H, NCH2CH3), 1.53-1.66 (m, 2H, O2CCH2CH2CH3), 1.68-1.81 (m, 2H, CH2CH2CH3), 1.97-2.12 (m, 2H, OCH2CH2CH3), 2.24 (t, J=7.5 Hz, 2H, O2CCH2), 2.60 (m, 4H, 2 NCH2), 2.61 (t, J=5.7 Hz, 2H, NCH2CH2O), 2.72 (t, J=7.5 Hz, 2H, CH2CH2CH3), 3.10 (m, 4H, 2 SO2NCH2), 4.13 (t, J=6.0 Hz, 2H, NCH2CH2O), 4.24 (t, J=6.6 Hz, 2H, OCH2CH2CH3), 4.46 (q, J=7.2 Hz, 2H, NCH2CH3), 6.97 (s, 1H, H-2), 7.13 (d, J=8.7 Hz, 1H, H-3′), 7.80 (dd, J=8.7 Hz, 2.7 Hz, 1H, H-4′), 8.89 (d, J=2.7 Hz, 1H, H-6′), 10.69 (br s, 1H, NH);
MS (FAB) m/z 602 (MH+).
The titled compound was prepared as described in Example 5 by using 2-{5-[4-(2-butyryloxyethyl)piperazin-1-ylsulfonyl]-2-n-propoxyphenyl}-5-ethyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one and 10% H2SO4 in EtOH in place of 2-{5-[4-(2-acetoxyethyl)piperazin-1-ylsulfonyl]-2-ethoxyphenyl}-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one and 10% H2SO4 in THF.
yield: 82%
IR (neat) 1741 (C═O), 1677 (C═O) cm−1;
1H NMR (DMSO-d6) δ 0.88 (t, J=7.5 Hz, 3H, O2CCH2CH2CH3), 0.93 (t, J=7.2 Hz, 3H, CH2CH2CH3), 0.97 (t, J=7.5 Hz, 3H, OCH2CH2CH3), 1.36 (t, J=7.2 Hz, 3H, NCH2CH3), 1.48-1.82 (m, 6H, O2CCH2CH2CH3, CH2CH2CH3, and OCH2CH2CH3), 2.31 (t, J=7.2 Hz, 2H, O2CCH2CH2CH3), 2.58 (t, J=7.5 Hz, 2H, CH2CH2CH3), 2.53-2.78 (m, 2H, 2 SO2NCHax), 3.14-3.37 (m, 2H, 2 SO2NCHeq), 3.38-3.49 (m, 2H, NCH2CH2O), 3.50-3.66 (m, 2H, 2H+NCHax), 3.67-3.90 (m, 2H, 2H+NCHeq), 4.15 (t, J=6.5 Hz, 2H, OCH2CH2CH3), 4.30 (m, 2H, NCH2CH2O), 4.38 (q, J=7.2 Hz, 2H, NCH2CH3), 7.34 (s, 1H, H-2), 7.44 (d, J=9.0 Hz, 1H, H-3′), 7.87 (dd, J=9.0 Hz, 2.4 Hz, 1H, H-4′), 7.98 (d, J=2.4 Hz, 1H, H-6′), 9.37 (br s, 1H, NH+), 11.78 (br s, 1H, NH).
The titled compound was prepared as described in Example 4 by using 5-ethyl-2-{5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]-2-n-propoxyphenyl}-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one and isobutyric anhydride in place of 2-{2-ethoxy-5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]phenyl}-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one and acetic anhydride.
