WO1997017969A1 - Dihydropirimidines et leurs emplois - Google Patents

Dihydropirimidines et leurs emplois Download PDF

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Publication number
WO1997017969A1
WO1997017969A1 PCT/US1996/018573 US9618573W WO9717969A1 WO 1997017969 A1 WO1997017969 A1 WO 1997017969A1 US 9618573 W US9618573 W US 9618573W WO 9717969 A1 WO9717969 A1 WO 9717969A1
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WIPO (PCT)
Prior art keywords
compound
branched
straight chained
amount
subject
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PCT/US1996/018573
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English (en)
Inventor
Dhanapalan Nagarathnam
Wai C. Wong
Shou Wu Miao
Michael A. Patane
Charles Gluchowski
Original Assignee
Synaptic Pharmaceutical Corporation
Merck & Co., Inc.
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Priority claimed from PCT/US1995/015025 external-priority patent/WO1996014846A1/fr
Application filed by Synaptic Pharmaceutical Corporation, Merck & Co., Inc. filed Critical Synaptic Pharmaceutical Corporation
Priority to JP9519157A priority Critical patent/JP2000500470A/ja
Priority to US09/068,782 priority patent/US6228861B1/en
Priority to AU10558/97A priority patent/AU714287B2/en
Priority to EP96941406A priority patent/EP0866708A4/fr
Publication of WO1997017969A1 publication Critical patent/WO1997017969A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • ⁇ 1A is the appellation recently approved by the IUPHAR Nomenclature Committee for the previously designated “ ⁇ 1C " cloned subtype as outlined in the 1995 Receptor and Ion Channel Nomenclature Supplement (Watson and Girdlestone, 1995).
  • the designation ⁇ 1A is used throughout this application and the supporting tables and figures to refer to this receptor subtype.
  • the receptor formerly designated ⁇ 1A was renamed ⁇ 1D .
  • the new nomenclature is used throughout this application. Stable cell lines expressing these receptors are described herein; however, these cell lines were deposited with the American Type Culture Collection (ATCC) under the old nomenclature (infra).
  • Benign Prostatic Hyperplasia also called Benign Prostatic Hypertrophy
  • Benign Prostatic Hypertrophy is a progressive condition which is characterized by a nodular enlargement of prostatic tissue resulting in obstruction of the urethra. This results in increased frequency of urination, nocturia, a poor urine stream and hesitancy or delay in starting the urine flow.
  • Chronic consequences of BPH can include hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection.
  • the specific biochemical, histological and pharmacological properties of the prostate adenoma leading to the bladder outlet obstruction are not yet known. However, the development of BPH is considered to be an inescapable phenomenon for the aging male population.
  • Rev., 9, 407-533, 19 ⁇ 9 are specific neuroreceptor proteins located in the peripheral and central nervous systems on tissues and organs throughout the body. These receptors are important switches for controlling many physiological functions and, thus, represent important targets for drug development. In fact, many ⁇ -adrenergic drugs have been developed over the past 40 years. Examples include clonidine, phenoxybenzamine and prazosin (treatment of hypertension), naphazoline (nasal decongestant), and apraclonidine (treating glaucoma).
  • ⁇ -Adrenergic drugs can be broken down into two distinct classes: agonists (clonidine and naphazoline are agonists), which mimic the receptor activation properties of the endogenous neurotransmitter norepinephrine, and antagonists (phenoxybenzamine and prazosin are antagonists), which act to block the effects of norepinephrine. Many cf these drugs are effective but also produce unwanted side effects (for example, clonidine produces dry mouth and sedation in addition to its antihypertensive effects).
  • ⁇ -adrenergic receptors which exist throughout the central and peripheral nervous systems: ⁇ 1A (new nomenclature), ⁇ 1B , ⁇ 1D (new nomenclature), ⁇ 2A , ⁇ 2B and ⁇ 2C (Bylund, D.B., FASEB J., 6, 832 (1992)).
  • ⁇ 1A new nomenclature
  • ⁇ 1B new nomenclature
  • ⁇ 1D new nomenclature
  • ⁇ 2A , ⁇ 2B and ⁇ 2C Bolund, D.B., FASEB J., 6, 832 (1992)
  • current ⁇ -adrenergic drugs are not selective for any particular ⁇ -adrenergic receptor. Many of these drugs produce untoward side effects which may be attributed to their poor ⁇ -adrenergic receptor selectivity.
  • ⁇ 1A receptor is responsible for mediating the contraction of human prostate smooth muscle (Gluchowski, C. et. al., WO 94/10989, 1994; Forray, C. et. al., Mol. Pharmacol. 45, 703, 1994). This discovery indicates that the ⁇ 1A antagonists may be effective agents for the treatment of BPH with decreased side effects. Further studies have indicated that the ⁇ 1A receptor may also be present in other lower urinary tract tissues, such as urethral smooth muscle (Ford et al. Br. J. Pharmacol., 114, 24P, (1995)).
  • This invention is directed to dihydropyrimidine compounds which are selective antagonists for cloned human ⁇ 1A receptors.
  • This invention is also related to uses of these compounds for lowering intraocular pressure (Zhan, et. al. Ophthalmol. Vis. Sci., 34 Abst. #1133, 928, 1993), inhibiting cholesterol synthesis (D'Eletto and Javitt, J. Cardiovascular Pharmacol., 13 (Suppl. 2) S1-S4, 1989), benign prostatic hyperplasia, impotency (Milne and Wyllie, EP 0 459 666 A2, 1991), sympathetically mediated pain (Campbell, WO 92/14453, 1992), cardiac arrhythmia (Spiers, et. al., J. Cardiovascular Pharmacol., 16, 824-830, 1990) and for the treatment of any disease where antagonism of the ⁇ 1A receptor may be useful. Summary of the Invention
  • This invention is directed to dihydrcpyrimidine compounds which are selective antagonists for human a 1A receptors.
