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WO2007039809A1 - Métabolites de 2- {3-[4-(5-fluoro-2-isopropoxy-phényl)-pipérazin-1-yl]-propyl} -5,6-dihydroxy-hexahydro-isoindol-1,3-dione - Google Patents

Métabolites de 2- {3-[4-(5-fluoro-2-isopropoxy-phényl)-pipérazin-1-yl]-propyl} -5,6-dihydroxy-hexahydro-isoindol-1,3-dione Download PDF

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Publication number
WO2007039809A1
WO2007039809A1 PCT/IB2006/002758 IB2006002758W WO2007039809A1 WO 2007039809 A1 WO2007039809 A1 WO 2007039809A1 IB 2006002758 W IB2006002758 W IB 2006002758W WO 2007039809 A1 WO2007039809 A1 WO 2007039809A1
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Prior art keywords
compound
formula
fluoro
piperazin
isopropoxyphenyl
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English (en)
Inventor
Pakala Kumara Savithru Sarma
Praful Gupta
Vekata P. Palle
Mukkavilli Subba Rao
Rajan S. Kombu
Kamal Rauthan
Vikram Krishna Ramanathan
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • the present invention relates to metabolites of 2- ⁇ 3-[4-(5-fiuoro-2-isopropoxy- phenyl)-piperazin- 1 -yl] -propyl ⁇ -5 ,6-dihydroxyhexahydro- lH-isoindole- 1 ,3 (2H)-dione of Formula I.
  • the compounds described herein can function as ⁇ la -adrenoceptor antagonists and thus can be used to treat benign prostatic hyperplasia (BPH) and related symptoms thereof. Processes for preparing such metabolites, pharmaceutical compositions thereof, and methods of treating BPH and related symptoms thereof are also provided.
  • the ⁇ -adrenoceptor antagonists are in clinical use for symptomatic treatment of benign prostatic hyperplasia (BPH) (Oesterling, Drug Therapy, 332(2) :99-l 10, 1995; Chappie, Br. J. Urology, 1:47-55, 1995). It is disclosed that the effects of Oc 1 -adrenoceptor antagonists result from antagonism of noradrenaline induced contraction of prostatic smooth muscle that occurs via Ot 1 adrenoceptors (Hieble et al, European Journal of Pharmacology, 107:111-117, 1985). However, as Ct 1 -adrenoceptors are widely distributed, poor organ selectivity limits therapeutic usefulness for this class of drugs.
  • BP ⁇ 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 BP ⁇ can include hypertrophy of bladder smooth muscle, a decompensated bladder and increased incidence of urinary tract infection.
  • the method of choice for treating BP ⁇ reportedly is surgery (Lepor, et al, The Journal of Urology, 143:553-537, 1990).
  • Limitations of surgical treatments of BP ⁇ 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.
  • Such metabolites can be used in safe and effective treatments of BP ⁇ 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 BP ⁇ or related symptoms thereof.
  • 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 carxiers, and optionally included excipients, are also included, which can be useful for safe and effective treatment of BPH or related symptoms thereof.
  • R 1 , R 2 and R 4 can be independently hydrogen or hydroxy; R 3 can be hydrogen or isopropyl; and 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 desisopropylated, hydroxylated, or N-oxide metabolites of 2- ⁇ 3-[4-(5-fluoro-2-isopropoxy-phenyl)-piperazin-l-yl]propyl ⁇ - 5,6-dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione of Formula I.
  • Conjugates can be sulfate, phosphate or glucuronide derivatives.
  • Prodrugs can be carbamoyl, (CrC ⁇ -alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, (CrC ⁇ -alkylsulfonyl or arylsulphonyl derivatives.
  • Compounds of Formula II can include desisopropylated metabolite 2- ⁇ 3-[4-(5- fluoro-2-hydroxyphenyl)piperazin-l-yl]propyl ⁇ -5,6-dihydroxyhexahydro-lH-isoindole- l,3(2H)-dione.
  • the metabolite can have a molecular ion peak of m/z 422.2 and its retention time can be 9.3 or 12.6 minutes.
  • the fragmentation pattern of the metabolite can be 422.2, 226.1, 208.1, 198.1, 180.2 m/z.
  • Compounds of Formula II can include hydroxylated metabolite 2- ⁇ 3-[4-(5-fluoro- 2-isopropoxyphenyl)piperazin- 1 -yljpropyl ⁇ -4,5,6-trihydroxyhexahydro- lH-isoindole- l,3(2H)-dione.
