EP0988295A1 - Piperidines a substitution heterocyclique et utilisations de ces dernieres - Google Patents

Piperidines a substitution heterocyclique et utilisations de ces dernieres

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Publication number
EP0988295A1
EP0988295A1 EP98931350A EP98931350A EP0988295A1 EP 0988295 A1 EP0988295 A1 EP 0988295A1 EP 98931350 A EP98931350 A EP 98931350A EP 98931350 A EP98931350 A EP 98931350A EP 0988295 A1 EP0988295 A1 EP 0988295A1
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European Patent Office
Prior art keywords
branched
straight chained
alkyl
compound
aryl
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.)
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Application number
EP98931350A
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German (de)
English (en)
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EP0988295A4 (fr
Inventor
Bharat Lagu
T. G. Murali Dhar
Dhanapalan Nagarathnam
Yoon T. Jeon
Mohammad R. Marzabadi
Wai C. Wong
Charles Gluchowski
Dake Tian
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Synaptic Pharmaceutical Corp
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Synaptic Pharmaceutical Corp
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Publication of EP0988295A1 publication Critical patent/EP0988295A1/fr
Publication of EP0988295A4 publication Critical patent/EP0988295A4/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • 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
    • 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
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • 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
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • ⁇ 1A is the designation recently approved by the IUPHAR Nomenclature Committee for the previously designated " ⁇ lc " 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) .
  • ATCC American Type Culture Collection
  • 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 s arting 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 (Lepor, H., Urol . Clinics North Amer .. 17, 651 (1990)). Over 400,000 prostatectomies are performed annually (data from 1986) .
  • Transurethral resection of the prostate was used in approximately 180,000 men in the United States in 1996. This surgical procedure results in significant benefit. However, because of its potential adverse consequences, surgery is an unattractive alternative for many patients and is not recommended for elderly patients due to the potential for complications.
  • Another surgical procedure, transurethral needle ablation (TUNA) was recently approved by the FDA and may have the advantage of possible use on an out-patient basis under local anesthesia.
  • TUNA transurethral needle ablation
  • -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.
  • -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 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
  • ⁇ 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).
  • ⁇ 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 oxazolidinone 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. #1133, 928, 1993), inhibiting cholesterol synthesis (D'Eletto and Javitt, J. Cardiovascular Pharmacol., 13 (Suppl. 2) Sl- 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 .
  • This invention is directed to a compound having the structure:
  • each X is independently 0 or S;
  • each R 2 is independently H; -(CH 2 ) t XR 3 ; - (CH 2 ) t C(X)NR 3 ; - (CH 2 ) t C0 2 R 3 ; -C0 2 R 3 ; straight chained or branched C x -C 7 alkyl, aminoalkyl , carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl ;
  • each t is an integer from 1 to 4 inclusive;
  • each R 3 is independently H; straight chained or branched C ⁇ C, alkyl, straight chained or branched C 2 -C 7 alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl ;
  • R 4 is aryl, heteroaryl, C ⁇ C, alkyl substituted with one or two aryl, or C ⁇ C, alkyl substituted with one or two heteroaryl ; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, - CN, -N0 2 , -N(R 3 ) 2 , -C0R 3 , -(CH 2 ) t XR 3 , - (CH 2 ) n C (X) NR 3 , - (CH 2 ) n C0 2 R 3 , straight chained or branched C ⁇ C, alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C 2 -C 7 aminoalkyl, alkenyl or alkynyl, or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl
  • n independently is an integer from 0 to 7 inclusive;
  • R 5 is H; aryl, C j ⁇ -C, alkyl substituted with aryl, heteroaryl, or C 1 -C 7 alkyl substituted with heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -CN, -N0 2 , -N(R 3 ) 2 , -C0R 3 , - (CH 2 ) t XR 3 , - (CH 2 ) n C(X)NR 3 , - (CH 2 ) n C0 2 R 3 , straight chained or branched C ⁇ C, alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C 2 - C 7 aminoalkyl, alkenyl or alkynyl, or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl;
  • R 5 and one R 2 on adjacent carbon atoms together may form aryl, heteroaryl, indane or tetrahydronaphthyl, C 3 -C 7 cycloalkyl, or heterocycloalkyl wherein one or two heteroatoms may be 0, N or S;
  • 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; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH 2 ) n XR 3 , -C0R 3 , -(CH 2 ) n C(X)N(R 3 ) 2 ,-(CH 2 ) n C0 2 R 3 , -CN, -N0 2 , -N(R 3 ) 2 , - S0 2 R 3 ,
  • each R 7 is independently H; F; Cl; Br;. I; -C0R 3 ; - C0 2 R 3 ; -(CH 2 ) n XR 3 ; -COR 3 ; - (CH 2 ) n C (X) N (R 3 ) 2 ; - (CH 2 ) n C0 2 R 3 ; - CN; -N0 2 ; -N(R 3 ) 2 ; straight chained or branched C ⁇ C, alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C 5 -C 7 cycloalkenyl, wherein the alkyl,
  • each R 10 is independently H; (CH 2 ) t XR 3 ; (CH 2 ) t C(X)NR 3 ; (CH 2 ) t C0 2 R 3 ; straight chained or branched C- L -C, alkyl or carboxamidoalkyl; straight chained or branched C 2 -C 7 aminoalkyl, alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl;
  • R ⁇ l is aryl, heteroaryl, C ⁇ , alkyl substituted with one or two aryl, or C 1 -C 7 alkyl substituted with one or two heteroaryl; wherein any aryl or heteroaryl independently may be substituted with one or more of F, Cl, Br, I, -CN, -N0 2 , -N(R 3 ) 2 , -C0R 3 , -(CH 2 ) n XR 3 , - (Ch 2 ) n C(X)NR 3 , - (CH 2 ) n C0 2 R 3 , straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl , polyfluoroalkyl , or carboxamidoalkyl, straight chained or branched C 2 -C 7 aminoalkyl, alkenyl, or alkynyl, or C 3 -C 7 cycloalkyl or C 5 -C 7
  • each m independently is an integer from 0 to 3 inclusive;
  • R 8 is H; (CH 2 ) t XR 3 ; (CH 2 ) t C (X)NR 3 ; (CH 2 ) t C0 2 R 3 ; straight chained or branched C ⁇ C, alkyl, carboxamidoalkyl; straight chained or branched C 2 -C 7 aminoalkyl, alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl;
  • each R 9 is independenLly H; F; Cl; Br; I ; (CH 2 ) m XR 3 ; (CH 2 ) m C(X)NR 3 ; (CH 2 ) m C0 2 R 3 ; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl , aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl;
