US20020077476A1 - Novel phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia - Google Patents

Novel phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia Download PDF

Info

Publication number
US20020077476A1
US20020077476A1 US10/014,979 US1497901A US2002077476A1 US 20020077476 A1 US20020077476 A1 US 20020077476A1 US 1497901 A US1497901 A US 1497901A US 2002077476 A1 US2002077476 A1 US 2002077476A1
Authority
US
United States
Prior art keywords
alkyl
phenyl
hydrogen
alkoxy
halogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/014,979
Other languages
English (en)
Inventor
Gee-Hong Kuo
William Murray
Catherine Prouty
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US09/489,744 external-priority patent/US6362338B1/en
Application filed by Individual filed Critical Individual
Priority to US10/014,979 priority Critical patent/US20020077476A1/en
Publication of US20020077476A1 publication Critical patent/US20020077476A1/en
Priority to US10/207,473 priority patent/US6780994B2/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/08Drugs for disorders of the urinary system of the prostate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/10Drugs for disorders of the urinary system of the bladder
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/24Drugs for disorders of the endocrine system of the sex hormones
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to a series of phthalimido arylpiperazine derivatives, pharmaceutical compositions containing them as well as processes and intermediates used in their manufacture.
  • the compounds of the invention selectively inhibit binding to the ⁇ 1 a 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.
  • 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.
  • 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 ( ⁇ 1-ARs).
  • ⁇ 1-ARs alpha 1 adrenergic receptors
  • 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 preferred 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).
  • finasteride is a potent 5 ⁇ -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).
  • ⁇ 1-AR blockers adrenergic receptor blocking agents
  • terazosin, prazosin, and doxazosin adrenergic receptor blocking agents
  • doxazosin adrenergic receptor blocking agents
  • the ⁇ 1-AR blocking agents In comparison to the 5 ⁇ -reductase inhibitors, the ⁇ 1-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).
  • ⁇ 1-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).
  • ⁇ 1-AR receptor subtypes ⁇ 1 a -AR, ⁇ 1 b -AR and ⁇ 1 d -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).
  • the compounds of this invention selectively bind to the ⁇ 1 a -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 ⁇ 1-AR antagonists.
  • the invention includes compounds of Formula I
  • R 1 is hydrogen, halogen, C 1-5 alkoxy, hydroxyl, or C 1-5 alkyl;
  • R 2 is C 1-6 alkyl, substituted C 1-6 alkyl
  • alkyl substituents are independently selected from one or more halogens
  • phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, C 1-5 alkoxy, and trihaloC 1-5 alkyl,
  • phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and trihaloC 1-5 alkyl;
  • R 3 is hydrogen, hydroxy or C 1-5 alkoxy if the hashed line is absent or is oxygen if the hashed line is present;
  • R 4 is hydrogen, C 1-5 alkyl, phenylC 1-5 alkyl or substituted phenylC 1-5 -alkyl
  • phenyl substitutents are independently selected from one or more members of the group consisting of C 1-5 alkyl, C 1-5 alkoxy, and trihaloC 1-5 alkyl;
  • R 5 is hydrogen, halogen, hydroxy, C 1-8 alkyl, substituted C 1-8 alkyl
  • alkyl substitutents are independently selected from one or more halogens
  • R 6 is hydrogen, halogen, hydroxy, C 1-8 alkyl, substituted C 1-8 alkyl
  • alkyl substitutents are independently selected from one or more halogens
  • R 7 is hydrogen, halogen, hydroxy, C 1-8 alkyl, substituted C 1-8 alkyl
  • alkyl substitutents are independently selected from one or more halogens
  • A is nitrogen or carbon
  • B is nitrogen or carbon
  • E is nitrogen or carbon
  • this invention contemplates pharmaceutical compositions containing an effective dose of compounds of Formula I. Still further this invention contemplates methods of treating diseases associated with the ⁇ 1 a adrenergic receptor consisting of administering an effective dose of a compound of Formula I to a mammal. This invention also contemplates a method of treating benign prostatic hyperplasia consisting of administering an effective dose of a compound of Formula I to a mammal.
