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WO2007029078A2 - Derives de succinimide et de glutarimide comme antagonistes de recepteurs adrenergiques - Google Patents

Derives de succinimide et de glutarimide comme antagonistes de recepteurs adrenergiques Download PDF

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WO2007029078A2
WO2007029078A2 PCT/IB2006/002370 IB2006002370W WO2007029078A2 WO 2007029078 A2 WO2007029078 A2 WO 2007029078A2 IB 2006002370 W IB2006002370 W IB 2006002370W WO 2007029078 A2 WO2007029078 A2 WO 2007029078A2
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compound
hydrochloride salt
formula
dione
propyl
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PCT/IB2006/002370
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WO2007029078A3 (fr
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Pakala Kumara Savithru Sarma
Sandeep Y Shelke
K. Ashani
Praful Gupta
Arani Pal
Atul Kondaskar
Sankaranarayanan Dharmarajan
Somesh Sharma
Anita Chugh
Atul Tiwari
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Ranbaxy Laboratories Limited
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Publication of WO2007029078A2 publication Critical patent/WO2007029078A2/fr
Publication of WO2007029078A3 publication Critical patent/WO2007029078A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
    • 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • 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
    • C07D209/52—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 condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
    • C07D221/24—Camphidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to succinimide and glutarimide derivatives, which can be used to treat a disease or disorder mediated through ⁇ la and/or au adrenergic receptors.
  • Compounds and pharmaceutical compositions disclosed herein can be used to treat benign prostatic hyperplasia (BPH) and related symptoms thereof. Further, such compounds can be used to treat lower urinary tract symptoms that may or may not be associated with BPH.
  • BPH benign prostatic hyperplasia
  • the present invention also relates to processes to prepare the disclosed compounds, pharmaceutical compositions thereof, and methods of treating BPH or related symptoms thereof.
  • Benign prostatic hyperplasia is a condition that typically develops in elderly males. BPH causes benign overgrowth of the stromal and epithelial elements of the prostate with aging. Symptoms of BPH can vary and commonly involve changes or problems with urination, such as hesitation, interruption, weak stream, urgency, leaking, dribbling or increased frequency, particularly at night. BPH can consequently cause hypertrophy of bladder smooth muscle, a decompensated bladder or an increased incidence of urinary tract infection. The symptoms of BPH are a result of two pathological components affecting the prostate gland: a static component and a dynamic component.
  • the static component is related to enlargement of the prostate gland, which may result in compression of the urethra and obstruction to the flow of the urine from the bladder.
  • the dynamic component is related to increased smooth muscle tone of the bladder neck and prostate itself and is regulated by Gt 1 adrenergic receptor.
  • TURP transurethral resection of the prostate
  • C. Chappie, Br. Med. Journal, 304:1198-1199 (1992) a surgical procedure known as transurethral resection of the prostate
  • TURP is directed both to the static and dynamic components of the BPH.
  • TURP is associated with mortality (1 %), adverse events, e.g., incontinence (2-4 %), infection (5-10 %), and impotence (5-10 %). Therefore, noninvasive alternative treatments are highly desirable.
  • Some drug therapies address the static component of BPH.
  • Administration of finasteride is one such therapy, which is indicated for the treatment of symptomatic BPH.
  • This drug is a competitive inhibitor of the enzyme 5 ⁇ - reductase that is responsible for the conversion of testosterone to dihydrotestosterone in the prostate gland.
  • Dihydrotestosterone appears to be the major mitogen for prostate growth and agents, which inhibit 5 ⁇ - reductase, reduce the size of the prostate and improve urine flow through the prostatic urethra.
  • finasteride is a potent 5 ⁇ - reductase inhibitor that causes a marked decrease in serum and tissue concentrations of dihydrotestosterone, it is moderately effective in the treatment of symptomatic BPH. The effects of finasteride take 6-12 months to become evident and for many men the clinical development is minimal.
  • adrenergic receptor blocking agents which act by decreasing the smooth muscle tone within the prostate gland.
  • ⁇ la AR antagonists for example, terazosin, doxazosin, prazosin, alfuzosin and tamulosin, have been investigated for the treatment of symptomatic bladder outlet obstruction due to BPH.
  • these drugs are associated with vascular side effects (e.g., postural hypertension, syncope, dizziness, headache etc.) due to lack of selectivity of action between prostatic and vascular a ⁇ adrenoceptors.
  • succinimide and glutarimide derivatives which can be used to treat disease or disorder mediated through ⁇ la and/or ⁇ lc j subtype adrenergic receptors.
  • Compounds disclosed herein can be used to treat benign prostatic hyperplasia (BPH) and related symptoms thereof or lower urinary tract symptoms (LUTS) associated with or without BPH.
