AU8149898A - Heterocyclic substituted piperidines and uses thereof - Google Patents
Heterocyclic substituted piperidines and uses thereof Download PDFInfo
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- AU8149898A AU8149898A AU81498/98A AU8149898A AU8149898A AU 8149898 A AU8149898 A AU 8149898A AU 81498/98 A AU81498/98 A AU 81498/98A AU 8149898 A AU8149898 A AU 8149898A AU 8149898 A AU8149898 A AU 8149898A
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- 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
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- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- 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
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Description
WO 98/57940 PCT/US98/12668 -1 HETEROCYCLIC SUBSTITUTED PIPERIDINES AND USES THEREOF Throughout this application, various references are 5 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. 10 Background of the Invention The designation "OlA" is the appellation recently approved by the IUPHAR Nomenclature Committee for the 15 previously designated "'aic" cloned subtype as outlined in the 1995 Receptor and Ion Channel Nomenclature Supplement (Watson and Girdlestone, 1995). The designation aA is used throughout this application and the supporting tables and figures to refer to this 20 receptor subtype. At the same time, the receptor formerly designated a1A was renamed alD. The new nomenclature is used throughout this application. Stable cell lines expressing these receptors are described herein; however, these cell lines were 25 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 30 is characterized by a nodular enlargement of prostatic tissue resulting in obstruction of the urethra. This results in increased frequency of urination, nocturia, a poor urine stream and hesitancy or delay in starting the urine flow. Chronic consequences of BPH can include 35 hypertrophy of bladder smooth muscle, a decompensated WO98/57940 PCT/US98/12668 -2 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 5 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 10 (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 15 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 20 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 25 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 30 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. 35 WO 98/57940 PCTIUS98/12668 -3 a-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 5 are important switches for controlling many physiological functions and, thus, represent important targets for drug development. In fact, many a adrenergic drugs have been developed over the past 40 years. Examples include clonidine, phenoxybenzamine and 10 prazosin (treatment of hypertension), naphazoline (nasal decongestant), and apraclonidine (treating glaucoma). a-Adrenergic drugs can be broken down into two distinct classes: agonists (clonidine and naphazoline are agonists), which mimic the receptor activation 15 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 20 example, clonidine produces dry mouth and sedation in addition to its antihypertensive effects). During the past 15 years a more precise understanding of a-adrenergic receptors and their drugs has evolved 25 through increased scientific scrutiny. Prior to 1977, only one a-adrenergic receptor was known to exist. Between 1977 and 1988, it was accepted by the scientific community that at least two a-adrenergic receptors--al and o 2 --existed in the central and peripheral nervous 30 systems. Since 1988, new techniques in molecular biology have led to the identification of at least six a-adrenergic receptors which exist throughout the central and peripheral nervous systems: alA (new nomenclature), alB, alD (new nomenclature), a 2 A, 2 B and a 2 C 35 (Bylund, D.B., FASEB J., 6, 832 (1992)). In many cases, WO98/57940 PCT/US98/12668 -4 it is not known precisely which physiological responses in the body are controlled by each of these receptors. In addition, current a-adrenergic drugs are not selective for any particular a-adrenergic receptor. 5 Many of these drugs produce untoward side effects which may be attributed to their poor a-adrenergic receptor selectivity. Since the mid 1970's, nonselective a-antagonists have 10 been prescribed to treat BPH. In 1976, M. Caine, et al. (Brit. J. Urol., 48, 255 (1976)), reported that the nonselective a-antagonist phenoxybenzamine was useful in relieving the symptoms of BPH. This drug may produce its effects by interacting with as-receptors located on 15 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 a-adrenergic antagonists prazosin and terazosin have also been found 20 to be useful for treating BPH. However, these drugs also produce untoward side effects. It has recently been discovered that the aA receptor is responsible for mediating the contraction of human prostate smooth muscle (Gluchowski, C. et. al., WO 94/10989, 1994; 25 Forray, C. et. al., Mol. Pharmacol. 45, 703, 1994). This discovery indicates that the alA antagonists may be effective agents for the treatment of BPH with decreased side effects. Further studies have indicated that the UlA receptor may also be present in other lower urinary 30 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 a1A 35 receptors. This invention is also related to uses of WO98/57940 PCT/US98/12668 -5 these compounds for lowering intraocular pressure (Zhan, et. al. Ophthalmol. Vis. Sci., 34 Abst. #1133, 928, 1993), inhibiting cholesterol synthesis (D'Eletto and Javitt, J. Cardiovascular Pharmacol., 13 (Suppl. 2) Sl 5 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 10 the treatment of any disease where antagonism of the a1A receptor may be useful.
WO 98/57940 PCT/US98/12668 -6 Summary of the Invention This invention is directed to a compound having the structure:
R
5 R4 x R 5
R
4 N,-R1 or R2 qR 2
R
5
R
4 5 wherein each X is independently 0 or S; wherein q is 1 or 2; 10 wherein each R 2 is independently H; -(CH 2 ) tXR 3 ; (CH 2
)
t
C(X)NR
3 ; -(CH 2
)
t
CO
2
R
3 ; -C0 2
R
3 ; straight chained or branched Ci-C 7 alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C 2
-C
7 alkenyl, or alkynyl; or C 3
-C
7 cycloalkyl or Cs-C 7 cycloalkenyl; 15 wherein each t is an integer from 1 to 4 inclusive; wherein each R 3 is independently H; straight chained or branched Cl-C alkyl, straight chained or branched C 2
-C
7 20 alkenyl, or alkynyl; or C 3 -C., cycloalkyl or Cs-C 7 WO98/57940 PCT/US98/12668 -7 cycloalkenyl; wherein R 4 is aryl, heteroaryl, Cz-C7 alkyl substituted with one or two aryl, or Ci-C7 alkyl substituted with 5 one or two heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, CN, -NO 2 , -N(R 3
)
2 , -COR 3 , -(CH 2 )tXR 3 , -(CH 2 )nC(X)NR 3 , (CH 2 )nCO 2
R
3 , straight chained or branched Ci-C7 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or 10 straight chained or branched C2-C7 aminoalkyl, alkenyl or alkynyl, or C3-C7 cycloalkyl or Cs-C7 cycloalkenyl; wherein each n independently is an integer from 0 to 7 inclusive; 15 wherein R s is H; aryl, Ci-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, -NO 2 , -N(R 3
)
2 , -COR 3 , 20 (CH 2 )tXR 3 , -(CH 2 )nC(X)NR 3 , -(CH 2 )nCO 2
R
3 , straight chained or branched Ci-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C2 C 7 aminoalkyl, alkenyl or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl; 25 where R s and one R 2 on adjacent carbon atoms together may form aryl, heteroaryl, indane or tetrahydronaphthyl, C3-C7 cycloalkyl, or heterocycloalkyl wherein one or two heteroatoms may be O, N or S; 30 WO 98/57940 PCT/US98/12668 -8 wherein R 1 is
R
10
R
10 5 [ m Rg / ] mR 7 R1 1R10 10 15 RR0 R 1 0 R,04.-9 -Rio ,Z-N N-R
R
1 qR 20 Ro 1 0
R
1 0 Rio [m Rg N N 25 m JfR 7 or 30 35 WO 98/57940 PCT/US98/12668 -9 0 Ro 10 5R 5 R1q 10 m R10 N-Rjj iol qR m IR0 10 R10R1 where each R 6 is independently H; straight chained or 15 branched Ci-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 20 heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH 2 )nXR 3 ,
-COR
3 , -(CH2)nC(X)N(R 3
)
2, 1- (CH2)nCO 2
R
3 , -CN, -NO 2 , -N(R 3
)
2 , SO 2
R
3 , straight chained or branched Ci-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or 25 branched C 2
-C
7 alkenyl or alkynyl, or C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or Cs-C 7 cycloalkenyl; where each R 7 is independently H; F; Cl; Br;. I; -COR 3 ; 30 CO 2
R
3 ; -(CH 2 ) nXR 3 ; -COR 3 ; -(CH 2 ) n
C
(X) N (R 3
)
2 ; -(CH 2 ) nCO 2
R
3 ; CN; -NO 2 ; -N(R 3
)
2 ; straight chained or branched Ci-C 7 alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; 35 C 3 -C., cycloalkyl, monofluorocycloalkyl, WO 98/57940 PCT/US98/12668 -10 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 5 heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH 2 ) nXR 3 , -COR 3 , -(CH 2 ) nC (X)N(R 3 ) 2 , -(CH 2 ) nCO 2
R
3 , CN, -NO 2 , -N(R 3
)
2 , -S0 2
R
3 , straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C 2
-C
7 alkenyl or alkynyl, 10 or C 3 -C, cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or Cs5-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 )nXR 3 ,
-COR
3 , -(CH 2 ) nC(X)N(R 3
)
2
,
-
(CH
2 ) nCO 2
R
3 , -CN, -NO 2 , -N(R 3
)
2 , 15 S0 2
R
3 , straight chained or branched Ci-C7 alkyl, straight chained or branched Ci-C 7 , monofluoroalkyl or polyfluoroalkyl, straight chained or branched C 2
-C
7 alkenyl or alkynyl, or C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or Cs-C 7 , 20 cycloalkenyl; wherein each Rio is independently H; (CH 2 )tXR 3 ;
(CH
2 ) C(X)NR 3 ; (CH 2 )tCO 2
R
3 ; straight chained or branched
C
1 -C, alkyl or carboxamidoalkyl; straight chained or 25 branched C2-C 7 aminoalkyl, alkenyl, or alkynyl; or C3-C7 cycloalkyl or C 5
-C
7 , cycloalkenyl; wherein R 11 is aryl, heteroaryl, Ci-C7 alkyl substituted with one or two aryl, or Cx-C 7 alkyl substituted with 30 one or two heteroaryl; wherein any aryl or heteroaryl independently may be substituted with one or more of F, Cl, Br, I, -CN, -NO 2 , -N(R 3
)
2 , -COR 3 , -(CH 2 )nXR 3 , (CH 2 )nC(X)NR 3 , -(CH 2 )nCO 2
R
3 , straight chained or branched
CI-C
7 , alkyl, monofluoroalkyl, polyfluoroalkyl, or 35 carboxamidoalkyl, straight chained or branched C 2
-C
7 WO 98/57940 PCTIUS98/12668 -11 aminoalkyl, alkenyl, or alkynyl, or C 3
-C
7 cycloalkyl or Cs-C 7 cycloalkenyl; wherein each m independently is an integer from 0 to 3 5 inclusive; wherein Z is o
R
2 R10 10 n R2 R9 10 15 2 R 20 R n9 O 2 R10 30 R n R2 R R 0 R9 35 WO 98/57940 PCT/US98/12668 -12 5 R10 R i 10 R0 R9 R2 R10 15 0 R2
R
9 R9 20 n~ R m H n R2 R9 m R1 0 25 0 Rlo R1o m [ RSR Ro 30 m 35 R10 R3 o R9
R
10 35 WO 98/57940 PCT/US98/12668 -13 5 0 R 2 R10 9 or mt R or 10 12 R2 R9 R10 15 200 O R 9 20 R2 R2 R10 or C2-C7 alkenyl, wherein the C2-C7 alkenyl may be 25 unsubstituted or substituted with one or more R 9 groups; where R 8 is H; (CH 2 ) tXR 3 ; (CH 2 )tC(X)NR 3 ; (CH2) tCO 2
R
3 ; straight chained or branched C-C7 alkyl, carboxamidoalkyl; straight chained or branched C2-C7 30 aminoalkyl, alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl; where each R 9 is independently H; F; Cl; Br; I;
(CH
2 )mXR 3 ; (CH 2 )mC(X)NR 3 ; (CH 2 )mCO 2
R
3 ; straight chained or 35 branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, WO 98/57940 PCT/US98/12668 -14 aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C, alkenyl, or alkynyl; or C 3
-C
7 cycloalkyl or C 5
-C
7 cycloalkenyl; 5 wherein Y is S, O, or NR 8 ; or a pharmaceutically acceptable salt thereof. The present invention is additionally directed to a 10 compound having the structure: F F 15 \ Ph \ CO 2
CH
3 20 H N N 3 0 This invention is additionally directed to a compound 25 having the structure: x 30 X4 NRl E w X R 5 35 W1 R 4 35 WO98/57940 PCT/US98/12668 -15 wherein each W is an integer from 0 to 3 inclusive; wherein each W1 is an integer from 0 to 3 inclusive; 5 wherein each X is independently 0 or S; wherein Xl is O, S, NR 3 ; wherein each R 2 is independently H; -(CH 2 )tXR 3 ; 10 (CH 2 )tC(X)NR 3 ; -(CH 2 )tCO 2
R
3 ; -C0 2
R
3 ; straight chained or branched Ci-C 7 alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C 2
-C
7 alkenyl, or alkynyl; or C 3
-C
7 cycloalkyl or C,-C 7 cycloalkenyl; 15 wherein each t is an integer from 1 to 4 inclusive; wherein each R 3 is independently H; straight chained or branched Ci-C 7 alkyl, straight chained or branched
C
2
-C
7 alkenyl, or alkynyl; or C 3
-C
7 cycloalkyl or C,-C 7 20 cycloalkenyl; wherein R 4 is aryl, heteroaryl, Ci-C 7 alkyl substituted with one or two aryl, or C,-C 7 alkyl substituted with one or two heteroaryl; wherein the aryl or heteroaryl 25 may be substituted with one or more of F, Cl, Br, I, CN, -NO 2 , -N(R 3
)
2 , -COR 3 , -(CH 2 )tXR 3 , -(CH 2 )nC(X)NR 3 , (CH 2 )nCO 2
R
3 , straight chained or branched Ci-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C 2
-C
7 aminoalkyl, 30 alkenyl or alkynyl, or C 3
-C
7 cycloalkyl or Cs-C7 cycloalkenyl; wherein each n independently is an integer from 0 to 7 inclusive; 35 WO 98/57940 PCT/US98/12668 -16 wherein R s is H; aryl, C 1
-C
7 alkyl substituted with aryl, heteroaryl, or C,-C 7 alkyl substituted with heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -CN, 5 NO 2 , -N(R 3
)
2 , -COR 3 , -(CH 2 ) t
XR
3 , -(CH 2 )nC(X)NR 3 , (CH 2 )nCO 2
R
3 , straight chained or branched C,-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 C5-C 7 10 cycloalkenyl; wherein R 1 is 15 RI0 R10 Z-N 20 R7 R10 Xm R1 0 25 30 35 WO 98/57940 PCT/US98/12668 -17 RR0R 10 .0--Z -
N-R
1 1 lo R1q.[ R10
R
1 0
R
1 0 o :.[ R10J[7m4 R7 or 20 o R 10 JK[R0 M R6 N N N-R 1 25 R 7 R0R 1 0 where each R 6 is independently H; straight chained or branched C 1
-C
7 alkyl, hydroxyalkyl, aminoalkyl, 30 alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl;
C
3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C.-C 7 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be 35 substituted with one or more of F, Cl, Br, I, -(CH 2 )nXR 3
,
WO 98/57940 PCT/US98/12668 -18
-COR
3 , -(CH 2 )nC(X)N(R 3
)
2 , - (CH 2 )nCO 2
R
3 , -CN, -NO 2 , -N(R 3
)
2 , S0 2
R
3 , straight chained or branched Ci-C7 alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, 5 monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl; where each R 7 is independently H; F; Cl; Br; I; -COR 3 ; C0 2
R
3 ; -(CH 2 )nXR 3 ; (CH 2 )nC(X)N(R 3
)
2 ; -(CH 2 )nCO 2
R
3 ; -CN; -NO2; 10 -N(R 3
)
2 ; straight chained or branched C-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 15 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, C1, Br, I, -(CH 2 )nXR 3 , 20 -COR 3 , -(CH 2 )nC (X)N(R 3 ) 2,-(C 2 )nCO 2
R
3 , -CN, -NO 2 , -N(R 3 ) 2, S0 2
R
3 , straight chained or branched C -C7 alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 25 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, C1, Br, I, -(CH 2 )nXR 3 , -COR 3 , -(CH 2 )nC(X)N(R 3
)
2
,-(CH
2 )nCO 2
R
3 , CN, -NO 2 , -N(R 3
)
2 , -S0 2
R
3 , straight chained or branched C1-C7 alkyl, straight chained or branched C-C7 30 monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or Cs-C7 cycloalkenyl; 35 wherein each Ro 10 is independently H; (CH 2 )tXR 3
;
WO 98/57940 PCT/US98/12668 -19
(CH
2 )tC(X)NR 3 ; (CH 2 )tCO 2
R
3 ; straight chained or branched Ci-C 7 alkyl or carboxamidoalkyl; straight chained or branched C 2
-C
7 aminoalkyl, alkenyl, or alkynyl; or C3-C 7 cycloalkyl or C 5 s-C 7 cycloalkenyl; 5 wherein R. is aryl, heteroaryl, Ci-C 7 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, 10 Cl, Br, I, -CN, -NO 2 , -N(R 3
)
2 , -COR 3 , -(CH2)nXR 3 , (CH 2 )nC(X)NR 3 , -(CH 2 )nCO 2
R
3 , straight chained or branched Ci-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 15 Cs-C 7 cycloalkenyl; wherein each m independently is an integer from 0 to 3 inclusive; 20 wherein Z is 25 O R 2 R10 9 R2 R9 R10 30 35 WO 98/57940 PCT/US98/12668 -20 R2 R 25 n R2 R9R10 RR 10 O R2 10 5R9 n R2 R9 R10 20 25 10 0 R2 9
R
O 30 Y R0 R9 R2 R10 35 WO 98/57940 PCT/US98/12668 -21 0 R2
R
9 mR 5 n R2 R10 10 15 R2
R
2 R0 m R t n t R2 RI0 R2
R
9 20 2s 0 R10 R10 Nm R8R9 R10 ] m or 30 3 R10 R10 R9 R5o 35 WO98/57940 PCTIUS98/12668 -22 0
R
9 R 2 R2 R10 5 m 2 2 R10 or C 2
-C
7 alkenyl, wherein the C 2
-C
7 alkenyl may be 10 unsubstituted or substituted with one or more R 9 groups; where R 8 is H; (CH 2 )tXR 3 ; (CH 2 )tC(X)NR 3 ; (CH 2 ) CO 2
R
3 ; straight chained or branched Ci-C 7 alkyl, carboxamidoalkyl; straight chained or branched C 2
-C
7 15 aminoalkyl, alkenyl, or alkynyl; or C 3
-C
7 cycloalkyl or
C,-C
7 cycloalkenyl; where each R 9 is independently H; F; Cl; Br; I;
(CH
2 )mXR 3 ; (CH 2 )mC(X)NR 3 ; (CH 2 )mCO 2
R
3 ; straight chained or 20 branched Ci-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; 25 wherein Y is S, O, or NR,; or a pharmaceutically acceptable salt thereof. This invention is also related to uses of these 30 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 a1A receptor may be 35 useful. The invention further provides pharmaceutical WO98/57940 PCT/US98/12668 -23 compositions comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.
WO98/57940 PCTIUS98/12668 -24 Brief Description of the Fiqures Ficrure 1 Figures 1A-IM show the structures of the compounds described hereinbelow in the 5 Examples.
