WO2006092710A1 - Metabolites of 2-{3-[4-(2-isopropoxyphenyl) piperazin-1-yl]-propyl}-3a,4,7,7a-tetrahydro-1h-isoindole-1,3-(2h)-dione - Google Patents

Metabolites of 2-{3-[4-(2-isopropoxyphenyl) piperazin-1-yl]-propyl}-3a,4,7,7a-tetrahydro-1h-isoindole-1,3-(2h)-dione Download PDF

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WO2006092710A1
WO2006092710A1 PCT/IB2006/000436 IB2006000436W WO2006092710A1 WO 2006092710 A1 WO2006092710 A1 WO 2006092710A1 IB 2006000436 W IB2006000436 W IB 2006000436W WO 2006092710 A1 WO2006092710 A1 WO 2006092710A1
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formula
compound
hydrogen
hydroxy
isopropyl
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PCT/IB2006/000436
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French (fr)
Inventor
Nitya Anand
Mohammad Salman
Gyan Chand Yadav
Somesh Sharma
Sanjay Jain
Neelima Sinha
Gobind Singh Kapkoti
Anita Chugh
Brijesh Varshney
Jyoti Kumar Paliwal
Kamna Nanda
Sonali Kakar
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Ranbaxy Laboratories Limited
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Publication of WO2006092710A1 publication Critical patent/WO2006092710A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention relates to metabolites of 2- ⁇ 3-[4-(2-isopropoxyphenyl) piperazin-l-yl]-propyl ⁇ -3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione of Formula I.
  • the disclosed compounds can function as ⁇ i a -adrenoceptor antagonists and thus can be used for the treatment of benign prostatic hyperplasia (BPH) and related symptoms thereof.
  • BPH benign prostatic hyperplasia
  • Processes for preparing such metabolites, pharmaceutical compositions containing such metabolites and methods of treating BPH and related symptoms thereof are also provided.
  • cci -adrenoceptor antagonists are in clinical use for symptomatic treatment of benign prostatic hyperplasia (BPH) (Oesterling, Drug Therapy, 332(2): 99-110, 1995;
  • BPH benign prostatic hypertrophy
  • BPH is characterized by a nodular enlargement of prostatic tissue resulting in obstruction of the urethra, resulting in increased frequency of urination, nocturia, a poor urine stream and hesitancy or delay in starting the urine flow.
  • Chronic consequences of BPH can include hypertrophy of bladder smooth muscle, a decompensated bladder and increased incidence of urinary tract infection.
  • the method of choice for treating BPH reportedly is surgery (Lepor, et al, The Journal of Urology, 143:553-537, 1990).
  • Limitations of surgical treatments of BPH include high morbidity rates of an operative procedure in elderly men, persistence or recurrence of obstructive and irritative symptoms, as well as high costs of surgery.
  • metabolites of 2- ⁇ 3-[4-(2-isopropoxyphenyl)piperazin-l- yl]-propyl ⁇ -3a,4,7,7a-tetrahydro-lH-isoindole-l,3-(2H)-dione can be used in safe and effective treatments of BPH or related symptoms thereof.
  • Processes for the synthesis of these metabolites, as well as pharmaceutical compositions thereof, are also provided.
  • Encompassed pharmaceutical compositions may also contain one or more pharmaceutically acceptable carriers or diluents.
  • compositions comprising the metabolites of the present invention, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, conjugates, or prodrugs in combination with one or more pharmaceutically acceptable carriers, and optionally included excipients, are also included, which can be useful for safe and effective treatment of BPH or related symptoms thereof.
  • Formula I pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymorphs, conjugates or prodrugs thereof, wherein the metabolite can be an aromatized, desisopropylated, hydroxylated, epoxylated, or N-oxide derivative or conjugate or prodrug thereof.
  • compounds having the structure of Formula II are compounds having the structure of Formula II,
  • Ri can be hydrogen or isopropyl
  • R 2 can be hydrogen or hydroxyl
  • n can be an integer 0 or 1.
  • Embodiments of the compounds of Formula II may include one or more of the following.
  • compounds of Formula II can be an aromatized, desisopropylated, hydroxylated, epoxylated, or N-oxide metabolite of 2- ⁇ 3-[4-(2-Isopropoxyphenyl)-piperazin- 1 -yl]-propyl ⁇ -3a,4,7,7a-tetrahydro-lH-isoindole-l,3-(2H)-dione of Formula I.
  • Conjugates can be a sulfate, phosphate or glucuronate derivative.
  • Prodrugs can be a carbamoyl, (Ci-C 4 )-alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, (C]-C 4 )-alkylsulfonyl or arylsulphonyl derivative.
  • Compounds of Formula II can include desisopropylated metabolite 2- ⁇ 3-[4-(2- hydroxyphenyl)-piperazin-l -yl]-propyl ⁇ -3a,4,7,7a-tetrahydroisoindole-l,3-dione.
  • the metabolite can have a molecular ion peak of m/z 370.
  • a sulphate conjugate of the metabolite can also have a molecular ion peak of m/z 448.
  • a glucuronate conjugate of the metabolite can have a molecular ion peak of m/z 546.
  • Compounds of Formula II can include aromatized metabolite 2- ⁇ 3-[4-(2- isopropoxyphenyl)-piperazin-l-yl]-propyl ⁇ -isoindole-l,3-dione.
  • the metabolite can have a molecular ion peak of m/z 408.
  • Compounds of Formula II can include N-oxide metabolite 2- ⁇ 3-[l-oxy-4-(2- isopropoxyphenyl)-piperazin-l-yl]-propyl ⁇ -3a,4,7,7a -tetrahydroisoindole-l,3-dione.
  • the metabolite can have a molecular ion peak of m/z 428.
  • Compounds of Formula II can include hydroxylated metabolite 2- ⁇ 2-hydroxy-3-[4-(2- isopropoxyphenyl)-piperazin-l-yl]-propyl ⁇ -3a,4,7,7a-tetrahydroisoindole-l,3-dione.
  • the metabolite can have a molecular ion peak of m/z 428.
  • Compounds of Formula II can include hydroxylated metabolite 4,7-dihydroxy-2-[3-4-
  • the metabolite can have a molecular ion peak of m/z 444.
  • Compounds of Formula II can include hydroxylated metabolite 4-hydroxy-2- ⁇ 3-(4-(2- isopropoxy-phenyl)-piperazin-l-yl ⁇ -propyl ⁇ -3a,4,7,7a-tetrahydroisoindole-l,3-dione.
  • the metabolite can have a molecular ion peak of m/z 428.
  • Compounds of Formula II can include epoxylated metabolite 4- ⁇ 3-[4-(2- isopropoxyphenyl)-piperazin-l-yl]-propyl ⁇ -hexahydro-l-oxa-4-aza-cyclopropa[f]indene-3,5- dione.
  • the metabolite can have a molecular ion peak of m/z 428.
  • Compounds of Formula II can include hydroxylated metabolite 4- ⁇ 2-Hydroxy-3-[4- (2-isopropoxyphenyl)-piperazin- 1 -yl] -propyl ⁇ -hexahydro- 1 -oxa-4-aza- cyclopropa[f]indene3,5-dione.
  • the metabolite can have a molecular ion peak of m/z 444.
  • Compounds of Formula II can include hydroxylated metabolite 5,6-Dihydroxy-2- ⁇ 3- [4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl ⁇ -hexahydro-isoindole-l,3-dione.
  • the metabolite can have a molecular ion peak of m/z 446.
  • a glucuronate conjugate of the metabolite can have a molecular ion peak m/z 622.
  • Compounds of Formula II can include hydroxylated metabolite 2- ⁇ 2-Hydroxy-3-[4- (2-hydroxy-phenyl)-piperazin- 1 -yl] -propyl ⁇ -3a,4, 7,7a-tetrahydro isoindole- 1 ,3 -dione.
  • the metabolite can have a molecular ion peak m/z 386.
  • a sulphate conjugate of the metabolite can have a molecular ion peak m/z 466.
  • Compounds of Formula II can include 2- ⁇ 3-[4-(2-isopropoxyphenyl)-l- oxidopiperazin-l-yl ⁇ -propyl ⁇ -3a,4,7,7a-tetrahydroisoindole-l,3-dione or 5,6-Dihydroxy-2- ⁇ 3 -[4-(2-isopropoxy-phenyl)-piperazin- 1 -yl]-propyl ⁇ -hexahydroisoindole- 1 ,3 -dione .
  • Compounds of Formula II can also include:
  • compositions comprising therapeutically effective amounts of one or more compounds of Formula II,
  • Ri can be hydrogen or isopropyl
  • R 2 can be hydrogen or hydroxyl
  • n can be an integer 0 or 1.
  • Embodiments of the pharmaceutical compositions can encompass one or more of the following.
  • the pharmaceutical compositions can contain conjugates that include, for example, a sulfate, phosphate or glucuronate derivatives.
  • the pharmaceutical compositions can also contain prodrugs that include, for example, carbamoyl, (Ci-C 4 )-alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, (Ci-C 4 )-alkylsulfonyl or arylsulphonyl derivatives.
  • provided herein are methods for treating a disease or disorder mediated through ccia adrenoceptor comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein.
  • a disease or disorder selected from high intraocular pressure, disorder associated with high cholesterol, cardiac arrhythmia, impotency, sympathetically mediated pain and migraine comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein.
  • kits for the treating benign prostatic hyperplasia comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein.
  • Embodiments of this method can include one or more of the following aspects.
  • administration of the compound does not cause a fall in blood pressure.
  • the compound can also relax lower urinary tract tissues, for example, the prostate smooth .muscle.
  • methods for treating a disease or disorder mediated through ecu adrenoceptor comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition disclosed herein.
  • a disease or disorder selected from high intraocular pressure, disorder associated with high cholesterol, cardiac arrhythmia, impotency, sympathetically mediated pain and migraine comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition disclosed herein.
  • provided herein are methods for treating benign prostatic hyperplasia comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition disclosed herein.
  • R 2 can be hydrogen or hydroxy, with one or more peroxyacids to form a compound of Formula IV,
  • R 2 can be hydrogen or hydroxy
  • R 2 can be hydrogen or hydroxy, with one or more peroxyacids to form a compound of Formula V,
  • R 2 can be hydrogen or hydroxy, or c) reacting a compound of Formula III
  • R 2 can be hydrogen or hydroxy, with one or more peroxyacids to form a compound of Formula Va
  • R 2 can be hydrogen or hydroxy
  • Embodiments of the processes can include one or more of the following.
  • reaction a), b) or c) can be carried out in one or more solvents selected from, for example, dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, dimethyl sulphoxide or mixtures thereof.
  • Peroxyacids in reaction a), b) or c) can be, for example, magnesium monoperoxyphthalate, potassium peroxomonosulfate, m-chloroperbenzoic acid or mixtures thereof.
  • processes for preparing compounds of Formula XI or Formula XII or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, polymer, conjugate or prodrugs thereof comprising: a) reacting 3a,4,7,7a-tetrahydro isoindole-l,3-dione of Formula VI
  • Xi can be chlorine or bromine, to form 2-oxiranylmethyl-3a,4,7,7a- tetrahydroisoindole- 1 ,3 -dione of Formula VIII,
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy, to form a compound of Formula XI,
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy, or b) reacting a compound of Formula XI
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy, with one or more peroxyacids to form a compound of Formula XII,
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy.
  • Embodiments of the processes can include one or more of the following.
  • the reaction of the compound of Formula VI with the compound of Formula VII can be carried out in one or more solvents selected from, for example, acetone, ethylmethylketone, dimethylformamide, n-butanol, acetonitrile, toluene, chlorobenzene or mixtures thereof.
  • the reaction can also be carried out in the presence of one or more inorganic or organic bases selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, triethylamine, trimethylamme, diethylisopropyl amine or mixtures thereof.
  • the reaction of the compound of Formula VIII with one or more peroxyacids can be carried out in one or more solvents selected from, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or mixtures thereof.
  • the reaction of the compound of Formula VIII to form the compound of Formula IX or the reaction of the compound of Formula XI to form the compound of Formula XII can be carried out using one or more peroxyacids selected from, for example, magnesium monoperoxyphthalate, potassium peroxomonosulfate, m-chloroperbenzoic acid or mixtures thereof.
  • the reaction of the compound of Formula IX with a compound of Formula X can be carried out in one or more solvents selected from, for example, methanol, ethanol, propanol, n-butanol or mixtures thereof.
  • the reaction of the compound of Formula XI with one or more peroxyacids can be carried out in one or more solvents selected from, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or mixtures thereof.
  • processes for preparing compounds of Formula XIII or Formula XIV or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, polymorph, conjugate or prodrug thereof comprising: a) reacting 2-oxiranylmethyl-3a,4,7,7a-tetrahydroisoindole- 1 ,3-dione of Formula VIII
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy, to form a compound of Formula XIII,
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy, or b) reacting a compound of Formula XIII,
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy, with one or more peroxyacids to form a compound of Formula XIV,
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy.
  • Embodiments of the processes can include one or more of the following.
  • the reaction of the compound of Formula VIII with the compound of Formula X can be carried out in one or more solvents selected from, for example, methanol, ethanol, propanol, n-butanol or mixture thereof.
  • the reaction of the compound of Formula VIII with the compound of Formula X can be carried out in the presence of one or more organic or inorganic bases selected from, for example, trimethylamine, triethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate or mixtures thereof.
  • the reaction of the compound of Formula XIII with one or more peroxyacids can be carried out in one or more solvents selected from, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or mixtures thereof.
  • Suitable peroxyacids include, for example, magnesium monoperoxyphthalate, potassium peroxomonosulfate, m-chloroperbenzoic acid or mixtures thereof.
  • processes for preparing compounds of Formula XVI or Formula XVII or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymers, conjugates or prodrugs thereof comprising: a) reacting 3a,4,7,7a-tetrahydroisoindole-l,3-dione of Formula VI
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy, to form a compound of Formula XVI,
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy, or b) reacting a compound of Formula XVI,
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy, with peroxyacid to form a compound of Formula XVII,
  • R] can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy.
  • Embodiments of the processes include one or more of the following.
  • the reaction of the compound of Formula VI with 1,3-dihalopropane can be carried out in one or more solvents selected from, for example, acetonitrile, acetone, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or mixtures thereof.
  • the reaction can also be carried out in the presence of one or more organic or inorganic halides selected from, for example, tetrabutylammonium bromide, tetrabutylammonium chloride, potassium iodide or mixtures thereof.
  • the reaction can also be carried out in the presence of one or more inorganic bases selected from, for example, barium carbonate, cesium carbonate, potassium carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate or mixture thereof.
  • the reaction of the compound of Formula XVI with 1,3-dihalopropane can be carried out in one or more solvents selected from, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or mixtures thereof.
  • the reaction of the compound of Formula XVI to form the compound of Formula XVII can also be carried out using one or more peroxyacids selected from, for example, magnesium monoperoxyphthalate, potassium peroxomonosulfate, m-chloroperbenzoic acid or mixtures thereof.
  • processes for preparing compounds of Formula XIX or Formula XX or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, conjugate or prodrug thereof comprising: a) reacting 2-(3-halopropyl)-3a,4,7,7a-tetrahydroisoindole- 1 ,3-dione of Formula xv,
  • Y can be F, Cl, Br or I, which can be reacted with a compound of Formula X
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy, to form a compound of Formula XIX,
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy, or b) reacting a compound of Formula XIX
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy, with peroxyacid to form a compound of Formula XX
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy.
  • Embodiments of the processes can include one or more of the following.
  • the reaction of the compound of Formula XV with one or more peroxyacids can be carried out in one or more solvents selected from, for example, dichloroethane, tetrahydrofuran, dimethylformamide dimethylsulfoxide, ethanol, butanol or mixtures thereof.
  • Suitable peroxyacids include selected from, for example, magnesium monoperoxyphthalate, potassium peroxomonosulfate, m-chloroperbenzoic acid or mixtures thereof.
  • reaction of the compound of Formula XVIII with the compound of Formula X or the reaction of the compound of Formula XIX with one or more peroxyacids can be carried out in one or more solvents selected from, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or mixtures thereof.
  • solvents selected from, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or mixtures thereof.
  • the reaction can also be carried out in the presence of one or more inorganic bases selected from, for example, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate or mixtures thereof.
  • R can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy, with acrylonitrile to form a compound of Formula XXI,
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy, which can be reduced to form a compound of Formula XXII,
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy, which can be reacted with fufan-2,5-dione to form a compound of Formula XXIII,
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy, which can be hydro lyzed to give a compound of Formula XXVI,
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy, or b) reacting a compound of Formula XXVI
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy, with one or more peroxyacids to form a compound of Formula XXVIII,
  • R 1 can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy, or c) reacting a compound of Formula XXIII
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy, or d) reacting a compound of Formula XXVII
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy.
  • Embodiments of the processes can include one or more of the following.
  • the reaction of the compound of Formula X with acrylonitrile, the reduction of the compound of Formula XXI, the hydrolysis of a compound of Formula XXV or the hydrolysis of a compound of Formula XXIV can be carried out in one or more solvents selected from, for example, methanol, ethanol, propanol, n-butanol or mixtures thereof.
  • the reaction of the compound of Formula XXII with furan-2,5-dione can be carried out in one or more solvents selected from, for example, toluene, benzene, xylene, tetrahydrofuran, acetonitrile or mixtures thereof.
  • reaction of the compound of Formula XXIII with l-acetoxy-1,3- butadiene or the reaction of the compound of Formula XXIII with l,4-diacetoxy-l,3- butadiene can be carried out in one or more solvents selected from, for example, toluene, benzene, xylene or mixtures thereof.
  • reaction of the compound of Formula XXVI with one or more peroxyacids or the reaction of the compound of Formula XXVII with one or more peroxyacids can be carried out in one or more solvents selected from, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or mixtures thereof.
  • the reaction of the compound of Formula XXVI to form the compound of Formula XVIII or the reaction of the compound of Formula XXVII to form the compound of Formula XXIX can be carried out using one or more peroxyacids selected from, for example, magnesium monoperoxyphthalate, potassium peroxomonosulfate, m-chloroperbenzoic acid or mixtures thereof.
  • the reduction of the compound of Formula XXI can be carried out in the presence of one or more reducing agents selected from, for example, palladium on carbon and carbon in ammonia and one or more alcoholic solvents; or Raney Nickel and hydrogen in ammonia and one or more alcoholic solvents.
  • processes for preparing compounds of Formula XXXII or Formula XXXIII or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymorphs, conjugates or prodrugs thereof comprising: a) reacting isoindole- 1 ,3 -dione of Formula XXX
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy, to form a compound of Formula XXXII
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy, or b) reacting a compound of Formula XXXII
  • Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy.
  • Embodiments of the processes can include one or more of the following.
  • the reaction of the compound of Formula XXX with 1,3-dihalopropane can be carried out in one or more solvents selected from, for example, acetonitrile, acetone, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or mixtures thereof.
  • the reaction of isoindole-1,3- dione of Formula XXX with 1,3-dihalopropane can be carried out in the presence of one or more organic halides selected from, for example, tetrabutylammonium chloride, tetrabutylammonium bromide or mixtures thereof.
  • the reaction can also be carried out in the presence of one or more inorganic bases selected from, for example, barium carbonate, cesium carbonate, potassium carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate or mixtures thereof.
  • the reaction of the compound of Formula XXXI with the compound of Formula X or the reaction of a compound of Formula XXXII to form the compound of Formula XXXIII can be carried out in a solvent selected from, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide and dimethylsulfoxide.
  • the compound of Formula XXXI with a compound of Formula X can be carried out in the presence of one or more inorganic base selected from, for example, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate or mixtures thereof.
  • reaction of the compound of Formula XXXII to form the compound of Formula XXXIII can be carried out using one or more peroxyacids selected from, for example, magnesium monoperoxyphthalate, potassium peroxomonosulfate, m-chloroperbenzoic acid or mixtures thereof.
  • prodrugs having the structure of Formula XXXVa,
  • Formula XXXVa a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, polymorph or conjugate thereof, wherein Y and Z, when taken together represent the fused ring systems including:
  • R 3 , R 4 , R 5 and R 6 can independently be hydrogen, hydroxyl or -O-W-
  • X can be -CHR 7 , wherein R 7 can be hydrogen, hydroxyl or -0-W-R;
  • Ri can be hydrogen or isopropyl
  • R 2 can be hydrogen, hydroxyl or 0-W-R n can be an integer 0 or 1 , and at least one of R 2 , R 3 , R 4 , R 5 , R 6 or X can be -0-W-R, wherein W can be -SO 2 , -CO-, -CONR 8 , wherein R 8 can be (Ci-C 4 )- alkyl or aryl, and
  • R can be (C ⁇ -C 4 )-alkyl, aryl or aralkyl.
  • Embodiments of the prodrugs can include one or more of the following.
  • the aryl can be phenyl or naphthyl.
  • the aralkyl can be benzyl.