  • Y is S, 0, or NR 8 ;
  • the present invention is additionally directed to a compound having the structure:
  • This invention is additionally directed to a compound having the structure:
  • each W is an integer from 0 to 3 inclusive;
  • each Wl is an integer from 0 to 3 inclusive;
  • each X is independently 0 or S;
  • XI is 0, S, NR 3 ;
  • each R 2 is independently H; -(CH 2 ) t XR 3 ; - (CH 2 ) t C(X)NR 3 ; - (CH 2 ) t C0 2 R 3 ; -C0 2 R 3 ; straight chained or branched C ⁇ C, alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl;
  • each t is an integer from 1 to 4 inclusive;
  • each R 3 is independently H; straight chained or branched C 1 -C 7 alkyl, straight chained or branched C 2 -C 7 alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl;
  • R 4 is aryl, heteroaryl, C 1 -C 7 alkyl substituted with one or two aryl, or C x -C 7 alkyl substituted with one or two heteroaryl ; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, - CN, -N0 2 , -N(R 3 ) 2 , -C0R 3 , -(CH 2 ) t XR 3 , - (CH 2 ) n C (X) NR 3 , - (CH 2 ) n C0 2 R 3 , straight chained or branched C x -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C 2 -C 7 aminoalkyl, alkenyl or alkynyl, or C 3 -C 7 cycloalkyl or C 5 -C
  • each n independently is an integer from 0 to 7 inclusive; wherein R 5 is H; aryl, C 1 -C 7 alkyl substituted with aryl, heteroaryl, or C 1 -C 7 alkyl substituted with heteroaryl ; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -CN, - N0 2 , -N(R 3 ) 2 , -C0R 3 , -(CH 2 ) t XR 3 , - (CH 2 ) n C (X) NR 3 , -
  • (CH 2 ) n C0 2 R 3 straight chained or branched C ⁇ C, alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C 2 -C 7 aminoalkyl, alkenyl or alkynyl, or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl;
  • 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 C 5 -C 7 cycloalkenyl; aryl or heteroaryl , wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH 2 ) n XR 3 , -COR 3 , -(CH 2 ) n C(X)N(R 3 ) 2 ,-(CH 2 ) n C0 2 R 3 , -CN, -N0 2 , -N(R 3 ) 2 , - S0 2 R
  • each R 7 is independently H; F; Cl; Br; I; . -COR 3 ; - C0 2 R 3 ; -(CH 2 ) n XR 3 ; (CH 2 ) n C (X) N (R 3 ) 2 ; - (CH 2 ) n C0 2 R 3 ; -CN; -N0 2 ; -N(R 3 ) 2 ; straight chained or branched C ⁇ C, alkyl, hydroxyalkyl , aminoalkyl , carboxamidoalkyl , alkoxyalkyl , monofluoroalkyl or polyfluoroalkyl ; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C 5 -C 7 cycloalkenyl, wherein the alkyl, aminoalkyl,
  • each R 10 is independently H; (CH 2 ) t XR 3 ; (CH 2 ) t C(X)NR 3 ; (CH 2 ) t C0 2 R 3 ; straight chained or branched C j ⁇ -C, alkyl or carboxamidoalkyl; straight chained or branched C 2 -C 7 aminoalkyl, alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl;
  • R n is aryl, heteroaryl, C ⁇ C, alkyl substituted with one or two aryl, or C ⁇ C, alkyl substituted with one or two heteroaryl; wherein any aryl or heteroaryl independently may be substituted with one or more of F, Cl, Br, I, -CN, -N0 2 , -N(R 3 ) 2 , -COR 3 , -(CH 2 ) n XR 3 , -
  • each m independently is an integer from 0 to 3 inclusive;
  • R 8 is H; (CH 2 ) t XR 3 ; (CH 2 ) t C (X)NR 3 ; (CH 2 ) c C0 2 R 3 ; straight chained or branched C ⁇ C, alkyl, carboxamidoalkyl; straight chained or branched C 2 -C 7 aminoalkyl, alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl;
  • each R 9 is independently H; F; Cl; Br; I ; (CH 2 ) m XR 3 ; (CH 2 ) m C(X)NR 3 ; (CH 2 ) m C0 2 R 3 ; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl , polyfluoroalkyl , aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl;
  • Y is S, 0, or NR
  • 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 pharmaceutical compositions comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.
  • Ficrure 1 Figures 1A-1M show the structures of the compounds described hereinbelow in the Examples .
  • the present invention is directed to compounds having the structure:
  • each X is independently 0 or S;
  • each R 2 is independently H; -(CH 2 ) t XR 3 ; - (CH 2 ) t C(X)NR 3 ; - (CH 2 ) t C0 2 R 3 ; -C0 2 R 3 ; straight chained or branched C ⁇ C, alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl;
  • each t is an integer from 1 to 4 inclusive;
  • each R 3 is independently H; straight chained or branched C ⁇ C, alkyl, straight chained or branched C 2 -C 7 alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl;
  • R 4 is aryl, heteroaryl, C ⁇ C, alkyl substituted with one or two aryl, or C ⁇ C, alkyl substituted with one or two heteroaryl ; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, - CN, -N0 2 , -N(R 3 ) 2 , -C0R 3 , -(CH 2 ) t XR 3 , - (CH 2 ) n C (X) NR 3 , - (CH 2 ) n C0 2 R 3 , straight chained or branched C ⁇ C, alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C 2 -C 7 aminoalkyl, alkenyl or alkynyl, or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl
  • n independently is an integer from 0 to 7 inclusive;
  • R 5 is H; aryl, C x -C 7 alkyl substituted with aryl, heteroaryl, or C ⁇ C, alkyl substituted with heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -CN, -N0 2 , -N(R 3 ) 2 , -C0R 3 , - (CH 2 ) t XR 3 , -(CH 2 ) n C(X)NR 3 , - (CH 2 ) n C0 2 R 3 , straight chained or branched C ⁇ C, alkyl, monofluoroalkyl , polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C 2 - C 7 aminoalkyl, alkenyl or alkynyl, or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl;
  • R 5 and one R 2 on adjacent carbon atoms together may form aryl, heteroaryl, indane or tetrahydronaphthyl, C 3 -C 7 cycloalkyl, or heterocycloalkyl wherein one or two heteroatoms may be 0, N or S;
  • 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; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH 2 ) n XR 3 , -C0R 3 , -(CH 2 ) n C(X)N(R 3 ) 2 ,-(CH 2 ) n C0 2 R 3 , -CN, -N0 2 , -N(R 3 ) 2 , - S0 2 R 3 , straight chained
  • each R 7 is independently H; F; Cl; Br; I; -COR 3 ; -
  • CN -N0 2 ; -N(R 3 ) 2 ; straight chained or branched C ⁇ C, alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl;
  • each R 10 is independently H; (CH 2 ) C XR 3 ;
  • R is aryl, heteroaryl, C 1 -C 7 alkyl substituted with one or two aryl, or C x -C 7 alkyl substituted with one or two heteroaryl; wherein any aryl or heteroaryl independently may be substituted with one or more of F, Cl, Br, I, -CN, -N0 2 , -N(R 3 ) 2 , -C0R 3 , -(CH 2 ) n XR 3 , -
  • R 8 is H; (CH 2 ) t XR 3 ; (CH 2 ) C C (X) NR 3 ; (CH 2 ) t C0 2 R 3 ; straight chained or branched C x -C 7 alkyl, carboxamidoalkyl; straight chained or branched C 2 -C 7 aminoalkyl, alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl;
  • each R 9 is independently H; F; Cl; Br; I; (CH 2 ) m XR 3 ; (CH 2 ) m C(X)NR 3 ; (CH 2 ) ra C0 2 R 3 ; straight chained or branched C x -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl;
  • Y is S, 0, or NR tile or a pharmaceutically acceptable salt thereof.
