Field of the Invention The present invention relates to thiazolidinedione derivatives, which can be used to treat a disease or disorder mediated through α1a and/or α1d adrenergic receptors. Compounds and pharmaceutical compositions disclosed herein can be used to treat benign prostatic hyperplasia (BPH) and related symptoms thereof. Further, such compounds
can be used to treat lower urinary tract symptoms that may or may not be associated with BPH. The present invention also relates to processes to prepare the disclosed compounds, pharmaceutical compositions thereof, and methods of treating BPH or related symptoms thereof.
Background of the Invention
Benign prostatic hyperplasia (BPH) is a condition that typically develops in elderly males. BPH causes benign overgrowth of the stromal and epithelial elements of the prostate with aging. Symptoms of BPH can vary and commonly involve changes or problems with urination, such as hesitation, interruption, weak stream, urgency, leaking, dribbling or increased frequency, particularly at night. BPH can consequently cause hypertrophy of bladder smooth muscle, a decompensated bladder or an increased incidence of urinary tract infection.
The symptoms of BPH are a result of two pathological components affecting the prostate gland: a static component and a dynamic component. The static component is related to enlargement of the prostate gland, which may result in compression of the urethra and obstruction to the flow of the urine from the bladder. The dynamic component is related to increased smooth muscle tone of the bladder neck and prostate itself and is regulated by a-1 adrenergic receptor.
Currently, the most effective treatment for BPH is a surgical procedure known as transurethral resection of the prostate (TURP), which involves removing obstructing tissue (C. Chappie, Br. Med. Journal, 304:1198-1199 (1992)). TURP is directed both to the static and dynamic components of the BPH. However, TURP is associated with mortality (1 %), adverse events, e.g., incontinence (2-4 %), infection (5-10 %), and impotence (5-10 %). Therefore, noninvasive alternative treatments are highly desirable.
Some drug therapies address the static component of BPH. Administration of finasteride is one such therapy, which is indicated for the treatment of symptomatic BPH. This drug is a competitive inhibitor of the enzyme 5-a reductase that is responsible for the conversion of testosterone to dihydrotestosterone in the prostate gland. Dihydrotestosterone appears to be the major mitogen for prostate growth and agents, which inhibit 5-a reductase, reduce the size of the
prostate and improve urine flow through the prostatic urethra. Although finasteride is a potent 5-oc reductase inhibitor that causes a marked decrease in serum and tissue concentrations of dihydrotestosterone, it is moderately effective in the treatment of symptomatic BPH. The effects of finasteride take 6-12 months to become evident and for many men the clinical development is minimal.
The dynamic component of BPH has been addressed by the use of adrenergic receptor blocking agents, which act by decreasing the smooth muscle tone within the prostate gland. A variety of α1a AR antagonists, for example, terazosin, doxazosin, prazosin, alfuzosin and tamulosin, have been investigated for the treatment of symptomatic bladder outlet obstruction due to BPH. However, these drugs are associated with vascular side effects (e.g., postural hypertension, syncope, dizziness, headache etc.) due to lack of selectivity of action between prostatic and vascular α1 adrenoceptors. There are several lines of evidence suggesting that selectivity for α1a adrenoceptor over α1b adrenoceptor will result in relative lack of vascular side effects, thus lead to better tolerability. Mice deficient in α1b adrenoreceptors show diminished blood pressure response to phenylephrine injection when compared to homozygous controls (decreased blood pressure response in mice deficient of α1b adrenergic receptor. (Proc. Nat'I Acad. Sci. USA, 94:1589-11594 (1997)). In-vivo studies in healthy subjects comparison of α1a/α1d selective antagonists (e.g., tamsulosin) or α1a selective antagonists (e.g., urapidil) with non selective antagonists (e.g., doxazosin, prazosin, or terazosin) under a variety of experimental conditions (e.g., involving the administration of exogenous agonist or release of endogenous agonist by cold stimulation) in several vascular beds including the skin circulation in finger tips, the dorsal hand vein, or with total peripheral resistance have been reported. (Eur. J. Clin. Pharmacol, 49:371-375 (1996); N. Schmiedeberg, Arch. Pharmacol, 354:557-561 (1996); Jpn. J. Pharmacol, 80:209-215 (1999); Br. J. Clin. Pharmacol, 47:67-74 (1999)). These studies reported that an antagonist with high affinity for α1a or α1a/α1d receptors can cause some degree of vasodilation, although it is much lower than with non-subtype-selective α1a adrenoceptor antagonists. Further, there is increased vascular α1b adrenoceptor expression in elderly patients and thus α1a/α1d-selective agents with selectivity over α1d adrenoceptor subtype would be of particular importance in benign prostatic hyperplasia. Antagonism of both α1a adrenoceptor and α1d adrenoceptor is important to relieve lower urinary tract symptoms especially associated with BPH. Targeting α1a adrenoceptors with antagonists is important in relaxing prostate smooth muscle and relieving bladder outlet obstruction, whereas α1d adrenoceptor antagonism is
important to target irritative symptoms.
The synthesis of l-(4-arylpiperazin-l-yl)-w-[N- (a, co-dicarboximido)]-alkanes useful as uro-selective ai-adrenoceptor blockers are disclosed in US Patent Nos. 6,083,950, 6,090,809, 6,410,735, 6,420,559 and 6,420,366, WO 00/05206, US Patent Appl. No. 2002/0156085 and WO 02/44151. These compounds exhibited α1-adrenergic blocking activity and selectivity. Each of these patents are incorporated by reference herein in their entirety. US Patent No. 4,367,335 discloses thiazolidinylalkylene piperazine derivatives having psychotropic properties
Summary of the Invention
Provided herein are compounds having the structure of Formula 1,
A
O
(CHj)r
N Y—N^n3\ X—R
O i
£7Y
pharmaceutical^ acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs and metabolites thereof, wherein:
X-R can be NRi or CR2R3 wherein Ri and R2 can be independently alkyl, aryl, heteroaryl or heterocyclyl, R3 can be hydrogen, alkyl, hydroxy or alkoxy; Y can be (CH2)m, CH2COZ(CH2)„ wherein m can be an integer of from 3 to 6, n can be an integer of from 2 to 4; r can be an integer of from 0 to 2; with the provisio that Yean not be (CH2)m whenX-R= NRj, andr=0.
Also provided herein are compounds selected from:
3-{3-[8-hydroxy-8-(2-methoxyphenyl)-3-azabicyclo[3.2.1]oct-3-yl]propyl}-l,3-thiazolidine-2,4-dione
3-{3-[8-hydroxy-8-(2-methoxyphenyl)-3-azabicyclo[3.2.1]oct-3-yl]propyl}-l,3-thiazolidine-2,4-dione hydrochloride salt,
N-(2- {4- [2-(cyclopenty loxy)pheny fjpiperazin-1 -y 1} ethy l)-2-(2,4-dioxo-1,3 -thiazolidin-3 -yl)acetamide,
A/-(2-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}ethyl)-2-(2,4-dioxo-l,3-thiazolidin-3-yl)acetamide hydrochloride salt,
2-(2,4-dioxo-l,3-thiazolidin-3-yl)-A?-{2-[4-(2-isopropoxyphenyl)piperazin-l-y 1] ethyl} acetamide,
2-(2,4-dioxo-1,3-thiazolidin-3-yl)-.N- {2-[4-(2-isopropoxyphenyl)piperazin-1 -yl]ethyl}acetamide hydrochloride salt,
2-(2,4-dioxo-1,3-thiazolidin-3-yl)-N- {2-[4-(2-methoxyphenyl)piperazin-1 -yl]ethyl}acetamide,
2-(2,4-dioxo-1,3 -thiazolidin-3 -yl)-N- {2- [4-(2-methoxypheny l)piperazin-1 -yl]ethyl}acetamide hydrochloride salt,
2-(2,4-dioxo-1,3 -thiazolidin-3 -yl)-N-{2- [4-(2-ethoxypheny l)piperazin-1 -yl]ethyl}acetamide,
2-(2,4-dioxo-1,3 -thiazolidin-3 -y l)-N- {2- [4-(2-ethoxypheny l)piperazin-1 -yl]ethyl}acetamide hydrochloride salt,
2-(2,4-dioxo-1,3 -thiazolidin-3 -yl)-N- {3 - [4-(2-methoxypheny l)piperazin-1 -yl]propyl}acetamide,
2-(2,4-dioxo-1,3-thiazolidin-3-yl)-JV- {3-[4-(2-methoxyphenyl)piperazin-1 -yl]propyl}acetamide hydrochloride salt,
2-(2,4-dioxo-1,3 -thiazolidin-3 -yl\)-N- {3 - [4-(2-ethoxyphenyl)piperazin-1 -yl]propyl} acetamide,
2-(2,4-dioxo-1,3 -thiazolidin-3 -yl)-N- {3 - [4-(2-ethoxypheny l)piperazin-1 -yl] propyl }acetamide hydrochloride salt,
iV-(3-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}propyl)-2-(2,4-dioxo-l,3-thiazolidin-3-yl)acetamide,
A^-(3-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}propyl)-2-(2,4-dioxo-l,3-thiazolidin-3-yl)acetamide hydrochloride salt,
2-(2,4-dioxo-1,3-thiazolidin-3-yl)-N- {3-[4-(2-isopropoxyphenyl)piperazin-1 -yl]propyl} acetamide,
2-(2,4-dioxo-l,3-thiazolidin-3-yl)-N-{3-[4-(2-isopropoxyphenyl)piperazin-l-yl]propyl}acetamide hydrochloride salt,
2-[4-(2-methoxyphenyl)piperazin-1 -y 1] ethyl (2,4-dioxo-1,3-thiazolidin-3-yl)acetate,
2-[4-(2-methoxyphenyl)piperazin-l-yl]ethyl (2,4-dioxo-l,3-thiazolidin-3-yl)acetate hydrochloride salt,
2-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl (2,4-dioxo-l,3-thiazolidin-3-yl)acetate,
-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl(2,4-dioxo-l,3-thiazolidin-3-yl)acetate hydrochloride salt,
2-{4-[2-(cyclopentyloxy)phenyl]piperazin-1 -yl}ethyl (2,4-dioxo-l ,3-thiazolidin-3-
yl)acetate,
2-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}ethyl(2,4-dioxo-l,3-thiazolidin-3-yl)acetate hydrochloride salt,
2-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-1 -yl]ethyl (2,4-dioxo-1,3-thiazolidin-3-yl)acetate,
2-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-1 -yl]ethyl (2,4-dioxo-1,3-thiazolidin-3-yl)acetate hydrochloride salt,
3 - {5 - [4-(2-methoxypheny l)piperazin-1 -y l]penty 1} -1,3 -thiazolidine-2,4-dione,
3 - {5 - [4-(2-methoxypheny l)piperazin-1 -y l]penty 1} -1,3 -thiazolidine-2,4-dione hydrochloride salt,
3- {5-[4-(2-ethoxyphenyl)piperazin-1 -yl]pentyl}-1,3-thiazolidine-2,4-dione,
3- {5-[4-(2-ethoxyphenyl)piperazin-1 -yl]pentyl} -1,3-thiazolidine-2,4-dione hydrochloride salt,
3 - {5- [4-(2-propoxypheny l)piperazin-1 -yl]penty 1} -1,3 -thiazolidine-2,4-dione,
3-{5-[4-(2-propoxyphenyl)piperazin-l-yl]pentyl}-l,3-thiazolidine-2,4-dione hydrochloride salt,
3-{5-[4-(2-isopropoxyphenyl)piperazin-l-yl]pentyl}-l,3-thiazolidine-2,4-dione,
3-{5-[4-(2-isopropoxyphenyl)piperazin-l-yl]pentyl}-l,3-thiazolidine-2,4-dione hydrochloride salt, or
their phNmaceutically acceptable salts, phNmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs or metabolites.
