WO1999025345A1 - Alpha-1a adrenergic receptor antagonists - Google Patents

Alpha-1a adrenergic receptor antagonists Download PDF

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Publication number
WO1999025345A1
WO1999025345A1 PCT/US1998/024148 US9824148W WO9925345A1 WO 1999025345 A1 WO1999025345 A1 WO 1999025345A1 US 9824148 W US9824148 W US 9824148W WO 9925345 A1 WO9925345 A1 WO 9925345A1
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Prior art keywords
difluorophenyl
cyclopentylcarbamoyl
alkyl
alpha
cycloalkyl
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PCT/US1998/024148
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French (fr)
Inventor
James Barrow
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Merck & Co., Inc.
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Priority claimed from GBGB9807940.3A external-priority patent/GB9807940D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU14030/99A priority Critical patent/AU1403099A/en
Publication of WO1999025345A1 publication Critical patent/WO1999025345A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C07D211/64—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having an aryl radical as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as alpha-1a adrenergic receptor antagonists. One application of these compounds is in the treatment of benign prostatic hyperplasia. These compounds are selective in their ability to relax smooth muscle tissue enriched in the alpha-1a receptor subtype without at the same time inducing hypotension. One such tissue is found surrounding the urethral lining. Therefore, one utility of the instant compounds is to provide acute relief to males suffering from benign prostatic hyperplasia, by permitting less hindered urine flow. Another utility of the instant compounds is provided by combination with a human 5-alpha reductase inhibitory compound, such that both acute and chronic relief from the effects of benign prostatic hyperplasia are achieved.

Description

TITLE OF THE INVENTION
ALPHA- la ADRENERGIC RECEPTOR ANTAGONISTS
CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional
Application No. 60/065,996, filed November 14, 1997 and U.S. Provisional Application No. 60/066,483, filed November 24, 1997.
FIELD OF THE INVENTION This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as alpha- la adrenoceptor antagonists. More particularly, the compounds of the present invention are useful for treating benign prostatic hyperplasia (BPH).
BACKGROUND OF THE INVENTION
Human adrenergic receptors are integral membrane proteins which have been classified into two broad classes, the alpha and the beta adrenergic receptors. Both types mediate the action of the peripheral sympathetic nervous system upon binding of catecholamines, norepinephrine and epinephrine.
Norepinephrine is produced by adrenergic nerve endings, while epinephrine is produced by the adrenal medulla. The binding affinity of adrenergic receptors for these compounds forms one basis of the classification: alpha receptors bind norepinephrine more strongly than epinephrine and much more strongly than the synthetic compound isoproterenol. The binding affinity of these hormones is reversed for the beta receptors. In many tissues, the functional responses, such as smooth muscle contraction, induced by alpha receptor activation are opposed to responses induced by beta receptor binding.
Subsequently, the functional distinction between alpha and beta receptors was further highlighted and refined by the pharmacological characterization of these receptors from various animal and tissue sources. As a result, alpha and beta adrenergic receptors were further subdivided into alpha-1. alpha-2, βi, and β2 subtypes. Functional differences between alpha- 1 and alpha-2 receptors have been recognized, and compounds which exhibit selective binding between these two subtypes have been developed.
For a general background on the alpha adrenergic receptors, the reader's attention is directed to Robert R. Ruffolo, Jr., α: Adrenoreceptors: Molecular Biology. Biochemistry and Pharmacology. (Pro ress in Basic and Clinical Pharmacology series, Karger, 1991), wherein the basis of alpha- l/alpha-2 subclassification, the molecular biology, signal transduction (G-protein interaction and location of the significant site for this and ligand binding activity away from the 3'- terminus of alpha adrenergic receptors), agonist structure-activity relationships, receptor functions, and therapeutic applications for compounds exhibiting alpha-adrenergic receptor affinity was explored. The cloning, sequencing and expression of alpha receptor subtypes from animal tissues has led to the subclassification of the alpha- 1 receptors into alpha- Id (formerly known as alpha- la or la/Id), alpha- lb and alpha-la (formerly known as alpha-lc) subtypes. Each alpha- 1 receptor subtype exhibits its own pharmacologic and tissue specificities. The designation "alpha- la" is the appellation recently approved by the IUPHAR Nomenclature Committee for the previously designated "alpha-lc" cloned subtype as outlined in the 1995 Receptor and Ion Channel Nomenclature Supplement (Watson and Girdlestone, 1995). The designation alpha- la is used throughout this application to refer to this subtype. At the same time, the receptor formerly designated alpha- la was renamed alpha- Id. The new nomenclature is used throughout this application. Stable cell lines expressing these alpha- 1 receptor subtypes are referred to herein; however, these cell lines were deposited with the American Type Culture Collection (ATCC) under the old nomenclature. For a review of the classification of alpha-1
* adrenoceptor subtypes, see, Martin C. Michel, et al., Naunyn-
Schmiedeberg's Arch. Pharmacol. (1995) 352:1-10.
The differences in the alpha adrenergic receptor subtypes have relevance in pathophysiologic conditions. Benign prostatic hyperplasia, also known as benign prostatic hypertrophy or BPH, is an illness typically affecting men over fifty years of age, increasing in severity with increasing age. The symptoms of the condition include, but are not limited to, increased difficulty in urination and sexual dysfunction. These symptoms are induced by enlargement, or hyperplasia, of the prostate gland. As the prostate increases in size, it impinges on free-flow of fluids through the male urethra.
Concommitantly, the increased noradrenergic innervation of the enlarged prostate leads to an increased adrenergic tone of the bladder neck and urethra, further restricting the flow of urine through the urethra. In benign prostatic hyperplasia, the male hormone δalpha- dihydrotestosterone has been identified as the principal culprit. The continual production of 5α-dihydrotestosterone by the male testes induces incremental growth of the prostate gland throughout the life of the male. Beyond the age of about fifty years, in many men, this enlarged gland begins to obstruct the urethra with the pathologic symptoms noted above.
The elucidation of the mechanism summarized above has resulted in the recent development of effective agents to control, and in many cases reverse, the pernicious advance of BPH. In the forefront of these agents is Merck & Co., Inc.s' product PROSCAR® (finasteride). The effect of this compound is to inhibit the enzyme testosterone 5-α reductase, which converts testosterone into 5α-dihydrotesterone, resulting in a reduced rate of prostatic enlargement, and often reduction in prostatic mass. The development of such agents as PROSCAR® bodes well for the long-term control of BPH. However, as may be appreciated from the lengthy development of the syndrome, its reversal also is not immediate. In the interim, those males suffering with BPH continue to suffer, and may in fact lose hope that the agents are working sufficiently rapidly.
In response to this problem, one solution is to identify pharmaceutically active compounds which complement slower-acting therapeutics by providing acute relief. Agents which induce relaxation of the lower urinary tract tissue, by binding to alpha- 1 adrenergic receptors, thus reducing the increased adrenergic tone due to the disease, would be good candidates for this activity. Thus, one such agent is alfuzosin, which is reported in EP 0 204597 to induce urination in cases of prostatic hyperplasia. Likewise, in WO 92/0073, the selective ability of the R(+) enantiomer of terazosin to bind to adrenergic receptors of the alpha- 1 subtype was reported. In addition, in WO 92/161213, combinations of 5α-reductase inhibitory compounds and alpha-1- adrenergic receptor blockers (terazosin, doxazosin, prazosin, bunazosin, indoramin, alfuzosin) were disclosed. However, no information as to the alpha-Id, alpha- lb, or alpha-la subtype specificity of these compounds was provided as this data and its relevancy to the treatment of BPH was not known. Current therapy for BPH uses existing non-selective alpha- 1 antagonists such as prazosin (Minipress, Pfizer), Terazosin (Hytrin, Abbott) or doxazosin mesylate (Cardura, Pfizer). These non-selective antagonists suffer from side effects related to antagonism of the alpha- Id and alpha- lb receptors in the peripheral vasculature, e.g., hypotension and syncope.
The recent cloning of the human alpha- la adrenergic receptor (ATCC CRL 11140) and the use of a screening assay utilizing the cloned human alpha- la receptor enables identification of compounds which specifically interact with the human alpha- la adrenergic receptor. [PCT International Application Publication Nos. WO94/08040, published 14 April 1994 and WO94/10989, published 26 May 1994] As disclosed in the instant patent disclosure, a cloned human alpha- la adrenergic receptor and a method for identifying compounds which bind the human alpha- la receptor has now made possible the identification of selective human alpha- la adrenergic receptor antagonists useful for treating BPH. The instant patent disclosure discloses novel compounds which selectively bind to the human alpha- la receptor. These compounds are further tested for binding to other human alpha- 1 receptor subtypes, as well as counterscreened against other types of receptors (e.g., alpha-2), thus defining the specificity of the compounds of the present invention for the human alpha- la adrenergic receptor.
It is an object of the present invention to identify compounds which bind to the alpha- la adrenergic receptor. It is a further object of the invention to identify compounds which act as antagonists of the alpha- la adrenergic receptor. It is another object of the invention to identify alpha- la adrenergic receptor antagonist compounds which are useful agents for treating BPH in animals, preferably mammals, especially humans. Still another object of the invention is to identify alpha- la adrenergic receptor antagonists which are useful for relaxing lower urinary tract tissue in animals, preferably mammals, especially humans.
It has now been found that the compounds of the present invention are alpha-la adrenergic receptor antagonists. Thus, the compounds of the present invention are useful for treating BPH in mammals. Additionally, it has been found that the alpha- la adrenergic receptor antagonists of the present invention are also useful for relaxing lower urinary tract tissue in mammals.
SUMMARY OF THE INVENTION
The present invention provides compounds for the treatment of urinary obstruction caused by benign prostatic hyperplasia (BPH). The compounds antagonize the human alpha-la adrenergic receptor at nanomolar and subnanomolar concentrations while exhibiting at least ten fold lower affinity for the alpha- Id and alpha- lb human adrenergic receptors and many other G-protein coupled receptors. This invention has the advantage over non-selective alpha-1 adrenoceptor antagonists of reduced side effects related to peripheral adrenergic blockade. Such side effects include hypotension, syncope, lethargy, etc. The compounds of the present invention have the structure:
Figure imgf000007_0001
wherein A is selected from
Figure imgf000008_0001
Figure imgf000008_0002
Figure imgf000008_0004
Figure imgf000008_0003
J is selected from unsubstituted, mono- or poly- substituted phenyl wherein the substituents on the phenyl ring are independently selected from halogen, CF3, cyano, nitro, N(Rn)2, NRnCOR12, NRnCON(R12)2, NR11S02R10, NR11S02N(R12)2, OR10, (CH2)0.4CO2Rn, (CH2)0.4CON(Rn)2, (CH2)0-4SO2N(Rn)2, (CH2)o-4S0 R or C1.4 alkyl; or unsubstituted, mono- or poly- substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, N(RX1)2, (CH2)0.4CO2Rn, (CH2)0-4CON(Rn)2,
(CH2)o-4S02N(Rn)2, (CH2)0-4SO2R10, phenyl, OR10, halogen, Cχ.4 alkyl or C3.8 cycloalkyl;
G is selected from hydrogen, cyano, OR , C02R , CON(R )2, S02R ,
11 S0 N(R )2, tetrazole, isooxadiazole, unsubstituted, mono- or poly- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, cyano, nitro, OR , (CH2)0-4CO2Rn, (CH2)o-4CON(Rn)2, N(RU)2, NRnCOR10, NR11CON(R12)2, NRnS02R10, NRnS02N(R12)2, (CH^Q^SO^R11)^ (CH2)o-4S02R or C1.4 alkyl; or unsubstituted, mono- or poly- substituted pyridyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, thienyl, furanyl or naphthyl are independently selected from CF3, (CH2)o-4C02R11, (CH2)o-4CON(Rn)2, (CH2)0-4SO2N(R11)2, (CH2)o-4S02R10, phenyl, OR10, halogen, C1..4 alkyl or C3.8 cycloalkyl;
R is selected from hydrogen, Cι„8 alkyl, C4.8 cycloalkyl, (CH2)0.4CO2R10, (CH2)θ-4CON(R11)2, (CH2)0.4COR10, (CH2)2.4OR10, (CH2)ι_4CF3, (CH2)1.4S02R1°, (CH2)o.4S02N(Rn)2 or (CH2)ι.4CN;
R1 is selected from COR10, (CH2)0-4CN, (CH2)0-4CF3, (CH2)0-4CO2Rn, (CH2)0^CON(Rn)2, (CH2)o-4S02R10 or (CH2)0-4SO2N(R11)2;
2 10 R is selected from hydrogen, Cj.g alkyl, C3.8 cycloalkyl, (CH2)ι_4θR or (CH2)o-4CF3;
3 4 5
R , R , and R are each independently selected from hydrogen, Cι_8 alkyl, C3.8 cycloalkyl, (CH2)2-4θR10 or (CH2)0-4CF3; 6 7
R and R are each independently selected from hydrogen, Cι_8 alkyl or
C3-8 cycloalkyl;
8 10 R is selected from hydrogen, Cι_8 alkyl, C3.8 cycloalkyl, (CH )ι_4θR ,
(CH )o-4CF3, unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(RX1)2, OR10, (CH2)θ-4CON(Rn)2, (CH2)θ-4C02Rn or Cι_4 alkyl; or unsubstituted, mono- or poly-substituted: pyridyl, pyrazinyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, OR , halogen, C1.4 alkyl or C3.8 cycloalkyl;
9 10 R is selected from hydrogen, Ci-8 alkyl, C3.8 cycloalkyl, (CH )θ-4θR or (CH2)o-4CF3;
R is selected from hydrogen, Cι_8 alkyl, C3.8 cycloalkyl or (CH2)0-4CF3;
11 12 R and R are each independently selected from hydrogen, C ι_8 alkyl,
C3.8 cycloalkyl or (CH2)ι_4CF3;
W is O or NR6;
D is N or C, provided that when D is N, then G is absent; each X is independently selected from halogen, cyano, nitro, Cι„8 alkyl, C3.8 cycloalkyl, (CH2)0-4θR10 or (CH2)0.4CF3;
m, n, o, and p are each independently an integer from zero to three;
s and t are each independently an integer from zero to four;
and the pharmaceutically acceptable salts thereof.
