WO1998057940A1 - Heterocyclic substituted piperidines and uses thereof - Google Patents

Heterocyclic substituted piperidines and uses thereof Download PDF

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Publication number
WO1998057940A1
WO1998057940A1 PCT/US1998/012668 US9812668W WO9857940A1 WO 1998057940 A1 WO1998057940 A1 WO 1998057940A1 US 9812668 W US9812668 W US 9812668W WO 9857940 A1 WO9857940 A1 WO 9857940A1
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branched
straight chained
alkyl
compound
aryl
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PCT/US1998/012668
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French (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 Corporation
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Priority to AU81498/98A priority Critical patent/AU740064B2/en
Priority to CA002294549A priority patent/CA2294549A1/en
Priority to JP50477899A priority patent/JP2002505683A/en
Priority to EP98931350A priority patent/EP0988295A4/en
Publication of WO1998057940A1 publication Critical patent/WO1998057940A1/en

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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

This invention is directed to oxazolidinone compounds which are selective antagonists for human α1A 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 the antagonism of the α1A receptor may be useful. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.

Description

HETEROCYCLIC SUBSTITUTED PIPERIDINES AND USES THEREOF
Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains .
Background of the Invention
The designation "α1A" is the appellation recently approved by the IUPHAR Nomenclature Committee for the previously designated "αlc" cloned subtype as outlined in the 1995 Receptor and Ion Channel Nomenclature Supplement (Watson and Girdlestone, 1995). The designation α1A is used throughout this application and the supporting tables and figures to refer to this receptor subtype. At the same time, the receptor formerly designated α1A was renamed α1D. The new nomenclature is used throughout this application. Stable cell lines expressing these receptors are described herein; however, these cell lines were deposited with the American Type Culture Collection (ATCC) under the old nomenclature (infra) .
Benign Prostatic Hyperplasia (BPH) , also called 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. Currently, in the United States, 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 (TURP) 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. However, initial results of a recent study comparing TURP and TUNA show a lower level of efficacy in TUNA than in TURP with respect to increasing urinary flow.
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 (McGrath, et. al . Med. Res . Rev. , 9, 407-533, 1989) 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 α- adrenergic drugs have been developed over the past 40 years. Examples include clonidine, phenoxybenzamine and prazosin (treatment of hypertension) , naphazoline (nasal decongestant) , and apraclonidine (treating glaucoma) . -Adrenergic drugs can be broken down into two distinct classes: agonists (clonidine and naphazoline are agonists), which mimic the receptor activation properties of the endogenous neurotransmitter norepinephrine, and antagonists (phenoxybenzamine and prazosin are antagonists) , which act to block the effects of norepinephrine. Many 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).
During the past 15 years a more precise understanding of α-adrenergic receptors and their drugs has evolved through increased scientific scrutiny. Prior to 1977, only one α-adrenergic receptor was known to exist. Between 1977 and 1988, it was accepted by the scientific community that at least two α-adrenergic receptors--α1 and α2--existed in the central and peripheral nervous systems. Since 1988, new techniques in molecular biology have led to the identification of at least six α-adrenergic receptors which exist throughout the central and peripheral nervous systems: α1A (new nomenclature) , α1B, α1D (new nomenclature) , α2A, α2B and α2c (Bylund, D.B., FASEB J. , 6, 832 (1992)). In many cases, it is not known precisely which physiological responses in the body are controlled by each of these receptors . In addition, current α-adrenergic drugs are not selective for any particular α-adrenergic receptor. Many of these drugs produce untoward side effects which may be attributed to their poor α-adrenergic receptor selectivity.
Since the mid 1970 's, nonselective α-antagonists have been prescribed to treat BPH. In 1976, M. Caine, et al . (Brit. J. Urol., 48, 255 (1976)), reported that the nonselective α-antagonist phenoxybenzamine was useful in relieving the symptoms of BPH. This drug may produce its effects by interacting with α-receptors located on the prostate. However, this drug also produces significant side effects such as dizziness and asthenia which severely limit its use in treating patients on a chronic basis. More recently, the α-adrenergic antagonists prazosin and terazosin have also been found to be useful for treating BPH. However, these drugs also produce untoward side effects. It has recently been discovered that the α1A receptor is responsible for mediating the contraction of human prostate smooth muscle (Gluchowski, C. et . al . , WO 94/10989, 1994; Forray, C. et . al . , Mol . Pharmacol . 45, 703, 1994).
This discovery indicates that the α1A antagonists may be effective agents for the treatment of BPH with decreased side effects. Further studies have indicated that the α1A 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 α1A 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 α1A receptor may be useful .
Sunimarv of the Invention
This invention is directed to a compound having the structure:
Figure imgf000008_0001
wherein each X is independently 0 or S;
wherein q is 1 or 2;
wherein each R2 is independently H; -(CH2)tXR3; - (CH2)tC(X)NR3; - (CH2) tC02R3 ; -C02R3; straight chained or branched Cx-C7 alkyl, aminoalkyl , carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl ;
wherein each t is an integer from 1 to 4 inclusive;
wherein each R3 is independently H; straight chained or branched C^C, alkyl, straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl ;
wherein R4 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, -N02, -N(R3)2, -C0R3, -(CH2)tXR3, - (CH2) nC (X) NR3 , - (CH2)nC02R3, straight chained or branched C^C, alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C2-C7 aminoalkyl, alkenyl or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein each n independently is an integer from 0 to 7 inclusive;
wherein R5 is H; aryl, Cj^-C, alkyl substituted with aryl, heteroaryl, or C1-C7 alkyl substituted with heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -CN, -N02, -N(R3)2, -C0R3, - (CH2)tXR3, - (CH2)nC(X)NR3, - (CH2) nC02R3 , straight chained or branched C^C, alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C2- C7 aminoalkyl, alkenyl or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
where R5 and one R2 on adjacent carbon atoms together may form aryl, heteroaryl, indane or tetrahydronaphthyl, C3-C7 cycloalkyl, or heterocycloalkyl wherein one or two heteroatoms may be 0, N or S;
wherein R is
Figure imgf000010_0001
Figure imgf000010_0002
Figure imgf000011_0001
where each R6 is independently H; straight chained or branched C1-C7 alkyl, hydroxyalkyl , aminoalkyl, alkoxyalkyl , monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 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, -(CH2)nXR3, -C0R3, -(CH2)nC(X)N(R3)2,-(CH2)nC02R3, -CN, -N02, -N(R3)2, - S02R3, straight chained or branched C^C, alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl ;
where each R7 is independently H; F; Cl; Br;. I; -C0R3; - C02R3; -(CH2)nXR3; -COR3; - (CH2) nC (X) N (R3) 2 ; - (CH2) nC02R3 ; - CN; -N02; -N(R3)2; straight chained or branched C^C, alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl, wherein the alkyl, aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted with one or more aryl or heteroaryl , wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH2)nXR3, -COR3, - (CH2) nC (X) N (R3) 2 , - (CH2) nC02R3 , - CN, -N02, -N(R3)2, -S02R3, straight chained or branched C^C, alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl , polyfluorocycloalkyl or C5-C7 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH2)nXR3, -COR3, -(CH2)nC(X)N(R3)2,-(CH2)nC02R3, -CN, -N02, -N(R3)2, - S02R3, straight chained or branched Cx-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl;
wherein each R10 is independently H; (CH2)tXR3; (CH2) tC(X)NR3; (CH2)tC02R3; straight chained or branched C-L-C, alkyl or carboxamidoalkyl; straight chained or branched C2-C7 aminoalkyl, alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein Rλl is aryl, heteroaryl, C^ , alkyl substituted with one or two aryl, or C1-C7 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, -N02, -N(R3)2, -C0R3, -(CH2)nXR3, - (Ch2)nC(X)NR3, - (CH2)nC02R3, straight chained or branched C1-C7 alkyl, monofluoroalkyl , polyfluoroalkyl , or carboxamidoalkyl, straight chained or branched C2-C7 aminoalkyl, alkenyl, or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein each m independently is an integer from 0 to 3 inclusive;
wherein Z is
Figure imgf000013_0001
Figure imgf000013_0002
Figure imgf000013_0003
Figure imgf000014_0001
15
Figure imgf000014_0002
25
Figure imgf000014_0003
35
Figure imgf000015_0001
Figure imgf000015_0002
or C2-C7 alkenyl, wherein the C2-C7 alkenyl may be unsubstituted or substituted with one or more R9 groups;
where R8 is H; (CH2)tXR3; (CH2) tC (X)NR3; (CH2)tC02R3; straight chained or branched C^C, alkyl, carboxamidoalkyl; straight chained or branched C2-C7 aminoalkyl, alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
where each R9 is independenLly H; F; Cl; Br; I ; (CH2)mXR3; (CH2)mC(X)NR3; (CH2)mC02R3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl , aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein Y is S, 0, or NR8;
or a pharmaceutically acceptable salt thereof.
The present invention is additionally directed to a compound having the structure:
Figure imgf000016_0001
This invention is additionally directed to a compound having the structure:
Figure imgf000016_0002
wherein each W is an integer from 0 to 3 inclusive;
wherein each Wl is an integer from 0 to 3 inclusive;
wherein each X is independently 0 or S;
wherein XI is 0, S, NR3;
wherein each R2 is independently H; -(CH2)tXR3; - (CH2)tC(X)NR3; - (CH2) tC02R3 ; -C02R3; straight chained or branched C^C, alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein each t is an integer from 1 to 4 inclusive;
wherein each R3 is independently H; straight chained or branched C1-C7 alkyl, straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein R4 is aryl, heteroaryl, C1-C7 alkyl substituted with one or two aryl, or Cx-C7 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, -N02, -N(R3)2, -C0R3, -(CH2)tXR3, - (CH2) nC (X) NR3 , - (CH2)nC02R3, straight chained or branched Cx-C7 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C2-C7 aminoalkyl, alkenyl or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl ;
wherein each n independently is an integer from 0 to 7 inclusive; wherein R5 is H; aryl, C1-C7 alkyl substituted with aryl, heteroaryl, or C1-C7 alkyl substituted with heteroaryl ; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -CN, - N02, -N(R3)2, -C0R3, -(CH2)tXR3, - (CH2) nC (X) NR3 , -
(CH2)nC02R3, straight chained or branched C^C, alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C2-C7 aminoalkyl, alkenyl or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein Rx is
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000019_0002
where each R6 is independently H; straight chained or branched C^C, alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl ; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl , polyfluorocycloalkyl or C5-C7 cycloalkenyl; aryl or heteroaryl , wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH2)nXR3, -COR3, -(CH2)nC(X)N(R3)2,-(CH2)nC02R3, -CN, -N02, -N(R3)2, - S02R3, straight chained or branched C^C, alkyl, monofluoroalkyl or polyfluoroalkyl , straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl ;
where each R7 is independently H; F; Cl; Br; I; . -COR3; - C02R3; -(CH2)nXR3; (CH2) nC (X) N (R3) 2 ; - (CH2) nC02R3 ; -CN; -N02; -N(R3)2; straight chained or branched C^C, alkyl, hydroxyalkyl , aminoalkyl , carboxamidoalkyl , alkoxyalkyl , monofluoroalkyl or polyfluoroalkyl ; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl, wherein the alkyl, aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted with one or more aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH2)nXR3, -C0R3, -(CH2)nC(X)N(R3)2,-(CH2)nC02R3, -CN, -N02 , -N(R3)2, - S02R3, straight chained or branched Cx-C7 alkyl, monofluoroalkyl or polyfluoroalkyl , straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH2)nXR3, -C0R3, - (CH2) nC (X) N (R3) 2 , - (CH2) nC02R3 , - CN, -N02, -N(R3)2, -S02R3, straight chained or branched C^C, alkyl, straight chained or branched C^C, monofluoroalkyl or polyfluoroalkyl , straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl ;
wherein each R10 is independently H; (CH2)tXR3; (CH2) tC(X)NR3; (CH2)tC02R3; straight chained or branched Cj^-C, alkyl or carboxamidoalkyl; straight chained or branched C2-C7 aminoalkyl, alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein Rn 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, -N02, -N(R3)2, -COR3, -(CH2)nXR3, -
(CH2)nC(X)NR3, - (CH2)nC02R3, straight chained or branched C^C, alkyl, monofluoroalkyl, polyfluoroalkyl , or carboxamidoalkyl, straight chained or branched C2-C7 aminoalkyl, alkenyl, or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein each m independently is an integer from 0 to 3 inclusive;
wherein Z is
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000022_0002
Figure imgf000022_0003
Figure imgf000023_0001
10
Figure imgf000023_0002
Figure imgf000023_0003
35
Figure imgf000024_0001
or C2-C7 alkenyl, wherein the C2-C7 alkenyl may be unsubstituted or substituted with one or more R9 groups;
where R8 is H; (CH2)tXR3; (CH2) tC (X)NR3; (CH2) cC02R3; straight chained or branched C^C, alkyl, carboxamidoalkyl; straight chained or branched C2-C7 aminoalkyl, alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
where each R9 is independently H; F; Cl; Br; I ; (CH2)mXR3; (CH2)mC(X)NR3; (CH2)mC02R3; straight chained or branched C1-C7 alkyl, monofluoroalkyl , polyfluoroalkyl , aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein Y is S, 0, or NR
or a pharmaceutically acceptable salt thereof .
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 α1A 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.
Brief Description of the Figures
Ficrure 1 Figures 1A-1M show the structures of the compounds described hereinbelow in the Examples .
Detailed Description of the Invention
The present invention is directed to compounds having the structure:
Figure imgf000027_0001
wherein each X is independently 0 or S;
wherein q is 1 or 2;
wherein each R2 is independently H; -(CH2)tXR3; - (CH2)tC(X)NR3; - (CH2) tC02R3 ; -C02R3; straight chained or branched C^C, alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein each t is an integer from 1 to 4 inclusive;
wherein each R3 is independently H; straight chained or branched C^C, alkyl, straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein R4 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, -N02, -N(R3)2, -C0R3, -(CH2)tXR3, - (CH2) nC (X) NR3, - (CH2)nC02R3, straight chained or branched C^C, alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C2-C7 aminoalkyl, alkenyl or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein each n independently is an integer from 0 to 7 inclusive;
wherein R5 is H; aryl, Cx-C7 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, -N02, -N(R3)2, -C0R3, - (CH2)tXR3, -(CH2)nC(X)NR3, - (CH2) nC02R3 , straight chained or branched C^C, alkyl, monofluoroalkyl , polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C2- C7 aminoalkyl, alkenyl or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
where R5 and one R2 on adjacent carbon atoms together may form aryl, heteroaryl, indane or tetrahydronaphthyl, C3-C7 cycloalkyl, or heterocycloalkyl wherein one or two heteroatoms may be 0, N or S;
wherein Rx is
Figure imgf000029_0001
Figure imgf000029_0002
Figure imgf000030_0001
where each R6 is independently H; straight chained or branched C^C, alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl ; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 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, -(CH2)nXR3, -C0R3, -(CH2)nC(X)N(R3)2,-(CH2)nC02R3, -CN, -N02 , -N(R3)2, - S02R3, straight chained or branched C^C, alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl;
where each R7 is independently H; F; Cl; Br; I; -COR3; -
C02R3; -(CH2)nXR3; -COR3; - (CH2) nC (X) N (R3) 2 ; - (CH2) nC02R3 ; -
CN; -N02; -N(R3)2; straight chained or branched C^C, alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl;
C3-C7 cycloalkyl, monofluorocycloalkyl , polyfluorocycloalkyl or C5-C7 cycloalkenyl, wherein the alkyl, aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted with one or more aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH2)nXR3, -C0R3, - (CH2) nC (X) N (R3) 2 , - (CH2) nC02R3 , - CN, -N02, -N(R3)2, -S02R3, straight chained or branched C1-C1 alkyl, monofluoroalkyl or polyfluoroalkyl , straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl , polyfluorocycloalkyl or C5-C7 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH2)nXR3, -C0R3, -(CH2)nC(X)N(R3)2,-(CH2)nC02R3, -CN, -N02 , -N(R3)2, - S02R3, straight chained or branched C^ , alkyl, straight chained or branched C^C, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl ;
wherein each R10 is independently H; (CH2)CXR3;
(CH2)tC(X)NR3; (CH2) tC02R3 ; straight chained or branched Cx-C7 alkyl or carboxamidoalkyl; straight chained or branched C2-C7 aminoalkyl, alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein R is aryl, heteroaryl, C1-C7 alkyl substituted with one or two aryl, or Cx-C7 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, -N02, -N(R3)2, -C0R3, -(CH2)nXR3, -
(CH2)nC(X)NR3, -(CH2)nC02R3, straight chained or branched Cx-C7 alkyl, monofluoroalkyl , polyfluoroalkyl , or carboxamidoalkyl, straight chained υr branched C2-C7 aminoalkyl, alkenyl, or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl; wherein each m independently is an integer from 0 to 3 inclusive;
wherein Z is
Figure imgf000032_0001
Figure imgf000032_0002
Figure imgf000032_0003
Figure imgf000033_0001
Figure imgf000033_0002
Figure imgf000033_0003
Figure imgf000034_0001
Figure imgf000034_0002
or C2-C7 alkenyl, wherein the C2-C7 alkenyl may be unsubstituted or substituted with one or more R9 groups;
where R8 is H; (CH2)tXR3; (CH2) CC (X) NR3 ; (CH2) tC02R3 ; straight chained or branched Cx-C7 alkyl, carboxamidoalkyl; straight chained or branched C2-C7 aminoalkyl, alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
where each R9 is independently H; F; Cl; Br; I; (CH2)mXR3; (CH2)mC(X)NR3; (CH2)raC02R3; straight chained or branched Cx-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein Y is S, 0, or NR„ 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.
In the present invention the term "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 α1A receptor than for the human α1B or human α1D receptor.
In one embodiment of the present invention R1 is
Figure imgf000035_0001
R4 is aryl or heteroaryl, where the aryl may be substituted with one or more of F, Cl, -(CH2)t0R3, - (CH2)nC0NR3, - (CH2 ) nC02R3 , straight chained or branched Cx- C7 alkyl or monofluoroalkyl ; and
Z is
Figure imgf000036_0001
or
Figure imgf000036_0002
In another embodiment of the present invention R4 is pyridyl or phenyl, where the phenyl may be substituted with one or more of F, Cl, -(CH2)t0R3, - (CH2) nC (0)NR3 , - (CH2)nC02R3, straight chained or branched C^C, alkyl or monofluoroalkyl .
In yet another embodiment of the present invention each R6 is independently aryl or heteroaryl, where the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH2)nXR3, -COR3, - (CH2) nC (X) N (R3) 2 , -
(CH2)nC02R3, -CN, -N02, -N(R3)2, -S02R3, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl .
In a further embodiment of the present invention R7 is H; -CN; -CO,R,; -C(0)NR,; - (CH? ) mXR3 ; unsubstituted or substituted aryl; Cx-C3 alkyl; or -OCOR.
In another embodiment of the present invention R4 is phenyl which may be substituted with at least one of F or Cl.
In yet another embodiment of the present invention the compound has the structure:
Figure imgf000037_0001
or In another embodiment of the present invention Z is
Figure imgf000038_0001
In a further embodiment of the present invention q is 1 and R, is
Figure imgf000038_0002
In a further embodiment of the present invention at least one R2 is Cx-C3 alkyl. In another embodiment of the present invention R4 is phenyl substituted with at least one of F or Cl .
In a further embodiment of the present invention R4 is phenyl substituted with at least two F.
In an embodiment of the present invention R4 is 3,4- difluorophenyl .
In an additional embodiment of the present invention R6 is pyridyl, phenyl, or phenyl substituted with one or more of F, Cl, Br, I, -(CH2)nXR3, -COR3, - (CH2)nC(X)N(R3)2,-(CH2)nC02R3, -CN, -N02 , -N(R3)2, -S02R3, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl .
In a further embodiment of the present invention R7 is H; -CN; or -C02R3.
In another embodiment of the present invention R9 is F; -OH; Cx-C3 alkyl; or -,fcCH2)mXR3.
In an embodiment, when R9 is -OH or F, the other R9 on the same carbon atom is not -OH. In yet another embodiment, when R9 is F, the other R9 on the same carbon atom is Cx-C3 alkyl, F, Cl, Br, or I .
In yet another embodiment of the present invention R6 is 4-fluoropheny1.
In one embodiment of the invention , the compound is a trans ( + ) isomer having the structure
Figure imgf000040_0001
This invention is additionally directed to a compound having the structure:
Figure imgf000040_0002
This invention is additionally directed to a compound having the structure:
Figure imgf000041_0001
This invention is additionally directed to a compound having the structure:
Figure imgf000041_0002
This invention is additionally directed to a compound having the structure:
Figure imgf000041_0003
This invention includes a compound having the structure:
Figure imgf000042_0001
wherein each W is an integer from 0 to 3 inclusive;
wherein each Wl is an integer from 0 to 3 inclusive;
wherein each X is independently O or S;
wherein each XI is O, S, NR, ;
wherein each R2 is independently H; -(CH2)tXR3; - (CH2)tC(X)NR3; - (CH2) tC02R3 ; -C02R3; straight chained or branched Cx-C7 alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein each t is an integer from 1 to 4 inclusive;
wherein each R3 is independently H; straight chained or branched C^C, alkyl, straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl ; wherein R4 is aryl, heteroaryl, Cx-C7 alkyl substituted with one or two aryl, or Cx-C7 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, -N02, -N(R3)2, -C0R3, -(CH2)tXR3, - (CH2) nC (X) NR3 , - (CH2)nC02R3, straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C2-C7 aminoalkyl, alkenyl or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein each n independently is an integer from 0 to 7 inclusive;
wherein R5 is H; aryl, Cx-C7 alkyl substituted with aryl, heteroaryl, or Cx-C7 alkyl substituted with heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -CN, -N02, -N(R3)2, -COR3, - (CH2)tXR3, - (CH2)nC(X)NR3, - (CH2) nC02R3 , straight chained or branched Cx-C7 alkyl, monofluoroalkyl , polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C2- C7 aminoalkyl, alkenyl or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein Rx is
Figure imgf000044_0001
Figure imgf000044_0002
Figure imgf000045_0001
wherein each R6 is independently H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl ; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl; aryl or heteroaryl , wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, - (CH2)nXR3, -COR3, -(CH2)nC(X)N(R3)2,-(CH2)nC02R3, -CN, -
N02, -N(R3)2, -S02R3, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl , straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl;
wherein each R7 is independently H; F; Cl; Br; I; - C0R3; -C02R3; -(CH2)nXR3; (CH2) nC (X) N (R3) 2; - (CH2) nC02R3 ; - CN; -N02; -N(R3)2; straight chained or branched Cx-C7 alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl ; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl, wherein the alkyl, aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted with one or more aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH2)nXR3, -COR3, - (CH2) nC (X)N (R3) 2, - (CH2)nC02R3, -CN, -N02, -N(R3)2, -S02R3, straight chained or branched Cx-C7 alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH2)nXR3, -COR3, - (CH2) nC (X)N (R3) 2, - (CH2)nC02R3, -CN, -N02, -N(R3)2, -S02R3, straight chained or branched C1-C7 alkyl, straight chained or branched -L-C, monofluoroalkyl or polyfluoroalkyl , straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl , polyfluorocycloalkyl or C5-C7 cycloalkenyl;
wherein each R10 is independently H; (CH2)tXR3;
(CH2) tC(X)NR3; (CH2) tC02R3 ; straight chained or branched C-L-C, alkyl or carboxamidoalkyl; straight chained or branched C2-C7 aminoalkyl, alkenyl, or alkynyl; or C3- C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein Rxl is aryl, heteroaryl, Cx-C7 alkyl substituted with one or two aryl, or Cx-C7 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, -N02, -N(R3)2, - COR3, -(CH2)nXR3, -(CH2)nC(X)NR3, - (CH2) nC02R3 , straight chained or branched C1-C7 alkyl, monofluoroalkyl , polyfluoroalkyl, or carboxamidoalkyl, straight chained or branched C2-C7 aminoalkyl, alkenyl, or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl; wherein each m independently is an integer from 0 to 3 inclusive;
wherein Z is
Figure imgf000047_0001
Figure imgf000047_0002
Figure imgf000047_0003
Figure imgf000048_0001
Figure imgf000048_0002
Figure imgf000048_0003
Figure imgf000049_0001
or
Figure imgf000049_0002
or C2-C7 alkenyl, wherein the C2-C7 alkenyl may be unsubstituted or substituted with one or more R9 groups;
where R8 is H; (CH2)tXR3; (CH2) tC (X) NR3; (CH2)tC02R3; straight chained or branched C^C, alkyl, carboxamidoalkyl; straight chained or branched C2-C7 aminoalkyl, alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
where each R9 is independently H; F; Cl; Br; I ;
(CH2)mXR3; (CH2)mC(X)NR3; (CH2)mC02R3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl ; straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl; wherein Y is S , O , or NR8 ;
or a pharmaceutically acceptable salt thereof.
The present invention is additionally directed to a compound having the structure:
Figure imgf000050_0001
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. In one embodiment, cis and trans designate the relative positions of aryl and alkyl on adjacent carbons in the oxazolidinone ring (see Examples 18 and 19) .
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: 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, morpholine, piperazine and guanidine. This invention further encompasses hydrates and polymorphs of all of the compounds described herein.
The invention further provides pharmaceutical compositions comprising a therapeutically effective amount of any of the compounds described above and a pharmaceutically acceptable carrier. In the subject invention 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. In one embodiment, the therapeutically effective amount is an amount from about 0.01 mg to about 800 mg. In another embodiment, the therapeutically effective amount is an amount from about 0.01 mg to about 500 mg. In another embodiment, the therapeutically effective amount from about 0.01 mg to about 250 mg. In another embodiment, the therapeutically effective amount is an amount from about 0.1 mg to about 60 mg. In another embodiment, the therapeutically effective amount is an amount from about 1 mg to about 20 mg. In one embodiment 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. In the practice of this invention the "pharmaceutically acceptable carrier" is any physiological carrier known to those of ordinary skill in the art as being useful in formulating pharmaceutical compositions.
In one embodiment the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution. In another embodiment, the pharmaceutically acceptable carrier is a solid and the composition is in the form of a powder or tablet. In a further embodiment, the pharmaceutical carrier is a gel and the composition is in the form of a suppository or cream. In a further embodiment 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 . In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, 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) . For parenteral administration, 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. In a preferred embodiment the compound of the pharmaceutical composition additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia. In one preferred embodiment 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 α1A 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. In one preferred embodiment 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 α1A 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 α1A antagonist. The most preferred dosage administered to the subject is about 5 mg per subject per day of finasteride in combination with an α1A 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 . In one embodiment 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. In one embodiment the lower urinary tract tissue is prostatic smooth muscle. In one preferred embodiment 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. In one preferred embodiment 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. In one preferred embodiment 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 αlA 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 α1A 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 α1A 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 α1A 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 α1A 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 α1A 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.
In the preceding methods 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.
The compound may also be administered orally either in liquid or solid composition form. 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. In the practice of this invention, the term "lower urinary tract tissue" is used to include prostatic capsule, prostate urethra, and bladder neck.
One skilled in the art will readily appreciate that appropriate biological assays will be used to determine the therapeutic potential of the claimed compounds for the treating the above noted disorders .
This invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.
Experi ental Details
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,
0.18 mol) in MeOH (500 mL) in a round bottom flask, was bubbled ammonia gas for two hours at room teperature. The flask was then cooled to 0°C and trimethylsilyl cyanide
(1.3 eq. , 0.23 mmol) was then added slowly. The reaction mixture was stirred for 2 h when TLC analysis indicated that the reaction was complete (R£ = 0.35, 3:2 hexane/EtOAc) . Solvent was removed in vacuo and the residue was subjected to flash column chromatography on silica gel to obtain 25.0 g (81%) of amino- (3,4- difluorophenyl) -acetonitrile as a yellow syrup. b. Amino- (3, 4-difluorophenyl) -acetic acid methyl ester To a well stirred solution of amino- (3 , 4-difluorophenyl) - acetonitrile (22.0 g, 0.130 mol), a solution of HCl in MeOH (200 mL) was added at room temperature. The resulting yellow solution was stirred at room temperature for 10 h and then heated to reflux for 1.5 h. After cooling, the solvent was removed in vacuo and the resulting yellow solid was dissolved in water (200 mL) . The aqueous solution was then carefully basified with 20% NaOH solution to pH 9. The aqueous layer was extracted with CH2C12 (3 x 100 mL) . The organic layer was separated and dried over Na2S04, filtered and the solvent was removed in vacuo to obtain 22.2 g (84%) of amino- (3 , 4-difluorophenyl) - acetic acid methyl ester as a brownish yellow liquid. It was used in the next step without purification. c. 2-Amino-2- (3, 4-difluorophenyl) -ethanol
To a well stirred suspension of LiAlH4 (4.7 g, 0.125 mol) in THF (120 mL) in a 3-necked round bottom flask fitted with a condenser and a dropping funnel, was added a solution of amino- (3 , 4-difluorophenyl) -acetic acid methyl ester (10.0 g, 0.05 mol) in THF (100 mL) dropwise at 0°C. The . resulting greenish brown suspension was then heated to reflux for 2 h. The reaction mixture was cooled to 0°C and then carefully quenched sequentially with 5 mL of water, 5 mL of 3N NaOH followed by 15 mL of water. The resulting suspension was filtered through a fritted glass funnel. To the residue was added 100 mL Et20 and the suspension was heated to reflux for 20 min. The suspension was filtered and was combined with the previous filtrate, dried over MgS04, filtered and the solvent was removed in vacuo. 2-amino-2- (3 , 4-difluorophenyl) -ethanol was obtained as a yellow glassy syrup (8.6 g, 99%) which was used in the next step without further purification.
