Thiophene substituted piperazines useful in the treatment of benign prostatic hyperplasia

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 α-la 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: This invention relates to a series of aryl piperazine substituted heterocycles, pharmaceutical compositions containing them and intermediates used in their manufacture. The compounds of the invention selectively inhibit binding to the α-la 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. BACKGROUND Benign prostatic hyperplasia (BPH), a nonmalignant 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 a third of these men have clinical symptoms consistent with bladder outlet obstruction (Hieble and Caine, 1986). In the U.S., benign and malignant diseases of the prostate are responsible for more surgery than diseases of any other organ in men over the age of fifty. There are two components of BPH, a static and a dynamic component. The static component is due to enlargement of the prostate gland, which may result in compression of the urethra and obstruction to the flow of urine from the bladder. The dynamic component is due to increased smooth muscle tone of the bladder neck and the prostate itself (which interferes with emptying of the bladder) and is regulated by alpha 1 adrenergic receptors (α1-ARs). The medical treatments available for BPH address these components to varying degrees, and the therapeutic choices are expanding. Surgical treatment options address the static component of BPH and include transurethral resection of the prostate (TURP), transurethral incision of the prostate (TUIP), open prostatectomy, balloon dilatation, hyperthermia, stents and laser ablation. TURP is the gold standard treatment for patients with BPH and approximately 320,000 TURPs were performed in the U.S. in 1990 at an estimated cost of $2.2 billion (Weis et al., 1993). Although an effective treatment for most men with symptomatic BPH, approximately 20 - 25% of patients do not have a satisfactory long-term outcome (Lepor and Rigaud, 1990). Complications include retrograde ejaculation (70-75% of patients), impotence (5-10%), postoperative urinary tract infection (5-10%), and some degree of urinary incontinence (2-4%) (Mebust et al., 1989). Furthermore, the rate of reoperation is approximately 15-20% in men evaluated for 10 years or longer (Wennberg et al., 1987). Apart from surgical approaches, there are some drug therapies which address the static component of this condition. Finasteride (Proscar", Merck), is one such therapy which is indicated for the treatment of symptomatic BPH. This drug is a competitive inhibitor of the enzyme 5a-reductase which is responsible for the conversion of testosterone to dihydrotestosterone in the prostate gland (Gormley et al., 1992). Dihydrotestosterone appears to be the major mitogen for prostate growth, and agents which inhibit 5a-reductase reduce the size of the prostate and improve urine flow through the prostatic urethra. Although finasteride is a potent 5a-reductase inhibitor and causes a marked decrease in serum and tissue concentrations of dihydrotestosterone, it is only moderately effective in treating 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 BPH has been addressed by the use of adrenergic receptor blocking agents (α1-AR blockers) which 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 bladder outlet obstruction due to BPH, with terazosin (Hytrin", Abbott) being the most extensively studied. Although the α1-AR blockers are well-tolerated, approximately 10-15% of patients develop a clinically adverse event (Lepor, 1995). The undesirable effects of all members of this class are similar, with postural hypotension being the most commonly experienced side effect (Lepor et al., 1992). In comparison to the 5a-reductase inhibitors, the a1-AR blocking agents have a more rapid onset of action (Steers, 1995). However, their therapeutic effect, as measured by improvement in the symptom score and the peak urinary flow rate, is moderate. (Oesterling, 1995) The use of α1-AR antagonists in the treatment of BPH is related to their ability to decrease the tone of prostatic smooth muscle, leading to relief of the obstructive symptoms. Adrenergic receptors are found throughout the body play a dominant role in the control of blood pressure, nasal congestion, prostrate