  • This invention is also related to uses of these compounds for lowering intraocular pressure, inhibiting cholesterol synthesis, relaxing lower urinary tract tissue, the treatment of benign prostatic hyperplasia, impotency, cardiac arrhythmia and for the treatment of any disease where antagonism of the ⁇ 1A receptor may be useful.
  • the invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.
  • the present invention is directed to compounds having the structures:
  • each of Y 1 , Y 2 , Y 3 , Y, and Y 5 independently may be -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I; -NO 2 ; -N(R 3 ) 2 ; -N 3 ; -CN; -OR 3 ; -OCOR 3 ; -COR 3 ; -CON(R 3 ) 2 ; or -CO 2 R 3 ; or wherein two of Y 1 , Y 2 , Y 3 , Y 4 and Y s are present on adjacent carbon atoms
  • R 1 may be -H; -NO 2 ; -CN; straight chained cr branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 - C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -CO 2 R 3 ; or -CON(R 3 ) 2 , wherein any p independently is an integer from 1 to 7 inclusive; where R 2 may be -H; straight chained or branched C 1 -C 7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chaine
  • 2 may be C 2 -C 7 alkenyl or alkynyl
  • NR 3 NR 3 ; m is an integer from 0 to 3 inclusive; R 5 and R 6 each independently may be -H; -F,
  • C 1 -C 7 polyfluoroalkyl C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, or C 3 -C 7 cycloalkenyl, wherein the alkyl,
  • alkynyl, cycloalkyl or cycloalkenyl may be
  • heteroaryl aryl or heteroaryl wherein the
  • aryl or heteroaryl may be unsubstituted or
  • R 7 may be -H; straight chained or branched
  • aryl includes benzyl, benzoyl, naphthyl, or phenyl and heteroaryl includes pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, quinolyl, aminophenyl, benzimidazolyl or 2-keto-1-benzimidazolinyl.
  • the compounds of the present invention may be present as enantiomers, disteriomers, isomers or two or more of the compounds may be present to form a racemic mixture
  • the compounds of the present invention are preferably at least 80% pure, more preferably 90. pure, and most preferably 95% pure.
  • the invention further provides for the (+) enantiomer of any of the compounds described herein which is a cis isomer or trans isomer.
  • the invention also provides for the (-) enantiomer of any of the compounds described herein which is a cis isomer or trans isomer.
  • the compound is not (+)-6-(3,4-Difluorophenyl)-1-(N-[2-(4-cyano-4-phenyl-cyclohexylamino)ethyl] ⁇ carboxam ⁇ do-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1,2,3,6-tetrahydropyrimidine hydrochloride.
  • Preferred embodiments of the present invention include a compound selected from the group consisting of: and
  • R 4 is
  • R 4 is
  • the invention also provides for compounds having the following structure:
  • M is polyfluorophenyl and R 5 and R 6 are independently substituted or unsubstituted phenyl or pyridyl.
  • R 1 is -CO 2 CH 3 , -COCH 3 , or -CONH 2
  • R 2 is CH 2 OCH 3 , methyl or ethyl
  • R 6 is H, -CN, or CO 2 CH 3 .
  • the invention also provides for compounds having the following structure:
  • the invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compounds described above and a pharmaceutically acceptable carrier.
  • a "therapeutically effective amount” is any amount of a compound which, when administered to a subject suffering from a disease against which the compounds are effective, causes reduction, remission, or regression of the disease
  • the therapeutically effective amount is an amount from about 0.01 mg per subject per day to about 500 mg per subject per day, preferably from about 0.1 mg per subject per day to about 60 mg per subject per day and most preferably from about 1 mg per subject per day to about 20 mg per subject per day.
  • the "pharmaceutically acceptable carrier” is any physiological carrier known to those of ordinary skill in the art useful in formulating pharmaceutical compositions.
  • the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution.
  • the pharmaceutically acceptable carrier is a solid and the composition is in the form of a powder or tablet.
  • the pharmaceutical carrier is a gel and the composition is in the form of a suppository or cream.
  • the invention provides a method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject any one of the compounds described herein effective to treat benign prostatic hyperplasia.
  • the invention further provides that the compound additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.
  • the compound effects treatment of benign prostatic hyperplasia by relaxing lower urinary tract tissue and in particular where the lower urinary tract tissue is prostatic smooth muscle.
  • the invention further provides a method of treating a subject suffering from elevated intraocular pressure which comprises administering to the subject one of the compounds described herein effective to lower intraocular pressure.
  • the invention further provides a method of treating a subject suffering from a disorder associated with elevated blood cholesterol which comprises administering to the subject one of the compounds described herein effective to inhibit cholesterol synthesis.
  • the invention also provides a method of treating a disease which is susceptible to treatment by antagonism of the ⁇ 1A receptor which comprises administering to the subject one of the compounds described herein effective to treat the disease.
  • the invention further provides a method of treating a subject suffering from impotency which comprises administenng to the subject one of the compounds described herein effective to treat impotency.
  • the invention further provides a method of treating a subject suffering from sympathetically mediated pair, which comprises administering to the subject one of the compounds described herein effective to treat sympathetically mediated pain.
  • the invention provides a method of treating a subject suffering from cardiac arrhythmia which comprises administering to the subject one of the compounds described herein effective to treat cardiac arrhythmia.
