WO2006117760A1 - Antagonistes de recepteurs adrenergiques - Google Patents

Antagonistes de recepteurs adrenergiques Download PDF

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Publication number
WO2006117760A1
WO2006117760A1 PCT/IB2006/051392 IB2006051392W WO2006117760A1 WO 2006117760 A1 WO2006117760 A1 WO 2006117760A1 IB 2006051392 W IB2006051392 W IB 2006051392W WO 2006117760 A1 WO2006117760 A1 WO 2006117760A1
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Prior art keywords
piperazin
propyl
benzotriazin
hydrochloride salt
formula
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PCT/IB2006/051392
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English (en)
Inventor
Pakala Kumara Savithru Sarma
Somesh Sharma
Sankaranarayanan Dharmarajan
Sandeep Y. Shelke
Arani Pal
Atul Kondaskar
Praful Gupta
Anita Chugh
Atul Tiwari
Kamna Nanda
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Ranbaxy Laboratories Limited
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Publication of WO2006117760A1 publication Critical patent/WO2006117760A1/fr

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    • 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
    • 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
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to ⁇ la and/or ai d adrenergic receptor antagonists, which can be used to treat a disease or disorder mediated through ⁇ la and/or ai d 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 ⁇ -1 adrenergic receptor.
  • TURP transurethral resection of the prostate
  • 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 ⁇ i adrenoceptors.
  • Antagonism of both (Xi a adrenoceptor and (Xid adrenoceptor is important to relieve lower urinary tract symptoms especially associated with BPH.
  • Targeting (Xi a adrenoceptors with antagonists is important in relaxing prostate smooth muscle and relieving bladder outlet obstruction, whereas (Xi d adrenoceptor antagonism is important to target irritative symptoms.
  • Xi a adrenoceptor antagonists for benign prostatic hyperplasia which would avoid the cardiovascular side effects, associated with currently used drugs. Many selective antagonists have been described in the literature.
  • Xi can be N or CR 4 ;
  • R 4 can be hydrogen, hydroxyl or alkyl
  • A can be aryl, aryloxy, heterocyclyl, alkyl, alkoxy, cycloalkyl, NHCORio or CHR 10 R 11 ; Rio and Rn can independently be alkyl, COO-alkyl, aryl or heterocyclyl;
  • R 1 , R 2 and R3 independently in each occurrence can be hydrogen, halogen, C 1 -3 alkyl, alkoxy, alkyl, nitro, cyano, cycloalkoxy, R 6 or S(0)o-2Rs;
  • R 5 can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl; R 2 and R3 together with Xi to which they are attached can form a ring of the form
  • Mi and M 2 can independently be hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl, alkoxy or acyl; or Ml and M2 together can form a bridging group (C 0-3 ); W can be N, CH or COH;
  • R 6 can be
  • R 7 , Rs and Rg are independently hydrogen, hydroxyl, amino, S(0)o- 2 R 5 or NHSO 2 R 5 ;
  • L can be a linker; and • can be a point of attachment. Also provided are compounds selected from:
  • compositions comprising therapeutically effective amounts of one or more compounds having the structure of the Formula I
  • Xi can be N or CR 4 ;
  • R 4 can be hydrogen, hydroxyl or alkyl;
  • A can be aryl, aryloxy, heterocyclyl, alkyl, alkoxy, cycloalkyl, N ⁇ CORio or C ⁇ RioRn;
  • Rio and Rn can independently be alkyl, COO-alkyl, aryl or heterocyclyl;
  • R 1 , R 2 and R 3 independently in each occurrence can be hydrogen, halogen, C 1 - 3 alkyl, alkoxy, alkyl, nitro, cyano, cycloalkoxy, R 6 or S(0)o-2Rs;
  • R 5 can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl; R 2 and R 3 together with Xi to which they are attached can form a ring of the form
  • Mi and M 2 can independently be hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl, alkoxy or acyl; or Ml and M2 together form a bridging group (C 0-3 );
  • R 7 , R 8 and R 9 can independently be hydrogen, hydroxyl, amino,
  • L can be a linker
  • a disease or disorder mediated through ⁇ la and/or ai d adrenergic receptors comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds having the structure of the Formula I
  • Xi can be N or CR 4 ;
  • R 4 can be hydrogen, hydroxyl or alkyl;
  • A can be aryl, aryloxy, heterocyclyl, alkyl, alkoxy, cycloalkyl, NHCORio or
  • Rio and Rn can independently be alkyl, COO-alkyl, aryl or heterocyclyl;
  • R 1 , R 2 and R3 independently in each occurrence can be hydrogen, halogen, C 1 -3 alkyl, alkoxy, alkyl, nitro, cyano, cycloalkoxy, R 6 or S(0)o-2Rs;
  • R 5 can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl;
  • R 2 and R3 together with Xi to which they are attached can form a ring of the form
  • Mi and M 2 can independently be hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl, alkoxy or acyl; or Ml and M2 together form a bridging group (C 0-3 );
  • R 7 , Rs and R 9 can independently be hydrogen, hydroxyl, amino,
  • L can be a linker; and • can be a point of attachment
  • the diseases or disorder can be benign prostatic hyperplasia or lower urinary tract symptoms.