function and other processes (Harrison et al., 1991). However, there are a number of cloned a1-AR receptor subtypes: α1a-AR, α1b-AR and α1d-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 labs have characterized the α1-ARs in human prostate by functional, radioligand binding, and molecular biological techniques (Forray et al., 1994; Hatano et al., 1994; Marshall et al., 1992; Marshall et al., 1995; Yamada et al., 1994). These studies provide evidence in support of the concept that the α1a-AR subtype comprises the majority of α1-ARs in human prostatic smooth muscle and mediates contraction in this tissue. These findings suggest that the development of a subtype-selective α1a-AR antagonist might result in a therapeutically effective agent with reduced side effects for the treatment of BPH. The compounds of this invention selectively bind to the α1a-AR receptor, antagonize the activity of said receptor and are selective for prostate tissue over aortic tissue. As such, these represent a viable treatment for BHP without the side effects associated with known α1-AR antagonists. SUMMARY OF THE INVENTION The invention relates to compounds of Formula I: wherein: R 1 is halogen, C 1-5 alkoxy, hydroxyl or C 1-6 alkyl; R 2 is C 1-6 alkyl, substituted C 1-6 alkyl (where the alkyl substituent is one or more halogens), phenyl, substituted phenyl (where the phenyl substituent is one or more of C 1-5 alkyl, C 1-5 alkoxy and trihaloC 1-5 alkyl), phenylC 1-5 alkyl or substituted phenylC 1-5 alkyl (where the phenyl substituent is one or more of C 1-5 alkyl, halogen, C 1-5 alkoxy and trihaloC 1-5 alkyl); R 3 is hydrogen, C 1-5 alkoxycarbonyl, C 1-5 alkyl, hydroxyC 1-5 alkyl, formyl, acetyl, amido or oxygen where, if R 3 is oxygen, the hashed line is a solid and is taken together with the other solid line to represent a double bond and if R 3 is not oxygen, the hashed line represents a single bond affixed to a hydrogen; A is where the points of attachment are depicted by the hashed bonds, one point of attachment is bonded to the methylene adjacent to the depicted piperazine and the second point of attachment is bonded to the other methylene; R 4 is hydrogen or C 1-5 alkyl; B is hydrogen or oxygen where, if B is oxygen, the hashed line is a solid and is taken together with the other solid line to represent a double bond and if B is hydrogen, the hashed line represents a single bond affixed to a hydrogen; Z is -(CH 2 ) n - where n is 1 to 5 or -CH 2 -CR 5 R 6 -CH 2 - or -CHR 5 R 6 CH- where R 5 and R 6 are hydrogen or C 1-5 alkyl or, taken together, form a C 3-8 cycloalkane or wherein ring X is an aromatic ring of 6 members; or pharmaceutically acceptable salts thereof. The invention further relates to the use of a compound of Formula I: for the manufacture of a medicament for the treatment of a disease mediated by the α-1 a adrenergic receptor; wherein: R 1 is hydrogen, halogen, C 1-5 alkoxy, hydroxyl or C 1-6 alkyl; R 2 is C 1-6 alkyl, substituted C 1-6 alkyl (where the alkyl substituent is one or more halogens), phenyl, substituted phenyl (where the phenyl substituent is one or more of C 1-5 alkyl, C 1-5 alkoxy and trihaloC 1-5 alkyl), phenylC 1-5 alkyl or substituted phenylC 1-5 alkyl (where the phenyl substituent is one or more of C 1-5 alkyl, halogen, C 1-5 alkoxy and trihaloC 1-5 alkyl); R 3 is hydrogen, C 1-5 alkoxycarbonyl, C 1-5 alkyl, hydroxyC 1-5 alkyl, formyl, acetyl, amido or oxygen where, if R 3 is oxygen, the hashed line is a solid and is taken together with the other solid line to represent a double bond and, if R 3 is not oxygen, the hashed line represents a single bond affixed to a hydrogen; A is where the points of attachment are depicted by the hashed bonds, one point of attachment is bonded to the methylene adjacent to the depicted piperazine and the second point of attachment is bonded to the other methylene; R 4 is hydrogen or C 1-5 alkyl; B is hydrogen or oxygen where, if B is oxygen, the hashed line is a solid and is taken together with the other solid line to represent a double bond and, if B is hydrogen, the hashed line represents a single bond affixed to a hydrogen; Z is -(CH 2 ) n - where n is 1 to 5 or -CH 2 -CR 5 R 6 -CH 2 - or -CHR 5 R 6 CH- where R 5 and R 6 are hydrogen or C 1-5 alkyl or, taken together, form a C 3-8 cycloalkane or wherein ring X is an aromatic ring of 6 