METHOD B : Synthesis of 2-amino-2- (3 , -difluorophenyl) - ethanol by different route. (Scheme 6) a. 1-Hydroxy- (3, 4-difluorophenyl) -acetophenone
To a solution of KOH (56 g, 1.0 mol) in MeOH (500 mL) was added 3 , 4-difluoroacetophenone (15.6 g, 0.1 mol) dropwise over 15 min at 0°C. Phenyliodosodiacetate (64.4 g, 0.2 mol) was added in small portions over 20 min period and the resulting yello-orange solution was stirred overnight at room temperature. The solvent was removed in vacuo to obtain yellow-orange gum. The residue was dissolved in 100 mL of water and 100 mL of brine and was thoroughly extracted with ethyl acetate (3 X 150 mL) . The organic layer was dried over Na2S04 and was decanted. 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. NaHC03 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 MgS04, filtered and the solvent was removed in vacuo to obtain yellow solid. The yellow solid was washed with cold hexane ( to remove iodobenzene impurities) and dried to obtain 11.4 g (66% yield) of 1-hydroxy- (3 , 4-difluorophenyl) -acetophenone as pale yellow solid. The product was shown to be > 90% pure by NMR and was used in the next step without further purification. b. 1-Hydroxy- (3, 4-difluorophenyl) -acetophenone oxime To a solution of 1-hydroxy- (3 , 4-difluorophenyl) - acetophenone (6.0 g, 34.9 mmol) in 150 mL of MeOH was added hydroxylamine hydrochloride (3.16 g, 45.6 mmol) and sodium acetate ("9.6 g, 69.6 mmol) at room temperature and the resulting solution was stirred overnight. The solvent was removed and the residue was dissolved in methylene chloride (150 mL) and was washed with 100 mL of sat. NaHC03 solution followed by brine. The organic layer was separated and dried over MgS04, filtered and the solvent was removed in vacuo to obtain 1-hydroxy- (3 , 4-difluorophenyl) -acetophenone-oxime as a yellow solid (5.6 g, 86%) . It was used in the next step without any purification. c. 2-Amino-2- (3, 4-difluorophenyl) -ethanol To a well stirred suspension of LiAlH4 (3.4 g, 89.5 mmol) in THB (120 mL) in a 3 -necked round bottom flask fitted with a condenser and a dropping funnel, was added a solution of 1-hydroxy- (3 , 4-difluorophenyl) - acetophenone-oxime (4.6 g, 24.6 mmol) in THF (50 mL) dropwise at 0°C. The resulting greyish yellow suspension was then heated to reflux for 2 h. The reaction mixture was cooled to 0°C and then carefully quenched sequentially with 3.4 mL of water, 3.4 mL of 3N NaOH followed by 10 mL of water. The resulting suspension was filtered thro' a fritted glass funnel. To the residue was added 100 mL Et20 and the suspension was heated to reflux for 20 min. The suspension was filtered and was combined with the previous filtrate, dried over MgS04, filtered and the solvent was removed in vacuo. 2-Amino-2- (3 , 4-difluorophenyl) -ethanol was obtained as a yellow glassy syrup (4.1 g, 96%) which was used in the next step without further purification. d. [1- (3, 4-Difluorophenyl) -2-hydroxy-ethyl] -carbamic acid-tert-butyl ester
To a solution of 2-amino-2- (3 , 4-difluorophenyl) -ethanol (8.6 g, 49.7 mmol) in CHC13 (150 mL) at 0°C was added a solution of di-tert-butyl dicarbonate (11.4 g, 52.0 mmol) in CHC13 (50 mL) in one portion and the resulting solution was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel (2:1 hexane-EtOAc followed by EtOAc) to obtain [l-(3,4- difluorophenyl) -2-hydroxy-ethyl] -carbamic acid-tert- butyl ester as white solid (10.0 g,74%). e. (+) -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. The biphasic mixture was extracted with 100 mL of Et20, washed with brine, filtered and the solvent was removed in vacuo. The gummy residue thus obtained was purified by column chromatography over silica gel (Rf = 0.15, 3:2 hexane- EtOAc) to obtain (+) -4- (3 , 4-difluorophenyl) -oxazolidin- 2-one as a white flaky solid (2.8 g, 77%). The enantiomers were separated by using Chiralcel OD (4.6 x 250 mm) using 80% hexane/20% isopropyl alcohol/ 0.1 %Diethylamine as the eluting system under isothermal conditions (U.V. 254 nM) . The retention times for the two isomers were 16.19 min and 20.08 min respectively. First isomer: [α]D = + 62.9 (c = 0.67, acetone); Anal. Calcd. for C9H7N02F2 : C, 54.28; H, 3.54; N, 7.03. Found: C, 54.16; H, 3.44; N, 6.96. Second isomer: [α]D = - 56.9 (c = 0.75, acetone); Anal. Calcd. for C9H7N02F2 : C,
54.28; H, 3.54; N, 7.03. Found: C, 54.31; H, 3.46; N, 6.98. The first isomer was used in the next step. f . 4- (3, 4-Difluorophenyl) -2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester To a suspension of NaH (0.14 g, 5.30 mmol) in 20 mL of anhydrous THF under argon, a solution of (+) -4- (3 , 4- difluorophenyl) -oxazolidin-2-one (0.88 g, 4.42 mmol) in THF was added dropwise via an dropping funnel . The resulting suspension was stirred at room temperature for 30 min. This suspension was then added dropwise via cannula into another round bottom flask containing a solution of 4-nitrophenylchloroformate (1.11 g, 5.30 mmol) in 25 mL of THF and cooled at -78°C over a period of 15 min. The stirring was continued for 2 h after which the solvent was removed and the residue was purified by column chromatography on silica gel with 1:1 hexane/CH2Cl2 followed by CH2C12 (Rf= 0.4, CH2C12) to obtain 4- (3 , 4-difluorophenyl) -2-oxo-oxazolidine-3- carboxylic acid-4-nitro-phenyl ester as a white solid (1.55g, 86%) . g. 3-Amino -propyl-4-pyridyl-piperidine
1- (3-Aminopropyl) -4- [pyrid-2-yl]pyridinium bromide hydrobromide
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 Et20 and dried. The mother liquor was concentrated to remove Et20 and then heated to 90-95°C for 4 h. The solvent was evaporated and the white residue was triturated with Et20 (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. Anal. Calcd. for C13H16N3Br .HBr .0.5 H20: C, 40.65; H, 4.72; N, 10.94. Found: C, 40.83; H, 4.37; N, 11.05.
3- (3 ■ , 6 ■ -Dihydro-2 » -H- [2,4 ' ]bipyridinyl-l • -yl) - propylamine
To a solution of 1- (3-aminopropyl) -4- [pyrid-2- yl]pyridinium bromide hydrobromide (0.66 g, 1.75 mmol) in 20.0 mL MeOH was added NaBH4 (0.101 g, 2.62 mmol) in small portions. The reaction mixture was stirred for 30 min and then quenched with 6M HCl solution. The solution was concentrated to 20.0 mL and basified with 50% NaOH solution to pH 12. Extracted with CHC13 (5 x 30.0 L) , dried over MgS04 and the solvent was removed to give 3- (3 ' , 6 ' -Dihydro-2 ' -H- [2 , 4 ' ]bipyridinyl-l ' -yl) - propylamine as an oil (0.37 g, 96% yield) . It is used in the next step immediately without purification. 3-(3, #4,,5, 6' -Tetrahydro-2 ' -H- [2,4 ' ]bipyridinyl-l ' -yl) - propylamine To a solution of 3- (3 ' , 6 ' -Dihydro-2 ' -H-
[2 , 4 ' ]bipyridinyl-l ' -yl) -propylamine (3.48 g crude, 15.9 mmol) in MeOH (40 mL) , was added 1.0 g of Pearlman's catalyst. The suspension was hydrogenated under 120 psi for 10 h after which the reaction mixture was filtered thro' a pad of celite and the solvent was removed. The residue was purified by column chromatography over silica gel using CH2C12/methanol/2M NH3 in MeOH (90:8:4 to 90:40:40) as the eluting system. The product was obtained as a pale yellow oil (3.21 g, 91%) . 3- (3 • , 4 • , 5 ' , 6 ' -Tetrahydro-2 • -H- [2,4 ' ]bipyridinyl-l ' -yl) - propylamine
To a solution of 1- (3 -aminopropyl) -4- [pyrid-2- yl ] pyridinium bromide hydrobromide (0.53 g) 10.0 mL of 2M NH3 in MeOH was added Pt02 (0.1 g) and the reaction mixture was hydrogenated at 110 psi for 6 h and then at 130 psi for 12 h. The catalyst was removed via filtration thro' a pad of celite, washed with MeOH and the solvent was removed. The NMR showed i t to be the required product al though the accurate weight of the product was not determined due to the presence of ammonium bromide generated during the course of the reaction . h. (+) -4- (3,4-Difluoro-phenyl) -2-oxo-oxazolidine-3- carboxylic acid [3- (3 • ,4 ' , 5 * , 6" -tetrahydro-2 'H- [2,4']bipyridinyl-1 * -y1) -propyl] -amide
To a solution of 3-amino-propyl-4-pyridyl piperidine (1.1 g, 5.1 mmol) in 100 mL of THF 4- (3, 4- difluorophenyl) -2-oxo-oxazolidine-3-carboxylic acid-4- nitro-phenyl ester (1.55 g, 4.24 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 10 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with EtOAC followed by 15% MeOH in EtOAC as the eluting systems (Rf = 0.4, 1:1 MeOH/EtOAC) to obtain a pale yellow glassy oil. It was dissolved in EtOAc (150 mL) and washed throughly with 5% KOH solution (4 x 25 mL) in order to remove traces of 4-nitrophenol in the product. . The organic layer was separated, washed with brine (25 mL) and then dried over Na2S04. The solvent was removed and 4- (3 , 4-Difluoro-phenyl) -2-oxo-oxazolidine-3-carboxylic acid [3-(3',4',5' , 6 ' -tetrahydro-2 'H-[2,4' ]bipyridinyl- 1 ' -yl) -propyl] -amide was obtained as a colorless glassy oil (1.55 g, 82%) which develops some brownish color after 2 h.
To a solution of 4- (3 , 4-Difluoro-phenyl) -2-oxo- oxazolidine-3 -carboxylic acid [3- (3 ' , 4 ' , 5 ' , 6 ' - tetrahydro-2 ' H- [2, 4 ' ]bipyridinyl-l ' -yl) -propyl] -amide (1.53 g, 3.45 mmol) in 10.0 mL of anhydrous EtOH was added a warm solution of 95% fumaric acid (0.48 g, 4.06 mmol) in 8.0 L EtOH and the resulting solution was kept under a gentle stream of argon for 30 min. Hexane (5 x 1.0 mL) was added over 2 h and the solution was kept under argon atmosphere overnight. Pale yellowish-white small crystals thus obtained were filtered, washed successively with EtOH (10.0 mL) and hexane (10.0 mL) . The crystals were pulverized and dried under vacuum at 40°C. The white non-hygroscopic powder (1.6 g, 84%) was found out to be the monofumarate salt after NMR and elemental analysis as shown below. M.P. 142-144°C; [α]D = + 47.4 (c = 0.52, MeOH); Anal. Calcd. for C27H30N4O7F2. H20 : C, 56.05; H, 5.57; N, 9.68. Found: C, 56.18; H, 5.51; N, 9.54.
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
To a stirred suspension of sodium hydride (203 mg, 8.04 mmol) in THF (5 mL) at 0°C under argon, was added a solution of 4- (3 , 4-difluorophenyl) oxazolidinone (800 mg, 4.02 mmol) in the mixed solvent of THF (4 ml) and HMPA(0.7 ml, 4.02 mmol) and stirred for 30 min. To this 1, 5-dibromopentane (2.17 ml, 16 mmol) was added and the mixture was heated to reflux for 70 min, after which the reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by column chromatography over silica gel with CH2C12 followed by 5% EtOAc in CH2C12 as the eluting system (Rf = 0.72, CH2C12: EtOAc = 3:1) to obtain 4- (3, 4- difluorophenyl) -1- (5-bromopentyl) oxazolidinone as a brown liquid (0.70 g, 50%). b. 4- (3, 4-Difluorophenyl) -3-{5-[4- (2-methoxy-phenyl) - piperazin-1-yl] -pentyl}-oxazolidin-2-one To a solution of 4- (3 , 4-difluorophenyl) -1- (5- bromopentyl) oxazolidinone (60 mg, 0.17 mmol) in 1,6- dioxane (20 ml) at room temperature, were added 1- (2- methoxyphenyl) -piperazine (33.8 mg, 0.17 mmol) and K2C03 (23.8 mg, 0.52 mmol) . The resulting mixture was heated to reflux for 12 h after which the reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in water and extracted with CH2C12 (2 X 30 ml), dried over Na2S04. The solvent was then removed in vacuo and the residue was purified by column chromatography over silica gel with
EtOAc followed by 5% MeOH in EtOAc as the eluting system (Rf = 0.24, MeOH: EtOAc = 1:8) to obtain 4- (3, 4- difluorophenyl) -3-{5-[4- (2-methoxy-ρhenyl) -piperazin-1- yl] -pentyl}-oxazolidin-2-one as a brown oil (69 mg, 88%) . The compound was dissolved in CH2C12 (3 mL) and was treated with IN HCl in ether (1 mL) . The solvent was removed in vacuo to give the corresponding hydrochloride salt as a yellow solid. M.P. 174-178°C; Anal. Calcd. For C25H33N303F2C12 • 0.65 CH2C12: C, 52.43; H, 5.88; N, 7.15. Found: C, 52.12; H, 6.36; N, 6.84.
Example 3: 4- (3,4-Difluoro-phenyl) -2-oxo-oxazolidine-3- carboxylic acid {3- [4- (5-bromo-2-methoxy-phenyl) -4- phβnyl-piperidin-1-yl] -propyl} -amide a. 4- (5-bromo-2-methoxy)-phenyl-4-phenyl-piperidine hydrochloride
To a 100 mL round bottom flask equipped with a rubber septum and a stirring bar was added 4-hydroxy-4-phenyl- piperidine (5 g, 30.0 mmol) followed by 30 mL of 4- bromoanisole. The resulting solution was stirred at room temperature under argon atmosphere and then AlCl3 (8.0 g, 60.0 mmol) was added in one portion. An exotherm was observed. The reaction mixture was stiired for 8 h (brownish green color) , then poured carefully over 600 ml of ice-water and stirred for 10 h. The white suspension was diluted with 100 mL of diethyl ether. The white solid that precipitated out was filtered and washed thoroughly with water (600 mL) followed by diethyl ether (500 mL) to obtain 4- (5-bromo-2-methoxy) - phenyl-4-phenyl-piperidine hydrochloride as a greyish white solid (6.0 g, 52%). b. 3- [4- (5-bromo-2-methoxy)phenyl-4-phenyl-piperidin-l- yl]propylamine To a solution of 4- (5-bromo-2-methoxy) -phenyl-4-phenyl- piperidine hydrochloride (2.5 g, 6.3 mmol) in 100 mL dioxane was added 3-bromo-N-tert-butoxycarbonyl- propylamine (2.25 g, 9.4 mmol) and K2C03 (3.48 g, 25.2 mmol) and the resulting suspension was heated to reflux for 10 h. The suspension was allowed to cool, filtered and the solvent was evaporated to obtain yellow residue which was purified by column chromatography (Rf = 0.4, 3:1 EtOAc/MeOH) to obtain 3- [4- (5-bromo-2- methoxy)phenyl-4-phenyl-piperidin-l-yl] -N-tert- butoxycarbonyl-propylamine as a yellow oil (3.15 g) . It was dissolved in 35 mL of CH2C12 and 6.0 mL of trifluoroacetic acid was added with stirring at room temperature under argon atmosphere. After 1 h the solvent was evaporated in vacuo and the residue was basified to pH 10 by adding minimum amount of 1 N KOH solution. The product was extracted with CH2C12 (3 X 35 mL) , dried over MgS04, filtered and the solvent was removed in vacuo to obtain 3- [4- (5-bromo-2- methoxy)phenyl-4-phenyl-piperidin-l-yl]propylamine as a viscous yellow oil (2.26 g, 89% for two steps) . It was used in the next step without further purification. The above mentioned steps a and b are representative examples of synthesis of all the 4,4-diaryl piperidine containing side chains described in this document. c. 4- (3, 4-Difluoro-phenyl) -2-oxo-oxazolidine-3- carboxyliσ acid {3- [4- (5-bromo-2-methoxy-phenyl) -4- phenyl-piperidin-1-yl] -propyl} -amide To a solution of 3-amino-propyl-4- (5-bromo-2- methoxy) phenyl-4-phenyl piperidine (2.0 g, 4.96 mmol) in 100 mL of THF was added 4- (3 , 4-difluorophenyl) -2-oxo- oxazolidine-3-carboxylic acid-4-nitro-phenyl ester (1.81 g, 4.96 mmol) and the resulting yellow solution was stirred under argon atmosphere for 3 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 50% hexane/EtOAC followed by 5% MeOH in EtOAC as the eluting systems (Rf = 0.4, 1:3 MeOH/EtOAC) to obtain the product as white foam (wt= 2.2 g) . It was dissolved in EtOAc (150 mL) and washed throughly with 5% NaOH solution (4 x 25 mL) in order to remove traces of 4-nitrophenol from the product. The organic layer was separated, washed with brine (25 mL) and then dried over Na2S04. The solvent was removed after filtration and (+)-l-{3-{3, 4-difluorophenyl) -2-oxo-oxazolidine-3- carbonyl) -amino-propyl} (5-bromo-2-methoxy) phenyl-4- phenyl-piperidine was obtained as a colorless glassy oil(1.84 g, 60%). [α]D = + 34.3 (c = 0.3, MeOH); The compound was dissolved in CHC13 (10 mL) and was treated with IN HCl in ether (5 mL) . The solvent was removed in vacuo to give the corresponding hydrochloride salt as a white solid (2.0 g) . M.P. 142-144°C; Anal. Calcd. for C31H33N404BrClF2.0.3 CHC13 : C, 53.65; H, 4.79; N, 6.00. Found: C, 53.89; H, 4.73; N, 5.74.
Example 4: l-{3- [ (2-Oxo-4-phenyl- [1, 3] oxazinane-3- carbonyl) -amino-propyl} -4-phenyl-piperidine-4-carboxylic acid methyl ester ( Scheme 7 ) a. 3-Amino-3-phenyl-propan-1-ol
To a well stirred suspension of LiAlH4 (1.3 g, 35.0 mmol) in THF (75 mL) in a round bottom flask fitted with a condenser was added 3-amino-3-phenyl-propionic acid (2.5 g, 15.0 mmol) in small portions at 0°C. The resulting grey suspension was then heated to reflux for 2 h. The reaction mixture was cooled to 0°C and then carefully quenched sequentially with 1.3 mL of water, 1.3' mL of 3N NaOH followed by 4.0 mL of water. The resulting suspension was filtered thro' a fritted glass funnel. To the residue was added 100 mL Et20 and the suspension was heated to reflux for 20 min. The suspension was filtered and was combined with the previous filtrate, dried over MgS04, filtered and the solvent was removed in vacuo. 3-amino-3-phenyl-propan-l- ol was obtained as a white solid (2.30 g, 100%) which was used in the next step without further purification. b. (3-Hydroxy-1-phenyl-propyl) -carbamic acid-tert-butyl ester
To a solution of 3-amino-3-phenyl-propan-l-ol (2.30 g, 15.0 mmol) in CHC13 (50 mL) at 0°C was added a solution of di-tert-butyl dicarbonate (3.75 g, 17.1 mmol) in
CHC13 (25 mL) in one portion and the resulting solution was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel (2:1 hexane-EtOAc followed by EtOAc) to obtain ( 3 -hydroxy-1-phenyl- propyl) -carbamic acid-tert-butyl ester as white solid (4.0 g, 100%) . c. 4-Phenyl-oxazinan-2-one
To a well stirred suspension of 95% NaH (0.24 g, 10.0 mmol) in THF (20 mL) at r.t. was added a solution of (3- hydroxy-1-phenyl-propyl) -carbamic acid-tert-butyl ester (1.0 g, 4.0 mmol) in 10 mL THF via a dropping funnel at room temperature. The resulting suspension was stirred for 3 h and then quenched carefully with 10 mL of water. The biphasic mixture was extracted with 100 mL of Et20, washed with brine, filtered and the solvent was removed in vacuo. The gummy residue thus obtained was purified by column chromatography over silica gel (R£ = 0.2, 3:2 hexane-EtOAc) to obtain 4-phenyl-oxazinan-2-one as a white flaky solid (0.44 g, 62%). d. 2-Oxo-4-phenyl- [1, 3] -oxazinane-3-carboxylic acid-4- nitro-phenyl ester
To a suspension of NaH (0.07 g, 2.78 mmol) in 10 mL of anhydrous THF under argon, a solution of 4-phenyl- oxazinan-2-one (0.41 g, 2.31 mmol) in THF was added dropwise via an dropping funnel. The resulting suspension was stirred at room temperature for 30 min. This suspension was then added dropwise via cannula into another round bottom flask containing a solution of 4- nitrophenylchloroformate (0.60 g, 3.0 mmol) in 20 mL of THF and cooled at -78°C over a- period of 15 min. The stirring was continued for 2 h after which the solvent was removed and the residue was purified by column chromatography on silica gel with 1:1 hexane/CH2Cl2 followed by CH2C12 (Rf= 0.4, CH2C12) to obtain 2-oxo-4- phenyl- [1,3] -oxazinane-3-carboxylic acid-4-nitro-phenyl ester as a white solid (0.65 g, 82%). e. l-{3- [ (2-Oxo-4-phenyl- [1, 3] oxazinane-3-carbonyl) - amino-propyl} -4-phenyl-piperidine-4-carboxylic acid methyl ester
To a solution of 3-amino-propyl- (4-carbomethoxy-4- phenyl) piperidine (55 mg, 0.20 mmol) in 5 mL of THF, 2- oxo-4-phenyl- [1,3] -oxazinane-3 -carboxylic acid-4-nitro- phenyl ester (51 mg, 0.15 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 10 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with EtOAC followed by 15% MeOH in EtOAC as the eluting systems (Rf = 0.4, 1:1 MeOH/EtOAC) to obtain 2-oxo-4-phenyl- [1, 3 ] - oxazinane-3 -carboxylic acid-3- (4-carbomethoxy-4-phenyl) - piperidin-1-yl] -propyl amide as a pale yellow glassy oil (35 mg, 49% yield) . It was converted into hydrochloride salt for characterization. Hygroscopic yellow solid. Anal. Calcd. for C27H34N305Cl .2.5 H20: C, 57.80; H, 7.01; N, 7.49. Found: C, 57.98; H, 6.68; N, 6.86.
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. 1- (3-hydroxypropyl)-4- [pyrid-2-yl]pyridinium bromide.
A solution of 2 , 4 ' -dipyridyl (3.0 g, 18.6 mmol) and 3- bromo-1-propanol (2.02 ml, 22.4 mmol) in acetonitrile (100 mL) was heated to reflux for 2 days. After cooling, the solvent was removed in vacuo and the yellow-brown liquid (8.0 g) was directly used for next step without further purification. b. 3- (3 ' , 6 ■ -Dihydro-2 • -H- [2,4'] bipyridinyl-1 ' -yl) - propanol . To a solution of 1- (3-hydroxypropyl ) -4- [pyrid-2- yl ] pyridinium bromide (8 g) in 100 mL EtOH was added NaBH4 (1.41 g, 37.2 mmol) in small portions. The reaction mixture was stirred at room temperature for 12 h and then quenched with drops of water. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:4 MeOH/EtOAc followed by 1:4 (2M NH3 in MeOH) /EtOAc as the eluting system (Rf = 0.6, (2M NH3 in MeOH) /EtOAc = 1:4) to obtain 3- (3 ' , 6 ' -dihydro-2 ' -H-[2,4' ]bipyridinyl-l ' -yl) - propanol as an oil (1.58 g, 39% over two steps) . c . 3-hydroxy-propyl-4-pyridyl-piperidine. To a solution of 3- (3 ' , 6 ' -dihydro-2 ' -H-
[2, 4 ' ]bipyridinyl-l ' -yl) -propanol (1.30 g, 5.93 mmol) in mixed solvent (40 mL) of MeOH and 2N Hcl (1:1), was added 0.5 g of Pearlman's catalyst. The suspension was hydrogenated under 80 psi at 50°C for 10 h after which the reaction mixture was filtered through a pad of celite and the solvent was removed. The residue was basified by 20% NaOH and extracted by CHC13 (7 X 40 ml) , dried over Na2S04. The solvent was removed in vacuo to obtain a brown oil (785 mg, 60%) . d. 4- (3, 5-Difluoro-phenyl) -2-oxo-oxazolidine-3- carboxylic acid [3- (3 ' ,4 ■ ,5 ' , 6' -tetrahydro-2 Η-
[2,4' ]bipyridinyl-l* -yl) -propyl] -ester To a solution of 4- (3 , 5-difluorobenzyl) -2-oxo- oxazolidine-3-carboxylic acid-4-nitro-phenyl ester (50 mg, 0.137 mmol) in 1,6-dioxane (20 ml) at room temperature, were added 3 -hydroxy-propyl-4-pyridyl- piperidine (30 mg, 0.136 mmol) and K2C03 (23.8 mg, 0.52 mmol) . The resulting mixture was heated to reflux for 12 h after which the reaction mixture was cooled to room temperature and the solvent was removed in vacuo . The residue was purified by column chromatography over silica gel with EtOAc followed by 15% MeOH in EtOAc as the eluting system (Rf = 0.30, MeOH: EtOAc = 1:1) to obtain 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 (20 mg, 33%). The compound was dissolved in anhydrous EtOH (1 mL) and was treated with a warm solution of 95% fumaric acid (5.3 mg, 0.045 mmol) in EtOH (3 ml). The resulting solution was kept under gentle stream of argon for 30 min after which hexane (2 ml) was added over lh and the solution was kept under argon overnight. Grey small crystals thus obtained were filtered, washed with EtOH (1 ml) and hexane (1 ml) and dried under vacuum. M.P. 171-173°C; Anal. Calcd. For C27H29N308F2 • 0.27CHC13 : C, 55.16; H, 4.97; N, 7.08. Found: C, 55.17; H, 4.98; N, 6.53.
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. The reaction mixture was poured on crushed ice very slowly and then basified (pH 9) with 50% solution of NaOH. The aqueous layer was extracted several times with EtOAc, dried over K2C03, filtered and the solvent was evaporated. l-(2- carboxamidophenyl) piperazine was obtained as an off- white solid (1.2 g, 73%) . It was used in the next step without further purification. b. 2-OXO-4- (3,4, 5-trifluoro-phenyl) -oxazolidine-3- carboxylic acid{3- [4- (2-carbamoyl-phenyl) -piperazin-1- yl] -propyl} -amide To a solution of 1- (3-amino-propyl) -4- (2-carboxamido) - phenyl-piperazine (100 mg, 0.38 mmol) in 10 mL of THF, 4- (3 , 4 , 5-trifluorophenyl) -2-oxo-oxazolidine-3 -carboxylic acid-4-nitro-phenyl ester (130 mg, 0.34 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature . The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by 1:9 MeOH/EtOAc (Rf= 0.64, MeOH/EtOAc=l:3 ) to obtain (+) -1- {3- {3 , 4 , 5- trifluorophenyl) -2-oxo-oxazolidine-3 -carboxylic acid{3- [4- (2-carbomoyl-phenyl) -piperazin-1-yl] -propyl} -amide (135 mg, 79%) . The compound was dissolved in CH2C12 (3 mL) and was treated with IN HCl in ether (1 mL) . The solvent was removed in vacuo to give the corresponding hydrochloride salt as a yellow solid. M. P. 164-168°C; [α]D = +50.5, (c = 0:28, MeOH); Anal. Calcd. For C24H28N5O4F3Cl2-0.25 CHC13 : C, 47.89; H, 4.68; N, 11.51. Found: C, 48.18; H, 5.03; N, 11.14.
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
To a solution of methyl 2-bromobenzoate (1.63 g, 17.8 mmol) in 1,4-dioxane (100 ml) at room temperature, were added piperazine (15.3 g, 178 mmol) and K2C03 (4.92 g, 35 mmol) . The resulting mixture was heated to reflux for 7 days after which the reaction mixture was cooled to room temperature and the solvent and the excess piperazine were removed in vacuo and heating with a hot water bath. The residue was dissolved in IN NaOH solution and extracted with CH2C12 (6 X 30 ml) , dried over Na2S04. The solvent was removed in vacuo to obtain 1- (2-carbomethoxyphenyl) -piperazine as a yellow oil (1.0 g, 26%) . b. 2- [4- (3-{ [4- (3, 5-Difluoro-phenyl) -2-oxo-oxazolidine- 3-carbonyl] -amino} -propyl) -piperazin-1-yl] -benzoic acid methyl ester To a solution of 1- (3 -amino-propyl) -4- (2- carbomethoxyphenyl) -piperazine (25 mg, 0.090 mmol) in 10 mL of THF, 4- (3 , 5-difluorophenyl ) -2-oxo-oxazolidine-3- carboxylic acid-4-nitro-phenyl ester (30 mg, 0.082 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature . The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by 1:9 MeOH/EtOAc (Rf= 0.75, MeOH/EtOAc=l:3 ) to obtain 2- [4- (3- { [4- (3 , 5-difluoro- phenyl) -2-oxo-oxazolidine-3-carbonyl] -amino} -propyl) - piperazin-1-yl] -benzoic acid methyl ester (31 mg, 69%). The compound was dissolved in CH2C12 (3 mL) and was treated with IN HCl in ether (1 mL) . The solvent was removed in vacuo to give the corresponding hydrochloride salt as a yellow solid. M. P. 93-96°C; [α]D = +45.3, (c = 0.29, MeOH); Anal. Calcd. For C25H30N4O5F2Cl2 • 0.58 CH2C12 : C, 50.48; H, 5.16; N, 9.20. Found: C, 50.46; H, 5.56; N,8.91.
Example 8: 4- (3,4-Difluoro-phenyl) -2-oxo-oxazolidine-3- carboxylic acid [4- (4-phenyl-piperidin-1-yl) -butyl] - amide
To a solution of 1- (4-amino-butyl) -4-phenyl-piperidine (35 mg, 0.151 mmol) in 10 mL of THF, 4- (3, 5- difluorophenyl) -2-oxo-oxazolidine-3 -carboxylic acid-4- nitro-phenyl ester (40 mg, 0.110 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature . The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by 1:19 MeOH/EtOAc (Rf= 0.33, MeOH/EtOAc=l : 3 ) to obtain 4- (3 , 4-difluoro-phenyl) -2-oxo-oxazolidine-3- carboxylic acid [4- (4-phenyl-piperidin-l-yl) -butyl] - amide (42 mg, 83%) . The compound was dissolved in CH2C12 (3 mL) and was treated with IN HCl in ether (1 mL) . The solvent was removed in vacuo to give the corresponding hydrochloride salt as a yellow solid. M.P. 80-84°C; Anal. Calcd. For C25H30N3O3F2Cl • 0.5 CH2C12 : C, 57.09; H, 5.82; N, 7.83. Found: C, 57.08; H, 6.21; N, 7.36.