  • This invention also provides a method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject an amount of any of the compounds described above in combination with a 5 alpha-reductase inhibitor effective to treat benign prostatic hyperplasia.
  • the 5-alpha reductase inhibitor is finasteride.
  • the dosage administered to the subject is about 0.01 mg per subject per day to 50 mg per subject per day of finasteride in combination with an ⁇ 1A antagonist.
  • a preferred dosage administered to the subject is about 0.2 mg per subject per day to 10 mg per subject per day of finasteride in combination with an ⁇ 1A antagonist.
  • a more preferred dosage administered to the subject is about 1 mg per subject per day to 7 mg per subject per day of finasteride in combination with an ⁇ 1A antagonist.
  • the most preferred dosage administered to the subject is about 5 mg per subject per day of finasteride in combination with an ⁇ 1A antagonist.
  • the invention also provides for a pharmaceutical composition comprising a therapeutically effective amount of a combination of any of the compounds described herein in combination with finasteride and a pharmaceutically acceptable carrier.
  • tne pnarmaceutical composition is a therapeutically effective amount of a combination comprising an amount from about 0.01 mg per subject per day to about 500 mg per subject per day of any one of the compounds ⁇ escnoed herein and an amount cf finasteride of about 5 mg per subject per day.
  • a more preferred embodiment of the pharmaceutical composition is a therapeutically effective amount of a combination comprising an amount from about 0.1 mg per subject per day to about 60 mg per subject per day of any one of the compounds described herein and an amount of the finasteride of about 5 mg per subject per day.
  • the most preferred embodiment of the pharmaceutical composition is a therapeutically effective amount of a combination comprising from about 1 mg per subject per day to about 20 mg per subject per day of any one of the compounds described herein and an amount of the finasteride of about 5 mg per subject per day.
  • the invention further provides a method of relaxing lower urinary tract tissue which comprises contacting the lower urinary tract tissue with an amount of one of the compounds described herein effective to relax lower urinary tract tissue.
  • the lower urinary tract tissue is prostatic smooth muscle.
  • the compound additionally does not cause a fall in blood pressure when it is effective to relax lower urinary tract tissue.
  • the invention provides a method of relaxing lower urinary tract tissue in a subject which comprises administering to the subject an amount of one of the compounds described herein effective to relax lower urinary tract tissue.
  • the compound does not cause a fall in blood pressure and the lower urinary tract tissue is prostatic smooth muscle.
  • the invention further provides for a method of innibiting contraction of prostatic tissue, which comprises administering to the subject an amount of any of the compounds described herein effective to inhibit contraction of prostatic tissue.
  • the prostatic tissue is prostatic smooth muscle and the compound additionally does not cause a fall in blood pressure.
  • the invention provides for the use of the compounds described herein for the preparation of a pharmaceutical composition for lowering intraocular pressure, inhibiting cholesterol synthesis, and the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the ⁇ 1A receptor may be useful.
  • the invention provides for the use of the compounds described herein for the preparation of a pharmaceutical composition for relaxing lower urinary tract tissue and in particular prostatic smooth muscle.
  • the invention further provides for the use of any of compounds described herein for the preparation of a pharmaceutical composition, where the compound additionally does not cause a fall in blood pressure at dosages effective to lower intraocular pressure, to inhibit cholesterol synthesis, and for the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the ⁇ 1A receptor may be useful.
  • the invention provides for the use of the compounds described herein in the preparation of a medicament for lowering intraocular pressure, inhibiting cholesterol synthesis, and for the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the ⁇ 1A receptor may be useful.
  • the invention provides for the use of the compounds described herein in the preparation of a medicament for relaxing lower urinary tract tissue and in particular prostatic smooth muscle.
  • the invention further provides for the use of any of compounds described herein in the preparation of a medicament, where the compound additionally does not cause a fall in blood pressure at dosages effective to lower intraocular pressure, to inhibit cholesterol syntnesis, and for the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the ⁇ 1A receptor may be useful.
  • the invention provides for a drug which is useful for lowering intraocular pressure, inhibiting cholesterol synthesis, and the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the ⁇ 1A receptor may be useful, the effective ingredient of the said drug being any of the compounds described herein.
  • the invention further provides the drug described herein additionally does not cause a fall in blood pressure at dosages effective to lower intraocular pressure, to inhibit cholesterol synthesis, and for the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the ⁇ 1A receptor may be useful.
  • the invention provides for a drug which is useful for relaxing lower urinary tract tissue and in particular prostatic smooth muscle, the effective ingredient of the drug being any of the compounds described herein.
  • the invention further provides the drug which is useful for relaxing lower urinary tract tissue additionally does not cause a fall in blood pressure at dosages effective to relax lower urinary tract tissue.
  • the invention also provides for the (-) and (+) enantiomers of all compounds of the subject application described herein. Included in this invention are pharmaceutically acceptable salts and complexes of all of the compounds described herein.
  • the salts include but are not limited to the following acids and bases.
  • the following inorganic aci ⁇ s, nydrocnloric acid, hydrofluoric acid, hydronromic acid, hydroiodic acid, sulfuric acid and boric acid The organic acids, acetic acid, trifluoroacetic acid, formic acid, oxalic acid, malonic acid, succiinc acid, fumaric acid tartaric acid, maleic acid, citric acid, methanesulfoinc acid, trifluoromethanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid.
  • the following inorganic bases ammonia, hydroxyethylamine and hydrazine.
  • the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution.
  • the pharmaceutically acceptable carrier is a solid and the composition is in the form of a powder or tablet.