  • the compounds described herein can cause minimal fall or no fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.
  • Xi can be N or CR 4 ;
  • R 4 can be hydrogen, hydroxyl or alkyl;
  • A can be aryl, aryloxy, heterocyclyl, alkyl, alkoxy, cycloalkyl, NHCORio or CHRioRii;
  • Rio and Rn can independently be alkyl, COO-alkyl, aryl or heterocyclyl;
  • Ri can be hydrogen, halogen, C 1 -3 alkyl, alkoxy, alkyl, nitro, cyano, cycloalkoxy,
  • R 5 can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl;
  • R 6 can be
  • Mi and M 2 can independently be hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl, alkoxy or acyl; or Ml and M2 together form a bridging group (C 0 - 3 );
  • R 7 , Rs and R 9 can independently be hydrogen, hydroxyl, amino, S(0)o- 2 Rs or NHSO 2 R 5 ;
  • L can be a linker.
  • Xi can be N or CR 4 ;
  • R 4 can eb hydrogen, hydroxyl or alkyl
  • A can be aryl, aryloxy, heterocyclyl, alkyl, alkoxy, cycloalkyl, NHCORi 0 or CHRi 0 Rn; Ri 0 and Rn can independently be alkyl, COO-alkyl, aryl or heterocyclyl;
  • Ri can be hydrogen, halogen, C 1 -3 alkyl, alkoxy, alkyl, nitro, cyano, cycloalkoxy, R6 ⁇ r S(0) o _ 2 R 5 ;
  • R 5 can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl; and R 6 can be
  • Mi and M 2 can independently be hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl, alkoxy or acyl; or Ml and M2 together form a bridging group (Co-3);
  • R 7 , Rs and R 9 can independently be hydrogen, hydroxyl, amino, S(0)o- 2 Rs or NHSO 2 R 5
  • Xi can be N or CR 4 ;
  • R 4 can be hydrogen, hydroxyl or alkyl;
  • A can be aryl, aryloxy, heterocyclyl, alkyl, alkoxy, cycloalkyl, NHCORio or CHR 10 R 11 ;
  • Rio and Rn can independently be alkyl, COO-alkyl, aryl or heterocyclyl;
  • Ri can be hydrogen, halogen, C 1 - 3 alkyl, alkoxy, alkyl, nitro, cyano, cycloalkoxy,
  • R 5 can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl;
  • R 6 can be
  • Mi and M 2 can independently be hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl, alkoxy or acyl; or Ml and M2 together form a bridging group (C0-3); and
  • A can be aryl, aryloxy, heterocyclyl, alkyl, alkoxy, cycloalkyl, NHCORio or
  • Rio and Rn can independently be alkyl, COO-alkyl, aryl or heterocyclyl;
  • Ri can be hydrogen, halogen, Ci_ 3 alkyl, alkoxy, alkyl, nitro, cyano, cycloalkoxy, R 5 can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl;
  • R 6 can be
  • the present invention provides ⁇ la and/or aw adrenergic receptor antagonists, which can be used to treat benign prostatic hyperplasia (BPH) or related symptoms thereof, or lower urinary tract symptoms (LUTS) with or without BPH.
  • BPH benign prostatic hyperplasia
  • LUTS lower urinary tract symptoms
  • the present invention also provides for processes for the synthesis of such compounds.
