EP1021185A1 - Dihydropyrimidines et leurs emplois - Google Patents
Dihydropyrimidines et leurs emploisInfo
- Publication number
- EP1021185A1 EP1021185A1 EP97924745A EP97924745A EP1021185A1 EP 1021185 A1 EP1021185 A1 EP 1021185A1 EP 97924745 A EP97924745 A EP 97924745A EP 97924745 A EP97924745 A EP 97924745A EP 1021185 A1 EP1021185 A1 EP 1021185A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- branched
- straight chained
- mmol
- cycloalkyl
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- 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
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- 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
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- C—CHEMISTRY; METALLURGY
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- 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
- C07D401/06—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 carbon chain containing only aliphatic carbon atoms
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- 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
- C07D401/10—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 carbon chain containing aromatic rings
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- 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
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- 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
- C07D401/14—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 three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
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- 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 used throughout this application and the supporting tables and figures to refer to this receptor subtype.
- the receptor formerly designated ⁇ 1A was renamed c ⁇ 1D .
- the new nomenclature is used throughout this application.
- 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.
- BPH is observed in approximately 70% of males over the age of 70.
- the method of choice for treating BPH is surgery (epor, H., Urol . Clinics North Amer., 17, 651 (1990)) .
- Over 400,000 prostatectomies are performed annually (data from 1986) .
- a medicinal alternative to surgery is clearly very desirable.
- the limitations of surgery for treating BPH include the morbidity rate of an operative procedure in elderly men, persistence or recurrence of obstructive and irritative symptoms, as well as the significant cost of surgery.
- ⁇ -Adrenergic receptors 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
- Many of 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
- the ⁇ 1A receptor is responsible for mediating the contraction of human. prostate smooth muscle (Gluchowski, c. e . 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. Qphthalmol. Vis. Sci. , 34 Abst.
- This invention is directed to dihydropyrimidine compounds which are selective antagonists for human ⁇ 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 ⁇ IA receptor may be useful.
- the invention further provides a pharmaceutical composition comprising a therapeuticaily effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.
- the present invention is directed to compounds having the structure:
- each of Y lf Y 2 , Y 3 , Y 4 and Y 5 is independently -H; straight chained or branched C -C ⁇ 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; -N0 2 ; -N 3 ; -CN; -0R 3 , -OCOR 3 , -COR 3 , -CONHR 3 , -CON(R 3 ) 2 , or -COOR 3 ; or any two of Y 1( Y 2 , Y 3 , Y ⁇ and Y 5 present on adjacent carbon atoms can constitute a methylened
- X is S; O; or NR 3 ;
- R x is -H; -N0 2 ; -CN; straight chained or branched C 1 -C ⁇ 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 ; -0R 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; - C0 2 R 3 ; or -CON(R 3 ) 2 ;
- R 2 is -H; straight chained or branched Ci-C-, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl , monof luorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C 3 -C 10 cycloalkyl-Cj-Ci o -alkyl, C 3 -C 10 cycloalkyl-C ⁇ C ⁇ - monofluoroalkyl or C 3 -C 10 cycloalkyl - C l -C 10 - polyfluoroalkyl; -CN; -CH 2 XR 3 , -CH 2 X(CH 2 ) p NHR 3 ,
- each p is independently an integer from 1 to 7; wherein each n is independently an integer from 0 to 5; wherein each R 3 is independently -H; straight chained or branched C,-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;
- Z' is (CH 2 ) 0 , CO, (CH 2 ) 0 CO, or CO(CH 2 ) 0 ;
- each V is independently O; S; CH 2 ; CR 5 R 7 ; C(R 7 ) 2 ; or NR 7 ;
- each m is independently an integer from 0 to 3; wherein o is an integer from 1 to 3;
- each R is independently -H; -F; straight chained or branched 0,-0, alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -C0 2 R 3 ; or -0R 3 ;
- R 5 and R 7 each independently may be -H; F; Cl; Br; I; -C0R 3 ; -C0 2 R 3 ; -CON(R 3 ) 2 ; -CN; -N0 2 ; -N(R 3 ) 2 ; -0R 3 ; -SR 3 ; -(CH 2 ) p OR 3 ; -(CH 2 ) p SR 3 ; straight chained or branched C,-C 7 alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl, or C 3 -C 7 cycloalkyl or cycloalkenyl; wherein the alkyl, aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted with one or more aryl or heteroaryl, wherein
- each R 6 is independently -H; straight chained or branched C 1 -C 7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; or -0R 3 ;
- the invention further provides for the (+) enantiomer of any of the compounds described herein which is a cis isomer or a trans isomer.
- the invention also provides for the (-) enantiomer of any of the compounds described herein which is a cis or a trans isomer.
- the compounds of the present invention are preferably at least 80% pure, more preferably 90% pure, and most preferably 95% pure.
- Z' is CO and n is 0.