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
To a solution of 3 , 4-difluorobenzaldehyde (2.86 g, 20.0 mmol) in MeOH (20 mL) in a round bottom flask was added trimethylsilyl cyanide (4.0 mL., 30.0 mmol) at 0°C. The reaction mixture was stirred at room temperature for 10 h when TLC analysis indicated that the reaction was complete (Rf = 0.4, 3:2 hexane/EtOAc) . Solvent was removed in vacuo and hydroxy- (3 , 4-difluorophenyl) - acetonitrile was obtained as a colorless liquid (crude wt. = 3.4 g). It was used in the next step. without purification. b. 2-Amino-1- (3, 4-difluorophenyl) -ethanol
To a well stirred solution of hydroxy- (3 , 4- difluorophenyl) -acetonitrile (3.34 g, 20 mmol), was added a 1.0 M solution of LiAlH4 in ether (40 mL, 40 mmol) dropwise at 0°C. 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 1.5 mL of water, 1.5 mL of 3N NaOH followed by 4.5 mL of water. The resulting suspension was filtered thro' a fritted glass funnel. To the residue was added 100 mL Et20 and the suspension was heated to reflux for 20 min. The suspension was filtered and was combined with the previous filtrate, dried over MgS04, filtered and the solvent was removed in vacuo. 2-amino-l- (3 , 4-difluorophenyl) -ethanol was obtained as a yellow glassy syrup (3.3 g, 99%) which was used in the next step without further purification. c. [1- (3,4-Difluorophenyl) -2-hydroxy-ethyl] -carbamic acid-tert-butyl ester
To a solution of 2-amino-l- (3 , 4-difluorophenyl) -ethanol (3.2 g, 19.8 mmol) in CHC13 (15 mL) at 0°C was added a solution of di-tert-butyl dicarbonate (4.36 g, 20.0 mmol) in CHC13 (10 mL) in one portion and the resulting solution was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel (2:1 hexane-EtOAc followed by EtOAc) to obtain [2- (3,4- difluorophenyl) -2-hydroxy-ethyl] -carbamic acid-tert- butyl ester as white solid (3.2 g, 59.4%). d. 5- (3,4-Difluorophenyl) -oxazolidin-2-one
To a well stirred suspension of 95% NaH (0.55 g, 11.8 mmol) in THF (20 mL) at room temperature was added a solution of [2- (3 , 4-difluorophenyl) -2-hydroxy-ethyl] - carbamic acid-tert-butyl ester (3.2 g, 23.0 mmol) in THF via a dropping funnel at room temperature . The resulting suspension was stirred for 3 h and then quenched carefully with 10 L of water. The biphasic mixture was extracted with 100 mL of Et20, washed with brine, filtered and the solvent was removed in vacuo. The gummy residue thus obtained was purified by column chromatography over silica gel (Rf = 0.15, 3:2 hexane- EtOAc) to obtain 5- (3 , 4-difluoro-phenyl) -oxazolidin-2- one as a white solid (1.1 g, 47%) . e. 5- (3, 4-Difluorophenyl) -2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester
To a suspension of 95% NaH (0.08 g, 3.0 mmol) in 5.0 mL of anhydrous THF under argon, a solution of 5- (3, 4- difluorophenyl) -oxazolidin-2-one (0.5 g, 2.51 mmol) in 5.0 mL THF was added dropwise via an dropping funnel .
The resulting suspension was stirred at room temperature for 30 min. This suspension was then added dropwise via cannula into another round bottom flask containing a solution of 4-nitrophenylchloroformate (0.07 g, 3.26 mmol) in 20 mL of THF, cooled at -78°C,- over a period of 15 min. The stirring was continued for 2 h after which the solvent was removed and the residue was purified by column chromatography on silica gel with 1:1 hexane/CH2Cl2 followed by CH2C12 (Rf= 0.4, CH2C12) to obtain 5- (3 , 4-difluorophenyl) -2-oxo-oxazolidine-3- carboxylic acid-4-nitro-phenyl ester as a white solid (0.7 g, 76%) . f . 1- (3-{ [5-{3- (3,4-Difluorophenyl) -2-oxo-oxazolidine-3- carbonyl] -amino} -propyl) -4-phenyl-piperidine-4- carboxylic acid methyl ester
To a solution of 3-amino-propyl-4-carbomethoxy-4-phenyl piperidine (0.04 g, 0.13 mmol) in 10 mL of THF 5- (3,4- difluorophenyl) -2-oxo-oxazolidine-3-carboxylic acid-4- nitro-phenyl ester (0.04 g, 0.10 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 10 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with EtOAC followed by 15% MeOH in EtOAC as the eluting systems (Rf = 0.4, 1:1 MeOH/EtOAC) to obtain 1- (3- { [5- {3- (3 , 4- difluorophenyl) -2-oxo-oxazolidine-3-carbonyl] -amino}- propyl) -4-phenyl-piperidine-4-carboxylic acid methyl ester as a pale yellow glassy oil (0.03 g, 60%) . It was converted into its hydrochloride salt. M.P. = 121- 125°C; Anal. Calcd. for C26H80N3O4F2Cl2.0.2 H20: C, 57.66; H, 5.66; N, 7.76. Found: C, 57.80; H, 6.15; N, 7.95.
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)
To a solution of 3-amino-propyl-4 , 4-diphenyl piperidine (0.04 g, 0.1 mmol) in 5 mL of THF was added 4-(3-chloro- 4-fluorophenyl) -2-oxo-oxazolidine-3-carboxylic acid-4- nitro-phenyl ester (0.04 g, 0.12 mmol) and the resulting yellow solution was stirred under argon atmosphere for 3 h at room temperature . The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 50% hexane/EtOAC followed by 5% MeOH in EtOAC as the eluting systems (Rf = 0.45, 1:3 MeOH/EtOAC) to obtain 4- (3-Chloro-4-fluoro-phenyl) -2- oxo-oxazolidine-3-carboxylic acid [3- (4 , 4-diphenyl- piperidin-1-yl) -propyl] -amide as white foam (wt = 0.03 g) . It was converted into its hydrochloride salt. M.P. 112-115°C; Anal. Calcd. for C30H32N3O3Cl2F .0.5 CHC13 : C, 57.95; H, 5.18; N, 6.65. Found: C, 58.06; H, 5.74; N, 6.30.
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
To a solution of 2-amino-2- (3 , 4-difluorophenyl) - ethanol (600 mg, 3.46 mmol) in CH2C12 (20 ml) at room temperature, was added 1, 1 ' -thiocarbonyldiimadazole (755 mg, 3.81 mmol) . The resulting solution was heated by a pre-heated oil-bath (110°C) to reflux for 10 h after which the reaction mixture was cooled to room temperature and the solvent was removed in vacuo . The residue was purified by column chromatography over silica gel with CH2C12 as the eluting system (Rf = 0.68, CH2C12: EtOAc = 3:1) to obtain 4- (3 , 4-difluorophenyl) - oxazolidine-2-thione a brown oil (290 mg, 39%) . b. 4- (3, 4-Difluorophenyl) -2-thione-oxazolidine-3- carboxylic acid-4-nitro-phenyl ester.
To a suspension of NaH (41 mg, 1.62 mmol) in 20 mL of anhydrous THF under argon, a solution of 4- (3,4- difluorophenyl) -oxazolidine-2-thione (290 mg, 1.35 mmol) in THF was added dropwise via an dropping funnel . The resulting suspension was stirred at room temperature for 30 min. This suspension was then added dropwise via cannula into another round bottom flask containing a solution of 4-nitrophenylchloroformate (336 mg, 1.62 mmol) in 20 mL of THF and cooled at -78°C over a period of 15 min. The stirring was continued for 2 h after which the solvent was removed and the residue was purified by column chromatography on silica gel with 1:1 hexane/CH2Cl2 , then 3:7 hexane/CH2Cl2 followed by CH2C12 (R£= 0.50) to obtain 4- (3 , 4-difluorophenyl) -2- thione-oxazolidine-3 -carboxylic acid-4-nitro-phenyl ester as a yellow solid (130 mg, 25%) . c. 4- (3,4-Difluoro-phenyl) -2-thioxo-oxazolidine-3- carboxylic acid [3- (4-o-toluyl-4-p-toluyl-piperidin-l- yl) -propyl] -amide To a solution of 1- (3-amino-propyl) -4- (4-methyl) -phenyl- 4- (2-methyl) -phenyl-piperidine (60 mg, 0.186 mmol) in 10 L of THF, 4- (3, 4-Difluorophenyl) -2-thione-oxazolidine-3- carboxylic acid-4-nitro-phenyl ester (30 mg, 0.079 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by 1:19 MeOH/EtOAc (Rf= 0.66, MeOH/EtOAc=l:3 ) to obtain 4- (3 , 4-Difluoro-phenyl) -2- thioxo-oxazolidine-3-carboxylic acid [3- (4-o-toluyl-4-p- toluyl-piperidin-1-yl) -propyl] -amide (16 mg, 36%). The compound was dissolved in CH2C12 (3 mL) and was treated with IN HCl in ether (1 mL) . The solvent was removed in vacuo to give the corresponding hydrochloride salt as a yellow solid. M.P.= 132-136°C; Anal. Calcd. for
C32H36N3O2SCl-0.60 CH2C12: C, 60.14; H, 5.76; N, 6.45. Found: C, 59.97; H, 6.14; N, 6.12.
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
To a solution of (S) - (+) -2-Phenylglycinol (1.40 g, 10 mmol) in IN KOH/H20 (10 ml) at room temperature, was added carbon disulfide (3 ml, 50 mmol) . The resulting solution was heated by a pre-heated oil-bath (110°C) to reflux for 20 h after which the reaction mixture was cooled to room temperature and extracted with CH2C12 (3 X 30 ml), dried over Na2S04. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/CH2Cl2 followed by CH2C12 as the eluting system (R£ = 0.09, CH2Cl2: hexane = 7:3) to obtain 4 (S) -phenyl-thiazolidine- 2-thione (170 mg, 9%) . b. 4-(S)-Phenyl-2-thione-thiazolidine-3-carboxylic acid- 4-nitro-phenyl ester.
To a suspension of NaH (26 mg, 1.04 mmol) in 10 mL of anhydrous THF under argon, a solution of 4 (S) -Phenyl- thiazolidine-2-thione (170 mg, 0.87 mmol) in THF was added dropwise via an dropping funnel . The resulting suspension was stirred at room temperature for 30 min. This suspension was then added dropwise via cannula into another round bottom flask containing a solution of 4- nitrophenylchloroformate (217 mg, 1.04 mmol) in 20 mL of THF and cooled at -78°C over a period of 15 min. The stirring was continued for 2 h after which the solvent was removed and the residue was purified by column chromatography on silica gel with 1:1 hexane/CH2Cl2 , then 3:7 hexane/CH2Cl2 followed by CH2C12 (Rf= 0.50) to obtain (+) -4 (S) -phenyl-2-thione-thiazolidine-3- carboxylic acid-4-nitro-phenyl ester as a pale yellow solid (200 mg, 64%) . c. 4-phenyl-2-thioxo-thiazolidine-3-carboxylic acid [3- (3' ,4' ,5' ,6' -tetrahydro-2 ■H- [2 , 4 ' J biphenyl-1 ' -yl) - propyl] -amide
To a solution of 3-amino-propyl-4-pyridyl-piperidine (35 mg, 0.159 mmol) in 10 mL of THF, (+) -4 (S) -Phenyl-2- thione-thiazolidine-3-carboxylic acid-4-nitro-phenyl ester (50 mg, 0.139 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by 1:9
MeOH/EtOAc (Rf= 0.21, MeOH/EtOAc=l : 3 ) to obtain 4- (3,4- Difluoro-phenyl) -2-thioxo-thiazolidine-3 -carboxylic acid [3- ( 3 ' , 4 ' y ,6,-tetrahydro-2'H-[2,4' ]bipyridinyl-l ' -yl) - propyl] -amide (10 mg, 14%). The compound was . dissolved in CH2C12 (3 mL) and was treated with IN HCl in ether (1 mL) . The solvent was removed in vacuo to give the corresponding hydrochloride salt as a yellow solid. M.P.= 67-70°C; Anal. Calcd. for C23H31N4OS2Cl2 • 0.67 CHC13: C, 47.82; H, 5.37; N, 9.42. Found: C, 47.85; H, 6.12; N, 6 . 52 .
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, βa-tetrahydro-l(S) -oxa-3 (R) - aza-cyclopenta [a] inden-2-one
To a solution of (IR, 2S) - (+) -cis-l-amino-2-indanol (1.0 g, 6.7 mmol) in 30 ml methylene chloride in 100-ml round bottom flask equipped with a stirring bar, was added 1, 1 ' -carbonyldimidazole (1.20 g, 7.4 mmol) at room temperature. The resulting solution was heated by a preheated oil-bath (110°C) to reflux for 10 h after which the reaction mixture was cooled to room temperature and the formation of white crystal was observed. The white crystal was filtered off , washed with minmum CH2C12 (2 mL) and then dried in vacuo. (+) -3 , 3a, 8 , 8a-Tetrahydro- 1 (S) -oxa-3 (R) -aza-cyclopenta [a] inden-2-one was obtained as a white crystal (500 mg, 43%).[α]D = -71.1 (c = 0.28, acetone). M.P. 203-204°C. Anal. Calcd. for C10H9NO2 : C, 68.56; H, 5.18; N, 8.00. Found: C, 68.44; H, 5.12; N, 7.98. b.2-Oxo-l,3a,8, 8a-tetrahydro-2H-3-aza- cyclopenta [a] indene-3-carboxylic acid 4-nitro-phenyl ester.
To a suspension of NaH (73 mg, 2.88 mmol) in 20 mL of anhydrous THF under argon, a solution of 3,3a, 8,8a- tetrahydro-1 (R) -oxa-3 (S) -aza-cyclopenta [a] inden-2-one (420 mg, 2.40 mmol) in THF was added dropwise via an dropping funnel. The resulting suspension was stirred at room temperature for 30 min. This suspension was then added dropwise via cannula into another round bottom flask containing a solution of 4- nitrophenylchloroformate (598 mg, 2.88 mmol) in 25 mL of THF and cooled at -78°C over a period of 15 min. The stirring was continued for 2 h after which the solvent was removed and the residue was purified by column chromatography on silica gel with 4:1 hexane/EtOAc followed by 3 : 2 hexane/EtOAc (R£= 0.51, hexane/EtOAc=l : 1) to obtain a white solid (680 mg, 83%). c. (-) -2-OXO-8, 8a-dihydro-3aH-l- (S) -oxa-3- (R) -aza- cyclopent [1] indene-3-carboxylic acid- [3- (l-4-cyano-4- phenyl-piperidin-1-yl) -propyl-amide To a solution of 1- (3 -amino-propyl ) -4-cyano-4-phenyl- piperidine (25 mg, 0.103 mmol) in 10 mL of THF, 2-0xo- 1, 3a, 8, 8a-tetrahydro-2H-3-aza-cyclopenta [a] indene-3- carboxylic acid 4-nitro-phenyl ester (40 mg, 0.118 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature . The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by EtOAc (R£= 0.35 ) to obtain (-) -2-OXO-8, 8a-dihydro-3aH-l- (S) -oxa-3- (R) -aza- eyelopent [1] indene-3 -carboxylic acid- [3- (l-4-cyano-4- phenyl-piperidin-1-yl) -propyl-amide (19 mg, 35%). The compound was dissolved in CH2C12 (3 mL) and was treated with IN HCl in ether (1 mL) . The solvent was removed in vacuo to give the corresponding hydrochloride salt as a white solid. M. P. 98-102°C; [α]D = -96.5, (c = 0.21, MeOH); Anal. Calcd. For C26H29N403C1 • 0.48 CH2C12: C, 60.96; H, 5.79; N, 10.74. Found: C, 60.94; H, 6.69; N, 8.02.
Example 14: 4- (3,4-Difluoro-phenyl) -2-oxo-oxazolidine-3- carboxylic acid {3- [2-methyl-4- (2-nitχ-o-phenyl) - piperazin-1-yl) -propyl} -amide a. (S) - (+) -3-mev:hyl-l- (2-rιitrophenyl) -piperazine
To a solution of 2-bromo-nitrobenzene (0.6 g, 3.0 mmol) in 1,4-dioxane (15 mL) was added (S)-(+)-2- methylpiperazine (0.5 g, 0.5 mmol) and powdered K2C03 (15.0 mmol, 1.5 g) and the resulting suspension was heated at reflux for 10 h. After the suspension was cooled, it was filtered through a sintered glass funnel and the solvent was evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (1:1 hexane/EtOAc followed by 4:1 EtOAc/MeOH) to yield (S) -(+) -3-methyl-l- (2-nitrophenyl) -piperazine as an orange oil (0.53 g, 80%) . It was converted into (S)- (+) -3-methyl-l- (2-nitrophenyl) -4- (3 -aminopropyl) - piperazine by the usual procedure. b. 4- (3, 4-Difluoro-phenyl) -2-oxo-oxazolidine-3- carboxyliσ acid {3- [2-methyl-4- (2-nitro-phenyl) - piperazin-1-yl) -propyl} -amide
To a solution of (S) -(+) -3-methyl-l- (2-nitrophenyl) -4- (3 -aminopropyl) -piperazine (35 mg, 0.126 mmol) in 10 mL of THF, 4- (3 , 4-difluorophenyl) -2-oxo-oxazolidine-3- carboxylic acid-4-nitro-phenyl ester (50 mg, 0.137 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature . The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by MeOH: EtOAc=l : 9 (R£= 0.58, MeOH:EtOAc=l:3 ) to obtain 4- (3 , 4-Difluoro-phenyl ) -2- oxo-oxazolidine-3-carboxylic acid {3- [2-methyl-4- (2- nitro-phenyl) -piperazin-1-yl) -propyl} -amide (55 mg, 87%) . The compound was dissolved in CH2C12 (3 L) and was treated with IN HCl in ether (1 mL) . The solvent was removed in vacuo to give the corresponding hydrochloride salt as a pale yellow solid. M. P. 115- 119°C; [α]D = +38.3, (c = 0.22, CH2C12) ; Anal. Calcd. For C24H28N505F2C1 • 0.72 C6H12 : C, 56.50; H, 6.38; N, 11.63. Found: C, 56.63; H, 6.35; N, 10.08. 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. NH4C1 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 Na2S04, 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) . b. 1-Benzyl-4-methyl-4-phenyl piperidine To a solution of l-benzyl-4-methyl-4-piperidinol (3.6 g, 17.5 mmol) in 75 mL of benzene was added A1C13 (11.7 g, 87.7 mmol) in one portion at room temperature. After stirring at room temperaure for 30 min, the reaction mixture was heated to reflux for 8 h. The red colored solution was allowed to cool and then poured over 100 g of ice-water. It was extracted with EtOAc (2 X 100 mL) and the organic layer was washed with solution of Rochelle's salt. The organic layer was separated, dried over Na2S04, filtered and the solvent was removed in vacuo to obtain l-benzyl-4-methyl-4-phenyl piperidine as a red oil (4.5 g, 97% yield) . It was used in the next step without further purification. c. 4-Methyl-4-phenyl piperidine To a cooled suspension of 10% Pd-C (0.5 g) in 10 mL methanol was added a solution of l-benzyl-4-methyl-4- phenyl piperidine (4.5 g, 17.0 mmol) in 40 mL of methanol and the resulting suspension was hydrogenated in a Parr bomb under 250 psi of hydrogen for two days. The suspension was filtered through a pad of celite and the solvent was removed from the filtrate to obtain 4- methyl-4-phenyl piperidine as a yellow solid (3.3 g, 99% yield) . d. 4- (3, 4-Difluoro-phenyl) -2-oxo-oxazolidine-3- carboxylic acid {3- [4-methyl-4-phenyl-piperidin-1-yl) - propyl} -amide
To a solution of 1- (3 -amino-propyl ) -4-methyl-4-phenyl- piperidine (60 mg, 0.258 mmol) in 10 mL of THF, 4- (3, 4- difluorophenyl) -2-oxo-oxazolidine-3-carboxylic acid-4- nitro-phenyl ester (60 mg, 0.165 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by MeOH:EtOAc=l : 19 (R£= 0.45, MeOH:EtOAc=l : 3 ) to obtain 4- (3 , 4-difluoro-phenyl) -2-oxo-oxazolidine-3- carboxylic acid {3- [4-methyl-4-phenyl-piperidin-l-yl) - propyl} -amide (56 mg, 74%) . The compound was dissolved in CH2C12 (3 mL) and was treated with IN HCl in ether (1 mL) . The solvent was removed in vacuo to give the corresponding hydrochloride salt as a pale yellow solid. M. P. 176-178°C; [α]D = +76.9, (c = 0.23, MeOH); Anal. Calcd. For C25H30N3O3F2Cl • 0.60 CH2C12: C, 56.32; H, 5.94; N, 7.70. Found: C, 56.30; H, 5.80; N, 7.35.
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
To a solution of ethylmagnesium bromide in ether (38.0 mL, 38.0 mmol) at 0°C, was added a solution of 3 ',4'- difluoroacetophenone (5.0 g, 32.0 mmol) in diethyl ether (35mL) . The reaction mixture was stirred at 0°C for 1 h when TLC analysis indicated that the reaction was complete (Rf = 0.3, 3:1 hexane/EtOAc) . The reaction was quenched carefully by adding 38 mL of water. It was extracted with diethyl ether (2 X 30 mL) , washed with Rochelle's salt followed by brine and the organic layer was dried over Na2S04. The solvent was removed in vacuo after filtration and 2- (3 , 4-difluorophenyl) propan-2-ol was obtained as a colorless oil (crude wt . = 5.4 g, 97%) which looked > 90% pure by NMR. It was used in the next step without purification. b. 1, 2-Difluoro-4-isopropenyl-benzene
To a solution of 2- (3 , 4-difluorophenyl) propan-2-ol (1.0 g, 5.8 mmol) in 40 mL benzene was added 0.1 g of p- toluenesulfonic acid and the solution was heated to 60 °C. TLC analysis showed disappearance of the starting material. After cooling, the solution was extracted with EtOAc, washed with saturated NaHC03, dried over Na2S04, filtered and the solvent was removed in vacuo. 1, 2-difluoro-4-isopropenyl-benzene was obtained as a yellow oil (0.82 g, 92% yield). c . 2- (3, 4-Difluorophenyl) -2-methyl-oxirane To a biphasic solution of 1, 2-difluoro-4-isopropenyl- benzene (0.81 g, 5.1 mmol) in CH2C12 (50 mL) and 50 mL of phosphate buffer (made by dissolving 0.3 g of NaHP04 and 0.35 g of NaH2P04 in 50 mL water, pH = 8) at 0°C, was added a solution of 3-chloroperoxybenzoic acid (approx. 75% solid, 3.32 g, 10.2 mmol) via a dropping funnel fitted with a cotton plug dropwise in two batches. The solution was stirred at room temperature overnight. It was extracted with CH2C12, washed with sat. Na2S204 solution followed by water. The organic layer was finally washed with sat. NaHC03, separated, dried over Na2S04, filtered and solvnt was removed in vacuo. 2- (3 , 4-Difluorophenyl) -2-methyl-oxirane was obtained as a pale yellow oil (0.65 g, 74% yield) . It was used in the next step without purification. d. l-Amino-2- (3, 4-difluorophenyl) -propan-2-ol and 2- Amino-2- (3, 4-difluorophenyl) -propan-l-ol
To a solution of 2- (3 , 4-difluorophenyl) -2-methyl-oxirane (1.2 g, 7.06 mmol) in 10 mL of acetonitrile was added sodium azide (0.69g, 10.6 mmol) followed by lithium perchlorate (1.13 g, 10.6 mmol) and the suspension was heated to reflux overnight. After cooling, it was extraced with EtOAc, washed with saturated NaHC03, dried over Na2S04, filtered and the solvent was removed in vacuo. 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 Et20 and the suspension was heated to reflux for 20 min. The suspension was filtered and was combined with the previous filtrate, dried over MgS04, filtered and the solvent was removed in vacuo. l-Amino-2- (3 , 4- difluorophenyl) -propan-2-ol and 2-amino-2- (3 , 4- difluorophenyl) -propan-1-ol was obtained as a yellow glassy syrup (1.16 g, 87%) which was used in the next step immediately without further purification. e. [2- (3, 4-Difluorophenyl) -2-hydroxy-propyl] -carbamic acid-tert-butyl ester and [1- (3,4-Difluorophenyl) -2- hydroxy-propyl] -carbamic acid-tert-butyl ester To a solution of 1-amino-2- (3 , 4-difluorophenyl) -propan- 2-ol and 2-amino-2- (3 , 4-difluorophenyl) -propan-1-ol (1.2 g, 6.4 mmol) in CHC13 (50 mL) at 0°C was added a solution of di-tert-butyl dicarbonate (1.74 g, 7.9 mmol) in CHC13 (10 mL) in one portion and the resulting solution was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel (2:1 hexane-EtOAc followed by EtOAc) to obtain [2- (3, 4- difluorophenyl) -2-hydroxy-propyl] -carbamic acid-tert- butyl ester and [1- (3 , 4-Difluorophenyl) -2-hydroxy- propyl] -carbamic acid-tert-butyl ester as a white solid (1.1 g, 60.1%) . f. 5- (3,4-Difluorophenyl) -5-methyl-oxazolidin-2-one and 4- (3, 4-Difluorophenyl) -4-methyl-oxazolidin-2-one To a well stirred solution of [2- (3 , 4-difluorophenyl) -2- hydroxy-propyl] -carbamic acid-tert-butyl ester and [1- (3 , 4-Difluorophenyl) -2-hydroxy-propyl] -carbamic acid- tert-butyl ester (1.1 g, 3.8 mmol) THF (50 mL) was added 95% NaH (0.23 g, 9.6 mmol) at room temperature. The resulting suspension was heated to reflux for 1 h and then stirred at room temperature overnight. It was quenched carefully with ice. The biphasic mixture was extracted with 100 mL of EtOAc, washed with brine, dried over Na2S04, filtered and the solvent was removed in vacuo. The two diastereomers were separated by column chromatography over silica gel. The first diastereomer that came out was 4- (3 , 4-difluorophenyl) -4-methy1- oxazolidin-2-one (0.05 g, Rf = 0.3, 3:2 hexane-EtOAc) and the second isomer was 5- (3 , 4-difluorophenyl) -5- methyl-oxazolidin-2-one (0.61 g, R£ = 0.2, 3:2 hexane- EtOAc) . g. 4- (3, 4-Difluorophenyl) -4-methyl-2-oxo-oxazolidine-3- carboxylic acid-4-nitro-phenyl ester To a a solution of 4- (3 , 4-Difluorophenyl) -4-methy1- oxazolidin-2-one (0.05 g, 0.23 mmol) in 5.0 mL THF was added 95% NaH (0.01 g, 0.28 mmol) in one portion. The resulting suspension was stirred at room temperature for 20 min. This suspension was then added dropwise via a syringe into another round bottom flask containing a solution of 4-nitrophenylchloroformate (0.06 g, 0.28 mmol) in 5 mL of THF, cooled at -78°C, over a period of 15 min. The stirring was continued for 1 h after which the solvent was removed and the residue was purified by column chromatography on silica gel with 3:2 hexane/EtOAc (Rf= 0.5) to obtain 4- (3 , 4-difluorophenyl) - 4-methyl-2-oxo-oxazolidine-3-carboxylic acid-4-nitro- phenyl ester as a white solid (0.06 g, 69%) . h. 5- (3, 4-Difluorophenyl) -5-methyl-2-oxo-oxazolidine-3- carboxylic acid-4-nitro-phenyl ester
To a a solution of 4- (3 , 4-Difluorophenyl) -4-methy1- oxazolidin-2-one (0.61 g, 2.86 mmol) in 20 mL THF was added 95% NaH (0.07 g, 3.0 mmol) in one portion. The resulting suspension was stirred at room temperature for 20 min. This suspension was then added dropwise via a cannula into another round bottom flask containing a solution of 4-nitrophenylchloroformate (0.62 g, 3.1 mmol) in 20 mL of THF, cooled at -78°C, over a period of 15 min. The stirring was continued for 1 h after which the solvent was removed and the residue was purified by column chromatography on silica gel with 3:2 hexane/EtOAc (R£= 0.6) to obtain 4- (3 , 4-difluorophenyl) - 4-methyl-2-oxo-oxazolidine-3-carboxylic acid-4-nitro- phenyl ester as a white solid (0.7 g, 67%) . i. 4-(3,4-Difluorophenyl) -4-methyl-2-oxo-oxazolidine-3- carboxylic acid {3- [4- (2-methylphenyl) -4- (4- methylphenyl) -piperidin-1-yl] -propyl}amide
To a solution of 3-amino-propyl-4- (2-methyl) phenyl-4- (4- methyl) phenyl-piperidine (0.09 g, 0.27 mmol) in 10 mL of THF, 4- (3 , 4-Difluorophenyl) -4-methyl-2-oxo-oxazolidine- 3-carboxylic acid-4-nitro-phenyl ester (0.06 g, 0.15 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 10 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with EtOAC followed by 15% MeOH in EtOAC as the eluting systems (Rf = 0.3, 1:3 MeOH/EtOAC) to obtain 4- (3 , 4-difluorophenyl) -4-methyl-2-oxo-oxazolidine-3- carbonyl) -amino-propyl} -4- (2-methyl )phenyl-4- (4- methyl) phenyl-piperidine as a pale yellow glassy oil
(0.06 g, 73%) as a viscous oil. It was converted into its hydrochloride salt. M.P. = 98-101°C; Anal. Calcd. for C33H38N303F2C1.1.0 CH2C12: C, 59.79; H, 5.90; N, 6.15. Found: C, 59.40; H, 5.99; N, 5.92.
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) To a solution of 3-amino-propyl-4- (2-methoxy-5- methyl)phenyl-4- (4-methyl) phenyl-piperidine (0.09 g, 0.27 mmol) in 10 mL of THF, 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. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with EtOAC followed by 15% MeOH in EtOAC as the eluting systems (R£ = 0.3, 1:3 MeOH/EtOAC) to obtain 4- (3 , 4-difluorophenyl) - 4-methyl-2-oxo-oxazolidine-3-carboxylic acid {3- [4- (2- methoxy-5-methyl)phenyl-4- (4-methylphenyl) -piperidin-1- yl] propyl} amide as a pale yellow glassy oil (0.06 g, 85%) as a viscous oil. It was converted into its hydrochloride salt. M.P. = 82-85°C; Anal. Calcd. for C34H40N3O4F2Cl .0.7 CH2C12: C, 60.61; H, 6.07; N, 6.11. Found: C, 60.73; H, 6.46; N, 6.12.
