DIHYDROPYRIMIDINES AND USES THEREOF

Abstract: This invention is directed to dihydropyrimidine compounds which are selective antagonists for human alpha 1A receptors. This invention is also related to uses of these compounds for lowering intraocular pressure, inhibiting cholesterol synthesis, relaxing lower urinary tract tissue, the treatment of begnin prostatic hyperplasia, impotency, cardiac arrythmia and for the treatment of any disease where the antagonism of the alpha 1A receptor may be useful. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.

Description: DihvdropyrirnidineB and Usβa Thereof This application is a continuation-m-part of PCT International Application No. PCT/US95/15025, filed November 16, 1995, the contents of which are incorporated by reference. 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 "a^" is the appellation recently approved by the IUPHAR Nomenclature Comπiittee for the previously designated "a.- * ' cloned subtype as outlined in the 1995 Receptor and Ion Channel Nomenclature Supplement (Watson and Girdlestone, 1995) . The designation a^ 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 α lA was renamed αr- 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 ::ssus resulting n obstruction cf the uretr.ra. This results in increased frequency of urination, nocturia, a poor urine stream and hesitancy or delay in starting the urine flow. Chronic consequences of ΞFH can include hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection. The specific biochemical, histological and pharmacological properties of the prostate adenoma leading to the bladder outlet obstruction are not yet known. However, the development of 3PH is considered to be an inescapable phenomenon for the aging male population. 3?K is observed in approximately 70V of males over the age of 70. Currently, in the United States, the method of choice for treating BPH is surgery ( epor, H. , Urol . Clinics North Amer.. 17, 651 (1990)) . Over 400,000 prostatectomies are performed annually (data from 1986) . A medicinal alternative to surgery is clearly very desirable. The limitations of surgery for treating BPH include the morbidity rate of an operative procedure in elderly men, persistence or recurrence of obstructive and irritative symptoms, as well as the significant cost of surgery. α-Adrenergic receptors (McGrath, et . al. Med. Res. Rev. , 9, 407-533, 19Θ9) are specific neuroreceptor proteins located in the peripheral and central nervous systems on tissues and organs throughout the body. These receptors are important switches for controlling many physiological functions and, thus, represent important targets for drug development. In fact, many -adrenergic drugs have been developed over the past 40 years. Examples include clonidine, phenoxybenzamine and prazosin (treatment of hypertension) , naphazoline (nasal decongestant) , and apraclonidine (treating glaucoma) . cκ-Adrenergic drugs can be broken down into two distinct classes: agonists (clonidine and naphazolme are agonists/ , which mimic the receptor activation properties of the endogenous neurotransmitter norepinephπne, and antagonists 1 phenoxybenzamine and prazosm are antagonists) , which act to block the effects of norepmephrine . Many cf these drugs are effective but also produce unwanted side effects (for example, clonidine produces dry mouth and sedation in addition to its antihypertensive effects) . During the past 15 years a more precise understanding of α-adrenergic receptors and their drugs has evolved through increased scientific scrutiny. Prior to 1977, only one α-adrenergic receptor was known to exist. Between 1977 and 1988, it was accepted by the scientific community that at least two α-adrenergic receptors--α__ and or---existed in the central and peripheral nervous systems. Since 1988, new techniques in molecular biology have led to the identification of at least six α-adrenergic receptors which exist throughout the central and peripheral nervous systems : α 1A (new nomenclature) , cκ. B , 1D (new nomenclature) , αr^, α 2B and a 2C (Bylund, D.B., FASEB J., 6, 832 (1992)) . In many cases, it is not known precisely which physiological responses in the body are controlled by each of these receptors. In addition, current α-adrenergic drugs are not selective for any particular or-adrenergic receptor. Many of these drugs produce untoward side effects which may be attributed to their poor α-adrenergic receptor selectivity. Since the mid 1970' s, nonselective α-antagonists have been prescribed to treat BPH. In 1976, M. Caine, et al. (Brit. J. Urol . , 48, 255 (1976)) , reported that the nonselective α-antagonist phenoxybenzamine was useful in relieving the symptoms of BPH. This drug may produce its effects by interacting with α-receptors lccated on the prostate. However, this drug also produces significant side effects such as dizziness and asthenia which severely limit its use m treating patients on a chronic basis. More recently, the or-adrenergic antagonists prazcsm and terazosm have also been found to be useful for treating BPK. However, these drugs also produce untoward side effects. It has recently been discovered that the α lA receptor is responsible for mediating the contraction of human prostate smooth muscle (Gluchowski, C. e . al., WO 94/10989, 1994; Forray, C. et. al . , Mol . Pharmacol . 45, 703, 1994) . This discovery indicates that the α. A antagonists may be effective agents for the treatment of BPH with decreased side effects. Further studies have indicated that the α 1A receptor may also be present in other lower urinary tract tissues, such as urethral smooth muscle (Ford et al. Br. J. Pharmacol., 114, 24P, (1995) ) . This invention is directed to dihydropyrimidine compounds which are selective antagonists for cloned human α u receptors. This invention is also related to uses of these compounds for lowering intraocular pressure (Zhan, et. al. Qphthalmol . Vis. Sci.. 34 Abst . #1133, 928, 1993), inhibiting cholesterol synthesis (D'Eletto and Javitt, J. Cardiovascular Pharmacol., 13 (Suppl. 2) S1-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 α. A receptor may be useful. Summary of the Invention This invention is directed to dihydrcpyrimidine compounds which are selective antagonists for human a. Λ receptors. This invention is also related tc 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 α 1A receptor may be useful. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier. Detailed Description of the Invention The present invention is directed to compounds having the structures: M or M where M has the structure wherein each of Y-, Y 2 , Y 3 , Y, and Y 5 independently may be -H; straight chained or branched C--C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkylor cycloalkenyl -F, -Cl, -Br, or -I; -N0 2 ; -N(R 3 ) 2 ; -N 3 ; -C ; -OR 3 ; -OCOR 3 ; -COR 3 ; -CON(R 3 ) 2 ; or -CO;,R 3 ; or wherein two of Y., Y 2 , Y 3 , Y 4 and Y s are present on adjacent carbon atoms and together constitute a methylenedioxy group; - B - wnere R independently may oe -H; -F, ■ straight chained or branched C.-C- aikyl, monofluoroalkyl cr polyfluoroalkyl; straight chained or brancr.ed C t - C alkenyl or alkynyl ,- -N(R 3 ) 2# - -N0 2 ; -CN; - C 2 R, ; "(CH 2 ) p PO(OR 3 ) 2 ; ~ (CH 2 ) p PO(OR 3'3 ; or ~ 0R 3 : where R- may be -H; -N0 2 ; -CN; straight chained cr branched C.-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 - Cm alkenyl or alkynyl,- C 3 -C 7 cycloalkyi, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; - (CH 2 ) p OR 3 ; -COR.,- -C0 2 R 3 ; or -CON!R 3 ) 2 , wherein any p independently is an integer from 1 to 7 inclusive; where R 2 may be -H; straight chained or branched C--C 7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyi , monof luorocycloa lkyl , polyfluorocycloalkyl or cycloalkenyl; C 3 -C, 0 cycloalkyl-Ci-Cjo-alkyl, C 3 -C 10 monofluoroalkyl or C 3 -C 10 cycloalkyl-C--C 10 - polyfluoroalkyl; -CN; -CH 2 XR 3 , -CH 2 X(CH 2 ) p NHR 3 , -(CH 2 ) n NHR 3 , -CH 2 X(CH 2 ) p N(R 3 ) 2 , -CH 2 X (CH 2 ) p N 3 , or -CH 2 X(CH 2 ) p NHCXR 7 ; or -OR 3 ; wherein any n independently is an integer from 0 to 5 inclusive and p is as defined above; where each R 3 independently may be -H; straight chained or branched C_-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyi, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl,- -(CH-) p PO(OR 8 ) 2 ; -(CH 2 ) p PO(ORg. 3 ; or -(CH 2 } COO g; where R « has the structure wherein 2 may be j - ^ alkenyl or alkynyl,- CH 2 ; 0; CO; C0 2 ; CONR 3 CO; C0NR 3 ; S; SO; S0 2 ; or NR 3 ; is an integer from 0 to 3 inclusive; R 5 and R 6 each independently may be -H; -F, -Cl, -Br, -I; -C0 2 R 3 ; -C0R 3 ; -CON(R 3 ) 2 ; -CN; - N0 2 ; -N(R 3 ) 2 ; -0R 3 ; straight chained or branched C--C, alkyl, C.-C, monofluoroalkyl, C : -C 7 polyfluoroalkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, Cj-C 7 cycloalkyi, or C 3 -C 7 cycloalkenyl, wherein the alkyl, monofluoroalkyl, polyfluoroalkyl, alkenyl, alkynyl, cycloalkyi or cycloalkenyl may be unsubstituted or substituted with -H, aryl or heteroaryl; aryl or heteroaryl wherein the aryl or heteroaryl may be unsubstituted or substituted with -H, -F, -Cl, -Br, -I, -N0 2 , -CN, -N(R 3 )j, -OR,, -CORj, -C0 2 R 3 , or -CON(R 3 ) 2 ; straight chained or branched C t -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C 2 -C alkenyl or alkynyl, Cj-C 7 cycloalkyi, monofluorocycloalkyl, polyfluorocycloalkyl, or cycloalkenyl; R 7 may be -H; straight chained or branched C.-C 7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl ; straight chained cr branched C 2 -C 7 alkenyl or alkynyl,- C 3 -C. cycloalkyi, monofluorocycloalkyl , polyfluorocycloalkyl or cycloalkenyl; -CN; -C0 3 R 3 ; -COR 3 ; -C0N(R,) a ; cr -OR 3 ; where R θ is -H; straight chained or branched C,-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl ,- straight chained or branched C_,-C. alkenyl or alkynyl; C 3 -C 7 cycloalkyi, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; where R, may be -H; -CN; straight chained or branched C--C 7 alkyl, monofluoroalkyl or polyfluoroalkyl,* straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyi, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p OR 3 ; -C0R 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ; wherein X may be S; 0; or NR 3 ; and wherein B may be -H; straight chained or branched C--C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, alkoxy or thioalkyl; straight chained or branched C 2 - C η alkenyl; -SCH 2 C 6 H 4 OR 3 ; - (CH 2 ) n C 6 H 5 ; -CH 2 X(CH 2 ) n NHR 3 ; -(CH 2 ) n NHR 3 ; or -OR 3 ; or a pharmaceutically acceptable salt thereof In the present invention aryl includes benzyl, benzoyl, naphthyl, or phenyl and heteroaryl includes pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, quinolyl, aminophenyl, benzimidazolyl or 2-keto-l- benzimidazolinyl . The compounds of the present invention *nay ce present as enantiomers, disteriomers , isomers or two or more of the compounds may be present to form a racemic mixture Furthermore, the compounds of the present invention are preferably at least 80% pure, more preferably 90. pure, and most preferably 95% pure. The invention further provides for the (+) enantiomer of any of the compounds described herein which is a cis isomer or trans isomer. The invention also provides for the (-) enantiomer of any of the compounds described herein which is a cis isomer or trans isomer. In one embodiment of the invention the compound is not (+) -6- (3, 4-Difluorophenyl) -1- (N- [2- (4-cyano-4-phenyl- cyclohexylamino)ethyl] }carboxamιdo-5-methoxycarbonyl-4- methoxymethyl-2-oxo- 1,2,3, 6- tetrahydropyrimidme hydrochloride. Ten-fold selectivity differences are a minimum, but one skilled in the art will appreciate that compounds can be found that collectively have almost infinitely variable selective profiles. Compounds collectively having all possible combinations of selectivities are intended within the scope of this invention, provided that each of these compounds has at least a ten-fold greater affinity for the α^ receptor over the α 1B and/or of 1D receptors. Preferred embodiments of the present invention include a compound selected from the group consisting of: M R M and M In one preferred embodiment for the compounds described herein R 4 is and p is 2, 3 or 4. In one preferred embodiment for the compounds described herein R 4 is - 13 - The invention also provides for compounds having the following structure: H In one preferred embodiment of the present invention, M is polyfluorophenyl and R, and R- are independently substituted or unsubstituted phenyl or pyridyl. In a further embodiment of the present invention, R- is -C0 2 CH 3 , -C0CH,, or -C0NH 2 , R 2 is CH 2 OCH 3 , methyl or ethyl; and R « is H, -CN, or C0 2 CH 3 . The invention provides