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WO2006051399A1 - Derives de piperazine utiles en tant qu'antagonistes des recepteurs adrenergiques - Google Patents

Derives de piperazine utiles en tant qu'antagonistes des recepteurs adrenergiques Download PDF

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Publication number
WO2006051399A1
WO2006051399A1 PCT/IB2005/003373 IB2005003373W WO2006051399A1 WO 2006051399 A1 WO2006051399 A1 WO 2006051399A1 IB 2005003373 W IB2005003373 W IB 2005003373W WO 2006051399 A1 WO2006051399 A1 WO 2006051399A1
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Prior art keywords
alkyl
phenyl
ynyl
heterocycle
compound
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Mohammad Salman
Nitya Anand
Somesh Sharma
Gobind Singh Kapkoti
Anita Chugh
Kamna Nanda
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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
    • 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
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • 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
    • 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
    • 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
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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

Definitions

  • the present invention relates to ⁇ i a and/or an adrenergic receptor antagonists, which can be used to treat a disease or disorder mediated through ⁇ i a and/or ⁇ 1( i adrenergic receptors.
  • Compounds and pharmaceutical compositions described 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 described 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 ⁇ -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.
  • 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.
  • ⁇ i a 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 ⁇ i adrenoceptors.
  • mice deficient in a ⁇ adrenoreceptors show diminished blood pressure response to phenylephrine injection when compared to homozygous controls (decreased blood pressure response in mice deficient of ⁇ n > adrenergic receptor. (Proc. Nat 7 Acad. Sd. USA, 94:1589-11594 (1997)).
  • Antagonism of both ⁇ i a adrenoceptor and aid adrenoceptor is important to relieve lower urinary tract symptoms especially associated with BPH.
  • Targeting ⁇ i a adrenoceptors with antagonists is important in relaxing prostate smooth muscle and relieving bladder outlet obstruction, whereas an adrenoceptor antagonism is important to target irritative symptoms.
  • selective ⁇ la adrenoceptor antagonists include US Patent Nos. 6,376,503, 6,319,932 and 6,339,090, EP 711757, WO 99/42448, WO 99/42445, WO 98/57940, WO 98/57632, WO 98/30560 WO 97/23462, WO 03/084928 and WO 03/084541.
  • the present invention provides ⁇ la and/or ⁇ 1( i adrenergic receptor antagonists, which can be used to treat a disease or disorder mediated through ⁇ la and/or ⁇ 1( i adrenergic receptors, and processes for the synthesis of these compounds.
  • Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, polymorphs or N- oxide of these compounds having the same type of activity are also provided.
  • A can be
  • R 2 and R 3 can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle or -NRHRI 2 (wherein Ri 1 and Ri 2 can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocycle);
  • R 4 and R5 can be independently hydrogen, alkyl or phenyl
  • Re can be hydrogen, alkyl, phenyl, hydroxy or alkoxy
  • R 7 and R 8 can be independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl, (heterocycle)alkyl or R 9 Q(CH 2 ) m -
  • m can be an integer of from 0 to 3
  • R 9 can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycle,
  • Q can be oxygen, sulphur, carbonyl, carboxyl or -N(Ri 0 )W,
  • R 7 and Rg together can represent cycloalkyl, cycloalkenyl, bicyclic alkyl, bicyclic alkenyl, aryl or heterocycle;
  • X and Y can be independently methylene or carbonyl
  • Ri can be hydrogen or methyl
  • R can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl or (heterocycle)alkyl;
  • n can be an integer of from 1 to 3;
  • R 2 to R 5 can be the same as defined earlier; X and Y can be independently methylene or carbonyl; Ri can be hydrogen or methyl; R can be substituted aryl, wherein substituent can be, for example, alkoxy, cycloalkoxy, or phenyl.
  • R 2 to R 5 can be the same as defined earlier; X and Y can be independently methylene or carbonyl; Ri can be hydrogen or methyl; R can be substituted aryl, wherein substituent can be, for example, alkoxy, cycloalkoxy, or phenyl.