  • BPH benign prostatic hyperplasia
  • LUTS lower urinary tract symptoms
  • the present invention also provides processes for the synthesis of such compounds.
  • pharmaceutical compositions containing the disclosed compounds and one or more pharmaceutically acceptable carriers, excipients or diluents which can be used for the treatment of BPH or related symptoms thereof or LUTS with or without BPH.
  • n can be an integer 0 or 1 ;
  • Y can be alkylene;
  • R a -Rd can be hydrogen;
  • R a and R 0 or R a and R d or R b and R d together can form (CH 2 ) m , wherein m can be an integer of from 0 to 2;
  • X-R can be CR 1 R 2 or NR 3 ⁇ [wherein R 1 and R 2 can be independently hydrogen, hydroxy, alkyl, alkoxy, aryl, heteroaryl, heterocyclyl, cycloalkyl, NHCOR 4 or NHSO 2 R 4 (wherein R 4 can be allcyl, alkoxy, aryl, heteroaryl, heterocyclyl, CH 2 OCH 2 aryl or OCH 2 aryl,);
  • Rs can be COR 5 , SO
  • compositions comprising therapeutically effective amount of one or more compounds disclosed herein and optionally one or more pharmaceutically acceptable carriers, excipients or
  • BPH benign prostatic hyperplasia
  • LUTS lower urinary tract symptoms
  • methods for treating lower urinary tract symptoms comprising administering to a patient in need thereof a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein.
  • LUTS may include, for example, irritative symptoms (e.g., frequent urination, urgent urination, nocturia and unstable bladder contractions), obstructive symptoms (e.g., hesitancy, poor stream, prolong urination, and feeling of incomplete emptying).
  • muscarnic receptor antagonists e.g. solifenacin or darifinacin
  • bladder selective muscarinic receptor antagonists e.g. RBx-9841 or RBx-10416
  • testosterone 5 ⁇ - reductase inhibitors e.g. finasteride or dutasteride
  • HMG-COA reductase inhibitors e.g. atorvastatin, pravastatin, RBx-10558 or RBx-11901
  • endothelin antagonists e.g. atorvastatin, pravastatin, RBx-10558 or RBx-11901
  • endothelin antagonists e.g. atorvastatin, pravastatin, RBx-10558 or RBx-11901
  • endothelin antagonists e.g. atorvastatin, pravastatin, RBx-10558 or RBx-11901
  • endothelin antagonists e.g
  • the compounds disclosed herein are potent adrenergic receptor antagonists. Such compounds exhibit high affinity towards ⁇ la and ⁇ 1( j adrenoceptor subtypes and good selectivity for ⁇ la over oci b adrenoceptor. ⁇ la adrenoceptors are involved in relieving obstructive symptoms of LUTS, whereas ai d adrenoceptor antagonism is associated in alleviation of irritative symptoms of LUTS. The relatively lower affinity to an, adrenoceptors limits cardiovascular side effects, for example, orthostatic hypotension.
  • compositions for treating a disease or disorder mediated through ⁇ la and/or a ⁇ adrenoceptor subtypes are provided herein.
  • Compounds and pharmaceutical compositions described herein can be administered orally, parenterally, subcutaneously, transdermally or topically.
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, W
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • the substituents are attached to a ring atom, i.e., carbon or heteroatom in the ring.
  • heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, or benzoxazolyl, and the like.
  • halogen e.g., F, Cl, Br, I
  • Heterocyclyl can optionally include rings having one or more double bonds. Unless otherwise constrained by the definition, the substituents are attached to the ring atom, i.e., carbon or heteroatom in the ring. Also, unless otherwise constrained by the definition, the heterocyclyl ring optionally may contain one or more olefmic bond(s).
  • heterocyclyl groups include oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofliryl, azabicyclohexyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl or piperazinyl.
  • alkoxy stands for a radical represented by Formula O-alkyl and wherein alkyl is the same as defined above. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and the like.
  • the present invention also encompasses prodrugs of the compounds disclosed herein.
  • prodrugs will be functional derivatives of such compounds, which are readily convertible in vivo into the required compound.
  • Conventional procedures for selecting and preparing suitable prodrug derivatives are described in, for example, "Design of Prodrugs", ed. H. Bundgaard and, Elsevier, 1985.
  • the present invention also encompasses metabolites of the compounds disclosed herein, which become active upon introduction into a biological system. Compounds disclosed herein possess two chiral centers and may therefore exist as enantiomers or diastereomers. It is to be understood that all such isomers or racemic mixtures therefore are encompassed within the scope of the present invention. Crystalline or amorphous forms of compounds disclosed herein may exist as polymorphs and are encompassed in the present invention. Detailed Description of the Invention
  • the compounds described herein may be prepared by techniques well known to one of ordinary skill in the art.
