MXPA04009821A - Carboximide derivatives as useful uro-selective alpha-1a adrenoceptor blockers. - Google Patents

Abstract

Novel carboximide derivatives, which selectively inhibit binding to the alpha-1A adrenergic receptor, a receptor which has been shown to be important in the treatment of benign prostatic hyperplasia. The compounds of the present invention are potentially useful in the treatment of benign prostatic hyperplasia.

Description

CARBOXIMIDE DERIVATIVES AS USEFUL URO-SELECTIVE ALPHA-1A ADRENOCEPTOR BLOCKERS FIELD OF THE INVENTION This invention relates to certain novel carboximide derivatives that selectively inhibit binding to the adrenergic receptor, a receptor that has been shown to be important in the treatment of benign prostatic hyperplasia. The compounds of the present invention are potentially useful in the treatment of benign prostatic hyperplasia. This invention also relates to methods for synthesizing novel compounds, pharmaceutical compositions containing the compounds and method for treating benign prostatic hyperplasia using the compounds. BACKGROUND OF THE INVENTION Benign prostatic hyperplasia (BPH), a non-malignant enlargement of the prostate, is the most common benign tumor in men. Approximately 50% of all men older than 65 years have some degree of BPH and one third of these men have clinical symptoms consistent with obstruction of the bladder outlet (Hieble and Caine, Fed. Proc., 1986; 45: 2601). The world's benign and malignant diseases of the prostate are responsible for more surgery than the diseases of any other organ in men above the age of fifty.

It is generally accepted that there are two components of BPH, a static component and a dynamic component. The static component is due to the enlargement of the prostate gland, which can result in compression of the urethra and obstruction to the flow of urine from the bladder. The dynamic component is due to the increased smooth muscle tone of the bladder neck and the prostate itself (which interferes with the emptying of the bladder) and is regulated by alpha 1 adrenergic receptors (a? -ARs). Medical treatments available for BPH address these components to varying degrees, and therapeutic selections are expanding. Surgical treatment options target the static component of BPH and include transurethral reception of the prostate (TURP), open prostatectomy, balloon dilation, hyperthermia, stents, and laser ablation. Although, TURP is the standard target treatment for patients with BPH, approximately 20-25% of patients do not have a satisfactory long-term effect (Lepor and Rigaud, J. Urol., 1990; 143: 533). Post-operative urinary tract infection (5-10%), some degree of urinary incontinence (2-4%), as well as reoperation (15-20%) (Wennberg et al., JAMA, 1987; 257: 933) are some of the other risk factors involved. Apart from surgical procedures, there are some therapies or drugs that target the static component of this condition. Finasteride (Prosear, Merck), is a therapy of such kind that is indicated for the treatment of BPH. symptomatic This drug is a. competitive inhibitor of the enzyme 5-a-reductase which is responsible for the conversion of testosterone to dihydrotestosterone in the prosthetic gland (Gormley et al., N. Engl. J. Med., 1992; 327: 1185). Dihydrotestosterone is presented as the main mitogen for prostate growth, and agents that inhibit 5-a-reductase reduce the size of the prostate and improve the flow of urine through the prostatic urethra. Although finasteride is a potent inhibitor of 5-a-reductase and causes a marked decrease in the concentration of serum and tissue dihydrotestosterone, it is only moderately effective in the treatment of symptomatic BPH (Oesterling, N. Engl. Med., 1996; 332: 99). The effects of finasteride take 6-12 months to become apparent and for many men the clinical improvement is minimal. Due to the limited effectiveness of 5a-reductase inhibitors in terms of symptomatic and immediate urodynamic relief, other pharmacological procedures have been estimated in the clinical setting. The dynamic component of BPH has been targeted through the use of adrenergic receptor blocking agents (OII-AR blockers) that act by decreasing the smooth muscle tone within the prostate gland itself. The aj.-adrenergic receptor antagonists are shown to be much more effective and provide immediate subjective symptomatic improvements and therefore, are the preferred treatment modalities in the control of benign prostatic hypertrophy. Oi-adrenoceptors are also present in blood vessels and play an important role in regulating blood pressure. Thus, a? -adrenoceptor antagonists are of particular importance since they are originally developed as antihypertensive agents and are likely to also have a beneficial effect on lipid dysfunction in insulin resistance, which are commonly associated with hypertension. essential. The use of? -AR antagonists in the treatment of BPH is related to its ability to decrease prostatic smooth muscle tone, leading to the relief of obstructive symptoms. Adrenergic receptors found throughout the body play a dominant role in the control of blood pressure, nasal congestion, prostate function and other processes (Harrison et al., Trends Pharmacol, Sci., 1991).; 12:62). There are a number of subtypes of cloned OII-AR receptors: ociA-AR, a1B-AR and aiD-AR (Bruno et al., Biochem, Biophys, Res.