  • R 2 to R 5 can be the same as defined earlier; X and Y can be independently methylene or carbonyl; Ri can be hydrogen or methyl; R can be substituted aryl, wherein substituent can be, for example, alkoxy, cycloalkoxy, or phenyl.
  • R 2 to R 5 can be the same as defined earlier; X and Y can be independently methylene or carbonyl;
  • R 5 can be hydrogen; X and Y can be methylene; Ri can be hydrogen; and R can be, for example, 2-methoxyphenyl, 2-ethoxyphenyl, 2-isopropoxyphenyl, 2-cyclopentoxyphenyl, 2-trifluoroethoxyphenyl or biphenyl.
  • the disease or disorder can be benign prostatic hyperplasia.
  • the compound causes minimal decrease or no decrease in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.
  • Also provided herein are methods for treating a patient suffering from benign prostatic hyperplasia or lower urinary tract symptoms with or without benign prostatic hyperplasia comprising administering to a patient therapeutically effective amounts of one or more compounds (or compositions) described herein in combination with one or more other therapeutic agents, for example, muscarinic receptor antagonists, bladder selective muscarinic receptor antagonists, testosterone 5 alpha-reductase inhibitors, endothelin antagonists, melanocortin receptor agonists, cGMP elevators, HMG-CoA reductase inhibitors, 5 -HT antagonists or combination thereof.
  • muscarinic receptor antagonists for example, muscarinic receptor antagonists, bladder selective muscarinic receptor antagonists, testosterone 5 alpha-reductase inhibitors, endothelin antagonists, melanocortin receptor agonists, cGMP elevators, HMG-CoA reductase inhibitors, 5 -HT antagonists or combination thereof.
  • Also provided herein are methods for treating a patient suffering from benign prostatic hyperplasia or lower urinary tract symptoms with or without benign prostatic hyperplasia comprising administering to a patient therapeutically effective amounts of one or more compounds (or compositions) described herein in combination with one or more solifenacin, darifinacin, compounds described in PCT Publication Nos. WO 2004/005252 and WO 2004/089900 and PCT Application No. PCT/IB2004/004142, dutasteride, finasteride, pravastatin, simvastatin, atorvastatin, compounds described in PCT Publication No. WO 2004/106299 or combinations thereof.
  • A can be
  • R 2 and R 3 can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle or -NRi iRi 2 (wherein R 1 ⁇ and Ri 2 can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocycle);
  • R 4 and R 5 can be independently hydrogen, alkyl or phenyl
  • R 6 can be hydrogen, alkyl, phenyl, hydroxy or alkoxy
  • R 7 and R 8 can be independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl, (heterocycle)alkyl or R 9 Q(CH 2 ) m -;
  • m can be an integer of from 0 to 3
  • R 9 can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocycle, and Q can be oxygen, sulphur, carbonyl, carboxyl or -N(R 10 )W
  • W can be no atom, carbonyl, carboxyl, or amide, and R 10 can be hydrogen, alkyl, aryl, or heterocyclic)] or
  • R 7 and R 8 together can represent cycloalkyl, cycloalkenyl, bicyclic alkyl, bicyclic alkenyl, aryl or heterocycle;
  • X and Y can be independently methylene or carbonyl
  • Ri can be hydrogen or methyl
  • R can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl or (heterocycle)alkyl;
  • n can be an integer of from 1 to 3;
  • ⁇ can be optional double bond.
  • the method comprises:
  • reaction of a compound of Formula II can be carried out in the presence of tetrabutylammonium iodide and one or more bases , for example, potassium carbonate, barium carbonate, cesium carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate or mixtures thereof in one or more solvents, for example, methanol, chloroform, dichloromethane, acetonitrile, acetone, tetrahydrofuran or mixtures thereof.