  • R 8 is hydrogen, halogen, C 1-5 alkoxy, hydroxyl, or C 1-5 alkyl;
  • R 9 is C 1-6 alkyl, substituted C 1-6 alkyl
  • alkyl substituents are independently selected from one or more halogens
  • phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, C 1-5 alkoxy, and trihaloC 1-5 alkyl,
  • phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and trihaloC 1-5 alkyl;
  • R 10 is hydrogen, C 1-5 alkoxycarbonyl, phenylC 1-5 alkoxycarbonyl or allyloxycarbonyl;
  • R 11 is hydrogen, phenylC 1-5 alkyl, or substituted phenylC 1-5 alkyl
  • phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and nitro;
  • R 10 is C 1-5 alkoxycarbonyl, phenylC 1-5 alkoxycarbonyl, or allyloxycarbonyl;
  • R 1 is phenylC 1-5 alkyl, or substituted phenylC 1-5 alkyl
  • phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and nitro;
  • R 12 is halogen, mesyl, tosyl, or hydroxy.
  • R 10 is C 1-5 alkoxycarbonyl, phenylC 1-5 alkoxycarbonyl, or allyloxycarbonyl;
  • R 11 is phenylC 1-5 alkyl, or substituted phenylC 1-5 alkyl
  • phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and nitro;
  • R 12 is halogen, mesyl, tosyl, or hydroxy, with a piperazine derivative of Formula IV
  • R 8 is hydrogen, halogen, C 1-5 alkoxy, hydroxyl, or C 1-5 alkyl;
  • R 9 is C 1-6 alkyl, substituted C 1-6 alkyl
  • alkyl substituents are independently selected from one or more halogens
  • phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and trihaloC 1-5 alkyl;
  • R 8 is hydrogen, halogen, C 1-5 alkoxy, hydroxyl, or C 1-5 alkyl;
  • R 9 is C 1-6 alkyl, substituted C 1-6 alkyl
  • alkyl substituents are independently selected from one or more halogens
  • phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, C 1-5 alkoxy, and trihaloC 1-5 alkyl,
  • phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and trihaloC 1-5 alkyl;
  • R 10 is C 1-5 alkoxycarbonyl, phenylC 1-5 alkoxycarbonyl, or allyloxycarbonyl;
  • R 11 is phenylC 1-5 alkyl, or substituted phenylC 1-5 alkyl
  • phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and nitro;
  • R 8 is hydrogen, halogen, C 1-5 alkoxy, hydroxyl, or C 1-5 alkyl;
  • R 9 is C 1-6 alkyl, substituted C 1-6 alkyl
  • alkyl substituents are independently selected from one or more halogens
  • phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, C 1-5 alkoxy, and trihaloC 1-5 alkyl,
  • phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and trihaloC 1-5 alkyl;
  • R 10 is C 1-5 alkoxycarbonyl, phenylC 1-5 alkoxycarbonyl, or allyloxycarbonyl;
  • R 11 is phenylC 1-5 alkyl, or substituted phenylC 1-5 alkyl
  • phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and nitro;
  • R 8 is hydrogen, halogen, C 1-5 alkoxy, hydroxyl, or C 1-5 alkyl;
  • R 9 is C 1-6 alkyl, substituted C 1-6 alkyl
  • alkyl substituents are independently selected from one or more halogens
  • phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, C 1-5 alkoxy, and trihaloC 1-5 alkyl,
  • phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and trihaloC 1-5 alkyl;
  • R 10 is hydrogen
  • R 11 is phenylC 1-5 alkyl, or substituted phenylCalkyl
  • phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and nitro;
  • R 8 is hydrogen, halogen, C 1-5 alkoxy, hydroxyl, or C 1-5 alkyl;
  • R 9 is C 1-5 alkyl, substituted C 1-6 alkyl
  • alkyl substituents are independently selected from one or more halogens
  • phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, C 1-5 alkoxy, and trihaloC 1-5 alkyl,
  • phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and trihaloC 1-5 alkyl;
  • R 10 is hydrogen
  • R 11 is phenylC 1-5 alkyl, or substituted phenylC 1-5 alkyl
  • phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and nitro;
  • R 8 is hydrogen, halogen, C 1-5 alkoxy, hydroxyl, or C 1-5 alkyl;
  • R 9 is C 1-6 alkyl, substituted C 1-6 alkyl
  • alkyl substituents are independently selected from one or more halogens
  • phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, C 1-5 alkoxy, and trihaloC 1-5 alkyl,
  • phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, C 1-5 alkoxy, and trihaloC 1-5 alkyl;
  • R 10 is hydrogen
  • R 11 is hydrogen
  • HBSS Hank's Balanced Salt Solution. “Independently” means that when there are more than one substituent, the substitutents may be different.
  • alkyl refers to straight, cyclic and branched-chain alkyl groups and “alkoxy” refers 0-alkyl where alkyl is as defined supra.
  • DMAP dimethylaminopyridine
  • TFA trifluoroacetic acid
  • HOBT hydroxybenzotriazole hydrate