WO 98/57940 PCT/US98/12668 -25 Detailed Description of the Invention The present invention is directed to compounds having the structure: X X X N-R 1 N NR1 R2 R2 R2 R2 q q
R
5
R
4 x R 5
R
4 N R 1 or R2 R 2
R
5
R
4 5 wherein each X is independently 0 or S; wherein q is 1 or 2; 10 wherein each R 2 is independently H; -(CH 2 )tXR 3 ; (CH 2 ) tC(X)NR 3 ; -(CH 2 ) tCO 2
R
3 ; -C0 2
R
3 ; straight chained or branched C,-C 7 alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C 2
-C
7 alkenyl, or alkynyl; or C 3
-C
7 cycloalkyl or C,-C 7 cycloalkenyl; 15 wherein each t is an integer from 1 to 4 inclusive; wherein each R 3 is independently H; straight chained or branched Ci-C 7 alkyl, straight chained or branched C 2
-C
7 20 alkenyl, or alkynyl; or C 3
-C
7 cycloalkyl or C5-C 7 WO98/57940 PCT/US98/12668 -26 cycloalkenyl; wherein R 4 is aryl, heteroaryl, C1-C7 alkyl substituted with one or two aryl, or Cl-C7 alkyl substituted with 5 one or two heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, CN, -NO 2 , -N(R 3
)
2 , -COR 3 , -(CH 2 )tXR 3 , -(CH 2 )nC(X)NR 3 , (CH 2 )nCO 2
R
3 , straight chained or branched C -C7 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or 10 straight chained or branched C2-C7 aminoalkyl, alkenyl or alkynyl, or C 3
-C
7 cycloalkyl or Cs-C 7 cycloalkenyl; wherein each n independently is an integer from 0 to 7 inclusive; 15 wherein R s is H; aryl, C 1
-C
7 alkyl substituted with aryl, heteroaryl, or C-C7 alkyl substituted with heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -CN, -NO,, -N(R 3
)
2 , -COR 3 , 20 (CH 2 )tXR 3 , -(CH 2 )nC(X)NR 3 , -(CH 2 )nCO 2
R
3 , straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C2 C 7 aminoalkyl, alkenyl or alkynyl, or C3-C7 cycloalkyl or Cs-C7 cycloalkenyl; 25 where R s and one R 2 on adjacent carbon atoms together may form aryl, heteroaryl, indane or tetrahydronaphthyl, C3-C 7 cycloalkyl, or heterocycloalkyl wherein one or two heteroatoms may be O, N or S; 30 WO 98/57940 PCT/US98/12668 -27 wherein R. is RiO0 5 R1 m R ~Z-tN]3 Rio m R 101 15
RIOR
10
R
10 4 L Rio 20 --- Z- N-Rj 1 R10--qRiO Rj 0
R
10 0 25 [,,j...RO [ R6 N N mR or 30 35 WO 98/57940 PCT/US98/12668 -28 O
R
1 0 5 [, RI N NN-R1 qR\4m
RIO
1 10 where each R 6 is independently H; straight chained or branched C 1
-C
7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; 15 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, C1, Br, I, -(CH 2 )nXR 3 , 20 -COR 3 , -(CH 2 )nC(X)N(R 3
)
2
,-(CH
2 )nCO 2
R
3 , -CN, -NO 2 , -N(R 3
)
2 , S0 2
R
3 , straight chained or branched Ci-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 C5-C 7 25 cycloalkenyl; where each R 7 is independently H; F; Cl; Br; I; -COR 3 ; C0 2
R
3 ; -(CH 2 )nXR 3 ; -COR 3 ; -(CH 2 )n
C
(X)N(R
3
)
2 ; -(CH 2 )nCO 2
R
3 ; CN; -NO 2 ; -N(R 3
)
2 ; straight chained or branched Ci-C 7 30 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 Cs-C 7 cycloalkenyl, wherein the 35 alkyl, aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, WO98/57940 PCT/US98/12668 -29 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, -(CH 2 ) nXR 3 , -COR 3 , -(CH 2 ) nC(X) N (R 3
)
2 , - (CH 2 ) nCO 2
R
3 , 5 CN, -NO 2 , -N(R 3
)
2 , -S0 2
R
3 , straight chained or branched Ci-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; aryl or 10 heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH 2 )nXR 3 ,
-COR
3 , -(CH 2 )nC(X)N(R 3
)
2
,-(CH
2 )nCO 2
R
3 , -CN, -NO 2 , -N(R 3
)
2 , S0 2
R
3 , straight chained or branched Ci-C 7 alkyl, straight chained or branched C,-C 7 monofluoroalkyl or 15 polyfluoroalkyl, straight chained or branched C 2
-C
7 alkenyl or alkynyl, or C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C 7 cycloalkenyl; 20 wherein each Ro 10 is independently H; (CH 2 )tXR 3 ;
(CH
2 )tC(X)NR 3 ; (CH 2 )tCO 2
R
3 ; straight chained or branched Ci-C 7 alkyl or carboxamidoalkyl; straight chained or branched C 2
-C
7 aminoalkyl, alkenyl, or alkynyl; or C3-C 7 cycloalkyl or Cs-C 7 cycloalkenyl; 25 wherein R n is aryl, heteroaryl, Ci-C 7 alkyl substituted with one or two aryl, or CI-C 7 alkyl substituted with one or two heteroaryl; wherein any aryl or heteroaryl independently may be substituted with one or more of F, 30 Cl, Br, I, -CN, -NO 2,
-N(R
3
)
2 , -COR 3 , -(CH 2 )nXR 3 , (CH 2 )nC(X)NR 3 , -(CH 2 )nCO 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 35 C 5
-C
7 cycloalkenyl; WO 98/57940 PCT/US98/12668 -30 wherein each m independently is an integer from 0 to 3 inclusive; wherein Z is 5 o R 2 R10 R2 R9 R10 109 15 2 R10 n 20 R2 R9 R10 O0 R2 R10 25 R9 n n R2 R9 R10 30 35 WO 98/57940 PCT/US98/12668 -31 R10 R2 Ri10 5 0 i R10 R9 R2 R10 10 i00 O R2 15
R
9 mR ;n R2 R m R1 20 25 R2 O 2 R10 m R9 30 3R2
R
9 35 WO 98/57940 PCT/US98/12668 -32 0 Rio Rio R8
R
9 Rio R10 R10 R9 Ri0 or 10 R2 ,R2tR1 O Rt 15 R2 2 10 or C 2
-C
7 alkenyl, wherein the C 2
-C
7 alkenyl may be 20 unsubstituted or substituted with one or more R 9 groups; where R 8 is H; (CH 2 ) tXR 3 ; (CH 2 ) tC(X)NR 3 ; (CH 2 ) tCO 2
R
3 ; straight chained or branched C.-C 7 alkyl, carboxamidoalkyl; straight chained or branched C 2
-C
7 25 aminoalkyl, alkenyl, or alkynyl; or C 3
-C
7 cycloalkyl or Cs-C 7 cycloalkenyl; where each R 9 is independently H; F; Cl; Br; I;
(CH
2 )mXR 3 ; (CH 2 )mC(X)NR 3 ; (CH 2 )mCO 2
R
3 ; straight chained or 30 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 Cs-C 7 cycloalkenyl; 35 wherein Y is S, O, or NR 8
;
WO98/57940 PCT/US98/12668 -33 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 5 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 10 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 15 "heteroaryl" is used to include pyrazinyl, pyrryl, furanyl, thiophenyl, pyridyl, imidazolyl, indolyl, aminophenyl, benzamidyl, benzimidazolyl, benzfurazanyl, benzfuranyl, 2-keto-l-benzimidazolinyl or quinolyl. 20 The compounds of this invention exhibit at least ten fold greater affinity for the human a1A receptor than for the human a1B or human aID receptor. In one embodiment of the present invention R i is 25 R10 R10R 6 R10 35 R 4 is aryl or heteroaryl, where the aryl may be WO 98/57940 PCT/US98/12668 -34 substituted with one or more of F, Cl, -(CH 2 ) tOR 3 , (CH 2 ) nCONR 3 , -(CH 2 )nCO 2
R
3 , straight chained or branched Cl
C
7 alkyl or monofluoroalkyl; and 5 Z is O R 2 R10 10 n t t R2 R9 R10 2 R1 15 n R2 R9 Rl10 20 or 25 0 R1o Rlo m R8 R9 R10 30 M R10 R10 R9 R10 In another embodiment of the present invention R 4 is 35 pyridyl or phenyl, where the phenyl may be substituted WO 98/57940 PCT/US98/12668 -35 with one or more of F, Cl, -(CH 2 )tOR 3 , -(CH 2 )nC(O)NR 3 , (CH2)nCO 2
R
3 , straight chained or branched C--C 7 alkyl or monofluoroalkyl. 5 In yet another embodiment of the present invention 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 )nXR 3 , -COR 3 , -(CH 2 )nC(X)N(R 3
)
2
,
(CH
2 )nCO 2
R
3 , -CN, -NO 2 , -N(R 3
)
2 , -S0 2
R
3 , straight chained 10 or branched C,-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl. In a further embodiment of the present invention R 7 is H; -CN; -CO 2
R
3 ; -C(O)NR,; -(CH 2 )mXR 3 ; unsubstituted or 15 substituted aryl; Ci-C 3 alkyl; or -OCOR 3 . In another embodiment of the present invention R 4 is phenyl which may be substituted with at least one of F or Cl. 20 In yet another embodiment of the present invention the compound has the structure: 0 0 O N.-R 1 N,..- NR1 R2 R2 R2 AqR2
R
5 R4 R 5 R4 or WO 98/57940 PCT/US98/12668 -36 In another embodiment of the present invention Z is: 5
R
9 R2 R 1 0 10 NH 0 R2 R 1 0 15 20 In a further embodiment of the present invention q is 1 and R i is H H 25 m R6 Z-N H m R7 H 30 In a further embodiment of the present invention at least one R 2 is C.-C3 alkyl. 35 WO98/57940 PCT/US98/12668 -37 In another embodiment of the present invention R 4 is phenyl substituted with at least one of F or Cl. In a further embodiment of the present invention R 4 is 5 phenyl substituted with at least two F. In an embodiment of the present invention R 4 is 3,4 difluorophenyl. 10 In an additional embodiment of the present invention R 6 is pyridyl, phenyl, or phenyl substituted with one or more of F, Cl, Br, I, -(CH 2 )nXR 3 , -COR 3 , (CH 2 ) nC(X)N(R) 21
-(CH
2 ) nCO 2
R
3 , -CN, -NO2, -N(R 3
)
2 , -SO 2
R
3 , straight chained or branched C 1
-C
7 alkyl, 15 monofluoroalkyl or polyfluoroalkyl. In a further embodiment of the present invention R 7 is H; -CN; or -C0 2
R
3 . 20 In another embodiment of the present invention R 9 is F; -OH; Cz-C 3 alkyl; or -ACH 2 )mXR 3 . In an embodiment, when R 9 is -OH or F, the other R 9 on the same carbon atom is not -OH. In yet another 25 embodiment, when R 9 is F, the other R 9 on the same carbon atom is Ci-C 3 alkyl, F, Cl, Br, or I. In yet another embodiment of the present invention R 6 is 4-fluorophenyl. 30 In one embodiment of the invention, the compound is a trans (+) isomer having the structure: 35 WO 98/57940 PCT/US98/12668 -38 5o O O H H3C 10 H H F F F 15 This invention is additionally directed to a compound having the structure: 0 0 20 25 F F This invention is additionally directed to a compound 30 having the structure: 35 WO 98/57940 PCT/US98/12668 -39 o 0 )NNYN 5 10 This invention is additionally directed to a compound having the structure: 0 o 15 O N NN CN 20 F F This invention is additionally directed to a compound 25 having the structure: 0 0 30 O F CN 35F
F
WO 98/57940 PCT/US98/12668 -40 5 This invention includes a compound having the structure: x X", N-- RI 10 W X W1 A. 15 wherein each W is an integer from 0 to 3 inclusive; wherein each W1 is an integer from 0 to 3 inclusive; wherein each X is independently O or S; 20 wherein each Xl is O, S, NR 3 ; wherein each R 2 is independently H; -(CH 2 ) tXR 3 ; (CH 2
)
t
C(X)NR
3 ; -(CH 2
)
t
CO
2
R
3 ; -C0 2
R
3 ; straight chained or 25 branched Ci-C 7 alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C 2
-C
7 alkenyl, or alkynyl; or C 3
-C
7 cycloalkyl or Cs-C 7 cycloalkenyl; wherein each t is an integer from 1 to 4 inclusive; 30 wherein each R 3 is independently H; straight chained or branched C,-C 7 alkyl, straight chained or branched C 2
-C
7 alkenyl, or alkynyl; or C 3
-C
7 cycloalkyl or C5-C 7 cycloalkenyl; 35 WO 98/57940 PCT/US98/12668 -41 wherein R 4 is aryl, heteroaryl, C 1
-C
7 alkyl substituted with one or two aryl, or C 1
-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, 5 CN, -NO 2 , -N(R 3
)
2 , -COR 3 , -(CH 2 )tXR 3 , -(CH 2 )nC(X)NR 3 , (CH 2 )nCO 2
R
3 , straight chained or branched Cl-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 cycloalkenyl; 10 wherein each n independently is an integer from 0 to 7 inclusive; wherein R s is H; aryl, C 1
-C
7 alkyl substituted with aryl, 15 heteroaryl, or C -C 7 alkyl substituted with heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -CN, -NO 2 , -N(R 3
)
2 , -COR 3 , (CH 2 )tXR 3 , -(CH 2 )nC(X)NR 3 , -(CH 2 )nCO 2
R
3 , straight chained or branched Ci-C7 alkyl, monofluoroalkyl, polyfluoroalkyl 20 or carboxamidoalkyl, or straight chained or branched C 2 C 7 aminoalkyl, alkenyl or alkynyl, or C 3
-C
7 cycloalkyl or Cs-C 7 cycloalkenyl; WO 98/57940 PCT/US98/12668 -42 wherein R. is R10O 5 RIO m R6 Z-N RIO mR7 R10O 10 15 R OR1 20 R10 4 R10 ,Z-N N-Ry z
RIO---R
1 1 R Rj [ R 1 0 RloRlo 25 O [ Rio [mR 6 NN q yt1R 7 o Tm or 30 35 WO 98/57940 PCTIUS98/12668 -43 O Ri0 Rio R 4R1 5~ E E M 10 wherein each R 6 is independently H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; 15 straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or Cs-C7 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, 20 (CH 2 )nXR 3 , -COR 3 , -(CH 2 )nC(X)N(R 3
)
21
-(CH
2 )nCO 2
R
3 , -CN, NO 2 , -N(R 3
)
2 , -S0 2
R
3 , straight chained or branched Ci-C7 alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl 25 or C,-C 7 cycloalkenyl; wherein each R 7 is independently H; F; Cl; Br; I; COR3; -C0 2
R
3 ; - (CH 2 ) nXR 3 ; (CH 2 )nC (X) N (R) 2 ; -(CH 2 ) nC0 2
R
3 ; CN; -NO 2 ; -N(R 3
)
2 ; straight chained or branched C 1
-C
7 30 alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl, wherein 35 the alkyl, aminoalkyl, carboxamidoalkyl, alkenyl, WO 98/57940 PCT/US98/12668 -44 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, -(CH 2 )nXR 3 , -COR 3 , -(CH 2 )nC(X)N(R 3
)
2
,
5 (CH 2 )nCO 2
R
3 , -CN, -NO 2 , -N(R 3
)
2 , -SO 2
R
3 , straight chained or branched Ci-C7 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,-C 7 10 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH 2 )nXR 3 , -COR 3 , -(CH2)nC(X)N(R 3
)
2
,
(CH
2 )nCO 2
R
3 , -CN, -NO 2 , -N(R 3
)
2 , -SO 2
R
3 , straight chained or branched Ci-C 7 alkyl, straight chained or branched 15 Cl-C 7 monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C 5
-C
7 cycloalkenyl; 20 wherein each R 10 is independently H; (CH 2 )tXR 3 ;
(CH
2 )tC(X)NR 3 ; (CH 2 )tCO 2
R
3 ; straight chained or branched
C
1
-C
7 alkyl or carboxamidoalkyl; straight chained or branched C 2
-C
7 aminoalkyl, alkenyl, or alkynyl; or C3
C
7 cycloalkyl or C 5
-C
7 cycloalkenyl; 25 wherein R 11 is aryl, heteroaryl, Ci-C 7 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 30 with one or more of F, Cl, Br, I, -CN, -NO 2 , -N(R 3
)
2 , COR 3 , -(CH 2 )nXR 3 , -(CH 2 )nC(X)NR 3 , -(CH 2 )nCO 2
R
3 , straight chained or branched C-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or carboxamidoalkyl, straight chained or branched C2-C7 aminoalkyl, alkenyl, or alkynyl, or 35 C3-C7 cycloalkyl or C5-C7 cycloalkenyl; WO 98/57940 PCT/US98/12668 -45 wherein each m independently is an integer from 0 to 3 inclusive; wherein Z is 5 o R2 R10 10 R 10 t n R2 R R10 R9 15 2 10 20 R n r 2 RR10 R9 25 R2 Rio OR2 R10 30 R9 35 WO 98/57940 PCT/US98/12668 -46 R10 0 9 RI RR10 5t RI0 R9 R2 RI0 10 0 2 15R 9 m O R10 RRo m 20 25 0R O RR Ri 30 R3 R10 R R10 35 WO 98/57940 PCT/US98/12668 -47 5 R2R2 R10 R2R n R2 R2
R
9 R10 10 or 0 R 9 15 R R R R2 2 10 20 or C 2
-C
7 alkenyl, wherein the C 2
-C
7 alkenyl may be unsubstituted or substituted with one or more R 9 groups; where R 8 is H; (CH 2 ) t
XR
3 ; (CH 2 )tC(X)NR 3 ; (CH 2 ) t
CO
2
R
3 ; 25 straight chained or branched Ci-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; 30 where each R 9 is independently H; F; Cl; Br; I;
(CH
2 )mXR 3 ; (CH 2 )mC(X)NR 3 ; (CH 2 )mCO 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 35 or Cs-C 7 cycloalkenyl; WO98/57940 PCTUS98/12668 -48 wherein Y is S, O, or NR,; or a pharmaceutically acceptable salt thereof. 5 The present invention is additionally directed to a compound having the structure: F F 10 O Ph oPhCO 2
CH
3 15 3 0 The invention also encompasses the (-) and (+) 20 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 25 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). 30 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 35 acid, hydroiodic acid, sulfuric acid and boric acid; WO98/57940 PCTIUS98/12668 -49 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, 5 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, trimethylamine, triethylamine, 10 ethylenediamine, hydroxyethylamine, morpholine, piperazine and guanidine. This invention further encompasses hydrates and polymorphs of all of the compounds described herein. 15 The invention further provides pharmaceutical compositions comprising a therapeutically effective amount of any of the compounds described above and a 20 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 25 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 30 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 35 1 mg to about 20 mg. In one embodiment the WO98/57940 PCTIUS98/12668 -50 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 5 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 10 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 15 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 20 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, 25 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. 30 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 35 include, for example, calcium phosphate, magnesium WO98/57940 PCT/US98/12668 -51 stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. 5 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 10 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, 15 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 20 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. 25 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. 30 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 35 administered intravenously. The compounds may be WO98/57940 PCTIUS98/12668 -52 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 5 include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. The invention also provides a method of treating a 10 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 15 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 20 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 25 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 30 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. 35 The invention also provides a method of treating a WO98/57940 PCT/US98/12668 -53 disease which is susceptible to treatment by antagonism of the a1A receptor which comprises administering to the subject one of the compounds described herein effective to treat the disease. 5 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. 10 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 15 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 20 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 25 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 30 per day to 50 mg per subject per day of finasteride in combination with an a1A 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 a A antagonist. The 35 most preferred dosage administered to the subject is WO98/57940 PCT/US98/12668 -54 about 5 mg per subject per day of finasteride in combination with an cAn antagonist. The invention also provides a pharmaceutical composition 5 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 10 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 15 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 20 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 25 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 30 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 35 relax lower urinary tract tissue.
WO98/57940 PCT/US98/12668 -55 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 5 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 10 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 15 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 20 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 aA receptor may be useful. The invention provides for the 25 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 30 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, 35 cardiac arrhythmia and any disease where antagonism of WO98/57940 PCT/US98/12668 -56 the a A receptor may be useful. The invention provides for the use of the compounds described herein in the preparation of a medicament for 5 lowering intraocular pressure, inhibiting cholesterol synthesis, and for the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the aIA receptor may be useful. The invention provides for the use of the 10 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, 15 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 20 the aIA 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 25 hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the a1A 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 30 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 aA receptor may be 35 useful.
WO98/57940 PCT/US98/12668 -57 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 5 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. 10 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, 15 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 20 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 25 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 30 preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of 35 administration.
WO98/57940 PCT/US98/12668 -58 In the practice of this invention, the term "lower urinary tract tissue" is used to include prostatic capsule, prostate urethra, and bladder neck. 5 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. 10 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 15 the invention as described more fully in the claims which follow thereafter.
WO98/57940 PCT/US98/12668 -59 Experimental Details Example 1: 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3 carboxylic acid [ 3 -(3',4',5',6'-tetrahydro-2'H 5 [2,4']bipyridinyl-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 10 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 0 C and trimethylsilyl cyanide (1.3 eq., 0.23 mmol) was then added slowly. The reaction 15 mixture was stirred for 2 h when TLC analysis indicated that the reaction was complete (Rf = 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 20 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 HC1 in MeOH(200 mL) was added at room temperature. The resulting 25 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 30 solution to pH 9. The aqueous layer was extracted with
CH
2
CI
2 (3 x 100 mL). The organic layer was separated and dried over Na2SO4, 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 WO98/57940 PCT/US98/12668 -60 was used in the next step without purification. c. 2-Amino-2-(3,4-difluorophenyl)-ethanol To a well stirred suspension of LiAlH 4 (4.7 g, 0.125 mol) in THF (120 mL) in a 3-necked round bottom flask fitted 5 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 rL) dropwise at 0 0 C. The.resulting greenish brown suspension was then heated to reflux for 2 h. The reaction mixture was cooled to 0OC 10 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 Et 2 0 and the suspension was heated to reflux for 20 min. The 15 suspension was filtered and was combined with the previous filtrate, dried over MgSO 4 , 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. 20 METHOD B: Synthesis of 2-amino-2-(3,4-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) 25 was added 3,4-difluoroacetophenone (15.6 g, 0.1 mol) dropwise over 15 min at 0 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 30 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 Na 2
SO
4 and was decanted. The solvent was removed in vacuo to obtain 35 31.0 g of the acetal as thick yellow oil. It was WO98/57940 PCT/US98/12668 -61 dissolved in 200 mL of acetone and about 10 drops of conc. sulfuric acid. The reaction mixture was stirred at room temperature for 2 h till tlc analysis showed complete cosumption of the starting material. The 5 solvent was removed in vacuo and the solid that was obtained was basified by adding sat. NaHCO 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 MgSO 4 , filtered and the 10 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% 15 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 l-hydroxy-(3,4-difluorophenyl) acetophenone (6.0 g, 34.9 mmol) in 150 mL of MeOH was 20 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 25 with 100 mL of sat. NaHCO 3 solution followed by brine. The organic layer was separated and dried over MgSO 4 , 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 30 without any purification. c. 2-Amino-2-(3,4-difluorophenyl)-ethanol To a well stirred suspension of LiAlH 4 (3.4 g, 89.5 mmol) in THF (120 mnL) in a 3-necked round bottom flask fitted with a condenser and a dropping funnel, was added WO 98/57940 PCT/US98/12668 -62 a solution of l-hydroxy-(3,4-difluorophenyl) acetophenone-oxime (4.6 g, 24.6 mmol) in THF (50 mL) dropwise at 0 0 C. The resulting greyish yellow suspension was then heated to reflux for 2 h. The 5 reaction mixture was cooled to 0 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 Et 2 0 and the suspension 10 was heated to reflux for 20 min. The suspension was filtered and was combined with the previous filtrate, dried over MgSO 4 , 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 15 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 CHC1 3 (150 mL) at O'C was added a 20 solution of di-tert-butyl dicarbonate (11.4 g, 52.0 mmol) in CHC1 3 (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 25 hexane-EtOAc followed by EtOAc) to obtain [1-(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) 30 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 35 quenched carefully with 10 mL of water. The biphasic WO98/57940 PCT/US98/12668 -63 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 5 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 10 conditions (U.V. 254 nM). The retention times for the two isomers were 16.19 min and 20.08 min respectively. First isomer:[o]D = + 62.9 (c = 0.67, acetone); Anal. Calcd. for C 9
H
7
NO
2
F
2 : C, 54.28; H, 3.54; N, 7.03. Found: C, 54.16; H, 3.44; N, 6.96. Second isomer:[I]D = - 56.9 15 (c = 0.75, acetone); Anal. Calcd. for C 9
H
7
NO
2
F
2 : 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 20 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 25 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 0 C over a period of 15 min. The stirring was continued for 2 h after 30 which the solvent was removed and the residue was purified by column chromatography on silica gel with 1:1 hexane/CH 2 Cl 2 followed by CH 2 Cl 2 (Rf= 0.4, CH 2 C1 2 ) to obtain 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3 carboxylic acid-4-nitro-phenyl ester as a white solid 35 (1.55g, 86%).
