AU740064B2 - Heterocyclic substituted piperidines and uses thereof - Google Patents

Heterocyclic substituted piperidines and uses thereof Download PDF

Info

Publication number
AU740064B2
AU740064B2 AU81498/98A AU8149898A AU740064B2 AU 740064 B2 AU740064 B2 AU 740064B2 AU 81498/98 A AU81498/98 A AU 81498/98A AU 8149898 A AU8149898 A AU 8149898A AU 740064 B2 AU740064 B2 AU 740064B2
Authority
AU
Australia
Prior art keywords
branched
straight chained
alkyl
compound
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
AU81498/98A
Other versions
AU8149898A (en
Inventor
T. G. Murali Dhar
Charles Gluchowski
Yoon T Jeon
Bharat Lagu
Mohammad R Marzabadi
Dhanapalan Nagarathnam
Dake Tian
Wai C Wong
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
H Lundbeck AS
Original Assignee
Synaptic Pharmaceutical Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Synaptic Pharmaceutical Corp filed Critical Synaptic Pharmaceutical Corp
Publication of AU8149898A publication Critical patent/AU8149898A/en
Application granted granted Critical
Publication of AU740064B2 publication Critical patent/AU740064B2/en
Assigned to H. LUNDBECK A/S reassignment H. LUNDBECK A/S Alteration of Name(s) in Register under S187 Assignors: SYNAPTIC PHARMACEUTICAL CORPORATION
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Description