Commun., 1991; 179: 1485; Forray et al., Mol. Pharmacol., 1994; 45: 703; Hirasawa and collaborators, Biochem, Biphys. Res. Commun., 1993; 195: 902; Ramarao et al., J. Biol. Chem., 1992; 267-21936; Schwinn et al., JPET, 1995; 272: 134; Weinberg et al., Biochem. Biophys. Res. Commun., 1994; 201: 1296). A number of laboratories have characterized the -ARS in the human prostate, by the role of radioligand binding and molecular biological techniques (Forray et al., Mol.Pharmacol., 1994; 45: 703; Hatano et al., Br. J. Pharmacol, 1994; 113: 723; Marshall et al., Br. J. Pharmacol., 1992; 112: 59; Marshall et al., Br. J. Pharmacol., 1995; 115: 781; Yamada et al., Life Sci., 1994; 54: 1845). These studies provide evidence in support of the concept that the OIA-AR subtype comprises the greater part of a.-ARS in human prostatic smooth muscle and mediates contraction in this tissue. These findings suggest that the development of subtype-selective antagonist o / iA-ARs could result in a therapeutically effective agent with reduced side effects for the treatment of BPH. A variety of a? -AR blockers (terazosin, prazosin and doxazosin) have been investigated for the treatment of obstruction of symptomatic bladder outlet due to BPH, with terazosin (Hytrin, Abbott) being the most extensively studied. Although α-AR blockers are well tolerated, approximately 10-15% of patients develop a clinically adverse event. The undesirable effects of all members of this class are similar, with postural hypotension being the most commonly experienced side effect. Agents blocking to? -AR have a faster onset of action. However, its therapeutic use, as measured by improvement in symptom registration and peak urine flow rate, is moderate. (Oesterling, N. Engl. J. Med., 1995; 332: 99). Vascular side effects (eg posture hypertension, fading, headaches, etc.) associated with these drugs is due to the lack of selectivity of action between the α-adrenoreceptors. prostatic and vascular. Clearly, β-adrenoceptor antagonists that inherently have greater selectivity for prostatic oi-adrenoceptors offer the potential for increased urodynamic benefits. This emphasizes the importance of the discovery of selective prostatic ai-adrenoceptor antagonists that will confer urodynamic improvement without the side effects associated with existing drugs. There is a lot of description in the literature about the pharmacological activities associated with the a, w-dicarboximide derivatives. Eur. J. Med. Chem. Chemica Therapeutica; 1977; 12 (2): 173, J. Indian. Chem .. Soc, 1978; LV: 819; J, Indian Chem. Soc, 1979; LVI: 1002 discuss the synthesis of these derivatives with CNS and antihypertensive activity. Other references similar to the US patents Nos. ' 4, 524, 206; 4, 598, 078; 4, 567, 180; 4, 479, 954; 5,183,819; 4,748,240; 4,892,943; 4,797,488; 4,804,751, 4,824,999; 4,957,913; 5,420,278; 5,300,762; 4,543,355 and the applications of · |? CT Nos. WO 98/37893; WO 93/21179, also describe CNS and antihypertensive activity of these compounds. There is no mention of the adrenoceptor blocking activity of these compounds and thus their usefulness in the treatment of BPH was not raised. J. Med. Chem., 1983; 26: 203 reports the activity of dopamine and α-adrenergic activity of some Buspirone analogues. EP 078800 discusses the antagonistic activity of β-adrenergic receptor derivatives. pyrimidinedione, pyrimidinatrione and triazinedione. These compounds, however, have low α-adrenergic blocking activity as compared to known ai-antagonists. The previous synthesis of several 1- (4-arylpiperaz'in- • 1-yl) -3- (2-oxo-pyrrolidin-1-yl / piperidin-1-yl) alkanes and their usefulness as hypotensive and anti-ischemic agents is described in patent applications 496 / DEL / 95, 500 / DEL / 95 and 96 / DEL / 96. These compounds have low ai-adrenergic blocking activity (pKI ~ 6 as compared to >8 of the known ai-antagonists such as prazosin), and virtually no selectivity of the sub-class of adrenoceptor for the aiA adrenoceptors vs. I heard? or cxiD. In addition, the work showed that the structural modification of these compounds of lactam to dioxo compounds, that is, of 2-oxopyrrolidin to 2,5-dioxopyrrolidine and 2,6-dioxopiperidine, improves the blocking activity of adrenocept and also greatly increases the selectivity for < ¾iA compared to the blocking activity of aiB-adrenoceptor, an essential requirement for compounds that are good candidates for the treatment of benign prostatic hyperplasia (BPH) described in U.S. Patent Nos. 6,083,950 and 6,090 , 809 of the applicants, which are incorporated herein by reference. OBJECTS OF THE INVENTION Recently, it has been shown that prostate tissue of higher species similar to man and dog has a predominant concentration of the aiA-adrenoceptor subtype. This makes it possible to develop agents with selective action against these pathological urodynamic states. The present invention is directed to the development of novel a! -adrenoceptors and thus would offer a viable selective relief for prostatic hypertrophy as well as essential hypertension, without the side effects associated with the known aiA-AR antagonists. The aim of the present invention is to provide novel carboximide derivatives that show significantly greater a1A-adrenergic blocking potency than that available with the known compounds to provide the specific treatment for benign prosthetic hyperplasia. It is also an object of the invention to provide a process for the synthesis of novel compounds. A further object of the invention is to provide compositions containing the novel compounds that are useful in the treatment of benign prostatic hyperplasia. BRIEF DESCRIPTION OF THE INVENTION The objectives mentioned in the foregoing are obtained by means of novel carboximide derivatives represented by Formula I below:.