  • the pharmaceutical carrier is a gel and the composition is in the form of a suppository or cream.
  • the compound may be formulated as a part of a pharmaceutically acceptable transdermal patch.
  • a solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties in suicacle proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium pnosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmoregulators.
  • suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g.
  • cellulose derivatives preferably sodium carboxymethyl cellulose solution
  • alcohols including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil)
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by for example, intramuscular, intrathecal, epidural, intraperitoneal or subcutaneous injection.
  • Sterile solutions can also be administered intravenously.
  • the compounds may be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, cr other appropriate sterile injectable medium.
  • Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
  • the compound can be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents, for example, enough saline or glucose to make the solution isotonic, bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
  • a sterile solution or suspension containing other solutes or suspending agents, for example, enough saline or glucose to make the solution isotonic, bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
  • compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions.
  • forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.
  • Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.
  • This invention further provides for metabolites of the compounds of the present invention.
  • the in vivo activities and mechanisms of action of numerous enzymes responsiole for the generation of metabolites of pharmaceutical compounds are well-known in the art.
  • ethers may be modified to alcohols
  • esters may be modified by esterases
  • amides may be modified by amidases and peptidases.
  • This invention further provides a prodrug of the compounds disclosed herein.
  • Knowledge of metabolic activities allows the design of prodrug compounds which, when administered to a
  • the cyclohexylamino nitrogen may be modified by various substituents, such as methyl, alkanoyl, aroyl, or an alkyl or aryl carbamate may be formed, which are expected to yield the compounds of the present invention when acted upon in vivo by endogenous enzymes. As stated above, such modifications are intended only as
  • Scheme 1 illustrates the general synthetic scheme for the preparation of the compounds of the present invention. Specific references to synthetic steps from Schemes 2-8 are included in the Examples below where appropriate. All NMRs were obtained using a 300 MHz GE QEPLUS NMR machine.
  • (+)-5-(Benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(2,4-difluorophenyl)pyrimidine (Scheme 3; Step C-3).
  • (+)-5(benzyloxycarbonyl) -4-ethyl-1,6-dihydro-1- ⁇ N-[2-phenyl)ethyl] ⁇ carboxamido- 2-methoxy-6-(2,4-difluorophenyl)pyrimidine 11.15 g, 20.41 mmol
  • toluene 250 mL
  • 1,8-diazabicyclo[5,4,0]-undec-7-ene (4.04 g, 26.53 mmol
  • (+)-6-(2,4-difluorophenyl)-1,6- dihydro-2-methoxy-5-benzyloxycarbonyl-4-ethyl-1-(4- nitrophenoxy)-carbonylpyrimidine 6.50 g, 11.81 mmol
  • dichloromethane 150 mL
  • 1N HCl in ether 50 mL
  • Solvent was evaporated at reduced pressure and the residue was dried to give 6.31 g (100%) of the product as a white powder .
  • amidopyrimidine-5-carboxylic acid as a white solid (276 g, 98%).
  • the product was used in the next step without further purification.
  • j ( + ) - cis - 5 - Carboxamido - 6 - ( 2 , 4 -difluorophenyl) -1- ⁇ N- [2- (4-cyano-4-phenylcyclohexylamino)ethyl] ⁇ carboxamido-4-ethyl-2-oxo-1,2,3,6-tetrahydropyrimidine hydrochloride (Scheme 4; Step B-3).
  • the HCl salt was prepared by treatment of a solution of the free base in ether with 1N HCl in ether. M.p. 225-228 °C; Anal. Calcd. for C 29 H 33 N 6 O 3 F 2 Cl.0.38H 2 O.0.19CH 2 Cl 2 :C, 57.47; H, 5.64; N, 13.75. Found: C, 57.80; H, 5.56; N, 13.37.
  • the first major product to elute was (+)-5-methoxycarbonyl-4-methoxmethyl-1,6-dihydro-1- ⁇ N-[2-phenyl)ethyl] ⁇ carboxamido-2-methoxy-6- (3,4-difluorophenyl)pyrimidine (1.74 g, 44.5%), as an oil.
  • (+)-5-Methoxycarbonyl-1,6-dihydro-2-methoxy-4- methoxymethyl-6-(3,4-difluorophenyl)pyrimidine Scheme
  • the racemic 5-methoxycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine was resolved by chiral HPLC [Chiralcel OD 20 ⁇ 250 mm #369-703-30604; ⁇ 254 nm; hexanes/ethanol 95/5 and 0.01% diethylamine; 60 mg per injection; retention time of the desired enantiomer: 10.80 min., the first enantiomer peak to elute] to give (+)-5-methoxycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine.
  • (+)-6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1- (4-nitrophenoxy)-carbonylpyrimidine (0.305 g, 0.60 mmol) in dichloromethane (15 mL)
  • 1N HCl in ether (6 mL) was added at room temperature and the mixture was stirred at room temperature for 12 hours.
  • Solvent was evaporated at reduced pressure and the residue was dried to give 0.295 g (100%) of the product as a white powder.
  • ethylamine (0.567 g, 2.42 mmol) in dichloromethane (30 mL) was stirred at room temperature for 12 hours. It was washed with ice-cold 0.5N NaOH (2 ⁇ 10 mL) and dried over sodium sulfate. Solvent was evaporated at reduced pressure and the residue was purified by flash chromatography on silica gel (dichloromethane:MeOH:2M ammonia in MeOH, 90:8:4) to give 0.905 g (90%) as a white powder.