members; or pharmaceutically acceptable salts thereof. Aside from the compounds of Formula I, the invention contemplates compounds of Formula III. These compounds are useful as intermediates in the preparation of compounds of Formula I and are as follows: wherein: R 1 is hydrogen, halogen, C 1-5 alkoxy, hydroxyl, or C 1-6 alkyl; R 2 is C 1-6 alkyl, substituted C 1-6 alkyl (where the alkyl substituent is one or more halogens), phenyl, substituted phenyl (where the phenyl substituent is one or more of C 1-5 alkyl, C 1-5 alkoxy and trihaloC 1-5 alkyl), phenylC 1-5 alkyl or substituted phenylC 1-5 alkyl (where the phenyl substituent is one or more of C 1-5 alkyl, halogen, C 1-5 alkoxy and trihaloC 1-5 alkyl); R 7 is formyl, halomethyl, hydroxymethyl, t-butyldiphenylsilyloxymethyl, C 1-6 alkoxycarbonyl or carboxy; and Q is where the points of attachment are depicted by the hashed bonds, one point of attachment is bonded to the methylene adjacent to the depicted piperazine and the second point of attachment is bonded to R 7 . DETAILED DESCRIPTION OF THE INVENTION The terms used in describing the invention are commonly used and known to those skilled in the art. However, the terms that could have other meanings are defined. "HBSS" refers to Hank's Balanced Salt Solution. "Independently" means that when there are more than one substituent, the substitutents may be different. The term "alkyl" refers to straight, cyclic and branched-chain alkyl groups and "alkoxy" refers O-alkyl where alkyl is as defined supra. "LDA" refers to lithium diiopropylamide, and "LAH" refers to lithium aluminum hydride. The symbol "Ph" refers to phenyl, and "aryl" includes mono and fused aromatic rings such as phenyl and naphthyl. The symbol "CPDA" refers to 1,1-cyclopentanediacetimid -1-yl and "IID" refers to 1H-isoindole 1,3(2H)dion-1-yl. The compounds of the invention may be prepared by the following schemes, where some schemes produce more than one embodiment of the invention. In those cases, the choice of scheme is a matter of discretion which is within the capabilities of those skilled in the art. To prepare compounds where A is thiophene, Scheme 5 may be used. Reagent 5a, 2-bromo-5-thiophenecarboxaldehyde, may be treated with an analogue of 1a, NaBH(OAc) 3 and acetic acid in an inert solvent such as methylene chloride at room temperature for about 3-10 h to give the coupled product 5b. Treatment of 5b with a strong base such as n -butyllithium and DMF at -78 °C to 0 °C gives the aldehyde 5c. This intermediate may be treated with a reducing agent such as NaBH 4 to give the alcohol 5d. This alcohol is treated with thionyl chloride in an inert solvent such as methylene chloride at room temperature for about 6 h; and is subsequently treated with a cyclic lactam and a strong base such a NaH in an inert solvent such as DMF at room temperature to give a compound of Formula I. Although the illustrated product of Scheme 5 is a 2,5-substituted thiophene, the scheme may be used to produce 2,4-substitutied thiophenes. The 2,4-substituted compounds may be produced by substituting 2-bromo-4-thiophenecarboxaldehyde, for the illustrated reagent 5a. In addition this scheme may be used to prepare all of the R 1 , R 2 , R 3 , B and Z substitutions of the invention as discussed in previous schemes. The products of Scheme 5 may be used to prepare other compounds as illustrated by Scheme 6. To produce compounds of the invention where B is hydrogen, A is thiophene, R 2 is phenyl, R 3 is carboethoxy, and Z is (CH 2 ) 3 the 2-phenoxy analog of intermediate 5c may be treated with NaBH(OAc) 3 , triethyl amine and reactant 6a, 2-piperidinecarboxylic acid ethyl ester hydrochloride, at room temperature over 4-12 h to give the desired ester derivative of Formula I Aside from the illustrated ester derivative, Scheme 5 may be used to prepare the hydroxymethyl derivative by treating the ester with NaBH 4 and an inert solvent, such as methanol, at room temperature over 30 min. This hydroxymethyl derivative could be oxidized under standard Swern conditions to give the corresponding aldehyde. To prepare compounds of the invention where B is oxygen, A is thiophene, R 2 is phenyl, R 3 is carboethoxy and Z is (CH 2 ) 4 Scheme 8 may be used. Treatment of 3-thiophenemethanol with a silylating agent such as t -butyldiphenylchlorosilane and imidazole at room temperature