Formula I wherein X is selected from the group consisting of where the binding points are represented by labeled bonds, and where one point of attachment is bonded to the carbonyl adjacent to the nitrogen and the second point of attachment is linked to the other carbonyl; W is O, S, SO or S02? - (CHü) m-, CHjfjW- CHa- where m is one of the integers 2, 3 or 4; RH is independently selected from H, F, Cl, Br, I, OH, straight or branched chain lower (Ci-6) alkyl, lower (Ci-6) alkoxy, lower (C ^ g) perhaldalkyl, and perhaloalkoxy of (Ci-6) lower; And it is selected from the group that. it consists of Ri and R2 are independently selected from H, OH, CN, N02, Cl, F, Br, I, OR3, COR3, OCOR3, COOR3, NH2, N (R4, R5), lower (Ci-4) alkyl, alkoxy of (Ci-4) lower, lower alkylthio (Ci_4), lower (Ci-4) perhaloalkyl, lower (C 1-4) perhaloalkoxy, lower (C 1-4) alkoxy substituted with one or more of F, Cl, Br, I, OH, or OR3, an optionally substituted group selected from aryl, aryloxyalkyl, "heterocyclyl or heteroaryl and substituents that are H, F, Cl, Br, I, OH, 0R3, alkyl of LC1-4) lower, lower (C 1-4) alkyl substituted with one or more of F, Cl, Br, I, OH or OR 3, wherein R 3 is selected from the group consisting of H, straight or branched chain Ci-S alkyl and perhaloalkyl, R4 and R5 are independently selected from the group consisting of H, CHO, substituted or unsubstituted lower (C1-4) alkyl, lower (C1-4) alkoxy, COR3, COOR3, CH2CH (0R3) 2, CH2COOR3, CH2CHO and (CH2) 20R3, where R3 is the same as defined in the above; R6, R7, R8, R9 and Rio are independently selected from H, OH, CN, N02, Cl, F, Br, I, straight or branched chain lower alkyl (Ci-4) optionally substituted with one or more halogens, lower (Ci-4) alkoxy optionally substituted with one or more halohans, (C3-6) cycloalkoxy / NH2, lower (C1-4) alkylamino, N, N-di-alkylamino of (Ci-4) lower, N-alkylamino of (Cx-4) lower carbonyl, hydroxy substituted with five or six membered aromatic or non-aromatic ring, phenyl and phenyl substituted by Cl, F, Br, I, N02, NH2, alkyl of (C 1 -4) or (1-4C) alkoxy, perhaloalkyl of (Ci-4), perhaloalkoxy of (^ _4) where a dashed line () is a single bond or no bond. The present invention also provides pharmaceutical compositions for the treatment of benign prostatic hyperplasia. These compositions comprise an effective amount of at least one of the above compounds of Formula I and / or an effective amount of at least one physiologically acceptable acid addition salt thereof, with a pharmaceutically acceptable carrier and excipients optionally included. . An illustrative list of particular compounds of the invention is given below: l-Carboxycyclohex-4-ene-2- [N-. { 3- (2-Ethoxyphenyl) piperazin-1-yl-J-propyl] carboxamide, (Compound No. 1) l-Carboxycyclohex-4-ene-2- [N-. { 3- (2-isopropoxyphenyl) piperazin-1-yl Jpropyl] carboxamide, (Compound No. 2) l-C arboxycyclohex-4-ene-2- [N-. { 3- (2-methoxyphenyl) piperazine-1-11} -2-hydroxypropyl] carboxamide, (Compound No. 3) l-Carboxycyclohex-4-ene-2- [N-. { 3- (2-hydroxyphenyl) piperazin-1-yl} -2-hydroxypropyl] carboxamide, (Compound No. 4) 'l-Carboxycyclohex-4-ene-2- [N-. { 3- (2-isopropoxyphenyl) piperazin-1-yl} -2-hydroxypropyl] carboxamide, (Compound No. 5) l-Carboxycyclohex-4-ene-2- [N-. { 3- (2-ethoxyphenyl) piperazin-1-yl} -2-hydroxyphenyl] carboxamide, (Compound No. 6) 5- [N-. { 3- (2-hydroxyphenyl) iperazin-1-yl} ] -1-aminopropyl-5-oxo-pentan-1-oic (Compound No. 7) l-Carboxycyclohex-4-ene-2- [N-. { 3- (2-hydroxyphenyl) piperazin-1-yl} propyl] carboxamide, (Compound No. 8) 5- [N-. { 3- (2-Isopropoxyphenyl) piperazin-1-yl} -1-aminopropyl] -5-oxo-pentan-l-oic, (Compound No. 9) Methyl-5- [N-]. { 3- (2-methoxyphenyl) piperazin-1-yl} -1-aminopropyl] -5-oxo-pentanoate, (Compound No. 10) L-carboxymethylcyclohex-4-ene-? Hydrochloride. - [N-. { 3- (2-isopropoxyphenyl) piperazin-1-yl} -propyl] carboxamide, (Compound No. 11) 5- [N-. { 3- (2-methoxyphenyl) piperazin-1-yl} ] -2-hydroxypropylamino-5-oxo-pentan-l-oico (Compound No. 12). The non-toxic, pharmaceutically acceptable acid addition salts of the compounds of the present invention having the utility of the free bases of Formula I can be formed with inorganic or organic acids, by methods well known in the art and can be used instead of the free bases. Representative examples of acids suitable for the formation of such acid addition salts are malic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylene salicylic, methanesulfonic, ethane disulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfamic, phosphoric, hydrobromic, sulfuric, cyclohexylsulfamic, hydrochloric and nitric. The present invention also includes within its scope prodrugs of the compounds of Formula I. General, such prodrugs will be functional derivatives of these compounds that are easily converted in vivo to the defined compounds. Conventional procedures for the selection and preparation of suitable prodrugs are known. The invention also includes the enantiomers, diastereomers, N-oxides, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates of these compounds, as well as metabolites having the same type of activity. The invention further includes pharmaceutical compositions comprising the molecules of Formula I, or prodrugs, metabolites, enantiomers, diastereomers, N-oxides, polymorphs, solvates or pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable carrier and excipients optionally included . In still another aspect, the invention is directed to methods for selectively blocking iA receptors by delivery in the environment of the receptors, eg, to the extracellular medium (or when administering to a mammal possessing the receptors), at an effective amount. of the compounds of the invention. DETAILED DESCRIPTION OF THE INVENTION In order to. obtaining the objects mentioned in the foregoing and in accordance with the purpose of the invention as encompassed and widely described herein, provides a process for the synthesis of compounds of Formula I, as shown in Scheme I. Scheme I Formula II Base, A where the binding sites are represented by labeled bonds, and where one point of attachment is bonded to the carbonyl adjacent to the nitrogen and the second point of attachment is linked to the other carbonyl; W is 0, S, SO or S02? A -ÍCHü) m-, CHj < j > t- CHz-. CHzCHj- O- where m is one of the integers 2, 3 or 4; R11 is independently selected from H, F, Cl, Br, I, OH, straight or branched chain lower (C1-6) alkyl, lower (Ci-β) alkoxy, lower (Ci-6) perhaloalkyl and perhaloalkoxy from . { i-e) lower; And it is selected from the group consisting of RI and R2 are independently selected from H, OH, CN, N02, Cl, F, Br, I, 0R3, C0R3, 0C0R3 / COOR3, NH2, N (R4, R5), lower (C1-4) alkyl, alkoxy (C 1-4) lower, lower (C 1-4) alkylthio, lower (d-4) perhaloalkyl, lower (C 1-4) perhaloalkoxy, lower (C 1-4) alkoxy substituted with one or more of F , Cl, Br, I, OH, or OR3, an optionally substituted group selected from aryl, aryloxyalkyl, heterocyclyl or heteroaryl and substituents that are H, F, Cl, Br, I, OH, 0R3, alkyl (Ci-4) ) lower, lower C1-) alkyl substituted with one or more of F, Cl, Br, I, OH or OR3, wherein R3 is selected from the group consisting of H, straight or branched chain Ci-s alkyl and perhaloalkyl; R4 and R5 are independently selected from the group consisting of H, CHO, substituted or unsubstituted lower (C1-4) alkyl, lower (C1-4) alkoxy, COR3, COOR3, CH2CH (OR3) 2, CH2COOR3, CH2CHO and (CH2) 2OR3, wherein R3 is the same as defined above; R6, R7 /. R8, R9 and Rio sen independently selected from H, OH, CN, N02, Cl, F, Br, I, lower straight or branched chain (C1-4) alkyl optionally substituted with one or more halogens, alkoxy of. C1-4) lower optionally substituted with one or more hhalogens, (C3_6) cycloalkoxy, NH2, lower (C1-4) alkylamino, lower N, N-di-alkylamino of (C1-4), N-alkylamino (C 1-4) lower carbonyl, hydroxy substituted with five or six membered aromatic or non-aromatic ring, phenyl and phenyl substituted by Cl, F, Br., I, N02, NH2, (C1-4) alkyl or alkoxy of (C1-4), perhaloalkyl of (Ci_'4), perhaloalkoxy of (C1_4) where a line of dashes () is a single bond or no bond. The starting materials of Scheme I can be. adapt appropriately to produce the most specific compounds of Formula I.