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
To a solution of 3 , 4-difluorobenzaldehyde (5.0 g, 35.2 mmol) in diethyl ether (35 mL)in a round bottom flask was added a solution of ethylmagnesium bromide in THF (38.0 mL, 38.0 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 h when TLC analysis indicated that the reaction was complete (R£ = 0.5, 8:1 hexane/EtOAc) . The reaction was quenched carefully by adding 38 mL of water. It was extracted with diethyl ether (2 X 30 mL) , washed with brine and the organic layer was dried over Na2S04. The solvent was removed in vacuo after filtration and 1- (3 , 4-difluorophenyl )propan-l-ol was obtained as a yellow oil (crude wt . = 6.0 g) which looked > 90% pure by NMR. It was used in the next step without purification. b. 1- (3,4-Difluorophenyl)propan-1-one
In a round bottom flask containing pyridinium chlorochromate (12.5 g, 58.1 mmol) was added celite 545 (25 g) and with the help of a magnetic stirrer the solids were mixed together. 200 mL of CH2C12 was added followed by a solution of 1- (3 , 4-difluoro-phenyl) propan- l-ol (5.0 g, 29.1 mmol) in 10 mL of CH2C12 and the resulting brown suspension was stirred overnight at room temperature. The suspension was filtered through a sintered glass funnel and the solvent was removed in vacuo from the pale green colored filtrate. The green oil was then diluted with diethyl ether (200 mL) and it was filtered through a pad of celite to remove the metal impurities. The solvent was removed in vacuo to obtain 1- (3 , 4-difluorophenyl )propan-l-one as a pale yellow oil (3.4 g, 69% yield) . It was used in the next step without purification. c. 1- (3, 4-Difluorophenyl) -2-hydroxy-propan-l-one In a round bottom flask containing 200 mL of MeOH was added pellets of potassium hydroxide (23.0 g, 410.0 mmol). The solution was cooled to 0°C and l-(3,4- difluorophenyl) -2-hydroxy-propan-1-one (7.0 g, 41.2 mmol) in 10 mL MeOH was added dropwise. The solution was stirred for 10 min and then iodobenzene diacetate (22.5 g, 70 mmol) was added in two portions. The solution first became orange and then turned yellow. It was stirred overnight at room temperature and then solvent was removed in vacuo. The residue was dissolved in water and was extracted with ethyl acetate (3 X 100 mL) . The combined organic extracts were washed with brine and then dried over Na2S04. After filteration, the solvent was removed in vacuo to get l-(3,4- difluorophenyl) -2-hydroxy-propan-1-one dimethyl acetal as a yellow viscous oil (crude wt . = 9.2 g) . It was dissoled in 150 mL of acetone and 10 drops of concentrated sulfuric acid were added. After stirring for 3 h, TLC analysis indicated that the reaction was complete. Acetone was removed in vacuo and after basification with saturated NaHC03, the residue was extracted in EtOAc and was washed with brine. The organic layer was separated, dried over Na2S04 and then filtered. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (Rf = 0.4, 3:2 hexane/EtOAc) to obtain 1- (3 , 4-difluorophenyl) - 2-hydroxy-propan-l-one as a pale yellow oil (3.3 g, 51% yield over two steps) . d. 1- (3, 4-Difluorophenyl) -2-hydroxy-propan-l-one-oxime To a well stirred solution of 1- (3 , 4-difluorophenyl) -2- hydroxy-propan-1-one (5.5 g, 29.6 mmol) in MeOH (200 mL) was added hydroxylamine hydrochloride (2.6 g, 38.4 mmol) and sodium acetate (8.1 g, 59.2 mmol) and the the turbid solution was stirred overnight at room temperature. The solvent was evaporated and the residue was extracted with CH2C12. The organic layer was washed with sat. NaHC03, separated, dried over Na2S04 and then filtered. The solvent was removed in vacuo to obtain l-(3,4- difluorophenyl) -2-hydroxy-propan-1-one-oxime as an orangish yellow oil (5.8 g, 97%) . It was used in the next step without purification. e. 1-Amino-l- (3, 4-difluorophenyl) -propan-2-ol To a well stirred solution of 1- (3 , 4-difluorophenyl) -2- hydroxy-propan-1-one-oxime (5.8 g, 28.4 mmol), was added a 1.0 M solution of LiAlH4 in ether (90 mL, 90 mmol) dropwise at 0°C. 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 Et20 and the suspension was heated to reflux for 20 min. The suspension was filtered and was combined with the previous filtrate, dried over MgS04, filtered and the solvent was removed in vacuo. 1-amino-l- (3 , 4-difluorophenyl) -propan-2-ol was obtained as a yellow glassy syrup (3.6 g, 66%) which was used in the next step without further purification. f. [1- (3, 4-Difluorophenyl) -2-hydroxy-propyl] -carbamic acid-tert-butyl ester
To a solution of 1-amino-l- (3 , 4-difluorophenyl) -propan- 2-ol (3.5 g, 19.1 mmol) in CHC13 (15 mL) at 0°C was added a solution of di-tert-butyl dicarbonate (5.1 g, 23.6 mmol) in CHC13 (10 mL) in one portion and the resulting solution was stirred overnight at room temperature . The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel (2:1 hexane-EtOAc followed by EtOAc) to obtain [1- (3 , 4-difluorophenyl) -2-hydroxy-propyl] -carbamic acid- tert-butyl ester as a viscous oil (3.3 g, 60.2%). g. 4- (3,4-Difluorophenyl) -5-methyl-oxazolidin-2-one To a well stirred solution of [1- (3 , 4-difluorophenyl) -2- hydroxy-propyl] -carbamic acid-tert-butyl ester (0.43 g, 1.5 mmol) THF (20 mL) was added 95% NaH (0.09 g, 3.8 mmol) at room temperature. The resulting suspension was stirred for 3 h at about 35°C (warm water bath) and then quenched carefully with ice. The biphasic mixture was extracted with 100 mL of EtOAc, washed with brine, dried over Na2S04, filtered and the solvent was removed in vacuo. The two diastereomers were separated by column chromatography over silica gel (First isomer: 0.11 g, Rf = 0.6, 3:1 hexane-EtOAc; second isomer: 0.23 g, Rf = 0.5, 3:1 hexane-EtOAc) . NOE experiment suggested that the first diastereomer had the methyl and the aryl group in trans configuration while the second diastereomer had cis relationship between the two groups .
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) . The retention times for the two isomers of the trans-oxazolidinone were 12.1 min {[α]D = + 36.4 (c = o.25, acetone)} and 15.6 min {[α]D = - 30.8 (c = o.20, acetone)}, respectively . The retention times for the two isomers of the cis-oxazolidinone were 13.7 min {[α]D = + 65.8 (c = o.92, acetone)} and 19.9 min {[α]D = - 65.8 (c = o.74, acetone) } respectively. The next steps may be performed on each of the four enantiomers individually in the following manner, which describes the synthesis of the cis (+ ) enantiomer.
h. 4- (3,4-Difluorophenyl) -5-methyl-2-oxo-oxazolidine-3- carboxylic acid-4-nitro-phenyl ester
To a suspension of 95% NaH (0.01 g, 0.38 mmol) in 5.0 mL of anhydrous THF under argon, a solution of 4- (3, 4- difluorophenyl) -5-methyl-oxazolidin-2-one (0.07 g, 0.33 mmol) in 5.0 mL THF was added dropwise via a syringe. The resulting suspension was stirred at room temperature for 20 min. This suspension was then added dropwise via a syringe into another round bottom flask containing a solution of 4-nitrophenylchloroformate (0.08 g, 0.4 mmol) in 10 mL of THF, cooled at -78°C, over a period of 15 min. The stirring was continued for 1 h after which the solvent was removed and the residue was purified by column chromatography on silica gel with 1:1 hexane/CH2Cl2 followed by CH2C12 (R£= 0.4, CH2C12) to obtain 4- (3 , 4-difluorophenyl) -5-methyl-2-oxo- oxazolidine-3 -carboxylic acid-4-nitro-phenyl ester as a white solid (0.07 g, 56%).
i . 3- [4- (4-Fluoro-phenyl) -piperidin-1-yl] -propylamine
To a solution of 4-fluorophenylmagnesium bromide (110.0 mmol, 55.0 mL of 2.0 M solution) in 150.0 mL THF at 0°C was added l-benzyl-4-piperidone (55.0 mmol, 10.2 mL) dropwise. The resulting solution was stirred under argon atmosphere for 1.5 h and then quenched with 100.0 mL of saturated NH4C1 solution. The organic layer was separated and the aqueous layer was extracted with 100.0 mL of Et20. The combined organic extracts were washed with brine, separated and dried over Na2S04. The solution was filtered and the solvent was removed in vacuo to obtain a yellow oil which was purified by passing through a silica gel column with 4:1 hexane/EtOAc followed by 1 : 1 hexane/EtOAc as the eluting system. l-Benzyl-4- (4-fluoro-phenyl) -piperidin-4-ol was obtained as a pale yellow oil in 89% yield (13.9 g) . It was dissolved in 150.0 mL of toluene and p- toluenesulfonic acid monohydrate (50.0 mmol, 9.5 g) was added. The resulting suspension was heated to reflux for 8 h. After the suspension was cooled, it was basified with 3 N NaOH solution and was extracted with Et20 (2 X 50 mL) . The organic extracts were combined, washed with brine and the oraganic layer was dried over Na2S04. The solvent was removed in vacuo to obtain l-benzyl-4- (4- fluoro-phenyl) -1, 2 , 3 , 6-tetrahydro-pyridine as a yellow viscous oil (12.0 g, 92% yield) which was used in the next step without further purification.
To a solution of l-benzyl-4- (4-fluoro-phenyl) - 1, 2, 3, 6-tetrahydro-pyridine (45.0 mmol, 12.0 g) in 100 mL MeOH was added 1.0 g of Pd(OH)2 and the resulting suspension was hydrogenated under 200 psi of H2 in a stainless steel bomb for two days. The suspension was passed through a pad of celite and the filterate was concentrated in vacuo to obtain 4- (4-fluoro) -phenyl- piperidine (7.5 g, 94%) as a viscous oil. It was converted into 3- [4- (4-fluoro-phenyl) -piperidin-1-yl] - propylamine by the route described previously in Example 1.
j. cis (+)- (4- (3, -Difluorophenyl) -5-methyl-2-oxo- oxazolidine-3-carboxylic acid{3- [4- (4-fluorophenyl) - piperidin-1-yl]propyl}amide To a solution of 3-amino-propyl-4- (4-fluoro)phenyl- piperidine (0.04 g, 0.12 mmol) in 10 mL of THF (+)-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 cis diastereomer separated by column chromatography) was added and the resulting yellow solution was stirred under argon atmosphere for 10 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with EtOAC followed by 15% MeOH in EtOAC as the eluting systems (Rf = 0.4, 1:3 MeOH/EtOAC) to obtain (+)-(4- (3 , 4-Difluorophenyl) -5-methyl-2-oxo-oxazolidine-3- carboxylic acid{3- [4- (4-fluorophenyl) -piperidin-1- yl] propyl} amide as a pale yellow glassy oil (0.03 g,
66%) . It was converted into its hydrochloride salt. M. P. 108-112°C; [α]D = +56.7, (c = 0.20, MeOH); Anal. Calcd. For C25H29N303F3C1 • 0.36 CH2C12: C, 56.14; H, 5.52; N, 7.75. Found: C, 56.17; H, 5.90; N, 7.20.
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) In an analogous manner as described above for Example 18, Steps h-j , 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) -piperidin-1- yl] propyl} amide in 70% yield. It was converted into hydrochloride salt . M.P. = 80-83°C (shrinks around 58°C) ; [α]D = + 27.4 (c = 0.49, MeOH); Anal. Calcd. for C25H29N303F3C1.1.0 H20: C, 56.55; H 6.07; N 7.91 Found: C, 56.49; H, 5.88; N 7.80.
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
To -a well stirred suspension of LiAlH4 (0.48 g,.12.5 mmol) in THF (30 mL) in a round bottom flask fitted with a condenser was added 3 , 4-difluorophenyl alanine (1.0 g, 5.0 mmol) in small portions at 0°C. The resulting grey suspension was then heated to reflux for 2 h. The reaction mixture was cooled to 0°C and then carefully quenched sequentially with 0.5 mL of water, 0.5 mL of 3N NaOH followed by 1.5 mL of water. The resulting suspension was filtered through a fritted glass funnel. To the residue was added 50 mL Et20 and the suspension was heated to reflux for 20 min. The suspension was filtered and was combined with the previous filtrate, dried over MgS04, filtered and the solvent was removed in vacuo. 2-Amino-3- (3.4-difluoro) -phenyl-propan-1-ol was obtained as a white solid (0.5 g, 100%) which was used in the next step without further purification. b. (+) - [1- (3,4-Difluorobenzyl) -2-hydroxy-ethyl] -carbamic acid-tert-butyl ester
To a solution of 2-amino-3- (3.4-difluoro) -phenyl-propan- l-ol (0.5 g, 2.62 mmol.) in CHC13 (20 mL) at 0°C was added a solution of di-tert-butyl dicarbonate (0.64 g, 2.90 mmol) in CHC13 (10 mL) in one portion and the resulting solution was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel (2:1 hexane-EtOAc followed by EtOAc) to obtain (+)- [1- (3 , 4-difluorobenzyl) -2-hydroxy-ethyl] -carbamic acid- tert-butyl ester as white solid (0.64 g, 99%). c. (+) -4- (3, 4-Difluoro-benzyl) -oxazolidin-2-one
To a well stirred suspension of 95% NaH (0.12 g, 5.0 mmol) in THF (20 mL) at r.t. was added a solution of (+) - [1- (3 , 4-difluorobenzyl) -2-hydroxy-ethyl] -carbamic acid-tert-butyl ester (1.0 g, 4.0 mmol) in 10 mL THF via a dropping funnel at room temperature. The resulting suspension was stirred for 3 h and then quenched carefully with 10 mL of water. The biphasic mixture was extracted with 50 mL of Et20, washed with brine, filtered and the solvent was removed in vacuo. The gummy residue thus obtained was purified by column chromatography over silica gel (R£ = 0.25, 3:2 hexane- EtOAc) to obtain (+) -4- (3 , 4-difluoro-benzyl) -oxazolidin- 2-one as a white solid (0.32 g, 76%). d. (+) -4- (3, 4-Difluoro-benzyl) -oxazolidin-2-one-3- carboxylic acid-4-nitro-phenyl ester
To a suspension of NaH (0.03 g, 1.30 mmol) in 10 mL of anhydrous THF under argon, a solution of (+)-4-(3,4- difluoro-benzyl) -oxazolidin-2-one (0.21 g, 1.0 mmol) in 10 mL THF was added dropwise via an dropping funnel.
The resulting suspension was stirred at room temperature for 30 min. This suspension was then added dropwise via cannula into another round bottom flask containing a solution of 4-nitrophenylchloroformate (0.30 g, 1.5 mmol) in 20 mL of THF and cooled at -78°C over a period of 15 min. The stirring was continued for 2 h after which the solvent was removed and the residue was purified by column chromatography on silica gel with 1:1 hexane/CH2Cl2 followed by CH2C12 (R£= 0.4, CH2C12) to obtain (+) -4- (3 , 4-difluoro-benzyl) -oxazolidin-2-one-3- carboxylic acid-4-nitro-phenyl ester as a yellow solid (0.35 g, 82%) . e. 4- (3,4-Difluoro-benzyl) -2-θ2£θ-oxazoliditiθ-3- carboxylic acid {3- [4- (2-carbamoylphenyl) -piperazin-1- yl] -propyl}amide To a solution of 1- (3-amino-propyl) -4- (2-carboxamido) - phenyl-piperazine (30 mg, 0.114 mmol) in 10 mL of THF, 4- (3 , 4-difluorobenzyl) -2-oxo-oxazolidine-3 -carboxylic acid-4-nitro-phenyl ester (30 mg, 0.079 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature . The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by 1:19 MeOH/EtOAc (R£= 0.70, MeOH/EtOAc=l:3 ) to obtain 4- (3 , 4-Difluoro-benzyl) -2- oxo-oxazolidine-3 -carboxylic acid {3- [4- (2- carbamoylphenyl) -piperazin-1-yl] -propyl} amide (20 mg, 44%) . The compound was dissolved in CH2C12 (3 mL) and was treated with IN HCl in ether (1 mL) . The solvent was removed in vacuo to give the corresponding hydrochloride salt as a yellow solid. M. P. 82-85°C; [α]D = +34.3, (c = 0.49, MeOH); Anal. Calcd. For C25H31N504F2C12 • 3.5 H20: C, 47.10; H, 6.01; N, 10.99. Found: C, 47.12; H, 5.94; N, 10.94.
Example 21: 4- (3, 4-difluorophenyl) -2-oxo-oxazolidine-3- carboxylic acid{2- [4-phenylpiperidine-4- (carboxylic acid methyl ester) ] ethyl}amide (Scheme 5)
To a solution of 2-amino-ethyl-4-carbomethoxy-4-phenyl piperidine (0.03 g, 0.12 mmol) in 5 mL of THF was added 4- (3 , 4-difluorophenyl) -2-oxo-oxazolidine-3 -carboxylic acid-4-nitro-phenyl ester (0.04 g, 0.10 mmol) and the resulting yellow solution was stirred under argon atmosphere for 3 h at room temperature . The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 50% hexane/EtOAC followed by 5% MeOH in EtOAC as the eluting systems (Rf = 0.5, 1:3 MeOH/EtOAC) to obtain the product as colorless oil (wt= 0.02 g) . The compound was converted into its hydrochloride salt. M.P. 80-85°C; [α]D = + 51.6, (c = 0.11, MeOH) ; Anal. Calcd. for C25H28N305C1F2.0.5 CHC13: C, 52.48; H, 4.92; N, 7.20. Found: C, 52.54; H, 5.13; N, 7.27.
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 a. 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. The 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. NH4C1 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
Na2S04, filtered and the solvent was removed in vacuo to obtain yellow oil. It was purified by column chromatography over silica gel with 3:2 hexane-EtOAc as the eluting system to obtain l-benzyl-4- (5-fluoro-2- methyl) -phenyl-4-piperidinol as a yellow thick oil (1.1 g, 46% yield) . b. 1-Benzyl-4- (4-Fluoro-2-methyl) -phenyl-1,2,3,6- tetrahydropyridine
To a solution of l-benzyl-4- (5-fluoro-2-methyl ) -phenyl- 4-piperidinol (1.1 g, 3.68 mmol) in 100 mL toluene was added p-toluenesulfonic acid monohydrate (1.39 g, 7.35 mmol) and the resulting solution was heated to reflux for 8 h. The suspension was cooled and the basified with 10% KOH solution and extracted with EtOAc (2 X 50 mL) . The organic layer was washed with brine (30 L) . The organic layer was separated, dried over Na2S04, filtered and the solvent was removed in vacuo to obtain 1-benzyl- 4- (4-Fluoro-2-methyl) -phenyl-1 , 2,3, 6-tetrahydropyridine as a pale yellow oil (0.9 g, 87% yield) . It was used in the next step without further purification. c. 3-amino-propyl-4- (4-fluoro-2-methyl)phenyl-piperidine To a cooled suspension of 10% Pd-C (0.1 g) in 10 mL methanol was added a solution of l-benzyl-4- (4-Fluoro-2- methyl) -phenyl-1, 2 , 3 , 6-tetrahydropyridine (0.9 g, 3.2 mmol) in 20 mL of methanol and the resulting suspension was hydrogenated at room temperature under 1 atm of hydrogen for 10 h. The suspension was filtered through a pad of celite and the solvent was removed from the filtrate to obtain 4- (4-fluoro-2-methyl ) -phenyl- piperidine which was converted into its hydrochloride salt (0.62 g, 99% yield) . It was used in the next step without further purification. It was converted into 3- amino-propyl-4- (4-fluoro-2-methyl) phenyl-piperidine by the usual procedure . d. 4- (3,4-Difluoro-phenyl) -2-oxo-oxazolidine-3- carboxyliσ acid{3- [4- (4-fluoro-2-methyl-phenyl) - piperidin-1-yl] -propyl}amide
To a solution of 3-amino-propyl-4- (4-fluoro-2- methyl) phenyl-piperidine (0.03 g, 0.11 mmol) in 5 mL of THF was added 4- (3 , 4-difluorophenyl) -2-oxo-oxazolidine- 3-carboxylic acid-4-nitro-phenyl ester (0.04 g, 0.10 mmol) and the resulting yellow solution was stirred under argon atmosphere for 8 h at room temperature . The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 50% hexane/EtOAC followed by 5% MeOH in EtOAC as the eluting systems (Rf = 0.4, 1:3 MeOH/EtOAC) to obtain the product as colorless oil (wt= 0.02 g) . The compound was converted into its hydrochloride salt. Off-white solid. M.P. = 60-64°C; [α]D= + 36.6 (c = 0.15, MeOH); Anal. Calcd. for C25H29N303F3C1.0.25 CHC13 : C, 55.97; H, 5.44; N, 7.76. Found: C, 55.91; H, 5.66; N, 7.87.
Preparation of Side Chains. 1. 3- (4,4-Diphenylpiperidin-l-yl)propylamine. a. 4,4-Diphenylpiperidine hydrochloride. A mixture of 4-piperidone monohydrate hydrochloride (15.0 g, 0.0976 mol) and A1C13 (130 g, 0.976 mol, 10.0 eq) in anhydrous benzene (600 mL) were stirred at reflux for 4 hours. The mixture was cooled to room temperature, poured into ice (300 g) and water (50 mL) , and filtered. The solid was washed with toluene and dried to afford 19.2 g (72%) of an off-white solid, which was characterized spectroscopically . b. 3- (4,4-Diphenylpiperidin-l-yl)propiσnitrile. To a suspension of 4 , 4-diphenylpiperidine hydrochloride (0.195 g, 0.712 mmol) in EtOH (1.5 mL) was added Et3N (0.25 mL, 1.8 mmol, 2.6 eq) followed by acrylonitrile (0.13 mL, 2.01 mmol, 2.8 eq) . The resulting solution was stirred at room temperature under argon for 15 min and then concentrated. Water was added, and the mixture was extracted with EtOAc (3 X 10 mL) . The combined organic extracts were dried (MgS04) and concentrated to give 170 mg (87%) of a tan solid, which was characterized spectroscopically and used in the next reaction without purification. c. 3- (4,4-Diphenylpiperidin-l-yl)propylamine. To a stirred solution of 3- (4, 4-diphenylpiperidin-l- yDpropionitrile (2.00 g, 6.89 mmol) in anhydrous THF (20 mL) under argon was added a solution of BH3 in THF (1.0 M, 24.1 mL, 24 mmol, 3.5 eq) at room temperature. The mixture was refluxed for 4.5 hours and then cooled to room temperature. Aqueous HCl (6 N, 50 mL) was added and stirring was continued for 1 hour. The mixture was basified to pH 9 by addition of 6 N aq. NaOH, extracted with CH2C12 (3 X 10 mL) , dried (MgS04) and concentrated. The residue was purified by flash chromatography (Si02, EtOAc-MeOH-isopropylamine 9:1:0 to 4:1:0.2) to give 1.35 g (66%) of tan solid, which was characterized spectroscopically .
2. -3- (4-Cyano-4-phenylpiperidin-l-yl)propylamine. a. 3- (4-Cyano-4-phenylpiperidin-l-yl)propylphthalimide. A mixture of 4-cyano-4-phenylpiperidine hydrochloride (111 g, 0.5 mol), 3-bromopropylphthalimide (135.39 g, 0.505 mol), potassium carbonate (276.42 g, 2 mol), and potassium iodide (5.4 g) in DMF (1 L) was stirred and heated at 100-110 °C for 8 h. About 80% of the solvent was evaporated at reduced pressure, the residue was diluted with dichloromethane (1 L) and washed with brine (3 X 300 mL) and dried (Na2S04) . Solvent was evaporated from the dichloromethane solution and the residue was treated with isopropanol (400 mL) and cooled. The pale yellow crystalline product formed was filtered, washed with ice-cold isopropanol and dried (168.6 g, 90%); M.p. 96-98 °C. b. 3- (4-Cyano-4-phenylpiperidin-l-yl)propylamine. To a solution of 3-(4-cyano- 4-phenylpiperidin-l-yl)propylphthalimide (112 g, 0.3 mol) in methanol (1. 5 L) , hydrazine (30 mL) was added and the mixture was stirred and refluxed for 20 h. It was cooled, the white solid formed was filtered and washed with more methanol (200 mL) . Solvent was evaporated from the filtrate and residue was dried under vacuum for 4 h. Chloroform (500 mL) was added to this, stirred for 1 h and filtered. The white solid was washed with more chloroform (200 mL) , the solvent was evaporated from the combined filtrates to leave the product as an oil (70 g, 96%) . 3. 3- (4-Methoxycarbonyl-4-phenylpiperidin-l- yl)propylamine. a. 4-Methoxycarbonyl-4-phenylpiperidine. To a stirred solution of H2S04 (16 mL) in MeOH (400 mL) , 4- phenyl-4-piperidinecarboxylic acid 4- methylbenzenesulfonate (37.7 g, 0.1 mole) was added and the mixture was stirred and refluxed for 8 hours. Excess methanol 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 CH2C12 (3 X 150 mL) . The combined CH2C12 extracts were dried (MgS04) and the solvent evaporated to leave the desired product as a viscous oil. The product (20.2 g, 92%) was used without further purification. b. 3- (4-Methoxycarbonyl-4-phenylpiperidin-l- yl)propylamine.
A mixture of 4-methoxycarbonyl-4-phenylpiperidine (8.5 g, 0.039 mol), 3-bromopropylamine hydrobromide (12.7 g, 0.058 mol), potassium carbonate (13.475 g, 0.0957 mole), and KI (3.24 g, 0.0195 mol) in 1,4-dioxane (200 mL) was stirred and refluxed for 24 hours. Dioxane was evaporated at reduced pressure, the residue was treated with ice-cold 6 N NaOH (400 L) and extracted with
CH2C12 (4 X 120 mL) . Solvent was evaporated from the combined dried (K2C03) extracts and the residue was purified by column chromatography on silica gel using CHCl3/MeOH/2 M NH3 in MeOH (20:2:1) as the eluent to afford the product as a viscous oil (7.8 g, 72%) .
4. 3-Aminopropyl-4-pyridyl-piperidine a. 1- (3-Aminopropyl) -4- [pyrid-2-yl]pyridiniuϊή bromide hydrobromide. 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 Et20 and dried. The mother liquor was concentrated to remove Et20 and then heated at 90-95 °C for 4 h. The solvent was evaporated and the white residue was triturated with Et20 (100.0 mL) and filtered. The combined weight of the salt was 11.6 g (97%) . b. 3- (3 ' , 6 • -Dihydro-2 ' -H- [2,4']bipyridinyl-1 ' -yl) - propylamine .
To a solution of 1- (3 -aminopropyl) -4- [pyrid-2- yl]pyridinium bromide hydrobromide (0.66 g, 1.75 mmol) in 20.0 mL MeOH was added NaBH4 (0.101 g, 2.62 mmol) in small portions. The reaction mixture was stirred for 30 min and then quenched with 6M HCl solution. The solution was concentrated to 20.0 mL and basified with 50% NaOH solution to pH 12. Extracted with CHC13 (5 x 30.0 mL) , dried over MgS04 and the solvent was removed to give 3- (3 ' , 6 ' -dihydro-2 ■ -H- [2 , 4 ' ] bipyridinyl-1 ' -yl) - propylamine as an oil (0.37 g, 96% yield) . It is used in the next step immediately without purification. c. 3-Aminopropyl-4- (2-pyridyl)piperidine . To a solution of 3- (3 ' , 6 ' -dihydro-2 ' -H-
[2 , 4 ' ] bipyridinyl-1 ' -yl) -propylamine (3.48 g crude, 15.9 mmol) in MeOH (40 mL) , was added 1.0 g of Pearlman's catalyst. The suspension was hydrogenated under 120 psi for 10 h after which the reaction mixture was filtered through a pad of celite and the solvent was removed.
The residue was purified by column chromatography over silica gel using CH2Cl2/methanol/2M NH3 in MeOH (90:8:4 to 90:40:40) as the eluting system. The product was obtained as a pale yellow oil (3.21 g, 91%) . 5. 3- (4-Acetoxy-4-phenylpiperidin-l-yl)propylamine. a. N-Benzyloxycarbonyl-3- (4-hydroxy-4-phenylpiperidin-l- yl)propylamine.
A mixture of 4-hydroxy-4-phenylpiperidine (5 g, 0.0282 mol), N-benzyloxycarbonyl-3-bromopropylamine (8.445 g, 0:031 mol), and potassium carbonate (7.795 g, 0.0564 mole) in acetone (200 mL) was stirred and refluxed for 12 hours. Acetone was evaporated at reduced pressure, the residue was treated with ice-cold water (400 mL) and extracted with CH2C12 (4 X 120 mL) . Solvent was evaporated from the combined dried (sodium sulfate) extracts and the residue was found to be almost pure desired product (9.5 g, 91%) by tic and ^Η-NMR and was used as such without any further purification. b. N-Benzyloxycarbonyl-3- (4-acetoxy-4-phenylpiperidin-l- yl)propylamine .
To a solution of N-benzyloxycarbonyl-3- (4-hydroxy-4-phenylpiperidin-l-yl) propylamine (0.5 g, 1.36 mmol) in THF (20 mL) at 0 °C, sodium hydride (60% suspension in paraffin, 65 mg, 1.63 mmol, 1.2 eq. ) was added and the mixture was stirred for 1.5 h. To this acetyl bromide (0.12 mL, 1.63 mmol) was injected and the mixture was stirred at 0 °C for 30 minutes and at room temperature for 3 h. Solvent was evaporated, the residue was mixed with dichloromethane (100 mL) , and washed with water (2 X 20 mL) . Solvent was evaporated from the dried dichloromethane solution gave the product as a viscous oil (0.485 g, 87%). The 1H-NMR showed this product to be pure and was used in the next. step without any further purification.
c. 3- (4-Acetoxy-4-phenylpiperidin-l-yl)propylamine.
A mixture of N-benzyloxycarbonyi-3-
(4-acetoxy-4-phenylpiperidin-l-yl) propylamine (3.0 g, 7.3 mmol) and 10% Pd-C (0.3 g) in 1M ammonia in methanol(50 mL) was hydrogenated at 70 psi at room temperature for 4 h. The catalyst was removed by filtration and the solvent was evaporated to leave the product as a viscous oil (2.01 g, 99%), the ^-NMR showed it to be very pure and was used in the next step without any purification.
6. 3- (4-Cyano-4-phenylpiperidin-l-yl) -2- hydroxypropylamine. a. 3 - (4-Cyano-4-phenylpiperidin-l-yl) (2- hydroxypropyl)phthalimide
A mixture of 4-cyano-4-phenylpiperidine (10.0 g, 45 mmol) and 2 , 3-epoxypropylphthalimide (10.94 g, 54 mmol) in DMF (100 mL) was stirred and heated at 70 °C for 72 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using chloroform-methanol-2M ammonia in methanol (1000/28/14) as the eluent, to obtain the desired product as a viscous oil (16.45 g, 86%) . b. 3- (4-Cyano-4-phenylpiperidin-l-yl)-2- hydroxypropylamine .
A mixture of 3- (4-cyano-4-phenylpiperidin-l-yl) - (2- hydroxypropyl) phthalimide (10 g, 23.48 mmol) and hydrazine (6.01 g, 188 mmol, 8 eq.) in methanol (100 mL) was stirred and refluxed for 4.5 h. It was cooled, filtered, and the solid was washed with methanol (30 mL) . Evaporation of solvent from the filtrate gave the product as a viscous oil (5.53 g, 94%).
7. 3- (4-Cyano-4-phenylpiperidin-l-yl) -2- fluoropropylamine. a. 3 - (4-Cyano-4-phenylpiperidin-l-yl) (2- fluoropropyl)phthalimide
A mixture of 3- (4-cyano-4-phenylpiperidin-l-yl) - (2- hydroxypropyl) phthalimide (2.60 g, 6.1 mmol) and diethylaminosulfur trifluoride (DAST, 1.96 g, 12.2 mmol) in benzene (100 mL) was stirred and heated at 70 °C under argon atmosphere for 24 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using chloroform-methanol-2M ammonia in methanol (1000/28/14) as the eluent, to obtain the desired product as a viscous oil (1.30 g, 50%). b. 3- (4-Cyano-4-phenylpiperidin-l-yl) -2- fluoropropylamine .
A mixture of 3- (4-cyano-4-phenylpiperidin-l-yl) - (2- fluoropropyl) phthalimide (3.80 g, 8.88 mmol) and hydrazine (2.27 g, 71.04 mmol, 8 eq. ) in methanol (100 mL) was stirred and refluxed for 4.5 h. It was cooled, filtered, and the solid was washed with methanol (30 mL) . Evaporation of solvent from the filtrate gave the product as a viscous oil (1.9 g, 85%).