yield: 94%
mp 88-89° C. (ether/hexanes);
IR (neat) 3325 (NH), 1731 (C═O), 1686 (C═O) cm−1;
1H NMR (CDCl3/TMS) δ 1.00 (t, J=7.2 Hz, 3H, CH2CH2CH3), 1.11 (d, J=6.9 Hz, 6H, CH(CH3)2), 1.19 (t, J=7.5 Hz, 3H, OCH2CH2CH3), 1.48 (t, J=7.2 Hz, 3H, NCH2CH3), 1.68-1.80 (m, 2H, CH2CH2CH3), 1.99-2.10 (m, 2H, OCH2CH2CH3), 2.43-2.56 (m, 1H, O2CCH), 2.61 (m, 4H, 2 NCH2), 2.62 (t, J=5.7 Hz, 2H, NCH2CH2O), 2.72 (t, J=7.5 Hz, 2H, CH2CH2CH3), 3.09 (m, 4H, 2 SO2NCH2), 4.12 (t, J=5.7 Hz, 2H, NCH2CH2O), 4.24 (t, J=6.6 Hz, 2H, OCH2CH2CH3), 4.45 (q, J=7.2 Hz, 2H, NCH2CH3), 6.97 (s, 1H, H-2), 7.13 (d, J=8.7 Hz, 1H, H-3′), 7.80 (dd, J=8.7 Hz, 2.4 Hz, 1H, H-4′), 8.89 (d, J=2.4 Hz, 1H, H-6′), 10.69 (br s, 1H, NH);
MS (FAB) m/z 602 (MH+).
The titled compound was prepared as described in Example 5 by using 5-ethyl-2-{5-[4-(2-isobutyryloxyethyl)piperazin-1-ylsulfonyl]-2-n-propoxyphenyl}-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one and 10% H2SO4 in EtOH in place of 2-{5-[4-(2-acetoxyethyl)piperazin-1-ylsulfonyl]-2-ethoxyphenyl}-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one and 10% H2SO4 in THF.
yield: 99%
IR (neat) 1739 (C═O), 1683 (C═O) cm−1;
1H NMR (DMSO-d6) δ 0.93 (t, J=7.2 Hz, 3H, CH2CH2CH3), 0.97 (t, J=7.5 Hz, 3H, OCH2CH2CH3), 1.09 (d, J=6.9 Hz, 6H, CH(CH3)2), 1.36 (t, J=7.2 Hz, 3H, NCH2CH3), 1.58-1.82 (m, 4H, CH2CH2CH3 and OCH2CH2CH3), 2.53-2.78 (m, 5H, O2CCH, CH2CH2CH3, and 2 SO2NCHax), 3.17-3.38 (m, 2H, 2 SO2NCHeq), 3.42-3.51 (m, 2H, NCH2CH2O), 3.52-3.66 (m, 2H, 2H+NCHax), 3.71-3.88 (m, 2H, 2H+NCHeq), 4.15 (t, J=6.3 Hz, 2H, OCH2CH2CH3), 4.30 (m, 2H, NCH2CH2O), 4.38 (q, J=7.2 Hz, 2H, NCH2CH3), 7.35 (s, 1H, H-2), 7.45 (d, J=8.7 Hz, 1H, H-3′), 7.88 (dd, J=8.7 Hz, 2.7 Hz, 1H, H-4′), 7.98 (d, J=2.7 Hz, 1H, H-6′), 9.41 (br s, 1H, NH+).
The titled compound was prepared as described in Example 4 by using 5-ethyl-2-{5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]-2-n-propoxyphenyl}-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one and benzoic anhydride in place of 2-{2-ethoxy-5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]phenyl}-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one and acetic anhydride.
yield: 99%
mp 78-79° C. (EtOAc/ether);
IR (neat) 3338 (NH), 1722 (C═O), 1659 (C═O) cm−1;
1H NMR (CDCl3/TMS) δ 0.99 (t, J=7.2 Hz, 3H, CH2CH2CH3), 1.19 (t, J=7.5 Hz, 3H, OCH2CH2CH3), 1.48 (t, J=7.2 Hz, 3H, NCH2CH3), 1.67-1.80 (m, 2H, CH2CH2CH3), 1.98-2.10 (m, 2H, OCH2CH2CH3), 2.68 (m, 4H, 2 NCH2), 2.71 (t, J 7.5 Hz, 2H, CH2CH2CH3), 2.77 (t, J=5.7 Hz, 2H, NCH2CH2O), 3.11 (m, 4H, 2 SO2NCH2), 4.23 (t, J=6.6 Hz, 2H, OCH2CH2CH3), 4.38 (t, J=5.7 Hz, 2H, NCH2CH2O), 4.45 (q, J=7.2 Hz, 2H, NCH2CH3), 6.96 (s, 1H, H-2), 7.13 (d, J=8.7 Hz, 1H, H-3′), 7.38-7.43 (m, 2H, 2 Ph-H), 7.51-7.56 (m, 1H, Ph-H), 7.80 (dd, J=8.7 Hz, 2.4 Hz, 1H, H-4′), 7.96-7.98 (m, 2H, 2 Ph-H), 8.89 (d, J=2.4 Hz, 1H, H-6′), 10.68 (br s, 1H, NH);
MS (FAB) m/z 636 (MH+).