  • the HCl salt was prepared by treatment of a solution of the free base in ether with 1N HCl in ether. Anal. Calcd. for C 30 H 34 N 5 O 5 F 2 Cl:C, 58.30; H, 5.53; N, 11.06. Found: C, 57.99; H, 5.73; N, 11.20.
  • the HCl salts were prepared by treatment of a solution of the free base in ether with 1N HCl in ether.
  • Example 8 The cis isomer: M.P 145-146 °C; Anal. Calcd. for C 28 H 33 N 4 O 4 F 2 Cl 0.8H 2 O:C, 58.24; H, 6.04; N, 9.70. Found: C, 58.13; H, 5.83; N, 9.50.
  • Example 9 The trans isomer: M.P 156-157 °C; Anal. Calcd. for C 28 H 33 N 4 O 4 F 2 Cl 0.4CHCl 3 :C, 55.85; H, 5.51; N, 9.17. Found: C, 55.57; H, 5.76; N, 9.10.
  • (+)-6-(3,4-Difluorophenyl)-1,6-dihydro-2-oxo-5- methoxy-carbonyl-4-bromomethyl-1-[(4-nitrophenyloxy)carbonyl]pyrimidine Scheme 7; Step A).
  • (+)-6-(3,4- difluorophenyl) -1, 6-dihydro-2-methoxy-5- methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy) carbonyl]pyrimidine (1.5 mmol, 0.66 g) in 5 mL of chloroform was added a solution of bromine (1.5 mmol, 0.09 mL) in 3 mL of chloroform at 0°C and the solution was allowed to attain room temperature over 1.5 h. The solvent was removed in vacuo and the residue was again dissolved in CHCl 3 (20 mL) and washed with brine.
  • (+)-6-(3,4-Difluorophenyl)-1,6-dihydro-2-oxo-5-methoxycarbonyl-4-bromomethyl-1-[(4-nitrophenyloxy)carbcnyl]pyrimidine (1.5 mmol, 0.81 g) was heated in oil bath for 3 h (bath temperature 130°C.
  • (+)-5-benzyloxycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine as a viscous oil (1.25 g, 86%).
  • (+)-6-(3,4-difluorophenyl)-1- ⁇ N-[2-(4-cyano-4-phenylcyclohex-1-ylamino)-ethyl] ⁇ carboxamido-5-benzyloxycarbonyl-4-methoxymethyl-2-oxo 1,2,3,6-tetrahydropyrimidine 120 mg
  • methanol/water 9/1, 10 mL
  • 10% palladium on charcoal (20 mg) was added and the mixture was hydrogenated at 125 psi for 4 h.
  • the t1c analysis of the reaction indicated the completion of the reaction.
  • an oral composition cf a compound of this invention 100 mg of one of tr.e compounds described herein is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.
  • Binding affinities were measured for selected compounds of the invention at six cloned human alpha-1 and alpha- 2 receptor subtypes, as well as at the L-type calcium channel. The protocols for these experiments are given below.
  • ⁇ 1D Human ⁇ drenergic Receptor The entire coding region of ⁇ 1D (1719 bp), including 150 base pairs of 5' untranslated sequence (5' UT) and 300 bp of 3' untranslated sequence (3' UT), was cloned into the BamHI and ClaI sites of the polylinker-modified eukaryotic expression vector pCEXV-3, called EXJ.HR.
  • the construct involved the ligation of partial overlapping human lymphocyte genomic and hippocampal cDNA clones: 5' sequence were contained on a 1.2 kb SmaI-XhoI genomic fragment (the vector-derived BamHI site was used for subcloning instead of the internal insert-derived Smal site) and 3' sequences were contained on an 1.3 kb XhoI-ClaI cDNA fragment (the Clal site was from the vector polylinker).
  • Stable cell lines were obtained by cotransfection with the plasmid ⁇ 1A/EXJ (expression vector containing the ⁇ 1A receptor gene (old nomenclature)) and the plasmid pGCcos3neo (plasmid containing the aminoglycoside transferase gene) into LM(tk-) cells using calcium phosphate technique.
  • the cells were grown, in a controlled environment (37°C., 5% CO 2 ), as monolayers in Dulbecco's modified Eagle's Medium (GIBCO, Grand Island, NY) containing 25mM glucose and supplemented with 10% bovine calf serum, 100 units/ml penicillin g, and 100 ⁇ g/ml streptomycin sulfate.
  • the cell line expressing the human ⁇ 1D receptor used herein was designated L- ⁇ 1A (old nomenclature) and was deposited with the American Type Culture Collection, 12301 Parklavm Drive, Rockville, Maryland 20852, U.S.A. under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure.
  • the cell line expressing the human ⁇ 10 receptor was accorded ATCC Accession No.
  • ⁇ 1B Human Adrenergic Receptor The entire coding region of ⁇ 1B (1563 bp), including 200 base pairs and 5' untransiated sequence (5' UT) ana 600 bp cf 3' untranslated sequence (3' UT), was cloned into tne EcoRI site of pCEXV-3 eukaryotic expression vector The construct involved ligating the full-length containing EcoRI brainstem cDNA fragment from ⁇ ZapII into the expression vector. Stable cell lines were selected as described above.
  • the cell line used herein was designated L- ⁇ 1B and was deposited with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20832, U.S.A. under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure.
  • the cell line L- ⁇ 1B was accorded ATCC Accession No. CR 11139, on September 29, 1992.
  • ⁇ 1A Human ⁇ drenergic Receptor The entire coding region of ⁇ 1A (1401 bp), including 400 base pairs of 5' untranslated sequence (5' UT) and 200 bp of 3' untranslated sequence (3' UT), was cloned into the Kpnl site of the polylinker-modified pCEXV-3-derived eukaryotic expression vector, EXJ.RH.