8. 3- [4- (2-Pyridyl) -piperidin-1-yl) -3-methylpropylamine. a. 3-[4-(2-Pyridyl)-piperidin-l-yl)-2- methylpropionitrile.' A mixture of 4- (2 -pyridyl ) - piperidine (1.56 g, 10 mmol) and crotononitrile (1.34 g, 20 mmol, 2 eq) in ethanol (100 mL) was strirred and refluxed for 16 h and the solvent and excess crotononitrile were evaporated under vacuum. The residue was purified by column chromatography on silica gel using dichloromethane-methanol-2M ammonia in methanol (45/4/2) as the eluent to give the desired product as a viscous oil (2.09 g, 94%), which got solidified on standing. b. 3- [4- (2-Pyridyl) -piperidin-1-yl) -3-methylpropylamine. To a stirred solution of 3- [4- (2-pyridyl) -piperidin-1- yl) -3-methylpropionitrile (0.446 g, 2 mmol) in anhydrous THF (10 mL) under argon was added a solution of BH3 in THF (1.0 M, 10 mL, 10 mmol, 5 eq) at room temperature. The mixture was refluxed for 4.5 hours and then cooled to room temperature. Aqueous HCl (6 N, 50 mL) was added and stirring was continued for 1 hour. The mixture was basified to pH 9 by addition of 6 N aq. NaOH, extracted with CH2C12 (3 X 10 mL) , dried (potassium carbonate) and the solvent evaporated to leave the product as a viscous oil (0.42 g, 93%) the XH-NMR of it showed it to.be pure enough to use it in the next step.
9. 3- [4- (2-Pyridyl) -piperidin-1-yl) -2-methylpropylamine. a. 3- [4- (2-Pyridyl) -piperidin-1-yl) -2- methylpropionitrile. A mixture of 4- (2-pyridyl ) - piperidine (3.12 g, 20 mmol) and 1-methylacrylononitrile (5 mL) in methanol (100 mL) was strirred and refluxed for 48 h and the solvent and excess 1- methylacrylonitrile were evaporated under vacuum. The residue was purified by column chromatography on silica gel using dichloromethane-methanol-2M ammonia in methanol (45/4/2) as the eluent to give the desired product as a viscous oil (3.30 g, 74%), which got solidified on standing. b. 3- [4- (2-Pyridyl) -piperidin-1-yl) -2-methylpropylamine. To a stirred solution of 3- [4- (2-pyridyl) -piperidin-1- yl) -2-methylpropionitrile (0.446 g, 2 mmol) in anhydrous THF (10 mL) under argon was added a solution of BH3 in THF (1.0 M, 10 mL, 10 mmol, 5 eq) at room temperature. The mixture was refluxed for 4.5 hours and then cooled to room temperature. Aqueous HCl (6 N, 50 mL) was added and stirring was continued for 1 hour. The mixture was basified to pH 9 by addition of 6 N aq. NaOH, extracted with CH2C12 (3 X 10 mL) , dried (potassium carbonate) and the solvent evaporated to leave the product as a viscous oil (0.436 g, 96%) the XH-NMR of it showed it to be pure enough to use it in the next step.
Examples 23 and 24.
N3- [3- (4-Cyano-4-phenylpiperidino)propyl] -2-oxo-4,4- diphenyl-oxazolidine-3-carboxamide hydrochloride and N3- [3- (4,4-Diphenylpiperidino)propyl] -2-oxo-4,4-diphenyl- oxazolidine-3-carboxamide hydrochloride a) 1, 1-Diphenyl-2-hydroxyethylamine.
To stirred a solution of 2 , 2-diphenylglycine (5.0 g, 22 mmol) in THF (100 mL) at 0°C under argon atmosphere, a solution of LAH in THF (1M, 50 mL, 50 mmol) was added over a period of 15 minutes and the mixture was allowed to warm to room temperature. After 12 h, it was poured onto a mixture of ice (300 g) and 6N HCl (20 mL) and stirred for lh. The mixture was basified to pH 10-11 by the addition of 6N NaOH and extracted with dichloromethane (4 X 100 mL) . The combined extracts were dried (sodium sulfate) and the solvent evaporated to leave the product as a pale yellow viscous oil, which on trituration with hexane became white powder (4.7 g, -100%) . The XH-NMR showed this product to be pure and was used as is in the next step. b) 4, 4-Diphenyl-2-oxo-oxazolidine .
A mixture of 1, 1-dipheny1-2-hydroxyethylamine (4.26 g, 20 mmol), CDI (3.24 g, 20 mmol) in dichloromethane (200 mL) was refluxed for 20 h and the solvent evaporated. The residue was purified by column chromatography on silica gel using dichloromethane/ethyl acetate (9:1) to give the product as a viscous oil which solidified on standing (4.25 g, 89%). c) 4, 4-Diphenyl-1- (4-nitrophenyloxycarbonyl) -2-oxo- oxazolidine.
To a stirred suspension of sodium hydride (60% suspension in paraffin, 0.6 g, 15 mmol, 1.5 eq.) in THF (20 mL) at 0 °C, a solution of 4 , 4-diphenyl-2-oxo- oxazolidine (2.39 g, 10 mmol) in THF (5 mL) was added and stirred for 30 minutes. This suspension was added to a solution of 4-nitrophenyl chloroformate (2.41 g, 12 mmol) in THF (20 mL) at -78 °C under argon and the stirring was continued for 2 h. It was slowly warmed to room temperature and after 4 h the solvent was evaporated. The residue was mixed with dichloromethane (150 mL) , washed with 0.05 N sodium hydroxide (3 X 10 mL) , and dried (sodium sulfate) . Solvent was evaporated and the residue was purified by column chromatography on silica gel using chloroform/ethyl acetate (9:1) as the eluent to give the product as a white powder (3.72 g, 92%) . d) General procedure: Examples 23 and 24. A mixture of 4 , 4-diphenyl-3- (4-nitrophenyloxycarbonyl) - 2-oxo-oxazolidine (40 mg, 0.1 mmol) and an appropriate amine (0.15 mmol, 1.5 eq.) in THF (5 mL) was stirred at room temperature and the product formed was purified by preparative TLC on silica gel using ethyl acetate as the eluent. The HCl salt was made by treatment with IN HCl in ether .
N3- [3- (4-Cyano-4-phenylpipβridino)propyl] -2-oxo-4,4- diphenyl-oxazolidine-3-carboxamide hydrochloride Yield 93%; m.p.139-141 °C; Anal. Calcd. For: C31H32N403.HC1 .0.8CH2C12 : C, 60.77; H, 5.92; N, 9.51.
Found: C, 60.90; H, 5.80; N, 9.66. N3- [3- (4,4-Diphenylpiperidino)propyl] -2-oxo-4,4- diphenyl -oxazolidine- 3 -carboxamide hydrochloride Yield 92%; m.p.145-148 °C; Anal. Calcd. For: C34H37N303.HC1 .1.3CH2C12: C, 62.12; H, 6.00; N, 6.16.
Found: C, 62.19; H, 5.64; N, 6.14.
Examples 25, 2ό, 27, 28 and 29. a. 1- (3, 4 -Dif luorophenyl) -2-methyl-2-hydroxypropylamine. To a well-stirred solution of methyl 2-amino-2- (3 , 4- difluorophenyl) acetate (10.5 g, 52.19 mmol) in anhydrous ether (200 mL) at 0°C a solution of methylmagnesium bromide (3M, 87 mL, 261 mmol) in ether was added in 10 minutes. The mixture was stirred at 0°C for 2.5 h and allowed to warm to room temperature. After 12 h, the mixture was carefully poured onto a mixture of ice (300 g) and saturated ammonium chloride (50 g) . The ether layer was separated and the aqueous layer was extracted with more ether (4 X 200 mL) . The combined extracts were dried with magnesium sulfate and the solvent evaporated. The crude product was purified by column chromatography on silica gel using chloroform/methanol/2M ammonia in methanol (1000:20:10 mL, 1000:40:20 mL, 1000:80:40 mL) as eluents to give the product as an oil (6.5 g, 62%) . The :H-NMR and MS confirmed this to be the desired product. b. 4- (3, 4-Difluorophenyl) -5, 5-dimethyl-2-oxo- oxazolidine.
A mixture of 1- (3 , 4-difluorophenyl) -2-methyl-2- hydroxypropylamine (3.00 g, 14.9 mmol), CDI (2.418 g,
14.9 mmol) in dichloromethane (150 mL) was refluxed for 36 h and the solvent evaporated. The residue was purified by column chromatography on silica gel using chloroform/ethyl acetate (9:1) to give the product as a viscous oil which solidified on standing (1.80 g, 50%).
c. 4- (3, 4-Difluorophenyl) -5, 5-dimethyl-2-oxo-3- (4- nitrophenyloxycarbonyl) oxazolidine .
To a stirred suspension of sodium hydride (60% suspension in paraffin 203 mg, 1.4 eq.) in THF (20 mL) at 0 °C, a solution of 4- (3 , 4-difluorophenyl) -5 , 5- dimethyl-2-oxo-oxazolidine (870 mg, 3.622 mmol) in THF (5 mL) was added and stirred for 30 minutes. This suspension was added to a solution of 4-nitrophenyl chloroformate (950 mg, 4.71 mmol) in THF (20 mL) at -78 °C under argon and the stirring was continued for 2 h. It was slowly warmed to room temperature and after 4 h the solvent was evaporated. The residue was mixed with dichloromethane (150 mL) , washed with 0.05 N sodium hydroxide (3 X 10 mL) , and dried (sodium sulfate) .
Solvent was evaporated and the residue was purified by column chromatography on silica gel using chloroform/ethyl acetate (9:1) as the eluent to give the product as a white powder (860 mg, 59%) . d. General procedure:
A mixture of 4- (3 , 4-difluorophenyl) -5 , 5-dimethyl-3- (4- nitrophenyloxycarbonyl) -2-oxo-oxazolidine (50 mg, 0.123 mmol) and an appropriate amine (0.16 mmol, 1.3 eq.) in dichloromethane (6 mL) was stirred at room temperature and the product formed was purified by preparative TLC on silica gel using two elutions, first with chloroform/ethyl acetate (9:1) and then with chloroform/methanol (9:1) as eluents. The HCl salt was made by treatment with IN HCl in ether. Example 25:
Methyl l-[3-( [4- (3, 4-difluorophenyl) -5, 5-dimethyl-2-oxo- oxazolidine-3-yl] carbonylamino)propyl] -4-phenyl-4- piperidinecarboxylate hydrochloride Yield 56%; m.p. 208-210 °C; Anal. Calcd. For: C28H33F2N305.HC1 : C, 59.41; H, 6.05; N, 7.42. Found: C, 59.06; H, 5.83; N, 7.27.
Example 26:
1- [3-( [4-(3,4-Difluorophenyl)-5,5-dimethyl-2-oxo- oxazolidine-3-yl] carbonylamino) propyl] -4-phenyl-4- piperidyl acetate hydrochloride
Yield 29%; m.p. 116-118 °C; Anal. Calcd. For: C28H33F2N305.HC1 .0.3CH2C12: C, 57.46; H, 5.90; N, 7.50. Found: C, 57.38; H, 6.18; N, 7.67. Example 27 :
N3-3- [4- (2 -Pyridyl )piperidino] -3-methylpropyl-4- (3,4- di fluorophenyl) -5, 5-dimethyl-2-oxo-oxazolidine-3- carboxamide dihydrochloride Yield 64%; m.p. 87-90 °C; Anal. Calcd. For:
C26H32F2N403.2HC1 .1.1CHC13.1.1H20 : C, 45.81; H, 5.29; N, 7.88. Found: C, 45.73; H, 5.50; N, 8.07.
Example 28: N3- [3- (4-Cyano-4-phenylpiperidino) -2-hydroxypropyl] -4-
(3, 4-dif luorophenyl) -5, 5-dimethyl-2-oxo-oxazolidine-3- carboxamide hydrochloride
Yield 63%; m.p. 135-137 °C; Anal. Calcd. For: C27H30F2N4O4.HCl .1.2H20: C, 56.83; H, 5.90; N, 9.82. Found: C, 56.88; H, 5.98; N, 9.58.
Example 29:
N3- [3- (4-Cyano-4-phenylpiperidino) -2-fluoropropyl] -4- (3, 4-difluorophenyl) -5, 5-dimethyl-2-oxo-oxazolidine-3- carboxamide hydrochloride
Yield 39%; m.p. 120-122 °C; Anal. Calcd. For: C27H29F3N403.HC1 .0.8CH2C12: C, 53.95; H, 5.15; N, 9.05. Found: C, 53.89; H, 5.33; N, 8.95.
Example 30:
Methyl 1-5- [4- (3, 4-difluorophenyl) -5, 5-dimethyl-2-oxo- oxazolidin-3-yl]pentyl-4-phenyl-4-piperidinecarboxylate hydrochloride a. 4- (3, 4-Difluorophenyl) -5, 5-dimethyl-l- (5- bromopentyl) -2-oxo-oxazolidine.
To a stirred suspension of sodium hydride (60% suspension in paraffin 205 mg, 1.4 eq) in THF (20 mL) at 0 °C, a solution of 4- (3 , 4-difluorophenyl) -5 , 5-dimethyl- 2-oxo-oxazolidine (880 mg, 3.622 mmol) in THF (5 mL) was added and stirred for 30 minutes. To this 1,5- dibromopentane (3.37 g, 14.64 mmol, 4 eq. ) and HMPA (179 mg, 3.66 mmol) were added and the mixture was warmed to room temperature. It was heated at 55-60 °C for 12 h and the solvent evaporated. The residue was purified by column chromatography on silica gel using chloroform/ethyl acetate (9:1) as the eluent to give the product as a viscous oil (1.1 g) . b. Methyl 1-5- [4- (3, 4-difluorophenyl) -5, 5-dimethyl-2- oxo-oxazolidin-3-yl]pentyl-4-phenyl-4- piperidinecarboxylate hydrochloride
A mixture of 4- (3 , 4-difluorophenyl) -5 , 5-dimethyl-1- (5- bromopentyl) oxazolidinone (50 mg, 0.123 mmol), 4-phenyl-4-methoxycarbonylpiperidine (0.16 mmol , 1.3 eq.), potassium iodide (11.6 mg) , and potassium carbonate (58 mg, 0.42 mmol, 3 eq.) in acetone (6 mL) was stirred and refluxed for 12 h and the product formed was purified by preparative TLC on silica gel using ethyl acetate as the eluent. The HCl salts were made by treatment with IN HCl in ether. Yield 50%; m.p. 58-60 °C; Anal. Calcd. For: C29H36F2N204.HCl .0.8CH2C12 : C,
57.82; H, 6.28; N, 4.53. Found: C, 58.01; H, 6.53; N, 4.45.
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
(5 g, 23 mmol) and N- (2-bromoethy1) phthalimide (5.85 g, 23 mmol) in DMF (100 mL) was added potassium carbonate
(10 g) and potassium iodide (250 mg) and the mixture was stirred and heated at 65-70 °C for 2h. It was poured into ice-water (500 mL) , extracted with ether (4 X 75 mL) and dried (sodium sulfate) . Solvent was evaporated and the product was crystallized from methanol (8 g, 89%) . b. N- (2- [{4- (2-Keto-l-benzimidazolinyl)piperidin-l-yl] - ethyl) amine
A mixture of N- (2- [ {4- (2-keto-l- benzimidazolinyl)piperidin-l-yl] -ethyl) phthalimide (3.9 g, 10 mmol) and hydrazine (2 mL) in methanol was refluxed for 10 h and the solvent was evaporated. The residue was suspended in chloroform (50 mL) and filtered. The residue was washed with more chloroform (50 mL) . Solvent was evaporated from the combined filtrate and the residue was dried under vacuum to leave the desired product, which was used in the next step without further characterization. c . 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. Yield 25 mg; [α]D = +58.8 (c = 0.40 g, methanol); m.p. 227-230 °C; Anal. Calcd. For: C26H29F2N503.HCl .0.4 CH2C12: C, 54.30; H, 5.32; N, 11.99. Found: C, 54.52; H, 5.40; N, 11.82.
Example 32 :
4- (3,4-Difluorophenyl) -3- [ (3- [4- (2- pyridyl)piperidino]methylpiperidino) carbonyl] - oxazolidine-2-one dihydrochloride . a. l-Benzyl-4- [pyrid-2-yl]pyridinium bromide. A solution of 2 , 4 ' -dipyridyl (15.62 g, 0.1 mol) and benzyl bromide (17.104 g, O.lmol) in anhydrous EtOAc (600 L) for 24 h. The pale yellow crystalline product formed was filtered and dried (32.7 g, 100%) . b. l-Benzyl-4- (2-pyridyl) -1,2, 3, 6-tetrahydropyridine.
To a stirred solution of l-benzyl-4- [pyrid-2- yl ] pyridinium bromide (50 g, 0.152 mol) in ethanol (500 mL) at 0-5 °C, was added NaBH4 (23 g) in small portions over a period of 4 h. The mixture was allowed to warm to room temperature and the stirring continued for overnight. Solvent was evaporated the residue was mixed with ether (500 mL) , washed with 6N sodium hydroxide solution (200 mL) , brine (500 mL) , and dried (potassium carbonate) . Solvent was evaporated and the oily residue was used in the next step immediately without purification (33.4 g, 88%). c. 4- (2-Pyridyl)piperidine.
To a solution of l-benzyl-4- (2-pyridyl) -1, 2 , 3 , 6- tetrahydropyridine (25 g, 0.1 mol) in MeOH (400 mL) and 2M ammonia in methanol (100 mL) , was added Pearlman's catalyst (6 g) . The suspension was hydrogenated under 200 psi for 24 h after which the reaction mixture was filtered through a pad of celite and the solvent was removed. The residue was purified by column chromatography over silica gel using CH2C12/methanol/2M NH3 in MeOH (45:4:2 to 9:4:4) as the eluting system. The product was obtained as a pale yellow oil (12.4 g, 79%) . d. N- (t-Butyl-carbonate) -nipecotic acid. To a solution of nipecotic acid (3.865 g, 29.9 mmol) in dioxane (20 mL)at 0°C was added (Boc)20 (6.53 g, 29.9 mmol) and a solution of NaOH (2.63 g, 6.60 mmol)in water (10 mL) .
The resulting mixture was stirred overnight while warmed up to room temperature . The mixture was concentrated and the residue was acidified to pll=3 with 1 N HCl and then extracted with EtOAc (3 X 50 mL) , dried (MgS04) to afford crude product which was used in the next step without further purification.
e. 4- (2-Pyridyl)piperidine-N- (t-butyl-carbonate) - nipecotamide. To a solution of N- (t-butyl-carbonate) - nipecotic acid (6.85 g, 29.8 mmol) in CH2C12 (40 mL) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (DMAPECD) (11.426 g, 59.6 mmol) and DMAP (9.102 g, 74.5 mmol), then 4- (2-pyridyl) piperidine (4.834g, 29.8 mmol) was added. The resulting mixture was stirred for 24 hours and quenched with water (40 mL) . The mixture was extracted with CH2C12 (3 X40 mL) and the combined extracts was dried (K2C03) and concentrated. The residue was purified by flash chromatography on silica gel (CHCl3-MeOH-NH3 100:4:1) to afford the product as an oil (5.469 g, 49%). f. 4- (2-Pyridyl)-N- (2-piperidinyl)methyl-piperidine. A solution of 4- (2-pyridyl )piperidine-N- (t-butyl- carbonate) -nipecotamide (1.904 g, 5.084 mmol) in TFA ( 5.0 mL) was stirred at 0 °C overnight. The mixture was concentrated and the residue was dissolved in THF (30 mL) . The mixture was cooled to 0 °C and lithium aluminium hydride (LAH) (193 mg, 5.084 mmol) was added slowly. The reaction mixture was stirred for 12 hours while warmed to r.t. before quenched with water (1.0 mL) and 1 N NaOH (0.5 mL) . The mixture was basified to pH=10 with 1 N NaOH and extracted with CH2C12 (5 X 20 mL) , dried (K2C03) and concentrated. The residue was purified by flash chromatography (CHCl3-MeOH-NH3 100:10:2 to 100:20:5) to afford the product as an oil (0.804 g, 61%) . g. 4- (3,4-Difluorophenyl) -3- [ (3- [4- (2- pyridyl)piperidino]ιtιethylpiperidiήo) carbo yl] - oxazolidine-2-one dihydrochloride. Prepared from 4- (3 , 4-difluorophenyl) -3- (4- nitrophenyloxycarbonyl) -2-oxo-oxazolidine and 4- (2- pyridyl) -N- (2-piperidinyl)methyl-piperidine following the procedure described earlier. Yield 90%; m.p.= 176-178 °C; Anal. Calcd. For
C26H31N403F2.2HC1.1.2H20.1.2CH2C12: C47.90; H, 5.59, N,8.21. Found: C, 47.27; H, 5.41; N, 8.21.
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. To a stirred a solution of 4- (3 , 4-difluorophenyl) -2-oxo-oxazolidinone (398 mg, 2 mmol) in THF (20 mL) at 0 °C under argon atmosphere, LiHMDS (1M solution in THF, 2.2 mL, 2.2 mmol) was added and the mixture was warmed to room temperature. After 30 minutes it was cooled to 0 °C and to this benzyl bromoacetate (0.504 g, 2.2 mmol, 1.1 eq.) was added and the mixture was warmed to room temperature. After 12 h, solvent was evaporated and the residue was purified by column chromatography on silica gel using chloroform/ethyl acetate (9:1) as the eluent to give the product as a viscous oil (0.695 g, 88%). b. (+) -{2- [ (4- (3, 4-Difluorophenyl) -2-oxo-oxazolidine-l- acetic acid
The product obtained from the above reaction (0.592 g, 1.5 mmol) was dissolved in methanol/water (25/5 mL) , mixed with Pearlman's catalyst (120 mg) and hydrogenated at 100 psi for 3 h. The catalyst was removed by filtration and washed with methanol (20 mL) . Solvent was evaporated from the combined filtiate to obtain the product as a white powder (0.375 g, 97%). c. Wl- [2-(4-Cyano-4-phenylpiperidino)ethyl] -2- [4- (3,4- difluorophenyl) -2-oxo-oxazolidin-3-yl] acetamide hydrochloride
A mixture of (+)-{2-[(4-(3, 4-difluorophenyl) -2-oxo-oxazolidine-1- acetic acid (51.4 mg, 0.2 mmol), l-(3- dimethy1aminopropyl) -3-ethylcarbodiimide hydrochloride (100 mg) , and 4- (N,N-dimethylamino) pyridine (100 mg) , 2- [ (4-cyano-4-phenyl)piperidin-l-yl] propylamine (55 mg) in anhydrous dichloromethane (15 mL) was stirred at room temperature for 12 h. The mixture was diluted with 10 mL of dichloromethane and washed with saturated aqueous ammonium chloride solution (6 X 10 mL) . Solvent was evaporated from the dried (sodium sulfate) dichloromethane solution and the residue was purified by column chromatography on silica gel using chloroform- methanol-2M ammonia in methanol (100/2/1) as the eluent, to obtain the desired product as a white powder (82 mg) ; [α]D = +168.40 (c = 0.42 g, methanol). The HCl salt was prepared by treatment of a solution of the free base in ether with IN HCl in ether. M.p. 136-139 °C; Anal. Calcd. for C25H27N403F2C1.0.4CH2C12 : C, 56.38; H, 5.20; N, 10.40. Found: C, 56.38; H; 5.30; N, 10.52.
Example 34:
4-{4- [4- (3, 4-Difluoro-phenyl) -2-oxo-oxazolidine-3- carbonyl] -piperazin-1-yl} -1-phenyl- cyclohexanecarbonitrile a. l-Phenyl-4-piperazin-l-yl-cyclohexanecarbonitrile A mixture of 4-cyano-4-phenyl-eyelohexanone (0.23 g, 1.2 mmol) and piperazine (0.30 g, 3.5 mmol) in 20 ml of toluene was stirred at reflux for 2 h in presence of catalytic amount of p-toluenesulfonic acid. The reaction mixture was concentrated in vacuo to provide a white solid, which was redissolved in 20 ml of EtOH and stirred with NaBH4 (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 MgS04 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. b. 4-{4- [4- (3, 4-Difluoro-phenyl) -2-oxo-oxazolidine-3- carbonyl] -piperazin-1-yl} -1-phenyl- cyclohexanecarbonitrile
To a solution of 4- (3 , 4-difluoro-phenyl) -2-oxo- oxazolidine-3 -carboxylic acid 4-nitrophenyl ester (80 mg, 0.21 mmol) in 5 ml of THF was added l-phenyl-4- piperazin-1-yl-cyclohexanecarbonitrile (80 mg, 0.29 mmol) in a portion and the resulting solution was stirred for 12 h at 25 °C . Reaction mixture was concentrated in vacuo yielding a yellow oil, which was subjected to column chromatography (50% Hexane/EtOAc) to provide 53 mg (51%) of the desired product as a colorless oil. The product obtained was converted to the HCl salt and recrystallized from EtOAc-Et20 to afford 43 mg of the product as white solid: mp 148-151 °C; Anal. Calc . For C27H28F2N403.1.0HC1 requires C, 61.07; H, 5.50; N, 10.55. Found: C, 59.48; H, 5.41; N, 10.34.
Example 35:
(+) -4- (3,4-Difluoro-phenyl) -2-oxo-oxazolidine-3- carboxylic acid [3- (4-furan-2-yl-4-phenyl-piperidin-l- yl) -propyl] -amide a. 4-Phenyl-4-furan-2-yl-piperidine
To a solution of 4-hydroxy-4-phenyl-piperidine (0.50 g, 2.8 mmol) in 10 ml of CH2C12 at 25 °C was added furan (0.40 ml, 5.6 mmol) and aluminum chloride (0.75 g, 5.6 mmol) in a portion and the resulting heterogeneous solution was stirred for 3 h. Reaction mixture was poured into cold aqueous NaHC03 and extracted with EtOAc. Organic layer was dried over Na2S04 and concentrated in vacuo to provide oily residue, which was purified by column chromatography (30% NH3 sat'd
MeOH/EtOAc) to yield 0.48 g (76%) of the desired product as an oil. b. 3- [4- (4-furan-2-yl-4-Phenyl-phenyl) -piperidin-1-yl) ] - propyl-1-amine A solution of the amine (0.15 g, 0.66 mmol), (3-bromo- propyl) -carbamic acid tert-butyl ester (0.30 g, 1.3 mmol) and K2C03 (1.0 g, 7.4 mmol) in 10 ml of dioxane was stirred at reflux for 12 h. Reaction mixture was diluted with EtOAc and washed with brine several times. Organic layer was dried over Na2S04 and concentrated in vacuo to provide oily residue, which was purified by column chromatography (EtOAc, neat) to yield 120 mg of the desired product as tert-butyl carbamic ester. The ester was diluted in 5 ml of CH2C12 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 NaHC03. Organic layer was dried over Na2S04 and concentrated in vacuo to provide 86 mg (33%) of the desired product as a colorless oil. c. (+) -4- (3, 4-Difluoro-phenyl) -2-oxo-oxazolidine-3- carboxylie acid [3- (4-furan-2-yl-4-phenyl-piperidin-l- yl) -propyl] amide
To a solution of (+) -4- (3 , 4-difluoro-phenyl) -2-oxo- oxazolidine-3 -carboxylic acid 4-nitrophenyl ester (19 mg, 0.05 mmol) in 5 ml of CH2C12 was added 3- [4- (4- Phenyl-4-furan-2-yl-phenyl) -piperidin-1-yl) ] -propyl-1- amine (12 mg, 0.04 mmol) in a portion and the resulting solution was stirred for 4 h at 25 °C. Reaction mixture was concentrated in vacuo yielding a yellow oil, which was subjected to column chromatography (5% MeOH/CHCl3) to provide 18 mg (88%) of the desired product as a colorless oil. The product obtained was converted to the HCl salt and recrystallized from EtOAc-Et20 to afford 19 mg of the product as white solid: mp 149-151 °C; [α]D = + 49.4 (c=0.11, MeOH); Anal. Calc. For C28H29F2N3O4.1.0HCl requires C, 62.42; H, 5.42; N, 7.53. Found: C, 60.79; H, 5.49; N, 7.43.
Example 36:
(+) -4- (3, 4-Difluoro-phenyl) -2-oxo-oxazolidine-3- carboxylic acid {3- [4- (1-methyl-lH-pyrrol-2-yl) -4- phenyl-piperidin-1-yl] -propyl} -amide a. 4-Phenyl-4- (1-methyl-pyrrol) -2-yl-piperidine To a solution of 4-hydroxy-4-phenyl-piperidine ( 0.50 g, 2.8 mmol) in 10 ml of CH2C12 was added 1-methyl-pyrrole (0.51 ml, 5.6 mmol) and aluminum chloride (0.75 g, 5.6 mmol) in a portion and the resulting heterogeneous solution was stirred for 4 h at -78 °C . Reaction mixture was poured into cold aqueous NaHC03 and extracted with EtOAc. Organic layer was dried over Na2S04 and concentrated in vacuo to provide oily residue (0.81 g) , which was identified as the desired product by NMR analysis and subjected to the following reaction without any further purification. b. 3- [4- (l-methyl-lH-pyrrol-2-yl) -4-phenyl-piperidin-l- yl] -propyl-1-amine
A solution of the amine (0.81 g, 2.8 mmol), (3-bromo- propyl) -carbamic acid tert-butyl ester (1.0 g, 4.2 mmol), K2C03 (1.0 g, 7.4 mmol) and Nal (0.05 g) in 10 ml of dioxane was stirred at reflux for 12 h. Reaction mixture was diluted with EtOAc and washed with brine several times . Organic layer was dried over Na2S04 and concentrated in vacuo to provide oily residue, which was purified by column chromatography (2% MeOH/CHCl3) to yield 0.87 g (78%) of the desired product as tert-butyl carbamic ester. The ester was diluted in 10 ml of CH2C12 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 NaHC03. Organic layer was dried over Na2S04 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-Difluorophenyl)-2-oxo-oxazolidine-3- carboxyliσ acid {3- [4- (l-methyl-lH-pyrrol-2-yl) -4- phenyl-piperdin-1-yl] -propyl} -amide
To a solution of (+) -4- (3 , 4-difluoro-phenyl) -2-oxo- oxazolidine-3-carboxylic acid 4-nitrophenyl ester (30 mg, 0.08 mmol) in 5 ml of CH2C12 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 . Reaction mixture was concentrated in vacuo yielding a yellow oil, which was subjected to column chromatography (5% MeOH/CHCl3) to provide 14.4 mg (34%) of the desired product as a colorless oil. The product obtained was converted to the HCl salt and recrystallized from EtOAc- Et20 to afford 13.0 mg of the product as white solid: mp 135-138 °C; [α]D = + 34.1 (c=0.11, MeOH); Anal. Calc. For C28H29F2N304.1.0HC1 requires C, 62.42; H, 5.42; N, 7.53. Found: C, 60.79; H, 5.49; N, 7.43.