  • the compounds described herein may be prepared by, for example following the reaction sequences as shown in Schemes I, II, III, IV, V and VI.
  • Compounds Formula 6 can be prepared according to scheme I. Thus, compounds of Formula 2 can be reacted with dihalopentane of Formula 3 to form compounds of Formula 4 (wherein Hal is halogen). Compounds of Formula 4 can be reacted with compounds of Formula 5 to form compounds of Formula 6 (wherein R a -Rd 5 X and R are the same as defined earlier). Pharmaceutically acceptable salts can be prepared following the methods well known to one of ordinary skilled in the art.
  • Compounds of Formula 2 can be reacted in the presence of one or more inorganic bases, for example, potassium carbonate, sodium carbonate, sodium hydride, barium carbonate, calcium carbonate or mixture thereof, in one or more solvents, for example, ketones (e.g., acetone, ethylmethylketone or diethylketone), ethers (e.g., diethyl ether, tetrahydrofuran or dioxane), acetates (ethyl acetate or ethylformate).
  • inorganic bases for example, potassium carbonate, sodium carbonate, sodium hydride, barium carbonate, calcium carbonate or mixture thereof
  • solvents for example, ketones (e.g., acetone, ethylmethylketone or diethylketone), ethers (e.g., diethyl ether, tetrahydrofuran or dioxane), acetates (ethyl acetate or
  • Formula 4 can be reacted in the presence of potassium iodide and one or more inorganic bases, for example, potassium carbonate, sodium carbonate, sodium hydride, barium carbonate, calcium carbonate or mixture thereof.
  • Compounds of Formula 4 can also be reacted in one or more solvents, for example, ketones (e.g., acetone, ethylmethylketone or diethylketone), ethers (e.g., diethyl ether, tetrahydrofuran or dioxane), acetates (ethyl acetate or ethylformate).
  • ketones e.g., acetone, ethylmethylketone or diethylketone
  • ethers e.g., diethyl ether, tetrahydrofuran or dioxane
  • acetates ethyl acetate or ethylformate
  • Compounds of Formula 11 or 12 can be prepared, for example according to Scheme II.
  • glutarimide of Formula 7 can be reacted with dihalopropane of Formula 8 to fo ⁇ n compounds of Formula 9.
  • Compounds of Formula 9 can be reacted with compounds of Formula R 6 H to form compounds of Formula 10 (wherein R 6 is the same as defined earlier).
  • Amino compounds can be reacted with compounds of Formula R 7 Y (Y is hydrogen or halogen) to form compounds of Formula 11 or 12 (wherein R 7 can be morpholinyl, PhCH 2 OCH 2 CO, PhCO, CF 3 SO 2 , PhCH 2 OCO, C 2 H 5 OCO, CH 3 COOCH 2 CO, N(CHs) 2 SO 2 , CONHC 6 H 3 F 2 or SO 2 C 6 H 4 NO 2 ).
  • Pharmaceutically acceptable salts can be prepared following the methods well known to one of ordinary skilled in the art.
  • Glutarimide of Formula 7 can be reacted in the presence of one or more inorganic bases, for example, potassium carbonate, sodium carbonate, sodium hydride, barium carbonate, calcium carbonate or mixture thereof, in one or more solvents, for example, ketones (e.g. acetone, ethylmethylketone or diethylketone), ethers (e.g. diethyl ether, tetrahydrofuran or dioxane), acetates (ethyl acetate or ethylformate), chlorinated solvents (dichloromethane, chloroform, carbon tetrachloride or dichloroethane) or mixture thereof.
  • solvents for example, ketones (e.g. acetone, ethylmethylketone or diethylketone), ethers (e.g. diethyl ether, tetrahydrofuran or dioxane), acetates (ethyl acetate
  • Compounds of Formula 9 can be reacted in the presence of potassium iodide and one or more inorganic bases, for example, potassium carbonate, sodium carbonate, sodium hydride, barium carbonate, calcium carbonate or mixture thereof, in one or more solvents, for example, ketones (e.g. acetone, ethylmethylketone or diethylketone), ethers (e.g. diethyl ether, tetrahydrofuran or dioxane), acetates (e.g. ethyl acetate or ethylformate), chlorinated solvents (e.g. dichloromethane, chloroform, carbon tetrachloride or dichloroethane), nitriles (e.g. acetonitrile or propionitrile) or mixture thereof.
  • solvents for example, ketones (e.g. acetone, ethylmethylketone or diethylketone), ethers (e.g
  • mineral acid for example, hydrochloric acid or hydrobromic acid
  • solvents for example, ketones (e.g. acetone, ethylmethylketone or diethylketone), ethers (e.g. diethyl ether, tetrahydrofuran
  • acetonitrile or propionitrile e.g. methanol, ethanol, propanol or butanol
  • Amino compounds can be reacted in the presence or absence of trichloroacetic anhydride, in one or more solvents, for example, ketones (e.g. acetone, ethylmethylketone or diethylketone), ethers (e.g. diethyl ether, tetrahydrofuran or dioxane), acetates (e.g. ethyl acetate or ethylformate), chlorinated solvents (e.g.