WO98/57940 PCT/US98/12668 -64 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 5 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 0 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 10 Et 2 0 and then heated to 90-95 0 C for 4 h. The solvent was evaporated and the white residue was triturated with Et 2 O (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 15 (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 20 mL) and chloroform (2 x 20.0 mL) to yield 10.9 g as the first crop. Anal. Calcd. for C 13H 1 6N 3 Br.HBr.0.5 H 2 0: 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-1'-yl) 25 propylamine To a solution of l-(3-aminopropyl)-4-[pyrid-2 yl]pyridinium bromide hydrobromide (0.66 g, 1.75 mmol) in 20.0 mL MeOH was added NaBH 4 (0.101 g, 2.62 mmol) in small portions. The reaction mixture was stirred for 30 30 min and then quenched with 6M HC1 solution. The solution was concentrated to 20.0 mL and basified with 50% NaOH solution to pH 12. Extracted with CHC1 3 (5 x 30.0 mL), dried over MgSO 4 and the solvent was removed to give 3-(3',6'-Dihydro-2'-H-[2,4']bipyridinyl-1'-yl)- WO98/57940 PCT/US98/12668 -65 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-1'-yl) propylamine 5 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 10 thro' a pad of celite and the solvent was removed. The residue was purified by column chromatography over silica gel using CH 2 Cl 2 /methanol/2M NH 3 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%). 15 3-(3',4',5',6'-Tetrahydro-2'-H-[2,4']bipyridinyl-1'-yl) propylamine To a solution of l-(3-aminopropyl)-4-[pyrid-2 yl]pyridinium bromide hydrobromide (0.53 g) 10.0 mL of 2M NH 3 in MeOH was added PtO 2 (0.1 g) and the reaction 20 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 it to be the required product although the accurate weight of the 25 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 30 [2,4']bipyridinyl-1'-yl)-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 35 resulting yellow solution was stirred under argon WO 98/57940 PCTIUS98/12668 -66 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 5 = 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) 10 and then dried over Na 2
SO
4 . 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 l'-yl)-propyl]-amide was obtained as a colorless glassy oil(1.55 g, 82%) which develops some brownish color 15 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 20 added a warm solution of 95% fumaric acid (0.48 g, 4.06 mmol) in 8.0 mL 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 25 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 400C. The white non-hygroscopic powder (1.6 g, 84%) was found out to be the monofumarate salt after NMR and 30 elemental analysis as shown below. M.P. 142-144,C; [o]D = + 47.4 (c = 0.52, MeOH); Anal. Calcd. for
C
27
H
30
N
4 0 7
F
2
.H
2 0: C, 56.05; H, 5.57; N, 9.68. Found: C, 56.18; H, 5.51; N, 9.54. 35 Example 2: 4
-(
3
,
4 -Difluorophenyl)-3-{5-[4-(2-methoxy- WO 98/57940 PCT/US98/12668 -67 phenyl)-piperazin-1-yl]-pentyl}-oxazolidin-2-one a. 4-(3,4-Difluorophenyl)-1-(5-bromopentyl) oxazolidinone To a stirred suspension of sodium hydride (203 mg, 8.04 5 mmol) in THF(5 mL) at 0OC 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 10 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 CH 2 C1 2 followed by 5% EtOAc in CH 2 C1 2 as the eluting system (Rf 15 = 0.72, CH 2
CI
2 :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 20 To a solution of 4-(3,4-difluorophenyl)-i-(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 K 2
CO
3 (23.8 mg, 0.52 mmol). The resulting mixture was heated 25 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 CH 2 C1 2 (2 X 30 ml), dried over Na 2
SO
4 . The solvent was then removed in vacuo and the residue was 30 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-phenyl)-piperazin-1 yl]-pentyl}-oxazolidin-2-one as a brown oil (69 mg, 35 88%). The compound was dissolved in CH 2 C 2 (3 mL) and WO98/57940 PCT/US98/12668 -68 was treated with 1N HC1 in ether (1 mL). The solvent was removed in vacuo to give the corresponding hydrochloride salt as a yellow solid. M.P. 174-178 0 C; Anal. Calcd. For C 25
H
33
N
3 0 3
F
2
CI
2 0.65 CH 2 C1 2 : C, 52.43; H, 5 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 phenyl-piperidin-1-yl]-propyl}-amide 10 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 15 bromoanisole. The resulting solution was stirred at room temperature under argon atmosphere and then AIC1 3 (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 20 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) 25 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-1 yl]propylamine To a solution of 4 -(5-bromo-2-methoxy)-phenyl-4-phenyl 30 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 K 2
CO
3 (3.48 g, 25.2 mmol) and the resulting suspension was heated to reflux for 10 h. The suspension was allowed to cool, filtered WO98/57940 PCTIUS98/12668 -69 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 5 butoxycarbonyl-propylamine as a yellow oil (3.15 g). It was dissolved in 35 mL of CH 2 C1 2 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 10 basified to pH 10 by adding minimum amount of 1 N KOH solution. The product was extracted with CH 2 C1 2 (3 X 35 mL), dried over MgSO4, 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 15 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. 20 c. 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3 carboxylic 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 25 100 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 30 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% 35 NaOH solution (4 x 25 mL) in order to remove traces of WO98/57940 PCT/US98/12668 -70 4-nitrophenol from the product. The organic layer was separated, washed with brine (25 mL) and then dried over Na 2
SO
4 . The solvent was removed after filtration and (+)-l-{3-{3,4-difluorophenyl)-2-oxo-oxazolidine-3 5 carbonyl)-amino-propyl}(5-bromo-2-methoxy)phenyl-4 phenyl-piperidine was obtained as a colorless glassy oil(1.84 g, 60%). [a]D = + 34.3 (c = 0.3, MeOH); The compound was dissolved in CHC1 3 (10 mL) and was treated with IN HC1 in ether (5 mL). The solvent was removed in 10 vacuo to give the corresponding hydrochloride salt as a white solid (2.0 g). M.P. 142-144 0 C; Anal. Calcd. for
C
31
H
33
N
4 04BrC1F 2 .0.3 CHC13: C, 53.65; H, 4.79; N, 6.00. Found: C, 53.89; H, 4.73; N, 5.74. 15 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-l1-ol To a well stirred suspension of LiAlH 4 (1.3 g, 35.0 20 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 0 C. The resulting grey suspension was then heated to reflux for 2 h. The reaction mixture was cooled to 0 0 C and then 25 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 30 suspension was filtered and was combined with the previous filtrate, dried over MgSO 4 , 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.
WO 98/57940 PCTUS98/12668 -71 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 CHC1 3 (50 mL) at 0 0 C was added a solution 5 of di-tert-butyl dicarbonate (3.75 g, 17.1 mmol) in CHC1 3 (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 10 followed by EtOAc) to obtain (3-hydroxy-l-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 15 mmol) in THF (20 mL) at r.t. was added a solution of (3 hydroxy-l-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. 20 The biphasic mixture was extracted with 100 mL of Et 2 0, 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 = 0.2, 3:2 hexane-EtOAc) to obtain 4-phenyl-oxazinan-2-one as a 25 white flaky solid (0.44 g, 62%). d. 2-Oxo-4-phenyl-[I,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 30 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 35 nitrophenylchloroformate (0.60 g, 3.0 mmol) in 20 mL of WO98/57940 PCT/US98/12668 -72 THF and cooled at -78 0 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/CH 2 Cl 2 5 followed by CH 2 C1 2 (Rf= 0.4, CH 2 C1 2 ) 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) amuino-propyl}-4-phenyl-piperidine-4-carboxylic acid 10 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-[l,3]-oxazinane-3-carboxylic acid-4-nitro phenyl ester(51 mg, 0.15 mmol) was added and the 15 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 20 = 0.4, 1:1 MeOH/EtOAC) to obtain 2-oxo-4-phenyl-[l,3] oxazinane-3-carboxylic acid-3-(4-carbomethoxy-4-phenyl) piperidin-l-yl]-propyl amide as a pale yellow glassy oil (35 mg, 49% yield). It was converted into hydrochloride salt for characterization. Hygroscopic yellow solid. 25 Anal. Calcd. for C 27
H
34
N
3 0sC1.2.5 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 30 [2,4']bipyridinyl-1'-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-l-propanol (2.02 ml, 22.4 mmol) in acetonitrile (100 mL) was heated to reflux for 2 days. After 35 cooling, the solvent was removed in vacuo and the WO98/57940 PCT/US98/12668 -73 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. 5 To a solution of 1-(3-hydroxypropyl)-4-[pyrid-2 yl]pyridinium bromide (8 g) in 100 mL EtOH was added NaBH 4 (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 10 removed in vacuo and the residue was purified by column chromatography over silica gel with 1:4 MeOH/EtOAc followed by 1:4 (2M NH 3 in MeOH) /EtOAc as the eluting system (Rf = 0.6, (2M NH 3 in MeOH) /EtOAc = 1:4) to obtain 3-(3',6'-dihydro-2'-H-[2,4']bipyridinyl-1'-yl) 15 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 20 added 0.5 g of Pearlman's catalyst. The suspension was hydrogenated under 80 psi at 500C 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 CHC1 3 (7 X 40 ml), 25 dried over Na 2
SO
4 . 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'H [2,4']bipyridinyl-1'-yl)-propyl]-ester 30 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 K 2 C0 3 (23.8 mg, 0.52 WO98/57940 PCT/US98/12668 -74 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 5 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%). 10 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 15 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. 171-1730C; Anal. Calcd. For C 27
H
29
N
3 0F 2 '0.27CHC1 3 : C, 55.16; H, 4.97; N, 7.08. Found: C, 55.17; H, 4.98; N, 20 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 25 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 30 9) with 50% solution of NaOH. The aqueous layer was extracted several times with EtOAc, dried over K 2 C0 3 , filtered and the solvent was evaporated. 1-(2 carboxamidophenyl)piperazine was obtained as an off white solid (1.2 g, 73%). It was used in the next step WO98/57940 PCTIUS98/12668 -75 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 5 To a solution of l-( 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 10 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=1:3 ) to obtain (+)-1-{3-{3,4,5 15 trifluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid{3 [4-(2-carbomoyl-phenyl)-piperazin-l-yl]-propyl}-amide (135 mg, 79%). The compound was dissolved in CH 2
CI
2 (3 mL) and was treated with IN HC1 in ether (1 mL). The solvent was removed in vacuo to give the corresponding 20 hydrochloride salt as a yellow solid. M. P. 164-168 0 C; [a]D = +50.5, (c = 0.28, MeOH); Anal. Calcd. For
C
24
H
28
N
5 0 4
F
3 C1 2 '0.25 CHC1 3 : C, 47.89; H, 4.68; N, 11.51. Found: C, 48.18; H, 5.03; N, 11.14. 25 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 30 mmol) in 1,4-dioxane (100 ml) at room temperature, were added piperazine (15.3 g, 178 mmol) and K 2 CO3 (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 WO98/57940 PCT/US98/12668 -76 piperazine were removed in vacuo and heating with a hot water bath. The residue was dissolved in IN NaOH solution and extracted with CH 2 Cl 2 (6 X 30 ml), dried over Na 2
SO
4 . The solvent was removed in vacuo to obtain 5 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 10 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 15 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=1:3 ) to obtain 2 -[4-(3-{[4-(3,5-difluoro 20 phenyl)-2-oxo-oxazolidine-3-carbonyl]-amino}-propyl) piperazin-l-yl]-benzoic acid methyl ester (31 mg, 69%). The compound was dissolved in CH 2
CI
2 (3 mL) and was treated with IN HC1 in ether (1 mL). The solvent was removed in vacuo to give the corresponding hydrochloride 25 salt as a yellow solid. M. P. 93-960C; [aIU]D = +45.3, (c = 0.29, MeOH); Anal. Calcd. For C 25
H
30
N
4 0sF 2 C1 2 .0 .58 CH 2 C1 2 : C, 50.48; H, 5.16; N, 9.20. Found: C, 50.46; H, 5.56; N,8.91. 30 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 l-(4-amino-butyl)-4-phenyl-piperidine (35 mg, 0.151 mmol) in 10 mL of THF, 4-(3,5- WO 98/57940 PCT/US98/12668 -77 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 5 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=1:3 ) to obtain 4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3 carboxylic acid [4-(4-phenyl-piperidin-l-yl)-butyl] 10 amide (42 mg, 83%). The compound was dissolved in CH 2 C1 2 (3 mL) and was treated with IN HC1 in ether (1 mL). The solvent was removed in vacuo to give the corresponding hydrochloride salt as a yellow solid. M.P. 80-840C; Anal. Calcd. For C 25
H
30
N
3 0 3
F
2 C1 -0.5 CH 2 C1 2 : C, 57.09; H, 15 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) 20 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 00C. The reaction mixture was stirred at room temperature for 10 25 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 30 purification. b. 2-Amino-l-(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 LiAlH 4 in ether (40 mL, 40 WO98/57940 PCTIUS98/12668 -78 mmol) dropwise at 0OC. The resulting yellow solution was then stirred at room temperature for 2 h. The reaction mixture was cooled to 0 0 C and then carefully quenched sequentially with 1.5 mL of water, 1.5 mL of 3N NaOH 5 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, 10 dried over MgSO 4 , 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. [El-(3,4-Difluorophenyl)-2-hydroxy-ethyl]-carbamic 15 acid-tert-butyl ester To a solution of 2-amino-l-(3,4-difluorophenyl)-ethanol (3.2 g, 19.8 mmol) in CHC1I 3 (15 mL) at O'C was added a solution of di-tert-butyl dicarbonate (4.36 g, 20.0 mmol) in CHC1 3 (10 mL) in one portion and the resulting 20 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 25 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-ethyll 30 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 mL of water. The biphasic mixture was extracted with 100 mL of Et20, washed with 35 brine, filtered and the solvent was removed in vacuo.
WO98/57940 PCT/US98/12668 -79 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%). 5 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 10 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 15 mmol) in 20 mL of THF, cooled at -78 0 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/CH 2 Cl 2 followed by CH 2 C1 2 (Rf= 0.4, CH 2
CI
2 ) to 20 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 25 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 30 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 35 = 0.4, 1:1 MeOH/EtOAC) to obtain 1-(3-{[5-{3-(3,4- WO 98/57940 PCTIUS98/12668 -80 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 5 125oC; Anal. Calcd. for C 26
H
8 oN 3 0 4
F
2 C1 2 .0.2 H 2 0: 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 10 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 15 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 20 MeOH/EtOAC) to obtain 4-(3-Chloro-4-fluoro-phenyl)-2 oxo-oxazolidine-3-carboxylic acid [3-(4,4-diphenyl piperidin-l-yl)-propyl]-amide as white foam (wt = 0.03 g). It was converted into its hydrochloride salt. M.P. 112-115oC; Anal. Calcd. for C 30
H
32
N
3 0 3 C1 2 F.0.5 CHC1 3 : C, 25 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 30 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 CH 2 C1 2 (20 ml) at room temperature, was added l,l'-thiocarbonyldiimadazole (755 WO 98/57940 PCT/US98/12668 -81 mg, 3.81 mmol). The resulting solution was heated by a pre-heated oil-bath (110oC) to reflux for 10 h after which the reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The 5 residue was purified by column chromatography over silica gel with CH 2 C1 2 as the eluting system (Rf = 0.68,
CH
2 Cl 2 :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 10 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 15 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 0 C over a period 20 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/CH2Cl 2 , then 3:7 hexane/CH 2 C1 2 followed by
CH
2
CI
2 (Rf= 0.50) to obtain 4-(3,4-difluorophenyl)-2 25 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-1 yl)-propyl] -amide 30 To a solution of l-( 3 -amino-propyl)-4-(4-methyl)-phenyl 4
-(
2 -methyl)-phenyl-piperidine (60 mg, 0.186 mmol) in 10 mL of THF,4-(3,4-Difluorophenyl)-2-thione-oxazolidine-3 carboxylic acid-4-nitro-phenyl ester(30 mg, 0.079 mmnol) was added and the resulting yellow solution was stirred 35 under argon atmosphere for 2 h at room temperature. The WO98/57940 PCT/US98/12668 -82 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=1:3 ) to obtain 4 -(3,4-Difluoro-phenyl)-2 5 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 CH 2 C1 2 (3 mL) and was treated with 1N HC1 in ether (1 mL). The solvent was removed in vacuo to give the corresponding hydrochloride salt as a 10 yellow solid. M.P.= 132-136 0 C; Anal. Calcd. for
C
32
H
36
N
3 0 2 SCl-0.60 CH 2 C1 2 : 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 15 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/H 2 0 (10 ml) at room temperature, was 20 added carbon disulfide (3 ml, 50 mmol). The resulting solution was heated by a pre-heated oil-bath (110 0 C) to reflux for 20 h after which the reaction mixture was cooled to room temperature and extracted with CH 2 C1 2 (3 X 30 ml), dried over Na 2
SO
4 . The solvent was removed in 25 vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/CH 2 Cl 2 followed by CH 2 C1 2 as the eluting system (Rf = 0.09,
CH
2 Cl 2 :hexane = 7:3) to obtain 4(S)-phenyl-thiazolidine 2-thione (170 mg, 9%). 30 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- WO98/57940 PCTIUS98/12668 -83 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 5 another round bottom flask containing a solution of 4 nitrophenylchloroformate (217 mg, 1.04 mmol) in 20 mL of THF and cooled at -78 0 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 10 chromatography on silica gel with 1:1 hexane/CH 2 Cl 2 then 3:7 hexane/CH 2 Cl 2 followed by CH 2 C1 2 (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%). 15 c. 4-phenyl-2-thioxo-thiazolidine-3-carboxylic acid [3 (3',4',5',6'-tetrahydro-2'H-[2,4']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 20 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 25 over silica gel with 1:1 hexane/EtOAc followed by 1:9 MeOH/EtOAc (Rf= 0.21, MeOH/EtOAc=1:3 ) to obtain 4-(3,4 Difluoro-phenyl)-2-thioxo-thiazolidine-3-carboxylic acid [3-(3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-l'-yl) propyl]-amide (10 mg, 14%). The compound was.dissolved 30 in CH 2 C1 2 (3 mL) and was treated with 1N HC1 in ether (1 mL). The solvent was removed in vacuo to give the corresponding hydrochloride salt as a yellow solid. M.P.= 67-70 0 C; Anal. Calcd. for C 23
H
3 3N 4 0S 2 Cl 2 .0.67 CHC1 3 : C, 47.82; H, 5.37; N, 9.42. Found: C, 47.85; H, 6.12; N, WO 98/57940 PCT/US98/12668 -84 6.52. Example 13: (-)-2-Oxo-8,8a-dihydro-3aH-1-(S)-oxa-3-(R) aza-cyclopent[1]indene-3-carboxylic acid-[3-(1-4-cyano 5 4-phenyl-piperidin-1-yl)-propyl-amide (Scheme 10) a. Synthesis of (+)-3,3a,8,8a-tetrahydro-1(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 10 bottom flask equipped with a stirring bar, was added 1,l'-carbonyldimidazole (1.20 g, 7.4 mmol) at room temperature. The resulting solution was heated by a pre heated oil-bath (110 0 C) to reflux for 10 h after which the reaction mixture was cooled to room temperature and 15 the formation of white crystal was observed. The white crystal was filtered off , washed with minmum CH 2 C1 2 (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 %).[a]D = -71.1 (c = 0.28, 20 acetone). M.P. 203-204 0 C. Anal. Calcd. for C 1 oH 9 N0 2 : C, 68.56; H, 5.18; N, 8.00. Found: C, 68.44; H, 5.12; N, 7.98. b.2-Oxo-1,3a,8,8a-tetrahydro-2H-3-aza cyclopenta[a]indene-3-carboxylic acid 4-nitro-phenyl 25 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-l(R)-oxa-3(S)-aza-cyclopenta[la]inden-2-one (420 mg, 2.40 mmol) in THF was added dropwise via an 30 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 WO98/57940 PCTIUS98/12668 -85 THF and cooled at -78 0 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 5 followed by 3:2 hexane/EtOAc (Rf= 0.51, hexane/EtOAc=l:l) to obtain a white solid (680 mg, 83%). c. (-)-2-Oxo-8,8a-dihydro-3aH-1-(S)-oxa-3-(R)-aza cyclopent[1]indene-3-carboxylic acid-[3-(1-4-cyano-4 phenyl-piperidin-1-yl)-propyl-amide 10 To a solution of l-(3-amino-propyl)-4-cyano-4-phenyl piperidine (25 mg, 0.103 mmol) in 10 mL of THF, 2-Oxo 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 15 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 (Rf= 0.35 ) to obtain (-)-2-Oxo-8,8a-dihydro-3aH-1-(S)-oxa-3-(R)-aza 20 cyclopent[l]indene-3-carboxylic acid-[3-(l-4-cyano-4 phenyl-piperidin-l-yl)-propyl-amide (19 mg, 35%). The compound was dissolved in CH 2
CI
2 (3 mL) and was treated with 1N HC1 in ether (1 mL). The solvent was removed in vacuo to give the corresponding hydrochloride salt as a 25 white solid. M. P. 98-1020C; [a]D = -96.5, (c = 0.21, MeOH); Anal. Calcd. For C 26
H
29
N
4 0 3 Cl- 0.48 CH 2 C12: C, 60.96; H, 5.79; N, 10.74. Found: C, 60.94; H, 6.69; N, 8.02. 30 Example 14: 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3 carboxylic acid {3-[2-methyl-4-(2-nitro-phenyl) piperazin-1-yl)-propyl}-amide a. (S)-(+)-3-methyl-1-(2-nitrophenyl)-piperazine To a solution of 2-bromo-nitrobenzene (0.6 g, 3.0 mmol) WO 98/57940 PCTIUS98/12668 -86 in 1,4-dioxane (15 mL) was added (S)-(+)-2 methylpiperazine (0.5 g, 0.5 mmol) and powdered K 2
CO
3 (15.0 mmol, 1.5 g) and the resulting suspension was heated at reflux for 10 h. After the suspension was 5 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 10 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 carboxylic acid {3-[2-methyl-4-(2-nitro-phenyl) 15 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) 20 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=1:9 (Rf= 0.58, 25 MeOH:EtOAc=1:3 ) to obtain 4-(3,4-Difluoro-phenyl)-2 oxo-oxazolidine-3-carboxylic acid {3-[2-methyl-4-(2 nitro-phenyl)-piperazin-l-yl)-propyl}-amide (55 mg, 87%). The compound was dissolved in CH 2 Cl 2 (3 mL) and was treated with 1N HC1 in ether (1 mL). The solvent 30 was removed in vacuo to give the corresponding hydrochloride salt as a pale yellow solid. M. P. 115 119 0 C; [a]D = +38.3, (c = 0.22, CH 2 Cl 2 ); Anal. Calcd. For
C
24
H
28
N
5 0 5
F
2 C1*. 0.72 C 6
H
12 : C, 56.50; H, 6.38; N, 11.63. Found: C, 56.63; H, 6.35; N, 10.08.