SCHEME I Scheme I shows the synthesis of the compounds of Formula I, wherein X, Y, A, R6, R7, R8, Rg and Rio are as defined in the foregoing. The preparation comprises the reaction of,? -dicarboximides of Formula II with a suitable strong base, at a temperature ranging from 20-100 ° C for a period ranging in one or several hours to produce the corresponding compounds of Formula I The suitable base is selected from the group consisting of sodium hydroxide and potassium hydroxide. More specifically, the hydrolysis of the compound of Formula II is carried out in a solution of the base made in a polar solvent selected from the group consisting of water, methanol and ethanol. The preferable temperature conditions for the reaction are 90-100 ° C. The starting compound of Formula II can be prepared by the process as described in the applicant's internal application number RLL-236WO, filed concurrently with the present. The invention is explained in detail in the example given below which is provided by way of illustration only and therefore should not be considered to limit the scope of the present invention. Example Preparation of 1-carboxy cyclohex-4-ene-2-N-. { 3- (2-ethoxyphenyl) piperazin-1-yl} propyl] carboxamide. (Compound No. 1) · Hydrochloride 2- [3-. { 4- (2-Ethoxyphenyl) piperazin-1-yl} propyl-3a, 4, 7, 7a-tetrahydro-lH-isoindol-l, 3 (2H) -dione (0.5 g, 1.15 mmol) was dissolved in an aqueous sodium hydroxide solution (11.5 ml, 0.2 N) and heated to reflux for about 2 hours. After the reaction has ended, the pH of the reaction is adjusted to about 7 using glacial acetic acid and extracted with chloroform (2x15 ml). The solvent was concentrated under reduced pressure and the crude product was crystallized from chloroform and diethyl ether to give the title product 0.13 g (25%), m.p. 128-131 ° C MS m / z 430.5 (H *) IR (KBr cm'1): 1645.8 (C = 0) 1H NMR (300MHz, TFA) d: 1.72-1.74 (3H, d), 2.59 (2H, br s), 2.80 (3H, br s), 2.93- 2.99 (1H, d), 3.53 (1H, br s) , 3.69 (1 H, br s), 3.86-3.98 (m, 4H), 4.47-4.50 (6H, m), 4.75-4.79 (2H, m), 5.11-5.19 (1H, m), 6.00-6.13 ( 2H, br d), 7.39-7.49 (2H, m), 7.82-7.88 (2H, m) The following compounds were prepared in a similar manner: l-Carboxycyclohex-4-ene-2- [N-. { 3- (2-isopropoxyphenyl) piperazin-1-yl} propyl] carboxamide; p.f. -186-188 ° C, (Compound No. 2). l-Carboxycyclohex-4-ene-2- [N-. { 3- (2-methoxyphenyl) piperazin-1-yl} -2-hydroxypropyl] carboxamide; p.f. 140-143 ° C, (Compound No. 3) l-Carboxycyclohex-4-ene-2- [N-. { 3- (2-hydroxyphenyl) piperazin-1-yl} -2-hydroxypropyl] carboxamide; p.f. 124-127 ° C, (Compound No. 4) l-Carboxycyclohex-4-ene-2- [N-. { 3- (2-isopropoxyphenyl) piperazin-1-yl} -2-hydroxypropyl] carboxamide; p.f. 159-162 ° C, (Compound No. 5) l-Carboxycyclohex-4-ene-2- [N-. { 3- (2-ethoxyphenyl) piperazin-1-yl} -2-hydroxyphenyl] carboxamide; p.f. 118-121 ° C, (Compound No. 6) Acid 5- [N-. { 3- (2-hydroxyphenyl) piperazin-1-yl} ] -1-aminopropyl-5-oxo-pentan-l-oic; p.f. 200-202 ° C, (Compound No.7) l-Carboxycyclohex-4-ene-2- [N-. { 3- (2-hydroxyphenyl) piperazin-1-yl-1-propyl] carboxamide; p.f. 165-170 ° C, (Compound No. 8) Acid 5- [N-. { 3- (2-isopropoxyphenyl) piperazin-1-yl} -1-aminopropyl] -5-oxo-pentan-l-oic; p.f. 121-125 ° C, (Compound No. 9) Methyl-5- Hydrochloride [N-. { 3- (2-methoxyphenyl) piperazin-1-yl} -1-aminopropyl] -5-oxo-pentanoate; p.f. 191-194 ° C, (Compound No. 10) L-carboxymethylcyclohex-4-ene-2- [N-] hydrochloride. { 3- (2-isopropoxyphenyl) piperazin-1-yl-J-propyl] carboxamide, (Compound No. 11) 5- [N-. { 3 (2-methoxyphenyl) piperazin-1-yl} ] -2-hydroxypropylamino-5-oxo-pentan-l-oico; p.f. 140-144 ° C, (Compound No. 12). Results of the Pharmacological Test Receptor Binding Assays Receptor binding assays were performed using native α-adrenoceptors. The affinity of the different compounds for the adrenoceptor subtypes u and OIBIB was evaluated when studying their ability to displace the binding of [3H] prazosin specific to the membranes of the sybmaxillary gland and rat liver, respectively (Michel et al., 6th J Pharmacoi, 1989; 98: 883). The binding assays were performed according to U 'Prichard et al. (Eur J Pharmacoi., 1978; 50:87) with minor modifications. The submaxillary glands were isolated immediately after sacrifice. The liver was perfused with buffer (50 mM Tris HC1, 100 mM NaCl, 10 mM EDTA pH 7.4). The tissues were homogenized in 10 volumes of buffer solution (50 mM Tris HC1, 100 mM NaCl, 10 mM EDTA pH 7.4). The homogenate was filtered through two layers of wet thickness and the filtrate was centrifuged at 500 g for 10 min. The supernatant was subsequently centrifuged at 40,000 g for 45 min. The pellet thus obtained was resuspended in the same volume of assay buffer (50 mM Tris HC1, 5 mM EDTA pH 7.) and stored at -70 ° C until the time of the assay. The membrane homogenates (150-250) protein ig) were incubated in 250 μ? of assay regulatory solution (50 mM Tris HC1, 5 mM EDTA, pH 7.) at 24-25 ° C for 1 hour. No specific binding was determined in the presence of 300 nM prazosin. Incubation was terminated by vacuum filtration on GF / B fiber filters. The filters were then washed with 50 mM Tris HC1 buffer solution cooled with ice (pH 7.4). The filter mats were dried and the bound radioactivity retained in the filters was counted. The IC50 and Kd were estimated using the non-linear curve fitting program using the G Pad Prism software. The value of the constant Ki inhibition was calculated from the competitive binding studies using the Cheng & Prusoff (Cheng &Prusoff, Biochem Pharmacol, 1973, 22: 3099), Ki = IC60 / (1 + L / Kd) where L is the concentration of [3 H] prazosin used in the particular experiment (Table 1). In Vitro Functional Studies To study the selectivity of action of these compounds towards different subtypes of α-adrenoceptors, the ability of these compounds to anagenate the aorta (¾D), prostate (a ??) and spleen (is) was studied. The tissues of the aorta, prostate and spleen were isolated from male wister rats anesthetized with urethane (1.5 g / kg). The isolated tissues were mounted in an organ bath containing Krebs Henseleit buffer of the following composition (mM): NaCl 118; KC1 4.7; CaCl2 2.5; MgSO 7H20 1.2; NaHCO 3 25; KH2P04 1.2; glucose 11.5. The buffer solution was maintained at 37 ° C and was aerated with a 95% mixture of 02 and 5% C02. A resting tension of 2g (aorta) or lg (spleen and prostate) was applied to the tissues. The contractile response was inspected using a. force displacement transducer and was recorded on chart recorders. The tissues were allowed to equilibrate for 2 hours. At the end of the equilibration period, the concentration response curves for norepinephrine (aorta) and phenylepinephrine (spleen and prostate) were obtained in the absence and presence of the compound tested (at concentrations 0.1, 1 and 10 μ?). The affinity of the antagonist was calculated and expressed as the pKB values in Table II. In vivo Uroselectivity Study To estimate uroselectivity in vivo, the effects of these compounds were studied in mean arterial pressure (MAP) and intraurethral pressure (IUP) in conscious pachones according to the method of Bruñe et al. (Pharmacol) ., 1996, 53: 356). Briefly, male dogs were instrumented for chronic continuous measurement of arterial blood pressure by implanting a telemetry transmitter (TL11M2-D70-PCT, Data Sci, International, St. Paul, MN, USA) in the femoral artery, two weeks before of the study. During the recovery period, the animal was acclimated to remain in the sling fixation. On the day of the test, the animal fasted during the night was placed in the sling fixation. A Swan-Ganz Globe point catheter was inserted into the urethra at the level of the prostate and the balloon inflated (Bruñe et al., 1996). After recording the base line readings, the effect of 16 μg / kg of phenylephrine (i.v.) of MAP and IUP was recorded. The response of phenylephrine to MAP and IUP were recorded at 0.5, 1, 2, 3, 4, 6, 9 and 24 hours after oral administration of the test drug vehicle. Changes in MAP were recorded online using the Dataquest Software (Data Sci. International, St. Paul, MN.USA). The change in the phenylephrine response in the administration of MAP and IUP after the administration of the test drug was calculated as the percent change of that of the control values. The area under the curve was calculated and the relationship of the values for MAP and IUP was used to calculate the uroselectivity. Table 1: Radioligand Link Studies: Affinity of the compounds for the Alpha-1 Adrenoceptor Subtypes S. Compound No. "1A" IB "IB /" IA (Submaxiliar (Rat's Liver) Rat) 1 1 20 > 1000 > 50 2 2 19 > 1000 > 53 3 3 > 1000 > 1000 4 4 1892 9743 5 5 5 21 1759 84 6 6 398 1239 3 7 7 12640 12970 1 8 8 593 5082 9 9 9 777 2097 3 10 10 139 > 1000 > 7 11 11 3.15 99 31 12 12 > 1000 > 10000 1 Table II: In Vitro Functional Tests While the present invention has been described in terms of its specific embodiments,. certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims (10)