  • the invention further provides for the (+) enantiomer of any of the compounds described herein which may be a cis isomer or a trans isomer.
  • the invention also provides for the (-) enantiomer of any of the compounds described herein which may be a cis or a trans isomer.
  • the compounds of the present invention are preferably at least 80% pure, more preferably at least 90% pure, and most preferably at least 95% pure.
  • aryl is used to include phenyl, benzyl, benzoyl or naphthyl and the term “heteroaryl” is used to include pyrazinyl, pyrryl , furanyl, thiophenyl, pyridyl, imidazolyl, indolyl, aminophenyl, benzamidyl, benzimidazolyl , benzfurazanyl , benzfuranyl, 2-keto-l-benzimidazolinyl or quinolyl .
  • the compounds of this invention exhibit at least tenfold greater affinity for the human ⁇ 1A receptor than for the human ⁇ 1B or human ⁇ 1D receptor.
  • R 1 is
  • R 4 is aryl or heteroaryl, where the aryl may be substituted with one or more of F, Cl, -(CH 2 ) t 0R 3 , - (CH 2 ) n C0NR 3 , - (CH 2 ) n C0 2 R 3 , straight chained or branched C x - C 7 alkyl or monofluoroalkyl ; and
  • R 4 is pyridyl or phenyl, where the phenyl may be substituted with one or more of F, Cl, -(CH 2 ) t 0R 3 , - (CH 2 ) n C (0)NR 3 , - (CH 2 ) n C0 2 R 3 , straight chained or branched C ⁇ C, alkyl or monofluoroalkyl .
  • each R 6 is independently aryl or heteroaryl, where the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH 2 ) n XR 3 , -COR 3 , - (CH 2 ) n C (X) N (R 3 ) 2 , -
  • R 7 is H; -CN; -CO,R,; -C(0)NR,; - (CH ? ) m XR 3 ; unsubstituted or substituted aryl; C x -C 3 alkyl; or -OCOR.
  • R 4 is phenyl which may be substituted with at least one of F or Cl.
  • At least one R 2 is C x -C 3 alkyl.
  • R 4 is phenyl substituted with at least one of F or Cl .
  • R 4 is phenyl substituted with at least two F.
  • R 4 is 3,4- difluorophenyl .
  • R 6 is pyridyl, phenyl, or phenyl substituted with one or more of F, Cl, Br, I, -(CH 2 ) n XR 3 , -COR 3 , - (CH 2 ) n C(X)N(R 3 ) 2 ,-(CH 2 ) n C0 2 R 3 , -CN, -N0 2 , -N(R 3 ) 2 , -S0 2 R 3 , straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl .
  • R 7 is H; -CN; or -C0 2 R 3 .
  • R 9 is F; -OH; C x -C 3 alkyl; or -,fcCH 2 ) m XR 3 .
  • R 9 when R 9 is -OH or F, the other R 9 on the same carbon atom is not -OH. In yet another embodiment, when R 9 is F, the other R 9 on the same carbon atom is C x -C 3 alkyl, F, Cl, Br, or I .
  • R 6 is 4-fluoropheny1.