In one embodiment of the present invention is the compound of the formula:
Figure imgf000011_0001
wherein A is selected from
Figure imgf000011_0002
Figure imgf000011_0003
; preferably, A is
Figure imgf000012_0001
J is selected from unsubstituted, mono-, di-, or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(Rn)2, NRnCOR12, NRnCON(R12)2,
NR11S02R10, NR11S02N(R12)2, OR10, (CH2)0-4CO2R11,
(CH2)o-4CON(Rn)2, (CH2)0-4SO2N(Rn)2, (CH2)o.4S02R10 or Cι_4 alkyl; or unsubstituted, mono-, di-, or tri-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, amino, (CH2)0.4CO2R11, (CH2)θ-4CON(R11)2,
(CH2)0-4SO2N(Rn)2, (CH2)o-4S02R10, phenyl, OR10, halogen, C1..4 alkyl or C3. cycloalkyl;
G is selected from hydrogen, cyano, OR , C02R , CON(R )2, S02R , S02N(R ) , tetrazole, isooxadiazole, unsubstituted, mono- or di- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, cyano, nitro, OR , (CH2)0-4CO2Rn, (CH2)0-4CON(Rn)2, N(RH)2, NRnCOR10, NRnCON(R12)2, NR11S02R10, NRnS02N(R12)2, (CH2)0-4SO2N(Rn)2, (CH2)o-4S02R10 or Cχ.4 alkyl;
R is selected from hydrogen, Cι_6 alkyl, C4.6 cycloalkyl,
(CH2)0.4CO2R10, (CH2)o-4CON(Rn)2, (CH2)0.4COR10, (CH2)2.4OR10, (CH2)ι.4CF3, (CH2)ι. S02R10, (CH2)θ-4S02N(R1:L)2 or
Figure imgf000013_0001
3 4 5
R , R , and R are each independently selected from hydrogen, Cι_6 alkyl, C3.6 cycloalkyl, (CH2)2.4OR10 or (CH2)o.4CF3;
8 10 R is selected from hydrogen, Cι_ alkyl, C3. cycloalkyl, (CH )ι_4θR ,
(CH2)o-4CF3, unsubstituted, mono-, di-, or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR10, (CH2)o-4CON(Rn) , (CH2)o-4C02R or C1.4 alkyl; or unsubstituted, mono-, di- or tri- substituted: pyridyl, pyrazinyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, furanyl or naphthyl are independently selected from CF3, cyano, nitro, amino, phenyl, OR , halogen, C1-.4 alkyl or C3.8 cycloalkyl;
9 10 R is selected from hydrogen, C .β alkyl, C3.6 cycloalkyl, (CH2)θ-4θR or (CH2)o.4CF3;
0 and p are each independently an integer from zero to two; preferably, o and p are both two;
and all other variables are as defined previously;
and the pharmaceutically acceptable salts thereof.
In a class of the instant invention is the compound of the formula:
Figure imgf000014_0001
wherein A is selected from
Figure imgf000014_0002
R is selected from hydrogen, Cι_6 alkyl, C4.6 cycloalkyl, or (CH2)i-4CF3;
R1 is selected from COR10, (CH2)0-4CN, (CH2)0. CO2R11, S02R10 or (CH2)o-2CON(Rn)2;
2 10
R is selected from hydrogen, C .g alkyl, C^.Q cycloalkyl, (CH2)χ_3θR or (CH2)0-3CF3;
8 9 R and R are each independently selected from hydrogen or Cι_8 alkyl;
R is selected from hydrogen, C .Q alkyl, C3.6 cycloalkyl, or (CH2)0-3CF3;
R is selected from hydrogen, C .Q alkyl, C3.6 cycloalkyl, or (CH2)ι_4CF3;
and all other variables are as defined previously;
and the pharmaceutically acceptable salts thereof. In a subclass of the invention is the compound of the formula:
Figure imgf000015_0001
wherein A is selected from
Figure imgf000015_0002
Q is C-Y or N;
G is selected from hydrogen, cyano, hydroxy, C02R 11 , CON(R 11 ) , S02R10 or S02N(Rn)2;
each Y is independently selected from hydrogen, halogen, CF3, cyano, nitro, amino, OR10, C02Rn, CON©1 ^2 or C1.4 alkyl;
8 9 R and R are each independently selected from hydrogen or C1-.4 alkyl;
each X is halogen;
r is an integer from zero to two; s is an integer from zero to three; t is equal to one; and all other variables are as defined previously; and the pharmaceutically acceptable salts thereof.
Illustrative of the invention is a compound selected from:
3-[(lR,3S)-3-(4-Cyano-4-phenylpiperidin-l-yl)-cyclopentylcarbamoyl]-4- (3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydro- pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lR,3R)-3-(4-Cyano-4-phenylpiperidin-l-yl)-cyclopentylcarbamoyl]- 4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydro- pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lS,3R)-3-(4-Cyano-4-phenylpiperidin-l-yl)-cyclopentylcarbamoyl]- 4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydro- pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lS,3S)-3-(4-Cyano-4-phenylpiperidin-l-yl)-cyclopentylcarbamoyl]- 4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydro- pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lR,3R)-3-(4-Cyano-4-phenylpiperidin-l-yl)-cyclopentylcarbamoyl]- 4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydro- pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lR,3R)-3-(4-(2-Pyridyl)-piperidin-l-yl)-cyclopentylcarbamoyl]-4- (3,4-difluorophenyl)-6-methoxyxnethyl-2-oxo-l,2,3,4-tetrahydro- pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lR,3S)-3-(4-(2-Pyridyl)-piperidin-l-yl)-cyclopentylcarbamoyl]-4- (3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydro- pyrimidine-5-carboxylic acid, methyl ester; (4S)-3-[(lS,3R)-3-(4-(2-Pyridyl)-piperidin-l-yl)-cyclopentylcarbamoyl]-4- (3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydro- pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lS,3S)-3-(4-(2-Pyridyl)-piperidin-l-yl)-cyclopentylcarbamoyl]-4- (3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydro- pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lR,3S)-3-(4-(2-Pyridyl)-piperidin-l-yl)-cyclopentylcarbamoyl]-4- (3,4-difluorophenyl)-2-oxazolidinone;
(4S)-3-[(lR,3R)-3-(4-(2-Pyridyl)-piperidin-l-yl)-cyclopentylcarbamoyl]-4- (3,4-difluorophenyl)-2-oxazolidinone;
(4S)-3-[(lS,3R)-3-(4-(2-Pyridyl)-piperidin-l-yl)-cyclopentylcarbamoyl]-4- (3,4-difluorophenyl)-2-oxazolidinone;
(4S)-3-[(lS,3S)-3-(4-(2-Pyridyl)-piperidin-l-yl)-cyclopentylcarbamoyl]-4- (3,4-difluorophenyl)-2-oxazolidinone;
(4S)-3-[(lR,3S)-3-(4-(2-Cyanophenyl)-piperidin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lR,3R)-3-(4-(2-Cyanophenyl)-piperidin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lS,3R)-3-(4-(2-Cyanophenyl)-piperidin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methox3πιιethyl-2-oxo- l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lS,3S)-3-(4-(2-Cyanophenyl)-piperidin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, methyl ester; (4S)-3-[(lR,3R)-3-(4-(2-Cyanophenyl)-piperidin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-2-oxazolidinone;
(4S)-3-[(lS,3R)-3-(4-(2-Cyanophenyl)-piperidin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-2-oxazolidinone;
(4S)-3-[( lS,3S)-3-(4-(2-Cyanophenyl)-piperidin- 1-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-2-oxazolidinone;
(4S)-3-[(lR,3S)-3-(4-(2-Cyanophenyl)-piperidin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-2-oxazolidinone;
(4S)-3-[QS,3R)-3-(4-(2-Cyanophenyl)-piperazin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-2-oxazolidinone;
(4S)-3-[(lS,3S)-3-(4-(2-Cyanophenyl)-piperazin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-2-oxazolidinone;
(4S)-3-[(lR,3R)-3-(4-(2-Cyanophenyl)-piperazin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-2-oxazolidinone;
(4S)-3-[(lR,3S)-3-(4-(2-Cyanophenyl)-piperazin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-2-oxazolidinone;
(4S)-3-[(lR,3S)-3-(4-(2-Cyanophenyl)-piperazin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lS,3R)-3-(4-(2-Cyanophenyl)-piperazin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydro-p3π-imidine-5-carboxylic acid, methyl ester; (4S)-3-[( lS,3S)-3-(4-(2-Cyanophenyl)-piperazin- 1-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[( lR,3R)-3-(4-(2-Cyanophenyl)-piperazin- 1-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, methyl ester;
(2R and S)-2-(3,4-Difluorophenyl)-3-methyl-N-[(lR,3R)-3-(4-cyano-4- phenyl-piperidin- l-yl)-cyclopentyl]-butyramide;
(2R or S)-2-(3,4-Difluorophenyl)-3-methyl-N-[( lR,3R)-3-(4-orthotolyl-4- piperidin-l-yl)-cyclopentyl]-butyr amide;
(2R or S)-2-(3,4-Difluorophenyl)-3-methyl-N-[(lS,3R)-3-(4-orthotolyl-4- cyanopiperidin-l-yl)-cyclopentyl]-butyramide;
(2R or S)-2-(3,4-Difluorophenyl)-3-methyl-N-[(lS,3R)-3-(4-orthotolyl-4- cyanopiperidin-l-yl)-cyclopentyl]-butyramide;
(2R or S)-2-(3,4-Difluorophenyl)-3-methyl-N-[(lS,3S)-3-(4-orthotolyl-4- cyanopiperidin-l-yl)-cyclopentyl]-butyramide; or
(2R or S)-2-(3,4-Difluorophenyl)-3-methyl-N-[(lR,3R)-3-(4-(4- fluorophenyl )piperidin- l-yl)-cyclopentyl]-butyramide;
and the pharmaceutically acceptable salts thereof.
An illustration of the invention is a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described above and a pharmaceutically acceptable carrier. An example of the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier. Another illustration of the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
Exemplifying the invention is the composition further comprising a therapeutically effective amount of a testosterone 5-alpha reductase inhibitor. Preferably, the testosterone 5-alpha reductase inhibitor is a type 1, a type 2, both a type 1 and a type 2 (i.e., a three component combination comprising any of the compounds described above combined with both a type 1 testosterone 5-alpha reductase inhibitor and a type 2 testosterone 5-alpha reductase inhibitor) or a dual type 1 and type 2 testosterone 5-alpha reductase inhibitor. More preferably, the testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5-alpha reductase inhibitor. Most preferably, the testosterone 5-alpha reductase inhibitor is finasteride.
More specifically illustrating the invention is a method of treating benign prostatic hyperplasia in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compounds (or any of the compositions) described above.
Further exemplifying the invention is the method of treating BPH wherein the compound (or composition) additionally does not cause a fall in blood pressure at dosages effective to alleviate BPH.
Another example of the invention is the method of treating benign prostatic hyperplasia wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor. Preferably, the testosterone 5-alpha reductase inhibitor is finasteride.
Further illustrating the invention is a method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compounds (or any of the compositions) described above.
More specifically exemplifying the invention is the method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue wherein the compound (or composition) additionally does not cause a fall in blood pressures at dosages effective to inhibit contraction of prostate tissue or relax lower urinary tract tissue. More particularly illustrating the invention is the method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue wherein the compound (or composition) is administered in combination with a testosterone 5-alpha reductase inhibitor; preferably, the testosterone 5-alpha reductase inhibitor is finasteride.
More particularly exemplifying the invention is a method of treating a disease which is susceptible to treatment by antagonism of the alpha- la receptor which comprises administering to a subject in need thereof an amount of any of the compounds described above effective to treat the disease. Diseases which are susceptible to treatment by antagonism of the alpha- la receptor include, but are not limited to, BPH, high intraocular pressure, high cholesterol, impotency, sympathetically mediated pain, migraine (see, K.A. Vatz, Headache 1997:37: 107-108) and cardiac arrhythmia. An additional illustration of the invention is the use of any of the compounds described above in the preparation of a medicament for: a) the treatment of benign prostatic hyperplasia; b) relaxing lower urinary tract tissue; or c) inhibiting contraction of prostate tissue; in a subject in need thereof. An additional example of the invention is the use of any of the alpha- la antagonist compounds described above and a 5-alpha reductase inhibitor for the manufacture of a medicament for: a) treating benign prostatic hyperplasia; b) relaxing lower urinary tract tissue; or c) inhibiting contraction of prostate tissue which comprises an effective amount of the alpha- la antagonist compound and the 5-alpha reductase inhibitor, together or separately.
DETAILED DESCRIPTION OF THE INVENTION
Representative compounds of the present invention exhibit high selectivity for the human alpha- la adrenergic receptor. One implication of this selectivity is that these compounds display selectivity for lowering intraurethral pressure without substantially affecting diastolic blood pressure.
Representative compounds of this invention display submicromolar affinity for the human alpha- la adrenergic receptor subtype while displaying at least ten-fold lower affinity for the human alpha- Id and alpha- lb adrenergic receptor subtypes, and many other G- protein coupled human receptors. Particular representative compounds of this invention exhibit nanomolar and subnanomolar affinity for the human alpha- la adrenergic receptor subtype while displaying at least 30 fold lower affinity for the human alpha- Id and alpha- lb adrenergic receptor subtypes, and many other G-protein coupled human receptors (e.g., serotonin, dopamine, alpha-2 adrenergic, beta adrenergic or muscarinic receptors).
These compounds are administered in dosages effective to antagonize the alpha- la receptor where such treatment is needed, as in BPH. For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts." Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following: Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate, Mucate, Napsylate, Nitrate, N-methylglucamine ammonium salt, Oleate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate,
Polygalacturonate, Salicylate, Stearate, Sulfate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide and Valerate.
Compounds of this invention are used to reduce the acute symptoms of BPH. Thus, compounds of this invention may be used alone or in conjunction with a more long-term anti-BPH therapeutics, such as testosterone 5-α reductase inhibitors, including PROSCAR® (finasteride). Aside from their utility as anti-BPH agents, these compounds may be used to induce highly tissue-specific, localized alpha- la adrenergic receptor blockade whenever this is desired. Effects of this blockade include reduction of intra-ocular pressure, control of cardiac arrhythmias, and possibly a host of alpha-la receptor mediated central nervous system events.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu. Where the compounds according to the invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more chiral centers, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates are also encompassed within the scope of this invention.
The term "alkyl" shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range (i.e., methyl, ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.).
The term "alkenyl" shall mean straight or branched chain alkenes of two to ten total carbon atoms, or any number within this range. The term "aryl" as used herein, except where otherwise specifically defined, refers to unsubstituted, mono- or poly-substituted aromatic groups such as phenyl or naphthyl.
The term "cycloalkyl" shall mean cyclic rings of alkanes of three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g., aralkoxyaryloxy) it shall be interpreted as including those limitations given above for "alkyl" and "aryl." Designated numbers of carbon atoms (e.g., Cχ.χo) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
The term "halogen" shall include iodine, bromine, chlorine and fluorine. The term "substituted" shall be deemed to include multiple degrees of substitution by a named substitutent. The term "poly- substituted" as used herein shall include di-, tri-, tetra- and penta- substitution by a named substituent. Preferably, a poly-substituted moiety is di-, tri- or tetra-substituted by the named substituents, most preferably, di- or tri-substituted.
It is intended that the definition of any substituent or variable (e.g., X, R^, Rl2) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, - N(R )2 represents -NH2, -NHCH3, -NHC2H5, -N(CH3)C2Hδ, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth below.
Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. The term heterocycle or heterocyclic ring, as used herein, represents an unsubstituted or substituted stable 5- to 7-membered monocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from N, 0 or S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.
The term "thienyl," as used herein, refers to the group
Figure imgf000026_0001
The term "selective alpha- la adrenergic receptor antagonist," as used herein, refers to an alpha- la antagonist compound which is at least ten fold selective for the human alpha- la adrenergic receptor as compared to the human alpha- lb, alpha- Id, alpha-2a, alpha- 2b and alpha-2c adrenergic receptors. The term "lower urinary tract tissue," as used herein, refers to and includes, but is not limited to, prostatic smooth muscle, the prostatic capsule, the urethra and the bladder neck.
The term "subject," as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated. When referring to methods of treating BPH, inhibiting contraction of prostate tissue or of relaxing lower urinary tract tissue with a combination of two or more agents, or a composition comprising two or more agents, for example an alpha- la antagonist and a 5-alpha reductase inhibitor, the "therapeutically effective amount" is that amount of the combination of the agents taken together so that the combined effect elicits the desired biological or medicinal response. For example, the therapeutically effective amount of a composition comprising an alpha-la antagonist compound of the present invention and finasteride would be the amount of alpha- la antagonist and finasteride that when taken together have a combined effect that is therapeutically effective.
The present invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto- injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin. Where the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column. During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic
Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. The specificity of binding of compounds showing affinity for the alpha- la receptor is shown by comparing affinity to membranes obtained from tranfected cell lines that express the alpha- la receptor and membranes from cell lines or tissues known to express other types of alpha (e.g., alpha- Id, alpha- lb) or beta adrenergic receptors. Expression of the cloned human alpha- Id, alpha- lb, and alpha- la receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities. Antagonism by these compounds of the human alpha- la adrenergic receptor subtype may be functionally demonstrated in anesthetized animals. These compounds may be used to increase urine flow without exhibiting hypotensive effects.
The ability of compounds of the present invention to specifically bind to the alpha- la receptor makes them useful for the treatment of BPH. The specificity of binding of compounds showing affinity for the alpha- la receptor is compared against the binding affinities to other types of alpha or beta adrenergic receptors. The human alpha adrenergic receptor of the la subtype was recently identified, cloned and expressed as described in PCT International Application Publication Nos. WO94/08040, published 14 April 1994 and WO 94/21660, published 29 September 1994. The cloned human alpha- la receptor, when expressed in mammalian cell lines, is used to discover ligands that bind to the receptor and alter its function. Expression of the cloned human alpha-Id, alpha- lb, and alpha-la receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities.
Compounds of this invention exhibiting human alpha- la adrenergic receptor antagonism may further be defined by counterscreening. This is accomplished according to methods known in the art using other receptors responsible for mediating diverse biological functions. fSee e.g.. PCT International Application Publication No. WO94/10989, published 26 May 1994; U.S. Patent No. 5,403,847, issued April 4, 1995]. Compounds which are both selective amongst the various human alpha- 1 adrenergic receptor subtypes and which have low affinity for other receptors, such as the alpha-2 adrenergic receptors, the β-adrenergic receptors, the muscarinic receptors, the serotonin receptors, and others are particularly preferred. The absence of these non-specific activities may be confirmed by using cloned and expressed receptors in an analogous fashion to the method disclosed herein for identifying compounds which have high affinity for the various human alpha- 1 adrenergic receptors. Furthermore, functional biological tests are used to confirm the effects of identified compounds as alpha- la adrenergic receptor antagonists. The present invention also has the objective of providing suitable topical, oral, systemic and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention. The compositions containing compounds of this invention as the active ingredient for use in the specific antagonism of human alpha- la adrenergic receptors can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic administration. For example, the compounds can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or by injection. Likewise, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, topical with or without occlusion, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non- toxic amount of the compound desired can be employed as an alpha- la antagonistic agent.
Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
The liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. Other dispersing agents which may be employed include glycerin and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired. The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinyl- pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl- amidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl- eneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific blockade of the human alpha- la adrenergic receptor is required.
The daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0 and 100 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg kg to about 20 mg/kg of body weight per day. Preferably, the range is from about 0.001 to 10 mg/kg of body weight per day, and especially from about 0.001 mg/kg to 7 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day.
Compounds of this patent disclosure may be used alone at appropriate dosages defined by routine testing in order to obtain optimal antagonism of the human alpha- la adrenergic receptor while minimizing any potential toxicity. In addition, co-administration or sequential administration of other agents which alleviate the effects of BPH is desirable. Thus, in one embodiment, this includes administration of compounds of this invention and a human testosterone 5-α reductase inhibitor. Included with this embodiment are inhibitors of 5-alpha reductase isoenzyme 2. Many such compounds are now well known in the art and include such compounds as PROSCAR®, (also known as finasteride, a 4-Aza-steroid; see US Patents 4,377,584 and 4,760,071, for example). In addition to PROSCAR®, which is principally active in prostatic tissue due to its selectivity for human 5-α reductase isozyme 2, combinations of compounds which are specifically active in inhibiting testosterone 5-alpha reductase isozyme 1 and compounds which act as dual inhibitors of both isozymes 1 and 2, are useful in combination with compounds of this invention. Compounds that are active as 5α-reductase inhibitors have been described in WO93/23420, EP 0572166; WO 93/23050; WO93/23038, ; WO93/23048; WO93/23041; WO93/23040; WO93/23039; W093/23376; W093/23419, EP 0572165; WO93/23051.
The dosages of the alpha- la adrenergic receptor and testosterone 5-alpha reductase inhibitors are adjusted when combined to achieve desired effects. As those skilled in the art will appreciate, dosages of the 5-alpha reductase inhibitor and the alpha- la adrenergic receptor antagonist may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were used alone. In accordance with the method of the present invention, the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.
Thus, in one preferred embodiment of the present invention, a method of treating BPH is provided which comprises administering to a subject in need of treatment any of the compounds of the present invention in combination with finasteride effective to treat BPH. The dosage of finasteride administered to the subject is about 0.01 mg per subject per day to about 50 mg per subject per day in combination with an alpha- la antagonist. Preferably, the dosage of finasteride in the combination is about 0.2 mg per subject per day to about 10 mg per subject per day, more preferably, about 1 to about 7 mg per subject to day, most preferably, about 5 mg per subject per day.
For the treatment of benign prostatic hyperplasia, compounds of this invention exhibiting alpha- la adrenergic receptor blockade can be combined with a therapeutically effective amount of a 5α-reductase 2 inhibitor, such as finasteride, in addition to a 5α- reductase 1 inhibitor, such as 4,7β-dimethyl-4-aza-5α-cholestan-3- one, in a single oral, systemic, or parenteral pharmaceutical dosage formulation. Alternatively, a combined therapy can be employed wherein the alpha- la adrenergic receptor antagonist and the 5α- reductase 1 or 2 inhibitor are administered in separate oral, systemic, or parenteral dosage formulations. See, e.g., U.S. Patent No.'s 4,377,584 and 4,760,071 which describe dosages and formulations for 5α-reductase inhibitors.