for the preferred embodiment having the following structures: 20 35 10 20 ^° 25 35 10 35 and The i nvention also provides for compounds having the following structure: In another embodiment of the present invention M is polyfluorophenyl and R_- is substituted or unsubstituted phenyl or pyridyl. The invention also provides a pharmaceutical composition comprising a therapeutically effective amount 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 per subject per day to about 500 mg per subject per day, preferably from about 0.1 mg per subject per day to about 60 mg per subject per day and most preferably from about 1 mg per subject per day to about 20 mg per subject per day. In the practice of this invention the "pharmaceutically acceptable carrier" is any physiological carrier known to those of ordinary skill m the art useful in formulating pharmaceutical compositions. In one preferred embodiment the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution. In another equally preferred embodiment, the pharmaceutically acceptable carrier is a solid and the composition is m t.e 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. The invention provides a method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject any one of the compounds described herein effective to treat benign prostatic hyperplasia. The invention further provides that the compound additionally does not cause a fall m 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 the lower urinary tract tissue is prostatic smooth muscle. The invention further provides a method of treating a subject suffering from elevated intraocular pressure which comprises administering to the subject one of the compounds described herein effective to lower intraocular pressure. The invention further provides a method of treating a subject suffering from a disorder associated with elevated blood cholesterol which comprises administering to the subject one of the compounds described herein effective to inhibit cholesterol synthesis. The invention also provides a method of treating a disease which is susceptible to treatment by antagonism of the α 1A receptor which comprises administering to the subject one of the compounds described herein effective to treat the disease. The invention further provides a method of treating a subject suffering from impotency which comprises admin stenng to the suo ect one of the ccmpcunds described herein effective to treat impotency. The invention further provides a method of treating a subject suffering from sympathetically mediated pair, 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. This invention also provides a method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject an amount of any of the compounds described above in combination with a 5 alpha-reductase inhibitor effective to treat benign prostatic hyperplasia. Preferably, the 5-alpha reductase inhibitor is finasteride. The dosage administered to the subject is about 0.01 mg per subject per day to 50 mg per subject per day of finasteride in combination with an α u antagonist. A preferred dosage administered to the subject is about 0.2 mg per subject per day to 10 mg per subject per day of finasteride in combination with an α^ 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 α lA antagonist. The most preferred dosage administered to the subject is about 5 mg per subject per day of finasteride in combination with an α u antagonist. The invention also provides for 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 tne pnarmaceutical 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 escnoed herein and an amount cf finasteride of about 5 mg per subject per day. A more preferred embodiment of the pharmaceutical composition is a therapeutically effective amount of a combination comprising an amount from about 0.1 mg per subject per day to about 60 mg per subject per day of any one of the compounds described herein and an amount of the finasteride of about 5 mg per subject per day. The most preferred embodiment of the pharmaceutical composition is a therapeutically effective amount of a combination comprising from about 1 mg per subject per day to about 20 mg per subject per day of any one of the compounds described herein and an amount of the finasteride of about 5 mg per subject per day. The invention further provides a method of relaxing lower urinary tract tissue which comprises contacting the lower urinary tract tissue with an amount of one of the compounds described herein effective to relax lower urinary tract tissue . In one embodiment the lower urinary tract tissue is prostatic smooth muscle. In one preferred embodiment the compound additionally does not cause a fall in blood pressure when it is effective to relax lower urinary tract tissue. The invention provides a method of relaxing lower urinary tract tissue in a subject which comprises administering to the subject an amount of one of the compounds described herein effective to relax lower urinary tract tissue. In one preferred embodiment the compound does not cause a fall in blood pressure and the lower urinary tract tissue is prostatic smooth muscle. The invention further provides for a method of in ibitmg contraction of prostatic tissue, wnich comprises administering to the subject an amount of any of the compounds described herein effective to inhibit contraction of prostatic tissue. In one preferred em.Dodiment 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 α^ receptor may be useful. The invention provides for the use of the compounds described herein for the preparation of a pharmaceutical composition for relaxing lower urinary tract tissue and in particular prostatic smooth muscle. The invention further provides for the use of any of compounds described herein for the preparation of a pharmaceutical composition, where the compound additionally does not cause a fall in blood pressure at dosages effective to lower intraocular pressure, to inhibit cholesterol synthesis, and for the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the α^ 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 α^ 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 m 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 m blood pressure at dosages effective to lower intraocular pressure, to inhibit cholesterol syntnesis, and for the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the c_- A receptor may be useful. The invention provides for a drug which is useful for lowering intraocular pressure, inhibiting cholesterol synthesis, and the ' treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the α lA 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 αr^ receptor may be useful. The invention provides for a drug which is useful for relaxing lower urinary tract tissue and in particular prostatic smooth muscle, the effective ingredient of the drug being any of the compounds described herein. The invention further provides the drug which is useful for relaxing lower urinary tract tissue additionally does not cause a fall in blood pressure at dosages effective to relax lower urinary tract tissue. The invention also provides for the (-) and (+) enantiomers of all compounds of the subject application described herein. Included in this invention are pharmaceutically acceptable salts and complexes of all of the compounds described herein. The salts include but are not limited to the following acids and bases. The following inorganic aciαs, nydrocnloric aciα, hydrofluoric acid, hydronromic acid, hydroiodic acid, sulfuric acid and boric acid The organic acids, acetic acid, trifluoroacetic acid, formic acid, oxalic acid, alonic acid, succimc acid, fumaric acid tartaric acid, maleic acid, citric acid, methanesulfomc acid, trifluoromethanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid. The following inorganic bases,- ammonia, hydroxyethylamine and hydrazme. The following organic bases, methylamine, ethylamme, propylamme, dimethylamine, diethylamme , trimethylamme , triethylamme, ethylenediamine, hydroxyethylamine, morpholme, piperazme and guanidme. This invention further provides for the hydrates and polymorphs of all of the compounds described herein. In one preferred embodiment the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution. In another equally preferred 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 suicacle 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 pnosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvmylpyrrolidine, 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, i traperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compounds may be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, cr other appropriate sterile injectable medium. Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. The compound can be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents, for example, enough saline or glucose to make the solution isotonic, bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like. The compound can 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. This invention further provides for metabolites of the compounds of the present invention. The in vivo activities and mechanisms of action of numerous enzymes responsiole for the generation of metabolites of pharmaceutical compounds are well-known in the art. For example, ethers may be modified to alcohols, esters may be modified by esterases, or amides may be modified by amidases and peptidases. This invention further provides a prodrug of the compounds disclosed herein. Knowledge of metabolic activities allows the design of prodrug compounds which, when administered to a subject, such as a human, are expected to yield metabolites which include the compounds of the present invention. For example, the cyclohexylamino nitrogen may be modified by various substituents, such as methyl, alkanoyl, aroyl, or an alkyl or aryl carbamate may be formed, which are expected to yield the compounds of the present invention when acted upon in vivo by endogenous enzymes. As stated above, such modifications are intended only as illustrative examples, and are not intended to limit the scope of the present invention, as such modifications and techniques therefore are well-known in the art. One skilled the art will readily appreciate tnat appropriate biological assays will be used to determine the tnerapeutic potential of the claimed compounds for treating the aoove 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. Experimental Details For Examples 1-17 Scheme 1 illustrates the general synthetic scheme for the preparation of the compounds of the present invention. Specific references to synthetic steps from Schemes 2-8 are included in the Examples below where appropriate. All NMRs were obtained using a 300 MHz GE QEPLUS NMR machine. Example 1 cis-6- (3, 4 -Di fluorophenyl) -1-{N- [2- (4-cyano-4-phenyl- cyclohexylamino) ethyl] }carboxamido-5-mβthoxycarbonyl- 4 -methyl -2-oxo-l, 2 , 3 , 6-tβtrahydropyrimidine hydrochloridβ . Part-1 a) General procedure for 2- [4-Cyano-4-aryl- cyclohβxylamino] ethylamine (Scheme 2; Part-1). A mixture of 4-cyano-4-aryl-cyclohexanone (48.7 mmol) and ethylenediamine (8.78 g, 146 mmol) and p- toluenesulfonic acid (92 mg) in benzene (200 m ) was refluxed for 4 h in Dean-Stark trap to remove the water that formed. Solvent was evaporated and the residue was redissolved in ethanol (60 mL) and cooled to 0 °C. Sodium borohydride (6.4 5 g) was added in portions and SUBSTITUTE 5HEET(RULE26) the mixture was stirred at room temperature for 3 h. Solvent was evaporated, the residue was dissolved in dichloromethane (300 mL) , washed with brine (3 X 500 mL) , dried (potassium carbonate) , and the solvent evaporated to leave the product as a pale yellow viscous oil (90-95%) . The product was found to contain the cis/ trans isomers in the ratio of about 9:1. Careful chromatography of this mixture with chloroform/methanol/2M ammonia in methanol (100/10/5 to 100/20/10) yielded several some earlier fractions enriched in the trans isomer with respect to the amino and cyano groups. Later fractions eluted contained almost pure cis isomer relative to the amino and cyano groups. Part-2 b) Methyl 2-{ (3,4-difluorophenyl)methylene}-3- oxobutyratβ (Scheme 2; Step C) . A mixture of 3,4- difluorobenzaldehyde (14.2 g, 0.1 mol) , methyl acetoacetate (12.2 g, 0.105 mol) , piperidine (0.430 g, 5 mmol) , and acetic acid (0.30 g, 5 mmol) in benzene (150 mL) was stirred and refluxed with a Dean-Stark trap for 8 hours. Benzene was evaporated, the residue was dissolved in ethyl acetate (200 mL) and washed with brine (50 mL) , saturated potassium bisulfate solution (50 mL) , and saturated sodium bicarbonate solution in sequence. The ethyl acetate solution was dried (magnesium sulfate) , solvent removed under