1. A compound that has the structure of the Formula I, Formula I and its pharmaceutically acceptable salts, enantiomers, diastereomers, pharmaceutically acceptable N-oxides, prodrugs, metabolites, polymorphs or solvates, characterized in that X is selected from the group consisting of where the points of. junction are represented by labeled bonds, wherein one point of attachment is bonded to the carbonyl adjacent to the nitrogen and the second point of attachment is linked to the other carbonyl; W is in. where m is one of the integers 2, 3 or 4; Rn is independently selected from H, F, Cl, Br, I, OH, straight or branched chain lower (Ci-6) alkyl, lower (Ci_6) alkoxy, and lower (Ci_5) perhaloalkyl; And it is selected from the group consisting of Ri and R2 are independently selected from H, OH, CN, N02, Cl, F ,. Br, I, 0R3 COR3 OCOR3, COOR3, NH2N (R4, R5), lower (Ci-4) alkyl, lower (Ci_4) alkoxy, lower alkyl (Ci-4), perhaloalkyl (Ci-4) lower, lower (C1-4) perhaloalkoxy, lower (C1-4) alkoxy substituted with one or more of F, Cl, Br, I, OH, or OR3, an optionally substituted group selected from aryl, aryloxy, araalkyl, heterocyclyl or heteroaryl and substituents which are H, F, Cl, Br, I, OH, 0R3, lower (C1-4) alkyl, lower (C1-4) alkyl substituted with one or more of F, Cl , Br, I, OH or OR3, wherein R3 is selected from the group consisting of H, straight or branched chain Ci-6 alkyl and perhaloalkyl; R4 and R5 are independently selected from the group consisting of H, CHO, substituted or unsubstituted lower (C1-4) alkyl, lower (Ci_4) alkoxy, COR3 / COOR3, CH2CH (OR3) 2, CH2COOR3, CH2CHO and ( CH2) 2OR3, where R3 is the same as defined above; R6, R7, R ^ R9 and Rio are independently selected from H, OH, CN, N02, Cl, F, Br, I, lower straight or branched chain (C1-4) alkyl optionally substituted with one or more halogens, lower (C 1-4) alkoxy optionally substituted with one or more halogens, (C 3-6) cycloalkoxy, NH 2, lower (C 1-4) alkylamino, N, N-di-alkylamino of - (C 1-4) ) lower, lower (C 1-4) alkylaminocarbonyl, hydroxy substituted with five or six membered aromatic or non-aromatic ring, phenyl and phenyl substituted by Cl, F, Br, I, N02, NH2, alkyl of (C1) -4) or (C 1-4) alkoxy, perhaloalquild of (C 1-4), perhaloalkoxy of (C 1-4) where a line of quions () is a single bond or no bond.

2. A compound selected from the group consisting of l-Carboxy-cyclohex-4-ene-2- [N-. { 3- (2-ethoxyphenyl) piperazin-1-ylpropyl] carboxamide; l-Carboxy-cyclohex-4-ene-2- [N-. { 3- (2-isopropoxyphenyl) piperazin-1-yl Jpropyl] carboxamide; 1-Carboxy, cyclohex-4-ene-2- [N-. { 3- (2-methoxyphenyl) piperazin-1-yl} -2-hydroxypropyl] carboxamide; 1-Carboxy cyclohex-4-ene-2- [N-. { 3- (2-hydroxyphenyl) piperazin-1-yl} -2-hydroxypropyl] carboxamide 1-Carboxycyclohex-4-ene-2- [N-. { 3- (2-isopropoxyphenyl) piperazin-1-yl} -2-hydroxypropyl] carboxamide; 1-Carboxy cyclohex-4-ene-2- [N-. { 3- (2-ethoxyphenyl) piperazin-1-yl} -2-hydroxyphenyl] carboxamide; Acid 5- [N-. { 3- (2-hydroxyphenyl) piperazin-1-yl} ] -1-aminopropyl-5-oxo-pentan-l-oic; 1-Carboxy cyclohex-4-ene-2- [N-. { 3- (2-hydroxyphenyl) piperazin-1-yl} propyl] carboxamide; Acid 5- [N-. { 3- (2-isopropoxyphenyl) piperazin-1-yl} -l-aminopropyl] -5-oxo-pentan-l-oico; Methyl-5- hydrochloride [N-. { 3- (2-methoxyphenyl) piperazin-1-yl} -1-aminopropyl] -5-oxo-pentanoate; L-carboxymethylcyclohex-4-ene-2- [N-] hydrochloride. { 3- (2-isopropoxyphenyl) piperazin-1-yl} -propyl] carboxamide; Acid 5- [N-. { 3- (2-methoxyphenyl) piperazin-1-yl} ] -2-hydroxypropylamino-5-oxo-pentan-l-oico.

3. A method for selectively antagonizing ai-adrenergic receptors in a mammal, characterized in that. comprises administering to the mammal a therapeutically effective amount of a compound having the structure of Formula I:ou. Formula I and its pharmaceutically acceptable salts, enantiomers, diastereomers, pharmaceutically acceptable N-oxides, prodrugs, metabolites, polymorphs or solvates, wherein X is selected from the group consisting of wherein the binding sites are represented by labeled bonds, and wherein one point of attachment is linked to the carbonyl adjacent to the nitrogen and the second point of attachment is linked to the other carbonyl; is O, S, SO or S02 A «- (CHü) m-, ?? ? - CHz-, CHaCHí-? OR- where m is one of the integers 2, 3 or 4; R is independently selected from H, F, Cl, Br, I, OH, straight or branched chain lower (Ci-6) alkyl, lower (Ci-6) alkoxy, and lower (Ci-6) perhaloalkyl; And it is selected from the group consisting of Ri and R2 are independently selected from H, OH, GN, N02, Cl, F, Br, I, 0R3, COR3, OCOR3, COOR3, NH2, N (k4, R5), lower (C1-4) alkyl, alkoxy (C 1-4) lower, lower (C 1-4) alkylthio, lower (C 1-4) perhaloalkyl, lower (C 1-4) perhaloalkoxy, lower (C 1-4) alkoxy substituted with one or more of F, Cl, Br, I, OH, or OR3, an optionally substituted group selected from aryl, aryloxy, aralalkyl, heterocyclyl or heteroaryl and substituents which are H, F, Cl, Br, I, OH, OR3, alkyl ( C1-4) lower, lower (C1-4) alkyl substituted with one or more of F, Cl, Br, I, OH or OR3, wherein R3 is selected from the group consisting of H, C1-6 alkyl; straight or branched chain and perhaloalkyl; R4 and R5 are independently selected from the group consisting of H, CHO, substituted or unsubstituted lower (C1-4) alkyl, lower (C1-4) alkoxy, COR3, COOR3, CH2CH (OR3) 2 / CH2COOR3, CH2CHO and (CH2) 2OR3, wherein R3 is the same as defined above; R6, R7, Ra, R9 and Rio are independently selected from H, OH, CN, N02, Cl, F, Br, I, lower straight or branched chain (C1-4) alkyl optionally substituted with one or more halogens, lower (Ci-4) alkoxy optionally substituted with one or more halogens, (C3_6) cycloalkoxy, NH2, lower (Ci-4) N-alkylamino, lower N, N-di-alkylamino of (C1-4), Lower (C 1-4) alkylaminocarbonyl, hydroxy substituted with five or six membered aromatic or non-aromatic ring, phenyl and phenyl substituted by Cl, F, Br, I, N02, NH 2, (C 1-4) alkyl or (Ci-4) alkoxy, (1-4C) perhaloalkyl, (Ci_4) perhaloalkoxy wherein a dashed line () is a single bond or no bond.