  • the construct involved ligating three partial overlapping fragments: a 5' 0.6kb Hindi genomic clone, a central 1.8 EcoRI hippocampal cDNA clone, and a 3' 0.6Kb PstI genomic clone.
  • the hippocampal cDNA fragment overlaps with the 5' and 3' genomic clones so that the Hindi and Pstl sites at the 5' and 3' ends of the cDNA clone, respectively, were utilized for ligation.
  • This full- length clone was cloned into the Kpnl site of the expression vector, using the 5' and 3' Kpnl sites of the fragment, derived from vector (i.e., pBluescript) and 3'-untranslated sequences, respectively.
  • Stable cell lines were selected as described above.
  • the stable cell line expressing the human ⁇ 1A receptor used herein was designated L- ⁇ 1C (old nomenclature) and was deposited with the American Type Culture Collection, 12301 Parkiawn Drive, Rockvilie, Maryland 20852, U.S.A. under the provisions of the Budapest Treaty for tne International Recognition of the Deposit of Microorganisms for the Purposes of Patent Proce ⁇ ure
  • the cell line expressing the human ⁇ 1A receptor was accorded Accession No. CR 11140, on September 25, 1992.
  • Radioligand Binding Assays Transfected cells from culture flasks were scraped into 5ml of 5mM Tris-HCl, 5mM EDTA, pH 7.5, and lysed by soincation. The cell lysates were centrifuged at 1000 rpm for 5 min at 4°C, and the supernatant was centrifuged at 30,000 x g for 20 min at 4°C. The pellet was suspended in 50mM Tris-HCl, 1mM MgCl 2 , and 0.1% ascorbic acid at pH 7.5.
  • Binding of the ⁇ 1 antagonist [ 3 H]prazos ⁇ n (0.5 nM, specific activity 76.2 Ci/mmol) to membrane preparations of LM(tk-) cells was done in a final volume of 0.25 ml and incubated at 37°C for 20 min. Nonspecific binding was determined in the presence of 10 ⁇ M phentolamine. The reaction was stopped by filtration through GF/B filters using a cell harvester. Inhibition experiments, routinely consisting of 7 concentrations of the tested compounds, were analyzed using a non-linear regression curve-fitting computer program to obtain Ki values.
  • LM(tk-) cell lines stably transfected with the genes encoding the ⁇ 2A , ⁇ 2B , and a 2C receptors were used.
  • the cell line expressing the ⁇ 2A receptor is designated L- ⁇ 2A , and was deposited on November 6, 1992 under ATCC Accession No. CRL 11180.
  • the cell line expressing the ⁇ 2B receptor is designated L-NGC- ⁇ 2B , and was deposited on October 25, 1989 under ATCC Accession No. CRL10275.
  • the cell line expressing the ⁇ 2C receptor is designated L- ⁇ 2C , and was deposited on November 6, 1992 under ATCC Accession No. CRL-11181. Ail the cell lines were deposited with the
  • the compounds described above were assayed using cloned human alpha adrenergic receptors and the rat calcium channel.
  • the preferred compounds were found to be ⁇ 1A selective antagonists.
  • the compounds described herein were also found to exhibit weak binding affinity to the rat L-type calcium channel.
  • the alpha adrenergic receptor binding affinities of compounds 2-5, 7, 11, 13 and 14 are illustrated in Table 1 as follows:
  • optionally substituted cycloalkanone is refluxed with a diaminoalkane to form the corresponding (cycloalk-1-yl)aminoalkylimine, which on treatment with Na3O. yields (cycloalk-1-yl) aminoalkylamine.
  • the diamine is added to a 1-[(4-nitrophenyl)oxycarbonyl]pyrimidine to yield the final product.
  • cyclohexanone is shown, the process is equally applicable to substituted cycloalkanones from cyclobutanone through cyclooctanone.
  • replacement of the diaminoalkane of Part 1 with an aminoalkanol yields esters in Part 3 instead of amides.
  • Similar compounds may be produced by substitution of the 1,4-dibromobutane with other dibromoalkanes, including branched compounds in order to produce the alkyl-linked cycloalkylamine derivatives of the subject dihydropyrimidines.

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Abstract

Cette invention concerne des composés de dihydropirimidines constituants des antagonistes sélectifs des récepteurs α1A humains. Cette invention concerne également des utilisations de ces composés pour abaisser la pression intra-occulaire, inhiber la synthèse du cholestérol, décontracter les tissus des voies urinaires inférieures, le traitement de l'adénome prostatique, de l'impuissance, de l'arythmie cardiaque et dans le traitement de toutes maladies dans lesquelles l'antagonisme du récepteur α1A peut être utile. L'invention concerne en outre une composition pharmaceutique comprenant une dose thérapeutique efficace des composés ci-dessus définis ainsi qu'un excipient pharmaceutiquement acceptable.