  • W and R can respectively be, SO 2 and (Ci-C 4 )-alkyl; SO 2 and methyl; SO 2 and aryl; SO 2 and phenyl; CO and (Ci-C 4 )- alkyl; CO and methyl; CO and ethyl; CO and aralkyl; CO and benzyl; CONR 8 and (Ci-C 4 )- alkyl, wherein R 8 can be (Ci-C 4 )-alkyl; CONR 8 and methyl, wherein R 8 methyl; CONR 8 and aryl, wherein R 8 can be (Ci-C 4 )-alkyl; CONR 8 and phenyl, wherein R 8 can be methyl; CONR 8 and aryl, wherein R 8 can be aryl;
  • prodrugs examples include:
  • Formula XXXVa a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, polymorph, conjugate or prodrug thereof, wherein Y and Z, when taken together represent the fused ring systems including:
  • R 3 , R 4 , R 5 and R 6 can independently be hydrogen, hydroxyl or -O-W-
  • X can be -CHR 7 , wherein R 7 can be hydrogen, hydroxyl or -0-W-R;
  • Ri can be hydrogen or isopropyl
  • R 2 can be hydrogen, hydroxyl or 0-W-R n can be an integer 0 or 1 , and at least one of R 2 , R 3 , R 4 , Rs, RO or X can be -0-W-R, wherein W can be -SO 2 , -CO-, -CONR 8 , wherein R 8 can be (Ci-C 4 )- alkyl or aryl, and
  • R can be (Ci-C 4 )-alkyl, aryl or aralkyl, which process comprises reacting a hydroxylated metabolite of Formula XXXIVa
  • R 3 , R 4 , R 5 and R ⁇ can independently be hydrogen or hydroxyl;
  • X can be -CHR 7 , wherein R 7 can be hydrogen or hydroxyl;
  • Ri can be hydrogen or isopropyl;
  • R 2 can be hydrogen or hydroxyl;
  • n can be an integer 0 or 1 ; and at least one of R 2, R 3 , R 4 , R5, R 6 or X can be hydroxyl, wherein W can be -SO 2 , -CO-, -CONR 8 , wherein R 8 can be (Ci-C 4 )- alkyl or aryl, and
  • R can be (Ci-C 4 )-alkyl, aryl or aralkyl, with a compound of Formula Cl-W-R, wherein W can be -SO 2 , -CO-, -CONR 8 , wherein R 8 can be (Ci-C 4 )-alkyl or aryl, and R can be (Ci-C 4 )-alkyl, aryl or aralkyl, to form a prodrug of Formula XXXVa.
  • Embodiments of the processes can include one or more of the following.
  • reaction of the hydroxylated metabolite of Formula XXXIVa with the compound of Formula Cl-W-R can be carried out in one or more solvents selected from, for example, tetrahydrofuran, dimethylformamide or mixtures thereof.
  • the reaction of the hydroxylated metabolite of Formula XXXIVa with the compound of Formula XXXVa can be carried out in the presence of one or more inorganic bases selected from, for example, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride or mixtures thereof.
  • the invention provides metabolites of 2- ⁇ 3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]- propyl ⁇ -3a,4,7,7a-tetrahydro-lH-isoindole-l,3-(2H)-dione (Compound No. 1) of Formula I,
  • metabolites comprise aromatized, desisopropylated, hydroxylated, epoxylated or N-oxides of Formula I.
  • An aromatized, desisopropylated, hydroxylated, epoxylated or N-oxide metabolite of compound of Formula I can be a metabolite represented by the general Formula II,
  • Y and Z when taken together include the fused ring systems including,
  • Rj, R 4 , R 5 and R 6 can be independently selected from hydrogen or hydroxyl
  • X can be -CHR 7 , wherein R 7 can be hydrogen or hydroxyl
  • Ri can be hydrogen or isopropyl
  • R 2 can be hydrogen or hydroxyl; n can be an integer 0 or 1. Examples of metabolites encompassed herein include, but are not limited to,
  • pharmaceutically acceptable salts refer to a salt prepared from one or more pharmaceutically acceptable non-toxic inorganic or organic acids.
  • inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitrous, nitric, carbonic, sulfuric, phosphoric acid, and the like.
  • organic acids include, but are not limited to, aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids, for example, formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, panthenic acid, toluenesulfonic acid, 2- hydroxyethanesulfonic acid and the like.
  • Pharmaceutically acceptable salts can be prepared following procedures well known to the skilled
  • solvates refers to solvates with water (i.e., hydrates) or pharmaceutically acceptable organic solvents. Such solvates are also encompassed herein. Furthermore, some crystalline forms of the compounds described herein can exist as polymorphs and as such are intended to be encompassed herein. Where metabolites encompassed by the invention have at least one chiral center, they may accordingly exist as enantiomers. It is to be understood that all such optically active isomers and racemic mixture therefore are encompassed herein.
  • the conjugates disclosed herein include sulfate or glucuronate derivatives of hydroxylated metabolites.
  • Prodrugs of hydroxylated metabolites are also encompassed herein.
  • Prodrugs include, but are not limited to, derivatives of metabolites having one or more carbamoyl, (Ci-C 4 )-alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkylsulfonyl, or arylsulfonyl groups and the like.
  • prodrugs as disclosed herein include, but are not limited to:
  • compositions comprising metabolites of 2- ⁇ 3-[4-(2-isopropoxy phenyl) piperazin-l-yl]-propyl ⁇ -3a,4,7,7a-tetrahydro-lH-isoindole-l, 3- (2H)-dione (Formula I), their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymorphs, conjugates or prodrugs and one or more pharmaceutically acceptable carriers or excipients.
  • compositions disclosed herein contain one or more metabolites in compositions that are suitable for oral, parenteral, topical, transdermal, colonic, buccal, sublingual or intravaginal administration.
  • the compositions may be formulated to provide immediate or sustained-release of the therapeutic agents.
  • the agents described herein can be administered alone, but will generally be administered as an admixture with one or more suitable pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier(s) refers to non-toxic, inert solid, semi-solid or liquid filter, diluent, encapsulating material or formulation auxiliary of any type.
  • Solid form preparations for oral administration include capsules, tablets, pills, powder, granules or suppositories.
  • one or more active metabolites can be mixed with one or more inert, pharmaceutically acceptable excipients or carriers (e.g., sodium citrate, dicalcium phosphate, filter or mixtures thereof), one or more extenders (e.g., starch, lactose, sucrose, glucose, mannitol, silicic acid or mixtures thereof), one or more binders (e.g., carboxymethyl cellulose, alginates, gelatins, polyvinylpyrrolidinone, sucrose, acacia or mixtures thereof), one or more disintegrating agents (e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate or mixtures thereof); one or more absorption accelerators (e.g., quaternary ammonium compounds); one or more wetting agents (e.g., cetyl alcohol, glycerol, monostearate or mixtures thereof); one or more adsorbionate,
  • Capsules, tablets or pills can also comprise one or more buffering agents.
  • the solid preparation of tablets, capsules, pills, granules can be prepared using one or more coatings and/or shells (e.g., enteric coating and other coatings well known in the pharmaceutical formulating art).
  • Liquid form preparations for oral administration include one or more pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs or mixtures thereof.
  • one or more metabolites can be mixed with water or one or more other solvents, solubilizing agents and/or emulsif ⁇ ers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, one or more oils (for example, cottonseed, groundnut, corn, germ, olive, castor or sesame oil), glycerol, fatty acid ester of sorbitan or mixture thereof.
  • oils for example, cottonseed, groundnut, corn, germ, olive, castor or sesame oil
  • glycerol fatty acid ester of sorbitan or mixture thereof.
  • the oral composition can also include one or more adjuvants, for example, a wetting agent, an emulsifying agent, a suspending agent, a sweetening agent, a flavoring agent, a perfuming agent or mixtures thereof.
  • adjuvants for example, a wetting agent, an emulsifying agent, a suspending agent, a sweetening agent, a flavoring agent, a perfuming agent or mixtures thereof.
  • Injectable preparations e.g., sterile injections, aqueous or oleaginous suspensions
  • suitable dispersing or wetting suspending agents include water, Ringers solution, U. S. P., isotonic sodium chloride or mixtures thereof.
  • Dosage forms for topical or transdermal administration includes ointments, pastes, creams, lotions, gel, powders, solutions, spray, inhalants or patches.
  • one or more metabolites are admixed under sterile condition with one or more pharmaceutically acceptable carriers and any preservatives or buffers as may be desirable.
  • the pharmaceutical preparations are desirably in unit dosage form. In such forms, the preparations are subdivided into unit doses containing therapeutic quantities of one or more active metabolites.
  • the formulations described herein may be formulated so as to provide quick-released or delayed-release of the active ingredient(s) after administration to the patient by utilizing procedures well known to the skill artisan.
  • patient refers to an animal, a mammal, or a human, who is the subject of treatment, observation or experiment.
  • compositions may be administered as depot formulations that permit sustained release, limit access to general circulation, and increase the prostate- and/or bladder-specific localization of the compositions.
  • Such formulations may be provided as slow release implants, be microencapsulated, or attached to biodegradable polymers or one or more prostate-specific immunoglobulins.
  • Sustained release formulations are preparations that release active metabolites over extended periods of time.
  • Sustained release formulations are prepared by applying one or more biodegradable, bioerodible or bioabsorbable polymeric formulations that are compatible on the surface of active metabolites. Effective release of metabolites is regulated by slow erosion of biodegradable, bioerodible or bioabsorbable polymeric formulations.
  • compositions may additionally contain 6 to 50 % w/w of other pharmaceutically acceptable excipients, for example, gas generating component, swelling agent, lubricant and filler.
  • compositions according to the invention may be formulated as capsules or tablets. Tablet formulations can be prepared by wet granulation, dry granulation, direct compression or by any other techniques known in the pharmaceutical art. Tablets can be coated with a layer of rapidly dissolving water-soluble polymer or pharmaceutical excipient(s).
  • biodegradable refers to the degradation of polymeric formulations over time by action of enzymes, by hydro lytic action and/or by other similar mechanisms in the human body.
  • bioerodible refers to a polymeric formulation erodes or degrades over time due, at least in part, to contact with substances found in the surrounding tissue fluids or cellular action.
  • bioabsorbable refers to polymeric formulations that are broken down and absorbed within the human body, for example, by a cell or tissue.
  • biocompatible refers to polymeric formulations that do not cause substantial tissue irritation or necrosis.
  • Metabolites described herein can also be administered in the form of liposome delivery systems, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, for example, cholesterol, stearylamine or phosphatidylcholines.
  • Aqueous parenteral compositions containing therapeutically effective amounts of one or more metabolites are disclosed herein. Methods of delivery such that direct intraprostatic injection of therapeutically effective amounts of compositions encompasses herein result in the relief of the obstructive symptoms associated with benign prostatic hyperplasia.
  • Intraprostatic injection can be accomplished by, for example, utilizing a long, fine needle inserted into the prostate under digital rectal control and/or ultrasonic guidance while the patient is under local anesthesia. Injection solutions may be diluted with, for example, lidocaine. During injections, needles may be frequently relocated in order to obtain the best possible distribution of the composition.
  • routes of administration include by transurethral intraprostatic (intralesional) injection. Alternatively, transperineal or transrectal routes of prostatic injection can be used.
  • Metabolites disclosed herein can be prepared by techniques known to one of ordinary skill in the art. In addition, metabolites described herein can be prepared by the following reaction sequences as depicted in Schemes I, II, III, IV, V, VI and VII.
  • Formula Va Compounds of Formula Va or Formula V can be prepared according to methods in
  • the methods comprise oxidizing a compound of Formula III to form a compound of Formula IV, which on reaction with one or more peroxyacids forms a compound of Formula V, wherein R 2 can be hydrogen or hydroxy.
  • the methods also comprise reacting a compound of Formula III with one or more peroxyacids to form a compound of Formula Va, wherein R 2 can be hydrogen or hydroxy.
  • Suitable peroxyacids include, for example, m- chloroperbenzoic acid, monoperoxyphthalate, potassium peroxomonosulfate or mixtures thereof.
  • the oxidation of a compound of Formula III to form a compound of Formula IV via path (a) can be carried out with one or more oxidizing agents (e.g., potassium permanganate) in one or more alcoholic solvents (e.g., methanol, ethanol, propanol, n-butanol or mixtures thereof).
  • oxidizing agents e.g., potassium permanganate
  • alcoholic solvents e.g., methanol, ethanol, propanol, n-butanol or mixtures thereof.
  • This reaction can also be carried out in one or more solvents, for example, dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, dimethylsulphoxide, or mixtures thereof.
  • Compounds of Formula XII can be prepared according to methods in Scheme II.
  • the methods comprise reacting 3a,4,7,7a-tetrahydroisoindole-l,3-dione of Formula VI with a compound of Formula VII (wherein Xi can be to chlorine or bromine) to form 2- oxiranylmethyl-3a,4,7,7a-tetrahydroisoindole-l,3-dione of Formula VIII.
  • the compound of Formula VIII can react with one or more peroxyacids to form 4-oxiranylmethylhexa-l-oxa-4- aza-cyclopropa[f]indene-3,5-dione of Formula IX.
  • Suitable peroxyacids include, for example, m-chloroperbenzoic acid, monoperoxyphthalate, potassium peroxomonosulfate or mixtures thereof.
  • the compound of Formula IX can react with a compound of Formula X to form a compound of Formula XI, wherein Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy.
  • the compound of Formula XI can be treated with one or more peroxyacids to form a compound of Formula XII, wherein Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy.
  • Suitable peroxyacids include, for example, m-chloroperbenzoic acid, monoperoxyphthalate, potassium peroxomonosulfate or mixtures thereof.
  • reaction of 3a,4,7,7a-tetrahydroisoindole-l,3-dione of Formula VI with compounds of Formula VII can be carried out in one or more solvents, for example, acetone, ethylmethylketone, dimethylformamide, n-butanol, acetonitrile, toluene, chlorobenzene or mixtures thereof.
  • This reaction can also be carried out in the presence of one or more inorganic bases or organic bases, for example, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, trimethylamine, triethylamine, diethylisopropylamine or mixtures thereof.
  • the reaction of 4-oxiranylmethylhexa-l-oxa-4-aza- cyclopropa[f]indene-3,5-dione of Formula IX with a compound of Formula X to form a compound of Formula XI can be carried out in one or more alcoholic solvents, for example, methanol, ethanol, propanol, n-butanol or mixtures thereof.
  • alcoholic solvents for example, methanol, ethanol, propanol, n-butanol or mixtures thereof.
  • reaction of a compound of Formula XI with one or more peroxyacids to form a compound of Formula XII can be carried out in one or more solvents, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or mixtures thereof.
  • Compounds of Formula XIV can be prepared according to methods in Scheme III.
  • the methods comprise reacting 2-oxiranylmethyl-3a,4,7,7a-tetrahydroisoindole-l,3-dione of Formula VIII with a compound of Formula X to form a compound of Formula XIII, wherein Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy.
  • the compound Formula XIII can be reacted with one or more peroxyacids to form a compound of Formula XIV, wherein R
  • Suitable peroxyacids include, for example, m-chloroperbenzoic acid, monoperoxyphthalate, potassium peroxomonosulfate or mixtures thereof.
  • the reaction of 2-oxiranylmethyl-3a,4,7,7a-tetrahydroisoindole-l,3-dione of Formula VIII with a compound of Formula X to form a compound of Formula XIII can be carried out in the presence of one or more organic or inorganic bases, for example, trimethylamine, triethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate or mixtures thereof.
  • This reaction can also be carried out in the presence of one or more alcoholic solvents, for example, methanol, ethanol, propanol, isopropanol, n-butanol or mixtures thereof.
  • reaction of a compound of Formula XIII with one or more peroxyacids to form a compound of Formula XIV can be carried out in one or more solvents, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or mixtures thereof.
  • Compounds of Formula XVII can be prepared according to methods in Scheme IV.
  • the methods comprise reacting 3a,4,7,7a-tetrahydroisoindole-l,3-dione of Formula XVI with a 1,3-dihalopropane (e.g., 1,3-dibromopropane, 1,3-dichlropropane, 1,3-diiodopropane, 1,3- difluoropropane, wherein Y is F, Cl, Br or I) to form a compound of Formula XV.
  • a 1,3-dihalopropane e.g., 1,3-dibromopropane, 1,3-dichlropropane, 1,3-diiodopropane, 1,3- difluoropropane, wherein Y is F, Cl, Br or I
  • the compound of Formula XV can be reacted with a compound of Formula X to form a compound of Formula XVI, wherein Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy.
  • the compound of Formula XVI can be reacted with one or more peroxyacids to form a compound of Formula XVII, wherein Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy.
  • Suitable peroxyacids include, for example, m- chloroperbenzoic acid, monoperoxyphthalate, potassium peroxomonosulfate or mixtures thereof.
  • reaction of 3a,4,7,7a-tetrahydroisoindole-l,3-dione of Formula VI with 1,3- dihalopropane to form a compound of Formula XV can be carried out in one or more solvents, for example, acetonitrile, acetone, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or mixtures thereof.
  • This reaction can also be carried out in the presence of one or more organic or inorganic halides (e.g.
  • tetrabutyl ammonium chloride tetrabutyl ammonium bromide, potassium iodide or mixtures thereof
  • inorganic bases e.g., barium carbonate, cesium carbonate, potassium carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate or mixtures thereof.
  • the reaction of 2-(3-halopropyl)-3a,4,7,7a-tetrahydroisoindole-l,3-dione of Formula XV with a compound of Formula X to form a compound of Formula XVI can be carried out in one or more solvents, for example, acetonitrile, ethanol, butanol, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or mixtures thereof.
  • This reaction can also be carried out in the presence of one or more inorganic bases (e.g., potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate or mixtures thereof).
  • reaction of a compound of Formula XVI with one or more peroxyacids to form a compound of Formula XVII can be carried out in one or more solvents, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or mixtures thereof.
  • Compounds of Formula XX can be prepared according to the methods in Scheme V.
  • the methods comprise reacting 2-(3-halopropyl)-3a,4,7,7a-tetrahydroisoindole- 1,3-dione of Formula XV (wherein Y is F, Cl, Br or I) with one or more peroxyacids to form 4-(3-halopropyl)-hexahydro-l-oxa-4-aza-cyclopropa[f]indene-3,5-dione of Formula XVIII (wherein Y is F, Cl, Br or I).
  • the compound of Formula XVIII can be reacted with a compound of Formula X to form a compound of Formula XIX, wherein Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy.
  • the compound of Formula XIX can be treated with one or more peroxyacids to form a compound of Formula XX, wherein Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy.
  • Suitable peroxyacids include, for example, m-chloroperbenzoic acid, monoperoxyphthalate, potassium peroxomonosulfate or mixtures thereof.
  • the reaction of 4-(3-halopropyl)-hexahydro-l-oxa-4-aza-cyclopropa[f]indene-3,5- dione of Formula XVIII with a compound of Formula X to form a compound of Formula XIX can be carried out in one or more solvents, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or mixtures thereof.
  • This reaction can also be carried out in the presence of one or more inorganic bases, for example, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate or mixtures thereof.
  • reaction of a compound of Formula XIX with one or more peroxyacids to form a compound of Formula XX can be carried out in one or more solvents, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or mixtures thereof.
  • Compounds of Formula XXVIII and compounds of Formula XXIX can be prepared according to methods in Scheme VI.
  • the methods comprise reacting a compound of Formula X with acrylonitrile to form a compound of Formula XXI, which on reduction forms a compound of Formula XXII.
  • the compound of Formula XXII can react with furan-2,5-dione to form a compound of Formula XXIII, which on reaction with 1-acetoxy- 1,3 -butadiene or l,4-diacetoxy-l,3-butadiene forms (a) a compound of Formula XXIV, which can be hydrolyzed to form a compound of
  • Suitable peroxyacids include, for example, m-chloroperbenzoic acid, monoperoxyphthalate, potassium peroxomonosulfate or mixtures thereof.
  • reaction of a compound of Formula X with acrylonitrile to form a compound of Formula XXI can be carried out in one or more alcoholic solvents, for example, methanol, ethanol, propanol, n-butanol or mixtures thereof.
  • the reduction of a compound of Formula XXI to form a compound of Formula XXII can be carried out in the presence of one or more reducing agents, for example, palladium on carbon and hydrogen in ammonia and one or more alcohols (e.g., methanol, ethanol, propanol, n-butanol or mixtures thereof); or Raney nickel and hydrogen in ammonia and one or more alcohols (e.g., methanol, ethanol, propanol, n-butanol or mixtures thereof).
  • one or more reducing agents for example, palladium on carbon and hydrogen in ammonia and one or more alcohols (e.g., methanol, ethanol, propanol, n-butanol or mixtures thereof); or Raney nickel and hydrogen in ammonia and one or more alcohols (e.g., methanol, ethanol, propanol, n-butanol or mixtures thereof).
  • reaction of a compound of Formula XXII with furan-2,5-dione to form a compound of Formula XXIII can be carried out in one or more solvents, for example, toluene, benzene, tetrahydrofuran, acetonitrile, xylene or mixtures thereof.
  • reaction of a compound of Formula XXIII with 1-acetoxy- 1,3 -butadiene or 1,4- diacetoxy- 1,3 -butadiene to form a compound of Formula XXIV or XXV can be carried out in one or more solvents, for example, toluene, benzene, xylene or mixtures thereof.
  • the hydrolysis of compound of Formula XXIV and XXV to form compounds of Formula XXVII and XXVI, respectively can be carried out in one or more alcoholic solvents, for example, methanol, ethanol, propanol, n-butanol or mixtures thereof.
  • the reaction of compounds of Formula XXVI and XXVII with one or more peroxyacids to form compounds of Formula XXVIII and XXIX respectively can be carried out in one or more solvents, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or mixtures thereof.
  • Compounds of Formula XXXIII can be prepared according to the methods in Scheme VII.
  • the methods can comprise reacting isoindole-l,3-dione of Formula XXX with 1,3- dihalopropane ⁇ e.g., 1,3-dibromopropane, 1,3-dichlropropane, 1,3-diiodopropane, 1,3- difluoropropane, wherein Y is Br, Cl, I or F) to form 2-(3-halopropyl)isoindole-l,3-dione of Formula XXXI, which on reaction with a compound of Formula X forms a compound of Formula XXXII, wherein Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy.
  • a compound of Formula XXXII can be finally reacted with one or more peroxyacids to form a compound of Formula XXXIII, wherein Ri can be hydrogen or isopropyl and R 2 can be hydrogen or hydroxy.