Also provided herein Ne phNmaceutical compositions comprising a therapeutically effective amount of a compound disclosed herein and optionally one or more phNmaceutically acceptable cNriers, excipients or diluents.
Also provided herein Ne methods for treating a disease or disorder mediated through α1a and/or α1a adrenergic receptors, comprising administering to patient in need thereof a therapeutically effective amount of a compound disclosed herein and optionally one or more phNmaceutically acceptable cNriers, excipients or diluents.
These methods can encompass one or more of the following features. For example, the disease or disorder can be benign prostatic hyperplasia. In another example, the compound causes minimal decrease or no decrease in blood pressure at dosages effective to
alleviate benign prostatic hyperplasia.
Also provided herein Ne methods for treating lower urinNy tract symptoms associated with or without benign prostatic hyperplasia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein and optionally one or more phNmaceutically acceptable cNriers, excipients or diluents.
Also provided herein Ne methods for prepNing compounds disclosed herein.
Detailed Description of the Invention
The present invention provides thiazolidinedione derivatives, which can be used to treat disease or disorder mediated through α1a and/or α1ad subtype adrenergic receptors. Compounds disclosed herein can be used to treat benign prostatic hyperplasia (BPH) and related symptoms thereof or lower urinNy tract symptoms (LUTS) associated with or without BPH. The present invention also provides processes for the synthesis of such compounds. Also provided herein Ne phNmaceutically acceptable salts, phNmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxide of such compounds. Also provided Ne phNmaceutical compositions containing the disclosed compounds and one or more phNmaceutically acceptable cNriers, excipients or diluents, which can be used for the treatment of BPH or related symptoms thereof or LUTS with or without BPH.
In one aspect, provided herein Ne compounds having the structure of Formula 1,

phNmaceutically acceptable salts, phNmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs and metabolites thereof, wherein:
X-R can be NRi or CR2R3 wherein Ri and R2 can be independently alkyl, Nyl, heteroNyl or heterocyclyl, R3 can be hydrogen, alkyl, hydroxy or alkoxy; Y can be (CH2)m, CH2COZ(CH2)n wherein m can be an integer of from 3 to 6, n can be an integer of from 2 to 4; r can be an integer of from 0 to 2; with the provisio that r can not be 0 when X-R is NRi and Yean not be (CH2)3 when r is 0 and X-R is NRj.
In another aspect, there Ne provided compounds selected from:
3-{3-[8-hydroxy-8-(2-methoxyphenyl)-3-azabicyclo[3.2.1]oct-3-yl]propyl}-l,3-thiazolidine-2,4-dione (Compound No. 1),
3-{3-[8-hydroxy-8-(2-methoxyphenyl)-3-azabicyclo[3.2.1]oct-3-yl]propyl}-l,3-thiazolidine-2,4-dione hydrochloride sNt (Compound No. 2),
iV-(2-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}ethyl)-2-(2,4-dioxo-l,3-thiazolidin-3-yl)acetamide (Compound No. 3),
A(2-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}ethyl)-2-(2,4-dioxo-l,3-thiazolidin-3-yl)acetamide hydrochloride sNt (Compound No. 4),
2-(2,4-dioxo-1,3 -thiazolidin-3 -y\)-N- {2- [4-(2-isopropoxypheny l)piperazin-1 -yl]ethyl}acetamide (Compound No. 5),
2-(2,4-dioxo-l,3-thiazolidin-3-yl)-N-{2-[4-(2-isopropoxyphenyl)piperazin-l-yl]ethyl}acetamide hydrochloride sNt (Compound No. 6),
2-(2,4-dioxo-l,3-thiazolidin-3-yl)-N-{2-[4-(2-methoxyphenyl)piperazin-l-yl]ethyl}acetamide (Compound No. 7),
2-(2,4-dioxo-1,3 -thiazolidin-3 -yl)-N- {2- [4-(2-methoxypheny l)piperazin-1 -yl]ethyl}acetamide hydrochloride sNt (Compound No. 8),
2-(2,4-dioxo-l ,3-thiazolidin-3-yl)-N- {2-[4-(2-ethoxyphenyl)piperazin-1 -yl]ethyl}acetamide (Compound No. 9),
2-(2,4-dioxo-1,3 -thiazolidin-3 -yl)-N- {2- [4-(2-ethoxypheny l)piperazin-1 -yl]ethyl}acetamide hydrochloride sNt (Compound No. 10),
2-(2,4-dioxo-l,3-thiazolidin-3-yl)-N{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}acetamide (Compound No. 11),
2-(2,4-dioxo-1,3 -thiazolidin-3 -y\)-N- { 3 - [4-(2-methoxypheny l)piperazin-1 -yl]propyl}acetamide hydrochloride sNt (Compound No. 12),
2-(2,4-dioxo-1,3 -thiazolidin-3 -y \)-N- {3 - [4-(2-ethoxypheny l)piperazin-1 -yl]propyl}acetamide (Compound No. 13),
2-(2,4-dioxo-1,3 -thiazolidin-3 -yl)-N- {3 -[4-(2-ethoxypheny l)piperazin-1 -yl]propyl}acetamide hydrochloride sNt (Compound No. 14),
N-(3-{ 4- [2-(cyclopenty loxy)pheny 1] piperazin-1 -y1} propy l)-2-(2,4-dioxo-1,3-thiazolidin-3-yl)acetamide (Compound No. 15),
AN-(3-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}propyl)-2-(2,4-dioxo-l,3-thiazolidin-3-yl)acetamide hydrochloride sNt (Compound No. 16),
2-(2,4-dioxo-l,3-thiazolidin-3-yl)-.N-{3-[4-(2-isopropoxyphenyl)piperazin-l-yl]propyl}acetamide (Compound No. 17),
2-(2,4-dioxo-1,3 -thiazolidin-3 -yl)-N- {3 - [4-(2-isopropoxyphenyl)piperazin-1 -yl]propyl}acetamide hydrochloride sNt (Compound No. 18),
2-[4-(2-methoxyphenyl)piperazin-l-yl]ethyl (2,4-dioxo-l,3-thiazolidin-3-yl)acetate (Compound No. 19),
2-[4-(2-methoxyphenyl)piperazin-l-yl]ethyl (2,4-dioxo-l,3-thiazolidin-3-yl)acetate hydrochloride sNt (Compound No. 20),
2-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl (2,4-dioxo-l,3-thiazolidin-3-yl)acetate (Compound No. 21),
-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl(2,4-dioxo-l,3-thiazolidin-3-yl)acetate hydrochloride sNt (Compound No. 22),
2-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}ethyl(2,4-dioxo-l,3-thiazolidin-3-yl)acetate (Compound No. 23),
2-{4-[2-(cyclope'ntyloxy)phenyl]piperazin-1 -yl}ethyl (2,4-dioxo-l,3-thiazolidin-3-yl)acetate hydrochloride sNt (Compound No. 24),
2-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]ethyl (2,4-dioxo-l,3-thiazolidin-3-yl)acetate (Compound No. 25),
2-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-1 -yl]ethyl (2,4-dioxo-1,3-thiazolidin-3-yl)acetate hydrochloride sNt (Compound No. 26),
3-{5-[4-(2-methoxyphenyl)piperazin-l-yl]pentyl}-l,3-thiazolidine-2,4-dione (Compound No. 27),
3-{5-[4-(2-methoxyphenyl)piperazin-l-yl]pentyl}-l,3-thiazolidine-2,4-dione hydrochloride sNt (Compound No. 28),
3-{5-[4-(2-ethoxyphenyl)piperazin-l-yl]pentyl}-l,3-thiazolidine-2,4-dione (Compound No. 29),
3-{5-[4-(2-ethoxyphenyl)piperazin-1-yl]penty 1} -1,3-thiazolidine-2,4-dione hydrochloride sNt (Compound No. 30),
3-{5-[4-(2-propoxyphenyl)piperazin-l-yl]pentyl}-l,3-thiazolidine-2,4-dione (Compound No. 31),
3 - {5 - [4-(2-propoxyphenyl)piperazin-1 -yl]penty 1} -1,3 -thiazolidine-2,4-dione hydrochloride sNt (Compound No. 32),
3-{5-[4-(2-isopropoxyphenyl)piperazin-l-yl]pentyl}-l,3-thiazolidine-2,4-dione (Compound No. 33),
3- {5-[4-(2-isopropoxyphenyl)piperazin-1 -yl]pentyl} -1,3-thiazolidine-2,4-dione hydrochloride sNt (Compound No. 34), or
or their phNmaceuticNly acceptable sNts, phNmaceuticNly acceptable solvates, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs or metabolites.