PCT/US1996/018573 1995-11-16 1996-11-15 Dihydropirimidines et leurs emplois WO1997017969A1 (fr)

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JP9519157A JP2000500470A (ja) 1995-11-16 1996-11-15 ジヒドロピリミジンおよびその使用
US09/068,782 US6228861B1 (en) 1995-11-16 1996-11-15 Dihydropyrimidines and uses thereof
AU10558/97A AU714287B2 (en) 1995-11-16 1996-11-15 Dihydropyrimidines and uses thereof
EP96941406A EP0866708A4 (fr) 1995-11-16 1996-11-15 Dihydropirimidines et leurs emplois

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Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6037354A (en) * 1997-06-18 2000-03-14 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
EP0988295A1 (fr) * 1997-06-18 2000-03-29 Synaptic Pharmaceutical Corporation Piperidines a substitution heterocyclique et utilisations de ces dernieres
US6057350A (en) * 1997-06-18 2000-05-02 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
US6080760A (en) * 1997-06-18 2000-06-27 Merck & Co., Inc. Alpha 1A adrenergic receptor antagonists
EP1014973A1 (fr) * 1997-06-18 2000-07-05 Merck & Co., Inc. ANTAGONISTES DES ADRENORECEPTEURS ALPHA 1a
US6143750A (en) * 1997-06-18 2000-11-07 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
WO2000078730A1 (fr) * 1999-06-23 2000-12-28 Ajinomoto Co., Inc. Nouveaux derives dihydropyrimidiniques
US6172066B1 (en) * 1996-05-16 2001-01-09 Synaptic Pharmaceutical Corporation Dihydropyrimidines and uses thereof
US6214832B1 (en) 1997-06-18 2001-04-10 Merck & Co., Inc. Bis-piperidinyl-pyrimidin-2-ones as alpha 1a adrenergic receptor antagonists
US6228870B1 (en) 1998-11-10 2001-05-08 Merck & Co., Inc. Oxazolidinones useful as alpha 1a adrenoceptor antagonists
US6232318B1 (en) 1998-11-12 2001-05-15 Merck & Co., Ltd. Pyrimidinedione derivatives useful as alpha 1A adrenoceptor antagonists
US6235759B1 (en) 1998-10-29 2001-05-22 Merck & Co., Inc. Dihydropyridinones and pyrrolinones useful as alpha 1A adrenoceptor antagonists
US6316437B1 (en) 1999-09-30 2001-11-13 Merck & Co., Inc. Spirohydantoin compounds and uses thereof
US6319932B1 (en) 1998-11-10 2001-11-20 Merck & Co., Inc. Oxazolidinones useful as alpha 1A adrenoceptor antagonists
US6326372B1 (en) 1999-09-30 2001-12-04 Merck & Co., Inc. Lactam and cyclic urea derivatives useful as alpha 1a adrenoceptor antagonists
US6329393B1 (en) 1998-12-17 2001-12-11 Merck & Co., Inc. Crystalline pharmaceutically acceptable salts of an oxazolidinone derivative
US6339090B1 (en) 1998-07-30 2002-01-15 Merck & Co., Inc. Alpha 1A adrenergic receptor antagonists
US6358959B1 (en) 1999-01-26 2002-03-19 Merck & Co., Inc. Polyazanaphthalenone derivatives useful as alpha 1a adrenoceptor antagonists
US6376503B1 (en) 1997-06-18 2002-04-23 Merck & Co., Inc Alpha 1a adrenergic receptor antagonists
US6387893B1 (en) 1999-09-30 2002-05-14 Merck & Co., Inc. Spirotricyclic substituted azacycloalkane derivatives and uses thereof
US6436962B1 (en) 1999-09-30 2002-08-20 Merck & Co., Inc. Arylhydantoin derivatives and uses thereof
US6809102B2 (en) 2001-03-29 2004-10-26 Bristol-Myers Squibb Company Cyano-substituted dihydropyrimidine compounds and their use to treat diseases
US6900214B2 (en) 2001-03-29 2005-05-31 Bristol-Myers Squibb Company Cyano-substituted dihydropyrimidine compounds and their use to treat diseases
EP1734963A2 (fr) * 2004-04-02 2006-12-27 Merck & Co., Inc. Methode destinee a traiter des hommes presentant des troubles metaboliques et anthropometriques
US7157461B2 (en) 2003-07-23 2007-01-02 Bristol-Myers Squibb Co. Substituted dihydropyrimidine inhibitors of calcium channel function
US7166603B2 (en) 2003-07-23 2007-01-23 Bristol-Myers Squibb Co. Dihydropyrimidone inhibitors of calcium channel function
US8835449B2 (en) 2011-11-11 2014-09-16 Pfizer Inc. 2-thiopyrimidinones
US9771332B2 (en) 2015-05-05 2017-09-26 Pfizer Inc. 2-thiopyrimidinones
US9908908B2 (en) 2012-08-30 2018-03-06 Jiangsu Hansoh Pharmaceutical Co., Ltd. Tenofovir prodrug and pharmaceutical uses thereof
RU2712210C1 (ru) * 2019-07-10 2020-01-27 Общество с ограниченной ответственностью "Технофарм" Лекарственное средство для стимуляции приживления сетчатого имплантата после пластики вентральных грыж

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JPS5659778A (en) * 1979-10-23 1981-05-23 Showa Denko Kk Dimethylthienopyrimidione derivative
US4703120A (en) * 1986-04-28 1987-10-27 Ortho Pharmaceutical Corporation Furo(3,4-d)pyrimidine-2,4-dione derivatives and intermediates thereof

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JPS5659778A (en) * 1979-10-23 1981-05-23 Showa Denko Kk Dimethylthienopyrimidione derivative
US4703120A (en) * 1986-04-28 1987-10-27 Ortho Pharmaceutical Corporation Furo(3,4-d)pyrimidine-2,4-dione derivatives and intermediates thereof