  • the reaction of isoindole-l,3-dione of Formula XXX with 1,3-dihalopropane to form a compound of Formula XXXI can be carried out in one or more solvents, for example, acetonitrile, acetone, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or mixtures thereof.
  • This reaction can be carried out in the presence of one or more organic halides, for example, tetrabutyl ammonium chloride, tetrabutyl ammonium bromide or mixtures thereof, and one or more inorganic bases, for example, barium carbonate, cesium carbonate, potassium carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate or mixtures thereof.
  • organic halides for example, tetrabutyl ammonium chloride, tetrabutyl ammonium bromide or mixtures thereof
  • inorganic bases for example, barium carbonate, cesium carbonate, potassium carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate or mixtures thereof.
  • the reaction of 2-(3-halopropyl)isoindole-l,3-dione of Formula XXXI with a compound of Formula X to form a compound of Formula XXXII can be carried out in one or more solvents, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or mixtures thereof.
  • This reaction can be carried out in the presence of one or more inorganic bases, for example, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate or mixtures thereof.
  • reaction of a compound of Formula XXXII with peroxyacid to a form a compound of Formula XXXIII can be carried out in one or more solvents, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or mixtures thereof.
  • W can be -SO 2 -, -CO-, -CONR 8 (wherein R 8 can be alkyl of from one to four carbon atoms or aryl, e.g., phenyl or naphthyl); R can be alkyl of from one to four carbon atoms, aryl (e.g., phenyl or naphthyl), or aralkyl (e.g., benzyl), and the circle represents main structure of any compound described herein including, for example, the main structure of Formulae II, IV, V, Va, XI, XII, XIII, XIV, XVI, XVII, XIX, XX, XXVI, XXVII, XXVIII, XXIX, XXII, or XXXIII.
  • Compounds of Formula X-W-R may also be used in place of Cl-W-R in this reaction, wherein X can be a
  • reaction of the hydroxylated metabolites of Formula XXXIV with a compound of Formula Cl-W-R to form compound of Formula XXXV can be carried out in one or more solvents, for example, tetrahydrofuran, dimethylformamide or mixtures thereof.
  • This reaction can also be carried out in the presence of one or more inorganic bases (e.g., sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride or mixtures thereof).
  • Prodrugs encompassed herein include compounds of Formula XXXV, wherein W and R are respectively, SO 2 and (Ci-C 4 )-alkyl; SO 2 and methyl; SO 2 and aryl; SO 2 and phenyl; CO and (Ci-C 4 )-alkyl; CO and methyl; CO and ethyl; CO and aralkyl; CO and benzyl; CONR 8 and (Ci-C 4 )-alkyl, wherein Rg is alkyl of from one to four carbon atoms; CONR 8 and methyl, wherein R 8 methyl; CONR 8 and aryl, wherein R 8 is (Ci-C 4 )-alkyl; CONR 8 and phenyl, wherein R 8 is methyl; CONR 8 and aryl, wherein R 8 is aryl; or CONR 8 and phenyl, wherein R 8 is phenyl.
  • prodrugs encompassed herein include compounds having the structure of Formula XXXVa,
  • Formula XXXVa a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, polymorph, conjugate or prodrug thereof, wherein Y and Z, when taken together represent the fused ring systems including:
  • R 3 , R 4 , R5 and R 6 are independently hydrogen, hydroxyl or -OW-R;
  • X is -CHR 7 , wherein R 7 is hydrogen, hydroxyl or -0-W-R;
  • Ri is hydrogen or isopropyl
  • R 2 is hydrogen, hydroxyl or 0-W-R n is an integer 0 or 1 , and at least one of R 2 , R 3 , R 4 , R5, R 6 or X is -0-W-R, wherein W is -SO 2 , -CO-, -CONR 8 , wherein R 8 is (C
  • R is (Ci-C 4 )-alkyl, aryl or aralkyl.
  • Prodrugs having a structure of Formula XXXVa can be prepared by processes comprising reacting a hydroxy lated metabolite of Formula XXXIVa
  • R 3 , R 4 , R 5 and R 6 are independently hydrogen or hydroxyl;
  • X is -CHR 7 , wherein R 7 is hydrogen or hydroxyl;
  • Ri is hydrogen or isopropyl;
  • R 2 is hydrogen or hydroxyl;
  • n is an integer O or 1 ; and at least one Of R 2 , R3, R 4 , R 5 , Re or X is hydroxyl, wherein W is -SO 2 , -CO-, -CONR 8 , wherein R 8 is (C r C 4 )-alkyl or aryl, and R is (Ci-GO-alkyl, aryl or aralkyl, with a compound of Formula Cl-W-R, wherein W is -SO 2 , -CO-, -CONR 8 , wherein R 8 is (Ci-C 4 )-alkyl or aryl, and R is (Ci-C 4 )-alkyl, aryl or aralky
  • the reaction of the hydroxylated metabolite of Formula XXXIVa with the compound of Formula Cl-W-R can be carried out in one or more solvents selected from tetrahydrofuran, dimethylformamide or mixtures thereof.
  • the reaction of the hydroxylated metabolite of Formula XXXIVa with the compound of Formula XXXVa can also be carried out in the presence of one or more inorganic bases selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride or mixtures thereof.
  • Example 7 Preparation of 2-(3-bromopropyl)-3a,4,7,7a-tetrahydroisoindole-l,3-dione A mixture of 3a,4,7,7a-tetrahydroisoindole-l,3-dione (5.0 g, 0.033 mole), 1,3- dibromopropane (10 g, 0.05 mole), potassium carbonate (6.9 g, 0.05 mole) and tetrabutylammonium iodide (0.24 g, 0.00065 mole) in acetone (30 mL) was stirred at 40 0 C for about 8 hours.
  • Example 8 Preparation of 2-(3-bromopropyl ' )-isoindole-l,3-dione
  • isoindole-l,3-dione 5.0 g, 0.034 mole
  • 1,3-dibromopropane (10.3 g,0.051 mole)
  • potassium carbonate 7.04 g,0.051 mole
  • tetrabutylammonium iodide (0.25 g, 0.00068 mole ) in acetone (30 mL) was stirred at 40 0 C for about 8 hours.
  • Inorganics were filtered, washed with acetone, solvent thus obtained was removed under pressure and the residue was suspended in water.
  • Example 12 Preparation of 2- ⁇ 2-hydroxy-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl ' ]- propyl
  • Example 14 Preparation of 4- ⁇ 3-
  • Example 15 Preparation of 2- j3-[4-(2-hvdroxy-phenyl)-piperazin-l-vH-propyU-3a,4,7,7a- tetrahydroisoindole-U-dione hydrochloride salt (Compound No.2)
  • a solution of N-(3-bromopropyl)-phthalimide (1.0 g, 0.0036 mole), anhydrous potassium carbonate (0.5 g, 0.0036 mole) and l-(2-hydroxyphenyl) piperazine (0.654 g, 0.0036 mole) in dimethyl formamide (15 mL) was heated at 75-80 0 C for about 6-8 hours.
  • the reaction mixture was quenched by adding water (20 mL), extracted with ethyl acetate, concentrated and purified on silica gel (60-120 mesh) column using dichloromethane and methanol as eluent.
  • Example 16 Preparation of 4-hydroxy-2- j3-(4-f2-isopropoxy-phenyl)-piperazin-l-yll- propyl ⁇ -3aA7Ja tetrahydro-isoindole-l,3-dione hydrochloride salt (Compound No. 6)
  • Inorganics were filtered through celite pad, washed with methanol and concentrated to yield the crude product. It was purified on silica gel (60-120 mesh) column using dichloromethane and methanol as eluent to yield 0.30 g (50 %) of the product.
  • Example 17 Preparation of 4,7-dihydroxy-2-f3-4-[2-isopropoxy-phenyl)-piperazin-l-yl]- propyl
  • Aqueous standard sample of 2- ⁇ 3-[4-(2-isopropoxyphenyl) piperazin-l-yl]-propyl ⁇ - 3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione and its metabolites were injected under gradient HPLC conditions.
  • the metabolites were identified if the retention time of observed peak matches retention of aqueous standard of metabolites.
  • the identified peaks were collected and product ion scan was performed on LC-MS/MS, (Table I). The metabolites were confirmed when their retention time and mass fragmentation pattern matches with that of synthetic standard.
  • the molecular ion peak (m/z), product ion peak (m/z) and the retention time (RT) identified are given in Table I.
  • the urine samples were processed by two different methods.
  • the urine samples were processed by solid phase extraction (SPE) method as follows:
  • the sample was washed with 2 mL of wash solution (2 % acetic acid solution), followed by 2 mL of methanol and dried for 2 minutes under vacuum.
  • Bile samples were precipitated with equal volume of methanol, vortexed, centrifuged and the supernatant was analysed by HPLC under gradient conditions.
  • the molecular in peak (m/z), product ion peak (m/z) and the retention time (RT) of metabolites in rat (urine, plasma, bile and faeces) are given in Table II.
  • the sample was washed with 2 mL of wash solution (2 % acetic acid solution), followed by 2 mL of methanol and dried for 2 minutes under vacuum.
  • 2- ⁇ 3-[4-(2-isopropoxyphenyl) piperazin-1- yl]-propyl ⁇ -3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione and its metabolites were eluted twice with 2 mL of elution solution (2 % ammonia in ethyl acetate).
  • the dried fractions were reconstituted in 500 ⁇ L of mobile phase and the samples were analysed by LC-MS.
  • the molecular ion peak (m/z), product ion peak (m/z) and the retention time (RT) of metabolites identified in dog plasma and the molecular ion peak (m/z) of conjugates of metabolites identified in dog urine are given in Table III and IV, respectively.
  • the molecular ion peak (m/z), product ion peak (m/z) and the retention time (RT) in HPLC and LC-MS of all the metabolites identified in rat and dog are listed in Table V. Chromatographic conditions (HPLC)
  • Example 20 Estimation of Compound No. 9 and Compound No. 1 1 in plasma (rat and dog) by LC/MS/MS
  • 100mg/3cc cartridges were used for processing the samples.
  • the cartridges were conditioned on vacuum manifold at constant pressure using 2 mL of methanol and 2 mL of potassium dihydrogen phosphate buffer (0.1M, pH 4.7 ⁇ 0.1) followed by loading of sample.
  • the cartridges were washed using 2 mL of wash solution (2 % acetic acid solution) and dried for 2 minutes under vacuum followed by washing with 2 mL of methanol and dried for 2 minutes under vacuum.
  • Submaxillary glands were isolated immediately after sacrifice.
  • the liver was perfused with buffer (Tris HCl 50 raM, pH 7.4).
  • the tissues were homogenized with 10 volume of buffer (Tris HCL 50 mM, NaCl 100 mM, EDTA ImM, pH 7.4) with a polytron.
  • the homogenate was filtered through two layers of wet gauze and filtrate was centrifuged at 3000g for 10 minutes. The supernatant was subsequently centrifuged at 60,000 G for 45 minutes.
  • the pellet thus obtained was resuspended in a same volume of assay buffer (Tris HCl 50 mM, EDTA ImM, pH 7.4) and were stored at -70 0 C until the time of assay.
  • the membrane homogenates (150-250 ⁇ g protein) were incubated in titre plates in 250 ⁇ L of assay buffer (Tris HCl 50 mM, EDTAi mM, pH 7.4) at 24-25 0 C for 1 hour. Non-specific binding was determined in the presence of 300 mM prazosin or 10 ⁇ M terazosin.
  • the incubation was terminated by vacuum filtration over 0.5 % polyethyleneimine pre-treated GF/B fibers using a skatron cell harvester. The filters were then washed with ice cooled 50 mM Tris HCl buffer (pH 7.4). The filtrates were dried and transferred to 24 well plates (PET A No cross talk).
  • Radioactivity retained on filters was counted in 600 ⁇ L of supermix in microbeta with a counting efficiency of 46 %.
  • the IC50 value was determined using the nonlinear curve fitting program using G pad prism software. Saturation binding assays were used to determine Kd (apparent dissociation constant) for [ 3 H] prazosin.
  • Ki was calculated from competitive binding studies by using Cheng and Prusoff equation (Cheng and Prusoff, Biochem. Pharmacol. , 22:3099-3108 (1973)):
  • Ki IC5o/(l+L/Kd wherein L is the concentration of [ H] prazosin used in the particular experiment.
  • Subtype selective by ( ⁇ i a Vs ⁇ ib) is expressed as ratio of mean Ki at ⁇ jb receptors to mean Ki at ⁇ j a receptor (Table VII).
  • the affinities of metabolites at rat ⁇ ⁇ -adrenoceptor (Ki) for Compound Nos. 2-1 1 ranged from of about 65 nM to about 0.2 nM, from about 3 nM to about 0.2 nM, or from about 17 nM to about 0.2 nM.
  • affinities of metabolites at rat oti b -adrenoceptor (Ki) for Compound Nos. 2-1 1 ranged from of about 40 nM to about 1000 nM, from about 40 nM to about 700 nM, and even from about 40 nM to about 400 nM.
  • Example 22 In vitro functional studies: In vitro alpha- 1 adrenoceptor selectivity
  • alpha- 1 adrenoceptor agonist induced contractile response of aorta (alpha- Id), prostate (alpha- Ia) and spleen (alpha-lb) was studied.
  • Aorta, prostate and spleen tissue were isolated from thiopentane anaesthetized ( ⁇ 300 mg/Kg) male wistar rats. Isolated tissues were mounted in an organ bath containing Krebs Henseleit buffer of the following composition (mM): NaCl 118; KCl 4.7; CaCl 2 2.5; MgSO 4 .
  • concentration response curves to norepinephrine (aorta) and phenylephirine (spleen and prostate) were obtained in the absence and presence of the tested compound (at concentration of 0.1, 1 and 10 ⁇ M).
  • Antagonist affinities for Compound Nos. 2-11 were calculated and expressed as pK ⁇ values for OC IA , ot I B and CC I D adrenoreceptor W
  • Antagonist affinities for a ⁇ adrenoreceptor subtype ranged having a pK ⁇ from about 7.7 to about 9.8; having a pK ⁇ from about 8.4 to about 9.6; and even having a pK ⁇ from about 8.7 to about 9.3.
  • Antagonist affinities for CC I B adrenoreceptor subtype ranged having a pK ⁇ from about 7.0 to about 9.0; having a pK ⁇ from about 7.2 to about 8.1; and even having a pK ⁇ from about 7.8 to about 8.0.
  • Antagonist affinities for ctio adrenoreceptor subtype ranged having a pK ⁇ from about 7.5 to about 8.9; having a pK ⁇ from about 7.7 to about 8.7; and even having a pK B from about 8.0 to about 8.6.
  • Example 23 Preparation of benzenesulfonic acid 2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro isoindol-2-yl)- 1 -[ 1 -hvdroxy-4-(2-isopropoxyphenyl)-piperazin- 1 -ylmethyl "
  • Methylcarbamic acid-2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l-[l-oxy-4-(2- hydroxyphenyl) piperazin- 1 -ylmethyl] ethyl ester (Compound No. 17).

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Abstract

The present invention relates to the metabolites of 2-{3-[4-(2-isopropoxyphenyl) piperazin-1-yl]-propyl}-3a,4,7,7a -tetrahydro-1H-isoindole-1,3(2H)-dione of Formula I. The disclosed compounds can function as 1a-adrenoceptor antagonists and thus can be used for the treatment of benign prostatic hyperplasia (BPH) and related symptoms thereof. Processes for preparing the metabolites, pharmaceutical composition containing these metabolites and the method of treating BPH and related symptoms thereof are also provided.

Description

METABOLITES OF 2-{3- [4-(2-ISOPROPOXYPHENYL) PIPERAZIN-1-YL]- PROPYL}-3a,4,7,7a-TETRAHYDRO-lH-ISOINDOLE-l,3-(2H)-DIONE
Field of the Invention The present invention relates to metabolites of 2- {3-[4-(2-isopropoxyphenyl) piperazin-l-yl]-propyl}-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione of Formula I.
Figure imgf000003_0001
The disclosed compounds can function as αia-adrenoceptor antagonists and thus can be used for the treatment of benign prostatic hyperplasia (BPH) and related symptoms thereof. Processes for preparing such metabolites, pharmaceutical compositions containing such metabolites and methods of treating BPH and related symptoms thereof are also provided.
Background of the Invention cci -adrenoceptor antagonists are in clinical use for symptomatic treatment of benign prostatic hyperplasia (BPH) (Oesterling, Drug Therapy, 332(2): 99-110, 1995;
Chappie, Br. J. Urology, 1:47-55, 1995). It is disclosed that the effects of cti -adrenoceptor antagonists result from antagonism of noradrenaline induced contraction of prostatic smooth muscle that occurs via oci adrenoceptors (Hieble et al, European Journal of Pharmacology, 107: 1 11-117, 1985). However, as αi -adrenoceptors are widely distributed, poor organ selectivity limits therapeutic usefulness for this class of drugs. In recent years, the existence of at least three distinct subtypes of cti -adrenoceptors designated as ocia, otib and aid has been established. Several studies have indicated that ctia-adrenoceptor mediate the contraction of human and dog prostatic smooth muscle (Marshall et al., Br. J. Pharmacol, 112:59p, 1992; Forray et al., Molecular Pharmacology, 45:703-708, 1994). It has been suggested that selective α ^-antagonists would be more efficacious and better-tolerated agents for symptomatic BPH.
2-{3-[4-(2-Isopropoxyphenyl)piperazin-l-yl]-propyl}-3a,4,7,7a-tetrahydro-lH- isoindole-l,3-(2H)-dione is disclosed in WO 02/44151 as a α ^-adrenoceptor antagonist for the treatment of benign prostatic hypertrophy, also known as BPH. BPH is highly prevalent in men beyond the age of 50 and increases in severity and incidence with increase in age. The incidence is 70 % at 70 years of age and becomes nearly universal with advancing age, reaching about 90 % incidence at 80 years of age. BPH is characterized by a nodular enlargement of prostatic tissue resulting in obstruction of the urethra, resulting in increased frequency of urination, nocturia, a poor urine stream and hesitancy or delay in starting the urine flow. Chronic consequences of BPH can include hypertrophy of bladder smooth muscle, a decompensated bladder and increased incidence of urinary tract infection. The method of choice for treating BPH reportedly is surgery (Lepor, et al, The Journal of Urology, 143:553-537, 1990). Limitations of surgical treatments of BPH include high morbidity rates of an operative procedure in elderly men, persistence or recurrence of obstructive and irritative symptoms, as well as high costs of surgery.
Accordingly, there is a need for a medicinal alternative to surgery in treating BPH and in particular, a drug-based therapy in treating BPH. Summary of the Invention
Generally provided are metabolites of 2-{3-[4-(2-isopropoxyphenyl)piperazin-l- yl]-propyl}-3a,4,7,7a-tetrahydro-lH-isoindole-l,3-(2H)-dione. Such metabolites can be used in safe and effective treatments of BPH or related symptoms thereof. Processes for the synthesis of these metabolites, as well as pharmaceutical compositions thereof, are also provided. Encompassed pharmaceutical compositions may also contain one or more pharmaceutically acceptable carriers or diluents.
Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, conjugates, or prodrugs of such metabolites having the same type of activity are also provided, which can be useful for safe and effective treatment of BPH or related symptoms thereof. Pharmaceutical compositions comprising the metabolites of the present invention, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, conjugates, or prodrugs in combination with one or more pharmaceutically acceptable carriers, and optionally included excipients, are also included, which can be useful for safe and effective treatment of BPH or related symptoms thereof.
Other aspect and properties of this matter will be set forth in description which follows, and will be apparent from the description or may be learnt by the practice thereof.
In one aspect, provided herein are metabolites of 2-{3-[4-(2-Isopropoxyphenyl)- piperazin-l-yl]-propyl}-3a,4,7,7a-tetrahydro-lH-isoindole-l,3-(2H)-dione of Formula I,
Formula I pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymorphs, conjugates or prodrugs thereof, wherein the metabolite can be an aromatized, desisopropylated, hydroxylated, epoxylated, or N-oxide derivative or conjugate or prodrug thereof. In another aspect, provided herein are compounds having the structure of Formula II,
Figure imgf000005_0002
Formula Il pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymorphs, conjugates or prodrugs thereof, wherein Y and Z, when taken together can represent the fused ring systems including:
Figure imgf000006_0001
wherein R3, R4, R5 and RO can independently be hydrogen or hydroxyl; X can be -CHR7, wherein R7 can be hydrogen or hydroxyl;
Ri can be hydrogen or isopropyl; R2 can be hydrogen or hydroxyl and n can be an integer 0 or 1.
Embodiments of the compounds of Formula II may include one or more of the following. For example, compounds of Formula II can be an aromatized, desisopropylated, hydroxylated, epoxylated, or N-oxide metabolite of 2-{3-[4-(2-Isopropoxyphenyl)-piperazin- 1 -yl]-propyl}-3a,4,7,7a-tetrahydro-lH-isoindole-l,3-(2H)-dione of Formula I.
Figure imgf000006_0002
Conjugates can be a sulfate, phosphate or glucuronate derivative. Prodrugs can be a carbamoyl, (Ci-C4)-alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, (C]-C4)-alkylsulfonyl or arylsulphonyl derivative.
Compounds of Formula II can include desisopropylated metabolite 2-{3-[4-(2- hydroxyphenyl)-piperazin-l -yl]-propyl}-3a,4,7,7a-tetrahydroisoindole-l,3-dione. The metabolite can have a molecular ion peak of m/z 370. A sulphate conjugate of the metabolite can also have a molecular ion peak of m/z 448. A glucuronate conjugate of the metabolite can have a molecular ion peak of m/z 546. Compounds of Formula II can include aromatized metabolite 2-{3-[4-(2- isopropoxyphenyl)-piperazin-l-yl]-propyl}-isoindole-l,3-dione. The metabolite can have a molecular ion peak of m/z 408.