A mixture of 5-ethyl-2-{5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]-2-n-propoxyphenyl}-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (300 mg, 0.56 mmol), ethyl 4-nitrophenycarbonate (131 mg, 0.62 mmol), and DMAP (14 mg, 0.11 mmol) in pyridine (10 mL) was stirred overnight at 80-90° C. The reaction mixture was evaporated to dryness under reduced pressure. The crude residue was purified by MPLC on silica gel (3% MeOH in EtOAc) to afford the titled compound (198 mg, 58%) as a white solid.
mp 135-136° C. (EtOAc/ether);
IR (neat) 3330 (NH), 1744 (C═O), 1688 (C═O) cm−1;
1H NMR (CDCl3/TMS) δ 1.00 (t, J=7.5 Hz, 3H, CH2CH2CH3), 1.19 (t, J=7.5 Hz, 3H, OCH2CH2CH3), 1.25 (t, J=7.2 Hz, 3H, OCO2CH2CH3), 1.48 (t, J=7.2 Hz, 3H, NCH2CH3), 1.68-1.81 (m, 2H, CH2CH2CH3), 1.99-2.11 (m, 2H, OCH2CH2CH3), 2.61 (m, 4H, 2 NCH2), 2.65 (t, J=5.7 Hz, 2H, NCH2CH2O), 2.72 (t, J=7.5 Hz, 2H, CH2CH2CH3), 3.10 (m, 4H, 2 SO2NCH2), 4.13 (q, J=7.2 Hz, 2H, OCO2CH2CH3), 4.17 (t, J=5.7 Hz, 2H, NCH2CH2O), 4.25 (t, J=6.6 Hz, 2H, OCH2CH2CH3), 4.45 (q, J=7.2 Hz, 2H, NCH2CH3), 6.97 (s, 1H, H-2), 7.13 (d, J=8.7 Hz, 1H, H-3′), 7.80 (dd, J=8.7 Hz, 2.4 Hz, 1H, H-4′), 8.89 (d, J=2.4 Hz, 1H, H-6′), 10.69 (br s, 1H, NH);
MS (FAB) m/z 604 (MH+).
The titled compound was prepared as described in Example 5 by using 2-{5-[4-(2-ethoxycarbonyloxyethyl)piperazin-1-ylsulfonyl]-2-n-propoxyphenyl}-5-ethyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one and 10% H2SO4 in EtOH in place of 2-{5-[4-(2-acetoxyethyl)piperazin-1-ylsulfonyl]-2-ethoxyphenyl}-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one and 10% H2SO4 in THF.
yield: 97%
IR (neat) 1748 (C═O), 1719 (C═O) cm−1;
1H NMR (DMSO-d6) δ 0.92 (t, J=7.2 Hz, 3H, CH2CH2CH3), 0.95 (t, J=7.5 Hz, 3H, OCH2CH2CH3), 1.21 (t, J=7.2 Hz, 3H, OCO2CH2CH3), 1.37 (t, J=7.2 Hz, 3H, NCH2CH3), 1.57-1.80 (m, 4H, CH2CH2CH3 and OCH2CH2CH3), 2.58 (t, J=7.5 Hz, 2H, CH2CH2CH3), 2.62-2.81 (m, 2H, 2 SO2NCHax), 3.17-3.37 (m, 2H, 2 SO2NCHeq), 3.45-3.88 (m, 6H, NCH2CH2O, 2H+NCHax and 2H+NCHeq), 4.09-4.20 (m, 4H, OCO2CH2CH3 and OCH2CH2CH3), 4.33-4.45 (m, 4H, NCH2CH3 and NCH2CH2O), 7.42 (s, 1H, H-2), 7.47 (d, J=8.7 Hz, 1H, H-3′), 7.92 (d, J=8.7 Hz, 1H, H-4′), 8.02 (s, 1H, H-6′).