- the invention provides for compounds having the following structures:
- the present invention is also directed to compounds having the structure:
- each of Y,, Y 2 , Y 3 , Y 4 and Y 3 is independently -H; straight chained or branched C,-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; -N0 2 ; -N 3 ; -CN; -0R 3 , -OCOR 3 , -COR 3 , -CONHR 3 , -CON(R 3 ) 2 , or -COOR 3 ; or any two of Y lf ⁇ 2# Y 3 , Y 4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group
- X is S; 0; or NR 3 ;
- R ⁇ is -H; -N0 2 ; -CN; straight chained or branched Cj-C, 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 ; - C0 2 R 3 ; or -CON(R 3 ) 2 ;
- R 2 is -H; straight chained or branched Ci-C-, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl , monofluorocycloalkyl , polyfluorocycloalkyl or cycloalkenyl; C 3 -C 10 cycloalkyl-Ci-CiQ-al yl, C 3 -C 10 cycloalkyl-C ⁇ C ⁇ - monofluoroalkyl or C 3 -C 10 polyfluoroalkyl; -CN; -CH 2 XR 3 , -CH 2 X(CH 2 ) p NHR 3 ,
- each p is independently an integer from l to 7; wherein each n is independently an integer from 0 to 5;
- each R 3 is independently -H; straight chained or branched C ⁇ C, alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein 4 is
- Z is C 2 -C 7 alkenyl or alkynyl; CH 2 ; O; CO; C0 2 ; CONR 3 ; S; SO; S0 2 ; or NR 3 ;
- Z' is (CH 2 ) 0 , CO, (CH 2 ) o C0, or C0(CH 2 ) o ;
- each D is independently CH 2 ; O; S; NR 3 ; CO; or CS;
- each V is independently 0; S; CH 2 ; CR 5 R 7 ; C(R 7 ) 2 ; or NR 7 ; provided that when V is CR S R 7 the remaining carbons on the ring may only be substituted with R 6 ;
- each m is independently an integer from 0 to 3; wherein o is an integer from 1 to 3;
- each R is independently -H; -F; straight chained or branched C x -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -C0 2 R 3 ; or -0R 3 ;
- R 5 is aryl or heteroaryl substituted with one or more of F; Cl; Br; I; C0R 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -0R 3 , -SR 3 ; (CH 2 ) o 0R 3 ; (CH 2 ) 0 SR 3 ; straight chained or branched Cj-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched
- each R 6 is independently -H; straight chained or branched C ⁇ C, alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; or -0R 3 ; wherein R 7 is aryl or heteroaryl substituted with one or more of F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -0R 3 , -SR 3 ; (CH 2 ) c OR 3 ; (CH 2 ) C SR 3 ; straight chained or branched C ⁇ -C
- R B is -H; substituted or unsubstituted benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl or 2-keto-l-benzimidazolinyl, wherein the benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl or 2-keto-l-benzimidazolinyl is substituted with -H, -F, -Cl, -Br, -I, -N0 2 , -CN,
- V is selected from CR 5 R 7 or NR 7 and p is selected from 1-3.
- the present invention is also directed to compounds having the structure:
- each of Y,, Y 2 , Y 3f Y 4 and Y 5 is independently -H; straight chained or branched C,-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; -N0 2 ; -N 3 ; -CN; -0R 4 , -OCOR 4 , -COR 4 , -CONHR 4 , -CON(R 4 ) 2 , or -COOR 4 ; or any two of Y 3 , Y 2 , Y 3 , Y 4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group;
- X is S; 0; or NR 4 ;
- B is -H; straight chained or branched -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, alkoxy or thioalkyl; straight chained or branched C 2 -C 7 alkenyl; -SCH 2 C 6 H 4 OR 4 ; - (CH 2 ) n C 6 H s ; -CH 2 X(CH 2 ) n NHR 4 ; - (CH 2 ) ⁇ NHR 4 ; or -0R 4 ;
- R 3 is -H; -N0 2 ; -CN; straight chained or branched C ⁇ C, 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 4 ) 2 ; -0R 4 ; -(CH 2 ) p OR 4 ; -C0R 4 ; -
- R 2 is -H; straight chained or branched C x -C 7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl , monofluorocycloalkyl , polyfluorocycloalkyl or cycloalkenyl; C 3 -C 10 cycloalkyl-C j -C ⁇ -alkyl, C 3 -C 10 cycloalkyl-C ⁇ C ⁇ - monofluoroalkyl or C 3 -C 10 polyfluoroalkyl; -CN; -CH 2 XR 4 , -CH 2 X(CH 2 ) p NHR 4 , -(CH 2 ) n NHR 4 , -CH 2 X(CH 2 ) p N
- each p is independently an integer from 1 to 7; wherein each n is independently an integer from 0 to 5; wherein R 3 is
- Z is C ⁇ C, alkenyl or alkynyl; CH 2 ; O; CO; C0 2 ; CONR 4 ; S; SO; S0 2 ; or NR ⁇ ;
- Z' is (CH 2 ) march, CO, (CH 2 ) 0 CO, or C0(CH 2 ) o ;
- each D is independently CH 2 ; O; S; NR ⁇ * CO; or CS;