WO 98/57940 PCT/US98/12668 -1- HETEROCYCLIC SUBSTITUTED PIPERIDINES AND USES THEREOF Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
Background of the Invention The designation is the appellation recently approved by the IUPHAR Nomenclature Committee for the previously designated cloned subtype as outlined in the 1995 Receptor and Ion Channel Nomenclature Supplement (Watson and Girdlestone, 1995). The designation 1A is used throughout this application and the supporting tables and figures to refer to this receptor subtype. At the same time, the receptor formerly designated a1A was renamed a,.D The new nomenclature is used throughout this application.
Stable cell lines expressing these receptors are described herein; however, these cell lines were deposited with the American Type Culture Collection (ATCC) under the old nomenclature (infra).
Benign Prostatic Hyperplasia (BPH), also called Benign Prostatic Hypertrophy, is a progressive condition which is characterized by a nodular enlargement of prostatic tissue resulting in obstruction of the urethra. This results in increased frequency of urination, nocturia, a poor urine stream and hesitancy or delay in starting the urine flow. Chronic consequences of BPH can include hypertrophy of bladder smooth muscle, a decompensated WO 98/57940 PCT/US98/12668 -2bladder and an increased incidence of urinary tract infection. The specific biochemical, histological and pharmacological properties of the prostate adenoma leading to the bladder outlet obstruction are not yet known. However, the development of BPH is considered to be an inescapable phenomenon for the aging male population. BPH is observed in approximately 70% of males over the age of 70. Currently, in the United States, the method of choice for treating BPH is surgery (Lepor, Urol. Clinics North Amer., 17, 651 (1990)) Over 400,000 prostatectomies are performed annually (data from 1986) Transurethral resection of the prostate (TURP) was used in approximately 180,000 men in the United States in 1996. This surgical procedure results in significant benefit. However, because of its potential adverse consequences, surgery is an unattractive alternative for many patients and is not recommended for elderly patients due to the potential for complications.
Another surgical procedure, transurethral needle ablation (TUNA), was recently approved by the FDA and may have the advantage of possible use on an out-patient basis under local anesthesia. However, initial results of a recent study comparing TURP and TUNA show a lower level of efficacy in TUNA than in TURP with respect to increasing urinary flow.
A medicinal alternative to surgery is clearly very desirable. The limitations of surgery for treating BPH include the morbidity rate of an operative procedure in elderly men, persistence or recurrence of obstructive and irritative symptoms, as well as the significant cosL of surgery.
WO 98/57940 PCTIUS98/12668 -3a-Adrenergic receptors (McGrath, et. al. Med. Res. Rev., 9, 407-533, 1989) are specific neuroreceptor proteins located in the peripheral and central nervous systems on tissues and organs throughout the body. These receptors are important switches for controlling many physiological functions and, thus, represent important targets for drug development. In fact, many aadrenergic drugs have been developed over the past years. Examples include clonidine, phenoxybenzamine and 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 properties of the endogenous neurotransmitter norepinephrine, and antagonists (phenoxybenzamine and prazosin are antagonists), which act to block the effects of norepinephrine. Many of these drugs are effective but also produce unwanted side effects (for example, clonidine produces dry mouth and sedation in addition to its antihypertensive effects).
During the past 15 years a more precise understanding of a-adrenergic receptors and their drugs has evolved 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--a and ac--existed in the central and peripheral nervous 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: aA (new nomenclature), alB, alD (new nomenclature), a 2 A, a2B and a2c (Bylund, FASEB 6, 832 (1992)). In many cases, WO 98/57940 PCTIUS98/12668 -4it 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.
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 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 a-receptors located on the prostate. However, this drug also produces significant side effects such as dizziness and asthenia which severely limit its use in treating patients on a chronic basis. More recently, the a-adrenergic antagonists prazosin and terazosin have also been found to be useful for treating BPH. However, these drugs also produce untoward side effects. It has recently been discovered that the a A receptor is responsible for mediating the contraction of human prostate smooth muscle (Gluchowski, C. et. al., WO 94/10989, 1994; Forray, C. et. al., Mol. Pharmacol. 45, 703, 1994).
This discovery indicates that the a1A antagonists may be effective agents for the treatment of BPH with decreased side effects. Further studies have indicated that the alA receptor may also be present in other lower urinary tract tissues, such as urethral smooth muscle (Ford et al. Br. J. Pharmacol., 114, 24P, (1995)).
This invention is directed to oxazolidinone compounds which are selective antagonists for cloned human alA receptors. This invention is also related to uses of WO 98/57940 PCT/US98/12668 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- S4, 1989), benign prostatic hyperplasia, impotency (Milne and Wyllie, EP 0 459 666 A2, 1991), sympathetically mediated pain (Campbell, WO 92/14453, 1992), cardiac arrhythmia (Spiers, et. al.,J.
Cardiovascular Pharmacol., 16, 824-830, 1990) and for the treatment of any disease where antagonism of the cIA receptor may be useful.
WO 98/57940 WO 9857940PCTIUS98/1 2668 -6- Sumimary of the Invent ion This invention is directed to a compound having the structure: x X1K MRl R2 R2 q
R
5 R4 or x R2
R
R
5
R
4 x NR2
R
5
R
4 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
(CH
2 )tC(X)NR 3
(CH
2 )tCO 2
R
3 -C0 2
R
3 straight chained or branched Cl-C. alkyl, aininoalkyl, carboxamidoalkyl; straight chained or branched C 2 -C.7 alkenyl, or alkynyl; or C 3
-C
7 cycjloalkyl or C,-C 7 cycloalkenyl; wherein each t is an integer from 1 to 4 inclusive; 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 cycloalkyl or C 5-C-7 WO 98/57940 PCT[US98/12668 -7cycloalkenyl; wherein R 4 is aryl, heteroaryl, Ci-C 7 alkyl substituted with one or two aryl, or Cl-C alkyl substituted with one or two heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, CN, -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 C-C, alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C 2
-C
7 aminoalkyl, alkenyl or alkynyl, or C 3 cycloalkyl or C 5 cycloalkenyl; wherein each n independently is an integer from 0 to 7 inclusive; wherein R 5 is H; aryl, C.-C alkyl substituted with aryl, heteroaryl, or C 1 -C 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 )tXR3, -(CH 2 )n
C
(X)NR
3 nCO 2 R, straight chained or branched C 1 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C 2 C, aminoalkyl, alkenyl or alkynyl, or C 3
-C
7 cycloalkyl or
C
5 cycloalkenyl; where R s and one R 2 on adjacent carbon atoms together may form aryl, heteroaryl, indane or tetrahydronaphthyl,
C
3 cycloalkyl, or heterocycloalkyl wherein one or two heteroatoms may be O, N or S; WO 98/57940 WO 9S57940PCTIUS98/1 2668 -8wherein R 1 is Rj 0 Rj 0 in
R
6 Z-N
R-
IR
R
1 07 )KE/t- R0X N N 101 whr each neednl tagtcando brnce C 1 C1lyhdoyakl mnakl al o x a k y o of uo o lk l o r o y l or a k strightchaie or branepncedtl H; staieny orhaikndor is brnched 7 cy-Calkyl,' onfuroycllkyl, mnakl ployalymnfluorocoalkyl or C 5 C pccolkel; raryl;o 20 heteroaryl, wherein the aryl or heteroaryl may be substituted with oneor more of F, Cl, Br, I, (CH 2 )nXR 3 -CaR 3
(CH
2 )nC(M)N (RO) 21
(CH
2
C
2 -CN, -NO 2 -N (RO) 2 1 S0 2
R
3 straight chained or branched Cl1-C, alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or' branched C 2 -C7 alkenyJlior alkynyl, or C 3 -C7 cycloalkyl, *.*monofluorocycl oalkyl, polyfluorocycloalkyi orCS7 cycloalkenyl; where each R. is independently H; F; Cl; Br;. I; -COR 3 C0 2
R
3
-(CH
2
).XR
3
COR
3
-(CH
2
).C(X)N(R
3 2
-(CH
2 )nCO 2
R
3 CN; -NO 2
-N(R
3 2 straight chained or branched C 1 -C7 alkyl, hydroxyalkyl, aminoalkyl,- carboxamidoalkyl, alkoxyalkyl, monotluoroalkyl or polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl;
C
3 cycloalkyl, mono fluorocyc loalkyl, WO 98/57940 PCTIUS98/12668 polyfluorocycloalkyl or C C. cycloailkenyl, wherein the alkyl, aininoalkyl, 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, 01, Br, 1, (CH 2 )nXR 3 -00R 3
(CH
2 3 2 1
(CH
2 ),,oO 2
R
3 ON, -NO 2
-N(R
3 2 -S0 2
R
3 straight chained or branched C1-O7 alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched 02-07 alkenyl or alkynyl, or 03-07 cycloalkyl, mono fluorocycl1oalkyl, polyfluorocycloalkyl or 05-07 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 -C0R 3
-(CH
2 )nC(X)N(R 3 2 1
-(CH
2
,CO
2
R
3 -ON, -NO 2
-N(R
3 2 S0 2 straight chained or branched 01-07, alkyl, straight chained or branched 01-07 monofluoroalkyl or polyfluoroalkyl, straight chained or branched 02-07 alkenyl or alkynyl, or C3-C7 cycloalkyl, mono fluorocyc loalkyl, polyfluorocycloalkyl or 05-07 cycl-oalkenyl; wherein each Rio is independently H; (OH 2 tXR 3
(CH
2
)C(X)NR
3
(OH
2 C0 2
R
3 straight chained or branched O1-C7 alky]l or carboxamidoalkyl; straight chained or branched 02-07 aininoalkyl, alkenyl, or alkynyl; or 030C7 cycloalkyl or 05-07 cycloalkenyl; wherein R 11 is aryl, heteroaryl, Ci-C7 alkyl substituted with one or two aryl, or 01-07 al.kyl substituted with one or two heteroaryl; wherein any aryl or heteroaryl.
independently may be substituted with one or more of F, 01, Br, I, -ON, -NO 2 -N (RO) 2 1 -CaR 3
(CH
2
XR
3 1
(CH
2 C NR 3
(OH
2 nCO 2
R
3 straight chained or branched Ol-O7 alkyl, monof luoroalkyl, polyf luoroalkyl, or carboxamidoalkyl, straight chained or branched 02-07 WO 98/57940 PCTIUS98/12668 aminoalkyl, alkenyl, or alkynyl, or C 3
-C
7 cycloalkyl or
C
5 cycloalkenyl; wherein each m independently is an integer from 0 to 3 inclusive; wherein Z is 252
R
2 R9 R 10 2 WO 98/57940 PCTIUS98/1 2668 -12- 0 .t Rio Rio it<Pl Rio WO 98/57940 PCTIUS98/12668 -13- 502 1R 1
R
200 or C 2 alkenyl, wherein the C 2
-C
7 alkenyl may be unsubstituted or substituted with one or more R 9 groups; where R. 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, carboxainidoalkyl; straight chained or branched C 2
-C
7 aminoalkyl, alkenyl, or alkynyl; or C cycloalkyl or C.-C.7 cycloalkenyl; where each R 9 is independently 1-I; F; Cl; Br; I;
(CH
2 )mXR 3
(CH
2 )mC(X)NR 3
(CH
2
).CO
2
R
3 straight chained or branched C 1
-C
7 alkyl, mono fluoroalkyl, polyfluoroalkyl, WO 98/57940 PCT/US98/12668 -14aminoalkyl, or carboxamidoalkyl; straight chained or branched alkenyl, or alkynyl; or C 3 cycloalkyl or Cs-C cycloalkenyl; wherein Y is S, O, or NR,; or a pharmaceutically acceptable salt thereof.
The present invention is additionally directed to a .0 compound having the structure: This invention is additionally directed to a compound having the structure: WO 98/57940 PCT/US98/12668 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; wherein X1 is O, S, NR 3 wherein each R 2 is independently H; -(CH 2 ),XR3;
(CH
2 )tC(X)NR 3
-(CH
2 )tCO 2 -C0 2
R
3 straight chained or branched Cl-C, alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C 2 alkenyl, or alkynyl; or C 3
-C
7 cycloalkyl or C 5 -C cycloalkenyl; wherein each t is an integer from 1 to 4 inclusive; wherein each R 3 is independently H; straight chained or branched C 1 alkyl, straight chained or branched
C
2
-C
7 alkenyl, or alkynyl; or C 3
-C
7 cycloalkyl or cycloalkenyl; wherein R 4 is aryl, heteroaryl, CI-C 7 alkyl substituted with one or two aryl, or 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
),XR
3
-(CH
2 )nC(X)NR 3
(CH
2 )nCO,R 3 straight chained or branched C 1 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C 2 -C aminoalkyl, alkenyl or alkynyl, or C 3
-C
7 cycloalkyl or C,-C, cycloalkenyl; wherein each n independently is an integer from 0 to 7 inclusive; WO 98/57940 WO 9857940PCT/US98/1 2668 -16wherein R. is Hi; aryl, Cl-C 7 alkyl substituted with aryl, heteroaryl, or C 1 alkyl substituted with heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, 1, -CN, N0 2
-N(R
3 2
-COR
3
-(CH.),XR
3
-(CH
2
),,C(X)NR
3
(CH
2 ),Co 2
R
3 straight chained or branched C 1 alkyl, inonofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C 2 aininoalkyl, alkenyl or alkynyl, or C 3
-C
7 cycloalkyl or 57 cycloalkenyl; wherein R 1 is 151 ]R7 WO 98/57940 PCT[US98/12668 -17-
R
10
R
10 """.Z-N-Rll 200 [/tq lo MR or N N where ~C eac 7 6 i neednl tagtcando brnce R 1 C lyhdoylyinokl 1 aloylymnfura~y Rplflooakl stereaigtchaR indebrnedtl H;-staieny orhaiknyl;
C
3 -c 7 cycloalkyl, mono fluorocyc loa lkyl, poly fluorocycloalkyl1 or C 5
-C
7 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH 2
).XR
3 WO 98/57940 PCTIUS98/12668
-COR
3
(CH
2 N(R 3 2
-(CH
2 ,Co 2
R
3 -CN, -NO 2 N(R 3 2 1 S0 2 R 3 straight chained or branched alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C 2
-C
7 alkenyl or alkynyl, or C 3 cycloalkyl, mono fluorocyc loalkyl, polyfluorocycloalkyl or 57 cycloalkenyl; where each R 7 is independently H; F; Cl; Br; I; COR 3 C0 2
R
3
-(CH
2 nXR 3
(CH
2
N(R
3 2 (CH 2 1CO 2 R 3 -CN; -NO 2 -N(R 3 2 straight chained or branched C 1
-C
7 alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 alkenyl or alkynyl; C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl orC -7 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 heteroary. may be substituted with one or more of F, Cl, Br, I, -(CH 2 XR 3
-COR
3 -(CH 2 )nC N(R 3 2
,-(CH
2
)CO
2
R
3 -CN, -NO 2
-N(R
3 2 S0 2 R 3 1 straight chained or branched C 1
-C
7 alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C 2
-C
7 alkenyl or alkynyl, or C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH 2
XR
3
-COR
3
(CH
2 3 21
-(CH
2 nCO 2
R
3 1 CN, -NO 2
-N(R
3 2 -S0 2 R 3 straight chained or branched
C
1
-C
7 alkyl, straight chained or branched C 1
-C.
monofluoroalkyl or polyfluoroalkyl, straight chained or branched C 2
-C
7 alkenyl or alkynyl, or C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein each Rio 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
C
1 alkyl or carboxamidoalkyl; straight chained or branched C 2
-C
7 aminoalkyl, alkenyl, or alkynyl; or C3-C, cycloalkyl or C 5 cycloalkenyl; wherein R 1 is aryl, heteroaryl, C 1 alkyl substituted with one or two aryl, or C 1 alkyl substituted with one or two heteroaryl; wherein any aryl or heteroaryl independently may be substituted with one or more of F, Cl, Br, I, -CN, 2
-N(R)
2
-COR
3
-(CH
2
)XR
3
(CH
2 )nC(X)NR 3
-(CH
2
CO
2
R
3 straight chained or branched
C
1 alkyl, monofluoroalkyl, polyfluoroalkyl, or carboxamidoalkyl, straight chained or branched C 2
-C
7 aminoalkyl, alkenyl, or alkynyl, or C 3
-C
7 cycloalkyl or Cs-C, cycloalkenyl; wherein each m independently is an integer from 0 to 3 inclusive; wherein Z is 0 R n R2 R9 WO 98/57940 PCTIUS98/1 2668 0 2 t 9n t R2 Rg Rjo WO 98/57940 WO 9857940PCTIUS98/1 2668 -21- 0 2 t m R2 R2 n R0 or
R
9 WO 98/57940 PCT/S98/12668 -22- 0 R9 m R9 R2 2 or C 2 -C alkenyl, wherein the C 2
-C
7 alkenyl may be unsubstituted or substituted with one or more R 9 groups; where R, is H; (CH 2
XR
3
(CH
2
C(X)NR
3
(CH
2
CO
2
R
3 straight chained or branched C-C, alkyl, carboxamidoalkyl; straight chained or branched C 2
-C
7 aminoalkyl, alkenyl, or alkynyl; or C 3
-C
7 cycloalkyl or Cs-C, cycloalkenyl; where each R 9 is independently H; F; Cl; Br; I;
(CH
2
XR
3
(CH
2 )C (X)NR 3
(CH
2 )mCO 2
R
3 straight chained or branched C,-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C alkenyl, or alkynyl; or C 3
-C
7 cycloalkyl or Cs-C, cycloalkenyl; wherein Y is S, 0, or NR,; or a pharmaceutically acceptable salt thereof.
This invention is also related to uses of these compounds for lowering intraocular pressure, inhibiting cholesterol synthesis, relaxing lower urinary tract tissue, the treatment of benign prostatic hyperplasia, impotency, cardiac arrhythmia and for the treatment of any disease where antagonism of the c1A receptor may be useful. The invention further provides pharmaceutical WO 98/57940 PCT/US98/12668 -23compositions comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.
WO 98/57940 PCTIUS98/12668 -24- Brief Description of the Fimiures Ficrure 1 Figures lA-iM show the structures of the compounds described hereinbelow in the Examples.
WO 98/57940 PCT/US98/12668 Detailed Descriiption of the Invention The present invention is directed to compounds having the structure: x x X".I n,-Rl MRl R2 R2R22 RS R 4 x. RS R 4 or q2R
R
5
R
4 wherein each X is independently 0 or S; wherein q is 1 or 2; wherein each R 2 is independently H; -(CH 2
),XR
3
(CH
2 )IC NR 3
(CH
2 tC0 2
R
3 -C0 2
R
3 straight chained or branched C 1 -C.7 alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C 2 alkenyl, or alkynyl; or C 3 cycloalkyl or C 5 cycloalkenyl; wherein each t is an integer from 1 to 4 inclusive; wherein each R 3 is independently H; straighL chained or branched alkyl, straight chained or branched C 2
-C,
alkenyl, or alkynyl; or C 3 cycloalkyl or C.-C, WO 98/57940 PCT/US98/12668 -26cycloalkenyl; wherein R 4 is aryl, heteroaryl, C 1 alkyl substituted with one or two aryl, or C 1 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,),XR
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 aminoalkyl, alkenyl or alkynyl, or C 3 cycloalkyl or C 5 cycloalkenyl; wherein each n independently is an integer from 0 to 7 inclusive; wherein R 5 is H; aryl, C 1
-C
7 alkyl substituted with aryl, heteroaryl, or Cl-C, alkyl substituted with heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -CN, -N(R 3 2
-COR
3 (CH2) XR,, -(CH2) C(X)NR 3
-(CH,
2
)CO
2
R
3 straight chained or branched C 1
-C
7 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C 2 C, aminoalkyl, alkenyl or alkynyl, or C 3
-C
7 cycloalkyl or Cs-C, cycloalkenyl; where R 5 and one R, on adjacent carbon atoms together may form aryl, heteroaryl, indane or tetrahydronaphthyl,
C
3 cycloalkyl, or heterocycloalkyl wherein one or two heteroatoms may be O, N or S; WO 98/57940 WO 9857940PCTIUS98/1 2668 -27wherein R 1 is 0R N N R7 -28-
AI
100 where each R 6 is independently H; straight chained or branched C 1 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl1, mnono fluoroalky-l -or poly-uoroa--kyl; straight chained or branched C 2 -C7 alkenyl or alky-nyl;'
C
3
-C
7 -cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C 5 -C7 cycloalkenyl; aryl or *heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of Cl, Br, 1, (CH 2 )x 3
-COR
3
(CH
2
(X).N(R
3 21
-(CH
2 Co 2
R
3 1 -CN, NO 2 ,I -N (R 3 2 SO SR 3 straight chained or branched Cl -C.7 alkyl,' monofluoroalkyl or polyfluoroalkyl, straight chained or *branched
C
2 alkenyl or alkynyl, or C -C 7 cycloalkyl, monof luorocycloalkyl, polyf luorocycloalky. or ,C cycloalkenyl; where each R 7 is independently H; F; Cl; Br-; 1; -COR 3 C0 2
(CH
2
).XR
3
-COR
3
(CH
2
).C(X)N(R
3 2
(C.H
2
).CO
2
R
3 CN; -NO 2
-N(R
3 2' straight chained or branched Cl-C, alkyl, hydroxyalkyl, aminoalkyl, carboxaiidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C,-C 7 alkenyl or alkynyl;
C
3 cycloalkyl, mono 'Lluorocycl1oalkyl, polyfluorocycloalkyl or cycloalkenyl, wherein the alkyl, aminoalkyl,. carboxamidoalkyl, alkenyl, alkynyl, WO "/57940 PCTIUS98/12668 -29cycloalkyl or cycloalkenyl may be substituted with one or more aryl or heteroaryl, wherein the aryl or heteroary. may be substituted with one or more of F, Cl, Br, I, -(CH 2
XR
3 ,I -CaR 3 ,I -(CH 2
C(X)N(R
3 2 1-(CH 2
ICO
2 R 3 CN, -NO 2 ,I -N(R 3 2 -S0 2
R
3 'straight chained or branched alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C 2 C, alkenyl or alkynyl, or C 3 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C 5 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl, may be substituted with one or more of F, Cl, Br, I, -(CH 2 )n XR 3 -COR 3 -(CH 2 )nC (X)N(R 3 2 1
-(CH
2 ,Co 2 R 3 1 -CN, -NO 2
-NC(R
3 2 S0 2
R
3 straight chained or branched C 1
-C
7 alkyl, straight chained or branched C 1
-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 57 cycloalkenyl; wherein each Rio is independently H; (CH 2
XR
3
(CH
2 C(X)NR 3 (CH 2 tC0 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 3C cycloalkyl or C 5
-C
7 cycloalkenyl; wherein R 11 is aryl, heteroaryl, C 1
-C
7 alkyl substituted with one or two aryl, or C,-C 7 alkyl substituted with one or two heteroaryl; wherein any aryl or heteroaryl, independently may be substituted with one or more of F, C1, Br, I, -CN, -NO 2 -NCR 3 2
-COR
3 I (CH 2
,XR
3 1
(CH
2 ~C (X)NR 3
(CH
2
CO
2
R
3 I straight chained or branched
C
1
-C
7 alkyl, monofluoroalkyl, polyfluoroalkyl, or carboxamidoalkyl, straight chai-ned or branched C 2
-C,
aminoalkyl, alkenyl, or alkynyl, or C 3
C
7 cycloalky. or cycloalkenyl; WO 98/57940 PCT/US98/12668 wherein each mn independently is an integer from 0 to 3 inclusive; wherein Z is
F
t n 2R9 Rio 0
R
9 WO 98/57940 PCTIUS98/1 2668 -31-
-U
WO 98/57940 PCTIUS98/12668 -32- I
I
or C 2 alkenyl, wherein the C 2
-C
7 alkenyl may be unsubstituted or substituted with one or more R 9 groups; where R. is H; (CH 2 tXR 3
(CH
2 )tC NR 3
(CH
2 tCO 2
R
3 straight chained or branched C 1
-C
7 alkyl, carboxainidoalkyl; straight chained or branched C 2
-C,
aininoalkyl, alkenyl, or alkynyl; or C 3 cycloalkyl or cycloalkenyl; where each R 9 is independently H; F; Cl; Br; I;
(CH
2 mXR 3
(CH
2 )mC NR 3
(CH
2 mCo 2
R
3 straight chained or branched C1-c., alkyl, mono fluoroalkyl, 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; wherein Y is S, 0, or NR,; WO 98/57940 PCT/US98/12668 -33or a pharmaceutically acceptable salt thereof.
The invention further provides for the enantiomer of any of the compounds described herein which may be a cis isomer or a trans isomer. The invention also provides for the enantiomer of any of the compounds described herein which may be a cis or a trans isomer.
The compounds of the present invention are preferably at least 80% pure, more preferably at least 90% pure, and most preferably at least 95% pure.
In the present invention the term "aryl" is used to include phenyl, benzyl, benzoyl or naphthyl and the term "heteroaryl" is used to include pyrazinyl, pyrryl, furanyl, thiophenyl, pyridyl, imidazolyl, indolyl, aminophenyl, benzamidyl, benzimidazolyl, benzfurazanyl, benzfuranyl, 2-keto-l-benzimidazolinyl or quinolyl.
The compounds of this invention exhibit at least tenfold greater affinity for the human a1A receptor than for the human aB or human a 1 receptor.
In one embodiment of the present invention R i is 6 m Rg
Z-N
r R
R
4 is aryl or heteroaryl, where the aryl may be WO 98/57940 PCTIUS98/12668 -34substituted with one or more of F, Cl, -(CH 2
OR
3
(CH
2
,CONR
3 (CH 2
)CO
2 R 3 'straight chained or branched C.-
C
7 alkyl or monofluoroalkyl; and Z is 0 .R9 t n n2
R
tV
A
lR 9 t n R9 In another embodiment of the present invention R 4 is pyridyl or phenyl, where the phenyl may be substituted WO 98/57940 PCT/US98/12668 with one or more of F, Cl, -(CH 2
),OR
3
-(CH
2 )nC(O)NR,
(CH
2
CO
2
R
3 straight chained or branched C 1 alkyl or monofluoroalkyl.
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
-NR
3 2 -S0R 3 straight chained or branched C.-C alkyl, monofluoroalkyl or polyfluoroalkyl.
In a further embodiment of the present invention R, is H; -CN; -C0 2
R
3
-(CH
2 )mXR 3 unsubstituted or substituted aryl; Ci-C, alkyl; or -OCOR.
In another embodiment of the present invention R 4 is phenyl which may be substituted with at least one of F or Cl.
In yet another embodiment of the present invention the compound has the structure: WO 98/57940 WO 9857940PCTIUS98/12668 -36- In another embodiment of the present invention Z is: In a further embodiment of the present invention q is 1 and R 1 is
H
M R
Z-N
]R7 Ht In a further embodiment of the present invention aic least one R 2 is C 1
-C
3 alkyl.
WO 98/57940 PCTIUS98/12668 -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 phenyl substituted with at least two F.
In an embodiment of the present invention R 4 is 3,4difluorophenyl.
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
),C(X)N(R
3 2
,-(CH
2
CO
2
R
3 -CN, -N(R 3 2
-SO
2
R
3 straight chained or branched C 1 alkyl, monofluoroalkyl or polyfluoroalkyl.
In a further embodiment of the present invention R 7 is H; -CN; or -CO 2
R
3 In another embodiment of the present invention R 9 is F; -OH; Ci-C 3 alkyl; or -ACH 2
XR.
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 embodiment, when R 9 is F, the other R 9 on the same carbon atom is C 1
-C
3 alkyl, F, Cl, Br, or I.
In yet another embodiment of the present invention R 6 is 4-fluorophenyl.
In one embodiment of the invention, the compound is a trans isomer having the structure: WO 98/57940 PCT/US98/12668 -38- This invention is additionally directed to a compound having the structure: This invention is additionally directed to a compound having the structure: WO 98/57940 PCT/US98/12668 -39- This invention is additionally directed to a compound having the structure: This invention is additionally directed to a compound having the structure: 0 0
I
WO 98/57940 PCT[UJS98/12668 This invention includes a compound having the structure: xR XNr1 w 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; wherein each X1 is 0, S, NR 3 wherein each R 2 is independently H; -(CH 2 )tXR 3
(CH
2 )tC(X)NR 3
-(CH
2 )tCO 2
R
3 -C0,R 3 straight chained or branched Ci-C alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C 2
-C
7 alkenyl, or alkynyl; or C 3 cycloalkyl or C 5
-C
7 cycloalkenyl; wherein each t is an integer from 1 to 4 inclusive; wherein each R 3 is independently H; straight chained or branched C 1
-C
7 alkyl, straight chained or branched C 2
-C
7 alkenyl, or alkynyl; or C 3 -C cycloalkyl or C,-C, cycloalkenyl; WO 98/57940 PCTIUS98/12668 -41wherein R 4 is aryl, heteroaryl, C 1 alkyl substituted with one or two aryl, or Cl-C. alkyl substituted with one or two heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, CN, -NO 2
-N(R
3 2
-COR
3
(CH
2
),XR
3
(CH
2 )nC(X)NR 3
(CH
2
),,CO
2
R
3 straight chained or branched C 1
C
7 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C 2
-C
7 arninoalkyl, alkenyl or alkynyl, or C 3 -C.7 cycloalky. or C 5
-C
7 cycloalkenyl; wherein each n independently is an integer from 0 to 7 inclusive; wherein R 5 is H; aryl, C 1
-C
7 alkyl substituted with aryl, heteroaryl, or C 1
-C
7 alkyl substituted with heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -CN, -NO 2
-N(R
3 2
-COR
3
(CH
2 tXR 3
(CH
2
,C(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 C 2
C
7 arninoalkyl, alkenyl or alkynyl, or C 3
-C
7 cycloalkyl or
C
5 cycloalkenyl; WO "/57940 WO 9857940PCT/US98/12668 -42wherein R 1 is q YR7 ~~4~Iq ~t mR or WO "/57940 PCT[US98/12668 -43-
R
10 101 wherein each R 6 is independently H; straight chained or branched C 1 alkyl, hydroxyalkyl, aininoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; chained or branched C 2
-C
7 alkenyl or alkynyl; C 3
-C
7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C 5 -C7, cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, C1, Br, I, (CH 2
,XR
3 -COR 3
-(CH
2 ,C(X)N(R 3 2
'-(CH
2 C0 2
R
3 -CN, NO 2 -N(R 3 2
-SO
2
R
3 .1 straight chained or branched C 1
-C
7 alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C 2 -C7. alkenyl or alkynyl, or C3C cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C 5 cycloalkenyl; wherein each R 7 is independently H; F; Cl; Br; I; COR 3 -C0 2
R
3
(CH
2 XR 3
(CH
2 N(R 3 2
(CH
2 1CO 2
R
3 CN; -NO 2
-N(R
3 2 straight chained or branched C 1
-C
7 alkyl, hydroxyalkyl, axinoalkyl, carboxaridoalkyl, alkoxyalkyl, inonofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2
-C
7 alkenyl or alkynyl; C 3 -C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C 5-C. cycloalkenyl, wherein the alkyl, aminoalkyl, carboxainidoalkyl, alkenyl, WO 98/57940 PCTIUS98/12668 -44alkynyl, cycloalkyl or cycloalkenyl may be substituted with one or more aryl or heteroaryl, wherein the aryl or heteroary. may be substituted with one or more of F, Cl, Br, 1, (CH 2
,XR
3
-COR
3
(CH
2 )IC N(R 3 21
(CH
2
ICO
2
R
3 -CN, -NO 2
-N(R
3 2
-SO
2
R
3 I straight chained or branched C.-C 7 alkyl, *mono fluoroalkyl or polyfluoroalkyl, straight chained or branched C 2
-C.
alkenyl or alkynyl, or C 3 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C,-C, cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -(CH 2
),,XR
3
-COR
3 7(CH 2 )nC(X)N(R 3 2 1-
(CH
2
),,CO
2
R
3 -CN, -NO 2
-N(R
3 2 -S0 2
R
3 straight chained or branched C 1 alkyl, straight chained or branched
C
1 monofluoroalkyl or polyfiluoroalkyl, straight chained or branched C 2 alkenyl or alkynyl, or C 3 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C 5 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 alkyl or carboxamidoalkyl; straight chained or branched C 2 aiinoalkyl, alkenyl, or alkynyl; or C 3 cycloalkyl or C.-C.7 cycloalkenyl; wherein R 11 is aryl, heteroaryl, C 1 alkyl substituted with one or two aryl, or C 1 alkyl substituted with one or two heteroaryl; wherein any aryl or heteroaryl independently may be substituted with one or more of F, Cl, Br, I, -CN, -NO 2 -N (RO) 2 1
COR
3
-(CH
2
),,XR
3
-(CH
2 )nC(X)NR 3
-(CH
2
,CO
2
R
3 straight chained or branched C 1 alkyl, mono fluoroalkyl, polyfluoroalkyl, or carboxamidoalkyl, straight chained or branched C 2 aininoalkyl, alkenyl, or alkynyl, or
C
3 cycloalkyl or C 5 -C.7 cycloalkenyl; WO 98/57940 WO 9857940PCTIUS98/1 2668 wherein each mn independently is an integer from 0 to 3 inclusive; wherein Z is 4 R2 n
R
9
R
9 t t n WO 98/57940 PCTIUS98/1 2668 -46- WO "/57940 WO 9S57940PCT/US98/12668 -47-
N>
02 t In I n R9
K
R
1
O
or C 2 alkenyl, wherein the C 2
-C
7 alkenyl may be unsubstituted or substituted with one or more R 9 groups; where R. is H; (CH 2
),XR
3
(CH
2
),C(X)NR
3
(CH
2
)ICO
2
R
3 straight chained or branched C 1 alkyl., carboxamidoalkyl; straight chained or branched C 2
-C,
aminoalkyl, alkenyl, or alkynyl; or C 3 cycloalkyl or
C
5 cycloalkenyl; where each R 9 is independently H; F; tl; Br; I;
(CH
2 )mXR 3
(CH
2 C (X)NR 3
(CH
2 )mCO 2
R
3 straight chained or branched C.-C7 alkyl, mono fluoroalkyl, polyfluoroalkyl, aminoalkyl, or carbOXaU(Lidoalkyl; straight chained or branched C 2 alkenyl, or alkynyl; or C 3 -C.7 cycloalkyl or cycloalkenyl; WO 98/57940 PCT/US98/12668 -48wherein Y is S, O, or NR,; or a pharmaceutically acceptable salt thereof.
The present invention is additionally directed to a compound having the structure:
F
F
0 6 Ph Ph CO 2
CH
3 HN N3 The invention also encompasses the and enantiomers of all compounds described herein. The invention further includes cis and trans isomers of all of the compounds described herein, the terms "cis" and "trans" corresponding to relative stereochemistry, as determined, for example, by NOE (Nuclear Overhauser Effect) experiments. In one embodiment, cis and trans designate the relative positions of aryl and alkyl on adjacent carbons in the oxazolidinone ring (see Examples 18 and 19).
Included in this invention are pharmaceutically acceptable salts and complexes of all of the compounds described herein. The salts include but are not limited to the following acids and bases: inorganic acids such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid; WO 98/57940 PCTIUS98/12668 -49organic acids such as acetic acid, trifluoroacetic acid, formic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid; inorganic bases such as ammonia and hydrazine; and organic bases such as methylamine, ethylamine, hydroxyethylamine, propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, ethylenediamine, hydroxyethylamine, morpholine, piperazine and guanidine. This invention further encompasses hydrates and polymorphs of all of the compounds described herein...
The invention further provides pharmaceutical compositions comprising a therapeutically effective amount of any of the compounds described above and a pharmaceutically acceptable carrier. In the subject invention a "therapeutically effective amount" is any amount of a compound which, when administered to a subject suffering from a disease against which the compounds are effective, causes reduction, remission, or regression of the disease. In one embodiment, the therapeutically effective amount is an amount from about 0.01 mg to about 800 mg. In another embodiment, the therapeutically effective amount is an amount from about 0.01 mg to about 500 mg. In another embodiment, the therapeutically effective amount from about 0.01 mg to about 250 mg. In another embodiment, the therapeutically effective amount is an amount from about 0.1 mg to about 60 mg. In another embodiment, the therapeutically effective amount is an amount from about 1 mg to about 20 mg. In one embodiment the WO 98/57940 PCTIUS98/1 2668 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, from about 1 mg per subject per day to about 50 mg per subject per day. In the practice of this invention the "pharmaceutically acceptable carrier" is any physiological carrier known to those of ordinary skill in the art as being useful in formulating pharmaceutical compositions.
In one embodiment the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution. In another embodiment, the pharmaceutically acceptable carrier is a solid and the composition is in the form of a powder or tablet. In a further embodiment, the pharmaceutical carrier is a gel and the composition is in the form of a suppository or cream. In a further embodiment the compound may be formulated as a part of a pharmaceutically acceptable transdermal patch.
A solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium WO 98/57940 PCT/US98/12668 -51stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g.
glycols) and their derivatives, and oils (e.g.
fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by for example, intramuscular, intrathecal, epidural, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compounds may be WO 98/57940 PCTIUS98/12668 -52prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium. Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
The invention also provides a method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject any one of the compounds described herein in an amount effective to treat benign prostatic hyperplasia. In a preferred embodiment the compound of the pharmaceutical composition additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia. In one preferred embodiment the compound effects treatment of benign prostatic hyperplasia by relaxing lower urinary tract tissue and in particular where lower urinary tract tissue is prostatic smooth muscle.
The invention further provides a method of treating a subject suffering from elevated intraocular pressure which comprises administering to the subject one of the compounds described herein effective to lower intraocular pressure.
The invention further provides a method of treating a subject suffering from a disorder associated with elevated blood cholesterol which comprises administering to the subject one of the compounds described herein effective to inhibit cholesterol synthesis.
The invention also provides a method of treating a WO 98/57940 PCT/US98/1 2668 -53disease which is susceptible to treatment by antagonism of the alA receptor which comprises administering to the subject one of the compounds described herein effective to treat the disease.
The invention further provides a method of treating a subject suffering from impotency which comprises administering to the subject one of the compounds described herein effective to treat impotency.
The invention further provides a method of treating a subject suffering from sympathetically mediated pain which comprises administering to the subject one of the compounds described herein effective to treat sympathetically mediated pain.
The invention provides a method of treating a subject suffering from cardiac arrhythmia which comprises administering to the subject one of the compounds described herein effective to treat cardiac arrhythmia.
The invention provides a method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject one of the compounds described herein in combination with a alpha-reductase inhibitor effective to treat benign prostatic hyperplasia. In one preferred embodiment the reductase inhibitor is finasteride. The dosage administered to the subject is about 0.01 mg per subject per day to 50 mg per subject per day of finasteride in combination with an alA 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 a1A antagonist. The most preferred dosage administered to the subject is WO 98/57940 PCTIUS98/1 2668 -54about 5 mg per subject per day of finasteride in combination with an a1A antagonist.
The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a combination of any of the compounds described herein in combination with finasteride and a pharmaceutically acceptable carrier. In one embodiment the pharmaceutical composition is a therapeutically effective amount of a combination comprising an amount from about 0.01 mg per subject per day to about 500 mg per subject per day of any one of the compounds described herein and an amount of finasteride of about mg per subject per day. A more preferred embodiment of the pharmaceutical composition is a therapeutically effective amount of a combination comprising an amount from about 0.1 mg per subject per day to about 60 mg per subject per day of any one of the compounds described herein and an amount of the finasteride of about 5 mg per subject per day. The most preferred embodiment of the pharmaceutical composition is a therapeutically effective amount of a combination comprising from about 1 mg per subject per day to about 20 mg per subject per day of any one of the compounds described herein and an amount of finasteride of about 5 mg per subject per day.
The invention further provides a method of relaxing lower urinary tract tissue which comprises contacting the lower urinary tract tissue with an amount of one of the compounds described herein effective to relax lower urinary tract tissue. In one embodiment the lower urinary tract tissue is prostatic smooth muscle. In one preferred embodiment the compound additionally does not cause a fall in blood pressure when it is effective to relax lower urinary tract tissue.
WO 98/57940 PCTIUS98/1 2668 The invention provides a method of relaxing lower urinary tract tissue in a subject which comprises administering to the subject an amount of one of the compounds described herein effective to relax lower urinary tract tissue. In one preferred embodiment the compound does not cause a fall in blood pressure and the lower urinary tract tissue is prostatic smooth muscle.
The invention further provides for a method of inhibiting contraction of prostatic tissue, which comprises administering to the subject an amount of any of the compounds described herein effective to inhibit contraction of prostatic tissue. In one preferred embodiment the prostatic tissue is prostatic smooth muscle and the compound additionally does not cause a fall in blood pressure.
The invention provides for the use of the compounds described herein for the preparation of a pharmaceutical composition for lowering intraocular pressure, inhibiting cholesterol synthesis, and the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the axA receptor may be useful. The invention provides for the use of the compounds described herein for the preparation of a pharmaceutical composition for relaxing lower urinary tract tissue and in particular prostatic smooth muscle. The invention further provides for the use of any of compounds described herein for the preparation of a pharmaceutical composition, where the compound additionally does not cause a fall in blood pressure at dosages effective to lower intraocular pressure, to inhibit cholesterol synthesis, and for the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of WO 98/57940 PCT/US98/12668 -56the a1A receptor may be useful.