  • the compound is a trans ( + ) isomer having the structure
  • This invention is additionally directed to a compound having the structure:
  • This invention is additionally directed to a compound having the structure:
  • This invention is additionally directed to a compound having the structure:
  • This invention is additionally directed to a compound having the structure:
  • This invention includes a compound having the structure:
  • each W is an integer from 0 to 3 inclusive;
  • each Wl is an integer from 0 to 3 inclusive;
  • each X is independently O or S;
  • each XI is O, S, NR, ;
  • each R 2 is independently H; -(CH 2 ) t XR 3 ; - (CH 2 ) t C(X)NR 3 ; - (CH 2 ) t C0 2 R 3 ; -C0 2 R 3 ; straight chained or branched C x -C 7 alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl;
  • each t is an integer from 1 to 4 inclusive;
  • each R 3 is independently H; straight chained or branched C ⁇ C, alkyl, straight chained or branched C 2 -C 7 alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl ; wherein R 4 is aryl, heteroaryl, C x -C 7 alkyl substituted with one or two aryl, or C x -C 7 alkyl substituted with one or two heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, - CN, -N0 2 , -N(R 3 ) 2 , -C0R 3 , -(CH 2 ) t XR 3 , - (CH 2 ) n C (X) NR 3 , - (CH 2 ) n C0 2 R 3 , straight chained or branched C 1 -C 7
  • n independently is an integer from 0 to 7 inclusive;
  • R 5 is H; aryl, C x -C 7 alkyl substituted with aryl, heteroaryl, or C x -C 7 alkyl substituted with heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -CN, -N0 2 , -N(R 3 ) 2 , -COR 3 , - (CH 2 ) t XR 3 , - (CH 2 ) n C(X)NR 3 , - (CH 2 ) n C0 2 R 3 , straight chained or branched C x -C 7 alkyl, monofluoroalkyl , polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C 2 - C 7 aminoalkyl, alkenyl or alkynyl, or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalken
  • 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 C 5 -C 7 cycloalkenyl; aryl or heteroaryl , wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, - (CH 2 ) n XR 3 , -COR 3 , -(CH 2 ) n C(X)N(R 3 ) 2 ,-(CH 2 ) n C0 2 R 3 , -CN, -
  • N0 2 , -N(R 3 ) 2 , -S0 2 R 3 straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl , straight chained or branched C 2 -C 7 alkenyl or alkynyl, or C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C 5 -C 7 cycloalkenyl;
  • each R 7 is independently H; F; Cl; Br; I; - C0R 3 ; -C0 2 R 3 ; -(CH 2 ) n XR 3 ; (CH 2 ) n C (X) N (R 3 ) 2 ; - (CH 2 ) n C0 2 R 3 ; - CN; -N0 2 ; -N(R 3 ) 2 ; straight chained or branched C x -C 7 alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl ; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C 5 -C 7 cycloalkenyl, wherein the alkyl, aminoalkyl,
  • each R 10 is independently H; (CH 2 ) t XR 3 ;
  • R xl is aryl, heteroaryl, C x -C 7 alkyl substituted with one or two aryl, or C x -C 7 alkyl substituted with one or two heteroaryl; wherein any aryl or heteroaryl independently may be substituted with one or more of F, Cl, Br, I, -CN, -N0 2 , -N(R 3 ) 2 , - COR 3 , -(CH 2 ) n XR 3 , -(CH 2 ) n C(X)NR 3 , - (CH 2 ) n C0 2 R 3 , straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl , polyfluoroalkyl, or carboxamidoalkyl, straight chained or branched C 2 -C 7 aminoalkyl, alkenyl, or alkynyl, or C 3 -C 7 cycloalkyl or C 5 -
  • R 8 is H; (CH 2 ) t XR 3 ; (CH 2 ) t C (X) NR 3 ; (CH 2 ) t C0 2 R 3 ; straight chained or branched C ⁇ C, alkyl, carboxamidoalkyl; straight chained or branched C 2 -C 7 aminoalkyl, alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl;
  • each R 9 is independently H; F; Cl; Br; I ;
  • the present invention is additionally directed to a compound having the structure:
  • the invention also encompasses the (-) and (+) enantiomers of all compounds described herein.
  • the invention further includes cis and trans isomers of all of the compounds described herein, the terms " cis” and “trans” corresponding to relative stereochemistry, as determined, for example, by NOE (Nuclear Overhauser Effect) experiments.
  • cis and trans designate the relative positions of aryl and alkyl on adjacent carbons in the oxazolidinone ring (see Examples 18 and 19) .
  • the salts include but are not limited to the following acids and bases: inorganic acids such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid; organic acids such as 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; inorganic bases such as ammonia and hydrazine; and organic bases such as methylamine, ethylamine, hydroxyethylamine , propylamine, dimethylamine, diethylamine, trimethyla ine , triethylamine, ethylenediamine, hydroxyethylamine,
  • the invention further provides pharmaceutical compositions comprising a therapeutically effective amount of any 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 to about 800 mg.
  • the therapeutically effective amount is an amount from about 0.01 mg to about 500 mg.
  • the therapeutically effective amount from about 0.01 mg to about 250 mg.
  • the therapeutically effective amount is an amount from about 0.1 mg to about 60 mg.
  • the therapeutically effective amount is an amount from about 1 mg to about 20 mg.
  • 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 100 mg per subject per day, e.g., from about 1 mg per subject per day to about 50 mg per subject per day.
  • the "pharmaceutically acceptable carrier” is any physiological carrier known to those of ordinary skill in the art as being 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 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 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 invention also 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 in an amount 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 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 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 .
  • the pharmaceutical 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 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 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 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 ⁇ lA 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 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 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 a 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 compound may 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 co adjust dosages, including subject age, weight, gender, diet, and time of administration.
  • the term "lower urinary tract tissue" is used to include prostatic capsule, prostate urethra, and bladder neck.
  • Example 1 4- (3,4-Difluoro-phenyl ) -2-oxo-oxazolidine-3- carboxylic acid [3- (3 ' , 4 • , 5 ' , 6 ' -tetrahydro-2 'H- [2,4* lbipyridinyl-1" -yl)-propyl] -amide (Schemes 5 and 6) It is a typical procedure for the synthesis of oxazolidinone compounds which are described below.
  • METHOD A a. Amino- (3,4-difluorophenyl) -acetonitrile Through a solution of 3 , 4-difluorobenzaldehyde (25.0 g,
  • the solvent was removed in vacuo to obtain 31.0 g of the acetal as thick yellow oil. It was dissolved in 200 mL of acetone and about 10 drops of cone, sulfuric acid. The reaction mixture was stirred at room temperature for 2 h till tic analysis showed complete cosumption of the starting material. The solvent was removed in vacuo and the solid that was obtained was basified by adding sat. NaHC0 3 solution and then it was extracted with ethyl acetate (300 mL) . The organic layer was separated and washed with brine. The organic layer was dried over MgS0 4 , filtered and the solvent was removed in vacuo to obtain yellow solid.
  • (+) -4- (3, 4-Difluorophenyl) -oxazolidin-2-one To a well stirred suspension of NaH (1.1 g, 45.8 mmol) in THF (40 mL) at room temperature was added a solution of [1- (3 , 4-difluorophenyl) -2-hydroxy-ethyl] -carbamic acid-tert-butyl ester (5.0 g, 18.3 mmol) in THF 20 mL via a dropping funnel at room temperature . The resulting suspension was stirred for 3 h and then quenched carefully with 10 mL of water.
  • Method A A solution of 2 , 4 ' -dipyridyl (5.0 g, 32.0 mmol) and 3-bromopropylamine hydrobromide (7.0 g, 32.0 mmol) in DMF (50.0 mL) and acetonitrile (50.0 mL) was heated at 90-95°C for 1 h. After cooling, the white solid that came out was filtered, washed with Et 2 0 and dried. The mother liquor was concentrated to remove Et 2 0 and then heated to 90-95°C for 4 h. The solvent was evaporated and the white residue was triturated with Et 2 0 (100.0 mL) and filtered. The combined weight of the salt was 11.6 g (97%).
  • Method B A well-stirred solution of 2 , 4 ' -dipyridyl (12.8 g, 0.08 mol) and N-tert-butoxycarbonyl-3-bromo- propylamine (21.3 g, 0.09 mol) in acetonitrile (40.0 mL) was heated to reflux for 6 h. The reaction mixture was cooled to room temperature and filtered. The white solid thus obtained was washed with acetone (2 x 20.0 mL) and chloroform (2 x 20.0 mL) to yield 10.9 g as the first crop.