  • HATU O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetrametyluronium hexafluorophosphate
  • EDCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • Ph refers to phenyl
  • aryl includes mono and fused aromatic rings such as phenyl and naphthyl.
  • CPDA 1,1-cyclopentanediacetimid-1-yl
  • IID 1H-isoindole 1,3-(2H)dion-1-yl
  • ES electrospray
  • MS mass spectrum
  • 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 synthetic chemists.
  • a compound of Formula I where A, B, and E are carbon, R 1 is hydrogen, R 2 is phenyl, R 3 is hydroxy, R 4 is hydrogen, and R 5 is 3-trifluoromethyl may be prepared using Scheme 1.
  • the scheme assembles two halves of the desired molecule and couples them together using peptide coupling reagents.
  • One 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 for about 16-24 h to give the carboxy substituted phthalimido derivative 1c.
  • the other half is prepared in two steps.
  • 1-azido-3-(p-toluenesulfonyloxy)propan-2-ol 1d is heated at about 100° C. with an appropriately substituted piperazine derivative, 1e for about 2-5 days to give the azide 1f.
  • This azide is treated with Pd/C and H 2 (50 psi) in an inert solvent over 16 h to give the free amine 1g.
  • This amine is treated with 1c, HOBT, DMAP, EDCl, and N,N′-diisopropylethylamine in methylene chloride at about room temperature for 2-6 h to give the desired compound of Formula I.
  • 1c and 1g may be coupled using other peptide coupling agents such as HATU and DMAP.
  • This scheme may be used to prepare a number of compounds of Formula I. For example, if compounds where A, B or E is nitrogen are desired, replace 1b with an amino pyridine derivative such as 2-aminopyridine and follow the remaining steps of the scheme.
  • the illustrated product was prepared from the racemic azide 1d, the pure enantiomers of this azide are known and can be used in this scheme.
  • Compounds where R 3 is carbonyl may be prepared by treating the products of Scheme 1 with an oxidizing agent such as the Swern's reagent (formed with oxalyl chloride and DMSO) at ⁇ 78° C. to room temperature over 30 min to 1 h.
  • an oxidizing agent such as the Swern's reagent (formed with oxalyl chloride and DMSO) at ⁇ 78° C. to room temperature over 30 min to 1 h.
  • Scheme 2 may be used to prepare compounds of Formula I where A is nitrogen, R 1 is fluoro, R 2 is ethyl, R 3 is hydrogen, R 4 is hydrogen, and R 5 is hydrogen.
  • An appropriately substituted piperazine derivative 2d is treated with the N-BOC protected 3-bromopropylamine and cesium carbonate in acetonitrile at reflux for 16 h 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 over 2-6 h.
  • Derivatives 2g and 2c were coupled using HOBT, DMAP, EDCl, and N,N′-diisopropylethylamine in methylene chloride at about room temperature for 2-6 h to give the desired compound of Formula I. As described in Scheme 1, Scheme 2 may be modified to give all of the compounds of Formula I.
  • Scheme 3 may be used.
  • the amino group of intermediate 2g may be treated with an aldehyde 3a such as benzaldehyde to give the imine 3b.
  • This intermediate may be reduce with NaBH 4 at room temperature to give the 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 h to give the desired compound of Formula I.
  • Scheme 3 may be modified to give a number of compounds of Formula I. For example, to produce a compound where R 3 is hydroxy, replace 2g with intermediate 1g and follow the remaining steps of Scheme 3.
  • Scheme 4 may be used to produce compounds of the invention where R 3 is C 1-5 alkoxy.
  • This intermediate is treated with two equivalents of a strong organic base, such as sodium hydride in an inert solvent, such as THF, at 0° C. for about 1-5 h; followed by treatment with an additional equivalent of base and an alkylating agent such as ethyl iodide, at 0° C. for about 1-5 h to give the ether 4c.
  • This ether is treated with Pd/C and H 2 (ca.
  • This intermediate may be treated with piperazine derivative, 5c, a basic reagents, such as potassium hydroxide, sodium hydroxide, or lithium hydroxide, in an alcoholic solvent such as methanol at about 0° C. to about room temperature over about 1 to about 3 days to give the coupled derivative 5d.
  • a basic reagents such as potassium hydroxide, sodium hydroxide, or lithium hydroxide
  • an alcoholic solvent such as methanol
  • This amine may be debenzylated with using a reducing agents, such as palladium catalyst and ammonium formate, sodium in liquid ammonia, or palladium and hydrogen, in an alcoholic solvent such as EtOH at about 45-60° C over 20 h to give the primary amine 5f.