  • the metabolite can have a molecular ion peak of m/z 480.1 and its retention time can be 16.4 or 17.2.
  • the fragmentation pattern of the metabolite can be 480.3, 438.2, 285.2, 271.2, 242.2, 224.2, 214.2, 196.1, 178.1 m/z.
  • Compounds of Formula II can include hydroxylated metabolite 2- ⁇ 3-[4-(5-fluoro- 2-isopropoxyphenyl)piperazin-l-yl]-2-hydroxypropyl ⁇ -5,6-dihydroxyhexahydro-lH- isoindole-l,3(2H)-dione.
  • the metabolite can have a molecular ion peak of m/z 480.1 and its retention time can be 14.7.
  • the fragmentation pattern of the metabolite can be 480.3,
  • Compounds of Formula II can include hydroxylated metabolite 2- ⁇ 3-[4-(5-fiuoro- 4-hydroxy-2-isopropoxyphenyl)piperazin- 1 -yl]propyl ⁇ -5,6-dihydroxyhexahydro- IH- isoindole-l,3(2H)-dione.
  • the metabolite can have a molecular ion peak of m/z 480.1 and its retention time can be 13.0 minutes.
  • the fragmentation pattern of the metabolite can be
  • Compounds of Formula II can include desisopropylated hydroxylated metabolite 2- ⁇ 3-[4-(5-fluoro-2-hydroxyphenyl)piperazm-l-yl]-2-hydroxypropyl ⁇ -5,6-dihydroxy- hexahydro- lH-isoindole- 1 ,3 (2H)-dione.
  • Compounds of Formula II can include desisopropylated hydroxylated metabolite 2- ⁇ 3-[4-(5-fluoro-2,4-dihydroxyphenyl)piperazin-l-yl]-2-hydroxypropyl ⁇ -5,6- dihydroxyhexahydro- lH-isoindole- 1 ,3 (2H)-dione.
  • Compounds of Formula II can include N-oxide metabolite l-[3-(5,6-dihydroxy- l,3-dioxooctahydro-2H-isoindol-2-yl)propyl]-4-(5-fluoro-2-isopropoxyphenyl)-l- oxypiperazin-1-ium.
  • Compounds of Formula II can include hydroxylated N-oxide metabolite 4-(5-fluoro-2-isopropoxyphenyl)-l-oxy-l-[3-(4,5,6-trihydroxy-l,3- dioxooctahydro-2H-isoindol-2-yl)propyl]piperazin- 1 -ium.
  • R 1 , R 2 and R 4 can be independently hydrogen or hydroxy;
  • R 3 can be hydrogen or isopropyl;
  • R 5 can be hydrogen or methyl; and
  • n can be an integer 0 or 1.
  • Embodiments of the compounds of Formula III may include one or more of the following.
  • compounds of Formula III can include ring opened or ring opened hydroxylated metabolites of 2- ⁇ 3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l- yljpropyl ⁇ -5,6-dihydroxy-hexahydro- lH-isoindole- 1 ,3(2H)-dione of Formula I.
  • Compounds of Formula III can include ring opened metabolite 2-[( ⁇ 3-[4-(5-fluoro-2- isopropoxyphenyl)piperazin- 1 -yl]propyl ⁇ amino)carbonyl] -4,5 - • dihydroxycyclohexanecarboxylic acid.
  • the metabolite can have molecular ion peak m/z 482.2 and its retention time can be 13.4 minutes.
  • a glucuronide conjugate of the metabolite can have molecular ion peak m/z 658.1 and its retention time can be 11.7 or 12.2 minute.
  • the fragmentation pattern of the metabolite can be 482.2, 296.2, 279.2, 251.3, 244.1, 226.1, 208.2, 198.2 and 180.1 m/z.
  • the fragmentation pattern of glucuronide conjugate of metabolite can be 658.2, 482.2, 420.1, 296.3, 279.4, 244.1, 226.1, 208. land 198.1 m/z.
  • Compounds of Formula III can include ring opened hydroxylated metabolite 2-[( ⁇ 3-[4-(5- fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl ⁇ amino)carbonyl]-3,4,5- trihydroxycyclohexanecarboxylic acid.
  • the metabolite can have molecular ion peak m/z 498.2 and its retention time can be 13.5 minutes.
  • the fragmentation pattern of the metabolite can be 498.4, 296.3, 279.3, 260.2, 251.3, 242.2, 224.2, 209.2, 196.1 and 180.2 m/z.