reduced pressure and the residue was purified by column chromatography (Si02, EtOAc/hexane, 10%-15%) . The product, methyl 2-{ (3, -difluorophenyl)methylene} -3- oxobutyrate, was obtained as a yellow oil (0.98 g, 98.3%) and was used in the next step without any further characterization. c ) 6 - ( 3 , -Dif luorophenyl) - 1 , 6 -dihydro- 2 -methoxy- 5 -methoxycarbonyl-4-methylpyri___idine (Scheme 2 ; Step D) . A mixture of methyl 2-{ ( , 4-α fluorophenyl) methylene}-3-oxobutyrate (8.8 g, 36.6 mmol) , 0- methylisourea hydrogen sulfate (9.4 g, 55 mmol) , and NaHC0 3 (12.3 g, 0.146 mol) in DMF (30 mL) was stirred and heated at 70 °C for 16 hours. The mixture was cooled, diluted with EtOAc (300 mL) and washed with water (5 X 300 mL) , brine (300 mL) , and dried (MgSO . Solvent was evaporated and the crude product was purified by flash column chromatography on silica gel using 10% through 20% EtOAc in hexane as the gradient eluent, to leave the product as an oil (3.82 g, 30.2%) . d) 6- (3,4-Difluorophenyl) -1, 6-dihydro-2- ethoxy- 5-methoxycarbonyl-4-___ethyl-l- [ (4-nitrophenyloxy)carbo nyl]pyrimidine (Scheme 2; E) . To a solution of 6- (3, -difluorophenyl) -1,6-dihydro-2- methoxy-5-methoxycarbonyl-4-methylpyrimidine (2.82 g, 9.52 mmol) and 4-dimethylaminopyridine (1.16 g, 9.52 mmol) in CH 2 C1 2 (50 mL) ,at 0-5 °C, 4-nitrophenyl chloroformate (1.82 g, 9.04 mmol) was added and the mixture was allowed to warm to room temperature. After 12 hours solvent was evaporated and the residue was purified by flash column chromatography (Si0 2 , EtOAc/hexane, 10%-15%)to obtain the product as white crystals (3.72, 84.7%); .p. 172-174 °C. e) 6- (3,4-Dlfluorophenyl) -1,2,3,6-tβtrahydro-2-oxo-5- ethoxycarbonyl- -methyl-1- (4-nitrophenoxy) carbonylpyrimidinβ (Scheme 2; Step P) . To a well stirred solution of 6- (3,4-difluorophenyl) - 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1- (4- nitrophenoxy)carbonylpyrimidine (10 g) in TTTF (200 mL) at room temperature was added aqueous 6N hydrochloric acid (10 mL) . The stirring was continued for 3 h. Solvent was evaporated and the residue was dried under vacuum to obtain the product as a white powder (9.7 g, 100%) ; m.p. 185-186 °C. Part-3 f ) cis-6- (3 , 4 -Di fluorophenyl) -1-{N- [2- (4-cyano-4- p h e n l - cyclohexylamino) ethyl] }carbox____αido-5-methoxycarbonyl- 4-methyl -2-oxo-l, 2, 3 , 6-tetrahydropyrimidine hydrochloride (Scheme 2; Step G) . A solution of 5- methoxycarbonyl-4-methyl-l, 2,3, 6-tetrahydro-2-oxo-6- (3 , 4-dif luorophenyl) -1- [ (4-nιtrophenyloxy) carbonyl] pyrimidine (500 mg, 1.15 mmol) and cιs-2- [4- cyano-4-phenyl-cyclohexylammo] ethylamine (351 mg, 1.5 mmol) in dichloromethane (50 mL) was stirred at room temperature for 12 hours. The solution was washed with ice-cold 0.5N NaOH (2 X 10 mL) and dried over sodium sulf te. Solvent was evaporated at reduced pressure and the residue was purified by flash chromatography on silica gel (dichloromethane :MeOH:2M ammonia in MeOH, 90:8:4) to give 0.55 g (87%) as a white powder. The HC1 salt was prepared by treatment of a solution of the free base in ether with IN HC1 in ether. M.P. 172-174 °C; Anal. Calcd. for C 29 H 31 N s 0 4 F 2 Cl .1.3H 2 0: C, 56.96; H, 5.70; N, 11.45. Found: C, 57.10; H, 5.69; N, 11.12. Example 2 cis-6- (3,4, 5 -Trif luorophenyl) -1-{N- [2- ( -cyano- - p h e ny l - c y c l o h e x y l a m i n o ) e t hy l ] } - carboxamido - 5-acβtyl- -me hoxymβ thyl - 2 - oxo - 1,2,3,6- tβtrahydropyrimidinβ hydrochloride a) 3-{ (3 , , 5-Trif uorophenyl)mβthylβnβ}-2,4- pentanedione (Scheme 2; Step C) . A mixture of 3,4,5- trifluorobenzaldehyde (4.2 g, 26.2 mmol), 2,4- pentanedione (2.62 g, 26.2 mmol), piperidine (0.430 g, 5 mmol) in benzene (150 mL) was stirred and refluxed with a Dean-Stark trap for 8 hours. Benzene was evaporated and the yellow oily residue, 2-{ (3,4,5- trifluorophenyl)methylene}-2,4-pentanedione, was used in the next step without any further purification. b) 6- (3,4, 5-Trifluorophenyl) -1, 6-dihydro-2-methoxy- 5-acetyl-4-methylpyrimidine (Scheme 2; Step D) . A mixture of 2- { ( 3 , 4 , 5-trιfluorophenyl) methylene} -2 , - pentanedione (26.2 mmol) , O-methylisourea nydrogen Ξ sulfate (3.22 g, 39.3 mmol) , and NaHCO, (6.6 g, 78.6 mmol) in EtOH (400 mL) was stirred and heated at 95-100 °C for 6 hours. The mixture was filtered and the solid residue was washed with ethanol (100 mL) . Solvent was evaporated from the combined filtrate and the crude 0 product was purified by flash column chromatography on silica gel using 10% through 25% EtOAc hexane as the gradient eluent, to leave the product as an oil (2.80 g, 36%) . 5 c) 6- (3,4, 5-Trifluorophenyl) -1, 6-dihydro-2-methoxy- 5-acetyl-4-methyl-1- [ (4-nitrophβnyloxy)carbonyl]pyrim idine (Scheme 2; Step E) . To a solution of 6- (3 , 4 , 5-trifluorophenyl) - 1, 6-dihydro-2-methoxy-5-acetyl-4-methylpyrimidine (2.8 0 g, 9.38 mmol) and pyridine (10 mL) in CH 2 C1 2 (200 mL) at 0-5 °C was added 4-nitrophenyl chloroformate (1.886 g, 9.38 mmol) and the mixture was allowed to warm to room temperature. After 12 hours solvent was evaporated and the residue was purified by flash column chromatography 5 (Si0 2 , dichloromethane/EtOAc, 10%-15%)to obtain the product as a white powder (4.0 g, 92%) . d) 6- (3,4,5-Trifluorophenyl) -1,2,3, 6-tetrahydro-2-oxo- 5-acβtyl-4-mβthyl-l- [ (4-nitrophenyloxy)carbonyl]pyrim 0 idine (Scheme 2; Step F) . To a well-stirred solution of 6- (3,4, 5-trifluoro phenyl) -1, 6-dihydro-2-methoxy-5-acetyl-4-methyl-1- [ (4-nitrophenyloxy) carbonyl]pyri idine (4.0 g, 8.63 mmol) in THF (100 mL) at 0-5 °C, 6N aqueous HC1 (4 mL) 5 was added and the mixture was allowed to warm to room temperature. After 2 h, solvent was evaporated and the product dried under vacuum. The title compound was ootained as a pure single component and used un the next step without further purification (3.88 g, 100%) . e) cis -6- (3,4, 5 -Trif luorophenyl) -1-{N- [2- (4-cyano-4- p h e n y l - c y c l o h e x y l a m i n o ) e t h y l ] } - carboxamido- 5-acetyl-4-methoxymethyl-2 - oxo - 1,2,3,6- tetrahydropyrimidine hydrochloride ( Scheme 2 ; Step G) . A mixture of 6- (3 , 4 , 5-trif luorophenyl) - 1 , 2 , 3 , 6- tetra hydro-2-oxo-5 -acetyl- -methyl- 1- [ (4-nitrophenyloxy) carbonyl] pyrimidine (44.9 mg, 0.1 mmol) and cis-2-(4- cyano-4 -phenyl -cyclohexylamino) ethylamine (23.4 mg, 0.23 mmol) in THF (10 mL) was stirred at room temperature for 10 h and the solvent evaporated. The residue was redissolved in dichloromethane (10 mL) , washed with ice-cold 0.5 N NaOH (2 X 5 mL) , dried and solvent evaporated. The residue was purified by preparative thin layer chromatography on silica gel using chloroform-methanol-2M ammonia in methanol (100/2/1) as the eluent to afford the product as a white powder (53 mg, 88%) . The HCl salt was prepared by treatment with IN HCl in ether to give the product as a white powder. Anal. Calcd. for C 30 H 3 -N 5 O 3 ClF 3 0.5CH 2 C1 2 : C, 56.66; H, 5.30; N, 10.83. Found: C, 56.51; H, 5.12; N, 11.09. Example 3 ( + ) -cis -5 -Carboxamido- 6- (2, 4-dif luorophenyl) -1-{N- [ 2 - ( 4 - c y a n o - 4 - p h β n y l - cyclohexylamino) ethyl] }carboxamido-4-ethyl-2 -oxo- 1,2,3,6- tetrahydropyrimidine hydrochloride . a) Benzyl 2- [ (2, 4-dif luorophenyl) methylenβ] -3-oxopentanoatβ (Scheme 2; Step C) . A solution of benzyl propionylacetate (157 g, 0.758 mol) , 2, 4-dif luorobenzaldehyde (107.65 g, 0.758 mol) , and piperidinium acetate (5.49 g, 38 mmol) in benzene (1 L) were stirred at room temperature for 96 h. The mixture was washed with water (2 X 100 L) , dried (magnesium sulfate) and the solvent evaporated under reduced pressure to yield the product as a pale yellow syrup (251.2 g) which was used in the next step without further purification. b) 5- (Benzyloxycarbonyl) -1, 6-dihydro-2-methoxy-4-ethyl- 6- (2,4-difluorophenyl)pyrimidine (Scheme 2; Step D) . A suspension of benzyl 2- [ (2, 4-difluorophenyl) methylene] -3-oxopentanoate (80.0 g, 0.241 mol) , O- methylisourea hemisulfate (63.8 g, 0.362 mol, 1.5 eq.j , NaHC0 3 (60.48 g, 0.72 mol) in ethanol (800 mL) was stirred at 60-70 °C for 20 h. After cooling to room temperature, the mixture was filtered, and the solid was washed with ethanol (200 mL) . The solvent was evaporated from the combined filtrates and the residue was purified by column chromatography (Si0 2 , EtOAc/Hexane, 10%-30%) to yield 5- (benzyloxycarbonyl) - 1, 6-dihydro-2-methoxy-4-ethyl-6- (2, 4-difluorophenyl) pyrimidine as a pale yellow oil (39 g, 42%) . X H-NMR analysis showed the product to be a mixture of amine/imine tautomers, which was used as is in the next step. c) 5- (Benzyloxycarbonyl) -4-βthyl-l, 6-dihydro-2-mβt_hoxy- 6- (2, 4-dif luorophenyl) -1- [(4-nitrophenyloxy) carbonyl] pyrimidine (Scheme 2; Step F) . To a well stirred solution of 5- (benzyloxycarbonyl) -1, 6- dihydro- 2-methoxy-4-ethyl-6- (2 , 4-dif luorophenyl) pyrimidine (22.5 g, 59.3 mmol) and 4- (N,N-dimethylamino)pyridine (9.3 g, 75.8 mmol) in CH 2 C1 2 (200 mL) was added powdered 4-nitrophenyl chloroformate (15.3 g, 75.8 mmol) at 0 °C. The reaction mixture was stirred for 12 h at room temperature and then water (50 mL) was added. The pH of the aqueous layer was adjusted to 10-11 by the addition of 6 N sodium hydroxide. The dichloromethane layer was separated and dried (Na ; S0 4 ) . Solvent was evaporated in vacuo and the residue was purified by column chromatography (Si0 2 , dichloromethane/hexane, 20%-50%) to yield the product as a viscous oil (32. C g, 98%) . d) 5- (Benzyloxycarbonyl) -4-ethyl-l, 6-dihydro-l-{N- [2- phenyl) ethyl] }carboxamido-2-me hoxy-6- (2, 4-difluoro phenyl)pyrimidine (Scheme 3; Steps C-1 & C-2) . To a stirred solution of 5- (benzyloxycarbonyl) -4-ethyl-l, 6- dihydro-2 -methoxy-6 - (2,4-dιfluorophenyl) -1- [ ( 4 - nitrophenyloxy) carbonyl] pyrimidine (32 g, 58.17 mmol) in dichloromethane (200 mL) was added R- (+)-_.- methylbenzylamine (9.16, 75.6 mmol) at room temperature. The mixture was stirred for 12 h and then was diluted with more dichloromethane (200 mL) and washed with 0.5 N NaOH solution (2 x 60 mL) . The organic layer was dried over Na 2 S0 4 , filtered and solvent was evaporated. The resulting mixture of diastereomers was separated by column chromatography (Si0 2 , 3% EtOAc in toluene) . The first major product to elute was (+) -5- (benzyloxycarbonyl) -4-ethyl-l, 6- dihydro-l-{N- [2-phenyl)ethyl] }carboxamido-2-methoxy-6- (2, 4-difluorophenyl)pyrimidine (12.15 g, 38%) . [α] D = +214 (c = 1.5 g in 100 mL CHC1 3 ) . e) (+) -5- (Benzyloxycarbonyl) -1, 6-dihydro-2-methoxy-4- ethyl-6- (2,4-difluorophenyl)pyrimidine (Scheme 3; Step C-3) . To a stirred solution of (-t-) -5 (benzyloxycarbonyl) -4-ethyl-l, 6-dihydro-l-{N- [2-phenyl)ethyl] }carboxamido- 2-methoxy-6- (2, 4-difluorophenyl)pyrimidine (11.15 g, 20.41 mmol) in toluene (250 mL) was added 1,8- diazabicyclo [5, 4, 0] -undec-7-ene (4.04 g, 26.53 mmol) and the mixture was stirred at room temperature for 14 h. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel with 3:1 EtOAc/hexane as eluent to give (-t-)-5- (benzyloxycarbonyl) -1, 6 -dιhydro-2-methoxy-4-ethyl-6 - (2 , -difluorophenyl) pyrimidine as a viscous oil (6.15 g, 78%) . Ξ f) (+) -5- (Benzyloxycarbonyl) -4-ethyl-l, 6-dihydro-2- methoxy-6- (2,4-difluorophenyl) -1- [ (4-nitrophenyl -oxy) carbonyl]pyrimidine (Scheme 2; Step E) . To a well stirred solution of (+) -5- (benzyloxycarbonyl) -1, 6- dihydro-2-methoxy- -ethyl-6- (2 , 4-difluorophenyl) 0 pyrimidine (4.1 g, 10.62 mmol) and 4-(N,N- dimethylamino) pyridine (1.69 g, 13.80 mmol) in CH,C1 ; (200 mL) was added solid 4-nitrophenyl chloroformate (2.78 g, 13.80 mol) at room temperature. The reaction mixture was stirred for 12 h and washed with 0.5 N NaOH 5 solution (2 X 50 mL) . The organic layer was separated and dried (Na 2 S0 4 , . The solvent was evaporated and the residue was purified by column chromatography on silica gel using dichloromethane/hexane (20%-50%) as the eluent to give (+) -5- (benzyloxycarbonyl) -4-ethyl-l, 6- 0 dihydro- 2 -methoxy-6 - (2,4 -difluorophenyl) - 1 - [ (4 - nitrophenyloxy) carbonyl]pyrimidine (5.37 g, 92%) as a viscous oil . g) (+) -5-Benzyloxycarbonyl-4-ethyl-1,2,3,6-tβtrahydro-2- 5 oxo-6- (2,4-difluorophenyl) -1- [ ( -nitrophenyloxy) carbonyl] yrimidine (Scheme 4; Step λ) . To a solution of (+) -6- (2, 4-difluorophenyl) -l, 6- dihydro-2- ethoxy-5-benzyloxycarbonyl- -ethyl-1- (4 - nitrophenoxy) -carbonylpyrimidine (6.50 g, 11.81 mmol) C in dichloromethane (150 mL) at room temperature was added IN HCl in ether (50 mL) and the mixture was stirred at room temperature for 12 hours. Solvent was evaporated at reduced pressure and the residue was dried to give 6.31 g (100%) of the product as a white 5 powder. h) ( + ) - 5 - (Benzyloxycarbonyl) - 6 - (2 , 4 -dif luorophenyl) -4 - SUBSTΪTUTE SHEET (RULE 26) ethyl-2 -oxo- 1,2,3,6 -tetrahydro-1-{N- [2- (4-cyano-4- phenyl-cyclohexylamino) ethyl] }carboxamidopyrimidine (Scheme 4; Step B-l) . A mixture of (+) -5-benzyloxycarbonyl-4-ethyl-1, 2 , 3 , 6- Ξ tetrahydro-2-oxo-6- (2, 4 -dif luorophenyl! -1- [ (4 - nitrophenyloxy) carbonyl] pyrimidine (537 mg, l mmol) and cis-2- (4-cyano-4-phenyl-cyclohexylamino) ethylamine (281 mg, 1.2 mmol) in THF (20 mL) was stirred at room temperature for 10 h and the solvent evaporated. It 0 was redissolved in dichloromethane (10 mL) , washed with ice-cold 0.5 N NaOH (2 X 5 mL) , dried and solvent evaporated. The residue was purified by preparative thin layer chromatography on silica gel using chloroform-methanol-2M ammonia in methanol (100/2/1) as 5 the eluent to afford the product as a white powder (603 mg, 94%) . i) (+) -6- (2,4-Difluorophenyl) -4-ethyl-2-oxo-l,2, 3, 6- tetrahydro - l - {N- [2 - ( 4 - cyano- 4 -phβnyl - 0 cyclohexylamino) ethyl] }carboxamidopyrimidine-5- carboxylic acid (Scheme 4; Step B-2) . To a suspension of 10% Pd-C (100 mg) in MeOH (40 mL) and H 2 0 (8 mL) was added a solution of (+) -5- (benzyloxycarbonyl) -6- (2,4-difluorophenyl) -4-ethyl-2- 5 oxo-1 ,2,3, 6-tetrahydro-1- (N- [2- (4 -cyano-4-phenyl- cyclohexylamino) -ethyl] Jcarboxamidopyrimidine (320 mg, 0.5 mmol) in methanol (10 mL) and the mixture was hydrogenated at 80 psi for 6 h. The black suspension was filtered through a pad of celite and washed 0 thoroughly with MeOH (2.0 L) and methanol/chloroform (1:2, 200 mL) . Solvent was evaporated from the combined filtrate to yield the product (+) -cis-6- (2, 4- difluorophenyl) -4 -ethyl-2-oxo- 1,2,3, 6-tetrahydro- 1 - { N - [ 2 - ( 4 - c y a n o - 4 - p h e n y l - 5 cyclohexylamino) -ethyl] Jcarbox amidopyrimidine-5-carboxylic acid as a white solid (276 g, 98%) . The product was used in the next step without further puri cation. j ) ( + ) - c i s - 5 - C a rb o x am i d o - 6 - ( 2 , 4 - difluorophenyl) -1-{N- [2- (4 -cyano-4-phenyl- cyclohexylamino) ethyl] }carboxamido-4-ethyl-2 -oxo- 1,2,3,6-tetrahydropyrimidine hydrochloride (Scheme 4; Step B-3) . A mixture of (+) -c s-6- (2, 4-difluorophenyl) -4-ethyl-2- oxo-1, 2,3, 6-tetrahydro-1- (N- [2- (4-cyano-4-phenyl- cyclohexylamino) ethyl] } carboxamidopyrimidme- 5 - carboxylic acid (141 mg, 0.25 mmol) , l-(3- dimethylaminopropyl) -3-ethylcarbodιιmιde hydrochloride (71.3 mg, 0.372 mmol) , and 4- (N,N-dimethylammo) pyrid e (45.4 mg, 0.372 mmol) n anhydrous dichloromethane (30 mL) was stirred at room temperature for 2 h. 40% Aqueous ammonia (4090, 0.5 mL) was added to this mixture and the stirring was continued for 12 h. The mixture was diluted with 20 mL of dichloromethane and washed with saturated aqueous ammonium chloride solution (3 X 10 mL) . Solvent was evaporated from the dried (sodium sulfate) dichloromethane solution and the residue was purified by column chromatography on silica gel using chloroform-methanol-2M ammonia in methanol (100/2/1) as the eluent, to obtain the desired product as a white powder (120 mg, 88%) ; [or]-, = +107 (c = 1.38 g, dichloromethane) . The HCl salt was prepared by treatment of a solution of the free base in ether with IN HCl in ether. M.p. 225-228 °C; Anal. Calcd. for C 2» H 33 N β O 3 F 2 Cl.0.38H 2 O.0.19CH 2 Cl 2 :C, 57.47; H, 5.64; N, 13.75. Found: C, 57.80; H, 5.56; N, 13.37. Example 4 ( + ) -cis-6- (3, 4 -Dif luorophenyl) -1-{N- [2- (4-cyano-4- cyclohexyl amino) ethyl] } carboxamido -5 -me thoxycarbonyl- 4 - met hoxy βthyl- 2-oxo-l, 2,3, 6 -tetrahydropyrimidine hydrochloride Part-2 a) Methyl 2- [ (3,4-difluorophenyl)methylene] -3-oxo-4- methoxybutyrate (Scheme 2; C) . To a solution of methyl 4-methoxyacetoacetate (84.32 g, 0.577 mol) , 3 , 4-difluorobenzaldehyde (82 g, 0.577 mmol) , and piperidinium acetate (5.86 g, 0.068 mol) m benzene (1.5 L) were added molecular sieves (400 g) ana the mixture was stirred at room temperature for 48 h. The molecular sieves were removed by filtration and the solvent was evaporated from the filtrate under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform/ethyl acetate (100:3) to get the product as an oil (67 g, 47%) . This product was a mixture of cis and trans isomers . b) 5-Mβthoxycarbonyl-l, 6 -dihydro-2 -methoxy-4- mβthoxymβthyl-6- (3,4-difluorophenyl)pyrimidine (Scheme 2; Step D) . A suspension of methyl 2- [(3,4- difluorophenyl)methylene] -3-oxo-4-methoxybutyrate (7.50 g, 27.75 mmol) , O-methylisourea hemisulfate (7.17 g, 41.63 mmol, 1.5 eq.) , and sodium bicarbonate (6.99 g, 83.25 mmol, 3 eq.) in ethanol (400 mL) was stirred at 50-55 °C for 6 h. The solvent was evaporated from the combined filtrates and the residue was purified by column chromatography (Si0 2 , EtOAc/hexane, 10%-30%) to give 5-methoxycarbonyl-l , 6-dihydro-2-methoxy-4 - methoxymethyl-6- (3,4-difluorophenyl)pyrimidine as a pale yellow oil (4.3 g, 47%) . c) 5-Methoxycarbony1- -methoxy ethy1-1,6-dihydro-2- mβthoxy- 6 - ( 3 , 4 -difluorophβnyl ) - 1 - [ ( 4 - nitrophenyloxy)carbonyl] yrimidine (Scheme 3; Step B) . To a well stirred solution of 5-methoxycarbonyl-l, 6- dihydro-2-methoxy-4-methoxymethyl-6- (3 , 4-difluoro pnenyl) pyrimidine .4.3 g, 13.18 mmol) and 4-(N,N- dιmethylamιno)pyπdιne (2.09 g, 17.13 mmol) m CH 2 Cl-_ '100 mL) was added solid 4 -nitrophenyl chlorof ormate 13.45 g, 17.13 mmol) at 0 °C . The reaction mixture was stirred for 12 h at room temperature and the solid formed was removed by filtration. Solvent was evaporated from the filtrate and the residue was purified by column chromatography (Si0 2 , dichloromethane/hexane, 20% -50%) to yield the product as a viscous oil (3.85 g, 59%) . d) 5-Methoxycarbonyl-4-methoxymethyl-l, 6-dihydro-l-{N- [2 -phenyl) ethyl] } carboxamido- 2 -methoxy-6 - (3,4- dif luorophenyl ) pyrimidine (Scheme 3; Steps C-1 & C-2) . To a stirred solution of 5-methoxycarbonyl-4- methoxymethyl-1 , 6-dihydro-2-methoxy-6- ( 3 , 4 - dif luorophenyl) -1- [ (4-nitrophenyloxy) carbonyl] pyrimidine (3.82 g, 7.77 mmol) in THF (140 mL) was added R- (+) -α-methylbenzylamine (1.13 g, 9.33 mmol, 1.2 eq.) at room temperature and the stirring was continued for 12 h. Solvent was evaporated and the residue was purified by column chromatography (Si0 2 , 10-20% EtOAc in hexane) . The first major product to elute was (+)-5- methoxycarbonyl-4-methoxmethyl-l , 6-dihydro-l- {N- [2- phenyl) ethyl] }carboxamido-2-methoxy-6- (3 , 4- dif luorophenyl) pyrimidine (1.74 g, 44.5%), as an oil. [c_] D = +205.5 (c = 5.1 g in 100 mL CHC1 3 ) . e) (+) -5-Mβthoxycarbonyl-l, 6 -dihydro-2 -mβthoxy-4- methoxymethyl-6- (3, 4- dif luorophenyl) pyrimidine (Scheme 3; Step C-3) . To a stirred solution of (+) -5-methoxycarbonyl-4- methoxymethyl-1, 6-dihydro-l- {N- [2-phenyl) ethyl] } carboxamido- 2 -methoxy-6- (3 , 4-dif luorophenyl) pyrimidine (1.74 g, 3.67 mmol) in toluene (40 mL) was added 1,8- diazabicyclo [5, 4, 0] -undec-7-ene (0.250 g, 1.64 mmol) and the mixture was stirred at 70-80 °C for 1.5 h. -41- Solvent was evaporated and the residue was purifiec oy flash column chromatography on silica gel with 9:1 CHCl 3 /EtOAc as eluent to give ( + ) - 5 - ethoxycarbonyi -1,6- dιhydro-2-methoxy-4 -methoxymethyl -6 - (3,4 -dif iuorc phenyl ) pyrimidine as a viscous oil fl.ll g, 92.5%) f) Chiral HPLC separation of (+) -5 -Methoxycarbonyi - 1 , 6 -dihydro- 2 -methoxy-4 -methoxymethyl - 6 - (3,4- di fluorophenyl) pyrimidine (Scheme 3; Step A) . The racemic 5-methoxycarbonyl-l , 6 -dihydro- 2 -methoxy-4 - methoxymethyl -6- (3 , 4-dif luorophenyl) pyrimidine was resolved by chiral HPLC [Chiralcel 0D 20 X 250 mm #369- 703-30604; λ 254 nm; hexanes/ethanol 95/5 and 0.01% diethylamine; 60 mg per injection; retention time of the desired enantiomer: 10.80 mm., the first enantiomer peak to elute] to give ( + ) -5- methoxycarbonyl - 1 , 6 -dihydro- 2 -methoxy-4 -methoxymethyl - 6 - ( 3 , 4 -dif luorophenyl ) pyrimidine . g) ( + ) -5-Methoxycarbonyl-4-methoxymβthyl-l, 6-dihydro-2- methoxy-6- (3 , 4-dif luorophenyl) -1- [ (4-nitrophenyl oxy) carbonyl] pyrimidine (Scheme 2; Step E) . To a well stirred solution of (+) -5 -methoxycarbonyi - 1 , 6-dih dro-2-methoxy-4-methoxymethyl-6- (3 , 4 - dif luorophenyl) pyrimidine (1.11 g, 3.4 mmol) and 4- (N,N-dimethylamino)pyridine (0.54 g, 4.42 mmol) in CH 2 C1 2 (200 mL) was added powdered 4-nitrophenyl chloroformate (0.891 g, 4.42 mmol) at room temperature. Solvent was evaporated and the residue was purified by column chromatography on silica gel using CHCl 3 /EtOAc (20%-50%) as the eluent to give (+) -5 -methoxycarbonyi - 4 -methoxymethyl -l,6-dihydro-2-methoxy-6- (3,4- diflurophenyl) -1- [ (4-nitrophenyloxy) carbonyl] pyrimidine (1.30 g, 78%) as a viscous oil. [cr] D = +262.2 (c = 2.3 g in 100 mL CHC1 3 ) . h) (+) -5-Mβthoxycarbonyl-4-mβthoxymethyl-l, 2,3,6- tetrahydro-2-oxo-6- (3,4-difluorophenyl) -1- [ (4- nitrophenyloxy) carbonyl]pyrimidine (Scheme 2; Step P) . To a solution of (+) -6- (3, -difluorophenyl) -1, 6- dihydro-2-methoxy-5-methoxycarbonyi-4-methoxymethyl-1- (4-nitrophenoxy) -carbonylpyπmidme (0.305 g, 0.60 mmol) in dichloromethane (15 mL) , IN HCl in ether (6 mL) was added at room temperature and the mixture was stirred at room temperature for 12 hours. Solvent was evaporated at reduced pressure and the residue was dried to give 0.295 g (100%) of the product as a white powder. Part-3 i) (+) -cis-6- (3,4-Difluorophenyl)-l-{N- [2- (4-cyano-4- p h e n y 1 cyclohexylamino)ethyl] }carboxamido-5-me hoxycarbonyi- 4-methoxymethyl-2-oxo-l,2,3, 6- etrahydropyrimidine hydrochloride (Scheme 2; Step G) . A solution of (+)-5- methoxycarbonyl-4-methoxymethyl-l,2,3,6-tetrahydro-2- oxo-6- (3,4-difluorophenyl) -l- [ (4-nitrophenyloxy) carbonyl]pyrimidine (0.850 g, 1.73 mmol) and cis-2-(4- cyano-4-phenyl-cyclohexylamino)ethyla ine (0.567 g, 2.42 mmol) in dichloromethane (50 mL) was stirred at room temperature for 12 hours. It was washed with ice- cold 0.5N NaOH (2 X 10 mL) and dried over sodium sulfate. Solvent was evaporated at reduced pressure and the residue was purified by flash chromatography on silica gel (dichloromethane:MeOH:2M ammonia in MeOH, 90:8:4) to give 0.905 g (90%) as a white powder. The HCl salt was prepared by treatment of a solution of the free base in ether with IN HCl in ether. The white powder was dried and recrystallized from anhydrous isopropanol. M.P. 233-235 °C; [α] D = +131.16 (c = 0.735, MeOH); Anal. Calcd. for C 30 H 34 N S 0 5 F 2 C1: C, 58.30; H, 5.53; N, 11.06. Found: C, 57.91; H, 5.53; N, 11.10. Example 5 ( + ) -trans -6- (3 , 4 -Dif luorophenyl) -1-{N- [2 - (4 -cyano-4 - h e n y l cyclohexylamino ) ethyl] }carboxamido-5-methoxycarbonyl- 4 -methoxymethyl-2 -oxo-1, 2,3, 6-tetrahydropyrimidine hydrochloride (Scheme 2; Step F) . A solution of (+) -5-methoxycarbonyi-4-methoxymethyl - l,2,3,6-tetrahydro-2-oxo-6- (3 , 4-difluorophenyl) -1- [ (4- nitrophenyloxy) carbonyl] pyrimidine (0.850 g, 1.73 mmol) and trans-2- ( 4-cyano-4-phenyl-cyclchexylamino) ethylamine (0.567 g, 2.42 mmol) in dichloromethane (30 mL) was stirred at room temperature for 12 hours. It was washed with ice-cold 0.5N NaOH (2 X 10 mL) and dried over sodium sulfate. Solvent was evaporated at reduced pressure and the residue was purified by flash chromatography on silica gel (dichloromethane : eOH: 2M ammonia in MeOH, 90:8:4) to give 0.905 g (90%) as a white powder. The HCl salt was prepared by treatment of a solution of the free base in ether with IN HCl in ether. Anal. Calcd. for C 30 H 34 N 5 O 5 F 2 Cl :C, 58.30; H, 5.53; N, 11.06. Found: C, 57.99; H, 5.73; N, 11.20. Example 6 (-) -cis-6- (3, 4-Difluorophenyl) -1-{N- [2- (4-cyano-4- p h e l cyclohexylamino ) ethyl] }carboxamido-5-methoxycarbonyi- 4-me hoxymethyl- -oxo-1,2, 3, 6-tetrahydropyrimidine hydrochloride. a) (-) -5-Methoxycarbonyi-4-mβthoxymathyl-1,6-dihydro-2- mβthoxy- 6 - ( 3 , 4 -dif luorophenyl ) - 1 - [ ( 4 - nitrophβnyloxy) carbonyl] pyrimidine (Scheme 2; Step E) . To a well stirred solution of (+) -5 -methoxycarbonyi - 1 , 6 -dihydro- 2 -methoxy-4 -methoxymethyl - 6 - (3,4- di fluorophenyl) pyrimidine (1.167 g, 3.576 mmol) and 4- (N, N - dime thylamino)pyr idine (0.655 g, 5.364 mmol) in CH 2 C1 2 (20 mL) was added powdered 4-nitrophenyl chloroformate (0.937 g, 4.65 mmol) at room temperature. Solvent was evaporated ana the residue was purified by column chromatography on silica gel using hexanes/EtCAc (7/3%) as the eluent to g ve (-)- 5 -methoxycarbonyi -4 - ethoxymethyl -1, 6-dιhydro-2 -methoxy-6- (3 , 4 - dif lurophenyl ) - 1- [ ( 4-nitrophenyloxy) carbonyl] pyrimidine (1.761 g, 100%) as a viscous oil. [ ] D = -335.3 (c = 1.0 g in 100 mL CHCl 3 ) . b) (-)-cis-6-(3, -Difluorophenyl) -1-{N- [2- (4-cyano-4- phenylcyclohexylamino) ethyl] }carboxa__-ido-5-methθ-cycar b o n y l - 4 - m e t h o x y m e t h y l - 2 - o x o - 1,2,3, 6-tetrahydropyrimidine hydrochloride (Scheme 2; G & Step P) . A solution of ( - ) -5-methoxycarbonyi-4 - methoxymethyl-l, 6-dihydro-2-methoxy-6- (3 , 4 - diflurophenyl) -1- [ (4-nitrophenyloxy) carbonyl] pyrimidine (0.103 g, 0.21 mmol) and cιs-2- (4- cyano-4-phenyl-cyclohexylamino)ethylamine (0.059 g, 0.251 mmol) in dichloromethane (50 mL) was stirred at room temperature for 12 hours. It was washed with lce- cold 0.5N NaOH (2 X 10 mL) and dried ever sodium sulfate. Solvent was evaporated at reduced pressure and the residue was purified by flash chromatography on silica gel (dichloromethane:MeOH:2M ammonia in MeOH, 90:8:4) to give 0.121 g (100%) as an oil. It was dissolved in THF (2 mL) , treated with 0.2 mL of 6N HCl and stirred at room temperature for 4 h. Solvent was evaporated and the residue was dried in vacuo to give the product as a white powder (130 mg, 100%) . M.P. 220- 222 °C; [cr] D = -124.29 (c = 0.535, MeOH); Anal. Calcd. for C 30 H 34 N S 0 5 F 2 C1 : C, 58.30; H, 5.53; N, 11.06. Found: C, 57.20; H, 5.57; N, 11.30. Example 7 ( + ) -trans- 6- ( 3 , 4 -Dif luorophenyl) -l-{N- [2- (4-(2- pyridyl) -cyclohexylamino) ethyl] } carboxamido- 5- methoxycarbonyl - 4 -me thoxymethyl - 2 - oxo - 1,2,3,6- tetrahydropyrimidine hydrochloride a) General procedure for 2 - {4 -arylcyclohexy lamino] ethylamine (Scheme 2; Step A) . A mixture of -arylcyclohexaπcne I 16- mmol) (i.e. 4- 2 -pyridyl) -cyclohexanone) and ethy lenediamiπe (3.73 g, 146 mmol) and p-tcluer.esu fcπic acid (92 rr.g) in benzene (200 L/ was refluxed for 4 h in Dean-Stark trap to remove the water that formed. Solvent was evaporated and the residue was redissolved in methanol (60 mL) and cooled to 0 • C . Tc th s, sodium borchydride (6.4 5 g) was added in portions and the mixture was stirred at room temperature for 3 h. Solvent was evaporated, the residue was dissolved in dichloromethane ( 300 mL) , washed with brine (3 X 500 mL) , dried (potassium carbonate. , and the solvent evaporated to leave the product as a pale yellow viscous oil (90-95%) . The product was pure and found to ccntain the c s/trans isomers. A careful chromatography of this mixture with chloroform/mechanol/2M ammonia in methanol (100/10/5 to 100/20/10 ) gave some earlier fractions enriched in the cis isomer. The fractions eluted at the end were almost pure trans isomer. b) (♦) -trans -6- (3, -Dif luorophenyl) -1-{ - [2- (4- (2- p y r i d y l ) cyclohexylamino) ethyl] } carboxamido -5 -methoxycarbonyi - 4 -methoxymethyl - -oxo-1, 2,3,6- .etrahydrσ pyrimidine hydrochloride (Scheme 2; Step G) . A solution of {+) -5 -methoxycarbonyi -4 -methoxymethyl - 1,2,3, 6 -tetrahydro- 2 -oxo- 6- (3 , 4-dif luorophenyl) -1- [ (4- nitrcphenyloxy) carbonyl] pyrimidine (49.1 mg, 0.1 mmol) and crans-2- (4- (2-pyridyicyclohsxγlamino) ethyla ine (30 mg, 0.136 mmol) in ΗF (10 mL) was stirred at room temperature for 12 hours. It was washed with ice-ccld C .5N NaOH (2 X 5 mL) and dried over sodium sulfate. Solvent was evaporated at reduced pressure and the residue was purified by preparative tic on silica gel . ethyl acetate :MeOH, 10:1) to g ve 43 mg (78%) as a white powder. The HCl salt was prepared by treatment of a solution of the free base in ether with IN HCl in ether. 180-184 a C; [or] -, = +186 (c = 0.65, methanol. ; Ξ .Anal. Calcd. for C 2 .H 3; N«0.F 2 C1, .0.4CH_,C1_ :C, 51.33; H, 5.43; N, 9.54. Found: C, 51.31; H, 5.43; N.9.69. Examples 8 and 9 cis-6- ( 3, 4-Dif luorophenyl) -1-{N- [2- (4-phenyl- 0 cyclohexylamino) ethyl] } carboxamido -5 -methoxycarbonyi - 4-mβthyl-2-oxo-l,2, 3, 6-tβtrahydropyrimidine hydrochloride and trans-6- (3 , -Dif luorophenyl) - 1 - { N - [2 - ( 4 - 5 phβnylcyclohβxylamino) ethyl] } carboxamido- 5- mβthoxy carbonyl -4 -me thyl - 2 -oxo- 1,2,3,6- tetrahydro pyrimidine hydrochloride a) 2- [4-Phβnylcyclohexylimino] βthylaminβ (Scheme 5; 0 Step λ) . A mixture of 4 -phenyl eye lohexanone (4.00 g, 22.96 mmol) and ethylenediamine (1.66 g, 27.5 mmol) and p- toluenesulfonic acid (437 mg) in benzene (200 mL) was refluxed for 4 h in Dean-Stark trap to remove the water 5 that formed. Tic analysis indicated the completion of the reaction. Solvent was evaporated and the product was used in the next step without any further purification. 0 b) ciβ-β- (3 , -Dif luorophenyl) -1-{N- [2- (4- phβnylcyclohexylamino) ethyl] } carboxamido- 5 - βthox car bonyl- -mβthyl-2-oxo-l, 2,3, 6 -tetrahydropyrimidine hydrochloride and 35 tranβ-6- (3 , 4-Dif luorophenyl) - 1 - {N- [2- (4- phβnylcyclohβxylamino) ethyl] } carboxamido- 5 -me hoxy carbonyl- -me thyl- -oxo- 1,2, 3, 6 -tetrahydropyrimidine hydrochloride (Scheme 5; Step B) . A solution of 5- methoxycarbonyl-4- e hy1-1, 2, 3, 6-tetrahydro-2 -oxo- - (3 , 4-difluorophenyl) -1- [ (4-nitrophenyloxy) carbonyl] pyrimidine (120 mg, 0.269 mmol) and 2- [ -phenyl- cyclohexylimino] ethylamir.e (69.3 mg, 0.33 mcL) in dichloromethane (20 mL) was stirred at room temperature for 12 hours. Solvent was evaporated, the residue was redissolved in ethanol (10 mL) and cooled to 0 °C. To this sodium borohydride (61 mg, 1.614 mmol) was added and the stirring continued for 2 h. Solvent was evaporated and the residue was purified by preparative tic on silica gel using (dichloromethane .-MeOH:2M ammonia in MeOH, 100:8:4) as eluent. Two products were isolated, the upper band corresponds to cis-6- (3,4- Difluorophenyl) -1-{N- [2- (4-phenyl-cyclσhexylamino) ethyl] }carboxyamido-5-methoxycarbonyi-4-methyl-2-oxo- 1,2,3 , 6-tetrahydropyrimidine (16 mg) , and the lower band to traπs-6- (3 , 4-Difluorophenyl) -1- (N- [2- (4- phenylcyclohexylamino) ethyl] }carboxamido-5-methoxycar bonyl-4-methyl-2-oxo-l,2, 3 , 6-tetrahydropyrimidine (42 mg) . The HCl salts were prepared by treatment of a solution of the free base in ether with IN HCl in ether. Example θ: The cis isomer: M.P 145-146 °C; Anal. Calcd. for 0.8H 2 O:C, 58.24; H, 6.04; N, 9.70. Found: C, 58.13; H, 5.83; N, 9.50. Example 9: The trans isomer: M.P 156-157 °C; Anal. Calcd. for C 2t H 33 N 4 0F 2 Cl 0.4CHC1 3 :C, 55.85; H, 5.51; N, 9.17. Found: C, 55.57; H, 5.76; N, 9.10. Example 10 trans-6- (3, 4-Difluorophβ yl) -1-{N- [2 - [ ( 4 - p h β n y l c y c l o h β x y l ) - m e t h y l - amino] ethyl] } carboxamido- 5 -methoxycarbonyi - -methyl- 2- oxo -1,2,3,6- tetrahydropyrimidine hydrochloride ( Scheme 97/17969 -48- 5; Step C) . A mixture of crans-6- ( 3,4-difluorophenyl) -1- {N- [2- ' - p h e n y l ¬ cyclohexylammo) ethyl] }carboxamido-5-methoxycarccnyl- = 4-methyl-2-oxo-l,2, 3,6-tetrahydropyrimidine ι60 rr. 0.114 mmol), methyl iodide (19.4 mg, 0.137 mmol, 1. 2 eq.), and potassium carbonate (31.5 mg, 0.23 mmol) m acetone ( 10 mL) was stirred and refluxed for 12 h and the solid was removed by filtration. Solvent was 0 evaporated from the filtrate and the residue was purified by flash chromatography on silica el (dichloromethane:MeOH:2M ammonia in MeOH, 90:8:4) to give the product as an oil. The HCl salt was prepared by treatment of a solution of the free base in ether 5 with IN HCl in ether (14 mg) . M.P. 140-142 °C, Anal Calcd. for C 2 ,H 35 N 4 0 4 F 2 C1.0.33hexanes.0.59CHC1 3 :C, 56.07, H, 5.99; N, 8.28. Found: C, 56.37; H, 6.21; N, 7 90. Example 11 0 ( + ) -cis- 6 - (3 , 4 -Difluorophβnyl) - 1 - {N- 12 - ( 4 - m e t h o x y c a r b o n y l - 4 - p h e n y l - cyclohβxyl amino) ethyl] }carbox ami do - 5 -methoxycarbonyi -4 -methoxymethyl - 2 -oxo- 1,2,3,6- tetrahydropyrimidine hydrochloride 5 a ) 2 - [4 -Methoxycarbonyi - 4 -phenyl - cyclohβxylamino]βthylaminβ (Scheme 2; Step B) . A m i x t u r e o f 2 - [ 4 - c y a n o - 4 - phenylcyclohexylamino]ethylamme (2.34 g, 10 mmol) and 0 concentrated sulfuric acid (20 mL) was heated at 80-85 °C for 10 h. It was cooled to room temperature, mixed with anhydrous methanol (200 mL) , and refluxed for 20 h. Solvent was evaporated and the residue was poured onto ice (200 g) and basified to pH 11 by addition 6N 35 NaOH. It was extracted with dichloromethane (4 X 125 mL) , dried (potassium carbonate) and solvent evaporated to leave the product as an oil (2.1 g, 76%). This prcαuct was a pure mixture of ci s ana trans isomers. It was used m the next step witnout any furtner purification. b) ( + ) - c i s - 6 - ( 3 , 4 -Difluorophenyl ) - 1 - {N- [2 - (4-methoxycarbonyi-4-phenyl-cyclohexylamino)ethyl] } carboxamido-5-methoxycarbonyi-4-methoxymβthyl-2-oxo- 1,2, 3, 6-tetrahydropyrimidine hydrochloride (Scheme 2; Step G) . A solution cf (+) -5-methoxycarbonyi-4-methoxymethyl- 1,2,3, 6-tetrahydro-2-oxo-6- (3, 4-difluorophenyl) -l- [ (4- nitrophenyloxy) carbonyl]pyrimidine (128 mg, 0.26 mmol) and 2- ( -methoxcarbonyl- -phenylcyclohexylam o) ethylamme (70 mg, 0.26 mmol) m dichloromethane (15 mL) was stirred at room temperature for 12 hours. It was washed with ice-cold 0.5N NaOH (2 X 5 mL) and dried over sodium sulfate. Solvent was evaporated at reduced pressure and the residue was purified by flash chromatography on silica gel (dichloromethane:MeOH:2M ammonia in MeOK, 90:8:4) to give 78 mg (781) as a white powder. The HCl salt was prepared by treatment of a solution of the free base m ether with IN HCl in ether. 112-114 °C; [ot] D = +136 (c = 0.55, CHC1 3 ) ,- Anal. Calcd. for C 31 H 37 N 4 0,F 2 C1.0.4CH 2 C1 2 :C, 55.05; H, 5.56; N, 8.18. Found: C, 55.05; H, 5.50; N, 8.16. Example 12 (♦) -6- (3, 4-Difluorophenyl) -1-{N- [2- ( , 4-diphenyl- cyclohexylamino)ethyl] }carboxamido-5-methoxycarbonyi- 4-methoxymethyl-2-oxo-1,2,3,6-tetrahydro pyrimidine hydrochloride a) 2- [4,4-Diphenyleyelohβxylamino] βthylaminβ (Scheme 2; Step A) . A mixture of 4,4-diphenylcyclohexanone (2.5 g) and ethylenediamine (10 g) and p-toluenesulfonic acid (100 mg) in benzene (200 mL) was refluxed for 4 h in Dean- SUBSTΪTUTESHEET(RULE26) ≤tar trap to remove the water that formed. Solven t was evaporated and the residue was redissolved in methanol ( 60 L ) and cooled to 0 °C. To this, sodium borohydride (2 g) was added in portions and the mixture was stirred at room temperature for 3 h. Solvent as evaporated, the residue was dissolved dichloromethane (300 mL) , washed with brine (3 X 500 mL ) , dried ( potassium carbonate) , and the solvent evaporated to leave the product as a colorless viscous oil (2.94 g, 100%) . The 'H-NMR showed this product to D pure and was used in the next step without any further purification. b) ( + ) -6 - ( 3 , 4-Difluorophenyl) -1-{N- [2- (4,4- diphenylcyclohexylamino)ethyl] }carboxamido-5-methoxyc arbonyl-4-methoxymethyl-2-oxo-1,2,3,6- etrahydro pyrimidine hydrochloride (Scheme 2; Step G) . A solution of ( +) -5-methoxycarbonyl-4-methoxymethyl- 1,2,3, 6-tetrahydro-2-oxo-6- (3, 4-difluorophenyl) -1- [ (4- nitrophenyloxy) carbonyl] yrimidine (125 mg, 0.254 mmol) and 2- (4,4-diphenylcyclohexylamino)ethylamine (125 mg, 0.446 mmol) in THF (15 mL) was stirred at room temperature for 12 hours. It was washed with ice-cold 0.5N NaOH (2 X 5 mL) and dried over sodium sulfate. Solvent was evaporated at reduced pressure and the residue was purified by flash chromatography on silica gel (dichloromethane:MeOH:2M ammonia in MeOH, 90:8:4) to give 147 mg (92%) of the product as a white powder. The HCl salt was prepared by treatment of a solution of the free base in ether with IN HCl in ether. 160-162 °C,* [αr] D = +184 (c = 0.68, methanol) ; Anal. Calcd. for C 35 H 3 ^O 5 F 2 Cl.0.19CH 2 Cl 2 :C, 61.68; H, 5.79; N, 8.18. Found: C, 62.82; H, 5.87; N, 8.37. Example 13 (♦) -cis-6- (3,4-Difluorophenyl) -1-{H- [2- (4-cyano-4- (2- fluorophenyl) -cyclohexylamino) ethyl] }carboxamido-5- SUBSTΓΓUTE SHEET (RULE 26) methoxycarbonyl-4 -methyl -2 -oxo-1, 2 , 3 , 6 - tetrahydropyrimidine hydrochloride (Scheme 2; Step G) . A mixture of (+) -6- (3,4-difluorophenyl)-1, 6-dihydro-5- methoxycarbonyi-4-methyl-1- (4-nitro)phenoxycarbonyl-2- Ξ cyrimidone (60 mg, 0.138 mmol), cis - 2 - [4-cyanc- - (2 - fluorophenyl)cyclohexylamino] ethylamme (50 mg, 0.15 mmol) and methylene chloride (4 mL) was stirred at room temperature overnight. After being washed with IN aOH solution, the organic layer was concentrated and 0 purified by preparative TLC (eluent: 10/1 ethyl acetate/2M ammonia in methanol) to give the title compound in 41% yield (32 mg) as a yellow foam: DCIMS, m/z = 570 (MH * ) . Treatment of the free base with 1 equivalent of IM HCl in ether gave the HCl salt as an 5 off-white solid: m.p. 172-176°C. [α] D = 114.7 (1.9 mg/mL MeOH). Anal. Calc. for C 2 ,H 30 F 3 Ν s O, HCl 0.5CHC1 3 : C, 53.22; H, 4.77; N, 10.52. Found: C, 53.34; H, 4.77; N, 10.45. 0 Example 14 (+) -ciβ-6- (3,4-Difluorophenyl) -1-{N- [2- (4-cyano-4- (2- pyridyl) -cyclohexylamino) ethyl] }carboxamido-5 - methoxycarbonyi-4-methoxymβthyl-2-oxo-l, 2, 3, 6- tetrahydropyrimidine hydrochloride (Scheme 2; Step G) . 5 A mixture of (+) -6- (3,4-difluorophenyl) -1,6-dihydro-5- methoxycarbonyl-4-methoxymethyl-1- (4-nitro)phenoxy carbonyl-2-pyrimidone (50 mg, 0.107 mmol), cis-2-[4- cyano-4- (2-pyridyl)cyclohexylamino]ethylamine (40 mg, 0 0.164 mmol) and methylene chloride (4 mL) was stirred at room temperature overnight. After being washed with IN ΝaOH solution, the organic layer was concentrated and purified by preparative TLC (eluent: 10/1 ethyl acetate/2M ammonia in methanol) to give the title 35 compound in 50% yield (31 mg) as a yellow oil: CIMS, m/z = 583 (MH * ) . Treatment of the free base with 2 equivalents of IM HCl in ether gave the HCl salt as an cff-whlte solid: m.p. 148-152 3 C. [cr j - = 110.9 (1.65 mg/mL MeOH) . Anal. Calc. for C ; ,H, : F 2 N 6 0 2HC10.65CHC1 3 : C, 48.58; H, 4.76; N, 11.46. Found: C, 48.30; H, 4 .87; N, 11.20. Example 15 cis-6- (3, 4-Dif luorophenyl) -1-{N- [3- (4 -cyano-4 -phenyl - cyclohexylamino ) propyl] } carboxamido- 5 -methoxycarbonyi -4 -mβthyl-2 -oxo- 1 , 2 , 3 , 6 - tetrahydropyrimidine hydrochloride a) General procedure for 3 - [4 -Cyano- 4 - aryl cyclohexylamino] propyla ine . a) 3- [4-Cyano-4-phβnylcyclohexylamino] propylamine (Scheme 6; Step λ) . A mixture of 4-cyano-4-phenylcyclohexanone (5.0 g, 25.09 mmol) and 1, 3 -diaminopropane (5.58 g, 75.3 mmol) and p-toluenesulfonic acid (23 mg) in benzene (50 mL) was refluxed for 4 h in Dean-Stark trap to remove the water that formed. Solvent was evaporated and the residue was redissolved in methanol (40 mL) and cooled to 0 °C. To this, sodium borohydride (6.4 5 g) was added in portions and the mixture was stirred at room temperature for 3 h. Solvent was evaporated, the residue was dissolved in dichloromethane (300 mL) , washed with brine (3 X 500 mL) , dried (potassium carbonate) , and the solvent evaporated to leave the product as a pale yellow viscous oil (4.5 g, 72%) . The -H-NMR showed this product to be pure and found to contain the cis/ trans isomers in the ratio of about 4 :1. b) cis-6- (3, -Dif luorophenyl) -1-{N- [3- (4-cyano-4- cyclohexylamino) propyl] } carboxamido -5 -methoxycarbonyi -4 -me thyl - -oxo-l,2,3,6-tβtrahydropyrimidine -53- hydrochloride (Scheme 6; Step B) . A solution of 5-methoxycarbonyl-4-methyl-l, 2 , 3 , - tetrahydro-2-oxo-6- (3,4-difluorophenyl) -1- ( (4 - nitrophenyloxy) carbonyl] pyrimidine (0.500 g, 1.15 mmol) and 3 - [4 -cyano-4 -phenylcyclohexylarrtino] propylamine (0.371 g, 1.49 mmol) in dichloromethane (50 mL) was stirred at room temperature for 12 hours. It was washed with ice-cold 0.5N NaOH (2 X 10 mL) and dried over sodium sulfate. Solvent was evaporated at reduced pressure and the residue was purified by flash chromatography on silica gel (dichloromethane :MeOH: 2M ammonia in MeOH, 90:8:4) to give 0.570 g (87.6%) of the product as a white powder. The HCl salt was prepared by treatment of a solution of the free base in ether w th IN HCl in ether. M.p. 163-165 °C; Anal. Calcd. for C 30 H 3 N 5 O,F 2 C1.1.2 H 2 0:C, 57.77; H, 5.88; N, 11.23. Found: C, 57.65; H, 5.71; N, 11.20. Example 16 (+)-cis-l-3-{ [4- (3, 4 -Dif luorophenyl) -2, 5-dioxo- 1,2,3,4, 5,7-hβxahydro-4H-furo [3,4-d] -pyrimidine- 3- carbonyl] amino} -ethyl- (4-cyano-4-phenylcyclohexyl) amine hydrochloride . a) ( + ) -6- (3, 4-Dif luorophenyl) -1, 6-dihydro-2 -oxo-5- methoxy- carbonyl - -bromomβthyl-1- £ (4-nitroρhβnyl- oxy) carbonyl] pyrimidine (Scheme 7; Step A) . To a well stirred solution of (+) -6- (3,4- dif luorophenyl) - 1 , 6 -dihydro-2 -methoxy- 5- methoxycarbonyi- 4 -methyl- l- [ (4-nitrophenyloxy) carbonyl] pyrimidine (1.5 mmol, 0.66 g) in 5 mL of chloroform was added a solution of bromine (1.5 mmol, 0.09 mL) in 3 mL of chloroform at 0°C and the solution was allowed to attain room temperature over 1.5 h. The solvent was removed in vacuo and the residue was again dissolved in CHC1 3 (20 mL) and washed with brine. The organic layer was separated, dried over Na 2 S0 4 , filtered and the solvent was removed in vacuo to get 0.81 g cf ■ * ) -6- '3,4-difluorophenyl) -l, 6-dihydro-2-oxo-Ξ- methoxycarbonyl-4 -bromomethyl-1- [ (4 -nitrophenyloxy) carbonyl] pyrimidine as a yellow foam. It was used in tne next step without any purification. b) (+) -4- (3,4-Difluorophenyl) -2, 5-dioxo-l, 2,4, 5, 6,7- hexahydro-cyclopentapyrimidinβ-3-carboxylic acid-4- nitrophenyl ester (Scheme 7; Step B) . (+) -6- (3, -Difluorophenyl) -1, 6-dihydro-2-oxo-5-methoxy¬ carbonyi-4-bromomethyl-l- [ ( -nitrophenyloxy) carbcnyl] pyrimidine (1.5 mmol, 0.81 g) was heated m oil bath for 3 h (bath temperature 130°C. The brown residue thus obtained was washed with CHC1 3 and (+) -4- (3 , 4-difiuoro- phenyl) -2 , 5 -dioxo- l , 2 , 4 , 5 , 6 , 7 -hexahydro - cyclopentapyrιmidine-3-carboxylic acid-4-nitrophenyl ester was obtained as a pale brown solid which was used in the next step without further purification (crude wt. o .5ig) . c) (+)-cis-l-3-{[4- (3, -Difluorophenyl) -2,5-dioxo- 1,2,3,4,5, 7-hβxahydro-4H-furo [3,4-d] -pyrimidine-3 - carbonyl]amino}-ethyl- (4-cyano-4-phβnylcyclohβxyl) amine hydrochloride (Scheme 7; Step C) . A solution of (+) -4- (3,4-difluorophenyl) -2, 5-dioxo- 1,2,4,5,6, 7-hexahydro-cyclopenta pyrimidine- - carboxylic acid-4-nitrophenyl ester (86 mg, 0.20 mmol) and cis-2- (4-cyano-4-phenylcyclohexylamino) ethyl amine (70 mg, 0.3 mmol) in THF (5 L) was stirred at room temperature for 12 hours. It was purified by preparative tic on silica gel (ethyl acetate/methanol, 90:10) to give 91 mg (85%) as a white powder. The HCl salt was prepared by treatment of a solution of the free base in ether with IN HCl in ether. [cr] 0 =- +102 (c = ■ 0.75, MeOH) ; Anal. Calcd. for C at H, 7 N s O « F,Cl.0.38CH-C1 2 * . C, 56.41; H, 4.80; N, 11.59. Found: C, 56.80; H, 4.96; N, 11.29. Ξxample 17 -55- (+) ' Cia - 6 - (3, 4-Difluorophenyl) -1- [4- (4-cyano-4-phenyl- cyclohexylamino)butyl] -5-methoxycarbonyi-2, 4-dimethyl- 1, 6-dihydropyrimidine hydrochloride (Scheme 8). To a suspension of NaH (50 mg, 60% dispersion in mineral oil) in THF (7 mL) was added a solution of 6- (3,4-difluorophenyl) -1,6-dihydro-S-methoxycarbonyl-2,4- dimethylpyrimidine (0.32 g, 1.14 mmol.) and HMPA (0.205g, 1.14 mmol.) in THF (8 L) at 0°C. After 15 min, 1, 4-dibromcbutane (0.47 mL, 4.0 mmol.) was added. The reaction mixture was then refluxed for 10 mm. The solid was filtered off. After the removal of the solvent, the residue was flash chro atographed over silica gel (eluent: ethyl acetate) to give the product 44% yield (0.2 g) as a yellow oil. A mixture of 1- (4-bromobutyl) -6- (3 ,4-difluorophenyl) - 1,6-dihydro-5-methoxycarbonyi-2,4-dimethylpyrimidine (0.1 g, 0.43 mmol) , cis-4-cyano-4-phenylcyclohexylamine (0.18 g, 0.9 mmol) , potassium carbonate (0.3 g, 2.1 mmol), sodium iodide (65 mg, 0.43 mmol) and acetone (6 mL) was refluxed overnight. After removal of the solid and solvent, the residue was purified by preparative TLC (eluent: 100/20 v/v ethyl acetate-2M ammonia in methanol) to give the product in quantitative yield (0.23 g) as a pair of diastereomers. HPLC separation (Column: Chiralcel OD 20x250 mm,* Eluent: 60/40/0.1 hexane/2-propanol/diethylamine) gave the pure title compound as a yellow oil: DCIMS, m/z » 535 (MH * ) . Treatment of the free base with 2 equivalents of IM HCl in ether gave the HCl salt as a white solid: m.p. 169- 172°C. [cr] D - 68.6 (2.2 mg/mL MeOH) . Anal. Calc for C 31 H 36 FjN 4 0, 2HC10.9CHC1 3 : C, 53.59; H, 5.48; N, 7.84. Found: C, 53.61; H, 5.67; N, 7.81. It is understood that additional compounds may be synthesized under the general synthetic schemes referred to herein using appropriately substituted starting materials . Example 18 (+) -6- (3, 4-Difluorophenyl) -1-{N- [2- (4-cyano-4- phenylcyclohex-1-ylamino) -ethyl] }carboxamido-5-methoxycarbonyi- 4-hydroxymethyl-2-oxo-1,2,3,6-tetrahydropyrimidine. To well-stirred solution of (+) -6- (3 , 4-difluorophenyl) -l- {N- [2- ( -cyano-4-phenylcyclohex-1-ylammo) -ethyl] Jcarboxamido- 5-me hoxycarbonyi-4-methoxymethyl-2-oxo- 1, 2, 3 , 6-tetrahydropyrimidine (0.108 g, 0.184 mmol) in dichloromethane (8 mL) at -78°C was added a IM solution of boron tribromide (0.55 mL) dropwise and the cooling bath was removed. After stirring the mixture at room temperature for 4 h, it was quenched by the addition of methanol (5 mL) . Solvent was evaporated and the residue was purified by preparative th layer chromatography on silica gel using chloroform/methanol/2M ammonia in methanol (95/4/1) as the eluent. The faster moving component (Rf = 0.6, TLC on silica gel plates elutmg with 25:2:1 CHC1 3 :CH 3 0H: 2M NH 3 CH 3 0H) corresponded to (+) -6- (3,4-difluorophenyl) -1-{N- [2- (4-cyano-4- phenylcyclohex-1-ylam o) -ethyl] }carboxamido-5-methoxycarbonyi-4- bromomethyl-2-oxo-l,2, 3 , 6-tetrahydropyrimidine and it was converted to the hydrochloride salt by treatment with IN HCl m ether (10 mg) ; MH+ = 630; M.P. 225-227 °C; [ ] D = +126 (c = 0.115, MeOH) ; Anal. Calcd. for C 29 H 31 N 5 0 4 F 2 C1.0.2CH 2 C1 2 : C, 51.28; H, 4.63; N, 10.24. Found: C, 51.40; H; 4.58; N, 10.12. A second component (Rf = 0.5, TLC on silica gel plates eluting with 25:2:1 CHC1 3 : CH 3 0H: 2M NH 3 in CH 3 0H) was identified as (+) -6- (3 , 4-difluorophenyl) -1- {N- [2- (4-cyano-4-phenyl- eyelohex-1-ylammo) -ethyl] }carboxamido-5-methoxycarbonyl-4-hydrox ymethyl-2-oxo-1, 2, 3 , 6-tetrahydropyrimidine (45 mg) ; MH+ = 568; M.P. 230-232 °C; [at] D = +123 (c = 0.275, MeOH) ; Anal. Calcd. for C 29 H 31 N 5 O 5 F 2 .0.35CH 2 Cl 2 : C, 59.02; H, 5.35; N, 11.72. Found: C, 58.93; H; 5.50; N, 11.68. -57- Example 19 (+) -6- (3, 4-Difluorophenyl) -1-{N- [2- <4-cyano-4- phenylcyclohex-1-ylamino) -ethyl] }carboxamido-4-methoxymethyl-2- oxo 1,2, , 6-tetrahydropyrimidine-5-carboxylic acid. a) Benzyl 2- [ (3,4-difluorophenyl)methylene] -3-oxo-4- methoxybutyrate. To a solution of benzyl 4-methoxyacetoacetate (84 g, 0.37 mol) , , 4-difluorobenzaldehyde (52.5 g, 0.0.37 mmol) , and piperidmium acetate (1.58 g, 2.63 mmol) benzene (ID were added molecular sieves (400 g) and the mixture was stirred at room temperature for 48 h. The molecular sieves were removed by filtration and the solvent was evaporated from the filtrate under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform/ethyl acetate (100:3) to get the product as a white powder (118 g, 91%) . The NMR showed this product to be a mixture of cis and trans lsomers. b) 5-Benzyloxycarbonyl-l,6-dihydro-2-methoxy-4-methoxymethyl-6- (3,4-difluorophenyl)pyrimidine. A suspension of benzyl 2- [(3,4- difluorophenyl)methylene] -3-oxo-4-methoxybutyrate (60 g, 0.181 mol) , O-methylisourea hemisulfate (46.77 g, 0.271 mol, 1.5 eq.) , and sodium bicarbonate (53.25 g, 0.634 mol, 3.5 eq.) in ethanol (400 L) was stirred at 50-55°C for 6 h. The solvent was evaporated from the combined filtrates and the residue was purified by column chromatography (Si0 2 , EtOAc/hexane, l0%-30%) to give 5-benzyloxycarbonyl-1, 6-dihydro-2-methoxy-4- methoxymethyl-6- (3 ,4-difluorophenyl)pyrimidine as a pale yellow oil (24.7 g, 35%) . c) 5-Benzyloxycarbonyl-4-methoxymethyl-1, 6-dihydro-2-methσxy-6- (3,4-difluorophenyl) -1- [ (4-nitrophenyloxy)carbonyl]pyrimidine. To a well-stirred solution of 5-benzyloxycarbonyl-1, 6-dihydro-2- methoxy- -methoxymethyl-6- (3,4-difluorophenyl)pyrimidine (12 g, 29 mmol) and pyridine (10 mL) CH 2 Cl 2 (100 mL) was added powdered 4-nitrophenyl chloroformate (8.69 g, 43 mmol) at 0°C. The reaction mixture was stirred for 12 h at room temperature and the solvent was evaporated from the filtrate and the residue was purified by column chromatography (Sι0 2 , dichloromethane/hexane, 20%-50%) to give the product as a foam (14.2 g, 86%) . d) (+) -5-Benzyloxycarbonyl-4-methoxymethyl-l, 6-dihydro-l- {N- [2- phenyl) ethyl] }carboxamido-2-methoxy-6- (3,4- difluorophenyl)pyrimidine. To a stirred solution of 5- benzyloxycarbonyl-4-methoxymethyl-1, 6-dihydro-2-methoxy-6- (3,4- difluorophenyl) -1- [ (4-nitrophenyloxy) carbonyl]pyrimidine (6 g, 10.5 mmol) in THF (120 mL) was added R- (+) -α-methylbenzylamine (1.8 g, 15 mmol) at room temperature and the stirring was continued for 12 h. Solvent was evaporated and the residue was purified by column chromatography (Si0 2 , 10-20% EtOAc m hexane) . The first major product to elute was (+) -5-benzyloxycarbonyl-4- methoxmethyl-1, 6-dihydro-l- {N- [2-phenyl) ethyl] }carboxamido-2 - methoxy-6- (3 , 4-difluorophenyl) pyrimidine (2.1) , as an oil. e) (+) -5-Benzyloxycarbonyl-l, 6-dihydro-2-methoxy-4-methoxymethyl- 6- (3,4-difluorophenyl)pyrimidine. To a stirred solution of (+) -5- benzyloxycarbonyl-4-methoxymethyl-l, 6-dihydro-l- {N- [2- phenyl) ethyl] }carboxamido-2-methoxy-6- (3,4- difluorophenyl)pyrimidine (2 g, 3.5 mmol) in dichloromethane (200 mL) was added 1, 8-diazabicyclo [5 , 4 , 0] -undec-7-ene (0.6 mL) and the mixture was stirred at room temperature for 12 h. Solvent was evaporated and the residue was purified by flash column chromatography on silica gel with 30-40% EtOAc in hexane as eluent to give (+) -5-benzyloxycarbonyl-1, 6-dihydro-2-methoxy-4- methoxymethyl-6- (3 ,4-difluorophenyl) pyrimidine as a viscous oil (1.25 g, 86%) . f) (+) -5-Benzyloxycarbonyl-4-methoxymethyl-1,6-dihydro-2-methoxy- 6- (3,4-difluorophenyl) -1- [ (4-nitrophenyloxy) carbonyl]pyrimidine. To a well stirred solution of (+) -5-benzyloxycarbonyl-1, 6- dihydro-2-methoxy-4-methoxymethyl-6- (3,4- difluorophenyl) pyrimidine (1.25 g, 3.0 mmol) and pyridine (2 mL) in CH 2 C1 2 (20 L) was added powdered 4-nitrophenyl chloroformate (1 g, 5 mmol) at room temperature. Solvent was evaporated and the residue was purified by column chromatography on silica gel using CHClj/EtOAc (20%-50%) as the eluent to give (+)-5- benzyloxycarbonyl-4-methoxymethyl-l, 6-dihydro-2-methoxy-6- (3,4- diflurophenyl) -1- [ (4-nitrophenyloxy) carbonyl] yrimidine (1.70 g, 86%) as a viscous oil. [cr] D = +200 (c = 1.215 g m 100 L CHC1 3 ) . g) (+) -6- (3,4-Difluorophenyl) -1-{N- [2- (4-cyano-4- phenylcyclohex-1-ylamino) -ethyl] }carboxamido-5-benzyloxycarbonyl- 4-methoxymethyl-2-oxo 1,2,3, 6-tetrahydropyrimidine (cis isomer) . A solution of (+) -6- (3 , 4-difluorophenyl) -1, 6-dihydro-2-methoxy-5- benzyloxycarbonyl-4-methoxymethyl-1- (4-nitrophenoxy) - carbonylpyπmidine (0.100 g) and 2- [4-cyano-4-phenylcyclohex-1- yl] ammoethylamine (0.05 g) m THF (5 mL) was stirred at room temperature for 12 hours. To this 6N HCl (0.5 ml) was added and the stirring was continued for 2 h. Solvent was evaporated, the residue was mixed with dichloromethane (10 mL) , washed with ice- cold 0.5N NaOH (2 X 10 mL) and dried over sodium sulfate. Solvent was evaporated at reduced pressure and the residue was purified by flash chromatography on silica gel (dichloromethane:MeOH:2M ammonia in MeOH, 90:8:4) to give 0.12 g of the product as a white powder. The NMR showed this product to be pure and was used m the next step without any further characterization. h) (+) -6- (3,4-Difluorophenyl) -1-{N- [2- (4-cyano-4- phenylcyclohex-1-ylamino) -ethyl] }carboxamido-4-methoxymethyl-2- oxo 1,2,3, 6-tetrahydropyrimidine-5-carboxylic acid. To a solution of (+) -6- (3, -difluorophenyl) -1- {N- [2- (4-cyano-4- phenylcyclohex-1-ylammo) -ethyl] }carboxamido-5-benzyloxycarbonyl- 4-methoxymethyl-2-oxo 1,2, 3 , 6- etrahydropyrimidine (120 mg) in methanol/water (9/1, 10 mL) , 10% palladium on charcoal (20 mg) was added and the mixture was hydrogenated at 125 psi for 4 h. The tic analysis of the reaction indicated the completion of the reaction. The catalyst was removed by filtration and the solvent was evaporated to leave the product as a pale yellow powder (86 mg) ; m.p 188-191°C; Anal. Calcd. for C 29 H 31 N 5 O s F 2 0.5H 2 0 : C, 60.41; H, 5.59; N, 12.15. Found: C, 60.28; H; 5.62; N, 12.34. Exa p l e 20 As a specific embodiment of an oral composition cf a compound of this invention, 100 mg of one of tr.ε 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. Pharmacological Profiles of the Compounds in Cloned Hnπ___τ_ Adrenergjc ReceotorB. Binding affinities were measured for selected compounds of the invention at six cloned human alpha-1 and alpha- 2 receptor subtypes, as well as at the L-type calcium channel. The protocols for these experiments are given below. Protocol for the Determination of the Potency of a l 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 geno ic DNA or constructs containing both genomic DNA and cDNA encoding the human αt-adrenergic receptors as follows: α- a Human λdrenergic Receptor: The entire coding region of α- D (1719 bp) , including 150 base pairs of 5' untranslated sequence (5' UT) and 300 bp of 3' untranslated sequence (3' UT) , was cloned into the BamHI and Clal sites of the polylinker-modified eukaryotic expression vector pCEXV-3, called EXJ.HR. The construct involved the ligation of partial overlapping human lymphccyte genomic and hippocampal cDNA clones: 5' sequence were contained on a 1.2 kb Smal-Xhol genomic fragment (the vector-derived 3am_-_I site was used for subcloning instead of the internal insert-derived Smal site) and 3' sequences were contained on an 1.3 kb Xhol-Clal cDNA fragment (the Clal site was from the vector polylinker) . Stable cell lines were obtained by cotransfection with the plasmid -xlA/EXJ (expression vector containing the αlA receptor gene (old nomenclature) ) and the plasmid pGCcos3neo (plasmid containing the am oglycoside transferase gene) into LM(tk-) cells using calcium phosphate technique. The cells were grown, m a controlled environment (37°C. , 5% C0 2 ) , as monolayers in Dulbecco's modified Eagle's Medium (GIBCO, Grand Island, NY) containing 25mM glucose and supplemented with 10% bovine calf serum, 100 units/ml penicillin g, and 100 μg/ml streptomycin sulfate. Stable clones were then selected for resistance to the antibiotic G-418 (1 mg/ml) , and membranes were harvested and assayed for their ability to bind [ } H]prazosin as described below (see "Radioligand Binding assays") . The cell line expressing the human α- D receptor used herein was designated - ^ (old nomenclature) and was deposited with the American Type Culture Collection, 12301 Parklav 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 <__ l0 receptor, was accorded ATCC Accession No. CRL 11138, and was deposited on September 25, 1992. α u Human λdrenergic Receptor: The entire coding region of αlB (1563 bp) , including 200 base pairs and 5' untransiated sequence (5' UT] ana 600 bp cf 3' untranslated sequence (3' UT) , was cloned nto tne ΞcoRI site of pCEXV-3 eukaryotic expression vector The construct involved ligating the full-length containing EcoRI brainstem cDNA fragment from λ ZapII into the expression vector. Stable cell lines were selected as described above. The cell line used herein was designated L-αr :B and was deposited with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20832, 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-αr. B was accorded ATCC Accession No. CR 11139, on September 29, 1992. α-^ Human λdrenergic Receptor: The entire coding region of _.__ (1401 bp) , including 400 base pairs of 5' untranslated sequence (5' UT) and 200 bp of 3' untranslated sequence (3' UT) , was cloned into the Kpnl site of the polylinker-modified pCEXV-3-derived eukaryotic expression vector, ΞXJ.RH. The construct involved ligating three partial overlapping fragments: a 5' 0.6kb Hindi genomic clone, a central 1.8 EcoRI hippocampal cDNA clone, and a 3' 0.6Kb Pstl genomic clone. The hippocampal cDNA fragment overlaps with the 5' and 3' genomic clones so that the Hindi and Pstl sites at the 5' and 3' ends of the cDNA clone, respectively, were utilized for ligation. This full- length clone was cloned into the Kpnl site of the expression vector, using the 5' and 3' Kpnl sites of the fragment, derived from vector (i.e., pBluescript) and 3' -untranslated sequences, respectively. Stable cell lines were selected as described above. The stable cell line expressing the human α^ receptor used herein was designated L-α lc (old nomenclature) and was deposited with the American Type Culture Collection, 12301 Parkiawn Drive, Rockvilie, Maryland 20852, U.S.A. under the provisions of the Budapest Treaty for tne International Recognition of the Deposit cf Microorganisms for the Purposes of Patent Proceαure The cell line expressing t e human c_ lA receptor was accorded Accession No. CR 11140, on September 25, 1992. Radioligand Binding Assays: Transfected cells from culture flasks were scraped into 5ml of 5mM Tris-HCl, 5mM EDTA, pH 7.5, and lysed by somcation. The cell lysates were centrifuged at 1000 rpm for 5 mm at 4°C, and the supernatant was centrifuged at 30,000 x g for 20 mm at 4°C. The pellet was suspended in 50mM Tris- HC1, ImM MgCl 2 , and 0.1% ascorbic acid at pH 7.5. Binding of the crl antagonist [ 3 H]prazosιn (0.5 nM, specific activity 76.2 Ci/m ol) to membrane preparations of LM(tk-) cells was done m a final volume of 0.25 ml and incubated at 37°C for 20 mm. Nonspecific binding was determined in the presence of 10 μM phentolamine. The reaction was stopped by filtration through GF/B filters using a cell harvester. Inhibition experiments, routinely consisting of 7 concentrations of the tested compounds, were analyzed using a non-linear regression curve-fitting computer program to obtain Ki values. or, Human λdrenergic Receptors: To determine the potency of - antagonists at the α 2 receptors, LM(tk-) cell lines stably transfected with the genes encoding the or-jj, a„, and a 2C receptors were used. The cell line expressing the a^ receptor is designated L-α 2A , and was deposited on November 6, 1992 under ATCC Accession No. CRL 11180. The cell line expressing the αr 2B receptor is designated L-NGC-α. 2B , and was deposited on October 25, 1989 under ATCC Accession No. CRL10275. The cell line expressing the α- c receptor is designated L-α 2c , and was deposited on November 6, 1992 under ATCC Accession No. CRL-1 181. Ail the cell lines were deposited with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A. under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for tne Purposes of Patent Procedure. Cell lysates were prepared as described above (see Radioligand Binding Assays) , and suspended in 25mM glycylglycme buffer (pH 7.6 at room temperature) . Equilibrium competition binding assay were performed using [3H] rauwoiscine (0.5nM) , and nonspecific binding was determined by incubation with lOμM phentolamine. The bound radioligand was separated by filtration through GF/B filters using a cell harvester. Determination of the Activity of or. Antagonists at Calcium Channels The potency of α_ antagonists at calcium channels was determined in competition binding assays of [ J H]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 was minced and homogenized in 50mM Tris-HCl (pH 7.4) containing 0. ImM phenylmethylsulfonyl fluoride. The homogenates were centrifuged at 1000 g for 15 minutes, the resulting supernatant was centrifuged at 45,000 g for 15 minutes. The 45,000 g pellet was suspended in buffer and centrifuged a second time. Aliquots of membrane protein were incubated for 30 minutes at 37°C in the presence of [ 3 H] nitrendipme (InM) , and nonspecific binding was determined in the presence of lOμM nifedipine. The bound radioligand was separated by filtration through GF/B filters using a cell harvester. The compounds described above were assayed using cloned human alpha adrenergic receptors and the rat calcium channel. The preferred compounds were found to be α. A selective antagonists. The compounds described herein were also found to exhibit weak binding affinity to the rat L-type calcium channel. The alpha adrenerσic receptor binding affinities of compounds 2-5, 7, n, 13 and 14 are illustrated in Table 1 as follows: Table 1 Binding affinities of selected compounds at cloned human alpha-1 adrenergic rece tors P»rt 1 SCHEME 1 ' PTS • p-c-tluan.. -aul.oiuc acid In Part 1 of the general syntnetic scheme, an optionally substituted cycloalkanone is refluxed with a diaminoalkane to form the corresponding (cycloalk-1- yl) aminoalkylimme, which on treatment w th Na30. yields (cycioalk-1-yl) aminoalkyiamme . In part 3 the dia ine is added to a 1- [ (4-nitrophenyl)oxycarbonyl] pyrimidine to yield the final product. Although cyclohexanone is shown, the process is equally applicable to substituted cycloalkanones from cyclobutanone through cyclσ- octanone. In addition, replacement of the diamino¬ alkane of Part 1 with an ammoalkanol yields esters in Part 3 instead of amides. In the schemes which fellow, the diaminoalkane is shown for clarity as either ethyl, propyl or butyl; however, any suitable alkyl, branched alkyl or substituted alkyl as shown in Scheme 1 may be used, wherein R is as defined in the specification. In Part 2 of the general synthetic scheme, it is important to note that the use of the O-methylisourea (R" n = OMe) in Step D allows the production of several different 2-substituents on the dihydropyrimidine . In particular, addition of primary amines (i.e., NH 2 R 3 ) to the 2-methoxy pyrimidines affords 2-amino pyrimidines. Alternatively, when R"" = OMe is replaced with 4- methoxybenzylthiol, 2-thioxodihydropyrimidines may be produced by treatment of the product with ethanethiol and TFA. R" • H. CH. ?h λ_ • Pti. . -py-idyl. . rPri H,M * ■ :-0 ' ." -CX *! • «.. --pyτt_y.. i-rwi ■• 0. BnO . Mm M_ . εt. M_OCH • CM*. H SCHEME 2 ' Ml - pftaπyl b. •n • _»__ry_ la inβ diaatβrβoβ ( ♦ ) and 1-1 enuitic SCHEME 3 ' DBO • 1, t-di*xa icyclo(S.4. Olundec-"" -βnβ SCHEME 4 *"B-D • 1- O-DlM-hylaainopiopyl) -3 --tttylcaxbodiiα--- hydrochloride b '__MA_> • 4-Dι___it yla__nopyιl-_na PTS ,„H 2 • := Ph B*nz«n* -O. SCHEME 5 SCHEME 6 H SCHEME 7 K.CO. NaT SCHEME 8 HMPA • he._j__at1ylp._osp-i0ra_u.de DBU = 1 , 8 diarabi . yr] o. '», 4.0 I tin.1CM / ι ι ι_ Scheme 10. PreparftCiα. of Exanp le 19. Similar compounds may be produced by substitution of the 1, -dibromobutane with other dibromoaikanes, including branched compounds __r. order to produce the alkyl-linked cycloalkylamine derivatives of the subject dihydropyrimidines.

Claims: What is claimed is: 1. A compound having the structure tt 11 R M or tt where M has the structure wherein each of Y- , Y 2 , Y 3 , Y 4 and Y s independently may be -H; straight chained or branched C--C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyi, monofluorocycloalkyl , polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I; -NO. -N(R 3 3) ' 2 ' -N 3 ' -CN; -0R 3 -OCOR 3 ' ■ COR 3 ' •CON(R 3 or -C0 2 R 3 ; or wherein two of Y., Y 2 , Y 3 , Y 4 and Y c are present on adjacent carbon atoms and together constitute a methylenedioxy group; where R independently may be -H; -F; straight chained or branched C : -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl , straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -C0 2 R 3 ; - (CH 2 ) p P0(0R 3 ) 2 ; - (CH 2 ) p P0(0R 3 ) 3 ; or -0R 3 ; where R- may be -H; -N0 2 ; -CN; straight chained or branched C.-C-, alkyl, monofluoroalkyl or polyfluoroalkyl,- straight chained or branched C 3 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyi, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl,- -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 , wherein any p independently is an integer from 1 to 7 inclusive; where R 2 may be -H; straight chained or branched C_-C 7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C η alkenyl or alkynyl; C 3 -C 7 cycloalkyi, monofluorocycloalkyl , polyfluorocycloalkyl or cycloalkenyl; C 3 -C 10 cycloalkyi-C--C 10 -alkyl, C 3 -C-„cycloalkyi-C--C 10 -monofluoroalkyl or C 3 -C l0 cycloalkyl-C.-C 10 -polyfluoroalkyl; -CN; -CH 2 XR 3 , -CH 2 X(CH 2 ) p NHR 3 , -(CH 2 ) n NHR 3 , -CH 2 X(CH 2 ) p N(R 3 ) 2 , -CH 2 X(CH 2 ) p N 3 , or -CH 2 X(CH 2 ) p NHCXR-,; or -0R 3 ; wherein any n independently is an integer from 0 to 5 inclusive and p is as defined above; where each R 3 independently may be -H; straight chained or branched C--C-, alkyl, monofluoroalkyl or polyfluoroalkyl,- straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -C 7 cycloalkyi, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; - ,CH 2 ) p P0 (0R 8 ) 2 ,- - (CH 2 ) p P0 (0R β ) 3 ; or - (CH 2 ) p COOR β ; where R, has the structure wherein Z may be C 2 -C 7 alkenyl or alkynyl; CH 2 ; 0; CO; C0 2 ; C0NR 3 C0; C0NR 3 ; S; SO; S0 2 ; or NR 3 ; m is an integer from 0 to 3 inclusive; R 5 and R 6 each independently may be -H; -F, -Cl, -Br, -I; -C0 2 R 3 ; -COR 3 ' ■ C0N(R, -CN; -NO, -N(R -0R 3 ; straight chained or branched C--C-, alkyl, C l - C 1 monofluoroalkyl, C.-C7 polyfluoroalkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C cycloalkyi, or C 3 -C 7 cycloalkenyl, wherein the alkyl, monofluoroalkyl, polyfluoroalkyl, alkenyl, alkynyl, cycloalkyi or cycloalkenyl may be unsubstituted or substituted with -H, aryl or heteroaryl; aryl or heteroaryl wherein the aryl or heteroaryl may be unsubstituted or substituted with -H, -F, -Cl, -Br, -I, -N0 2 , -CN, -N(R 3 ) 2 , - -OR_. 3 ., -COR, •C0 2 R 3 , or -CON(R 3 ) 2 ; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl or alkynyl, C 3 -C 7 cycloalkyi, monofluorocycloalkyl, polyfluorocycloalkyl, or cycloalkenyl; R 7 may be -H; straight chained or branched C 3 -C 7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyi, monofluorocycloalkyl , polyfluorocycloalkyl or cycloalkenyl; -CN; -C0 2 R 3 ; -COR 3 ; -CON(R 3 ) 2 ; or -0R 3 ; where R β is -H, * straight chained or branched C--C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyi, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; where R 9 may be -H; -CN; straight chained or branched C ^ - C ^ alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyi, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ; wherein X may be S; 0; or NR 3 ; and wherein B may be -H; straight chained or branched C_-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, alkoxy or thioalkyl; straight chained or branched C 2 -C 7 alkenyl; -SCH 2 C 6 H 4 OR 3 ,- - (CH 2 ) n C 6 H s ; -CH 2 X(CH 2 ) π NHR 3 ; - (CH 2 ) n NHR 3 ; or -0R 3 ; or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein the compound comprises the (+) enantiomer. The compound of claim 1, wherein the compound comprises the (-) enantiomer. The compound of claim 1, wherein the compound is selected from the group consisting of: R and tt The compound of claim 4, wherein R 4 is and p is 2, 3 or 4 6. The compound of claim 5, wherein R„ is The compound of claim 6, having the structure 8. The compound of claim 7, wherein M is polyfluorophenyl and R 5 is substituted or unsubstituted phenyl or pyridyl. 9. The compound of claim 8, wherein R- is -C0 2 CH 3 , -COCH 3 , or -CONH 2 ; R 2 is -CH 2 OCH 3 , methyl or ethyl; and R 6 is H, -CN, or CO-CH.. 10. The compound of claim 6, wherein the compound is selected from the group consisting of: /' and The compound of claim 10 , wherein the compound is the (+) enantiomer. 12. The compound of claim 10, wherein the compound is the (-) enantiomer. 13. The compound of claim 6, having the structure 14. The compound of claim 13, wherein M is polyfluorophenyl and R 5 is substituted or unsubstituted phenyl or pyridyl. 15. The compound of claim 14, wherein the compound is 16. The compound of claim 15, wherein the compound is the (+) enantiomer. 17. The compound of claim 15, wherein the compound is the (-) enantiomer. 18. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier. 19. The pharmaceutical composition of claim 18, wherein the amount of the compound is an amount from about 0.01 mg to about 500 mg. 20. The pharmaceutical composition of claim 19, wherein the amount of the compound is from about 0.1 mg to about 60 mg. 21. The pharmaceutical composition of claim 20, wherein the amount of the compound is from about 1 mg to about 20 mg. 22. The pharmaceutical composition of claim 18, wherein the carrier is a liquid and the composition is a solution. 23. The pharmaceutical composition of claim 18, wherein the carrier is a solid and the composition is a tablet. 24. The pharmaceutical composition of claim 18, wherein the carrier is a gel and the composition is a suppository. 25. The pharmaceutical composition of claim 18, wherein the compound is formulated as a part of a pharmaceutically acceptable transdermal patch. 26. 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. 27. A method of claim 26, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia. 28. The method of claim 27, wherein the compound effects treatment of benign prostatic hyperplasia by relaxing lower urinary tract tissue. 29. The method of claim 28, wherein the lower urinary tract tissue is prostatic smooth muscle. 30. A method of treating a subject suffering from elevated intraocular pressure which comprises administering to the subject an amount of the compound of claim 1 effective to lower intraocular pressure. 31. A method of treating a subject suffering from a disorder associated with elevated blood cholesterol which comprises administering to the subject an amount of the compound of claim 1 effective to inhibit cholesterol synthesis. 32. A method of treating a disease which is susceptible to treatment by antagonism of the αlA receptor which comprises administering to the subject an amount of the compound of claim 1 effective to treat the disease. 33. 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. 34. A method of treating a subject suffering from sympathetically mediated pain which comprises administering to the subject an amount of the compound of claim 1 effective to treat sympathetically mediated pain. 35. 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. 36. A method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject the compound of claim 1 m combination with a 5 alpha-reductase inhibitor in an amount effective to treat benign prostatic hyperplasia. 37. The method of claim 36, wherein the 5-alpha reductase inhibitor is finasteride. 38. A pharmaceutical composition comprising a therapeutically effective amount of a combination of the compound of claim 1 and finasteride and a pharmaceutically acceptable carrier. 39. The pharmaceutical composition of claim 38, comprising from about 0.01 mg to about 500 mg of the compound and about 5 mg finasteride. 40. The pharmaceutical composition of claim 38, comprising from about 0.1 mg to about 60 mg of the compound and about 5 mg finasteride. 41. The pharmaceutical composition of claim 38, comprising from about 1 mg to about 20 mg of the compound and about 5 mg finasteride. 42. A method of relaxing lower urinary tract tissue which comprises contacting lower urinary tract tissue with an amount of the compound of claim 1 effective to relax lower urinary tract tissue. 43. The method of claim 42, wherein the lower urinary tract tissue is prostatic smooth muscle. 44. The method of claim 43, wherein the compound additionally does not cause a fall m blood pressure. 45. A method of relaxing lower urinary tract tissue in a sub j ect, which comprises administering to the subject an amount of the compound of claim 1 effective to relax lower urinary tract tissue. 46. The method of claim 45, wherein the lower urinary tract tissue is prostatic smooth muscle. 47. The method of claim 46, wherein the compound additionally does not cause a fall in blood pressure. 48. A method of inhibiting contraction of prostatic tissue, which comprises administering to the subject an amount of the compound of claim 1 effective to inhibit contraction of prostatic tissue. 49. The method of claim 48, wherein the prostatic tissue is prostatic smooth muscle. 50. The method of claim 49, wherein the compound additionally does not cause a fall in blood pressure. 51. The method of relaxing lower urinary tract tissue of claim 42, wherein the compound is administered in combination with finasteride.

Inventors: GLUCHOWSKI CHARLES, MIAO SHOU WU, NAGARATHNAM DHANAPALAN, PATANE MICHAEL A, WONG WAI C, GLUCHOWSKI, CHARLES, MIAO, SHOU, WU, NAGARATHNAM, DHANAPALAN, PATANE, MICHAEL, A., WONG, WAI, C.
Applicants: GLUCHOWSKI CHARLES, MERCK & CO INC, MIAO SHOU WU, NAGARATHNAM DHANAPALAN, PATANE MICHAEL A, SYNAPTIC PHARMA CORP, WONG WAI C, GLUCHOWSKI, CHARLES, MERCK AND CO., INC., MIAO, SHOU, WU, NAGARATHNAM, DHANAPALAN, PATANE, MICHAEL, A., SYNAPTIC PHARMACEUTICAL CORPORATION, WONG, WAI, C.
Application year: 1996
Main classification: A61K31
IPC codes: A61K31, A61P3, A61P9, A61P15, A61P27, C07D239, C07D401, C07D491