in an inert solvent such as DMF over 10-48 h gives intermediate 8a. This intermediate may be formylated with DMF and a strong base such as t -butyllithium at about -78 °C over 30 min to 2 h to give the aldehyde 8b. Reductive amination of the aldehyde with intermediate 1a , NaBH(OAc) 3 and glacial acetic acid at room temperature over 3-6 h gives the coupled intermediate 8c. This intermediate may be deprotected with tetrabutylammonium fluoride in THF at room temperature to give alcohol 8d. This alcohol may be chlorinated with thionyl chloride and an inert solvent such as methylene chloride at room temperature for 1-10 h and subsequently coupled with reagent 8e. A strong base such as NaH and a suitable solvent such as DMF facilitate this reaction which proceeds at room temperature over 10-24 h to give the desired compound of Formula 1. In addition to the illustrated product, Scheme 8 may be used to produce compounds of the invention where B is hydrogen. Replacement of reagent 8e with another cyclic lactam such as proline methyl ester gives a compound of the invention where B is hydrogen, A is thiophene, R 2 is phenyl, R 3 is carboethoxy and Z is (CH 2 ) 2 . Compounds where B is hydrogen and R 3 is hydrogen may also be prepared in this manner by this scheme. Replacement of 8d with proline gives a compound of the invention where B is hydrogen, A is thiophene, R 2 is phenyl, R 3 is hydrogen and Z is (CH 2 ) 2 . Aside from the aforementioned products, Scheme 8 may be used to prepare all of the R 1 , R 2 R 3 , B and Z substitutions of the invention as discussed in previous schemes. As indicated by the biological activity, the compounds of Formula I may be used in pharmaceutical compositions to treat patients (humans and other primates) with disorders related to inhibiting the activity of the α1a adrenergic receptor. The preferred route is oral administration, however compounds may be administered by intravenous infusion. Oral doses range from about 1-100 mg/kg daily. Infusion doses can range from about 0.01-1 mg/kg/min of inhibitor, admixed with a pharmaceutical carrier over a period ranging from several minutes to several days. The pharmaceutical compositions can be prepared using conventional pharmaceutical excipients and compounding techniques. Oral dosage forms may be elixers, syrups, capsules tablets and the like. Where the typical solid carrier is an inert substance such as lactose, starch, glucose, methyl cellulose, magnesium sterate, dicalcium phosphate, mannitol and the like; and typical liquid oral excipients include ethanol, glycerol, water and the like. All excipients may be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known to those skilled in the art of preparing dosage forms. Parenteral dosage forms may be prepared using water or another sterile carrier. Typically the compounds of Formula I are isolated and used as free bases, however the compounds may be isolated and used as their pharmaceutically acceptable salts. Examples of such salts include hydrobromic, hydroiodic, hydrochloric, perchloric, sulfuric, maleic, fumaric, malic, tartatic, citric, benzoic, mandelic, methanesulfonic, hydroethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic and saccharic. In order to illustrate the invention the following examples are included. These examples do not limit the invention. They are meant only to suggest a method of practicing the invention. Those skilled in the art may find other methods of practicing the invention, which are obvious to them. However those methods are deemed to be within the scope of this invention. PREPARATIVE EXAMPLES Example 20 Glacial AcOH (1.8 mL, 31.4 mmol) and NaBH(OAc) 3 (8.65 g, 40.8 mmol) were successively added to a stirred solution of 1-(2-methoxyphenyl)piperazine (6.4 g, 31.4 mmol) and 5-bromo-2-thiophenecarboxaldehyde (6.0 g, 31.4 mmol) in CH 2 Cl 2 at room temperature. The mixture was stirred for 4 h and partitioned between ether and satd. Na 2 CO 3 . This mixture was extracted with several portions of ether and the combined organic extracts were washed with brine, dried (Na 2 SO 4 ), and concentrated. The residue was flushed through a short silica gel plug eluting with EtOAc to obtain compound 20: 1 HNMR (300 MHz, CDCl 3 ) δ (ppm) 6.84 - 7.03 (m, 5H), 6.68 (d, J = 3.6 Hz, 1H), 3.85 (s, 3H), 3.71 (s, 2H), 3.09 (bs, 4H), 2.69 (bs, 4H); MS m/z 