  • a reducing agents such as palladium catalyst and ammonium formate, sodium in liquid ammonia, or palladium and hydrogen
  • EtOH alcoholic solvent
  • This amine may be coupled to acids of type 5g using peptide coupling agents such as HATU to give a compound of Formula I.
  • Scheme 5 may be modified to give a number of compounds of Formula I.
  • the claimed compounds are useful as antagonists of ⁇ 1 a -AR, some compounds are more active than others and are either preferred or particularly preferred.
  • the preferred compounds of Formula I include:
  • R 1 is halogen or hydroxy
  • R 2 is phenylC 1-5 alkyl or hydrogen
  • R 3 is C 1-5 alkoxy
  • R 4 is C 1-5 alkyl
  • R 5 , R 6 , and R 7 are independently selected from hydrogen, nitrile and amino,
  • A is nitrogen or carbon
  • C is carbon
  • the particularly preferred compounds of Formula I include compounds where:
  • R 1 is hydrogen
  • R 2 is C 1-6 alkyl, phenyl or substituted phenyl,
  • R 3 is hydrogen, hydroxy
  • R 4 is hydrogen
  • R 5 , R 6 , and R 7 are independently selected from halogen, hydrogen, hydroxy, C 1-8 alkyl, C 1-5 alkoxy, and diC 1-5 alkylamino,
  • A is carbon
  • E is carbon
  • the preferred compounds of Formula II include compound where
  • R 8 is hydrogen
  • R 9 is C 1-6 alkyl
  • R 10 is hydrogen, C 1-5 alkoxycarbonyl, phenylC 1-5 alkoxycarbonyl, and
  • R 11 is hydrogen, phenylC 1-5 alkyl, or C 1-5 alkoxy substituted phenyl.
  • the particularly preferred compounds of Formula II include compounds where
  • R 8 is hydrogen
  • R 9 is isopropyl
  • R 10 is hydrogen, t-butoxycarbonyl, benzyloxycarbonyl, and
  • R 11 is hydrogen, benzyl.
  • the preferred compounds of Formula III include compound where
  • R 10 is C 1-5 alkoxycarbonyl
  • R 11 is phenylC 1-5 alkyl, or C 1-5 alkoxy substituted phenyl
  • R 12 is hydrogen or halogen.
  • the particularly preferred compounds of Formula III include compounds where
  • R 10 is t-butoxycarbonyl
  • R 11 is benzyl
  • R 12 is chlorine
  • the preferred basic reagent for producing a compound of Formula II is potassium hydroxide.
  • the preferred acidic reagent for treating a compound of Formula III is trifluoroacetic acid.
  • the preferred reducing agent for treating a compound of Formula II is ammonium formate and Pd/C.
  • 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 ⁇ 1 a adrenergic receptor.
  • the preferred route is oral administration, however compounds may be administered by intravenous infusion.
  • Oral doses range from about 0.01 to about 100 mg/kg daily; where the optimal dose range is about 0.1 to about 25 mg/kg/per day.
  • Infusion doses can range from about 0.001-1 mg/kg/min of inhibitor, admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
  • compositions can be prepared using conventional pharmaceutical excipients and compounding techniques.
  • Oral dosage forms may be elixers, syrups, capsules tablets and the like.
  • 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.
  • 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.
  • 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.
  • Boc 2 O (11 g, 50.1 mmol) and triethylamine (10.12 g, 100 mmol) were dissolved in THF (25 mL) and cooled to 0° C.
  • the amine 15 (10 g, 50.1 mmol) was added in portions and stirred for 20 h while the temperature was warmed up to 20° C. overnight.
  • the solvent was concentrated in vacuo and water wasadded.
  • the mixture was extracted with ether (3 ⁇ ), dried (Na 2 SO 4 ) and concentrated.
  • the crude residue was recrystallized from EtOAc/hexane to give 9.9 g (66%) of 16 as a white crystalline solid.
  • the biological activity and selectivity of the compounds of the invention was demonstrated by the following assays.
  • the first assay tested the ability of compounds of Formula I to bind to membrane bound receptors ⁇ 1 a -AR, ⁇ 1 b -AR and ⁇ 1 d -AR.
  • Radioligand binding assay 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 ([1251]-HEAT, [3H]-prazosin). Each ⁇ 1 receptor subtype was cloned from poly A+ RNA by the standard method of reverse transcription-polymerase chain reaction (RT-PCR).
  • ⁇ 1 a -AR human hippocampus and prostate
  • ⁇ 1 b -AR human hippocampus
  • ⁇ 1 d -AR human hippocampus
  • the resulting cDNAs were cloned into the pcDNA3 mammalian expression vector (Invitrogen Corp., San Diego Calif.). 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 ⁇ 1-AR subtypes (a, b, d) were transfected into COS cells using a standard DEAE-dextran procedure with a chloroquine shock.