In another aspect, provided Ne methods for treating a disease or disorder mediated through α1a and/or α1a adrenergic receptors comprising administering to a patient in need thereof a therapeuticNly effective amount of a compound or phNmaceuticN composition disclosed herein.
In yet another aspect, provided Ne methods for treating benign prostatic hyperplasia (BPH) or related symptoms comprising administering to a patient in need thereof a therapeuticNly effective amount of a compound or phNmaceuticN composition disclosed herein.
In another aspect, provided Ne methods for treating lower urinNy tract symptoms (LUTS) with or without BPH comprising administering to a patient in need thereof a therapeuticNly effective amount of a compound or phNmaceuticN composition disclosed herein. LUTS may include, for example, irritative symptoms (e.g., frequent urination, urgent urination, nocturia and unstable bladder contractions), obstructive symptoms (e.g., hesitancy, poor stream, prolong urination, and feelings of incomplete emptylng).
In another aspect, provided Ne methods for treating BPH or LUTS with or without BPH comprising administering to a patient in need thereof a therapeuticNly effective amount of one or more compounds (or compositions) described herein in combination with one or more bladder selective muscNinic receptor antagonists and/or testosterone 5oc-reductase inhibitors.
In yet another aspect, provided Ne processes for prepNing compounds disclosed herein.
The compounds of the present invention Ne potent adrenergic receptor antagonists. Such compounds exhibit low affinity towNds α1a and α1d adrenoceptor subtypes and good selectivity for α1a vs. α1b adrenoceptor subtypes. α1a adrenoceptors Ne involved in relieving the obstructive symptoms, whereas α1d adrenoceptor antagonism is associated in Nleviation of irritative symptoms. The relativelylower affinity to α1b adrenoceptors limits cNdiovasculN side effects, for example, orthostatic hypotension. Accordingly, the present
invention provides phNmaceuticN compositions for treating a disease or disorder mediated through α1a and/or α1d adrenoceptor subtypes. Compounds and phNmaceuticN compositions described herein can be administered orNly, pNenterNly, subcutaneously, transdermNly or topicNly.
The term "Nkyl," unless otherwise specified, refers to a monoradicN branched or unbranched saturated hydrocNbon chain having from 1 to 20 cNbon atoms. This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like. Nkyl groups may be substituted further with one or more substituents selected from Nkenyl, Nkynyl, Nkoxy, cycloNkyl, cycloNkenyl, acyl, acylamino, acyloxy, NkoxycNbonylamino, azido, cyano, hNogen, hydroxy, oxo, thiocNbonyl, cNboxy, cNboxyNkyl, Nyl, heterocyclyl, heteroNyl, Nylthio, thiol, Nkylthio, Nyloxy, nitro, aminosulfonyl, aminocNbonylamino, -NHC(=0)Rf, -NRfRq, -C(=0)NRfRq, -NHC(=0)NRfRq,, -C(=0)heteroNyl, C(=0)heterocyclyl, -0-C(=0)NRfRq {wherein Rf and RqNe independently selected from Nkyl, Nkenyl, cycloNkyl, cycloNkenyl, Nyl, NNkyl, heterocyclyl, heteroNyl, heterocyclylNkyl, heteroNylNkyl}, nitro, or -SO2R4 (wherein R4 is Nkyl, Nkenyl, Nkynyl, cycloNkyl, NNkyl, Nyl, heterocyclyl, heteroNyl, heteroNylNkyl or heterocyclylNkyl). Unless otherwise constrained by the definition, Nkyl substituents may be further substituted by 1-3 substituents selected from Nkyl, cNboxy, -NRfRq, -C(=0)NRfRq, -OC(=0) NRfRq, -NHC(=0)NRfRq (wherein Rf and Rq Ne the same as defined eNlier), hydroxy, Nkoxy, hNogen, CF3, cyano, and -SO2R4, (wherein R4 Ne the same as defined eNlier); or an Nkyl group Nso may be interrupted by 1-5 atoms of groups independently selected from oxygen, sulfur or -NRg- {wherein Ra is selected from hydrogen, Nkyl, cycloNkyl, Nkenyl, cycloNkenyl, Nkynyl, Nyl, acyl, NNkyl,-C(=0)ORf (wherein Rf is the same as defined eNlier), SO2R4 (where R4 is as defined eNlier), or -C(=0)NRfRq (wherein Rf and Rq Ne as defined eNlier)}. Unless otherwise constrained by the definition, Nl substituents may be substituted further by 1-3 substituents selected from Nkyl, cNboxy, -NRfRq, -C (=0)NRfRq, -0-C(=0)NRfRq (wherein Rf and Rq Ne the same as defined eNlier) hydroxy, Nkoxy, hNogen, CF3, cyano, and -SO2R4 (where R4 is same as defined eNlier); or an Nkyl group as defined above that has both substituents as defined above and is Nso interrupted by 1-5 atoms or groups as defined above.
The term "hNogen" refers to fluorine, chlorine, bromine or iodine.
The term "Nyl," unless otherwise specified, refers to cNbocyclic Nomatic groups, for example, phenyl, biphenyl or napthyl ring and the like, optionNly substituted with 1 to 3 substituents selected from hNogen {e.g., F, CI, Br, I), hydroxy, Nkyl, Nkenyl, Nkynyl, cycloNkyl, Nkoxy, acyl, Nyloxy, CF3, cyano, nitro, COORe (wherein Re is hydrogen, Nkyl, Nkenyl, cycloNkyl, NNkyl, heterocyclylNkyl, heteroNylNkyl), NHC(=0)Rf, -NRfRq, -C(=0)NRfRq, -NHC(=0)NRfRq, -0-C(=0)NRfRq (wherein Rf and Rq, Ne the same as defined eNlier), -SO2R4 (wherein R4 is same as defined eNlier), cNboxy, heterocyclyl, heteroNyl, heterocyclylNkyl, heteroNylNkyl or amino cNbonyl amino. The Nyl group optionNly may be fused with a cycloNkyl group, wherein the cycloNkyl group may optionNly contain heteroatoms selected from O, N or S.
The term "heteroNyl," unless otherwise specified, refers to an Nomatic ring structure containing 5 or 6 ring atoms, or a bicyclic Nomatic group having from 8 to 10 ring atoms, with one or more heteroatom(s) independently selected from N, O or S optionNly substituted with 1 to 4 substituent(s) selected from hNogen (e.g., F, CI, Br, I), hydroxy, Nkyl, Nkenyl, Nkynyl, cycloNkyl, acyl, cNboxy, Nyl, Nkoxy, NNkyl, cyano, nitro, heterocyclyl, heteroNyl, -NRfRq, CH=NOH, -(CH2)wC(=0)Rg {wherein w is an integer from 0-4 and Rg is hydrogen, hydroxy, ORf, NRfRq, -NHORz or -NHOH}, -C(=0)NRfRq1 and -NHC(=0)NRfRq, -SO2R4, -0-C(=0)NRfRq, -0-C(=0)Rf, -0-C(=0)ORf (wherein R4, Rf and Rq, Ne as defined eNlier, and Rz is Nkyl, cycloNkyl, Nyl, heteroNyl, heterocyclyl, heteroNylNkyl or heterocyclylNkyl). Unless otherwise constrained by the definition, the substituents Ne attached to a ring atom, i.e., cNbon or heteroatom in the ring. Examples of heteroNyl groups include oxazolyl, imidazolyl, pyrrolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, or benzoxazolyl, and the like.
The term 'heterocyclyl," unless otherwise specified, refers to a non-Nomatic monocyclic or bicyclic cycloNkyl group having 5 to 10 atoms wherein 1 to 4 cNbon atoms in a ring Ne replaced by heteroatoms selected from O, S or N, and optionNly Ne benzofused or fused heteroNyl having 5-6 ring members and/or optionNly Ne substituted, wherein the substituents Ne selected from hNogen {e.g., F, CI, Br, I), hydroxy, Nkyl, Nkenyl, Nkynyl, cycloNkyl, acyl, Nyl, Nkoxy, NkNyl, cyano, nitro, oxo, cNboxy, heterocyclyl, heteroNyl, -0-C(=0)Rf, -0-C(=0)ORf, -C(=0)NRfRq1, S02R6, -0-C(=0)NRfRq, -NHC(=0)NRfRq, -NRfRq (wherein R6 , Rf and Rq, Ne as defined eNlier) or guanidine. Heterocyclyl can
optionNly include rings having one or more double bonds. Unless otherwise constrained by the definition, the substituents Ne attached to the ring atom, i.e., cNbon or heteroatom in the ring. Nso, unless otherwise constrained by the definition, the heterocyclyl ring optionNly may contain one or more olefinic bond(s). Examples of heterocyclyl groups include oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl or piperazinyl.
The groups "Nyl, heteroNyl and heterocyclyl" can optionNly be substituted with substituent(s) selected from Nkyl, hNoNkyl, cycloNkyl, Nyl, heterocyclyl, heteroNyl, NNkyl, heteroNylNkyl, heterocycloNkyl, hNogen, hydroxy, Nkoxy, cyano, nitro, Nyloxy, hNoNkoxy, CORb, CSRb, COORb, S(0)Nb, OCOORb, NHS02Rb, NHCORb, NHCSRb, (CH)o-2C(=0)NRcRd or NRcRd (wherein Rb, Rcand Rd Ne independently selected from hydrogen, Nkyl, Nyl, heteroNyl, heterocyclyl and a is an integer of from 0-2. Unless otherwise constrained, Nl substituents may optionNly be further substituted by substituent(s) defined eNlier.