  • Example 2 4- (3,4-Difluorophenyl) -3- ⁇ 5- [4- (2-methoxy- phenyl) -piperazin-1-yl] -pentyl ⁇ -oxazolidin-2-one a. 4- (3, 4-Difluorophenyl)-l-( 5-bromopentyl) oxazolidinone
  • Example 3 4- (3,4-Difluoro-phenyl) -2-oxo-oxazolidine-3- carboxylic acid ⁇ 3- [4- (5-bromo-2-methoxy-phenyl) -4- ph ⁇ nyl-piperidin-1-yl] -propyl ⁇ -amide a. 4- (5-bromo-2-methoxy)-phenyl-4-phenyl-piperidine hydrochloride
  • Example 5 4- (3, 5-Difluoro-phenyl) -2-oxo-oxazolidine-3- carboxylic acid [3- (3 ' ,4 ' , 5 ⁇ , 6 ' -tetrahydro-2 ' H- [2,4' ]bipyridinyl-l' -yl) -propyl] -ester a.
  • Example 6 2-Oxo-4- (3,4, 5-trifluoro-phenyl) -oxazolidine- 3-carboxylic acid ⁇ 3- [4- (2-carbamoyl-phenyl) -piperazin-1- yl] -propyl ⁇ -amide a. 2- [4- (3-amino-propyl) -piperazin-1-yl] -benzamide Concentrated sulfuric acid (15 mL) was added to 1- (2- cyanophenyl) piperazine (1.5 g, 8.0 mmol) placed in a round bottom flask and. the resulting slurry was stirred at room temperature for 48 h.
  • Example 7 2- [4- (3- ⁇ [4- (3, 5-Difluoro-phenyl) -2-oxo- oxazolidine-3-carbonyl] -amino ⁇ -propyl) -piperazin-1-yl] - benzoic acid methyl ester (Schemes 1 and 5) a. 1- (2-Carbomethoxyphenyl) -piperazine
  • Example 8 4- (3,4-Difluoro-phenyl) -2-oxo-oxazolidine-3- carboxylic acid [4- (4-phenyl-piperidin-1-yl) -butyl] - amide
  • Example 9 1- (3- ⁇ [5- ⁇ 3- (3,4-Difluorophenyl) -2-oxo- oxazolidine-3-carbonyl] -amino ⁇ -propyl) -4-phenyl- piperidine-4-carboxylic acid methyl ester (Scheme 8) a. Hydroxy- (3, 4-difluorophenyl) -acetonitrile
  • Example 10 4- (3-Chloro-4-fluoro-phenyl) -2-oxo- oxazolidine-3-carboxylic acid [3- (4,4-diphenyl- piperidin-1-yl) -propyl] -amide (Schemes 2 and 5)
  • Example 11 4- (3,4-Difluoro-phenyl) -2-thioxo- oxazolidine-3-carboxylic acid [3- (4-o-toluyl-4-p-toluyl- piperidin-1-yl) -propyl] -amide (Scheme 9) a. 4- (3, 4-Difluorophenyl) -oxazolidine-2-thione
  • Example 12 4-phenyl-2-thioxo-thiazolidine-3-carboxylic acid [3- (3 ' ,4 ⁇ , 5 ' , 6 • -tetrahydro-2 'H- [2,4 ' ]bipyridinyl- 1 ⁇ -yl) -propyl] -amide ( Scheme 9 ) a. 4- (S) -Phenyl-thiazolidine-2-thione
  • Example 13 (-) -2-Oxo-8, 8a-dihydro-3aH-l- (S) -oxa-3- (R) - aza-cyclopent [1] indene-3-carboxylic acid- [3- (1-4-cyano- 4-phenyl-piperidin-1-yl) -propyl-amide (Scheme 10) a. Synthesis of (+) -3, 3a, 8, ⁇ a-tetrahydro-l(S) -oxa-3 (R) - aza-cyclopenta [a] inden-2-one
  • Example 14 4- (3,4-Difluoro-phenyl) -2-oxo-oxazolidine-3- carboxylic acid ⁇ 3- [2-methyl-4- (2-nit ⁇ -o-phenyl) - piperazin-1-yl) -propyl ⁇ -amide a. (S) - (+) -3-mev:hyl-l- (2-r ⁇ itrophenyl) -piperazine
  • Example 15 4- (3,4-Difluoro-phenyl) -2-oxo-oxazolidine-3- carboxylic acid ⁇ 3- [4-methyl-4-phenyl-piperidin-l-yl) - propyl ⁇ -amide a.
  • 1-Benzyl-4-methyl-4-piperidinol To a solution of l-benzyl-4-piperidone (5.6 mL, 30.0 mmol) in 50 mL THF was added a solution of methyllithium in THF (24.0 mL, 36 mmol) dropwise at 0°C over 15 min. The reaction mixture was allowed to warm to room temperature over 3 h and then quenched with 30 mL of sat. NH 4 C1 solution.
  • the oragnic layer was extracted with diehtyl ether (2 X 100 mL) and the combined organic layer was washed with brine (100 mL) .
  • the organic layer was separated, dried over Na 2 S0 4 , filtered and the solvent was removed in vacuo to obtain yellow gum. It was purified by column chromatography over silica gel with 9:1 EtOAc-MeOH as the eluting system to obtain 1- benzyl-4-methyl-4-piperidinol as a yellow thick oil (3.6 g, 59% yield) .
  • Example 16 4- (3, 4-Difluorophenyl) -4-methyl-2-oxo- oxazolidine-3-carboxylic acid ⁇ 3- [4- (2-methylphenyl) -4- (4-methylphenyi) -piperidin-1-yl] -propyl ⁇ amide (Scheme 11) a. 2- (3, 4-Difluorophenyl)propan-2-ol
  • the light bron oil that was obtained was a 10:1 mixture of l-azido-2- (3 , 4-difluorophenyl) -propan-2-ol and 2-azido-2- (3 , 4-difluorophenyl) -propan-1-ol (crude wt 2.0 g). It was dissolved in 40 mL of diethyl ether, cooled to 0°C and then treated with a solution of lithium aluminum hydride (20.0 mL, 20 mmol) . The resulting yellow suspension was then stirred at room temperature for 2 h.