The titled compound was prepared as described in Example 4 by using 5-ethyl-7-(3-fluoropropyl)-2-{5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]-2-n-propoxyphenyl}-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one in place of 2-{2-ethoxy-5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]phenyl}-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one.
yield: 80%
mp 134-135° C. (EtOAc/hexanes);
IR (neat) 3319 (NH), 1740 (C═O), 1689 (C═O) cm−1;
1H NMR (CDCl3/TMS) δ 1.20 (t, J=7.5 Hz, 3H, CH2CH2CH3), 1.49 (t, J=7.2 Hz, 3H, NCH2CH3), 2.00-2.23 (m, 4H, CH2CH2CH3 and CH2CH2CH2F), 2.01 (s, 3H, O2CCH3), 2.60 (m, 4H, 2 NCH2), 2.62 (t, J=5.7 Hz, 2H, NCH2CH2O), 2.87 (t, J=7.5 Hz, 2H, CH2CH2CH2F), 3.10 (m, 4H, 2 SO2NCH2), 4.12 (t, J=5.7 Hz, 2H, NCH2CH2O), 4.25 (t, J=6.3 Hz, 2H, CH2CH2CH3), 4.46 (q, J=7.2 Hz, 2H, NCH2CH3), 4.52 (dt, J=47.1 Hz, 5.7 Hz, 2H, CH2CH2CH2F), 7.00 (s, 1H, H-2), 7.14 (d, J=8.7 Hz, 1H, H-3′), 7.81 (dd, J=8.7 Hz, 2.4 Hz, 1H, H-4′), 8.88 (d, J=2.4 Hz, 1H, H-6′), 10.73 (br s, 1H, NH);
MS (FAB) m/z 592 (MH+).
To a mixture of 2-{2-ethoxy-5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]phenyl}-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (200 mg, 0.40 mmol), N-(tert-butoxycarbonyl)-L-valine (172 mg, 0.79 mmol), and DMAP (10 mg, 0.08 mmol) in CH2Cl2 (10 mL) was added EDC (114 mg, 0.59 mmol), and the mixture was stirred for 2 hours at room temperature. The reaction mixture was washed with dilute NaHCO3 aqueous solution (30 mL), and the aqueous layer was further extracted with CH2Cl2 (30 mL). The combined organic layer was dried (MgSO4), filtered, and the filtrate was evaporated to dryness under reduced pressure. The crude residue was purified by MPLC on silica gel (1.5% MeOH in CHCl3) to afford the titled compound (258 mg, 92%) as a pale yellow solid.
mp 166.5° C. (dec) (EtOAc/ether/hexanes);
IR (neat) 3333 (NH), 1722 (C═O), 1677 (C═O) cm−1;
1H NMR (CDCl3/TMS) δ 0.81 (d, J=6.9 Hz, 3H, CHCH3), 0.89 (d, J=6.9 Hz, 3H, CHCH3), 1.00 (t, J=7.5 Hz, 3H, CH2CH2CH3), 1.41 (s, 9H, 3 CH3), 1.64 (t, J=6.9 Hz, 3H, OCH2CH3), 1.66-1.80 (m, 2H, CH2CH2CH3), 1.98-2.11 (m, 1H, CHCH3), 2.57 (m, 4H, 2 NCH2), 2.62 (t, J=5.7 Hz, 2H, NCH2CH2O), 2.71 (t, J=7.5 Hz, 2H, CH2CH2CH3), 3.09 (m, 4H, 2 SO2NCH2), 4.08 (s, 3H, NCH3), 4.15 (t, J=5.7 Hz, 2H, NCH2CH2O), 4.18-4.29 (m, 1H, COCH), 4.36 (q, J=6.9 Hz, 2H, OCH2CH3), 4.94 (br d, J=9.3 Hz, 1H, NHBoc), 6.88 (s, 1H, H-2), 7.13 (d, J=8.7 Hz, 1H, H-3′), 7.80 (dd, J=8.7 Hz, 2.4 Hz, 1H, H-4′), 8.87 (d, J=2.4 Hz, 1, H-6′), 10.64 (br s, 1H, NH);
MS (FAB) m/z 704 (MH+).