WO 98/57940 PCT/US98/12668 -87 Example 15: 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3 carboxylic acid {3-[4-methyl-4-phenyl-piperidin-1-yl) propyl}-amide a. 1-Benzyl-4-methyl-4-piperidinol 5 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 0OC over 15 min. The reaction mixture was allowed to warm to room temperature over 3 h and then quenched with 30 mL of 10 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
SO
4 , filtered and the solvent was removed in vacuo to obtain yellow gum. It 15 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 20 To a solution of l-benzyl-4-methyl-4-piperidinol (3.6 g, 17.5 mmol) in 75 mL of benzene was added AlC1 3 (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 25 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 Na 2 S0 4 , filtered and the solvent was removed in 30 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 WO98/57940 PCT/US98/12668 -88 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. 5 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 10 carboxylic acid {3-[4-methyl-4-phenyl-piperidin-1-yl) propyl}-amide To a solution of l-(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 15 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 20 followed by MeOH:EtOAc=1:19 (Rf= 0.45, MeOH:EtOAc=1:3 ) 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 CH 2
CI
2 (3 mL) and was treated with 1N HC1 in ether (1 25 mL). The solvent was removed in vacuo to give the corresponding hydrochloride salt as a pale yellow solid. M. P. 176-1780C; [a]D = +76.9, (c = 0.23, MeOH); Anal. Calcd. For C 25
H
30
N
3 0 3
F
2 C1- 0.60 CH 2 C1 2 : C, 56.32; H, 5.94; N, 7.70. Found: C, 56.30; H, 5.80; N, 7.35. 30 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) WO 98/57940 PCTIUS98/12668 -89 a. 2-(3,4-Difluorophenyl)propan-2-ol To a solution of ethylmagnesium bromide in ether (38.0 mL, 38.0 mmol) at 0 0 C, was added a solution of 3',4' difluoroacetophenone (5.0 g, 32.0 mmol) in diethyl ether 5 (35mL). The reaction mixture was stirred at 0 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 10 Rochelle's salt followed by brine and the organic layer was dried over Na 2
SO
4 . 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 15 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 20 60 0 C. TLC analysis showed disappearance of the starting material. After cooling, the solution was extracted with EtOAc, washed with saturated NaHC03, dried over Na 2
SO
4 , filtered and the solvent was removed in vacuo. 1,2-difluoro-4-isopropenyl-benzene was obtained as a 25 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 CH 2 C1 2 (50 mL) and 50 mL of phosphate buffer (made by dissolving 0.3 g of NaHP0 4 30 and 0.35 g of NaH 2
PO
4 in 50 mL water, pH = 8) at 0 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 35 overnight. It was extracted with CH 2 C1 2 , washed with WO 98/57940 PCT/US98/12668 -90 sat. Na 2 S20 4 solution followed by water. The organic layer was finally washed with sat. NaHCO 3 , separated, dried over Na 2
SO
4 , filtered and solvnt was removed in vacuo. 2-(3,4-Difluorophenyl)-2-methyl-oxirane was 5 obtained as a pale yellow oil (0.65 g, 74% yield). It was used in the next step without purification. d. 1-Amino-2-(3,4-difluorophenyl)-propan-2-ol and 2 Amino-2-(3,4-difluorophenyl)-propan-1-ol To a solution of 2-(3,4-difluorophenyl)-2-methyl-oxirane 10 (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 15 over Na 2
SO
4 , filtered and the solvent was removed in vacuo. The light bron oil that was obtained was a 10:1 mixture of 1-azido-2-(3,4-difluorophenyl)-propan-2-ol and 2-azido-2-(3,4-difluorophenyl)-propan-l-ol (crude wt 2.0 g). It was dissolved in 40 mL of diethyl ether, 20 cooled to 0 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 00C and then carefully quenched sequentially with 0.8 mL 25 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 30 previous filtrate, dried over MgSO 4 , 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-l-ol was obtained as a yellow glassy syrup (1.16 g, 87%) which was used in the next WO98/57940 PCT/US98/12668 -91 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 5 To a solution of l-amino-2-(3,4-difluorophenyl)-propan 2-ol and 2-amino-2-(3,4-difluorophenyl)-propan-l-ol (1.2 g, 6.4 mmol) in CHC1 3 (50 mL) at 0oC was added a solution of di-tert-butyl dicarbonate (1.74 g, 7.9 mmol) in CHC1 3 (10 mL) in one portion and the resulting 10 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 15 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 20 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 25 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 Na2SO4, filtered and the solvent was removed in 30 vacuo. The two diastereomers were separated by column chromatography over silica gel. The first diastereomer that came out was 4-(3,4-difluorophenyl)-4-methyl oxazolidin-2-one (0.05 g, Rf = 0.3, 3:2 hexane-EtOAc) and the second isomer was 5-(3,4-difluorophenyl)-5- WO98/57940 PCTIUS98/12668 -92 methyl-oxazolidin-2-one (0.61 g, Rf = 0.2, 3:2 hexane EtOAc). g. 4-(3,4-Difluorophenyl)-4-methyl-2-oxo-oxazolidine-3 carboxylic acid-4-nitro-phenyl ester 5 To a a solution of 4-(3,4-Difluorophenyl)-4-methyl 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 10 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 0 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 15 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 20 carboxylic acid-4-nitro-phenyl ester To a a solution of 4-(3,4-Difluorophenyl)-4-methyl oxazolidin-2-one (0.61 g, 2.86 mmol) in 20 mL THE was added 95% NaH (0.07 g, 3.0 mmol) in one portion. The resulting suspension was stirred at room temperature for 25 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 0 C, over a period of 15 min. The stirring was continued for 1 h after which 30 the solvent was removed and the residue was purified by column chromatography on silica gel with 3:2 hexane/EtOAc (Rf= 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%). 35 i. 4-(3,4-Difluorophenyl)-4-methyl-2-oxo-oxazolidine-3- WO 98/57940 PCT/US98/12668 -93 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 5 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 10 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 15 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 0 C; Anal. Calcd. for C 33
H
38
N
3 0 3
F
2 C1.l.0 CH 2 C1 2 : C, 59.79; H, 5.90; N, 6.15. Found: C, 59.40; H, 5.99; N, 5.92. 20 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) 25 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 30 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 WO98/57940 PCTIUS98/12668 -94 = 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-l yl]propyl}amide as a pale yellow glassy oil (0.06 g, 5 85%) as a viscous oil. It was converted into its hydrochloride salt. M.P. = 82-85OC; Anal. Calcd. for
C
34
H
40
N
3 0 4
F
2 C1.0.7 CH 2 C1 2 : C, 60.61; H, 6.07; N, 6.11. Found: C, 60.73; H, 6.46; N, 6.12. 10 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-1-ol To a solution of 3,4-difluorobenzaldehyde (5.0 g, 35.2 15 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 0 C. The reaction mixture was stirred at 0 0 C for 1 h when TLC analysis indicated that the reaction was complete (Rf = 0.5, 8:1 hexane/EtOAc). 20 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 Na 2
SO
4 . The solvent was removed in vacuo after filtration and 1-(3,4-difluorophenyl)propan-l-ol was 25 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 30 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 CH 2 C1 2 was added followed by a solution of 1-(3,4-difluoro-phenyl)propan 1-ol (5.0 g, 29.1 mmol) in 10 mL of CH 2 C1 2 and the WO98/57940 PCT/US98/12668 -95 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 5 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 l-(3,4-difluorophenyl)propan-l-one as a pale yellow oil (3.4 g, 69% yield). It was used in the next step without 10 purification. c. 1-(3,4-Difluorophenyl)-2-hydroxy-propan-1-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 0OC and 1-(3,4 15 difluorophenyl)-2-hydroxy-propan-l-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 20 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 Na 2
SO
4 . After filteration, the 25 solvent was removed in vacuo to get 1-(3,4 difluorophenyl)-2-hydroxy-propan-l-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 30 for 3 h, TLC analysis indicated that the reaction was complete. Acetone was removed in vacuo and after basification with saturated NaHCO 3 , the residue was extracted in EtOAc and was washed with brine. The organic layer was separated, dried over Na 2
SO
4 and then 35 filtered. The solvent was removed in vacuo and the WO98/57940 PCT/US98/12668 -96 residue was purified by silica gel chromatography (Rf = 0.4, 3:2 hexane/EtOAc) to obtain l-(3,4-difluorophenyl) 2-hydroxy-propan-l-one as a pale yellow oil (3.3 g, 51% yield over two steps). 5 d. 1-(3,4-Difluorophenyl)-2-hydroxy-propan-1-one-oxime To a well stirred solution of 1-(3,4-difluorophenyl)-2 hydroxy-propan-l-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 10 solution was stirred overnight at room temperature. The solvent was evaporated and the residue was extracted with CH 2 C1 2 . The organic layer was washed with sat. NaHCO 3 , separated, dried over Na2SO4 and then filtered. The solvent was removed in vacuo to obtain 1-(3,4 15 difluorophenyl)-2-hydroxy-propan-l-one-oxime as an orangish yellow oil (5.8 g, 97%). It was used in the next step without purification. e. 1-Amino-1-(3,4-difluorophenyl)-propan-2-ol To a well stirred solution of l-(3,4-difluorophenyl)-2 20 hydroxy-propan-1-one-oxime (5.8 g, 28.4 mmol), was added a 1.0 M solution of LiAlH 4 in ether (90 mL, 90 mmol) dropwise at 0 0 C. The resulting yellow solution was then stirred at room temperature for 2 h. The reaction mixture was cooled to 0 0 C and then carefully quenched 25 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 30 filtered and was combined with the previous filtrate, dried over MgSO 4 , filtered and the solvent was removed in vacuo. l-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. 35 f. [1-(3,4-Difluorophenyl)-2-hydroxy-propyl]-carbamic WO98/57940 PCT/US98/12668 -97 acid-tert-butyl ester To a solution of l-amino-l-(3,4-difluorophenyl)-propan 2-ol (3.5 g, 19.1 mmol) in CHC1 3 (15 mL) at 0 0 C was added a solution of di-tert-butyl dicarbonate (5.1 g, 5 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 10 (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 [l-(3,4-difluorophenyl)-2 hydroxy-propyl]-carbamic acid-tert-butyl ester (0.43 g, 15 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 0 C (warm water bath) and then quenched carefully with ice. The biphasic mixture was extracted with 100 mL of EtOAc, washed with brine, dried 20 over Na 2
SO
4 , 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 25 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) 30 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 {[a]D = + 36.4 (c = o.25, acetone)} and 35 15.6 min {[a]D = - 30.8 (c = 0.20, acetone)}, WO98/57940 PCT/US98/12668 -98 respectively. The retention times for the two isomers of the cis-oxazolidinone were 13.7 min {[a]D = + 65.8 (c = o.92, acetone)} and 19.9 min {[a]D = - 65.8 (c = 0.74, acetone)} respectively. The next steps may be performed 5 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 10 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. 15 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 -780C, over a period of 20 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/CH 2 Cl 2 followed by CH 2 C1 2 (Rf= 0.4, CH 2 C 2) to obtain 4-(3,4-difluorophenyl)-5-methyl-2-oxo 25 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 30 mmol, 55.0 mL of 2.0 M solution) in 150.0 mL THF at 0 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 NH 4 C1 solution. The organic layer was WO 98/57940 PCT/US98/12668 -99 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 Na 2
SO
4 . The solution was filtered and the solvent was removed in 5 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 10 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 Et 2 0 (2 X 15 50 mL). The organic extracts were combined, washed with brine and the oraganic layer was dried over Na 2
SO
4 . 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 20 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 25 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-l-yl] 30 propylamine by the route described previously in Example 1. j. cis (+)-(4-(3,4-Difluorophenyl)-5-mnethyl-2-oxo oxazolidine-3-carboxylic acid{3-[4-(4-fluorophenyl) 35 piperidin-l1-yl]propyl})amnide WO 98/57940 PCT/US98/12668 -100 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) 5 (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 10 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-l 15 yl]propyl}amide as a pale yellow glassy oil(0.03 g, 66%). It was converted into its hydrochloride salt. M. P. 108-112 0 C; [O]D = +56.7, (c = 0.20, MeOH); Anal. Calcd. For C 25
H
29
N
3 0 3
F
3 Cl 0.36 CH 2 C12: C, 56.14; H, 5.52; N, 7.75. Found: C, 56.17; H, 5.90; N, 7.20. 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 25 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 (+) 30 4-(3,4-difluorophenyl)-5-methyl-2-oxo-oxazolidine-3 carboxylic acid{3-[4-(4-fluorophenyl)-piperidin-l yllpropyl}amide in 70% yield. It was converted into hydrochloride salt. M.P. = 80-83 0 C (shrinks around 58 0 C); [C]D = + 27.4 (c = WO 98/57940 PCT/US98/12668 -101 0.49, MeOH); Anal. Calcd. for C 25
H
29
N
3 0 3
F
3 C1. 1.0 H 2 0: 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 5 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 LiAlH 4 (0.48 g, .12.5 mmol) in THF (30 mL) in a round bottom flask fitted with 10 a condenser was added 3,4-difluorophenyl alanine (1.0 g, 5.0 mmol) in small portions at 0 0 C. The resulting grey suspension was then heated to reflux for 2 h. The reaction mixture was cooled to 0 0 C and then carefully quenched sequentially with 0.5 mL of water, 0.5 mL of 3N 15 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, 20 dried over MgSO 4 , filtered and the solvent was removed in vacuo. 2-Amino-3-(3.4-difluoro)-phenyl-propan-l-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 25 acid-tert-butyl ester To a solution of 2-amino-3-(3.4-difluoro)-phenyl-propan 1-ol (0.5 g, 2.62 mmol) in CHCl 3 (20 mL) at 00C was added a solution of di-tert-butyl dicarbonate (0.64 g, 2.90 mmol) in CHC1 3 (10 mL) in one portion and the 30 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 35 tert-butyl ester as white solid (0.64 g, 99%).
WO 98/57940 PCT/US98/12668 -102 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 5 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, 10 filtered and the solvent was removed in vacuo. The gummy residue thus obtained was purified by column chromatography over silica gel (Rf = 0.25, 3:2 hexane EtOAc) to obtain (+)-4-(3,4-difluoro-benzyl)-oxazolidin 2-one as a white solid (0.32 g, 76%). 15 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 20 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 25 mmol) in 20 mL of THF and cooled at -780C 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/CH 2 Cl 2 followed by CH 2 C1 2 (Rf= 0.4, CH 2 C1 2 ) to 30 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-oxo-oxazolidine-3 carboxylic acid {3-[4-(2-carbamoylphenyl)-piperazin-1 35 yl]-propyl}amide WO 98/57940 PCT/US98/12668 -103 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 5 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= 0.70, 10 MeOH/EtOAc=1:3 ) 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 CH 2
CI
2 (3 mL) and was treated with 1N HC1 in ether (1 mL). The solvent 15 was removed in vacuo to give the corresponding hydrochloride salt as a yellow solid. M. P. 82-85oC; [o]D = +34.3, (c = 0.49, MeOH); Anal. Calcd. For
C
2 sH 31 NsO 4
F
2 C1 2 *3.5 H 2 0: C, 47.10; H, 6.01; N, 10.99. Found: C, 47.12; H, 5.94; N,10.94. 20 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 25 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 30 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 WO98/57940 PCT/US98/12668 -104 into its hydrochloride salt. M.P. 80-85oC; [a]D = + 51.6, (c = 0.11, MeOH); Anal. Calcd. for
C
25
H
28
N
3 0sC1F 2 .0.5 CHC1 3 : C, 52.48; H, 4.92; N, 7.20. Found: C, 52.54; H, 5.13; N, 7.27. 5 Example 22: 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3 carboxylic acid{3-[4-(4-fluoro-2-methyl-phenyl) piperidin-1-yll-propyl} amide a. 1-Benzyl-4-(5-fluoro-2-methyl)-phenyl-4-piperidinol 10 To a cooled solution of n-BuLi (6.0 mL, 15.0 mmol) in 20 mL THF was added 2-Bromo-5-fluoro toluene (1.9 mL, 15.0 mmol) dropwise at -78 0 C over 15. min. The reaction mixture was allowed to warm to 0 0 C over 1 h and then cooled to -78 0 C. l-Benzyl-4-piperidone (1.48 mL, 8.0 15 mmol) was added the white slurry and the reaction mixture was warmed to 0 0 C over 2 h. The reaction was then quenched with 10 mL of sat. NH 4 Cl solution. The oragnic layer was extracted with diehtyl ether (2 X 50 mL) and the combined organic layer was washed with brine 20 (100 mL). The organic layer was separated, dried over Na 2
SO
4 , 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 1-benzyl-4-(5-fluoro-2 25 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 30 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). 35 The organic layer was washed with brine (30 mL). The WO98/57940 PCT/US98/12668 -105 organic layer was separated, dried over Na 2
SO
4 , filtered and the solvent was removed in vacuo to obtain l-benzyl 4-(4-Fluoro-2-methyl)-phenyl-l,2,3,6-tetrahydropyridine as a pale yellow oil (0.9 g, 87% yield). It was used in 5 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-l,2,3,6-tetrahydropyridine (0.9 g, 3.2 10 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 15 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. 20 d. 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3 carboxylic acid{3-[4-(4-fluoro-2-methyl-phenyl) piperidin-l1-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 25 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 30 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. 35 M.P. = 60-64oC; [a]D= + 36.6 (c = 0.15, MeOH); Anal.
WO98/57940 PCT/US98/12668 -106 Calcd. for C 25
H
29
N
3 0 3
F
3 C1.0.25 CHCl 3 : C, 55.97; H, 5.44; N, 7.76. Found: C, 55.91; H, 5.66; N, 7.87. Preparation of Side Chains. 5 1. 3-(4,4-Diphenylpiperidin-1-yl)propylamine. a. 4,4-Diphenylpiperidine hydrochloride. A mixture of 4-piperidone monohydrate hydrochloride (15.0 g, 0.0976 mol) and AIC 3 (130 g, 0.976 mol, 10.0 eq) in anhydrous benzene (600 mL) were stirred at reflux for 4 hours. 10 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. 15 b. 3-(4,4-Diphenylpiperidin-1-yl)propionitrile. To a suspension of 4,4-diphenylpiperidine hydrochloride (0.195 g, 0.712 mmol) in EtOH (1.5 mL) was added Et 3 N (0.25 mL, 1.8 mmol, 2.6 eq) followed by acrylonitrile (0.13 mL, 2.01 mmol, 2.8 eq). The resulting solution 20 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 (MgSO ) and concentrated to give 170 mg (87%) of a tan solid, which was 25 characterized spectroscopically and used in the next reaction without purification. c. 3-(4,4-Diphenylpiperidin-1-yl)propylamine. To a stirred solution of 3-(4,4-diphenylpiperidin-l yl)propionitrile (2.00 g, 6.89 mmol) in anhydrous THF 30 (20 mL) under argon was added a solution of BH 3 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 HC1 (6 N, 50 mL) was added and stirring was continued for 1 hour. The mixture was WO98/57940 PCT/US98/12668 -107 basified to pH 9 by addition of 6 N aq. NaOH, extracted with CH 2 C1 2 (3 X 10 mL), dried (MgS04) and concentrated. The residue was purified by flash chromatography (SiO 2 , EtOAc-MeOH-isopropylamine 9:1:0 to 4:1:0.2) to give 1.35 5 g (66%) of tan solid, which was characterized spectroscopically. 2. .3-(4-Cyano-4-phenylpiperidin-1-yl)propylamine. a. 3-(4-Cyano-4-phenylpiperidin-1-yl)propylphthalimide. 10 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 oC for 8 h. About 80% of the solvent 15 was evaporated at reduced pressure, the residue was diluted with dichloromethane (1 L) and washed with brine (3 X 300 mL) and dried (Na 2
SO
4 ). Solvent was evaporated from the dichloromethane solution and the residue was treated with isopropanol (400 mL) and cooled. The pale 20 yellow crystalline product formed was filtered, washed with ice-cold isopropanol and dried (168.6 g, 90%); M.p. 96-98 oC. b. 3-(4-Cyano-4-phenylpiperidin-1-yl)propylamine. To a solution of 3-(4-cyano 25 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 30 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 35 product as an oil (70 g, 96%).
WO 98/57940 PCT/US98/12668 -108 3. 3-(4-Methoxycarbonyl-4-phenylpiperidin-1 yl)propylamine. a. 4-Methoxycarbonyl-4-phenylpiperidine. To a 5 stirred solution of H 2
SO
4 (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 10 the residue was poured into a mixture of ice and 6 N NaOH. The pH was adjusted to 10-11 by adding more 6 N NaOH and extracted with CH 2 C1 2 (3 X 150 mL). The combined CH2C 2 extracts were dried (MgSO 4 ) and the solvent evaporated to leave the desired product as a 15 viscous oil. The product (20.2 g, 92%) was used without further purification. b. 3-(4-Methoxycarbonyl-4-phenylpiperidin-1 yl)propylamine. A mixture of 4-methoxycarbonyl-4-phenylpiperidine (8.5 20 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 25 with ice-cold 6 N NaOH (400 mL) and extracted with
CH
2 C1 2 (4 X 120 mL). Solvent was evaporated from the combined dried (K 2
CO
3 ) extracts and the residue was purified by column chromatography on silica gel using CHC1 3 /MeOH/2 M NH 3 in MeOH (20:2:1) as the eluent to 30 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]pyridiniua bromide hydrobromide.