  • the reaction mixture was cooled to 0°C and then carefully quenched sequentially with 0.8 mL of water, 0.8 mL of 3N NaOH followed by 2.5 mL of water.
  • the resulting suspension was filtered thro' a fritted glass funnel.
  • To the residue was added 100 mL Et 2 0 and the suspension was heated to reflux for 20 min.
  • the suspension was filtered and was combined with the previous filtrate, dried over MgS0 4 , filtered and the solvent was removed in vacuo.
  • Example 17 5- (3,4-Difluorophenyl) -5-methyl-2-oxo- oxazolidine-3-carboxylic acid ⁇ 3- [4- (2-methoxy-5- methyl)phenyl-4- (4-methylphenyl) -piperidin-1- yl]propyl ⁇ amide (Scheme 11)
  • 3-amino-propyl-4- (2-methoxy-5- methyl)phenyl-4- (4-methyl) phenyl-piperidine (0.09 g, 0.27 mmol)
  • 5- (3 , 4-Difluorophenyl) -5- methyl-2-oxo-oxazolidine-3-carboxylic acid-4-nitro- phenyl ester (0.04 g, 0.11 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 10 h at room temperature.
  • Example 18 cis (+) -4- (3,4-Difluorophenyl) -5-methyl-2- oxo-oxazolidine-3-carboxylic acid ⁇ 3- [4- (4-fluorophenyl) - piperidin-1-yl] propyl ⁇ amide (Scheme 12) a. 1- (3,4-Difluorophenyl)propan-l-ol
  • the resulting yellow solution was then stirred at room temperature for 2 h.
  • the reaction mixture was cooled to 0°C and then carefully quenched sequentially with 3.5 mL of water, 3.5 mL of 3N NaOH followed by 10.5 mL of water.
  • the resulting suspension was filtered thro' a fritted glass funnel. To the residue was added 100 mL Et 2 0 and the suspension was heated to reflux for 20 min. The suspension was filtered and was combined with the previous filtrate, dried over MgS0 4 , filtered and the solvent was removed in vacuo.
  • Enantiomers of each of these diastereoisomers were separated by HPLC by using Chiralcel OD (4.6 x 250 mm) using 80% hexane/20% isopropyl alcohol/ 0.1% diethylamine as the eluting system (12 mL/min) under isothermal conditions (U.V. 254 nM) .
  • Example 19 trans (+) -4- (3, 4-Difluorophenyl) -5-methyl-2- oxo-oxazolidine-3-carboxylic acid ⁇ 3- [4- (4-fluorophenyl) - piperidin-1-yl]propyl ⁇ amide (Scheme 12)
  • the trans (+) -4- (3 , 4-difluorophenyl) -5- methyl-2-oxo-oxazolidine-3-carboxylic acid-4-nitro- phenyl ester (0.03 g, 0.08 mmol) (made from the ( + )- enantiomer from HPLC of the trans diastereomer separated by column chromatography) was converted into trans (+)- 4- (3 , 4-difluorophenyl) -5-methyl-2-oxo-oxazolidine-3- carboxylic acid ⁇ 3- [4- (4-fluorophenyl) -
  • Example 20 4- (3,4-Difluoro-benzyl) -2-oxo-oxazolidine-3- carboxylic acid ⁇ 3- [4- (2-carbamoylphenyl) -piperazin-1- yl] -propyl ⁇ amide a. 2-Amino-3- (3,4-difluoro) -phenyl-propan-1-ol
  • (+)- [1- (3 , 4-difluorobenzyl) -2-hydroxy-ethyl] -carbamic acid- tert-butyl ester as white solid (0.64 g, 99%).
  • Example 21 4- (3, 4-difluorophenyl) -2-oxo-oxazolidine-3- carboxylic acid ⁇ 2- [4-phenylpiperidine-4- (carboxylic acid methyl ester) ] ethyl ⁇ amide (Scheme 5)
  • Example 22 4- (3,4-Difluoro-phenyl) -2-oxo-oxazolidine-3- carboxylic acid ⁇ 3- [4- (4-fluoro-2-methyl-phenyl) - piperidin-1-yl] -propyl ⁇ amide
  • l-Benzyl-4- (5-fluoro-2-methyl) -phenyl-4-piperidinol To a cooled solution of n-BuLi (6.0 mL, 15.0 mmol) in 20 L THF was added 2-Bromo-5-fluoro toluene (1.9 mL, 15.0 mmol) dropwise at -78°C over 15 min.
  • reaction mixture was allowed to warm to 0°C over 1 h and then cooled to -78°C.
  • l-Benzyl-4-piperidone (1.48 mL, 8.0 mmol) was added the white slurry and the reaction mixture was warmed to 0°C over 2 h.
  • the reaction was then quenched with 10 mL of sat. NH 4 C1 solution.
  • the oragnic layer was extracted with diehtyl ether (2 X 50 mL) and the combined organic layer was washed with brine (100 mL) .
  • the organic layer was separated, dried over
  • Example 31 W3-2- [4- (2-Oxo-2, 3-dihydro-lH-benzo [d] imidazol-1- yl)piperidino]ethyl-4- (3, 4-difluorophenyl) -5, 5-dimethyl- 2-oxo-oxazolidine-3-carboxamide hydrochloride a. N-(2- [ ⁇ 4-(2-Keto-l-benzimidazolinyl)piperidin-l-yl] - ethyl)phthalimide. To a solution of 4- (2-keto-l-benzimidazolinyl) piperidine
  • N3-2- [4- (2-Oxo-2, 3-dihydro-lH-benzo [d] imidazol-1- yl)piperidino] ethyl-4- (3 , 4-difluorophenyl) -5, 5-dimethyl- 2-oxo-oxazolidine-3-carboxamide hydrochloride Prepared from 4- (3 , 4-difluorophenyl) -5 , 5-dimethyl-3- (4- nitrophenyloxycarbonyl) -2-oxo-oxazolidine (20 mg) and N- (2- [ ⁇ 4- (2-keto-l-benzimidazolinyl)piperidin-l-yl] - ethyl) amine (20 mg) as described earlier.
  • Example 33 Wl- [2-(4-Cyano-4-phenylpiperidino)ethyl] -2- [4- (3,4- difluorophenyl) -2-oxo-oxazolidin-3-yl] acetamide hydrochloride a. (+) - ⁇ 2- [ (4- (3, 4-Difluorophenyl) -2-oxo-oxazolidine-l- acetic acid benzyl ester.