To a cooled solution of 2-{5-[4-(2-(N-(tert-Butoxycarbonyl)-L-valinyl)oxyethyl)piperazin-1-ylsulfonyl]-2-ethoxyphenyl}-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (150 mg, 0.21 mmol) in CH2Cl2 (5 mL) at 0° C. was added slowly CF3CO2H (49 μL, 6.39 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness under vacuum. The crude residue was dissolved in THF (2 mL), and a 6 N aqueous HCl solution (89 μL, 0.53 mmol) was added to the solution at 0° C. The mixture was evaporated to dryness under vacuum, and the residue was purified by crystallization from MeOH/ether to afford the desired product (137 mg, 95%) as white crystals. The product was dissolved in H2O (20 mL), filtered through a membrane filter (0.45 μL), and the filtrate was freeze-dried to afford the titled compound as a white solid.
IR (neat) 3339 (NH), 1755 (C═O), 1680 (C═O) cm−1;
1H NMR (DMSO-d6) δ 0.94 (t, J=7.5 Hz, 3H, CH2CH2CH3), 0.96 (d, J=7.2 Hz, 3H, CHCH3), 0.99 (d, J=6.9 Hz, 3H, CHCH3), 1.37 (t, J=6.9 Hz, 3H, OCH2CH3), 1.59-1.71 (m, 2H, CH2CH2CH3), 2.14-2.28 (m, 1H, CHCH3), 2.59 (t, J=7.5 Hz, 2H, CH2CH2CH3), 2.91-3.16 (m, 2H, 2 SO2NCHax), 3.04-3.92 (m, 9H, 2 SO2NCHeq, NCH2CH2O, 2H+NCHax, 2H+NCHeq, COCH), 3.99 (s, 3H, NCH3), 4.25 (q, J=6.9 Hz, 2H, OCH2CH3), 4.42-4.61 (m, 2H, NCH2CH2O), 7.22 (s, 1H, H-2), 7.41 (d, J=9.0 Hz, 1H, H-3′), 7.87 (dd, J=9.0 Hz, 2.7 Hz, 1H, H-4′), 8.03 (d, J=2.7 Hz, 1H, H-6′), 8.67 (br s, 2H, 2H+);
MS (FAB) m/z 604 (MH+-2 HCl).
The titled compound was prepared as described in Example 20 by using 2-{2-ethoxy-5-[4-(3-hydroxypropyl)piperazin-1-ylsulfonyl]phenyl}-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one in place of 2-{2-ethoxy-5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]phenyl}-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one.