Compounds of Formula II can include N-oxide metabolite 2-{3-[l-oxy-4-(2- isopropoxyphenyl)-piperazin-l-yl]-propyl}-3a,4,7,7a -tetrahydroisoindole-l,3-dione. The metabolite can have a molecular ion peak of m/z 428.
Compounds of Formula II can include hydroxylated metabolite 2-{2-hydroxy-3-[4-(2- isopropoxyphenyl)-piperazin-l-yl]-propyl}-3a,4,7,7a-tetrahydroisoindole-l,3-dione. The metabolite can have a molecular ion peak of m/z 428. Compounds of Formula II can include hydroxylated metabolite 4,7-dihydroxy-2-[3-4-
[2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-3a,4,7,7a-tetrahydroisoindole-l,3-dione. The metabolite can have a molecular ion peak of m/z 444.
Compounds of Formula II can include hydroxylated metabolite 4-hydroxy-2-{3-(4-(2- isopropoxy-phenyl)-piperazin-l-yl}-propyl}-3a,4,7,7a-tetrahydroisoindole-l,3-dione. The metabolite can have a molecular ion peak of m/z 428.
Compounds of Formula II can include epoxylated metabolite 4-{3-[4-(2- isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-l-oxa-4-aza-cyclopropa[f]indene-3,5- dione. The metabolite can have a molecular ion peak of m/z 428.
Compounds of Formula II can include hydroxylated metabolite 4-{2-Hydroxy-3-[4- (2-isopropoxyphenyl)-piperazin- 1 -yl] -propyl} -hexahydro- 1 -oxa-4-aza- cyclopropa[f]indene3,5-dione. The metabolite can have a molecular ion peak of m/z 444.
Compounds of Formula II can include hydroxylated metabolite 5,6-Dihydroxy-2-{3- [4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-l,3-dione. The metabolite can have a molecular ion peak of m/z 446. A glucuronate conjugate of the metabolite can have a molecular ion peak m/z 622.
Compounds of Formula II can include hydroxylated metabolite 2-{2-Hydroxy-3-[4- (2-hydroxy-phenyl)-piperazin- 1 -yl] -propyl } -3a,4, 7,7a-tetrahydro isoindole- 1 ,3 -dione. The metabolite can have a molecular ion peak m/z 386. A sulphate conjugate of the metabolite can have a molecular ion peak m/z 466. Compounds of Formula II can include 2-{3-[4-(2-isopropoxyphenyl)-l- oxidopiperazin-l-yl}-propyl}-3a,4,7,7a-tetrahydroisoindole-l,3-dione or 5,6-Dihydroxy-2- {3 -[4-(2-isopropoxy-phenyl)-piperazin- 1 -yl]-propyl } -hexahydroisoindole- 1 ,3 -dione .
Compounds of Formula II can also include:
Benzenesulfonic acid-2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l-[l-oxy-4-
(2-hydroxyphenyl)-piperazin- 1 -ylmethyl]-ethyl ester,
Phenylcarbamic acid-2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l-[l-oxy-4- (2-hydroxyphenyl)-piperazin- 1 -ylmethyl] -ethyl ester,
Methanesulfonic acid-2-(l ,3-dioxo- 1 ,3,3a,4,7,7a-hexahydroisoindol-2-yl)- 1 -[ 1 -oxy-4- (2-hydroxyphenyl)-piperazin-l-ylmethyl]-ethyl ester,
Acetic acid-2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l-[l-oxy-4-(2- hydroxyphenyl)-piperazin-l-ylmethyl]-ethyl ester, or
Methylcarbamic acid-2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l-[l-oxy-4- (2-hydroxyphenyl)-piperazin- 1 -ylmethyl] -ethyl ester.
In another aspect, provided herein are pharmaceutical compositions comprising therapeutically effective amounts of one or more compounds of Formula II,
Figure imgf000008_0001
Formula Il pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymorphs, conjugates or prodrugs thereof, and a pharmaceutically acceptable carrier, wherein Y and Z, when taken together can represent the fused ring systems including:
Figure imgf000009_0001
wherein R3, R4, R5 and R<, can independently be hydrogen or hydroxyl; X can be -CHR7, wherein R7 can be hydrogen or hydroxyl;
Ri can be hydrogen or isopropyl; R2 can be hydrogen or hydroxyl and n can be an integer 0 or 1.
Embodiments of the pharmaceutical compositions can encompass one or more of the following. The pharmaceutical compositions can contain conjugates that include, for example, a sulfate, phosphate or glucuronate derivatives. The pharmaceutical compositions can also contain prodrugs that include, for example, carbamoyl, (Ci-C4)-alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, (Ci-C4)-alkylsulfonyl or arylsulphonyl derivatives.
In one aspect, provided herein are methods for treating a disease or disorder mediated through ccia adrenoceptor comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein.
In another aspect, provided herein are methods for treating a disease or disorder selected from high intraocular pressure, disorder associated with high cholesterol, cardiac arrhythmia, impotency, sympathetically mediated pain and migraine, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein.
In another aspect, provided herein are methods for the treating benign prostatic hyperplasia comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein. Embodiments of this method can include one or more of the following aspects. For example, administration of the compound does not cause a fall in blood pressure. The compound can also relax lower urinary tract tissues, for example, the prostate smooth .muscle. In another aspect, provided herein are methods for treating a disease or disorder mediated through ecu adrenoceptor comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition disclosed herein.
In another aspect, provided herein are methods for treating a disease or disorder selected from high intraocular pressure, disorder associated with high cholesterol, cardiac arrhythmia, impotency, sympathetically mediated pain and migraine comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition disclosed herein.
In yet another aspect, provided herein are methods for treating benign prostatic hyperplasia comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition disclosed herein.
In another aspect, provided herein are processes for preparing compounds of Formula IV, Formula V or Formula Va or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, conjugates or prodrugs thereof comprising: a) reacting a compound of Formula III
Figure imgf000010_0001
wherein R2 can be hydrogen or hydroxy, with one or more peroxyacids to form a compound of Formula IV,
Figure imgf000011_0001
Formula IV
wherein R2 can be hydrogen or hydroxy, b) reacting a compound of Formula IV,
Figure imgf000011_0002
Formula IV
wherein R2 can be hydrogen or hydroxy, with one or more peroxyacids to form a compound of Formula V,
Figure imgf000011_0003
Formula V
wherein R2 can be hydrogen or hydroxy, or c) reacting a compound of Formula III
Figure imgf000012_0001
Formula III
wherein R2 can be hydrogen or hydroxy, with one or more peroxyacids to form a compound of Formula Va
Figure imgf000012_0002
Formula Va
wherein R2 can be hydrogen or hydroxy.
Embodiments of the processes can include one or more of the following. For example, reaction a), b) or c) can be carried out in one or more solvents selected from, for example, dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, dimethyl sulphoxide or mixtures thereof. Peroxyacids in reaction a), b) or c) can be, for example, magnesium monoperoxyphthalate, potassium peroxomonosulfate, m-chloroperbenzoic acid or mixtures thereof.
In another aspect, provided herein are processes for preparing compounds of Formula XI or Formula XII or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, polymer, conjugate or prodrugs thereof comprising: a) reacting 3a,4,7,7a-tetrahydro isoindole-l,3-dione of Formula VI
Figure imgf000013_0001
Formula Vl
with a compound of Formula VII,
Figure imgf000013_0002
Formula VII
wherein Xi can be chlorine or bromine, to form 2-oxiranylmethyl-3a,4,7,7a- tetrahydroisoindole- 1 ,3 -dione of Formula VIII,
Figure imgf000013_0003
Formula VIII
which can be reacted with one or more peroxyacids to form 4-oxiranylmethylhexa-l-oxa-4- aza-cyclopropa[f]indene-3,5-dione of Formula IX,
Figure imgf000013_0004
which can be reacted with a compound of Formula X
Figure imgf000014_0001
Formula X
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy, to form a compound of Formula XI,
Figure imgf000014_0002
Formula Xl
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy, or b) reacting a compound of Formula XI
Figure imgf000014_0003
Formula Xl
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy, with one or more peroxyacids to form a compound of Formula XII,
Figure imgf000015_0001
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy.
Embodiments of the processes can include one or more of the following. For example, the reaction of the compound of Formula VI with the compound of Formula VII can be carried out in one or more solvents selected from, for example, acetone, ethylmethylketone, dimethylformamide, n-butanol, acetonitrile, toluene, chlorobenzene or mixtures thereof. The reaction can also be carried out in the presence of one or more inorganic or organic bases selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, triethylamine, trimethylamme, diethylisopropyl amine or mixtures thereof.
The reaction of the compound of Formula VIII with one or more peroxyacids can be carried out in one or more solvents selected from, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or mixtures thereof. The reaction of the compound of Formula VIII to form the compound of Formula IX or the reaction of the compound of Formula XI to form the compound of Formula XII can be carried out using one or more peroxyacids selected from, for example, magnesium monoperoxyphthalate, potassium peroxomonosulfate, m-chloroperbenzoic acid or mixtures thereof.
The reaction of the compound of Formula IX with a compound of Formula X can be carried out in one or more solvents selected from, for example, methanol, ethanol, propanol, n-butanol or mixtures thereof. The reaction of the compound of Formula XI with one or more peroxyacids can be carried out in one or more solvents selected from, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or mixtures thereof. In another aspect, provided herein are processes for preparing compounds of Formula XIII or Formula XIV or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, polymorph, conjugate or prodrug thereof comprising: a) reacting 2-oxiranylmethyl-3a,4,7,7a-tetrahydroisoindole- 1 ,3-dione of Formula VIII
Figure imgf000016_0001
Formula VIII
with a compound of Formula X,
Figure imgf000016_0002
Formula X
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy, to form a compound of Formula XIII,
Figure imgf000016_0003
Formula XlII
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy, or b) reacting a compound of Formula XIII,
Figure imgf000017_0001
Formula XIII
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy, with one or more peroxyacids to form a compound of Formula XIV,
Figure imgf000017_0002
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy.
Embodiments of the processes can include one or more of the following. For example, the reaction of the compound of Formula VIII with the compound of Formula X can be carried out in one or more solvents selected from, for example, methanol, ethanol, propanol, n-butanol or mixture thereof. The reaction of the compound of Formula VIII with the compound of Formula X can be carried out in the presence of one or more organic or inorganic bases selected from, for example, trimethylamine, triethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate or mixtures thereof.
The reaction of the compound of Formula XIII with one or more peroxyacids can be carried out in one or more solvents selected from, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or mixtures thereof. Suitable peroxyacids include, for example, magnesium monoperoxyphthalate, potassium peroxomonosulfate, m-chloroperbenzoic acid or mixtures thereof. In another aspect, provided herein are processes for preparing compounds of Formula XVI or Formula XVII or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymers, conjugates or prodrugs thereof comprising: a) reacting 3a,4,7,7a-tetrahydroisoindole-l,3-dione of Formula VI
Figure imgf000018_0001
Formula Vl
with 1,3-dihalopropane (Y-CH2CH2CH2-Y) to form 2-(3-halopropyl)-3a,4,7,7a- tetrahydroisoindole-l,3-dione of Formula XV,
Figure imgf000018_0002
Formula XV wherein Y can be F, Cl, Br or I, which can be reacted with a compound of Formula X,
Figure imgf000018_0003
Formula X
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy, to form a compound of Formula XVI,
Figure imgf000019_0001
Formula XVI
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy, or b) reacting a compound of Formula XVI,
Figure imgf000019_0002
Formula ><VI
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy, with peroxyacid to form a compound of Formula XVII,
Figure imgf000019_0003
Formula XVIl
wherein R] can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy.
Embodiments of the processes include one or more of the following. For example, the reaction of the compound of Formula VI with 1,3-dihalopropane can be carried out in one or more solvents selected from, for example, acetonitrile, acetone, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or mixtures thereof. The reaction can also be carried out in the presence of one or more organic or inorganic halides selected from, for example, tetrabutylammonium bromide, tetrabutylammonium chloride, potassium iodide or mixtures thereof. The reaction can also be carried out in the presence of one or more inorganic bases selected from, for example, barium carbonate, cesium carbonate, potassium carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate or mixture thereof.
The reaction of the compound of Formula XVI with 1,3-dihalopropane can be carried out in one or more solvents selected from, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or mixtures thereof. The reaction of the compound of Formula XVI to form the compound of Formula XVII can also be carried out using one or more peroxyacids selected from, for example, magnesium monoperoxyphthalate, potassium peroxomonosulfate, m-chloroperbenzoic acid or mixtures thereof.
In another aspect, provided herein are processes for preparing compounds of Formula XIX or Formula XX or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, conjugate or prodrug thereof comprising: a) reacting 2-(3-halopropyl)-3a,4,7,7a-tetrahydroisoindole- 1 ,3-dione of Formula xv,
Figure imgf000020_0001
Formula XV wherein Y can be F, Cl, Br or I, with one or more peroxyacids to form 4-(3- halopropyl)-hexahydro-l-oxa-4-aza-cyclopropa[f]indene-3,5-dione of Formula XVIII,
Figure imgf000020_0002
wherein Y can be F, Cl, Br or I, which can be reacted with a compound of Formula X
Figure imgf000021_0001
Formula X
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy, to form a compound of Formula XIX,
Figure imgf000021_0002
Formula XlX
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy, or b) reacting a compound of Formula XIX
Figure imgf000021_0003
Formula XIX
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy, with peroxyacid to form a compound of Formula XX
Figure imgf000022_0001
Formula XX
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy.
Embodiments of the processes can include one or more of the following. For example, the reaction of the compound of Formula XV with one or more peroxyacids can be carried out in one or more solvents selected from, for example, dichloroethane, tetrahydrofuran, dimethylformamide dimethylsulfoxide, ethanol, butanol or mixtures thereof. Suitable peroxyacids include selected from, for example, magnesium monoperoxyphthalate, potassium peroxomonosulfate, m-chloroperbenzoic acid or mixtures thereof.
The reaction of the compound of Formula XVIII with the compound of Formula X or the reaction of the compound of Formula XIX with one or more peroxyacids can be carried out in one or more solvents selected from, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or mixtures thereof. The reaction can also be carried out in the presence of one or more inorganic bases selected from, for example, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate or mixtures thereof.
In another aspect, provided herein are processes for preparing compound of Formula XXVI, Formula XXVII, Formula XXVIII or Formula XXIX or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, polymorph, conjugate or prodrug thereof comprising: a) reacting a compound of Formula X
Figure imgf000023_0001
Formula X
wherein R) can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy, with acrylonitrile to form a compound of Formula XXI,
Figure imgf000023_0002
Formula XXl
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy, which can be reduced to form a compound of Formula XXII,
Figure imgf000023_0003
Formula XXII
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy, which can be reacted with fufan-2,5-dione to form a compound of Formula XXIII,
Figure imgf000023_0004
Formula XXIII wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy, which can be reacted with 1-acetoxy- 1,3 -butadiene to form a compound of Formula XXV,
Figure imgf000024_0001
Formula XXV
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy, which can be hydro lyzed to give a compound of Formula XXVI,
Figure imgf000024_0002
Formula XXVI
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy, or b) reacting a compound of Formula XXVI
Figure imgf000024_0003
Formula XXVI
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy, with one or more peroxyacids to form a compound of Formula XXVIII,
Figure imgf000025_0001
Formula XXVIII
wherein R1 can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy, or c) reacting a compound of Formula XXIII
Figure imgf000025_0002
Formula XXIII
with 1 ,4-diacetoxy- 1,3 -butadiene to form a compound of Formula XXIV,
Figure imgf000025_0003
which can be hydrolyzed to form a compound of Formula XXVII,
Figure imgf000026_0001
Formula XWII
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy, or d) reacting a compound of Formula XXVII
Figure imgf000026_0002
Formula XXVII
with one or more peroxyacids to form a compound of Formula XXIX
Figure imgf000026_0003
Formula XXIX
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy.
Embodiments of the processes can include one or more of the following. For example, the reaction of the compound of Formula X with acrylonitrile, the reduction of the compound of Formula XXI, the hydrolysis of a compound of Formula XXV or the hydrolysis of a compound of Formula XXIV can be carried out in one or more solvents selected from, for example, methanol, ethanol, propanol, n-butanol or mixtures thereof. The reaction of the compound of Formula XXII with furan-2,5-dione can be carried out in one or more solvents selected from, for example, toluene, benzene, xylene, tetrahydrofuran, acetonitrile or mixtures thereof. The reaction of the compound of Formula XXIII with l-acetoxy-1,3- butadiene or the reaction of the compound of Formula XXIII with l,4-diacetoxy-l,3- butadiene can be carried out in one or more solvents selected from, for example, toluene, benzene, xylene or mixtures thereof.
The reaction of the compound of Formula XXVI with one or more peroxyacids or the reaction of the compound of Formula XXVII with one or more peroxyacids can be carried out in one or more solvents selected from, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or mixtures thereof. The reaction of the compound of Formula XXVI to form the compound of Formula XVIII or the reaction of the compound of Formula XXVII to form the compound of Formula XXIX can be carried out using one or more peroxyacids selected from, for example, magnesium monoperoxyphthalate, potassium peroxomonosulfate, m-chloroperbenzoic acid or mixtures thereof. The reduction of the compound of Formula XXI can be carried out in the presence of one or more reducing agents selected from, for example, palladium on carbon and carbon in ammonia and one or more alcoholic solvents; or Raney Nickel and hydrogen in ammonia and one or more alcoholic solvents.
In another aspect, provided herein are processes for preparing compounds of Formula XXXII or Formula XXXIII or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymorphs, conjugates or prodrugs thereof comprising: a) reacting isoindole- 1 ,3 -dione of Formula XXX
Figure imgf000027_0001
Formula XXX with 1,3-dihalopropane to form 2-(3-halopropyl)-isoindole-l ,3-dione of Formula XXXI,
Figure imgf000028_0001
Formula XXXI wherein Y can be F, Cl, Br or I, which can be reacted with a compound of Formula X,
Figure imgf000028_0002
Formula X
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy, to form a compound of Formula XXXII
Figure imgf000028_0003
Formula XXXlI
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy, or b) reacting a compound of Formula XXXII
Figure imgf000029_0001
Formula XXXII
with peroxyacid to give a compound of Formula XXXIII
Figure imgf000029_0002
Formula XXXIII
wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy.
Embodiments of the processes can include one or more of the following. For example, the reaction of the compound of Formula XXX with 1,3-dihalopropane can be carried out in one or more solvents selected from, for example, acetonitrile, acetone, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or mixtures thereof. The reaction of isoindole-1,3- dione of Formula XXX with 1,3-dihalopropane can be carried out in the presence of one or more organic halides selected from, for example, tetrabutylammonium chloride, tetrabutylammonium bromide or mixtures thereof. The reaction can also be carried out in the presence of one or more inorganic bases selected from, for example, barium carbonate, cesium carbonate, potassium carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate or mixtures thereof.
The reaction of the compound of Formula XXXI with the compound of Formula X or the reaction of a compound of Formula XXXII to form the compound of Formula XXXIII can be carried out in a solvent selected from, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide and dimethylsulfoxide. The compound of Formula XXXI with a compound of Formula X can be carried out in the presence of one or more inorganic base selected from, for example, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate or mixtures thereof. The reaction of the compound of Formula XXXII to form the compound of Formula XXXIII can be carried out using one or more peroxyacids selected from, for example, magnesium monoperoxyphthalate, potassium peroxomonosulfate, m-chloroperbenzoic acid or mixtures thereof.
In another aspect, provided herein are prodrugs having the structure of Formula XXXVa,
Figure imgf000030_0001
Formula XXXVa a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, polymorph or conjugate thereof, wherein Y and Z, when taken together represent the fused ring systems including:
Figure imgf000030_0002
wherein R3, R4, R5 and R6 can independently be hydrogen, hydroxyl or -O-W-
R;
X can be -CHR7, wherein R7 can be hydrogen, hydroxyl or -0-W-R;
Ri can be hydrogen or isopropyl;
R2 can be hydrogen, hydroxyl or 0-W-R n can be an integer 0 or 1 , and at least one of R2, R3, R4, R5, R6 or X can be -0-W-R, wherein W can be -SO2, -CO-, -CONR8, wherein R8 can be (Ci-C4)- alkyl or aryl, and
R can be (Cι-C4)-alkyl, aryl or aralkyl.
Embodiments of the prodrugs can include one or more of the following. For example, the aryl can be phenyl or naphthyl. The aralkyl can be benzyl. W and R can respectively be, SO2 and (Ci-C4)-alkyl; SO2 and methyl; SO2 and aryl; SO2 and phenyl; CO and (Ci-C4)- alkyl; CO and methyl; CO and ethyl; CO and aralkyl; CO and benzyl; CONR8 and (Ci-C4)- alkyl, wherein R8 can be (Ci-C4)-alkyl; CONR8 and methyl, wherein R8 methyl; CONR8 and aryl, wherein R8 can be (Ci-C4)-alkyl; CONR8 and phenyl, wherein R8 can be methyl; CONR8 and aryl, wherein R8 can be aryl; or CONR8 and phenyl, wherein R8 can be phenyl.
Examples of prodrugs include:
Benzenesulfonic acid 2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l- [l-oxy-4-(2-hydroxyphenyl) piperazin-1-ylmethyl] ethyl ester,
Phenylcarbamic acid 2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l-[l- oxy-4-(2-hydroxyphenyl) piperazin-1-ylmethyl] ethyl ester,
Methanesulfonic acid 2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l- [l-oxy-4-(2-hydroxyphenyl) piperazin-1-ylmethyl] ethyl ester,
Acetic acid 2-(l,3-dioxo-l ,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l-[l-oxy-4-(2- hydroxyphenyl) piperazin-1-ylmethyl] ethyl ester, or Methylcarbamic acid 2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l-[l- oxy-4-(2-hydroxyphenyl) piperazin-1-ylmethyl] ethyl ester.