  • ketones e.g. acetone, ethylmethylketone or diethylketone
  • ethers e.g. diethyl ether, tetrahydrofuran or dioxane
  • acetates e.g. ethyl acetate or ethylformate
  • dichloromethane chloroform, carbon tetrachloride or dichloroethane
  • nitriles e.g. acetonitrile or propionitrile
  • alcohols e.g. methanol, ethanol, propanol or butanol
  • the reaction can also be carried out in the presence of triphosgene and one or more organic bases, for example, triethylamine, trimethylamine, diethylamine, tributylamine, pyridine or A- dimethylaminopyridine.
  • Compounds of Formula 15 can be prepared, for example according to Scheme III.
  • glutarimide of Formula 7 can be reacted with compounds of Formula 13 (wherein Hal is halogen) to form compound of Formula 14.
  • Compound of Formula 14 can be reacted with compounds of Formula 5 to form compounds of Formula 15 (wherein R a -R d , X and R are the same as defined earlier).
  • Pharmaceutically acceptable salts can be prepared following the methods well known to one of ordinary skilled in the art.
  • Glutarimide of Formula 7 can be reacted in the presence of one or more inorganic bases, for example, potassium carbonate, sodium carbonate, sodium hydride, barium carbonate, calcium carbonate or mixture thereof, in one or more solvents, for example, ketones (e.g., acetone, ethyhnethylketone or diethylketone), ethers (e.g., diethyl ether, tetrahydrofuran or dioxane), acetates (ethyl acetate or ethylformate), chlorinated solvents (dichloromethane, chloroform, carbon tetrachloride or dichloroethane) or mixture thereof.
  • solvents for example, ketones (e.g., acetone, ethyhnethylketone or diethylketone), ethers (e.g., diethyl ether, tetrahydrofuran or dioxane), acetates
  • Compound of Formula 14 can be reacted in the presence of one or more organic bases, for example, triethylamine, trimethylamine, diethylamine, tributylamine, pyridine or 4-dimethylaminopyridine, in one or more solvents, for example, ketones (e.g., acetone, ethylmethylketone or diethylketone), ethers (e.g., diethyl ether, tetrahydrofuran or dioxane), acetates (e.g., ethyl acetate or ethylformate), chlorinated solvents (e.g., dichloromethane, chloroform, carbon tetrachloride or dichloroethane), polar aprotic solvents (e.g., dimethylformamide or dimethylsulfoxide) or mixture thereof.
  • organic bases for example, triethylamine, trimethylamine, diethylamine, tributylamine
  • Compounds of Formula 18 can be prepared, for example, according to Scheme IV.
  • glutarimide of Formula 7 can be reacted with bromoacetic acid tert-butyl ester to form (2,6-dioxo-piperidin-l-yl) acetic acid tert-butyl ester of Formula 16.
  • Compound of Formula 16 can be hydrolyzed to form (2,6-dioxo-piperidin-l-yl) acetic acid of Formula 16a.
  • Compound of Formula 16a can be reacted with compounds of Formula 17 to form compounds of Formula 18 (wherein R a -R d , X and R are the same as defined earlier).
  • Pharmaceutically acceptable salts can be prepared following the methods well known to one of ordinary skilled in the art.
  • Glutarimide of Formula 7 can be reacted in the presence of one or more inorganic bases, for example, potassium carbonate, sodium carbonate, sodium hydride, barium carbonate, calcium carbonate or mixture thereof, in one or more solvents, for example, ketones (e.g., acetone, ethylmethylketone or diethylketone), ethers (e.g., diethyl ether, tetrahydrofuran or dioxane), acetates (e.g., ethyl acetate or ethylformate), chlorinated solvents (e.g., dichloromethane, chloroform, carbon tetrachloride or dichloroethane), polar aprotic solvents (e.g., dimethylformamide or dimethylsulfoxide) or mixture thereof.
  • solvents for example, ketones (e.g., acetone, ethylmethylketone or diethylketone), ethers
  • Compound of Formula 16 can be hydrolyzed in the presence of acid, for example, trifluroacetic acid, acetic acid, or trichloroacetic acid, in one or more solvents, for example, ketones (e.g., acetone, ethylmethylketone or diethylketone), ethers (e.g., diethyl ether, tetrahydrofuran or dioxane), acetates (e.g., ethyl acetate or ethylformate), chlorinated solvents (e.g., dichloromethane, chloroform, carbon tetrachloride or dichloroethane), polar aprotic solvents (e.g., dimethylformamide or dimethylsulfoxide) or mixture thereof.