  • each tissue culture dish (100 mm) was inoculated with 3.5 ⁇ 10 6 cells and transfected with 10 ⁇ g of DNA.
  • the cells were harvested and COS membranes were prepared.
  • Transfected COS cells from 25 plates (100 mm) were scraped and suspended in 15 mL of TE buffer (50 mM Tris-HCl, 5 mM EDTA, pH7.4). The suspension was disrupted with a homogenizer.
  • each compound was assessed in a receptor binding assay.
  • [1251]-HEAT a non-selective ⁇ 1-AR ligand, was used as the radiolabeled ligand.
  • Each well of a 96-well plate received: 140 ⁇ L TNE, 25 mL [1251]-HEAT diluted in TNE (50,000 cpm; final concentration 50 pM), 10 ⁇ L test compound diluted in DMSO (final concentration 1 pM-10 ⁇ M), 25 mL COS cell membrane preparation expressing one of the three ⁇ 1-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 through D list the IC 50 values expressed in nanomolar concentration for select compounds of the invention in all receptor subtypes. TABLE A Cpd.
  • Compound 9 inhibited the contractile response in aortic tissue with an IC 50 of 6.5 ⁇ M and in prostate tissue with an IC 50 of 0.23 ⁇ M.
  • Compound 45 inhibited the contractile response in aortic tissue with an IC 50 of 3.3 ⁇ M and in prostate tissue with an IC 50 of 0.04 ⁇ M.
  • Compound 34 inhibited the contractile response in aortic tissue with an IC 50 of 42.5 ⁇ M and in prostate tissue with an IC 50 of 0.75 ⁇ M.
  • Compound 21 inhibited the contractile response in aortic tissue with an IC 50 of 22.4 ⁇ M and in prostate tissue with an IC 50 of 0.81 ⁇ M.
  • IUP intraurethral pressure
  • MAP Mean arterial pressure
  • PE phenylephrine
  • IUP and MAP were recorded following each dose until the IUP returned to baseline.
  • the dogs then were given an i.v. bolus dose of the antagonist compound, followed by i.v. PE challenges of ascending doses, as in the control agonist dose-response curve.
  • IUP and MAP measurements following each PE challenge were recorded.
  • the antagonist compound was tested over a dose range of 3 to 300 ug/kg in half-log increments. The interval between antagonist doses was at least 45 min and three experiments were performed for each test compound.
  • the graphs below illustrates the mean percentage reductions in IUP and MAP for compounds 21 and 46 respectively.
  • the duration of select compounds of the invention was determined by the measuring the IUP and MAP responses to repeated PE challenges in conscious dogs over time.
  • Male beagles dogs were instrumented for the continuous measurement of arterial blood pressure by implanting a catheter containing a pressure transducer into the abdominal aorta via the femoral artery.
  • the telemetry transmitter was positioned subcutaneously in the animal's flank.
  • IUP was monitored with a catheter positioned in the prostatic urethra.
  • the IUP and MAP responses to a 20 ⁇ g/kg i.v. dose of PE were determined and repeated several times to establish a baseline (100% maximal) response.
  • An oral bolus dose of antagonist was administered, followed by a 20 ⁇ g/kg i.v. PE challenge at 0.5, 1, 1.5, 2, 4, 6, 12, and 24 hours post dosing.
  • the IUP and MAP responses following each PE challenge were recorded.
  • Compound 33 was tested at doses of 0.1, 0.3, and 1 mg/kg.
  • the IUP and MAP responses at each time point following the PE challenge are presented in the following graphs as the percent of the maximal response.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Urology & Nephrology (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)
US10/014,979 1998-02-20 2001-12-11 Novel phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia Abandoned US20020077476A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US10/014,979 US20020077476A1 (en) 1998-02-20 2001-12-11 Novel phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia
US10/207,473 US6780994B2 (en) 1998-02-20 2002-07-29 Phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US7551098P 1998-02-20 1998-02-20
US09/489,744 US6362338B1 (en) 1998-02-20 2000-01-21 Phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia
US10/014,979 US20020077476A1 (en) 1998-02-20 2001-12-11 Novel phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US09/489,744 Division US6362338B1 (en) 1998-02-20 2000-01-21 Phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US10/207,473 Division US6780994B2 (en) 1998-02-20 2002-07-29 Phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia

Publications (1)

Publication Number Publication Date
US20020077476A1 true US20020077476A1 (en) 2002-06-20

Family

ID=22126243

Family Applications (2)

Application Number Title Priority Date Filing Date
US10/014,979 Abandoned US20020077476A1 (en) 1998-02-20 2001-12-11 Novel phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia
US10/207,473 Expired - Lifetime US6780994B2 (en) 1998-02-20 2002-07-29 Phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia

Family Applications After (1)

Application Number Title Priority Date Filing Date
US10/207,473 Expired - Lifetime US6780994B2 (en) 1998-02-20 2002-07-29 Phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia

Country Status (21)

Country Link
US (2) US20020077476A1 (xx)
EP (1) EP1056720B1 (xx)
JP (1) JP2002503722A (xx)
KR (1) KR100608473B1 (xx)
CN (1) CN1172911C (xx)
AR (1) AR015521A1 (xx)
AT (1) ATE280156T1 (xx)
AU (1) AU766411B2 (xx)
BR (1) BR9908122A (xx)
DE (1) DE69921300T2 (xx)
ES (1) ES2233023T3 (xx)
HK (1) HK1031872A1 (xx)
HU (1) HUP0100704A3 (xx)
IL (2) IL137953A0 (xx)
NO (1) NO317104B1 (xx)
NZ (1) NZ506461A (xx)
PL (1) PL194649B1 (xx)
PT (1) PT1056720E (xx)
TR (1) TR200003224T2 (xx)
WO (1) WO1999042445A1 (xx)
ZA (1) ZA991319B (xx)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI20010164A1 (it) * 2001-01-30 2002-07-30 Recordati Chem Pharm Alfa 1 antagonisti selettivi a + d
CN103387531A (zh) * 2012-05-10 2013-11-13 广州医学院 酰胺类芳基哌嗪衍生物及其制备方法和在抗良性前列腺增生中的应用
HUP1400294A2 (hu) 2014-06-13 2015-12-28 Skillpharm Kft Clopidogrel új alkalmazása
CN106966940B (zh) * 2015-07-30 2019-03-19 新发药业有限公司 一种西他列汀磷酸盐中间体n-芳甲基-2s-氰基甲基吖啶的制备方法