Abbreviations used in the instant specification, particularly the Schemes and Examples, are as follows:
Aq = aqueous BCE = bromochloroethane
Boc or BOC = t-butyloxycarbonyl BOC20 = di-t.ert.-butyl dicarbonate
BOPC1 = bis(2-oxo-3-oxazolidinyl)phosphinic chloride
Cbz = benzyloxycarbonyl Cbz-Cl = benzyloxycarbonyl chloride
DEAD = diethylazodicarboxylate
DMF = N,N-dimethylformamide
DMSO = dimethylsulfoxide
DPPA = diphenylphosphoryl azide EDC = l-(3-Dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride
Et = ethyl
Et3N = triethylamine
EtOAc = ethyl acetate EtOH = ethanol
FABLRMS = fast atom bombardment low resolution mass spectroscopy
HPLC = high performance liquid chromatography
HOAc = acetic acid HOAt = l-hydroxy-7-aza-benzotriazole HOBt = 1-hydroxy benzotriazole hydrate i-PrOH = 2-propanol i-Pr2NEt = diisopropylethylamine
KOtBu = potassium ter-.-buto.ride LAH = lithium aluminum hydride mCPBA = meta-chloroperbenzoic acid
Me = methyl
Me OH = methanol
NMR = nuclear magnetic resonance Nu- = nucleophile
PCTLC = preparative centrifugal thin layer chromatography
PEI = polyethylenimine
Ph = phenyl RT = retention time tBuOH = tert-butanol
TEBAC = benzyltriethylammonium chloride
TFA = trifluoroacetic acid
THF = tetrahydrofuran TLC = thin layer chromatography
TMS = trimethylsilyl
The compounds of the present invention can be prepared readily according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Unless otherwise indicated, all variables are as defined above. In general, compounds claimed within this invention are accessable from a cyclic alkenone intermediate, Scheme 1. Cyclopentadiene monoepoxide is opened up to (+.) cis-3-azido-l- trimethylsiloxy-2-cyclopentene, which is then resolved and separated. The resulting S and R cyclopentanols are oxidized to the corresponding cyclopentanone intermediates useful for the compounds of this invention.
Some of the examples described within this invention were prepared as outlined in Scheme 2. The cyclopentanone intermediate is converted to the piperadinyl substituted cyclopentane via reductive amination. The Boc protected amino group is deprotected, and acylation or alkylation provides the desired analog.
The piperazinyl substituted cyclopentane compounds were synthesized as described in Scheme 3. The procedures are the same as described in Scheme 2, except that a substituted piperazine, as opposed to a substituted piperadine, is added during the reductive amination step.
Some of the examples described within this invention are described as shown in Scheme 4. The procedures are the same as described in Scheme 2, except Step C is modified to an EDC/HOAt mediated acylation with α-isopropyl-3,4-diphenylacetic acid.
The activated termini species comprising the "A" groups are readily prepared by one of ordinary skill in the art. For example, oxazolidinones are prepared and activated in general by published and well developed chemistry, in particular, of Evans. [Evans, D.A.; Nelson, J.V.; Taber, T.R. Top. Stereochem. 13, 1 (1982); Gage, J.R.; Evans, D.A., Organic Synthesis, 1990, 68, 77-82.] The starting materials, in general, are natural and unnatural amino acids. For instance, some of the preferred compounds are prepared from substituted phenyl glycine derivatives, which after reduction of the carboxylate and a phosgene equivalent mediated cyclization provides the substituted oxazolidinone ring system. Deprotonation with n-butyl lithium and addition to a THF solution of p-nitrophenylchloroformate produces the stable, isolable "activated'Oxazolidinone (oxa). Dihydropyrimidinones are prepared by condensation reaction of the aldehyde, urea and a 1,3-acetoacetate type derivative catalyzed by a Lewis Acid, a copper (I) species and acetic acid. Activation was accomplished by treatment with a strong base, for instance, LiN(TMS)2, followed by addition to a THF solution of p- nitrophenylchloroformate. A description of the synthesis of the mentioned types of dihydropyrimidinones can be found in WO 97/21687, published June 19, 1997.
The dihydropyrimidinones and oxazolidinones were synthesized independently in racemic form, and then separated utilizing preparative chiral HPLC. Their optical rotations were recorded. Then they were activated and reacted with prerequisite amines. From the receptor binding studies, a preferred isomer was identified, the (+) rotational isomer in each case. The absolute configurations were determined to be (S) for both the dihydropyrimidinones and oxazolidinones by correlating their optical rotations with x-ray crystal structures obtained of fragments involved in the production of the antagonists.
Scheme 1
Figure imgf000038_0001
(9%1 ,2 isomer)
1 ) HCI
2) vinyl acetate, pancreatin, THF
3) Boc20, Pd/C, H2
Figure imgf000038_0002
(COCI)2, DMSO (COCI)2, DMSO
Et3N, CH2CI2 Et3N, CH2CI2
93% 93%
O-^/N^ NHBoc O ^X... NHBoc
Figure imgf000039_0001
NHBoc
NHBoc
Figure imgf000039_0002
Figure imgf000039_0003
Scheme 4 (examples 28-35)
NHBoc(from s ep A, scheme 2)
Figure imgf000040_0001
Figure imgf000040_0002
The following examples are provided to further define the invention without, however, limiting the invention to the particulars of these examples.
EXAMPLE 1
Figure imgf000040_0003
(±) 2
(±.cis)-3-azido-l-trimethylsilyloxy-2-cvclopentene (2) To a 0°C solution of 0.97 g (0.84 mmol) tetrakistriphenylphosphine palladium(O) and 5.0 ml (38 mmol) azidotrimethylsilane (TMSN3 in 150 ml THF was slowly added a 15 ml THF solution of 2.97 g (36 mmol) cyclopenadiene monoepoxide (1 ml THF rinse). After stirring 3h at 0 °C, 0.5 ml more TMSN3 was added and the reaction stirred 30 more min, then concentrated in vacuo. The resulting paste was immediately purified by flash chromatography (6.5x10 cm silica gel, 1:1 CH2Cl2:hexanes, followed by 3x10 cm silica gel, 1:1 CH2Cl :hexanes). lH NMR (300 MHz, CDCI3) δ 6.00 (ddd, IH, J = 1.95, 1.95, 5.38 Hz); 5.87 (ddd, IH, J = 1.96, 1.96, and 5.37 Hz); 4.73 (m, IH); 4.15 (m, IH); 2.67
(ddd, IH, J= 7.09, 7.57, and 13.9 Hz); 1.68 (ddd, IH, J = 4.88, 4.88 and 13.9 Hz); 0.18 (s, 9H). TLC Rf = 0.36 (1:1 CH Cl :hexanes).
EXAMPLE 2 NHBoc
Figure imgf000041_0001
(LR, 3£)-3- ertButylcarboxyamino-l-acetoxycyclopentane, (3)
(IS. 3.R)-3-t:ert.Butylcarboxyamino-l-cvclopentanol. (4) To a solution of 4.35g (22 mmol) 2 in 400 ml EtOAc was added 100 ml 1M aq. HCI solution and the mixture shaken vigorusly for 3 min.
The layers were separated and the organic layer was washed with 100 ml saturated NaHCθ3 and 100 ml brine, dried over Na2Sθ4, and concentrated. The resulting oil was dissolved in 80 ml THF and to this was added 20 ml (217 mmol) vinyl acetate and 10 g pancreatin. After 1 hr 20 min, the reaction was filtered through a plug of celite (filtercake rinsed 5x50 ml EtOAc) and concentrated. The resulting oil was dissolved in 20 ml EtOAc and added to a solution of 4 g 10% Pd/C and
4.92g (22.5 mmol) dit-e/ -butyldicarbonate in 20 ml EtOAc. The reaction vessel was charged to 60 psi H2, shaken gently for 5 h, filtered and concentrated. Purification by flash chromatography (5x12 cm silica gel, linear gradient 20-70% EtOAc:hexanes) afforded 3 and 4.
3: !H NMR (300 MHz, CDCI3) δ 5.15 (dt, IH, J = 5.86 and 2.93 Hz);
4.65 (br m, IH); 4.11 (br m, IH); 2.30 (m, IH); 2.04 (s, 3H); 2.00 (m, IH); 1.92 (m, IH); 1.85 (m, IH); 1.62 (m, 2H); 1.46 (s, 9H)
4: !H NMR (300 MHz, CDCI3) δ 5.06 (br s, IH); 4.36 (br m, IH); 4.04
(br m, IH); 2.09 (m, 3H); 1.78 (m, 3H); 1.62 br d, IH, J = 5.62 Hz); 1.44 (s, 9H): TCL Rf (0.09 30% EtOAc:hexanes). EXAMPLE 3
NHBoc
Figure imgf000042_0001
(3-R)-3-fert.Butylcarboxyamino-l-cvclopentanone. (7)
To a -78 °C solution of 0.27 ml (3.1 mmol) oxalyl chloride in CH2C12 was added 0.45 ml (6.4 mmol) DMSO and the reaction stirred 35 min at -78 °C. To this was added 0.42g (2 mmol) 4 as a solution in 2 ml CH2C12
(1 ml rinse) via cannula, and the resulting cloudy white solution stirred at -78 °C for 30 min. To this was added 0.90 ml (6.5 mmol) Et3N and the reaction was warmed to 0 °C for 30 min. The reaction was diluted with 200 ml CH2C12 and washed with 100 ml saturated aqueous NH4CI solution. The aqueous layer was extracted with 50 ml CH2C12 and the combined organic extracts were washed with 150 ml brine, dried over Na S04, filtered and concentrated. Purification by flash chromatography (3x14 cm silica gel, linear gradient 30-50% EtOAc:hexanes) afforded 7. iH NMR (300 MHz, CDCI3) δ 4.59 (br s, IH):
4.22 (br d, IH, J = 5.86 Hz); 2.63 (dd, IH, J = 18.8 and 7.57 Hz); 2.34 (m, 2H); 2.23 (dd, IH, J = 14.9 and 5.61 Hz); 2.11 (dd, IH, J = 18.8 and 8.06 Hz); 1.85 (m, IH); 1.46 (s, 9H). TLC Rf = 0.33 (40% EtOAc.hexanes).
EXAMPLE 4
.ιNHBoc
(3»S^-3-t.erffiutylcarboxyamino-l-cvclopentanone. (6)
To a solution of 0.76 g (2.9 mmol) acetate 3 in 25 ml methanol was added 0.55 g (4.0 mmol) K2C03. After 3 h of vigorus stirring the reaction mixture was diluted with 300 ml EtOAc and extracted with 200 ml 10% aq KHSO4 solution. The aqueous layer was extracted with 50 ml EtOAc and the combined organic extracts were washed with brine, dried over Na S04, filtered and concentrated. Purification by flash chromatography (3x15 cm silica gel, linear gradient 30-70% EtOAc:hexanes) afforded 5 which had spectral characteristics identical to 4 except for optical rotation. Swern oxidation under identical conditions as described converting 4 to 7, as described in Example 3, afforded ketone 6. Separation of 6 and 7 by chiral HPLC (Chiralpak AD 250 x 4.6 mm, 9:1 hexane:ethanol) demonstrated the material to be of 86 - 94% ee.
EXAMPLE 5
Figure imgf000044_0001
3 - [(1R, 3S) - 3 - (4 - cyano- 4 - phenylpiperidin - 1 - yl) - cyclopentylcarbamoyl] - 4 - (3, 4 - difluorophenyl) -6-methoxymethyl-2- oxo-1.2.3.4-tetrahvdro-pyrimidine-5-carboxylic acid, methyl ester
STEP A: Reductive Amination: To a solution of 0.197 g (1.06 mmol) 4- cyano-4-phenyl piperidine and 0.2087g (1.05 mmol) ketone 7 in 2 ml
MeOH was added 0.35 ml (6.1 mmol) acetic acid and the reaction mixture was stirred 30 min at room temperature. To this was then added 1.5 ml (1.5 mmol) of a 1M THF solution of sodium cyanoborohydride. The reaction was stirred 18 h, then diluted with 300 ml EtOAc and washed with 200 ml saturated NaHCθ3 solution. The aqueous layer was extracted with 50 ml EtOAc and the combined organic extracts were washed with 200 ml brine, dried over Na2S04, filtered and concentrated. Purification by flash chromatography (3x16 cm silica gel, linear gradient 2-5% MeOH:CH2Cl2 followed by 2.5x16 cm silica gel, linear gradient 2-5% MeOH:CH2Cl2 on the mixed fractions) afforded cis and trans products 9 and 8. (UR, 3S)-3-[4-cyano-4-phenypiperid-l-yl-l-fer -
Butylcai xyammocyclopentane 9 (cis): !H NMR (300 MHz, CDCI3) d
7.52 (m, 2H); 7.40 (m, 2H); 7.33 (m, IH); 4.62 (br s, IH); 3.98 (br m, IH); 3.12 (m, 2H); 2.70 (quint, IH, J = 7.08 Hz); 2.46 (m, 2H); 2.31 (m, IH); 2.12 (m, 3H); 2.10-1.89 (m, 2H); 1.64 (m, IH); 1.54 (m, IH); 1.45 (s, 9H); 1.34 (dt, 1H, = 12.2, 8.79 Hz).