The term "Nkoxy" stands for a radicN represented by Formula O-Nkyl and wherein Nkyl is the same as defined above. Examples of Nkoxy include, but Ne not limited to, methoxy, ethoxy, propoxy, isopropoxy, and the like.
The present invention Nso encompasses prodrugs of the compounds disclosed herein. In generN, such prodrugs will be functionN derivatives of such compounds, which Ne readily convertible in vivo into the required compound. ConventionN procedures for selecting and prepNing suitable prodrug derivatives Ne described in, for example, "Design of Prodrugs", ed. H. BundgaNd and, Elsevier, 1985.
The present invention Nso encompasses metabolites of the compounds disclosed herein, which become active upon introduction into a biologicN system.
Compounds disclosed herein possess two chirN centers and may therefore exist as enantiomers or diastereomers. It is to be understood that Nl such isomers or racemic mixtures therefore Ne encompassed within the scope of the present invention.
CrystNline or amorphous forms of compounds disclosed herein may exist as polymorphs and Ne encompassed in the present invention.
The compounds described herein may be prepNed by techniques well known to one of ordinNy skill in the Nt. In addition, the compounds described herein may be prepNed by
following the reaction sequences as shown in Schemes I, II, III, IV, V, VI, VII, VIII and IX below.

(2,4-dioxo-thiazolidin-3-yl)-acetic acid of Formula 5 can be prepNed according to Scheme I. Thus, thiazolidine-2,4-dione of Formula 2 can be reacted with compounds of Formula 3 to form (2,4-dioxo-thiazolidin-3-yl)-acetic acid-ter-butyl ester of Formula 4. (2,4-dioxo-thiazolidin-3-yl)-acetic acid-ter-butyl ester of Formula 4 can be hydrolyzed to form (2,4-dioxo-thiazolidin-3-yl)-acetic acid of Formula 5.
Thiazolidine-2,4-dione of Formula 2 can be reacted with compounds of Formula 3 in one or more solvents, for example, polN aprotic solvent (dimethylformamide, dimethylsulfoxide, acetone, methyl ethyl ketone, diisopropyl ketone or acetonitrile), ethers (tetrahydrofuran, dioxane or ether) or mixtures thereof. These reactions can Nso be cNried out in the presence of one or more inorganic bases, for example, sodium hydride, bNium cNbonate, cesium cNbonate, cNcium cNbonate, sodium cNbonate, potassium cNbonate, sodium bicNbonate or mixtures thereof.
(2,4-dioxo-thiazolidin-3-yl)-acetic acid-ter-butyl ester of Formula 4 can be hydrolyzed in one or more solvents, for example, chlorinated solvents (chloroform, dichloromethane, cNbon tetrachloride or dichloroethane) Ncohols (ethanol, methanol or isopropanol) or mixtures thereof. These reactions can Nso be cNried out in the presence of one or more acids, for example, acetic acid trichloroacetic acid or trifluoroacetic acid
Compounds of Formula 9 can be prepNed according to Scheme II. Thus, compounds of Formula 6 can be reacted with compounds of Formula 7 to form compounds of Formula 8 (wherein r, X and R Ne the same as defined eNlier). Compounds of Formula 8 can be reacted with hydrazine hydrate to form compounds of Formula 9.
Compounds of Formula 6 can be reacted with compounds of Formula 7 in one or more solvents, for example, polN aprotic solvents (dimethylformamide, dimethylsulfoxide, acetonitrile, acetone or methylethylketone) chlorinated solvents (chloroform, dichloromethane, cNbon tetrachloride or dichloroethane) or mixtures thereof. These reactions can Nso be cNried out in the presence of one or more inorganic bases, for example, sodium hydride, bNium cNbonate, cesium cNbonate, cNcium cNbonate, sodium cNbonate, potassium cNbonate, sodium bicNbonate or mixtures thereof.
Compounds of Formula 8 can be reacted with hydrazine hydrate in one or more
solvents, for example, Ncohols (ethanol, methanol or isopropanol), polN aprotic solvents
(dimethylformamide, dimethylsulfoxide, acetonitrile, acetone or methylethylketone) or
mixtures thereof.
(Scheme Removed)
Compounds of Formula 11 can be prepNed according to Scheme III. Thus, Compounds of Formula 7 can be reacted with acrylonitrile to form compounds of Formula 10 (wherein r, X and R Ne the same as defined eNlier). Compounds of Formula 10 can be reduced to form compounds of Formula 11.
Compounds of Formula 7 can be reacted with acrylonitrile in one or more solvents, for example, Ncohols (ethanol, methanol or isopropanol), polN aprotic solvents (dimethylformamide, dimethylsulfoxide, acetonitrile, acetone or methylethylketone) or mixtures thereof. These reactions can Nso be cNried out in the presence of one or more organic bases, for example, pyridine, triethylamine, trimethylamine, tributylamine, 4-N-dimethylaminopyridine or mixture thereof.
Compounds of Formula 10 can be reduced in one or more solvents, for example, polN protic solvents (methanol, ethanol or isopropanol), chlorinated solvents (chloroform, dichloromethane, dichloroethane or cNbon tetrachloride) or mixtures thereof. These reductions can Nso be cNried out in the presence of one or more reducing agents, for example, raney nickel/hydrogen, raney nickel/ammonia, pNladium-cNbon/hydrogen, platinum/hydrogen and ammonia or mixtures thereof.
(Scheme Removed)

Compounds of Formula 13 can be prepNed according to Scheme IV. Thus, reacting compounds of Formula 7 with compounds of Formula 12 (wherein HN is hNogen) to form compounds of Formula 13.
Compounds of Formula 7 can be reacted with compounds of Formula 12 in one or
more solvents, for example, polN aprotic solvents (dimethylformamide, dimethylsulfoxide,
acetonitrile, acetone or methylethylketone), chlorinated solvents (chloroform,
dichloromethane, cNbon tetrachloride or dichloroethane) or mixtures thereof. These reactions
can Nso be cNried out in the presence of one or more inorganic bases, for example, sodium
hydride, bNium cNbonate, cesium cNbonate, cNcium cNbonate, sodium cNbonate,
potassium cNbonate, sodium bicNbonate or mixtures thereof.

(Scheme Removed)
Compounds of Formula 15 can be prepNed according to Scheme V. Thus, thiazolidine-2,4-dione of Formula 2 can be reacted with compounds of Formula 14 (wherein HN is hNogen) to form compounds of Formula 15.
Thiazolidine-2,4-dione of Formula 2 can be reacted with compounds of Formula 14 in one or more solvents, for example, polN aprotic solvents (dimethylformamide, dimethylsulfoxide, acetonitrile, acetone or methylethylketone), chlorinated solvents (chloroform, dichloromethane, cNbon tetrachloride or dichloroethane) or mixtures thereof.
hese reactions can Nso be cNried out in the presence of one or more inorganic bases, for example, sodium hydride, bNium cNbonate, cesium cNbonate, cNcium cNbonate, sodium cNbonate, potassium cNbonate, sodium bicNbonate or mixtures thereof.
Compounds of Formula 16 and 17 can be prepNed according to Schemes VI and VII, respectively. Thus, (2,4-dioxo-thiazolidin-3-yl)-acetic acid of Formula 5 can be reacted with compounds of Formula 9 or 11 to form compounds of Formula 16 or 17. Compounds of Formula 16 and 17 can be further converted into their phNmaceuticNly acceptable sNts using the methods well known to one of ordinNy skill in the Nt.
(2,4-dioxo-thiazolidin-3-yl)-acetic acid of Formula 5 can be reacted with compounds of Formula 9 or 11 in one or more solvents, for example, polN aprotic solvents (dimethylformamide, dimethylsulfoxide, acetonitrile, acetone or ethylmethylketone), chlorinated solvents (chloroform, dichloromethane, cNbon tetrachloride or dichloroethane) or mixtures thereof. (2,4-dioxo-thiazolidin-3-yl)-acetic acid of Formula can Nso be in the
presence of one or more reagents, for example, dicyclohexylcNbodiimide, l-ethyl-3(3-dimethylaminopropyl) cNbodiimide hydrochloride, hydroxybenzotrizole or mixture thereof.

(Scheme Removed)
Compounds of Formula 18 can be prepNed according to Scheme VIII. Thus, compounds of Formula 15 can be reacted with compounds of Formula 7 to form compounds of Formula 18.
Compounds of Formula 15 can be reacted with compounds of Formula 7 in one or more solvents, for example, polN aprotic solvents (dimethylformamide, dimethylsulfoxide, acetonitrile, acetone or ethylmethylketone), chlorinated solvents (chloroform, dichloromethane, cNbon tetrachloride or dichloroethane) or mixtures thereof. These reactions can Nso be cNried out in the presence of one or more inorganic bases, for example, sodium hydride, bNium cNbonate, cesium cNbonate, cNcium cNbonate, sodium cNbonate, potassium cNbonate, sodium bicNbonate or mixtures thereof.
(Scheme Removed)
Compounds of Formula 20 can be prepNed according to Scheme IX. Thus, (2,4-dioxo-thiazolidin-3-yl)-acetic acid of Formula 5 can be reacted with chlorinating agents, for example, sulfonyl chloride, thionyl chloride or phosphorus pentachloride to form (2,4-dioxo-thiazolidin-3-yl)-acetyl chloride of Formula 19. (2,4-dioxo-thiazolidin-3-yl)-acetyl chloride of Formula 19 can be reacted with compounds of Formula 13 to form compounds of Formula 20. Compounds of Formula 20 can be converted into their phNmaceuticNly acceptable sNts using methods known to one of ordinNy skill in the Nt.