- each V is independently O; S; CH 2 ; CR 5 R 7 ; C(R 7 ) 2 ; or NR 7 ; provided that when V is CR S R 7 the remaining carbons on the ring may only be substituted with R 6 ;
- each m is independently an integer from 0 to 3; wherein o is an integer from 1 to 3 ;
- each R is independently -H; -F; straight chained or branched C ⁇ C, alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C-, alkenyl or alkynyl; -N(R 4 ) 2 ; -N0 2 ; -CN; -C0 2 R 4 ; or -OR 4 ;
- each R 4 is independently -H; straight chained or branched C ⁇ C-, alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
- R 5 is aryl or heteroaryl substituted with one or more of F; Cl; Br; I; C0R 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -0R 3 , -SR 3 ; (CH 2 ) 0 0R 3 ; (CH 2 ) 0 SR 3 ; straight chained or branched C ⁇ C, alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein each R 6 is independently -H; straight chained or branched C ⁇ C, alkyl
- R 7 is aryl or heteroaryl substituted with one or more of F; Cl; Br; I; C0R 3 ; C0 2 R 3 ; -C0N(R 3 ) 2 ;
- Ci-C. alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; and
- R 8 is -H; substituted or unsubstituted benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl or 2-keto-l-benzimidazolinyl, wherein the benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl or 2-keto-l-benzimidazolinyl is substituted with -H, -F, -Cl, -Br, -I, -N0 2 , -CN,
- the present invention is also directed to compounds having the structure:
- each of Y,, Y 2 , Y 3 , Y 4 and Y 5 is independently -H; straight chained or branched C,-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; -N0 2 ; -N 3 ; -CN; -0R 4 -OCOR 4 , -COR*, -CONHR,, -CON( 4 ) 2 , or -COOR,; or any two of Y, Y 2 , Y 3 , Y and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group;
- X is S; 0; or NR,
- B is -H; straight chained or branched C,-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, alkoxy or thioalkyl; straight chained or branched C 2 - ⁇ alkenyl; -SC C ⁇ OR,; -(CH 2 ) felicitC 6 H $ ; -CH 2 X(CH 2 ) n NHR 4 ;
- R is -H; -N0 2 ; -CN; straight chained or branched C,-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 4 ) 2 ; -OR,; -(CH 2 ) p OR,; -COR,; - C0 2 R,; or -CON(R 4 ) 2 ;
- R 2 is -H; straight chained or branched C,-C 7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl , monofluorocycloalkyl , polyfluorocycloalkyl or cycloalkenyl; C 3 -C l0 cycloalkyl-C,-C, 0 -alkyl, C 3 -C 10 cycloalkyl-C,-C 10 - monofluoroalkyl or C 3 -C, 0 cycloalkyl-C,-C, 0 - polyfluoroalkyl; -CN; -CH 2 XR 4 , -CH 2 X(CH 2 ) p NHR 4 , -(CH 2 )
- each p is independently an integer from 1 to 7; wherein each n is independently an integer from 0 to 5; wherein R 3 is
- Z' is (CH 2 ) of CO, (CH 2 ) 0 CO, or CO(CH 2 ) endeavour;
- each V is independently O; S; CH 2 ; CR S R 7 ; C(R 7 ) 2 ; or NR 7 ;
- each m is independently an integer from 0 to 3; wherein o is an integer from 1 to 3;
- each R is independently -H; -F; straight chained or branched C,-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R,) 2 ; -N0 2 ; -CN; -C0 2 R,; or -OR,;
- each R is independently -H; straight chained or branched C,-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;
- R 5 and R 7 each independently may be -H; F; Cl; Br; I; -COR 3 ; -C0 2 R 3 ; -CON(R 3 ) 2 ; -CN; -N0 2 ; -N(R 3 ) 2 ; -0R 3 ; -SR 3 ; -(CH 2 ) p OR 3 ; -(CH 2 ) p SR 3 ; straight chained or branched C,-C 7 alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl, or C 3 -C 7 cycloalkyl or cycloalkenyl; wherein the alkyl, aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted with one or more aryl or heteroaryl, wherein the al
- each R 6 is independently -H; straight chained or branched Cj-C 7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 - C ⁇ alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; or -OR 4 ;
- aryl includes phenyl, benzyl, benzoyl or naphthyl and heteroaryl includes pyrazinyl, pyrryl, furanyl, thiophenyl, pyridyl, imidazolyl, indolyl, aminophenyl, benzamidyl, benzimidazolyl, benzfurazanyl, benzfuranyl, 2-keto-l-benzimidazolinyl or quinolyl .
- the invention further provides for a pharmaceutical composition
- a pharmaceutical composition comprising a therapeuticaily effective amount of any of the compounds described above and a pharmaceutically acceptable carrier.