  • solvents for example, ketones (e.g., acetone, ethylmethylketone or diethylketone), ethers (e.g., diethyl
  • Compound of Formula 16a can be reacted in the presence of coupling agents, for example, l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride or DCC in one or more solvents, for example, ketones (e.g., acetone, ethylmethylketone or diethylketone), ethers (e.g., diethyl ether, tetrahydrofuran or dioxane), acetates (e.g., ethyl acetate or ethylformate), chlorinated solvents (e.g., dichloromethane, chloroform, carbon tetrachloride or dichloroethane), polar aprotic solvents (e.g., dimethylformamide or dimethylsulfoxide) or mixture thereof.
  • solvents for example, ketones (e.g., acetone, ethylmethylketone or diethylketone),
  • Compounds of Formula 22 can be prepared, for example, according to Scheme V.
  • compounds of Formula can be reacted with (3-benzyl-3-azabicyclo[3.1.0]hex-6- yl)methylamine of Formula 19 to form l-[3-(3-benzyl-3-azabicyclo[3.1.0]hex-6ylamino)- propyl]-piperidine-2,6-dione of Formula 20.
  • Compound of Formula 20 can be debenzylated to form l-[3-(3-azabicyclo[3.1.0]hex-6ylamino)-propyl]-piperidine-2,6- dione of Formula 21.
  • Compound of Formula can be reacted with compounds of Formula R 8 COCl to form compounds of Formula 22 (wherein R 8 can be CH 2 OCH 2 aryl, OCH 2 aryl,), aryl, heteroaryl or heterocyclyl).
  • R 8 can be CH 2 OCH 2 aryl, OCH 2 aryl,), aryl, heteroaryl or heterocyclyl.
  • Pharmaceutically acceptable salts can be prepared following the methods well known to one of ordinary skilled in the art.
  • Compounds of Formula 24 can be prepared, for example, according to Scheme VI.
  • compounds of Formula 9 can be reacted with compounds of Formula 23 to form compounds of Formula 24 (wherein R a -R d , R b R 2 and n are the same as defined earlier).
  • Pharmaceutically acceptable salts can be prepared following the methods well known to one of ordinary skilled in the art. The following illustrative compounds were prepared. l- ⁇ 3-[4-hydroxy-4-(2-methoxyphenyl)piperidin-l-yl]propyl ⁇ piperidine-2,6-dione (Compound No. 1) and its hydrochloride salt (Compound No.
  • the compounds described herein are basic and can form organic or inorganic acid addition salts, which can be suitably admmisterable in humans and other animals without undue toxicity, irritation, allergic response, and the like.
  • the resulting addition salts are useful alone or in pharmaceutical compositions.
  • salts may be prepared by methods known to one of ordinary skill in the art, for example, suspending the compound in water and then adding one equivalent of one or more organic acids, e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, adipic acid, ascorbic acid, camphoenic acid, nicotinic acid, butyric acid, lactic acid, glucuronic acid or mixtures thereof, and/or one or more inorganic acids, e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, boric acid, perchloric acid or mixtures thereof.
  • organic acids e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, adipic acid, ascorbic acid, camphoenic acid, nicotinic acid, butyric acid,
  • Neutral solutions of addition salts can be subjected to rotary evaporation under reduced pressure to volumes sufficient to facilitate precipitation of the salt upon cooling, which is then filtered and dried.
  • the salts of the present invention may also be prepared under strictly non-aqueous conditions.
  • free base can be dissolved in one or more suitable organic solvents, for example, ethanol, methanol, isopropanol, dichloromethane, diethyl ether or mixtures thereof, to form a solution; one equivalent of a suitable acid can be added to the solution; and the solution can be stirred at temperatures of between about 0 0 C to 5 0 C, precipitating corresponding acid addition salts, which can then be filtered, washed with one or more solvents and dried.
  • solvent can be completely removed by reduced pressure to obtain addition salts.
  • Such salts are typically preferable for use in formulating pharmaceutical compositions of the invention because they are crystalline, relatively more stable and water-soluble.
  • compositions of the present invention can comprise pharmaceutically effective amounts of one or more compounds of the present invention formulated together with one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carriers is intended to include 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, cachets or suppositories.
  • one or more active compounds can be mixed with one or more inert, pharmaceutically acceptable excipients or carriers, for example, sodium citrate, dicalcium phosphate and/or one or more fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol, silicic acid or mixtures thereof; one or more binders, for example, carboxymethylcellulose, alginates, gelatins, polyvinylpyrolidinone, sucrose, acacia or mixtures thereof; disintegrating agents, for example, agar-agar, calcium carbonate, potato starch, alginic acid, certain silicates, sodium carbonate or mixtures thereof; absorption accelators, for example, quaternary ammonium compounds; wetting agents, for example, cetyl alcohol, glycerol, monostearate or mixtures thereof;
  • dosage forms can also comprise one or more buffering agents.