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
To a solution of 2-methyl-thiophene (1.0 ml, 10 mmol) in 40 ml of dry THF was added tert-butyl lithium (1.7 M solution in ether, 6.5 ml , 11 mmol) dropwise and the resulting solution was stirred for 1 h at -40 °C . To the solution was added N-tert-butoxycarbonyl-4- piperidinone (1.0 g, 5.0 mmol) in a portion and the resulting solution was stirred for 2 h. Reaction was quenched by adding a few drops of water. Reaction mixture was diluted with EtOAc and washed with brine several times . Organic layer was dried over Na2S04 and concentrated in vacuo to provide an oil, which was identified as the desired product by NMR analysis and subjected to the following reaction without any further purification. b. 4- (5-Methyl-thiophen-2-yl) -piperidine
A solution of the carbamic ester (1.3 g, 4.4 mmol) and triisopropylsilane (1.0 ml, 8.2 mmol) in 10 ml of CH2C12 was added 10 ml of trifluoroacetic acid and the resulting solution was stirred for 2 h at 0 °C . Reaction mixture was concentrated in vacuo, yielding a dark oil, which was redissolved in EtOAc and washed with aqueous NaHC03. Organic layer was dried over Na2S04 and concentrated in vacuo to provide oily residue, which was purified by column chromatography (5% MeOH/CHC13) to yield 0.73 g (87%) of the desired product as an oil. c. 3- [4- (5-methyl-thiophene-2-yl) -piperidin-1-yl] - propyl-1-amine
A solution of the amine (0.73 g, 4.0 mmol), (3-bromo- propyl) -carbamic acid tert-butyl ester (1.8 g, 7.5 mmol), K2C03 (1.0 g, 7.4 mmol) and Nal (0.05 g) in 25 ml of acetone was stirred at reflux for 12 h. Reaction mixture was diluted with EtOAc and washed with brine several times . Organic layer was dried over Na2S04 and concentrated in vacuo to provide oily residue, which was purified by column chromatography (5% MeOH/CHCl3) to yield 0.60 g (44%) of the desired product as tert-butyl carbamic ester. The ester was diluted in 10 ml of CH2C12 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 NaHC03. Organic layer was dried over Na2S04 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 {3- [4- (5-methyl-thiophen-2-yl) - piperidin-1-yl] -propyl} -amide To a solution of (+) -4- (3 , 4-difluoro-phenyl) -2-oxo- oxazolidine-3-carboxylic acid 4-nitrophenyl ester (46 mg, 0.12 mmol) in 5 ml of CH2C12 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 . Reaction mixture was concentrated in vacuo yielding a yellow oil, which was subjected to column chromatography (5% MeOH/CH2Cl2) to provide 41 mg (74%) of the desired product as a colorless oil. The product obtained was converted to the HCl salt and recrystallized from EtOAc-Et20 to afford 43 mg of the product as white solid: mp 143-146 °C; [α]D = + 41.0 (c=0.11, MeOH); Anal. Calc . For C23H27F2N304.1.0HC1 requires C, 55.25; H, 5.64; N, 8.40. Found: C, 57.01; H, 5.54; N, 8.29.
General Procedure for the Preparation of the 4, -Diary1 Piperidines: A mixture of 0.5 g of 4-aryl-4-hydroxy piperidine, 3 mL of the aromatic substrate, and 1 g of aluminum chloride were stirred at room temperature for 3 days. The 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 .
4-Phenyl-4- (4-thiomethoxy-phenyl) -piperidine, Hydrochloride: From 4-phenyl-4-hydroxy-piperidine and thioanisole (82%), Anal. Calc. for C^H^N^+HCl+O .2H20:
C, 66.83; H, 6.98; N, 4.33. Found: C, 66.71; H, 6.81; N, 4.24.
4- (4-Fluoro-phenyl-4- (4-thio ethoxy-phenyl) -piperidine, Hydrochloride: From 4- (4-fluoro-phenyl-4-hydroxy- piperidine and thioanisole (59%), Anal. Calc. for C18H20F1N1S1+HC1+0.35CH2C12: C, 60.14; H, 5.56; N, 3.90. Found: C, 59.96; H, 5.95; N, 3.81.
4- (4-Fluoro-phenyl-4- (2-methoxy-5-fluoro-phenyl) - piperidine, Hydrochloride: From 4- (4-fluoro-phenyl) -4- hydroxy-piperidine and 4-fluoroanisole (78%), Anal. Calc. for
Figure imgf000133_0001
C, 62.96; H, 5.99; N, 4.08. Found: C, 62.72; H, 6.06; N, 4.06.
Bis- (4-fluoro-phenyl)piperidine, Hydrochloride: From 4- (4-fluoro-phenyl) -4-hydroxy-piperidine and 3 mL of fluorobenzene (69%).
4- (4-Bromo-phenyl-4- (4-methoxy-phenyl) -piperidine, Hydrochloride: From 4- (4-bromo-phenyl-4-hydroxy- piperidine and thioanisole (66%), Anal. Calc. for
Figure imgf000133_0002
: C, 54.21; H, 5.30; N, 3.51. Found: C, 54.43; H, 5.22; N, 3.41.
General Procedure for the Preparation of the 4,4-Diaryl- 1- (3-amino-propyl) iperidines : A solution of 1.00 mmol of diarylpiperidine, 1.30 mmol of N-B0C-3- bromopropylamine, 1.00 mL of diisopropylethylamine and 2 mL of dioxane were heated at reflux temperature for 36 hours, cooled, applied to prep-tic plates and eluted with the appropriate solvent. The product was used in the next step after spectral characterization. A solution of the N-BOC protected amine in 1:1 TFA-water was stirred at room temperature for 2 hours (monitored by tic) , solvent removed in vacuo, the product was dissolved in dichloromethane, washed with saturated Na2C03 solution, dried (Na2S04) , solvent removed in vacuo, and the product was used after spectral characterization .
[4- (4-methanesulfonyl-phenyl) -4-phenyl] -3- aminopropyl-piperidine: A mixture of 644 mg of [4- (4-thiomethyl-phenyl) -4-phenyl] -3-aminopropyl-piperidine (TFA salt, 1.13 mmol), 853 mg of 50-60% 3- chlorophenylperbenzoic acid (2.72 mmol, assuming 55% purity) , 2 mL of trifluoroacetic acid and 10 mL of chloroform were stirred at room temperature for 36 hours, solvent removed in vacuo, and the product was chromatographed (X2) (NH3-MeOH-CHCl3) to give 270 mg of the desired product.
General procedure for the synthesis of Examples 38, 39, 40, 41 and 42.
A solution of (+) -4Λ (3 , 4-difluoro-phenyl) -2-oxo- oxazolidine-3-carboxylic acid 4-nitro-phenyl ester (25 mg, 0.069 mmol), the 4, 4-diaryl-l- (3 -amino-propyl) piperidine (1.2 eqiv.) in 5 ml of methylene chloride were stirred at room temperature for 12 hours. The reaction mixture was washed with 3 N KOH solution. The organic phase was chromatographed on preparative TLC (CH2C12/methanol/ 2 N NH3 in methanol = 40 /2/1) to obtain the title compound. The hydrochloride salt of the free base was prepared by addition of 1 N HCl in ether to a solution of the free base in ethyl acetate until no more precipitate was observed.
Example 38:
4- (3, 4-Difluoro-phenyl) -2-oxo-oxazolidine-3-carboxylic acid {3- [4- (4-bromo-phenyl) -4- (4-methoxy-phenyl) - piperidin-1-yl] -propyl} -amide
33 mg of the free base was obtained (55% yield) . Anal. Calc. For C31H32BrF2N304 + 1.5 HCl: C, 54.50 % ; H, 4.94 %; N, 6.15 %. Found: C, 54.62 %; H, 4.88 %; N, 5.88 %. M.p. of the salt: 123 ~ 126 °C. [α]D 22 = + 53.93 .
Example 39:
4- (3, 4-difluoro-phenyl) -2-oxo-oxazolidine-3-carboxylic acid {3- [4- (4-fluoro-phenyl) -4- (4-methylsulfany1- phenyl) -piperidin-1-yl] -propyl} -amide
20 mg of the free base was obtained (55% yield) . Anal. Calc. For C31H32F3N303S + 1.75 HCl + 0.75 EtOAc: C, 57.23 %; H, 5.61 %; N, 5.8"9 %. Found: C, 57.28 %; H, 5.73 %; N, 5.83 %. M.p. of the salt: 121 ~ 124 °C [α]D 22 = + 33.33.
Example 40:
4- (3, 4-dif luoro-phenyl) -2 -oxo-oxazolidine- 3 -carboxylic acid {3- [4, 4-bis- (4-f luoro-phenyl) -piperidin-1-yl] - propyl} -amide. 24 mg of the free base was obtained (63 % yield) . Anal. Calc. For C30H2lF4N3O3 + 2.0 HCl + 0.125 CHC13: C, 56.24 %; H, 4.88 %; N, 6.52 %. Found: C,
56.39 %; H, 4.88 %; N, 6.10 %. M.p. of the salt: 124 ~ 126 °C. [α]D 22 = + 47.33 .
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
24 mg of the free base of the tittle product was obtained ( 59% yield). Anal. Calc. For C31H31F4N304 + 2.0 HCl + 0.5 EtOAc: C, 56.42 % ; H, 5.31 %; N, 5.98 %. Found: C, 56.61 %; H, 5.18 %; N, 5.77 %. M.p. of the salt: 130 ~ 133 °C [α]D 22= + 38.86.
Example 42 :
(+) -4- (3, 4-Difluoro-phenyl) -2-oxo-oxazolidine-3-carboxyl ic acid
{ 3- [4- (4 -methanesulfonyl -phenyl) -4 -phenyl -piper idin-1-yl
] - propyl} - amide, hydrochloride 18 mg of the free base was obtained : Anal . Calc . For
C31H31F4N304 + 2 . 0 HCl + EtOAc : C , 55 . 41 % ; H , 5 . 71 % ; N,
5 . 54 % . Found : C , 55 . 82 % ; H, 5 . 19 % ; N, 5 . 49 % .
Example 43 : 4- (3,4-Difluorophenyl)-l-(3- (4- (2-pyridyl)piperidin-1- yl) -propyl) aminocarbonyl-2-imidazolidone . a. 2-Amino-2- (3, 4-difluorophenyl) -acetonitrile:
To a mixture of 3 , 4-difluorobenzaldehyde (2.0 g, 14.07 mmol) and trimethyIsilylcyanide (2.34 ml, 17.59 mmol), catalytic amount of Zinc Iodide was added at 0°C. After stirring for 15 minutes at room temperature a saturated solution of methanolic ammonia (15 ml) was added in one lot at 0°C. The reaction mixture was then stirred for 4 hours at 40 °C . After evaporation of the solvent the residue was purified by column chromatography
(hexanes : ethyl acetate; 3 :2) to yield 1.98 g of the product as a brown syrup. b. 1- (3,4-Difluorophenyl)ethane-l,2-diamine:
To Lithium aluminium hydride in ether (50.7 ml, 50.76 mmol) , at 0°C, cyano amine 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) . The mixture was then filtered, the residue was repeatedly washed with ethylacetate. The solution was then concentrated to yied 2.71 g (93%) of the crude product as an oil which was then used for the subsequent step. c. 4- (3, 4-Difluorophenyl) -2-imidazolidone:
To the diammine (1.667 g, 9.68 mmol) in dichloromethane (20ml), triethylamine (1.34 ml, 9.68 mmol) was added slowly and the reaction was cooled to -78°c. Then triphosgene (3.01 g, 10.16 mmol) was added to the solution over a period of 30 minutes. The reaction mixture was then stirred at -78°C for 5 minutes. The reaction mixture was quenched with water and partitioned between dichloromethane (20 ml) and water, washed with 10 ml 10% KOH solution, dried over sodium sulfate, filtered and concentrated. The product was then purified by column purified (hexanes : ethyl acetate 2:3) to yield 0.995 g (52%) of a yellow solid. d. 4- (3,4-Difluorophenyl) -2-imidazolidone-l-carboxylic acid 4-nitrophenyl ester: To sodium hydride (0.069 g, 2.74 mmol) in THF (10 ml),
4- (3 , 4-difluorophenyl) -2-imidazolidone (0.5g, 2.49 mmol) was added at 0°C. The solution was then stirred at room temperature for 15 minutes . It was then added to a solution of 4-nitrophenyl chloroformate (0.552g, 2.74 mmol) at -78°C via a cannula. The reaction mixture was then allowed to stir at room temperature for 8 hours . It was then concentrated and partitioned between ethyl acetate (20 ml) a d water (5 ml) , washed with 10 %KOH (10 ml) , dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (hexanes:ethylacetate 2:3) yielded 0.04 g (4.4 %) of the product as a light brown syrup. e. 4- (3, 4-Difluorophenyl) -1- (3- (4- (2-pyridyl)piperidin- 1-yl) -propyl) aminocarbonyl-2-imidazolidone: To 4- (3 , 4-difluorophenyl) -1- (4-nitrophenoxy) carbonyl-2- imidazolidone (0.05 g, 0.137 mmol) in THF (10 mL) was added 1- (3-aminopropyl) -4- (2-pyridyl) piperidine (0.036 g, 0.165 mmol) and the solution was stirred at room temperature for 16 hours. The solution was then concentrated and the residue flash chromatographed
(ethyl acetate:methanol 4:1) to yield 0.038 g (59%) of the product as a brown syrup. It was dissolved in dichloromethane (2 mL) and treated with IN HCl in ether (0.5 mL) . The solution was concentrated under reduced pressure. Recrystallization of the residue from ether gave 0.029 g (60 %) of the hydrochloride salt as a brown solid: mp 148-150°C. Anal. Calcd. for C23H29F2N4O3Cl2"0.5 CC14: C, 51.90; H,4.90; N, 11.0. Found: C, 54.23; H 5.17; N, 10.84.
Example 44:
3- (4- (4-Cyano-4-phenylpiperidin-l-yl)piperidin-l- yl) carbonyl-4- (3, 4-difluorophenyl) -2-imidazolidone. a. 4- (3, 4-Difluorophenyl) -2-imidazolidone-3-carboxylic acid 4-nitrophenyl ester:
To sodium hydride (0.069 g, 2.74 mmol) in THF (10 ml), 4- (3 , 4-difluorophenyl) -imidazolidin-2-one (0.5g, 2.49 mmol) was added at 0°C. The solution was then stirred at room temperature for 15 minutes . It was then added to a solution of 4-nitrophenylchloroformate (0.552g,
2.74 mmol) at -78°C via a cannula. The reaction mixture was then allowed to stir at room temperature for 8 hours . It was then concentrated and partitioned between ethyl acetate (20 ml) and water (5 ml) , washed with 10 %KOH (10 ml) , dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (hexanes:ethylacetate; 2:3) to yield 0.04 g (4.4 %) of the product as a light brown syrup. b. 3- (4- (4-Cyano-4-phenylpiperidin-l-yl)piperidin-l- yl) carbonyl-4- (3, 4-difluorophenyl) -2-imidazolidone: To 4- (3 , 4-difluorophenyl) -3- (4-nitrophenoxy) carbonyl-2- imidazolidone (0.04 g, 0.110 mmol) in THF (10 L) was added 4- (4-cyano-4-phenylpiperidin-l-yl) piperidine (0.0355 g, 0.132 mmol) and the solution was stirred at room temperature for 16 hours. The solution was then concentrated and the residue flash chromatographed (ethyl acetate:methanol 4:1) to yield 0.024 g (44%) of the product as a brown syrup. It was dissolved in dichloromethane (2 mL) and treated with IN HCl in ether (0.5 mL) . The solution was concentrated under reduced pressure. Recrystallization of the residue from ether gave 0.029 g (96%) of the hydrochloride salt as a white solid: mp 243-245°C Anal. Calcd. for C27H30ClF2N5O2-0.4 CHC13: C, 56.96; H,5.30; N, 12.12. Found: C, 57.08; H 5.20; N, 11.90.
Example 45
4- (3, 4-Difluorophenyl) -3-methyl-l- (3- (4- (2- pyridyl)piperidin-1-yl)propyl) aminocarbonyl-2- imidazolidone.
a. 2- (3, 4-Difluorophenyl) -2-methylamino-acetonitrile:
To a mixture of 3 , 4-difluorobenzaldehyde (4.0 g, 28.0 mmol) and trimethylsilylcyanide (4.69 mL, 35.1 mmol), catalytic amount of Zinc Iodide was added at 0°C. After stirring for 15 minutes at room temperature a saturated solution of methylammonia (15 L) was added in one lot at 0°C. The reaction mixture was then stirred for 4 hours at 40°C. After evaporation of the solvent the residue was purified by column chromatography (hexanes :ethylacetate 3:2) to yield 4.719 g (92%) of the product as a brown syrup. b. 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) . The mixture was then filtered, the residue was repeatedly washed with ethylacetate. The solution was then concentrated to yield 2.71 g (93%) of the crude product as an oil. c. 4- (3, 4-Difluorophenyl) -3-methyl-2-imidazolidone: To 2- (3 , 4-difluorophenyl) -2-methylamino-ethylamine
(1.048 g, 5.68 mmol) in dichloromethane (20mL) , 1,1- carbonyldiimidazole (1.09 g, 6.75 mmol) was added slowly and the reaction was stirred at room temperature for 24 hours. It was then concentrated and purified by column chromatography (hexanes : ethylacetate; 1:4) to yield 0.876 g (73%) of a yellow solid. d. 4- (3, 4-Difluorophenyl) -3-methyl-l- (3- (4- (2- pyridyl)piperidin-l-yl)propyl) aminocarbonyl-2- imidazolidone.
To a solution of 4- (3 , 4-difluorophenyl) -3-methyl-2- imidazolidone (0.15 g, 0.706 mmol) in THF (10 mL) cooled at 0°C, lithium bis (trimethylsilyl) amide in THF (0.848 mL, 0.848 mmol) was added slowly and the solution was stirred at room temperature for 15 minutes. After cooling to -78°C, phosgene (0.729 g, 7.06 mmol) was added and he solution was stirred at -78°C for 1 hour. It was then concentrated to give an intermediate (0.194g, 0.703 mmol) which was immediately dissolved in THF (10 mL) at -78°C and treated with 1- (3-aminopropyl ) - 4- (2-pyridyl) piperidine (0.231 g, 1.05 mmol) and triethylamine (0.106 g, 1.055 mmol), and the solution was stirred at room temperature for 24 hours. It was then concentrated, and the residue partitioned between dichloromethane (25 mL) and water (5 mL) . The organic layer was washed with 10% KOH solution (5 mL) , dried over sodium sulfate, filtered and concentrated. Purification of the residue by flash chromatography (ethyl acetate: methanol 24:1) yielded 0.030 g (9%) of the product as a syrup. It was dissolved in dichloromethane (2 mL) and treated with IN HCl in ether (0.5 mL) . The solution was concentrated under reduced pressure. Recrystallization of the residue from ether gave 0.030 g (88%) of the dihydrochloride salt as a pale yellow solid: mp 120-122°C. Anal. Calcd. for C24H31ClF2N5O2-0.95 CHC13: C46.54; H,5.00; N, 10.88. Found: C, 46.30; H 5.35; N, 11.20.
Example 46:
4-(3,4-Difluorophenyl)-3~(3-(4-(2-methoxyl-5- methyl)phenyl-4-phenylpiperidin-1- yl)propyl) aminocarbonyl-2-imidazolidone . a. 1- (3, 4-Difluorophenyl) -2-tritylamino-ethylamine: To a solution of 1- (3 , 4-difluorophenyl) -ethane-1, 2- diamine (6 g, 35.6 mmol) in dichloromethane (100 ml), diazabicycloundecane (DBU)(5.87 mL, 39.2 mmol) was added and the solution cooled to 0°C. 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. b. 4- (3, 4-Difluorophenyl) -l-trityl-2-imidazolidone:
To a solution of 1- (3 , 4-difluorophenyl) -2-tritylamino- ethylamine (6.75g, 16.44 mmol) in THF (200 mL) , 1,1- carbonyldiimidazole (3.2 g, 19.7 mmol) was added and the solution was stirred at room temperature for 12 hours . The solution was concentrated and purified by column chromatography (hexanes : ethylacetate 3:2) to yield 5.55 g (77%) of the product as a white solid. c. 4- (3, 4-Difluorophenyl) -l-trityl-2-imidazolidone-3- carboxylic acid 4-nitrophenyl ester:
To sodium hydride (95 %) (0.189 g, 7.49 mmol) in THF (150 ml) , 4- (3 , 4-Difluorophenyl) -l-trityl-2-imidazolidone (3.0 g, 6.81 mmol) was added at 0°C. The solution was then stirred at room temperature for 15 minutes. It was then added to a solution of 4-nitrophenylchloroformate (1.647 g, 8.17 mmol) at -78°C via a cannula. The reaction mixture was then allowed to stir at room temperature for 12 hours . It was then concentrated and partitioned between ethyl acetate (30 ml) and water (5 ml) , washed with 10 KOH (10 ml) , dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (hexanes : ethylacetate; 2:3) to yield 2.1 g (51%) of the product as a light brown syrup. d. 4- (3, 4-Difluorophenyl) -3- (3- (4- (2-methoxy-5- ethyl)phenyl-4-phenylpiperidin-1- yl)propyl) aminocarbonyl-l-trityl-2-imidazolidone : To 4- (3 , 4-difluorophenyl) -3- (4-nitrophenoxy) carbonyl-1- trityl-2-imidazolidone (0.089, 0.147 mmol) in THF (5 mL) was added 3- (4- (2-methoxy-5-methyl) phenyl-4- phenylpiperidin-1-yl) propylamine (0.055 g, 0.162 mmol) and the solution was stirred at room temperature for 16 hours . The solution was then concentrated and the residue flash chromatographed (hexanes : ethyl acetate 1:4) to yield 0.08 g (68%) of the product as a syrup. e. 4- (3, 4-Difluorophenyl) -3- (3- (4- (2-methoxyl-5- methyl)phβnyl-4-phenylpiperidin-1- yl)propyl) aminocarbonyl-2-imidazolidone : To 4-(3,4-Difluorophenyl)-3-(3-(4- (2-methoxyl-5- methy1) phenyl-4-phenylpiperidin-1- yl) propyl) aminocarbonyl-l-trityl-2-imidazolidone (0.100 g, 0.124 mmol) in dichloromethane (2 mL) at 0°C, trifluoroacetic acid (4 mL) in dichloromethane (2 mL) was slowly added and the solution was stirred at room temperature for 20 minutes. The solution was then concentrated, neutralized with 10% KOH and extracted into dichloromethane (20 mL) . The organic layer was dried over sodium sulfate, filtered and concentrated. Purification of the residue by flash chromatography
(ethyl acetate) yielded 0.06 g (87%) of a white foam. To it in dichloromethane (2 mL) , IN HCl in ether (0.5 mL) was added, and the solution concentrated under reduced pressure. Recrystallization of the residue from ether gave 0.061 g (96 %) of a hydrochloride salt as a white solid: mp 173-175°C. Anal. Calcd. for C32H36C1F2N403-1.20 CHC13: C, 53.72; H,5.19; N, 7.55. Found: C, 53.76; H 5.01; N, 7.36.
Example 47:
(-) -3- (3- (4-Cyano-4-phenylpiperidin-1-yl) -2 (S) - meth lpropyl) -aminocarbonyl-4- (3, 4-difluorophenyl) -2- imidazolidone. a. 4-Cyano-1- (3-hydroxy-2 (S) -methylpropyl) -4- phenylpiperidine:
A mixture of 4-cyano-4-phenylpiperidine hydrochloride (1.89 g, 8.49 mmol) and (S) -3-bromo-2-methyl-l-propanol (1.0 g, 6.53 mmol), potassium carbonate (2.709 g, 19.6 mmol) and sodium iodide (1.17 g, 7.84 mmol) in acetone (20 mL) was refluxed for 12 hours. The solution was cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate (25 mL) and water (10 mL) . The organic layer was dried over sodium sulfate, filtered and concentrated. Purification of the residue by flash chromatography (hexanes : ethyl acetate 2:3) yielded 1.45 g (86%) of the product as a syrup . b. 1- (3-Azido-2 (S) -methylpropyl) -4-cyano-4- phenylpiperidine: To a solution of 4-cyano-l- (3-hydroxy-2 (S) - methylpropyl) -4-phenylpiperidine (1.0 g, 3.87 mmol), triphenyl phospine (1.01 g, 3.87 mmol)and diethyl azodicarboxylate (0.609 g, 3.87 mmol) in THF (20 mL) was slowly added diphenylphosporylazide (0.83 mL, 3.87 mmol) and the solution was stirred at room temperature for 24 hours. The solution was then concentrated and flash chromatographed (hexanes : ethyl acetate 3:2) to yield 0.963 g (88%) of the product as a light brown syrup. c . 1- (3-Amino-2 (S) -methylpropyl) -4-cyano-4- phenylpiperidine:
To a solution of 1- (3 -azido-2 (S) -methylpropyl) -4-cyano- 4-phenylpiperidine (0.96 g, 3.39 mmol) in ethyl acetate (10 mL) was added trimethylphosphine (8.4 mL, 8.49 mmol) and water (0.30 mL, 16.9 mmol) and the solution was stirred at roomtemperature for 24 hours. The solution was then concentrated and flash chromatographed (ethyl acetate:methanol :methanolic ammonia 3:1:1) to yield 0.60 g (69%) of the crude product as a syrup. d. (-) -3- (3- (4-Cyano-4-phenylpiperidine-l-yl) -2 (S) - methylpropyl) -aminocarbonyl-4-(3,4-difluoro)phenyl-1- trityl-2-imidazolidone:
To 4- (3 , 4-difluoro)phenyl-3- (4-nitrophenoxy) carbonyl-1- trityl-2-imidazolidone (0.49 g, 0.809 mmol) in THF (10 mL) was added 1- (3-amino-2 (S) -methyl) propyl-4-cyano-4- phenylpiperidine (0.250 g, 0.92 mmol) and the solution was stirred at room temperature for 16 hours. The solution was then concentrated and flash chromatographed (ethyl acetate:methanol 4:1) to yield 0.441 g (73%) of the product as a syrup. e. (-) -3- (3- (4-Cyano-4-phenylpiperidin-l-yl) -2 (S) - methyl)propyl-aminocarbonyl-4- (3, 4-difluorophenyl) -2- imidazolidone : To (-) -3- (3- (4-Cyano-4-phenylpiperidine-l-yl) -2 (S) - methylpropyl) -aminocarbonyl-4- (3 , 4-difluoro) phenyl-1- trityl-2-imidazolidone (0.441 g, 0.607 mmol) in dichloromethane (2 mL) at 0°C was added trifluoroacetic acid (4 mL) in dichloromethane (2 mL) and the solution was stirred at room temperature for 20 minutes. The solution was then concentrated, neutralized with 10% KOH and extracted into dichloromethane (20 mL) . The organic layer was dried over sodium sulfate, filtered and concentrated. Purification of the residue by column chromatography (ethyl acetate) yielded 0.293 g (100%) of the product as a syrup. The two diastereomers were seperated by using Chiralcel OD (20 x 250 mm) column with hexanes/2-propanol/diethylamine (60 : 40 : 0.1) as the eluent.
To the desired diastereomer (0.016 g, 0.0332 mmol) in dichloromethane (2 mL) was added IN HCl in ether (0.5 mL) and the solution concentrated under reduced pressure. Recrystallization of the residue from ether gave 0.016 g (94%) of the hydrochloride salt as a white solid: [α]D = - 5.32 (8.0 mg/mL MeOH); mp 265-267°C. Anal. Calcd. for C26H30ClF2N5O2-0.15 CHC13 : C, 58.61; H, 5.67; N, 12.07. Found: C, 58.50; H 5.90; N, 12.10.
Example 48:
(+) -3- (3- (4-cyano-4- (2, 4-dichloro)phenylpiperidin-l- yl)propyl) aminocarbonyl-4- (3, 4-difluorophenyl) -2- oxazolidinone . a. 4-Cyano-4- (2,4-dichlorophenyl) -piperidine-1- carboxylic acid tert-butyl ester:
To bis (2-chloroethyl) -carbamic acid tert-butyl ester (l.Og, 3.8 mmol) and (2 , 4-dichloro) henyl acetonitrile (0.708 g, 3.8 mmol) in DMF (35 mL) was added NaH (95 %) (0.258 g, 9.68 mmol) in one lot at 0°C. The solution was stirred for 10 minutes at room temperature. When the foaming subsided, the solution was heated at 60°C for 24 hours. It was then quenched with water at 0°C and concentrated. The residue was extracted with ethyl acetate (25 mL) and washed with water (3 x 15 mL) . The organic layer was dried over sodium sulfate, filtered and concentrated. Purification of the residue by column chromatography (hexane : ethyl acetate 4:1) yielded 0.620 g (45%) of the product as a syrup. b. {3- [4-Cyano-4 (2, 4-dichlorophenyl) -piperidin-1-yl} - propyl} -carbamic acid tert-butyl ester:
To 4-cyano-4- (2, 4-dichlorophenyl) -piperidine-1- carboxylic acid tert-butyl ester (0.620 g, 1.74 mmol) in dichloromethane (5 mL) , trifluoroacetic acid (2 mL) was added and the solution stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10 % KOH solution and extracted into 25 ml of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.442 g (99%) of 4- (2, 4-dichlorophenyl) -piperidine-4- carbonitrile which was used as such for the subsequent step. To a stirred solution of the 4- (2, 4- dichlorophenyl)piperidine-4-carbonitrile (0.736 g, 2.88 mmol) in acetone (20 mL) was added N-(tert- butoxycarbonyl) -3-bromopropylamine (0.754 g, 3.17 mmol, potassium carbonate (1.594 g, 11.53 mmol) and sodium iodide (0.865 g, 5.7 mmol) and the solution refluxed for 24 hours. The reaction mixture was cooled to room temperature, concentrated and partitioned between chloroform (30 mL) and water (5 mL) . The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate) to yield 0.925 g (78 %) of the required product as a colorless oil. c. (+) -3- (3- (4-cyano-4- (2, 4-dichloro)phenylpiperidin-1- yl)propyl) aminocarbonyl-4- (3, 4-difluorophenyl) -2- oxazolidinone :
To 3- [4-cyano-4- (2, 4-dichlorophenyl) -piperidin-1-yl] - propyl-carbamic acid tert-butyl ester (0.589, 1.42 mmol) in dichloromethane (5 mL) , trifluoroacetic acid (1 mL) was added and the solution stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10 % KOH solution and extracted into 25 mL of dichloromethane . The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.423 g (93%) of 1- ( 3-aminopropyl) -4- (2, 4-dichlorophenyl) - piperidine-4-carbonitrile which was used as such for the subsequent step.
To 4- (3 , 4-difluorophenyl) -2-oxazolidinone-3- carboxylic acid 4-nitrophenyl ester (0.03 g, 0.0823 mmol) in dry THF (10 mL) was added 1- (3 -aminopropyl) -4- (2, 4-dichlorophenyl)piperidine-4-carbonitrile (0.03 g, 0.0823 mmol) and the solution was stirred at room temperature for 24 hours. The reaction mixture was concentrated and purified by column chromatography (hexanes -.ethyl acetate 1:4) to yield 0.04 g (91%) of the product as a foamy syrup. To the syrup (0.040 g, 0.0744 mmol) in 4 mL of dichloromethane, 5 mL of IN HCl in ether was added, and the solution concentrated under reduced pressure. Recrystallization of the residue from ether gave 0.040 g (94 %) of the product as a white solid: mp 204-206 °C; [ ]D = 48.8 (1.55 mg/mL MeOH) .
Anal. Calcd. for C25H25F2N403C12.0.60 CH2C12: C, 49.21; H,
4.21; N, 8.97. Found: C, 49.44; H 4.39; N, 8.66.