(1-β, 3β)-3-[4-cyano-4-phenypiperid-l-yl-l-fer - Butylcarboxyaniinocyclopentane 8 (trans): !H NMR (300 MHz, CDCI3) d 7.51 (m, 2H); 7.40 (m, 2H); 7.34 (m, IH); 4.50 (br s, IH); 4.06 (br s, IH); 3.09
(br t, 2H, J = 10.5 Hz); 2.84 (quint, IH, J = 8.05 Hz); 2.47 (m, 3H); 2.12 (m,
3H); 2.03 (m, IH); 1.91 (m, IH); 1.79 (m, IH); 1.50 (m, 2H); 1.45 (s, 9H);
1.39 (m, IH).
STEP B: Boc Removal To a 0 °C solution of 0.22 g 9 in 15 ml EtOAc was bubbled through HCI gas for 10 min and then concentrated in vacuo to give 0.2g of the amine hydrochloride as a white solid. Calc for C 7H25N3Cl : C=59.65%, H=7.36%, N=12.27%; found C=59.27%, H=7.36%, N=12.36%.
STEP C: End Group Coupling: To a solution of 0.79g (0.23 mmol) amine hydrochloride in 10 ml DMF was added 0.13 ml (0.93 mmol) Et3N and
0.113g (0.24 mmol) (+) - (S) - (4 - nitrophenyloxycarbonyl) - 4 - (3, 4 - difluorophenyl) - 6 - methoxymethyl - 2 - oxo - 1,2,3,4 - tetrahydropyrimidine - 5 - carboxylic acid methyl ester. After 2 h at ambient temperature, the reaction was diluted with 200 ml EtOAc, washed with 200 ml aqueous 10% K2Cθ3 solution, 200 ml dilute brine, and 200ml brine, then dried over Na S04, filtered and concentrated. Purification by flash chromatography (2 x 16 cm silica gel, linear gradient 1-4% MeOH/CH2Cl2) followed by rewashing with aqueous 10%
K2Cθ3 solution and brine, and a final chromatography (2 x 16 cm silica gel, linear gradient 80-100% EtOAc/hexanes) afforded the title compound. NMR (300 MHz, CDCI3) d 8.88 (d, IH, J = 6.84 Hz); 7.67 (s, IH); 7.52-7.03 (m, 8H); 6.67 (s, IH); 4.68 (s, 2H); 4.17 (m, IH); 3.71 (s, 3H);
3.49 (s, 3H); 3.10 (br t, 2H, J = 11.7 Hz); 2.74 (m, IH); 2.20 (m, 3H); 2.07 (m,
4H); 1.96 (m, IH); 1.62 (m, 3H); 1.41 (m, IH)
This was dissolved in EtOAc, cooled to 0 °C and 0.5 ml (O.δmmol, 1M sol'n in Et 0) HCI was added. After 10 min at 0 °C the reaction was concentrated in vacuo to afford the HCI salt of the title compound. Calculated for C3 H36N5θ5F2Cl»0.25 H20:C= 59.25% H=5.67%
N= 10.80%. Found C=59.25% H=5.58% N=10.40%.
The following compounds were prepared by procedures substantially as described above in Example 5 in steps A, B, and C. The cis and trans isomers from step A were separated in all cases and both used in steps B and C. In the case of examples 13-16 and 21-27, the (+)- OS) -3-(4- nitrophenyloxycarbonyl) - 4 - (3, 4 - difluorophenyl) - oxazolidin 2 - one was substituted for the (+) - OS) - (4 - nitrophenyloxycarbonyl) - 4 - (3, 4 - difluorophenyl) - 6 - methoxymethyl - 2 - oxo - 1,2,3,4 - tetrahydropyrimidine - 5 - carboxylic acid methyl ester.
EXAMPLE 6
Figure imgf000046_0001
(4S) - 3 - [(1R, 3R) - 3 - (4 - Cyano - 4 - phenylpiperidin - 1 - yl) - cyclopentylcarbamoyl] - 4 - (3, 4 - difluorophenyl) -6-methoxymethyl-2- oxo-1.2.3.4-tetrahvdro-pyrimidine-5-carboxylic acid, methyl ester
Calculated for C32H36N5θ5F2Cl»0.35 H2O»0.05 EtOAc:C= 59.06%
H=5.71% N=10.70%. Found C=59.34% H=5.51% N=10.30%.
EXAMPLE 7
Figure imgf000046_0002
(4S) - 3 - [(IS, 3R) - 3 - (4 - Cyano - 4 - phenylpiperidin - 1 - yl) - cyclopentylcarbamoyl] - 4 - (3, 4 - difluorophenyl) -6-methoxymethyl-2- oxo-1.2t3.4-tetrahvdro-pyrimidine-5-carboxylic acid, methyl ester
Calculated for C32H36N5θ5F2Cl»0.1 H20 »0.1 EtOAc:C= 59.43%
H=5.70% N= 10.70%. Found C=59.48% H=5.80% N=10.44%.
EXAMPLE 8
Figure imgf000047_0001
(4S) - 3 - [(IS, 3S) - 3 - (4 - Cyano - 4 - phenylpiperidin - 1 - yl) - cyclopentylcarbamoyl] - 4 - (3, 4 - difluorophenyl) -6-methoxymethyl-2- oxo-1.2.3.4-tetrahvdro-pyrimidine-5-carboxylic acid, methyl ester
Calculated for C32H36N5θ5F2Cl»0.1 H20 «0.1 EtOAc:C= 59.43%
H=5.70% N=10.70%. Found C=59.43% H=5.58% N=10.20%.
EXAMPLE 9
Figure imgf000047_0002
(4S)-3-[(lR, 3R)-3-(4-(2-Pyridyl)-piperidin-l-yl)-cyclopentylcarbamoyl]-4- (3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydro- pyrimidine-5-carboxylic acid, methyl ester, dihydrochloride salt Calculated for C3oH37N5θ5F2Cl2 «0.95 H20 •0.35
EtOAc:C=53.53% H=5.97% N=9.94%. Found: C=53.53% H=5.90% N=9.93%
EXAMPLE 10
Figure imgf000048_0001
(4S)-3-[(lR, 3S)-3-(4-(2-Pyridyl)-piperidin-l-yl)-cyclopentylcarbamoyl]-4-
(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydro- pyrimidine-5-carboxylic acid, methyl ester, dihydrochloride salt
Calculated for C30H37N5θ5F2Cl2 » 1.25 H20: C=53.06% H=5.86%
N=10.31 %. Found: C=53.09% H=5.72% N= 10.28%
EXAMPLE 11
Figure imgf000048_0002
(4S)-3-[( IS, 3R)-3-(4-(2-Pyridyl)-piperidin- l-yl)-cyclopentylcarbamoyl]-4-
(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydro- pyrim ine-5-carboxylic acid, methyl ester, dihydrochloride salt
Calculated for C30H37N5θ F2Cl2 »1.5 H20, 0.35 EtOAc: C=52.79%
H=6.04% N=9.80 %. Found: C=52.81% H=5.95% N=9.62% EXAMPLE 12
Figure imgf000049_0001
(4S)-3-[( IS, 3S)-3-(4-(2-Pyridyl)-piperidin- l-yl)-cyclopentylcarbamoyl]-4- (3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydro- yrimidine-5-carboxylic acid, methyl ester, dihydrochloride salt
Calculated for C3oH37N5θ5F2Cl2 » 1.7 H20, 0.4 EtOAc: C=52.53%
H=6.08% N=9.70 %. Found: C=52.53% H=5.41% N=9.24%
EXAMPLE 13
Figure imgf000049_0002
(4S)-3-[(lR, 3S)-3-(4-(2-Pyridyl)-piperidin-l-yl)-cyclopentylcarbamoyl]-4-
(3.4-difluorophenyl)-2-oxazolidinone. dihydrochloride salt
Calculated for C 5H3θN4θ3F2Cl2 «0.7 H20, 0.2 EtOAc: C=54.01%
H=5.80% N=9.77 %. Found: C=54.01% H=5.70% N=9.76% EXAMPLE 14
Figure imgf000050_0001
(4S)-3-[( 1R, 3R)-3-(4-(2-Pyridyl)-piperidin- l-yl)-cyclopentylcarbamoyl]-4-
(3.4-difluorophenyl)-2-oxazolidinone. dihydrochloride salt
Calculated for C 5H3oN4θ3F2Cl2 » 1.15 H20, 0.4 EtOAc: C=53.30%
H=5.97% N=9.35 %. Found: C=53.30% H=5.89% N=9.02%
EXAMPLE 15
Figure imgf000050_0002
(4S)-3-[(lS, 3R)-3-(4-(2-Pyridyl)-piperidin- •l-yl)-cyclopen tylcarbamoyl] -4- (3.4-difluorophenvl)-2-oxazolidinone
Calculated for C 5H 8N4θ F2 «0.35 H20: C=62.97% H=6.07% N=11.75 %. Found: C=63.00% H=6.00% N=11.52% EXAMPLE 16
Figure imgf000051_0001
(4S)-3-[(lS, 3S)-3-(4-(2-Pyridyl)-piperidin-l-yl)-cyclopentylcarbamoyl]-4-
(3.4-difluorophenyl)-2-oxazolidinone
Calculated for C25H28N4O3F2 »0.2 H20: C=63.33% H=6.04%
N=11.82 %. Found: C=63.30% H=6.07% N=11.68%
EXAMPLE 17
Figure imgf000051_0002
(4S)-3-[(lR, 3S)-3-(4-(2-Cyanophenyl)-piperidin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, methyl ester, hydrochloride salt
Calculated for C32H36N5θ5F2Clι» 1.0 H 0, 0.1 EtOAc: C=58.00% H=5.83% N=10.44 %. Found: C=57.90% H=5.91% N= 10.54% EXAMPLE 18
Figure imgf000052_0001
(4S)-3-[( 1R, 3R)-3-(4-(2-Cyanophenyl)-piperidin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, methyl ester, hydrochloride salt
Calculated for C32H36N5θ5F2Clι»2.35 H 0, 0.05 EtOAc:
C=55.98% H=6.00% N= 10.14 %. Found: C=55.76% H=5.41% N=9.90%
EXAMPLE 19
Figure imgf000052_0002
(4S)-3-[(lS, 3R)-3-(4-(2-Cyanophenyl)-piperidin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, methyl ester, hydrochloride salt
Calculated for C32H36N5θ5F2Clι- l.l H 0, 0.05 EtOAc: C=57.86%
H=5.82% N= 10.48 %. Found: C=57.54% H=5.43% N= 10.76% EXAMPLE 20
Figure imgf000053_0001
(4S)-3-[(lS, 3S)-3-(4-(2-Cyanophenyl)-piperidin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, methyl ester, hydrochloride salt
Calculated for C32H36N5O5F2Clι-0.9 H20, 0.45 EtOAc: C=57.99%
H=5.96% N=10.01 %. Found: C=57.97% H=5.66% N=9.82%.
EXAMPLE 21
Figure imgf000053_0002
(4S)-3-[( 1R, 3R)-3-(4-(2-Cyanophenyl)-piperidin- 1-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-2-oxazolidinone, hydrochloride salt
Calculated for C27H29N O3F Cl*0.95 H20, 0.25 EtOAc: C=58.98%
H=5.82% N=9.83 %. Found: C=58.94% H=5.79% N=9.70% EXAMPLE 22
Figure imgf000054_0001
(4S)-3-[(lS, 3R)-3-(4-(2-Cyanophenyl)-piperidin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-2-oxazolidinone, hydrochloride salt
Calculated for C27H29N O3F2Cl»0.35 H20: C=60.35% H=5.57%
N=10.43 %. Found: C=60.37% H=5.42% N= 10.07%
EXAMPLE 23
Figure imgf000054_0002
(4S)-3-[(lS, 3S)-3-(4-(2-Cyanophenyl)-piperidin-l-yD- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-2-oxazolidinone, hydrochloride salt
Calculated for C27H29N4O3F2OI.O5 H20, 0.2 EtOAc: C=58.93% H=5.64% N=9.89 %. Found: C=58.93% H=5.65% N=9.70% EXAMPLE 24
Figure imgf000055_0001
(4S)-3-[(lR, 3S)-3-(4-(2-Cyanophenyl)-piperazin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-2-oxazolidinone, hydrochloride salt
FAB Mass Spectrum Calculated for C 7H27N4θ3F2+H:496.