- a "therapeuticaily 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 compound of the pharmaceutical composition 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 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 administering 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 pain 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.
- the invention provides a method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject one of the compounds described herein 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 more preferred dosage administered to the subject is about 1 rag 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 therapeuticaily effective amount of a combination of any of the compounds described herein in combination with finasteride and a pharmaceutically acceptable carrier.
- the pharmaceutical composition is a therapeuticaily 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 described herein and an amount of finasteride of about 5 mg per subject per day.
- a more preferred embodiment of the pharmaceutical composition is a therapeuticaily 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 therapeuticaily 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 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 inhibiting 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 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 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 acids; hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid.
- the organic acids acetic acid, trifluoroacetic acid, formic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid.
- the following inorganic bases ammonia, hydroxyethylamine and hydrazine.
- the following organic bases methylamine, ethylamine, propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, ethylenediamine, hydroxyethylamine, morpholine, piperazine and guanidine.
- This invention further provides for the hydrates and polymorphs of all of the compounds described herein.
- 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 table -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 suitable 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 phosphate, 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 osmo- regulators.
- 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)
- 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, or 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 compound was prepared from 1, 6-dihydro-5-methoxycarbonyl-2- [ ⁇ (4-methoxyphenyl) methyljthio] -4-methyl-6- (4-nitrophenyl) -1- [ (4-nitroph enyloxy) carbonyl]pyrimidine (0.77 g, 1.3 mmol) , 3- [4- phenylpiperidin-l-yl] propylamine (0.34 g, 1.56 mmol,
- Cyano-4-phenylpiperidine hydrochloride (5.01 g, 22.5 mmol) was added to water (100 mL) , and the solution was basified to pH 10-11 by addition of 6 N aqueous NaOH. The mixture was extracted with CH 2 C1 2 (3 x 100 mL) . The combined organic extracts were dried (MgS0 4 ) and concentrated. To the residue were added 3- bromopropylamine hydrobromide (4.92 g, 22.5 mmol) , anhydrous K 2 C0 3 (3.42 g, 24.8 mmol, 1.10 eq) , and 1,4- dioxane (100 mL) .
- This compound was prepared from 1, 6-dihydro-5-methoxy carbonyl-2- [ ⁇ (4-methoxyphenyl)methyl ⁇ thio] -4-methyl-6 - (4-nitrophenyl) -1- [ (4-nitrophenyloxy) carbonyl]pyrimi dine (0.592 g, 1 mmol) , 3- [4-cyano-4-phenyl piperidin-1-yl]propylamine (0.292 g, 1.2 mmol, 1.2 eq) and purified using similar conditions described in Example 1 (0.445 g, 64%) ; m.p.
- This compound was prepared from 1, 6-dihydro-5-methoxycarbonyl -2- [ ⁇ (4-methoxyphenyl)methyl ⁇ thio] -4-methyl-6- (4-nitr ophenyl) -1- [ (4-nitrophenyl-oxy)carbonyl]pyrimidine (1.0 g, 1.69 mmol) , 3- [4-methoxycarbonyl-4-phenyl piperidin-1-yl]propylamine (0.56 g, 2.03 mmol, 1.2 eq) and purified using similar conditions described in Example 1 (1.085 g, 88%) ; m.p. 140-141 °C; -NMR
- the mixture was basified to pH 9 by addition of 6 N aq. NaOH and extracted with CH 2 C1 2 (3 x 75 mL) .
- the combined organic solutions were dried (MgS0 4 ) and concentrated.
- the residue was dissolved in CH 2 C1 2 (10 mL) and treated with HCl in ether (1.0 M, 9.0 mL, 2.0 eq) .
- the solvents were removed, ether (30 mL) was added, the mixture was filtered, and the filter cake was washed with ether (2 x 10 mL) .
- Water (20 mL) was added to the resulting white solid, the pH was adjusted to 10 with 1 N NaOH, and the aqueous phase was extracted with CH 2 C1 2 (3 x 40 mL) .
- the combined organic extracts were dried (MgS0 4 ) and concentrated to give 610 mg (43%) of white solid, which was characterized spectroscopically.
- Example 7 a 4-Ethoxycarbonyl-4-phenylpiperidine.
- H 2 S0 4 (1.62 g, 16.56 mmol) in EtOH (200 mL)
- 4-phenyl-4-piperidine-carboxylic acid 4-methyl benzenesulfonate 25 g, 66.23 mmol
- Excess ethanol was evaporated at reduced pressure and the residue was poured into a mixture of ice and 6 N NaOH. The pH was adjusted to 10-11 by adding more 6 N NaOH and extracted with CH 2 Cl 2 (3 X 100 mL) .
- the crude product was purified by flash column chromatography on silica gel using 10% through 30% EtOAc in hexane as the gradient eluent (9.8 g, 64%) .
- the Hl-NMR analysis of the product showed it to be a 19:1 mixture of the amine/imine tautomers which was used as such in the next step.