  • Compounds of Formula III can include ring opened hydroxylated metabolite 2-[( ⁇ 3-[4-(5- fluoro-2-isopropoxyphenyl)piperazin-l-yl]-2-liydroxypropyl ⁇ amino)carbonyl]-4,5- dihydroxycyclohexanecarboxylic acid.
  • the metabolite can have molecular ion peak m/z 498.2 and its retention time can be 13.5 minutes.
  • the fragmentation pattern of the metabolite can be 498.4, 296.3, 279.3, 260.2, 251.3, 242.2, 224.2, 209.2, 196.1 and 180.2 m/z.
  • Compounds of Formula III can include ring opened hydroxylated metabolite 2- [( ⁇ 3-[4-(5-fluoro-4-hydroxy-2-isopropoxyphenyl)piperazin-l-yl]-2- hydroxypropyl ⁇ amino)carbonyl]-4,5-dihydroxycyclohexanecarboxylic acid.
  • compositions comprising therapeutically effective amounts of one or more compounds of Formula II and/or III,
  • R 1 , R 2 and R 4 can be independently hydrogen or hydroxy; R 3 can be hydrogen or isopropyl; R 5 can be hydrogen or methyl; 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 glucuronide derivatives.
  • the pharmaceutical compositions can also contain prodrugs that include, for example, carbamoyl, (C 1 -C 4 )- alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, (Q-C ⁇ -alkylsulfonyl or arylsulphonyl derivatives.
  • methods for treating a disease or disorder mediated through ⁇ la adrenoceptor comprising administering to a patient in need thereof a therapeutically effective amount of at least one 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 at least one compound disclosed herein.
  • kits for treating benign prostatic hyperplasia comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound disclosed herein.
  • Embodiments of this method can include one or more of the following.
  • compound does not cause a fall in blood pressure.
  • the compound can also relax the lower urinary tract tissue, for example, the prostate smooth muscle.
  • provided herein are methods for treating a disease or disorder mediated through ⁇ la adrenoceptor comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition disclosed herein.
  • 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.
  • methods for treating benign prostatic hyperplasia comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition disclosed herein.
  • prodrugs having the structure of Formula IV,
  • W can be -SO 2 , -CO-, -CONR 6 , wherein R 6 can be (C 1 -C 4 )- alkyl or aryl; R can be (Q-C ⁇ -alkyl, aryl or aralkyl; the circle can be the structure of any compound of Formula II or III.
  • 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 (C 1 -C 4 )-alkyl; CO and methyl; CO and ethyl; CO and aralkyl; CO and benzyl; CONR 6 and (CrC ⁇ -alkyl, wherein R 6 can be (Q-C ⁇ -alkyl; CONR 6 and methyl, wherein R 6 methyl; CONR 6 and aryl, wherein R 6 can be (CrC ⁇ -alkyl; CONR 6 and phenyl, wherein R 6 can be methyl; CONR 6 and aryl, wherein R 6 can be aryl; or CONR 6 and pheny
  • prodrugs can include, but are not limited to:
  • the invention provides metabolites of 2- ⁇ 3-[4-(5-fluoro-2-isopropoxyphenyl)- piperazin-l-yl]propyl ⁇ -5,6-dihydroxyhexahydro-lH-isoindole-l,3(2H)-dione (Compound No. 1) of Formula I,
  • metabolites can comprise desisopropylated, hydroxylated or N-oxide derivatives of Formula I.
  • Desisopropylated, hydroxylated or N-oxide derivatives of compound of Formula I can be represented by the general Formula II,
  • R 1 , R 2 and R 4 can be independently hydrogen or hydroxy; R 3 can be hydrogen or isopropyl; and n can be an integer 0 or 1.
  • this invention provides metabolites of 2- ⁇ 3-[4-(5-Fluoro-2-isopropoxy- phenyl)-piperazin- 1 -yl] -propyl ⁇ -5 ,6-dihydroxyhexahydro-isoindole- 1 ,3-dione having the structure of Formula III,
  • R 1 , R 2 and R 4 can be independently hydrogen or hydroxy; R 3 can be hydrogen or isopropyl; R 5 can be hydrogen or methyl; and n can be an integer 0 or 1.
  • R 1 , R 2 and R 4 can be independently hydrogen or hydroxy; R 3 can be hydrogen or isopropyl; R 5 can be hydrogen or methyl; and 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.