  • bases for example, potassium carbonate, barium carbonate, cesium carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate or mixtures thereof in one or more solvents, for example, methanol, chloroform, dichloromethane, acetonitrile, acetone, tetrahydrofuran or mixtures thereof.
  • reaction of a compound of Formula IV can be carried out in the presence of potassium iodide and one or more bases, for example, potassium carbonate, barium carbonate, cesium carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate or mixtures thereof in one or more solvents, for example, methanol, ethanol, acetone, acetonitrile, chloroform, dimethylformamide, dimethylsulfoxide or mixtures thereof
  • bases for example, potassium carbonate, barium carbonate, cesium carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate or mixtures thereof
  • solvents for example, methanol, ethanol, acetone, acetonitrile, chloroform, dimethylformamide, dimethylsulfoxide or mixtures thereof
  • A can be
  • R 2 and R 3 can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle or -NRnRi 2 (wherein Rn and Ri 2 can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocycle);
  • R 4 and R5 can be independently hydrogen, alkyl or phenyl
  • R 6 can be hydrogen, alkyl, phenyl, hydroxy or alkoxy
  • R 7 and R 8 can be independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl, (heterocycle)alkyl or R 9 Q(CH 2 ) m -;
  • m can be an integer of from 0 to 3;
  • R 9 can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycle;
  • Q can be oxygen, sulphur, carbonyl, carboxyl or -N(Ri 0 )W;
  • W can be no atom, carbonyl, carboxyl, amide
  • Rio can be hydrogen, alkyl, aryl, heterocyclic)] or
  • R 7 and Rs together can represent cycloalkyl, cycloalkenyl, bicyclic alkyl, bicyclic alkenyl, aryl or heterocycle;
  • X and Y can be independently methylene or carbonyl
  • Ri can be hydrogen or methyl
  • R can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl or (heterocycle)alkyl;
  • n can be an integer of from 1 to 3;
  • the method comprises:
  • reaction of a compound of Formula IV can he carried out in the presence of one or more bases, for example, barium carbonate, potassium carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate or mixtures thereof.
  • reaction of a compound of Formula VIII with oxalyl chloride can be carried out in the presence of one or more bases, for example, triethylamine, diethylamine, 4- dimethylaminopyridine, N-methylpyrrolidone or mixtures thereof in one or more solvents, for example, from acetone, dichloromethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetonitrile or mixtures thereof.
  • A can be
  • R 2 and R 3 can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle or -NRi 1 R 12
  • Rn and Ri 2 can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocycle);
  • R 4 and R 5 can be independently hydrogen, alkyl or phenyl
  • R 6 can be hydrogen, alkyl, phenyl, hydroxy or alkoxy
  • R 7 and R 8 can be independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl, (heterocycle)alkyl or R 9 Q(CH 2 ) m -
  • m can be an integer of from 0 to 3;
  • R 9 can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycle;
  • Q can be oxygen, sulphur, carbonyl, carboxyl or -N(Ri 0 )W
  • W can be no atom, carbonyl, carboxyl, amide
  • Rio can be hydrogen, alkyl, aryl, heterocyclic)] or
  • R 7 and R 8 together can represent cycloalkyl, cycloalkenyl, bicyclic alkyl, bicyclic alkenyl, aryl or heterocycle;
  • X and Y can be independently methylene or carbonyl
  • Ri can be hydrogen or methyl
  • R can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, aralkyl or (heterocycle)alkyl;
  • n can be an integer of from 1 to 3;
  • R 2 to R 5 can be the same as defined earlier; X and Y can be independently methylene or carbonyl; Ri can be hydrogen or methyl; R can be substituted aryl, wherein substituent can be, for example, alkoxy, cycloalkoxy, or phenyl.
  • R 2 to R 5 can be hydrogen; X and Y can be methylene; Ri can be hydrogen; and R can be, for example, 2-methoxyphenyl, 2-ethoxyphenyl, 2- isopropoxyphenyl, 2-cyclopentoxyphenyl, 2-trifluoroethoxyphenyl or biphenyl.