Found:496
EXAMPLE 25
Figure imgf000055_0002
(4S)-3-[(lS, 3R)-3-(4-(2-Cyanophenyl)-piperazin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-2-oxazolidinone, hydrochloride salt
Calculated for C26H28N5θ3F2CM.15 H 0, 0.25 EtOAc: C=56.42%
H=5.66% N=12.19%. Found: C=56.38% H=5.47% N=12.18% EXAMPLE 26
Figure imgf000056_0001
(4S)-3-[(lS, 3S)-3-(4-(2-Cyanophenyl)-piperazin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-2-oxazolidinone, hydrochloride salt
Calculated for C26H28N5θ3F2Cl* 1.65 H20, 0.75 EtOAc: C=55.48%
H=5.99% N=11.16%. Found: C=55.47% H=5.94% N=11.07%
EXAMPLE 27
Figure imgf000056_0002
(4S)-3-[(lR, 3R)-3-(4-(2-Cyanophenyl)-piperazin-l-yl)- cvclopentylcarbamovn-4-(3.4-difluorophenyl)-2-oxazolidinone
Calculated for C26H27N5θ3F2: C=63.01% H=5.49% N= 14.13%.
Found: C=63.20% H=5.81% N= 14.14% EXAMPLE 28
Figure imgf000057_0001
(4S)-3-[(lR, 3S)-3-(4-(2-Cyanophenyl)-piperazin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, methyl ester, hydrochloride salt
Calculated for C 1H34N6θ5F2Clι»1.10 H20, 0.4 EtOAc: C=56.00%
H=5.68% N= 12.02 %. Found: C=56.02% H=5.51% N=11.75%
EXAMPLE 29
Figure imgf000057_0002
(4S)-3-[(lS, 3R)-3-(4-(2-Cyanophenyl)-piperazin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, methyl ester, hydrochloride salt
Calculated for C3iH34N6θ5F2Clι»0.3 H20: C=57.32% H=5.37%
N=12.94%. Found: C=57.35% H=5.63% N= 13.16% EXAMPLE 30
Figure imgf000058_0001
(4S)-3-[(lS, 3S)-3-(4-(2-Cyanophenyl)-piperazin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methox3 nethyl-2-oxo- l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, methyl ester, hydrochloride salt
Calculated for C3iH34N6θ5F2Clι«0.95 H20, 0.4 EtOAc: C=56.14%
H=5.67% N=12.05%. Found: C=56.17% H=5.67% N= 12.05%
EXAMPLE 31
Figure imgf000058_0002
(4S)-3-[(lR, 3R)-3-(4-(2-Cyanophenyl)-piperazin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-
1.2.3.4-tetrahydro-pyrimidine-5-carboxylic acid, methyl ester Calculated for C3iH33N6θ5F2Clχ -0.3 H20: C=60.73% H=5.52%
N= 13.71%. Found: C=60.72% H=5.60% N=13.76%
In the following examples, Step C was modified as follows (See Scheme 4): To a 0 °C solution of 0.0212 g (0.062 mmol) amine hydrochloride in
1 ml DMF was added 0.017 ml (0.12 mmol) triethylamine, 0.0137g (0.06 mmol) (±) isopropyl-3,4-difluorophenylacetic acid, 0.013g (0.1 mmol)
HOAt, and 0.0141 g (0.07 mmol) EDC. The reaction mixture was stirred 2 h at 0 °C and 1 h at 23 °C, then diluted with 75 ml EtOAc, washed with 70 ml saturated aqueous NaHCθ3 solution, 70 ml dilute brine, and 70 ml brine, then dried over Na2S04, filtered and concentrated. Purification by flash chromatography (1.5 x 10 cm silica gel, linear gradient 80% EtOAc/hexane to 100% EtOAc) to afford of the desired amide. (±) isopropyl-3,4-difluorophenylacetic acid is disclosed and its synthesis described in U.S. Patent No. 5,661,163, issued on August 26, 1997.
EXAMPLE 32
Figure imgf000059_0001
(2R and S)-2-(3,4-Difluorophenyl)-3-methyl-n-[(lR, 3R) - 3 - (4- cyano- 4 , phenyl - piperidin-l-yl)-cvclopentvn-butyramide
Calculated for C 8iH33N3OF2: C=72.23% H=7.14% N=9.03%.
Found: C=72.30% H=7.30% N=9.04%
EXAMPLE 33
Figure imgf000059_0002
(2R or S)-2-(3,4-Difluorophenyl)-3-methyl-n-[(lR, 3R) - 3 - (4 - orthotolyl -4- cyano- piperidin-l-yl)-cyclopentyl]-butyramide (* derived from (-) isoproDyl-3.4-difluorophenylacetic acid)
Calculated for C29H35N3θF2 «0.65 H O»0.2hexane C=71.32%
H=7.75% N=8.26%. Found: C=71.33% H=7.59% N=7.91%
EXAMPLE 34
Figure imgf000060_0001
(2Ror S)-2-(3,4-Difluorophenyl)-3-methyl-n-[(lS, 3R) - 3 - (4 - orthotolyl -4- cyano- piperidin-l-yl)-cyclopentyl]-butyramide (* derived from (+) isopropyl-3.4-difluorophenylacetic acid)
Mass Spectrum Calculated for C2gH35N3θF2H: 480, Found: 480.4
EXAMPLE 35
Figure imgf000060_0002
(2R or S)-2-(3,4-Difluorophenyl)-3-methyl-n-[(lS, 3R) - 3 - (4 - orthotolyl -4- cyano- piperidin-l-yl)-cyclopentyl]-butyramide (* derived from (-) isopropyl-3.4-difluorophenylacetic acid)
Mass Spectrum Calculated for C2gH35N3θF H: 480, Found: 480.4 EXAMPLE 36
Figure imgf000061_0001
(2R or S)-2-(3,4-Difluorophenyl)-3-methyl-n-[(lS, 3S) - 3 - (4 - orthotolyl - 4- cyano-piperidin-l-yl)-cyclopentyl]-butyramide (* derived from (+) isopropyl-3.4-difluorophenylacetic acid)
Mass Spectrum Calculated for C2gH35N3θF2H: 480, Found: 480.4
EXAMPLE 37
Figure imgf000061_0002
(2R or S)-2-(3,4-Difluorophenyl)-3-methyl-n-[(lS, 3S) - 3 - (4 - orthotolyl - 4- cyano-piperidin-l-yl)-cyclopentyl]-butyramide (* derived from (-) isopropyl-3.4-difluorophenylacetic acid)
Mass Spectrum Calculated for C29H35N3θF2H: 480, Found: 480.4
EXAMPLE 38
Figure imgf000061_0003
(2R or S)-2-(3,4-Difluorophenyl)-3-methyl-n-[(lR, 3R) - 3 - (4 - (4- fluorophenyl) piperidin-l-yl)-cyclopentyl]-butyramide (* derived from (-) isopropyl-3.4-difluorophenylacetic acid)
Calculated for C27H33N OF3* HCI • 0.65 H2O»0.1hexane C=64.32%
H=7.18% N=5.44%. Found: C=64.35% H=6.99% N=5.05%
EXAMPLE 39
Figure imgf000062_0001
(2R or S)-2-(3,4-Difluorophenyl)-3-methyl-n-[(lR, 3R) - 3 - (4 - (4- fluorophenyl) piperidin-l-yl)-cyclopentyl]-butyramide (* derived from
(+) isopropyl-3.4-difluorophenylacetic acid)
Calculated for C27H33N2OF3 »HC1»0.69 H2O-0.1hexane C=63.76%
H=7.21% N=5.39%. Found: C=63.80% H=6.85% N=5.01%
EXAMPLE 40
Figure imgf000062_0002
2-Amino-2-(3.4-difluorophenyl)-ethanol
To a 0 °C solution of 10.7g (283 mmol) sodium borohydride in 300 ml THF, 22g (118 mmol) of solid 3,4-difluorophenylglycine was slowly added. After gas evolution had subsided, a solution of 30g (118 mmol) iodine in 75 ml THF was slowly added via dropping funnel over 45 minutes. The ice bath was removed and the reaction was heated to reflux for 16 hours, then cooled to 0 °C. Next, 10 ml methanol was slowly added and the resulting solution was concentrated in vacuo, dissolved in a solution of 45g KOH in 250 ml H20, and stirred for 4 hours at room temperature. The reaction mixture was extracted 4x200 ml CH2C12 and the combined extracts were washed with 350 ml brine, dried over Na-jSO^ filtered and concentrated to give a yellow solid that was used without further purification. H NMR (300 MHz, CDCI3) δ 7.15 (m, 3H);
4.05 (dd, IH, J = 7.81, and 4.39 Hz); 3.72 (dd, IH, J = 10.7, and 4.15 Hz); 3.51 (dd, IH, J = 10.7 and 8.06 Hz).
EXAMPLE 41
Figure imgf000063_0001
4-(3.4-Difluorophenyl)-oxazolidin-2-one
To a 0 °C solution of 5.4g (31 mmol) 2-amino-2-(3,4-difluorophenyl)- ethanol in 100 ml CH2C12 was added 13 ml (75 mmol) diisopropylethylamine followed by slow addition of 3.24g (11 mmol) triphosgene. After stirring the reaction mixture 2 hours at 0 °C, the reaction mixture was diluted with 400 ml CH2C12 and washed with 300 ml 10% aqueous KHS04 solution. The aqueous layer was extracted 2x150 ml CH2C12 and the combined organic extracts were washed with 200 ml brine, dried over Na2S04, filtered and concentrated. Crystallization from 150 ml ether afforded the title compound. *H NMR (300 MHz, CDCI3) δ 7.25-7.05 (m, 3H); 6.22 (br 2, IH); 4.95 (dd, IH, J = 6.0, and 6.0 Hz); 4.75 (t, IH, J = 7.0 Hz); 4.15 (dd, IH, J = 7.0 and 6.0 Hz). Enantiomers were separated by preparative HPLC on a Chiralpak AS 2x25 cm column. EXAMPLE 42
Figure imgf000064_0001
4-(3,4-Difluorophenyl)-oxazolidin-2-one-3-carboxylic acid-4-nitro-phenyl ester To a -78 °C solution of 1.5 g (7.5 mmol) 4-(3,4-difluorophenyl)- oxazolidin-2-one in 75 mL THF, 3.3 ml (8.25 mmol, 2.5M in hexanes) of n-butyllithium in hexane was added dropwise via a syringe under an argon atmosphere. The resulting yellow solution was stirred at -78 °C for 5 min. This solution was then added via a cannula into another round bottom flask containing a -78 °C solution of 1.58g (7.8 mmol) 4- nitrophenylchloroformate in 40 mL of THF. After 15 minutes, the reaction was diluted with 500 ml ether, washed 3x200 ml 10% aqueous KjCOg and 1x200 ml brine. The organic layer was dried over Na2S04, filtered and concentrated. Crystallization from 70 ml of 1:1 EtOAc:hexanes afforded 1.87 g of the title compound. Η NMR (CDC13) d 8.25 (d, 2H, J = 9.28 Hz); 7.30-7.17 (m, 5H); 5.40 (dd, IH, J = 8.55, and 3.91 Hz); 4.81 (t, IH, J = 9.27 Hz); 4.35 (dd, IH, J = 9.28 and 4.15 Hz).
EXAMPLE 43
As a specific embodiment of an oral composition, 100 mg of the compound of Example 39 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule. EXAMPLE 44
Screening assay: Alpha- la Adrenergic Receptor Binding
Membranes prepared from the stably transfected human alpha- la cell line (ATCC CRL 11140) were used to identify compounds that bind to the human alpha- la adrenergic receptor. These competition binding reactions (total volume = 200 μl) contained 50 mM Tris-HCl pH. 7.4, 5 mM EDTA, 150 mM NaCl, 100 pM [125 I]-HEAT, membranes prepared from the alpha- la cell line and increasing amounts of unlabeled ligand. Reactions were incubated at room temperature for one hour with shaking. Reactions were filtered onto Whatman GF/C glass fiber filters with a Inotec 96 well cell harvester. Filters were washed three times with ice cold buffer and bound radioactivity was determined (Ki). Representative compounds of the present invention were found to have Ki values < 50 nM.