  • organic acids for example, formic acid, acetic acid, propionic acid
  • salt forms can differ from the metabolites described herein in certain physical properties, for example, solubility.
  • Pharmaceutically acceptable salts can be prepared following procedures well known to the skilled artisan.
  • 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 glucuronide derivatives of particular hydroxylated compounds. Prodrugs of particular hydroxylated compounds are also encompassed herein.
  • Prodrugs include, but are not limited to, derivatives of compounds having one or more carbamoyl, (CrC ⁇ -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-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]propyl ⁇ -5,6-dihydroxy-hexahydro- isoindole-l,3-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, semisolid 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.
  • 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, hi liquid form preparations, one or more metabolites can be mixed with water or one or more other solvents, solubilizing agents and/or emulsifiers, 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.
  • solubilizing agents and/or emulsifiers for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,
  • 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 e.g., sterile injections, aqueous or oleaginous suspensions
  • suitable dispersing or wetting suspending agents e.g., sterile injections, aqueous or oleaginous suspensions
  • suitable dispersing or wetting suspending agents e.g., sterile injections, aqueous or oleaginous suspensions
  • Dosage forms for topical or transdermal administration include 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.
  • the preparations are subdivided into unit doses containing therapeutic quantities of one or more active metabolites.
  • 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 skilled 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 hydrolytic 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.
  • 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.
  • 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.
  • metabolites described herein can be prepared by following reaction sequences, for example, as depicted in Schemes I, II and III.
  • Compounds of Formula VIII can be prepared, for example, according to Scheme I.
  • the preparation can comprise reacting a compound of Formula V with a compound of Formula VI to give a compound of Formula VII (wherein R 2 and R 4 can be hydrogen or hydroxy, R 3 can be hydrogen or isopropyl), which on reaction with one or more peroxyacids can give a compound of Formula VIII.
  • Suitable peroxyacids include, for example, m-chloroperbenzoic acid, monoperoxyphthalate, potassium peroxymonosulfate or mixture thereof.
  • the reaction of a compound of Formula V with a compound of Formula VI can be carried out in presence of alkali metal halides (e.g., sodium iodide, potassium iodide or sodium chloride), one or more inorganic base (e.g., potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, calcium carbonate, barium carbonate or sodium hydride) in one or more solvents, for example, acetonitrile, acetone, tetrahydrofuran, cyclohexane, toluene, dimethylformamide, dimethylsulfoxide or mixtures thereof.
  • alkali metal halides e.g., sodium iodide, potassium iodide or sodium chloride
  • one or more inorganic base e.g., potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, calcium carbonate, barium carbonate or sodium hydride
  • solvents for example, acetonitrile, acetone
  • reaction of a compound of Formula VII can be carried out in one or more solvents, for example, chloroform, dichloromethane, tetrahydrofuran, acetonitrile or mixtures thereof.
  • Compounds of Formula XI can be prepared, for example, according to Scheme II.
  • the methods can comprise reacting a compound of Formula IX with a compound of Formula VI to give a compound of Formula X (wherein R 2 can be hydrogen or hydroxy, R 3 can be hydrogen or isopropyl), which on reaction with one or more peroxyacids can give a compound of Formula XI.
  • Suitable peroxyacids include, for example, m- chloroperbenzoic acid, monoperoxyphthalate, potassium peroxymonosulfate or mixtures thereof.
  • reaction of a compound of Formula IX with a compound of Formula VI can be carried out in one or more alcoholic solvents, for example, methanol, ethanol, isopropanol, n-butanol or mixtures thereof.
  • the reaction of the compound of Formula X to give a compound of Formula XI can be carried out in one or more solvents, for example, chloroform, dichloromethane, tetrahydrofuran, acetonitrile or mixtures thereof.
  • Compounds of Formula XIV and XVI can be prepared, for example, according to methods in Scheme III.
  • the methods can comprise reacting a compound of Formula XII with an inorganic base, for example, sodium hydroxide or potassium hydroxide to give a ' compound of Formula XIII (wherein R 2 can be hydrogen or hydroxy, R 3 can be hydrogen ) or isopropyl), which on (a) reaction with one or more peroxyacids can give a compound of Formula XIV, (b) reaction with methanol and hydrochloric acid can give a compound of Formula XV, which on reaction with one or more peroxyacids can give a compound of Formula XVI.
  • an inorganic base for example, sodium hydroxide or potassium hydroxide
  • Suitable peroxyacids include, for example, m-chloroperbenzoic acid, monoperoxyphthalate, potassium peroxymonosulfate or mixture thereof.