  • pharmaceutical compositions containing the described compounds and one or more pharmaceutically acceptable carriers, excipients or diluents which can be used to treat BPH or related symptoms thereof or LUTS with or without BPH.
  • Xi can be N or CR 4 , wherein
  • R 4 can be hydrogen, hydroxyl or alkyl
  • A can be aryl, aryloxy, heterocyclyl, alkyl, alkoxy, cycloalkyl, NHCORio or CHRi 0 Ri i, wherein
  • Ri 0 and Rn can be independently alkyl, COO-alkyl, aryl or heterocyclyl;
  • R 1 , R 2 and R3 independently in each occurrence can be hydrogen, halogen, C 1 -3 alkyl, alkoxy, alkyl, nitro, cyano, cycloalkoxy, R 6 or S(0)o -2 Rs, wherein R 5 can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl; and R 2 and R3 together with Xi to which they are attached may also form a ring of the form
  • heteroatom(s) selected from O, S or N, wherein
  • Mi and M 2 can independently be hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl, alkoxy or acyl; or Ml and M2 together can form a bridging group
  • W can be N, CH or COH
  • R 7 , Rs and R 9 can be independently hydrogen, hydroxyl, amino, S(0)o-2Rs or NHSO 2 R 5 ;
  • L can be a linker; and • can be point of attachment.
  • compositions comprising therapeutically effective amounts of one or more compounds described herein together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • provided herein are methods for treating a disease or disorder mediated through HL and/or Qu adrenergic receptors, comprising administering to a patient in need thereof therapeutically effective amounts of one or more compounds or compositions described herein.
  • BP ⁇ benign prostatic hyperplasia
  • LUTS lower urinary tract symptoms
  • compounds described herein cause minimal decrease or no decrease in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.
  • 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).
  • BP ⁇ or LUTS methods for treating BP ⁇ or LUTS with or without BP ⁇ comprising administering to a patient in need thereof therapeutically effective amounts of one or more compounds or compositions described herein in combination with one or more agents selected from bladder selective muscarinic receptor antagonist, testosterone 5 alpha-reductase inhibitor, endothelin antagonists, melanocortin receptor agonist, cGMP elevators, HMG-CoA reductase inhibitors, e.g., statins, 5- ⁇ T antagonists or combination thereof.
  • the compounds of this invention are potent adrenergic receptor antagonists.
  • Compounds described herein have good selectivity for ⁇ la v/s ⁇ i b .
  • Alpha Ia adrenergic receptors are involved in relieving the obstructive symptoms whereas aw adrenoreceptor antagonism is associated with alleviation of irritative symptoms.
  • the relatively low affinity at the (Xi b adrenergic receptor limits the cardiovascular side effects, for example, orthostatic hypotension.
  • the present invention therefore provides pharmaceutical compositions for treatment of a disease or disorder mediated through ⁇ la adrenoceptors.
  • alkyl refers to straight or branched saturated hydrocarbon having one to six carbon atom(s). Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl and butyl, and the like.
  • alkenyl or alkynyl stands for unsaturated hydrocarbon having two to six carbon atoms. One or more hydrogen of said alkenyl or alkynyl can be replaced by halogen. Examples of alkenyl and alkynyl include, but are not limited to, ethylene, propylene, ethynyl, propynyl, and the like.
  • cycloalkyl refers to saturated carbocyclic ring having three to seven carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl and cyclopentyl, and the like.
  • cycloalkenyl refers to unsaturated carbocyclic ring having three to seven carbon atoms. Examples of cycloalkenyl include, but are not limited to, cyclopropenyl and cyclobutenyl, and the like.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • aryl stands for an aromatic radical having 6 to 14 carbon atoms. Examples of aryl include, but are not limited to, phenyl, napthyl, anthryl and biphenyl, and the like.
  • aralkyl stands for an aryl radical having 7 to 14 carbon atoms, which is bonded to an alkylene chain. Examples of aralkyl include, but are not limited to, benzyl, napthylmethyl, phenethyl and phenylpropyl, and the like.
  • heterocyclyl refers to non-aromatic or aromatic ring system having one or more heteroatom (s) wherein the said hetero atom (s) is/ are selected from the group comprising of nitrogen, sulphur and oxygen and the ring system includes mono, bi or tricyclic.