367 (MM + ) and 369 (MH + ). Example 21 1.7M t -Butyllithium (7.9 mL, 13.4 mmol) was added to a solution of compound 20 (4.1 g, 11.2 mmol) in THF at -78 °C. DMF (2.0 mL, 25.8 mmol) was added after 1 h and the resulting mixture was stirred for another 6 h at -78 °C. The reaction mixture was warmed to 0 °C, quenched by addition of satd. NH 4 Cl and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na 2 SO 4 ), and concentrated in vacuo . The material was flushed through a short silica gel plug and eluted with EtOAc to afford compound 21: 1 HNMR (300 MHz, CDCl 3 ) δ (ppm) 9.85 (s, 1h), 7.64 (d, J = 3.7 Hz, 1H), 7.06 (d, J = 3.7 Hz, 1H), 6.84 - 7.01 (m, 4H), 3.85 (s, 3H), 3.81 (s, 2H), 3.11 (bs, 4H), 2.73 (t, J = 4.5 Hz, 4H); MS m/z 317 (MH + ). Example 22 NaBH 4 (1.26 g, 34.1 mmol) was added portionwise to a solution of the above compound 21 (3.6 g, 11.4 mmol) in MeOH at ambient temperature. The solvent was removed after 0.5 h and sat'd. NH 4 Cl was added to the residue. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with brine, dried (Na 2 SO 4 ), and concentrated in vacuo. The residue was was purified by flash chromatography on silica gel using ethyl acetate/hexanes (20 - 30 % EtOAc in hexanes) as an eluent to give compound 21: 1 HNMR (300 MHz, CDCl 3 ) δ (ppm) 6.79 - 7.02 (m, 6H), 4.77 (s, 2H), 3.85 (s, 3H), 3.75 (s, 2H), 3.09 (bs, 4H), 2.70 (bs, 4H), 1.99 (bs, 1H); MS m/z 319 (MH + ). Example 23 SOCl 2 (3.0 mL, excess) was added to compound 22 (0.182 g, 0.57 mmol) in CH 2 Cl 2 (5.0 mL). The reaction was stirred for 6 h and concentrated in vacuo to give the crude chloro derivative. In a separate flask pyrrolidinone (0.098 g, 1.16 mmol) was added slowly to a suspension of NaH (0.055 g, 2.3 mmol) in DMF. After 0.5 h a solution of the chloro derivative in DMF (1.0 mL) was injected dropwise to the later. The resulting mixture was stirred for 18 h, quenched by the addition of sat'd. NH 4 Cl and extracted with EtOAc. The combined extracts were successively washed with water and brine, dried (Na 2 SO 4 ), and concentrated in vacuo . The residue was purified by column chromotography on silica gel chromatography using EtOAc/hexanes (10-25%) to give compound 23 1 HNMR (300 MHz, CDCl 3 ) δ (ppm) 6.77 - 7.00 (m, 6H), 4.57 (s, 2H), 3.85 (s, 3H), 3.74 (s, 2H), 3.37 (t, J = 7.0 Hz, 2H), 3.10 (bs, 4H), 2.69 (bs, 4H), 2.42 (t, J = 8.1 Hz, 2H), 2.01 (quin, J = 7.5 Hz, 2H); MS m/z 386 (MH + ). Example 24 Et 3 N (1.05 mL, 7.5 mmol) and NaBH(OAc) 3 (1.73g, 8.2 mmol) were successively added to a stirred solution of compound 21 (2.0 g, 6.3 mmol) and L-proline methyl ester hydrochloride (1.04 g, 6.3 mmol) in CH 2 Cl 2 at room temperature. After 6 h the reaction mixture was quenched with sat'd. Na 2 CO 3 , and extracted with CH 2 Cl 2 . The combined organic extracts were washed with brine, dried (Na 2 SO 4 ), and concentrated. The residue was purified by flash chromotography on silica gel using EtOAc/hexanes [10-20 %]to give compound 24: 1 H NMR (300 MHz, CDCl 3 ) δ (ppm) 6.78 - 7.02 (m, 4H), 6.76 (d, J = 3.4 Hz, 1H), 6.74 (d, J = 3.4 Hz, 1H), 4.03 (d, J = 14.0 Hz, 1H), 3.86 (d, J = 14.0 Hz, 1H), 3.85 (s, 3H), 3.74 (s, 2H), 3.70 (s, 3H), 3.33 (dd, J = 5.8 Hz, 8.7 Hz, 1H), 3.10 (bm, 5H), 2.70 (bs, 4H), 2.55 (dd, J = 6.5 Hz, 8.0 Hz, 1H), 1.61 - 2.18 (m, 4H); MS m/z 430 (MH + ). Example 29 t -Butyldiphenylchlorosilane (11.3 mL, 43.3 mmol) was added to a stirred solution of 3-thiophenemethanol (4.5 g, 39.4 mmol) and imidazole (5.9 g, 86.7 mmol) in DMF at room temperature. After 24 h the reaction mixture was quenched with brine and worked up using EtOAc. The combined organic extracts were washed with brine, dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified on a silica gel pad, eluting with ether and concentrating in vacuo to give the compound 29: 1 HNMR (300 MHz, CDCl 3 ) δ (ppm) 7.69 (m, 4H), 7.34 - 7.43 (m, 6H), 7.27 (dd, J = 1.7 Hz, 3.1 Hz, 1H), 7.15 (dd, J = 1.4 Hz, 2.6 Hz, 1H), 6.99 (dd, J = 1.0 Hz, 3.6 Hz, 1H), 4.76 (s, 2H), 1.08 (s, 9H). Example 30 t-Butyllithium (1.7 M; 0.84 mL, 1.4 mmol) was added to a solution of 3-(t-butyldiphenylsilyloxymethyl)thiophene (0.42 g, 1.2 mmol) in THF at -78 °C. DMF (0.23 mL, 3.0 mmol) was added after 1 h and stirring continued for another 6 h at -78 °C. The mixture was allowed to warm to 0 °C, quenched by addition of sat'd. NH 4 Cl and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na 