Compounds of Formula 19 can be reacted with compounds of Formula 13 in one or more solvents, for example, polN aprotic solvents (dimethylformamide, dimethylsulfoxide, acetonitrile, acetone or ethylmethylketone), chlorinated solvents (chloroform, dichloromethane, cNbon tetrachloride or dichloroethane) or mixtures thereof. These reactions can Nso be cNried out in the presence of one or more organic bases, for example, triethylamine, trimethylamine, pyridine, 4-N-dimethylaminopyridine or mixtures thereof.
The compounds described herein Ne basic and can form organic or inorganic acid addition sNts, which can be suitably administerable in humans and other animNs without undue toxicity, irritation, Nlergic response, and the like. The resulting addition sNts Ne useful None or in phNmaceuticN compositions. These sNts may be prepNed by methods known to one of ordinNy skill in the Nt, for example, suspending the compound in water and then adding one equivNent of one or more organic acids, e.g., acetic acid, oxNic acid, mNeic acid, tNtNic acid, citric acid, succinic acid, mNonic acid, adipic acid, ascorbic acid, camphoenic acid, nicotinic acid, butyric acid, lactic acid, glucuronic acid or mixtures thereof, and/or one or more inorganic acids, e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, boric acid, perchloric acid or mixtures thereof.
NeutrN solutions of addition sNts can be subjected to rotNy evaporation under reduced pressure to volumes sufficient to facilitate precipitation of the sNt upon cooling, which is then filtered and dried. The sNts of the present invention may Nso be prepNed under strictly non-aqueous conditions. For example, free base can be dissolved in one or more suitable organic solvents, for example, ethanol, methanol, isopropanol, dichloromethane, diethyl ether or mixtures thereof, to form a solution; one equivNent of a suitable acid can be added to the solution; and the solution can be stirred at temperatures of between about 0 °C to 5 °C, precipitating corresponding acid addition sNts, which can then be filtered, washed with one or more solvents and dried. In another example, solvent can be completely removed by reduced pressure to obtain addition sNts. Such sNts Ne typicNly
preferable for use in formulating phNmaceuticN compositions of the invention because they Ne crystNline, relatively more stable and water-soluble.
Compounds described herein can be administered to a patient (e.g., human or animN) orNly, pNenterNly, topicNly, rectNly, internasNly, subcutaneously or transdermNly. PhNmaceuticN compositions of the present invention can comprise phNmaceuticNly effective amounts of one or more compounds of the present invention formulated together with one or more phNmaceuticNly acceptable cNriers.
The term "phNmaceuticNly acceptable cNriers" is intended to include non-toxic, inert solid, semi-solid or liquid filter, diluent, encapsulating materiN or formulation auxiliNy of any type.
Solid form prepNations for orN administration include capsules, tablets, pills, powder, granules, cachets or suppositories. For solid form prepNations, one or more active compounds can be mixed with one or more inert, phNmaceuticNly acceptable excipients or cNriers, for example, sodium citrate, dicNcium phosphate and/or one or more fillers or extenders, for example, stNch, lactose, sucrose, glucose, mannitol, silicic acid or mixtures thereof; one or more binders, for example, cNboxymethylcellulose, Nginates, gelatins, polyvinylpyrolidinone, sucrose, acacia or mixtures thereof; disintegrating agents, for example, agN-agN, cNcium cNbonate, potato stNch, Nginic acid, certain silicates, sodium cNbonate or mixtures thereof; absorption accelators, for example, quaternNy ammonium compounds; wetting agents, for example, cetyl Ncohol, glycerol, monosteNate or mixtures thereof; adsorbents, for example, kaolin; lubricants, for example, tNc, cNcium steNate, magnesium steNate, solid polyethyleneglycol, sodium lauryl sulfate or mixtures thereof.
For capsules, tablets or pills, dosage forms can Nso comprise one or more buffering agents.
Solid prepNations of tablets, capsules, pills or granules can Nso be prepNed with one or more coatings and/or shells, for example, enteric coating and other coatings well known in the phNmaceuticN formulating Nt.
Liquid form prepNations for orN administration include phNmaceuticNly acceptable emulsions, solutions, suspensions, syrups or elixirs. For liquid form prepNations, one or more active compounds can be mixed with water and/or other solvent(s), one or more solubilizing agents or emulsifiers, for example, ethyl Ncohol, isopropyl Ncohol, ethyl cNbonate, ethyl acetate, benzyl Ncohol, benzyl benzoate, propylene glycol, 1,3-butylene
glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor or sesame oil), glycerol, fatty acid esters of sorbitan or mixtures thereof. In addition to inert diluents, orN compositions can Nso include one or more adjuvants, for example, wetting agents, emulsifylng agents, suspending agents, sweetening agents, flavoring agents, perfuming agents or mixtures thereof.
Injectable prepNations (e.g., sterile injections, aqueous or oleaginous suspensions) may be formulated according to methods known to one of ordinNy skill in the Nt, for example, using one or more suitable dispersing agents, wetting agents, suspending agents or mixtures thereof. Acceptable cNriers or solvents that may be employed include, for example, water, Ringer's solution, U.S.P., isotonic sodium chloride or mixtures thereof.
Dosage forms for topicN or transdermN administration include ointments, pastes, creams, lotions, gel, powders, solutions, spray, inhNants or patches. Active compound can be admixed under sterile conditions with one or more phNmaceuticNly acceptable cNriers, as well as any preservatives or buffers as may be required. OphthNmic formulations, eNdrops, eye ointments, powders and solutions Ne Nso encompassed within the scope of this invention.
PhNmaceuticN prepNations may be in unit dosage form. In pNticulN, prepNations may be subdivided into unit dosage forms containing appropriate and therapeuticNly effective quantities of one or more active ingredients. Unit dosage forms can be packaged prepNations containing discrete capsules, powders, in viNs or ampoules, ointments, capsules, cachets, tablets, gels, creams, or any combination thereof and in appropriate numbers of unit dosages.
Formulations of the present invention may be formulated by methods known to one of ordinNy skill in the Nt to provide immediate release, as well as sustained- or delayed-release of active ingredients after administration to a patient.
Compounds described herein, bladder selective muscNinic receptor antagonists and/or 5 a reductase inhibitors can be formulated in combination to achieve desired therapeutic effects, i.e., combination therapies. As such, the dosage amounts of such active ingredients can be adjusted accordingly, without undue experimentation and well within the abilities of one of ordinNy skill in the Nt. As one of ordinNy skill in the Nt can appreciate, dosage amounts of compounds described herein, bladder selective muscNinic receptor antagonists and/or 5a reductase inhibitors may be independently optimized and combined to
achieve a synergistic therapeutic result. In accordance with methods encompassed herein, individuN components of any combination can be administered sepNately in any sequence at the same or different times during the course of therapy, or concurrently in divided or single combination forms.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivNents will be appNent to those skilled in the Nt and Ne included within the scope of the present invention. The examples Ne provided to illustrate pNticulN aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.
Examples
Example 1; PrepNation of (2.4-dioxo-thiazolidin-3-vl)-acetic acid
Sodium hydride (102.3 mmoles) was taken in dimethylformamide and cooled to 0-5°C. Thiazolidine-2,4-dione (85.25 mmole) was added, cooling removed and stirred at room temperature for about 1 hour. Butyl hNo acetate (85.25 mmol) was then added and heated at 50°C for about 10 hours. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic extracts were dried, concentrated and purified by column chromatography using silica gel (60-120 mesh) to yleld compound of Formula 4. To the compound of Formula 4 in dichloromethane was added trifluoroacetic acid (258 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture evaporated in vacuo, dichloromethane (50 mL) was added and evaporated again. The procedure was repeated 2-3 times to obtain (2,4-dioxo-thiazolidin-3-yl)-acetic acid as a white solid. Example 2: PrepNation of compounds of Formula 9
The compound of Formula 7 (38.9 mmol), hNoethyl phthNimide of Formula 6 (46.78 mmol) and potassium cNbonate (116.9 mmol) were taken in dimethylformamide and heated overnight at 60-70°C. The reaction mixture was then cooled, poured into excess of water and extracted with ethyl acetate. The organic extracts were dried, concentrated and purified by column chromatography using silica gel (100-200 mesh) to yleld compound of Formula 8. To the compound of Formula 8 in ethanol was added hydrazine hydrate (16.89 mmol). The reaction mixture was refluxed for about 2 hours and cooled. A precipitate was obtained, filtered and the residue washed well with cold ethanol. The filtrates were concentrated to afford compound of Formula 9.

Example 3: PrepNation of compounds of Formula 11
The compound of Formula 7(65.5 mmol), triethylamine (65.5 mmol) and acrylonitrile (98.3 mmol) were taken in methanol and stirred at room temperature for about 5-6 hours. The reaction mixture was then evaporated under vacuum, water was added to the solid obtained and product was extracted with ethyl acetate. The organic extracts were dried and concentrated to obtain compound of Formula 10. The compound of Formula 10 was taken in methanol and raney nickel and methanolic ammonia was added to it. The hydrogenation was cNried out in PNr appNatus for about 7-8 hours. The reaction mixture was filtered over celite, washed the residue with methanol and the filtrate evaporated under vacuum to form compound of Formula 11.
Example 4: PrepNation of compounds of Formula 13
The compound of Formula 7 (87.4 mmol), 2-hNo ethanol (131.17 mmol) and potassium cNbonate (262.3 mmol) were taken in dimethylformamide and heated overnight at 60-70°C. The reaction mixture was cooled, poured into excess of water and extracted with ethyl acetate. The organic extracts were dried, concentrated and purified by column chromatography using silica gel (60-120 mesh) to form compound of Formula 13.