yield: 80%
mp 132-134° C. (EtOAc/ether/hexanes);
IR (neat) 3329 (NH), 1749 (C═O), 1681 (C═O) cm−1;
1H NMR (CDCl3/TMS) δ 0.85 (d, J=6.6 Hz, 3H, CHCH3), 0.92 (d, J=6.9 Hz, 3H, CHCH3), 0.99 (t, J=7.5 Hz, 3H, CH2CH2CH3), 1.42 (s, 9H, 3 CH3), 1.64 (t, J=6.9 Hz, 3H, OCH2CH3), 1.69-1.82 (m, 4H, CH2CH2CH3 and CH2CH2CH2O), 2.01-2.14 (m, 1H, CHCH3), 2.41 (t, J=6.6 Hz, 2H, CH2CH2CH2O), 2.52 (m, 4H, 2 NCH2), 2.71 (t, J=7.5 Hz, 2H, CH2CH2CH3), 3.08 (m, 4H, 2 SO2NCH2), 4.08 (s, 3H, NCH3), 4.11 (t, J=6.6 Hz, 2H, CH2CH2CH2O), 4.10-4.20 (m, 1H, COCH), 4.36 (q, J=6.9 Hz, 2H, OCH2CH3), 4.95 (br d, J=9.0 Hz, 1H, NHBoc), 6.88 (s, 1H, H-2), 7.13 (d, J=8.7 Hz, 1H, H-3′), 7.80 (dd, J=8.7 Hz, 2.7 Hz, 1H, H-4′), 8.87 (d, J=2.7 Hz, 1H, H-6′), 10.61 (br s, 1H, NH);
MS (FAB) m/z 717 (MH+).
The titled compound was prepared as described in Example 21 by using 2-{5-[4-(3-(N-(tert-Butoxycarbonyl)-L-valinyl)oxypropyl)piperazin-1-ylsulfonyl]-2-ethoxyphenyl}-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrmidin-4-one in place of 2-{5-[4-(2-(N-(tert-Butoxycarbonyl)-L-valinyl)oxyethyl)piperazin-1-ylsulfonyl]-2-ethoxyphenyl}-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one.
yield: 98%
IR (neat) 3332 (NH), 1739 (C═O), 1678 (C═O) cm−1;
1H NMR (DMSO-d6) δ 0.93 (t, J=7.5 Hz, 3H, CH2CH2CH3), 0.95 (d, J=7.2 Hz, 3H, CHCH3), 0.98 (d, J=6.6 Hz, 3H, CHCH3), 1.36 (t, J=6.9 Hz, 3H, OCH2CH3), 1.57-1.70 (m, 2H, CH2CH2CH3), 2.01-2.25 (m, 3H, CH2CH2CH2O and CHCH3), 2.59 (t, J=7.5 Hz, 2H, CH2CH2CH3), 2.82-2.96 (m, 2H, 2 SO2NCHax), 3.10-3.32 (m, 4H, 2 SO2NCHeq and CH2CH2CH2O), 3.50-3.62 (m, 2H, 2H+NCHax), 3.76-3.88 (m, 3H, 2H+NCHeq and COCH), 3.99 (s, 3H, NCH3), 4.23 (t, J=7.2 Hz, 2H, CH2CH2CH2O), 4.24 (q, J=6.9 Hz, 2H, OCH2CH3), 7.26 (s, 1H, H-2), 7.42 (d, J=9.0 Hz, 1H, H-3′), 7.88 (dd, J=9.0 Hz, 2.7 Hz, 1H, H-4′), 8.00 (d, J=2.7 Hz, 1H, H-6′), 8.67 (br s, 2H, 2H+);
MS (FAB) m/z 617 (MH+-2 HCl).
The titled compound was prepared as described in Example 20 by using 5-ethyl-2-{5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]-2-n-propoxyphenyl}-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one and phenylacetic acid in place of 2-{2-ethoxy-5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]phenyl}-5-methyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one and N-(tert-butoxycarbonyl)-L-valine.
yield: 96%
IR (neat) 3331 (NH), 1735 (C═O), 1665 (C═O) cm−1;
1H NMR (CDCl3/TMS) δ 1.00 (t, J=7.2 Hz, 3H, CH2CH2CH3), 1.20 (t, J=7.5 Hz, 3H, OCH2CH2CH3), 1.48 (t, J 7.2 Hz, 3H, NCH2CH3), 1.69-1.81 (m, 2H, CH2CH2CH3), 1.99-2.11 (m, 2H, OCH2CH2CH3), 2.51 (m, 4H, 2 NCH2), 2.58 (t, J=5.7 Hz, 2H, NCH2CH2O), 2.73 (t, J=7.5 Hz, 2H, CH2CH2CH3), 3.02 (m, 4H, 2 SO2NCH2), 3.57 (s, 2H, O2CCH2), 4.14 (t, J=5.7 Hz, 2H, NCH2CH2O), 4.25 (t, J=6.6 Hz, 2H, OCH2CH2CH3), 4.46 (q, J=7.2 Hz, 2H, NCH2CH3), 6.97 (s, 1H, H-2), 7.14 (d, J=8.7 Hz, 1H, H-3′), 7.17-7.25 (m, 5H, 5 Ph-H), 7.80 (dd, J=8.7 Hz, 2.7 Hz, 1H, H-4′), 8.90 (d, J=2.7 Hz, 1H, H-6′), 10.71 (br s, 1H, NH);
MS (FAB) m/z 650 (MH+).