  • the reaction of a compound of Formula XIII to give a compound of Formula XIV and the reaction of a compound of Formula XV to give a compound of Formula XVI can be carried out in one or more solvents, for example, chloroform, dichloromethane, tetrahydrofuran, acetonitrile or mixture thereof.
  • W can be -SO 2 -, -CO-, -CONR 6 , wherein R 6 can be C 1 -C 4 alkyl or aryl (e.g., phenyl or naphthyl); R can be C 1 -C 4 alkyl, aryl (e.g., phenyl or naphthyl) or aralkyl (e.g., benzyl), and the circle represents any compound described herein including, for example, compounds of Formulae II or III.
  • 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.
  • reaction of the hydroxylated metabolites of Formula XVII with a compound of Formula X-W-R to form a compound of Formula IV can be carried out in one or more solvents, for example, chloroform, dichloromethane, tetrahydrofuran, dimethylformamide or mixtures thereof.
  • This reaction can also be carried out in the presence of an organic base like triethylamine or 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 XVII, wherein W and R are respectively, SO 2 and (Ci-GO-alkyl; SO 2 and methyl; SO 2 and aryl; SO 2 and phenyl; CO and (Q-C ⁇ -alkyl; CO and methyl; CO and ethyl; CO and aralkyl; CO and benzyl; CONR 6 and (Ci-C 4 )-alkyl, wherein R 6 is (C 1 -C 4 ) alkyl; CONR 6 and methyl, wherein R 6 is methyl; CONR 6 and aryl, wherein R 6 is (CrC 4 )-alkyl; CONR 6 and phenyl, wherein R 6 is methyl; CONR 6 and aryl, wherein R 6 is aryl; or CONR 6 and phenyl, wherein R 6 is phenyl. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled
  • Example 1 Preparation of a compound of Formula VII A mixture of a compound of Formula V (50 equiv.), a compound of Formula VI
  • a mixture of a compound of Formula IX (1.1 equiv.), a compound of Formula VI (1 equiv.) and triethylamine (1.1 equiv.) in ethanol (10-15 mL) is refluxed for about 4 to 5 hours. After completion of the reaction, it is concentrated, purified on a silica gel (60-120 mesh) column using dichloromethane and methanol as eluent.
  • Example 6 Preparation of hydrochloride salt of a compound of Formula VIL VIIL LX, X, XL XIIL XLV, XV or XVI
  • Sample preparation The incubated in-vitro metabolism samples were vortexed and centrifuged at 12000 rpm for about 10 min. Supernatant was injected on to LC-MS/MS for analysis. Enhanced MS (EMS) scan followed by enhanced product ion (EPI) scans were performed to identify the metabolites. Further, neutral loss scan was performed to confirm the glucuronidation.
  • EMS Enhanced MS
  • EPI enhanced product ion
  • parent compound and its metabolites are eluted with 3 mL each of elution solution (2% ammoniated ethyl acetate).
  • elution solution 2% ammoniated ethyl acetate.
  • the eluate is dried at 50 0 C under 10 psi of nitrogen.
  • the residue is reconstituted in 200 ⁇ L of mobile phase 20 ⁇ L of this solution is injected on LC/MS/MS for analysis.
  • Submaxillary glands are isolated immediately after sacrifice.
  • the liver is perfused with buffer (Tris HCl 50 mM, pH 7.4).
  • the tissues are homogenized 10 volume of buffer (Tris HCL 50 mM, NaCl 100 mM, EDTA ImM, pH 7.4) with a polytron.
  • the homogenate is filtered through two layers of wet guaze and filtrate is centrifuged at 3000g for lO min. The supernatant is subsequently centrifuged at 60,00Og for 45 min.
  • the pellet thus obtained is resuspended in same volume of assay buffer (Tris HCl 50 mM, EDTA ImM, pH 7.4) and are stored at -70°C until the time of assay.
  • the membrane homogenates (150-250 ⁇ g protein) are incubated in titre plates in 250 ⁇ l of assay buffer (Tris HCl 50 mM, EDTA 1 mM, pH 7.4) at 24-25 0 C for 1 hour. Non-specific binding is determined in the presence of 300 mM prazosin or 10 ⁇ M terazosin.
  • the in cubation is terminated by vaccum filtration over 0.5% polyethylenimine pre-treated GF/B fibers using skatron cell harvester.