  • compositions comprising one or more compounds of Formula I, optionally together with one or more pharmaceutically acceptable carriers, excipients, diluents or mixture thereof.
  • provided are methods for treating a disease or disorder mediated through oci a and/or a ⁇ adrenergic receptors comprising administering to a patient in need thereof a therapeutically effective amount of a compound or pharmaceutical composition described herein.
  • 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 described 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 feelings of incomplete emptying).
  • methods for treating a patient suffering from benign prostatic hyperplasia or lower urinary tract symptoms with or without benign prostatic hyperplasia comprising administering to a patient therapeutically effective amounts of one or more compounds (or compositions) described herein in combination with one or more other therapeutic agent, for example, muscarinic receptor antagonists, bladder selective muscarinic receptor antagonists, testosterone 5 alpha-reductase inhibitors, endothelin antagonists, melanocortin receptor agonists, cGMP elevators, HMG-CoA reductase inhibitors, 5-HT antagonists or combination thereof.
  • muscarinic receptor antagonists for example, muscarinic receptor antagonists, bladder selective muscarinic receptor antagonists, testosterone 5 alpha-reductase inhibitors, endothelin antagonists, melanocortin receptor agonists, cGMP elevators, HMG-CoA reductase inhibitors, 5-HT antagonists or combination thereof.
  • methods for treating a patient suffering from benign prostatic hyperplasia or lower urinary tract symptoms with or without benign prostatic hyperplasia comprising administering to a patient therapeutically effective amounts of one or more compounds (or compositions) described herein in combination with one or more solifenacin, darifinacin, compounds described in PCT Publication Nos. WO 2004/005252 and WO 2004/089900 and PCT Application No. PCT/IB2004/004142, dutasteride, finasteride, pravastatin, simvastatin, atorvastatin, compounds described in PCT Publication No. WO 2004/106299 or combinations thereof.
  • the described compounds can be used for relaxing lower urinary tract tissues and thus alleviating irritative symptoms in-patient. Therefore, the present invention provides pharmaceutical compositions for treatment of a disease or disorder mediated through ⁇ la adrenoceptor.
  • the described compounds of the present invention can also be used for treatment of lower urinary tract symptoms.
  • Compounds and compositions described herein can be administered orally, parenterally, subcutaneously, transdermally or topically.
  • the compounds described herein may be prepared by techniques well known in the art and familiar to the average synthetic organic chemist. In addition, the compounds described herein may be prepared by the following reaction sequence as depicted in schemes I and II below.
  • the compound of Formula VI can be prepared, for example, according to Scheme I.
  • compound of Formula II can be reacted with a compound of Formula III to form a compound of Formula FV.
  • the compound of Formula FV can be reacted with a compound of Formula V to form a compound of Formula VI.
  • reaction of a compound of Formula II 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 tetrabutyl ammonium chloride and one or more bases, for example, barium carbonate, cesium carbonate, potassium carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate or mixtures thereof.
  • the reaction of a compound of Formula IV can be carried out in one or more solvents, for example, acetone, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetonitrile or mixtures thereof.
  • the reaction can also be carried out in the presence of potassium iodide and one or more bases, for example, potassium carbonate, barium carbonate, cesium carbonate, calcium carbonate, sodium hydride, sodium carbonate, sodium bicarbonate or mixtures thereof.
  • the compound of Formula IX can be prepared, for example, according to Scheme II.
  • the compound of Formula IV can be reacted with a compound of Formula VII to form a compound of Formula VIII.
  • the compound of Formula VIII can be treated with oxalyl chloride to form a compound of Formula IX.
  • the reaction of a compound of Formula IV can be carried out in the presence of one or more bases, for example, barium carbonate, potassium carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate or mixtures thereof.
  • reaction of a compound of Formula VIII can be carried out in one or more solvents, for example, acetone, dichloromethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetonitrile or mixtures thereof.
  • solvents for example, acetone, dichloromethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetonitrile or mixtures thereof.