The active ingredient was sieved and blended with the excipients. The resultant mix was compressed into tablets.
Alternatively, the active ingredient and lactose were dissolved in water and freeze-dried. Then, the dried mixture was blended with the excipients and was compressed into tablets.
The active ingredient was sieved and blended with the lactose and starch. The polysorbate 80 was dissolved in purified water. Suitable volumes of the polysorbate 80 solution were added and the powders were granulated. After drying, the granules were screened and blended with the colloidal silicon dioxide and magnesium stearate. The granules were then compressed into tablets.
The active ingredient was sieved and blended with the excipients. The mix was filled into No. 5 hard gelatin capsules using suitable equipment.
The rabbit platelet PDE V was prepared using the method described by Hidaka et al. (Biochim. Biophys. Acta., 429: 485-497, 1976) with minor modification. The platelet-rich plasma (PRP) was prepared by centrifugation of freshly obtained heparinized whole blood at 360 g. Platelets were isolated from the PRP by centrifugation at 1,200 g. Platelet homogenates were prepared in the homogenization buffer (50 mM Tris-HCl buffer containing 1 mM MgCl2, pH 7.4) by sonication for 30 s per 1 mL. The homogenized solutions were then centrifuged at 40,000×g for 2 h at 4° C. The supernatant was loaded on the DEAE-cellulose column (20 mL bed volume, Sigma) pre-equilibrated with equilibration buffer (50 mM Tris-acetate containing 3.75 mM 2-mercaptoethanol, pH 6.0). The column was then washed with 60 mL of equilibration buffer. The PDE isozymes were eluted using a continuous gradient of 0 to 600 mM sodium acetate in the equilibration buffer (60 mL total volume). The 1.0 mL fractions were collected. A flow rate of 60 mL/h was used throughout the ion-exchange chromatography procedure. PDE activities on cAMP and cGMP were characterized as described below. The characterized fractions were pooled and stored at −80° C. until the inhibition studies.
The cyclic nucleotide PDE V activity was determined using PDE SPA assay kit (Amersham Pharmacia biotech, UK). Each reaction mixture (100 μL total volume) consisted of the column elute containing PDE V (10 μL), [3H]-cGMP (5 μCi/mL), bovine serum albumin (0.5 mg/mL), and MgCl2 (5 mM) in Tris-HCl buffer (15 mM, pH 7.5). The reactions were initiated by the addition of PDE V and the samples were incubated at 30° C. for 30 min, after which the reaction was stopped by the addition of 50 μL of SPA beads. The reaction tube was then settled for 20 min and was counted on the scintillation counter (Tri-carb 1500, Packard, USA). For the inhibition study of PDE V activity, the test compounds were dissolved in dimethyl sulfoxide (DMSO) and was diluted with distilled water. The final concentration of DMSO was less than 0.2% (v/v). All the inhibition experiments were conducted under the conditions where the level of cGMP hydrolysis did not exceed 15%, and the product formation increased linearly with time and the amount of enzyme.
The following Table illustrates the in vitro activities for a range of the compounds of the invention as inhibitors of cGMP PDE V.
Several compounds of the invention have been tested at doses of up to 10 mg/kg p. o. in rats with no untoward effects being observed, and up to 100 mg/kg p. o. in rats with no death being observed.