In another aspect, provided herein are processes for preparing prodrugs having a structure of Formula XXXVa,
Figure imgf000031_0001
Formula XXXVa a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, polymorph, conjugate or prodrug thereof, wherein Y and Z, when taken together represent the fused ring systems including:
Figure imgf000032_0001
wherein R3, R4, R5 and R6 can independently be hydrogen, hydroxyl or -O-W-
R;
X can be -CHR7, wherein R7 can be hydrogen, hydroxyl or -0-W-R;
Ri can be hydrogen or isopropyl;
R2 can be hydrogen, hydroxyl or 0-W-R n can be an integer 0 or 1 , and at least one of R2, R3, R4, Rs, RO or X can be -0-W-R, wherein W can be -SO2, -CO-, -CONR8, wherein R8 can be (Ci-C4)- alkyl or aryl, and
R can be (Ci-C4)-alkyl, aryl or aralkyl, which process comprises reacting a hydroxylated metabolite of Formula XXXIVa
Figure imgf000032_0002
Formula XXXIVa wherein R3, R4, R5 and R^ can independently be hydrogen or hydroxyl; X can be -CHR7, wherein R7 can be hydrogen or hydroxyl; Ri can be hydrogen or isopropyl; R2 can be hydrogen or hydroxyl; n can be an integer 0 or 1 ; and at least one of R2, R3, R4, R5, R6 or X can be hydroxyl, wherein W can be -SO2, -CO-, -CONR8, wherein R8 can be (Ci-C4)- alkyl or aryl, and
R can be (Ci-C4)-alkyl, aryl or aralkyl, with a compound of Formula Cl-W-R, wherein W can be -SO2, -CO-, -CONR8, wherein R8 can be (Ci-C4)-alkyl or aryl, and R can be (Ci-C4)-alkyl, aryl or aralkyl, to form a prodrug of Formula XXXVa. Embodiments of the processes can include one or more of the following. For example, the reaction of the hydroxylated metabolite of Formula XXXIVa with the compound of Formula Cl-W-R can be carried out in one or more solvents selected from, for example, tetrahydrofuran, dimethylformamide or mixtures thereof. The reaction of the hydroxylated metabolite of Formula XXXIVa with the compound of Formula XXXVa can be carried out in the presence of one or more inorganic bases selected from, for example, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride or mixtures thereof.
Detailed Description of the Invention
The invention provides metabolites of 2-{3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]- propyl}-3a,4,7,7a-tetrahydro-lH-isoindole-l,3-(2H)-dione (Compound No. 1) of Formula I,
Figure imgf000033_0001
wherein the metabolites comprise aromatized, desisopropylated, hydroxylated, epoxylated or N-oxides of Formula I.
An aromatized, desisopropylated, hydroxylated, epoxylated or N-oxide metabolite of compound of Formula I can be a metabolite represented by the general Formula II,
Figure imgf000034_0001
and pharmaceutically acceptable salts, solvates, polymorphs, conjugates or prodrugs thereof, wherein
Y and Z when taken together include the fused ring systems including,
Figure imgf000034_0002
wherein Rj, R4, R5 and R6 can be independently selected from hydrogen or hydroxyl;
X can be -CHR7, wherein R7 can be hydrogen or hydroxyl;
Ri can be hydrogen or isopropyl;
R2 can be hydrogen or hydroxyl; n can be an integer 0 or 1. Examples of metabolites encompassed herein include, but are not limited to,
2-{3-[4-(2-Hydroxyphenyl)-piperazin-l-yl]-propyl}-3a,4,7,7a-tetrahydroisoindole- 1,3-dione hydrochloride salt (Compound No. 2), 2-{3-[4-(2-Isopropoxyphenyl)-piperazin-l-yl]-propyl}-isoindole-l,3-dione hydrochloride salt (Compound No. 3),
2-{2-Hydroxy-3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-3a,4,7,7a- tetrahydroisoindole-l,3-dione hydrochloride salt (Compound No. 4),
4,7-Dihydroxy-2-{3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-3a,4,7,7a- tetrahydroisoindole-l,3-dione hydrochloride salt (Compound No. 5),
4-Hydroxy-2- { 3 - [4-(2-isopropoxyphenyl)-piperazin- 1 -yl] -propyl } -3 a,4 ,7 ,7a- tetrahydroisoindole-l,3-dione hydrochloride salt (Compound No. 6),
4-{3-[4-(2-Isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-l-oxa-4-aza- cyclopropa[f]indene-3,5-dione (Compound No. 7),
4- {2-Hydroxy-3 -[4-(2-isopropoxyphenyl)-piperazin- 1 -yl]-propyl} -hexahydro- 1 -oxa- 4-aza-cyclopropa[f]indene-3,5-dione (Compound No. 8),
5,6-Dihydroxy-2-{3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}- hexahydroisoindole-l,3-dione hydrochloride salt (Compound No. 9),
2-{2-Hydroxy-3-[4-(2-hydroxyphenyl)-piperazin-l-yl]-propyl}-3a,4,7,7a- tetrahydroisoindole-l,3-dione hydrochloride salt (Compound No. 10),
2- {3-[4-(2-isopropoxyphenyl)-l-oxidopiperazin-l-yl} -propyl} -3a,4,7,7a- tetrahydroisoindole-l,3-dione (Compound No. 11)
5,6-Dihydroxy-2-{3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}- hexahydroisoindole-l,3-dione (Compound No. 12)
2-{3-[l-oxy-4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-3a,4,7,7a- tetrahydroisoindole-1 ,3-dione.
The term "pharmaceutically acceptable salts," unless otherwise specified, refer to a salt prepared from one or more pharmaceutically acceptable non-toxic inorganic or organic acids. Examples of such inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitrous, nitric, carbonic, sulfuric, phosphoric acid, and the like. Appropriate organic acids include, but are not limited to, aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids, for example, formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, panthenic acid, toluenesulfonic acid, 2- hydroxyethanesulfonic acid and the like. Pharmaceutically acceptable salts can be prepared following procedures well known to the skilled artisan.
The term "pharmaceutically acceptable solvates," unless otherwise specified, refers to solvates with water (i.e., hydrates) or pharmaceutically acceptable organic solvents. Such solvates are also encompassed herein. Furthermore, some crystalline forms of the compounds described herein can exist as polymorphs and as such are intended to be encompassed herein. Where metabolites encompassed by the invention have at least one chiral center, they may accordingly exist as enantiomers. It is to be understood that all such optically active isomers and racemic mixture therefore are encompassed herein.
The conjugates disclosed herein include sulfate or glucuronate derivatives of hydroxylated metabolites. Prodrugs of hydroxylated metabolites are also encompassed herein. Prodrugs include, but are not limited to, derivatives of metabolites having one or more carbamoyl, (Ci-C4)-alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkylsulfonyl, or arylsulfonyl groups and the like.
Examples of prodrugs as disclosed herein include, but are not limited to:
Benzenesulfonic acid-2-( 1 ,3-dioxo- 1 ,3,3a,4,7,7a-hexahydroisoindol-2-yl)- 1 -[ 1 -oxy-4-
(2-hydroxyphenyl)-piperazin-l-ylmethyl]-ethyl ester (Compound No. 13),
Phenylcarbamic acid-2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l-[l-oxy-4- (2-hydroxyphenyl)-piperazin-l-ylmethyl] -ethyl ester (Compound No. 14), Methanesulfonic acid-2-( 1 ,3-dioxo- 1 ,3 ,3a,4,7,7a-hexahydroisoindol-2-yl)- 1 -[ 1 -oxy-4- (2-hydroxyphenyl)-piperazin-l-ylmethyl]-ethyl ester (Compound No. 15),
Acetic acid-2-( 1 ,3-dioxo- 1 ,3,3a,4,7,7a-hexahydroisoindol-2-yl)- 1 -[ 1 -oxy-4-(2- hydroxyphenyl)-piperazin-l-ylmethyl]-ethyl ester (Compound No. 16),
Methylcarbamic acid-2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l-[l-oxy-4-
(2-hydroxyphenyl)-piperazin-l-ylmethyl]-ethyl ester (Compound No. 17).
Also included herein are pharmaceutical compositions comprising metabolites of 2- {3-[4-(2-isopropoxy phenyl) piperazin-l-yl]-propyl}-3a,4,7,7a-tetrahydro-lH-isoindole-l, 3- (2H)-dione (Formula I), their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymorphs, conjugates or prodrugs and one or more pharmaceutically acceptable carriers or excipients.
The compositions disclosed herein contain one or more metabolites in compositions that are suitable for oral, parenteral, topical, transdermal, colonic, buccal, sublingual or intravaginal administration. The compositions may be formulated to provide immediate or sustained-release of the therapeutic agents. The agents described herein can be administered alone, but will generally be administered as an admixture with one or more suitable pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier(s)," unless specified otherwise, refers to non-toxic, inert solid, semi-solid or liquid filter, diluent, encapsulating material or formulation auxiliary of any type. Solid form preparations for oral administration include capsules, tablets, pills, powder, granules or suppositories. In solid form preparations, one or more active metabolites can be mixed with one or more inert, pharmaceutically acceptable excipients or carriers (e.g., sodium citrate, dicalcium phosphate, filter or mixtures thereof), one or more extenders (e.g., starch, lactose, sucrose, glucose, mannitol, silicic acid or mixtures thereof), one or more binders (e.g., carboxymethyl cellulose, alginates, gelatins, polyvinylpyrrolidinone, sucrose, acacia or mixtures thereof), one or more disintegrating agents (e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate or mixtures thereof); one or more absorption accelerators (e.g., quaternary ammonium compounds); one or more wetting agents (e.g., cetyl alcohol, glycerol, monostearate or mixtures thereof); one or more adsorbents (e.g., kaolin); one or more lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium lauryl sulphate or mixtures thereof); or mixtures thereof.
Capsules, tablets or pills can also comprise one or more buffering agents. The solid preparation of tablets, capsules, pills, granules can be prepared using one or more coatings and/or shells (e.g., enteric coating and other coatings well known in the pharmaceutical formulating art).
Liquid form preparations for oral administration include one or more pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs or mixtures thereof. In liquid form preparations, one or more metabolites can be mixed with water or one or more other solvents, solubilizing agents and/or emulsifϊers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, one or more oils (for example, cottonseed, groundnut, corn, germ, olive, castor or sesame oil), glycerol, fatty acid ester of sorbitan or mixture thereof.
Besides inert diluents, the oral composition can also include one or more adjuvants, for example, a wetting agent, an emulsifying agent, a suspending agent, a sweetening agent, a flavoring agent, a perfuming agent or mixtures thereof.
Injectable preparations (e.g., sterile injections, aqueous or oleaginous suspensions) can be formulated according to the art using one or more suitable dispersing or wetting suspending agents. Among the acceptable vehicles and solvents that may be employed include water, Ringers solution, U. S. P., isotonic sodium chloride or mixtures thereof.
Dosage forms for topical or transdermal administration includes ointments, pastes, creams, lotions, gel, powders, solutions, spray, inhalants or patches. Typically, one or more metabolites are admixed under sterile condition with one or more pharmaceutically acceptable carriers and any preservatives or buffers as may be desirable.
The pharmaceutical preparations are desirably in unit dosage form. In such forms, the preparations are subdivided into unit doses containing therapeutic quantities of one or more active metabolites. The formulations described herein may be formulated so as to provide quick-released or delayed-release of the active ingredient(s) after administration to the patient by utilizing procedures well known to the skill artisan.
The term "patient," as used herein, refers to an animal, a mammal, or a human, who is the subject of treatment, observation or experiment.
The compositions may be administered as depot formulations that permit sustained release, limit access to general circulation, and increase the prostate- and/or bladder-specific localization of the compositions. Such formulations may be provided as slow release implants, be microencapsulated, or attached to biodegradable polymers or one or more prostate-specific immunoglobulins. Sustained release formulations are preparations that release active metabolites over extended periods of time. Sustained release formulations are prepared by applying one or more biodegradable, bioerodible or bioabsorbable polymeric formulations that are compatible on the surface of active metabolites. Effective release of metabolites is regulated by slow erosion of biodegradable, bioerodible or bioabsorbable polymeric formulations. One or more polymers form the polymer matrix, wherein such one or more polymers are recognized by an artisan skilled in the art of pharmaceutical compounding for release-retarding properties. Metabolites are entrapped within this polymeric matrix. The rate of release of metabolite for such a system is primarily dependent on rate of water imbibitions, resultant rate of swelling of matrix, drug dissolution and diffusion from the matrix. In addition to the rate controlling polymers, compositions may additionally contain 6 to 50 % w/w of other pharmaceutically acceptable excipients, for example, gas generating component, swelling agent, lubricant and filler. Examples of pharmaceutically acceptable rate-controlling polymers used in accordance with the present invention include, but are not limited to, hydroxypropylmethylcellulose (HPMC), hydrogenated vegetable oil (HVO), ethylcellulose, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacryl - amidephenol, polyhydroxy - ethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues, polyacetic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyano acrylates. Compositions according to the invention may be formulated as capsules or tablets. Tablet formulations can be prepared by wet granulation, dry granulation, direct compression or by any other techniques known in the pharmaceutical art. Tablets can be coated with a layer of rapidly dissolving water-soluble polymer or pharmaceutical excipient(s).
The term "biodegradable" refers to the degradation of polymeric formulations over time by action of enzymes, by hydro lytic action and/or by other similar mechanisms in the human body.
The term "bioerodible" refers to a polymeric formulation erodes or degrades over time due, at least in part, to contact with substances found in the surrounding tissue fluids or cellular action.
The term "bioabsorbable" refers to polymeric formulations that are broken down and absorbed within the human body, for example, by a cell or tissue.
The term "biocompatible" refers to polymeric formulations that do not cause substantial tissue irritation or necrosis.
Metabolites described herein can also be administered in the form of liposome delivery systems, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, for example, cholesterol, stearylamine or phosphatidylcholines.
Aqueous parenteral compositions containing therapeutically effective amounts of one or more metabolites are disclosed herein. Methods of delivery such that direct intraprostatic injection of therapeutically effective amounts of compositions encompasses herein result in the relief of the obstructive symptoms associated with benign prostatic hyperplasia.
Intraprostatic injection can be accomplished by, for example, utilizing a long, fine needle inserted into the prostate under digital rectal control and/or ultrasonic guidance while the patient is under local anesthesia. Injection solutions may be diluted with, for example, lidocaine. During injections, needles may be frequently relocated in order to obtain the best possible distribution of the composition. Several routes of administration are available for introducing the compositions herein into the prostate. Preferred routes of administration include by transurethral intraprostatic (intralesional) injection. Alternatively, transperineal or transrectal routes of prostatic injection can be used. Metabolites disclosed herein can be prepared by techniques known to one of ordinary skill in the art. In addition, metabolites described herein can be prepared by the following reaction sequences as depicted in Schemes I, II, III, IV, V, VI and VII.
Scheme I
Figure imgf000041_0001
Figure imgf000041_0002
Formula Va
Figure imgf000041_0003
Compounds of Formula Va or Formula V can be prepared according to methods in
Scheme I. The methods comprise oxidizing a compound of Formula III to form a compound of Formula IV, which on reaction with one or more peroxyacids forms a compound of Formula V, wherein R2 can be hydrogen or hydroxy. The methods also comprise reacting a compound of Formula III with one or more peroxyacids to form a compound of Formula Va, wherein R2 can be hydrogen or hydroxy. Suitable peroxyacids include, for example, m- chloroperbenzoic acid, monoperoxyphthalate, potassium peroxomonosulfate or mixtures thereof.
The oxidation of a compound of Formula III to form a compound of Formula IV via path (a) can be carried out with one or more oxidizing agents (e.g., potassium permanganate) in one or more alcoholic solvents (e.g., methanol, ethanol, propanol, n-butanol or mixtures thereof). This reaction can also be carried out in one or more solvents, for example, dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, dimethylsulphoxide, or mixtures thereof.
Figure imgf000042_0001
Formula XlI
Compounds of Formula XII can be prepared according to methods in Scheme II. The methods comprise reacting 3a,4,7,7a-tetrahydroisoindole-l,3-dione of Formula VI with a compound of Formula VII (wherein Xi can be to chlorine or bromine) to form 2- oxiranylmethyl-3a,4,7,7a-tetrahydroisoindole-l,3-dione of Formula VIII. The compound of Formula VIII can react with one or more peroxyacids to form 4-oxiranylmethylhexa-l-oxa-4- aza-cyclopropa[f]indene-3,5-dione of Formula IX. Suitable peroxyacids include, for example, m-chloroperbenzoic acid, monoperoxyphthalate, potassium peroxomonosulfate or mixtures thereof. The compound of Formula IX can react with a compound of Formula X to form a compound of Formula XI, wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy. The compound of Formula XI can be treated with one or more peroxyacids to form a compound of Formula XII, wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy. Suitable peroxyacids include, for example, m-chloroperbenzoic acid, monoperoxyphthalate, potassium peroxomonosulfate or mixtures thereof. The reaction of 3a,4,7,7a-tetrahydroisoindole-l,3-dione of Formula VI with compounds of Formula VII can be carried out in one or more solvents, for example, acetone, ethylmethylketone, dimethylformamide, n-butanol, acetonitrile, toluene, chlorobenzene or mixtures thereof. This reaction can also be carried out in the presence of one or more inorganic bases or organic bases, for example, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, trimethylamine, triethylamine, diethylisopropylamine or mixtures thereof.
The reaction of 2-oxiranylmethyl-3a,4,7,7a-tetrahydroisoindole-l,3-dione of Formula VIII with one or more peroxyacids to form 4-oxiranylmethylhexa-l-oxa-4-aza- cyclopropa[f]indene-3,5-dione of Formula IX can be carried out in one or more solvents, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or mixtures thereof. The reaction of 4-oxiranylmethylhexa-l-oxa-4-aza- cyclopropa[f]indene-3,5-dione of Formula IX with a compound of Formula X to form a compound of Formula XI can be carried out in one or more alcoholic solvents, for example, methanol, ethanol, propanol, n-butanol or mixtures thereof.
The reaction of a compound of Formula XI with one or more peroxyacids to form a compound of Formula XII can be carried out in one or more solvents, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or mixtures thereof.
Scheme I
Figure imgf000043_0001
Compounds of Formula XIV can be prepared according to methods in Scheme III. The methods comprise reacting 2-oxiranylmethyl-3a,4,7,7a-tetrahydroisoindole-l,3-dione of Formula VIII with a compound of Formula X to form a compound of Formula XIII, wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy. The compound Formula XIII can be reacted with one or more peroxyacids to form a compound of Formula XIV, wherein R| can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy. Suitable peroxyacids include, for example, m-chloroperbenzoic acid, monoperoxyphthalate, potassium peroxomonosulfate or mixtures thereof.
The reaction of 2-oxiranylmethyl-3a,4,7,7a-tetrahydroisoindole-l,3-dione of Formula VIII with a compound of Formula X to form a compound of Formula XIII can be carried out in the presence of one or more organic or inorganic bases, for example, trimethylamine, triethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate or mixtures thereof. This reaction can also be carried out in the presence of one or more alcoholic solvents, for example, methanol, ethanol, propanol, isopropanol, n-butanol or mixtures thereof.
The reaction of a compound of Formula XIII with one or more peroxyacids to form a compound of Formula XIV can be carried out in one or more solvents, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or mixtures thereof.
Figure imgf000045_0001
Formula XVII
Compounds of Formula XVII can be prepared according to methods in Scheme IV. The methods comprise reacting 3a,4,7,7a-tetrahydroisoindole-l,3-dione of Formula XVI with a 1,3-dihalopropane (e.g., 1,3-dibromopropane, 1,3-dichlropropane, 1,3-diiodopropane, 1,3- difluoropropane, wherein Y is F, Cl, Br or I) to form a compound of Formula XV. The compound of Formula XV can be reacted with a compound of Formula X to form a compound of Formula XVI, wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy. The compound of Formula XVI can be reacted with one or more peroxyacids to form a compound of Formula XVII, wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy. Suitable peroxyacids include, for example, m- chloroperbenzoic acid, monoperoxyphthalate, potassium peroxomonosulfate or mixtures thereof.
The reaction of 3a,4,7,7a-tetrahydroisoindole-l,3-dione of Formula VI with 1,3- dihalopropane to form a compound of Formula XV can be carried out in one or more solvents, for example, acetonitrile, acetone, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or mixtures thereof. This reaction can also be carried out in the presence of one or more organic or inorganic halides (e.g. , tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, potassium iodide or mixtures thereof) and one or more inorganic bases (e.g., barium carbonate, cesium carbonate, potassium carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate or mixtures thereof).
The reaction of 2-(3-halopropyl)-3a,4,7,7a-tetrahydroisoindole-l,3-dione of Formula XV with a compound of Formula X to form a compound of Formula XVI can be carried out in one or more solvents, for example, acetonitrile, ethanol, butanol, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or mixtures thereof. This reaction can also be carried out in the presence of one or more inorganic bases (e.g., potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate or mixtures thereof).
The reaction of a compound of Formula XVI with one or more peroxyacids to form a compound of Formula XVII can be carried out in one or more solvents, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or mixtures thereof.