WO98/57940 PCTIUS98/12668 -109 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 oC for 1 h. After cooling, the white solid that came 5 out was filtered, washed with Et20 and dried. The mother liquor was concentrated to remove Et20 and then heated at 90-95 0 C for 4 h. The solvent was evaporated and the white residue was triturated with Et 2 O (100.0 mL) and filtered. The combined weight of the salt was 10 11.6 g (97%). b. 3-(3',6'-Dihydro-2'-H-[2,4']bipyridinyl-1'-yl) propylamine. To a solution of l-(3-aminopropyl)-4-[pyrid-2 yl]pyridinium bromide hydrobromide (0.66 g, 1.75 mmol) 15 in 20.0 mL MeOH was added NaBH 4 (0.101 g, 2.62 mmol) in small portions. The reaction mixture was stirred for 30 min and then quenched with 6M HC1 solution. The solution was concentrated to 20.0 mL and basified with 50% NaOH solution to pH 12. Extracted with CHC1 3 (5 x 20 30.0 mL), dried over MgSO 4 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. c. 3-Aminopropyl-4-(2-pyridyl)piperidine. 25 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 30 through a pad of celite and the solvent was removed. The residue was purified by column chromatography over silica gel using CH 2 Cl 2 /methanol/2M NH 3 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%). 35 WO 98/57940 PCT/US98/12668 -110 5. 3-(4-Acetoxy-4-phenylpiperidin-1-yl)propylamine. a. N-Benzyloxycarbonyl-3-(4-hydroxy-4-phenylpiperidin-1 yl)propylamine. A mixture of 4-hydroxy-4-phenylpiperidine (5 g, 0.0282 5 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 10 extracted with CH 2 C1 2 (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 tlc and IH-NMR and was used as such without any further purification. 15 b. N-Benzyloxycarbonyl-3-(4-acetoxy-4-phenylpiperidin-1 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 oC, sodium hydride (60% 20 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 25 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 H-NMR showed this product to be pure and was used in the next.step without 30 any further purification. c. 3-(4-Acetoxy-4-phenylpiperidin-1-yl)propylamine. A mixture of N-benzyloxycarbonyl-3
(
4 -acetoxy-4-phenylpiperidin-l-yl)propylamine (3.0 g, 35 7.3 mmol) and 10% Pd-C (0.3 g) in lM ammonia in WO 98/57940 PCT/US98/12668 -111 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 'H-NMR 5 showed it to be very pure and was used in the next step without any purification. 6. 3-(4-Cyano-4-phenylpiperidin-1-yl)-2 hydroxypropylamine. 10 a. 3 -(4-Cyano-4-phenylpiperidin-1-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 oC for 72 15 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%). 20 b. 3-(4-Cyano-4-phenylpiperidin-1-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) 25 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%). 30 7. 3-(4-Cyano-4-phenylpiperidin-1-yl)-2 fluoropropylamine. a. 3 -(4-Cyano-4-phenylpiperidin-1-yl)(2 fluoropropyl)phthalimide A mixture of 3-(4-cyano-4-phenylpiperidin-l-yl)-(2 35 hydroxypropyl)phthalimide (2.60 g, 6.1 mmol) and WO98/57940 PCT/US98/12668 -112 diethylaminosulfur trifluoride (DAST, 1.96 g, 12.2 mmol) in benzene (100 mL) was stirred and heated at 70 0C under argon atmosphere for 24 h. The solvent was evaporated under reduced pressure and the residue was 5 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-1-yl)-2 10 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, 15 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. 20 a. 3-[4-(2-Pyridyl)-piperidin-1-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 25 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 30 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 BH 3 in WO 98/57940 PCT/US98/12668 -113 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 HC1 (6 N, 50 mL) was added and stirring was continued for 1 hour. The mixture was 5 basified to pH 9 by addition of 6 N aq. NaOH, extracted with CH 2 C1 2 (3 X 10 mL), dried (potassium carbonate) and the solvent evaporated to leave the product as a viscous oil (0.42 g, 93%) the 1 H-NMR of it showed it to.be pure enough to use it in the next step. 10 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 15 (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 20 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-l 25 yl)-2-methylpropionitrile (0.446 g, 2 mmol) in anhydrous THF (10 mL) under argon was added a solution of BH 3 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 HC1 (6 N, 50 mL) was added 30 and stirring was continued for 1 hour. The mixture was basified to pH 9 by addition of 6 N aq. NaOH, extracted with CH 2 C1 2 (3 X 10 mL), dried (potassium carbonate) and the solvent evaporated to leave the product as a viscous oil (0.436 g, 96%) the 1 H-NMR of it showed it to be pure WO98/57940 PCTIUS98/12668 -114 enough to use it in the next step. Examples 23 and 24. N3-[3-(4-Cyano-4-phenylpiperidino)propyl]-2-oxo-4,4 5 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 10 mmol) in THF (100 mL) at 0 0 C under argon atmosphere, a solution of LAH in THF (1IM, 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 HC1 (20 mL) and 15 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 20 on trituration with hexane became white powder (4.7 g, -100%). The 'H-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 l,l-diphenyl-2-hydroxyethylamine (4.26 g, 25 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 30 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 35 (20 mL) at 0 oC, a solution of 4,4-diphenyl-2-oxo- WO98/57940 PCTIUS98/12668 -115 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 5 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 10 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. 15 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 20 eluent. The HC1 salt was made by treatment with 1N HC1 in ether. N3-[3-(4-Cyano-4-phenylpiperidino)propyl]-2-oxo-4,4 diphenyl-oxazolidine-3-carboxamide hydrochloride Yield 93%; m.p.139-141 oC; Anal. Calcd. For: 25 C 31
H
32
N
4 0 3 .HC1 .0.8CH 2 C1 2 : 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 0C; Anal. Calcd. For: 30 C 34
H
37
N
3 0 3 .HC1 .1.3CH 2 C1 2 : C, 62.12; H, 6.00; N, 6.16. Found: C, 62.19; H, 5.64; N, 6.14. Examples 25, 26, 27, 28 and 29. a. 1-(3,4-Difluorophenyl)-2-methyl-2-hydroxypropylamine. 35 To a well-stirred solution of methyl 2-amino-2-(3,4- WO 98/57940 PCT/US98/12668 -116 difluorophenyl)acetate (10.5 g, 52.19 mmol) in anhydrous ether (200 mL) at 0 0 C a solution of methylmagnesium bromide (3M, 87 mL, 261 mmol) in ether was added in 10 minutes. The mixture was stirred at 0OC for 2.5 h and 5 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 10 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 15 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 20 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 25 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% 30 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 35 chloroformate (950 mg, 4.71 mmol) in THF (20 mL) at -78 WO98/57940 PCT/US98/12668 -117 oC 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 5 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%). 10 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 15 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 HC1 salt was made by treatment with lN HC1 in ether. 20 Example 25: Methyl 1-[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 0C; Anal. Calcd. For: 25 C 28
H
33
F
2
N
3 0s.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 30 oxazolidine-3-yl]carbonylamino)propyl]-4-phenyl-4 piperidyl acetate hydrochloride Yield 29%; m.p. 116-118 0C; Anal. Calcd. For:
C
28
H
33
F
2
N
3 0s.HC1 .0.3CH 2 C1 2 : C, 57.46; H, 5.90; N, 7.50. Found: C, 57.38; H, 6.18; N, 7.67. 35 WO 98/57940 PCTIUS98/12668 -118 Example 27: N3-3-[4-(2-Pyridyl)piperidino]-3-methylpropyl-4-(3,4 difluorophenyl)-5,5-dimethyl-2-oxo-oxazolidine-3 carboxamide dihydrochloride 5 Yield 64%; m.p. 87-90 oC; Anal. Calcd. For:
C
26
H
32
F
2
N
4 0 3 .2HC1 .1.lCHC1 3 .1.1H20: C, 45.81; H, 5.29; N, 7.88. Found: C, 45.73; H, 5.50; N, 8.07. Example 28: 10 N3-[3-(4-Cyano-4-phenylpiperidino)-2-hydroxypropyl]-4 (3,4-difluorophenyl)-5,5-dimethyl-2-oxo-oxazolidine-3 carboxamide hydrochloride Yield 63%; m.p. 135-137 0C; Anal. Calcd. For:
C
27
H
30
F
2
N
4 0 4 .HC1 .1.2H 2 0: C, 56.83; H, 5.90; N, 9.82. 15 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 20 carboxamide hydrochloride Yield 39%; m.p. 120-122 oC; Anal. Calcd. For:
C
27
H
29
F
3
N
4 0 3 .HC1 .0.8CH 2 C1 2 : C, 53.95; H, 5.15; N, 9.05. Found: C, 53.89; H, 5.33; N, 8.95. 25 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-1-(5 30 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 oC, a solution of 4
-(
3 ,4-difluorophenyl)-5,5-dimethyl 2-oxo-oxazolidine (880 mg, 3.622 mmol) in THF (5 mL) was 35 added and stirred for 30 minutes. To this 1,5- WO 98/57940 PCT/US98/12668 -119 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 5 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 10 piperidinecarboxylate hydrochloride A mixture of 4-(3,4-difluorophenyl)-5,5-dimethyl-l-(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 15 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 HC1 salts were made by treatment with 1N HC1 in ether. Yield 50%; m.p. 58-60 20 oC; Anal. Calcd. For: C 29
H
36
F
2
N
2 0 4 .HC1 .0.8CH 2 C1 2 : C, 57.82; H, 6.28; N, 4.53. Found: C, 58.01; H, 6.53; N, 4.45. Example 31: 25 N3-2-[4-(2-Oxo-2,3-dihydro-1H-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-1-benzimidazolinyl)piperidin-1-yl] ethyl)phthalimide. 30 To a solution of 4-(2-keto-l-benzimidazolinyl)piperidine (5 g, 23 mmol) and N-(2-bromoethyl)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 WO98/57940 PCT/US98/12668 -120 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%). 5 b. N-(2-[(4-(2-Keto-1-benzimidazolinyl)piperidin-1-yll 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 10 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 15 the desired product, which was used in the next step without further characterization. c. N3-2-[4-(2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-1 yl)piperidino]ethyl-4-(3,4-difluorophenyl)-5,5-dimethyl 2-oxo-oxazolidine-3-carboxamide hydrochloride 20 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-1-yl] ethyl)amine (20 mg) as described earlier. Yield 25 mg; [a]D = +58.8 (c = 0.40 g, methanol); m.p. 227-230 oC; 25 Anal. Calcd. For: C 26
H
29
F
2
N
5 0 3 .HC1.0.4 CH 2 C1 2 : 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 30 pyridyl)piperidino]methylpiperidino)carbonyl] oxazolidine-2-one dihydrochloride. a. 1-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, 0.1mol) in anhydrous EtOAc WO98/57940 PCT/US98/12668 -121 (600 mL) for 24 h. The pale yellow crystalline product formed was filtered and dried (32.7 g, 100%). b. 1-Benzyl-4-(2-pyridyl)-1,2,3,6-tetrahydropyridine. To a stirred solution of l-benzyl-4-[pyrid-2 5 yl]pyridinium bromide (50 g, 0.152 mol) in ethanol (500 mL) at 0-5 oC, was added NaBH 4 (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 10 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%). 15 c. 4-(2-Pyridyl)piperidine. To a solution of l-benzyl-4-(2-pyridyl)-l,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 20 200 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 CH 2 Cl 2 /methanol/2M
NH
3 in MeOH (45:4:2 to 9:4:4) as the eluting system. 25 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 0 C was added (Boc) 2 0 (6.53 g, 29.9 mmol) and a 30 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 pH=3 with 1 N HC1 and then extracted with EtOAc (3 X 50 mL), dried (MgSO 4 ) to WO98/57940 PCT/US98/12668 -122 afford crude product which was used in the next step without further purification. e. 4-(2-Pyridyl)piperidine-N-(t-butyl-carbonate) 5 nipecotamide. To a solution of N-(t-butyl-carbonate) nipecotic acid (6.85 g, 29.8 mmol) in CH 2 C1 2 (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 10 (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 CH 2 C1 2 (3 X40 mL) and the combined extracts was dried (K 2
CO
3 ) and concentrated. The residue was purified by flash 15 chromatography on silica gel(CHC1 3 -MeOH-NH 3 100:4:1) 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 ( 20 5.0 mL) was stirred at 0 oC overnight. The mixture was concentrated and the residue was dissolved in THF (30 mL). The mixture was cooled to 0 oC and lithium aluminium hydride (LAH) (193 mg, 5.084 mmol) was added slowly. The reaction mixture was stirred for 12 hours 25 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 CH 2 C1 2 (5 X 20 mL), dried (K 2
CO
3 ) and concentrated. The residue was purified by flash chromatography (CHC1 3 -MeOH 7
NH
3 30 100:10:2 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]ethylpiperidino)carboiyl] oxazolidine-2-one dihydrochloride.
WO 98/57940 PCT/US98/12668 -123 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. 5 Yield 90%; m.p.= 176-178 oC; Anal. Calcd. For
C
26
H
31
N
4 0 3
F
2 .2HC1.1.2H 2 0.1.2CH 2 C1 2 : C,47.90; H, 5.59, N,8.21. Found: C, 47.27; H, 5.41; N, 8.21. Example 33: 10 Nl-[2-(4-Cyano-4-phenylpiperidino)ethyl]-2-[4-(3,4 difluorophenyl)-2-oxo-oxazolidin-3-yl]lacetamide hydrochloride a. (+)-{2-[(4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-1 acetic acid benzyl ester. To a stirred a solution of 4 15 (3,4-difluorophenyl)-2-oxo-oxazolidinone (398 mg, 2 mmol) in THF (20 mL) at 0 oC 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 oC and to this benzyl 20 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 25 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), 30 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 filtrate to obtain the product as a white powder (0.375 g, 97%).
WO 98/57940 PCT/US98/12668 -124 c. N1-[2-(4-Cyano-4-phenylpiperidino)ethyl]-2-[4-(3,4 difluorophenyl)-2-oxo-oxazolidin-3-yl]acetamide hydrochloride A mixture of 5 (+)-{ 2
-[(
4 -(3,4-difluorophenyl)-2-oxo-oxazolidine-1 acetic acid (51.4 mg, 0.2 mmol), 1-(3 dimethylaminopropyl)-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 10 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) 15 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); [a]D = +168.40 (c = 0.42 g, methanol). The HC1 salt was 20 prepared by treatment of a solution of the free base in ether with 1N HC1 in ether. M.p. 136-139 'C; Anal. Calcd. for C 25
H
27
N
4 0 3
F
2 C1.0.4CH 2 C12 :C, 56.38; H, 5.20; N, 10.40. Found: C, 56.38; H; 5.30; N, 10.52. 25 Example 34: 4-{4-[4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3 carbonyl]-piperazin-1-yl}-l1-phenyl cyclohexanecarbonitrile a. l-Phenyl- 4 -piperazin-1-yl-cyclohexanecarbonitrile 30 A mixture of 4 -cyano-4-phenyl-cyclohexanone (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 35 white solid, which was redissolved in 20 ml of EtOH and WO 98/57940 PCT/US98/12668 -125 stirred with NaBH 4 (0.30 g, 80 mmol) for 12 h at 25 oC. Reaction mixture was diluted with 100 ml of EtOAc and washed with brine several times. Organic layer was dried over MgSO 4 and concentrated in vacuo, to provide 5 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 10 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-l-yl-cyclohexanecarbonitrile (80 mg, 0.29 15 mmol) in a portion and the resulting solution was stirred for 12 h at 25 OC. 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 20 colorless oil. The product obtained was converted to the HC1 salt and recrystallized from EtOAc-Et20 to afford 43 mg of the product as white solid: mp 148-151 oC; Anal. Calc. For C 27
H
28
F
2
N
4 0 3 .1.0HC1 requires C, 61.07; H, 5.50; N, 10.55. Found: C, 59.48; H, 5.41; N, 10.34. 25 Example 35: (+)-4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3 carboxylic acid [3-(4-furan-2-yl-4-phenyl-piperidin-1 yl)-propyl]-amide 30 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 CH 2 C1 2 at 25 0C 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 WO98/57940 PCT/US98/12668 -126 solution was stirred for 3 h. Reaction mixture was poured into cold aqueous NaHCO 3 and extracted with EtOAc. Organic layer was dried over Na 2
S
04 and concentrated in vacuo to provide oily residue, which was 5 purified by column chromatography (30% NH 3 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 10 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 K 2
CO
3 (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. 15 Organic layer was dried over Na2SO4 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 CH 2 C1 2 and 1 ml of 20 trifluoroacetic acid, and stirred for 2 h at 25 oC. Reaction mixture was concentrated in vacuo, yielding an oil, which was diluted with EtOAc and washed with aqueous NaHCO 3 . Organic layer was dried over Na 2
SO
4 and concentrated in vacuo to provide 86 mg (33%) of the 25 desired product as a colorless oil. c. (+)-4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3 carboxylic acid [3-(4-furan-2-yl-4-phenyl-piperidin-1 yl)-propyl] amide To a solution of (+)-4-(3,4-difluoro-phenyl)-2-oxo 30 oxazolidine-3-carboxylic acid 4-nitrophenyl ester (19 mg, 0.05 mmol) in 5 ml of CH 2 C1 2 was added 3-[4-(4 Phenyl-4-furan-2-yl-phenyl)-piperidin-1-yl)]-propyl-l amine (12 mg, 0.04 mmol) in a portion and the resulting solution was stirred for 4 h at 25 oC. Reaction mixture 35 was concentrated in vacuo yielding a yellow oil, which WO 98/57940 PCT/US98/12668 -127 was subjected to column chromatography (5% MeOH/CHC1 3 ) to provide 18 mg (88%) of the desired product as a colorless oil. The product obtained was converted to the HC1 salt and recrystallized from EtOAc-Et 2 0 to 5 afford 19 mg of the product as white solid: mp 149-151 oC; [a)D = + 49.4 (c=0.11, MeOH); Anal. Calc. For
C
28
H
29
F
2
N
3 0 4 .1.0HC1 requires C, 62.42; H, 5.42; N, 7.53. Found: C, 60.79; H, 5.49; N, 7.43. 10 Example 36: (+)-4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3 carboxylic acid {3-[4-(1-methyl-1H-pyrrol-2-yl)-4 phenyl-piperidin-1-yl]-propyl}-amide a. 4-Phenyl-4-(1-methyl-pyrrol)-2-yl-piperidine 15 To a solution of 4-hydroxy-4-phenyl-piperidine(0.50 g, 2.8 mmol) in 10 ml of CH 2 C1 2 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 20 mixture was poured into cold aqueous NaHCO 3 and extracted with EtOAc. Organic layer was dried over Na 2
SO
4 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 25 without any further purification. b. 3-[4-(1-methyl-1H-pyrrol-2-yl)-4-phenyl-piperidin-1 yl]-propyl-l-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 30 mmol), K 2
CO
3 (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 Na 2
SO
4 and concentrated in vacuo to provide oily residue, which was 35 purified by column chromatography (2% MeOH/CHC1 3 ) to WO98/57940 PCT/US98/12668 -128 yield 0.87 g (78%) of the desired product as tert-butyl carbamic ester. The ester was diluted in 10 ml of
CH
2
CI
2 and 1 ml of trifluoro-acetic acid, and stirred for 2 h at 25 'C. Reaction mixture was concentrated in 5 vacuo, yielding an oil, which was diluted with EtOAc and washed with aqueous NaHCO 3 . Organic layer was dried over Na 2
SO
4 and concentrated in vacuo to provide 0.63 g (75% for two steps) of the desired product as a colorless oil. 10 c. (+)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3 carboxylic acid {3-[4-(1-methyl-1H-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 15 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-l-yl}-propyl 1-amine (24 mg, 0.08 mmol) in a portion and the resulting solution was stirred for 4 h at 25 oC. Reaction mixture was concentrated in vacuo yielding a 20 yellow oil, which was subjected to column chromatography (5% MeOH/CHC13) to provide 14.4 mg (34%) of the desired product as a colorless oil. The product obtained was converted to the HC1 salt and recrystallized from EtOAc Et20 to afford 13.0 mg of the product as white solid: mp 25 135-138 OC; [I]D = + 34.1 (c=0.11, MeOH); Anal. Calc. For C 28
H
29
F
2
N
3 0 4 .1.0HC1 requires C, 62.42; H, 5.42; N, 7.53. Found: C, 60.79; H, 5.49; N, 7.43. Example 37: 30 (+)-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 35 40 ml of dry THF was added tert-butyl lithium (1.7 M WO 98/57940 PCT/US98/12668 -129 solution in ether, 6.5 ml, 11 mmol) dropwise and the resulting solution was stirred for 1 h at -40 oC. To the solution was added N-tert-butoxycarbonyl-4 piperidinone (1.0 g, 5.0 mmol) in a portion and the 5 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 Na 2
SO
4 and concentrated in vacuo to provide an oil, which was 10 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 15 triisopropylsilane (1.0 ml, 8.2 mmol) in 10 ml of CH 2
CI
2 was added 10 ml of trifluoroacetic acid and the resulting solution was stirred for 2 h at 0 oC. Reaction mixture was concentrated in vacuo, yielding a dark oil, which was redissolved in EtOAc and washed with 20 aqueous NaHCO 3 . Organic layer was dried over Na2SO4 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] 25 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), K 2
CO
3 (1.0 g, 7.4 mmol) and Nal (0.05 g) in 25 ml of acetone was stirred at reflux for 12 h. Reaction 30 mixture was diluted with EtOAc and washed with brine several times. Organic layer was dried over Na 2
SO
4 and concentrated in vacuo to provide oily residue, which was purified by column chromatography (5% MeOH/CHC1 3 ) to yield 0.60 g (44%) of the desired product as tert-butyl 35 carbamic ester. The ester was diluted in 10 ml of WO98/57940 PCT/US98/12668 -130
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 NaHCO 3 . Organic layer was dried 5 over Na 2
SO
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 (3-[4-(5-methyl-thiophen-2-yl) piperidin-1-yl]-propyl}-amide 10 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 CH 2
CI
2 was added 3-[4-(5 methyl-thiophen-2-yl)-piperidin-l-yl]-propyl-l-amine (30 mg, 0.13 mmol) in a portion and the resulting solution 15 was stirred for 12 h at 25 oC. Reaction mixture was concentrated in vacuo yielding a yellow oil, which was subjected to column chromatography (5% MeOH/CH 2 Cl 2 ) to provide 41 mg (74%) of the desired product as a colorless oil. The product obtained was converted to 20 the HC1 salt and recrystallized from EtOAc-Et 2 0 to afford 43 mg of the product as white solid: mp 143-146 oC; [a4]D = + 41.0 (c=0.11, MeOH); Anal. Calc. For
C
23
H
27
F
2
N
3 0 4 .1.0HC1 requires C, 55.25; H, 5.64; N, 8.40. Found: C, 57.01; H, 5.54; N, 8.29. 25 General Procedure for the Preparation of the 4,4-Diaryl Piperidines: A mixture of 0.5 g of 4-aryl-4-hydroxy piperidine, 3 mL of the aromatic substrate, and 1 g of 30 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 WO98/57940 PCT/US98/12668 -131 characterization. 4-Phenyl-4-(4-thiomethoxy-phenyl)-piperidine, Hydrochloride: From 4-phenyl-4-hydroxy-piperidine and 5 thioanisole (82%), Anal. Calc. for C 18
H
21
N
1
S
1 +HCl+0.2H 2 0: 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-thiomnethoxy-phenyl)-piperidine, 10 Hydrochloride: From 4-(4-fluoro-phenyl-4-hydroxy piperidine and thioanisole (59%), Anal. Calc. for
C
18
H
20 FNS+HC+0.35CH 2 C1 2 : C, 60.14; H, 5.56; N, 3.90. Found: C, 59.96; H, 5.95; N, 3.81. 15 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 C 18
H
19
NF
2 0 1 +HCl+0.2H20: C, 62.96; H, 5.99; N, 4.08. Found: C, 62.72; H, 6.06; N, 4.06. 20 Bis-(4-fluoro-phenyl)piperidine, Hydrochloride: From 4 (4-fluoro-phenyl)-4-hydroxy-piperidine and 3 mL of fluorobenzene (69%). 25 4-(4-Bromo-phenyl-4-(4-methoxy-phenyl)-piperidine, Hydrochloride: From 4-(4-bromo-phenyl-4-hydroxy piperidine and thioanisole (66%), Anal. Calc. for
C
18
H
20 Br 1
N
1 Sl+HC1: C, 54.21; H, 5.30; N, 3.51. Found: C, 54.43; H, 5.22; N, 3.41. 30 General Procedure for the Preparation of the 4,4-Diaryl 1-(3-amino-propyl)Piperidines: A solution of 1.00 mmol of diarylpiperidine, 1.30 mmol of N-BOC-3 bromopropylamine, 1.00 mL of diisopropylethylamine and 2 WO98/57940 PCT/US98/12668 -132 mL of dioxane were heated at reflux temperature for 36 hours, cooled, applied to prep-tlc plates and eluted with the appropriate solvent. The product was used in the next step after spectral characterization. A 5 solution of the N-BOC protected amine in 1:1 TFA-water was stirred at room temperature for 2 hours (monitored by t1c), solvent removed in vacuo, the product was dissolved in dichloromethane, washed with saturated Na 2
CO
3 solution, dried (Na 2
SO
4 ), solvent removed in 10 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 15 (4-thiomethyl-phenyl)-4-phenyll]-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 20 hours, solvent removed in vacuo, and the product was chromatographed (X2) (NH 3 -MeOH-CHC13) to give 270 mg of the desired product. General procedure for the synthesis of Examples 38, 39, 25 40, 41 and 42. A solution of (+)-4a(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 30 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
(CH
2 Cl 2 /methanol/ 2 N NH 3 in methanol = 40 /2/1) to obtain the title compound. The hydrochloride salt of WO 98/57940 PCT/US98/12668 -133 the free base was prepared by addition of 1 N HC1 in ether to a solution of the free base in ethyl acetate until no more precipitate was observed. 5 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. 10 Calc. For C 3 1
H
3 2 BrF 2
N
3 04 + 1.5 HC1: 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. [a]D 22 = + 53.93 . 15 Example 39: 4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid (3-[4-(4-fluoro-phenyl)-4-(4-methylsulfanyl phenyl)-piperidin- l-yl] -propyl } -amide 20 mg of the free base was obtained (55% yield). Anal. 20 Calc. For C 31
H
32
F
3
N
3 0 3 S + 1.75 HCI + 0.75 EtOAc: C, 57.23 %; H, 5.61 %; N, 5.89 %. Found: C, 57.28 %; H, 5.73 %; N, 5.83 %. M.p. of the salt: 121 - 124 oC []D 2 = + 33.33. 25 Example 40: 4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid (3-[4,4-bis-(4-fluoro-phenyl)-piperidin-i-yl] propyl}-amide. 24 mg of the free base was obtained (63 % yield). Anal. Calc. For C 30
H
2 1F 4
N
3 0 3 + 2.0 HC1 + 0.125 30 CHC1 3 : 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 oC. [] 2M 2 = + 47.33 Example 41: WO 98/57940 PCT/US98/12668 -134 4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid (3-[4-(4-fluoro-phenyl)-4-(2-methoxy-5-fluoro phenyl)-piperidin-1-yl]-propyl}-amide 24 mg of the free base of the tittle product was 5 obtained ( 59% yield). Anal. Calc. For C 31
H
3
,F
4
N
3 0 4 + 2.0 HC1 + 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 oC [a]D 22= + 38.86. 10 Example 42: (+)-4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carboxyl ic acid {3-[4-(4-methanesulfonyl-phenyl)-4-phenyl-piperidin-1-yl ]- propyl}- amide, hydrochloride 15 18 mg of the free base was obtained: Anal. Calc. For
C
31
H
31
F
4
N