EXAMPLE 45
Selective Binding assays Membranes prepared from stably transfected human alpha- Id and alpha- lb cell lines (ATCC CRL 11138 and CRL 11139, respectively) were used to identify compounds that selectively bind to the human alpha- la adrenergic receptor. These competition binding reactions (total volume = 200 μl) contained 50 mM Tris-HCl pH. 7.4, 5 mM EDTA, 150 mM NaCl, 100 pM [125 rj-HEAT, membranes prepared from cell lines transfected with the respective alpha- 1 subtype expression plasmid and increasing amounts of unlabeled ligand. Reactions were incubated at room temperature for one hour with shaking. Reactions were filtered onto Whatman GF/C glass fiber filters with a Inotec 96 well cell harvester. Filters were washed three times with ice cold buffer and bound radioactivity was determined (Ki). EXAMPLE 46
EXEMPLARY COUNTERSCREENS
1. Assay Title: Dopamine D2, D3, D4 in vitro screen
Objective of the Assav:
The objective of this assay is to eliminate agents which specifically affect binding of [3H] spiperone to cells expressing human dopamine receptors D2, D3 or D4.
Method:
Modified from VanTol et al (1991); Nature (Vol 350) Pg 610- 613. Frozen pellets containing specific dopamine receptor subtypes stably expressed in clonal cell lines are lysed in 2 ml lysing buffer (lOraM Tris-HCl 5mM Mg, pH 7.4). Pellets obtained after centrifuging these membranes (15' at 24,450 rpm) are resuspended in 50mM Tris-HCl pH 7.4 containing EDTA, MgCl[2], KC1, NaCl, CaCl[2] and ascorbate to give a 1 Mg/mL suspension. The assay is initiated by adding 50-75 μg membranes in a total volume of 500 μl containing 0.2 nM [3H]-spiperone. Non-specific binding is defined using 10 μM apomorphine. The assay is terminated after a 2 hour incubation at room temperature by rapid filtration over GF/B filters presoaked in 0.3% PEI, using 50mM Tris-HCl pH 7.4.
2. Assav Title: Serotonin 5HT la
Objective of the Assay The objective of this assay is to eliminate agents which specifically affect binding to cloned human 5HTla receptor
Method:
Modified from Schelegel and Peroutka Biochemical Pharmacology 35: 1943-1949 (1986). Mammalian cells expressing cloned human 5HTla receptors are lysed in ice-cold 5 mM Tris-HCl , 2 mM EDTA (pH 7.4) and homogenized with a polytron homogenizer. The homogenate is centrifuged at lOOOXg for 30', and then the supernatant is centrifuged again at 38,000Xg for 30'. The binding assay contains 0.25 nM [3H]8-OH- DPAT (8-hydroxy-2-dipropylamino-l,2,3,4-tetrahydronaphthalene) in 50 mM Tris-HCl, 4 mM CaC12 and lmg/ml ascorbate. Non-specific binding is defined using 10 μM propranolol. The assay is terminated after a 1 hour incubation at room temperature by rapid filtration over GF/Cfilters
EXAMPLE 47
EXEMPLARY FUNCTIONAL ASSAYS
In order to confirm the specificity of compounds for the human alpha- la adrenergic receptor and to define the biological activity of the compounds, the following functional tests may be performed:
1. In vitro Rat, Dog and Human Prostate and Dog Urethra
Taconic Farms Sprague-Dawley male rats, weighing 250- 400 grams are sacrificed by cervical dislocation under anesthesia (methohexital; 50 mg/kg, i.p.). An incision is made into the lower abdomen to remove the ventral lobes of the prostate. Each prostate removed from a mongrel dog is cut into 6-8 pieces longitudinally along the urethra opening and stored in ice-cold oxygenated Krebs solution overnight before use if necessary. Dog urethra proximal to prostate is cut into approximately 5 mm rings, the rings are then cut open for contractile measurement of circular muscles. Human prostate chips from transurethral surgery of benign prostate hyperplasia are also stored overnight in ice-cold Krebs solution if needed. The tissue is placed in a Petri dish containing oxygenated
Krebs solution [NaCl, 118 mM; KC1, 4.7 mM; CaCl2, 2.5 mM; KH2PO4, 1.2 mM; MgSθ4, 1.2 mM; NaHCθ3, 2.0 mM; dextrose, 11 mM] warmed to 37°C. Excess lipid material and connective tissue are carefully removed. Tissue segments are attached to glass tissue holders with 4-0 surgical silk and placed in a 5 ml jacketed tissue bath containing Krebs buffer at 37°C, bubbled with 5% 00^95% 02. The tissues are connected to a Statham-Gould force transducer; 1 gram (rat, human) or 1.5 gram (dog) of tension is applied and the tissues are allowed to equilibrate for one hour. Contractions are recorded on a Hewlett-Packard 7700 series strip chart recorder.
After a single priming dose of 3 μM (for rat), 10 μM (for dog) and 20 μM (for human) of phenylephrine, a cumulative concentration response curve to an agonist is generated; the tissues are washed every 10 minutes for one hour. Vehicle or antagonist is added to the bath and allowed to incubate for one hour, then another cumulative concentration response curve to the agonist is generated.
EC50 values are calculated for each group using GraphPad Inplot software. pA2 (-log Kb) values were obtained from Schild plot when three or more concentrations were tested. When less than three concentrations of antagonist are tested, K values are calculated according to the following formula Kb = fBI. x-1 where x is the ratio of EC50 of agonist in the presence and absence of antagonist and [B] is the antagonist concentration.
2. Measurement of Intra-Urethral Pressure in Anesthetized Dogs
PURPOSE: Benign prostatic hyperplasia causes a decreased urine flow rate that may be produced by both passive physical obstruction of the prostatic urethra from increased prostate mass as well as active obstruction due to prostatic contraction. Alpha adrenergic receptor antagonists such as prazosin and terazosin prevent active prostatic contraction, thus improve urine flow rate and provide symptomatic relief in man. However, these are non-selective alpha- 1 receptor antagonists which also have pronounced vascular effects. Because we have identified the alpha- la receptor subtype as the predominent subtype in the human prostate, it is now possible to specifically target this receptor to inhibit prostatic contraction without concomitant changes in the vasculature. The following model is used to measure adrenergically mediated changes in intra-urethral pressure and arterial pressure in anesthetized dogs in order to evaluate the efficacy and potency of selective alpha adrenergic receptor antagonists. The goals are to: 1) identify the alpha- 1 receptor subtypes responsible for prostatic/urethral contraction and vascular responses, and 2) use this model to evaluate novel selective alpha adrenergic antagonists. Novel and standard alpha adrenergic antagonists may be evaluated in this manner.
METHODS: Male mongrel dogs (7-12 kg) are used in this study. The dogs are anesthetized with pentobarbital sodium (35 mg/kg, i.v. plus 4 mg/kg/hr iv infusion). An endotracheal tube is inserted and the animal ventilated with room air using a Harvard instruments positive displacement large animal ventilator. Catheters (PE 240 or 260) are placed in the aorta via the femoral artery and vena cava via the femoral veins (2 catheters, one in each vein) for the measurement of arterial pressure and the administration of drugs, respectively. A supra-pubic incision -1/2 inch lateral to the penis is made to expose the urethers, bladder and urethra. The urethers are ligated and cannulated so that urine flows freely into beakers. The dome of the bladder is retracted to facilitate dissection of the proximal and distal urethra. Umbilical tape is passed beneath the urethra at the bladder neck and another piece of umbilical tape is placed under the distal urethra approximately 1-2 cm distal to the prostate. The bladder is incised and a Millar micro-tip pressure transducer is advanced into the urethra. The bladder incision is sutured with 2-0 or 3-0 silk (purse-string suture) to hold the transducer. The tip of the transducer is placed in the prostatic urethra and the position of the Millar catheter is verified by gently squeezing the prostate and noting the large change in urethral pressure.
Phenylephrine, an alpha- 1 adrenergic agonist, is administered (0.1-100 ug/kg, iv; 0.05 ml/kg volume) in order to construct dose response curves for changes in intra-urethral and arterial pressure. Following administration of increasing doses of an alpha adrenergic antagonist (or vehicle), the effects of phenylephrine on arterial pressure and intra-urethral pressure are re-evaluated. Four or five phenylephrine dose-response curves are generated in each animal (one control, three or four doses of antagonist or vehicle). The relative antagonist potency on phenylephrine induced changes in arterial and intra-urethral pressure are determined by Schild analysis. The family of averaged curves are fit simultaneously (using ALLFIT software package) with a four paramenter logistic equation constraining the slope, minimum response, and maximum response to be constant among curves. The dose ratios for the antagonist doses (rightward shift in the dose-response curves from control) are calculated as the ratio of the EDδo's for the respective curves. These dose-ratios are then used to construct a Schild plot and the Kb (expressed as ug/kg, iv) determined. The Kb (dose of antagonist causing a 2-fold rightward shift of the phenylephrine dose-response curve) is used to compare the relative potency of the antagonists on inhibiting phenylephrine responses for intra-urethral and arterial pressure. The relative selectivity is calculated as the ratio of arterial pressure and intra-urethral pressure Kb's. Effects of the alpha- 1 antagonists on baseline arterial pressure are also monitored. Comparison of the relative antagonist potency on changes in arterial pressure and intra-urethral pressure provide insight as to whether the alpha receptor subtype responsible for increasing intra-urethral pressure is also present in the systemic vasculature. According to this method, one is able to confirm the selectivity of alpha- la adrenergic receptor antagonists that prevent the increase in intra-urethral pressure to phenylephrine without any activity at the vasculature.
While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

Claims

WHAT IS CLAIMED IS:
1. A compound of the formula:
Figure imgf000071_0001
wherein A is selected from
Figure imgf000071_0002
Figure imgf000071_0003
Figure imgf000071_0005
Figure imgf000071_0004
J is selected from unsubstituted, mono- or poly- substituted phenyl wherein the substituents on the phenyl ring are independently selected from halogen, CF3, cyano, nitro, N(R )2, NR COR ,
NRnCON(R12)2, NRnS02R10, NR1:LS02N(R12)2, OR10, (CH2)o-4C02Rn, (CH2)0_4CON(Rn)2, (CH2)o.4S02N(R11)2, (CH2)o-4S02R or Cχ.4 alkyl; or unsubstituted, mono- or poly- substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, N(RX1)2, (CH2)0-4CO2R11, (CH2)0. CON(R11)2,
(CH2)0-4SO2N(Rn)2, (CH2)0-4SO2R10, phenyl, OR10, halogen, Cχ.4 alkyl or C3. cycloalkyl;
G is selected from hydrogen, cyano, OR , C02R , CON(R )2, S02R , S02N(R )2, tetrazole, isooxadiazole, unsubstituted, mono- or poly- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, cyano, nitro, OR , (CH2)o-4C02Rn, (CH2)o-4CON(Rn)2, N(RH)2, NRnCOR10, NRnCON(R12)2, NR11S02R1°, NR11S02N(R12)2, (CH2)o-4S02N(Rn)2, (CH2)θ-4Sθ2R or Cχ.4 alkyl; or unsubstituted, mono- or poly- substituted pyridyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, thienyl, furanyl or naphthyl are independently selected from CF3, (CH2)o-4C02R , (CH2)Q.
4CON(Rn)2, (CH2)o.4S02N(Rn)2, (CH2)o_ S02R10, phenyl, OR10, halogen, Cχ.4 alkyl or C3. cycloalkyl;
R is selected from hydrogen, Cχ_8 alkyl, C4. cycloalkyl, (CH2)o- C02R10, (CH2)0.4CON(Rn)2, (CH2)0-4COR10, (CH2)2-4θR10, (CH2)ι_4CF3, (CH2)ι.4S02R10, (CH2)0.4SO2N(Rn)2 or (CH2)i-4CN; R1 is selected from COR10, (CH2)0-4CN, (CH2)0-4CF3, (CH2)0-4CO2R11, (CH2)o^CON(Rn)2, (CH2)0^SO2R10 or (CH2)o.4S02N(Rn)2;
2 10 R is selected from hydrogen, C _ alkyl, C3.8 cycloalkyl, (CH2)χ.4θR or (CH2)o.4CF3;
3 4 5 R , R , and R are each independently selected from hydrogen,
C╬╣_8 alkyl, C3.8 cycloalkyl, (CH2)2.4OR10 or (CH2)0-4CF3; fi 7
R and R are each independently selected from hydrogen, Cχ_8 alkyl or
C3-8 cycloalkyl;
8 1 R is selected from hydrogen, C _ alkyl, C3.8 cycloalkyl, (CH2)χ_4θR , (CH )o-4CF3, unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(R1:L)2OR10, (CH2)0-4CON(R1:L)2, (CH2)0-4CO2R1:L or Cχ_4 alkyl; or unsubstituted, mono- or poly-substituted: pyridyl, pyrazinyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, OR , halogen, Cχ.4 alkyl or C3.8 cycloalkyl;
9 10 R is selected from hydrogen, Cχ_8 alkyl, C3. cycloalkyl, (CH2)θ-4θR or (CH2)o-4CF3;
R is selected from hydrogen, C _ alkyl, C3.8 cycloalkyl or (CH2)o-4CF3;
11 12
R and R are each independently selected from hydrogen, C _ alkyl,
C3.8 cycloalkyl or (CH2)χ.4CF3;
W is O or NR6;
D is N or C, provided that when D is N, then G is absent; each X is independently selected from halogen, cyano, nitro, Cχ_8 alkyl, C3.8 cycloalkyl, CH2)0-4θR10 or (CH2)0-4CF3;
m, n, o, and p are each independently an integer from zero to three;
s and t are each independently an integer from zero to four;
and the pharmaceutically acceptable salts thereof.