  • bases for example, triethylamine, diethylamine, 4- dimethylamino Pyridine, N-methylpyrrolidone or mixtures thereof.
  • reaction temperature and duration may be adjusted according to the desired needs.
  • 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 fo ⁇ n 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
  • 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.
  • compositions may be in unit dosage form.
  • 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. In 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.
  • Step 1 Preparation of l-(4-ChIoro-but-2-ynyl)-piperadine-2,6-dione
  • Step 2 Preparation of l- ⁇ 4-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-but-2-ynyl ⁇ - piperidine-2,6-dione (Compound No. 1)
  • Step 3 Preparation of l- ⁇ 4-[4-(2-Methoxy-phenyl)-piperazin-l-yI]-but-2-ynyI ⁇ - piperidine-2,6-dione hydrochloride salt
  • Step 1 Preparation of l- ⁇ 4-[2-(2-Methoxy-phenylamine)-ethyIamino]-but-2-ynyl ⁇ - piperidine-2,6-dione
  • Step 2 Preparation of l-[4-(2,6-Dioxo-4--piperidin-l-yl)-but-2-ynyl]-4-(2-methoxy- phenyl)-piperazine-2,3-dione
  • the compound is purified by silica gel (60-120 mesh) column chromatography using dichloromethane-methanol (98:2) as eluent.
  • the hydrochloride salt can be prepared by adding an equimolar quantity of isopropyl alcohol and hydrochloric acid to l-[4-(2,6-Dioxo-4 ⁇ piperidin-l-yl)-but-2-ynyl]-4-(2-methoxy-phenyl)-piperazine- 2,3-dione. The solid, which precipitates, is then filtered.
  • Receptor binding assays were performed using native ⁇ -1 adrenoceptors. The affinity of different compounds for ⁇ la and ⁇ i b adrenoceptor subtypes was evaluated by studing 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 were performed according to U'Prichard et al. (Eur. J. Pharmacol., 50:87-89 (1978) with minor modifications.
  • Submaxillary glands were isolated immediately after sacrifice.
  • the liver was perfused with buffer (Tris HCl 50 mM, NaCl 100 mM, 10 mM EDTA pH 7.4).
  • the tissues were homogenized in 10 volumes of buffer (Tris HCl 50 mM, NaCl 100 mM, EDTA 10 mM, pH 7.4).
  • the homogenate was filtered through two layers of wet guaze and filtrate was centrifuged at 500g for 10 min.
  • the supernatant was subsequently centrifuged at 40,00Og for 45 min.
  • the pellet thus obtained was resuspended in the same volume of assay buffer (Tris HCl 50 mM, EDTA 5 mM, 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 250 ⁇ l of assay buffer (Tris HCl 50 mM, EDTA 5 mM, pH 7.4) at 24-25 0 C for 1 hour. Non-specific binding was determined in the presence of 300 nM prazosin. 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 filtermats were dried and bound radioactivity retained on filters was counted. The IC 50 and K d were estimated by using the non-linear curve-fitting program using G pad prism software.
  • K IC 50 /(1+L/Kd) where L is the concentration of [ 3 H] prazosin used in the particular experiment.
  • Isolated tissues were mounted in organ bath containing Krebs Henseleit buffer of the following composition (niM): NaCl 118; KCl 4.7; CaCl 2 2.5; MgSO 4 . 7H 2 O 1.2; NaHCO 3 25; KH 2 PO 4 1.2; glucose 11.1. Buffer was maintained at 37 0 C. and aerated with a mixture of 95% 02 and 5% CO 2 . 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.
  • concentration response curves to norepinephrine (aorta) and phenylephrine (spleen and prostate) were obtained in the absence and presence of the tested compound (at concentration of 0.1, 1 and 10 ⁇ M).