  • Solid preparations of tablets, capsules, pills or granules can also be prepared with one or more coatings and/or shells, for example, enteric coating and other coatings well known in the pharmaceutical formulating art.
  • Liquid form preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • one or more active compounds can be mixed with water and/or other solvent(s), one or more solubilizing agents or emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor or sesame oil), glycerol, fatty acid esters of sorbitan or mixtures thereof.
  • solubilizing agents or emulsifiers for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol
  • oral compositions can also include one or more adjuvants, for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents or mixtures thereof.
  • adjuvants for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents or mixtures thereof.
  • Injectable preparations may be formulated according to methods known to one of ordinary skill in the art, for example, using one or more suitable dispersing agents, wetting agents, suspending agents or mixtures thereof.
  • Acceptable carriers or solvents include, for example, water, Ringer's 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.
  • Active compound can be admixed under sterile conditions with one or more pharmaceutically acceptable carriers, as well as any preservatives or buffers as may be required.
  • Ophthalmic formulations, eardrops, eye ointments, powders and solutions are also encompassed within the scope of this invention.
  • Pharmaceutical preparations may be in unit dosage form. In particular, preparations may be subdivided into unit dosage forms containing appropriate and therapeutically effective quantities of one or more active ingredients.
  • Unit dosage forms can be packaged preparations containing discrete capsules, powders, in vials or ampoules, ointments, capsules, cachets, tablets, gels, creams, or any combination thereof and in appropriate numbers of unit dosages.
  • Formulations of the present invention may be formulated by methods known to one of ordinary skill in the art to provide immediate release, as well as sustained- or delayed-release of active ingredients after administration to a patient.
  • bladder selective muscarinic receptor antagonists and/or 5 ⁇ reductase inhibitors can be formulated in combination to achieve desired therapeutic effects, i.e., combination therapies. As such, the dosage amounts of such active ingredients can be adjusted accordingly, without undue experimentation and well within the abilities of one of ordinary skill in the art. As one of ordinary skill in the art can appreciate, dosage amounts of compounds described herein, bladder selective muscarinic receptor antagonists and/or 5 ⁇ reductase inhibitors may be independently optimized and combined to achieve a synergistic therapeutic result, hi accordance with methods encompassed herein, individual components of any combination can be administered separately in any sequence at the same or different times during the course of therapy, or concurrently in divided or single combination forms.
  • a compound of Formula 2, potassium carbonate (2.0 equiv.) and a compound of Formula 3 were dissolved in acetone and heated at about 60 0 C for about 24 hours.
  • the reaction mixture was cooled to room temperature, filtered, washed with acetone and ethyl acetate. The filtrate thus obtained was concentrated and purified by column chromatography to form a compound of Formula 4.
  • a compound of Formula 4, potassium carbonate (3.0 equiv.), potassium iodide (0.05 g) and compound of Formula 5 (1.1 equiv.) were taken in ethyl methyl ketone and then heated at about 80 0 C for about 16 hours.
  • the reaction mixture was filtered though G- 3 sintered funnel, washed with dichloromethane and then the solvent was evaporated.
  • the crude product thus formed was purified by preparative tliin layer chromatography to form a compound of Formula 6.
  • a compound of Formula 10 was dissolved in dichloromethane followed by adiition of ethanol-hydrochloric acid (3.5 N, 1.1 equiv.). The solvent was evaporated completely. Hexane was added and then sonicated. The solvent was then evaporated to form amino compound of Formula 10a.
  • Method B Amino compound of Formula 10a was dissolved in dichloromethane and added triethylamine (2.0 equiv.) to it, cooled to 0 °C and then a compound of Formula R 7 Y (1.5 equiv.) was added, stirred at an ambient temperature for about 16 hours. Sodium bicarbonate solution was added to it and stirred for about 15 minutes. The reaction mixture was extracted with dichloromethane, washed with water, and brine. The solvent was evaporated and the product thus obtained was purified by column chromatography to form a compound of Formula 11.
  • Example 7 Preparation of a compound of Formula 12 Same as described in method B of example 6.
  • Example 8 Preparation of a compound of Formula 14
  • (2,6-dioxo-piperidin-l-yl) acetic acid tert-butyl ester of Formula 16 was dissolved in dichloromethane and trifluro acetic acid (5.0 equiv.) was added to it and then the reaction mixture was stirred at an ambient temperature for overnight. The solvent was evaporated, followed by addition of dichloromethane. The solvent was then evaporated under vacuum to form (2,6-dioxo-piperidin-l-yl) acetic acid of Formula 16a.