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1382742A (en) 1972-09-19 1975-02-05 Labaz Benzofuran derivatives and process for preparing the same
CH585693A5 (xx) 1974-02-08 1977-03-15 Ciba Geigy Ag
HU177702B (en) 1977-10-24 1981-12-28 Noevenyvedelmi Kutato Intezet Plant growth regulator and process for preparing the active materials
PT82077B (fr) * 1985-02-26 1987-09-25 Sanofi Sa Procede pour l'obtention des derives aminoalcools peptidiques inhibiteurs de la renine et des proteases acides
FR2678271B1 (fr) * 1991-06-27 1995-01-13 Synthelabo Derives de pyrimidine-4-carboxamide, leur preparation et leur application en therapeutique.
US5428037A (en) * 1993-04-09 1995-06-27 Syntex Pharmaceuticals, Ltd. Heterocyclic derivatives in the treatment of Ischaemia and related diseases
HUP0100048A3 (en) * 1997-05-12 2002-12-28 Ortho Mcneil Pharm Inc Arylsubstituted piperazine-derivatives, useful in the treatement of benign prostatic hyperlasia use of them for producing pharmaceutical compositions and pharmaceutical compositions containing them

Also Published As

Publication number Publication date
KR20010041118A (ko) 2001-05-15
KR100608473B1 (ko) 2006-08-09
PL342357A1 (en) 2001-06-04
ATE280156T1 (de) 2004-11-15
US6780994B2 (en) 2004-08-24
ES2233023T3 (es) 2005-06-01
PT1056720E (pt) 2005-02-28
AU766411B2 (en) 2003-10-16
NZ506461A (en) 2003-08-29
CN1172911C (zh) 2004-10-27
BR9908122A (pt) 2001-11-13
HUP0100704A2 (hu) 2001-10-28
IL137953A0 (en) 2001-10-31
NO317104B1 (no) 2004-08-09
IL137953A (en) 2006-12-31
EP1056720B1 (en) 2004-10-20
WO1999042445A1 (en) 1999-08-26
JP2002503722A (ja) 2002-02-05
HK1031872A1 (en) 2001-06-29
US20030088099A1 (en) 2003-05-08
CN1291185A (zh) 2001-04-11
AU2776599A (en) 1999-09-06
HUP0100704A3 (en) 2002-10-28
DE69921300T2 (de) 2006-03-09
NO20004142D0 (no) 2000-08-18
TR200003224T2 (tr) 2001-03-21
AR015521A1 (es) 2001-05-02
EP1056720A1 (en) 2000-12-06
ZA991319B (en) 2000-11-20
PL194649B1 (pl) 2007-06-29
DE69921300D1 (de) 2004-11-25
NO20004142L (no) 2000-10-19

Similar Documents

Publication Publication Date Title
US6218396B1 (en) Substituted pyridino arylpiperazines useful in the treatment of benign prostatic hyperplasia
US6071915A (en) Arylsubstituted piperazines useful in the treatment of benign prostatic hyperplasia
US6384035B1 (en) Heterocycles useful in the treatment of benign prostatic hyperplasia
US6780994B2 (en) Phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia
US6362338B1 (en) Phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia
US6063785A (en) Phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia
EP1346983A2 (en) Phthalimido arylpiperazines as alpha 1A receptor antagonists useful in the treatment of benign prostatic hyperplasia
MXPA00008219A (en) Phtalimido arylpiperazines as alpha 1a receptor antagonists useful in the treatment of benign prostatic hyperplasia
CZ20003045A3 (cs) Ftalimidoarylpiperaziny jako antagonisty alfa IA receptorů použitelné při léčení benigního zbytnění prostaty
MXPA00008220A (en) Novel substituted pyridino arylpiperazines useful in the treatment of benign prostatic hyperplasia

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION