MXPA00008219A - Phtalimido arylpiperazines as alpha 1a receptor antagonists useful in the treatment of benign prostatic hyperplasia - Google Patents

Abstract

This invention relates to a series of heterocyclic substituted piperazines of Formula (I), pharmaceutical compositions containing them and intermediates used in their manufacture. The compounds of the invention selectively inhibit binding to the&agr;-1a adrenergic receptor, a receptor which has been implicated in benign prostatic hyperplasia. As such the compounds are potentially useful in the treatment of this disease.

Description

FTALAMIDO ARILPIPERAZINAS AS ANTAGONISTS OF THE ALPHA RECEPTOR 1 TO USEFUL IN THE TREATMENT OF PROSTATE HYPERPLASIA BENIGNA FIELD OF THE INVENTION This invention relates to a series of phthalamidoarylpiperazine derivatives, pharmaceutical compositions containing them as well as to processes and intermediates used in their preparation. The 10 compounds of the invention selectively inhibit receptor binding • adrenergic a1a, a receptor that has been implicated in benign prostatic hyperplasia. As such, the compounds are potentially useful in the treatment of this disease.

BACKGROUND OF THE INVENTION f Benign prostatic hyperplasia (BPH), non-benign enlargement of the prostate, is the most common benign tumor in men.

• Approximately 50% of all men over 65 have a certain degree of BPH and a third of these men have clinical symptoms compatible with obstruction of bladder outlet ( Caine, 1986). In the United States, benign and malignant diseases of the prostate are responsible for more surgery than in diseases of any other organ in men beyond the age of fifty. There are two components of HPB, 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 of the flow of urine from the bladder. The dynamic component is due to the increased tone of the smooth muscle of the neck of the bladder and the prostate itself (which interferes with the evacuation of the bladder) and is regulated by alpha 1 adrenergic receptors (a1-AR). The medical treatments available for the 10 HPB target these components to varying degrees and the therapeutic alternatives are increased. Surgical treatment options address the static component of BPH that include transurethral resection of the prostate (TURP), the transurethral incision of the prostate (ITUP), prostatectomy open, balloon dilation, hyperthermia, graft bras and laser abrasion. TURP is the treatment used for patients with BPH and is • made approximately 320,000 TURPs in the United States in 1990 with an estimated cost of 2.2 billion dollars (Weis et al., 1993). Although it is an effective treatment for most men with symptomatic BPH 20, approximately 20-25% of patients do not have satisfactory long-term results (Lepor and Riguad, 1990). Complications include retrograde ejaculation (70-75% of patients), impotence (5-10%), postoperative infection of the urinary tract (5-10%) and some degree of urinary incontinence (2-4%) (Mebust et al., 1989). In addition, the proportion of reoperation is approximately 15-20% in men evaluated for 10 years or more (Wennberg et al., 1987). Apart from surgical approaches, there are some therapies with 5 drugs that target the static component of this condition. Finasteride (Prosear, Merck) is one of such therapies that is indicated for the treatment of symptomatic BPH This drug is a competitor inhibitor of the enzyme 5a-reductase which is responsible for the conversion of tetosterone to anhydrotetosterone in the gland Prostatic (Gormeley et al., 1992). Dihydrotetosterone seems to be the main mitogen for the • Growth of the prostate and agents that inhibit 5a-reductase reduce the size of the prostate and improve the flow of urine through the prostatic urea. Although finasteride is a potent inhibitor of 5a-reductase and causes a marked decrease in serum and concentrations of dihydrotesterone in tissues, is only moderately effective in the treatment of symptomatic BPH (Oesterling, 1995). The effects of finasteride take 6-12 months to become evident and for many men the clinical improvement is minimal (Barry, 1997). The dynamic component of the HPB has been handled through the use of adrenergic receptor blocking agents (a1-AR blockers) that act by decreasing the smooth muscle tone within the prostate gland itself. A variety of α1-AR blockers (terazosin, prazosin, and doxazosin) have been investigated for the treatment of symptomatic obstruction of bladder outlet due to BPH, with terazosin (Hytrin, Abbott) being the most extensively studied. Although a1-AR blockers are well tolerated, approximately 10-15% of patients develop a chemically adverse case (Lepor, 1995). The undesirable effects of all members of this class are similar, postural hypotension being the most commonly experienced side effect (Lepor et al., 1992). Compared with 5a-reductase inhibitors, a1-AR blocking agents have a more rapid onset of action (Steers, 1995). However, its therapeutic effect, measured by the improvement of the result of the symptoms and the maximum proportion of the urinary flow, is moderate (Oesterling, 1995). The use of a1-AR antagonists in the treatment of BPH is related to its ability to decrease prostate smooth muscle tone, leading to the relief of obstructive symptoms. It has been discovered that adrenergic receptors throughout the body play a dominant role in the control of blood pressure, nasal congestion, prostate function and other procedures (Harrison et al., 1991). However, there are a number of cloned subtypes of a1-AR receptor: a1a-AR, a1b-AR and a1d-AR. (Bruno et al., 1991, Forray et al., 1994, Hirasawa et al., 1993, Ramarao et al., 1992, Schwinn et al., 1995, Weinberg et al., 1994). A number of laboratories have characterized a1-AR in the human prostate by functional techniques, radioligand binding and molecular biology (Forray et al., 1994, Hatano et al., 1994, Marshall et al., 1992, Marshall et al. al., 1995; Yamada et al., 1994). These studies provide evidence in support of the concept that the a1a-AR subtype comprises most a1-ARs in human prostatic smooth muscle and mediates contraction in this tissue. These findings suggest that the development of a subtype selective a1a-RA antagonist could result in a therapeutically effective agent with reduced secondary agents for the treatment of BPH.

BRIEF DESCRIPTION OF THE INVENTION The compounds of this invention selectively bind to the a1a-AR receptor, antagonize the activity of said receptor and are selective for prostatic tissue over the aortic tissue. As such, they represent a viable treatment for BPH without the side effects associated with the known a1-AR antagonists. The invention includes compounds in the formula I where: R-i is hydrogen, halogen, C? -5 alkoxy, hydroxyl or C? -5 alkyl; R 2 is Ci-β alkyl, substituted C 1-6 alkyl, wherein the alkyl substituents are independently selected from one or more halogen, phenyl, substituted phenyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C? -5 alkyl, C1-5 alkoxy and C? -5 trihaloalkyl, C1-5 phenylalkyl, or substituted C? -5 phenylalkyl, wherein substituents are selected from phenyl independently between one or more members of the group which consists of C-α-5 alkyl, halogen, C 1-5 alkoxy and C tri-5 trihaloalkyl; R3 is hydrogen, hydroxy, C-- -5 alkoxy, if the shaded line is absent or is oxygen if the shaded line is present; R4 is hydrogen, C? -5 alkyl; phenylalkyl of C 1-5, or substituted phenylalkyl of C-? - 5,20, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C? -5 alkyl, C? -5 alkoxy and C1-5 trihalogenoalkyl; R5 is hydrogen, halogen, hydroxy, is Cis alkyl, substituted C? -8 alkyl, wherein the alkyl substituents are independently selected from one or more halogens, d-5 alkoxy, amino, C? Alkylamino? -5, dialkylamino of C? -5, alkylcarbonyl of C? -5, alkoxycarbonyl of C? -5, nitrile or nitro; R6 is hydrogen, halogen, hydroxy, is Ci-s alkyl, substituted C-β-8 alkyl, wherein the alkyl substituents are independently selected from one or more halogens, ds, amino alkyloxy, alkylamino of C ? -5, dialkylamino of C? -5, alkylcarbonyl of C? -5, alkoxycarbonyl of C? -5, nitrile or nitro; R7 is hydrogen, halogen, hydroxy, is C? -8 alkyl, substituted C1-8 alkyl, wherein the alkyl substituents are selected • independently of one or more halogens, C -? - 5 alkoxy, amino, C -? - 5 alkylamino, C? - 5 dialkylamino, C? - 5 alkylcarbonyl, C? - 5 alkoxycarbonyl, nitrile or nitro; A is nitrogen or carbon; B is nitrogen or carbon; E is nitrogen or carbon; with the proviso that only one of A, B or E is nitrogen, pharmaceutically acceptable salts thereof; and stereoisomers, racemic mixtures, as well as enantiomers thereof. In addition, this invention contemplates pharmaceutical compositions containing an effective dose of the compounds of the formula I. Moreover, this invention contemplates methods of treating diseases associated with the adrenergic receptor 1aa consisting of administering an effective dose of a compound of the formula I to a mammal. This invention also contemplates a method of treating benign prostatic hyperplasia that comprises administering an effective dose of a compound of the formula I to a mammal. In addition to the compounds of formula I, this invention contemplates intermediate compounds of formula II and formula III. These intermediates are useful in the preparation of the compounds of the formula I and are as follows: Formula II wherein Rs is hydrogen, halogen, d-s alkoxy, hydroxyl or C-? -5 alkyl; R 9 is C 1-6 alkyl, C 1-6 alkyl, substituted, wherein the alkyl substituents are independently selected from one or more halogens, phenyl, substituted phenyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of alkyl of d-5, alkoxy of d-5 and trihalogenoalkyl of C 1-5, phenylalkyl of C 1-5. or substituted C.sub.1-5 phenylalkyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C -? - alkyl, halogen, C -? - alkoxy and C1 - trihaloalkyl. -5; R-io is hydrogen, d-5-alkoxycarbonyl, d-5-phenylalkoxycarbonyl or allyloxycarbonyl; R11 is hydrogen, d-5-phenylalkyl, or substituted C---phenylalkyl, wherein the phenyl substituents are selected from one or more members of the group consisting of d-5, halogen, alkoxy, C? -5 and nitro; Formula wherein Rio is C?-5 alkoxycarbonyl, C?-5 phenylalkoxycarbonyl or allyloxycarbonyl; R11 is C5-5 phenylalkyl, or substituted C1-5 phenylalkyl, wherein the phenyl substituents are selected from one or more members of the group consisting of C1-5 alkyl, halogen, d-s alkoxy and nitro; R 2 is halogen, mesyl, tosyl or hydroxy. Moreover, the invention contemplates methods of making compounds of formula II. These methods are as follows: Reacting a compound of formula III wherein Rio is C?-5 alkoxycarbonyl, C?-5 phenylalkoxycarbonyl or allyloxycarbonyl; R n is C 5 -5 phenylalkyl, or substituted C 1-5 -alkylalkyl, wherein the phenyl substituents are selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 5 alkoxy and nitro; R 12 is halogen, mesyl, tosyl or hydroxy; with a piperazine derivative of the formula IV IV wherein R8 is hydrogen, halogen, C? -5 alkoxy, hydroxyl or C? -5 alkyl; Rg is d-6 alkyl, d-6 alkyl, substituted, wherein the alkyl substituents are independently selected from one or more halogen, phenyl, substituted phenyl, wherein phenylphenyl substituents are independently selected from one or more members of the group consisting of C1-5 alkyl. C1.5 alkoxy and trihalogenoalkyl of C? -5, phenylalkyl of C? -5, or phenylalkyl of d-5, substituted, wherein the phenyl substituents are independently selected from one or more members of the group consisting of alkyl of d-5, halogen, C 1-5 alkoxy and trihalogenoalkyl of C? -5; in the presence of a basic reagent to produce a compound of the formula wherein Rs is hydrogen, halogen, d-5 alkoxy, hydroxyl or d-5 alkyl; Rg is C?-Alkyl, d-β alkyl, substituted, wherein the alkyl substituents are independently selected from one or more halogens, phenyl, substituted phenyl, wherein the phenyl substituents are independently selected from one or more members of the group Which consists of C1-5alkyl, C5-5alkoxy and trihalogenoalkyl of C? -5, phenylalkyl of d-5, or phenylalkyl of C? -, substituted, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C? -5alkyl, halogen, d-5alkoxy and trihaloalkyl of C? -5; River is d-5 alkoxycarbonyl, d-5 phenylalkoxycarbonyl or allyloxycarbonyl; Rn is C fen-5 phenylalkyl, or substituted Ci-s phenylalkyl, wherein the phenyl substituents are selected from one or more members of the group consisting of C?-5 alkyl, halogen, C? Alkoxy 5 and nitro; by reacting a compound of formula II wherein R8 is hydrogen, halogen, C?-5 alkoxy, hydroxyl or d-5 alkyl; Rg is C?-Alkyl, d-6 alkyl, substituted, wherein the alkyl substituents are independently selected from one or more halogens, phenyl, substituted phenyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C? -5 alkyl, C? -5 alkoxy and C? -5 trihaloalkyl, d-5 phenylalkyl, or substituted C1-5 phenylalkyl, wherein phenyl substituents are selected independently between one or more members of the group consisting of C? -5alkyl, halogen, d-5alkoxy and trihaloalkyl of ds; Rio is alkoxycarbonyl of C? -5, phenylalkoxycarbonyl of d-5 or allyloxycarbonyl; R 11 is d-5 phenylalkyl, or substituted d-5 phenylalkyl, wherein the phenyl substituents are selected from one or more members of the group consisting of d-s alkyl, halogen, C 5 -alkoxy, and nitro; 10 with a reagent to give a compound of formula II Wherein R8 is hydrogen, halogen, C? -5 alkoxy, hydroxyl or C? -5 alkyl; Rg is C?-Alkyl, substituted C 1-6 alkyl, wherein the alkyl substituents are independently selected from one or more halogen, phenyl, substituted phenyl, wherein phenyl substituents are independently selected from one or more members of the group consisting of alkyl of d-5, alkoxy of ds and trihalogenoalkyl of C? -5, phenylalkyl of d-5, or L-phenylalkyl of C? -5, substituted, w where substituents are selected of phenyl independently of one or more members of the group consisting of C?-5 alkyl, halogen, C? alkoxy and d-5 trihaloalkyl; Rio is hydrogen; Rn is d-5 phenylalkyl, or substituted C?-5 phenylalkyl, wherein the phenyl substituents are selected from one or more members of the group consisting of C 1-5 alkyl. halogen, C?-5 alkoxy and nitro; by reacting a compound of formula II wherein R8 is hydrogen, halogen, d-5 alkoxy, hydroxyl or C? -5 alkyl; Rg is C? -6 alkyl, substituted C? -6 alkyl, wherein the alkyl substituents are independently selected from one or more halogen, phenyl, substituted phenyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of d-5 alkyl, C? -5 alkoxy, and C? -5-trihaloalkyl, C? -5 phenylalkyl, or substituted phenylalkyl, wherein the phenyl substituents are independently selected between one or more members of the group consisting of C? -5 alkyl, halogen, C? -5 alkoxy and ds-trihaloalkyl; Rio is hydrogen; R11 is d-5 phenylalkyl, or substituted C? -5-phenylalkyl wherein the phenyl substituents are selected from one or more members of the group consisting of d-5 alkyl, halogen, C? -5 alkoxy and nitro; with a reducing agent to give formula II wherein Rs is hydrogen, halogen, C?-5 alkoxy, hydroxyl or d-5 alkyl; Rg is C?-Alkyl, substituted C 1-6 alkyl, wherein the alkyl substituents are independently selected from one or more halogens, phenyl, substituted phenyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of d-5alkyl, d-5alkyl, and thhalogenoalkyl of C? -, phenylalkyl of C? -5, or phenylalkyl of C? -5, substituted, wherein phenyl substituents are independently selected between one or more members of the group consisting of d-5 alkyl, halogen, d-5 alkoxy and tri-haloalkyl of C? -5; Rio is hydrogen; R11 is hydrogen; DETAILED DESCRIPTION OF THE INVENTION The terms used in describing the invention are commonly used and known to those skilled in the art. However, other terms are defined that could have other meanings. "HBSS" refers to Hank's balanced salt solution. "Independently" means that when there is more than one substituent, the substituents may be different. The term "alkyl" refers to straight, cyclic and branched alkyl groups and "alkoxy" refers to an O-alkyl wherein alkyl is as defined above. "DMAP" refers to dimethylaminopyridine, "TFA" refers to trifluoroacetic acid, "HOBT" refers to hydroxybenzoitriazole hydrate, "HATU" refers to O- (7-azabenzotriazole-1-yl) -1 hexafluorophosphate , 1, 3,3-tetramethyluronium, and "EDCI" refers to 1- (3-dimethylaminopropyl) -3-ethylcarbodilimide hydrochloride. The symbol "Ph" refers to phenyl and "aryl" includes unique or fused aromatic rings such as phenyl and naphthyl. The symbol "CPDA" refers to 1,1-cyclopentanediacetimid-1-yl and "II D" refers to 1 H-isoindol-1, 3- (2H) dion-1-yl. The symbol "EA" refers to electroasperción and the symbol "EM" refers to mass spectrum. Some of the compounds of the formula I include a chiral carbon atom. Such compounds can therefore be prepared as stereoisomers, reciemic mixtures or pure enantiomers. All stereoisomers, pure enantiomers and racemic mixtures are considered to be within the scope of this invention. The compounds of the invention can be prepared by the following schemes, wherein some schemes produce more than one embodiment of the invention. In those cases, the choice of scheme is a matter of agency that is within the capacity of synthetic chemists. A compound of the formula I can be prepared in which A, B and E are carbon, Ri is hydrogen, R 2 is phenyl, R 3 is hydroxy, R 4 is hydrogen and R 5 is 3-trifluoromethyl. using scheme 1. The scheme assembles two halves of the desired molecule and couples them together using peptide coupling reagents. A half is prepared by treating 1, 2,4-benzenetricarboxylic anhydride, 1a, with a substituted aniline derivative, 1b, at about 130 ° C in an acidic solvent such as glacial acetic acid 10 for about 16-24 hours to give the derivative of carboxy-substituted phthalamide 1c. The other half is prepared in two steps. First, 1-azido-3- (p-toluenesulfonyloxy) propan-2-ol Id is heated to about 100 ° C with an appropriately substituted piperazine derivative, le, for about 2-5 days to give azide 1f. This azide is treated with Pd / C and 15 H2 (3.51 kg / cm2) in an inert solvent for 16 hours to give the free amine 1 g. This amine is treated with 1c, HOBT, DMAP, EDCI, and N.N 'diisopropylethylamine in methylene chloride at about room temperature for 2-6 hours to give the desired compound of the formula! Alternatively, 1c and 1g can be coupled using other peptide coupling agents such as HATU and DMAP. This scheme can be used to prepare a quantity of compounds of formula I. For example, if compounds are desired wherein A, B or E is nitrogen, replace Ib with an aminopyridine derivative such as 2-aminopyridine and follow the remaining steps of scheme. To prepare compounds where Ri and R2 vary, simply replace the one illustrated with any known substituted piperazines. Although the illustrated product was prepared from the recidic azide Id, the pure enantiomers of this azide are known and can be used in this scheme. Compounds can be prepared wherein R3 is carbonyl, treating the products of scheme 1 with an oxidizing agent such as Swern's reagent (formed with oxalyl chloride and DMSO) at -78 ° C at room temperature for 30 minutes to 1 hour. 10 w • SCHEME 1 1 B Scheme 2 can be used to prepare compounds of the formula! wherein A is nitrogen, Ri is fluoro, R2 is ethyl, R3 is hydrogen, R4 is hydrogen and R5 is hydrogen. The treatment of 1, 2,4-benzenetricarboxylic anhydride, 2a, with the aniline derivative, 2b, gives the phthalimide 2c. An appropriately substituted piperazine 2d derivative is treated with the 3-bromopropylamine protected with N-BOC and cesium carbonate in acetonitrile at reflux for 10 hours to give the substituted piperazine derivative 2f. This derivative is converted to the free amine, 2g, by treatment with TFA and methylene chloride at room temperature for 2-6 hours. The derivatives 2g and 2c, using HOBT, DMAP, EDCI and N.N'-diisopropylethylamine in methylene chloride at about room temperature for 2-6 hours to give the desired compound of formula I. As described in scheme 1, Scheme 2 can be modified to give all the compounds of formula I.

• SCHEME 2 2b To produce the compounds of the invention wherein R 4 is different from hydrogen, Scheme 3 can be used. The amino group of intermediate 2g can be treated with an aldehyde 3a such as benzaldehyde to give imine 3b. This intermediate can be reduced with NaBH 4 at room temperature to give monoamine 3c. This amine is coupled with a substituted phthalimide derivative, 2c, using HATU, DMAP and diisopropylethylamine in methylene chloride at about room temperature for 2-6 hours to give the desired compound of formula I. As described in the previous schemes, Scheme 3 can be modified to give an amount of compounds of formula I. For example, to produce a compound wherein R3 is hydroxy, replace 2g with the intermediate and follow the remaining steps of Scheme 3. 10 SCHEME 3 To produce the compounds of the invention wherein R3 is C? -5 alkoxy, scheme 4 can be used. Treatment of this azide derivative Id with an appropriately substituted piperazine, such as 4a at-about 100 ° C for about 2-5 days gives the 5 intermediary 4b. This intermediate is treated with two equivalents of a strong organic base, such as sodium hydride in inert solvent, such as THF, at 0 ° C for about 1-5 hours; followed by treatment with an additional equivalent of base and an alkylating agent such as ethyl iodide, at 0 ° C for about 1-5 hours to give ether 4c. This is about ether with Pd / c and H2 (approximately 3.51 kg / cm2) in an inert solvent for 16 hours to give the free amine 4d. This amine is coupled to a phthalimido derivative such as 4e with HATU and DMAP to give the desired compounds of the invention. As discussed in Schemes 1-3, scheme 4 can be modified in the same way to give all the compounds of the formula I *5 SCHEME 4 4a To produce in pure enantiomers of the compounds of formula I wherein R3 is hydroxy, scheme 5 can be used. (S) (+) epichlorohydrin (97% ee) can be treated with benzylamine in a suitable organic solvent such as hexane at about room temperature for about 48-72 hours to give the hydroxy compound 5a. This intermediate can be treated with a BOC reactive agent such as di-tert-butyl dicarbonate and an organic base such as triethylamine in an inert solvent such as THF at about 0 ° C and up to about room temperature for 10 to 24 hours to give the N-protected derivative 5b. This intermediate can be treated with piperazine derivative, 5c, basic reagents, such as potassium hydroxide, sodium hydroxide or lithium hydroxide, in an alcohol solvent such as methanol at about 0 ° C and up to about room temperature for about 1 to about 3 days to give the applied derivative 5d. This compound can be deprotected by treatment with acid reagents, such as TFA or 1-6N HCL, at about room temperature for 18-24 hours to give the free amine 5e. This amine can be debenzylated using reducing agents, such as palladium catalyst and ammonium formate, sodium in liquid ammonia or palladium and hydrogen, in an alcohol solvent such as EtOH at about 45-60 ° C for 20 hours to give the primary amine 5f. This amine can be coupled to acids of the 5g type using peptide coupling agents such as HATU to give a compound of the formula I. As described in scheme 1, scheme 5 can be modified to give an amount of compounds of the formula I.

SCHOOLS 5d 5f Although the claimed compounds are useful as a1a-AR antagonists, some compounds are more active than others and are already preferred already particularly preferred. Preferred compounds of the formula I include: Ri is halogen or hydroxy, R 2 is phenylalkyl of d-5 or hydrogen, R 3 is d-5 alkoxy, R 4 is C 1 -C 5 alkyl, R 5. Re and R7 are independently selected from hydrogen, 10 nitrile and amino, # A is nitrogen or carbon, B is carbon and C is carbon. Particularly preferred compounds of formula I include compounds in which: R 1 is hydrogen, R 2 is C 6 -alkyl, phenyl or substituted phenyl R 3 is hydrogen, hydroxy, R 4 is hydrogen, R 5, R 6 and R are selected independently between halogen, hydrogen, hydroxy, C? -8 alkyl, d-5 alkoxy and C? -5 alkylamino, A is carbon, B is carbon and E is carbon. Preferred compounds of formula II include compounds in which ^^? Rs is hydrogen, Rg is alkyl of d-6, Rio is hydrogen, alkoxycarbonyl of C? -5, phenylalkoxycarbonyl of C? -5, and R11 is hydrogen, phenylalkyl of C1-5 or phenyl substituted by alkoxy of C? 5. Particularly preferred compounds of formula II include compounds in which Rs is hydrogen, Rg is isopropyl, R10 is hydrogen, t-butoxycarbonyl, benzyloxycarbonyl, and R11 is hydrogen, benzyl. Preferred compounds of the formula III include compounds in which R10 is C5-5 alkoxycarbonyl, R11 is C5-5 phenylalkyl or substituted phenyl with C5-5 alkoxy, and R12 is hydrogen or halogen. Particularly preferred compounds of the formula III include compounds in which R10 is t-butoxycarbonyl Rn is benzyl, and R2 is chloro. The preferred basic reagent for producing a compound of formula II is potassium hydroxide. The preferred acid reagent for treating a compound of the formula III is trifluoroacetic acid. The preferred reducing agent for treating a compound of formula II is ammonium formate and Pd / C As indicated by the biological activity, the compounds of the formula I can be used in pharmaceutical compositions to treat 10 patients (humans and other primates) with disorders related to inhibiting the activity of the adrenergic receptor a1a. The preferred route is oral administration, but the compounds can be administered by intravenous infusion. Oral doses vary from approximately 0.01 to approximately 100 mg / kg daily; wherein the optimum range of 15 doses is from about 0.01 to about 25 mg / kg / day. The infusion dose may vary from about 0.001-1 mg / kg / min of inhibitor, mixed with a pharmaceutical carrier for a period ranging from several minutes to several days. The pharmaceutical compositions can be prepared using pharmaceutical excipients and conventional composition techniques. Oral dosage forms may be elixirs, syrups, capsules, tablets and the like. If the typical solid carrier is an inert substance such as lactose, starch, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, mannitol and the like; and typical liquid oral excipients include ethanol, glycerol, water and the like. All excipients can be mixed with disintegrants, diluents, regulating agents, lubricants, binders and the like, using conventional techniques known to those skilled in the art of preparing dosage forms. Parenteral dosage forms can be prepared using water or another sterile carrier. Typically, the compounds of the formula I are isolated and used as free bases, but the compounds can be isolated and used as their pharmaceutically acceptable salts. Examples of such salts include hydrobromic, hydroiodic, hydrochloric, perchloric, sulfuric, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic., hydroethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-nephthalenesulfonic, p-toluenesulfonic, cyclohexansulfamic and saccharic. In order to illustrate the invention, the following examples are included. These examples do not limit the invention. They are only intended to suggest a method of practicing the invention. Those skilled in the art can find other methods of practicing the invention, which are obvious to them. However, it is judged that those methods are within the scope of this invention.

PREPARED EXAMPLES EXAMPLE 1 Compound 1 The salt fumarate of 1- (2-isopropoxyphenyl) -piperazine was based (3.91 g, 12 mmol) with 20% NaOH (aq) (100 mL) and extracted with methylene chloride. The combined organic layers were dried (Na2SO4) and concentrated to give an oil (2.74 g). A mixture of the oil and 1-azido-3 - (- p-toluenesulfonyloxy) propan-2-ol (3.25 g, 12 mmol, Antonin Holy, Collect, Czech, Chem. Comm. 1989, 54 (2), 446). The cooled mixture was diluted with water and extracted with ether, dried (Na2SO4) and concentrated. The product was purified by column chromatography (SiO2) to yield compound 1 (2.92 g, 76%) as a light brown solid: MS (EA) m / z: 320 (MH +); Anal. Calculated for C 16 H 25 N 502: C, 60.14; H, 7.89; N, 21.93. Found: C, 60.45; H, 7.83: N, 22.01.

EXAMPLE 2 Compound 2 % HCl (6 ml) was added to a mixture of compound 1 (2.43 g, 7.6 mmol) and 10% Pd / C (1.22 g) in MeOH (60 ml) and the mixture was hydrogenated under H2 (3.51 kg). / cm2) on a Parr shaker for 16 hours at 20 ° C. HE Filter the mixture through celite and concentrate the filtrate. The residue was basified with 20% NaOH and extracted with methylene chloride. The combined organic layers were dried (Na2SO) and concentrated to yield compound 2 as a yellowish oil (2.2 g, 95%): MS (EA) m / z: 294 (MH +) 15 EXAMPLE 3 Set 3 A mixture of 1,4-benzenetricarboxylic anhydride (10 g, 52 mmol) and 3-fluoroaniline (5.77 g, 52 mmol) in glacial acetic acid (200 ml) was stirred at 130 ° C for 16 hours. The light brown solution was cooled to 20 ° C to give a yellow solid precipitate. The yellow solid was collected by filtration and washed thoroughly with water to remove the vestigial amount of acetic acid. The product was dried at 60 ° C for 36 hours under vacuum to yield a yellow solid (11.41 g, 77%): MS (EA) m / z: 284 (MH +).

EXAMPLE 4 Compound 4 A mixture of compound 2 (226 mg, 0.77 mmol), compound 3 (220 mg, 0.77 mmol), EDCI (151 mg, 0.78 mmol), HOBT (105 mg, 0.78 mmol), was stirred at 20 ° C for 3 hours. DMAP (cat.) And N, N-diisopropylethylamine (0.52 ml) in methylene chloride (6 ml). The mixture was concentrated, diluted with water and extracted with EtOAc. The combined organic layer was dried (Na2SO) and concentrated. The product was purified by column chromatography (SiO2) and recrystallized in addition to EtOAc / hexane to yield compound 4 (101 mg, 23%) as a yellow solid: 1 H NMR (300 MHz, CDCl 3) d 8.34 (s, 1 H), 8.30 (d, J = 7.8 Hz, 1 H), 8.04 (d, J = 7.8 Hz, 1 H), 7.48 (m, 1 H), 7.26 (m, 1 H), 7.14 (m, 1 H), 6.91 (m, 1 H), 4.02 (m, 1 H), 3.79 (m, 1 H), 3.45 (m, 1 H), 3.13 (m, 4 H), 2.87 (m, 2 H), 2.62 (m, 2H), 2.50 (m, 2H), 1.34 (d, J = 6.0 Hz, 6H); MS (EA) m / z: 561 (mH +).

Compound 5 10-Bromopropylamine bromohydride (5g, 22.8 mmol) was dissolved in 10% NaOH (50 mL), extracted with methylene chloride and concentrated. To the free base in methylene chloride was added (Boc) 2 O (5.23 g, 23.9 mmol) and this mixture was stirred at 20 ° C for 4 hours. The methylene chloride layer was washed with H 2 O, diluted citric acid (6%), NaHCO 3 and solution NaCl saturated, dried and concentrated. The product was purified by column chromatography (SiO2) to yield the protected amino (4.84 g, 89%). The salt was fumarated with 1- (2-isopropoxyphenyl) -piperazine (5.1 g, 15 mmol) with NaOH (aC) at 20% (100 ml), extracted with methylene chloride, dried (Na2SO4) and concentrated to give a yellow oil (3.15 g). It warmed up After refluxing overnight, a mixture of the oil, the protected amine (3.42 g, 14.3 mmol), and Cs2CO3 (4.66 g, 14.3 mmol) in CH3CN (50 mL). The solid was filtered off and the filtrate was evaporated. The product was purified by column chromatography (SiO2) to yield compound 5 (4.4 g, 81%): MS (EA) m / z: 378 (MH +) EXAMPLE 6 Compound 6 The compound was dissolved (3.97 g, 11.4 mmole) in 25% TFA / methylene chloride (50 ml). The fraction was stirred at room temperature for 5 hours, the solvent was evaporated and a solid residue was obtained. This solid was dissolved in NaOH (aq) at 20% (10 ml) and stirred at 40 minutes. The free base was then extracted with methylene chloride (3x). A light yellow oil was obtained (3.0 g, 95%). A solution of this free amine (3.0 g, 10.8 mmol) and diisopropylethylamine (5.6 g, 43.3 mmol) in methylene chloride (80 mL) was added to a mixture containing EDCI (2.08 g, 10.8 mmol) HOBT (1.46 g, 10.8 mmoles), a catalytic amount of DMAP and compound 3 (3.09 g, 10.8 mmol). The reaction was stirred overnight at 20 ° C under N2. The reaction mixture was washed with water (3x). The product was purified by column chromatography (SiO2) to yield compound 6 (1.34 g, 23%): 1 H NMR (300 MHz, CDCl 3) d 8.34 (m, 2 H), 7.99 (d, J = 8.1 Hz, 1 H), 7.46 (q, J = 8.0, 6.4 Hz, 1 H), 7.18 (m, 2H), 6.89 (m, 4H), 4.57 (q, J = 12.0, 6.0 Hz, 1 H), 3.67 (m , 2H), 3.09 (brs, 4H), 2.71 (m, 6H), 1.87 (m, 2H), 1.33 (d, J = 6.1 Hz, 6H), MS (ES) m / z: 545 (MH +). Anal. Calculated for C3? H33FN4O4: C, 68.37; H, 6.11; N, 10.29. Found: C, 68.13; H, 6.10; N, 10.17 EXAMPLE 7 f Compound 7 The 1- (2-isopropoxyphenyl) -piperazine fumarate salt (112.5 g, 345 mmol) was basified with 20% NaOH (aC) (500 ml) and extracted with methylene chloride (3x). The combined organic extracts were dried over (Na2SO) and concentrated to give approximately 70 g of oil. A mixture of the oil and (2S) -3-azido-2-hydroxypropyl p-toluenesulfonate (91 g, 335 mmol, Kristina Juricova, Collect, Czech, Chem. Comm. 1995, 60, 237) was stirred at 100 ° C in NMP in the presence of triethylamine (70 g, 690 moles) for 30 hours. The cooled mixture was diluted with water and extracted with ether (3 x 500 ml), washed once more with NaCl (sat) (100 ml), and dried over (Na2SO4) and concentrated. The product was purified by column chromatography (SiO2) to yield compound 7 (70.6 g, 66%) (98.8% test with chiral AD column) as a white solid after recrystallization from methylene chloride / hexane: [ a] D25-3.6 ° (c = 1, CH 3 OH); 1 H NMR (300 MHz, CDCl 3) d 6.91 (m, 4 H), 4.59 (m, 1 H), 3.93 (m, 1 H), 3.67 (brs, 1 H), 3.42 (dd, J = 12.6, 3.8 Hz , 1 H), • * 5 3.23 (dd, J = 12.6, 5.4 Hz, 1 H), 3.12 (m, 4H), 2.83 (m, 2H), 2.53 (m, 3H), 2.42 (dd, J = 12.2, 3.8 Hz, 1 H), 1.34 (d, J = 6.0 Hz, 6H); MS (ES) m / z: (MH +).

EXAMPLE 8 Compound 8 % HCl (6 ml) of a mixture of compound 7 (15 g, 15 47 mmol) and 10% Pd / C (4 g) in MeOH (100 ml) was added and the mixture was hydrogenated under H2 (50 psi). ) on a Parr shaker for 21 hours at 20 ° C. The resulting mixture was filtered through celite and the filtrate was concentrated. HE •• basified the residue with 20% NaOH (aq) and extracted 75 ml with methylene chloride (3x), dried over (Na 2 S 4) and concentrated to yield compound 8 as a yellowish oil (14 g). , ~ 100%): [a] D25 + 23.6 ° C (c = 1, CHCI3); 1 H NMR (300 MHz, CDCl 3) d 6.91 (m, 4 H), 4.59 (m, 1 H), 3.76 (m, 1 H), 3.12 (m, 4 H), 2.83 (dd, J = 12.7, 3.7 Hz, 2H), 2.82 (m, 1 H), 2.25-2.68 (m, 8H), 1.34 (d, J = 6.1 Hz, 6H); MS (ES) m / z: 294 (MH +).

EXAMPLE 9 Compound 9 Compound 8 (1 g, 3.41 mmol) was dissolved in a mixture of diisopropylethylamine (2.3 ml, 13.6 mmol) and methylene chloride (10 ml). To the previous light yellowish solution, compound 3 (970 mg, 3.4 mmol) and HATU (1296 g, 3.41 mmol) were added and stirred at 20 ° C for 18 hours, concentrate. 10% K2CO3 (aq) was added and the mixture extracted with ether (3x), dried over (Na2SO), and concentrated. The product was purified by column chromatography (SiO2, EtOAc / Hexane then methylene chloride / Acetone) to give an oily solid. The product was recrystallized further with EtOAc / hexane to give compound 9 as a yellow solid. (830 mg, 43%): [OC] D25 + 8.3 ° (C = 1, CHCl3); 1 H NMR (300 MHz, CDCl 3) d 8.34 (s, 1 H), 8.30 (d, J = 7.8 Hz, 1 H), 8.04 (d, J = 7.8 Hz), 7.48 (m, 1 H), 7.26 ( m, 1 H), 7.14 (m, 1 H), 6.91 (m, 6 H), 4.59 (m, 1 H), 4.02 (m, 1 H), 3.79 (m, 1 H), 3.45 (m, 1 H ), 3.13 (m, 4H), 2.87 (m, 2H), 2.62 (m, 2H), 2.50 (m, 2H), 1.34 (d, J = 6.0 Hz, 6H); MS (ES) m / z: 561 (MH +).

EXAMPLE 10 Compound 10 A mixture of anhydridol, 2,4-benzenetricarboxylic acid (2 g, 10.4 mmol), and 3-aminopyridine (0.98 g, 10.4 mmol) in acidic glacial acid (40 ml) was stirred at 130 ° C for 16 hours. The mixture was cooled and the white solid filtered and washed once more with water. The product was dried for 24 hours in vacuo to give a compound 10 as the white solid (2.55 g, 91%): MS (ES) m / z: 267 (MH +).

EXAMPLE 11 Compound 11 A mixture of compound 2 (0.2 g, 0.68 mmol), EDCI (132 mg, 0.68 mmol), HOBT (94 mg, 0.68 mmol), DMAP (cat.), Compound 10 (0.18 g, 0.68 mmol) was stirred. ) and N, N-diisopropyletilamine (0.46 ml, 2.72 mmol) in methylene chloride (6 ml) at 20 ° C overnight. The mixture was concentrated and purified by column chromatography (SiO2, methylene chloride / acetone = 10: 1 to 1: 1) to yield compound 11 as a solid (67 mg, 18%): MS (ES) m / z: 544 (MH +).

EXAMPLE 12 Compound 12 Compound 1 (0.8 g, 2.5 mmol) was dissolved in anhydrous THF (50 ml). The solution was cooled to 0 ° C and 60% NaH (0.2 g, 5.0 mmol) was added. The solution was stirred for 10 minutes and CH3I (0.53 g, 3.8 mmol) was added. The reaction mixture was stirred at 0 ° C for 2 hours, NaH (0.1 g, 2.5 mmol) and CH3I (0.15 ml) were added and this mixture was stirred for another 2 hours. The reaction was triturated with sat. NH 4 Cl, and the solvent was evaporated, further the aqueous layer was washed with methylene chloride (3x), dried over (Na 2 S 4), and concentrated. The product was purified by column chromatography (silica gel) to yield compound 12 (0.69 g, 83%): MS (ES) m / z: 334 (MH +).

EXAMPLE 13 Compound 13 % HCl AL (0.3 ml) was added to a mixture of compound 12 (0.64 g, 1.9 mmol) and Pd / C AL 10% (0.13 g) in MeOH (5 mL). This mixture was hydrogenated under H2 (50 psi) on a Parr shaker overnight, filtered through celite and the filtrate was concentrated. The residue was basified with 20% NaOH AL and extracted with methylene chloride (3x), dried over (Na2SO) and concentrated to give a yellow oil at quantitative yield. MS (ES) m / z: 308 (MH +).

EXAMPLE 14 Compound 14 Compound 13 (0.15 g, 0.49 mmol) was dissolved in methylene chloride (4 ml) and 4 equivalents of diisopropylethylamine (0.25 g, 1.95 mmol) were added. A mixture of HATU, (0.185 g, 0.49 mmol) and compound 3 (0.14 g, 0.49 mmol) was added to this solution and the reaction was stirred overnight under N2 at RT. The solvent was evaporated and the product was purified by flash chromatography (SIO2, methylene chloride / acetone = 10: 1, 8: 1, 6: 1, 4: 1, 2: 1). The product was recrystallized from EtOAc / hexane to yield a light yellow solid 0.08 g (29%): 1 NMR (300 MHz, CDCl 3) d 8.36 (m, 2H), 8.18 (brs, 1 H), 8.02 (d , J = 7.69 Hz, 1 H), 7.47 (m, 1 H), 7.22 (m, 3 H), 7.00 (m, 1 H), 6.87 (m, 3 H), 4.57 (m, 1 H), 3.76 ( m, 3H), 3.50 (s, 3H), 3.22 (m, 10H), 1.35 (d, J = 6.0 Hz, 6H); MS (ES) m / z: 575 (MH +).

EXAMPLE 15 Compound 15 A mixture of (S) - (+) - epichlorohydrin (10 g, 108.1 mmol, Aldrich, 97% ee) and benzylamine (11.57 g, 108.1 mmol) in hexane was stirred. (40 ml) at 20 ° C for 62 hours. The white solid precipitated. More hexane (~ 350ml) was added, stirred for 20 minutes and treated with sound to break the large pieces of white solid. The white solid was collected by filtration and washed with hexane, dried in vacuo to give 19.8 g (92%) of white solid. The white solid was recrystallized from EtOAc / hexane to give 17.76 g (82%) of compound 15 as a white crystalline solid; 1 H NMR (300 MHz, CDCl 3) d 7.31 (m, 5 H), 3.88 (m, 1 H), 3.79 (m, 2 H), 3.53 (d, J = 5.3 Hz, 2 H), 2.89 (m, 2 H), 2.81 (dd, J = 12.4, 4.1 Hz, 1 H), 2.69 (dd, J = 12.2, 7.9 Hz, 1 H); MS (ES): 200 (MH +); analysis calculated for C10H14NOCI: C, 60.15; H, 7.07; N, 7.01. Found: C, 60.10; H, 7.02; N, 6.92.

EXAMPLE 16 Compound 16 Boc2O (11 g, 50.1 mmol) and triethylamine (10.12 g, 100 mmol) were dissolved in THF (25 mL) and cooled to 0 ° C. Amine 15 (10 g, 50.1 mmol) was added in portions and stirred for 20 hours while the temperature was heated to 20 ° C overnight. The solvent was concentrated in vacuo and water was added. The mixture was extracted with ether (3x), dried (Na 2 SO 4) and concentrated The crude residue was recrystallized from EtOAc / hexane to give 9.9 g (66%) of compound 16 as a white crystalline solid. filtrate (3.1 g as an oil) and more product was purified by column chromatography (short column, 8 cm height of SiO 2, EtOAc / hexane as solvent). The oil was recrystallized with EtOAc / hexane to give another amount of 2.78 g (18%) of 16 as a white crystalline solid: [a] D25 = -10.2 ° (c = 1, CHCl3); H NMR (300 MHz, CDCI3) d 7.22-7.36 (m, 5H), 4.52 ( m, 2H), 4.30 (brs, 0.5H), 3.96 (m, 1 H), 3.36-3.97 (m, 4H), 1.47 (s, 9H), MS (ES): 322 (M + Na); calculated for C? 5H22NO3CI: C, 60.10; H, 7.40; N, 4.67. Found: C, 60.26, H, 7.42; N, 4.63.

EXAMPLE 17 10 Compound 17 15 KOH (11.23 g, 200.5 mmol) was dissolved in methanol (280 ml), and the fumarate salt of 1- (2-isopropoxyphenyl) -piperazine (10.9 g, 33.4 g) was added.

W mmoles) and stirred at 20 ° C for 20 minutes, then cooled to 0 ° C. The Boc-protected amine 16 (10 g, 33.4 mmol) was added to the methanol solution at 0 ° C and stirred for 20 hours while the temperature was raised to 20 ° C overnight. The solvent was removed, water was added and the mixture was extracted with ether (3x), dried over (Na2SO4) and concentrated. The product was purified by column chromatography (short column, 8 cm height SiO2, EtOAc / hexane as solvent) to give 10.22 g (63%) of 17 (-100% ee, Chirapak OD 4.6x250 mm, 1 ml / min. , 254 nm, mobile phase: 90/100 hexane / IPA / 0.1% diethylamine) as a yellowish oil; 1 NMR (300 MHz, CDCl 3) d 7.26-7.35 (m, 5H), 6.91 (m, 4H), 4.68 (d, J = 15.6 Hz, 1 H), 4.59 (m, 3H), 3.95 (m, 1 H), 3.35 (m, 2H), 3.11 (m, 4H), 2.75 (m, 2H), 2.54 (m, 2 H), 2.38 (m, 2 H), 1.45 (m, 9 H), 1.34 ( d, J = 6.1 Hz, 6 H); MS (ES): 484 (MH +).

EXAMPLE 18 Compound 18 A mixture of compound 17 (233 mg, 0.48 mmol) and 25% TFA / methylene chloride (3 ml) was stirred at 20 ° C for 18 hours. Concentrate in vacuo and basify the residue with 20% NaOH (aq), extract with methylene chloride (3x), dry over (Na2SO) and concentrate to give 174 mg (-95%) compound 18 as a oil that was used directly without further purification; MS (ES): 384 (MH +).

EXAMPLE 19 Alternative Preparation of Compound 8 Compound 19 To a mixture of 18 (~ 154 mg, 0.4 mmol) and 10% Pd / C (154 mg) in EtOH (3 ml) was added ammonium formate (151 mg, 2.4 mmol) and stirred at 55-60. ° C for 20 hours. The mixture was filtered through celite and washed with methanol. The filtrate was concentrated. The product was purified by a short column of (5 cm height of SiO2) to give 63 mg (54%) of compound 19 as an oil; 15 [a] D25 + 23.6 ° (c = 1, CHCl3); 1 H NMR (300 MHz, CDCl 3) d 6.91 (m, 4 H), 4.59 (m, H), 3.76 (m, 1 H), 3.12 (m, 4 H), 2.83 (dd, J = 12.7, 3.7 Hz , 2 H), 2.82 (m, 1 H), 2.25-2.68 (m, 8 H), 1.34 (d, J = 6.1 Hz, 6 H); MS (ES): 294 (MH +).

EXAMPLE 20 Compound 20 A mixture of 1,4-benzenetricarboxylic anhydride (7 g, 36.4 mmol) and N, N-dimethyl-1,4-phenylenediamine (4.96 g, 36.4 mmol) in acidic acidic acid (120 ml) was stirred 130 ° C for 16 hours. The solution was cooled to 20 ° C and the light brown solid precipitated. The solid was collected through filtration and washed thoroughly and thoroughly with water to remove trace amounts of acetic acid. The product was dried at 40 ° C for 36 hours under vacuum to yield 8.0 g (71%) of compound 20 as a light brown solid: 1 H NMR (300 MHz, DMSO-d 6) d 8.40 (d, J = 8.5 Hz, 1 H), 8.28 (s, 1 H), 8.05 (d, J = 7.8 Hz, 1 H), 7.22 (d, J = 8.9 Hz, 2 H), 6.82 (d, J = 8.9 Hz, 2 H), 2.96 (s, 6 H); MS (ES): 309 (MH +).

EXAMPLE 21 (S) -2-f4- (d-methylammon) phenyl-2,3-dihydro-N-r2-hydroxy-3-r4-r2- (1-methylethoxy) phen.p-1-piperazinylpropyl -l, 3-dioxo-1 H-isoindol-5-carboxamide fifteen The piperazine 19 (0.4 g, 1.36 mmol) was dissolved in a mixture of diisopropylethylamine (0.7 g, 5.46 mmol) and methylene chloride (10 mL). Compound 20 (420 mg, 1.36 mmol) and HATU (0.52 g, 1.36 mmol) was added to the above solution and stirred at 20 ° C for 18 hours. The reaction mixture was washed with 3% K2CO3 (aq) and the organic layer was dried over (Na2SO), and concentrated. The product was purified by column chromatography (SiO2) CH2Cl2 / acetone = 10: 1, 8: 1, 6: 1, 4: 1, 2: 1) to give 0.33 g (41%) of comp. 21 as a light brown solid: 1 H NMR (300 MHz, CDCl 3) d 8.27 (m, 2 H), 8.00 (d, J = 7.7 Hz, 1 H), 7.23 (s, 1 H), 6.90 (m, 5 H), 6.79 (d, J = 8.9 Hz, 2 H), 4.59 (m, 1 H), 4.00 (m, 1 H), 3.83 (m, 1 H), 3.44 (m, 1 H), 3.12 ( brs, 4 H), 3.00 (s, 6 H), 2.85 (m, 2 H), 2.52 (m, 4 H), 1.34 (d, J = 6.1 Hz); MS (ES): 586 (MH +) [a] D25 = 9.6 ° (C = 0.2, CHCl3).

BIOLOGICAL EXAMPLES The biological activity and selection ability of the compounds of the invention were demonstrated by the following tests. The first test demonstrated the ability of the compounds of formula I to bind membrane binding receptors a1a-AR, to AR and a1a-AR.

EXAMPLE 22 DNA sequences of the human a1-AR subtypes cloned three times have been published. In addition, the cloned cDNAs have been expressed both transiently in COS cells and stably in a variety of mammalian cell lines (HeLa, LM (tk-), CHO, fibroblast rat-1) and have been shown to retain an activity of radioligand binding and a capacity to be coupled to phosphoinositide hydrolysis. Published information on DNA sequences was used to design primers for use in the RT-PCR amplification of each subtype and obtain cloned cDNAs. A poly A + human RNA was obtained from commercially available sources and samples from the hippocampus and prostate were included, sources that have been cited in the literature. For the main selection, a radioligand binding assay was used which used membrane preparations from cells expressing the individual cloned receptor cDNAs. Ligands Radiolabeled with binding activity in all three subtypes (non-selective) are commercially available as ([125L] -HEAT, [3H] -prazosin). Each a1 receptor subtype was cloned from poly A + RNA by the standard reverse transcription polymerase chain reaction (RT-PCR) method. The following poly sources were used A + RNA for the cloning of subtypes of human a1: a1a-AR, hippocampus and prostate, a1b-AR, human hippocampus, human hippocampus a1d-AR. The resulting cDNAs were cloned into the mammalian expression vector pcDNA3 (Invitrogen Corp., San Diego CA). The sequence of each was determined DNA for verification and to detect any possible mutation introduced during the amplification procedure. Any deviation in the sequence from the published consensus of each receptor subtype was corrected by site-directed mutagenesis.

The three a1-AR subtypes (a, b, d) were transfected into COS cells using a standard DEAE-dextran procedure with a chloroquine shock. In this procedure, each tissue culture box (100mm) was inoculated with 3.5 x 106 cells and transfected with 10 μg of DNA. Approximately 72 hours after the transfection, the cells were cultured and COS membranes prepared. Transfected COS cells from 25 plates (100mm) were divided and suspended in 15 ml of pH regulator TE (50mM Tris-HCl, 5mM EDTA, pH7.4). The suspension was interrupted with a homogenizer. Then it was centrifuged at 1000xg for 10 minutes at 4 ° C. The supernatant was centrifuged at 34.500xg for 20 minutes at 4 ° C. The pellet was resuspended in 5 ml of pH regulator TNE (50 mM Tris-HCl, 5 mM EDTA, 150 mM NaCl, pH7.4). The resulting membrane preparation was divided into aliquots and stored at -70 ° C. The protein concentration was determined after membrane solubilization with TritonX-100. The ability of each compound to bind to other types or subtypes of a1-AR in a receptor binding assay was evaluated. [1251] -HEAT, a non-selective a1-AR ligand, was used as the radiolabelled ligand. Each well of a 96-well plate received: 140 μL TNE, 25 ml [125I] -HEAT diluted in TNE (50,000 comp: final concentration 50 pM), 10 μL compound test diluted in DMSO (final concentration 1 pM-10 μM ), 25 ml COS cell membrane preparation expressing one of the three a1-AR subtypes (membrane protein 0.05-0.2 mg). The plate was incubated 1 hour at 5 Room temperature and the reaction mixtures were filtered through a Packard GF / C Unifilter filter plate. The filter plate was dried for 1 hour in a vacuum oven. Scintillation fluid (25 ml) was added to each well, and the filter plate was counted in a Packard Topcount scintillation counter. the data was analyzed using GraphPad Prism software. Tables A to D list IC50 values expressed in nanomolar concentration for selected compounds of the invention in all receptor subtypes.

TABLE A Comp. R1 R2 R * R7 a1a a1b a1d 4 H i-propyl 3-F H H 1.5 1835 76 48 H i-propyl 4-acetyl H H 1.0 > 2000 60 ^ fK 49 H i-propyl 3-CH 3 H H 0.9 > 2000 73 50 H i-propyl 4-F H H 1.5 > 2000 111 51 H i-propyl H H H 0.9 > 2000 65 52 H i-propyl 4-CH 3 H H 0.66 > 2000 62 53 H i-propyl 4-Cl H H 0.95 606 55 54 H i-propyl 3-CI H H 0.73 669 37 55 H i-propyl 4-OCH 3 H H 0.77 > 2000 51 56 H -propyl 3-Cl 4-Cl H 0.81 1225 40 57 H -propyl 3-CF3 H H 0.74 > 2000 89 58 H -propyl 4-OH H H 0.88 > 2000 28 26 H -propyl 2-OCH 3 H H 1.6 1639 74 27 H -propyl ** 3-F H H 8 > 2000 63 9 H -propyl * 3-F H H 1.0 > 2000 190 28 H -propyl 4-N (CH 3) 2 H H 0.80 > 2000 44 29 H -propyl 3-F 5-F H 0.89 886 38 H -propyl 4-NO2 H H 1.8 > 2000 38 31 H -propyl ** 4-OCH 3 H H 2.2 > 2000 52 32 H -propyl * 4-OCH3 H H 0.23 1750 124 21 H -propyl * 4-N (CH 3) 2 H H 0.36 > 2000 52 34 H -propyl * 4-CH3 H H 0.16 1650 37 H -propyl * 4-OH H H 0.46 > 2000 137 36 H i -propyl * 2-OCH 3 H 4 -OCH 3 0.59 > 2000 56 37 H i -propyl * 5-OCH 3 3-OCH 3 4-OCH 3 0.62 > 2000 51 38 H i -propyl * H 3-OCH 3 4-OCH 3 0.93 > 2000 175 39 H i -propyl H 3 -CH 3 4 -CH 3 0.44 > 2000 73 40 H i -propyl * H 3 -CH 3 4-CH 3 0.26 > 2000 121 41 H -propyl H H 4 -t-butyl 3.5 > 2000 75 42 H [Ethyl 3-F H H 4.25 > 2000 136 43 H rilil 3-F H H 22 > 2000 540 Indicates stereochemistry "S" 20"denotes stereochemistry" R " TABLE B RWJ Ri R2 R5 Re R7 a1a a1 b ald 6 H -propyl 3-FHH 0.41 482 22 44 H -propyl HH 4-N (CH3) 2 0.18 465 15 45 H -propyl HH 4-OCH3 0.11 361 16 46 H -propyl HH 4-CH3 0.1 > 2000 37 47 H -propyl H H 4 -OH 0.2 255 13 TABLE C Comp R1 Rs Re 7 a1a a1 b ald 15 11 H i-propyl H H H 1.9 > 2000 31 Comp R, Rs Re R? a1a a1 b ald 14 H i-propyl 3-F H H 7 > 2000 407 EXAMPLE 23 The ability of the compounds of the invention to be selected for prostate tissues on the aortic tissues was demonstrated as follows. The 5 contraction responses of rat prostate tissue and rat aortic tissue were examined in the presence and absence of antagonist compounds. As an indication of the antagonism selection capacity, the effects of the compound on vascular smooth muscle and its contraction capacity (a1b-AR and a1d-AR) were compared with the effects on the prostatic smooth muscle (a1a-AR). Strips of prostatic tissue and ^ aortic rings were obtained from male Long Evans rats derived with a weight of 275 grams and sacrificed by cervical dislocation. The prostate tissue was placed under a tension of 1 gram in a 10 ml bath containing saline regulated with pH phosphate pH 7.4 at 32 ° C and the isometric tension was measured with force transducers. Aortic tissue was placed under tension of 2 grams in a 10 ml bath containing saline regulated with pH phosphate pH 7.4 at 37 ° C. The ability of the test compound to reduce the norepinephrine-induced contraction response to 50% (IC50) was determined. Compound 4 inhibited the contraction response in the aortic tissue with a IC50 of 63.2 μM and in prostate tissue with an IC50 of 0.64 μM. Compound 6 inhibited the contraction response in aortic tissue with an IC 50 of 2.8 μM and in prostate tissue with an IC 50 of 0.13 μM. Compound 9 inhibited the contraction response in aortic tissue with an IC 50 of 6.5 μM and prostate tissue with an IC 50 of 0.23 μM. Compound 45 inhibited the contraction response in aortic tissue with an IC 50 of 3.3 μM and prostate tissue with an IC 50 of 0.04 μM. Compound 34 inhibited the contraction response in aortic tissue with an IC 50 of 42.5 μM and prostate tissue with an IC 50 of 5 0.75 μM. Compound 21 inhibited the contraction response in aortic tissue with an IC 0 of 22.4 μM and prostate tissue with an IC 50 of 0.81 μM.

EXAMPLE 24 Selected compounds of the invention were tested **** to determine its ability to antagonize increases induced by phenylephrine (PE) in intraurethral pressure in dogs. The ability to select these compounds was demonstrated by comparing their effect on increases induced by PE in the main blood pressure (MAP) in the dog. 15 Male beagle dogs were anaesthetized and catheter was introduced to measure intraurethral pressure (IUP) in the prostatic urethra. The main blood pressure (MAP) was measured using a catheter placed in the artery •• femoral. Six doses of bolus i.v. were initially administered to the dogs. (1 a < 32 mg / kg) of phenylephrine (PE) to establish a control against the curve of response to the dose. LUP and MAP were followed followed by each dose until lUP returned to the baseline. Dogs were given a bolus dose i.v. of the antagonist compound, followed by attempts PE i.v. of ascending doses, as in the response curve to the control agonist dose. The lUP and MAP measurements were recorded followed by each PE attempt. The antagonist compound was tested on a dose scale of 3 to 300 ug / kg in increments of average log. The interval between antagonist doses * was at least 45 and three experiments were developed for each test compound. The graphs below illustrate the major percent reductions in lUP and MAP for compounds 21 and 46 respectively.

EXAMPLE 25 The duration of selected compounds of the invention was determined by measuring the lUP and MAP responses for repeated PE attempts in conscious dogs at intervals. Beagle male dogs were instrumented to obtain the continuous measurement of arterial blood pressure implanting a catheter containing a pressure transducer in the abdominal aorta via the femoral artery. A telemetry transmitter was placed subcutaneously on the flank of the animal. LUP was monitored with a catheter placed • f in the prostatic urethra. Before administering the antagonist test compound, the lUP and MAP responses were determined at a dose of 20%. μg / kg i.v. of PE and repeated several times to establish a baseline response (maximum 100%). An oral bolus dose of antagonist was administered followed by a PE attempt of 20 μg / kg i.v. to 0.5, 1, 1.5, 2, 4, 6, 12 and 24 hours after dosing. The lUP and MAP responses were recorded followed by the PE attempt. Compound 33 was tested at doses of 0.1, 0.3 and 1 mg / kg. The responses of lUP and MAP are presented at each time point followed by the PE attempt in the following graphs as the percentage of the maximum response.

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Gormley G, Stoner E, Bruskewitz RC et al. (1992) The effect of finasteride in men with benign prostatic hyperplasia (Effect of finasteride in men with benign prostatic hyperplasia) N. Engl. J. Med. 327: 1185-1191. Hatano A, Takahashi H, Tamaki M, Komeyama T, Koizumi T, and Takeda M (1994) Pharmacological evidence of distinct a1-adrenoceptor subtypes mediating the contraction of human prostatic urethra and peripheral artery. (Pharmacological evidence of subtypes of a1 -adrenoceptors that mediate the contraction of the human prostatic urethra and the peripheral artery) Br. J. Pharmacol. 113: 723-728. Harrison JK, Pearson WR, and Lynch KR (1991) Molecular characterization of a1-and a2-adrenoceptors. (Molecular characterization of a1- and a2-adrenoceptors) Trends Pharmacol. Sci. 12: 62-67. Hieble JP and Caine M (1986) Etiology of benign prostatic hyperplasia and approaches to pharmacological management (Etiology of benign prostatic hyperplasia and approaches to pharmacological management) Fed Proc. 45: 2601-2603. Hirasawa A, Horie K, Tanaka T, Takagaki K, Murai M, Yano J, and Tsujimoto G (1993) Cloning, functional expression and tissue distribution of human cDNA for the a1c-adrenergic receptor (Cloning, functional expression and tissue distribution of human cDNA for the a1c-adrenergic receptor) Biochem. Biophys. Res. Commun. 195: 902-909. Lepor H and Rigaud G (1990) The efficacy of transurethral resection of the prostate in men with modérate symptoms of prostatism. (The efficacy of transurethral reception of the prostate in men with moderate symptoms of prostatism) J. Urol. 143: 533-537. Lepor H, Auerbach S, Puras-Baez A et al. (1992) A randomized, placebocontrolled multicenter study of the efficacy and safety of terazosin in the treatment of benign prostatic hyperplasia (A randomized, placebo-controlled, multiple-center study of the efficacy and safety of terazosin in the treatment of benign prostatic hyperplasia) J. Urol. 148: 1467-1474 Lepor H (1995) a- Blockade for benign prostatic hyperplasia (BPH) (a-block for benign prostatic hyperplasia) Clin. Endocrinol Metab. 10 80: 750-753. • Marshall I, Burt RP, Andersson PO, Chapple CR, Greengrass PM, Johnson Gl, and Wyllie MG (1992) Human a1c-adrenoceptor: functional characterization in prostate. (human a1c-adrenoceptor: functional characterization in prostate) Br. J. Pharmacol. 107 (Proc. Suppl. Dea): 327P. 15 Marshall I, Burt RP, and Chapple CR (1995) Noradrenaline contractions of human prostate mediated by a1A- (alc-) adrenoceptor subtype. (Contractions of noradrenaline in human prostate mediated by subtype of a1A- (alc-) adrenoceptor) Br. J. Pharmacol. 115: 781-786. Mebust WK, Holtgrewe HL, Cockett ATK, and Peters PC (1989) Transurethral prostatectomy: immediate and postoperative disorders. (Transurethral prostatectomy: immediate and postoperative complications). A cooperative study of 13 participating institutions evaluating 3,885 patients) J. Urol., 141: 243-247.

Oesterling JE (1995) Benign prostatic hyperplasia. Medical and minimally invasive treatment options. (benign prostatic hyperplasia, medical and invasive treatment options to a minimum) N. Engl. J. Med. 332: 99-109. Ramarao Cs, Kincade Denker JM, Pérez DM, Gaivin RJ, Riek RP, and Graham RM (1992) Genomic organization and expression of the human a1 B-adrenergic receptor. (Genomic organization and expression of human a-B-adrenergic receptor) J. Biol Chem. 267: 21936-21945. Schwinn DA, Johnston Gl, Page SO, Mosley MJ, Wilson KH, Worman NP, Campbell S, Fidock MD, Furness LM, Parry-Smith DJ, Peter B, and Bailey DS (1995) Cloning pharmacological characterization of human alpha-1 adrenergic receptors: sequence corrections and direct comparison with other species homologues (Cloning and pharmacological characterization of human alpha-1 adrenergic receptors: corrections of sequences and direct comparison with other homologous species) JPET 272: 134-142. William D. Steers & Burkhart Zorn, Beniqn Prostatic Hyperplasia, in Disease-a-Month (benign prostatic hyperplasia, in a month of illness) M. Grenbeerger et al. Eds., 1995). Weinberg DH, Trivedi P, Tan CP, Mitra S, Perkins-Barrow A, Brokowski D, Strader CD, and Bayne M (1994) Cloning, expression and characterization of human to adrenergic receptors a1a, a1B, and a1C (Cloning, expression and characterization of human adrenergic receptors a1a, a1 B, and a1 C) Biochem. Biophys. Res. Commun. 201: 1296-1304. Weis KA, Epstein RS, Huse DM, Deverka PA and oster G (1993) The costs of prostatectomy for benign prostatic hyperplasia. (Prostatectomy costs for benign prostatic hyperplasia) Prostate 22: 325-334. Wennberg JE, Roos N, Sola L, Schori A, and Jaffe R (1987) Use of claims data systems to evaluate health care outcomes: mortality and reoperation following prostatectomy. (Use of claim data systems to evaluate the salient points in health care: mortality and new operation after prostatectomy) JAMA 257: 933-936. Yamada S, Tanaka C, Kimura R, and Kawabe K (1994) Alpha 1-Adrenoceptors in human prostate: characterization and binding characteristics of alpha 1 -antagonists. (Adrenoceptors alpha -1 in human prostate: characterization and binding characteristics of alpha 1 -antagonists) Life Sci. 54: 1845-1854.