  • a compound of Formula 9 (1.0 equiv.), (3-benzyl-3-azabicyclo[3.1.0]hex-6- yl)methylamine of Formula 19 (1.0 equiv.) and potassium carbonate (2.0 equiv.) were taken in dimethylformamide and heated under argon at about 90 0 C for overnight.
  • the reaction mixture was cooled, poured in to water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated and then purified by column chromatography to form l-[3-(3-benzyl-3-azabicyclo[3.1.0]hex-6ylamino)-propyl]-piperidine-2,6-dione of Formula 20.
  • Example 14 Preparation of l-
  • reaction mixture was filtered through celite bed, washed with methanol, concentrated to form l-[3-(3- azabicyclo[3.1.0]hex-6ylamino)-propyi]-piperidine-2,6-dione of Formula 21.
  • Example 15 Preparation of a compound of Formula 22 l-[3-(3-azabicyclo[3.1.0]hex-6ylamino)-pro ⁇ yl]-piperidine-2,6-dione of Formula
  • a mixture of a compound of Formula 9 (1.0 equiv.), compound of Formula 23 (1.1 equiv.), potassium carbonate (2.0 equiv.) and potassium iodide in dimethylformamide was heated at about 90 0 C for overnight.
  • the reaction mixture was cooled, poured into water, extracted with ethyl acetate and then purified by column chromatography to form a compound of Formula 24.
  • a compound of Formula 6, 11, 12, 15, 18, 22 or 24 was dissolved in dichloromethane followed by addition of ethanol-hydrochloric acid (3.5 N, 1.1 equiv.). The solvent was evaporated completely. ⁇ exane was added and then sonicated. The solvent was then evaporated to form the desired product.
  • Receptor binding assays were performed using recombinant cells expressing human alpha-la and alpha-lb adrenoceptors. The affinity of different compounds for ⁇ la and oc ⁇ adrenoceptor subtypes was evaluated by studying their ability to displace specific [ H] prazosin binding from the membranes of recombinant clones expressing alpha-la and alpha-lb adrenoceptors. The binding assays were performed according to U'Prichard et al, Eur J Pharmacol, 50:87-89 (1978) with minor modifications.
  • Human embryonic kidney (HEK) cells which had been stably transfected with human alpha-la and alpha-lb adrenoceptors were cultured in an atmosphere of 5 % CO 2 at 37 0 C in DMEM medium supplemented with 10%heat inactivated fetal calf serum, 1 mM glutamine, 100 U/mL penicillin and 0.1 mg/mL streptomycin. Selection pressure was maintained by regular addition of puromycin (3 ⁇ g/mL) to the culture medium. The cells were homogenized in 5-10 volumes of buffer (Tris HCl 5 mM, EDTA 5 mM, pH 7.4) using a polytron homogenizer.
  • buffer Tris HCl 5 mM, EDTA 5 mM, pH 7.4
  • the homogenate was centrifuged at 40,000 g for 20 min at 4 0 C.
  • the pellet thus obtained was resuspended in assay buffer (Tris HCl 5 mM, EDTA 5 mM, pH 7.4) and were stored at -70 0 C until the time of assay.
  • Competition radioligand binding to the cloned subtypes of a t -adrenoceptors was performed using [ 3 H] prazosin as the radioligand.
  • the membrane homogenates (5-10 ⁇ g protein) were incubated in 250 ⁇ L of assay buffer (Tris HCl 50 mM, EDTA 5 mM, pH 7.4) at 24-25 C for 1 hour.
  • Non-specific binding was determined in the presence of 10- ⁇ M terazosin. The incubation was terminated by vacuum filtration over GF/B fiber filters. The filters were then washed with ice-cold 50 mM Tris HCl buffer (pH 7.4). The filter mats were dried and bounded radioactivity retained on filters was counted. The IC 50 and Kd were estimated by using the non-linear curve-fitting program using Graph pad prism software.
  • Ki IC 50 /(1+L/Kd) where L is the concentration of [ 3 H] prazosin used in the particular experiment.
  • the results of the human recombinant assays of the compounds disclosed herein are as follows: a) The compounds specifically disclosed herein exhibited ⁇ la Ki (nM) values of between about 0.3 nM to about greater than 2500 nM, for example, between about 0.3 nM to about 1000 nM, or between about 0.3 nM to about 100 nM, and for example between about 0.3 nM to about 10 Nm, b) The compounds specifically disclosed herein exhibited a ⁇ Ki (nM) values of between about 5.3 nM to about greater than 1333 nM, for example, between about 5.3 nM to about 1000 nM, between about 5.3 nM to about 600 nM, and for example, between about 5.3 nM to about 100 nM.