- the first major product to elute was (-) -1, 6-dihydro-2-methoxy-5-methoxy carbonyl-4-methyl-6- ( -nitrophenyl) -1- ⁇ N- [ (2-phenyl) ethyl] ⁇ carboxamidopyrimidine and this compound was crystallized from isopropyl ether (0.85 g, 33.6%) ; m.p.
- Second major product to elute was (-) -5- (benzyloxycarbonyl) -4-ethyl- 1, 6-dihydro-1- ⁇ N- [2-phenyl) ethyl] ⁇ carboxamido-2- methoxy-6- (3,4-diflurophenyl)pyrimidine. Colorless oil.
- (+) -5- (Benzyloxycarbonyl) -1, 6-dihydro-2-methoxy-4- ethyl-6- (3,4-diflurophenyl)pyrimidine To a stirred solution of (+) -5- (benzyloxycarbonyl) -4-ethyl-l, 6- dihydro-l- ⁇ N- [2-phenyl) ethyl] ⁇ carboxamido-2-methoxy-6- (3 ,4-diflurophenyl)pyrimidine (1.83 mmol, 1.0 g) in toluene (10 mL) was added 1, 8-diazabicyclo [5, 4, 0] - undec-7-ene (0.81 mmol, 0.12 mL) at room temperature and the resulting solution was heated to reflux for 5h and then stirred for 12h at room temperature.
- 6- (3, 4-Difluorophenyl) -1, 6-dihydro-2-methoxy- 5-methoxycarbonyl-4-methyl-1- [ (4-nitrophenyloxy) carbo nyl]pyrimidine To a solution of 6- (3 , 4-difluorophenyl) -1, 6-dihydro-2- methoxy-5-methoxycarbonyl-4-methylpyrimidine (2.82 g, 9.52 mmol) and 4-dimethylaminopyridine (1.16 g, 9.52 mmol) in CH 2 C1 2 (50 mL) , at 0-5 °C, 4-nitrophenyl chloroformate (1.82 g, 9.04 mmol) was added and the mixture was allowed to warm to room temperature. After 12 hours solvent was evaporated and the residue was purified by flash column chromatography (Si0 2 ,
- 5-Methylbenzfuroxan 4-Methyl-2-nitroaniline (100 g, 0.650 mol) was suspended in saturated alcoholic sodium hydroxide solution (1.50 1) . To this suspension was added with cooling (5 °C) commercial aqueous sodium hypochlorite till the red color disappeared. The fluffy yellow precipitate formed was filtered, washed with cold water and recrystallized from ethanol to get 5-Methylbenzfuroxan (88.2 g, 89 % yield) as a pale solid.
- 5-Methylbenzofurazan To 5-Methylbenzfuroxan (88.2 g, 0.59. mol) in refluxing EtOH (75 ml) was added dropwise P(OEt) 3 (150 ml ) . When addition was complete, refluxing was continued for 1 more hour. The solvent was removed by rotary evaporation and the residue shaken with water (200 mL) and allowed to stand overnight at (0-5 °C) . The brown solid so obtained was filtered, washed with water and chromatograghed on silica gel to yield 5-Methylbenzofurazan (70 g, 87 %) as white needle.
- 5-Dibromomethylbenzofurazan 5-Methylbenzofurazan (70 g, 0.52 mol), NBS (325 g) , and benzoyl peroxide (0.5 g) were refluxed with stirring in carbon tetrachloride (1.5 L) with exclusion of moisture for 30 hours. The reaction mixture was washed with water (2X0.5L) , dried (NaS0 4 ) , and the solvent was removed in vacuo. The residue was chromatographed (silica, EtOAc- hexane, 1:150) to give 122 g (80%) of the title compound. The resulting white solid was used in the next step without any further characterization.
- 6- (benzofurazan-5-yl) -1 6-dihydro-
- Example 17 6- (3,4-Difluorophenyl) -1,6-dihydro-5-methoxycarbonyl-l- (5- (4-methoxycarbonyl-4-phenylpiperidin-1-yl) -pentyl) - 2,4-dimethylpyrimidine (Scheme 9) .
- 6- (3,4-Difluorophenyl) -1, 6-dihydro-2,4-dimethyl- 5-methoxycarbonylpyrimidine To a solution of acetamidine hydrochloride (1.53 g, 16.2 mmol.) in DMF (10 mL) were added a solution of potassium tert- butoxide (1.33 g, 11.8 mmol.) in DMF (10 mL) and a solution of methyl (2- (3,4-difluorophenyl) methylene ⁇ - 3-oxobutanoate (2.6 g, 10.8 mmol.) in DMF (10 mL) at 0°C.
- the combined yield of these products is (65 mg + 65 mg) 24%.
- Examples 14 and 15 are two diastereomeric products derived from the (+)enantiomer at the pyrimidine part and the two possible enantiomeric compounds with respect to the fluoromethylene chiral center.