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See also references of EP0866708A4 *

Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6172066B1 (en) * 1996-05-16 2001-01-09 Synaptic Pharmaceutical Corporation Dihydropyrimidines and uses thereof
US6255315B1 (en) 1997-06-18 2001-07-03 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
EP0988295A1 (fr) * 1997-06-18 2000-03-29 Synaptic Pharmaceutical Corporation Piperidines a substitution heterocyclique et utilisations de ces dernieres
US6057350A (en) * 1997-06-18 2000-05-02 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
US6080760A (en) * 1997-06-18 2000-06-27 Merck & Co., Inc. Alpha 1A adrenergic receptor antagonists
EP1014973A1 (fr) * 1997-06-18 2000-07-05 Merck & Co., Inc. ANTAGONISTES DES ADRENORECEPTEURS ALPHA 1a
EP1014973A4 (fr) * 1997-06-18 2000-09-20 Merck & Co Inc ANTAGONISTES DES ADRENORECEPTEURS ALPHA 1a
US6143750A (en) * 1997-06-18 2000-11-07 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
EP0988295A4 (fr) * 1997-06-18 2003-08-13 Synaptic Pharma Corp Piperidines a substitution heterocyclique et utilisations de ces dernieres
US6214832B1 (en) 1997-06-18 2001-04-10 Merck & Co., Inc. Bis-piperidinyl-pyrimidin-2-ones as alpha 1a adrenergic receptor antagonists
US6376503B1 (en) 1997-06-18 2002-04-23 Merck & Co., Inc Alpha 1a adrenergic receptor antagonists
US6037354A (en) * 1997-06-18 2000-03-14 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
US6339090B1 (en) 1998-07-30 2002-01-15 Merck & Co., Inc. Alpha 1A adrenergic receptor antagonists
US6235759B1 (en) 1998-10-29 2001-05-22 Merck & Co., Inc. Dihydropyridinones and pyrrolinones useful as alpha 1A adrenoceptor antagonists
US6319932B1 (en) 1998-11-10 2001-11-20 Merck & Co., Inc. Oxazolidinones useful as alpha 1A adrenoceptor antagonists
US6228870B1 (en) 1998-11-10 2001-05-08 Merck & Co., Inc. Oxazolidinones useful as alpha 1a adrenoceptor antagonists
US6232318B1 (en) 1998-11-12 2001-05-15 Merck & Co., Ltd. Pyrimidinedione derivatives useful as alpha 1A adrenoceptor antagonists
US6329393B1 (en) 1998-12-17 2001-12-11 Merck & Co., Inc. Crystalline pharmaceutically acceptable salts of an oxazolidinone derivative
US6358959B1 (en) 1999-01-26 2002-03-19 Merck & Co., Inc. Polyazanaphthalenone derivatives useful as alpha 1a adrenoceptor antagonists
US6855716B2 (en) 1999-06-23 2005-02-15 Ajinomoto Co., Inc. Dihydropyrimidine compounds and compositions containing the same
WO2000078730A1 (fr) * 1999-06-23 2000-12-28 Ajinomoto Co., Inc. Nouveaux derives dihydropyrimidiniques
US6326372B1 (en) 1999-09-30 2001-12-04 Merck & Co., Inc. Lactam and cyclic urea derivatives useful as alpha 1a adrenoceptor antagonists
US6387893B1 (en) 1999-09-30 2002-05-14 Merck & Co., Inc. Spirotricyclic substituted azacycloalkane derivatives and uses thereof
US6436962B1 (en) 1999-09-30 2002-08-20 Merck & Co., Inc. Arylhydantoin derivatives and uses thereof
US6316437B1 (en) 1999-09-30 2001-11-13 Merck & Co., Inc. Spirohydantoin compounds and uses thereof
US6809102B2 (en) 2001-03-29 2004-10-26 Bristol-Myers Squibb Company Cyano-substituted dihydropyrimidine compounds and their use to treat diseases
US6900214B2 (en) 2001-03-29 2005-05-31 Bristol-Myers Squibb Company Cyano-substituted dihydropyrimidine compounds and their use to treat diseases
US7157461B2 (en) 2003-07-23 2007-01-02 Bristol-Myers Squibb Co. Substituted dihydropyrimidine inhibitors of calcium channel function
US7166603B2 (en) 2003-07-23 2007-01-23 Bristol-Myers Squibb Co. Dihydropyrimidone inhibitors of calcium channel function
EP1734963A2 (fr) * 2004-04-02 2006-12-27 Merck & Co., Inc. Methode destinee a traiter des hommes presentant des troubles metaboliques et anthropometriques
EP1734963A4 (fr) * 2004-04-02 2008-06-18 Merck & Co Inc Methode destinee a traiter des hommes presentant des troubles metaboliques et anthropometriques
EP2305352A1 (fr) * 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
US8835449B2 (en) 2011-11-11 2014-09-16 Pfizer Inc. 2-thiopyrimidinones
US8841314B2 (en) 2011-11-11 2014-09-23 Pfizer Inc. 2-Thiopyrimidinones
US9399626B2 (en) 2011-11-11 2016-07-26 Pfizer Inc. 2-thiopyrimidinones
US9873673B2 (en) 2011-11-11 2018-01-23 Pfizer Inc. 2-thiopyrimidinones
US9908908B2 (en) 2012-08-30 2018-03-06 Jiangsu Hansoh Pharmaceutical Co., Ltd. Tenofovir prodrug and pharmaceutical uses thereof
US9771332B2 (en) 2015-05-05 2017-09-26 Pfizer Inc. 2-thiopyrimidinones
RU2712210C1 (ru) * 2019-07-10 2020-01-27 Общество с ограниченной ответственностью "Технофарм" Лекарственное средство для стимуляции приживления сетчатого имплантата после пластики вентральных грыж

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