4. A method for treating benign prostatic hyperplasia in a mammal, characterized in that it comprises administering to the mammal a therapeutically effective amount of a compound having the structure of Formula I: Formula I and its pharmaceutically acceptable salts, enantiomers, diastereomers, pharmaceutically acceptable N-oxides, prodrugs, metabolites, polymorphs or solvates, wherein X is selected from the group consisting of wherein the binding sites are represented by labeled bonds, and wherein one point of attachment is linked to the carbonyl adjacent to the nitrogen and the second point of attachment is linked to the other carbonyl; W is O, S, SO or S02 A _ - (CHüJm-, CH¿jH-0 -. CHjCHz-? C- R11 where m is one of the integers 2, 3 or 4; Rn is independently selected from H, F, Cl, Br, I, OH, lower straight or branched chain (Ci-6) alkyl, lower (Ci-6) alkoxy, and lower (Ci-6) perhaloalkyl; Y is selected from the group consisting of Ri and R2 are independently selected from H, OH, CN, N02, Cl, F, Br, I, OR3, COR3, OCOR3, COOR3, · NH2, "N (R4, .R5), (C1-4) alkyl lower, lower (Ci_4) alkoxy, lower (Ci_4) alkylthio, lower (C1-4) perhaloalkyl, lower (C1-4) perhaloalkoxy, lower (C1-4) alkoxy substituted with one or more of F , Cl, Br, I, OH, or OR3, an optionally substituted group selected from aryl, aryloxy, aralalkyl, heterocyclyl or heteroaryl and substituents which are H, F, Cl, Br, I, OH, 0R3, alkyl of (C1 -4), lower (C1-4) alkylated substituted with one or more of F, Cl, Br, I, OH or 0R3, wherein R3 is selected from the group consisting of H, C1-6 alkyl chain straight or branched and perhaloalkyl; R4 and R5 are independently selected from the group consisting of H, CHO, substituted or unsubstituted lower (C1-4) alkyl, lower (C1-4) alkoxy, COR3, COOR3, CH2CH (OR3) 2, CH2COOR3, CH2CHO and (CH2) 2OR3, wherein R3 is the same as defined above; R6, R7, Rs R9 and Rio. are independently selected from H, OH, CN, N02, Cl, F, Br, I, lower straight or branched chain (Ci_ 4) alkyl optionally substituted with one or more halogen, lower (Ci_4) alkoxy optionally substituted with one or more halogens, (C3-6) cycloalkoxy, NH2, lower (Ci_) N-alkylamino, lower (C 1-4) N, N-di-alkylamino, lower C 1-4 -alkylaminocarbonyl, hydroxy substituted with five or six membered aromatic or non-aromatic ring, phenyl, phenyl substituted by Cl, F, Br, I, N02, NH2, alkyl of (Ci_4) or alkoxy of (C ^), perhaloalkyl de- 4), perhaloalcoxi from (Ci-4) where a line of dashes () is a single link or no link. -

5. A pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of a compound as defined in claim 1 or 2 and a pharmaceutically acceptable carrier.

6. A method for selectively antagonizing oti-adrenergic receptors in a mammal, characterized in that it comprises the step of administering to the mammal a therapeutically effective amount of the pharmaceutical composition according to claim 5.

7. A method for treating benign prostatic hyperplasia in a mammal, characterized in that it comprises the step of administering to the mammal a therapeutically effective amount of the pharmaceutical composition according to claim 5.

8. A process for preparing a compound of Formula I Formula I or its pharmaceutically acceptable salts, enantiomers, diastereomers, pharmaceutically acceptable N-oxides, prodrugs, metabolites, polymorphs and solvates, wherein X is selected from the group consisting of wherein the binding sites are represented by labeled bonds, and wherein one point of attachment is linked to the carbonyl adjacent to the nitrogen and the second point of attachment is linked to the other carbonyl; W is 0, S, SO or S02 where m is one of the integers 2, 3 or 4; Rn is independently selected from H, F, Cl, 'Br, I, OH, straight or branched chain lower (Ci_6) alkyl, lower (Ci_6) alkoxy, and lower (Ci-6) perhaloalkyl; And it is selected from the group consisting of Ri and R2 are independently selected from H, OH, CN, NO2 / Cl, F, Br, I, 0R3, COR3, OCOR3, COOR3, NH2, N (R4, R5), lower (C1-4) alkyl, alkoxy (C 1-4) lower, lower (C 1-4) alkylthio, lower (C 1-4) perhaloalkyl, lower (C 1-4) perhaloalkoxy, lower (C 1-4) alkoxy substituted with one or more F , Cl, Br, I, OH, or OR3, an optionally substituted group selected from aryl, aryloxy, aralalkyl, heterocyclyl or heteroaryl and substituents which are H, F, Cl, Br, I, OH, 0R3, alkyl of (C1 -4) lower, lower (C 1-4) alkyl substituted with one or more of F, Cl, Br, I, OH or OR 3, wherein R 3 is selected from the group consisting of H, straight chain Ci_6 alkyl or branched and perhaloalkyl; R4 and R5 are independently selected from the group consisting of H, CHO, substituted or unsubstituted lower (C1-4) alkyl, lower (C1-4) alkoxy, COR3, COOR3, CH2CH (0R3) 2, CH2COOR3, CH2CHO and (CH2) 2OR3, wherein R3 is the same as defined above; Re, R7, Re r 9 and Rio are independently selected from H, OH, CN, N02, Cl, F, Br, I, lower straight or branched chain (C 1-4) alkyl optionally substituted with one or more halogens, (Ci_4) lower alkoxy optionally substituted with one or more halogen, (C3-6) cycloalkoxy / Base Formula, Formula I NH2, N-lower alkylamino of (C1-4), N, N-di-alkylamino of (C1-4) lower, N-lower alkylaminocarbonylcarbonyl, hydroxy substituted with five or six aromatic or non-aromatic ring, phenyl, phenyl substituted by Cl, F, Br, I, N02, NH2 , (C 1-4) alkyl or (C 1-4) alkoxy, (C 1-4) perhalkralkyl, (C 1-4) perhaloalkoxy wherein a dashed line () is a single bond or no bond; characterized in that it comprises reacting a compound of the Formula II with a suitable base in a suitable solvent to give the compound of the Formula I as shown in the above: wherein all the symbols are as defined above.

9. The process according to claim 8, characterized in that the base is selected from the group consisting of potassium hydroxide and sodium hydroxide.

10. The process according to claim 8, characterized in that the suitable solvent is selected from the group consisting of water, methanol and ethanol.