Example 49: (+) -3- (3- (4-Aminocarbonyl-4- (4-chloro)phenylpiperidin-1- yl) -propyl) aminocarbonyl-4- (3, 4-difluoro)phenyl-2- oxazolidinone. a. 3- (4-Cyano-4(4-chlorophenyl)piperidin-l- yl)propylcarbamic acid tert-butyl ester:
To bis (2-chloroethyl) -carbamic acid tert-butyl ester (1.0 g, 3.8 mmol) and (4-chloro) phenyl acetonitrile (0.624 g, 4.12 mmol) in DMF (35 mL) was added NaH (95 %) (0.260 g, 10.30 mmol) in one lot at 0°C. The solution was stirred for 10 minutes at room temperature. When the foaming subsided, the solution was heated at 60°C for 45 minutes. It was then quenched with water at 0°C, . partitioned between ethyl acetate (25 mL) and brine (3 x 20 mL) . The organic layer was dried over sodium sulfate, filtered and concentrated to yield 0.76 g (56 %) of the crude product which was used as such for the subsequent step.
To 4-cyano-4- (4-chlorophenyl)piperidine-l-carboxylic acid tert-butyl ester (0.85 g, 2.64 mmol) in dichloromethane (2 mL) was added 2 mL of trifluoroacetic acid and the solution stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10 % KOH solution and extracted into 25 mL of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography (ethyl acetate :methanol :methanolic ammonia 8:1:1) yielded 0.482 g (82 %) of the product as a syrup . b. 3- (4- (4-Chlorophenyl) -4-cyanopiperidin-l- yl)propylcarbamic acid tert-butyl ester:
To a stirred solution of the 4- (4- chlorophenyl)piperidine-4-carbonitrile (0.482 g, 2.18 mmol) in acetone (20 mL) was added N-(tert- butoxycarbonyl) -3-bromopropylamine (0.572 g, 2.4 mmol, potassium carbonate (1.20 g, 8.7 mmol) and sodium iodide (0.655 g, 4.36 mmol) and the solution refluxed for 24 hours . The reaction mixture was cooled to room temperature, concentrated and partitioned between chloroform (20 mL) and water (5 mL) . The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate) to yield 0.655 g (71 %) of the required product as a colorless oil. c . (+) -3- (3- (4-Aminocarbonyl-4- (4- chloro) phenylpiperidin-1-yl) -propyl) aminocarbonyl-4- (3 , 4-difluoro) phenyl-2-oxazolidinone: 3- (4- (4-chlorophenyl) -4-cyanopiperidin-l- yl)propylcarbamic acid tert-butyl ester (0.150 g, 5.39 mmol) in cone. H2S04 (1 mL) was stirred at room temperature for 30 hours. The solution was concentrated, neutralized with 10 % KOH solution and extracted into 25 mL of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.185 g (79%) of 1- (3-aminopropyl ) - 4- (4-chlorophenyl)piperidine-4-carboxamide which was used as such for the subsequent step. To 4- (3, 4-difluorophenyl) -3- (4- nitrophenoxy) carbonyl-2-oxazolidinone (0.040 g, 0.109 mmol) in 10 L of dry THF was added 1- (3-aminopropyl) -4- (4-chlorophenyl) -piperidine-4-carboxamide (0.042 g, 0.141 mmol) and the solution was stirred at room temperature for 24 hours. The reaction mixture was concentrated and purified by column chromatography (ethyl acetate: MeOH 9:1) to yield 0.025 g (44%) of the product as a foamy syrup. To the syrup (0.025 g, 0.048 mmol) in dichloromethane (2 mL) was added IN HCl in ether (0.5 mL) and the solution concentrated under reduced pressure. Recrystallization of the residue from ether gave 0.021 g (80 %) of the product as a white solid: mp 140-142 °C; [α]D = 52.0(1.3 mg/mL MeOH). Anal. Calcd. for C25H27C12F2N404-1.7 CH2C12: C, 45.70; H, 4.51; N, 7.96. Found: C, 45.75; H 4.64; N,7.96.
Example 50:
(+) -3- (5- (4-Cyano-4-phenylpiperidin-l-yl)pent-2 (E) -en-1- yl) -4- (3,4-difluoro)phenyl-2-oxazolidinone. To a solution of 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. After 30 min, 1 , 5-dibromo-2-pentene (0.34 g, 1.5 mmol) was added to the mixture, the mixture was stirred at room temperature for 4 h. After removal of solvent, the residue was flash chromatographed over silica gel (1:1 hexane-ethyl acetate) to give a mixture of two isomers in 40% yield as a yellow oil.
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. HPLC separation (column: Primesphere Si02 5μm, 21.2 x 250 mm, eluent: 75:25:0.1 ethyl acetate-hexane- triethylamine) gave the desired product (20 mg) as a yellow oil. It was treated with 1.0 equivalent of HCl to give a salt as a yellow solid: mp 168-170°C; ESMS m/e = 452 (MH+) ; [α]D = 45.0 (0.4 mg/mL CH2C12) . Anal. Calcd. for C26H27F2N3O2ΗCri.0H2O: C, 61.72; H, 5.98; N, 8.30. Found: C, 61.79; H, 5.88; N, 8.26.
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 . b. trans (+) -4- (3, 4-Difluorophenyl) -5-methyl-2-oxo- oxazolidine-3-carboxylic acid{3- [4- (4-fluoro-2- methylphenyl) -piperidin-1-yl]propyl}amide As described in Example 18, 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. It was converted into the hydrochloride salt. M.P. = 80-83°C; [α]D = + 23.0 (c = 0.12, MeOH); Anal. Calcd. for C25H29N303F3C1.0.23 H20: C, 58.91; H, 5.98; N, 7.93. Found: C, 58.91; H, 6.37; N, 7.73.
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
To a solution of 3 , 4-difluorobenzylamine (9.8 g, 69 mmol) and benzophenone (13.0 g, 71.0 mmol) in toluene (200 mL) was added a catalytic amount of BF3.0Et2 and the resulting solution was stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo, yielding an oil (21 g, >95%) , which was characterized by NMR analysis and subjected to the following reaction without any further purification. b. 1- [ (Benzhydryliden-amino) - (3, 4-difluorophenyl)methyl] -cyclobutanol
To a solution of the imine (2.5 g, 8.1 mmol) in 50 mL of dry THF was added tert-butyllithium (1.7 M, 6.2 mL) dropwise and the resulting solution was stirred at -78°C for 0.5 h. To the solution was added cyclobutanone
(0.74 ml, 9.9 mmol) in 10 ml of THF and the solution was stirred at -78 °C for 2 h and 25 °C for 1 h. The reaction was quenched by adding 1.0 mL of dilute acetic acid. Reaction mixture was diluted with 100 ml of Et20 and washed with brine. The organic layer was dried over Na2S04 and concentrated in vacuo, yielding 1- [ (benzhydryliden-amino) - (3 , 4-difluoro-phenyl) methyl] - cyclobutanol as an oil, which was subjected to the following reaction without purification.
c. 1- [Amino- (3, 4-difluoro-phenyl)methyl] -cyclobutanol The crude batch of 1- [ (benzhydryliden-amino) - (3 , 4- difluoro-phenyl) methyl] -cyclobutanol obtained from the above reaction and MeONH2.HCl (1.35 g, 16.2 mmol) was dissolved in 125.0 mL of MeOH and stirred for 12 h. The reaction mixture was concentrated in vacuo, yielding oily residue which was redissolved in 100 ml of EtOAc and was washed with 2.0 M NaOH followed by brine. The organic layer was separated, dried over Na2S04 and then concentrated in vacuo to give 1- [amino- (3 , 4-Difluorophenyl) methyl] -cyclobutanol as an oil which was used in the next step without any purification. d. [ (3, 4-Difluorophenyl) - (1-hydroxy-cyclobutyl) -methyl] - carbamic acid-tert-butyl ester
To a solution of 1- [amino- (3 , 4-difluoro-phenyl) methyl] - cyclobutanol (approximately 8.1 mmol) in CH2C12 (50 mL) at 0°C was added a solution of di-tert-butyl dicarbonate (3.5 g, 16.2 mmol) in one portion and the resulting solution was stirred for 2 h at room temperature. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel (9:1 cyclohexane-EtOAc followed by 4:1 cyclohexane-EtOAc) to obtain [ (3 , 4-difluorophenyl) - (1-hydroxy-cyclobutyl) - methyl] -carbamic acid-tert-butyl ester as a viscous oil (1.0 g, 40% yield over four steps) .
e. 8- (3, 4-Difluorophenyl) -5-oxa-7-aza-spiro[3.4] octan-6- one
To a well stirred solution of [ (3 , 4-difluorophenyl) - (1- hydroxy-cyclobutyl) -methyl] -carbamic acid-tert-butyl ester (1.0 g, 3.2 mmol) in THF (20 mL) was added 95% NaH (0.2 g, 8.3 mmol) at room temperature. The resulting suspension was stirred for 3 h at about 35°C (warm water bath) and then quenched carefully with ice. The biphasic mixture was extracted with 100 mL of EtOAc, washed with brine, dried over Na2S04, filtered and the solvent was removed in vacuo to yield 8- (3,4- difluorophenyl) -5-oxa-7-aza-spiro [3.4] octan-6-one in racemic form as a white solid.
The (+) 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 retention times for the two isomers of were 12.1 min {[a]D = - 20.0 (c = o.35, MeOH)} and 15.6 min {[a]D = + 23.7 (c = 0.52 ,MeOH) Respectively. The (-) -enantiomer was used in the next step (0.30g, 35% yield) .
f . (+) -8- (3, 4-Difluorophenyl) -6-oxo-5-oxa-7-aza- spiro[3.4] octan-7-carboxylic acid-4-nitrophenylJester To 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. The resulting yellow solution was stirred at -78°C for 50 min. This solution was then added dropwise via a cannula into another round bottom flask containing a solution of 4- nitrophenylchloroformate (0.15 g, 0.76 mmol) inlO mL of THF, cooled at -78°C, over a period of 15 min. After five minutes, the flask was removed from the cooling bath and stirring was continued for 1 h. The reaction was quenched by adding ice and it was extracted with
EtOAc. The organic extracts were washed with brine and the organic layer was dried over Na2S04. The solvent was removed after filtration and the residue was purified by column chromatography on silica gel with 4:1 eyelohexane-ethyl acetate to obtain (+)-8-(3,4- difluorophenyl) -6-oxo-5-oxa-7-aza-spiro [3.4] octan-7- carboxylic acid-4-nitrophenyl] ester as a thick syrup which solidified upon standing (0.19 g, 75%) . [a]D = + 42.0 (c = 0.65, MeOH) .
g. (+) -8- (3, 4-Difluorophenyl) -6-oxo-5-oxa-7-aza- spiro[3.4]octan-7-carboxylic acid-{3- [4- (4- fluoro)phenyl) -piperidin-1-yl] -propyl} -amide
To a solution of 3- [4- (4- fluorophenyl )piperidin-l-yl] propylamine (0.02 g, 0.08 mmol) in 10 mL of THF (+) -8- (3 , 4-difluorophenyl) -6-oxo- 5-oxa-7-aza-spiro [3.4] octan-7-carboxylic acid-4- nitrophenyl] ester (0.02 g, 0.05 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 10 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with EtOAC followed by 15% MeOH in EtOAC as the eluting systems (Rf = 0.4, 1:3 MeOH/EtOAC) to obtain (+)-8-(3,4- difluorophenyl) -6-oxo-5-oxa-7-aza-spiro [3.4] octan-7- carboxylic acid- {3- [4- (4-fluoro) phenyl) -piperidin-1-yl] - propyl}-amide as a pale yellow oil(0.02 g, 89%). It was converted into its hydrochloride salt by dissolving it into 5 mL of EtOAc and then treating it with 1.0 mL of HCl in Et20 (1.0 M) . Mass spectrum showed M+l peak.
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. 2- (Benzhydryliden-amino) -l-cyclopropyl-2- (3,4- difluoro-phenyl) -ethanol To a solution of benzhydrylindene- (3 , 4-difluoro-benzyl) - amine (2.5 g, 8.1 mmol) in 50 mL of dry THF was added tert-butyllithium (1.7 M, 6.2 mL) dropwise and the resulting solution was stirred at -78°C for 0.5 h. To the solution was added cyclopropanecarboxaldehyde (0.90 ml, 12 0 mmol) in 10 ml of THF and the solution was stirred at -78 °C for 2 h and 25 °C for 1 h. The reaction was quenched by adding 1.0 L of dilute acetic acid. Reaction mixture was diluted with 100 ml of Et20 and washed with brine. The organic layer was dried over Na2S04 and concentrated in vacuo, yielding 2- (benzhydryliden-amino) -l-cyclopropyl-2- (3 , 4-difluoro- phenyl) -ethanol as a yellow oil, which was subjected to the following reaction without purification.
b. 2-Amino-l-cyclopropyl-2- (3, 4-difluoro-phenyl) -ethanol
The crude batch of 2- (benzhydryliden-amino) -1- cyclopropyl-2- (3 , 4-difluoro-phenyl) -ethanol obtained from the above reaction (approximately 16.2 mmol) and MeONH2.HCl (4.0 g, 48.0 mmol) was dissolved in 125.0 mL of MeOH and stirred for 12 h. The reaction mixture was concentrated in vacuo, yielding oily residue which was redissolved in 100 ml of EtOAc and was washed with 2.0 M NaOH followed by brine. The organic layer was separated, dried over Na2S0 and then concentrated in vacuo to give the crude product as a yellow oil. It was purified by column chromatography over silica gel (95:5 CHC13/10% ammonia in MeOH) to yield 3.2 g (93% yield) of 2-amino-l-cyclopropyl-2- (3 , 4-difluoro-phenyl) -ethanol as a pale yellow oil. c. [2-Cyclopropyl-l- (3, 4-difluorophenyl) -2-hydroxy- ethyl] -carbamic acid-tert-butyl ester To a solution of 2-amino-l-cyclopropyl-2- (3 , 4-difluorophenyl) -ethanol (1.7 g, 8.1 mmol) in CH2C12 (50 L) at 0°C was added a solution of di-tert-butyl dicarbonate (3.5 g, 16.2 mmol) in one portion and the resulting solution was stirred for 2 h at room temperature. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel (4:1 cyclohexane/EtOAc) to obtain [2-cyclopropyl-l- (3 , 4- difluorophenyl) -2-hydroxy-ethyl] -carbamic acid-tert- butyl ester as a viscous oil (1.7 g, 68% yield) .
e. 5-Cyclopropyl-4- (3, 4-Difluorophenyl) -oxazolidin-2-one To a well stirred solution of [2-cyclopropyl-l- (3 , 4- difluorophenyl) -2-hydroxy-ethyl] -carbamic acid-tert- butyl ester (1.7 g, 5.4 mmol) in THF (20 mL) was added 95% NaH (0.4 g, 16.2 mmol) at room temperature. The resulting suspension was stirred for 3 h at about 35°C (warm water bath) and then quenched carefully with ice. The biphasic mixture was extracted with 100 mL of EtOAc, washed with brine, dried over Na2S04, filtered and the solvent was removed in vacuo to yield 5-cyclopropyl-4- (3 , 4-difluorophenyl) -oxazolidin-2-one (1.3 g, 93% yield) as a 3 : 1 mixture of the trans: cis diastereomers. The diastereomers were separated by column chromatography over silica gel with 7:3 cyclohexane/ethyl acetate as the eluting system. The trans isomer eluted first (Rf = 2.5, 0.65 g) followed by the cis isomer (Rf = 2.0, 0.2 g) . The relative streochemistry was assigned by comparing the XH NMR of the two isomers of 5- cyclopropyl-4- (3 , 4-difluorophenyl) -oxazolidin-2-one to the corresponding isomers of 4- (3 , 4-difluorophenyl) -5- methyl-oxazolidin-2-one as described in Example 19. The (+) 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 retention times for the two enantiomers were 12.0 min {[a]D = + 1.8 (c = o.35, MeOH)} and 15.5 min respectively. The (+) -enantiomer was used in the next step. f . (+) -5-Cyclopropyl-4- (3, 4-difluorophenyl) -2-oxo- oxazolidine-3-carboxylic acid-4-nitrophenyl] ester
To a solution of (+) -5-cyclopropyl-4- (3 , 4- Difluorophenyl) -oxazolidin-2-one (0.16 g, 0.66 mmol) in 10 mL THF was added a solution of n-butyllithium in hexane (0.49 mL, 0.79 mmol) dropwise via a syringe under argon atmosphere at -78°C. The resulting yellow solution was stirred at -78°C for 50 min. This solution was then added dropwise via a cannula into another round bottom flask containing a solution of 4- nitrophenylchloroformate (0.16 g, 0.79 mmol) inlO mL of THF, cooled at -78°C, over a period of 15 min. After five minutes, the flask was removed from the cooling bath and stirring was continued for 1 h. The reaction was quenched by adding ice and it was extracted with
EtOAc. The organic extracts were washed with brine and the organic layer was dried over Na2S04. The solvent was removed after filtration and the residue was purified by column chromatography on silica gel with 4:1 eyelohexane-ethyl acetate to obtain (+) -5-cyclopropyl-4- (3 , 4-difluorophenyl) -2-oxo-oxazolidine-3-carboxylic acid-4-nitrophenyl] ester as a thick syrup (0.17 mg, 58%) .
g. (+)-5-Cyclopropyl-4-(3,4-difluorophenyl)-2-oxo- oxazolidine-3-carboxylic acid-{3- [4- (4-fluoro-2-methyl- phenyl) -piperidinl-yl] -propyl} -amide
To a solution of 3- [4- (4-fluoro-2-methyl-phenyl) - piperidin-1-yl] propylamine (0.02 g, 0.05 mmol) in 10 mL of CH2C12, (+) -5-cyclopropyl-4- (3, 4-difluorophenyl) -2- oxo-oxazolidine-3-carboxylic acid-4- nitrophenyl] ester (0.01 g, 0.03 mmol) was added and the resulting yellow solution was stirred for 10 h at room temperature . The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with EtOAC followed by 15% MeOH in EtOAC as the eluting systems (Rf = 0.4, 1:3 MeOH/EtOAC) to obtain (+) -5-cyclopropyl-4- (3 , 4-difluorophenyl) -2-oxo- oxazolidine-3-carboxylic acid- {3- [4- (4-fluoro-2-methyl- phenyl) -piperidinl-yl] -propyl} -amide as a pale yellow oil(0.01 g, 80%). It was converted into its hydrochloride salt by dissolving it into 5 mL of EtOAc and then treating it with 1.0 mL of HCl in Et20 (1.0 M) . Mass spectrum showed M+l peak.
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. Methanol was distilled off using a short path distillation apparatus to obtain 2- hydroxy-1-pyrrolidin-l-yl-propan-l-one as a yellow oil. It was used in the next reaction without further purification. b. 2- (tert-Butyl-dimethyl-silanyloxy) -1-pyrrolidin-1-yl- propan-1-one To a solution of 2-hydroxy-1-pyrrolidin-1-yl-propan-1- one (47.0 mmol, 6.72 g) in DMF (25 mL) was added imidazole (70.5 mmol, 4.8 g) , N, N-dimethyl-4- aminopyridine (4.7 mmol, 0.57 g) at room temperature. Tert-butyl-dimethylsilyl chloride (48.5 mmol, 7.31 g) was then added while stirring. Some exotherm was observed. The initial pale yellow solution turned brwn- red in color and some precipitate was observed after 30 min. The reaction mixture was allowed to stir overnight and then filtered through a sintered glass funnel. The solid was washed with some Et20. The filtrate was diluted with water (150 mL) and it was extracted with Et20 (2 X 100 mL) . The organic extrats were combined and washed successively with water (100 mL) , sat. NH4C1 solution and the organic layer was separated. It was dried over Na2S04, filtered and the solvent was removed in vacuo to obtain 2- (tert-butyl-dimethyl-silanyloxy) -1- pyrrolidin-1-yl-propan-l-one as a golden yellow oil
(10.4 g, 86% yield) . The product was judged to be > 95% pure by NMR and was used in next step without any purification. c. 2- (tert-Butyl-dimethyl-silanyloxy) -1- (3,4-difluoro- phenyl) -1-yl-propan-1-one
To a round bottom flask containing 72.0 mL of THF at - 78°C was added a solution of n-butyllithium in hexane (72.0 mmol, 45.0 L) under an argon atmosphere followed by l-bromo-3 , 4-difluorobenzene (72.0 mmol, 8.1 mL) . A solution of 2- ( tert-butyl-dimethyl-silanyloxy) -1- pyrrolidin-1-yl-propan-l-one (60.0 mmol, 15.4 g) in 10.0 mL THF was then added ina steady stream and .the orange colored solution was stirred for 35 min at -78°C. It was quenched with 20.0 mL of sat. NH4C1 solution and was allowed to attain room temperature. The solution was extracted with Et20 (2 X 50 mL) , washed with brine and the organic layer was dried over Na2S04. The solution was filtered and the solvent was removed in vacuo to obtain the product as an orange oil. The crude product was subjected to silica gel flash column chromatography (9:1 hexane/EtOAc to 4 : 1 hexane/EtOAc as the eluent system). 2- (tert-Butyl-dimethyl-silanyloxy) -1- (3 , 4- difluoro-phenyl) -1-yl-propan-l-one was obtained as a pale yellow oil (14.1 g, 78% yield, 96% based on the recovered starting material) .
d. 2- (tert-Butyl-dimethyl-silanyloxy) -1- (3, 4-difluorophenyl) -1-yl-propan-1-one-oxime
To a solution of 2- ( tert-Butyl-dimethyl-silanyloxy) -1- (3 , 4-difluoro-phenyl) -1-yl-propan-l-one (13.7 mmol, 4.1 g) in 60.0 mL of methanol was added sodium acetate ( mmol, 3.76 g) and hydroxylamine hydrochloride ( mmol, 1.24 g) and the resulting solution was stirred at room temperature overnight. Methanol was then removed in vacuo and the resultind residue was extracted with EtOAc (2 X 50 mL) and brine. The organic layer was separated, dried over Na2S04, filtered and the solvent was remoced in vacuo. 2- ( tert-Butyl-dimethyl-silanyloxy) -1- (3 , 4- difluoro-phenyl) -1-yl-propan-l-one-oxime was obtained as a colorless oil (4.04 g, 94% yield) . It was used in the next step without further purification. e. 1-Amino-l- (3, 4-difluorophenyl) -propan-2-ol
To a solution of 2- ( tert-butyl-dimethyl-silanyloxy) -1- (3 , 4-difluoro-phenyl) -1-yl-propan-l-one-oxime (12.2 mmol, 3.84 g) in 20.0 mL of Et20 was added a 1.0 M solution of lithium aluminum hydride (25.0 mmol, 25.0 mL) at 0°C under an argon atmosphere. After 1 h, the solution was heated to reflux for 2 h at which time some solid was observed. The reaction mixture was cooled to 0°C and then quenched sequentially with water (1.0 mL) , 1.0 N KOH (1.0 mL) and water (3.0 L) . The residue was filtered and the solid was washed with warm Et20 (20.0 mL) . The filtrates were combined and dried' over Na2S04. The solution was filtered and the solvent was removed in vacuo to obtain 1-amino-l- (3 , 4-difluorophenyl) -propan-2- ol as a colorless oil as a mixture of two diastereomers which solidified into a low melting solid (2.1 g, 92% yield) . It was used in the next step without purification.
It was converted into 4- (3 , 4-difluorophenyl) -5-methy1- oxazolidin-2-one by the general procedure as described before. f . [1- (3, 4-Difluorophenyl) -2-hydroxy-propyl] -carbamic acid-tert-butyl ester
To a solution of 1-amino-1- (3 , 4-difluorophenyl) -propan- 2-ol (3.5 g, 19.1 mmol) in CHC13 (15 mL) at 0°C was added a solution of di-tert-butyl dicarbonate (5.1 g, 23.6 mmol) in CHC13 (10 mL) in one portion and the resulting solution was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel (2:1 hexane-EtOAc followed by EtOAc) to obtain [1- (3 , 4-difluorophenyl) -2-hydroxy-propyl] -carbamic acid- tert-butyl ester as a viscous oil (3.3 g, 60.2%). g. 4- (3, 4-Difluorophenyl) -5-methyl-oxazolidin-2-one
To a well stirred solution of [1- (3 , 4-difluorophenyl) -2- hydroxy-propyl] -carbamic acid-tert-butyl ester (0.43 g, 1.5 mmol) THF (20 mL) was added 95% NaH (0.09 g, 3.8 mmol) at room temperature. The resulting suspension was stirred for 3 h at about 35°C (warm water bath) and then quenched carefully with ice. The biphasic mixture was extracted with 100 mL of EtOAc, washed with brine, dried over Na2S04, filtered and the solvent was removed in vacuo. The two diastereomers were separated by column chromatography over silica gel (First isomer: 0.11 g, Rf = 0.6, 3:1 hexane-EtOAc; second isomer: 0.23 g, Rf = 0.5, 3:1 hexane-EtOAc) . NOE experiment suggested that the first diastereomer had the methyl and the aryl group in trans configuration while the second diastereomer had cis relationship between the two groups. 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) . The HPLC analysis also confimed that the enantiomeric purity of the diastereomer was >99% because no peak corresponding to (-) -isomer was observed. Since the absolute stereochemistry of the starting material [ (S) -(+) -methyl lactate] is known, the absolute stereochemistry of the (+) -isomer of the trans- oxazolidinone must be (S,S) at the two stereocenters . This enantiomerically pure oxazolidinone can be converted into the required final products by using similar methodology as described before in example 19.
General synthetic schemes: In addition to the specific examples of compounds described above, typical procedures for the synthesis of the compounds of this invention are shown in Schemes 32-35. In Scheme 34, the synthesis may be carried out using a procedure similar to Koo, J. (J. Am. Chem. Soc, 1953, 75, 723), Anderson, P. (Tetrahedron Lett., 1971, 2787), and Bean, N. P. et al. (Tetrahedron, 1993, 49, 3193). In Scheme 35, the synthesis may be carried out using a procedure similar to Belkon, Y. et al . ( J. Chem. Soc. Perkin Trans. I, 1986, 1865), Novikov, M. S. et al . (Tetrahedron Lett., 1997, 38, 4187), and Meyers, A. et al . (J. Amer . Chem. Soc. , 1984, 106, 1146) .
Example 55
As a specific embodiment of an oral composition of a compound of this invention, 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.
Pharmacoloσical Profiles of the Compounds in Cloned Human Adrenerσic Receptors .
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.
Protocol for the Determination of the Potency of 1 Antagonists
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 α-adrenergic receptors as follows :
α1D Human Adrenergic Receptor: The entire coding region of α1D (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 αlA/EXJ (expression vector containing the αlA 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% C02) , 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 μg/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 [3H] prazosin as described below (see "Radioligand Binding assays").
The cell line expressing the human α1D receptor used herein was designated L-α1A (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 α1D receptor, was accorded ATCC Accession No. CRL 11138, and was deposited on September 25, 1992.
α1B Human Adrenergic Receptor: The entire coding region of αlB (1563 bp) , including 200 base pairs and 5' untranslated sequence (51 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 λ ZapII into the expression vector. Stable cell lines were selected as described above. The cell line used herein was designated L-α1B 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-α1B was accorded ATCC Accession. No. CR 11139, on September 29, 1992.
α^ Human Adrenergic Receptor: The entire coding region of α1A (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 α1A receptor used herein was designated L-αlc (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 α1A receptor was accorded Accession No. CR 11140, on September 25, 1992.
Radioligand Binding Assays: Transfected cells from culture flasks were scraped into 5ml of 5mM Tris-HCl, 5mM EDTA, pH 7.5, and lysed by 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 MgCl2, and 0.1% ascorbic acid at pH 7.5. Binding of the αl antagonist [3H] 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 μM 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.
α2 Human Adrenergic Receptors : To determine the potency of a antagonists at the α2 receptors, LM(tk-) cell lines stably transfected with the genes encoding the α2A, α2B, and α2c receptors were used. The cell line expressing the α2A receptor is designated L-α2A, and was deposited on November 6, 1992 under ATCC Accession No. CRL 11180. The cell line expressing the α2B receptor is designated L-NGC-α2B, and was deposited on October 25, 1989 under ATCC Accession No. CRL10275. The cell line expressing the α2c receptor is designated L-α2c, 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) . Equilibrium competition binding assay were performed using [3H] rauwolscine (0.5nM), and nonspecific binding was determined by incubation with lOμM phentolamine . The bound radioligand was separated by filtration through GF/B filters using a cell harvester.
Determination of the Activity of αx Antagonists at Calcium Channels
The potency of αx 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. Aliquots of membrane protein are then incubated for 30 minutes at 37°C in the presence of [3H] nitrendipine (1 nM) , and nonspecific binding determined in the presence of lOμM nifedipine. The bound radioligand is separated by filtration through GF/B filters using a cell harvester.
The compounds described above were assayed using cloned human alpha adrenergic receptors. The preferred compounds were found to be selective α1A antagonists . The binding affinities of several compounds are illustrated in the following table.
Binding affinities of selected compounds of the present invention at cloned human α1D, α1B and α1A receptors.
Figure imgf000171_0001
h = human
Scheme 1
Figure imgf000172_0001
Figure imgf000172_0002
Figure imgf000172_0003
Scb.«M 1: General Synthesis of Piperazine side chains
Scheme 2
Figure imgf000173_0001
Figure imgf000173_0002
Figure imgf000173_0003
Figure imgf000173_0004
Ar ,- 1- Br-(CH2 ) n-NHBoc AT
R ^ 2. TFA R ^ n = 2, 3. 4. : R * H, Me. Ar'
Scheme 2: General Synthesis of Piperidine Side Chains
Figure imgf000174_0001
Figure imgf000174_0002
Scheme 3 : Synthesis .of Pyridyl piperidine containing side chains
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000176_0002
Scheme 5t General Synthesis of Oxazol idinones (Examples i, 3, g t ηt
10, 14 and 22),
Figure imgf000177_0001
-
H2N0H.HC1
NaOAC. MeOH
Figure imgf000177_0002
Figure imgf000177_0003
Scheme 6t Alternate Synthesis of Oxazolidinones described in Scheme
Figure imgf000178_0001
ormate
Figure imgf000178_0003
Figure imgf000178_0002
Figure imgf000178_0004
Scheme 7: General Synthesis of Oxazinones (Example 4)
Figure imgf000179_0001
I
Figure imgf000179_0002
Scheme β» Synthesis of Regioisomeric Oxazolidinones (Example 9)
Figure imgf000180_0001
Thiazolidin-thione (Examples 11. 12)
Scheme 9. Synthesis of Oxazolidin-thione and
Figure imgf000180_0002
Figure imgf000180_0003
Figure imgf000181_0001
- s
Figure imgf000181_0002
Scheme 10 General Synthesis for Example 13
Figure imgf000182_0001
00 o
I
Figure imgf000182_0002
Figure imgf000182_0003
Synthesis of Methylated Oxazolidinones (Examples 16, 17)
Scheme 11
Figure imgf000183_0001
Figure imgf000183_0002
I
0
1. BOC20, CHCI3
2. NaH, THF
Figure imgf000183_0003
elative βrereochemlstry shown for the els and trans isomers
0 o oAN*M «
Figure imgf000183_0004
only two of the possible four structures shown. Absolute stereochemistry was not established.
Scheme 121 Synthesis of Methylated Oxazolidinones (Examples 18, 19).
Figure imgf000184_0001
Figure imgf000184_0002
Figure imgf000184_0003
Synthesis of Benzyl Oxazolidinones (Example 20)
Scheme 13 t General
Figure imgf000185_0001
Ph
NC K -NH,
Figure imgf000185_0002
Figure imgf000185_0003
Figure imgf000185_0004
Scheme 14 . Preparation of Examples 23 and 24
Figure imgf000186_0001
Figure imgf000186_0002
Figure imgf000186_0003
κ2co3
KI Ph
NH ♦ Br H,
Me02C "\_ ,NH2 ► MeO,C o- 'N
Scheme 15. Preparation of Side Chains
Figure imgf000187_0001
Figure imgf000187_0002
Figure imgf000187_0003
NH,
Scheme 16. Preparation of Side Chains (contd.
Ar v Ar
Ar MeMσBr ^ ± CDI \ i
MeO,C^NH, --T ""a 0→
OH 0
2. -Nitrophenyl 0—t- H chloroformate
Figure imgf000188_0001
0
Scheme 17. Preparation of Examples 25-29 and 31.
Figure imgf000188_0002
Scheme 18. Preparation of Example 30,
Figure imgf000189_0001
Figure imgf000189_0002
Scheme 19: Preparation of Example 32
Figure imgf000190_0001
H,N-NH, Ph
'N NC o- H,
Scheme 20: Preparation of Side Chain
(0H)2/C
Figure imgf000190_0002
Figure imgf000190_0003
CN
Scheme 21: Preparation of Example 33
Figure imgf000191_0001
Figure imgf000191_0002
Figure imgf000192_0001
Figure imgf000192_0002
Figure imgf000192_0003
Scheme 23 iPrepnrallon of examples 35 , 36 and 37
Figure imgf000193_0001
Figure imgf000193_0003
Figure imgf000193_0002
Figure imgf000194_0001
Scheme 25 Preparation ol Examples 43 and 44,
Figure imgf000195_0001
Scheme 26 Preparation of Example 45.
TMSCN. NH,
Figure imgf000196_0001
MeOH. catZiiL
Figure imgf000196_0002
Figure imgf000196_0003
Scheme 27 Preparation of Examples 46 and 47,
Figure imgf000197_0001
•
Figure imgf000198_0002
(For example 5 W = 0, Wl = 0
MeONH2.HCl
Figure imgf000198_0001
Enantiomers separated 1. n-BuLi/THF by chiral HPLC column. 2. ClCOOPh-N02
Figure imgf000198_0004
Figure imgf000198_0003
o 0
Figure imgf000198_0005
Scheme 29: Synthesis of Example 52 and related compounds
Figure imgf000199_0001
MeONH2.HCl
68% yield (three steps)
Figure imgf000199_0002
Diastereomers separated 1. n-Buli/THF by chiral HPLC column. 2. ClCCO?h-N02
Enantiomers separated by chiral HPLC column.
Figure imgf000199_0004
Figure imgf000199_0003
Figure imgf000199_0005
Scheme 30: Synthesis of Example 53. TBDMSC1
Figure imgf000200_0001
OH L TBDMS -Λ>
Figure imgf000200_0002
LAH, Et2θ
Figure imgf000200_0003
Figure imgf000200_0004
Only the trans isomer shown.
Scheme 31: General synthesis of methylated oxazolidinone.
Figure imgf000201_0001
R
Figure imgf000201_0002
X 0,3
Scheme 32: General synthetic scheme.
Figure imgf000202_0001
n = 1, 2
Figure imgf000202_0002
Scheme 33: General synthetic scheme
Figure imgf000203_0001
1. NaH 1. NaH
2. ClCOOPh-NO2 2. ClCOOPh-NO2
3. H2NR j 3. H2NR
Figure imgf000203_0002
Scheme 34: General synthetic scheme.
Figure imgf000204_0001
OPh-N02
Figure imgf000204_0002
Figure imgf000204_0003
OPh-N0
Figure imgf000204_0004
Scheme 35: General synthetic scheme.
Figure imgf000204_0005

Claims

What is claimed is:
A compound having the structure:
Figure imgf000205_0001
wherein each X is independently 0 or S;
wherein q is 1 or 2;
wherein each R2 is independently H; - (CH2 ) tXR3 ; - (CH2)tC(X)NR3; - (CH2) tC02R3 ; -C02R3 ; straight chained or branched C^C, alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C2- C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl ;
wherein each t is an integer from 1 to 4 inclusive;
wherein each R3 is independently H; straight chained or branched C1-C7 alkyl, straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein R4 is aryl, heteroaryl, C^C, alkyl substituted with one or two aryl, or C1-C7 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, -N02, -N(R3)2, -COR3, - (CH2)tXR3, - (CH2)nC(X)NR3, - (CH2) nC02R3 , straight chained or branched C^C, alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C2-C7 aminoalkyl, alkenyl or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein each n independently is an integer from 0 to 7 inclusive;
wherein R5 is H; aryl, C1-C7 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,
-N02, -N(R3)2, -COR3, -(CH2)tXR3, - (CH2) nC (X) NR3 , - (CH2)nC02R3, straight chained or branched C^C, alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C2-C7 aminoalkyl, alkenyl or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
where R5 and one R2 on adjacent carbon atoms together may form aryl, heteroaryl, indane or tetrahydronaphthyl, C3-C7 cycloalkyl, or heterocycloalkyl wherein one or two heteroatoms may be 0, N or S; wherein Rx is
Figure imgf000207_0001
Figure imgf000207_0002
or
Figure imgf000208_0001
where each R6 is independently H; straight chained or branched C^C, alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl ; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl; aryl or heteroaryl , wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, - (CH2)nXR3, -C0R3, -(CH2)nC(X)N(R3)2,-(CH2)nC02R3, -CN,
-N02, -N(R3)2, -S02R3, straight chained or branched C-L- J alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl;
where each R7 is independently H; F; Cl; Br; I; - COR3; -C02R3; -(CH2)nXR3; (CH2) nC (X) N (R3) 2 ; - (CH2 ) nC02R3 ; -CN; -N02; -N(R3)2; straight chained or branched C^C, alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl, wherein the alkyl, aminoalkyl, carboxamidoalkyl , alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted with one or more aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH2)nXR3, -COR3, -(CH2)nC(X)N(R3)2,-(CH2)nC02R3, -
CN, -N02, -N(R3)2, -S02R3, straight chained or branched C^C, alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl , polyfluorocycloalkyl or C5-C7 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH2)nXR3, -COR3, - (CH2)nC(X)N(R3)2,-(CH2)nC02R3, -CN, -N02 , -N(R3)2, - S02R3 , straight chained or branched Cx-C7 alkyl, straight chained or branched C^C, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl;
wherein each R10 is independently H; (CH2)tXR3; (CH2)tC(X)NR3; (CH2)tC02R3; straight chained or branched C^C, alkyl or carboxamidoalkyl; straight chained or branched C2-C7 aminoalkyl, alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein RX1 is aryl, heteroaryl, C^C, alkyl substituted with one or two aryl, or C1-C7 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, -N02, - N(R3)2, -COR3, -(CH2)nXR3, - (CH2) nC (X) NR3 , - (CH2) nC02R3 , straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl , or carboxamidoalkyl , straight chained or branched C2- C7 aminoalkyl, alkenyl, or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein each m independently is an integer from 0 to 3 inclusive;
wherein Z- is
Figure imgf000210_0001
Figure imgf000210_0002
Figure imgf000210_0003
Figure imgf000211_0001
15
Figure imgf000211_0002
Figure imgf000211_0003
35
Figure imgf000212_0001
Figure imgf000212_0002
or C2-C7 alkenyl, wherein the C2-C7 alkenyl may be unsubstituted or substituted with one or more R9 groups ;
where R8 is H; (CH2)CXR3; (CH2) tC (X)NR3; (CH2)tC02R3; straight chained or branched Cx-C7 alkyl, carboxamidoalkyl; straight chained or branched C2- C7 aminoalkyl, alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
where each R9 is independently H; F; Cl; Br; I; (CH2)mXR3; (CH2)mC(X)NR3; (CH2 ) mC02R3 ; straight chained or branched C^C, alkyl, monofluoroalkyl , polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein Y is S, 0, or NR8;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein the compound comprises the (+) enantiomer.
3. The compound of claim 1, wherein the compound comprises the (-) enantiomer.
4. The compound of claim 1, wherein the compound comprises a cis isomer.
5. The compound of claim 1, wherein the compound comprises a trans isomer.
6. The compound of claim 1, wherein
Rx is
Figure imgf000213_0001
R4 is aryl or heteroaryl, wherein the aryl may be substituted with one or more of F, Cl, -(CH2)tOR3, - (CH2)nC(0)NR3, - (CH2)nC02R3, straight chained or branched C1-C7 alkyl or monofluoroalkyl ; and
Z is
Figure imgf000214_0001
Figure imgf000214_0002
or
Figure imgf000214_0003
The compound of claim 6, wherein R4 is pyridyl or phenyl, wherein the phenyl may be substituted with one or more of F, Cl, -(CH2)tOR3, - (CH2) nC (0)NR3, - (CH2)nC02R3, straight chained or branched C1-C7 alkyl or monofluoroalkyl .
The compound of claim 7, wherein each R6 is independently aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, - (CH2)nXR -COR,
(CH2)nC(X)N(R3)2,-(CH2)nC02R3, -CN, -N02 , -N(R3)2, S02R3, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl .
The compound of claim 8, wherein R7 is H; -CN; - C02R3; -C(0)NR3; -(CH2)mXR3; unsubst-ituted or substituted aryl; C1-C3 alkyl; or -OCOR3.
10. The compound of claim 9, wherein the R4 is phenyl, wherein the phenyl may be substituted with at least one of F or Cl .
11. The compound of claim 10 having the structure:
Figure imgf000215_0001
or
12. The compound of claim 11, wherein Z is:
Figure imgf000216_0001
13. The compound of claim 12, wherein q is 1 and R1 is
Figure imgf000216_0002
14. The compound of claim 13, wherein at least one R2 is C1-C3 alkyl.
15. The compound of claim 13 , wherein R4 is phenyl substituted with at least one of F or Cl .
16. The compound of claim 15, wherein R4 is phenyl substituted with at least two F.
17. The compound of claim 12, wherein R4 is 3,4- difluorophenyl .
18. The compound of claim 13, wherein R6 is pyridyl, phenyl, or phenyl substituted with one or more of F, Cl, Br, I, -(CH2)nXR3, -C0R3, - (CH2) nC (X) N (R3) 2 , -
(CH2)nC02R3, -CN, -N02, -N(R3)2, -S02R3, straight chained or branched Cx-C7 alkyl, monofluoroalkyl or polyfluoroalkyl .
19. The compound of claim 13, wherein R7 is H; -CN; or -C02R3.
20. The compound of claim 13, wherein R9 is F; -OH; Cx- C3 alkyl; or -(CH2)mXR3.
21. The compound of claim 18, wherein R6 is 4- fluorophenyl .
22. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.
23. The pharmaceutical composition of claim 22 wherein the amount of the compound is an amount from about 0.01 mg to about 800 mg.
24. The pharmaceutical composition of claim 23 wherein the amount of the compound is an amount from about 0.01 mg to about 500 mg.
25. The pharmaceutical composition of claim 24 wherein the amount of the compound is an amount from about 0.01 mg to about 250 mg .
26. The pharmaceutical composition of claim 25 wherein the amount of the compound is from about 0.1 mg to about 60 mg.
27. The pharmaceutical composition of claim 26 wherein the amount of the compound is from about 1 mg to about 20 mg .
28. The pharmaceutical composition of claim 22, wherein the carrier is a liquid and the composition is a solution.
29. The pharmaceutical composition of claim 22, wherein the carrier is a solid and the composition is a tablet.
30. The pharmaceutical composition of claim 22, wherein the carrier is a gel and the composition is a suppository.
31. The pharmaceutical composition of claim 22, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.
32. A method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject an amount of the compound of claim 1 effective to treat benign prostatic hyperplasia.
33. A method of claim 32, wherein the compound additionally does not cause a fall in blood pressure at dosages effective no alleviate benign prostatic hyperplasia.
34. The method of claim 33, wherein the compound effects treatment of benign prostatic hyperplasia by relaxing lower urinary tract tissue.
35. The method of claim 34, wherein lower urinary tract tissue is prostatic smooth muscle.
36. A method of treating a subject suffering from high intraocular pressure which comprises administering to the subject an amount of the compound of claim 1 effective to lower intraocular pressure.
37. A method of treating a subject suffering from a disorder associated with high cholesterol which comprises administering to the subject an amount of the compound of claim 1 effective to inhibit cholesterol synthesis.
38. A method of treating a disease which is susceptible to treatment by antagonism of the α1A receptor which comprises administering to the subject an amount of the compound of claim 1 effective to treat the disease .
39. A method of treating a subject suffering from impotency which comprises administering to the subject an amount of the compound of claim 1 effective to treat impotency.
40. A method of treating a subject suffering from sympathetically mediated pain which comprises administering to the subject an amount of the compound of claim 1 effective to treat sympathetically mediated pain.
41. A method of treating a subject suffering from cardiac arrhythmia which comprises administering to the subject an amount of the compound of claim 1 effective to treat cardiac arrhythmia.
42. A method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject an amount of the compound of claim 1 effective to treat benign prostatic hyperplasia.
43. The method of claim 42, wherein the compound effects treatment of benign prostatic hyperplasia by relaxing lower urinary tract tissue.
44. The method of claim 43, wherein lower urinary tract tissue is prostatic smooth muscle.
45. A method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject an amount of the compound of claim 1 in combination with a 5 alpha- reductase inhibitor effective to treat benign prostatic hyperplasia.
46. The method of claim 45, wherein the 5-alpha reductase inhibitor is finasteride.
47. A method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject an amount of the compound of claim 1 in combination with a 5 alpha- reductase inhibitor effective uo treat benign prostatic hyperplasia.
48. The method of claim 47, wherein the 5-alpha reductase inhibitor is finasteride.
49. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 in combination with a therapeutically effective amount of finasteride and a pharmaceutically acceptable carrier.
50. The pharmaceutical composition of claim 49 wherein the compound is present in an amount from about 0.01 mg to about 500 mg and the therapeutically effective amount of the finasteride is about 5 mg .
51. The pharmaceutical composition of -claim 50 wherein the compound is present in an amount from about 0.1 mg to about 60 mg and the therapeutically effective amount of finasteride is about 5 mg.
52. The pharmaceutical composition of claim 51 wherein the compound is present in an amount from about 1 mg to about 20 mg and the therapeutically effective amount of finasteride is about 5 mg .
53. A method of relaxing lower urinary tract tissue which comprises contacting the lower urinary tract tissue with an amount of the compound of claim 1 effective to relax lower urinary tract tissue.
54. The method of claim 53, wherein the lower urinary tract tissue is prostatic smooth muscle.
55. A method of relaxing lower urinary tract tissue in a subject which comprises administering to the subject an amount of the compound of claim 1 effective to relax lower urinary tract tissue.
56. The method of claim 55, wherein the lower urinary tract tissue is prostatic smooth muscle.
57. A trans (+) isomer of the compound of claim 21, wherein the compound has the structure:
Figure imgf000222_0001
58. The compound of claim 1, wherein the compound has the structure:
Figure imgf000222_0002
59. The compound of claim 1, wherein the compound has the structure:
Figure imgf000223_0001
60. The compound of claim 1, wherein the compound has the structure:
Figure imgf000223_0002
61. The compound of claim 1, wherein the compound has the structure:
Figure imgf000224_0001
62. A compound having the structure:
Figure imgf000224_0002
63. A compound having the structure:
Figure imgf000224_0003
wherein each W is an integer from 0 to 3 inclusive;
wherein each Wl is an integer from 0 to 3 inclusive;
wherein each X is independently 0 or S;
wherein XI is 0, S, NR3;
wherein each R2 is independently H; -(CH2)tXR3; -
(CH2) tC(X)NR3; - (CH2) tC02R3 ; -C02R3; straight chained or branched Cx-C7 alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C2- C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein each t is an integer from 1 to 4 inclusive;
wherein each R3 is independently H; straight chained or branched C^-C, alkyl, straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein R4 is aryl, heteroaryl, Cx-C7 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, -N02, -N(R3)2, -COR3, - (CH2)tXR3, -(CH2)nC(X)NR3, - (CH2) nC02R3 , straight chained or branched C^C, alkyl, monofluoroalkyl , polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C2-C7 aminoalkyl, alkenyl or alκynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein each n independently is an integer from 0 to 7 inclusive;
wherein R5 is H; aryl, C1-C7 alkyl substituted with aryl, heteroaryl, or C^ , alkyl substituted with heteroaryl ; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -CN, -N02, -N(R3)2, -COR3, -(CH2)tXR3, - (CH2) nC (X) NR3, - (CH2)nC02R3, straight chained or branched C^ , alkyl, monofluoroalkyl , polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched
C2-C7 aminoalkyl, alkenyl or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein Rx is
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000227_0002
where each R6 is independently H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl , polyfluorocycloalkyl or C5-C7 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteioaryl may be substituted with one or more of F, Cl, Br, I, - (CH2)nXR3, -COR3, -(CH2)nC(X)N(R3)2,-(CH2)nC02R3, -CN, -N02, -N(R3)2, -S02R3, straight chained or branched C^C, alkyl, monofluoroalkyl or polyfluoroalkyl , straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl , polyfluorocycloalkyl or C5-C7 cycloalkenyl;
where each R7 is independently H; F; Cl; Br; I; - COR3; -C02R3; -(CH2)nXR3; (CH2) nC (X) N (R3 ) 2 ; -. (CH2)nC02R3; -CN; -N02 ; -N(R3)2; straight chained or branched Cx-C7 alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl , polyfluorocycloalkyl or C5-C7 cycloalkenyl, wherein the alkyl, aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted with one or more aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH2)nXR3, -COR3, - (CH2) nC (X) N (R3 ) 2 , - (CH2) nC02R3 , -
CN, -N02, -N(R3)2, -S02R3, straight chained or branched C^C, alkyl, monofluoroalkyl or polyfluoroalkyl , straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH2)nXR3, -C0R3, - (CH2)nC(X)N(R3)2,-(CH2)nC02R3, -CN, -N02 , -N(R3)2, - S02R3, straight chained or branched Cx-C7 alkyl, straight chained or branched Cx-C7 monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl; wherein each R10 is independently H; (CH2)tXR3; (CH2)tC(X)NR3; (CH2) cC02R3 ; straight chained or branched Cx-C7 alkyl or carboxamidoalkyl; straight chained or branched C2-C7 aminoalkyl, alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein Rn is aryl, heteroaryl, C^C, alkyl substituted with one or two aryl, or Cx-C7 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, -N02, - N(R3)2, -COR3, -(CH2)nXR3, - (CH2) nC (X) NR3 , - (CH2) nC02R3 , straight chained or branched C^C, alkyl, monofluoroalkyl , polyfluoroalkyl , or carboxamidoalkyl, straight chained or branched C2- C7 aminoalkyl, alkenyl, or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein each m independently is an integer from 0 to 3 inclusive;
wherein Z is
Figure imgf000229_0001
Figure imgf000230_0001
10
Figure imgf000230_0002
Figure imgf000230_0003
30
35
Figure imgf000231_0001
15
Figure imgf000231_0002
25
Figure imgf000231_0003
35
Figure imgf000232_0001
or C2-C7 alkenyl, wherein the C2-C7 alkenyl may be unsubstituted or substituted with one or more R9 groups ;
where R8 is H; (CH2)tXR3; (CH2) tC (X) NR3 ; (CH2 ) tC02R3 ; straight chained or branched Cx-C7 alkyl, carboxamidoalkyl; straight chained or branched C2- C7 aminoalkyl, alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
where each R9 is independently H; F; Cl; Br; I; (CH2)mXR3; (CH2)mC(X)NR3; (CH2)mC02R3; straight chained or branched C^C, alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein Y is S, 0, or NR
or a pharmaceutically acceptable salt thereof.
64. A compound having the structure
Figure imgf000233_0001
wherein each X is independently 0 or S;
wherein q is 1 or 2 ;
wherein each R2 is independently H; -(CH2)tXR3; - (CH2)tC(X)NR3; - (CH2) tC02R3 ; -C02R3; straight chained or branched C^C, alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C2- C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl ;
wherein each t is an integer from 1 to 4 inclusive;
wherein each R3 is independently H; straight chained or branched Cx-C7 alkyl, straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein R4 is aryl, heteroaryl, C^C, alkyl substituted with one or two aryl, or Cx-C7 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, -N02, -N(R3)2, -COR3, - (CH2)tXR3, -(CH2)nC(X)NR3, - (CH2) nC02R3 , straight chained or branched Cx-C7 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C2-C7 aminoalkyl, alkenyl or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein each n independently is an integer from 0 to 7 inclusive;
wherein R5 is H; aryl, C1-C7 alkyl substituted with aryl, heteroaryl, or C1-C7 alkyl substituted with heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -CN,
-N02, -N(R3)2, -COR3, -(CH2)tXR3, - (CH2) nC (X) NR3 , - (CH2)nC02R3, straight chained or branched C^C, alkyl, monofluoroalkyl , polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C2-C7 aminoalkyl, alkenyl or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
where R5 and one R2 on adjacent carbon atoms together may form aryl , heteroaryl , indane or tetrahydronaphthyl, C3-C7 cycloalkyl, or heterocycloalkyl wherein one or two heteroatoms may be 0, N or S; wherein Rx is
Figure imgf000235_0001
Figure imgf000235_0002
or
Figure imgf000236_0001
where each R6 is independently H; straight chained or branched Cx-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl ; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl , polyfluorocycloalkyl or C5-C7 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, - (CH2)nXR3, -COR3, -(CH2)nC(X)N(R3)2,-(CH2)nC02R3, -CN,
-N02, -N(R3)2, -S02R3, straight chained or branched Cx-C7 alkyl, monofluoroalkyl or polyfluoroalkyl , straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl;
where each R7 is independently H; F; Cl; Br; I; - COR3; -C02R3; -(CH2)nXR3; (CH2) nC (X) N (R3) 2 ; - (CH2) nC02R3 ; -CN; -N02 ; -N(R3)2; straight chained or branched Cx-C7 alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl , polyfluorocycloalkyl or C5-C7 cycloalkenyl, wherein the alkyl, aminoalkyl, carboxamidoalkyl , alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted with one or more aryl or heteroaryl , wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH2)nXR3, -COR3, -(CH2)nC(X)N(R3)2,-(CH2)nC02R3, -
CN, -N02, -N(R3)2, -S02R3, straight chained or branched C^C, alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH2)nXR3, -COR3, - (CH2)nC(X)N(R3)2,-(CH2)nC02R3, -CN, -N02, -N(R3)2, - S02R3, straight chained or branched C^C, alkyl, straight chained or branched C1-C7 monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl;
wherein each R10 is independently H; (CH2)tXR3; (CH2) tC(X)NR3; (CH2)tC02R3; straight chained or branched C^C, alkyl or carboxamidoalkyl; straight chained or branched C2-C7 aminoalkyl, alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein Rxl 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, -N02, - N(R3)2, -COR3, -(CH2)nXR3, - (CH2) nC (X) NR3 , - (CH2) nC02R3 , straight chained or branched C^C, alkyl, monofluoroalkyl, polyfluoroalkyl , or carboxamidoalkyl, straight chained or branched C2- C7 aminoalkyl, alkenyl, or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein each m independently is an integer from 0 to 3 inclusive;
wherein Z is
Figure imgf000238_0001
Figure imgf000238_0002
Figure imgf000238_0003
Figure imgf000239_0001
Figure imgf000239_0002
Figure imgf000239_0003
Figure imgf000240_0001
or C2-C7 alkenyl, wherein the C2-C7 alkenyl may be unsubstituted or substituted with one or more R9 groups ;
where R8 is H; (CH2)tXR3; (CH2) tC (X) NR3; (CH2)tC02R3; straight chained or branched C1-C7 alkyl, carboxamidoalkyl; straight chained or branched C2- C7 aminoalkyl, alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl ;
where each R9 is independently H; F; Cl; Br; I ; (CH2)raXR3; (CH2)mC(X)NR3; (CH2) mC02R3 ; straight chained or branched C^C, alkyl, monofluoroalkyl , polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein Y is S, 0, or NR8;
or a pharmaceutically acceptable salt thereof.
PCT/US1998/012668 1997-06-18 1998-06-17 Heterocyclic substituted piperidines and uses thereof WO1998057940A1 (en)

Priority Applications (4)

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AU81498/98A AU740064B2 (en) 1997-06-18 1998-06-17 Heterocyclic substituted piperidines and uses thereof
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US6228870B1 (en) 1998-11-10 2001-05-08 Merck & Co., Inc. Oxazolidinones useful as alpha 1a adrenoceptor antagonists
EP1140906A1 (en) * 1998-12-17 2001-10-10 Synaptic Pharmaceutical Corporation Imidazolones and their use in treating benign prostatic hyperplasia and other disorders
US6316437B1 (en) 1999-09-30 2001-11-13 Merck & Co., Inc. Spirohydantoin compounds and uses thereof
US6319932B1 (en) 1998-11-10 2001-11-20 Merck & Co., Inc. Oxazolidinones useful as alpha 1A adrenoceptor antagonists
US6326372B1 (en) 1999-09-30 2001-12-04 Merck & Co., Inc. Lactam and cyclic urea derivatives useful as alpha 1a adrenoceptor antagonists
US6329393B1 (en) 1998-12-17 2001-12-11 Merck & Co., Inc. Crystalline pharmaceutically acceptable salts of an oxazolidinone derivative
US6372911B1 (en) * 1999-02-09 2002-04-16 Merck & Co., Inc. Process for preparing β-hydroxycarbamates and their conversion to oxazolidinones
US6387893B1 (en) 1999-09-30 2002-05-14 Merck & Co., Inc. Spirotricyclic substituted azacycloalkane derivatives and uses thereof
US6436962B1 (en) 1999-09-30 2002-08-20 Merck & Co., Inc. Arylhydantoin derivatives and uses thereof
US6645968B2 (en) 1999-08-03 2003-11-11 Abbott Laboratories Potassium channel openers
US8637505B2 (en) 2009-02-04 2014-01-28 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8680093B2 (en) 2009-04-30 2014-03-25 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8748444B2 (en) 2007-12-11 2014-06-10 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8754076B2 (en) 2008-07-25 2014-06-17 Vitae Pharmaceuticals, Inc./Boehringer-Ingelheim Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8765744B2 (en) 2010-06-25 2014-07-01 Boehringer Ingelheim International Gmbh Azaspirohexanones
US8835426B2 (en) 2007-02-26 2014-09-16 Vitae Pharmaceuticals, Inc. Cyclic urea and carbamate inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8846613B2 (en) 2010-11-02 2014-09-30 Boehringer Ingelheim International Gmbh Pharmaceutical combinations for the treatment of metabolic disorders
US8846668B2 (en) 2008-07-25 2014-09-30 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8883778B2 (en) 2009-07-01 2014-11-11 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11 beta-hydroxysteroid dehydrogenase 1
US8927539B2 (en) 2009-06-11 2015-01-06 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 based on the 1,3-oxazinan-2-one structure
US8933072B2 (en) 2010-06-16 2015-01-13 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US9079861B2 (en) 2007-11-07 2015-07-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US9969743B2 (en) 2012-10-11 2018-05-15 Southern Research Institute Urea and amide derivatives of aminoalkylpiperazines and use thereof
EP3883925A4 (en) * 2018-11-20 2021-12-29 Sironax Ltd Cyclic ureas
CN116003380A (en) * 2023-01-31 2023-04-25 天津大学 Fingerprint identification probe, developer and medium surface latent fingerprint fluorescence imaging method

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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
EP1140906A4 (en) * 1998-12-17 2002-03-13 Synaptic Pharma Corp Imidazolones and their use in treating benign prostatic hyperplasia and other disorders
US6329393B1 (en) 1998-12-17 2001-12-11 Merck & Co., Inc. Crystalline pharmaceutically acceptable salts of an oxazolidinone derivative
EP1140906A1 (en) * 1998-12-17 2001-10-10 Synaptic Pharmaceutical Corporation Imidazolones and their use in treating benign prostatic hyperplasia and other disorders
US6372911B1 (en) * 1999-02-09 2002-04-16 Merck & Co., Inc. Process for preparing β-hydroxycarbamates and their conversion to oxazolidinones
US6645968B2 (en) 1999-08-03 2003-11-11 Abbott Laboratories Potassium channel openers
US6316437B1 (en) 1999-09-30 2001-11-13 Merck & Co., Inc. Spirohydantoin compounds and uses thereof
US6326372B1 (en) 1999-09-30 2001-12-04 Merck & Co., Inc. Lactam and cyclic urea derivatives useful as alpha 1a adrenoceptor antagonists
US6387893B1 (en) 1999-09-30 2002-05-14 Merck & Co., Inc. Spirotricyclic substituted azacycloalkane derivatives and uses thereof
US6436962B1 (en) 1999-09-30 2002-08-20 Merck & Co., Inc. Arylhydantoin derivatives and uses thereof
US8835426B2 (en) 2007-02-26 2014-09-16 Vitae Pharmaceuticals, Inc. Cyclic urea and carbamate inhibitors of 11β-hydroxysteroid dehydrogenase 1
US9079861B2 (en) 2007-11-07 2015-07-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8748444B2 (en) 2007-12-11 2014-06-10 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8754076B2 (en) 2008-07-25 2014-06-17 Vitae Pharmaceuticals, Inc./Boehringer-Ingelheim Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8846668B2 (en) 2008-07-25 2014-09-30 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8637505B2 (en) 2009-02-04 2014-01-28 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8680093B2 (en) 2009-04-30 2014-03-25 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8927539B2 (en) 2009-06-11 2015-01-06 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 based on the 1,3-oxazinan-2-one structure
US8883778B2 (en) 2009-07-01 2014-11-11 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11 beta-hydroxysteroid dehydrogenase 1
US8933072B2 (en) 2010-06-16 2015-01-13 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US9090605B2 (en) 2010-06-16 2015-07-28 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US8765744B2 (en) 2010-06-25 2014-07-01 Boehringer Ingelheim International Gmbh Azaspirohexanones
US8846613B2 (en) 2010-11-02 2014-09-30 Boehringer Ingelheim International Gmbh Pharmaceutical combinations for the treatment of metabolic disorders
US9969743B2 (en) 2012-10-11 2018-05-15 Southern Research Institute Urea and amide derivatives of aminoalkylpiperazines and use thereof
AU2013329097B2 (en) * 2012-10-11 2018-10-18 Southern Research Institute Urea and amide derivatives of aminoalkylpiperazines and use thereof
EP3883925A4 (en) * 2018-11-20 2021-12-29 Sironax Ltd Cyclic ureas
CN116003380A (en) * 2023-01-31 2023-04-25 天津大学 Fingerprint identification probe, developer and medium surface latent fingerprint fluorescence imaging method

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AU8149898A (en) 1999-01-04
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CA2294549A1 (en) 1998-12-23
EP0988295A1 (en) 2000-03-29
JP2002505683A (en) 2002-02-19

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