3 0 4 + 2.0 HC1 + EtOAc: C, 55.41 %; H, 5.71 %; N, 5.54 %. Found: C, 55.82 %; H, 5.19 %; N, 5.49 %. Example 43: 20 4-(3,4-Difluorophenyl)-1-(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 trimethylsilylcyanide (2.34 ml, 17.59 mmol), 25 catalytic amount of Zinc Iodide was added at 00C. After stirring for 15 minutes at room temperature a saturated solution of methanolic ammonia (15 ml) was added in one lot at 00C. The reaction mixture was then stirred for 4 hours at 40 oC. After evaporation of the solvent the 30 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 WO98/57940 PCT/US98/12668 -135 mmol), at 0 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 0 C and quenched with water (2 5 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. 10 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 0 c. Then triphosgene (3.01 g, 10.16 mmol) was added to the 15 solution over a period of 30 minutes. The reaction mixture was then stirred at -78 0 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, 20 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-1-carboxylic acid 4-nitrophenyl ester: 25 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 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 30 mmol) at -78 0 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 35 concentrated. Purification by column chromatography WO 98/57940 PCT/US98/12668 -136 (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: 5 To 4-(3,4-difluorophenyl)-l-(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 10 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 1N HC1 in ether (0.5 mL). The solution was concentrated under reduced 15 pressure. Recrystallization of the residue from ether gave 0.029 g (60 %) of the hydrochloride salt as a brown solid: mp 148-1500C. Anal. Calcd. for C 23
H
29
F
2
N
4 0 3 C120.5 CC1 4 : C, 51.90; H,4.90; N, 11.0. Found: C, 54.23; H 5.17; N, 10.84. 20 Example 44: 3-(4-(4-Cyano-4-phenylpiperidin-1-yl)piperidin-1 yl)carbonyl-4-(3,4-difluorophenyl)-2-imidazolidone. a. 4-(3,4-Difluorophenyl)-2-imidazolidone-3-carboxylic 25 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 0 C. The solution was then stirred at room temperature for 15 minutes. It was then added 30 to a solution of 4-nitrophenylchloroformate (0.552g, 2.74 mmol) at -78 0 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 WO98/57940 PCT/US98/12668 -137 %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. 5 b. 3-(4-(4-Cyano-4-phenylpiperidin-1-yl)piperidin-1 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 mL) was added 4-(4-cyano-4-phenylpiperidin-l-yl)piperidine 10 (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 15 dichloromethane (2 mL) and treated with lN HC1 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 0 C. Anal. Calcd. for C 27
H
30 C1F 2 Ns02 0.4 20 CHC1 3 : 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 25 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 30 mmol) and trimethylsilylcyanide (4.69 mL, 35.1 mmol), catalytic amount of Zinc Iodide was added at 0 0 C. After stirring for 15 minutes at room temperature a saturated solution of methylammonia (15 mL) was added in one lot at 0 0 C. The reaction mixture was then stirred for 4 35 hours at 40 0 C. After evaporation of the solvent the WO98/57940 PCT/US98/12668 -138 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: 5 To Lithium aluminum hydride in ether (49.41 mL, 49.4 mmol), at 0OC, 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 10 reaction mixture was cooled to 0 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 15 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 20 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-1-(3-(4-(2 25 pyridyl)piperidin-1-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 0 C, lithium bis(trimethylsilyl)amide in THF (0.848 30 mL, 0.848 mmol) was added slowly and the solution was stirred at room temperature for 15 minutes. After cooling to -78 0 C, phosgene (0.729 g, 7.06 mmol) was added and che solution was stirred at -78 0 C for 1 hour. It was then concentrated to give an intermediate 35 (0.194g, 0.703 mmol) which was immediately dissolved in WO98/57940 PCT/US98/12668 -139 THF (10 mL) at -78 0 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 5 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 10 (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 1N HC1 in ether (0.5 mL). The solution was concentrated under reduced pressure. Recrystallization of the residue from ether 15 gave 0.030 g (88%) of the dihydrochloride salt as a pale yellow solid: mp 120-122 0 C. Anal. Calcd. for
C
24
H
31
CF
2
N
5 0 2 '0.95 CHC1 3 : C,46.54; H,5.00; N, 10.88. Found: C, 46.30; H 5.35; N, 11.20. 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: 25 To a solution of l-(3,4-difluorophenyl)-ethane-l,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 0OC. Trityl chloride (10.94 g, 39.2 mmol) in dichloromethane (100 ml) was added 30 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 1N KOH (10 mL), filtered, and concentrated. Purification 35 by column chromatography (hexanes:ethyl acetate 3:2) WO98/57940 PCT/US98/12668 -140 yielded 6.75 g (46 %) of the product as a brown syrup. b. 4-(3,4-Difluorophenyl)-1-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 5 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. 10 c. 4-(3,4-Difluorophenyl)-1-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 0OC. The solution was 15 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 0 C via a cannula. The reaction mixture was then allowed to stir at room temperature for 12 hours. It was then concentrated and 20 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. 25 d. 4-(3,4-Difluorophenyl)-3-(3-(4-(2-methoxy-5 methyl)phenyl-4-phenylpiperidin-1 yl)propyl)aminocarbonyl-1-trityl-2-imidazolidone: To 4-(3,4-difluorophenyl)-3-(4-nitrophenoxy)carbonyl-l trityl-2-imidazolidone (0.089, 0.147 mmol) in THF (5 mL) 30 was added 3-(4-(2-methoxy-5-methyl)phenyl-4 phenylpiperidin-l-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 WO98/57940 PCT/US98/12668 -141 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)phenyl-4-phenylpiperidin-1 yl)propyl)aminocarbonyl-2-imidazolidone: 5 To 4-(3,4-Difluorophenyl)-3-(3-(4-(2-methoxyl-5 methyl)phenyl-4-phenylpiperidin-l yl)propyl)aminocarbonyl-l-trityl-2-imidazolidone (0.100 g, 0.124 mmol) in dichloromethane (2 mL) at 0 0 C, trifluoroacetic acid (4 mL) in dichloromethane (2 mL) 10 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. 15 Purification of the residue by flash chromatography (ethyl acetate) yielded 0.06 g (87%) of a white foam. To it in dichloromethane (2 mL), 1N HC1 in ether (0.5 mL) was added, and the solution concentrated under reduced pressure. Recrystallization of the residue from ether 20 gave 0.061 g (96 %) of a hydrochloride salt as a white solid: mp 173-175oC. Anal. Calcd. for C 32
H
36 C1F 2
N
4 031.20 CHC1 3 : C, 53.72; H,5.19; N, 7.55. Found: C, 53.76; H 5.01; N, 7.36. 25 Example 47: (-)-3-(3-(4-Cyano-4-phenylpiperidin-1-yl)-2(S) methylpropyl)-aminocarbonyl-4-(3,4-difluorophenyl)-2 imidazolidone. a. 4-Cyano-1-(3-hydroxy-2(S)-methylpropyl)-4 30 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 35 (20 mL) was refluxed for 12 hours. The solution was WO98/57940 PCT/US98/12668 -142 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 5 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: 10 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) 15 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 20 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 25 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-1-yl)-2(S) 30 methylpropyl)-aminocarbonyl-4-(3,4-difluoro)phenyl-1 trityl-2-imidazolidone: To 4-(3,4-difluoro)phenyl-3-(4-nitrophenoxy)carbonyl-l trityl-2-imidazolidone (0.49 g, 0.809 mmol) in THF (10 mL) was added l-(3-amino-2(S)-methyl)propyl-4-cyano-4- WO 98/57940 PCT/US98/12668 -143 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 5 the product as a syrup. e. (-)-3-(3-(4-Cyano-4-phenylpiperidin-1-yl)-2(S) methyl)propyl-aminocarbonyl-4-(3,4-difluorophenyl)-2 imidazolidone: To (-)-3-(3-(4-Cyano-4-phenylpiperidine-l-yl)-2(S) 10 methylpropyl)-aminocarbonyl-4-(3,4-difluoro)phenyl-l trityl-2-imidazolidone (0.441 g, 0.607 mmol) in dichloromethane (2 mL) at 0 0 C was added trifluoroacetic acid (4 mL) in dichloromethane (2 mL) and the solution was stirred at room temperature for 20 minutes. The 15 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 20 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) 25 in dichloromethane (2 mL) was added 1N HC1 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: [a], = - 5.32 (8.0 mg/mL MeOH); mp 265-267 0 C. 30 Anal.Calcd. for C 26
H
30 C1F 2
N
5 0 2 '0.15 CHCl 3 : 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-1 35 yl)propyl)aminocarbonyl-4-(3,4-difluorophenyl)-2- WO 98/57940 PCT/US98/12668 -144 oxazolidinone. a. 4-Cyano-4-(2,4-dichlorophenyl)-piperidine-1 carboxylic acid tert-butyl ester: To bis(2-chloroethyl)-carbamic acid tert-butyl ester 5 (1.0g, 3.8 mmol) and (2,4-dichloro)phenyl 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 0oC. The solution was stirred for 10 minutes at room temperature. When the foaming subsided, the solution was heated at 10 60 0 C for 24 hours. It was then quenched with water at 0 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 15 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-l 20 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 25 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. 30 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 mmnol, potassium carbonate (1.594 g, 11.53 mmol) and sodium WO98/57940 PCT/US98/12668 -145 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 5 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 10 yl)propyl)aminocarbonyl-4-(3,4-difluorophenyl)-2 oxazolidinone: To 3-[4-cyano-4-(2,4-dichlorophenyl)-piperidin-l-yl] propyl-carbamic acid tert-butyl ester (0.589, 1.42 mmol) in dichloromethane (5 mL), trifluoroacetic acid (1 mL) 15 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 20 g (93%) of l-(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 25 mmol) in dry THF (10 mL) was added l-(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 30 (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 1N HC1 in ether was added, and the solution concentrated under reduced pressure. Recrystallization of the residue from WO 98/57940 PCTIUS98/12668 -146 ether gave 0.040 g (94 %) of the product as a white solid: mp 204-206 'C; [aID = 48.8 (1.55 mg/mL MeOH). Anal. Calcd. for C 2 sH2sF 2
N
4 0 3 C1 2 .0.60 CH 2 C1 2 : C, 49.21; H, 4.21; N, 8.97. Found: C, 49.44; H 4.39; N, 8.66. 5 Example 49: (+)-3-(3-(4-Aminocarbonyl-4-(4-chloro)phenylpiperidin-1 yl)-propyl)aminocarbonyl-4-(3,4-difluoro)phenyl-2 oxazolidinone. 10 a. 3-(4-Cyano-4(4-chlorophenyl)piperidin-1 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 15 %)(0.260 g, 10.30 mmol) in one lot at 00C. The solution was stirred for 10 minutes at room temperature. When the foaming subsided, the solution was heated at 600C for 45 minutes. It was then quenched with water at 00C,. partitioned between ethyl acetate (25 mL) and 20 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. 25 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 30 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 35 ammonia 8:1:1) yielded 0.482 g (82 %) of the product as WO98/57940 PCT/US98/12668 -147 a syrup. b. 3-(4-(4-Chlorophenyl)-4-cyanopiperidin-1 yl)propylcarbamic acid tert-butyl ester: To a stirred solution of the 4-(4 5 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 10 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 15 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-l-yl)-propyl)aminocarbonyl-4 (3,4-difluoro)phenyl-2-oxazolidinone: 20 3-(4-(4-chlorophenyl)-4-cyanopiperidin-l yl)propylcarbamic acid tert-butyl ester (0.150 g, 5.39 mmol) in conc. H 2
SO
4 (1 mL) was stirred at room temperature for 30 hours. The solution was concentrated, neutralized with 10 % KOH solution and 25 extracted into 25 mL of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.185 g (79%) of l-(3-aminopropyl) 4-(4-chlorophenyl)piperidine-4-carboxamide which was used as such for the subsequent step. 30 To 4-(3,4-difluorophenyl)-3-(4 nitrophenoxy)carbonyl-2-oxazolidinone (0.040 g, 0.109 mmol) in 10 mL of dry THF was added l-(3-aminopropyl)-4 (4-chlorophenyl)-piperidine-4-carboxamide (0.042 g, 0.141 mmol) and the solution was stirred at room 35 temperature for 24 hours. The reaction mixture was WO98/57940 PCT/US98/12668 -148 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 1N HCl in 5 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 oC; [a]D = 52.0(1.3 mg/mL MeOH). Anal. Calcd. for C 2 5
H
2 7C 2
F
2 N404'1.7 CH 2 C1 2 : C, 45.70; H, 10 4.51; N, 7.96. Found: C, 45.75; H 4.64; N,7.96. Example 50: (+)-3-(5-(4-Cyano-4-phenylpiperidin-1-yl)pent-2(E)-en-l yl)-4-(3,4-difluoro)phenyl-2-oxazolidinone. 15 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 20 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 25 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 30 give a mixture of two isomers in 22% yield as a yellow oil. HPLC separation (column: Primesphere SiO 2 5pm, 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 HC1 to 35 give a salt as a yellow solid: mp 168-170 0 C; ESMS m/e = WO98/57940 PCT/US98/12668 -149 452 (MH+); [aD = 45.0 (0.4 mg/mL CH 2 C1 2 ). Anal. Calcd. for C 26
H
27
F
2
N
3 02"HC1'1.0H 2 0: C, 61.72; H, 5.98; N, 8.30. Found: C, 61.79; H, 5.88; N, 8.26. 5 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-l-yl] propylamine was synthesized as described in Example 22, 10 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 15 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 20 fluoro-2-methylphenyl)-piperidin-l1-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 0 C; [a]D =+ 23.0 (c = 0.12, MeOH); Anal. Calcd. for C 25
H
29
N
3 0 3
F
3 C1.0.23 H 2 0: C, 58.91; H, 5.98; N, 25 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)phenyl)-piperidin-1-yl]-propyl)-amide 30 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 BF 3 .OEt 2 and the resulting solution was stirred at reflux for 12 h.
WO98/57940 PCT/US98/12668 -150 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. 5 b. 1-[(Benzhydryliden-amino)-(3,4-difluoro phenyl)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 10 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 oC 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 15 and washed with brine. The organic layer was dried over Na 2
SO
4 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. 20 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 MeONH 2 .HC1 (1.35 g, 16.2 mmol) was 25 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 Na 2
SO
4 and then 30 concentrated in vacuo to give l-[amino-(3,4-Difluoro phenyl)methyl]-cyclobutanol as an oil which was used in the next step without any purification.
WO 98/57940 PCT/US98/12668 -151 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 CH 2 Cl 2 (50 mL) 5 at 0 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 10 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). 15 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 20 (0.2 g, 8.3 mmol) at room temperature. The resulting suspension was stirred for 3 h at about 35 0 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 Na 2
SO
4 , filtered and the 25 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% 30 hexane/20% isopropyl alcohol/ 0.1 % diethylamine as the eluting system (12 mL/min) under isothermal conditions (U.V. 254 rnM). The retention times for the two isomers WO98/57940 PCT/US98/12668 -152 of were 12.1 min {[a]D = - 20.0 (c = 0.35, 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). 5 f. (+)-8-(3,4-Difluorophenyl)-6-oxo-5-oxa-7-aza spiro[3.4]octan-7-carboxylic acid-4-nitrophenyl]ester 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 10 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 0 C for 50 min. This solution was then added dropwise via a cannula into another round bottom 15 flask containing a solution of 4 nitrophenylchloroformate (0.15 g, 0.76 mmol) inlO mL of THF, cooled at -78 0 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 20 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 Na 2
SO
4 . The solvent was removed after filtration and the residue was purified by column chromatography on silica gel with 4:1 25 cyclohexane-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). 30 g. (+)-8-(3,4-Difluorophenyl)-6-oxo-5-oxa-7-aza spiro[3.4]octan-7-carboxylic acid-{3-[4-(4- WO 98/57940 PCTIUS98/12668 -153 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 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 10 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] 15 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 HC1 in Et 2 O (1.0 M). Mass spectrum showed M+1 peak. 20 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)-1-cyclopropyl-2-(3,4 difluoro-phenyl)-ethanol 25 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 30 ml, 12.0 mmol) in 10 ml of THF and the solution was stirred at -78 oC for 2 h and 25 C for 1 h. The reaction was quenched by adding 1.0 mL of dilute acetic WO98/57940 PCT/US98/12668 -154 acid. Reaction mixture was diluted with 100 ml of Et 2 O and washed with brine. The organic layer was dried over Na 2
SO
4 and concentrated in vacuo, yielding 2 (benzhydryliden-amino)-1-cyclopropyl-2-(3,4-difluoro 5 phenyl)-ethanol as a yellow oil, which was subjected to the following reaction without purification. b. 2-Amino-1-cyclopropyl-2-(3,4-difluoro-phenyl)-ethanol The crude batch of 2-(benzhydryliden-amino)-l 10 cyclopropyl-2-(3,4-difluoro-phenyl)-ethanol obtained from the above reaction (approximately 16.2 mmol) and MeONH 2 .HC1 (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 15 redissolved in 100 ml of EtOAc and was washed with 2.0 M NaOH followed by brine. The organic layer was separated, dried over Na 2
SO
4 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 20 CHC1 3 /10% ammonia in MeOH) to yield 3.2 g (93% yield) of 2-amino-1-cyclopropyl-2-(3,4-difluoro-phenyl)-ethanol as a pale yellow oil. c. [2-Cyclopropyl-1-(3,4-difluorophenyl)-2-hydroxy ethyl]-carbamic acid-tert-butyl ester 25 To a solution of 2-amino-1-cyclopropyl-2-(3,4-difluoro phenyl)-ethanol (1.7 g, 8.1 mmol) in CH 2 Cl 2 (50 mL) at 0 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 30 solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel (4:1 cyclohexane/EtOAc) to obtain [2-cyclopropyl-1-(3,4- WO 98/57940 PCT/US98/12668 -155 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 5 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 0 C 10 (warm water bath) and then quenched carefully with ice. The biphasic mixture was extracted with 100 mL of EtOAc, washed with brine, dried over Na 2
SO
4 , filtered and the solvent was removed in vacuo to yield 5-cyclopropyl-4 (3,4-difluorophenyl)-oxazolidin-2-one (1.3 g, 93% yield) 15 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 20 g). The relative streochemistry was assigned by comparing the 1 H 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. 25 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 30 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.
WO 98/57940 PCT/US98/12668 -156 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 5 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 0 C. The resulting yellow solution was stirred at -78 0 C for 50 min. This solution was then added dropwise via a cannula into another round 10 bottom flask containing a solution of 4 nitrophenylchloroformate (0.16 g, 0.79 mmol) inl0 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 15 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 Na 2
SO
4 . The solvent was removed after filtration and the residue was purified by column chromatography on silica gel with 4:1 20 cyclohexane-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%). 25 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-l-yl]propylamine (0.02 g, 0.05 mmol) in 10 mL 30 of CH 2 C 1 2 , (+)-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 WO98/57940 PCT/US98/12668 -157 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 5 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 10 hydrochloride salt by dissolving it into 5 mL of EtOAc and then treating it with 1.0 mL of HC1 in Et20 (1.0 M). Mass spectrum showed M+1 peak. 15 Example 54: Asymmetric Synthesis of 4-(3,4 Difluorophenyl)-5-methyl-oxazolidin-2-one a. 2-Hydroxy-1-pyrrolidin-1-yl-propan-1-one (The procedure reported by Vilarrasa et al. Tetrahedron Lett. 1997, 38, 1633 was used; see also Scheme 31) 20 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 25 hydroxy-l-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 30 To a solution of 2 -hydroxy-l-pyrrolidin-l-yl-propan-l one (47.0 mmol, 6.72 g) in DMF (25 mL) was added imidazole (70.5 mmol, 4.8 g), N,N-dimethyl-4- WO 98/57940 PCT/US98/12668 -158 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 5 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 10 Et 2 0 (2 X 100 mL). The organic extrats were combined and washed successively with water (100 mL), sat. NH 4 Cl solution and the organic layer was separated. It was dried over Na 2
SO
4 , filtered and the solvent was removed in vacuo to obtain 2-(tert-butyl-dimethyl-silanyloxy)-1 15 pyrrolidin-l-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 20 phenyl)-1-yl-propan-1-one To a round bottom flask containing 72.0 mL of THF at 78 0 C was added a solution of n-butyllithium in hexane (72.0 mmol, 45.0 mL) under an argon atmosphere followed by l-bromo-3,4-difluorobenzene (72.0 mmol, 8.1 mL). A 25 solution of 2-(tert-butyl-dimethyl-silanyloxy)-l pyrrolidin-l-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 0 C. It was quenched with 20.0 mL of sat. NH 4 C1 solution and was 30 allowed to attain room temperature. The solution was extracted with Et 2 0 (2 X 50 mL), washed with brine and the organic layer was dried over Na 2
SO
4 . The solution WO98/57940 PCT/US98/12668 -159 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 5 system). 2-(tert-Butyl-dimethyl-silanyloxy)-l-(3,4 difluoro-phenyl)-l-yl-propan-l-one was obtained as a pale yellow oil (14.1 g, 78% yield, 96% based on the recovered starting material). 10 d. 2-(tert-Butyl-dimethyl-silanyloxy)--(3,4-difluoro phenyl)-1-yl-propan-1-one-oxime To a solution of 2 -(tert-Butyl-dimethyl-silanyloxy)-l (3,4-difluoro-phenyl)-l-yl-propan-l-one (13.7 mmol, 4.1 g) in 60.0 mL of methanol was added sodium acetate ( 15 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, 20 dried over Na 2
SO
4 , filtered and the solvent was remoced in vacuo. 2-(tert-Butyl-dimethyl-silanyloxy)-l-(3,4 difluoro-phenyl)-l-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. 25 e. 1-Amino-l-(3,4-difluorophenyl)-propan-2-ol To a solution of 2-(tert-butyl-dimethyl-silanyloxy)-l (3,4-difluoro-phenyl)-l-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 30 mL) at 0 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 WO 98/57940 PCT/US98/12668 -160 00C and then quenched sequentially with water (1.0 mL), 1.0 N KOH (1.0 mL) and water (3.0 mL). The residue was filtered and the solid was washed with warm Et 2 0 (20.0 mL). The filtrates were combined and dried over Na 2
SO
4 . 5 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 10 purification. It was converted into 4-(3,4-difluorophenyl)-5-methyl oxazolidin-2-one by the general procedure as described before. f. [1-(3,4-Difluorophenyl)-2-hydroxy-propyl]-carbamic 15 acid-tert-butyl ester To a solution of 1-amino-l-(3,4-difluorophenyl)-propan 2-ol (3.5 g, 19.1 mmol) in CHC1 3 (15 mL) at 00C was added a solution of di-tert-butyl dicarbonate (5.1 g, 23.6 mmol) in CHC1I 3 (10 mL) in one portion and the 20 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 25 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 30 mmol) at room temperature. The resulting suspension was stirred for 3 h at about 350C (warm water bath) and then quenched carefully with ice. The biphasic mixture was WO98/57940 PCT/US98/12668 -161 extracted with 100 mL of EtOAc, washed with brine, dried over Na 2
SO
4 , 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 5 = 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. 10 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 15 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 20 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 25 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. 30 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 WO98/57940 PCT/US98/12668 -162 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 5 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). 10 Example 55 As a specific embodiment of an oral composition of a compound of this invention, 100mg of one of the compounds described herein is formulated with sufficient 15 finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gel capsule.
WO98/57940 PCTIUS98/12668 -163 Pharmacological Profiles of the Compounds in Cloned Human Adrenerric Receptors. Binding affinities were measured for selected compounds 5 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. 10 Protocol for the Determination of the Potency of a. 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. 15 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 a-adrenergic receptors as follows: 20 aD Human Adrenergic Receptor: The entire coding region of alD (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 25 expression vector pCEXV-3, called EXJ.HR. The construct involved the ligation of partial overlapping human lymphocyte genomic and hippocampal cDNA clones: 5' sequence were contained on a 1.2 kb SmaI-XhoI genomic fragment (the vector-derived BamHI site was used for 30 subcloning instead of the internal insert-derived SmaI site) and 3' sequences were contained on an 1.3 kb XhoI Clal cDNA fragment (the Clal site was from the vector polylinker). Stable cell lines were obtained by cotransfection with the plasmid alA/EXJ (expression WO98/57940 PCT/US98/12668 -164 vector containing the alA receptor gene (old nomenclature)) and the plasmid pGCcos3neo (plasmid containing the aminoglycoside transferase gene) into LM(tk-) cells using calcium phosphate technique. The 5 cells were grown, in a controlled environment (37 0 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 pg/ml streptomycin 10 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"). 15 The cell line expressing the human alD receptor used herein was designated L-alA (old nomenclature) and was deposited with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A. 20 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 a1D receptor, was accorded ATCC Accession No. CRL 11138, and was deposited 25 on September 25, 1992. aB Human Adrenergic Receptor: The entire coding region of alB (1563 bp), including 200 base pairs and 5' untranslated sequence (5' UT) and 600 bp of 3' 30 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 WO98/57940 PCT/US98/12668 -165 described above. The cell line used herein was designated L-a1B and was deposited with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A. under the provisions 5 of the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure. The cell line L-a1B was accorded ATCC Accession.No. CR 11139, on September 29, 1992. 10 ac Human Adrenergic Receptor: The entire coding region of a1A (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 KpnI site of the polylinker-modified pCEXV-3-derived 15 eukaryotic expression vector, EXJ.RH. The construct involved ligating three partial overlapping fragments: a 5' 0.6kb HincII 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 20 5' and 3' genomic clones so that the HincII 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 KpnI site of the expression vector, using the 5' and 3' KpnI sites of the 25 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 aAA receptor used herein was designated L-acc (old nomenclature) and was deposited 30 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.
WO98/57940 PCTIUS98/12668 -166 The cell line expressing the human a1A receptor was accorded Accession No. CR 11140, on September 25, 1992. Radioligand Binding Assays: Transfected cells from 5 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 4C, and the supernatant was centrifuged at 30,000 x g for 20 min at 4C. The pellet was suspended in 50mM Tris-HCl, 10 1mM MgCl 2 , and 0.1% ascorbic acid at pH 7.5. Binding of the al antagonist [ 3 H]prazosin (0.5 nM, specific activity 76.2 Ci/mmol) to membrane preparations of LM(tk-) cells was done in a final volume of 0.25 ml and incubated at 37 0 C for 20 min. Nonspecific binding was 15 determined in the presence of 10 pM 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 20 curve-fitting computer program to obtain Ki values. a 2 Human Adrenergic Receptors: To determine the potency of al antagonists at the a2 receptors, LM(tk-) cell lines stably transfected with the genes encoding the 25 a2A, a2B, and a2c receptors were used. The cell line expressing the a2A receptor is designated L-a 2 A, and was deposited on November 6, 1992 under ATCC Accession No. CRL 11180. The cell line expressing the a2B receptor is designated L-NGC-a 2 B, and was deposited on October 25, 30 1989 under ATCC Accession No. CRL10275. The cell line expressing the a2c receptor is designated L-a2c , 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, WO98/57940 PCT/US98/12668 -167 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 5 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 10 10pM phentolamine. The bound radioligand was separated by filtration through GF/B filters using a cell harvester. Determination of the Activity of al Antagonists at 15 Calcium Channels The potency of al 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 20 (Methods in Enzymology 109:513-550, 1985). Briefly, the tissue is minced and homogenized in 50mM Tris-HCl (pH 7.4) containing 0.1mM phenylmethylsulfonyl fluoride. The homogenates are centrifuged at 1000 g for 15 minutes, and the resulting supernatant centrifuged at 25 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 0 C in the presence of [3H]nitrendipine (1 nM), and nonspecific binding determined in the presence 30 of 10pM nifedipine. The bound radioligand is separated by filtration through GF/B filters using a cell harvester. The compounds described above were assayed using cloned 35 human alpha adrenergic receptors. The preferred WO 98/57940 PCT/US98/12668 -168 compounds were found to be selective a1A antagonists. The binding affinities of several compounds are illustrated in the following table.
WO 98/57940 PCT/US98/12668 -169 Binding affinities of selected compounds of the present invention at cloned human alD' a1B and a1A receptors. 5 Example halD ha 1B ha lA Ki Ki Ki 2 11 21 0.5 21 2455 891 21 28 3660 4012 0.7 10 h = human WO 98/57940 PCT/US98/12668 -170 Scheme 1 NH: N-C cone. 8 2 S0 4 ONe OMe O Dioxane 0 Br Reflux 0 2 N Heat r 3C H 3 C 1. Br-(CH2)3NN 2c c2. TFA R Schmm 1: General Synthesis of Piperazine side chains WO 98/57940 PCTIUS98/1 2668 -171 Scheme 2 A-ip-TsOH.H2O H2 N Pd-CN P Ph KPh KPh Ar OH Ar-H N L NA1C13N H H 0 H 3 C OH H 3 C Ph H 3 C Ph Ph-H H2 MeLA. __n.__,_ n_ -N .. . nAC NP N K Ph K Ph A11 Ph PdCH Ph' CO0OH Ph COO~e n. corc. H2S04 N HMeOH H A.. Br-(CH2)n-NHBOC Ar R>C 2. TFA n = 2, 3, 4. ; R =H, Me. Ar Scheme 2: General Synthesis of Piperidine Side Chains WO 98/57940 PCTUS98/1 2668 -172 ]L C )3NHo aSH 4 H 2 or:- (CH 2
)
3 -H2 EtOM 0 Pd-c NN N N NHO S~~.-(C2)mO 3:BH Nytei H2 yiy.pprdn cnann iecan WO 98/57940 PCT/US98/12668 -173 00 49 0 2 x tht Ce ( x -- 0 Os S0 0 0- I Ch WO 98/57940 PCT/US98/12668 -174 0~ a4 O cr4 o o zx 0 0 e- C . 0 m -Z ' °4 C too 0 0 10 d5 WO 98/57940 PCT/US98/1 2668 -175 Ln 0 . . z -d LI TM 0 z U) WO 98/57940 PCTIUS98/12668 -176 0 E uI 0 x 0 u - 0 0 x IW L&0 z 0a 0a 2z, WO 98/57940 PCTIUS98/12668 -177 0 00 M 00 (.4cc WO 98/57940 PCTIUS98/12668 -178 9-4 z -'4 x z z 00 '.4 M 10 A zz C. 0 o 0 r. z u S 0 -- 4 0 ~1-) 0 0 '.4 N - - z U 4. 0 z Aj WO 98/57940 PCT/US98/12668 -17 9 0 0 o 0 2 z ..4 r4 '-4 o 0 w 'a-I --4 a) -C o 0 = U = o c 0 ~ ~ z ~ z U2 - i4 - C4 V C a '.4 6
B'
WO 98/57940 PCTIUS98/12668 -180 h. 2 E lba h. x 16. C C P4 -4 0 01 .1 c lb 0 0 10 I.. 4,4 z 4.1 N 0 0
-Z
.- 4
E
WO 98/57940 PCTIUS98/12668 -181 a0 E 0 000 h. 0 i02 0) 0 00i 000 4)00 V,4 IV 0 0r 0 o~~ =< * 0 ... 04 0 A 000 C4, i~ WO 98/57940 PCT/US98/12668 -182 C1 00 0~,0 x 00 i-4 z 0 Ii 0< = 0 0 E Lu- WO 98/57940 PCT/US98/12668 -183 O K 2
CO
3 O Ph N H B NN'. N N NC __ 0 o
H
2
N-NH
2 NC N NH2 A1C11. :"CN += N Al~) Ph>K.j ------- n Ph> \ N O PhNH _ 2. BH 3 Ph N Ar Ar Ar A r CDI A Ar HO CX~n. X>NH 2 I_. >NH HO-C NOH 2 O OH 0 SNO Ar 0 Ar A= O R-N2 Ar O 1. NaH/THF 0 R N O _ N N 2.4-Nitrophenyl O---0 - H chloroformate 0 Scheme 14. Preparation of Examples 23 and 24 WO 98/57940 PCT/US98/12668 -184 0 K 2
CO
3 OR N C 0NC>CN% 00 0j DAST Ph N N-NH ------ NC 'C: -VI OR NNC H N-NH 2 N H F Ph NC N NH K2C03 NaH C PCHCOBr Ph N KI ah N N.COzBn n HONH , Br 2 HN'NOB N H H Ph .CO Bn Pd (OH) 2
/
C Ph AcO Hi "' N AcO C N - NCO K2C03 PhC N Br"RN. I Ph CN MeO N . Br NK MeOC N2 Scheme 15. Preparation of Side Chains WO 98/57940 PCTIUS98/12668 -185 0 0 ;c0 2 00 0
H
2
N-NH
2 N C--" R2 C+ § 3N B"3 NN Scheo 16. Preparationl of Side Chains (contd..
WO 98/57940 PCT/US98/12668 -186 Ar Ar Ar MeMgBr CDI N MeO, 2 C N2 O 0 -- 0 OH O 1.NaH/THF Ar 0 O2 R-NH2 N 1 0 N N 2.4-Nitrophenyl O--4 0-4 H chloroformate 0 0 Scheme 17. Preparation of Examples 25-29 and 31. r Ar HM Ar 1 .NaH / THF N NN 0 -B+ 0 -- 2 0-- 2.1, 5-Dibromopentane 0 0 Scheme 18. Preparation of Example 30.
WO 98/57940 PCT/US98/12668 -187 -187- /Br- NaBH 4 N Ph Br N N CO7H N Pd (OH) 2 /C -BOC N - 7w,?h N*1- NDMAPECD N J Ph DMAP 0 LiAIH 4 N 0 TFA N 0 N NBOC F F F -~ F 4 0 0N02 N 0 NO0 00A NH ON N N Scheme 19: Preparation of Example 32 WO 98/57940 PCT/US98/12668 -188 O ; co 3 o Ph >C NH NC NC __N-N2 ph N Sh=e 20: Preparation of Side Chain FF F F LiHMDS Pd(OH) 2 /C BrCH 2
CO
2
CH
2 Ph NHO Ph 0 04 F F F F Ph NC m N OH N N O - O DMAPECD, DMAP O O N 0 0 Ph CN Scheme 21: Prepar a tio n of Example 33 WO 98/57940 PCTIUS98/1 2668 -189 zi 0~C 0 E +U CN 0 0N czw WO 98/57940 PCT/US98/1 2668 -190 z9 zl CPO/) cNx z 6uE WO 98/57940 PCT/US98/12668 HOH N -B,., N \N HR 2 2. Trifluoroacetic acid K.. F F 0 0 NO- 2 I 0 R, = 4-F, 4-Br, 4-SCH 3
R.
2 = H, SO 2
CH
3 . 4-F. (2-0CH 3 ,5-F), 4-Br Schbm.24 :Preparation of Examples 38-42 WO 98/57940 PCT/US98/12668 -192 U. Z" zz U.. z U. = -Z 0 I z 1U 0 z < z z z I z U z -I 00 z zI N Z 0 . 0 LL . z 10 WO 98/57940 PCT[US98/12668 -193 LL zz z LL K' -z>=O zz LL.. Z U. 0 E I 0 0 E z Sz I ZJJ 0. E U- 00 U. Izz c WO 98/57940 PCTIUS98/1 2668 U.. -194 z z 0 = z U. /C U.. Nz zz CYO LLL z 'U zz LL = Z > ClCu z 0 00 U.z LL-z 0--U, WO 98/57940 PCTIUS98/1 2668 -195 z LL LL //= 0 >= -6 za 0 cis T. U-c U.R 00 WO 98/57940 PCT/US98/12668 -196 X1 W ]W1 OH
NH
2 - Benzophenone , N 1. t-BuLi / THF - N 0N Rx PhCH 3 , BF 3 .OEt 2 Rx 2. O Rx [ (For example 52, R = fluoro group, x = 2, X 1 W1 W = 0, W1 = 0, and Xl = CH 2 ) 0 MeONH 2 .HC NH 2 NHBoc ONH OH BOC20, CHC13 OH O NH _ -NaH, THF Rx - 3 W Rx W1 X 1 Rx Enantiomers separated 0 1. n-BuLi/THF 0 O NO 2 by chiral HPLC column. NH 2. ClCOOPh-NO2 0I JN ____ ____ ___ 0 NH- _ _ _ N I I I
X
1
I
1 i~[] Rx -- j o 0
H
2 N-R ON NA-R For example 52, R = X1 ]W x Scheme 29: Synthesis of Example 52 and related compounds WO 98/57940 PCT/US98/12668 -197 OH NH2 Benzophenone N 1. t-BuLi / THF N F PhCH3, BF3.OEt2 F F F F 2. >--CHO F O MeONH2.HC1 N2 NABoc OH Boc20, CHC13 OH 0 NH 68% yield j NaH, THF (three steps) F 91% F " F F F Diastereomers separated 0 1. n-BuLi/THF 0 O NO2 by chiral HPLC column. ONH 2. lcCOPh-NO2 0 0O __________ 0 IUNH 0__ _ ON Oc Enantiomers separated F by chiral HPLC column. F F F F 0 0 H2NN F O N k N No k Nb - F F F Scheme 30: Synthesis of Example 53.
WO98/57940 PCTIUS98/12668 -198 .H N O 0 O~H _ NTBDMSC1 OH OH TBDMS-O 0 F F O NOH LiS H2NOH.HCI DMS-0 F TBDM FS F F F LAH, Et20 OH NH 2 1. Boc20, CH2C12 F 2. NaH / THF 3. Separate diastereomers F by column chromatography O 0 O NH NH O N ,R + O\ -1. ClCOOPh-NO2 0H F2. R-NH2 F Only the trans isomer shown. Scheme 31: General synthesis of methylated oxazolidinone.
WO 98/57940 PCT/US98/12668 -199 00 C)) CNCN o 0 la4 0 Q) -IJ cq 41 Cl) C)~ 0 Cl)q C) In 44 U) Q ,q III WO 98/57940 PCT/US98/12668 -200 4
E
HN m C CNQ r C 0 0 0 rncq0 u 0u~ t-1 CN II U4 E-1 Eoo CN* HZ \I C')4 0UN P0Rt WO 98/57940 PCT/US98/1 2668 -201 0 00 0 (N cor a a 0) fn0 CNC~ 0 D4c' 0 N a P.,~ ((D 4I11 WO 98/57940 PCT/US98/1 2668 -202 0 L 0 L0 C9 ~J) z U) Q) (N 1* =A 0 (N Z 02 At 0 uUoL 0 U 0 u~ 0 ZUZ U)) C) (N S0 rl CQ) Cq) 00 zM
Claims (64)
1. A compound having the structure: x x X" N-..R1 N N-...R1 R2 R2 R2 q q qX R 5 R 4 X R 5 R 4 N--R1 or R2 R2 R5 R 4 5 wherein each X is independently 0 or S; wherein q is 1 or 2; wherein each R 2 is independently H; -(CH 2 )tXR 3 ; 10 (CH 2 ) tC(X)NR 3 ; - (CH 2 ) t C O 2 R 3 ; -CO 2 R,; straight chained or branched Ci-C7 alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C2 C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or Cs-C7 cycloalkenyl; 15 wherein each t is an integer from 1 to 4 inclusive; wherein each R 3 is independently H; straight chained or branched Ci-C7 alkyl, straight chained 20 or branched C2-C7 alkenyl, or alkynyl; or C 3-C7 WO 98/57940 PCT/US98/12668 -204 cycloalkyl or C 5 -C 7 cycloalkenyl; wherein R 4 is aryl, heteroaryl, C 1 -C 7 alkyl substituted with one or two aryl, or Ci-C 7 alkyl 5 substituted with one or two heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -CN, -NO 2 , -N(R 3 ) 2 , -COR 3 , (CH 2 )tXR 3 , -(CH2)nC(X)NR 3 , -(CH 2 )nCO 2 R 3 , straight chained or branched Ci-C 7 alkyl, monofluoroalkyl, 10 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; wherein each n independently is an integer from 0 15 to 7 inclusive; wherein R s 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 20 substituted with one or more of F, Cl, Br, I, -CN, -NO 2 , -N(R 3 ) 2 , -COR 3 , -(CH 2 )tXR 3 , -(CH 2 )nC(X)NR 3 , (CH 2 )nCO 2 R 3 , straight chained or branched Cl-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched 25 C 2 -C 7 aminoalkyl, alkenyl or alkynyl, or C3-C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; where R s and one R 2 on adjacent carbon atoms together may form aryl, heteroaryl, indane or 30 tetrahydronaphthyl, C 3 -C 7 cycloalkyl, or heterocycloalkyl wherein one or two heteroatoms may be O, N or S; WO 98/57940 PCT/US98/12668 -205 wherein R 1 is RIO0 5 Ri m R6 Z-N Rio m R7 R10 10 15 RoRo R10-R 1 Z-N ZN-Rya 200R10 [ R10 R 1 0 R 1 0 2s 10 [ m Rqgl ~jfj~Rlo~l or 30 35 WO 98/57940 PCT/US98/12668 -206 0 R 10 o R 10 5 R)K /wm N N--- . N-RI1 qR m RR0 R10 10 where each R 6 is independently H; straight chained or branched Cl-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; 15 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, 20 (CH 2 )nXR 3 , -COR 3 , -(CH 2 )nC(X)N(R 3 ) 2 ,-(CH 2 ) n CO 2 R 3 , -CN, -NO 2 , -N(R 3 ) 2 , -S0 2 R 3 , straight chained or branched C -C7 alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, 25 polyfluorocycloalkyl or C5-C7 cycloalkenyl; where each R 7 is independently H; F; Cl; Br; I; COR 3 ; -C0 2 R 3 ; - (CH 2 ) nXR 3 ; (CH 2 ) nC(X) N (R) 2 ; (CH 2 )nCO 2 R 3 ; -CN; -NO 2 ; -N(R 3 ) 2 ; straight chained or 30 branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or Cs-C7 35 cycloalkenyl, wherein the alkyl, aminoalkyl, WO98/57940 PCT/US98/12668 -207 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, 5 I, -(CH 2 ) nXR 3 , -COR 3 , -(CH 2 ) nC(X) N (R 3 )2, - (CH 2 ) nCO 2 R 3 , CN, -NO 2 , -N(R 3 ) 2 , -S0 2 R 3 , straight chained or branched Ci-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl or alkynyl, or C 3 -C 7 cycloalkyl, 10 monofluorocycloalkyl, polyfluorocycloalkyl or C,-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 ) nXR 3 , -COR 3 , (CH 2 )nC(X)N(R 3 ) 2 ,-(CH2)nCO 2 R 3 , -CN, -NO 2 , -N(R 3 ) 2 , 15 S0 2 R 3 , straight chained or branched C.-C 7 alkyl, straight chained or branched CI-C 7 monofluoroalkyl or polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl or alkynyl, or C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or Cs-C, 20 cycloalkenyl; wherein each R 10 is independently H; (CH 2 )tXR 3 ; (CH 2 )tC(X)NR 3 ; (CH 2 )tCO 2 R 3 ; straight chained or branched Ci-C 7 alkyl or carboxamidoalkyl; straight 25 chained or branched C 2 -C 7 aminoalkyl, alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; wherein R 1 is aryl, heteroaryl, Ci-C 7 alkyl substituted with one or two aryl, or C 1 -C 7 alkyl 30 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, -NO 2 , N(R 3 ) 2 , -COR 3 , -(CH 2 ) nXR 3 , -(CH 2 ) nC(X)NR 3 , -(CH 2 ) nCO 2 R 3 , straight chained or branched C 1 -C 7 alkyl, 35 monofluoroalkyl, polyfluoroalkyl, or WO 98/57940 PCT/US98/12668 -208 carboxamidoalkyl, straight chained or branched C 2 C7 aminoalkyl, alkenyl, or alkynyl, or C3-C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; 5 wherein each m independently is an integer from 0 to 3 inclusive; wherein Z. is 10 0 R2 R0 15 R2 R9 0 R2 R10 20 R9 n R2 R9 R1 0 25 O 2 R10 30 R n R2 R R10 R9 35 WO 98/57940 PCT/US98/12668 -209 5 R10 R[ 2 •R 9 RR10 10 RI0 R9 R2 R10 15 0 R2 R9 R9 n Im 20 R2 R m R10 R 9 m 25 O 0 Ri0 Ri0 m R8R9 Ri0 30 ]m m 30 R135 R10 R9 R 1 35 WO 98/57940 PCT/US98/12668 -210 R2R2 R10 R2 2 R9 or 10 O R 9 R2 [IR2 -R10 15 m 22 10R0o 20 or C2-C7 alkenyl, wherein the C2-C7 alkenyl may be unsubstituted or substituted with one or more R 9 groups; 25 where R2 is H; (CH2tXR 3 ; (CH 2 )tC(X)NR 3 ; (CH2tCO 2 R 3 ; straight chained or branched C 1 -C 7 alkyl, carboxamidoalkyl; straight chained or branched C2 C7 aminoalkyl, alkenyl, or alkynyl; or Cz-C, 30 cycloalkyl or C5-C7 cycloalkenyl; where each R 9 is independently H; F; Cl; Br; I; (CH 2 )mXR 3 ; (CH 2 )mC (X)NR 3 ; (CH 2 )mCO 2 R 3 ; straight chained or branched C0-C7 alkyl, monofluoroalkyl, 35 polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; WO 98/57940 PCT/US98/12668 -211 straight chained or branched C 2 -C 7 alkenyl, or alkynyl; or C 3 -C. 7 cycloalkyl or C 5 -C 7 cycloalkenyl; wherein Y is S, O, or NR,; 5 or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein the compound comprises the (+) enantiomer. 10
3. The compound of claim 1, wherein the compound comprises the (-) enantiomer.
4. The compound of claim 1, wherein the compound 15 comprises a cis isomer.
5. The compound of claim 1, wherein the compound comprises a trans isomer. 20
6. The compound of claim 1, wherein R i is R10 25 R10 R6 1t R6 30 Rio R4 is aryl or heteroaryl, wherein the aryl may be substituted with one or more of F, Cl, -(CH 2 )tOR 3 , 35 (CH 2 )nC(0)NR 3 , -(CH 2 )nCO 2 R 3 , straight chained or WO 98/57940 PCT/US98/12668 -212 branched C 1 -C 7 alkyl or monofluoroalkyl; and Z is 50 o R 2 R10 t n 10 R2 R9 Ri0 15 2 R9 20 R or 25 0 R10 Rlo 30N M Rg 10 R R10 R9 R 35
7. The compound of claim 6, wherein R 4 is pyridyl or WO 98/57940 PCT/US98/12668 -213 phenyl, wherein the phenyl may be substituted with one or more of F, Cl, -(CH 2 )tOR 3 , -(CH2)nC(O)NR 3 , (CH2)nCO 2 R 3 , straight chained or branched CI-C 7 alkyl or monofluoroalkyl. 5
8. The compound of claim 7, wherein each R 6 is independently aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH 2 )nXR 3 , -COR 3 , 10 (CH 2 )nC(X)N(R 3 ) 2 ,-(CH 2 ) nCO 2 R 3 , -CN, -NO 2 , -N(R 3 ) 2 , S0 2 R 3 , straight chained or branched Cl-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl.
9. The compound of claim 8, wherein R 7 is H; -CN; 15 CO 2 R 3 ; -C(O)NR 3 ; -(CH2)mXR 3 ; unsubst-ituted or substituted aryl; Ci-C 3 alkyl; or -OCOR 3 .
10. The compound of claim 9, wherein the R 4 is phenyl, wherein the phenyl may be substituted with at least 20 one of F or Cl.
11. The compound of claim 10 having the structure: 0 0 O N)KN Rl N.R1 R 2 ] R2 R2 4 R2 L 7 L q / q /q R 5 R4 R 5 R4 or WO 98/57940 PCT/US98/12668 -214
12. The compound of claim 11, wherein Z is: R9 5 R 2 R10 ti t 0 R2 R10 i00 10
13. The compound of claim 12, wherein q is 1 and R i is 15 Rio R 1 0 m R 6 Z-N 20 / ]R 7 RI R0 25
14. The compound of claim 13, wherein at least one R 2 is Ci-C 3 alkyl.
15. The compound of claim 13, wherein R 4 is phenyl 30 substituted with at least one of F or Cl.
16. The compound of claim 15, wherein R 4 is phenyl substituted with at least two F. 35
17. The compound of claim 12, wherein R 4 is 3,4- WO 98/57940 PCT/US98/12668 -215 difluorophenyl.
18. The compound of claim 13, wherein R 6 is pyridyl, phenyl, or phenyl substituted with one or more of 5 F, Cl, Br, I, -(CH 2 )nXR 3 , -COR 3 , -(CH2)nC(X)N(R 3 ) 2 , (CH2) nCO 2 R 3 , -CN, -NO 2 , -N(R 3 ) 2 , -S0 2 R 3 , straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl. 10
19. The compound of claim 13, wherein R 7 is H; -CN; or -CO 2 R 3 .
20. The compound of claim 13, wherein R 9 is F; -OH; C i C 3 alkyl; or -(CH 2 ) mXR 3 . 15
21. The compound of claim 18, wherein R 6 is 4 fluorophenyl.
22. A pharmaceutical composition comprising a 20 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 25 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. 30
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. 35
26. The pharmaceutical composition of claim 25 wherein WO 98/57940 PCT/US98/12668 -216 the amount of the compound is from about 0.1 mg to about 60 mg.
27. The pharmaceutical composition of claim 26 wherein 5 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 10 solution.
29. The pharmaceutical composition of claim 22, wherein the carrier is a solid and the composition is a tablet. 15
30. The pharmaceutical composition of claim 22, wherein the carrier is a gel and the composition is a suppository. 20
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. 25
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. 30
33. A method of claim 32, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia. 35 WO 98/57940 PCT/US98/12668 -217
34. The method of claim 33, wherein the compound effects treatment of benign prostatic hyperplasia by relaxing lower urinary tract tissue. 5
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 10 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 15 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 20 to treatment by antagonism of the a1A receptor which comprises administering to the subject an amount of the compound of claim 1 effective to treat the disease. 25
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. 30
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. 35 WO98/57940 PCT/US98/12668 -218
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. 5
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 10 prostatic hyperplasia.
43. The method of claim 42, wherein the compound effects treatment of benign prostatic hyperplasia by relaxing lower urinary tract tissue. 15
44. The method of claim 43, wherein lower urinary tract tissue is prostatic smooth muscle.
45. A method of treating a subject suffering from 20 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. 25
46. The method of claim 45, wherein the 5-alpha reductase inhibitor is finasteride.
47. A method of treating a subject suffering from 30 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. 35 WO98/57940 PCTIUS98/12668 -219
48. The method of claim 47, wherein the 5-alpha reductase inhibitor is finasteride.
49. A pharmaceutical composition comprising a 5 therapeutically effective amount of the compound of claim 1 in combination with a therapeutically effective amount of finasteride and a pharmaceutically acceptable carrier. 10
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. 15
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. 20
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. 25
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. 30
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 35 subject an amount of the compound of claim 1 WO 98/57940 PCT/US98/12668 -220 effective to relax lower urinary tract tissue.
56. The method of claim 55, wherein the lower urinary tract tissue is prostatic smooth muscle. 5
57. A trans (+) isomer of the compound of claim 21, wherein the compound has the structure: 0 0 OOA HF F F 10
58. The compound of claim 1, wherein the compound has the structure: 0 0 15 20 F F WO 98/57940 PCT/US98/12668 -221
59. The compound of claim 1, wherein the compound has the structure: 5 0 0 0 F 10 F F 15
60. The compound of claim 1, wherein the compound has the structure: 20 0 200 CN 25 F 30
61. The compound of claim 1, wherein the compound has the structure: 35 WO 98/57940 PCT/US98/12668 -222 0 0 O0 NH 5 CN 10
62. A compound having the structure: F 15 F 0 Ph o PCO 2 CH 3 20 EN ( 0 25
63. A compound having the structure: X 30 X IK Rl 3 0 Ew X 0 R 5 X T1 R 4 R 35 WO98/57940 PCT/US98/12668 -223 wherein each W is an integer from 0 to 3 inclusive; wherein each W1 is an integer from 0 to 3 inclusive; 5 wherein each X is independently O or S; wherein X1 is O, S, NR 3 ; 10 wherein each R 2 is independently H; -(CH 2 )tXR 3 ; (CH 2 )tC(X)NR 3 ; -(CH 2 )tCO 2 R 3 ; -C0 2 R 3 ; straight chained or branched Ci-C 7 alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C 2 C 7 alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or C,-C 7 15 cycloalkenyl; wherein each t is an integer from 1 to 4 inclusive; wherein each R 3 is independently H; straight 20 chained or branched Ci-C 7 alkyl, straight chained or branched C 2 -C 7 alkenyl, or alkynyl; or C3-C. cycloalkyl or Cs-C 7 cycloalkenyl; wherein R 4 is aryl, heteroaryl, Ci-C 7 alkyl 25 substituted with one or two aryl, or Ci-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, -NO 2, -N(R 3 ) 2 , -COR 3 , (CH 2 )tXR 3 , -(CH 2 )nC(X)NR 3 , -(CH 2 )nCO 2 R 3 , straight 30 chained or branched Ci-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 s-C 7 cycloalkenyl; 35 wherein each n independently is an integer from 0 WO 98/57940 PCT/US98/12668 -224 to 7 inclusive; wherein R s is H; aryl, Ci-C 7 alkyl substituted with aryl, heteroaryl, or C 1 -C 7 alkyl substituted with 5 heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -CN, -NO 2 , -N(R 3 ) 2 , -COR 3 , -(CH2)tXR 3 , -(CH2)nC(X)NR 3 , (CH 2 )nCO 2 R 3 , straight chained or branched Cl-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl or 10 carboxamidoalkyl, or straight chained or branched C 2 -C 7 aminoalkyl, alkenyl or alkynyl, or C3-C 7 cycloalkyl or Cs-C 7 cycloalkenyl; 15 wherein R i is Rio0 20 RIO mt R6 Z-tN 3 R10 Rio ]R Rio 25 30 35 WO 98/57940 PCT/US98/12668 -225 Rlo #JRlo /Z-N N-Rll R0 [ q R lO 10 R1oR10 10 20[ 10 EM R10 N N or 15 qR 0 R 1 0 RRR 1 0 N N N-R 1 RR 10 25 where each R 6 is independently H; straight chained or branched Cl-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; 30 straight chained or branched C 2 -C 7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C,-C7 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, 35 (CH 2 )nXR 3 , -COR 3 , -(CH2)nC(X)N(R 3 ) 2,- (CH2)nCO 2 R 3 , -CN, WO98/57940 PCT/US98/12668 -226 -NO 2 , -N(R 3 ) 2 , -SO 2 R 3 , straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, 5 polyfluorocycloalkyl or C5-C7 cycloalkenyl; where each R 7 is independently H; F; Cl; Br; I; COR3; -CO, 2 R 3 ; -(CH 2 ) nXR 3 ; (CH 2 ) nC(X)N(R 3 ) 2 ; (CH 2 )nCO 2 R 3 ; -CN; -NO 2 ; -N(R 3 ) 2 ; straight chained or 10 branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight.chained or branched C2-C 7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 15 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, 20 I, -(CH 2 ) nXR 3 , -COR 3 , -(CH 2 )nC (X)N(R 3 ) 2 , - (CH2) nCO 2 R 3 , CN, -NO 2 , -N(R 3 ) 2 , -S0 2 R 3 , straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C 7 alkenyl or alkynyl, or C3-C7 cycloalkyl, 25 monofluorocycloalkyl, polyfluorocycloalkyl or C-C7 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, CIL, Br, I, -(CH 2 )nXR 3 , -COR 3 , (CH 2 ) nC(X)N(R 3 ) 2 ,-(CH 2 ) nCO 2 R 3 , -CN, -NO 2 , -N(R 3 ) 2 , 30 SO 2 R 3 , straight chained or branched C1-C7 alkyl, straight chained or branched C_-C7 monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 35 cycloalkenyl; WO98/57940 PCT/US98/12668 -227 wherein each Ro 10 is independently H; (CH 2 )tXR 3 ; (CH 2 )tC(X)NR 3 ; (CH 2 )tCO 2 R 3 ; straight chained or branched CI-C 7 alkyl or carboxamidoalkyl; straight chained or branched C 2 -C 7 aminoalkyl, alkenyl, or 5 alkynyl; or C 3 -C 7 cycloalkyl or C,-C 7 cycloalkenyl; wherein Ril is aryl, heteroaryl, Ci-C 7 alkyl substituted with one or two aryl, or C,-C 7 alkyl substituted with one or two heteroaryl; wherein any 10 aryl or heteroaryl independently may be substituted with one or more of F, Cl, Br, I, -CN, -NO 2 , N(R 3 ) 2 , -COR 3 , -(CH 2 )nXR 3 , -(CH 2 )nC(X)NR 3 , -(CH 2 )nCO 2 R 3 , straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, or 15 carboxamidoalkyl, straight chained or branched C 2 C 7 aminoalkyl, alkenyl, or alkynyl, or C3-C 7 cycloalkyl or Cs-C 7 cycloalkenyl; wherein each m independently is an integer from 0 20 to 3 inclusive; wherein Z is 0 R10 R2 R9 R10 30 35 WO 98/57940 PCT/US98/12668 -228 R 2 10 R9 n 10 5R2 R10 R100R R9 25 0 R10 R10 R9 R2 R10 30 35 WO 98/57940 PCT/US98/12668 -229 5 0 R2 n R',2 R-10 R9m 10 15 O R1o R1o m R8R R1 o 20 m m R10 R10 R9 R 1 0 25 0 R 2 R10 R2 30 R n or SR2 R10 R2 R 35 WO98/57940 PCT/US98/12668 -230 O R 9 5 ~R2 R2 10 5 m R9 R2 R2 R10 10 or C 2 -C 7 alkenyl, wherein the C 2 -C 7 alkenyl may be unsubstituted or substituted with one or more R 9 groups; where R8 is H; (CH 2 ) tXR 3 ; (CH 2 ) tC(X)NR 3 ; (CH 2 ) tCO 2 R 3 ; 15 straight chained or branched Ci-C 7 alkyl, carboxamidoalkyl; straight chained or branched C 2 C 7 aminoalkyl, alkenyl, or alkynyl; or C3-C 7 cycloalkyl or C5-C 7 cycloalkenyl; 20 where each R 9 is independently H; F; Cl; Br; I; (CH 2 )mXR 3 ; (CH 2 )mC(X)NR 3 ; (CH 2 )mCO 2 R 3 ; straight chained or branched Ci-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, or 25 alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; wherein Y is S, O, or NR 8 ; or a pharmaceutically acceptable salt thereof. 30 WO 98/57940 PCT/US98/12668 -231
64. A compound having the structure: 0 xx NR 1 R 5 R 4 X R 5 R 4 N,..R 1 or R 2 R5 R4 5 wherein each X is independently 0 or S; wherein q is 1 or 2; wherein each R 2 is independently H; -(CH 2 ) t X R 3 ; 10 (CH 2 ) tC(X)NR 3 ; -(CH 2 ) tCO 2 R 3 ; -C0 2 R 3 ; straight chained or branched C -C7 alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C2 C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl; 15 wherein each t is an integer from 1 to 4 inclusive; wherein each R 3 is independently H; straight chained or branched Ci-C7 alkyl, straight chained 20 or branched C2-C7 alkenyl, or alkynyl; or C3-C7 WO 98/57940 PCT/US98/12668 -232 cycloalkyl or Cs-C 7 cycloalkenyl; wherein R 4 is aryl, heteroaryl, Cl-C 7 alkyl substituted with one or two aryl, or C 1 -C 7 alkyl 5 substituted with one or two heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -CN, -NO 2 , -N(R) 2 , -COR 3 , (CH 2 ) tXR 3 , - (CH 2 ) nC (X)NR 3 , - (CH 2 ) nCO 2 R 3 , straight chained or branched Ci-C 7 alkyl, monofluoroalkyl, 10 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; wherein each n independently is an integer from 0 15 to 7 inclusive; wherein R 5 is H; aryl, Cl-C 7 alkyl substituted with aryl, heteroaryl, or Cl-C 7 alkyl substituted with heteroaryl; wherein the aryl or heteroaryl may be 20 substituted with one or more of F, Cl, Br, I, -CN, -NO 2 , -N(R 3 ) 2 , -COR 3 , -(CH 2 )tXR 3 , -(CH 2 )nC(X)NR 3 , (CH 2 )nCO 2 R 3 , straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched 25 C 2 -C 7 aminoalkyl, alkenyl or alkynyl, or C3-C, cycloalkyl or Cs-C 7 cycloalkenyl; where R s 5 and one R 2 on adjacent carbon atoms together may form aryl, heteroaryl, indane or 30 tetrahydronaphthyl, C 3 -C 7 cycloalkyl, or heterocycloalkyl wherein one or two heteroatoms may be O, N or S; WO 98/57940 PCT/US98/12668 -233 wherein R 1 is R10 5 R10 m R6 Z-N ]R7 R10 m R R10 10 15 RR0R 10 R 1 0 4q- Rj 0 R'o Rj Z N-RIg 20 R 1 0 []qRo 25oRlo 0jR1 q ] mR7 or 30 35 WO 98/57940 PCT/US98/12668 -234 0 R 10 5 [ N----R1 R10 Rl0 10 where each R 6 is independently H; straight chained or branched C 1 -C 7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; 15 straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or Cs-C 7 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, 20 (CH 2 )nXR 3 , -COR 3 , -(CH 2 )n C (X)N(R) 2 1 -(CH 2 )nCO 2 R 3 , -CN, -NO 2 , -N(R 3 ) 2 , -S0 2 R 3 , straight chained or branched C 1 -C ' , alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl or alkynyl, or C 3 -C 7 cycloalkyl, monofluorocycloalkyl, 25 polyfluorocycloalkyl or C 5 -C 7 cycloalkenyl; where each R 7 is independently H; F; Cl; Br; I; COR 3 ; -C0 2 R 3 ; -(CH 2 ) nXR 3 ; (CH 2 ) nC (X) N (R 3 ) 2 ; (CH 2 )nCO 2 R 3 ; -CN; -NO 2 ; -N(R 3 ) 2; straight chained or 30 branched Ci-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 Cs-C 35 cycloalkenyl, wherein the alkyl, aminoalkyl, WO 98/57940 PCT/US98/12668 -235 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, 5 I, -(CH 2 ) nXR 3 , -COR 3 , - (CH 2 ) nC(X)N(R 3 ) 2 , - (CH 2 ) nCO 2 R 3 , CN, -NO 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, 10 monofluorocycloalkyl, polyfluorocycloalkyl or Cs-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 ) nXR 3 , -COR 3 , (CH 2 ) nC(X) N (R 3 ) 2 ,-(CH 2 ) nCO 2 R3, -CN, -NO 2 , -N(R 3 ) 2 , 15 S0 2 R 3 , straight chained or branched Cl-C 7 alkyl, straight chained or branched C,-C 7 monofluoroalkyl or polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl or alkynyl, or C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or Cs-C 7 20 cycloalkenyl; wherein each R 10 is independently H; (CH 2 )tXR 3 ; (CH 2 )tC(X)NR 3 ; (CH 2 )tCO 2 R 3 ; straight chained or branched C 1 -C 7 alkyl or carboxamidoalkyl; straight 25 chained or branched C 2 -C 7 aminoalkyl, alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or Cs-C 7 cycloalkenyl; wherein R 11 is aryl, heteroaryl, C 1 -C, alkyl substituted with one or two aryl, or C 1 -C, alkyl 30 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, -NO 2 , N(R 3 ) 2 , -COR 3 , -(CH 2 )nXR 3 , -(CH 2 )nC(X)NR 3 , -(CH 2 )nCO 2 R 3 , straight chained or branched Cl-C 7 alkyl, 35 monofluoroalkyl, polyfluoroalkyl, or WO 98/57940 PCT/US98/12668 -236 carboxamidoalkyl, straight chained or branched C 2 C 7 aminoalkyl, alkenyl, or alkynyl, or C3-C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; 5 wherein each m independently is an integer from 0 to 3 inclusive; wherein Z is 10 0 R2 R10 IR9 n 15 2 R 1 R2 R10 20 25 300 5 R2 R10 30 R n R2 R9 R10 35 WO 98/57940 PCT/US98/12668 -237 5 1io0 )10 09 J 10R2 R0 15 o R2 20 20 R2 nR10 25 O R10 R10 30 m R 1 0 R10 R9 R1, or 35 WO 98/57940 PCT/US98/12668 -238 5 O2 R2R1 10 15 20 or C 2 -C7 alkenyl, wherein the C 2 -C 7 alkenyl may be unsubstituted or substituted with one or more R 9 groups; 25 where R 8 is H; (CH 2 )tXR 3 ; (CH 2 )tC(X)NR 3 ; (CH 2 )tCO 2 R 3 ; straight chained or branched C 1 -C 7 alkyl, carboxamidoalkyl; straight chained or branched C 2 C 7 aminoalkyl, alkenyl, or alkynyl; or Cz-C, 30 cycloalkyl or C 5 -C 7 cycloalkenyl; where each R 9 is independently H; F; Cl; Br; I; (CH 2 )mXR 3 ; (CH 2 )mC (X)NR 3 ; (CH 2 )mCO 2 R 3 ; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl, 35 polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; WO 98/57940 PCT/US98/12668 -239 straight chained or branched C 2 -C 7 alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; wherein Y is S, 0, or NR,; 5 or a pharmaceutically acceptable salt thereof. 10 15 20 25 30 35
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US87784697A | 1997-06-18 | 1997-06-18 | |
| US08/877846 | 1997-06-18 | ||
| PCT/US1998/012668 WO1998057940A1 (en) | 1997-06-18 | 1998-06-17 | Heterocyclic substituted piperidines and uses thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU8149898A true AU8149898A (en) | 1999-01-04 |
| AU740064B2 AU740064B2 (en) | 2001-10-25 |
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|---|---|---|---|
| AU81498/98A Ceased AU740064B2 (en) | 1997-06-18 | 1998-06-17 | Heterocyclic substituted piperidines and uses thereof |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0988295A4 (en) |
| JP (1) | JP2002505683A (en) |
| AU (1) | AU740064B2 (en) |
| CA (1) | CA2294549A1 (en) |
| WO (1) | WO1998057940A1 (en) |
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| 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 |
| GB2344821A (en) | 1998-12-17 | 2000-06-21 | Merck & Co Inc | Crystalline pharmaceutically acceptable salt of an oxazolidinone derivative |
| US6046331A (en) * | 1998-12-17 | 2000-04-04 | 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 |
| GB2355264A (en) | 1999-09-30 | 2001-04-18 | Merck & Co Inc | Spirohydantoin derivatives useful as alpha 1a adrenoceptor antagonists |
| GB2355263A (en) | 1999-09-30 | 2001-04-18 | Merck & Co Inc | Lactam and cyclic urea derivatives useful as alpha 1a adrenoceptor antagonists |
| GB2355457A (en) | 1999-09-30 | 2001-04-25 | Merck & Co Inc | Novel spirotricyclic substituted azacycloalkane derivatives useful as alpha 1a adrenoceptor antagonists |
| GB2355456A (en) | 1999-09-30 | 2001-04-25 | Merck & Co Inc | Novel arylhydantoin derivatives useful as alpha 1a adrenoceptor antagonists |
| EP2125750B1 (en) | 2007-02-26 | 2014-05-21 | Vitae Pharmaceuticals, Inc. | Cyclic urea and carbamate inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
| AR069207A1 (en) | 2007-11-07 | 2010-01-06 | Vitae Pharmaceuticals Inc | CYCLIC UREAS AS INHIBITORS OF THE 11 BETA - HIDROXI-ESTEROIDE DESHIDROGENASA 1 |
| JP5490014B2 (en) | 2007-12-11 | 2014-05-14 | ヴァイティー ファーマシューティカルズ，インコーポレイテッド | 11β-hydroxysteroid dehydrogenase type 1 cyclic urea inhibitor |
| US8114868B2 (en) | 2008-07-25 | 2012-02-14 | Boehringer Ingelheim International Gmbh | Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 |
| TW201016691A (en) | 2008-07-25 | 2010-05-01 | Boehringer Ingelheim Int | Inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
| WO2010089303A1 (en) | 2009-02-04 | 2010-08-12 | Boehringer Ingelheim International Gmbh | CYCLIC INHIBITORS OF 11 β-HYDROXYSTEROID DEHYDROGENASE 1 |
| MA33216B1 (en) | 2009-04-30 | 2012-04-02 | Boehringer Ingelheim Int | 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 |
| WO2011002910A1 (en) | 2009-07-01 | 2011-01-06 | Vitae Pharmaceuticals, Inc. | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
| EP2582698B1 (en) | 2010-06-16 | 2016-09-14 | Vitae Pharmaceuticals, Inc. | Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use |
| EP2585444B1 (en) | 2010-06-25 | 2014-10-22 | Boehringer Ingelheim International GmbH | Azaspirohexanones as inhibitors of 11-beta-hsd1 for the treatment of metabolic disorders |
| BR112013010021A2 (en) | 2010-11-02 | 2019-09-24 | Boehringer Ingelheim Int | pharmaceutical combinations for the treatment of metabolic disorders. |
| EP2906221B1 (en) | 2012-10-11 | 2019-05-15 | Southern Research Institute | Urea and amide derivatives of aminoalkylpiperazines and use thereof |
| AU2019382504A1 (en) * | 2018-11-20 | 2021-06-03 | Sironax Ltd | Cyclic ureas |
| CN116003380B (en) * | 2023-01-31 | 2024-07-05 | 天津大学 | Fingerprint identification probe, developer and medium surface latent fingerprint fluorescence imaging method |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3334098A (en) * | 1964-05-07 | 1967-08-01 | American Cyanamid Co | 1-monocarbocyclic aryl-3-amino-alkanoyl-2-imidazolidinones |
| CH611898A5 (en) * | 1975-06-06 | 1979-06-29 | Hoffmann La Roche | |
| US4377578A (en) * | 1976-12-21 | 1983-03-22 | Janssen Pharmaceutica, N.V. | Piperazine derivatives |
| US4410540A (en) * | 1981-11-04 | 1983-10-18 | Merrell Dow Pharmaceuticals Inc. | Cardiotonic 4-aroylimidazolidin-2-ones |
| JPH0713017B2 (en) * | 1986-06-18 | 1995-02-15 | 日本ケミファ株式会社 | Pharmaceutical composition having brain cell protective action |
| JPH0755937B2 (en) * | 1986-07-29 | 1995-06-14 | 日本曹達株式会社 | Oxa (thia) zolidine derivative, its production method and acaricide |
| US5202345A (en) * | 1987-08-19 | 1993-04-13 | Shionogi & Co., Ltd. | Carbamoylpyrrolidone derivatives and drugs for senile dementia |
| FR2698359B1 (en) * | 1992-11-25 | 1995-10-27 | Rhone Poulenc Agrochimie | DERIVATIVES OF 2-ALKOXY 2-IMIDAZOLINE-5-ONES FUNGICIDES. |
| JPH09504272A (en) * | 1993-09-15 | 1997-04-28 | メルク シヤープ エンド ドーム リミテツド | Imidazolone and oxazolone derivatives as dopamine antagonists |
| NZ297278A (en) * | 1994-11-16 | 1999-06-29 | Synaptic Pharma Corp | 4-aryl dihydropyrimidine derivatives end medicaments |
| WO1997017969A1 (en) * | 1995-11-16 | 1997-05-22 | Synaptic Pharmaceutical Corporation | Dihydropyrimidines and uses thereof |
-
1998
- 1998-06-17 EP EP98931350A patent/EP0988295A4/en not_active Withdrawn
- 1998-06-17 CA CA002294549A patent/CA2294549A1/en not_active Abandoned
- 1998-06-17 AU AU81498/98A patent/AU740064B2/en not_active Ceased
- 1998-06-17 JP JP50477899A patent/JP2002505683A/en active Pending
- 1998-06-17 WO PCT/US1998/012668 patent/WO1998057940A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU740064B2 (en) | 2001-10-25 |
| EP0988295A1 (en) | 2000-03-29 |
| JP2002505683A (en) | 2002-02-19 |
| EP0988295A4 (en) | 2003-08-13 |
| CA2294549A1 (en) | 1998-12-23 |
| WO1998057940A1 (en) | 1998-12-23 |
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