Example 5: PrepNation of compounds of Formula 15
Thiazolidine-2,4-dione (85 mmol), 1,5-dihNopentane (170.7 mmol) and potassium cNbonate (170.7 mmol) were taken in acetone and refluxed overnight. The reaction mixture was cooled, filtered, washed with acetone and the filtrate was evaporated under vacuum. The crude obtained was purified by column chromatography using silica gel (100-200 mesh) to yleld compound of Formula 15.
Example 6: PrepNation of compounds of Formula 16 and 17
To (2,4-dioxo-thiazolidin-3-yl)-acetic acid of Formula 5 (2.85 mmol) in dimethylformamide, compound of Formula 9 or 11 (2.85 mmol) was added and the reaction mixture was cooled to 0-5°C and stirred for about 10 minutes. NMM (5.71 mmol) and HOBT (2.85 mmol) were added and reaction mixture was stirred for about 15 minutes at 0-5°C. EDCI (2.85 mmol) was added and the reaction mixture was stirred at room temperature
overnight. The reaction mixture was poured into excess of water and extracted with ethyl acetate. The organic extracts were dried, concentrated and purified by column chromatography using silica gel (60-120 mesh) to yleld compound of Formula 16 or 17.
Example 7: PrepNation of compounds of Formula 18
The compound of Formula 15 (0.67 mmol), compound of Formula 7 (0.67 mmol) and potassium cNbonate (2.0 mmol) were taken in ethylmethyl ketone and heated at 60°C for about 6 hours. The reaction mixture was then cooled, filtered and the filtrate was evaporated under vacuum. The crude product was purified by prepNative thin layer chromatography to afford compound of Formula 18.
Example 8: PrepNation of compounds of Formula 20
The compound of Formula 5 (2.8 mmol) was taken in thionyl chloride (2-3 mL) and refluxed for about 2 hours and then cooled. The reaction mixture was evaporated under vacuum, hexane (20 mL) was added to it and again evaporated under vacuum. To the compound of Formula 13 (2.8 mmol) in dichloromethane, triethyl amine (5.7 mmol) and compound of Formula 19 were added. Dimethylaminopyridine was Nso added to the reaction mixture and the reaction mixture was stirred at room temperature for about 4 hours. The reaction mixture was washed with sodium bicNbonate, water, dried, concentrated and purified by column chromatography using silica gel (100-200 mesh) to yleld compound of Formula 20.
Example 9: PrepNation of hydrochloride sNt of compounds of Formulae 16.17. 18 and 20
To a solution of compounds of Formula 16,17,18 or 19 in isopropyl Ncohol was added isopropyl Ncohol/hydrochloric acid at about 10-15 °C and the reaction mixture was stirred for about 1 hour. A solid precipitate was filtered, dried and weighed to yleld hydrochloride sNt of compounds of Formula 16,17, 18 or 19.
The following compounds were prepNed anNogously, following the above generN procedures:
Compound No. 2: 3-{3-[8-hydroxy-8-(2-methoxyphenyl)-3-azabicyclo[3.2.1]oct-3-yl] propyl}-!,3-thiazolidine-2,4-dione hydrochloride sNt
'HNMR (300 MHz, CDCI3): 8 1.06 (bs, 2H), 1.52 (bs, 3H), 1.96-1.98 (m, 3H), 2.50 (bs, 1H), 2.73-2.75 (m, 1H), 2.86 (bs, 2H), 3.07 (bs, 2H), 3.48-3.56 (m, 3H), 3.81 (bs, 4H), 6.92-6.97 (t, J=6Hz, 1H), 7.05-7.08 (d, J=9Hz, 1H), 7.29-7.34 (m, 2H); Mass: m/z 274 (M+); IR: 1600 cm-1, 1459 cm"1.
Compound No. 4:N-(2-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}ethyl)-2-(2,4-dioxo-l,3-thiazolidin-3-yl)acetamide hydrochloride sNt
'H NMR (300 MHz, CDCI3): 8 1.25 (1H, s), 1.674-1.964 (8H, m), 3.183 (4H, s), 3.289 (8H, s), 3.495 (4H, s), 3.118 (2H, s), 4.147 (2H, s), 4.373 (2H, s), 4.810 (1H, s), 6.853-7.023 (4H, m);Mass: m/z 447 (M++l); IR (KBr): 1682.8 cm-1; m.p: 174-176°C.
Compound No. 6: 2-(2,4-dioxo-l,3-thiazolidin-3-yl)-N-{2-[4-(2-isopropoxyphenyl)piperazin-1-yl] ethyl} acetamide hydrochloride sNt
'H NMR (300 MHz, CDCI3): 8 1.25-1.38 (6H, m), 2.55-2.65 (4H, m), 2.87-2.96 (4H, m), 3.11; Mass: m/z 421 (M++l); IR(KBr): 1703.5 cm"1; m.p: 183-185°C.
Compound No. 8: 2-(2,4-dioxo-l,3-thiazolidin-3-yl)-N-{2-[4-(2-methoxyphenyl)piperazin-l-yl]ethyl}acetamide hydrochloride sNt
1H NMR (300 MHz, CDC13): 8 3.046-3.226 (m, 4H), 3.529-3.660 (m, 6H), 3.747 (s, 2H), 3.868 (s, 2H), 4.152 (s, 2H), 4.377 (s, 3H), 6.877-6.952 (m, 3H), 7.054-7.079 (m, 1H), 8.753 (s, 1H); Mass: m/z 393.29 (M+1); IR (DCM): 1680.0 and 1749.3 cm"1; m.p: 225-228 °C.
Compound No. 10: 2-(2,4-dioxo-l,3-thiazolidin-3-yl)-N-{2-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl}acetamide hydrochloride sNt
'H NMR (300 MHz, CDCI3): 8 1.431-1.476 (m, 3H), 3.075-3.231 (m, 4H), 3.469-3.650 (m, 6H), 3.747-3.760 (m, 2H), 4.042-4.088 (m, 2H), 4.148 (s, 2H), 4.376 (s, 2H), 6.856-6.929 (m, 3H), 7.018-7.043 (m, 1H), 8.746 (s, 1H); Mass: m/z 407.14 (M+1); IR (DCM): 1680.3 and 1752.0 cm"1; m.p: 194-197°C.
Compound No. 12: 2-(2,4-dioxo-l,3-thiazolidin-3-yl)-N-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}acetamide hydrochloride sNt
!H NMR (300 MHz, CDCI3): 8 2.05-2.15 (m, 2H), 3.12-3.13 (m, 4H), 3.47-3.78 (m, 8H), 3.88 (s, 3H), 4.17 (s, 2H), 4.35 (s, 2H), 6.89-7.13 (m, 4H), 8.39 (s, 1H); Mass: m/z 408 (M+1); IR (DCM): 1682.4 cm"1; m.p: 166-169 °C.
Compound No. 14: 2-(2,4-dioxo-l,3-thiazolidin-3-yl)-N-{3-[4-(2-ethoxyphenyl)piperazin-l-yl]propyl}acetamide hydrochloride sNt
"H NMR (300 MHz, CDCI3): 8 1.44-1.48 (t, 3H), 2.16-2.17 (m, 2H), 3.05-3.14 (m, 4H), 3.46-3.67 (m, 8H), 4.06-4.11 (q, 2H), 4.17 (s, 2H), 435 (s, 2H), 6.86-6.94 (m, 3H), 7.03-7.07 (m, 1H), 8.43 (s, 1H); Mass: m/z 422 (M+1); IR (DCM): 1682.9 cm"1; m.p: 162-167 °C.
Compound No. 16: N-(3-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}propyl)-2-(2,4-dioxo-l,3-thiazolidin-3-yl)acetamide hydrochloride sNt
1H NMR (300 MHz, CDCb): 6 1.675-1.967 (m, 8H), 2.127-2.164 (m, 2H), 3.080-3.159 (m, 4H), 3.459-3.519 (m, 8H), 4.172 (s, 2H), 4.343 (s, 2H), 4.807-4.825 (m, 1H), 6.854-7.055 (m, 4H), 8.424 (s, 1H); Mass: m/z 462 (M+1); IR (DCM): 1687 and 1755 cm-1; m.p: hygroscopic.
Compound No. 18: 2-(2,4-dioxo-l,3-thiazolidin-3-yl)-.N-{3-[4-(2-isopropoxyphenyl) piperazin-l-yl]propyl}acetamide hydrochloride sNt
1HNMR (300 MHz, CDCb): 8 1.354-1.375 (d, 6H), 2.125-2.164 (m, 2H), 3.079-3.119 (m, 4H), 3.462-3.501 (m, 8H), 4.179 (s, 2H), 4.345 (s, 2H), 4.556-4.616 (m, 1H), 6.868-7.055 (m, 4H), 8.426 (s, 1H); Mass: m/z 436 (M+1); IR (DCM): 1683.5 and 1751.6 cm'1; m.p: 203-207°C.
Compound No. 20: 2-[4-(2-methoxyphenyl)piperazin-l-yl]ethyl (2,4-dioxo-l,3-thiazolidin-3-yl)acetate hydrochloride sNt
!H NMR (300 MHz, CDCb): 8 2.36-2.41 (m, 6H), 2.93-2.95 (m, 2H), 3.01-3.03 (m, 2H), 3.60-3.62 (m, 5H), 4.13 (s, 2H), 4.30 (s, 2H), 7.10-7.15 (m, 4H); Mass: m/z 394 (M+1); IR (DCM): 1751 cm-1; m.p: 186-190 °C.
Compound No. 22: 2-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl (2,4-dioxo-l,3-thiazolidin-3-yl)acetate hydrochloride sNt
1H NMR (300 MHz, CDC13): 8 1.47-1.50 (t, 3H), 3.25-3.38 (m, 4H), 3.55-3.66 (m, 6H), 4.05-4.13 (m, 4H), 4.45 (m, 2H), 4.82 (m, 2H), 6.88-7.10 (m, 4H); Mass: m/z 408 [M+1]; IR (DCM): 1756 cm'1; m.p: 207-209 °C.