Scheme V
Figure imgf000047_0001
Formula XX
Compounds of Formula XX can be prepared according to the methods in Scheme V. The methods comprise reacting 2-(3-halopropyl)-3a,4,7,7a-tetrahydroisoindole- 1,3-dione of Formula XV (wherein Y is F, Cl, Br or I) with one or more peroxyacids to form 4-(3-halopropyl)-hexahydro-l-oxa-4-aza-cyclopropa[f]indene-3,5-dione of Formula XVIII (wherein Y is F, Cl, Br or I). The compound of Formula XVIII can be reacted with a compound of Formula X to form a compound of Formula XIX, wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy. The compound of Formula XIX can be treated with one or more peroxyacids to form a compound of Formula XX, wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy. Suitable peroxyacids include, for example, m-chloroperbenzoic acid, monoperoxyphthalate, potassium peroxomonosulfate or mixtures thereof.
The reaction of 2-(3-halopropyl)-3a,4,7,7a-tetrahydroisoindole-l,3-dione of Formula XV with one or more peroxyacids to form (3-halopropyl) hexahydro-l-oxa-4-aza- cyclopropa[f]indene-3,5-dione of Formula XVIII can be carried out in one or more solvents, for example, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide, ethanol, butanol or mixtures thereof.
The reaction of 4-(3-halopropyl)-hexahydro-l-oxa-4-aza-cyclopropa[f]indene-3,5- dione of Formula XVIII with a compound of Formula X to form a compound of Formula XIX can be carried out in one or more solvents, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or mixtures thereof. This reaction can also be carried out in the presence of one or more inorganic bases, for example, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate or mixtures thereof. The reaction of a compound of Formula XIX with one or more peroxyacids to form a compound of Formula XX can be carried out in one or more solvents, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or mixtures thereof.
Scheme Vl
Figure imgf000049_0001
Formula X Formula XXI
Figure imgf000049_0002
Compounds of Formula XXVIII and compounds of Formula XXIX can be prepared according to methods in Scheme VI. The methods comprise reacting a compound of Formula X with acrylonitrile to form a compound of Formula XXI, which on reduction forms a compound of Formula XXII. The compound of Formula XXII can react with furan-2,5-dione to form a compound of Formula XXIII, which on reaction with 1-acetoxy- 1,3 -butadiene or l,4-diacetoxy-l,3-butadiene forms (a) a compound of Formula XXIV, which can be hydrolyzed to form a compound of
Formula XXVII, which can be finally reacted with one or more peroxyacids to give a compound of Formula XXIX, or
(b) a compound of Formula XXV, which can be hydrolyzed to form a compound of Formula XXVI, which can be finally reacted with one or more peroxyacids to form a compound of Formula XXVIII.
Suitable peroxyacids include, for example, m-chloroperbenzoic acid, monoperoxyphthalate, potassium peroxomonosulfate or mixtures thereof.
The reaction of a compound of Formula X with acrylonitrile to form a compound of Formula XXI can be carried out in one or more alcoholic solvents, for example, methanol, ethanol, propanol, n-butanol or mixtures thereof.
The reduction of a compound of Formula XXI to form a compound of Formula XXII can be carried out in the presence of one or more reducing agents, for example, palladium on carbon and hydrogen in ammonia and one or more alcohols (e.g., methanol, ethanol, propanol, n-butanol or mixtures thereof); or Raney nickel and hydrogen in ammonia and one or more alcohols (e.g., methanol, ethanol, propanol, n-butanol or mixtures thereof).
The reaction of a compound of Formula XXII with furan-2,5-dione to form a compound of Formula XXIII can be carried out in one or more solvents, for example, toluene, benzene, tetrahydrofuran, acetonitrile, xylene or mixtures thereof.
The reaction of a compound of Formula XXIII with 1-acetoxy- 1,3 -butadiene or 1,4- diacetoxy- 1,3 -butadiene to form a compound of Formula XXIV or XXV can be carried out in one or more solvents, for example, toluene, benzene, xylene or mixtures thereof.
The hydrolysis of compound of Formula XXIV and XXV to form compounds of Formula XXVII and XXVI, respectively can be carried out in one or more alcoholic solvents, for example, methanol, ethanol, propanol, n-butanol or mixtures thereof. The reaction of compounds of Formula XXVI and XXVII with one or more peroxyacids to form compounds of Formula XXVIII and XXIX respectively can be carried out in one or more solvents, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or mixtures thereof.
Scheme VII
or I
Figure imgf000051_0002
Figure imgf000051_0001
Formula XXX Formula XXXI
Figure imgf000051_0003
Compounds of Formula XXXIII can be prepared according to the methods in Scheme VII. The methods can comprise reacting isoindole-l,3-dione of Formula XXX with 1,3- dihalopropane {e.g., 1,3-dibromopropane, 1,3-dichlropropane, 1,3-diiodopropane, 1,3- difluoropropane, wherein Y is Br, Cl, I or F) to form 2-(3-halopropyl)isoindole-l,3-dione of Formula XXXI, which on reaction with a compound of Formula X forms a compound of Formula XXXII, wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy. A compound of Formula XXXII can be finally reacted with one or more peroxyacids to form a compound of Formula XXXIII, wherein Ri can be hydrogen or isopropyl and R2 can be hydrogen or hydroxy. The reaction of isoindole-l,3-dione of Formula XXX with 1,3-dihalopropane to form a compound of Formula XXXI can be carried out in one or more solvents, for example, acetonitrile, acetone, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or mixtures thereof. This reaction can be carried out in the presence of one or more organic halides, for example, tetrabutyl ammonium chloride, tetrabutyl ammonium bromide or mixtures thereof, and one or more inorganic bases, for example, barium carbonate, cesium carbonate, potassium carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate or mixtures thereof.
The reaction of 2-(3-halopropyl)isoindole-l,3-dione of Formula XXXI with a compound of Formula X to form a compound of Formula XXXII can be carried out in one or more solvents, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or mixtures thereof. This reaction can be carried out in the presence of one or more inorganic bases, for example, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate or mixtures thereof. The reaction of a compound of Formula XXXII with peroxyacid to a form a compound of Formula XXXIII can be carried out in one or more solvents, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or mixtures thereof.
Scheme VIII
Figure imgf000052_0001
Formula XXXIV Formula XXXV
(hydroxylated metabolite) (Prodrug) Compounds of Formula XXXV, which are prodrugs of hydroxylated metabolites, can be prepared according methods in Scheme VIII. The methods comprise reacting hydroxylated metabolites of Formula XXXIV with a compound of Formula
Cl-W-R, wherein
W can be -SO2-, -CO-, -CONR8 (wherein R8 can be alkyl of from one to four carbon atoms or aryl, e.g., phenyl or naphthyl); R can be alkyl of from one to four carbon atoms, aryl (e.g., phenyl or naphthyl), or aralkyl (e.g., benzyl), and the circle represents main structure of any compound described herein including, for example, the main structure of Formulae II, IV, V, Va, XI, XII, XIII, XIV, XVI, XVII, XIX, XX, XXVI, XXVII, XXVIII, XXIX, XXXII, or XXXIII. Compounds of Formula X-W-R may also be used in place of Cl-W-R in this reaction, wherein X can be a halogen atom, e.g., Br or I.
The reaction of the hydroxylated metabolites of Formula XXXIV with a compound of Formula Cl-W-R to form compound of Formula XXXV can be carried out in one or more solvents, for example, tetrahydrofuran, dimethylformamide or mixtures thereof. This reaction can also be carried out in the presence of one or more inorganic bases (e.g., sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride or mixtures thereof).
Prodrugs encompassed herein include compounds of Formula XXXV, wherein W and R are respectively, SO2 and (Ci-C4)-alkyl; SO2 and methyl; SO2 and aryl; SO2 and phenyl; CO and (Ci-C4)-alkyl; CO and methyl; CO and ethyl; CO and aralkyl; CO and benzyl; CONR8 and (Ci-C4)-alkyl, wherein Rg is alkyl of from one to four carbon atoms; CONR8 and methyl, wherein R8 methyl; CONR8 and aryl, wherein R8 is (Ci-C4)-alkyl; CONR8 and phenyl, wherein R8 is methyl; CONR8 and aryl, wherein R8 is aryl; or CONR8 and phenyl, wherein R8 is phenyl.
For example, prodrugs encompassed herein include compounds having the structure of Formula XXXVa,
Figure imgf000053_0001
Formula XXXVa a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, polymorph, conjugate or prodrug thereof, wherein Y and Z, when taken together represent the fused ring systems including:
Figure imgf000054_0001
wherein R3, R4, R5 and R6 are independently hydrogen, hydroxyl or -OW-R;
X is -CHR7, wherein R7 is hydrogen, hydroxyl or -0-W-R;
Ri is hydrogen or isopropyl;
R2 is hydrogen, hydroxyl or 0-W-R n is an integer 0 or 1 , and at least one of R2, R3, R4, R5, R6 or X is -0-W-R, wherein W is -SO2, -CO-, -CONR8, wherein R8 is (C|-C4)-alkyl or aryl, and
R is (Ci-C4)-alkyl, aryl or aralkyl.
Prodrugs having a structure of Formula XXXVa, can be prepared by processes comprising reacting a hydroxy lated metabolite of Formula XXXIVa
Figure imgf000054_0002
Formula XXXIVa wherein R3, R4, R5 and R6 are independently hydrogen or hydroxyl; X is -CHR7, wherein R7 is hydrogen or hydroxyl; Ri is hydrogen or isopropyl; R2 is hydrogen or hydroxyl; n is an integer O or 1 ; and at least one Of R2, R3, R4, R5, Re or X is hydroxyl, wherein W is -SO2, -CO-, -CONR8, wherein R8 is (CrC4)-alkyl or aryl, and R is (Ci-GO-alkyl, aryl or aralkyl, with a compound of Formula Cl-W-R, wherein W is -SO2, -CO-, -CONR8, wherein R8 is (Ci-C4)-alkyl or aryl, and R is (Ci-C4)-alkyl, aryl or aralkyl, to form a prodrug of Formula XXXVa.
The reaction of the hydroxylated metabolite of Formula XXXIVa with the compound of Formula Cl-W-R can be carried out in one or more solvents selected from tetrahydrofuran, dimethylformamide or mixtures thereof. The reaction of the hydroxylated metabolite of Formula XXXIVa with the compound of Formula XXXVa can also be carried out in the presence of one or more inorganic bases selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride or mixtures thereof.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.
The examples mentioned below demonstrate some illustrative synthetic procedures for preparing metabolites described herein. The examples are provided to illustrate particular aspect of the disclosure and do not limit the scope of the present invention as defined by the claims. Examples
Experimental Details
Solvents were dried using well-known literature procedures. IR spectra were recorded as nujol mulls or a thin film on a Perkin Elmer Paragon spectrophotometer (available from Perkin Elmer, Wellesley, MA). Nuclear magnetic resonance spectra were recorded on a Varian XL-200 instrument (available from Varian, Inc., Palo Alto, CA) using tetramethyl silane as internal standard. Example 1: Preparation of 2-oxiranylmethyl-3a,4,7,7a-tetrahydroisoindole-1.3-dione
A mixture of cis- 1,2,3, 6-tetrahydropthalimide (1.0 g, 0.0066 mole), epichlorohydrin (1.2 g, 0.0132mole) and anhydrous potassium carbonate in 2-butanone (15 niL) was refluxed for about 6-8 hours. Inorganics were filtered off and the filtrate was concentrated to yield the crude product. The crude product was purified on silica gel column using dichloromethane and methanol as eluent to yield 600 mg (44 %) of the title product.
Example 2: Preparation of 4-oxiranylmethylhexahvdro-l-oxa-4-azacycloproparf|indene-3,5- dione
To a solution of 2-oxiranylmethyl-3a,4,7,7a-tetrahydroisoindole-l,3-dione (0.5 g, 0.0024 mole) in dichloromethane was added metachloroperbenzoic acid (0.833 g, 0.0024 mole) in dichloromethane. The reaction mixture was stirred for about 6-8 hours. Ice chilled potassium carbonate solution (5 %) was added to the reaction mixture. The organic layer - was separated, dried over anhydrous sodium sulphate and concentrated to yield 0.47 g (87 %) of the title compound. Example 3: Preparation of 4-(3-bromopropyl) hexahydro-l-oxa-4-azacyclopropa[f]indene- 3,5-dione
To a solution of 2-(3-bromopropyl)-3a,4,7,7a-tetrahydroisoindole-l,3-dione (1.0 g, 0.0037 mole) in dichloromethane (10 mL) was added equimolar quantity of metachloroperbenzoic acid (1.33 g of 50 %, 0.0037mole) in dichloromethane at 0-5 0C. The reaction mixture was stirred for about 6-8 hours. Reaction mixture was poured into ice cold potassium carbonate solution (5 %) and concentrated to yield 0.8 g (75 %) of the desired product.
Example 4: Preparation of 3-[4-(2-isopropoxyphenyl) piperazin- 1 -yl] propionitrile
To a solution of 1 -(2-isopropoxyphenyl) piperazine (1.0 g, 0.0045 mole) in methanol (10 mL) was added acrylonitrile (0.29 g, 0.0054 mole) dropwise at 0-5 ° C. The reaction mixture was stirred for about 4-6 hours and was concentrated to give 1.18 g (95 %) of the desired compound. Example 5: Preparation of 3-["4-("2-isopropoxyphenyl) piperazin-1-yl] propylamine
To a solution of 3-[4-(2-isopropoxyphenyl) piperazin-1-yl] propionitrile (1.0 g, 0.0037 mole) in methanolic - ammonia (20 mL) was added palladium carbon (10 % wet, 0.2 g) and the reaction mixture was hydrogenated at 60-65 ° C for about 3-4 hours. The reaction mixture was filtered through celite pad, washed with methanol. The filtrate was concentrated to yield 1.0 g (99 %) of the desired compound.
Example 6: Preparation of l-(3-|"4-(2-isopropoxy phenyl)-piperazin-l-yll-propyl|-pyrrole- 2,5-dione
To a solution of 3-[4-(2-isopropoxyphenyl) piperazin-1-yl] propylamine (0.5 g, 0.0018 mole) in toluene (10 mL) was added maleic anhydride (0.177 g, O.OOlδmole) and reaction mixture was refluxed for about 1-2 hours. The reaction mixture was concentrated to give the crude product. It was purified on silica gel (60-120 mesh) column using dichloromethane and methanol as eluent to yield 0.6 g (93 %) of the product.
Example 7: Preparation of 2-(3-bromopropyl)-3a,4,7,7a-tetrahydroisoindole-l,3-dione A mixture of 3a,4,7,7a-tetrahydroisoindole-l,3-dione (5.0 g, 0.033 mole), 1,3- dibromopropane (10 g, 0.05 mole), potassium carbonate (6.9 g, 0.05 mole) and tetrabutylammonium iodide (0.24 g, 0.00065 mole) in acetone (30 mL) was stirred at 40 0C for about 8 hours. Inorganics were filtered, washed with acetone, solvent thus obtained was removed under pressure and the residue was suspended in water. The aqueous solution was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo to give the crude product. The crude product was purified on silica gel (60-120 mesh) column using dichloromethane as eluent to yield 6.5 g (72 %) of the product.
Example 8: Preparation of 2-(3-bromopropyl')-isoindole-l,3-dione A mixture of isoindole-l,3-dione (5.0 g, 0.034 mole ), 1,3-dibromopropane (10.3 g,0.051 mole), potassium carbonate (7.04 g,0.051 mole) and tetrabutylammonium iodide (0.25 g, 0.00068 mole ) in acetone (30 mL) was stirred at 40 0C for about 8 hours. Inorganics were filtered, washed with acetone, solvent thus obtained was removed under pressure and the residue was suspended in water. The aqueous solution was extracted with ethyl acetate. The combined organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo to give the crude product. The crude product was purified on silica gel (60-120 mesh) column using dichloromethane as eluent to yield 7.0 g (77 %) of the product. Example 9: Preparation of 5,6-dihydroxy-2-(3-[4-(2-isopropoxy-phenyl')-piperazin-l-yll- propyU-hexahvdroisoindole-l,3-dione hydrochloride salt (Compound No. 9)
To a solution of 2-{3-[4-(2-isopropoxyphenyl) piperazin-l-yl]-propyl}-3a,4,7,7a tetrahydroisoindole-l,3-dione (1 g, 0.0024 mole) in ethanol (15 mL) was added an aqueous solution of potassium permanganate (0.46 g, 0.0029 mole) at 0 to 5 C and reaction mixture was stirred for about 4-5 hours. The reaction mixture was filtered through sintered funnel, washed with ethanol. The filtrate thus obtained was concentrated to yield the crude product, which was purified on silica gel column using dichloromethane and methanol as eluent.
To the solution of 5,6-dihydroxy-2-{3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]- propyl}-hexahydroisoindole-l,3-dione in isopropyl alcohol (5 mL) was added equimolar quantity of isopropyl alcohol hydrochloric acid at 0-5 0C and reaction mixture stirred for about 30 minutes. Solid thus precipitated was filtered, dried and weighed to yield 400 mg (34 %) of the product.
1H NMR (300 MHz, DMSO-d6): δ 1.26-1.28 (6 H, d), 1.66-1.70 (2H,m), 1.89-1.93 (4H, m), 2.95-3.09 (8H, m), 3.36-3.50 (8H, m), 4.57-4.69 (2H, m), 6.85-6.98 (4H, m) Mass (m/z): 446.1 (M+ + 1)
Example 10: Preparation of 2-(3-r4-(2-isopropoxyphenyl)-l-oxidopiperazin-l-yl}-propyl}- 3a,4J,7a-tetrahydroisoindole-l,3-dione (Compound No. 1 1)
To a solution of 2-{3-[4-(2-isopropoxyphenyl)piperazin-l-yl]-propyl}-3a,4,7,7a tetrahydroisoindole-l,3-dione (1.0 g, 0.0024 mole) in dichloromethane was added meta- chloroperbenzoic acid (0.840 g, 0.0024 mole) of 50 % dissolved in dichloromethane at 0 to 5 0 C. The reaction mixture was stirred for about 2-3 hours. The reaction mixture was adsorbed on silica gel (60-120 mesh) and purified on a column using dichloromethane and methanol as eluent to yield 200 mg (20 %) of the product.
IR (DCM) Cm -1: 1696.2 1H NMR (300 MHz, CDCl3): δ 1.35-1.37 (6 H, d), 2.25-2.30 (2H,m), 2.60-2.65 (2H,m), 3.11- 3.40 (8H,m), 3.60-3.66 (4H,m), 4.55-4.61(lH,m), 5.90-5.9 l(2H,d), 6.85-7.0 l(4H,m)
Mass (m/z): 428.2 (M+ + 1)
Example 11 Preparation of 4-{2-hydroxy-3-|"4-(2-isopropoxy-phenyl)-piperazin-l-yl]- propyl I -hexahvdro-l-oxa-4-aza-cvclopropa[flindene-3,5-dione (Compound No. 8)
A mixture of 4-oxiranylmethylhexahydro-l-oxa-4-azacyclopropa[fJindene-3,5-dione (1 g, 0.0045 mole, example 4), l-(2-isopropoxyphenyl) piperazine monohydrochloride (1.15 g, 0.0045 mole) and anhydrous potassium carbonate (1.23 g, 0.009 mole) in dimethylformamide (10 mL) was heated for about 6-8 hours. The reaction mixture was quenched by adding water (20 mL), extracted with ethyl acetate, dried over anhydrous sodium sulphate and concentrated to yield the crude product. The crude product was purified on silica gel (60-120 mesh) column using dichloromethane and methanol as eluent to yield 0.56 g (25 %) of the desired compound.
IR (DCM) Cm "1: 1696.6 1H NMR (300 MHz, CDCl3): δ 1.32-1.34 (6H, d), 2.16-2.22(2H,m), 2.54-3.14 (10H,m), 3.58- 3.67(6H,m), 4.1 1-4.13(1 H,m), 4.56-4.60(lH,m), 6.84-6.95(4H,m)
Mass (m/z): 446 (M+ + 1)
Example 12: Preparation of 2-{2-hydroxy-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl']- propyl|-3a,4,7,7a-tetrahydro-isoindole-l ,3-dione hydrochloride salt (Compound No. 4) A mixture of 2-oxiranylmethyl-3a,4,7,7a-tetrahydroisoindole-l,3-dione (1.0 g, 0.0048 mole), l-(2-isopropoxyphenyl) piperazine monohydrochloride (1.23 g, 0.0048 mole) and triethylamine (0.48 g, 0.0048 mole) in ethanol (15 mL) was refluxed for about 4-5 hours. The reaction mixture was concentrated under vacuum, purified on silica gel (60-120 mesh) column using dichloromethane and methanol as eluent. To the solution of 2-{2-hydroxy-3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-
3a,4,7,7a-tetτahydro-isoindole-l,3-dione (0.8 g, 0.0187 mole) in isopropyl alcohol (2 mL) was added equimolar quantity of isopropyl alcohol hydrochloric acid at 0-5 0C and reaction mixture stirred for about 30 minutes. Solid thus precipitated was filtered, dried and weighed to yield 0.75 g (86 %) of compound. W
58
I R (KBr) Cm -1: 1695.3
1H NMR (300 MHz, CDCl3): δ 1.38-1.40 (6 H, d), 2.19-2.25 (2H,m), 2.57-2.62 (2H,m), 3.09- 3.24(4H,m), 3.51-3.75(6H,m), 4.57-4.64(2H,m), 5.89-5.91(2H,d), 6.88-7.10(4H,m), 12.85 (lH, brs) Mass (m/z): 429 (M+ + 1)
Example 13: Preparation of 2-(2-hydroxy-3-[4-(2-hydroxy-phenyl)-piperazin-l-yl]-propyl}- 3a.4,7,7a-tetrahydro isoindole-l ,3-dione hydrochloride salt (Compound 10)
A mixture of 2-oxiranylmethyl-3a,4,7,7a-tetrahydroisoindole-l,3-dione (1.0 g, 0.0048 mole) and 1 -(2 -hydroxy phenyl) piperazine (0.86 g, 0.0048 mole) in alcohol (15 mL) was refluxed for about 4-5 hours. The reaction mixture was concentrated under vacuum and the crude product was purified on silica gel (60-120 mesh) column using dichloromethane and methanol as eluent.