2 SO 4 ), and concentrated. Although the 1 HNMR of the crude residue showed compound 30 as the predominant product along with a trace of an unidentified material, the residue was used without further purification: 1 HNMR (300 MHz, CDCl 3 ) δ (ppm) 9.87 (s, 1H), 7.67 (dd, J = 1.4 Hz, 6.0 Hz, 4H), 7.61 (d, J = 0.8 Hz, 1H) 7.55 (bs, 1H), 7.36 - 7.44 (m, 6H), 4.74 (s, 2H), 1.09 (s, 9H):MS m/z 381 (MH + ). Example 31 Glacial AcOH (0.55 mL, 10.0 mmol) and NaBH(OAc) 3 (2.76 g, 13.0 mmol) were successively added to a stirred solution of 1-(2-isopropoxyphenyl)piperazine (2.2 g, 10.0 mmol) and compound 30 (3.8 g, 10.0 mmol) in CH 2 Cl 2 at room temperature. After 4 h the reaction mixture was quenched by slow addition of sat'd. Na 2 CO 3 and extracted with CH 2 Cl 2 . The combined organic extracts were washed with brine, dried (Ma 2 SO 4 ), and concentrated. The material was flushed through a short silica gel plug eluting with EtOAc to compound 31: 1 HNMR (300 MHz, CDCl 3 ) δ (ppm) 7.68 (d, J = 7.4 Hz, 4H), 7.35 - 7.44 (m, 6H), 7.06 (bs, 1H), 6.84 - 6.94 (m, 4H), 6.81 (bs, 1H), 4.70 (s, 2H), 4.59 (sept, J = 6.0 Hz, 1H), 3.72 (s, 2H), 3.13 (bs, 4H), 2.66 (bs, 4H), 1.33 (d, J = 6.0 Hz, 6H), 1.08 (s, 9H); MS m/z 585 (MH + ). Example 32 TBAF ( 1.0 M in THF; 11.7 mL, 11.7 mmol) was added to a solution of compound 31 (5.7 g, 9.8 mmol) in THF and the resulting mixture was stirred overnight. Brine was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na 2 SO 4 ), and concentrated. The residue was purified by flash chromatography on silica gel using 5-20% EtOAc/ hexanes as an eluent, to give the corresponding alcohol: 1 HNMR (300 MHz, CDCl 3 ) δ (ppm) 7.12 (s, 1H), 6.84 - 6.95 (m, 5H), 4.63 (s, 2H), 4.59 (sept, J = 6.2 Hz, 1H), 3.74 (s, 2H), 3.12 (bs, 4H), 2.67 (bs, 4H), 1.71 (bs, 1H), 1.34 (d, J = 6.2 Hz, 6H); MS m/z 347 (MH + ). SOCl 2 (3.0 mL, excess) was added to the alcohol (0.2 g, 0.57 mmol) in CH 2 Cl 2 (5.0 mL). The reaction was stirred for 6 h then concentrated in a rotary evaporator and dried in vacuo to obtain the crude foamy chloro derivative, which was used immediately without purification. Pyrrolidinone (0.098 g, 1.16 mmol) was added slowly to a suspension of NaH (0.055 g, 2.3 mmol) in DMF. After 0.5 h, a solution of the chloro derivative in DMF (1.0 mL) was injected to the reaction mixture and the reaction was stirred for 18 h. Sat'd. NH 4 Cl was added and the mixture was extracted with several portions of EtOAc. The combined extracts were successively washed with water and brine, dried (Na 2 SO 4 ), and concentrated. The product was purified by column chromatography on silica gel using 10-25% EtOAc/hexanes as an eluent to afforded compound 32: 1 HNMR (300 MHz, CDCl 3 ) δ (ppm) 7.02 (bs, 1H), 6.84 - 6.91 (m, 4H), 6.84 (bs, 1H), 4.59 (sept, J = 6.0 Hz, 1H), 4.39 (s, 2H), 3.72 (s, 2H), 3.31 (t, J = 7.0 Hz, 2H), 3.12 (bs, 4H), 2.65 (bs, 4H), 2.43 (t, J = 8.0 Hz, 2H), 2.00 (quin, J = 7.5 Hz, 2H), 1.34 (d, J = 6.0 Hz, 6H); MS m/z 414 (MH + ). BIOLOGICAL EXAMPLES Biological activity and selectivity of compounds of the invention was demonstrated by the following in vitro assays. The first assay tested the ability of compounds of Formula I to bind to membrane bound receptors α1 a -AR, α1 b -AR and α1 d -AR. Example 38 The DNA sequences of the three cloned human α1-AR subtypes have been published. Furthermore, the cloned cDNAs have been expressed both transiently in COS cells and stably in a variety of mammalian cell lines (HeLa, LM(tk-), CHO, rat -1 fibroblast) and have been shown to retain radioligand binding activity and the ability to couple to phosphoinositide hydrolysis. We used published DNA sequence information to design primers for use in RT-PCR amplification of each subtype to obtain cloned cDNAs. Human poly A+ RNA was obtained from commercially available sources and included hippocampus and prostate samples, sources which have been cited in the literature. For the primary screen a radio ligand binding assay was used which employed membrane preparations from cells expressing the individual cloned receptor cDNAs. Radiolabeled ligands with binding activity on all three subtypes (non-selective) are commercially available ([125I]-HEAT, [3H]-prazosin). Each α1 receptor subtype was cloned from poly A+ RNA by the standard method of reverse transcription-polymerase chain reaction (RT-PCR). The following sources of polyA+ RNA were used for the cloning of the α1 receptor subtypes: α1 a -AR, human hippocampus and prostate, α1 b -AR, human hippocampus, α1 d -AR, human hippocampus. The resulting cDNAs were cloned into the pcDNA3 mammalian expression vector (Invitrogen Corp., San Diego CA). Each DNA was sequenced for verification and to detect any possible mutations introduced during the amplification process. Any deviation in sequence from the published consensus for each receptor subtype was corrected by site-directed mutagenesis. The three α1-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 dish (100mm) was inoculated with 3.5 x 10 6 cells and transfected with 10 µg of DNA. Approximately 72 hours post-transfection, the cells were harvested and COS membranes were prepared. Transfected COS cells from 25 plates (100mm) were scraped and suspended in 15mL of TE buffer (50mM Tris-HCl, 5mM EDTA, pH7.4). The suspension was disrupted with a homogenizer. It was then 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 5mL TNE buffer (50mM Tris-HCl, 5mM EDTA, 150mM NaCl, pH7.4). The resulting membrane preparation was aliquoted and stored at -70°C. The protein concentration was determined following membrane solubilization with TritonX-100. The ability of each compound to bind to each of the α1-AR subtypes was assessed in a receptor binding assay. [125I]-HEAT, a non-selective α1-AR ligand, was used as the radiolabeled ligand. Each well of a 96-well plate received: 140 µL TNE, 25 µL [125I]-HEAT diluted in TNE (50,000 cpm; final concentration 50 pM), 10 µL test compound diluted in DMSO (final concentration 1 pM-10 µM), 25 mL COS cell membrane preparation expressing one of the three α1-AR subtypes (0.05-0.2 mg membrane protein). The plate was incubated for 1 hour at 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. Data was analyzed using GraphPad Prism software. Tables A -J list the IC 50 values expressed in nanomolar concentration for select compounds of the invention in all receptor subtypes. Cpd# R 1 R 2 R 3 B Z α1a α1b α1d Scheme 23 H CH 3 H O (CH 2 ) 2 80 >10000 46 5 24 H CH 3 CO 2 Et H (CH 2 ) 2 23 1188 30 6 48 H CH 3 H O (CH 2 ) 3 29 >10000 26 5 49 H CH 3 H O (CH 2 ) 4 37 >10000 24 5 50 H CH 3 CH 2 OH H (CH 2 ) 3 838 >5139 261 6 Cpd# R 1 R 2 R 3 B Z α1a α1b α1d Scheme 32 H i -propyl H O (CH 2 ) 2 0.83 620 24 8 55 H i -propyl H O (CH 2 ) 3 1.0 768 185 8 56 H i -propyl H O (CH 2 ) 4 3.7 1230 95 8 REFERENCES Breslin D, Fields DW, Chou T-C, Marion DN, Kane M, Vaughan ED, and Felsen D (1993) Medical management of benign prostatic hyperplasia: a canine model comparing the in vivo efficacy of alpha-1 adrenergic antagonists in the prostate. J. Urol. 149: 395-399. Bruno JF, Whittaker J, Song J, and Berelowitz M. (1991) Molecular cloning and sequencing of a cDNA encoding a human α1A adrenergic receptor. Biochem. Biophys. Res. Commun. 179: 1485-1490. Bylund DB, Eikenberg DC, Hieble JP, Langer SZ, Lefkowitz RJ, Minneman KP, Molinoff PB, Ruffolo RR, and Trendelenburg U (1994) IV. 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Claims: A compound of Formula I wherein: R 1 is halogen, C 1-5 alkoxy, hydroxyl or C 1-6 alkyl; R 2 is C 1-6 alkyl, substituted C 1-6 alkyl (where the alkyl substituent is one or more halogens), phenyl, substituted phenyl (where the phenyl substituent is one or more of C 1-5 alkyl, C 1-5 alkoxy and trihaloC 1-5 alkyl), phenylC 1-5 alkyl or substituted phenylC 1-5 alkyl (where the phenyl substituent is one or more of C 1-5 alkyl, halogen, C 1-5 alkoxy and trihaloC 1-5 alkyl); R 3 is hydrogen, C 1-5 alkoxycarbonyl, C 1-5 alkyl, hydroxyC 1-5 alkyl, formyl, acetyl, amido or oxygen where, if R 3 is oxygen, the hashed line is a solid and is taken together with the other solid line to represent a double bond and, if R 3 is not oxygen, the hashed line represents a single bond affixed to a hydrogen; A is where the points of attachment are depicted by the hashed bonds, one point of attachment is bonded to the methylene adjacent to the depicted piperazine and the second point of attachment is bonded to the other methylene; R 4 is hydrogen or C 1-5 alkyl; B is hydrogen or oxygen where, if B is oxygen, the hashed line is a solid and is taken together with the other solid line to represent a double bond and, if B is hydrogen, the hashed line represents a single bond