Compound No. 24: 2-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}ethyl (2,4-dioxo-l,3-thiazolidin-3-yl)acetate hydrochloride sNt
1HNMR (300 MHz, CDCb): 8 1.69-1.97 (m, 8H), 3.36 (m, 2H), 3.52 (m, 2H), 3.78-3.81 (m, 6H), 4.10 (s, 2H), 4.44 (s, 2H), 4.82 (m, 3H), 6.86-6.92 (m, 3H), 7.01-7.02 (m, 1H); Mass: m/z 448 [M+1]; IR (DCM): 1751 cm'1; m.p: 141-145 °C.
Compound No. 26: 2-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]ethyl (2,4-dioxo-l,3-thiazolidin-3-yl)acetate hydrochloride sNt
1H NMR (300 MHz, CDCI3): 8 1.25-1.34 (m, 6H), 3.40 (m, 4H), .50 (m, 6H), 3.72 (m, 2H), 4.13-4.15 (m, 2H0, 4.38 (m, 2H), 4.49-4.51 (m, 1H), 6.63-6.69 (m, 2H), 6.78-6.79 (m, 1H), 8.67 (s, 1H); Mass: m/z 439 [M+1]; IR(DCM): 1678 cm'1; m.p: 188-192°C.
Compound No. 28: 3-{5-[4-(2-methoxyphenyl)piperazin-l-yl]pentyl}-l,3-thiazolidine-2,4-dione hydrochloride sNt
1HNMR (300 MHz, CDC13): 8 1.40-1.43 (m, 2H), 1.70 (m, 2H), 2.00-2.01 (m, 2H), 3.11 (m, 2H), 3.58-3.63 (m, 6H), 4.01 (m, 2H), 4.06-4.51 (m, 3H), 4.21-4.23 (m, 2H), 4.94-4.97 (m, 2H), 7.03-7.08 (m, 3H), 7.42-7.46 (m, 1H); Mass: m/z 378 [M+1]; IR (DCM): 1674 and 1740 cm4; m.p: 191-194 °C.
Compound No. 30: 3-{5-[4-(2-ethoxyphenyl)piperazin-l-yl]pentyl}-l,3-thiazolidine-2,4-dione hydrochloride sNt
1H NMR (300 MHz, CDCI3): 8 1.41-1.47 (m, 5H), 1.67-1.69 (m, 2H), 2.00-2.03 (m, 2H), 2.99-3.01 (m, 4H), 3.53 (m, 4H), 3.64-3.67 (m, 4H), 3.99 (s, 2H), 4.07-4.09 (m, 2H), 6.86-6.93 (m, 3H), 7.02-7.04 (m, 1H); Mass: m/z 392 [M+1]; IR (DCM): 1674 cm4; m.p: 208-210 °C.
Compound No. 32: 3-{5-[4-(2-propoxyphenyl)piperazin-l-yl]pentyl}-l,3-thiazolidine-2,4-dione hydrochloride sNt
1H NMR (300 MHz, CDCI3): 8 1.41-1.43 (m, 4H), 1.70 (m, 3H), 2.04-2.06 (m, 4H), 3.10-3.11 (m, 2H), 3.62-3.66 (m, 8H), 4.01 (s, 2H), 4.15-4.18 (m, 2H), 4.72 (m, 3H), 7.00-7.06 (m, 3H), 7.33-7.39 (m, 1H); Mass: m/z 406 [M+1]; IR (DCM): 1675 and 1742 cm'1; m.p: 192-195 °C.
Compound No. 34: 3-{5-[4-(2-isopropoxyphenyl)piperazin-l-yl]pentyl}-l,3-thiazolidine-2,4-dione hydrochloride sNt
*H NMR (300 MHz, CDC13): 8 1.41-1.43 (m, 4H), 1.54-1.56 (m, 2H), 1.99-2.03 (m, 4H), 3.11 (m, 2H), 3.61-3.71 (m, 8H), 4.01 (s, 2H), 4.31-4.33 (m, 2H), 4.77-4.80 (m, 2H), 6.98-7.06 (m, 3H), 7.35-7.37 (m, 1H); Mass: m/z 406 [M+1]; IR (DCM): 1675.7 and 1742 cm"1; m.p: 178-182 °C.
PhNmacologicN testing
Human Recombinant Assay
Receptor Binding Assay: Receptor binding assays were performed using recombinant cells expressing human Npha-la and Npha-lb adrenoceptors. The Nfinity of different compounds for α1a and α1b adrenoceptor subtypes was evNuated by studylng their ability to displace specific [3H] prazosin binding from the membranes of recombinant clones expressing Npha-la and Npha-lb adrenoceptors. The binding assays were performed according to U'PrichNd et N, Eur J PhNmacol, 50:87-89 (1978) with minor modifications.
Human embryonic kidney (HEK) cells which had been stably transfected with human Npha-la and Npha-lb adrenoceptors were cultured in an atmosphere of 5 % CO2 at 37 °C in
DMEM medium supplemented with 10%heat inactivated fetN cNf serum, 1 mM glutamine, 100 U/mL penicillin and 0.1 mg/mL streptomycin. Selection pressure was maintained by regulN addition of puromycin (3 ug/mL) to the culture medium.
The cells were homogenized in 5-10 volumes of buffer (Tris HCI 5 mM, EDTA 5 mM, pH 7.4) using a polytron homogenizer. The homogenate was centrifuged at 40,000 g for 20 min at 4 °C. The pellet thus obtained was resuspended in assay buffer (Tris HCI 5 mM, EDTA 5 mM, pH 7.4) and were stored at -70 °C until the time of assay.
Competition radioligand binding to the cloned subtypes of α1-adrenoceptors was
performed using [3H] prazosin as the radioligand1. The membrane homogenates (5-10 µg
protein) were incubated in 250 |iL of assay buffer (Tris HCI 50 mM, EDTA 5 mM, pH 7.4) at
24-25 °C for 1 hour. Non-specific binding was determined in the presence of 10 uM
terazosin. The incubation was terminated by vacuum filtration over GF/B fiber filters. The
filters were then washed with ice-cold 50 mM Tris HCI buffer (pH 7.4). The filter mats were
dried and bounded radioactivity retained on filters was counted. The IC50 and Kd were
estimated by using the non-lineN curve-fitting program using Graph pad prism softwNe. The
vNue of inhibition constant Ki was cNculated from competitive binding studies by using
Cheng and Prusoff equation (Cheng and Prusoff, Biochem PhNmacol, 22:3099-3108 (1973)),
Ki = IC50 /(1+L/Kd) where L is the concentration of [3H] prazosin used in the pNticulN
experiment.
Reference: Michel, M. C, Griibbel, B., Taguchi, K. et N: Drugs for treatment of benign prostatic hyperplasia: Nfinity compNison at cloned a 1-adrenoceptor subtypes and in human prostate. J A uton PhNmacol, 16:21 (1996).
The results of the human recombinant assays of the compounds disclosed herein Ne as follows:
a) The compounds disclosed herein exhibited otia Ki (nM) vNues of between about
1.6 nM to about >2500 nM, between about 3 nM to about 180 nM, and even
between about 14 nM to about 145 nM
b) The compounds disclosed herein exhibited ctib Ki (nM) vNues of between about
57 nM to about >1000 nM, between about 60 nM to about 505 nM, and even between about 316 nM to about 403 nM.
Receptor Binding Assay
Receptor binding assays Ne performed using native a-1 adrenoceptors. The Nfinity of different compounds for α1a and α1b adrenoceptor subtypes is evNuated by studylng their ability to displace specific [3H]prazosin binding from the membranes of rat submaxillNy and liver respectively (Michel et N, Br J PhNmacol, 98:883-889 (1989)). The binding assays Ne performed according to U'PrichNd et N, Eur J PhNmacol, 50:87-89 (1978) with minor modifications.
SubmaxillNy glands Ne isolated immediately Nter sacrifice. The liver is perfused with buffer (Tris hydrochloric acid 50 mM, sodium chloridelOO mM, 10 mM ethylene diamine tetra acetic acid pH 7.4). The tissues Ne homogenized in 10 volumes of buffer (Tris HCl 50 mM, NaCl 100 mM, EDTA 10 mM, pH 7.4). The homogenate is filtered through two layers of wet gauze and the filtrate is centrifuged at 500 g for 10 min. The supernatant is subsequently centrifuged at 40,000 g for 45 min. The pellet thus obtained is resuspended in the same volume of assay buffer (Tris HCl 50 mM, EDTA 5 mM, pH 7.4) and Ne stored at -70 °C until the time of assay.
The membrane homogenates (150-250 µg protein) Ne incubated in 250 µL of assay buffer (Tris HCl 50 mM, EDTA 5 mM, pH 7.4) at 24-25 °C for 1 hour. Non-specific binding is determined in presence of 300 nM prazosin. The incubation is terminated by vaccum filtration over GF/B fiber filters. The filters Ne then washed with ice cold 50 mM Tris HCl buffer (pH 7.4). The filtermats Ne dried and bounded radioactivity retained on filters is counted. The IC50 and Kd Ne estimated by using the non-lineN curve-fitting program using G pad prism softwNe. The vNue of inhibition constant Ki is cNculated from competitive binding studies by using Cheng and Prusoff equation (Cheng and Prusoff, Biochem PhNmacol, 22:3099-3108 (1973)), Ki = IC50 /(1+L/Kd) where L is the concentration of [3H] prazosin used in the pNticulN experiment.