  • the filters are then washed with ice coed 50 mM Tris HCl buffer (pH 7.4). the filtermates are dried and transferred to 24 well plates (PET A No cross talk).
  • Radio activity retained on filters is counted in 600 ⁇ l of supermix in microbeta with a counting efficiency of 46%.
  • IC 50 value is determined using the non-linear curve fiting program using G pad prism software. Saturation binding assays are used to determined Kd (apparent dissociation constant) for [ 3 H] prazosin.
  • Ki inhibition constant
  • Subtype selective by ( ⁇ la Vs ⁇ ) is expressed as ratio of mean Ki at an, receptors to mean Ki at ⁇ la receptors.
  • Example 11 Preparation of 2-(5 ,6-dihydroxy- 1 ,3 -dioxooctahvdro ⁇ H-isoindol- ⁇ -yl)- 1 - ⁇ [4-(5-fluoro-2-isopropoxyphenyl ' )piperazm-l-yllmethvUethyl methanesulfonate (Compound No. 14),

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Abstract

La présente invention concerne des métabolites de 2-{3-[4-(5-fluoro-2-isopropoxy- phényl)-pipérazin-1-yl]-propyl}-5,6-dihydroxyhexahydro-1H-isoindol-1 ,3(2H;-dione de Formule I. Les composés de l’invention peuvent fonctionner comme des antagonistes de α1a-adrénocepteur et peuvent donc être utilisés pour le traitement d’hyperplasie prostatique bénigne (BPH) et des symptômes associés. L’invention concerne également des procédés de préparation desdits métabolites, des compositions pharmaceutiques contenant ces composés, et des procédés pour traiter la BPH et les symptômes associés.
PCT/IB2006/002758 2005-10-05 2006-10-04 Métabolites de 2- {3-[4-(5-fluoro-2-isopropoxy-phényl)-pipérazin-1-yl]-propyl} -5,6-dihydroxy-hexahydro-isoindol-1,3-dione Ceased WO2007039809A1 (fr)

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IN2671/DEL/2005 2005-10-05

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002044151A1 (fr) * 2000-11-30 2002-06-06 Ranbaxy Laboratories Limited Derives de piperazine 1,4-disubstitues utiles comme bloqueurs uroselectifs des recepteurs alpha1-adrenergiques
WO2003084928A1 (fr) * 2002-04-08 2003-10-16 Ranbaxy Laboratories Limited Derives d'alpha, omega-dicarboximide utiles en tant qu'inhibiteurs uroselectifs de l'adreno-recepteur ?1?
WO2005018643A1 (fr) * 2003-08-25 2005-03-03 Ranbaxy Laboratories Limited Metabolites de 1-{3-4`4-(2-methoxyphenyl)piperazin-1-yl!-propyl}-piperidine-2, 6-dione utilisables dans le traitement de l'hypertrophie benigne de la prostate
WO2005037282A1 (fr) * 2003-10-15 2005-04-28 Ranbaxy Laboratories Limited Derives de 1-alkylpiperazinyl-pyrrolidin-2,5-dione utiles comme antagonistes du recepteur adrenergique
WO2005118537A2 (fr) * 2004-05-31 2005-12-15 Ranbaxy Laboratories Limited Antagonistes des recepteurs adrenergiques

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002044151A1 (fr) * 2000-11-30 2002-06-06 Ranbaxy Laboratories Limited Derives de piperazine 1,4-disubstitues utiles comme bloqueurs uroselectifs des recepteurs alpha1-adrenergiques
WO2003084928A1 (fr) * 2002-04-08 2003-10-16 Ranbaxy Laboratories Limited Derives d'alpha, omega-dicarboximide utiles en tant qu'inhibiteurs uroselectifs de l'adreno-recepteur ?1?
WO2005018643A1 (fr) * 2003-08-25 2005-03-03 Ranbaxy Laboratories Limited Metabolites de 1-{3-4`4-(2-methoxyphenyl)piperazin-1-yl!-propyl}-piperidine-2, 6-dione utilisables dans le traitement de l'hypertrophie benigne de la prostate
WO2005037282A1 (fr) * 2003-10-15 2005-04-28 Ranbaxy Laboratories Limited Derives de 1-alkylpiperazinyl-pyrrolidin-2,5-dione utiles comme antagonistes du recepteur adrenergique
WO2005118537A2 (fr) * 2004-05-31 2005-12-15 Ranbaxy Laboratories Limited Antagonistes des recepteurs adrenergiques

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