Claims (37)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound of formula I wherein: R is hydrogen, halogen, C? -5 alkoxy, hydroxyl or C? -5 alkyl? Is d-? Alkyl, d-6 alkyl, substituted; wherein the alkyl substituents are independently selected from one or more halogens; phenyl, substituted phenyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C1..5 alkyl, C? -5 alkoxy and C? -5 trihaloalkyl, d-5 phenylalkyl , or substituted C 1-5 -alkylalkyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of d-5alkyl, halogen, d-5alkoxy and trihaloalkyl of C? -5; R3 is hydrogen, hydroxy, C? - alkoxy, if the shaded line is absent or is oxygen if the shaded line is present; R 4 is hydrogen, C 1-5 alkyl; phenylalkyl of C? -5, or substituted C? -5 phenylalkyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, d-5 alkoxy and trihaloalkyl d-5; R5 is hydrogen, halogen, hydroxy, is d-s alkyl, d-s alkyl, substituted, wherein the alkyl substituents are independently selected from one or more halogens; d-5 alkoxy, amino, d-5 alkylamino, C? -5 dialkylamino, C? -5 alkylcarbonyl, C? -5 alkoxycarbonyl, nitrile or nitro; RT is hydrogen, halogen, hydroxy, is ds alkyl, substituted C? -8 alkyl, wherein the alkyl substituents are independently selected from one or more halogen, d-5 alkoxy, amino, C1-5 alkylamino , dialkylamino of C? -5, alkylcarbonyl of C? -, alkoxycarbonyl of d-5, nitrile or nitro; R7 is hydrogen, halogen, hydroxy, is C? -8 alkyl, ds alkyl, substituted, wherein the alkyl substituents are independently selected from one or more halogen, C? -5 alkoxy, amino, alkylamino of d-? 5, C1-5 dialkylamino, d-5 alkylcarbonyl, C?-5 alkoxycarbonyl, nitrile or nitro; A is nitrogen or carbon; B is nitrogen or carbon; E is nitrogen or carbon; with the proviso that only A, B, or E is nitrogen; pharmaceutically acceptable salts thereof; and stereoisomers, racemic mixtures, as well as enantiomers thereof.
2. 2. The compound according to claim 1, wherein R1 is hydrogen, halogen or hydroxy; R 2 is alkyl of d-6, phenyl, substituted phenyl, phenylalkyl of d-6, or hydrogen, R 3 is hydrogen or hydroxy; R 4 is hydrogen, d-5 alkyl; R is hydrogen, halogen, hydroxy, C? -8 alkyl, C1.5 alkoxy, amino, C? -5 dialkylamino, C? -5 alkylcarbonyl, or nitrile; Re is hydrogen, halogen, hydroxy, is d-s alkyl, C? -5 alkoxy, amino, d-5 dialkylamino, d-5 alkylcarbonyl, or nitrile; R7 is hydrogen, halogen, hydroxy, C? -8 alkyl, C1-5 alkoxy, amino, dialkylamino of d-5, alkylcarbonyl of d-5, and A, B and E are carbon.
3. 3. The compound according to claim 1, wherein R1 is hydrogen; R2 is C? -6 alkyl, phenyl or substituted phenyl; R3 is hydroxy or hydrogen; R is hydrogen; R5 is hydrogen, halogen, hydroxy, d-alkyl, d-5-alkoxy, d-5-alkylcarbonyl, or d-5-dialkylamino; R6 is hydrogen, halogen, hydroxy, C? -8 alkyl, C? -5 alkoxy, C? -5 alkylcarbonyl, or C? -5 dialkylamino; R7 is hydrogen, halogen, hydroxy, d-alkyl, d-5 alkoxy, C? - alkylcarbonyl, or C? -5 dialkylamino, and A, B, and E are carbon.
4. 4. The compound according to claim 1, further characterized in that R1 is hydrogen; R2 is C? -6 alkyl, substituted phenyl; R3 is hydroxy; R is hydrogen; R5 is hydrogen, halogen, hydroxy, C? -8 alkyl, C? -5 alkoxy, C? -5 alkylcarbonyl, or C? -5 dialkylamino; Re is hydrogen, halogen, hydroxy, C? -8 alkyl, C? -5 alkoxy, C? - alkylcarbonyl, or C? -5 dialkylamino; R7 is hydrogen, halogen, hydroxy, C? -8 alkyl, C? -5 alkoxy, C? -5 alkylcarbonyl, or C? -5 dialkylamino, and A, B, and E are carbon. A, B and E are carbon.
5. 5. The compound according to claim 1, further characterized in that Ri is hydrogen, R 2 is sopropyl, R 3 is hydroxy, R 4 is hydrogen, R 5 is 4-dimethylamino and RQ and R are hydrogen.
6. 6. The compound according to claim 1, further characterized in that R1 is hydrogen, R2 is isopropyl, R3 is hydrogen, R is hydrogen, R5 is 4-methyl and Re and R7 are hydrogen.
7. 7. The compound according to claim 1, further characterized in that R3 is hydroxy and R5 is amino, alkylamino of d-5 or dialkylamino of d-5.
8. 8. The compound according to claim 1, selected from the group consisting of 2- [4- (fluoro) phenyl] -2,3-dihydro-N- [2-hydroxy-3- [4- [2 - (1-methylethoxy) phenyl] -1-piperazinyl] propyl] -1,3-dioxo-1 H-isoindole-5-carboxamide; 2- [3-fluorophenyl] -2,3-dihydro-N- [2-hydroxy-3- [4- [2- (1-methylethoxy) phenyl] -1-piperazinyl] propyl] -1,3-dioxo- 1 H-isoindol-5-carboxamide; 2- [4- (dimethylamino) phenyl] -2,3-dihydro-N- [2-hydroxy-3- [4- [2- (1-methylethoxy) phenyl] -1-piperazinyl] propyl] -1, 3-dioxo-1 H-isoindol-5-carboxamide; * 2- [4-methylphenyl-2,3- dihydro-N- [2-hydroxy-3- [4- [2- (1-methylethoxy) phenyl] -1-piperazinyl] propyl] -1,3-dioxo- '• 1 H-isoindol-5-carboxamide; 2- [3,4,5-trimethoxyphenyl] -2,3-dihydro-N- [2-hydroxy-3- [4- [2-methyletoxy) phenyl] -1-piperazinyl] propyl] -1, 3-dioxo -1 H-isoindol-5-carboxamide; 20 2- [4-chlorophenyl-2,3-dihydro-N- [2-hydroxy-3- [4- [2- (1-methylethoxy) phenyl] -1- piperazinyl] propyl] -1,3-dioxo- 1 H-isoindol-5-carboxamide; 2- [4-hydroxyphenyl] -2,3-dihydro-N- [2-hydroxy-3- [4- [2- (1-methylethoxy) phenyl] -1-piperazinyl] propyl] -1,3-dioxo- 1 H-isoindol-5-carboxamide; 2- [5-methoxyphenyl] -2,3-dihydro-N- [2-hydroxy-3- [4- [2- (1-methylethoxy) phenyl] -1-piperazinyl] propyl] -1,3-dioxo- 1 H-isoindol-5-carboxamide; and 2- [4-ethylphenyl] -2,3-dihydro-N- [2-hydroxy-3- [4- [2- (1-methylethoxy) phenyl] -1-piperazinyl] propyl] -1, 3 -dixo-1 H-isoindol-5-carboxamide.
9. 9. The compound according to claim 8, further characterized in that the stereochemistry of the chiral carbon is 'S'.
10. 10. The compound according to claim 4, further characterized in that the stereochemistry of the chiral carbon in R3 is 'S'.
11. 11. The compound according to claim 1, (S) -2- [4- (dimethylammono) phenyl] -2,3-dihydro-N- [2-hydroxy-3- [4- [2 - (1-methylethoxy) phenyl] -1-piperazinyl] propyl] -1,3-dioxo-1 H-isoindole-5-carboxamide.
12. 12. The compound according to claim 1, selected from the group consisting of 2- [4- (fluoro) phenyl] -2,3-dihydro-N- [3- [4- [2- (1-methylethoxy ) phenyl] -1-piperazinyl] propyl] -1,3-dioxo-1 H-isoindole-5-carboxamide; 2- [3-fluorophenyl] -2,3-dihydro-N- [3- [4- [2- (1-methylethoxy) phenyl] -1-piperazinyl] propyl] -1,3-dioxo-1 H-isoindol-5 -carboxamide; 2- [4- (dimethylamino) phenyl] -2,3-dihydro-N- [3- [4- [2- (1-methylethoxy) phenyl] -1-piperazinyl] propyl] -1,3-dioxo-1 H-isoindol-5-carboxamide; 2- [4-methylphenyl] -2,3-dihydro-N- [3- [4- [2- (1-methylethoxy) phenyl] -1-piperazinyl] propyl] -1,3-dioxo-1 H-isoindole -5-carboxamide; 2- [3,4,5-trimethoxyphenyl] -2,3-dihydro-N- [3- [4- [2- (1-methylethoxy) phenyl] -1-piperazinyl] propyl] -1,3-dioxo- 1 H-isoindol-5-carboxamide; 2- [4-chlorophenyl] -2,3-dihydro-N- [3- [4- [2- (1-methylethoxy) phenyl] -1-piperazinyl] propyl] -1,3-dioxo-1 H-isoindole -5-carboxamide; 2- [4-hydroxyphenyl] -2,3-dihydro-N- [3- [4- [2- (1-methylethoxy) phenyl] -1-piperazinyl] propyl] -1, 3-dioxo-1 H-isoindole -5-carboxamide; 2- [5-methoxyphenyl] -2,3-dihydro-N- [3- [4- [2- (1-methylethoxy) phenyl] -1-piperazinyl] propyl] -1,3-dioxo-1 H-isoindole -5-carboxamide; and 2- [4-ethylphenyl] -2,3-dihydro-N- [3- [4- [2- (1-methylethoxy) phenyl] -1-piperazinyl] propyl] -1,3-dioxo-1 H- isoindol-5-carboxamide.
13. 13. The use of a compound of claim 1, for the manufacture of a medicament for treating benign prostatic hyperplasia in a mammal.
14. 14. The use as claimed in claim 13, wherein the medicament provides from about 0.1 to about 25.0mg / kg of the compound of claim 1 to a mammal.
15. 15. The use of a compound of claim 1, for the manufacture of a medicament for treating diseases associated with the a1a adrenergic receptor in a mammal.
16. 16. The use of a compound of claim 15, wherein the medicament provides from about 0.1 to about 25.0mg / kg of the compound of claim 1 to a mammal.
17. 17. A pharmaceutical composition containing an effective dose of a compound of formula I.
18. 18. The pharmaceutical composition according to claim 17, wherein the effective dose of a compound of formula I is from about 0.01 to about 25.0. mg / kg. 19. - The pharmaceutical composition according to claim 17, wherein the effective dose of a compound of formula I is from about 0.01 to about 1.Omg / kg. 20. A compound of formula II wherein R8 is hydrogen, halogen, C?-5 alkoxy, hydroxyl or d-5 alkyl; Rg is C1-6 alkyl, substituted Ci-β alkyl; wherein the alkyl substituents are independently selected from one or more halogens, phenyl, substituted phenyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of d-5 alkyl, d-5 alkoxy and trihalogenoalkyl of C? -5, phenylalkyl of C? -5, or phenylalkyl of C? -5, substituted, wherein the phenyl substituents are independently selected from one or more members of the group consisting of alkyl of d-5, halogen, C? -5 alkoxy and trihalogenoalkyl of d-5; Rio is hydrogen, C?-5 alkoxycarbonyl, C?-5 phenylalkoxycarbonyl or allyloxycarbonyl; Rn is hydrogen, phenylalkyl of C? -5, or phenylalkyl of d-5, substituted, wherein the phenyl substituents are selected from one or more members of the group consisting of C? - alkyl, halogen, d-alkoxy 5 and nitro; 21. - The compound according to claim 20, wherein R8 is hydrogen or halogen; Rg is C 1-6 alkyl, phenyl or substituted phenyl; Rio is hydrogen or alkoxycarbonyl of d-5, and R-n is hydrogen, phenylalkyl of d-5, or phenylalkyl of C? -5, substituted by C? -5 alkoxy. • 22. The compound according to claim 20, wherein R8 is hydrogen, Rg is isopropyl, Rio is alkoxycarbonyl of C? -5, and R11 is phenylalkyl of C? -5. 23. The compound according to claim 20, wherein R8 is hydrogen, Rg is isopropyl, Rio is t-butoxycarbonyl and Rn is 10 benzyl. 24.- The compound according to claim 20, wherein R8 is hydrogen, Rg is isopropyl, Rio is hydrogen and Rn is benzyl. 25. The compound according to claim 20, wherein R8 is hydrogen, R9 is isopropyl, Rio is hydrogen and Rn is 15 hydrogen. 26.- A compound of formula III Wherein Rio is alkoxycarbonyl of C? -5, phenylalkoxycarbonyl of d-5 or allyloxycarbonyl; Rn is phenyl, phenylalkyl of C? -5, or phenylalkyl of C? -5, substituted, wherein the phenyl substituents are selected from one or more members of the group consisting of alkyl of d-5, halogen, alkoxy of C ? -5 and nitro; R 12 is halogen, hydroxyl, mesyl or tosyl. 27. The compound according to claim 26, wherein Rio is t-butoxycarbonyl and Rn is benzyl. 28. The compound according to claim 26, wherein R12 is chloro. 29.- Reacting a compound of Formula III lll wherein Rio is C5-alkoxycarbonyl, C5-5 phenylalkoxycarbonyl or allyloxycarbonyl; Rn is d-5 phenylalkyl, or substituted d-5 phenylalkyl, wherein the phenyl substituents are selected from one or more members of the group consisting of d-5 alkyl, halogen, C?-5 alkoxy and nitro; R 12 is halogen, mesyl or tosyl with a piperazine derived from formula IV: IV wherein R8 is hydrogen, halogen, d-5 alkoxy, hydroxyl or C? -5 alkyl; Rg is d-β alkyl, substituted d-β alkyl; wherein the alkyl substituents are independently selected from one or more halogens, phenyl, substituted phenyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C? -5 alkyl, d-alkoxy, 5 and C1-5 trihalogenoalkyl, d-5 phenylalkyl, or substituted d-5 phenylalkyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C1.5 alkyl, halogen, alkoxy of d-5 and trihalogenoalkyl of C? -5; in the presence of a basic reagent to produce a compound for formula II wherein R8 is hydrogen, halogen, d-5 alkoxy, hydroxyl or C? -5 alkyl; Rg is C 1-6 alkyl, substituted d-6 alkyl; wherein the alkyl substituents are independently selected from one or more halogens, phenyl, substituted phenyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C? -5 alkyl, d-alkoxy, 5 and C1-5 trihalogenoalkyl, C5-5 phenylalkyl, or substituted d-5 phenylalkyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C?-5 alkyl, halogen , d-5 alkoxy and trihalogenoalkyl of d-5; R10 is C1-5 alkoxycarbonyl, C5-5 phenylalkoxycarbonyl or allyloxycarbonyl; Rn is C? -5 phenylalkyl, or substituted C? -5 phenylalkyl, wherein the phenyl substituents are selected from one or more members of the group consisting of d-5 alkyl, halogen, d-5 alkoxy and nitro; 30. The method according to claim 29, wherein R8 is hydrogen, Rg is isopropyl, Rio is t-butoxycarbonyl and Rn is benzyl. 31.- Reacting a compound of Formula II 10 || w wherein R8 is hydrogen, halogen, d-5 alkoxy, hydroxyl or d-5 alkyl; R g is C 1-6 alkyl, substituted d-β alkyl; wherein the alkyl substituents are independently selected from one or more halogens, phenyl, substituted phenyl, wherein the phenyl substituents are selected Independently from one or more members of the group consisting of d-5 alkyl, C? -5 alkoxy and C? -5 trihaloalkyl, d-5 phenylalkyl, or substituted d-5 phenylalkyl, where they are selected the phenyl substituents independently between one or more members of the group consisting of C? -5 alkyl, halogen, C? _5 alkoxy and d-5 trihaloalkyl; in The presence of a basic reagent to produce a compound for formula II wherein R8 is hydrogen, halogen, d-5 alkoxy, hydroxyl or C? -5 alkyl; Rg is C? -6 alkyl, substituted C? -6 alkyl; wherein the alkyl substituents are independently selected from one or more halogens, phenyl, substituted phenyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of d-5 alkyl, d-alkoxy, 5 and trihalogenoalkyl of C? -5, phenylalkyl of d-5, or phenylalkyl of substituted d-5, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C? -5 alkyl, halogen , C? -5 alkoxy and trihalogenoalkyl of C? -5; Rio is d-5-alkoxycarbonyl, C? -5-phenylalkoxycarbonyl or allyloxycarbonyl; Rn is d-5 phenylalkyl, or substituted C?-5 phenylalkyl, wherein the phenyl substituents are selected from one or more members of the group consisting of d-5 alkyl, halogen, C?-5 alkoxy and nitro; with an acid reagent to give a compound of formula II wherein R8 is hydrogen, halogen, C? -5 alkoxy, hydroxyl or C? -5 alkyl; Rg is C? -6 alkyl, substituted C? -6 alkyl; wherein the alkyl substituents are independently selected from one or more halogens, phenyl, substituted phenyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C? -5 alkyl, C? -5 and trihalogenoalkyl of d-5, phenylalkyl of d-5, or phenylalkyl of substituted C? -5, wherein the phenyl substituents are independently selected from one or more members of the group consisting of d-5 alkyl, halogen , d-5 alkoxy and trihalogenoalkyl of d-5; Rio is hydrogen; Rn is C1-5 phenylalkyl. or substituted d-5 phenylalkyl, wherein the phenyl substituents are selected from one or more members of the group consisting of C 1-5 alkyl, halogen, d-5 alkoxy and nitro; 32. The method according to claim 31, wherein R8 is hydrogen, R9 is isopropyl and Rn is benzyl. 33.- Reacting a compound of Formula II "Wherein R8 is hydrogen, halogen, C?-5 alkoxy, hydroxyl or C 1-5 alkyl; R g is d 6 alkyl, substituted C 6 alkyl; wherein alkyl substituents are independently selected from one or more halogens, phenyl, substituted phenyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C? -5 alkyl, d-alkoxy, 5 and trihalogenoalkyl of d-5, phenylalkyl of d-5, or phenylalkyl of substituted C C-5, wherein the phenyl substituents are independently selected from one or more members of the group consisting of d-5 alkyl, halogen, C? -5 alkoxy and C? - trihalogenoalkyl; Rio is hydrogen; Rn is C fen-5 phenylalkyl, or substituted d-5 phenylalkyl, wherein the phenyl substituents are selected from one or more members of the group consisting of d-5 alkyl, halogen, C?-Alkoxy, and nitro; with a reducing agent to give a compound of formula II Wherein R8 is hydrogen, halogen, C? -5 alkoxy, hydroxyl or C? -5 alkyl; ^ w Rg is C? -6 alkyl, substituted C? -6 alkyl; wherein the alkyl substituents are independently selected from one or more halogens, phenyl, substituted phenyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C? -5 alkyl, C? -5 alkoxy and C? -5 trihaloalkyl, C? -5 phenylalkyl, or substituted C? -5 phenylalkyl, wherein the phenyl substituents are independently selected from one or more members of the group that consists 'f in d-5 alkyl, halogen, d-5 alkoxy and trihaloalkyl of d-5; Rio is hydrogen; Rn is hydrogen; 34.- The method according to claim 33, wherein R8 is hydrogen and R9 is isopropyl. 35. - The method according to claim 33, further characterized in that the reducing agent is ammonium formate and Pd / C. 36. The method according to claim 31, further characterized in that the acid reagent is trifluoroacetic acid. 37. The method according to claim 29, further characterized in that the basic reagent is potassium hydroxide.