To the solution of 2-{2-hydroxy-3-[4-(2-hydroxy-phenyl)-piperazin-l-yl]-propyl}- 3a,4,7,7a-tetrahydro isoindole-l,3-dione (1.0 g, 0.0026 mole) in isopropyl alcohol (5 mL) was added equimolar quantity of isopropyl alcohol hydrochloric acid at 0-5 0C and reaction mixture stirred for about 30 minutes. Solid thus precipitated was filtered, dried and weighed to yield 0.92 g (84 %) of the product.
I R (KBr) cm ■': 1695.4
1H NMR (300 MHz5TFA) δ: 2.62-2.67 (2 H, d), 2.89-2.94 (2H,m), 3.69 (2H, brs),4.08-4.18 (4H,m), 4.41-4.61 (6H,m), 5.06 (3H,brs), 6.24 (2H,brs), 7.41-7.43 (2H,m), 7.71 -7.9 l(2H,m)
Mass (m/z): 386.1 (M+ + 1)
Example 14: Preparation of 4-{3-|~4-(2-isopropoxyphenyl)-piperazin-l-yl1-propyli- hexahvdro-l-oxa-4-aza-cvclopropa|"f]indene-3,5-dione (Compound No. 7)
A mixture of 4-(3-bromopropyl)-hexahydro-l -oxa-4-azacycloprop[f]indene-3,5- dione (0.5 g, 0.0017 mole, example 3), 1 -(2-isopropoxy)-phenyl piperazine monohydrochloride (0.445 g, 0.0017mole), anhydrous potassium carbonate (0.239 g, 0.0017 mole) in dimethylformamide (10 mL) was heated at 50-550C for about 20-24 hours. The reaction mixture was quenched by adding water (30 mL) to it. It was extracted with ethyl acetate, dried over anhydrous sodium sulphate and concentrated to yield crude product, which was purified on silica gel column using dichloromethane and methanol as eluent to yield 0.46 g (40 %) of the product.
IR (DCM) Cm"1: 1698.6 1H NMR (300 MHz, CDCl3): δ 1.31-1.33(6H, d), 1.80-1.87 (2H, m), 2.14-2.19(2H,m), 2.59(4H,brs), 2.69-2.74(4H,m), 3.54-3.59(6H,m), 4.53-4.61(lH,brs), 6.82-6.92(4H,m)
Mass (m/z): 428 (M+ + 1)
Example 15: Preparation of 2- j3-[4-(2-hvdroxy-phenyl)-piperazin-l-vH-propyU-3a,4,7,7a- tetrahydroisoindole-U-dione hydrochloride salt (Compound No.2) A solution of N-(3-bromopropyl)-phthalimide (1.0 g, 0.0036 mole), anhydrous potassium carbonate (0.5 g, 0.0036 mole) and l-(2-hydroxyphenyl) piperazine (0.654 g, 0.0036 mole) in dimethyl formamide (15 mL) was heated at 75-80 0C for about 6-8 hours. The reaction mixture was quenched by adding water (20 mL), extracted with ethyl acetate, concentrated and purified on silica gel (60-120 mesh) column using dichloromethane and methanol as eluent.
To the solution of 2-{3-[4-(2-hydroxy-phenyl)-piperazin-l-yl]-propyl}-3a,4,7,7a- tetrahydroisoindole-l ,3-dione (1.2 g, 0.0033 mole) in isopropyl alcohol (5 mL) was added equimolar quantity of isopropyl alcohol hydrochloric acid at 0-5 0C and reaction mixture stirred for about 30 minutes. Solid thus precipitated was filtered, dried and weighed to yield 1.1 g (77 %) of the compound.
Example 16: Preparation of 4-hydroxy-2- j3-(4-f2-isopropoxy-phenyl)-piperazin-l-yll- propyl}-3aA7Ja tetrahydro-isoindole-l,3-dione hydrochloride salt (Compound No. 6)
A solution of l-{3-[4-(2-isopropoxyphenyl) piperazine- 1-yl] propyl} pyrrole-2,5- dione (0.5 g, 0.0014 mole) and 1-acetoxy- 1,3 -butadiene (0.156 g.0.0014 mole) in toluene was refluxed for about 3-4 hours. The reaction mixture was concentrated under vacuum and to the thick residue, thus, obtained was added mixture of methanol - hydrochloric acid (5N, 10 mL) at 10-15 0C and the reaction mixture was stirred for about 4-6 hours. Solid sodium bicarbonate was added in lots till the mixture became neutral. Inorganics were filtered through celite pad, washed with methanol and concentrated to yield the crude product. It was purified on silica gel (60-120 mesh) column using dichloromethane and methanol as eluent to yield 0.30 g (50 %) of the product.
To the solution of 4-hydroxy-2-{3-(4-(2-isopropoxy-phenyl)-piperazin-l-yl}-propyl}- 3a,4,7,7a tetrahydro-isoindole-l,3-dione in isopropyl alcohol (2 niL) was added equimolar quantity of isopropyl alcohol hydrochloric acid at 0-5 0C and reaction mixture stirred for about 30 minutes. Solid thus precipitated was filtered, dried and weighed to yield 0.29 g (89 %) of the compound.
IR (KBr) Cm-1: 1687.7, 3448.3
1H NMR (300 MHz, CDCl3): δ 1.35-1.37 (6H, d), 2.21-2.46 (3H, m), 2.78-2.84 (IH, m), 3.06-3.12 (6H,m),3.50-3.67 (8H,m),4.57-4.63 (2H,m), 5.96-6.14 (2H,m), 6.85-7.03(4H,m), 12.12(lH,brs)
Mass (m/z): 428.4 (M+ + 1)
Example 17: Preparation of 4,7-dihydroxy-2-f3-4-[2-isopropoxy-phenyl)-piperazin-l-yl]- propyl|-3aA7Ja -tetrahydro isoindole-1,3 -dione hydrochloride salt (Compound No. 5) It was prepared according the procedure as described in Example 16 using 1 ,4- diacetoxy-1 ,3-butadiene.
IR (KBr) Cm"1: 1705, 3443.1
1H NMR (300 MHz, CDCl3): δ 1.33-1.35 (6 H, d), 2.38 (2H, brs), 3.00-3.03 (4H, m), 3.18(2H,brs), 3.46(6H,m), 3.72(2H,m), 4.53-4.61 (lH,m), 4.75 -4.83(2H,m) 6.48(2H,brs) 6.84-7.03(4H,m)
Mass (m/z): 444.3 (M+ + 1)
Example 18: Preparation of 2- {3 -|"4-(2-isopropoxyphenyl)-piperazin-l-yl'|-propyU isoindole- 1,3-dione hydrochloride salt ("Compound No. 3)
A mixture of N-(3-bromopropyl) phthalimide (0.5 g, 0.00186 mole), anhydrous potassium carbonate (0.515 g, 0.00373 mole) and 2-isopropoxyphenylpiperazine (0.37 g, 0.00168 mole) in dimethylformamide (10 mL) was heated at 75-78 0C for about 6-8 hours. The reaction mixture was quenched by adding water (20 mL), extracted with ethyl acetate, concentrated and purified on silica gel (60-120 mesh) column using dichloromethane and methanol as eluent.
To the solution of 2-{3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-isoindole- 1,3-dione (0.6 g, 0.00147 mole) in isopropyl alcohol (2 mL) was added equimolar quantity of isopropyl alcohol hydrochloric acid at 0-5 0C and reaction mixture stirred for about 30 minutes. A precipitate was formed in solution, which was filtered, dried and weighed to yield 0.48 g (74 %) of the product.
IR (KBr) Cm"1: 1718.6
1H NMR (300 MHz, CDCl3): δ 1.34-1.35 (6H, d), 2.43 (2H, brs), 3.02 -3.1 1 (4H, m), 3.47- 3.53 (6H,brs), 3.86 (2H,brs), 4.56-4.60 (lH,m), 6.84-7.01 (4H,m), 7.76-7.86(4H,m), 12.85(lH,brs)
Mass (m/z): 408.3 (M+ + 1)
Example 19: Metabolites identification and quantification
In vitro identification of metabolites of 2-{3-[4-(2-isopropoxyphenyl) piperazin-1-yl]- propyl}-3a,4,7,7a-tetrahydro-lH-isoindole-l,3-(2H)-dione in rat, dog and human liver microsomes 2-{3-[4-(2-isopropoxyphenyl)piperazin-l-yl]-propyl}-3a,4,7,7a-tetrahydro-lH- isoindole-l,3-(2H)-dione was incubated with rat, dog and human liver microsomes at 37°C in the presence of NADPH regenerating system. Samples were collected at 0, 5, 15, 30, 60 and 90 minutes. The reaction was quenched at these time points with equal volume of 60 % perchloric acid. The samples were then vortexed, centrifuged and 50μL of supernatant was analyzed by HPLC under gradient conditions.
Aqueous standard sample of 2-{3-[4-(2-isopropoxyphenyl) piperazin-l-yl]-propyl}- 3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione and its metabolites were injected under gradient HPLC conditions. The metabolites were identified if the retention time of observed peak matches retention of aqueous standard of metabolites. The identified peaks were collected and product ion scan was performed on LC-MS/MS, (Table I). The metabolites were confirmed when their retention time and mass fragmentation pattern matches with that of synthetic standard. The molecular ion peak (m/z), product ion peak (m/z) and the retention time (RT) identified are given in Table I.
Chromatographic conditions (HPLC)
Instrument: Shimadzu HPLC (Class V.P Version 4.1) coupled to a Shimadu UV VIS detector (SPD 10 AVP)
A gradient solvent run was used and the conditions were as follows.
Solvent A: 95:5 Acetonitrile: Water
Solvent B: 2OmM Ammonium Acetate (pH = 4.50)
Flow: l.O mL/min
Column: Licrosphere-RP Select-B, 5μ (4.6 x 250 mm)
Column temperature: Ambient
Injection volume: 50-100 μL λmax: 240 nm
Figure imgf000064_0001
LC-MS/MS
Column: Lichrospher RP-Select B, 5μ (4 x 125 mm)
Mobile phase: 8 mM ammonium acetate buffer (pH~4.5): acetonitrile:: 40: 60
Flow: 0.3 mL/min
Injection volume: 100 μL
Instrument: Perkin-Elmer API 3000 LC/MS/MS system with Turbo Ion Spray source
Mode: Full scan (Ql Scan with mass range of 100-1000 amu) Table I
Figure imgf000065_0001
In vivo identification of metabolites of 2-{3-[4-(2-Isopropoxyphenyl) piperazin-1-yl]- propyl}-3a,4,7,7a-tetrahydro-lH-isoindole-l,3-(2H)-dione in rat (urine, plasma, faeces and bile).
URINE
The urine samples were processed by two different methods.
Method I:
The urine samples were precipitated with equal volume of acetonitrile, vortexed, centrifuged and the supernatant was analysed by HPLC under gradient conditions Method II:
The urine samples were processed by solid phase extraction (SPE) method as follows:
3 mL of urine was mixed with 1.5 mL of 0.1M KH2PO4 (pH = 4.70) and 1 mL of the sample was loaded on a Drug Test cartridge (lOOmg / 3 cc). The cartridge was conditioned with 3 mL of methanol followed by 3 mL of 0.1 M KH2PO4 (pH = 4.70) prior to loading the sample. The sample was washed with 2 mL of wash solution (2 % acetic acid solution), followed by 2 mL of methanol and dried for 2 minutes under vacuum. Finally 2-{3-[4-(2-isopropoxyphenyl) piperazin-l-yl]-propyl}-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione and its metabolites were eluted twice with 2 mL of elution solution (2 % ammonia in ethyl acetate). The dried fractions were reconstituted in 350 μL of mobile phase [20:80 acetonitrile: 2OmM ammonium acetate (pH = 4.50)] and the samples were analysed by HPLC under gradient conditions. PLASMA
(By solid phase extraction): 1 mL of plasma sample was mixed with 1.0 mL of 0.1M KH2PO4 (pH = 4.70) and the sample was loaded on a Drug Test cartridge (lOOmg / 3 cc). The cartridge was conditioned with 3 mL each of methanol followed by 3 mL of 0.1 M KH2PO4 (pH = 4.70) prior to loading the sample. The sample was washed with 2 mL of wash solution (2 % acetic acid solution), followed by 2 mL of methanol and dried for 2 minutes under vacuum. Finally 2-{3-[4-(2-isopropoxyphenyl) piperazin-l-yl]-propyl}-3a,4,7,7a- tetrahydro-lH-isoindole-l,3(2H)-dione and its metabolites were eluted twice with 2 mL of elution solution (2 % ammonia in ethyl acetate). The dried fractions were reconstituted in 350 μL of mobile phase [20:80 acetonitrile: 2OmM ammonium acetate (pH = 4.50)] and the samples were analysed by HPLC under gradient conditions.
FAECES
To 100 mg of dried faeces, 3 mL of ethyl acetate was added and shaken for 30 minutes. The samples were centrifuged, supernatant was evaporated to dryness, residue reconstituted in 350 μL of mobile phase [20:80 acetonitrile: 2OmM ammonium acetate (pH = 4.50)] and the samples were analysed by HPLC under gradient conditions.
BILE
Bile samples were precipitated with equal volume of methanol, vortexed, centrifuged and the supernatant was analysed by HPLC under gradient conditions. The molecular in peak (m/z), product ion peak (m/z) and the retention time (RT) of metabolites in rat (urine, plasma, bile and faeces) are given in Table II.
Table II
Figure imgf000067_0001
In vivo identification of metabolites of 2-{3-[4-(2-isopropoxyphenyl) piperazin-1-yl]- propyl}-3a,4,7,7a-tetrahydro-lH-isoindole-l,3-(2H)-dione in rat and dog (plasma or/and urine) Method (By solid phase extraction (SPE)): 1 mL of plasma/urine sample was mixed with 1.0 mL of 0. IM KH2PO4 (pH = 4.70) and the sample was loaded on a Drug Test cartridge (lOOmg / 3 cc). The cartridge was conditioned with 3 mL each of methanol followed by 3 mL of 0.1 M KH2PO4 (pH = 4.70) prior to loading the sample. The sample was washed with 2 mL of wash solution (2 % acetic acid solution), followed by 2 mL of methanol and dried for 2 minutes under vacuum. Finally 2-{3-[4-(2-isopropoxyphenyl) piperazin-1- yl]-propyl}-3a,4,7,7a-tetrahydro-lH-isoindole-l,3(2H)-dione and its metabolites were eluted twice with 2 mL of elution solution (2 % ammonia in ethyl acetate). The dried fractions were reconstituted in 500 μL of mobile phase and the samples were analysed by LC-MS. The molecular ion peak (m/z), product ion peak (m/z) and the retention time (RT) of metabolites identified in dog plasma and the molecular ion peak (m/z) of conjugates of metabolites identified in dog urine are given in Table III and IV, respectively. The molecular ion peak (m/z), product ion peak (m/z) and the retention time (RT) in HPLC and LC-MS of all the metabolites identified in rat and dog are listed in Table V. Chromatographic conditions (HPLC)
Instrument: Shimadzu HPLC (Class V.P Version 4.1) coupled to a Shimadu UV VIS detector (SPD 10 AVP)
A gradient solvent run was used and the conditions were as follows.
Solvent A: 95:5 Acetonitrile: Water
Solvent B: 2OmM Ammonium Acetate (pH = 4.50)
Flow: 1.0 mL/min
Column: Licrosphere-RP Select-B, 5μ (4.6 x 250 mm)
Column temperature: Ambient
Injection volume: 50 - lOOμL
λmax: 240nm
Figure imgf000068_0001
LC-MS/MS
Column: Lichrospher RP-Select B, 5μ (4 X 125 mm)
Mobile phase: 8 mM ammonium acetate buffer (pH~4.5):: acetonitrile: 40 : 60
Flow: 0.3 mL/min
Injection volume: 100 μL
Instrument: Perkin-Elmer API 3000 LC/MS/MS system with Turbo Ion Spray source
Mode: Full scan (Ql Scan with mass range of 100-1000 amu) Table III
Figure imgf000069_0001
Table IV
Figure imgf000069_0002
Table V
Figure imgf000069_0003
Example 20: Estimation of Compound No. 9 and Compound No. 1 1 in plasma (rat and dog) by LC/MS/MS
Method (By Solid phase extraction): To 250 μL of plasma, 250 μL of potassium dihydrogen phosphate buffer (0.1 M, pH4.7±0.1) and 50 μL of internal standard solution (RBx3768-100ng/mL) was added and vortexed to ensure proper mixing. Drug test
100mg/3cc cartridges were used for processing the samples. The cartridges were conditioned on vacuum manifold at constant pressure using 2 mL of methanol and 2 mL of potassium dihydrogen phosphate buffer (0.1M, pH 4.7±0.1) followed by loading of sample. The cartridges were washed using 2 mL of wash solution (2 % acetic acid solution) and dried for 2 minutes under vacuum followed by washing with 2 mL of methanol and dried for 2 minutes under vacuum. Finally 2-{3-[4-(2-isopropoxyphenyl) piperazin-l-yl]-propyl}-3a,4,7,7a- tetrahydro-lH-isoindole-l,3(2H)-dione and its metabolites were eluted twice with 2 mL of elution solution (2 % ammonia in ethyl acetate). The eluate was dried and reconstituted in lOOμL of mobile phase and 10 μL of this solution was injected on LC -MS/MS for analysis. The molecular ion peak (m/z), product ion peak (m/z) and retention time (RT) of metabolites in plasma (rat and dog) are given in Table VI.
Chromatographic conditions Column: Chromolith speed rod (4.6 X 50 mm) Mobile phase: 8 mM ammonium acetate buffer: acetonitrile:: 10: 90 Flow: 0.6 mL/min
Injection volume: 10 μL
Sample cooler temperature: 6 0C
Instrument: Perkin-Elmer API 3000 LC/MS/MS system with Turbo Ion Spray source
Mode: MRM Table VI
Figure imgf000071_0001
Example 21: Pharmacological activity Radioligand binding assay
The affinities of metabolites of 2-{3-[4-(2-Isopropoxyphenyl) piperazin-1-yl]- propyl}-3a,4,7,7a-tetrahydro-lH-isoindole-l,3-(2H)-dione for α]a and ctib adrenoceptor subtype were evaluated by studying their ability to displace specific [ H] prazosin binding from the membrane of rat submaxillary and liver respectively (Michel et al., Br. J. Pharmacol., 98(3):883-889 (1989)). These tissues are reported to have a homogeneous population of respective αi adrenoceptor subtype (Ford et al., Trends Pharmacol. Sci., 15: 167-170 (1994)). The binding assays were performed according to Prichard (Prichard et al., J. Supramol. Struct., 9(2): 189-206 (1978)) with minor modifications.
Submaxillary glands were isolated immediately after sacrifice. The liver was perfused with buffer (Tris HCl 50 raM, pH 7.4). The tissues were homogenized with 10 volume of buffer (Tris HCL 50 mM, NaCl 100 mM, EDTA ImM, pH 7.4) with a polytron. The homogenate was filtered through two layers of wet gauze and filtrate was centrifuged at 3000g for 10 minutes. The supernatant was subsequently centrifuged at 60,000 G for 45 minutes. The pellet thus obtained was resuspended in a same volume of assay buffer (Tris HCl 50 mM, EDTA ImM, pH 7.4) and were stored at -70 0C until the time of assay. The membrane homogenates (150-250 μg protein) were incubated in titre plates in 250 μL of assay buffer (Tris HCl 50 mM, EDTAi mM, pH 7.4) at 24-25 0C for 1 hour. Non-specific binding was determined in the presence of 300 mM prazosin or 10 μM terazosin. The incubation was terminated by vacuum filtration over 0.5 % polyethyleneimine pre-treated GF/B fibers using a skatron cell harvester. The filters were then washed with ice cooled 50 mM Tris HCl buffer (pH 7.4). The filtrates were dried and transferred to 24 well plates (PET A No cross talk). Radioactivity retained on filters was counted in 600 μL of supermix in microbeta with a counting efficiency of 46 %. The IC50 value was determined using the nonlinear curve fitting program using G pad prism software. Saturation binding assays were used to determine Kd (apparent dissociation constant) for [3H] prazosin. The value of inhibition constant Ki was calculated from competitive binding studies by using Cheng and Prusoff equation (Cheng and Prusoff, Biochem. Pharmacol. , 22:3099-3108 (1973)):
Ki = IC5o/(l+L/Kd wherein L is the concentration of [ H] prazosin used in the particular experiment. Subtype selective by (αia Vs αib) is expressed as ratio of mean Ki at αjb receptors to mean Ki at αja receptor (Table VII). The affinities of metabolites at rat α ^-adrenoceptor (Ki) for Compound Nos. 2-1 1 ranged from of about 65 nM to about 0.2 nM, from about 3 nM to about 0.2 nM, or from about 17 nM to about 0.2 nM. The affinities of metabolites at rat otib-adrenoceptor (Ki) for Compound Nos. 2-1 1 ranged from of about 40 nM to about 1000 nM, from about 40 nM to about 700 nM, and even from about 40 nM to about 400 nM. Example 22: In vitro functional studies: In vitro alpha- 1 adrenoceptor selectivity
In order to study selectivity of action of the present compounds towards different alpha- 1 adrenoceptor subtypes, the ability of these compounds to antagonize alpha- 1 adrenoceptor agonist induced contractile response of aorta (alpha- Id), prostate (alpha- Ia) and spleen (alpha-lb) was studied. Aorta, prostate and spleen tissue were isolated from thiopentane anaesthetized (^ 300 mg/Kg) male wistar rats. Isolated tissues were mounted in an organ bath containing Krebs Henseleit buffer of the following composition (mM): NaCl 118; KCl 4.7; CaCl2 2.5; MgSO4. 7H2O 1.2; NaHCO3 25; KH2PO4 1.2; glucose 11.1. The buffer was maintained at 37 0C and aerated with a mixture of 95 % O2 and 5 % CO2. A resting tension of 2 g (aorta and spleen) or 1 g (prostate) was applied to tissues. Contractile response was monitored using a force displacement transducer and recorded on chart recorders. Tissues were allowed to equilibrate for 1 and 1/2 hours. At the end of the equilibration period, concentration response curves to norepinephrine (aorta) and phenylephirine (spleen and prostate) were obtained in the absence and presence of the tested compound (at concentration of 0.1, 1 and 10 μM). Antagonist affinities for Compound Nos. 2-11 were calculated and expressed as pKβ values for OCIA, ot I B and CCI D adrenoreceptor W
71 subtypes. Antagonist affinities for a^ adrenoreceptor subtype ranged having a pKβ from about 7.7 to about 9.8; having a pKβ from about 8.4 to about 9.6; and even having a pKβ from about 8.7 to about 9.3. Antagonist affinities for CCI B adrenoreceptor subtype ranged having a pKβ from about 7.0 to about 9.0; having a pKβ from about 7.2 to about 8.1; and even having a pKβ from about 7.8 to about 8.0. Antagonist affinities for ctio adrenoreceptor subtype ranged having a pKβ from about 7.5 to about 8.9; having a pKβ from about 7.7 to about 8.7; and even having a pKB from about 8.0 to about 8.6.