affixed to a hydrogen; Z is -(CH 2 ) n - where n is 1 to 5 or -CH 2 -CR 5 R 6 -CH 2 - or -CHR 5 R 6 CH- where R 5 and R 6 are hydrogen or C 1-5 alkyl or, taken together, form a C 3-8 cycloalkane or wherein ring X is an aromatic ring of 6 members; or pharmaceutically acceptable salts thereof. The compounds of claim 1 where R 1 is C 1-6 alkyl, z is (CH 2 ) n , n is 1-4, and A is Any one of the following compounds or or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising an effective dose of a compound according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier or diluent. The composition of claim 4, wherein the effective dose is from 0.01 to 100 mg/kg daily, preferably 0.05 to 1.0 mg/kg daily. The compound of any one of claims 1 to 5 or the composition of claim 4 or claim 5 for use in treating a patient afflicted with a disease, such as benign prostatic hyperplasia, mediated by the α-1 a adrenergic receptor. The use of a compound of Formula I for the manufacture of a medicament for the treatment of a disease mediated by the α-1 a adrenergic receptor; wherein: R 1 is hydrogen, halogen, C 1-5 alkoxy, hydroxyl or C 1-6 alkyl; R 2 is C 1-6 alkyl, substituted C 1-6 alkyl (where the alkyl substituent is one or more halogens), phenyl, substituted phenyl (where the phenyl substituent is one or more of C 1-5 alkyl, C 1-5 alkoxy and trihaloC 1-5 alkyl), phenylC 1-5 alkyl or substituted phenylC 1-5 alkyl (where the phenyl substituent is one or more of C 1-5 alkyl, halogen, C 1-5 alkoxy and trihaloC 1-5 alkyl); R 3 is hydrogen, C 1-5 alkoxycarbonyl, C 1-5 alkyl, hydroxyC 1-5 alkyl, formyl, acetyl, amido or oxygen where, if R 3 is oxygen, the hashed line is a solid and is taken together with the other solid line to represent a double bond and, if R 3 is not oxygen, the hashed line represents a single bond affixed to a hydrogen; A is where the points of attachment are depicted by the hashed bonds, one point of attachment is bonded to the methylene adjacent to the depicted piperazine and the second point of attachment is bonded to the other methylene; R 4 is hydrogen or C 1-5 alkyl; B is hydrogen or oxygen where, if B is oxygen, the hashed line is a solid and is taken together with the other solid line to represent a double bond and, if B is hydrogen, the hashed line represents a single bond affixed to a hydrogen; Z is -(CH 2 ) n - where n is 1 to 5 or -CH 2 -CR 5 R 6 -CH 2 - or -CHR 5 R 6 CH- where R 5 and R 6 are hydrogen or C 1-5 alkyl or, taken together, form a C 3-8 cycloalkane or wherein ring X is an aromatic ring of 6 members; or pharmaceutically acceptable salts thereof. The use of claim 7 where R 1 is hydrogen or C 1-6 alkyl, z is (CH 2 ) n , n is 1-4 1 , and A is The use of claim 7 or claim 9 wherein the disease is benign prostatic hyperplasia. A compound of Formula III wherein: R 1 is hydrogen, halogen, C 1-5 alkoxy, hydroxyl, or C 1-6 alkyl; R 2 is C 1-6 alkyl, substituted C 1-6 alkyl (where the alkyl substituent is one or more halogens), phenyl, substituted phenyl (where the phenyl substituent is one or more of C 1-5 alkyl, C 1-5 alkoxy and trihaloC 1-5 alkyl), phenylC 1-5 alkyl or substituted phenylC 1-5 alkyl (where the phenyl substituent is one or more of C 1-5 alkyl, halogen, C 1-5 alkoxy and trihaloC 1-5 alkyl); R 7 is formyl, halomethyl, hydroxymethyl, t-butyldiphenylsilyloxymethyl, C 1-6 alkoxycarbonyl or carboxy; and Q is where the points of attachment are depicted by the hashed bonds, one point of attachment is bonded to the methylene adjacent to the depicted piperazine and the second point of attachment is bonded to R 7 . The compound of claim 10 where R 1 is hydrogen or C 1-6 alkyl, R 2 is C 1-6 alkyl, phenyl, or substituted phenyl (where the phenyl substituent is one or more of C 1-5 alkyl, C 1-5 alkoxy and trihaloC 1-5 alkyl).

Inventors: HUTCHINGS RICHARD H, KHATUYA HARIPADA, KUO GEE-HONG, LI XIAOBING, MARYANOFF CYNTHIA, MURRAY WILLIAM V, PROUTY CATHERINE, VILLANI FRANK, YIM NELSON C F, HUTCHINGS, RICHARD H., KHATUYA, HARIPADA, KUO, GEE-HONG, LI, XIAOBING, MARYANOFF, CYNTHIA, MURRAY, WILLIAM V., PROUTY, CATHERINE, VILLANI, FRANK, YIM, NELSON C.F.
Applicants: ORTHO MCNEIL PHARM INC, ORTHO-MCNEIL PHARMACEUTICAL, INC.
Application year: 1998
Main classification: C07D211
IPC codes: C07D409, C07D333, C07D263, C07D277, C07D213, C07D295, C07D211, C07D401, C07D413, C07D417, C07D261