  • Receptor binding assays are performed using native ⁇ -1 adrenoceptors.
  • the affinity of different compounds for ⁇ la and cc ⁇ adrenoceptor subtypes is evaluated by studying their ability to displace specific [ 3 H]prazosin binding from the membranes of rat submaxillary and liver respectively (Michel et al, Br J Pharmacol, 98:883-889 (1989)).
  • the binding assays are performed according to U'Prichard et al, Eur J Pharmacol, 50:87- 89 (1978) with minor modifications.
  • Submaxillary glands are isolated immediately after sacrifice.
  • the liver is perfused with buffer (Tris hydrochloric acid 50 mM, sodium chloridelOO mM, 10 mM ethylene diamine tetra acetic acid pH 7.4).
  • the tissues are homogenized in 10 volumes of buffer (Tris HCl 50 mM, NaCl 100 mM, EDTA 10 mM, pH 7.4).
  • the homogenate is filtered through two layers of wet gauze and the filtrate is centrifuged at 500 g for 10 min.
  • the supernatant is subsequently centrifuged at 40,000 g for 45 min.
  • the pellet thus obtained is resuspended in the same volume of assay buffer (Tris HCl 50 mM, EDTA 5 mM, pH 7.4) and are stored at -70 0 C until the time of assay.
  • Isolated tissues are mounted in organ bath containing Krebs Henseleit buffer of the following composition (mM): sodium chloride (NaCl) 118; potassium chloride (KCl) 4.7; calcium chloride (CaCl 2 ) 2.5; magnesium sulfate heptahydrate (MgSO 4 . 7H 2 O) 1.2; sodium bicarbonate (NaHCO 3 ) 25; potassium dihydrogen phosphate (KH 2 PO 4 ) 1.2; glucose 11.1.
  • the buffer is maintained at 37 0 C and aerated with a mixture of 95 % oxygen (O 2 ) and 5 % carbon dioxide (CO 2 ).

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Abstract

L'invention concerne des dérivés de succinimide et de glutarimine, que l'on peut utiliser pour traiter une maladie ou un trouble médié par le biais de récepteurs adrénergiques α1a et/ou α1d. Les composés et les compositions pharmaceutiques selon l'invention peuvent servir dans le traitement de l'hyperplasie prostatique bénigne (HPB) et des symptômes connexes. De plus, ces composés peuvent être utilisés pour traiter des symptômes des voies urinaires inférieures éventuellement associés ou non à HPB. L'invention concerne également des processus permettant de préparer lesdits composés, leurs compositions pharmaceutiques, ainsi que les procédés de traitement de HPB ou des symptômes connexes.
PCT/IB2006/002370 2005-09-05 2006-08-30 Derives de succinimide et de glutarimide comme antagonistes de recepteurs adrenergiques WO2007029078A2 (fr)

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EP2994457A4 (fr) * 2013-05-07 2016-09-28 Univ California Formulations pharmaceutiques d'atténuation de rayonnements
US10525050B2 (en) * 2017-01-06 2020-01-07 Florida A&M University Alkylated tetrahydroisoquinolines for binding to central nervous system receptors

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US3171839A (en) * 1961-05-18 1965-03-02 Searle & Co 4-alkyl-1-(cyclic imidoalkyl) piperidines
US6083950A (en) * 1997-11-13 2000-07-04 Ranbaxy Laboratories Limited 1-(4-arylpiperazin-1-yl)-ω-[n-(α,ω-dicarboximido)]-alka nes useful as uro-selective α1-adrenoceptor blockers
PT1106614E (pt) * 1999-12-10 2004-04-30 Pfizer Compostos de 1,4-dihidropiridina substituidos com heteroarilos de 5 membros como antagonistas de bradiquinina
WO2003003008A1 (fr) * 2001-06-29 2003-01-09 7Tm Pharma A/S Bibliotheques chimiques utiles aux procedes de decouvertes de medicaments
AU2002253429A1 (en) * 2002-04-08 2003-10-20 Ranbaxy Laboratories Limited ALPHA, OMEGA-DICARBOXIMIDE DERIVATIVES AS USEFUL URO-SELECTIVE Alpha1Alpha ADRENOCEPTOR BLOCKERS
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

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2994457A4 (fr) * 2013-05-07 2016-09-28 Univ California Formulations pharmaceutiques d'atténuation de rayonnements
US9783515B2 (en) 2013-05-07 2017-10-10 The Regents Of The University Of California Radiomitigating pharmaceutical formulations
US9840483B2 (en) 2013-05-07 2017-12-12 The Regents Of The University Of California Radiomitigating pharmaceutical formulations
US10525050B2 (en) * 2017-01-06 2020-01-07 Florida A&M University Alkylated tetrahydroisoquinolines for binding to central nervous system receptors

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