  • the affinity at ⁇ j a adrenoceptors expressed in terms of K; (nM) for all compounds ranged from low nanomolars to high nanomolars (for example, from about 7.5 nM to about 1.2 ⁇ M, or from about 7.5 nM to about 350 nM, or from about 7.5 nM to about 60 nM, or from about 7.5 nM to about 18 nM), for comparison, terazosin showed a Kj value of 6.17nM).
  • the affinity at Ot 11 , expressed as K; (nM) for all compounds was at least 900 nM, in comparison to terazosin with a K; value of 2.84 nM.
  • the selectivity of ⁇ la over ⁇ ib adrenoceptor for compounds examined was at least 0.75, for example, at least 5, for example at least 15 or for example at least 50, compared to 0.5 fold selectivity for terazosin.
  • compounds of the invention are relatively more selective for ⁇ i a over ⁇ ib adrenoceptors compared to terazosin.

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Abstract

La présente invention concerne des antagonistes des récepteurs adrénergiques a1a et/ou a1d, ayant la formule I et pouvant être utilisés pour traiter une maladie ou un trouble lié aux récepteurs adrénergiques a1a et/ou a1d. Les composés et les compositions pharmaceutiques de l'invention peuvent être utilisés pour traiter l'hyperplasie prostatique bénigne (benign prostatic hyperplasia / BPH) et les symptômes associés. De plus, ces composés peuvent être utilisés pour traiter des symptômes des voies urinaires inférieures qui peuvent être liés ou non à BPH. L'invention a également pour objet des procédés pour préparer les composés mentionnés, des compositions pharmaceutiques correspondantes, et des procédés pour traiter BPH ou des symptômes associés.
PCT/IB2005/003373 2004-11-11 2005-11-10 Derives de piperazine utiles en tant qu'antagonistes des recepteurs adrenergiques Ceased WO2006051399A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4745117A (en) * 1985-03-27 1988-05-17 Sumitomo Pharmaceuticals Company, Limited Imide derivatives and compositions for use as antipsychotic agents
US6090809A (en) * 1997-11-13 2000-07-18 Ranbaxy Laboratories Limited 1-(4-arylpiperazin-1-yl)-ω-[n-(α..omega.-dicarboximido)]-alkanes useful as uro-selective α1 -adrenoceptor blockers
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
US20020165219A1 (en) * 1997-10-09 2002-11-07 Hutchings Richard H. Novel heterocycles useful in the treatment of benign prostatic hyperplasia

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4745117A (en) * 1985-03-27 1988-05-17 Sumitomo Pharmaceuticals Company, Limited Imide derivatives and compositions for use as antipsychotic agents
US20020165219A1 (en) * 1997-10-09 2002-11-07 Hutchings Richard H. Novel heterocycles useful in the treatment of benign prostatic hyperplasia
US6090809A (en) * 1997-11-13 2000-07-18 Ranbaxy Laboratories Limited 1-(4-arylpiperazin-1-yl)-ω-[n-(α..omega.-dicarboximido)]-alkanes useful as uro-selective α1 -adrenoceptor blockers
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

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; KOMISSAROV, I. V. ET AL: "Anxiolytic activity of 1-(2-pyrimidinyl)piperazine derivatives", XP002371828, retrieved from STN Database accession no. 1991:505837 *
KHIMIKO-FARMATSEVTICHESKII ZHURNAL , 25(3), 40-2 CODEN: KHFZAN; ISSN: 0023-1134, 1991 *
LOPEZ-RODRIGUEZ, MARIA L. ET AL: "Synthesis and Structure-Activity Relationships of a New Model of Arylpiperazines. 4.1-[.omega.-(4-Arylpiperazin-1-yl)alkyl]-3- (diphenylmethylene)- 2,5-pyrrolidinediones and -3-(9H-fluoren-9-ylidene)- 2,5-pyrrolidinediones: Study of the Steric Requirements of the Terminal Amide Fragment on 5-HT1A Af", JOURNAL OF MEDICINAL CHEMISTRY , 42(1), 36-49 CODEN: JMCMAR; ISSN: 0022-2623, 1999, XP002329488 *

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