Example 23: Preparation of benzenesulfonic acid 2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydro isoindol-2-yl)- 1 -[ 1 -hvdroxy-4-(2-isopropoxyphenyl)-piperazin- 1 -ylmethyl"|-ethyl ester (Compound No. 13)
To a solution of 2-{2-hydroxy-3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}- 3a,4,7,7a -tetrahydroisoindole-l,3-dione (1 equiv, from Example 6) in dichloromethane (80- 100 mL) was added triethylamine (1.5 equiv) at 0-5 0C and reaction mixture was stirred for about 15-30 minutes. To the reaction mixture was added benzenesulfonyl chloride (1.5 equiv) at 0 0C to 5 0C over a period of about half to one hour. The reaction mixture was poured in sodium bicarbonate solution 5 %. The organic layer was separated and washed with water, dried over anhydrous sodium sulphate and solvent was removed under reduced pressure to yield the title compound.
The following prodrugs can be prepared similarly.
Phenylcarbamic acid 2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l-[l-oxy-4-(2- hydroxyphenyl) piperazin- 1 -ylmethyl] ethyl ester (Compound No. 14),
Methanesulfonic acid-2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l-[l-oxy-4-(2- hydroxyphenyl) piperazin- 1 -ylmethyl] ethyl ester (Compound No. 15),
Acetic acid-2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l-[l-oxy-4-(2- hydroxyphenyl) piperazin- 1 -ylmethyl] ethyl ester (Compound No. 16),
Methylcarbamic acid-2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l-[l-oxy-4-(2- hydroxyphenyl) piperazin- 1 -ylmethyl] ethyl ester (Compound No. 17).

Claims

We Claim: 1. A metabolite of 2-{3-[4-(2-Isopropoxyphenyl)-piperazin-l-yl]-propyl}-3a,4,7,7a- tetrahydro-lH-isoindole-l,3-(2H)-dione of Formula I,
Figure imgf000074_0001
Formula I pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, polymorphs, conjugates or prodrugs thereof, wherein the metabolite is an aromatized, desisopropylated, hydroxylated, epoxylated, or N-oxide derivative or conjugate or prodrug thereof.
2. A compound having the structure of Formula II,
Figure imgf000074_0002
Formula Il a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, polymorph, conjugate or prodrug thereof, wherein Y and Z, when taken together represent the fused ring systems
Figure imgf000074_0003
wherein R3, R4, R5 and Rβ are independently hydrogen or hydroxyl; X is -CHR7, wherein R7 is hydrogen or hydroxyl; R| is hydrogen or isopropyl; R2 is hydrogen or hydroxyl and n is an integer 0 or 1.
3. The compound of claim 2, wherein the compound of Formula II is an aromatized, desisopropylated, hydroxylated, epoxylated, or N-oxide metabolite of 2-{3-[4-(2- Isopropoxyphenyl)-piperazin-l-yl]-propyl}-3a,
4,7,7a-tetrahydro-lH-isoindole-l,3-(2H)- dione of Formula I.
Figure imgf000075_0001
Formula I 4. The compound of claim 2, wherein the conjugate is a sulfate, phosphate or glucuronate derivative.
5. The compound of claim 2, wherein the prodrug is a carbamoyl, (Ci-C4)-alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, (Ci-C4)-alkylsulfonyl or arylsulphonyl derivative.
6. The compound of claim 2, wherein the compound is desisopropylated metabolite 2- {3-[4-(2-hydroxyphenyl)-piperazin-l-yl]-propyl}-3a,4,7,7a-tetrahydroisoindole-l,3-dione.
7. The compound of claim 4, wherein the compound is a sulphate conjugate.
8. The compound of claim 4, wherein the compound is a glucuronate conjugate.
9. The compound of claim 2, wherein the compound is aromatized metabolite 2-{3-[4- (2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-isoindole-l,3-dione.
10. The compound of claim 2, wherein the compound is N-oxide metabolite 2-{3-[l-oxy- 4-(2-isopropoxyphenyl)-piperazin-l -yl]-propyl}-3a,4,7,7a -tetrahydroisoindole-l,3-dione.
1 1. The compound of claim 2, wherein the compound is hydroxylated metabolite 2-{2- hydroxy-3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-3a,4,7,7a-tetrahydroisoindole- 1,3-dione.
12. The compound of claim 2, wherein the compound is hydroxylated metabolite 4,7- dihydroxy-2-[3-4-[2-isopropoxy-phenyl)-piperazin- 1 -yl]-propyl} -3a,4,7,7a- tetrahydroisoindole-l,3-dione.
13. The compound of claim 2, wherein the compound is hydroxylated metabolite 4- hydroxy-2-{3-(4-(2-isopropoxy-phenyl)-piperazin-l-yl} -propyl} -3a,4,7,7a- tetrahydroisoindole-l,3-dione.
14. The compound of claim 2, wherein the compound is epoxylated metabolite 4-{3-[4- (2-isopropoxyphenyl)-piperazin- 1 -yl] -propyl } -hexahydro- 1 -oxa-4-aza-cyclopropa[f]indene- 3,5-dione.
15. The compound of claim 2, wherein the compound is hydroxylated metabolite 4-{2- Hydroxy-3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-l-oxa-4-aza- cyclopropa[f]indene3,5-dione.
16. The compound of claim 2, wherein the compound is hydroxylated metabolite 5,6- Dihydroxy-2-{3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-l,3- dione.
17. The compound of claim 2, wherein the compound is hydroxylated metabolite 2-{2- Hydroxy-3-[4-(2-hydroxy-phenyl)-piperazin-l-yl]-propyl}-3a,4,7,7a-tetrahydro isoindole- 1,3 -dione.
18. The compound of claim 2, wherein the compound is 2-{3-[4-(2-isopropoxyphenyl)-l- oxidopiperazin-l-yl}-propyl}-3a,4,7,7a-tetrahydroisoindole-l,3-dione or 5,6-Dihydroxy-2- {3-[4-(2-isopropoxy-phenyl)-piperazin-l-yl]-propyl}-hexahydroisoindole-l,3-dione.
19. The compound of claim 2, wherein the compound is:
Benzenesulfonic acid-2-( 1 ,3-dioxo- 1 ,3,3a,4,7,7a-hexahydroisoindol-2-yl)- 1 -[ 1 -oxy-4- (2-hydroxyphenyl)-piperazin-l-ylmethyl] -ethyl ester,
Phenylcarbamic acid-2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l-[l-oxy-4- (2-hydroxyphenyl)-piperazin-l-ylmethyl]-ethyl ester, Methanesulfonic acid-2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l-[l-oxy-4- (2-hydroxyphenyl)-piperazin-l-ylmethyl]-ethyl ester,
Acetic acid-2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l-[l-oxy-4-(2- hydroxyphenyl)-piperazin-l-ylmethyl]-ethyl ester, or
Methylcarbamic acid-2-( 1 ,3-dioxo- 1 ,3,3a,4,7,7a-hexahydroisoindol-2-yl)- 1 -[ 1 -oxy-4- (2-hydroxyphenyl)-piperazin-l-ylmethyl]-ethyl ester.
20. A pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure of Formula II,
Figure imgf000077_0001
Formula Il a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, polymorph, conjugate or prodrug thereof, and a pharmaceutically acceptable carrier, wherein Y and Z, when taken together represent
Figure imgf000077_0002
wherein R3, R4, R5 and Rβ are independently hydrogen or hydroxyl; X is -CHR7, wherein R7 is hydrogen or hydroxyl; Ri is hydrogen or isopropyl; R2 is hydrogen or hydroxyl and n is an integer 0 or 1.
21. A method for treating a disease or disorder mediated through αia adrenoceptor comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 2.
22. A method for treating a disease or disorder selected from high intraocular pressure, disorder associated with high cholesterol, cardiac arrhythmia, impotency, sympathetically mediated pain and migraine, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 2.
23. A method for the treating benign prostatic hyperplasia comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 2.
24. A method for treating a disease or disorder mediated through ctia adrenoceptor comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 20.
25. A method for treating a disease or disorder selected from high intraocular pressure, disorder associated with high cholesterol, cardiac arrhythmia, impotency, sympathetically mediated pain and migraine comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 20.
26. A method for treating benign prostatic hyperplasia comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 20.
27. A process for preparing compounds of Formula IV, Formula V or Formula Va or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, polymorph, conjugate or prodrug thereof comprising: a) reacting a compound of Formula III
Figure imgf000079_0001
Formula I
wherein R2 is hydrogen or hydroxy, with one or more peroxyacids to form a compound of Formula IV,
Figure imgf000079_0002
Formula IV
wherein R2 is hydrogen or hydroxy, b) reacting a compound of Formula IV,
Figure imgf000079_0003
Formula IV
R2 is hydrogen or hydroxy, with one or more peroxyacids to form a compound of Formula V,
Figure imgf000080_0001
Formula V
wherein R2 is hydrogen or hydroxy, or c) reacting a compound of Formula III
Figure imgf000080_0002
Formula
wherein R2 is hydrogen or hydroxy, with one or more peroxyacids to form a compound of Formula Va
Figure imgf000080_0003
Formula Va
R2 is hydrogen or hydroxy.
28. A process for preparing compounds of Formula XI or Formula XII or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, polymer, conjugate or prodrug thereof comprising: a) reacting 3a,4,7,7a-tetrahydro isoindole-l,3-dione of Formula VI
Figure imgf000081_0001
with a compound of Formula VII,
Figure imgf000081_0002
Formula VII
wherein Xi is chlorine or bromine, to form 2-oxiranylmethyl-3a,4,7,7a-tetrahydroisoindole- 1,3 -dione of Formula VIII,
Figure imgf000081_0003
Formula VIII
which is reacted with one or more peroxyacids to form 4-oxiranylmethylhexa-l -oxa-4-aza- cyclopropa[f]indene-3,5-dione of Formula IX,
Figure imgf000082_0001
which is reacted with a compound of Formula X
Figure imgf000082_0002
Formula X
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy, to form a compound of Formula XI,
Figure imgf000082_0003
Formula Xl
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy, or b) reacting a compound of Formula XI
Figure imgf000083_0001
Formula Xl
wherein R| is hydrogen or isopropyl and R2 is hydrogen or hydroxy, with one or more peroxyacids to form a compound of Formula XII,
Figure imgf000083_0002
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy.
29. A process for preparing compounds of Formula XIII or Formula XIV or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, polymorph, conjugate or prodrug thereof comprising: a) reacting 2-oxiranylmethyl-3a,4,7,7a-tetrahydroisoindole-l,3-dione of Formula VIII
Figure imgf000083_0003
Formula VIII
with a compound of Formula X,
Figure imgf000084_0001
Formula X
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy, to form a compound of Formula XIII,
Figure imgf000084_0002
Formula XIII
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy, or b) reacting a compound of Formula XIII,
Figure imgf000084_0003
Formula XIII
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy, with one or more peroxyacids to form a compound of Formula XIV,
Figure imgf000085_0001
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy.
30. A process for preparing compounds of Formula XVI or Formula XVII or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, polymer, conjugate or prodrug thereof comprising: a) reacting 3a,4,7,7a-tetrahydroisoindole-l,3-dione of Formula VI
Figure imgf000085_0002
with 1 ,3-dihalopropane (Y-CH2CH2CH2-Y) to form 2-(3-halopropyl)-3a,4,7,7a- tetrahydroisoindole- 1 ,3 -dione of Formula XV,
Figure imgf000085_0003
Formula XV wherein Y is F, Cl, Br or I, which is reacted with a compound of Formula X,
Figure imgf000086_0001
Formula X
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy, to form a compound of Formula XVI,
Figure imgf000086_0002
Formula XVI
wherein Rj is hydrogen or isopropyl and R2 is hydrogen or hydroxy, or b) reacting a compound of Formula XVI,
Figure imgf000086_0003
Formula XVI
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy, with peroxyacid to form a compound of Formula XVII,
Figure imgf000087_0001
Formula XVII
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy.
31. A process for preparing compounds of Formula XIX or Formula XX or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, conjugate or prodrug thereof comprising: a) reacting 2-(3-halopropyl)-3a,4,7,7a-tetrahydroisoindole-l,3-dione of Formula XV,
Figure imgf000087_0002
Formula XV wherein Y is F, Cl, Br or I, with one or more peroxyacids to form 4-(3-halopropyl)- hexahydro-l-oxa-4-aza-cyclopropa[f]indene-3,5-dione of Formula XVIII,
Figure imgf000087_0003
wherein Y is F, Cl, Br or I, which is reacted with a compound of Formula X
Figure imgf000088_0001
Formula X
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy, to form a compound of Formula XIX,
Figure imgf000088_0002
Formula XIX
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy, or b) reacting a compound of Formula XIX
Figure imgf000088_0003
Formula XIX
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy, with peroxyacid to form a compound of Formula XX
Figure imgf000089_0001
Formula XX
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy.
32. A process for preparing compound of Formula XXVI, Formula XXVII, Formula XXVIII or Formula XXIX or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, polymorph, conjugate or prodrug thereof comprising: a) reacting a compound of Formula X
Figure imgf000089_0002
Formula X
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy, with acrylonitrile to form a compound of Formula XXI,
Figure imgf000089_0003
Formula XXI
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy, which is reduced to form a compound of Formula XXII,
Figure imgf000090_0001
Formula XXII
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy, which is reacted with furan-2,5-dione to form a compound of Formula XXIII,
Figure imgf000090_0002
Formula XXlII
wherein Rj is hydrogen or isopropyl and R2 is hydrogen or hydroxy, which is reacted with 1- acetoxy- 1,3 -butadiene to form a compound of Formula XXV,
Figure imgf000090_0003
Formula XXV
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy, which is hydrolyzed to give a compound of Formula XXVI,
Figure imgf000091_0001
Formula XXVI
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy, or b) reacting a compound of Formula XXVI
Figure imgf000091_0002
Formula XXVI
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy, with one or more peroxyacids to form a compound of Formula XXVIII,
Figure imgf000091_0003
Formula XXVIII
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy, or c) reacting a compound of Formula XXIII
Figure imgf000092_0001
Formula XXlII
with l,4-diacetoxy-l,3-butadiene to form a compound of Formula XXIV,
Figure imgf000092_0002
which is hydrolyzed to form a compound of Formula XXVII,
Figure imgf000092_0003
Formula XXVII
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy, or d) reacting a compound of Formula XXVII
Figure imgf000093_0001
Formula XXVII
with one or more peroxyacids to form a compound of Formula XXIX
Figure imgf000093_0002
Formula XXIX
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy.
33. A process for preparing compounds of Formula XXXII or Formula XXXIII or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, polymorph, conjugate or prodrug thereof comprising: a) reacting isoindole-l,3-dione of Formula XXX
Figure imgf000093_0003
Formula XXX with 1,3-dihalopropane to form 2-(3-halopropyl)-isoindole-l,3-dione of Formula XXXI,
Figure imgf000094_0001
Formula XXXI wherein Y is F, Cl, Br or I, which is reacted with a compound of Formula X,
Figure imgf000094_0002
Formula X
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy, to form a compound of Formula XXXII
Figure imgf000094_0003
Formula XXXII
wherein R1 is hydrogen or isopropyl and R2 is hydrogen or hydroxy, or b) reacting a compound of Formula XXXII
Figure imgf000095_0001
Formula XXXlI
with peroxyacid to give a compound of Formula XXXIII
Figure imgf000095_0002
Formula XXXIII
wherein Ri is hydrogen or isopropyl and R2 is hydrogen or hydroxy.
34. A prodrug having the structure of Formula XXXVa,
Figure imgf000095_0003
Formula XXXVa a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, polymorph or conjugate thereof, wherein Y and Z, when taken together represent
Figure imgf000096_0001
wherein R3, R4, R5 and R6 are independently hydrogen, hydroxyl or -0-W-R; X is -CHR7, wherein R7 is hydrogen, hydroxyl or -0-W-R; Ri is hydrogen or isopropyl; R2 is hydrogen, hydroxyl or 0-W-R n is an integer 0 or 1 , and at least one of R2, R3, R4, R5, R6 or X is -0-W-R, wherein W is -SO2, -CO-, -CONR8, wherein R8 is (Ci-C4)-alkyl or aryl, and R is (C 1 -C4)-alkyl, aryl or aralkyl.
35. The prodrug of claim 34, wherein the aryl is phenyl or naphthyl.
36. The prodrug of claim 34, wherein the aralkyl is benzyl.
37. The prodrug of claim 34, wherein W and R are respectively, SO2 and (Cι-Gj)-alkyl; SO2 and methyl; SO2 and aryl; SO2 and phenyl; CO and (C|-C4)-alkyl; CO and methyl; CO and ethyl; CO and aralkyl; CO and benzyl; CONR8 and (Ci-C4)-alkyl, wherein R8 is (Ci-C4)- alkyl; CONR8 and methyl, wherein R8 methyl; CONR8 and aryl, wherein R8 is (Ci-C4)-alkyl; CONR8 and phenyl, wherein R8 is methyl; CONR8 and aryl, wherein R8 is aryl; or CONR8 and phenyl, wherein R8 is phenyl.
38. A prodrug of claim 34, wherein the prodrug is:
Benzenesulfonic acid 2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l-[l-oxy-4-
(2-hydroxyphenyl) piperazin-1-ylmethyl] ethyl ester,
Phenylcarbamic acid 2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l-[l-oxy-4- (2-hydroxyphenyl) piperazin-1-ylmethyl] ethyl ester, Methanesulfonic acid 2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l-[l-oxy-4- (2-hydroxyphenyl) piperazin-1-ylmethyl] ethyl ester,
Acetic acid 2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l-[l-oxy-4-(2- hydroxyphenyl) piperazin-1-ylmethyl] ethyl ester, or
Methylcarbamic acid 2-(l,3-dioxo-l,3,3a,4,7,7a-hexahydroisoindol-2-yl)-l-[l-oxy-4- (2-hydroxyphenyl) piperazin-1-ylmethyl] ethyl ester.
39. A process for preparing prodrugs having a structure of Formula XXXVa,
Figure imgf000097_0001
Formula XXXVa a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, polymorph, conjugate or prodrug thereof, wherein Y and Z, when taken together represent the fused ring systems
Figure imgf000097_0002
wherein R3, R4, R5 and R6 are independently hydrogen, hydroxyl or -O- W-R;
X is -CHR7, wherein R7 is hydrogen, hydroxyl or -0-W-R;
Ri is hydrogen or isopropyl;
R2 is hydrogen, hydroxyl or 0-W-R n is an integer 0 or 1, and at least one of R2, R3, R4, R5, R6 or X is -0-W-R, wherein W is -SO2, -CO-, -CONR8, wherein R8 is (Ci-C4)-alkyl or aryl, and R is (C i-C4)-alkyl, aryl or aralkyl, which process comprises reacting a hydroxylated metabolite of Formula XXXIVa
Figure imgf000098_0001
Formula XXXIVa wherein R3, R4, R5 and R6 are independently hydrogen or hydroxyl; X is -CHR7, wherein R7 is hydrogen or hydroxyl; Ri is hydrogen or isopropyl; R2 is hydrogen or hydroxyl; n is an integer 0 or 1 ; and at least one Of R2, R3, R4, R5, R6 or X is hydroxyl, wherein W is -SO2, -CO-, -CONR8, wherein R8 is (C i-C4)-alkyl or aryl, and R is (C 1 -C4)-alkyl, aryl or aralkyl, with a compound of Formula Cl-W-R, wherein W is -SO2, -CO-, -CONR8, wherein R8 is (Ci-C4)-alkyl or aryl, and R is (Ci-C4)-alkyl, aryl or aralkyl, to form a prodrug of Formula XXXVa.
PCT/IB2006/000436 2005-03-02 2006-03-01 Metabolites of 2-{3-[4-(2-isopropoxyphenyl) piperazin-1-yl]-propyl}-3a,4,7,7a-tetrahydro-1h-isoindole-1,3-(2h)-dione WO2006092710A1 (en)

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