The invention provides for the use of the compounds described herein in the preparation of a medicament for lowering intraocular pressure, inhibiting cholesterol synthesis, and for the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the a A receptor may be useful. The invention provides for the use of the compounds described herein in the preparation of a medicament for relaxing lower urinary tract tissue and in particular prostatic smooth muscle. The invention further provides for the use of any of compounds described herein in the preparation of a medicament, where the compound additionally does not cause a fall in blood pressure at dosages effective to lower intraocular pressure, to inhibit cholesterol synthesis, and for the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the clA receptor may be useful.
The invention provides a drug which is useful for lowering intraocular pressure, inhibiting cholesterol synthesis, and the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the aA receptor may be useful, the effective ingredient of the said drug being any of the compounds described herein. The invention further provides the drug described herein additionally does not cause a fall in blood pressure at dosages effective to lower intraocular pressure, to inhibit cholesterol synthesis, and for the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the aA receptor may be useful.
WO 98/57940 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 invention further provides a drug which is useful for relaxing lower urinary tract tissue additionally does not cause a fall in blood pressure at dosages effective to-relax lower urinary tract tissue.
In the preceding methods the compound may be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents, for example, enough saline or glucose to make the solution isotonic, bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
The compound may also be administered orally either in liquid or solid composition form. Compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.
Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of.the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.
WO 98/57940 PCTIUS98/12668 -58- In the practice of this invention, the term "lower urinary tract tissue" is used to include prostatic capsule, prostate urethra, and bladder neck.
One skilled in the art will readily appreciate that appropriate biological assays will be used to determine the therapeutic potential of the claimed compounds for the treating the above noted disorders.
This invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.
WO 98/57940 PCT/US98/12668 -59- Experimental Details Example 1: 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3carboxylic acid 3 3 4 ',5',6'-tetrahydro-2*H- 2 4 ']bipyridinyl-l'-yl)-propyl]-amide (Schemes 5 and 6) It is a typical procedure for the synthesis of oxazolidinone compounds which are described below.
METHOD A: a. Amino-(3,4-difluorophenyl)-acetonitrile Through a solution of 3,4-difluorobenzaldehyde (25.0 g, 0.18 mol) in MeOH (500 mL)in a round bottom flask, was bubbled ammonia gas for two hours at room teperature. The flask was then cooled to 0°C and trimethylsilyl cyanide (1.3 eq., 0.23 mmol) was then added slowly. The reaction mixture was stirred for 2 h when TLC analysis indicated that the reaction was complete (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 of amino-(3,4difluorophenyl)-acetonitrile as a yellow syrup.
b. Amino-(3,4-difluorophenyl)-acetin 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 yellow solution was stirred at room temperature for 10 h and then heated to reflux for 1.5 h. After cooling, the solvent was removed in vacuo and the resulting yellow solid was dissolved in water (200 mL). The aqueous solution was then carefully basified with 20% NaOH solution to pH 9. The aqueous layer was extracted with
CH
2 C1 2 (3 x 100 mL). The organic layer was separated and dried over Na 2
SO
4 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 WO 98/57940 PCTIS98/1 2668 was used in the next step without purification.
c. 2-Amino-2-(3,4-difluorophenyl)-ethanol To a well stirred suspension of LiA1H 4 (4.7 g, 0.125 mol) in THF (120 mL) in a 3-necked round bottom flask fitted with a condenser and a dropping funnel, was added a solution of amino-(3,4-difluorophenyl)-acetic acid methyl ester (10.0 g, 0.05 mol) in THF (100 mL) dropwise at 0°C.
The.resulting greenish brown suspension was then heated to reflux for 2 h. The reaction mixture was cooled to 0 C and then carefully quenched sequentially with 5 mL of water, 5 mL of 3N NaOH followed by 15 mL of water. The resulting suspension was filtered through a fritted glass funnel. To the residue was added 100 mL Et20 and the suspension was heated to reflux for 20 min. The suspension was filtered and was combined with the previous filtrate, dried over 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.
METHOD B: Synthesis of 2-amino-2-(3,4-difluorophenvl)ethanol by different route. (Scheme 6) a. 1-Hydroxy-(3,4-difluorophenyl)-acetophenone To a solution of KOH (56 g, 1.0 mol) in MeOH (500 mL) was added 3,4-difluoroacetophenone (15.6 g, 0.1 mol) dropwise over 15 min at 0°C. Phenyliodosodiacetate (64.4 g, 0.2 mol) was added in small portions over 20 min period and the resulting yello-orange solution was stirred overnight at room temperature. The solvent was removed in vacuo to obtain yellow-orange gum. The residue was dissolved in 100 mL of water and 100 mL of brine and was thoroughly extracted with ethyl acetate (3 X 150 mL). The organic layer was dried over Na 2
SO
4 and was decanted. The solvent was removed in vacuo to obtain 31.0 g of the acetal as thick yellow oil. It was WO 98/57940 PCT/US98/12668 -61dissolved 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 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 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 l-hydroxy-(3,4-difluorophenyl)-acetophenone as pale yellow solid. The product was shown to be 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 added hydroxylamine hydrochloride (3.16 g, 45.6 mmol) and sodium acetate (9.6 g, 69.6 mmol) at room temperature and the resulting solution was stirred overnight. The solvent was removed and the residue was dissolved in methylene chloride (150 mL) and was washed with 100 mL of sat. 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, It was used in the next step 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 mL) in a 3-necked round bottom flask fitted with a condenser and a dropping funnel, was added WO98/57940 PCT/US98/12668 -62a 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 reaction mixture was cooled to 0°C and then carefully quenched sequentially with 3.4 mL of water, 3.4 mL of 3N NaOH followed by 10 mL of water. The resulting suspension was filtered thro' a fritted glass funnel.
To the residue was added 100 mL EtO2 and the suspension 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 used in the next step without further purification.
d. [l-(3,4-Difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tert-butyl ester To a solution of 2 -amino-2-(3,4-difluorophenyl)-ethanol (8.6 g, 49.7 mmol) in CHC13 (150 mL) at 0°C was added a solution of di-tert-butyl dicarbonate (11.4 g, 52.0 mmol) in 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 hexane-EtOAc followed by EtOAc) to obtain difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tertbutyl ester as white solid (10.0 g,74%).
e. (+)-4-(3,4-Difluorophenyl)-oxazolidin-2-one To a well stirred suspension of NaH (1.1 g, 45.8 mmol) in THF (40 mL) at room temperature was added a solution of [1-(3,4-difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tert-butyl ester (5.0 g, 18.3 mmol) in THF 20 mL via a dropping funnel at room temperature. The resulting suspension was stirred for 3 h and then quenched carefully with 10 mL of water. The biphasic WO 98/57940 PCT/US98/12668 -63mixture was extracted with 100 mL of EtO2, washed with brine, filtered and the solvent was removed in vacuo.
The gummy residue thus obtained was purified by column chromatography over silica gel (Rf 0.15, 3:2 hexane- EtOAc) to obtain (+)-4-(3,4-difluorophenyl)-oxazolidin- 2-one as a white flaky solid (2.8 g, The enantiomers were separated by using Chiralcel OD (4.6 x 250 mm) using 80% hexane/20% isopropyl alcohol/ 0.1 %Diethylamine as the eluting system under isothermal conditions 254 nM). The retention times for the two isomers were 16.19 min and 20.08 min respectively.
First isomer: 62.9 (c 0.67, acetone); Anal.
Calcd. for CgHNO 2
F
2 C, 54.28; H, 3.54; N, 7.03. Found: C, 54.16; H, 3.44; N, 6.96. Second isomer:[a], 56.9 (c 0.75, acetone); Anal. Calcd. for CgHNOF 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 To a suspension of NaH (0.14 g, 5.30 mmol) in 20 mL of anhydrous THF under argon, a solution of difluorophenyl)-oxazolidin-2-one (0.88 g, 4.42 mmol) in THF was added dropwise via an dropping funnel. The resulting suspension was stirred at room temperature for 30 min. This suspension was then added dropwise via cannula into another round bottom flask containing a solution of 4-nitrophenylchloroformate (1.11 g, 5.30 mmol) in 25 mL of THF and cooled at -78 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 C1 2 to obtain 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3carboxylic acid-4-nitro-phenyl ester as a white solid (1.55g, 86%).
WO 98/57940 PCTIUS9/12668 -64g. 3-Amino -propyl-4-pyridyl-piperidine 1- (3-Aminopropyl) [pyrid-2-yl] pyridinium bromide hydrobromide Method A: A solution of 2,4'-dipyridyl (5.0 g, 32.0 mmol) and 3-bromopropylamine hydrobromide (7.0 g, 32.0 mmol) in DMF (50.0 mL) and acetonitrile (50.0 mL) was heated at 90-95 0 C for 1 h. After cooling, the white solid that came out was filtered, washed with EtO2 and dried. The mother liquor was concentrated to remove Et 2 O and then heated to 90-95 0 C for 4 h. The solvent was evaporated and the white residue was triturated with EtO2 (100.0 mL) and filtered. The combined weight of the salt was 11.6 g Method B: A well-stirred solution of 2,4'-dipyridyl (12.8 g, 0.08 mol) and N-tert-butoxycarbonyl-3-bromopropylamine (21.3 g, 0.09 mol) in acetonitrile (40.0 mL) was heated to reflux for 6 h. The reaction mixture was cooled to room temperature and filtered. The white solid thus obtained was washed with acetone (2 x 20.0 mL) and chloroform (2 x 20.0 mL) to yield 10.9 g as the first crop. Anal. Calcd. for C 13
H
16
N
3 Br.HBr.0.5 H20: C, 40.65; H, 4.72; N, 10.94. Found: C, 40.83; H, 4.37; N, 11.05.
-Dihydro-2'-H-[2,4']bipyridinyl-1'-yl)propylamine To a solution of 1-(3-aminopropyl)-4-[pyrid-2yl]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 min and then quenched with 6M HC1 solution. The solution was concentrated to 20.0 mL and basified with NaOH solution to pH 12. Extracted with CHCl 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-1l-yl)- WO 98/57940 PCT/US98/12668 propylamine as an oil (0.37 g, 96% yield). It is used in the next step immediately without purification.
6 '-Tetrahydro-2'-H-[2,4']bipyridinyl-1-yl) propylamine To a solution of 3-(3',6'-Dihydro-2'-H- [2, 4 ']bipyridinyl-1'-yl)-propylamine (3.48 g crude, 15.9 mmol) in MeOH (40 mL), was added 1.0 g of Pearlman's catalyst. The suspension was hydrogenated under 120 psi for 10 h after which the reaction mixture was filtered 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%).
6 '-Tetrahydro-2'-H-[2,4']bipyridinyl-1,-yl)propylamine To a solution of l-( 3 -aminopropyl)-4-[pyrid-2yl]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 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 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-3carboxylic acid 3 3 4 ',5',6'-tetrahydro-2'H- [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-(3,4difluorophenyl)- 2 -oxo-oxazolidine-3-carboxylic acid-4nitro-phenyl ester (1.55 g, 4.24 mmol) was added and the resulting yellow solution was stirred under argon WO 98/57940 PCT/US98/12668 -66atmosphere for 10 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with EtOAC followed by 15% MeOH in EtOAC as the eluting systems (R, 0.4, 1:1 MeOH/EtOAC) to obtain a pale yellow glassy oil. It was dissolved in EtOAc (150 mL) and washed throughly with 5% KOH solution (4 x 25 mL) in order to remove traces of 4-nitrophenol in the product. .The organic layer was separated, washed with brine (25 mL) and then dried over 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']bipyridinyll'-yl)-propyl]-amide was obtained as a colorless glassy oil(1.55 g, 82%) which develops some brownish color after 2 h.
To a solution of 4 -(3,4-Difluoro-phenyl)-2-oxooxazolidine-3-carboxylic acid tetrahydro-2'H-[2,4']bipyridinyl-l'-yl)-propyl]-amide (1.53 g, 3.45 mmol) in 10.0 mL of anhydrous EtOH was added a warm solution of 95% fumaric acid (0.48 g, 4.06 mmol) in 8.0 mL EtOH and the resulting solution was kept under a gentle stream of argon for 30 min. Hexane (5 x mL) was added over 2 h and the solution was kept under argon atmosphere overnight. Pale yellowish-white small crystals thus obtained were filtered, washed successively with EtOH (10.0 mL) and hexane (10.0 mL).
The crystals were pulverized and dried under vacuum at The white non-hygroscopic powder (1.6 g, 84%) was found out to be the monofumarate salt after NMR and elemental analysis as shown below. M.P. 142-144 0 C; [a]D 47.4 (c 0.52, MeOH); Anal. Calcd. for
C
27
H
3
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.
Example 2: 4 3 ,4-Difluorophenyl)-3-{5-[4-(2-methoxy- WO 98/57940 PCT/US98/12668 -67phenyl)-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 mmol) in THF(5 mL) at 0°C under argon, was added a solution of 4-( 3 4 -difluorophenyl)oxazolidinone (800 mg, 4.02 mmol) in the mixed solvent of THF(4 ml) and HMPA(0.7 ml, 4.02 mmol) and stirred for 30 min. To this (2.17 ml, 16 mmol) was added and the mixture was heated to reflux for 70 min, after which the reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by column chromatography over silica gel with CH 2 C1 2 followed by 5% EtOAc in CH 2 C1 2 as the eluting system (R, 0.72, CH 2 C1,:EtOAc 3:1) to obtain 4-(3,4oxazolidinone as a brown liquid (0.70 g, b. 4-(3,4-Difluorophenyl)-3-{5-[4-(2-methoxy-phenyl)piperazin-1-yl]-pentyl}-oxazolidin-2-one To a solution of 4-(3,4-difluorophenyl)-l-(5bromopentyl) oxazolidinone (60 mg, 0.17 mmol) in 1,6dioxane (20 ml) at room temperature, were added 1-(2methoxyphenyl)-piperazine (33.8 mg, 0.17 mmol) and K 2
CO
3 (23.8 mg, 0.52 mmol). The resulting mixture was heated to reflux for 12 h after which the reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in water and extracted with 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 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-(3,4difluorophenyl)-3-{5-[4-(2-methoxy-phenyl)-piperazin-1yl]-pentyl}-oxazolidin-2-one as a brown oil (69 mg, The compound was dissolved in CH1 2
C
2 (3 mL) and WO 98/57940 PCT/US98/12668 -68was 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 2
H
33
N
3
O
3 FC1, 0. 65 CH 2 C1 2 C, 52.43; H, 5.88; N, 7.15. Found: C, 52.12; H, 6.36; N, 6.84.
Example 3: 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3carboxylic acid (3-[4-(5-bromo-2-methoxy-phenyl)-4phenyl-piperidin-1-yl]-propyl)-amide a. 4-(5-bromo-2-methoxy)-phenyl-4-phenyl-piperidine hydrochloride To a 100 mL round bottom flask equipped with a rubber septum and a stirring bar was added 4-hydroxy-4-phenylpiperidine (5 g, 30.0 mmol) followed by 30 mL of 4bromoanisole. The resulting solution was stirred at room temperature under argon atmosphere and then AlC1 3 g, 60.0 mmol) was added in one portion. An exotherm was observed. The reaction mixture was stiired for 8 h (brownish green color), then poured carefully over 600 ml of ice-water and stirred for 10 h. The white suspension was diluted with 100 mL of diethyl ether. The white solid that precipitated out was filtered and washed thoroughly with water (600 mL) followed by diethyl ether (500 mL) to obtain 4-(5-bromo-2-methoxy)phenyl-4-phenyl-piperidine hydrochloride as a greyish white solid (6.0 g, 52%).
b. 3-[4-(5-bromo-2-methoxy)phenyl-4-phenyl-piperidin-1yl]propylamine To a solution of 4 -(5-bromo-2-methoxy)-phenyl-4-phenylpiperidine hydrochloride (2.5 g, 6.3 mmol) in 100 mL dioxane was added 3 -bromo-N-tert-butoxycarbonylpropylamine (2.25 g, 9.4 mmol) and K 2 C0 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 WO 98/57940 PCT/US98/12668 -69and 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-2methoxy)phenyl-4-phenyl-piperidin-l-yl]-N-tertbutoxycarbonyl-propylamine as a yellow oil (3.15 It was dissolved in 35 mL of CH 2 Cl1 and 6.0 mL of trifluoroacetic acid was added with stirring at room temperature under argon atmosphere. After 1 h the solvent was evaporated in vacuo and the residue was basified to pH 10 by adding minimum amount of 1 N KOH solution. The product was extracted with CH 2 C1 2 (3 X mL), dried over MgSO4, filtered and the solvent was removed in vacuo to obtain 3-[4-(5-bromo-2methoxy)phenyl- 4 -phenyl-piperidin-1-yl]propylamine as a viscous yellow oil (2.26 g, 89% for two steps). It was used in the next step without further purification. The above mentioned steps a and b are representative examples of synthesis of all the 4,4-diaryl piperidine containing side chains described in this document.
c. 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3carboxylic acid (3-[4-(5-bromo-2-methoxy-phenyl)-4phenyl-piperidin-1-yl]-propyl)-amide To a solution of 3-amino-propyl-4-(5-bromo-2methoxy)phenyl-4-phenyl piperidine (2.0 g, 4.96 mmol) in 100 mL of THF was added 4 3 4 -difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-4-nitro-phenyl ester (1.81 g, 4.96 mmol) and the resulting yellow solution was stirred under argon atmosphere for 3 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 50% hexane/EtOAC followed by 5% MeOH in EtOAC as the eluting systems (Rf 0.4, 1:3 MeOH/EtOAC) to obtain the product as white foam (wt= 2.2 It was dissolved in EtOAc (150 mL) and washed throughly with NaOH solution (4 x 25 mL) in order to remove traces of WO 98/57940 PCT/US98/12668 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-3carbonyl)-amino-propyl)(5-bromo-2-methoxy)phenyl-4phenyl-piperidine was obtained as a colorless glassy oil(1.84 g, [a)D 34.3 (c 0.3, MeOH); The compound was dissolved in CHC13 (10 mL) and was treated with 1N HC1 in ether (5 mL). The solvent was removed in vacuo to give the corresponding hydrochloride salt as a white solid (2.0 M.P. 142-144 0 C; Anal. Calcd. for
C
31
H
33
N
4 04BrC1F 2 .0.3 CHCl 3 C, 53.65; H, 4.79; N, 6.00.
Found: C, 53.89; H, 4.73; N, 5.74.
Example 4: 1-{ 3 2 -Oxo-4-phenyl-[1,3]oxazinane-3carbonyl)-amino-propyl}- 4 -phenyl-piperidine-4-carboxylic acid methyl ester (Scheme 7) a. 3-Amino-3-phenyl-propan-l-ol To a well stirred suspension of LiAlH 4 (1.3 g, 35.0 mmol) in THF (75 mL) in a round bottom flask fitted with a condenser was added 3 -amino-3-phenyl-propionic acid g, 15.0 mmol) in small portions at 0°C. The resulting grey suspension was then heated to reflux for 2 h. The reaction mixture was cooled to 0°C and then carefully quenched sequentially with 1.3 mL of water, 1.3 mL of 3N NaOH followed by 4.0 mL of water. The resulting suspension was filtered thro' a fritted glass funnel. To the residue was added 100 mL Et 2 O and the suspension 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. 3-amino-3-phenyl-propan-lol was obtained as a white solid (2.30 g, 100%) which was used in the next step without further purification.
WO 98/57940 PCT/US98/1 2668 -71b. (3-Hydroxy-l-phenyl-propyl)-carbamic acid-tert-butyl ester To a solution of 3-amino-3-phenyl-propan-l-ol (2.30 g, 15.0 mmol) in CHC13 (50 mL) at 0°C was added a solution of di-tert-butyl dicarbonate (3.75 g, 17.1 mmol) in CHC13 (25 mL) in one portion and the resulting solution was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel (2:1 hexane-EtOAc followed by EtOAc) to obtain (3-hydroxy-l-phenylpropyl)-carbamic acid-tert-butyl ester as white solid g, 100%).
c. 4-Phenyl-oxazinan-2-one To a well stirred suspension of 95% NaH (0.24 g, 10.0 mmol) in THF (20 mL) at r.t. was added a solution of (3hydroxy-l-phenyl-propyl)-carbamic acid-tert-butyl ester g, 4.0 mmol) in 10 mL THF via a dropping funnel at room temperature. The resulting suspension was stirred for 3 h and then quenched carefully with 10 mL of water.
The biphasic mixture was extracted with 100 mL of Et 2
O,
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 white flaky solid (0.44 g, 62%).
d. 2-Oxo-4-phenyl-[l,3]-oxazinane-3-carboxylic acid-4nitro-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-phenyloxazinan-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 4nitrophenylchloroformate (0.60 g, 3.0 mmol) in 20 mL of WO 98/57940 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 followed by CH 2 C1, (Rf= 0.4, CH 2 C1 2 to obtain 2-oxo-4phenyl-[1,3]-oxazinane-3-carboxylic acid-4-nitro-phenyl ester as a white solid (0.65 g, 82%).
e. 1-( 3 2 -Oxo-4-phenyl-[1,3]oxazinane-3-carbonyl)amino-propyl}-4-phenyl-piperidine-4-carboxylic acid methyl ester To a solution of 3 -amino-propyl-(4-carbomethoxy-4phenyl) piperidine (55 mg, 0.20 mmol) in 5 mL of THF, 2oxo-4-phenyl-[1,3]-oxazinane-3-carboxylic acid-4-nitrophenyl ester(51 mg, 0.15 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 10 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with EtOAC followed by 15% MeOH in EtOAC as the eluting systems (R, 0.4, 1:1 MeOH/EtOAC) to obtain 2-oxo-4-phenyl-[1,3]oxazinane-3-carboxylic acid-3-( 4 -carbomethoxy-4-phenyl)piperidin-l-yl]-propyl amide as a pale yellow glassy oil mg, 49% yield). It was converted into hydrochloride salt for characterization. Hygroscopic yellow solid.
Anal. Calcd. for C 27
H
34
N
3 0OC1.2.5 H 2 0: 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-3carboxylic acid 3 3 ',4',5',6'-tetrahydro-2'H- [2,4']bipyridinyl-l'-yl)-propyl]-ester a. 1-(3-hydroxypropyl)-4-[pyrid-2-yl]pyridinium bromide.
A solution of 2,4'-dipyridyl (3.0 g, 18.6 mmol) and 3bromo-l-propanol (2.02 ml, 22.4 mmol) in acetonitrile (100 mL) was heated to reflux for 2 days. After cooling, the solvent was removed in vacuo and the WO 98/57940 PCT/US98/12668 -73yellow-brown liquid (8.0 g) was directly used for next step without further purification.
b. 3 3 ',6'-Dihydro-2'-H-[2,4']bipyridinyl-1-yl)propanol.
To a solution of l-(3-hydroxypropyl)-4-[pyrid-2yl]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 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-l'-yl)propanol as an oil (1.58 g, 39% over two steps).
c. 3 -hydroxy-propyl-4-pyridyl-piperidine.
To a solution of 3 -(3',6'-dihydro-2'-H- 2 4 ']bipyridinyl-l'-yl)-propanol (1.30 g, 5.93 mmol) in mixed solvent (40 mL) of MeOH and 2N Hcl was added 0.5 g of Pearlman's catalyst. The suspension was hydrogenated under 80 psi at 50 0 C for 10 h after which the reaction mixture was filtered through a pad of celite and the solvent was removed. The residue was basified by 20% NaOH and extracted by CHC13 (7 X 40 ml), dried over Na 2
SO
4 The solvent was removed in vacuo to obtain a brown oil (785 mg, d. 4-(3,5-Difluoro-phenyl)-2-oxo-oxazolidine-3carboxylic acid 3 3 4 ',5',6'-tetrahydro-2'H- [2,4']bipyridinyl-1'-yl)-propyl]-ester To a solution of 4 3 ,5-difluorobenzyl)-2-oxooxazolidine-3-carboxylic acid-4-nitro-phenyl ester mg, 0.137 mmol) in 1,6-dioxane (20 ml) at room temperature, were added 3 -hydroxy-propyl-4-pyridylpiperidine (30 mg, 0.136 mmol) and K 2 CO, (23.8 mg, 0.52 WO 98/57940 PCT/US98/12668 -74mmol). The resulting mixture was heated to reflux for 12 h after which the reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by column chromatography over silica gel with EtOAc followed by 15% MeOH in EtOAc as the eluting system (Rf 0.30, MeOH:EtOAc 1:1) to obtain 4 3 ,5-difluoro-phenyl)-2-oxo-oxazolidine-3carboxylic acid 3 3 ',4',5',6'-tetrahydro-2'H-.
2 ,4']bipyridinyl-l'-yl)-propyl]-ester (20 mg, 33%).
The compound was dissolved in anhydrous EtOH (1 mL) and was treated with a warm solution of 95% fumaric acid (5.3 mg, 0.045 mmol) in EtOH (3 ml). The resulting solution was kept under gentle stream of argon for min after which hexane (2 ml) was added over lh and the solution was kept under argon overnight. Grey small crystals thus obtained were filtered, washed with EtOH (1 ml) and hexane (1 ml) and dried under vacuum. M.P.
171-173 0 C; Anal. Calcd. For C 27
H
29
N
3
O
8
F
2 0.27CHC13: C, 55.16; H, 4.97; N, 7.08. Found: C, 55.17; H, 4.98; N, 6.53.
Example 6: 2-Oxo-4-(3,4,5-trifluoro-phenyl)-oxazolidine- 3-carboxylic acid{3-[4-(2-carbamoyl-phenyl)-piperazin-1yl]-propyl)-amide a. 2-[4-(3-amino-propyl)-piperazin-1-yl]-benzamide Concentrated sulfuric acid (15 mL) was added to 1-(2cyanophenyl)piperazine (1.5 g, 8.0 mmol) placed in a round bottom flask and the resulting slurry was stirred at room temperature for 48 h. The reaction mixture was poured on crushed ice very slowly and then basified (pH 9) with 50% solution of NaOH. The aqueous layer was extracted several times with EtOAc, dried over K 2
CO
3 filtered and the solvent was evaporated. 1-(2carboxamidophenyl)piperazine was obtained as an offwhite solid (1.2 g, It was used in the next step WO 98/57940 PCT/US98/12668 without further purification.
b. 2-Oxo-4-(3,4,5-trifluoro-phenyl)-oxazolidine-3carboxylic acid{3-[4-(2-carbamoyl-phenyl)-piperazin-1yl]-propyl)-amide 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 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 0.64, MeOH/EtOAc=1:3 to obtain trifluorophenyl)- 2 -oxo-oxazolidine-3-carboxylic acid{3- 2 -carbomoyl-phenyl)-piperazin-l-yl]-propyl}-amide (135 mg, The compound was dissolved in CH 2 C1 (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. 164-168 0
C;
+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.
Example 7: 2 4 3 4 -(3,5-Difluoro-phenyl)-2-oxooxazolidine-3-carbonyl]-amino}-propyl)-piperazin-1-yl]benzoic acid methyl ester (Schemes 1 and a. 1-(2-Carbomethoxyphenyl)-piperazine To a solution of methyl 2-bromobenzoate (1.63 g, 17.8 mmol) in 1,4-dioxane (100 ml) at room temperature, were added piperazine (15.3 g, 178 mmol) and K 2
CO
3 (4.92 g, 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
F-
WO 98/57940 PCT/US98/12668 -76piperazine were removed in vacuo and heating with a hot water bath. The residue was dissolved in 1N NaOH solution and extracted with CH 2 C1 2 (6 X 30 ml), dried over Na 2
SO
4 The solvent was removed in vacuo to obtain l-(2-carbomethoxyphenyl)-piperazine as a yellow oil g, 26%).
b. 2 4 3 -{[4-(3,5-Difluoro-phenyl)-2-oxo-oxazolidine- 3-carbonyl]-amino)-propyl)-piperazin-l-yl]-benzoic acid methyl ester To a solution of 1-(3-amino-propyl)-4-(2carbomethoxyphenyl)-piperazine (25 mg, 0.090 mmol) in mL of THF, 4 3 5 -difluorophenyl)-2-oxo-oxazolidine-3carboxylic acid-4-nitro-phenyl ester(30 mg, 0.082 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by 1:9 MeOH/EtOAc (Rf= 0.75, MeOH/EtOAc=1:3 to obtain 2 4 -(3-{[4-(3,5-difluorophenyl)- 2 -oxo-oxazolidine-3-carbonyl]-amino}-propyl)piperazin-l-yl]-benzoic acid methyl ester (31 mg, 69%).
The compound was dissolved in CH 2 Cl 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. 93-96 0 C; [a]D +45.3, (c 0.29, MeOH) Anal. Calcd. For C2sH 30
N
4 0 5
F
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.
Example 8: 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3carboxylic acid [4-(4-phenyl-piperidin-1-yl)-butyl]amide To a solution of 1-( 4 -amino-butyl)-4-phenyl-piperidine mg, 0.151 mmol) in 10 mL of THF, 4-(3,5- WO 98/57940 PCT/US98/12668 -77difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4nitro-phenyl ester(40 mg, 0.110 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by 1:19 MeOH/EtOAc (Rf= 0.33, MeOH/EtOAc=1:3 to obtain 4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3carboxylic acid [4-(4-phenyl-piperidin-l-yl)-butyl]amide (42 mg, 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 yellow solid. M.P. 80-84oC; Anal. Calcd. For C 25
H
30
N
3 0 3
F
2 C1*0.5 CH 2 C1 2 C, 57.09; H, 5.82; N, 7.83. Found: C, 57.08; H, 6.21; N, 7.36.
Example 9: 1-(3-{[5-{3-(3,4-Difluorophenyl)-2-oxooxazolidine-3-carbonyl]-amino)-propyl)-4-phenylpiperidine-4-carboxylic acid methyl ester (Scheme 8) a. Hydroxy-(3,4-difluorophenyl)-acetonitrile To a solution of 3,4-difluorobenzaldehyde (2.86 g, 20.0 mmol) in MeOH (20 mL)in a round bottom flask was added trimethylsilyl cyanide (4.0 mL., 30.0 mmol) at 0°C. The reaction mixture was stirred at room temperature for 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 It was used in the next step.without purification.
b. 2-Amino-l-(3,4-difluorophenyl)-ethanol To a well stirred.solution of hydroxy-(3,4difluorophenyl)-acetonitrile (3.34 g, 20 mmol), was added a 1.0 M solution of LiAlH 4 in ether (40 mL, WO 98/57940 PCT/US98/12668 -78mmol) dropwise at 0 C. The resulting yellow solution was then stirred at room temperature for 2 h. The reaction mixture was cooled to 0°C and then carefully quenched sequentially with 1.5 mL of water, 1.5 mL of 3N NaOH followed by 4.5 mL of water. The resulting suspension was filtered thro' a fritted glass funnel. To the residue was added 100 mL Et 2 O and the suspension 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-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. [l-(3,4-Difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tert-butyl ester To a solution of 2 -amino-l-(3,4-difluorophenyl)-ethanol (3.2 g, 19.8 mmol) in CHC1 3 (15 mL) at 0°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 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 difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tertbutyl 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 3 4 -difluorophenyl)-2-hydroxy-ethyl]carbamic acid-tert-butyl ester (3.2 g, 23.0 mmol) in THF via a dropping funnel at room temperature. The resulting suspension was stirred for 3 h and then quenched carefully with 10 mL of water. The biphasic mixture was extracted with 100 mL of EtO2, washed with brine, filtered and the solvent was removed in vacuo.
WO 98/57940 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-2one as a white solid (1.1 g, 47%).
e. 5-(3,4-Difluorophenyl)- 2 -oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester To a suspension of 95% NaH (0.08 g, 3.0 mmol) in 5.0 mL of anhydrous THF under argon, a solution of 5-(3,4difluorophenyl)-oxazolidin-2-one (0.5 g, 2.51 mmol) in 5.0 mL THF was added dropwise via an dropping funnel.
The resulting suspension was stirred at room temperature for 30 min. This suspension was then added dropwise via cannula into another round bottom flask containing a solution of 4-nitrophenylchloroformate (0.07 g, 3.26 mmol) in 20 mL of THF, cooled at -78 0 C, over a period of 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 obtain 5-(3,4-difluorophenyl)-2-oxo-oxazolidine-3carboxylic acid-4-nitro-phenyl ester as a white solid (0.7 g, 76%).
f. 5 3 ,4-Difluorophenyl)-2-oxo-oxazolidine-3carbonyl]-amino}-propyl)-4-phenyl-piperidine-4carboxylic 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-(3,4difluorophenyl)- 2 -oxo-oxazolidine-3-carboxylic acid-4nitro-phenyl ester (0.04 g, 0.10 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 10 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with EtOAC followed by 15% MeOH in EtOAC as the eluting systems (Rf 0.4, 1:1 MeOH/EtOAC) to obtain WO 98/57940 PCTIUS98/1 2668 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, It was converted into its hydrochloride salt. M.P. 121- .125 0 C; Anal. Calcd. for C 26
H
80
N
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-oxooxazolidine-3-carboxylic acid [3-(4,4-diphenylpiperidin-1-yl)-propylj-amide (Schemes 2 and 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-4nitro-phenyl ester (0.04 g, 0.12 mmol) and the resulting yellow solution was stirred under argon atmosphere for 3 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 50% hexane/EtOAC followed by MeOH in EtOAC as the eluting systems (Rf 0.45, 1:3 MeOH/EtOAC) to obtain 4 -(3-Chloro-4-fluoro-phenyl)-2oxo-oxazolidine-3-carboxylic acid [3-(4,4-diphenylpiperidin-l-yl)-propyl]-amide as white foam (wt 0.03 It was converted into its hydrochloride salt. M.P.
112-115C; Anal. Calcd. for C 30
H
32
N
3 0 3 C1 2 F.O.5 CHC1 3
C,
57.95; H, 5.18; N, 6.65. Found: C, 58.06; H, 5.74; N, 6.30.
Example 11: 4-(3,4-Difluoro-phenyl)-2-thioxooxazolidine-3-carboxylic acid 4 -o-toluyl-4-p-toluylpiperidin-1-yl)-propyl)-anide (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 1,1'-thiocarbonyldiimadazole (755 WO 98/57940 PCT/US98/1 2668 -81mg, 3.81 mmol). The resulting solution was heated by a pre-heated oil-bath (110°C) to reflux for 10 h after which the reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by column chromatography over silica gel with CH 2 C1 as the eluting system (Rf 0.68,
CH
2
,C
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-3carboxylic 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-(3,4difluorophenyl)-oxazolidine-2-thione (290 mg, 1.35 mmol) in THF was added dropwise via an dropping funnel. The resulting suspension was stirred at room temperature for 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 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 then 3:7 hexane/CH 2 Cl 2 followed by
CH
2 C1 2 (Rf= 0.50) to obtain 4 -(3,4-difluorophenyl)-2thione-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester as a yellow solid (130 mg, c. 4-(3,4-Difluoro-phenyl)-2-thioxo-oxazolidine-3carboxylic acid 4 -o-toluyl-4-p-toluyl-piperidin-lyl)-propyl]-amide To a solution of l-( 3 -amino-propyl)-4-(4-methyl)-phenyl- 4-(2-methyl)-phenyl-piperidine (60 mg, 0.186 mmol) in mL of THF,4-( 3 4 -Difluorophenyl)-2-thione-oxazolidine-3carboxylic acid-4-nitro-phenyl ester(30 mg, 0.079 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature. The WO 98/57940 PCTIUS98/12668 -82solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by 1:19 MeOH/EtOAc (Rf= 0.66, MeOH/EtOAc=l:3 to obtain 4- 4-Difluoro-phenyl)-2thioxo-oxazolidine-3-carboxylic acid [3-(4-o-toluyl-4-ptoluyl-piperidin-l-yl)-propyl]-amide (16 mg, The compound was dissolved in CH 2 Cl 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. 132-136'C; Anal. Calcd. for
C
32
H
36
N
3
O
2 SCl-0 .60 CH 2 Cl 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-thioxothiazoidine3..carboxylic acid 3 3 i, 4 iS' 1 6-tetrahydro-2'H[2,4]bipyridinyl.
l'-yl)-.propyl]-amide (Scheme 9) a. 4- -Phenyl-thiazolidine-2-thione To a solution of (S)-(+)-2-Phenylglycinol(1.40 g, mmol) in 1N KQH/H.0 (10 ml) at room temperature, was added carbon disulfide (3 ml, 50 mmol). The resulting solution was heated by a pre-heated oil-bath (110*C) to ref lux for 20 h after whic h the reaction mixture was cooled to room temperature and extracted with CH 2 Cl 2 (3 X 30 ml), dried over Na 2
SO
4 The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/C-1 2 C1 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, b. 4- (3)-Pheny1-2-thionethiazoidine3..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- WO 98/57940 PCT/US98/12668 -83thiazolidine-2-thione (170 mg, 0.87 mmol) in THF was added dropwise via an dropping funnel. The resulting suspension was stirred at room temperature for 30 min.
This suspension was then added dropwise via cannula into another round bottom flask containing a solution of 4nitrophenylchloroformate (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 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-3carboxylic acid-4-nitro-phenyl ester as a pale yellow solid (200 mg, 64%).
c. 4 -phenyl-2-thioxo-thiazolidine-3-carboxylic acid [3- 3 4 ',5',6'-tetrahydro-2'H-[2,4']biphenyl-1'-yl)propyl]-amide To a solution of 3 -amino-propyl-4-pyridyl-piperidine mg, 0.159 mmol) in 10 mL of THF,(+)-4(S)-Phenyl-2thione-thiazolidine-3-carboxylic acid-4-nitro-phenyl ester (50 mg, 0.139 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by 1:9 MeOH/EtOAc (Rf= 0.21, MeOH/EtOAc=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-1'-yl)propyl]-amide (10 mg, The compound was.dissolved in CH 2 Cl 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.
67-70 0 C; Anal. Calcd. for C 2 3
H
3 1
N
4 0S 2 C1l 2 0.67 CHCl 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[l]indene-3-carboxylic acid-[3-(1-4-cyano- 4-phenyl-piperidin-1-yl)-propyl-amide (Scheme a. Synthesis of (+)-3,3a,8,8a-tetrahydro-1(S)-oxa-3(R)aza-cyclopenta[a]inden-2-one To a solution of (1R,2S)-(+)-cis-l-amino-2-indanol g, 6.7 mmol) in 30 ml methylene chloride in 100-ml round bottom flask equipped with a stirring bar, was added l,1'-carbonyldimidazole (1.20 g, 7.4 mmol) at room temperature. The resulting solution was heated by a preheated oil-bath (110°C) to reflux for 10 h after which the reaction mixture was cooled to room temperature and the formation of white crystal was observed. The white crystal was filtered off washed with minmum 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 -71.1 (c 0.28, acetone). M.P. 203-204 0 C. Anal. Calcd. for C 1 oH 9
NO
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-azacyclopenta[a]indene-3-carboxylic acid 4-nitro-phenyl ester.
To a suspension of NaH (73 mg, 2.88 mmol) in 20 mL of anhydrous THF under argon, a solution of 3,3a,8,8atetrahydro-l(R)-oxa-3(S)-aza-cyclopenta[a]inden-2-one (420 mg, 2.40 mmol) in THF was added dropwise via an dropping funnel. The resulting suspension was stirred at room temperature for 30 min. This suspension was then added dropwise via cannula into another round bottom flask containing a solution of 4nitrophenylchloroformate (598 mg, 2.88 mmol) in 25 mL of WO 98/57940 PCT/US98/12668 THF and cooled at -78°C over a period of 15 min. The stirring was continued for 2 h after which the solvent was removed and the residue was purified by column chromatography on silica gel with 4:1 hexane/EtOAc followed by 3:2 hexane/EtOAc (Rf= 0.51, hexane/EtOAc=l:1) to obtain a white solid (680 mg, 83%).
c. 2 -Oxo-8,8a-dihydro-3aH-l-(S)-oxa-3-(R)-azacyclopent[1]indene-3-carboxylic acid-[3-(l-4-cyano-4phenyl-piperidin-1-yl)-propyl-amide To a solution of l-( 3 -amino-propyl)-4-cyano-4-phenylpiperidine (25 mg, 0.103 mmol) in 10 mL of THF, 2-Oxo- 1,3a,8, 8 a-tetrahydro-2H-3-aza-cyclopenta[a]indene-3carboxylic acid 4-nitro-phenyl ester (40 mg, 0.118 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by EtOAc 0.35 to obtain (-)-2-Oxo-8,8a-dihydro-3aH-l-(S)-oxa-3-(R)-azacyclopent[l]indene-3-carboxylic acid-[3-(l-4-cyano-4phenyl-piperidin-l-yl)-propyl-amide (19 mg, 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 white solid. M. P. 98-102 0 C; [a]D -96.5, (c 0.21, MeOH); Anal. Calcd. For C 26
H
29
N
4 03C1 0.48 CH 2 C1 2
C,
60.96; H, 5.79; N, 10.74. Found: C, 60.94; H, 6.69; N, 8.02.
Example 14: 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3carboxylic acid (3-[2-methyl-4-(2-nitro-phenyl)piperazin-1-yl)-propyl}-amide a. (S)-(+)-3-meuhyl-1-(2-nitrophenyl)-piperazine To a solution of 2 -bromo-nitrobenzene (0.6 g, 3.0 mmol) WO 98/57940 PCT/US98/12668 -86in 1,4-dioxane (15 mL) was added 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 cooled, it was filtered through a sintered glass funnel and the solvent was evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (1:1 hexane/EtOAc followed by 4:1 EtOAc/MeOH) to yield (S)-(+)-3-methyl-l-(2-nitrophenyl)-piperazine as an orange oil (0.53 g, It was converted into (+)-3-methyl-l-(2-nitrophenyl)-4-(3-aminopropyl)piperazine by the usual procedure.
b. 4 3 4 -Difluoro-phenyl)-2-oxo-oxazolidine-3carboxylic acid {3-[2-methyl-4-(2-nitro-phenyl)piperazin-1-yl)-propyl}-amide To a solution of (S)-(+)-3-methyl-l-(2-nitrophenyl)-4- 3 -aminopropyl)-piperazine (35 mg, 0.126 mmol) in 10 mL of THF, 4-( 3 ,4-difluorophenyl)-2-oxo-oxazolidine-3carboxylic acid-4-nitro-phenyl ester (50 mg, 0.137 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by MeOH:EtOAc=l:9 0.58, MeOH:EtOAc=1:3 to obtain 4-(3,4-Difluoro-phenyl)-2oxo-oxazolidine-3-carboxylic acid {3-[2-methyl-4-(2nitro-phenyl)-piperazin-l-yl)-propyl}-amide (55 mg, The compound was dissolved in CH2C1 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 pale yellow solid. M. P. 115- 119 0 C; +38.3, (c 0.22, CH 2 C12); Anal. Calcd. For
C
24
H
2 sNsOsF 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-3carboxylic acid {3-[4-methyl-4-phenyl-piperidin-1-yl)propyl)-amide a. 1-Benzyl-4-methyl-4-piperidinol To a solution of l-benzyl-4-piperidone (5.6 mL, 30.0 mmol) in 50 mL THF was added a solution of methyllithium in THF (24.0 mL, 36 mmol) dropwise at 0°C over 15 min.
The reaction mixture was allowed to warm to room temperature over 3 h and then quenched with 30 mL of sat. NH 4 C1 solution. The oragnic layer was extracted with diehtyl ether (2 X 100 mL) and the combined organic layer was washed with brine (100 mL). The organic layer was separated, dried over Na 2
SO
4 filtered and the solvent was removed in vacuo to obtain yellow gum. It was purified by column chromatography over silica gel with 9:1 EtOAc-MeOH as the eluting system to obtain 1benzyl-4-methyl-4-piperidinol as a yellow thick oil (3.6 g, 59% yield).
b. l-Benzyl-4-methyl-4-phenyl piperidine To a solution of l-benzyl-4-methyl-4-piperidinol (3.6 g, 17.5 mmol) in 75 mL of benzene was added 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 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
SO
4 filtered and the solvent was removed in vacuo to obtain l-benzyl-4-methyl-4-phenyl piperidine as a red oil (4.5 g, 97% yield). It was used in the next step without further purification.
c. 4-Methyl-4-phenyl piperidine To a cooled suspension of 10% Pd-C (0.5 g) in 10 mL WO 98/57940 PCT/US98/12668 -88methanol was added a solution of l-benzyl-4-methyl-4phenyl piperidine (4.5 g, 17.0 mmol) in 40 mL of methanol and the resulting suspension was hydrogenated in a Parr bomb under 250 psi of hydrogen for two days.
The suspension was filtered through a pad of celite and the solvent was removed from the filtrate to obtain 4methyl-4-phenyl piperidine as a yellow solid (3.3 g, 99% yield).
d. 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3carboxylic acid (3-[4-methyl-4-phenyl-piperidin-1-yl)propyl}-amide To a solution of l-( 3 -amino-propyl)-4-methyl-4-phenylpiperidine (60 mg, 0.258 mmol) in 10 mL of THF, 4-(3,4difluorophenyl)- 2 -oxo-oxazolidine-3-carboxylic acid-4nitro-phenyl ester (60 mg, 0.165 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by MeOH:EtOAc=1:19 (Rf= 0.45, MeOH:EtOAc=l:3 to obtain 4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3carboxylic acid 4 -methyl-4-phenyl-piperidin-l-yl)propyl}-amide (56 mg, The compound was dissolved in CH 2 C1 2 (3 mL) and was treated with lN HC1 in ether (1 mL). The solvent was removed in vacuo to give the corresponding hydrochloride salt as a pale yellow solid.
M. P. 176-178C; [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.
Example 16: 4-(3,4-Difluorophenyl)-4-methyl-2-oxooxazolidine-3-carboxylic acid (3-[4-(2-methylphenyl)-4- (4-methylphenyl)-piperidin-1-yl]-propyi}amide (Scheme 11) WO 98/57940 PCT/US98/12668 -89a. 2-(3,4-Difluorophenyl)propan-2-ol To a solution of ethylmagnesium bromide in ether (38.0 mL, 38.0 mmol) at 0°C, was added a solution of difluoroacetophenone (5.0 g, 32.0 mmol) in diethyl ether (35mL). The reaction mixture was stirred at 0 C for 1 h when TLC analysis indicated that the reaction was complete 0.3, 3:1 hexane/EtOAc). The reaction was quenched carefully by adding 38 mL of water. It was extracted with diethyl ether (2 X 30 mL), washed with Rochelle's salt followed by brine and the organic layer was dried over 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 step without purification.
b. 1,2-Difluoro-4-isopropenyl-benzene To a solution of 2-(3,4-difluorophenyl)propan-2-ol g, 5.8 mmol) in 40 mL benzene was added 0.1 g of ptoluenesulfonic acid and the solution was heated to 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 yellow oil (0.82 g, 92% yield).
c. 2-(3,4-Difluorophenyl)-2-methyl-oxirane To a biphasic solution of 1,2-difluoro-4-isopropenylbenzene (0.81 g, 5.1 mmol) in CH 2 C1, (50 mL) and 50 mL of phosphate buffer (made by dissolving 0.3 g of NaHPO, and 0.35 g of NaH 2
PO
4 in 50 mL water, pH 8) at 0°C, was added a solution of 3-chloroperoxybenzoic acid (approx. 75% solid, 3.32 g, 10.2 mmol) via a dropping funnel fitted with a cotton plug dropwise in two batches. The solution was stirred at room temperature overnight. It was extracted with CH 2 C1l, washed with WO 98/57940 PCT/US98/1 2668 sat. Na 2
S
2 04 solution followed by water. The organic layer was finally washed with sat. NaHC03, separated, dried over Na 2
SO
4 filtered and solvnt was removed in vacuo. 2-(3,4-Difluorophenyl)-2-methyl-oxirane was obtained as a pale yellow oil (0.65 g, 74% yield). It was used in the next step without purification.
d. l-Amino-2-(3,4-difluorophenyl)-propan-2-ol and 2- Amino-2-(3,4-difluorophenyl)-propan-1-ol To a solution of 2-(3,4-difluorophenyl)-2-methyl-oxirane (1.2 g, 7.06 mmol) in 10 mL of acetonitrile was added sodium azide (0.69g, 10.6 mmol) followed by lithium perchlorate (1.13 g, 10.6 mmol). and the suspension was heated to reflux overnight. After cooling, it was extraced with EtOAc, washed with saturated NaHCO3, dried 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 It was dissolved in 40 mL of diethyl ether, cooled to 0 C and then treated with a solution of lithium aluminum hydride (20.0 mL, 20 mmol). The resulting yellow suspension was then stirred at room temperature for 2 h. The reaction mixture was cooled to 0°C and then carefully quenched sequentially with 0.8 mL of water, 0.8 mL of 3N NaOH followed by 2.5 mL of water.
The resulting suspension was filtered thro' a fritted glass funnel. To the residue was added 100 mL Et 2 O and the suspension was heated to reflux for 20 min. The suspension was filtered and was combined with the previous filtrate, dried over MgSO filtered and the solvent was removed in vacuo. 1-Amino-2-(3,4difluorophenyl)-propan-2-ol and 2-amino-2-(3,4difluorophenyl)-propan-l-ol was obtained as a yellow glassy syrup (1.16 g, 87%) which was used in the next WO 98/57940 PCT/US98/12668 -91step immediately without further purification.
e. [2-(3,4-Difluorophenyl)-2-hydroxy-propyl]-carbamic acid-tert-butyl ester and [1-(3,4-Difluorophenyl)-2hydroxy-propyl]-carbamic acid-tert-butyl ester To a solution of l-amino- 2 -(3,4-difluorophenyl)-propan- 2-ol and 2 -amino-2-(3,4-difluorophenyl)-propan-1-ol (1.2 g, 6.4 mmol) in CHCl 3 (50 mL) at 0 C was added a solution of di-tert-butyl dicarbonate (1.74 g, 7.9 mmol) in CHC13 (10 mL) in one portion and the resulting solution was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel (2:1 hexane-EtOAc followed by EtOAc) to obtain difluorophenyl)-2-hydroxy-propyl]-carbamic acid-tertbutyl ester and [1-(3,4-Difluorophenyl)-2-hydroxypropyl]-carbamic acid-tert-butyl ester as a white solid (1.1 g, 60.1%).
f. 5-(3,4-Difluorophenyl)-5-methyl-oxazolidin-2-one and 4-(3,4-Difluorophenyl)-4-methyl-oxazolidin-2-one To a well stirred solution of [2-(3,4-difluorophenyl)-2hydroxy-propyl]-carbamic acid-tert-butyl ester and [1- (3,4-Difluorophenyl)-2-hydroxy-propyl]-carbamic acidtert-butyl ester (1.1 g, 3.8 mmol) THF (50 mL) was added NaH (0.23 g, 9.6 mmol) at room temperature. The resulting suspension was heated to reflux for 1 h and then stirred at room temperature overnight. It was quenched carefully with ice. The biphasic mixture was extracted with 100 mL of EtOAc, washed with brine, dried over Na 2
SO
4 filtered and the solvent was removed in vacuo. The two diastereomers were separated by column chromatography over silica gel. The first diastereomer that came out was 4-(3,4-difluorophenyl)-4-methyloxazolidin-2-one (0.05 g, R 0.3, 3:2 hexane-EtOAc) and the second isomer was 5-( 3 WO 98/57940 PCT/US98/12668 -92methyl-oxazolidin-2-one (0.61 g, R, 0.2, 3:2 hexane- EtOAc).
g. 4-(3,4-Difluorophenyl)-4-methyl-2-oxo-oxazolidine-3carboxylic acid-4-nitro-phenyl ester To a a solution of 4-(3,4-Difluorophenyl)-4-methyloxazolidin-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 min. This suspension was then added dropwise via a syringe into another round bottom flask containing a solution of 4-nitrophenylchloroformate (0.06 g, 0.28 mmol) in 5 mL of THF, cooled at -78 0 C, over a period of min. The stirring was continued for 1 h after which the solvent was removed and the residue was purified by column chromatography on silica gel with 3:2 hexane/EtOAc 0.5) to obtain 4-(3,4-difluorophenyl)- 4-methyl-2-oxo-oxazolidine-3-carboxylic acid-4-nitrophenyl ester as a white solid (0.06 g, 69%).
h. 5-(3,4-Difluorophenyl)-5-methyl-2-oxo-oxazolidine-3carboxylic acid-4-nitro-phenyl ester To a a solution of 4-(3,4-Difluorophenyl)-4-methyloxazolidin-2-one (0.61 g, 2.86 mmol) in 20 mL THF was added 95% NaH (0.07 g, 3.0 mmol) in one portion. The resulting suspension was stirred at room temperature for 20 min. This suspension was then added dropwise via a cannula into another round bottom flask containing a solution of 4-nitrophenylchloroformate (0.62 g, 3.1 mmol) in 20 mL of THF, cooled at -78 0 C, over a period of min. The stirring was continued for 1 h after which the solvent was removed and the residue was purified by column chromatography on silica gel with 3:2 hexane/EtOAc (Rf= 0.6) to obtain 4-(3,4-difluorophenyl)- 4-methyl-2-oxo-oxazolidine-3-carboxylic acid-4-nitrophenyl ester as a white solid (0.7 g, 67%).
i. 4-(3,4-Difluorophenyl)-4-methyl-2-oxo-oxazolidine-3- WO 98/57940 PCT/US98/12668 -93carboxylic acid (3-[4-(2-methylphenyl)-4-(4methylphenyl)-piperidin-1-yl]-propyl}amide To a solution of 3 -amino-propyl-4-(2-methyl)phenyl-4-(4methyl)phenyl-piperidine (0.09 g, 0.27 mmol) in 10 mL of THF, 4-( 3 4 -Difluorophenyl)-4-methyl-2-oxo-oxazolidine- 3-carboxylic acid-4-nitro-phenyl ester (0.06 g, 0.15 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 10 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with EtOAC followed by 15% MeOH in EtOAC as the eluting systems (Rf 0.3, 1:3 MeOH/EtOAC) to obtain 4-( 3 4 -difluorophenyl)-4-methyl-2-oxo-oxazolidine-3carbonyl)-amino-propyl}-4-(2-methyl)phenyl-4-(4methyl)phenyl-piperidine as a pale yellow glassy oil (0.06 g, 73%) as a viscous oil. It was converted into its hydrochloride salt. M.P. 98-101°C; Anal. Calcd.
for C 33
H
38
N
3 0 3
F
2 C1.1.0 CH 2 C1 2 C, 59.79; H, 5.90; N, 6.15.
Found: C, 59.40; H, 5.99; N, 5.92.
Example 17: 5-(3,4-Difluorophenyl)-5--methyl-2-oxooxazolidine-3-carboxylic acid (3-[4-(2-methoxy-5methyl)phenyl-4-(4-methylphenyl)-piperidin-1yl]propyl)amide (Scheme 11) To a solution of 3-amino-propyl-4-(2-methoxy-5methyl)phenyl-4-(4-methyl)phenyl-piperidine (0.09 g, 0.27 mmol) in 10 mL of THF, 5-(3,4-Difluorophenyl)-5methyl-2-oxo-oxazolidine-3-carboxylic acid-4-nitrophenyl ester (0.04 g, 0.11 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 10 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with EtOAC followed by 15% MeOH in EtOAC as the eluting systems (Rf WO 98/57940 PCT/US98/12668 -94- 0.3, 1:3 MeOH/EtOAC) to obtain 4 3 4 -difluorophenyl)- 4-methyl-2-oxo-oxazolidine-3-carboxylic acid methoxy-5-methyl)phenyl-4-(4-methylphenyl)-piperidin-lyl]propyl}amide as a pale yellow glassy oil (0.06 g, 85%) as a viscous oil. It was converted into its hydrochloride salt. M.P. 82-850C; Anal. Calcd. for
C
34
H
0
NO
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.
Example 18: cis (+)-4-(3,4-Difluorophenyl)-5-methyl-2oxo-oxazolidine-3-carboxylic acid{3-[4-(4-fluorophenyl)piperidin-1-yl]propyl)amide (Scheme 12) a. l-(3,4-Difluorophenyl)propan-l-ol To a solution of 3,4-difluorobenzaldehyde (5.0 g, 35.2 mmol) in diethyl ether (35 mL)in a round bottom flask was added a solution of ethylmagnesium bromide in THF (38.0 mL, 38.0 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 h when TLC analysis indicated that the reaction was complete 0.5, 8:1 hexane/EtOAc).
The reaction was quenched carefully by adding 38 mL of water. It was extracted with diethyl ether (2 X 30 mL), washed with brine and the organic layer was dried over Na 2
SO
4 The solvent was removed in vacuo after filtration and l-(3,4-difluorophenyl)propan-l-ol was obtained as a yellow oil (crude wt. 6.0 g) which looked 90% pure by NMR. It was used in the next step without purification.
b. 1-(3,4-Difluorophenyl)propan-l-one In a round bottom flask containing pyridinium chlorochromate (12.5 g, 58.1 mmol) was added celite 545 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 l-(3,4-difluoro-phenyl)propan- 1-ol (5.0 g, 29.1 mmol) in 10 mL of CH 2 Cl2 and the WO 98/57940 PCT/US98/1 2668 resulting brown suspension was stirred overnight at room temperature. The suspension was filtered through a sintered glass funnel and the solvent was removed in vacuo from the pale green colored filtrate. The green oil was then diluted with diethyl ether (200 mL) and it was filtered through a pad of celite to remove the metal impurities. The solvent was removed in vacuo to obtain 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 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 0°C and 1-(3,4difluorophenyl)-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 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 solvent was removed in vacuo to get 1-(3,4difluorophenyl)-2-hydroxy-propan-l-one dimethyl acetal as a yellow viscous oil (crude wt. 9.2 It was dissoled in 150 mL of acetone and 10 drops of concentrated sulfuric acid were added. After stirring for 3 h, TLC analysis indicated that the reaction was complete. Acetone was removed in vacuo and after basification with saturated 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 filtered. The solvent was removed in vacuo and the WO 98/57940 PCTIUS98/12668 -96residue 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).
d. l-(3,4-Difluorophenyl)-2-hydroxy-propan-l-one-oxime To a well stirred solution of 1-(3,4-difluorophenyl)-2hydroxy-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 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 separated, dried over Na 2 SO, and then filtered.
The solvent was removed in vacuo to obtain 1-(3,4difluorophenyl)-2-hydroxy-propan-l-one-oxime as an orangish yellow oil (5.8 g, It was used in the next step without purification.
e. 1-Amino-l-(3,4-difluorophenyl)-propan-2-ol To a well stirred solution of l-(3,4-difluorophenyl)-2hydroxy-propan-l-one-oxime (5.8 g, 28.4 mmol), was added a 1.0 M solution of LiA1H 4 in ether (90 mL, 90 mmol) dropwise at 0°C. The resulting yellow solution was then stirred at room temperature for 2 h. The reaction mixture was cooled to 0 C and then carefully quenched sequentially with 3.5 mL of water, 3.5 mL of 3N NaOH followed by 10.5 mL of water. The resulting suspension was filtered thro' a fritted glass funnel. To the residue was added 100 mL EtO2 and the suspension was heated to reflux for 20 min. The suspension was filtered and was combined with the previous filtrate, dried over MgSO 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.
f. [1-(3,4-Difluorophenyl)-2-hydroxy-propyl]-carbamic WO 98/57940 PCT[US98/12668 -97acid-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 C was added a solution of di-tert-butyl dicarbonate (5.1 g, 23.6 mmol) in CHC1 3 (10 mL) in one portion and the resulting solution was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel (2:1 hexane-EtOAc followed by EtOAc) to obtain [1- (3,4-difluorophenyl)-2-hydroxy-propyl]-carbamic acidtert-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 3 ,4-difluorophenyl)-2hydroxy-propyl]-carbamic acid-tert-butyl ester (0.43 g, 1.5 mmol) THF (20 mL) was added 95% NaH (0.09 g, 3.8 mmol) at room temperature. The resulting suspension was stirred for 3 h at about 35°C (warm water bath) and then quenched carefully with ice. The biphasic mixture was extracted with 100 mL of EtOAc, washed with brine, dried over Na 2 S0 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, R, 3:1 hexane-EtOAc). NOE experiment suggested that the first diastereomer had the methyl and the aryl group in trans configuration while the second diastereomer had cis relationship between the two groups.
Enantiomers of each of these diastereoisomers were separated by HPLC by using Chiralcel OD (4.6 x 250 mm) using 80% hexane/20% isopropyl alcohol/ 0.1% diethylamine as the eluting system (12 mL/min) under isothermal conditions 254 nM). The retention times for the two isomers of the trans-oxazolidinone were 12.1 min 36.4 (c o.25, acetone)} and 15.6 min 30.8 (c o.20, acetone)}, WO 98/57940 PCT/US98/12668 -98respectively. The retention times for the two isomers of the cis-oxazolidinone were 13.7 min 65.8 (c o.92, acetone)) and 19.9 min 65.8 (c 0.74, acetone)} respectively. The next steps may be performed on each of the four enantiomers individually in the following manner, which describes the synthesis of the cis enantiomer.
h. 4-(3,4-Difluorophenyl)-5-methyl-2-oxo-oxazolidine-3carboxylic 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-(3,4difluorophenyl)-5-methyl-oxazolidin-2-one (0.07 g, 0.33 mmol) in 5.0 mL THF was added dropwise via a syringe.
The resulting suspension was stirred at room temperature for 20 min. This suspension was then added dropwise via a syringe into another round bottom flask containing a solution of 4-nitrophenylchloroformate (0.08 g, 0.4 mmol) in 10 mL of THF, cooled at -78 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 column chromatography on silica gel with 1:1 hexane/CH 2 C1 followed by CH 2 C1 2 (Rf= 0.4, CH 2 C1 2 to obtain 4-(3,4-difluorophenyl)-5-methyl-2-oxooxazolidine-3-carboxylic acid-4-nitro-phenyl ester as a white solid (0.07 g, 56%).
i. 3-[4-(4-Fluoro-phenyl)-piperidin-1-yl]-propylamine To a solution of 4-fluorophenylmagnesium bromide (110.0 mmol, 55.0 mL of 2.0 M solution) in 150.0 mL THF at 0 C was added l-benzyl-4-piperidone (55.0 mmol, 10.2 mL) dropwise. The resulting solution was stirred under argon atmosphere for 1.5 h and then quenched with 100.0 mL of saturated NH 4 Cl solution. The organic layer was WO 98/57940 PCTIUS98/12668 -99separated and the aqueous layer was extracted with 100.0 mL of EtO2. 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 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 It was dissolved in 150.0 mL of toluene and ptoluenesulfonic 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 EtO2 (2 X 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-(4fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine as a yellow viscous oil (12.0 g, 92% yield) which was used in the next step without further purification.
To a solution of l-benzyl-4-(4-fluoro-phenyl)- 1,2,3,6-tetrahydro-pyridine (45.0 mmol, 12.0 g) in 100 mL MeOH was added 1.0 g of Pd(OH)2 and the resulting suspension was hydrogenated under 200 psi of H 2 in a stainless steel bomb for two days. The suspension was passed through a pad of celite and the filterate was concentrated in vacuo to obtain 4-(4-fluoro)-phenylpiperidine (7.5 g, 94%) as a viscous oil. It was converted into 3-[4-(4-fluoro-phenyl)-piperidin-l-yl]propylamine by the route described previously in Example 1.
j. cis (+)-(4-(3,4-Difluorophenyl)-5-methyl-2-oxooxazolidine-3-carboxylic acid{3-[4-(4-fluorophenyl)piperidin-l-yl]propyl)amide WO 98/57940 PCT/US98/12668 -100- To a solution of 3-amino-propyl-4-(4-fluoro)phenylpiperidine (0.04 g, 0.12 mmol) in 10 mL of THF (3,4-Difluorophenyl)-5-methyl-2-oxo-oxazolidine-3carboxylic acid-4-nitro-phenyl ester (0.03 g, 0.08 mmol) (made from the (+)-enantiomer from HPLC of the cis diastereomer separated by column chromatography) was added and the resulting yellow solution was stirred under argon atmosphere for 10 h at room temperature.
The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with EtOAC followed by 15% MeOH in EtOAC as the eluting systems (Rf 0.4, 1:3 MeOH/EtOAC) to obtain (3,4-Difluorophenyl)-5-methyl-2-oxo-oxazolidine-3carboxylic acid{3-[4-(4-fluorophenyl)-piperidin-1yl]propyl}amide as a pale yellow glassy oil(0.03 g, It was converted into its hydrochloride salt. M.
P. 108-112 0 C; [a]D +56.7, (c 0.20, MeOH); Anal.
Calcd. For C 2
,H
29
N
3 0 3
F
3 Cl* 0.36 CH 2 C1 2 C, 56.14; H, 5.52; N, 7.75. Found: C, 56.17; H, 5.90; N, 7.20.
Example 19: trans (+)-4-(3,4-Difluorophenyl)-5-methyl-2oxo-oxazolidine-3-carboxylic acid{3- (4-fluorophenyl) piperidin-1-yl]propyl)amide (Scheme 12) In an analogous manner as described above for Example 18, Steps h-j, the trans (+)-4-(3,4-difluorophenyl)-5methyl-2-oxo-oxazolidine-3-carboxylic acid-4-nitrophenyl ester (0.03 g, 0.08 mmol) (made from the enantiomer from HPLC of the trans diastereomer separated by column chromatography) was converted into trans 4-( 3 4 -difluorophenyl)-5-methyl-2-oxo-oxazolidine-3carboxylic acid{3-[4-(4-fluorophenyl)-piperidin-1yl]propyl}amide in 70% yield. It was converted into hydrochloride salt.
M.P. 80-83 0 C (shrinks around 58 0 [a]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-3carboxylic acid (3-[4-(2-carbamoylphenyl)-piperazin-1yl]-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 a condenser was added 3,4-difluorophenyl alanine (1.0 g, mmol) in small portions at 0°C. The resulting grey suspension was then heated to reflux for 2 h. The reaction mixture was cooled to 0°C and then carefully quenched sequentially with 0.5 mL of water, 0.5 mL of 3N NaOH followed by 1.5 mL of water. The resulting suspension was filtered through a fritted glass funnel.
To the residue was added 50 mL Et 2 0 and the suspension was heated to reflux for 20 min. The suspension was filtered and was combined with the previous filtrate, dried over MgSO 4 filtered and the solvent was removed in vacuo. 2-Amino-3-(3.4-difluoro)-phenyl-propan-1-ol was obtained as a white solid (0.5 g, 100%) which was used in the next step.without further purification.
b. (+)-[l-(3,4-Difluorobenzyl)-2-hydroxy-ethyl]-carbamic 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 CHC1 3 (20 mL) at 0 C 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 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 acidtert-butyl ester as white solid (0.64 g, 99%).
WO 98/57940 PCT/US98/12668 -102c.(+)-4-(3,4-Difluoro-benzyl)-oxazolidin-2-one To a well stirred suspension of 95% NaH (0.12 g, mmol) in THF (20 mL) at r.t. was added a solution of (+)-[1-(3,4-difluorobenzyl)-2-hydroxy-ethyl]-carbamic acid-tert-butyl ester (1.0 g, 4.0 mmol) in 10 mL THF via a dropping funnel at room temperature. The resulting suspension was stirred for 3 h and then quenched carefully with 10 mL of water. The biphasic mixture was extracted with 50 mL of EtO2, 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 0.25, 3:2 hexane- EtOAc) to obtain (+)-4-(3,4-difluoro-benzyl)-oxazolidin- 2-one as a white solid (0.32 g, 76%).
d.(+)-4-(3,4-Difluoro-benzyl)-oxazolidin-2-one-3carboxylic 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 difluoro-benzyl)-oxazolidin-2-one (0.21 g, 1.0 mmol) in 10 mL THF was added dropwise via an dropping funnel.
The resulting suspension was stirred at room temperature for 30 min. This suspension was then added dropwise via cannula into another round bottom flask containing a solution of 4-nitrophenylchloroformate (0.30 g, 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 chromatography on silica gel with 1:1 hexane/CH 2 Cl 2 followed.by
CH
2 C1 2 0.4, CHC1,) to obtain (+)-4-(3,4-difluoro-benzyl)-oxazolidin-2-one-3carboxylic acid-4-nitro-phenyl ester as a yellow solid (0.35 g, 82%).
e. 4 -(3,4-Difluoro-benzyl)-2-oxo-oxazolidinie-.3carboxylic acid (3-[4-(2-carbamoylphenyl)-piperazin-1yl]-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 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/Et0Ac followed by 1:19 MeOH/EtOAc (Rf= 0.70, MeOH/EtOAc=1:3 to obtain 4 -(3,4-Difluoro-benzyl)-2oxo-oxazolidine-3-carboxylic acid carbamoylphenyl)-piperazin-l-yl]-propyl)amide (20 mg, The compound was dissolved in CHCl 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. 82-85 0
C;
[a]D +34.3, (c 0.49, MeOH); Anal. Calcd. For
C
25 Hz 3
N
s
O
4
F
2
C
2 1, 3.5 HO0: C, 47.10; H, 6.01; N, 10.99.
Found: C, 47.12; H, 5.94; N,10.94.
Example 21: 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3carboxylic acid(2-[4-phenylpiperidine-4-(carboxylic acid methyl ester)]ethyl}amide (Scheme To a solution of 2 -amino-ethyl-4-carbomethoxy-4-phenyl piperidine (0.03 g, 0.12 mmol) in 5 mL of THF was added 4-(3,4-difluorophenyl)- 2 -oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester (0.04 g, 0.10 mmol) and the resulting yellow solution was stirred under argon atmosphere for 3 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 50% hexane/EtOAC followed by 5% MeOH in EtOAC as the eluting systems (Rf 0.5, 1:3 MeOH/EtOAC) to obtain the product as colorless oil (wt= 0.02 The compound was converted WO 98/57940 PCT/US98/12668 -104into its hydrochloride salt. M.P. 80-85°C; [a]D 51.6, (c 0.11, MeOH); Anal. Calcd. for
C
25
H
28
N
3 ,0C1F 2 .0.5 CHC13: C, 52.48; H, 4.92; N, 7.20.
Found: C, 52.54; H, 5.13; N, 7.27.
Example 22: 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3carboxylic acid{3-[4-(4-fluoro-2-methyl-phenyl)piperidin-l-yl]-propyl) amide a. 1-Benzyl-4-(5-fluoro-2-methyl)-phenyl-4-piperidinol To a cooled solution of n-BuLi (6.0 mL, 15.0 mmol) in 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°C over 1 h and then cooled to -78 0 C. l-Benzyl-4-piperidone (1.48 mL, mmol) was added the white slurry and the reaction mixture was warmed to 0°C over 2 h. The reaction was then quenched with 10 mL of sat. NH 4 Cl solution. The oragnic layer was extracted with diehtyl ether (2 X 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 oil. It was purified by column chromatography over silica gel with 3:2 hexane-EtOAc as the eluting system to obtain l-benzyl-4-(5-fluoro-2methyl)-phenyl-4-piperidinol as a yellow thick oil (1.1 g, 46% yield).
b. l-Benzyl-4-(4-Fluoro-2-methyl)-phenyl-1,2,3,6tetrahydropyridine To a solution of l-benzyl-4-(5-fluoro-2-methyl)-phenyl- 4-piperidinol (1.1 g, 3.68 mmol) in 100 mL toluene was added p-toluenesulfonic acid monohydrate (1.39 g, 7.35 mmol) and the resulting solution was heated to reflux for 8 h. The suspension was cooled and the basified with KOH solution and extracted with EtOAc (2 X 50 mL).
The organic layer was washed with brine (30 mL). The WO 98/57940 PCT/US98/12668 -105organic 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-1,2,3,6-tetrahydropyridine as a pale yellow oil (0.9 g, 87% yield). It was used in the next step without further purification.
c. 3-amino-propyl-4-(4-fluoro-2-methyl)phenyl-piperidine To a cooled suspension of 10% Pd-C (0.1 g) in 10 mL methanol was added a solution of l-benzyl-4-(4-Fluoro-2methyl)-phenyl-1,2,3,6-tetrahydropyridine (0.9 g, 3.2 mmol) in 20 mL of methanol and the resulting suspension was hydrogenated at room temperature under 1 atm of hydrogen for 10 h. The suspension was filtered through a pad of celite and the solvent was removed from the filtrate to obtain 4-(4-fluoro-2-methyl)-phenylpiperidine 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 3amino-propyl-4-( 4 -fluoro-2-methyl)phenyl-piperidine by the usual procedure.
d. 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3carboxylic acid{3-[4-(4-fluoro-2-methyl-phenyl)piperidin-l-yl]-propyl)amide To a solution of 3 -amino-propyl-4-(4-fluoro-2methyl)phenyl-piperidine (0.03 g, 0.11 mmol) in 5 mL of THF was added 4 3 4 -difluorophenyl)-2-oxo-oxazolidine- 3-carboxylic acid-4-nitro-phenyl ester (0.04 g, 0.10 mmol) and the resulting yellow solution was stirred under argon atmosphere for 8 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 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 The compound was converted into its hydrochloride salt. Off-white solid.
M.P. 60-64oC; 36.6 (c 0.15, MeOH); Anal.
WO 98/57940 PCT/US98/12668 -106- Calcd. for C 25
H
29 N30 3 FC1.0.25 CHC1 3 C, 55.97; H, 5.44; N, 7.76. Found: C, 55.91; H, 5.66; N, 7.87.
Preparation of Side Chains.
1. 3-( 4 4 -Diphenylpiperidin-1-yl)propylamine.
a. 4,4-Diphenylpiperidine hydrochloride. A mixture of 4-piperidone monohydrate hydrochloride (15.0 g, 0.0976 mol) and AlC1 3 (130 g, 0.976 mol, 10.0 eq) in anhydrous benzene (600 mL) were stirred at reflux for 4 hours.
The mixture was cooled to room temperature, poured into ice (300 g) and water (50 mL), and filtered. The solid was washed with toluene and dried to afford 19.2 g (72%) of an off-white solid, which was characterized spectroscopically.
b. 3-( 4 ,4-Diphenylpiperidin-l-yl)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 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 4 and concentrated to give 170 mg of a tan solid, which was characterized spectroscopically and used in the next reaction without purification.
c. 3-(4,4-Diphenylpiperidin-l-yl)propylamine. To a stirred solution of 3-(4,4-diphenylpiperidin-lyl)propionitrile (2.00 g, 6.89 mmol) in anhydrous THF (20 mL) under argon was added a solution of BH 3 in THF 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 WO 98/57940 PCT/US98/12668 -107basified to pH 9 by addition of 6 N aq. NaOH, extracted with CH 2 C1 2 (3 X 10 mL) dried (MgSO,) 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 g of tan solid, which was characterized spectroscopically.
2. .3-(4-Cyano-4-phenylpiperidin-1-yl)propylamine.
a. 3-(4-Cyano-4-phenylpiperidin-l-yl)propylphthalimide.
A mixture of 4-cyano-4-phenylpiperidine hydrochloride (111 g, 0.5 mol), 3-bromopropylphthalimide (135.39 g, 0.505 mol), potassium carbonate (276.42 g, 2 mol), and potassium iodide (5.4 g) in DMF (1 L) was stirred and heated at 100-110 "C for 8 h. About 80% of the solvent was evaporated at reduced pressure, the residue was diluted with dichloromethane (1 L) and washed with brine (3 X 300 mL) and dried (Na 2
SO
4 Solvent was evaporated from the dichloromethane solution and the residue was treated with isopropanol (400 mL) and cooled. The pale yellow crystalline product formed was filtered, washed with ice-cold isopropanol and dried (168.6 g, M.p.
96-98 "C.
b. 3-(4-Cyano-4-phenylpiperidin-l-yl)propylamine.
To a solution of 3-(4-cyano- 4 -phenylpiperidin-l-yl)propylphthalimide (112 g, 0.3 mol) in methanol 5 hydrazine (30 mL) was added and the mixture was stirred and refluxed for 20 h. It was cooled, the white solid formed was filtered and washed with more methanol (200 mL). Solvent was evaporated from the filtrate and residue was dried under vacuum for 4 h. Chloroform (500 mL) was added to this, stirred for 1 h and filtered. The white solid was washed with more chloroform (200 mL), the solvent was evaporated from the combined filtrates to leave the product as an oil (70 g, 96%).
WO 98/57940 PCT/US98/12668 -108- 3. 3- (4-Methoxycarbonyl-4-phenylpiperidin-1yl) propylamine.
a. 4-Methoxycarbonyl-4-phenylpiperidine. To a stirred solution of H 2 SO, (16 mL) in MeOH (400 mL), 4phenyl-4-piperidinecarboxylic acid 4methylbenzenesulfonate (37.7 g, 0.1 mole) was added and the mixture was stirred and refluxed for 8 hours.
Excess methanol was evaporated at reduced pressure and the residue was poured into a mixture of ice and 6 N NaOH. The pH was adjusted to 10-11 by adding more 6 N NaOH and extracted with CH 2 C1 2 (3 X 150 mL). The combined CH 2 C1 2 extracts were dried (MgSO 4 and the solvent evaporated to leave the desired product as a viscous oil. The product (20.2 g, 92%) was used without further purification.
b. 3-(4-Methoxycarbonyl-4-phenylpiperidin-lyl)propylamine.
A mixture of 4-methoxycarbonyl-4-phenylpiperidine g, 0.039 mol), 3-bromopropylamine hydrobromide (12.7 g, 0.058 mol), potassium carbonate (13.475 g, 0.0957 mole), and KI (3.24 g, 0.0195 mol) in 1,4-dioxane (200 mL) was stirred and refluxed for 24 hours. Dioxane was evaporated at reduced pressure, the residue was treated with ice-cold 6 N NaOH (400 mL) and extracted with
CH
2 C1 (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 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]pyridinium bromide hydrobromide.
WO 98/57940 PCT/US98/12668 -109- A solution of 2,4'-dipyridyl (5.0 g, 32.0 mmol) and 3bromopropylamine hydrobromide (7.0 g, 32.0 mmol) in DMF (50.0 mL) and acetonitrile (50.0 mL) was heated at 90-95 °C for 1 h. After cooling, the white solid that came out was filtered, washed with EtO2 and dried. The mother liquor was concentrated to remove EtO2 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 11.6 g b. 3-(3',6'-Dihydro-2'-H-[2,4']bipyridinyl-1'-yl)propylamine.
To a solution of l-(3-aminopropyl)-4-[pyrid-2yl]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 min and then quenched with 6M HC1 solution. The solution was concentrated to 20.0 mL and basified with 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-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.
To a solution of 3-(3',6'-dihydro-2'-H- [2,4']bipyridinyl-1'-yl)-propylamine (3.48 g crude, 15.9 mmol) in MeOH (40 mL), was added 1.0 g of Pearlman's catalyst. The suspension was hydrogenated under 120 psi for 10 h after which the reaction mixture was filtered through a pad of celite and the solvent was removed.
The residue was purified by column chromatography over silica gel using 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%).
WO 98/57940 PCT/US98/12668 -110- 3-( 4 -Acetoxy-4-phenylpiperidin-l-yl)propylamine.
a. N-Benzyloxycarbonyl-3-(4-hydroxy-4-phenylpiperidin-lyl)propylamine.
A mixture of 4-hydroxy-4-phenylpiperidine (5 g, 0.0282 mol), N-benzyloxycarbonyl-3-bromopropylamine (8.445 g, 0.031 mol), and potassium carbonate (7.795 g, 0.0564 mole) in acetone (200 mL) was stirred and refluxed for 12 hours. Acetone was evaporated at reduced pressure, the residue was treated with ice-cold water (400 mL) and extracted with CH 2 Cl 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 'H-NMR and was used as such without any further purification.
b. N-Benzyloxycarbonyl-3-(4-acetoxy-4-phenylpiperidin-lyl)propylamine.
To a solution of N-benzyloxycarbonyl-3- (4-hydroxy-4-phenylpiperidin-1-yl)propylamine (0.5 g, 1.36 mmol) in THF (20 mL) at 0 sodium hydride 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 O oC for 30 minutes and at room temperature for 3 h. Solvent was evaporated, the residue was mixed with dichloromethane (100 mL), and washed with water (2 X 20 mL). Solvent was evaporated from the dried dichloromethane solution gave the product as a viscous oil (0.485 g, The 1 H-NMR showed this product to be pure and was used in the next.step without any further purification.
c. 3-(4-Acetoxy-4-phenylpiperidin-1-yl)propylamine.
A mixture of N-benzyloxycarbonyl-3- 4 -acetoxy- 4 -phenylpiperidin-1-yl)propylamine (3.0 g, 7.3 mmol) and 10% Pd-C (0.3 g) in 1M ammonia in WO 98/57940 PCT/US98/12668 -111mL) 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, the H-NMR showed it to be very pure and was used in the next step without any purification.
6. 3-(4-Cyano-4-phenylpiperidin-l-yl)-2hydroxypropylamine.
a. 3 -(4-Cyano-4-phenylpiperidin-l-yl)(2hydroxypropyl)phthalimide A mixture of 4-cyano-4-phenylpiperidine (10.0 g, mmol) and 2,3-epoxypropylphthalimide (10.94 g, 54 mmol) in DMF (100 mL) was stirred and heated at 70 °C for 72 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using chloroform-methanol-2M ammonia in methanol (1000/28/14) as the eluent, to obtain the desired product as a viscous oil (16.45 g, 86%).
b. 3-(4-Cyano-4-phenylpiperidin-l-yl)-2hydroxypropylamine.
A mixture of 3-(4-cyano-4-phenylpiperidin-l-yl)-(2hydroxypropyl)phthalimide (10 g, 23.48 mmol) and hydrazine (6.01 g, 188 mmol, 8 eq.) in methanol (100 mL) was stirred and refluxed for 4.5 h. It was cooled, filtered, and the solid was washed with methanol mL). Evaporation of solvent from the filtrate gave the product as a viscous oil (5.53 g, 94%).
7. 3-(4-Cyano-4-phenylpiperidin-l-yl)-2fluoropropylamine.
a. 3 -(4-Cyano-4-phenylpiperidin-l-yl)(2fluoropropyl)phthalimide A mixture of 3-( 4 -cyano-4-phenylpiperidin-l-yl)-(2hydroxypropyl)phthalimide (2.60 g, 6.1 mmol) and WO 98/57940 PCT/US98/12668 -112diethylaminosulfur trifluoride (DAST, 1.96 g, 12.2 mmol) in benzene (100 mL) was stirred and heated at 70 °C under argon atmosphere for 24 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using chloroform-methanol-2M ammonia in methanol (1000/28/14) as the eluent, to obtain the desired product as a viscous oil (1.30 g, b. 3-(4-Cyano-4-phenylpiperidin-l-yl)-2fluoropropylamine.
A mixture of 3-(4-cyano-4-phenylpiperidin-1-yl)-(2fluoropropyl)phthalimide (3.80.g, 8.88 mmol) and hydrazine (2.27 g, 71.04 mmol, 8 eq.) in methanol (100 mL) was stirred and refluxed for 4.5 h. It was cooled, filtered, and the solid was washed with methanol mL). Evaporation of solvent from the filtrate gave the product as a viscous oil (1.9 g, 8. 3- (2-Pyridyl)-piperidin-1-yl)-3-methylpropylamine.
a. 3-[4-(2-Pyridyl)-piperidin-1-yl)-2methylpropionitrile. A mixture of 4-(2-pyridyl)piperidine (1.56 g, 10 mmol) and crotononitrile (1.34 g, mmol, 2 eq) in ethanol (100 mL) was strirred and refluxed for 16 h and the solvent and excess crotononitrile were evaporated under vacuum. The residue was purified by column chromatography on silica gel using dichloromethane-methanol-2M ammonia in methanol (45/4/2) as the eluent to give the desired product as a viscous oil (2.09 g, which got solidified on standing.
b. 3-[4-(2-Pyridyl)-piperidin-1-yl)-3-methylpropylamine.
To a stirred solution of 3-[4-(2-pyridyl)-piperidin-lyl)-3-methylpropionitrile (0.446 g, 2 mmol) in anhydrous THF (10 mL) under argon was added a solution of BH3 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 basified to pH 9 by addition of 6 N aq. NaOH, extracted with CHC1 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.
9. 3-[4-(2-Pyridyl)-piperidin-1-yl)-2-methylpropylamine.
a. 3 -[4-(2-Pyridyl)-piperidin-1-yl)-2methylpropionitrile. A mixture of 4-(2-pyridyl)piperidine (3.12 g, 20 mmol) and l-methylacrylononitrile (5 mL) in methanol (100 mL) was strirred and refluxed for 48 h and the solvent and excess 1methylacrylonitrile were evaporated under vacuum. The residue was purified by column chromatography on silica gel using dichloromethane-methanol-2M ammonia in methanol (45/4/2) as the eluent to give the desired product as a viscous oil (3.30 g, 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-1yl)-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 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 'H-NMR of it showed it to be pure WO 98/57940 PCT/US98/1 2668 -114enough to use it in the next step.
Examples 23 and 24.
N3-[3-(4-Cyano-4-phenylpiperidino)propyl]-2-oxo-4,4diphenyl-oxazolidine-3-carboxamide hydrochloride and N3- [3-(4,4-Diphenylpiperidino)propyl]-2-oxo-4,4-diphenyloxazolidine-3-carboxamide hydrochloride a) 1,1-Diphenyl-2-hydroxyethylamine.
To stirred a solution of 2,2-diphenylglycine (5.0 g, 22 mmol) in THF (100 mL) at 0°C under argon atmosphere, a solution of LAH in THF (1M, 50 mL, 50 mmol) was added over a period of 15 minutes and the mixture was allowed to warm to room temperature. After 12 h, it was poured onto a mixture of ice (300 g) and 6N HC1 (20 mL) and stirred for lh. The mixture was basified to pH 10-11 by the addition of 6N NaOH and extracted with dichloromethane (4 X 100 mL). The combined extracts were dried (sodium sulfate) and the solvent evaporated to leave the product as a pale yellow viscous oil, which on trituration with hexane became white powder (4.7 g, 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 1,1-diphenyl-2-hydroxyethylamine (4.26 g, 20 mmol), CDI (3.24 g, 20 mmol.) in dichloromethane (200 mL) was refluxed for 20 h and the solvent evaporated.
The residue was purified by column chromatography on silica gel using dichloromethane/ethyl acetate to give the product as a viscous oil which solidified on standing (4.25 g, 89%).
c) 4,4-Diphenyl-1-(4-nitrophenyloxycarbonyl)-2-oxooxazolidine.
To a stirred suspension of sodium hydride suspension in paraffin, 0.6 g, 15 mmol, 1.5 eq.) in THF (20 mL) at 0 oC, a solution of 4 ,4-diphenyl-2-oxo- WO 98/57940 PCT/US98/12668 -115oxazolidine (2.39 g, 10 mmol) in THF (5 mL) was added and stirred for 30 minutes. This suspension was added to a solution of 4-nitrophenyl chloroformate (2.41 g, 12 mmol) in THF (20 mL) at -78 °C under argon and the stirring was continued for 2 h. It was slowly warmed to room temperature and after 4 h the solvent was evaporated. The residue was mixed with dichloromethane (150 mL), washed with 0.05 N sodium hydroxide (3 X mL), and dried (sodium sulfate). Solvent was evaporated and the residue was purified by column chromatography on silica gel using chloroform/ethyl acetate as the eluent to give the product as a white powder (3.72 g, 92%).
d) General procedure: Examples 23 and 24.
A mixture of 4,4-diphenyl-3-(4-nitrophenyloxycarbonyl)- 2-oxo-oxazolidine (40 mg, 0.1 mmol) and an appropriate amine (0.15 mmol, 1.5 eq.) in THF (5 mL) was stirred at room temperature and the product formed was purified by preparative TLC on silica gel using ethyl acetate as the eluent. The HC1 salt was made by treatment with IN HC1 in ether.
N3-[3-(4-Cyano-4-phenylpiperidino)propyl -2-oxo-4,4diphenyl-oxazolidine-3-carboxamide hydrochloride Yield 93%; m.p.139-141 Anal. Calcd. For: C3,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-4,4diphenyl-oxazolidine-3-carboxamide hydrochloride Yield 92%; m.p.145-148 Anal. Calcd. For:
C
34
H,
3
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.
To a well-stirred solution of methyl 2-amino-2-(3,4- WO 98/57940 PCT/US98/12668 -116difluorophenyl)acetate (10.5 g, 52.19 mmol) in anhydrous ether (200 mL) at 0°C a solution of methylmagnesium bromide (3M, 87 mL, 261 mmol) in ether was added in minutes. The mixture was stirred at 0 0 C for 2.5 h and allowed to warm to room temperature. After 12 h, the mixture was carefully poured onto a mixture of ice (300 g) and saturated ammonium chloride (50 The ether layer was separated and the aqueous layer was extracted with more ether (4 X 200 mL). The combined extracts were dried with magnesium sulfate and the solvent evaporated. The crude product was purified by column chromatography on silica gel using chloroform/methanol/2M ammonia in methanol (1000:20:10 mL, 1000:40:20 mL, 1000:80:40 mL) as eluents to give the product as an oil (6.5 g, The 1 H-NMR and MS confirmed this to be the desired product.
b. 4-(3,4-Difluorophenyl)-5,5-dimethyl-2-oxooxazolidine.
A mixture of l-(3,4-difluorophenyl)-2-methyl-2hydroxypropylamine (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 to give the product as a viscous oil which solidified on standing (1.80 g, c. 4-(3,4-Difluorophenyl)-5,5-dimethyl-2-oxo-3-(4nitrophenyloxycarbonyl)oxazolidine.
To a stirred suspension of sodium hydride suspension in paraffin 203 mg, 1.4 eq.) in THF (20 mL) at 0 a solution of 4 -(3,4-difluorophenyl)-5,5dimethyl-2-oxo-oxazolidine (870 mg, 3.622 mmol) in THF mL) was added and stirred for 30 minutes. This suspension was added to a solution of 4-nitrophenyl chloroformate (950 mg, 4.71 mmol) in THF (20 mL) at -78 WO 98/57940 PCT/US98/12668 -117- °C under argon and the stirring was continued for 2 h.
It was slowly warmed to room temperature and after 4 h the solvent was evaporated. The residue was mixed with dichloromethane (150 mL), washed with 0.05 N sodium hydroxide (3 X 10 mL), and dried (sodium sulfate).
Solvent was evaporated and the residue was purified by column chromatography on silica gel using chloroform/ethyl acetate as the eluent to give the product as a white powder (860 mg, 59%).
d. General procedure: A mixture of 4 -(3,4-difluorophenyl)-5,5-dimethyl-3-(4nitrophenyloxycarbonyl)-2-oxo-oxazolidine (50 mg, 0.123 mmol) and an appropriate amine (0.16 mmol, 1.3 eq.) in dichloromethane (6 mL) was stirred at room temperature and the product formed was purified by preparative TLC on silica gel using two elutions, first with chloroform/ethyl acetate and then with chloroform/methanol as eluents. The HC1 salt was made by treatment with lN HC1 in ether.
Example Methyl 1-[3-([4-(3,4-difluorophenyl)-5,5-dimethyl-2-oxooxazolidine-3-yl]carbonylamino)propyl]-4-phenyl-4piperidinecarboxylate hydrochloride Yield 56%; m.p. 208-210 oC; Anal. Calcd. For:
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-oxooxazolidine-3-yl]carbonylamino)propyl]-4-phenyl-4piperidyl acetate hydrochloride Yield 29%; m.p. 116-118 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.
WO 9,8/57940 PCT/US98/12668 Example 27: 113-3- (2-Pyridyl)piperidiio] -3-methylpropyl-4- (3,4difluorophenyl) -dimethyl-2-oxo-oxazolidine3carboxamide dihydrochioride Yield 64%; m-p. 87-90 0 C; Anal. Calcd. For:
C
2 6
H
32
F
2
N
4 0 3 2HC1 lCHCl 3 1H 2 0: C, 45.81; H, 5.29; N, 7.88. Found: C, 45.73; H, 5.50; N, 8.07.
Example 28: 113-[3- (4-Cyano-4-phenylpiperidino) -2-hydroxypropyl] -4- 4-difluorophenyl) -5,5-dimethyl-2-oxo-oxazoidine-3carboxamide hydrochloride Yield 63%; m.p. 135-137 Anal. Calcd. For:
C
2 7
H
3 0
F
2
N
4 0 4 .HC1 .1.2H 2 0: C, 56.83; H, 5.90; N, 9.82.
Found: C, 56.88; H, 5.98; N, 9.58.
Example 29: 173- 4 -Cyano-4-phenylpiperidino) -2-f luoropropyl) -4- (3,4-difluorophenyl) -5,5-dimethyl-2-oxo-oxazolidine3carboxamide hydrochloride Yield 39%; m.p. 120-122 0 C; Anal. Calcd. For:
C
2
,H
29
F
3
N
4 0 3 .HC1 .BCH 2 C1 2 C, 53.95; H, 5.15; N, 9.05.
Found: C, 53.89; H, 5.33; N, 8.95.
Example Methyl 1-5- (3,4-difluorophenyl) 5-dimethyl-2-oxooxazolidin-3-yl] pentyl- 4 -phenyl-4-piperidinecarboxylate hydrochloride a. 4 -(3,4-Difluorophenyl)-5,5-dimethyl..(5bromopentyl) -2-oxo-oxazolidine.
To a stirred suspension of sodium hydride suspension in paraffin 205 mug, 1.4 eq) in THF (20 muL) at 0 a solution of 4 3 4 2-oxo-oxazolidine (880 mug, 3.622 mumol) in THF (5 muL) was added and stirred for 30 minutes. To this WO 98/57940 PCT/US98/12668 -119dibromopentane (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 oC for 12 h and the solvent evaporated. The residue was purified by column chromatography on silica gel using chloroform/ethyl acetate 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-2oxo-oxazolidin-3-yl]pentyl-4-phenyl-4piperidinecarboxylate hydrochloride A mixture of 4-(3,4-difluorophenyl)-5,5-dimethyl-l-(5bromopentyl)oxazolidinone (50 mg, 0.123 mmol), 4-phenyl-4-methoxycarbonylpiperidine (0.16 mmol, 1.3 potassium iodide (11.6 mg), and potassium carbonate (58 mg, 0.42 mmol, 3 eq.) in acetone (6 mL) was stirred and refluxed for 12 h and the product formed was purified by preparative TLC on silica gel using ethyl acetate as the eluent. The HC1 salts were made by treatment with 1N HC1 in ether. Yield 50%; m.p. 58-60 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: N3-2-[4-(2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-lyl)piperidino]ethyl-4-(3,4-difluorophenyl)-5,5-dimethyl- 2-oxo-oxazolidine-3-carboxamide hydrochloride a. N-(2-[{4-(2-Keto-l-benzimidazolinyl)piperidin-1-yl]ethyl)phthalimide.
To a solution of 4-(2-keto-l-benzimidazolinyl)piperidine g, 23 mmol) and N-(2-bromoethyl)phthalimide (5.85 g, 23 mmol) in DMF (100 mL) was added potassium carbonate g) and potassium iodide (250 mg) and the mixture was stirred and heated at 65-70 °C for 2h. It was poured WO 98/57940 PCT/US98/12668 -120into ice-water (50QQmL), extracted with ether (4 X mL) and dried (sodium sulfate). Solvent was evaporated and the product was crystallized from methanol (8 g, 89%).
b. N-(2-[{4-(2-Keto-1-benzimidazolinyl)piperidin-l-yl]ethyl)amine A mixture of N-(2-[{4-(2-keto-lbenzimidazolinyl)piperidin-l-yl]-ethyl)phthalimide (3.9 g, 10 mmol) and hydrazine (2 mL) in methanol was refluxed for 10 h and the solvent was evaporated. The residue was suspended in chloroform (50 mL) and filtered. The residue was washed with more chloroform mL). Solvent was evaporated from the combined filtrate and the residue was dried under vacuum to leave the desired product, which was used in the next step without further characterization.
c. N3-2-[4-(2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-1yl)piperidino]ethyl-4-(3,4-difluorophenyl)-5,5-dimethyl- 2-oxo-oxazolidine-3-carboxamide hydrochloride Prepared from 4-(3,4-difluorophenyl)-5,5-dimethyl-3-(4nitrophenyloxycarbonyl)-2-oxo-oxazolidine (20 mg) and N- (2-[{4-(2-keto-1-benzimidazolinyl)piperidin-l-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; Anal. Calcd. For: C 26
H
29
F
2 NsO 3 .HC1.0.4 CHC1 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-(2pyridyl)piperidino]methylpiperidino)carbonyl]oxazolidine-2-one dihydrochloride.
a. l-Benzyl-4-[pyrid-2-yl]pyridinium bromide.
A solution of 2,4'-dipyridyl (15.62 g, 0.1 mol) and benzyl bromide (17.104 g, 0.lmol) in anhydrous EtOAc WO 98/57940 PCTfUS98/1 2668 -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-2yl]pyridinium bromide (50 g, 0.152 mol) in ethanol (500 mL) at 0-5 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 with ether (500 mL), washed with 6N sodium hydroxide solution (200 mL), brine (500 mL), and dried (potassium carbonate). Solvent was evaporated and the oily residue was used in the next step immediately without purification (33.4 g, 88%).
c. 4-(2-Pyridyl)piperidine.
To a solution of l-benzyl-4-(2-pyridyl)-1,2,3,6tetrahydropyridine (25 g, 0.1 mol) in MeOH (400 mL) and 2M ammonia in methanol (100 mL), was added Pearlman's catalyst (6 The suspension was hydrogenated under 200 psi for 24 h after which the reaction mixture was filtered through a pad of celite and the solvent was removed. The residue was purified by column chromatography over silica gel using CH,Cl/methanol/2M
NH
3 in MeOH (45:4:2 to 9:4:4) as the eluting system.
The product was obtained as a pale yellow oil (12.4 g, 79%).
d. N-(t-Butyl-carbonate)-nipecotic acid. To a solution of nipecotic acid (3.865 g, 29.9 mmol)in dioxane mL)at 0 C was added (Boc) 2 0 (6.53 g, 29.9 mmol) and a solution of NaOH (2.63 g, 6.60 mmol)in water (10 mL).
The resulting mixture was stirred overnight while warmed up to room temperature. The mixture was concentrated and the residue was acidified to pH=3 with 1 N HC1 and then extracted with EtOAc (3 X 50 mL), dried (MgSO 4 to WO 98/57940 PCT/US98/12668 -122afford crude product which was used in the next step without further purification.
e. 4-(2-Pyridyl)piperidine-N-(t-butyl-carbonate)nipecotamide. To a solution of N-(t-butyl-carbonate)nipecotic acid (6.85 g, 29.8 mmol) in CH 2
C
2 1 (40 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (DMAPECD) (11.426 g, 59.6 mmol)and DMAP (9.102 g, 74.5 mmol), then 4-(2-pyridyl)piperidine (4.834g, 29.8 mmol) was added. The resulting mixture was stirred for 24 hours and quenched with water mL). The mixture was extracted with CH 2 C1 2 (3 X40 mL) and the combined extracts was dried (K 2 CO3) and concentrated. The residue was purified by flash 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-butylcarbonate)-nipecotamide (1.904 g, 5.084 mmol) in TFA 5.0 mL) was stirred at 0 OC overnight. The mixture was concentrated and the residue was dissolved in THF 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 while warmed to r.t. before quenched with water (1.0 mL) and 1 N NaOH (0.5 mL). The mixture was basified to with 1 N NaOH and extracted with CH 2 C1 2 (5 X mL), dried (K 2
CO
3 and concentrated. The residue was purified by flash chromatography (CHC13-MeOH-NH 3 100:10:2 to 100:20:5) to afford the product as an oil (0.804 g, 61%).
g. 4-(3,4-Difluorophenyl)-3-[(3-[4-(2pyridyl)piperidino] ethylpiperidino)carboiyl]oxazolidine-2-one dihydrochloride.
WO 98/57940 PCT/US98/12668 -123- Prepared from 4-(3,4-difluorophenyl)-3-(4nitrophenyloxycarbonyl) -2-oxo-oxazolidine and 4-(2pyridyl)-N-(2-piperidinyl)methyl-piperidine following the procedure described earlier.
Yield 90%; 176-178 Anal. Calcd. For
C
26
H
3 lN 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: N1-[2-(4-Cyano-4-phenylpiperidino)ethyl]-2-[4-(3,4difluorophenyl)-2-oxo-oxazolidin-3-yl]acetamide hydrochloride a. 2 4 -(3,4-Difluorophenyl)-2-oxo-oxazolidine-lacetic acid benzyl ester. To a stirred a solution of 4- 3 4 -difluorophenyl)-2-oxo-oxazolidinone (398 mg, 2 mmol) in THF (20 mL) at 0 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 minutes it was cooled to 0 OC and to this benzyl bromoacetate (0.504 g, 2.2 mmol, 1.1 eq.) was added and the mixture was warmed to room temperature. After 12 h, solvent was evaporated and the residue was purified by column chromatography on silica gel using chloroform/ethyl acetate as the eluent to give the product as a viscous oil (0.695 g, 88%).
b. 2 4 -(3,4-Difluorophenyl)-2-oxo-oxazolidine-lacetic acid The product obtained from the above reaction (0.592 g, mmol) was dissolved in methanol/water (25/5 mL), mixed with Pearlman's catalyst (120 mg) and hydrogenated at 100 psi for 3 h. The catalyst was removed by filtration and washed with methanol (20 mL). Solvent was evaporated from the combined filtrate to obtain the product as a white powder (0.375 g, 97%).
WO 98/57940 PCTIUS98/12668 -124c. N1-[2-(4-Cyano-4-phenylpiperidino)ethyl]-2-[4-(3,4difluorophenyl)-2-oxo-oxazolidin-3-yl]acetamide hydrochloride A mixture of 2 4 -(3,4-difluorophenyl)-2-oxo-oxazolidine-lacetic acid (51.4 mg, 0.2 mmol), 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg), and 4-(N,N-dimethylamino)pyridine (100 mg), 2- 4 -cyano- 4 -phenyl)piperidin-l-yl]propylamine (55 mg) in anhydrous dichloromethane (15 mL) was stirred at room temperature for 12 h. The mixture was diluted with 10 mL of dichloromethane and washed with saturated aqueous ammonium chloride solution (6 X 10 mL). Solvent was evaporated from the dried (sodium sulfate) dichloromethane solution and the residue was purified by column chromatography on silica gel using chloroformmethanol-2M ammonia.in methanol (100/2/1) as the eluent, to obtain the desired product as a white powder (82 mg); +168.40 (c 0.42 g, methanol). The HC1 salt was prepared by treatment of a solution of the free base in ether with IN HC1 in ether. M.p. 136-139 Anal.
Calcd. for C2sH 2
,N
4 0 3
F
2 C1.0.4CH 2 C1 2 56.38; H, 5.20; N, 10.40. Found: C, 56.38; H; 5.30; N, 10.52.
Example 34: 4-{4-[4-(3,4-Difluoro-phenyl)- 2 -oxo-oxazolidine-3carbonyl]-piperazin-1-yl)-1-phenylcyclohexanecarbonitrile a. l-Phenyl- 4 -piperazin-1-yl-cyclohexanecarbonitrile 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 white solid, which was redissolved in 20 ml of EtOH and WO 98/57940 PCT/US98/12668 -125stirred with NaBH 4 (0.30 g, 80 mmol) for 12 h at 25 °C.
Reaction mixture was diluted with 100 ml of EtOAc and washed with brine several times. Organic layer was dried over MgSO 4 and concentrated in vacuo, to provide oily residue, which was subjected to column chromatography (10% MeOH/EtOAc) to yield 0.13 g of the desired product as an oil.
b. .4-4-[4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3carbonyl]-piperazin-l-yl}-1-phenylcyclohexanecarbonitrile To a solution of 4-(3,4-difluoro-phenyl)-2-oxooxazolidine-3-carboxylic acid 4-nitrophenyl ester mg, 0.21 mmol) in 5 ml of THF was added l-phenyl-4piperazin-l-yl-cyclohexanecarbonitrile (80 mg, 0.29 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 of the desired product as a colorless oil. The product obtained was converted to the HC1 salt and recrystallized from EtOAc-Et 2 O to afford 43 mg of the product as white solid: mp 148-151 oC; Anal. Calc. For C 27
H
2
,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.
Example (+)-4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3carboxylic acid 4 -furan-2-yl-4-phenyl-piperidin-lyl)-propyl]-amide a. 4-Phenyl-4-furan-2-yl-piperidine To a solution of 4 -hydroxy-4-phenyl-piperidine(0.50 g, 2.8 mmol) in 10 ml of CH 2 C1 at 25 °C was added furan (0.40 ml, 5.6 mmol) and aluminum chloride (0.75 g, 5.6 mmol) in a portion and the resulting heterogeneous WO 98/57940 PCT/US98/12668 -126solution 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
SO
4 and concentrated in vacuo to provide oily residue, which was purified by column chromatography (30% NH 3 sat'd MeOH/EtOAc) to yield 0.48 g of the desired product as an oil.
b. 3-[4-(4-furan-2-yl-4-Phenyl-phenyl)-piperidin-1-yl)]propyl-1-amine A solution of the amine (0.15 g, 0.66 mmol), (3-bromopropyl)-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.
Organic layer was dried over Na 2 SO, 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 Cl 2 and 1 ml of 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 of the desired product as a colorless oil.
c. (+)-4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3carboxylic acid [3-(4-furan-2-yl-4-phenyl-piperidin-lyl)-propyl]amide To a solution of (+)-4-(3,4-difluoro-phenyl)-2-oxooxazolidine-3-carboxylic acid 4-nitrophenyl ester (19 mg, 0.05 mmol) in 5 ml of CH 2 Cl 2 was added Phenyl-4-furan-2-yl-phenyl)-piperidin-1-yl)]-propyl-lamine (12 mg, 0.04 mmol) in a portion and the resulting solution was stirred for 4 h at 25 Reaction mixture was concentrated in vacuo yielding a yellow oil, which WO 98/57940 PCT/US98/12668 -127was subjected to column chromatography MeOH/CHC1 3 to provide 18 mg of the desired product as a colorless oil. The product obtained was converted to the HC1 salt and recrystallized from EtOAc-Et 2 O to 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
2
,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 36: (+)-4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3carboxylic acid (3-[4-(1-methyl-1H-pyrrol-2-yl)-4phenyl-piperidin-1-yl]-propyl)-amide a. 4-Phenyl-4-(l-methyl-pyrrol)-2-yl-piperidine To a solution of 4-hydroxy-4-phenyl-piperidine(0.50 g, 2.8 mmol) in 10 ml of CH 2 C12 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 Reaction mixture was poured into cold aqueous NaHCO 3 and extracted with EtOAc. Organic layer was dried over Na 2 SO, and concentrated in vacuo to provide oily residue (0.81 which was identified as the desired product by NMR analysis and subjected to the following reaction without any further purification.
b. 3-[4-(l-methyl-1H-pyrrol-2-yl)-4-phenyl-piperidin-lyl]-propyl-1-amine A solution of the amine (0.81 g, 2.8 mmol), (3-bromopropyl)-carbamic acid tert-butyl ester (1.0 g, 4.2 mmol), K 2 CO0 (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 and concentrated in vacuo to provide oily residue, which was purified by column chromatography MeOH/CHC13) to WO 98/57940 PCT/US98/12668 -128yield 0.87 g of the desired product as tert-butyl carbamic ester. The ester was diluted in 10 ml of
CH
2 C1 2 and 1 ml of trifluoro-acetic acid, and stirred for 2 h at 25 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 0.63 g for two steps) of the desired product as a colorless oil.
c. (+)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3carboxylic acid (3-[4-(1-methyl-1H-pyrrol-2-yl)-4phenyl-piperdin-1-yl]-propyl -amide To a solution of 4 -(3,4-difluoro-phenyl)-2-oxooxazolidine-3-carboxylic acid 4-nitrophenyl ester 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 yellow oil, which was subjected to column chromatography MeOH/CHC13) to provide 14.4 mg of the desired product as a colorless oil. The product obtained was converted to the HC1 salt and recrystallized from EtOAc- EtO2 to afford 13.0 mg of the product as white solid: mp 135-138 oC; [a]D 34.1 (c=0.11, MeOH); Anal. Calc.
For C 28
H
29
F
2
N
3
O
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: (+)-4-(3,4-Difluoro-phenyl)- 2 -oxo-oxazolidine-3carboxylic acid (3-[4-(5-methyl-thiophen-2-yl)piperidin-1-yl]-propyl)-amide a. 4-[4-Hydroxy-4-(5-methyl-thiophen-2-yl)]-piperidine To a solution of 2 -methyl-thiophene (1.0 ml, 10 mmol) in 40 ml of dry THF was added tert-butyl lithium (1.7 M WO 98/57940 PCT/US98/12668 -129solution 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-4piperidinone (1.0 g, 5.0 mmol) in a portion and the resulting solution was stirred for 2 h. Reaction was quenched by adding a few drops of water. Reaction mixture was diluted with EtOAc and washed with brine several times. Organic layer was dried over NaSO 4 and concentrated in vacuo to provide an oil, which was identified as the desired product by NMR analysis and subjected to the following reaction without any further purification.
b. 4-(5-Methyl-thiophen-2-yl)-piperidine A solution of the carbamic ester (1.3 g, 4.4 mmol) and triisopropylsilane (1.0 ml, 8.2 mmol) in 10 ml of CH 2 C12 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 aqueous NaHCO 3 Organic layer was dried over Na2S04 and concentrated in vacuo to provide oily residue, which was purified by column chromatography MeOH/CHC13) to yield 0.73 g of the desired product as an oil.
c. 3-[4-(5-methyl-thiophene-2-yl)-piperidin-1-yl]propyl-1-amine A solution of the amine (0.73 g, 4.0 mmol), (3-bromopropyl)-carbamic acid tert-butyl ester (1.8 g, 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 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 MIeOH/CHC13) to yield 0.60 g of the desired product as tert-butyl carbamic ester. The ester was diluted in 10 ml of WO 98/57940 PCT/US98/12668 -130-
CH
2 C1, and 1 ml of 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 Organic layer was dried 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-3carboxylic acid (3-[4-(5-methyl-thiophen-2-yl)piperidin-1-yl]-propyl}-amide To a solution of (+)-4-(3,4-difluoro-phenyl)-2-oxooxazolidine-3-carboxylic acid 4-nitrophenyl ester (46 mg, 0.12 mmol) in 5 ml of CH 2 Cl 2 was added methyl-thiophen-2-yl)-piperidin-1-yl]-propyl-l-amine mg, 0.13 mmol) in a portion and the resulting solution was stirred for 12 h at 25 Reaction mixture was concentrated in vacuo yielding a yellow oil, which was subjected to column chromatography MeOH/CH 2 Cl 2 to provide 41 mg of the desired product as a colorless oil. The product obtained was converted to the HC1 salt and recrystallized from EtOAc-EtO to afford 43 mg of the product as white solid: mp 143-146 oC; [a]D 41.0 (c=0.11, MeOH); Anal. Calc. For
C
23
H
27
F
2
N
3 0 4 .1.OHC1 requires C, 55.25; H, 5.64; N, 8.40.
Found: C, 57.01; H, 5.54; N, 8.29.
General Procedure for the Preparation of the 4,4-Diaryl Piperidines: A mixture of 0.5 g of 4-aryl-4-hydroxy piperidine, 3 mL of the aromatic substrate, and 1 g of 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 WO 98/57940 WO 9857940PCTIUS98/12668 -131characterization.
4-Phenyl-4- (4-thiomethoxy-phenyl) -piperidine, Hydrochloride: From 4-phenyl-4-hydroxy-piperidine and thioanisole Anal. Caic. for C 18
H
21
N
1
S
1 +HC1+ 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-thiomethoxy-phenyl) -piperidine, Hydrochloride: From 4- (4-f luoro-phenyl-4-hydroxypiperidine and thioanisole Anal. Caic. for
C
18
H
2 0
F
1
N
1
S
1 +HCl+0.35CH 2 C1 2 C, 60.14; H, 5.56; N, 3.90.
Found: C, 59.96; H, 5.95; N, 3.81.
4- (4-Fluoro-phenyl-4- (2-methoxy-5-fluoro-phenyl) piperidine, Hydrochloride: From 4- fluoro-phenyl) -4hydroxy-piperidine and 4-f luoroanisole Anal.
Caic. for C 18
H
19
N
1
F
2 0+HC1+0.2H 2 0: C, 62.96; H, 5.99; N, 4.08. Found: C, 62.72; H, 6.06; N, 4.06.
Bis- (4-f luoro-phenyl) piperidine, Hydrochloride: From 4- (4-f luoro-phenyl)-4-hydroxy-piperidine and 3 niL of fluorobenzene 4- (4-Bromo-phenyl-4- (4-methoxy-phenyl) -piperidine, Hydrochloride: From 4- (4-bromo-phenyl-4-hydroxypiperidine and thioanisole Anal. Caic. for
C
18
BH
20 Br 1
N
1
S
1 +HCl: C, 54.21; H, 5.30; N, 3.51. Found: C, 54.43; H, 5.22; N, 3.41.
General Procedure for the Preparation of the 4,4-Diaryll-(3-amino-propyl)Piperidines: A solution of 1.00 nimol of diarylpiperidine, 1.30 nimol of N-BOC-3bromopropylamine, 1.00 niL of diisopropylethylamine and 2 WO 98/57940 PCT/US98/12668 -132mL 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 solution of the N-BOC protected amine in 1:1 TFA-water was stirred at room temperature for 2 hours (monitored by tlc), solvent removed in vacuo, the product was dissolved in dichloromethane, washed with saturated Na 2
CO
3 solution, dried (Na 2 solvent removed in vacuo, and the product was used after spectral characterization.
[4-(4-methanesulfonyl-phenyl)-4-phenyl]-3aminopropyl-piperidine: A mixture of 644 mg of [4- (4-thiomethyl-phenyl)-4-phenyl]- 3 -aminopropyl-piperidine (TFA salt, 1.13 mmol), 853 mg of 50-60% 3chlorophenylperbenzoic acid (2.72 mmol, assuming purity), 2 mL of trifluoroacetic acid and 10 mL of chloroform were stirred at room temperature for 36 hours, solvent removed in vacuo, and the product was chromatographed (X2) (NH 3 -MeOH-CHC13) to give 270 mg of the desired product.
General procedure for the synthesis of Examples 38, 39, 40, 41 and 42.
A solution of (3,4-difluoro-phenyl)-2-oxooxazolidine-3-carboxylic acid 4-nitro-phenyl ester mg, 0.069 mmol), the 4 4 -diaryl-l-(3-amino-propyl) piperidine (1.2 eqiv.) in 5 ml of methylene chloride were stirred at room temperature for 12 hours. The reaction mixture was washed with 3 N KOH solution. The organic phase was chromatographed on preparative TLC
(CH
2 Cl 2 /methanol/ 2 N NH 3 in methanol 40 to obtain the title compound. The hydrochloride salt of WO 98/57940 PCT/US98/12668 -133the free base was prepared by addition of 1 N HCl in ether to a solution of the free base in ethyl acetate until no more precipitate was observed.
Example 38: 4-(3,4-Difluoro-phenyl)- 2 -oxo-oxazolidine-3-carboxylic acid (3-[4-(4-bromo-phenyl) -4-(4-methoxy-phenyl) piperidin-1-yl]-propyl)-amide 33 mg of the free base was obtained (55% yield). Anal.
Calc. For C 1
H
3 2 BrF 2
N
3 0 4 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 oC. [a]22 53.93 Example 39: 4-(3,4-difluoro-phenyl)- 2 -oxo-oxazolidine-3-carboxylic acid (3-[4-(4-fluoro-phenyl)-4-(4-methylsulfanylphenyl)-piperidin-1-yl]-propyl}-amide mg of the free base was obtained (55% yield). Anal.
Calc. For C 31
H
3
F
3
N
3 0 3 OS 1.75 HCl 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 [a] 2 2 33.33.
Example 4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid (3-[4,4-bis-(4-fluoro-phenyl)-piperidin-1-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 HCl 0.125 CHC13: C, 56.24 H, 4.88 N, 6.52 Found: C, 56.39 H, 4.88 N, 6.10 M.p. of the salt: 124 126 OC. [a] 22 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-fluorophenyl)-piperidin-1-yl]-propyl)-amide 24 mg of the free base of the tittle product was obtained 59% yield). Anal. Calc. For C 31
H
3
F
4
N
3 0 4 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.
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 18 mg of the free base was obtained: Anal. Calc. For
C
31
H
3
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: 4 3 4 -Difluorophenyl)-1-(3-(4-(2-pyridyl)piperidin-1yl)-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), catalytic amount of Zinc Iodide was added at 0°C. After stirring for 15 minutes at room temperature a saturated solution of methanolic ammonia (15 ml) was added in one lot at 0°C. The reaction mixture was then stirred for 4 hours at 40 oC. After evaporation of the solvent the residue was purified by column chromatography (hexanes:ethyl acetate;3:2) to yield 1.98 g of the product as a brown syrup.
b. 1-( 3 ,4-Difluorophenyl)ethane-1,2-diamine: To Lithium aluminium hydride in ether (50.7 ml, 50.76 WO 98/57940 PCTIUS98/12668 -135mmol), at 0°C, cyano amine in ether (80 ml) slowly over a period of 10 minutes. The solution was then allowed to stir at room temperature for 1 hour. The reaction mixture was cooled to 0°C and quenched with water (2 ml), 15% NaOH (2 ml) and water (10 ml). The mixture was then filtered, the residue was repeatedly washed with ethylacetate. The solution was then concentrated to yied 2.71 g of the crude product as an oil which was then used for the subsequent step.
c. 4-(3,4-Difluorophenyl)-2-imidazolidone: To the diammine (1.667 g, 9.68 mmol) in dichloromethane 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 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 ml 10% KOH solution, dried over sodium sulfate, filtered and concentrated. The product was then purified by column purified (hexanes:ethyl acetate 2:3) to yield 0.995 g of a yellow solid.
d. 4-(3,4-Difluorophenyl)- 2 -imidazolidone-l-carboxylic acid 4-nitrophenyl ester: To sodium hydride (0.069 g, 2.74 mmol) in THF (10 ml), 4 3 4 -difluorophenyl)-2-imidazolidone (0.5g, 2.49 mmol) was added at 0 C. The solution was then stirred at room temperature for 15 minutes. It was then added to a solution of 4-nitrophenyl chloroformate (0.552g, 2.74 mmol) at -78 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 ml), dried over sodium sulfate, filtered and 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: To 4-(3,4-difluorophenyl)-1-(4-nitrophenoxy)carbonyl-2imidazolidone (0.05 g, 0.137 mmol) in THF (10 mL) was added 1-(3-aminopropyl)-4-(2-pyridyl)piperidine (0.036 g, 0.165 mmol) and the solution was stirred at room temperature for 16 hours. The solution was then concentrated and the residue flash chromatographed (ethyl acetate:methanol 4:1) to yield 0.038 g of the product as a brown syrup. It was dissolved in dichloromethane (2 mL) and treated with 1N HC1 in ether mL). The solution was concentrated under reduced pressure. Recrystallization of the residue from ether gave 0.029 g (60 of the hydrochloride salt as a brown solid: mp 148-150 0 C. Anal. Calcd. for C 23
H
29
F
2
N
4
O
3 C120.5 CC14: C, 51.90; H,4.90; N, 11.0. Found: C, 54.23; H 5.17; N, 10.84.
Example 44: 3-(4-(4-Cyano-4-phenylpiperidin-l-yl)piperidin-lyl)carbonyl-4-(3,4-difluorophenyl)-2-imidazolidone.
a. 4-(3,4-Difluorophenyl)-2-imidazolidone-3-carboxylic acid 4-nitrophenyl ester: To sodium hydride (0.069 g, 2.74 mmol) in THF (10 ml), 4-(3,4-difluorophenyl)-imidazolidin-2-one (0.5g, 2.49 mmol) was added at 0°C. The solution was then stirred at room temperature for 15 minutes. It was then added to a solution of 4 -nitrophenylchloroformate (0.552g, 2.74 mmol) at -78 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 WO 98/57940 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.
b. 3-(4-(4-Cyano-4-phenylpiperidin-l-yl)piperidin-lyl)carbonyl-4-(3,4-difluorophenyl)-2-imidazolidone: To 4-(3,4-difluorophenyl)-3-(4-nitrophenoxy)carbonyl-2imidazolidone .(0.04 g, 0.110 mmol) in THF (10 rmL) was added 4-(4-cyano-4-phenylpiperidin-l-yl)piperidine (0.0355 g, 0.132 mmol) and the solution was stirred at room temperature for 16 hours. The solution was then concentrated and the residue flash chromatographed (ethyl acetate:methanol 4:1) to yield 0.024 g of the product as a brown syrup. It was dissolved in dichloromethane (2 mL) and treated with 1N HC1 in ether mL). The solution was concentrated under reduced pressure. Recrystallization of the residue from ether gave 0.029 g of the hydrochloride salt as a white solid: mp 243-2450C. Anal. Calcd. for C 27
H
30 C1F 2
N
5 02-0.4 CHCl 3 C,56.96; H,5.30; N, 12.12. Found: C, 57.08; H 5.20; N, 11.90.
Example 4-(3,4-Difluorophenyl)-3-methyl-1-(3-(4-(2pyridyl)piperidin-l-yl)propyl)aminocarbonyl-2imidazolidone.
a. 2-(3,4-Difluorophenyl)-2-methylamino-acetonitrile: To a mixture of 3,4-difluorobenzaldehyde (4.0 g, 28.0 mmol) and trimethylsilylcyanide (4.69 mL, 35.1 mmol), catalytic amount of Zinc Iodide was added at 0°C. After stirring for 15 minutes at room temperature a saturated solution of methylammonia (15 ni) was added in one lot at 0°C. The reaction mixture was then stirred for 4 hours at 400C. After evaporation of the solvent the WO 98/57940 PCT/US98/12668 -138residue was purified by column chromatography (hexanes:ethylacetate 3:2) to yield 4.719 g of the product as a brown syrup.
b. 2-(3,4-Difluorophenyl)-2-methylamino-ethylamine: To Lithium aluminum hydride in ether (49.41 mL, 49.4 mmol), at 0 C, 2-(3,4-difluorophenyl)-2-methylaminoacetonitrile (3.0 g, 16.47 mmol) in ether (80 mL) slowly over a period of 10 minutes. The solution was then allowed to stir at room temperature for 1 hour. The reaction mixture was cooled to 0°C and quenched with water (2 mL), 15% NaOH (2 mL) and water (10 mL). The mixture was then filtered, theresidue was repeatedly washed with ethylacetate. The solution was then concentrated to yield 2.71 g of the crude product as an oil.
c. 4-(3,4-Difluorophenyl)-3-methyl-2-imidazolidone: To 2-(3,4-difluorophenyl)-2-methylamino-ethylamine (1.048 g, 5.68 mmol) in dichloromethane (20mL), 1,1carbonyldiimidazole (1.09 g, 6.75 mmol) was added slowly and the reaction was stirred at room temperature for 24 hours. It was then concentrated and purified by column chromatography (hexanes:ethylacetate; 1:4) to yield 0.-876 g of a yellow solid.
d. 4-(3,4-Difluorophenyl)-3-methyl-1-(3-(4-(2pyridyl)piperidin-l-yl)propyl)aminocarbonyl-2imidazolidone.
To a solution of 4 -(3,4-difluorophenyl)-3-methyl-2imidazolidone (0.15 g, 0.706 mmol) in THF (10 mL) cooled at 0 C, lithium bis(trimethylsilyl)amide in THF (0.848 mL, 0.848 mmol) was added slowly and the solution was stirred at room temperature for 15 minutes. After cooling to -78°C, phosgene (0.729 g, 7.06 mmol) was added and che solution was stirred at -78 0 C for 1 hour.
It was then concentrated to give an intermediate (0.194g, 0.703 mmol) which was immediately dissolved in WO 98/57940 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 then concentrated, and the residue partitioned between dichloromethane (25 mL) and water (5 mL). The organic layer was washed with 10% KOH solution (5 mL), dried over sodium sulfate, filtered and concentrated.
Purification of the residue by flash chromatography (ethyl acetate: methanol 24:1) yielded 0.030 g of the product as a syrup. It was dissolved in dichloromethane (2 mL) and treated with 1N HC1 in ether mL). The solution was concentrated under reduced pressure. Recrystallization of the residue from ether gave 0.030 g of the dihydrochloride salt as a pale yellow solid: mp 120-122 0 C. Anal. Calcd. for
C
24
H
3 C1F 2 N0 2 *0.95 CHC13: C,46.54; H,5.00; N, 10.88.
Found: C, 46.30; H 5.35; N, 11.20.
Example 46: 4-(3,4-Difluorophenyl)-3-(3-(4-(2-methoxyl-5methyl)phenyl-4-phenylpiperidin-lyl)propyl)aminocarbonyl-2-imidazolidone.
a. 1-(3,4-Difluorophenyl)-2-tritylamino-ethylamine: To a solution of 1-(3,4-difluorophenyl)-ethane-1,2diamine (6 g, 35.6 mmol) in dichloromethane (100 ml), diazabicycloundecane (DBU)(5.87 mL, 39.2 mmol) was added and the solution cooled to 0°C. Trityl chloride (10.94 g, 39.2 mmol) in dichloromethane (100 ml) was added slowly.to the cooled solution. After addition the solution was stirred at room temperature for 24 hours.
The soution was then concentrated, partitioned between chloroform (100 ml) and water (25 ml), washed with 1N KOH (10 mL), filtered, and concentrated. Purification by column chromatography (hexanes:ethyl acetate 3:2) WO 98/57940 PCT/US98/12668 -140yielded 6.75 g (46 of the product as a brown syrup.
b. 4-(3,4-Difluorophenyl)-l-trityl-2-imidazolidone: To a solution of l-(3,4-difluorophenyl)-2-tritylaminoethylamine (6.75g, 16.44 mmol) in THF (200 mL), 1,1carbonyldiimidazole (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 of the product as a white solid.
c. 4-(3,4-Difluorophenyl)-l-trityl-2-imidazolidone-3carboxylic 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 g, 6.81 mmol) was added at 0°C. The solution was then stirred at room temperature for 15 minutes. It was then added to a solution of 4-nitrophenylchloroformate (1.647 g, 8.17 mmol) at -78 0 C via a cannula. The reaction mixture was then allowed to stir at room temperature for 12 hours. It was then concentrated and partitioned between ethyl acetate (30 ml) and water 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 of the product as a light brown syrup.
d. 4-(3,4-Difluorophenyl)-3-(3-(4-(2-methoxy-5methyl)phenyl-4-phenylpiperidin-1yl) propyl)aminocarbonyl-l-trityl-2 -imidazolidone: To 4 3 4 -difluorophenyl)-3-(4-nitrophenoxy)carbonyl-1trityl-2-imidazolidone (0.089, 0.147 mmol) in THF (5 mL) was added 3-(4-(2-methoxy-5-methyl)phenyl-4phenylpiperidin-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 WO 98/57940 PCT/US98/12668 -141- 1:4) to yield 0.08 g of the product as a syrup.
e. 4-(3,4-Difluorophenyl)-3-(3-(4-(2-methoxyl-5methyl)phenyl-4-phenylpiperidin-1yl)propyl)aminocarbonyl-2-imidazolidone: To 4-(3,4-Difluorophenyl)-3-(3-(4-(2-methoxyl-5methyl)phenyl-4-phenylpiperidin-lyl)propyl)aminocarbonyl-l-trityl-2-imidazolidone (0.100 g, 0.124 mmol) in dichloromethane (2 mL) at 0°C, trifluoroacetic acid (4 mL) in dichloromethane (2 mL) was slowly added and the solution was stirred at room temperature for 20 minutes. The solution was then concentrated, neutralized with 10% KOH and extracted into dichloromethane (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated.
Purification of the residue by flash chromatography (ethyl acetate) yielded 0.06 g of a white foam. To it in dichloromethane (2 mL), IN HC1 in ether (0.5 mL) was added, and the solution concentrated under reduced pressure. Recrystallization of the residue from ether gave 0.061 g (96 of a hydrochloride salt as a white solid: mp 173-175°C. Anal. Calcd. for C 32
H
36 C1F 2
N
4 0 3 1.20 CHC13: C, 53.72; H,5.19; N, 7.55. Found: C, 53.76; H 5.01; N, 7.36.
Example 47: (-)-3-(3-(4-Cyano-4-phenylpiperidin-1-yl)-2(S)methylpropyl)-aminocarbonyl-4 (3,4-difluorophenyl)-2imidazolidone.
a. 4-Cyano-l-(3-hydroxy-2(S)-methylpropyl)-4phenylpiperidine: A mixture of 4 -cyano-4-phenylpiperidine hydrochloride (1.89 g, 8.49 mmol) and (S)-3-bromo-2-methyl-l-propanol g, 6.53 mmol), potassium carbonate (2.709 g, 19.6 mmol) and sodium iodide (1.17 g, 7.84 mmol) in acetone (20 mL) was refluxed for 12 hours. The solution was WO 98/57940 PCT/US98/12668 -142cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate (25 mL) and water (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification of the residue by flash chromatography (hexanes:ethyl acetate 2:3) yielded 1.45 g of the product as a syrup.
b. 1-(3-Azido-2(S)-methylpropyl)-4-cyano-4phenylpiperidine: To a solution of 4-cyano-l-(3-hydroxy-2(S)methylpropyl)-4-phenylpiperidine (1.0 g, 3.87 mmol), triphenyl phospine (1.01 g, 3.87 mmol)and diethyl azodicarboxylate (0.609 g, 3.87 mmol) in THF (20 mL) was slowly added diphenylphosporylazide (0.83 mL, 3.87 mmol) and the solution was stirred at room temperature for 24 hours. The solution was then concentrated and flash chromatographed (hexanes:ethyl acetate 3:2) to yield 0.963 g of the product as a light brown syrup.
c. 1-(3-Amino-2(S)-methylpropyl)-4-cyano-4phenylpiperidine: To a solution of 1-(3-azido-2(S)-methylpropyl)-4-cyano- 4-phenylpiperidine (0.96.g, 3.39 mmol) in ethyl acetate mL) was added trimethylphosphine (8.4 mL, 8.49 mmol) and water (0.30 mL, 16.9 mmol) and the solution was stirred at roomtemperature for 24 hours. The solution was then concentrated and flash chromatographed (ethyl acetate:methanol:methanolic ammonia 3:1:1) to yield 0.60 g of the crude product as a syrup.
d. (-)-3-(3-(4-Cyano-4-phenylpiperidine-1-yl)-2(S)methylpropyl)-aminocarbonyl-4-(3,4-difluoro)phenyl-ltrityl-2-imidazolidone: To 4-(3,4-difluoro)phenyl-3-(4-nitrophenoxy)carbonyl-ltrityl-2-imidazolidone (0.49 g, 0.809 mmol) in THF mL) was added 1-(3-amino-2(S)-methyl)propyl-4-cyano-4- WO 98/57940 PCT/US98/12668 -143phenylpiperidine (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 of the product as a syrup.
e. (-)-3-(3-(4-Cyano-4-phenylpiperidin-l-yl)-2(S)methyl)propyl-aminocarbonyl-4-(3,4-difluorophenyl)-2imidazolidone:.
To (-)-3-(3-(4-Cyano-4-phenylpiperidine-l-yl)-2(S)methylpropyl)-aminocarbonyl-4-(3,4-difluoro)phenyl-ltrityl-2-imidazolidone (0.441 g, 0.607 mmol) in dichloromethane (2 mL) at 0°C was added trifluoroacetic acid (4 mL) in dichloromethane (2 mL) and the solution was stirred at room temperature for 20 minutes. The solution was then concentrated, neutralized with 10% KOH and extracted into dichloromethane (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification of the residue by column chromatography (ethyl acetate) yielded 0.293 g (100%)of the product as a syrup. The two diastereomers were seperated by using Chiralcel OD (20 x 250 mm) column with hexanes/2-propanol/diethylamine (60:40:0.1)as the eluent.
To the desired diastereomer (0.016 g, 0.0332 mmol) in dichloromethane (2 mL) was added IN HC1 in ether mL) and the solution concentrated under reduced pressure. Recrystallization of the residue from ether gave 0.016 g of the hydrochloride salt as a white solid: 5.32 (8.0 mg/mL MeOH); mp 265-267 0
C.
Anal.Calcd. for C 26
H
30 C1F 2
N
5 O200.15 CHCl 3 C, 58.61; H, 5.67; N, 12.07. Found: C, 58.50; H 5.90; N, 12.10.
Example 48: 4 -dichloro)phenylpiperidin-lyl)propyl)aminocarbonyl-4-(3,4-difluorophenyl)-2- WO 98/57940 PCT/US98/1 2668 -144oxazolidinone.
a. 4-Cyano-4-(2,4-dichlorophenyl)-piperidine-1carboxylic acid tert-butyl ester: To bis(2-chloroethyl)-carbamic acid tert-butyl ester (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 0°C. The solution was stirred for 10 minutes at room temperature.
When the foaming subsided, the solution was heated at 60 0 C for 24 hours. It was then quenched with water at 0°C and concentrated. The residue was extracted with ethyl acetate (25 mL) and washed with water (3 x 15 mL).
The organic layer was dried over sodium sulfate, filtered and concentrated. Purification of the residue by column chromatography (hexane:ethyl acetate 4:1) yielded 0.620 g 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-lcarboxylic 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 KOH solution and extracted into 25 ml of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.442 g of 4-(2,4-dichlorophenyl)-piperidine-4carbonitrile which was used as such for the subsequent step.
To a stirred solution of the 4-(2,4dichlorophenyl)piperidine-4-carbonitrile (0.736 g, 2.88 mmol) in acetone (20 mL) was added N-(tertbutoxycarbonyl)-3-bromopropylamine (0.754 g, 3.17 mmol, potassium carbonate (1.594 g, 11.53 mmol) and sodium WO 98/57940 PCT/US98/12668 -145iodide (0.865 g, 5.7 mmol) and the solution refluxed for 24 hours. The reaction mixture was cooled to room temperature, concentrated and partitioned between chloroform (30 mL) and water (5 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate) to yield 0.925 g (78 of the required product as a colorless oil.
c. 3 3 4 -cyano-4-(2,4-dichloro)phenylpiperidin-lyl)propyl)aminocarbonyl-4-(3,4-difluorophenyl)-2oxazolidinone: To 3-[4-cyano-4-(2,4-dichlorophenyl)-piperidin-1-yl]propyl-carbamic acid tert-butyl ester (0.589, 1.42 mmol) in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added and the solution stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10 KOH solution and extracted into 25 mL of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.423 g 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-3carboxylic acid 4-nitrophenyl ester (0.03 g, 0.0823 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 (hexanes:ethyl acetate 1:4) to yield 0.04 g 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 PCT/US98/12668 -146ether gave 0.040 g-(94 of the product as a white solid: mp 204-206 [a] D 48.8 (1.55 mg/mL MeOH).
Anal. Calcd. for C 2 5
H
2
F
2
N
4 0 3 C1 2 .0.60 CH 2 C1,: C, 49.21; H, 4.21; N, 8.97. Found: C, 49.44; H 4.39; N, 8.66.
Example 49: (+)-3-(3-(4-Aminocarbonyl-4-(4-chloro)phenylpiperidin-lyl)-propyl)aminocarbonyl-4-(3,4-difluoro)phenyl-2oxazolidinone.
a. 3-(4-Cyano-4(4-chlorophenyl)piperidin-1yl)propylcarbamic acid tert-butyl ester: To bis(2-chloroethyl)-carbamic acid tert-butyl ester g, 3.8 mmol) and (4-chloro)phenyl acetonitrile (0.624 g, 4.12 mmol) in DMF (35 mL) was added NaH %)(0.260 g, 10.30 mmol) in one lot at 0 C. The solution was stirred for 10 minutes at room temperature. When the foaming subsided, the solution was heated at 60 0
C
for 45 minutes. It was then quenched with water at partitioned between ethyl acetate (25 mL) and brine (3 x 20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to yield 0.76 g (56 of the crude product which was used as such for the subsequent step.
To 4-cyano-4-(4-chlorophenyl)piperidine-l-carboxylic acid tert-butyl ester (0.85 g, 2.64 mmol) in dichloromethane (2 mL) was added 2 mL of trifluoroacetic acid and the solution stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10 KOH solution and extracted into 25 mL of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography (ethyl acetate:methanol:methanolic ammonia 8:1:1) yielded 0.482 g (82 of the product as WO 98/57940 PCT/US98/12668 -147a syrup.
b. 3-(4-(4-Chlorophenyl)-4-cyanopiperidin-lyl)propylcarbamic acid tert-butyl ester: To a stirred solution of the 4-(4chlorophenyl)piperidine-4-carbonitrile (0.482 g, 2.18 mmol) in acetone (20 mL) was added N-(tertbutoxycarbonyl)-3-bromopropylamine (0.572 g, 2.4 mmol, potassium carbonate (1.20 g, 8.7 mmol) and sodium iodide (0.655 g, 4.36 mmol) and the solution refluxed for 24 hours. The reaction mixture was cooled to room temperature, concentrated and partitioned between chloroform (20 mL) and water (5 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate) to yield 0.655 g (71 of the required product as a colorless oil.
c. 3 -(3-(4-Aminocarbonyl-4-(4chloro)phenylpiperidin-1-yl)-propyl)aminocarbonyl-4- (3,4-difluoro)phenyl-2-oxazolidinone: 3-(4-(4-chlorophenyl)-4-cyanopiperidin-lyl)propylcarbamic acid tert-butyl ester (0.150 g, 5.39 mmol) in cone. H 2 SO, (1 mL) was stirred at room temperature for 30 hours. The solution was concentrated, neutralized with 10 KOH solution and extracted into 25 mL of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.185 g of l-(3-aminopropyl)- 4-(4-chlorophenyl)piperidine-4-carboxamide which was used as such for the subsequent step.
To 4-(3,4-difluorophenyl)-3-(4nitrophenoxy)carbonyl-2-oxazolidinone (0.040 g, 0.109 mmol) in 10 mL of dry THF was added 1-(3-aminopropyl)-4- (4-chlorophenyl)-piperidine-4-carboxamide (0.042 g, 0.141 mmol) and the solution was stirred at room temperature for 24 hours. The reaction mixture was WO 98/57940 PCTIUS98/12668 -148concentrated and purified by column chromatography (ethyl acetate: MeOH 9:1) to yield 0.025 g of the product as a foamy syrup. To the syrup (0.025 g, 0.048 mmol) in dichloromethane (2 mL) was added IN HC1 in ether (0.5 mL) and the solution concentrated under reduced pressure. Recrystallization of the residue from ether gave 0.021 g (80 of the product as a white solid: mp 140-142 52.0(1.3 mg/mL MeOH) Anal. Calcd. for C 25 H 2 ClF2N4041 .7 CH 2 C12: C, 45.70; H, 4.51; N, 7.96. Found: C, 45.75; H 4.64; N,7.96.
Example (+)-3-(5-(4-Cyano-4-phenylpiperidin-l-yl)pent-2(E)-en-1yl)-4-(3,4-difluoro)phenyl-2-oxazolidinone.
To a solution of 4 -(3,4-difluorophenyl)-2-oxazolidinone (0.2 g, 1 mmol) and HMPA (0.18 g, 1 mmol) in THF (6 mL) was added NaH (44 mg, 1.1 mmol, 60% in mineral oil) at room temperature. After 30 min, 1,5-dibromo-2-pentene (0.34 g, 1.5 mmol) was added to the mixture. the mixture was stirred at room temperature for 4 h. After removal of solvent, the residue was flash chromatographed over silica gel (1:1 hexane-ethyl acetate) to give a mixture of two isomers in 40% yield as a yellow oil.
This oil (0.14 g, 0.4 mmol) was mixed with 4-cyano- 4-phenylpiperidine hydrochloride (0.18 g, 0.8 mmol), potassium carbonate (0.2 g, 1.4 mmol), sodium iodide (61 mg, 0.4 mmol) in acetone (6 mL) and was refluxed overnight. After removal of the solvent, the residue was flash chromatographed over silica gel (ethyl acetate) to give a mixture of two isomers in 22% yield as a yellow oil. HPLC separation (column: Primesphere SiO 2 5pm, 21.2 x 250 mm, eluent: 75:25:0.1 ethyl acetate-hexanetriethylamine) gave the desired product (20 mg) as a yellow oil. It was treated with 1.0 equivalent of HC1 to give a salt as a yellow solid: mp 168-170 0 C; ESMS m/e WO "/57940 PCTIUS98/12668 -149- 4 52 [ailD 45. 0 (0.4 mg/mL CH 2 C1 2 Anal. Calcd.
for C2H7232H11O2:C, 61.72; H, 5.98; N, 8.30.
Found: C, 61.79; H, 5.88; N, 8.26.
Example 51: trans (+)-4-(3,4-Difluorophenyl)-5-methy.-2oxo-oxazolidine-3-carboxylic acid(3- (4-f luoro-2methyiphenyl) -piperidin- 1-Yl] propyl )amide a. (4-f luoro-2-methylphenyl) -piperidin-1-yfl propylamine was synthesized as described in Example 22, Step c, and was used in the next step without further purification.
b. trans (3,4-Difluorophenyl) -5-methyl-2-oxooxazolidine-3-carboxylic acid(3- (4-f luoro-2methyiphenyl) -piperidin- 1-yl] propyl) andde As described in Example 18, step i, the trans 4-difluorophenyl) -5-methyl-2-oxo-oxazolidine-3carboxylic acid-4-nitro-phenyl ester (0.03 g, 0.08 inmol) was converted into trans 4-difluorophenyl) methyl-2-oxo-oxazolidine-3-carboxylic acid{3-[4- (4fluoro-2-methylphenyl) -piperidin-1-yl] propyllamide, using the side chain'described in step a above, with yield. It was converted into the hydrochloride salt.
M. P. =80-83 0 C; D 23. 0 (c 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, 7.93. Found: C, 58.91; H, 6.37; N, 7.73.
Example 52: (+)-8-(3,4-Difluorophenyl) -6-oxo-5-oxa-7aza-spiroE3.4]octan-7-carboxylic acid-{3- (4fluoro) phenyl) -piperidin-1-yl] -pro pyl) -amide a. Eenzhydrylindene- 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 niL) was added a catalytic amount of BF 3 .OEt 2 and the resulting solution was stirred at ref lux for 12 h.
WO 98/57940 PCT/US98/12668 -150- The reaction mixture was concentrated in vacuo, yielding an oil (21 g, which was characterized by NMR analysis and subjected to the following reaction without any further purification.
b. 1-[(Benzhydryliden-amino)-(3,4-difluorophenyl)methyl]-cyclobutanol To a solution of the imine (2.5 g, 8.1 mmol) in 50 mL of dry THF was added tert-butyllithium (1.7 M, 6.2 mL) dropwise and the resulting solution was stirred at -78 0
C
for 0.5 h. To the solution was added cyclobutanone (0.74 ml, 9.9 mmol) in 10 ml of THF and the solution was stirred at -78 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 Et 2
O
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.
c. 1-[Amino-(3,4-difluoro-phenyl)methyl]-cyclobutanol The crude batch of 1-[(benzhydryliden-amino)-(3,4difluoro-phenyl)methyl]-cyclobutanol obtained from the above reaction and MeONH,.HC1 (1.35 g, 16.2 mmol) was dissolved in 125.0 mL of MeOH and stirred for 12 h. The reaction mixture was concentrated in vacuo, yielding oily residue which was redissolved in 100 ml of EtOAc and was washed with 2.0 M NaOH followed by brine. The organic layer was separated, dried over Na 2
SO
4 and then concentrated in vacuo to give 1-[amino-(3,4-Difluorophenyl)methyl]-cyclobutanol as an oil which was used in the next step without any purification.
WO 98/57940 PCT/US98/12668 -151d. [(3,4-Difluorophenyl)-(1-hydroxy-cyclobutyl)-methyl]carbamic acid-tert-butyl ester To a solution of l-[amino-(3,4-difluoro-phenyl)methyl]cyclobutanol (approximately 8.1 mmol) in CH 2 Cl 2 (50 mL) at 0°C was added a solution of di-tert-butyl dicarbonate g, 16.2 mmol) in one portion and the resulting solution was stirred for 2 h at room temperature. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel (9:1 cyclohexane-EtOAc followed by 4:1 cyclohexane-EtOAc) to obtain [(3,4-difluorophenyl)-(l-hydroxy-cyclobutyl)methyl]-carbamic acid-tert-butyl ester as a viscous oil g, 40% yield over four steps).
e. 8-(3,4-Difluorophenyl)-5-oxa-7-aza-spiro[3.4]octan-6one To a well stirred solution of [(3,4-difluorophenyl)-(1hydroxy-cyclobutyl)-methyl]-carbamic acid-tert-butyl ester (1.0 g, 3.2 mmol) in THF (20 mL) was added 95% NaH (0.2 g, 8.3 mmol) at room temperature. The resulting suspension was stirred for 3 h at about 35 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 solvent was removed in vacuo to yield 8-(3,4difluorophenyl)-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 hexane/20% isopropyl alcohol/ 0.1 diethylamine as the eluting system (12 mL/min) under isothermal conditions 254 nM). The retention times for the two isomers WO 98/57940 PCT/US98/1 2668 -152of were 12.1 min 20.0 (c o.35, MeOH)} and 15.6 min 23.7 (c 0.52,MeOH)}respectively.
The (-)-enantiomer was used in the next step (0.30g, yield).
f. 8 4 -Difluorophenyl)-6-oxo-5-oxa-7-azaspiro[3.4]octan-7-carboxylic acid-4-nitrophenyl]ester To a solution of 8 3 ,4-difluorophenyl)-5-oxa-7-azaspiro[3.4]octan-6-one (0.15 g, 0.63 mmol) in 10 mL THF was added a solution of n-butyllithium in hexane (0.47 mL, 0.76 mmol) dropwise via a syringe under argon atmosphere at -78C. 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 flask containing a solution of 4nitrophenylchloroformate (0.15 g, 0.76 mmol) inlO mL of THF, cooled at -78°C, over a period of 15 min. After five minutes, the flask was removed from the cooling bath and stirring was continued for 1 h. The reaction was quenched by adding ice and it was extracted with EtOAc. The organic extracts were washed with brine and the organic layer was dried over Na 2
SO
4 The solvent was removed after filtration and the residue was purified by column chromatography on silica gel with 4:1 cyclohexane-ethyl acetate to obtain difluorophenyl)-6-oxo-5-oxa-7-aza-spiro[3.4]octan-7carboxylic acid-4-nitrophenyl]ester as a thick syrup which solidified upon standing (0.19 g, [a]D 42.0 (c 0.65, MeOH).
g. (+)-8-(3,4-Difluorophenyl)-6-oxo-5-oxa-7-azaspiro[3.4]octan-7-carboxylic acid-{3-[4-(4- WO 98/57940 PCT/US98/12668 -153fluoro)phenyl)-piperidin-1-yl]-propyl)-amide To a solution of fluorophenyl)piperidin-l-yl]propylamine (0.02 g, 0.08 mmol) in 10 mL of THF (+)-8-(3,4-difluorophenyl)-6-oxo- 5-oxa-7-aza-spiro[3.4]octan-7-carboxylic acid-4nitrophenyl]ester (0.02 g, 0.05 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 10 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with EtOAC followed by 15% MeOH in EtOAC as the eluting systems (Rf 0.4, 1:3 MeOH/EtOAC) to obtain difluorophenyl)- 6 -oxo-5-oxa-7-aza-spiro[3.4]octan-7carboxylic acid-{3-[4-( 4 -fluoro)phenyl)-piperidin-l-yl]propyl}-amide as a pale yellow oil(0.02 g, 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 Mass spectrum showed M+1 peak.
Example 53: (+)-5-Cyclopropyl-4-(3,4-difluorophenyl)-2oxo-oxazolidine-3-carboxylic acid-{3-[4-(4-fluoro-2methyl-phenyl)-piperidinl-yl]-propyl}-amide a. 2-(Benzhydryliden-amino)-l-cyclopropyl-2-(3,4difluoro-phenyl)-ethanol To a solution of benzhydrylindene-(3,4-difluoro-benzyl)amine (2.5 g, 8.1 mmol) in 50 mL of dry THF was added tert-butyllithium (1.7 M, 6.2 mL) dropwise and the resulting solution was stirred at -780C for 0.5 h. To the solution was added cyclopropanecarboxaldehyde (0.90 ml, 12.0 mmol) in 10 ml of THF and the solution was stirred at -78 °C for 2 h and 25 OC for 1 h. The reaction was quenched by adding 1.0 mL of dilute acetic WO 98/57940 PCT/US98/12668 -154acid. 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)-l-cyclopropyl-2-(3,4-difluorophenyl)-ethanol as a yellow oil, which was subjected to the following reaction without purification.
b. 2-Amino-l-cyclopropyl-2-(3,4-difluoro-phenyl)-ethanol The crude batch of 2-(benzhydryliden-amino)-lcyclopropyl-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 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 SO4 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 CHC1 3 /10% ammonia in MeOH) to yield 3.2 g (93% yield) of 2-amino-l-cyclopropyl-2-(3,4-difluoro-phenyl)-ethanol as a pale yellow oil.
c. [2-Cyclopropyl-l-(3,4-difluorophenyl)-2-hydroxyethyl]-carbamic acid-tert-butyl ester To a solution of 2 -amino-l-cyclopropyl-2-(3,4-difluorophenyl)-ethanol (1.7 g, 8.1 mmol) in CH 2 C1 2 (50 mL) at 0°C was added a solution of di-tert-butyl dicarbonate g, 16.2 mmol) in one portion and the resulting solution was stirred for 2 h at room temperature. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel (4:1 cyclohexane/EtOAc) to obtain [2-cyclopropyl-l-(3,4- WO 98/57940 PCT/US98/12668 -155difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tertbutyl ester as a viscous oil (1.7 g, 68% yield).
e. 5-Cyclopropyl-4-(3,4-Difluorophenyl)-oxazolidin-2-one To a well stirred solution of 2 -cyclopropyl-l-(3,4difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tertbutyl ester (1.7 g, 5.4 mmol) in THF (20 mL) was added NaH (0.4 g, 16.2 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 solvent was removed in vacuo to yield 5-cyclopropyl-4- 3 4 -difluorophenyl)-oxazolidin-2-one (1.3 g, 93% yield) as a 3:1 mixture of the trans:cis diastereomers. The diastereomers were separated by column chromatography over silica gel with 7:3 cyclohexane/ethyl acetate as the eluting system. The trans isomer eluted first (Rf 0.65 g) followed by the cis isomer (Rf 2.0, 0.2 The relative streochemistry was assigned by comparing the 1H NMR of the two isomers of cyclopropyl-4-(3,4-difluorophenyl)-oxazolidin-2-one to the corresponding isomers of 4-(3,4-difluorophenyl)-5methyl-oxazolidin-2-one as described in Example 19.
The and enantiomers of the trans-isomer were separated by HPLC by using Chiralcel OD (4.6 x 250 mm) using 80% hexane/20% isopropyl alcohol/ 0.1 diethylamine as the eluting system (12 mL/min) under isothermal conditions 254 nM). The retention times for the two enantiomers were 12.0 min 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 -156f. (+)-5-Cyclopropyl-4-(3,4-difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-4-nitrophenyl]ester To a solution of (+)-5-cyclopropyl-4-(3,4- Difluorophenyl)-oxazolidin-2-one (0.16 g, 0.66 mmol) in 10 mL THF was added a solution of n-butyllithium in hexane (0.49 mL, 0.79 mmol) dropwise via a syringe under argon atmosphere at -78 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 bottom flask containing a solution of 4nitrophenylchloroformate (0.16 g, 0.79 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 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 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%).
g. (+)-5-Cyclopropyl-4-(3,4-difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-{3-[4-(4-fluoro-2-methylphenyl)-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 of CH 2 C1 2 (+)-5-cyclopropyl-4-( 3 ,4-difluorophenyl)-2oxo-oxazolidine-3-carboxylic acid-4nitrophenyl]ester(0.01 g, 0.03 mmol) was added and the WO 98/57940 PCT/US98/12668 -157resulting yellow solution was stirred for 10 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with EtOAC followed by 15% MeOH in EtOAC as the eluting systems (Rf 0.4, 1:3 MeOH/EtOAC) to obtain (+)-5-cyclopropyl-4-(3,4-difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-{3-[4-(4-fluoro-2-methylphenyl)-piperidinl-yl]-propyl}-amide as a pale yellow oil(0.01 g, 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 Et20 (1.0 M).
Mass spectrum showed M+1 peak.
Example 54: Asymmetric Synthesis of 4-(3,4- Difluorophenyl)-5-methyl-oxazolidin-2-one a. 2 -Hydroxy-l-pyrrolidin-l-yl-propan-l-one (The procedure reported by Vilarrasa et al. Tetrahedron Lett.
1997, 38, 1633 was used; see also Scheme 31) S-(+)-Methyl lactate (48.03 mmol, 5.0 g) and pyrrolidine (52.8 mmol, 4.4 mL) were mixed in a round bottom flask and the reaction mixture was allowed to stir at room temperature for four days. Methanol was distilled off using a short path distillation apparatus to obtain 2hydroxy-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-ylpropan-l-one To a solution of 2-hydroxy-l-pyrrolidin-l-yl-propan-lone (47.0 mmol, 6.72 g) in DMF (25 mL) was added imidazole (70.5 mmol, 4.8 N,N-dimethyl-4- WO 98/57940 PCT[US98/1 2668 -158aminopyridine (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 brwnred in color and some precipitate was observed after min. The reaction mixture was allowed to stir overnight and then filtered through a sintered glass funnel. The solid was washed with some Et 2 O. The filtrate was diluted with water (150 mL) and it was extracted with Et2O (2 X 100 mL). The organic extrats were combined and washed successively with water (100 mL), sat. NH 4 C1 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)-1pyrrolidin-1-yl-propan-l-one as a golden yellow oil (10.4 g, 86% yield). The product was judged to be pure by NMR and was used in next step without any purification.
c. 2-(tert-Butyl-dimethyl-silanyloxy)-1-(3,4-difluorophenyl)-l-yl-propan-l-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 solution of.
2 -(tert-butyl-dimethyl-silanyloxy)-lpyrrolidin-1-yl-propan-l-one (60.0 mmol, 15.4 g) in 10.0 mL THF was then added ina steady stream and.the orange colored solution was stirred for 35 min at -78 0 C. It was quenched with 20.0 mL of sat. NH 4 Cl solution and was allowed to attain room temperature. The solution was extracted with Et 2 O (2 X 50 mL), washed with brine and the organic layer was dried over Na 2
SO
4 The solution WO 98/57940 PCT/US98/12668 -159was filtered and the solvent was removed in vacuo to obtain the product as an orange oil. The crude product was subjected to silica gel flash column chromatography (9:1 hexane/EtOAc to 4:1 hexane/EtOAc as the eluent system). 2 -(tert-Butyl-dimethyl-silanyloxy)-l-(3,4difluoro-phenyl)-1-yl-propan-l-one was obtained as a pale yellow oil (14.1 g, 78% yield, 96% based on the recovered starting material).
d. 2-(tert-Butyl-dimethyl-silanyloxy)-l-(3,4-difluorophenyl)-l-yl-propan-l-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 mmol, 3.76 g) and hydroxylamine hydrochloride mmol, 1.24 g) and the resulting solution was stirred at room temperature overnight. Methanol was then removed in vacuo and the resultind residue was extracted with EtOAc (2 X 50 mL) and brine. The organic layer was separated, dried over Na 2
SO
4 filtered and the solvent was remoced in vacuo. 2-(tert-Butyl-dimethyl-silanyloxy)-1-(3,4difluoro-phenyl)-l-yl-propan-i-one-oxime was obtained as a colorless oil (4.04 g, 94% yield). It was used in the next step without further purification.
e. l-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 Et 2 O was added a 1.0 M solution of lithium aluminum hydride (25.0 mmol, 25.0 mL) at 0°C under an argon atmosphere. After 1 h, the solution was heated to reflux for 2 h at which time some solid was observed. The reaction mixture was cooled to WO 98/57940 PCT/US98/12668 -160- 0C and then quenched sequentially with water (1.0 mL), N KOH (1.0 mL) and water (3.0 mL). The residue was filtered and the solid was washed with warm Et 2 O (20.0 mL). The filtrates were combined and dried' over Na 2
SO
4 The solution was filtered and the solvent was removed in vacuo to obtain l-amino-l-(3,4-difluorophenyl)-propan-2ol as a colorless oil as a mixture of two diastereomers which solidified into a low melting solid (2.1 g, 92% yield). It was used in the next step without purification.
It was converted into 4-(3,4-difluorophenyl)-5-methyloxazolidin-2-one by the general procedure as described before.
f. [1-(3,4-Difluorophenyl)-2-hydroxy-propyl]-carbamic acid-tert-butyl ester To a solution of l-amino-l-( 3 ,4-difluorophenyl)-propan- 2-ol (3.5 g, 19.1 mmol) in CHC1 3 (15 mL) at 0C was added a solution of di-tert-butyl dicarbonate (5.1 g, 23.6 mmol) in CHC1 3 (10 mL) in one portion and the resulting solution was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel (2:1 hexane-EtOAc followed by EtOAc) to obtain [1- (3,4-difluorophenyl)-2-hydroxy-propyl]-carbamic acidtert-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)-2hydroxy-propyl]-carbamic acid-tert-butyl ester (0.43 g, 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 WO 98/57940 PCT/US98/1 2668 -161extracted 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 0.6, 3:1 hexane-EtOAc; second isomer: 0.23 g, Rf 3:1 hexane-EtOAc). NOE experiment suggested that the first diastereomer had the methyl and the aryl group in trans configuration while the second diastereomer had cis relationship between the two groups.
Each diastereomer was subjected to chiral HPLC analysis using Chiralcel OD (4.6 x 250 mm) using isopropyl alcohol/ 0.1% diethylamine as the eluting system (12 mL/min) under isothermal conditions 254 nM). The retention time for the transoxazolidinone was 13.0 min. This corresponds to the isomer of the trans oxazolidinone that was synthesized by a separate method as described in Example 19 (the retention time for the (+)-trans-oxazolidinone was 12.1 min). The HPLC analysis also confimed that the enantiomeric purity of the diastereomer was >99% because no peak corresponding to-(-)-isomer was observed. Since the absolute stereochemistry of the starting material lactate] is known, the absolute stereochemistry of the (+)-isomer of the transoxazolidinone must be at the two stereocenters.
This enantiomerically pure oxazolidinone can be converted into the required final products by using similar methodology as described before in example 19.
General synthetic schemes: In addition to the specific examples of compounds described above, typical procedures for the synthesis of the compounds of this invention are shown in Schemes 32-35. In Scheme 34, the WO 98/57940 PCT/US98/12668 -162synthesis may be carried out using a procedure similar to Koo, J. Am. Chem. Soc., 1953, 75, 723), Anderson, P. (Tetrahedron Lett., 1971, 2787), and Bean, N. P. et al. (Tetrahedron, 1993, 49, 3193). In Scheme 35, the synthesis may be carried out using a procedure similar to Belkon, Y. et al. J. Chem. Soc. Perkin Trans. I, 1986, 1865), Novikov, M. S. et al. (Tetrahedron Lett., 1997, 38, 4187), and Meyers, A. et al. Amer. Chem.
Soc., 1984, 106, 1146).
Examle 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 finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gel capsule.
WO 98/57940 PCT)IJS98/12668 -163- Pharmacological Profiles of the Compounds in Cloned Human Adrenerric Receptors.
Binding affinities were measured for selected compounds of the invention at six cloned human alpha-i and alpha-2 receptor subtypes, as well as at the L-type calcium channel. The protocols for these experiments are given below.
Protocol for the Determination of the Potency of c Antagonists The activity of compounds at the different human receptors was determined in vitro using cultured cell lines that selectively express the receptor of interest.
These cell lines were prepared by transfecting the cloned cDNA or cloned genomic DNA or constructs containing both genomic DNA and cDNA encoding the human a-adrenergic receptors as follows: a,D Human Adrenergic Receptor: The entire coding region of oD (1719 bp), including 150 base pairs of untranslated sequence UT) and 300 bp of 3' untranslated sequence UT), was cloned into the BamHI and Clal sites of the polylinker-modified eukaryotic expression vector pCEXV-3, called EXJ.HR. The construct involved the ligation of partial overlapping human lymphocyte genomic and hippocampal cDNA clones: sequence were contained on a 1.2 kb SmaI-XhoI genomic fragment (the vector-derived BamHI site was used for subcloning instead of the internal insert-derived SmaI site) and 3' sequences were contained on an 1.3 kb XhoI- ClaI cDNA fragment (the Clal site was from the vector polylinker). Stable cell lines were obtained by cotransfection with the plasmid alA/EXJ (expression WO 98/57940 PCT/US98/12668 -164vector 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 cells were grown, in a controlled environment (37 0
CO
2 as monolayers in Dulbecco's modified Eagle's Medium (GIBCO, Grand Island, NY) containing 25mM glucose and supplemented with 10% bovine calf serum, 100 units/ml penicillin g, and 100 pg/ml streptomycin sulfate. Stable clones were then selected for resistance to the antibiotic G-418 (1 mg/ml), and membranes were harvested and assayed for their ability to bind ['H]prazosin as described below (see "Radioligand Binding assays").
The cell line expressing the human aD 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.
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 aD receptor, was accorded ATCC Accession No. CRL 11138, and was deposited on September 25, 1992.
a, Human Adrenergic Receptor: The entire coding region of alB (1563 bp), including 200 base pairs and untranslated sequence UT) and 600 bp of 3' untranslated sequence 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 X ZapII into the expression vector. Stable cell lines were selected as WO 98/57940 PCT/US98/12668 -165described above. The cell line used herein was designated L-aB and was deposited with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A. under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure. The cell line L-al was accorded ATCC Accession.No. CR 11139, on September 29, 1992.
a. Human Adrenergic Receptor: The entire coding region of aA (1401 bp), including 400 base pairs of untranslated sequence UT) and 200 bp of 3' untranslated sequence UT), was cloned into the KpnI site of the polylinker-modified pCEXV-3-derived eukaryotic expression vector, EXJ.RH. The construct involved ligating three partial overlapping fragments: a 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 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 fulllength clone was cloned into the KpnI site of the expression vector, using the 5' and 3' KpnI sites of the fragment, derived from vector pBluescript) and 3'-untranslated sequences, respectively. Stable cell lines were selected as described above. The stable cell line expressing the human aA receptor used herein was designated L-ac (old nomenclature) and was deposited with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A. under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure.
WO 98/57940 PCT/US98/12668 -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 culture flasks were scraped into 5ml of 5mM Tris-HCl, EDTA, pH 7.5, and lysed by sonication. The cell lysates were centrifuged at 1000 rpm for 5 min at 4 0
C,
and the supernatant was centrifuged at 30,000 x g for min at 4 0 C. The pellet was suspended in 50mM Tris-HCl, ImM MgC1 2 and 0.1% ascorbic acid at pH 7.5. Binding of the al antagonist [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 determined in the presence of 10 uM phentolamine. The reaction was stopped by filtration through GF/B filters using a cell harvester. Inhibition experiments, routinely consisting of 7 concentrations of the tested compounds, were analyzed using a non-linear regression curve-fitting computer program to obtain Ki values.
a 2 Human Adrenergic Receptors: To determine the potency of al antagonists at the a 2 receptors, LM(tk-) cell lines stably transfected with the genes encoding the a2A, a2B, and a2c receptors were used. The cell line expressing the a 2 receptor is designated L- 2 A, and was deposited on November 6, 1992 under ATCC Accession No.
CRL 11180. The cell line expressing the ac 2 B receptor is designated L-NGC-a2B, and was deposited on October 1989 under ATCC Accession No. CRL10275. The cell line expressing the a 2 C 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, WO 98/57940 PCT[US98/1 2668 -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 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 10iM phentolamine. The bound radioligand was separated by filtration through GF/B filters using a cell harvester.
Determination of the Activity of al Antagonists at Calcium Channels The potency of a. antagonists at calcium channels may be determined in competition binding assays of [3H]nitrendipine to membrane fragments of rat cardiac muscle, essentially as described by Glossman and Ferry (Methods in Enzymology 109:513-550, 1985). Briefly, the tissue is minced and homogenized in 50mM Tris-HCl (pH 7.4) containing 0.1mM phenylmethylsulfonyl fluoride.
The homogenates are centrifuged at 1000 g for minutes, and the resulting supernatant centrifuged at 45,000 g for 15 minutes. The 45,000 g pellet is suspended in buffer and centrifuged a second time.
Aliquots of membrane protein are then incubated for minutes at 37 0 C in the presence of [3H]nitrendipine (1 nM), and nonspecific binding determined in the presence of 10M nifedipine. The bound radioligand is separated by filtration through GF/B filters using a cell harvester.
The compounds described above were assayed using cloned human alpha adrenergic receptors. The preferred WO 98/57940 PCT/US98/12668 -168compounds were found to be selective a1A antagonists.
The binding affinities of several compounds are illustrated in the following table.
WO "/57940 WO 9857940PCTIUS98/12668 -169- Binding affinities of selected compounds of the present invention at cloned human a 1DI ac1 and a 1A receptors.
Example hot,. ha 1B ha lA
K
1 2 11 21 21 2455 891 21 28 3660 1 4012 1 0.7h human WO 98/57940 PCT/US98/12668 -170- Scheme 1
NC
eonc. NH2 01~
NO
2 O- Dr
ON*
Br-
H
3
C
Diowi.
fef lux Heat Ome 0 02N
H
3
C
HN"71.b
R
1. Br-(CH2)3NBc 2. TFA H 2 NI Scbu 1: General Synthesis of Piperazine side chains WO 98/57940 WO 9857940PCTIUS98/12668 -17 1- Scheme 2 K Ph Ar-Li r 5
O
p-TsOH.H 2 0 Ar .6
N
M2 Pd-C Ax 'Ph Ar OH
H
Ar-H
H
0i Ph MeL.i.
H
3 C OH Ph-H A1C13
H
3 C Ph H12 Pd-C 11 3 C nuPh
H
ph- OOH
H
A
)CN
coTIc. 1 2 S04 MeOH 1. E-tCH 2
)-NHBOC
2. TFA Ph COOKe
H
n= 2. 3. 4. Ru H, Me. Ar' Scheme 2: General Synthesis of Piperidine Side Chains WO "/57940 WO 9857940PCTIUS98/I 2668 -17 2-
N
6N IL- C 3 NHB0c
N
Or 3z-(CH2)3-12
I
R*
N&BH
4 NaSH 4
H
2 N 2
N
ON
N
NH 2
ON
(CH
2 3
-OH
KBr
OH
Schame 3: Synthesi~s -of FyridyJ. piperidine containing side chains F F F F 1. Nail TIIF, IINPA 2. Or Or A F F F~ MeO K2C03, Dioxale, ReflIUX Scheme it Preparation of Example 2.
WO 98/57940 PCTIUS98/1 2668 -174z ~I 4 =r z ii 0) z I C0 0: r,
I
f-
I
a 1 a
L)
O
d r= '4' -4 U 0) -4 0.
E
K
x 0
C
4
T
-14 -4 0 x 0 o 0 1" 0 m -4
X
Ai r.
>1
U,
-4 0)
C
0) o
N
r, 9 a
I
N
z c Cp
C,
4
I
U
99 11 6r C *Jq tnv i i
-I
z '4 0 Col Pi IOAcI 2 K011. M(!flII
F
Acetone cat. 117904 0 IF-jt 'O" II? NOJI. l1Id NaOAC. HeOl LAII EL20 "Ila Boc2O. CHIC13 Hl4Doc F-91"-OH Nall, ThyF 0 NAil L -1
F
1. C1COOPhI-N02 2. R-NI1 2 o 0
F
Scheme Got Alternate Synthesis of Oxazolidinones described in Scheme 0 112NE l LAii 'rifF BO0C20
DOCIIN,
11 2
H'
Nall ITIIF R, -N112 Nil 0'1 0 I. Nall TIIF 2. p.Nitrophelyl chlorotonflate Scheme 7: General Synithesis of Oxazir'ones (Example 4) WO 98/57940 PCT/US98/1 2668 -177-
CI
0 C.4 o=z 0 2 o fa.
0
L&
0~
S
2
K
U,
C
0
C
-4 -4 -4 0
N
K
0
U
-4 0 2 0 a' -4 0 -4
U,
0
U,
-4
U'
4,
C
>1
S
S
I
U
S
dil CS2. CIICI 3 Ref luxK CS2. K011/1120 0 )Nil
S
S Nit I. ClCOOPI-N02 2. R-NI12 1. CICOOPh-NO2 2. R-NH2 S 0 S 0 net lux D£ae 9t Synthesis of Oxazolidifl-llione and Thiazolidin-thione (Examples 11, 12) ml, 01:1 il I. OC20 2. Nall t. CICOOPII-No 2 2. R"JI12
R
I S 1. B OC2 0 0 2. Nall 1. -CICOOPII-N02 2. Rh4I12 Scheme 10i General Synthesis for Example 13.
0 Cr 00 0 HeLL. Ft20
CIO)
Oil
-I)
p-T8OII. Pil m-CPDA, C1122C LAEI. Et2O 2. BOc20 3. Nak, TIW isr II jL NtN3. L!C1O4 -0 1
F
Separate regloigomerl by colui chromatography 1. C1COOPh-N02 2. R-NI12 0 o 0F Scheme 11: Synthesis of Methlylated oxazolidinones (Examples 16, 17).
0 F
I
0 I. tMgBr, E120 2. PCC. celite, CII2CI12F PIlIl OAc) 2 KOll, HeOll 0 F JO HOH I12NOH iC1 NaOAC, HeOli Oil I1 oil LAII El 1. Boc20, CIIC 2. Nall TIIF 0
F
1. Separate diastereomers by column chromatography 2. Enantiomers separated by ciral IIPLC column.
OANH
IF
0
OANU
Relative stereochemistry shown for the cia and trans isomers 1. CICOOPh-N02 2. RNH2 o o
F
O 0 OKN AH only two of the possible four structures shown.
Absolute stereochemistry was not established.
Rcheme 121 Synthesis of Methylated Oxazolidinones (Examples 18, 19).
F
0 ql) Oil ?4lS2 LAIS IIF B0C20 Hail 11SF
F
H il 0+ I. Nail TIIF 2. prNitropIhettyl chlorotOrl'
F
to\ IR -H12 b-4SOi Scheme 13t General synthesis of Beflzyl Oxazolidilofes (Exampl 00 WO 98/57940 WO 9857940PCTIUS98/12668 -183- Ph, C B NH3
K
2 C0 3 0 KI hN--
N
I 0 Ph
/N
0--CNH a AJ.C13 40 Ph- Ph Ph>& 2. BH 3 Ph>C/ E Ar \Ar HO-C IINH
LAM
Ar Ar
OH
CDi Ar .Ar
NH
0-4- 1 .NaH/THF 2.4-Nitrophenyl chlorof ormate 0-k!.
0 ArAr 0 0 Scheme 14. ?reparation of Examples 23 and 24 WO 98/57940 PCTIUS98/12668 -184- Ph
>CN/\
NC
0 0
K
2 C0 3 Ph
O
mc >CN>A 9
DAST
H
2
N-M
jIFH cPh c/
OH
F
Ph NH2 NC 2N
>CNM
HO
K
2 C0 3
RI
,C*
H
Ph
CO
HO
H
NaH CH,COBr Ph >Cl COBn Pd (OH) 2 IC Aco NH1 PhO >KZN
H
PhCN meo 2
C
K
2 C0 3 *Br NR H
O
meO 2 Cc NE2 Schumo 15. Preparation of Side Chains WO 98/57940 WO 9857940PCTIUS98/1 2668 -185- 0L 0 0 ADb ~2~2 NE
N
c N C7 rl C N
E
3 Sektume 1.6. Preparat~ion of Side Chains (contd.).
WO 98/57940 .Ar MeO 2 C N;2 PCT/US98/I 2668 -186- ?le~gBr Ar
OH
Ar
CDT
NE4 2..NaH/TF 2 .4-Nitropheny.
ckiloroformate 0 -4- 0
R-NH
2 Ar0 0 Scheme 1.7. Preparation of Examnples 25-29 and 31.
0 0 N a.H THFAr
M
5-Dibromopentane 0 Ar 0 Scheme 1.8. Preparat.ion of Example WO "8/57940 PCT/US98/12668 -187- .Br- NaBH 4
NI
Ph Br N Ph
NCO
2
H
NZ Ph Pd (OH) Z/C
NK
BOC
DtQPECD K7>,-~N 0 LiA1H 4 TFA C NX 1 -r No2 Scheme 19: Preparation of Example 32 WO 98/57940 WO 9857940PCTIUS98/1 2668 -188- 0 K 2
C-
3 0 Er K~I NC>c Ph
>CUH
NC
Schin 20: Preparationl of Side Chain
F
KFW
04 LiKKS BrCH 2
CO
2
CH
2 Ph Pd (OH) 2
/C
Ph
F
N OH 04 0 DMAPECM.
DMPP
0 0 Q- Ph
CN
Scheme 21: Preparation of Example 33 WO 98/57940 WO 9857940PCT/US98/1 2668 -189- U z WO 98/57940 WO 9857940PCTIUS98/12668 -190- E~4 z/z
E
w 1d
I
z 1 4 4.
WO 98/57940 WO 9857940PCT/US98/12668 -191- R2 (0 AlC13
R
2
H
Hfl di isopropylethylamine dioxa.ie, reflux 2. Trifluoroacetic acid R, 4-SCM 3
R
2 Ii, SO 2
CH
3 4-F, (2-0CH 3 S-F) 4-Br Scbam*24 Preparation of Examples 38-42 F 0 F -6 ff I1MSCN, NIl:, MoOH. cal ZnI 2
F
-F LAH. ETHER 0 14
F
N~
F~H
CI:, c CCI13
THF
IF
o 0 ~NOR P-C F NaH, ci A0 HN NH
THF
0 0a
NOR
F
F
HN 0 NaH.
THF
NH
It, 0
F
F
HN yN
N
0 0 yo D\/-14o 2 TfHF Scheme 25 :Preparatiotiol Examples 43 and 44.
TMSCN
MeNH 2 cat ZnI 2
F
N-
F
NH-Mo LAH, ETHER
F
F
NHtjHMO
N
phosgene
THF
THF
THF
Scheme 26 :Preparall of EXample TMSCN, NH 3 Meol 1. Cat 61
F
F1) LAH, Ether, 93 2) DBU. TrCI
NH
2 THF 0 -4
F
Tr HN NH 2 0
N
THF
F
TN yNH 0 NaH. THF CICQOPh-N02 fl-NH 2
THF
F
F
Tr'N N T1M:1
F
F
HN N
F
F
T r N Y Y
,Q
NO 2 TFA. CH 2
CI
2 (1:1) Scheme 27 P1reparation of Examples 46 and 47.
13t
CN
Scheme 28 :Prepartiofl of Example WO 98/57940 PCTIUS98/ 2668 -196-
NH
2
RX
Benzophenone PhCH 3
BF
3 .OEt 2 1. t-BuLi THF 0 2.
1
WI
(For example 52, R fluoro group, W 0, W1 0, and Xl CH 2 x 2, MeONH 2 .HC1 NH2 q-x OH R 1 3 I Boc 2 O, CHC1 3 NaH, THF 0 XI WRx Enantiomers separated by chiral HPLC column.
0 0 ANH [W lwi 1. n-BuLi/THF 2. ClCOOPh-NO2 O 0 N0 O N W w X1 ]W1 Rx
H
2
N-R
For example 52, R 0 0
H
N-R
XW I o Scheme 29: Synthesis of Example 52 and related compounds WO 98/57940 WO 9857940PCT/US98/12668 -197- F N 2 Berizophenone N F PhCH3, BF3.OEt2 F~ .F Ie 1. t-BuLi THF 2. [>-CHO MeONH2.HC1 o20 H1 68% yield NA(HBcO H1 (three steps) Fjp 91%
F
NHBo c
F
0 0 ANH NaH, THF
F
Diastereomers separated by chiral. HPLC column.
Enantiomers separated by chiral HPLC colulm.
0 0 ANH
F
F
1. n-Bi.Li/THF 2. ClCOIO?h-N02 O 0 NO 2 0ON JL0
F
F
XD-b -F 0 0 F
F
Scheme 30: Synthesis of Example 53.
WO 98/57940 WO 9857940PCT/US98/12668 -198- 0 -Y I OH
OH
0
,AN
OH D TBDMSCl H2NOH.HCl 0 TBDMHS -O K/ N'
OH
TBDMS-O F
F
Li 0
TBDMS-I
TBY-
F
IAH, Et2O OH NH2 elL-
F
F
1. BoC2O, CH2Cl2 2. NaH THF 3. Separate diastereomers by column chromatography 0
-NH
0
IP-F
F
0 k-NH 0O 1. ClCOOPh-N0 2 2. R-NH 2 Only the trans isomer shown.
Scheme 31: General synthesis of methylated oxazolidinone.
S
0 JNH NaH S8, 1. NaN YNCONHR n( 4 5 2. C1COOPh-NO2 L y R 2 2R5 3.H2NRn R 2 CS CHC1 3 ref lux Cs 2
KOH
ref lux n 1,2
S
.SZKH
S
1. NaH A NCONHR 2. ClCOOPh-N0 2 3. H 2 NR n( R 2
NH
2 Hy n R5~R 1. Boc 2
O
2. NaH 0 X i N R R2R5 0 1. NaH O P
NCONHR
2. C1COOPh-N0 2 3. H 2 NR n(R 2 X O,S Scheme 32: General synthetic scheme.
BocNH OH 1. TsCl BOCNH N 3 1. Ph 3 P, H 2 0 BocNHN~ TFA R22. NaN3 f(\ 7
R
2 2. TrCl (N (R n 1, 2 ,NHTr CDI 1. NaH NCNeW Cl O O TFA 3
RNH
2 No n( R 4 R2. CH 2 Cl 2
X
~)CDI X 0 .1PIN'JLN CTDI X =S 0 R1 NHCON""LNH n( I$-R2
S
RNHCONtNH 2n(R
CTDI
S. S HNJNWr 1. NaH
NC
C1COOPh-N02RHC n( R R2 2. RNH 2 n
TFA
CH
2 C1 Scheme 33: Schem 33: General synthetic scheme.
H
2
NOH
-"OEt )nPd/H 2 or NaBH 4 0 Lawesson's NH reagentR 2 R n R V. NaH 2C1COOPh-N0 2 3.H2NR I1. NaH 2. C1COOPh-N0 2 3 H 2
NR
0
S
R NCONHR R2
NCONHR
R)nR R n R Scheme 34: General synthetic scheme.
R
6 l- Ph 0 1. base R2N 2. MeONH2*HC1 R'k
N
S
Lawessons R reagent NH- I1. NaH 2. C1COOPh-N0 2 3. H 2
NR
0
NCOH
R
R
5 1i. NaH 2.Cl000Ph-N0 2 3.H2NR
S
NC'ONHR
R
R
S
LaesonsR 2
~I
reagent
N
INR2) 0 OMe
R
CH
3
NO
2 bae Raney Ni I1. NaH 1i. NaH 2. C1COOPh-N0 2 2. C1000Ph-N0 2 3. H 2 NR H 2
NR
0 S 2%\r JCL H
R
2 IJ
CNH
Scheme 35: General synthetic scheme.
P:OPER\KbmX81498-98 spc.doc-30i/0711 -202A Throughout this specification and claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that the prior art forms part of the common general knowledge in Australia.
*1 9o *oo o *o

Claims (51)

1. A compound having the structure: x x 1 A R, X N N N R 2 R4 R 2 R 2 R RS X or R N/R1 R R2 R straight chained or branched 20 wherein each X is an intege r from 1 to 4 *g incluswherein q is 1 or 2;ve; wherein each R3 is independently H; ostraiht 25 -(CH 2 )tC(X)NR 3 -(CH 2 )tCO 2 R 3 -C0 2 R 3 straight chained or branched Cl-C, alkyl, .aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 alkenyl or alkynyl; or C 3 -C 7 cycloalkyl or C 5 cycloalkenyl; wherein each t is an integer from 1 to 4 inclusive; wherein each R 3 is independently H; straight chained or branched C 1 alkyl; straight chained or branched C 2 alkenyl or alkynyl; or C,-C, -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 C 1 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 )XR 3 -(CH 2 )nC(X)NR 3 (CH) CO 2 R 3 straight chained or branched Cl-C, alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C 2 aminoalkyl, alkenyl or alkynyl, or C 3 -C cycloalkyl or C 5 cycloalkenyl; wherein each n independently is an integer from 0 to 7 inclusive; wherein R 5 is H; aryl, C 1 -C 7 alkyl substituted with aryl, heteroaryl, or 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 straight chained or branched C 1 -C, alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C 2 aminoalkyl, alkenyl or alkynyl, or C3-C, cycloalkyl or C 5 cycloalkenyl; where R 5 and one R 2 on adjacent carbon atoms together may form aryl, heteroaryl, indane or tetrahydronaphthyl, C 3 -C 7 cycloalkyl, or heterocycloalkyl wherein one or two heteroatoms may be O, N or S; -205- wherein R 1 is R0m R6 ~Z-N RiR7 1R1 110 \RAqRk4R R104Lq or -2 06- R1 R R N-Rl 1 q 101 where each R 6 is -independently H; straighit chained or branched C 1 -C 7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, mono fluorocyc loalkyl, polyfluorocycloalkyl or C 5 -C 7 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or mnore of F, Cl, Br, I, :20 (CH 2 ).XR 3 -COR 3 1 -(CH 2 N(R 3 2 1 -(CH 2 CO 2 R 3 1 -CN, -so R, straight chained or branched C 1 alkyl, monof luoroalkyl or polyf luoroalkyl, straight chained or branched C 2 -C.7 alkenyl or alkynyl, or C 3 -C 7 cycloalkyl, mono fluorocycloalkyl, polyfluorocycloalkyl or C 5 -C 7 cycloalkenyl; where each R. is independently H; F; Cl; Br; I;- COR 3 -C0 2 R 3 -(CH 2 ).XR 3 (CH 2 ).C(X)N(R 3 2 (CH 2 .CO 2 R 3 -CN; -NO 2 -N (R 3 2 straight chained or branched C 1 alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C 5 -C 7 cycloalkenyl, wherein the alkyl, aminoalkyl, -2 07- 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, 1, (CH 2 IXR 3 -COR 3 1 (CH 2 )IC N(RO) 21 -(CH 2 CO 2 R 3 1 CN, -NO 2 -N(R 3 2 -SO 2 R 3 straight chained or branched Cl-C7 alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C 2 -C, alkenyl or alkynyl, or C 3 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, (CH 2 IXR 3 I -COR 3 1 (CH 2 3 2 ,-(CH 2 ).CO 2 R 3 -CN, -NO 2 -N(R 3 2 S0 2 R 3 straight chained or branched C 1 -C 7 alkyl, straight chained or branched C 1 monofluoroalkyl or polyfluoroalkyl, straight chained or branched C 2 -C7 alkenyl or alkynyl, or C 3 -C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or Cs-C, cycloalkenyl; wherein each Rio is independently H; (CH 2 )tXR 3 (CH 2 NR 3 (CH 2 tCO 2 R 3 straight chained or branched C 1 alkyl or carboxamidoalkyl; straight chained or branched C 2 -C7 aminoalkyl, alkenyl, or alkynyl; or C 3 cycloalkyl or C 5 -C.7 cycloalkenyl; wherein R 11 is aryl, heteroaryl, C 1 alkyl substituted with one or two aryl, or C 1 alkyl substituted with one or two heteroaryl; wherein any aryl or heteroaryl independently may be substituted with one or more of F, Cl, Br, I, -CN, -NO 2 N(R 3 2 -CaR 3 -(CH 2 ),,XR 3 -(CH 2 ),,C(X)NR 3 -(CH 2 )nCO 2 R 3 straight chained or branched C 1 alkyl, monofluoroalkyl, polyfluoroalkyl, or -208- carboxamidoalkyl, straight chained or branched C 2 C, aminoalkyl, alkenyl, or alkynyl, or Cz-C, cycloalkyl or C 5 cycloalkenyl; wherein each m independently is an integer from 0 to 3 inclusive; wherein Z-is R 9 n R2 R is0 R2 302 30 H R n R2 R9 -209- isi R0 Rio Rg m j j r_ -210- 0 R22 m t R2 n R 9 itK. R 1 0 R~9 or C 2 alkenyl, wherein the C 2 alkenyl may be unsubstituted or substituted with one or more R 9 groups; where R. is H; (CH 2 ),XR 3 (CH 2 ),C(X)NR 3 (CH 2 )ICO 2 R 3 straight chained or branched C.-C.7 alkyl, carboxamidoalkyl; straight chained or branched C 2 C 7 cairinoalkyl, alkenyl, or alkynyl; or 3C cycloalkyl or C 5 cycloalkenyl; where each R 9 is independently H; F; Cl; Br; I; (CH 2 XR 3 (CH 2 C(X)NR 3 (CH 2 )mCO 2 R 3 straight chained or branched alkyl, monofluoroalkyl, polyfluoroalkyl, arinoalkyl, or carboxamidoalkyl; WO 98/57940 PCT/US98/12668 -211- straight chained or branched C 2 alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; wherein Y is S, O, or NR,; or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein the compound comprises the enantiomer.
3. The compound of claim 1, wherein the compound comprises the enantiomer.
4. The compound of claim 1, wherein the compound comprises a cis isomer. The compound of claim 1, wherein the compound comprises a trans isomer.
6. The compound of claim 1, wherein RI is R1R yZ-N R 1 0 R 4 is aryl or heteroaryl, wherein the aryl may be substituted with one or more of F, Cl, -(CH 2 )tOR 3 (CH2),C(O)NR 3 -(CH 2 )nCO 2 R 3 straight chained or WO 98/57940 WO 9857940PCT/1US98/1 2668 -212- branched al~kyl or inonofluoroalkyl; and Z is F 2 t n K R 1 O
7. The compound of claim 6, wherein R 4 is pyridyl or M .98/12668 6iaaS 07 JUL 1999 -213- phenyl, wherein the phenyl may be substituted with one or more of F, Cl, -(CH,)OR 3 -(CH,)nC(O)NR 3 (CH),nCOR 3 or straight chained or branched alkyl or monofluoroalkyl.
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,)nXR 3 -COR 3 (CH2)nC(X)N(R 3 2 (CH,),COR 3 -CN, -NO 2 -N(R 3 2 -SOR 3 or straight chained or branched Ci-C alkyl, monofluoroalkyl or polyfluoroalkyl.
9. The compound of claim 8, wherein R, is H; -CN; -COR 3 -C(O)N(R 3 -(CH,),XR 3 unsubstituted or substituted aryl; or CI-C, alkyl. The compound of claim 9, wherein the R4 is phenyl, wherein the phenyl may be substituted with at least one of F or Cl.
11. The compound of claim 10 having the structure: 0 0 /R R 0 N N N //or R 2 R 5 R2 R WO 98/57940 PCT/US98/12668 -214-
12. The compound of claim 11, wherein Z is:
13. The compound of claim 12, wherein q is 1 and R, is R R 1 0 Z-N ]mR7 R 1 R
14. The compound of claim 13, is Ci-C 3 alkyl. The compound of claim 13, substituted with at least
16. The compound of claim 15, substituted with at least
17. The compound of claim 12, wherein at least one R 2 wherein R 4 is phenyl one of F or Cl. wherein R 4 is phenyl two F. wherein R 4 is 3,4- WO 98/57940 PCTIUS98/12668 -215- difluorophenyl.
18. The compound of claim 13, wherein R 6 is pyridyl, phenyl, or phenyl substituted with one or more of F, Cl, Br, I, -(CH 2 )nXR 3 -COR,, -(CH 2 )nC(X)N(R) 2 (CH 2 )nCO 2 R 3 -CN, -NO 2 2 -S0 2 R 3 straight chained or branched C.-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl.
19. The compound of claim 13, wherein R, is H; -CN; or -C0 2 R 3 The compound of claim 13, wherein R 9 is F; -OH; C i C 3 alkyl; or -(CH 2 )mXR 3
21. The compound of claim 18, wherein R 6 is 4- fluorophenyl.
22. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.
23. The pharmaceutical composition of claim 22 wherein the amount of the compound is an amount from about 0.01 mg to about 800 mg.
24. The pharmaceutical composition of claim 23 wherein the amount of the compound is an amount from about 0.01 mg to about 500 mg. The pharmaceutical composition of claim 24 wherein the amount of the compound is an amount from about 0.01 mg to about 250 mg.
26. The pharmaceutical composition of claim 25 wherein WO 98/57940 PCTIUS98/12668 -216- the amount of the compound is from about 0.1 mg to about 60 mg.
27. The pharmaceutical composition of claim 26 wherein the amount of the compound is from about 1 mg to about 20 mg.
28. The pharmaceutical composition of claim 22, wherein the carrier is a liquid and the composition is a solution.
29. The pharmaceutical composition of claim 22, wherein the carrier is a solid and the composition is a tablet. The pharmaceutical composition of claim 22, wherein the carrier is a gel and the composition is a suppository.
31. The pharmaceutical composition of claim 22, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.
32. A method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject an amount of the compound of claim 1 effective to treat benign prostatic hyperplasia.
33. A method of claim 32, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia. WO 98/57940 PCTIUS98/1 2668 -217-
34. The method of claim 33, wherein the compound effects treatment of benign prostatic hyperplasia by relaxing lower urinary tract tissue.
35. The method of claim 34, wherein lower urinary tract tissue is prostatic smooth muscle.
36. A method of treating a subject suffering from high intraocular pressure which comprises administering to the subject an amount of the compound of claim 1 effective to lower intraocular pressure.
37. A method of treating a subject suffering from a disorder associated with high cholesterol which comprises administering to the subject an amount of the compound of claim 1 effective to inhibit cholesterol synthesis.
38. A method of treating a disease which is susceptible to treatment by antagonism of the aIA receptor which comprises administering to the subject an amount of the compound of claim 1 effective to treat the disease.
39. A method of treating a subject suffering from impotency which comprises administering to the subject an amount of the compound of claim 1 effective to treat impotency.
40. A method of treating a subject suffering from sympathetically mediated pain which comprises administering to the subject an amount of the compound of claim 1 effective to treat sympathetically mediated pain. -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.
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 in combination with a 5 alpha- reductase inhibitor effective to treat benign prostatic hyperplasia.
43. The method of claim 42, wherein the reductase inhibitor is finasteride.
44. A method of treating a subject suffering from S. benign prostatic hyperplasia which comprises administering to the subject an amount of the o compound of claim 1 in combination with a 5 alpha- reductase inhibitor effective to treat benign prostatic hyperplasia. *1. a* I\US 7 ooo ••goy -219- The method of claim 44, wherein the reductase inhibitor is finasteride.
46. A pharmaceutical composition comprising a pherapeutically effective amount of the compound of claim 1 in combination with a therapeutically effective amount of finasteride and a pharmaceutically acceptable carrier.
47. The pharmaceutical composition of claim 46 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. S S' S S S *55S
48. The pharmaceutical composition of claim 47 the compound is present in an amount froi.. mg to about 60 mg and the therapeutically amount of finasteride is about 5 mg.
49. The pharmaceutical composition of claim 48 the compound is present in an amount from mg to about 20 mg and the therapeutically amount of finasteride is about 5 mg. wherein about 0.1 effective wherein about 1 effective 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.
51. The method of claim 50, wherein the lower urinary tract tissue is prostatic smooth muscle.
52. A method of relaxing lower urinary tract tissue in a subject which comprises administering to the subject an amount of the compound of claim 1 -220- effective to relax lower urinary tract tissue.
53. The method of claim 52, wherein the lower urinary tract tissue is prostatic smooth muscle.
54. A trans isomer of the compound of claim 21, wherein the compound has the structure: OO O3~ 0 0* S S C
55. The compound of claim 1, wherein the compound has the structure: 0 O F F -221-
56. The compound of claim 1, wherein the compound. has the structure:. 0. *00*t* 0 0 0 0 *0 0 *000** a 0 9. 9* 0 6 0 *0 0@ *00* 0 0 *009 *00000 0 *000 0 0 0000. 5'7. The compound of claim 1, wherein the compound has the'structure:
58. The compound of claim 1, wherein the compound has the structure: -222-
59. A compound having the structure: S. S. S S 555 04 5' .0 0 S See... S 0 S 00 0 2 CH 3 0 *04 S 60. A compound having the structure: WO 98/57940 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; wherein each X is independently 0 or S; wherein X1 is O, S, NR 3 wherein each R 2 is independently H; -(CH 2 ,)XR 3 (CH 2 ),C(X)NR 3 -(CH 2 t CO 2 R 3 -C0 2 R 3 straight chained or branched Cl-C alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C 2 C, alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or cycloalkenyl; wherein each t is an integer from 1 to 4 inclusive; wherein each R 3 is independently H; straight chained or branched alkyl, straight chained or branched C 2 -C 7 alkenyl, or alkynyl; or C3-C, cycloalkyl or C 5 -C 7 cycloalkenyl; wherein R 4 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 the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -CN, -NO2, -N(R 3 2 -COR 3 (CH, 2 -(CH 2 ),,C(X)NR 3 (CH 2 CO 2 R 3 straight chained or branched C 1 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C 2 -C 7 aminoalkyl, alkenyl or alkynyl, or C 3 cycloalkyl or C 5 cycloalkenyl; wherein each n independently is an integer from 0 WO 98/57940 PCT/US98/12668 -224- to 7 inclusive; wherein R 5 is H; aryl, C 1 -C 7 alkyl. substituted with aryl, heteroaryl, or C 1 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 (RO) 2 -COR 3 (CH 2 tXR 3 (CH 2 NR 3 (CH 2 ),Co 2 R 3 straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C 2 -C 7 aininoalkyl, alkeny. or alkynyl, or 3C cycloalkyl or C,-C 7 cycloalkenyl; wherein R 1 is R 1 0 rn R6 ~Z-tN]I R1 m R7 WO 98/57940 PCTIUS98/12668 -225- R104 LqR"R io 0 RtoRo 100 M R 6 or q4JR7 0 R 10 m1-- R1 1 N N N-R 1 where each R 6 is independently H; straight chained or branched C 1 -C 7 ailkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, mono fluorocyc loalkyl, 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 ),,XR 3 -COR 3 1 -(CH 2 ),C(X)N(R 3 2 1 -(CH 2 ),Co 2 R 3 I -CN, WO 98/57940 PCTIUS98/12668 -226- -NO 2 1 -N(R 3 2 -S0 2 R 3 straight chained or branched C 1 -C 7 alkyl, monof luoroalkyl or polyf luoroalkyl, straight chained or branched C 2 alkenyl or alkynyl, or C 3 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C 5 cycloalkenyl; where each R 7 is independently H; F; Cl; Br; I;- COP. 3 -C0 2 R 3 (CH 2 ),,XR 3 (CH 2 )nC(X)NCR 3 2 (CH 2 )nCO 2 R 3 -CN; -NO 2 -N(R 3 2 straight chained or branched C 1 -C 7 alkyl, hydroxyalkyl, arninoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C7~ alkeny. or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl, wherein the alkyl, aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, cycloalky. 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, 1, (CH 2 ,XR3, -COR 3 (CH 2 N(RO) 21 -(CH 2 ,COR 3 CN, -NO 2 -N(R 3 2 -S0 2 R 3 straight chained or branched alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl or alkynyl, or C 3 -C.7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalky. or Cs-C, 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 3 2 1 -(CH 2 ),,CO 2 R 3 -CN, -NO 2 -N(R 3 2 S0 2 R 3 straight chained or branched C 1 alkyl, straight chained or branched C.-C 7 monofluoroalkyl or polyfluoroalkyl, straight chained or branched C 2 alkenyl or alkynyl, or C 3 -C 7 cycloalkyl, mono fluorocyc 1oalkyl, polyfluorocycloalkyl or C 5 -C 7 cycloalkenyl; WO 98/57940 PCT/US98/12668 -227- wherein each Rio is independently H; (CH 2 ),XR 3 (CH 2 NR 3 (CH 2 ICO 2 R 3 straight chained or branched C.-C. 7 alkyl or carboxaiidoalkyl; straight chained or branched C 2 -C 7 aminoalkyl, alkenyl, or alkynyl; or C 3 cycloalkyl or C 5 -C7 cycloalkenyl; wherein Rl 1 is aryl, heteroaryl, alkyl substituted with one or two aryl, or C.-C 7 alkyl. substituted with one or two heteroaryl; wherein any aryl. or heteroaryl independently may be substituted with one or more of F, Cl, Br, I, -CN, -NO 2 N (R 3 2' -COR 3 (CH 2 ,XR 3 (CH 2 (X)NR 3 (CH 2 ),,CO 2 R 3 straight chained or branched C,-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, or carboxamidoalkyl, straight chained or branched C 2 C. aininoalkyl, alkenyl, or alkyriyl, or 37 cycloalkyJ. or C,-C 7 cycloalkenyl; wherein each mn independently is an integer from 0 to 3 inclusive; wherein Z is WO 98/57940 PCTIUS98/1 2668 -226- F '-2 110i R 9 t n Rio0 2 r q t n R2 Rg Rjo WO 98/57940 WO 9857940PCT[US98/12668 -229- R 10 N> 0 '2 t In R2 R9 n R 9 t Rjo R 1 0 WO 98/57940 PCT/US98/12668 -230- or C 2 alkenyl, wherein the C 2 alkenyl may be unsubstituted or substituted with one or more R 9 groups; where R. is H; (CH 2 ),XR 3 (CH 2 )tC(X)NR 3 (CH 2 )tCO 2 R 3 straight chained or branched Cl-C?, aikyl, carboxamidoalkyl; straight chained or branched C 2 C aminoalkyl, alkenyl, or alkynyl; or C 3 cycloalkyl or cycloalkenyl; where each R, 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 alkyl, mono fluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 alkenyl, or alkynyl; or C 3 cycloalkyl or C 5 cycloalkenyl; wherein Y is S, 0, or NR,; or a pharmaceutically acceptable salt thereof.
231- A compound having the structure: I x x N R2~ R 2 x R2R a a a a *a.a.a 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 (CH 2 ),C(X)NR 3 (CH 2 )tCO 2 R 3 -C0 2 R 3 straight chained or branched Cl-C 7 alkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 alkenyl or alkynyl; or C 3 cycloalkyl or C7C cycloalkenyl; 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 -C7 alkenyl or alkynyl; or C 3 -C, WO 98/57940 WO 9857940PCT/US98/1 2668 -2 32- cycloalkyl or C 5 cycloalkenyl; wherein R 4 is aryl, heteroaryl, alkyl substituted with one or two aryl, or C 1 alkyl substituted with one or two heteroary.; wherein the aryl or heteroary. may be substituted with one or more of F, Cl,.Br, I, -CN, -NO 2 -N(R 3 2 -C0R 3 (CH 2 )tXR 3 -(CH 2 ),,C(X)NR 3 -(CH 2 ),ICO 2 R 3 straight chained or branched C 1 alkyl, mono fluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C 2 aiinoalkyl, alkenyl or alkynyl, or C 3 cycloalkyl or cycloalkenyl; wherein each n independently is an integer from 0 to 7 inclusive; wherein R. is H; aryl, C 1 -C.7 alkyl. substituted with aryl, heteroaryl, or Cl-C., 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 ).C(X)NR 3 (CH 2 nCo 2 R 3 straight chained or branched C,-C. alkyl, inonofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched aiinoalkyl, alkenyl. or alkynyl, or C 3 cycloalkyl. or C 5 cycloalkenyl; where R. and one R 2 on adjacent carbon atoms together may form aryl, heteroaryl, indane or tetrahydronaphthyl., C 3 cycloalkyl, or heterocycloalkyl wherein one or two heteroatoms may be 0, N or S; WO 98/57940 WO 9857940PCT/US98/1 2668 -233- wherein R 1 is /rt-q m R WO 98/57940 WO 9857940PCT[US98/1 2668 -234- R 1 R1, where each R 6 is independently H; straight chained or branched C.-C.7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 alkenyl or alkynyl; C 3 cycloalkyl, mono fluorocyc loalkyl, polyfluorocycloalkyl or C 5 -C. 7 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, 1, (CH 2 ),,XR 3 -COR 3 -(CH 2 3 2 ,-(CH 2 ),ICO 2 R 3 I -CN, -NO 2 -N (R 3 2 S0 2 R 3 straight chained or branched C 1 alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C 2 alkenyl or alkynyl, or C 3 cycloalky., mono fluorocycl1oalkyl, polyfluorocycloalkyl or cycloalkenyl; where each is independently H; F; Cl; Br; I; COR 3 -C0 2 R 3 (CH 2 ),,XR 3 (CH 2 )IC N(RO) 2 (CH 2 ),,COR 3 -CN; -NO 2 -N(R 3 2 straight chained or branched C 1 alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straighit chained or branched C 2 -C, alkeny. or alkynyl; C 3 -C 7 cycloalkyl, mono fluorocycl1oalkyl, polyfluorocycloalkyl or C,-C, cycloalkenyl, wherein the alkyl, aminoalkyl, WO 98/57940 WO 9857940PCTJUS98/'12668 -2 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, 1, (CH.),,XR 3 -COR 3 (CH 2 )IC N(RO) 2 1 (CH 2 -CO 2 R 3 CN, -NO 2 -N(R 3 2 -S0 2 R 3 straight chained or branched Cl-C. alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C 2 -C? alkenyl or alkynyl, or C 3 -C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalky. or CSC cycloalkenyl; aryl or heteroaryl, wherein the aryl. or heteroaryl may be substituted with one or more of F, Cl, Br, I, (CH 2 ).XR 3 -CaR 3 (CH 2 (X)N(R 3 2' (CH 2 ),,Co 2 R 3 I -CN, -NO 2 1 -N (R 3 )2 2' S0 2 R 3 straight chained or branched alkyl, straight chained or branched Cl-C. monof luoroalky. or polyfluoroalkyl, straight chained or branched C 2 -C7 alkenyl or alkynyl, or C 3 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or Cs-C, cycloalkenyl;. wherein each Rio is independently H; (CH 2 tXR 3 (CH 2 tC MX)NR 3 (CH 2 ICO 2 R 3 straight chained or branched C 1 alkyl or carboxamidoalkyl; straight chained or branched C 2 aminoalkyl, alkenyl, or alkynyl; or C 3 cycloalkyl or C 5 -C 7 cycloalkenyl; wherein R 11 is aryl, heteroaryl, Cl-C, alkyl substituted with one or two aryl, or Ca-C. alkyl substituted with one or two heteroaryl; wherein any aryl or heteroaryl independently may be substituted wit~h one or more of F, Cfl, Br, I, -CN, -NO 2 N (RO) 2 1 -COR 3 (CH 2 ),,XR 3 NR 3 1 (CH 2 ),,CO 2 R 3 straight chained or branched C.-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or WO 98/57940 WO 9857940PCTIUS98/I 2668 -2 36- carboxamidoalkyl, straight chained or branched C 2 C,7 aminoalkyl, alkenyl, or alkynyl, or 3C cycloalkyl or C 5 -C7 cycloalkenyl; wherein each mn independently is an integer fr om 0 to 3 inclusive; wherein Z is A t t n )2 R9 t R2 ,i 0 R9 -n R9 WO 98/57940 WO 9857940PCT/US98/1 2668 -237- R-in -4 100 Rio LR2 1 i RJO ,or WO 98/57940 WO 9857940PCTIUS98/1 2668 -238- or alkenyl, wherein the C,-C 7 alkenyl may be unsubstituted or substituted with one or more R 9 groups; where R. is H; (CH,)tXR 3 (CH,)tC(X)NR 3 (CH 2 ),COR 3 straight chained or branched C 1 alkyl, carboxainidoalkyl; straight chained or branched C 2 C. aminoalkyl., alkenyl, or alkynyl; or 37 cycloalkyl or C 5 -C 7 cycloalkenyl; where each R 9 is indepenaently H; F; Cl; Br; I; (CH 2 mXR 3 (CH 2 mC NR 3 .CO 2 R 3 straight chained or branched Cl-C 7 alkyl, mono fluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; P:\OPER\Kbm\81498-98 spec.doe-30/07/oI -239- straight chained or branched C 2 -C7 alkenyl, or alkynyl; or C 3 -C7 cycloalkyl or C 5 -C 7 cycloalkenyl; wherein Y is S, O, or NRs; or a pharmaceutically acceptable salt thereof. 62. A compound according to claim 1, substantially as hereinbefore described with reference to the Examples. '63. A pharmaceutical composition according to claim 22, substantially as hereinbefore described with reference to the Examples. 64. A method of treating a subject suffering from benign prostatic hyperplasia according to claim 32, substantially as hereinbefore described with reference to the Examples. 65. A method of treating a subject suffering from high intraocular pressure according to claim 36, substantially as hereinbefore described with reference to the Examples. 66. A method of treating a subject suffering from a disorder associated with high cholesterol according to claim 37, substantially as hereinbefore described with reference to the Examples. z ®r P:\OPER\Kbm\81498-98 spc.doc-30/07i1 -240- 67. A method of treating a disease which is susceptible to treatment by antagonism of the aIA receptor according to claim 38, substantially as hereinbefore described with reference to the Examples. 68. A method of treating a subject suffering from impotency according to claim 39, substantially as hereinbefore described with reference to the Examples. 69. A method of treating a subject suffering from sympathetically mediated pain according to claim 15 40, substantially as hereinbefore described with reference to the Examples. A method of treating a subject suffering from •cardiac arrhythmia according to claim 41, 20 substantially as hereinbefore described with reference to the Examples. 71. A method of relaxing lower urinary tract tissue according to claim 50, substantially as hereinbefore described with reference to the Examples. 72. A compound according to claim 59, substantially as hereinbefore described with reference to the Examples. P:OPERIKbm\81498-98 spcc.doc-30/07I 241 73. A compound according to claim 60, substantially as hereinbefore described with reference to the Examples. 74. A compound according to claim 61, substantially as hereinbefore described with reference to the Examples. DATED THIS 30 th day of July, 2001 Synaptic Pharmaceutical Corporation by DAVIES COLLISON CAVE Patent Attorneys for the Applicants
AU81498/98A 1997-06-18 1998-06-17 Heterocyclic substituted piperidines and uses thereof Ceased AU740064B2 (en)