  • reaction mixture was concentrated in vacuo to provide a white solid, which was redissolved in 20 ml of EtOH and stirred with NaBH 4 (0.30 g, 80 mmol) for 12 h at 25 °C .
  • Reaction mixture was diluted with 100 ml of EtOAc and washed with brine several times .
  • Organic layer was dried over MgS0 4 and concentrated in vacuo, to provide oily residue, which was subjected to column chromatography (10% MeOH/EtOAc) to yield 0.13 g (40%) of the desired product as an oil.
  • the ester was diluted in 10 ml of CH 2 C1 2 and 1 ml of trifluoro-acetic acid, and stirred for 2 h at 25 °C. Reaction mixture was concentrated in vacuo, yielding an oil, which was diluted with EtOAc and washed with aqueous NaHC0 3 . Organic layer was dried over Na 2 S0 4 and concentrated in vacuo to provide 0.63 g (75% for two steps) of the desired product as a colorless oil. c.
  • (+) -4- (3 , 4-difluoro-phenyl) -2-oxo- oxazolidine-3-carboxylic acid 4-nitrophenyl ester (30 mg, 0.08 mmol) in 5 ml of CH 2 C1 2 was added 3- ⁇ [4-phenyl- 4- (1-methyl-pyrrol) -2-yl-phenyl] -piperidin-1-yl ⁇ -propyl- 1-amine (24 mg, 0.08 mmol) in a portion and the resulting solution was stirred for 4 h at 25 °C .
  • Example 37 (+) -4- (3, 4-Difluoro-phenyl) -2-oxo-oxazolidine-3- carboxylic acid ⁇ 3- [4- (5-methyl-thiophen-2-yl) - piperidin-1-yl] -propyl ⁇ -amide a. 4- [4-Hydroxy-4- (5-methyl-thiophen-2-yl) ] -piperidine
  • the ester was diluted in 10 ml of CH 2 C1 2 and 1 ml of trifluoroacetic acid, and stirred for 2 h at 25 °C. Reaction mixture was concentrated in vacuo, yielding an oil, which was diluted with EtOAc and washed with aqueous NaHC0 3 . Organic layer was dried over Na 2 S0 4 and concentrated in vacuo to provide 0.40 g of the desired product as a colorless oil. d.
  • (+) -4- (3 , 4-difluoro-phenyl) -2-oxo- oxazolidine-3-carboxylic acid 4-nitrophenyl ester (46 mg, 0.12 mmol) in 5 ml of CH 2 C1 2 was added 3- [4- (5- methyl-thiophen-2-yl) -piperidin-1-yl] -propyl-1-amine (30 mg, 0.13 mmol) in a portion and the resulting solution was stirred for 12 h at 25 °C .
  • Example 41 4- (3, 4-difluoro-phenyl) -2-oxo-oxazolidine-3-carboxylic acid ⁇ 3- [4- (4-fluoro-phenyl) -4- (2-methoxy-5-fluorophenyl) -piperidin-1-yl] -propyl ⁇ -amide
  • Example 43 4- (3,4-Difluorophenyl)-l-(3- (4- (2-pyridyl)piperidin-1- yl) -propyl) aminocarbonyl-2-imidazolidone .
  • 2-Amino-2- (3, 4-difluorophenyl) -acetonitrile
  • 2- (3, 4-Difluorophenyl) -2-methylamino-ethylamine To Lithium aluminum hydride in ether (49.41 mL, 49.4 mmol), at 0°C, 2- (3 , 4-difluorophenyl) -2-methylamino- acetonitrile (3.0 g, 16.47 mmol) in ether (80 mL) slowly over a period of 10 minutes. The solution was then allowed to stir at room temperature for 1 hour. The reaction mixture was cooled to 0°C and quenched with water (2 mL) , 15% NaOH (2 mL) and water (10 mL) .
  • Trityl chloride (10.94 g, 39.2 mmol) in dichloromethane (100 ml) was added slowly. to the cooled solution. After addition the solution was stirred at room temperature for 24 hours. The soution was then concentrated, partitioned between chloroform (100 ml) and water (25 ml) , washed with IN KOH (10 mL) , filtered, and concentrated. Purification by column chromatography (hexanes : ethyl acetate 3:2) yielded 6.75 g (46 %) of the product as a brown syrup.
  • Example 49 (+) -3- (3- (4-Aminocarbonyl-4- (4-chloro)phenylpiperidin-1- yl) -propyl) aminocarbonyl-4- (3, 4-difluoro)phenyl-2- oxazolidinone.
  • 4- (3 , 4-difluorophenyl) -2-oxazolidinone (0.2 g, 1 mmol) and HMPA (0.18 g, 1 mmol) in THF (6 mL) was added NaH (44 mg, 1.1 mmol, 60% in mineral oil) at room temperature.
  • This oil (0.14 g, 0.4 mmol) was mixed with 4-cyano- 4-phenylpiperidine hydrochloride (0.18 g, 0.8 mmol), potassium carbonate (0.2 g, 1.4 mmol), sodium iodide (61 mg, 0.4 mmol) in acetone (6 mL) and was refluxed overnight. After removal of the solvent, the residue was flash chromatographed over silica gel (ethyl acetate) to give a mixture of two isomers in 22% yield as a yellow oil.
  • Example 51 trans (+) -4- (3,4-Difluorophenyl) -5-methyl-2- oxo-oxazolidine-3-carboxylic acid ⁇ 3- [4- (4-fluoro-2- methylphenyl) -piperidin-1-yl] propyl ⁇ amide
  • a. .3- [4- (4-fluoro-2-methylphenyl) -piperidin-1-yl] - propylamine was synthesized as described in Example 22, Step c, and was used in the next step without further purification .
  • step i the trans (+)-4- (3 , 4-difluorophenyl) -5-methyl-2-oxo-oxazolidine-3- carboxylic acid-4-nitro-phenyl ester (0.03 g, 0.08 mmol) was converted into trans (+) -4- (3 , 4-difluorophenyl) -5- methyl-2-oxo-oxazolidine-3-carboxylic acid ⁇ 3- [4- (4- fluoro-2-methylphenyl) -piperidin-1-yl] propyl ⁇ amide, using the side chain described in step a above, with 75% yield.
  • Example 52 (+) -8- (3,4-Difluorophenyl) -6-oxo-5-oxa-7- aza-spiro[3.4]octan-7-carboxylic acid- ⁇ 3- [4- (4- fluoro) henyl) -piperidin-1-yl] -propyl ⁇ -amide a. Benzhydrylindene-(3,4-difluoro-benzyl)-amine
  • (+) and (-) enantiomers were separated by HPLC by using Chiralcel OD (4.6 x 250 mm) using 80% hexane/20% isopropyl alcohol/ 0.1 % diethylamine as the eluting system (12 mL/min) under isothermal conditions (U.V. 254 nM) .