- the organic layer was dried over Na 2 S0 4 , filtered and solvent was evaporated. The resulting mixture of diastereomers was separated by column chromatography(Si0 2 , 3% EtOAc in toluene) .
- the first major product to elute was (+) -5- (benzyloxycarbonyl) -4- ethyl-1, 6-dihydro-l- ⁇ N- [2-phenyl) ethyl] ⁇ carboxamido-2- methoxy-6- (2,4-difluorophenyl)pyrimidine (12.15 g, 38%) .
- the second major product to elute was the other diastereomer and no effort was made to isolate it.
- reaction mixture was stirred for 12 h and washed with 0.5 N NaOH solution (2 X 50 mL) .
- the organic layer was separated and dried (Na 2 S0 4) .
- the solvent was evaporated and the residue was purified by column chromatography on silica gel using dichloromethane/hexane (20% -50%) as the eluent to give
- 1, 2, 3 , 6 -tetrahydropyrimidine (0.34 g, 0.57 mmol) in acetone (5 mL) at 0 °C, sodium hydroxide solution (1 N, 1.71 mL) was added drop wise and the stirring was continued until the disappearance of the starting material (1 hour) .
- Most of the acetone from the mixture was evaporated under reduced pressure while keeping the temperature at 0 °C and the residue was adjusted to pH 7.0 by the addition of IN hydrochloric acid.
- the first major product to elute was (+) -5- methoxycarbonyl-4-methoxmethyl-l, 6 -dihydro- 1- ⁇ N- [2- phenyl) ethyl] ⁇ carboxamido-2-methoxy-6- (3 , 4- dif luorophenyl) pyrimidine (1.74 g, 44.5%) .
- the second major product to elute was the other diastereomer and no effort was made to isolate it .
- Example 26 and Example 27 Syn and anti isomers of (+) -1,2,3, 6-tetrahydro-l- ⁇ N- [3- (4- (2-pyridyl) -piperidine-1-yl) - (2-hydroximino)propyl ] ⁇ carboxamido-5-methoxycarbonyl-2-oxo-6- (3,4-difluoro phenyl) -4-methoxymethylpyrimidine dihydrochloride
- the HCl salt was prepared by treatment with IN HCl in ether; m.p. 103-105 °C; Anal. Calcd. for C 28 H 34 N 6 0 6 F 2 C1 2 .2.2 H 2 O.0.22 CH 2 C1 2 : C, 47.74; H, 5.51; N, 11.84. Found: C, 48.01; H, 5.72; N, 11.57.
- (+)-6-(3,4- difluorophenyl) -l , 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 CHC1 3 (20 mL) and washed with brine.
- the distillate was dissolved in hexane (100 mL) and washed successively with water (20 mL) , concentrated sulfuric acid (4x30 mL) , water (20 mL) , NaOH solution (IN, 2x40 mL) , and water (20 mL) .
- the hexane solution was then dried (Na 2 S0 4 ) and concentrated to give the product in 31% yield (6.4 g) as a light yellow liquid.
- reaction mixture was poured over 10 mL of ice, diluted with t-butyl-methyl ether, the resulting hydrochloride salt was filtered, washed with water and ether, dried, and used in the next step after spectral characterization.
- N- (3-amino) -propylpiperidines A mixture of 4,4-diarylpiperidine hydrochloride (0.100 mmol), (3-bromopropyl) -carbamic acid tert- butyl ester (0.100 mmol) , diisopropylethylamine (1 mL) , and dioxane (2 mL) were heated at reflux temperature for 2 days, cooled, chromatographed
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Abstract
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Application Number | Priority Date | Filing Date | Title |
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US64876896A | 1996-05-16 | 1996-05-16 | |
US1780196P | 1996-05-16 | 1996-05-16 | |
US17801P | 1996-05-16 | ||
US648768 | 1996-05-16 | ||
PCT/US1997/008335 WO1997042956A1 (fr) | 1996-05-16 | 1997-05-16 | Dihydropyrimidines et leurs emplois |
Publications (2)
Publication Number | Publication Date |
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EP1021185A1 true EP1021185A1 (fr) | 2000-07-26 |
EP1021185A4 EP1021185A4 (fr) | 2005-09-07 |
Family
ID=26690328
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Application Number | Title | Priority Date | Filing Date |
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EP97924745A Withdrawn EP1021185A4 (fr) | 1996-05-16 | 1997-05-16 | Dihydropyrimidines et leurs emplois |
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EP (1) | EP1021185A4 (fr) |
JP (1) | JP2000506904A (fr) |
AU (1) | AU727972B2 (fr) |
CA (1) | CA2253862A1 (fr) |
WO (1) | WO1997042956A1 (fr) |
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US6268369B1 (en) | 1994-11-16 | 2001-07-31 | Synaptic Pharmaceutical Corporation | 5-(heterocyclic alkyl)-6-aryl-dihydropyrimidines |
SK60097A3 (en) | 1994-11-16 | 1998-01-14 | Synaptic Pharma Corp | Dihydropyrimidines, pharmaceutical composition containing same and use thereof |
US6228861B1 (en) | 1995-11-16 | 2001-05-08 | Synaptic Pharmaceutical Corporation | Dihydropyrimidines and uses thereof |
US6245773B1 (en) | 1996-05-16 | 2001-06-12 | Synaptic Pharmaceutical Corporation | 5-(heterocyclic alkyl)-6-aryl-dihydropyrimidines |
US6172066B1 (en) | 1996-05-16 | 2001-01-09 | Synaptic Pharmaceutical Corporation | Dihydropyrimidines and uses thereof |
US6080760A (en) * | 1997-06-18 | 2000-06-27 | Merck & Co., Inc. | Alpha 1A adrenergic receptor antagonists |
US6037354A (en) | 1997-06-18 | 2000-03-14 | Merck & Co., Inc. | Alpha 1a adrenergic receptor antagonists |
US6376503B1 (en) | 1997-06-18 | 2002-04-23 | Merck & Co., Inc | Alpha 1a adrenergic receptor antagonists |
US6143750A (en) * | 1997-06-18 | 2000-11-07 | Merck & Co., Inc. | Alpha 1a adrenergic receptor antagonists |
US6057350A (en) * | 1997-06-18 | 2000-05-02 | Merck & Co., Inc. | Alpha 1a adrenergic receptor antagonists |
US6214832B1 (en) | 1997-06-18 | 2001-04-10 | Merck & Co., Inc. | Bis-piperidinyl-pyrimidin-2-ones as alpha 1a adrenergic receptor antagonists |
SG72827A1 (en) * | 1997-06-23 | 2000-05-23 | Hoffmann La Roche | Phenyl-and aminophenyl-alkylsulfonamide and urea derivatives |
WO1999032486A1 (fr) * | 1997-12-23 | 1999-07-01 | Alcon Laboratories, Inc. | Agents muscariniques et leur utilisation pour traiter le glaucome, la myopie, et d'autres dysfonctionnements |
WO1999057131A1 (fr) | 1998-05-06 | 1999-11-11 | Duke University | Methode de traitement des affections du bas appareil urinaire et de la vessie |
AU5234899A (en) * | 1998-07-30 | 2000-02-21 | Merck & Co., Inc. | Alpha 1a adrenergic receptor antagonists |
HN1999000149A (es) | 1998-09-09 | 2000-01-12 | Pfizer Prod Inc | Derivados de 4,4-biarilpiperidina |
AU1808400A (en) | 1998-10-29 | 2000-05-22 | 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 |
AU1345600A (en) | 1998-11-12 | 2000-06-05 | Merck & Co., Inc. | Pyrimidinedione derivatives useful as alpha 1a adrenoceptor antagonists |
GB2344821A (en) | 1998-12-17 | 2000-06-21 | Merck & Co Inc | Crystalline pharmaceutically acceptable salt of an oxazolidinone derivative |
US6680323B2 (en) | 1998-12-23 | 2004-01-20 | Synaptic Pharmaceutical Corporation | Dihydropyrimidines and uses thereof |
US6274585B1 (en) * | 1998-12-23 | 2001-08-14 | Synaptic Pharmaceutical Corporation | Dihydropyrimidines and uses thereof |
AU2386800A (en) * | 1998-12-23 | 2000-07-12 | Synaptic Pharmaceutical Corporation | Dihydropyrimidines and uses thereof |
US6358959B1 (en) | 1999-01-26 | 2002-03-19 | Merck & Co., Inc. | Polyazanaphthalenone derivatives useful as alpha 1a adrenoceptor antagonists |
CN1344266A (zh) | 1999-03-26 | 2002-04-10 | 阿斯特拉曾尼卡有限公司 | 新的化合物 |
EP1193259A4 (fr) | 1999-06-23 | 2003-01-29 | Ajinomoto Kk | Derives dihydropyrimidiniques |
SE9902987D0 (sv) | 1999-08-24 | 1999-08-24 | Astra Pharma Prod | Novel compounds |
GB2355264A (en) | 1999-09-30 | 2001-04-18 | Merck & Co Inc | Spirohydantoin derivatives useful as alpha 1a adrenoceptor antagonists |
GB2355457A (en) | 1999-09-30 | 2001-04-25 | Merck & Co Inc | Novel spirotricyclic substituted azacycloalkane derivatives useful as alpha 1a adrenoceptor antagonists |
GB2355456A (en) | 1999-09-30 | 2001-04-25 | Merck & Co Inc | Novel arylhydantoin derivatives useful as alpha 1a adrenoceptor antagonists |
GB2355263A (en) | 1999-09-30 | 2001-04-18 | Merck & Co Inc | Lactam and cyclic urea derivatives useful as alpha 1a adrenoceptor antagonists |
GB0013060D0 (en) | 2000-05-31 | 2000-07-19 | Astrazeneca Ab | Chemical compounds |
US6720324B2 (en) | 2000-07-05 | 2004-04-13 | Synaptic Pharmaceutical Corporation | Selective melanin concentrating hormone-1 (MCH1) receptor antagonists and uses thereof |
WO2002006245A1 (fr) * | 2000-07-05 | 2002-01-24 | Synaptic Pharmarceutical Corporation | Antagonistes selectifs des recepteurs (mch1) d'hormone-1 de concentration de la melanine et utilisation de ceux-ci |
GB0021670D0 (en) | 2000-09-04 | 2000-10-18 | Astrazeneca Ab | Chemical compounds |
GB0104050D0 (en) | 2001-02-19 | 2001-04-04 | Astrazeneca Ab | Chemical compounds |
GB0107228D0 (en) | 2001-03-22 | 2001-05-16 | Astrazeneca Ab | Chemical compounds |
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 |
GB0117899D0 (en) | 2001-07-23 | 2001-09-12 | Astrazeneca Ab | Chemical compounds |
SE0103818D0 (sv) | 2001-11-15 | 2001-11-15 | Astrazeneca Ab | Chemical compounds |
BR0306625A (pt) * | 2002-05-23 | 2006-04-18 | Abbott Lab | acetamidas e benzamidas que são úteis no tratamento de disfunção sexual |
CA2485503C (fr) * | 2002-05-29 | 2011-07-19 | Eli Lilly And Company | Modulateurs de recepteur de vitamine d du type phenylthiophene |
SE0301369D0 (sv) | 2003-05-09 | 2003-05-09 | Astrazeneca Ab | Chemical compounds |
US7166603B2 (en) | 2003-07-23 | 2007-01-23 | Bristol-Myers Squibb Co. | Dihydropyrimidone inhibitors of calcium channel function |
WO2005007124A2 (fr) | 2003-07-23 | 2005-01-27 | Bristol-Myers Squibb Company | Inhibiteurs dihydropyrimidine substituee de la fonction canaux calciques |
FR2883284A1 (fr) * | 2005-03-15 | 2006-09-22 | Commissariat Energie Atomique | Nouveaux derives dihydropyrimidines et leur utilisation comme agents anti-cancereux |
WO2006138350A2 (fr) | 2005-06-15 | 2006-12-28 | Anormed Inc. | Composes de liaison au recepteur de la chimiokine |
CA2853024C (fr) | 2011-11-11 | 2017-08-22 | Pfizer Inc. | 2-thiopyrimidinones |
PE20180503A1 (es) | 2015-05-05 | 2018-03-09 | Pfizer | 2-tiopirimidinonas |
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US5403847A (en) * | 1992-11-13 | 1995-04-04 | Synaptic Pharmaceutical Corporation | Use of α1C specific compounds to treat benign prostatic hyperlasia |
WO1996014846A1 (fr) * | 1994-11-16 | 1996-05-23 | Synaptic Pharmaceutical Corporation | Dihydropyrimidines et leurs utilisations |
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US5202330A (en) * | 1985-06-03 | 1993-04-13 | E. R. Squibb & Sons, Inc. | 2-thio or oxo-4-aryl or heterocyclo-1,5(2H)-pyrimidinedicarboxylic acid diesters and 3-acyl-5-pyrimidinecarboxylic acids and esters |
US4855301A (en) * | 1986-10-09 | 1989-08-08 | E. R. Squibb & Sons, Inc. | 1,2,3,4-Tetrahydro-6-substituted-4-aryl(or heterocyclo)-3-((substituted amino)carbonyl)-2-thioxo (or oxo)-5-pyrimidinecarboxylic acids and esters |
-
1997
- 1997-05-16 EP EP97924745A patent/EP1021185A4/fr not_active Withdrawn
- 1997-05-16 JP JP9541146A patent/JP2000506904A/ja not_active Withdrawn
- 1997-05-16 WO PCT/US1997/008335 patent/WO1997042956A1/fr not_active Application Discontinuation
- 1997-05-16 AU AU30082/97A patent/AU727972B2/en not_active Ceased
- 1997-05-16 CA CA002253862A patent/CA2253862A1/fr not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5403847A (en) * | 1992-11-13 | 1995-04-04 | Synaptic Pharmaceutical Corporation | Use of α1C specific compounds to treat benign prostatic hyperlasia |
WO1996014846A1 (fr) * | 1994-11-16 | 1996-05-23 | Synaptic Pharmaceutical Corporation | Dihydropyrimidines et leurs utilisations |
Non-Patent Citations (1)
Title |
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See also references of WO9742956A1 * |
Also Published As
Publication number | Publication date |
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JP2000506904A (ja) | 2000-06-06 |
EP1021185A4 (fr) | 2005-09-07 |
AU3008297A (en) | 1997-12-05 |
CA2253862A1 (fr) | 1997-11-20 |
AU727972B2 (en) | 2001-01-04 |
WO1997042956A1 (fr) | 1997-11-20 |
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