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 AU8149898A (en) 1999-01-04
AU740064B2 true AU740064B2 (en) 2001-10-25

Family

ID=25370847

Family Applications (1)

Application Number Title Priority Date Filing Date
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)

Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6228870B1 (en) 1998-11-10 2001-05-08 Merck & Co., Inc. Oxazolidinones useful as alpha 1a adrenoceptor antagonists
US6319932B1 (en) 1998-11-10 2001-11-20 Merck & Co., Inc. Oxazolidinones useful as alpha 1A adrenoceptor antagonists
US6046331A (en) * 1998-12-17 2000-04-04 Synaptic Pharmaceutical Corporation Imidazolones and their use in treating benign prostatic hyperplasia and other disorders
GB2344821A (en) 1998-12-17 2000-06-21 Merck & Co Inc Crystalline pharmaceutically acceptable salt of an oxazolidinone derivative
US6372911B1 (en) * 1999-02-09 2002-04-16 Merck & Co., Inc. Process for preparing β-hydroxycarbamates and their conversion to oxazolidinones
US6645968B2 (en) 1999-08-03 2003-11-11 Abbott Laboratories Potassium channel openers
GB2355457A (en) 1999-09-30 2001-04-25 Merck & Co Inc Novel spirotricyclic substituted azacycloalkane derivatives useful as alpha 1a adrenoceptor antagonists
GB2355264A (en) 1999-09-30 2001-04-18 Merck & Co Inc Spirohydantoin derivatives useful as alpha 1a adrenoceptor antagonists
GB2355456A (en) 1999-09-30 2001-04-25 Merck & Co Inc Novel arylhydantoin derivatives useful as alpha 1a adrenoceptor antagonists
GB2355263A (en) 1999-09-30 2001-04-18 Merck & Co Inc Lactam and cyclic urea derivatives useful as alpha 1a adrenoceptor antagonists
WO2008106128A2 (en) 2007-02-26 2008-09-04 Vitae Pharmaceuticals, Inc. CYCLIC UREA AND CARBAMATE INHIBITORS OF 11β -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
US8440658B2 (en) 2007-12-11 2013-05-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
EP2324018B1 (en) 2008-07-25 2013-09-04 Boehringer Ingelheim International GmbH Cyclic inhibitors of 11 beta-hydroxysteroid dehydrogenase 1
JP5777030B2 (en) 2008-07-25 2015-09-09 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Inhibitor of 11β-hydroxysteroid dehydrogenase 1
US8637505B2 (en) 2009-02-04 2014-01-28 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
UA109255C2 (en) 2009-04-30 2015-08-10 Берінгер Інгельхайм Інтернешнл Гмбх 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
JP5749263B2 (en) 2009-07-01 2015-07-15 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 Cyclic inhibitor of 11β-hydroxysteroid dehydrogenase 1
US8933072B2 (en) 2010-06-16 2015-01-13 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
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
EP2635268A1 (en) 2010-11-02 2013-09-11 Boehringer Ingelheim International GmbH Pharmaceutical combinations for the treatment of metabolic disorders
WO2014059265A1 (en) 2012-10-11 2014-04-17 Southern Research Institute Urea and amide derivatives of aminoalkylpiperazines and use thereof
CA3120514A1 (en) * 2018-11-20 2020-05-28 Sironax Ltd Cyclic ureas
CN116003380A (en) * 2023-01-31 2023-04-25 天津大学 Fingerprint identification probe, developer and medium surface latent fingerprint fluorescence imaging method

Family Cites Families (11)

* Cited by examiner, † Cited by third party
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.
US5698573A (en) * 1993-09-15 1997-12-16 Merck, Sharp & Dohme, Ltd. Imidazolone and oxazolone derivatives as dopamine antagonists
EP0790826A4 (en) * 1994-11-16 1998-11-11 Synaptic Pharma Corp Dihydropyrimidines and uses thereof
WO1997017969A1 (en) * 1995-11-16 1997-05-22 Synaptic Pharmaceutical Corporation Dihydropyrimidines and uses thereof

Also Published As

Publication number Publication date
AU8149898A (en) 1999-01-04
JP2002505683A (en) 2002-02-19
CA2294549A1 (en) 1998-12-23
EP0988295A4 (en) 2003-08-13
EP0988295A1 (en) 2000-03-29
WO1998057940A1 (en) 1998-12-23

Similar Documents

Publication Publication Date Title
AU740064B2 (en) Heterocyclic substituted piperidines and uses thereof
US6620815B1 (en) Oxazolidinones and uses thereof
US6248747B1 (en) 5-(heterocyclic alkyl)-6-aryl-dihydropyrimidines
Moltzen et al. Bioisosteres of arecoline: 1, 2, 3, 6-tetrahydro-5-pyridyl-substituted and 3-piperidyl-substituted derivatives of tetrazoles and 1, 2, 3-triazoles. Synthesis and muscarinic activity
US6245773B1 (en) 5-(heterocyclic alkyl)-6-aryl-dihydropyrimidines
US6498170B2 (en) Cyclamine sulfonamides as β-3 adrenergic receptor agonists
US6521611B2 (en) Non-peptidyl vasopressin V1a antagonists
JP2004536104A (en) Substituted aniline-piperidine derivatives as MCH selective antagonists
NO178572B (en) New N-alkylene piperidino compounds and their enantiomeric and pharmaceutical compositions containing them
AU2006270039A1 (en) Beta-lactamyl phenylalanine, cysteine, and serine vasopressin antagonists
US7119083B2 (en) β-Lactamyl vasopressin V1a Antagonists
JP2013534229A (en) Substituted cyclic carboxamide derivatives and urea derivatives as vanilloid receptor ligands
US20050148583A1 (en) Phenoxyalkylamine derivatives useful as opioid delta receptor ligands
US6531471B2 (en) Morpholinone and morpholine derivatives and uses thereof
JP2918508B2 (en) Azetidines
WO2005035492A1 (en) 3-SUBSTITUTED β-LACTAMYL VASOPRESSIN V1A ANTAGONISTS
CN1780617A (en) Imidazolin-2-ylaminophenyl amides as IP antagonists.
AU769186C (en) Imidazolones and their use in treating benign prostatic hyperplasia and other disorders
KR20160043047A (en) Substituted imidazoles as n-type calcium channel blockers

Legal Events

Date Code Title Description
FGA Letters patent sealed or granted (standard patent)
PC Assignment registered

Owner name: H. LUNDBECK A/S

Free format text: FORMER OWNER WAS: SYNAPTIC PHARMACEUTICAL CORPORATION