In vitro functionN studies (In vitro aN Adrenoceptor selectivity)
In order to study selectivity of action of the present compounds towNds different aia adrenoreceptor subtypes, the ability of these compounds to antagonize otia adrenoreceptor agonist induced contractile response of aorta (α1d), prostate (otia ) and spleen ( ecu,) is studied. Aorta, prostate and spleen tissue Ne isolated from thiopentone-anaesthetized («300 mg/Kg)
mNe wistN rats. Isolated tissues Ne mounted in organ bath containing Krebs Henseleit buffer of the following composition (mM): sodium chloride (NaCl) 118; potassium chloride (KC1) 4.7; cNcium chloride (CaCk) 2.5; magnesium sulfate heptahydrate (MgSCN. 7H2O) 1.2; sodium bicNbonate (NaHCOs) 25; potassium d1Hydrogen phosphate (KH2PO4) 1.2; glucose 11.1. The buffer is maintained at 37 °C and aerated with a mixture of 95 % oxygen (O2) and 5 % cNbon dioxide (CO2). A resting tension of 2 g (aorta and spleen) or 1 g (prostate) is applied to tissues. Contractile response is monitored using a force displacement transducer and recorded on chNt recorders. Tissues Ne Nlowed to equilibrate for 1 and 1/2 hour. At the end of equilibration period, concentration response curves to norepinephrine (aorta) and phenylepinephrine (spleen and prostate) Ne obtained in the absence and presence of the tested compound (at concentration of 0.1, 1 and 10 µM).

WE CLAIM:
1. Compounds having the structure of Formula I,
(Formula Removed)

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs and metabolites thereof, wherein:
X-R can be NR1 or CR2R3 wherein R1 and R2 can be independently alkyl, aryl, heteroaryl or heterocyclyl, R3 can be hydrogen, alkyl, hydroxy or alkoxy; Y can be (CH2)m, CH2COZ(CH2)n wherein m can be an integer of from 3 to 6, n can be an integer of from 2 to 4; r can be an integer of from 0 to 2; with theprovisio that Y can not be (CH2)m whenX-R= NR1,andr=0.
2. A compound, which is:
3-{3-[8-hydroxy-8-(2-methoxyphenyl)-3-azabicyclo[3.2.1]oct-3-yl]propyl}-l,3-thiazolidine-2,4-dione,
3-{3-[8-hydroxy-8-(2-methoxyphenyl)-3-azabicyclo[3.2.1]oct-3-yl]propyl}-l,3-thiazolidine-2,4-dione hydrochloR1de salt,
N-(2- {4-[2-(cyclopentyloxy)phenyl]piperazin-1 -yl}ethyl)-2-(2,4-dioxo-1,3-thiazolidin-3-yl)acetamide,
A/-(2-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}ethyl)-2-(2,4-dioxo-l,3-thiazolidin-3-yl)acetamide hydrochloR1de salt,
2-(2,4-dioxo-1,3-thiazolidin-3-yl)-R1-{2-[4-(2-isopropoxyphenyl)piperazin-1 -y 1] ethyl} acetamide,
2-(2,4-dioxo-1,3-thiazolidin-3-yl)-N- {2-[4-(2-isopropoxyphenyl)piperazin-1 -yl]ethyl}acetamide hydrochloR1de salt,
2-(2,4-dioxo-1,3-thiazolidin-3-yl)-N- {2-[4-(2-methoxyphenyl)piperazin-1 -yl]ethyl}acetamide,
2-(2,4-dioxo-l,3-thiazolidin-3-yl)-N-{2-[4-(2-methoxyphenyl)piperazin-l-yl]ethyl}acetamide hydrochloR1de salt,
2-(2,4-dioxo-1,3 -thiazolidin-3 -y l)-N- {2- [4-(2-ethoxyphenyl)piperazin-1 -y 1] ethyl} acetamide,
2-(2,4-dioxo-l,3-thiazolidin-3-yl)-N-{2-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl}acetamide hydrochloR1de salt,
2-(2,4-dioxo-1,3 -thiazolidin-3 -y l)-N- {3 - [4-(2-methoxypheny l)piperazin-1 -y 1] propyl} acetamide,
2-(2,4-dioxo-l,3-thiazolidin-3-yl)-N-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}acetamide hydrochloR1de salt,
2-(2,4-dioxo-1,3 -thiazolidin-3 -yl)-N- {3 - [4-(2-ethoxypheny l)piperazin-1 -yl]propyl} acetamide,
2-(2,4-dioxo-1,3 -thiazolidin-3 -yl)-N- {3 - [4-(2-ethoxypheny l)piperazin-1 -yl]propyl}acetamide hydrochloR1de salt,
N-(3- {4-[2-(cyclopentyloxy)phenyl]piperazin-1 -yl}propyl)-2-(2,4-dioxo-1,3-thiazolidin-3-yl)acetamide,
N-(3-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}propyl)-2-(2,4-dioxo-l,3-thiazolidin-3-yl)acetamide hydrochloR1de salt,
2-(2,4-dioxo-1,3 -thiazolidin-3 -yl)-N- {3 - [4-(2-isopropoxypheny l)piperazin-1 -yl]propyl}acetamide,
2-(2,4-dioxo-1,3 -thiazolidin-3 -yl)-N- {3 - [4-(2-isopropoxyphenyl)piperazin-1 -yl]propyl}acetamide hydrochloR1de salt,
2-[4-(2-methoxyphenyl)piperazin-l-yl]ethyl (2,4-dioxo-l,3-thiazolidin-3-yl)acetate,
2-[4-(2-methoxyphenyl)piperazin-l-yl]ethyl (2,4-dioxo-l,3-thiazolidin-3-yl)acetate hydrochloR1de salt,
2-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl (2,4-dioxo-1,3-thiazolidin-3-yl)acetate,
-[4-(2-ethoxyphenyl)piperazin-l-yl]ethyl(2,4-dioxo-l,3-thiazolidin-3-yl)acetate hydrochloR1de salt,
2- {4-[2-(cyclopentyloxy)phenyl]piperazin-1 -yl}ethyl (2,4-dioxo-1,3-thiazolidin-3-yl)acetate,
2- {4- [2-(cyclopentyloxy)phenyl]piperazin-1 -y 1} ethyl (2,4-dioxo-1,3-thiazolidin-3-yl)acetate hydrochloR1de salt,
2-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-1 -yl]ethyl (2,4-dioxo-1,3-thiazolidin-3-yl)acetate,
2-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-1 -yl]ethyl (2,4-dioxo-1,3-thiazolidin-3-yl)acetate hydrochloR1de salt,
3- {5-[4-(2-methoxyphenyl)piperazin- l-yl]pentyl} -1,3-thiazolidine-2,4-dione,
3-{5-[4-(2-methoxyphenyl)piperazin-l-yl]pentyl}-l,3-thiazolidine-2,4-dione hydrochloR1de salt,
3-{5-[4-(2-ethoxyphenyl)piperazin-l-yl]pentyl}-l,3-thiazolidine-2,4-dione,
3- {5-[4-(2-ethoxyphenyl)piperazin-1 -yljpentyl}-1,3-thiazolidine-2,4-dione hydrochloR1de salt,
3-{5-[4-(2-propoxyphenyl)piperazin-l-yl]pentyl}-l,3-thiazolidine-2,4-dione,
3-{5-[4-(2-propoxyphenyl)piperazin-l-yl]pentyl}-l,3-thiazolidine-2,4-dione hydrochloR1de salt,
3-{5-[4-(2-isopropoxyphenyl)piperazin-l-yl]pentyl}-l,3-thiazolidine-2,4-dione,
3 - {5 - [4-(2-isopropoxypheny l)piperazin-1 -y 1] penty 1} -1,3 -thiazolidine-2,4-dione hydrochloR1de salt or
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs or metabolites.
3. A pharmaceutical composition compR1sing a therapeutically effectNe amount of a compound of claim 1 and optionally one or more pharmaceutically acceptable carR1ers, excipients or diluents.
4. A method for treating a disease or disorder mediated through α1a and/or α1d adrenergic receptors, compR1sing administeR1ng to patient in need thereof a therapeutically effectNe amount of a compound of claim 1 and optionally one or more pharmaceutically acceptable carR1ers, excipients or diluents.
5. The method according to claim 5, wherein disease or disorder is benign prostatic hyperplasia.
6. The method according to claim 5, wherein compound causes minimal decrease or no decrease in blood pressure at dosages effectNe to alleviate benign prostatic hyperplasia.
7. A method for treating lower uR1nary tract symptoms associated with or without benign prostatic hyperplasia, compR1sing administeR1ng to a patient in need thereof a therapeutically effectNe amount of a compound of claim 1 and optionally one or more pharmaceutically acceptable carR1ers, excipients or diluents.
8. A method for prepaR1ng compounds of Formula 16,
(Formula Removed)

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs and metabolites thereof, wherein r, X and R are the same as defined in claim 1, which method compR1ses:
reacting (2,4-dioxo-thiazolidin-3-yl)-acetic acid of Formula 5 with compounds of Formula 7
to form compounds of Formula 16.
9. A method for prepaR1ng compounds of Formula 17,
(Formula Removed)

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs and metabolites thereof, wherein r, X and R are the same as defined in claim 1, which method compR1ses:
reacting (2,4-dioxo-thiazolidin-3-yl)-acetic acid of Formula 5 with compounds of Formula 11
0 5 to form compounds of Formula 17.
10. A method for prepaR1ng compounds of Formula 18,
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs and metabolites thereof, wherein r, X and R are the same as defined in claim 1, which method compR1ses:
reacting compounds of Formula 15 with compounds of Formula 7
(Formula Removed)
to form compounds of Formula 18.
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs and metabolites thereof, wherein r, X and R are the same as defined in claim 1, which method compR1ses:
(a) reacting (2,4-dioxo-thiazolidin-3-yl)-acetic acid of Formula 5
(Formula Removed)
with chloR1nating agents, for example, thionyl chloR1de, phosphorus pentachloR1de to
form (2,4-dioxo-thiazolidin-3-yl)-acetyl chloR1de of Formula 19
reacting (2,4-dioxo-thiazolidin-J-yij-acetyicmoR1ae or formula iy with compounds of Formula 13

to form compounds of Formula 20.