2. The compound of Claim 1 of the formula:
Figure imgf000074_0001
wherein A is selected from
Figure imgf000074_0002
J is selected from unsubstituted, mono-, di-, or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(Rn)2, NRnCOR12, NRnCON(R12)2,
NRnS02R10, NRnS02N(R12)2, OR10, (CH2)0-4CO2Rn, (CH2)0.
4CON(Rn)2, (CH2)0.4SO2N(R11)2, (CH2)0.4SO2R10 or Cχ.4 alkyl; or unsubstituted, mono-, di-, or tri-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, amino,
(CH2)o^C02R11, (CH2)o-4CON(R11)2, (CH2)o.4S02N(Rn)2, (CH2)o-4S02R , phenyl, OR , halogen, Cχ.4 alkyl or C3. cycloalkyl;
G is selected from hydrogen, cyano, OR10, C02R11, CON(Rn)2, S02R10, S0 N(R )2, tetrazole, isooxadiazole, unsubstituted, mono- or di- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, cyano, nitro, OR ,
(CH2)0-4CO2Rn, (CH2)0_4CON(Rn)2, N(RH)2, NRnCOR10,
NRnCON(R12)2, NRnS02R10, NR13-S02N(R12)2, (CH2)0^SO2N(Rn)2, (CH2)0-4Sθ2R10 or Cχ.4 alkyl;
R is selected from hydrogen, Cχ.g alkyl, C4.Q cycloalkyl,
(CH2)0-4CO2R10, (CH2)o-4CON(Rn)2, (CH2)o. COR10, (CH2)2-4OR10, (CH2)χ.4CF3, (CH2)1.4S02R10, (CH2)o-4S02N(R11)2 or (CH2)ι. CN;
3 4 5
R , R , and R are each independently selected from Cχ_6 alkyl,
C3.6 cycloalkyl, (CH2)2-4╬╕R10, (CH2)0-4CF3;
8 1 Ω R is selected from hydrogen, Cχ_ alkyl, C3.8 cycloalkyl, (CH2)χ_4θR ,
(CH2)o-4CF3, unsubstituted, mono-, di-, or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR10, (CH2)o.4CON(Rn)2,
(CH2)θ-4Cθ2R or Cχ.4 alkyl; or unsubstituted, mono-, di- or tri- substituted: pyridyl, pyrazinyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, furanyl or naphthyl are independently selected from CF3, cyano, nitro, amino, phenyl, OR , halogen, Cχ.4 alkyl or C3.8 cycloalkyl; 9 10
R is selected from hydrogen, Cχ.β alkyl, C3.6 cycloalkyl, (CH2)θ-4θR
Figure imgf000076_0001
o and p are each independently an integer from one to two;
and the pharmaceutically acceptable salts thereof.
3. The compound of Claim 2 of the formula:
Figure imgf000076_0002
wherein A is selected from
Figure imgf000076_0003
R is selected from hydrogen, C _6 alkyl, C4.6 cycloalkyl, or (CH2)i-4CF3;
R1 is selected from COR10, (CH2)0-4CN, (CH2)0-2CO2Rn, S02R10 or (CH2)0-2CON(Rn)2;
2 10
R is selected from hydrogen, Cχ_6 alkyl, C3.6 cycloalkyl, (CH2) -3θR or (CH2)o-3CF3; 8 9
R and R are each independently selected from hydrogen or Cχ_8 alkyl;
R is selected from hydrogen, Cχ_6 alkyl, C3.6 cycloalkyl, or (CH2)o-3CF3;
R is selected from hydrogen, Cχ.g alkyl, C3.Q cycloalkyl, or (CH2)1-4CF3;
and the pharmaceutically acceptable salts thereof.
4. The compound of Claim 3, of the formula:
Figure imgf000077_0001
wherein A is selected from
Figure imgf000077_0002
Q is C-Y or N;
11 11
G is selected from hydrogen, cyano, hydroxy, CO2R , CON(R )2, S02R10, S02N(Rn)2; each Y is independently selected from hydrogen, halogen, CF3, cyano, nitro, amino, OR10, C02Rn, CON(Rn)2 or Cχ. alkyl;
R 8 and R 9 are each independently selected from hydrogen or Cχ.4 alkyl;
each X is halogen;
r is an integer from zero to two; s is an integer from zero to three; t is equal to one; and the pharmaceutically acceptable salts thereof.
5. The compound of Claim 4 selected from
3-[(lR,3S)-3-(4-Cyano-4-phenylpiperidin-l-yl)-cyclopentylcarbamoyl]-4- (3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydro- pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lR,3R)-3-(4-Cyano-4-phenylpiperidin-l-yl)-cyclopentylcarbamoyl]- 4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydro- pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lS,3R)-3-(4-Cyano-4-phenylpiperidin-l-yl)-cyclopentylcarbamoyl]- 4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydro- pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lS,3S)-3-(4-Cyano-4-phenylpiperidin-l-yl)-cyclopentylcarbamoyl]- 4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydro- pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lR,3R)-3-(4-Cyano-4-phenylpiperidin-l-yl)-cyclopentylcarbamoyl]- 4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydro- pyrimidine-5-carboxylic acid, methyl ester; (4S)-3-[(lR,3R)-3-(4-(2-Pyridyl)-piperidin-l-yl)-cyclopentylcarbamoyl]-4- (3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydro- pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lR,3S)-3-(4-(2-Pyridyl)-piperidin-l-yl)-cyclopentylcarbamoyl]-4- (3,4-oHfluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydro- pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lS,3R)-3-(4-(2-Pyridyl)-piperidin-l-yl)-cyclopentylcarbamoyl]-4- (3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydro- pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lS,3S)-3-(4-(2-Pyridyl)-piperidin-l-yl)-cyclopentylcarbamoyl]-4- (3,4-difluorophenyl)-6-methoxymethyl-2-oxo-l,2,3,4-tetrahydro- pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lR,3S)-3-(4-(2-Pyridyl)-piperidin-l-yl)-cyclopentylcarbamoyl]-4- (3,4-difluorophenyl)-2-oxazolidinone;
(4S)-3-[(lR,3R)-3-(4-(2-Pyridyl)-piperidin-l-yl)-cyclopentylcarbamoyl]-4- (3,4-difluorophenyl)-2-oxazolidinone;
(4S)-3-[(lS,3R)-3-(4-(2-Pyridyl)-piperidin-l-yl)-cyclopentylcarbamoyl]-4- (3,4-difluorophenyl)-2-oxazolidinone;
(4S)-3-[(lS,3S)-3-(4-(2-Pyridyl)-piperidin-l-yl)-cyclopentylcarbamoyl]-4- (3,4-difluorophenyl)-2-oxazolidinone;
(4S)-3-[(lR,3S)-3-(4-(2-Cyanophenyl)-piperidin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydro-p3πimidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lR,3R)-3-(4-(2-Cyanophenyl)-piperidin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, methyl ester; (4S)-3-[(lS,3R)-3-(4-(2-Cyanophenyl)-piperidin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[( lS,3S)-3-(4-(2-Cyanophenyl)-piperidin- 1-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydro-p3╬╕imidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lR,3R)-3-(4-(2-Cyanophenyl)-piperidin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-2-oxazolidinone;
(4S)-3-[(lS,3R)-3-(4-(2-Cyanophenyl)-piperidin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-2-oxazolidinone;
(4S)-3-[(lS,3S)-3-(4-(2-Cyanophenyl)-piperidin-l-yD- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-2-oxazolidinone;
(4S)-3-[(lR,3S)-3-(4-(2-Cyanophenyl)-piperidin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-2-oxazolidinone;
(4S)-3-[(lS,3R)-3-(4-(2-Cyanophenyl)-piperazin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-2-oxazolidinone;
(4S)-3-[(lS,3S)-3-(4-(2-Cyanophenyl)-piperazin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-2-oxazolidinone;
(4S)-3-[(lR,3R)-3-(4-(2-Cyanophenyl)-piperazin-l-yl)- cyclopentylcarbamoyl]-4-(3 ,4-difluorophenyl)-2-oxazolidinone ;
(4S)-3-[(lR,3S)-3-(4-(2-Cyanophenyl)-piperazin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-2-oxazolidinone; (4S)-3-[(lR,3S)-3-(4-(2-Cyanophenyl)-piperazin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lS,3R)-3-(4-(2-Cyanophenyl)-piperazin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[( lS,3S)-3-(4-(2-Cyanophenyl)-piperazin- 1-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, methyl ester;
(4S)-3-[(lR,3R)-3-(4-(2-Cyanophenyl)-piperazin-l-yl)- cyclopentylcarbamoyl]-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- l,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, methyl ester;
(2R and S)-2-(3,4-Difluorophenyl)-3-methyl-N-[(lR,3R)-3-(4-cyano-4- phenyl-piperidin-l-yl)-cyclopentyl]-butyramide;
(2R or S)-2-(3,4-Difluorophenyl)-3-methyl-N-[(lR,3R)-3-(4-orthotolyl-4- piperidin-l-yl)-cyclopentyl]-butyramide;
(2R or S)-2-(3,4-Difluorophenyl)-3-methyl-N-[(lS,3R)-3-(4-orthotolyl-4- cyanopiperidin-l-yl)-cyclopentyl]-butyramide;
(2R or S)-2-(3,4-Difluorophenyl)-3-methyl-N-[( lS,3R)-3-(4-orthotolyl-4- cyanopiperidin-l-yl)-cyclopentyl]-butyr amide;
(2R or S)-2-(3,4-Difluorophenyl)-3-methyl-N-[(lS,3S)-3-(4-orthotolyl-4- cyanopiperidin-l-yl)-cyclopentyl]-butyramide; or
(2R or S)-2-(3,4-Difluorophenyl)-3-methyl-N-[(lR,3R)-3-(4-(4- fluorophenyl)piperidin-l-yl)-cyclopentyl]-butyramide;
and the pharmaceutically acceptable salts thereof.
6. A pharmaceutical composition comprising the compound of Claim 1 and a pharmaceutically acceptable carrier.
7. A pharmaceutical composition made by combining a compound of Claim 1 and a pharmaceutically acceptable carrier.
8. A process for making a pharmaceutical composition comprising combining a compound of Claim 1 and a pharmaceutically acceptable carrier.
9. The composition of Claim 6 further comprising a testosterone 5-alpha reductase inhibitor.
10. The composition of Claim 9, wherein the testosterone 5-alpha reductase inhibitor is a type 1, a type 2, both a type 1 and a type 2 or a dual type 1 and type 2 testosterone 5-alpha reductase inhibitor.
11. The composition of Claim 10, wherein the testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5-alpha reductase inhibitor.
12. The composition of Claim 11, wherein the testosterone 5-alpha reductase inhibitor is finasteride.
13. A method of treating benign prostatic hyperplasia in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound of Claim 1.
14. The method of Claim 13, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.
15. The method of Claim 14, wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor.
16. The method of Claim 15, wherein the testosterone 5- alpha reductase inhibitor is finasteride.
17. A method of treating benign prostatic hyperplasia in a subject in need thereof which comprises administering a therapeutically effective amount of the composition of Claim 6.
18. The method of Claim 17, wherein the composition further comprises a therapeutically effective amoimt of a testosterone 5- alpha reductase inhibitor.
19. A method of relaxing lower urinary tract tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound of Claim 1.
20. The method of Claim 19, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to relax lower urinary tract tissue.
21. The method of Claim 19, wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor.
22. The method of Claim 21, wherein the testosterone 5- alpha reductase inhibitor is finasteride.
23. A method of treating a condition which is susceptible to treatment by antagonism of the alpha- la receptor which comprises administering to a subject in need thereof an amount of the compound of Claim 1 effective to treat the condition.
24. A method of eliciting an alpha-la antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the compound of Claim 1.
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