  • the (-) -enantiomer was used in the next step (0.30g, 35% yield) .
  • a solution of (-) -8- (3 , 4-difluorophenyl) -5-oxa-7-aza- spiro[3.4]octan-6-one (0.15 g, 0.63 mmol) in 10 mL THF was added a solution of n-butyllithium in hexane (0.47 mL, 0.76 mmol) dropwise via a syringe under argon atmosphere at -78°C.
  • Example 53 (+) -5-Cyclopropyl-4- (3, 4-difluorophenyl) -2- oxo-oxazolidine-3-carboxylic acid- ⁇ 3- [4- (4-fluoro-2- methyl-phenyl) -piperidinl-yl] -propyl ⁇ -amide a.
  • (+) and (-) enantiomers of the trans-isomer were separated by HPLC by using Chiralcel OD (4.6 x 250 mm) using 80% hexane/20% isopropyl alcohol/ 0.1 % diethylamine as the eluting system (12 mL/min) under isothermal conditions (U.V. 254 nM) .
  • the (+) -enantiomer was used in the next step. f .
  • Example 54 Asymmetric Synthesis of 4- (3,4- Difluorophenyl) -5-methyl-oxazolidin-2-one a. 2-Hydroxy-l-pyrrolidin-l-yl-propan-l-one (The procedure reported by Vilarrasa et al . Tetrahedron Lett. 1997, 38, 1633 was used; see also Scheme 31) S-(+) -Methyl lactate (48.03 mmol, 5.0 g) and pyrrolidine (52.8 mmol, 4.4 mL) were mixed in a round bottom flask and the reaction mixture was allowed to stir at room temperature for four days.
  • each diastereomer was subjected to chiral HPLC analysis using Chiralcel OD (4.6 x 250 mm) using 80% hexane/20% isopropyl alcohol/ 0.1% diethylamine as the eluting system (12 mL/min) under isothermal conditions (U.V. 254 nM) .
  • the retention time for the trans- oxazolidinone was 13.0 min. This corresponds to the (+)- isomer of the trans oxazolidinone that was synthesized by a separate method as described in Example 19 (the retention time for the (+) -trans-oxazolidinone was 12.1 min) .
  • lOOmg of one of the compounds described herein is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 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.
  • the activity of compounds at the different human receptors was determined in vitro using cultured cell lines that selectively express the receptor of interest. These cell lines were prepared by transfecting the cloned cDNA or cloned genomic DNA or constructs containing both genomic DNA and cDNA encoding the human ⁇ -adrenergic receptors as follows :
  • ⁇ 1D Human Adrenergic 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 Clal 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 Smal-Xhol 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 Xhol- Clal cDNA fragment (the Clal site was from the vector polylinker) .
  • Stable cell lines were obtained by cotransfection with the plasmid ⁇ lA/EXJ (expression vector containing the ⁇ lA 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% C0 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.
  • Stable clones were then selected for resistance to the antibiotic G-418 (1 mg/ml) , and membranes were harvested and assayed for their ability to bind [ 3 H] prazosin as described below (see “Radioligand Binding assays”).
  • 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 Parklawn 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 ⁇ 1D receptor was accorded ATCC Accession No. CRL 11138, and was deposited on September 25, 1992.
  • ⁇ 1B Human Adrenergic Receptor The entire coding region of ⁇ lB (1563 bp) , including 200 base pairs and 5' untranslated sequence (5 1 UT) and 600 bp of 3 ' untranslated sequence (3' UT) , was cloned into the 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 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 L- ⁇ 1B was accorded ATCC Accession. No. CR 11139, on September 29, 1992.
  • ⁇ Human Adrenergic 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 PstI 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- ⁇ lc (old nomenclature) and was deposited with the American Type Culture Collection, 12301
  • Radioligand Binding Assays Transfected cells from culture flasks were scraped into 5ml of 5mM Tris-HCl, 5mM EDTA, pH 7.5, and lysed by sonication. 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, ImM MgCl 2 , and 0.1% ascorbic acid at pH 7.5.
  • Binding of the ⁇ l antagonist [ 3 H] prazosin (0.5 nM, specific activity 76.2 Ci/ mol) 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 ⁇ 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. All the cell lines were deposited with the American Type Culture Collection, 12301 Parklawn 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. Cell lysates were prepared as described above (see Radioligand Binding Assays) , and suspended in 25 mM glycylglycine buffer (pH 7.6 at room temperature) .
  • the potency of ⁇ x antagonists at calcium channels may be determined in competition binding assays of [3H]nitrendipine to membrane fragments of rat cardiac muscle, essentially as described by Glossman and Ferry (Methods in Enzymology 109:513-550, 1985). Briefly, the tissue is minced and homogenized in 50mM Tris-HCl (pH 7.4) containing 0. ImM phenylmethylsulfonyl fluoride. The homogenates are centrifuged at 1000 g for 15 minutes, and the resulting supernatant centrifuged at 45,000 g for 15 minutes. The 45,000 g pellet is suspended in buffer and centrifuged a second time.
  • the compounds described above were assayed using cloned human alpha adrenergic receptors.
  • the preferred compounds were found to be selective ⁇ 1A antagonists .
  • the binding affinities of several compounds are illustrated in the following table.

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Abstract

Cette invention concerne des composés d'oxazolidinone qui sont des antagonistes sélectifs des récepteurs α1A humains. Cette invention concerne également les différentes utilisations de ces composés pour réduire la pression intra-oculaire, empêcher la synthèse du cholestérol, détendre les tissues du tractus urinaire inférieur, traiter l'hyperplasie prostatique bénigne, l'impuissance, l'arythmie cardiaque et pour traiter toute maladie dans laquelle l'antagoniste du récepteur α1A peut être utile. Cette invention concerne également une composition pharmaceutique contenant une quantité thérapeutiquement efficace des composés présentés ci-avant ainsi qu'un support pharmaceutiquement acceptable.
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JP2002505683A (ja) 2002-02-19
CA2294549A1 (fr) 1998-12-23
AU8149898A (en) 1999-01-04
WO1998057940A1 (fr) 1998-12-23
AU740064B2 (en) 2001-10-25
EP0988295A4 (fr) 2003-08-13

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