  • heterocycles include, but not limited to, azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, napthyridinyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolinyl, pyr
  • the said heterocyclyl may be fused with an aryl or heterocyclyl ring. Examples include, but not limited to, 1, 2, 3, 4-tetrahydro-quinoline, 1, 2, 3, 4-tetrahydro-isoquinoline, and the like.
  • the said alkyl, aryl, heterocyclyl and cycloalkyl may optionally be substituted with one or more substituent(s) independently selected from halogen, hydroxy, nitro, mercapto, cyano, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, alkoxy, haloalkoxy, thioalkyl, cycloalkoxy, -NRnRi 2 , -CONRHRI 2 , -COORI 2 , -CONHRi 2 , -OCORi 2 , -CORi 2 , - NHSO 2 Ri 2 and -SO 2 NHRi 2 wherein Rn and Ri 2 are independently selected from hydrogen or alky
  • alkoxy herein refers to 0R a wherein R a can be alkyl, alkenyl or alkynyl.
  • cycloalkoxy herein refers to ORb wherein Rb can be cycloalkyl.
  • 'linker' refers to CON(Rs) 2 , CS(Rs) 2 , [wherein R 8 can be selected from: hydrogen, alkylene, alkenylene], alkylene chain of from one to six carbon atoms, which may be saturated or unsaturated or may comprise a ring.
  • the chain may be interrupted at any point by one or more heteroatom(s) selected from N, S, and O and may be substituted with 'substituent(s)' as mentioned above.
  • leaving group refers to any group that leaves the molecule during substitution, elimination and addition-elimination reactions.
  • suitable leaving groups include, but are not limited to -F, -Cl, -Br, alkyl chlorides, alkyl bromides, alkyl iodides, alkyl sulfonates, alkyl benzenesulfonates, alkyl p- toluenesulfonates, alkylbenzenesulfonates, alkyl p-toluenesulfonates, alkyl methanesulfonates, triflate or nay group having a bisulfate, methyl sulfate or sulfonate ion.
  • polymorphs includes all crystalline form as well as amorphous form for compounds described herein and as such are intended to be included in the present invention.
  • pharmaceutically acceptable carriers is intended to include non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • salts refer to a salt prepared from pharmaceutically acceptable organic or inorganic acids, such salts includes hydrochlorides, sulfates, phosphates, tartarates, fumarates, citrates and the like.
  • the free base forms of compounds of the present invention may be prepared from the salt forms, if desired, by contacting the salt with dilute aqueous solution of a base.
  • the acid addition salts may differ from the free base forms of the compounds of this invention in such physical characteristics as solubility and melting point.
  • the salt forms differ from the compound described herein in certain physical properties such as solubility, but the salts are otherwise equivalent for purposes of this invention.
  • pharmaceutically acceptable means approved by regulatory agency of the federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • solvates refers to solvates with water (i.e hydrates, hemihydrate or sesquihydrate) or pharmaceutically acceptable solvents, for example solvates with common organic solvents as ethanol and the like. Such solvates are also encompassed within the scope of the disclosure.
  • the present invention also includes, within its scope, "prodrugs" of these agents.
  • prodrugs will be functional derivatives of these compounds, which are readily convertible in vivo into the required compound. They may be carrier-linked or bioprecursors.
  • the carrier-linked prodrugs may be bipartite, tripartite or mutual prodrugs. Prodrugs are intended to improve drug efficacy by improving solubility and consequently absorption and distribution as desired.
  • 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 sequences as depicted in Schemes I, II, III, and IV.
  • Compounds of Formula VI can be prepared according to Scheme I. Thus, compounds of Formula II can be reacted with compounds of Formula III (wherein X 2 and X 3 are leaving groups) to form compounds of Formula IV. Compounds of Formula IV can be treated with compounds of Formula V to form compounds of Formula VI (wherein L, R 7 , Rs, R 9 , W, Mi, M 2 , Xi, A, Y and Ri are the same as defined earlier). Compounds of Formula VI can be further converted into their pharmaceutically acceptable salts using the methods well known to one of ordinary skill in art.
  • Compounds of Formula II can be reacted in one or more solvents, for example, polar protic (e.g., methanol, ethanol or isopropanol), polar aprotic solvents (e.g., acetone, dimethylformamide, acetonitrile, dimethylsulfoxide or hexamethylphosphoric acid triamide) or mixtures thereof
  • polar protic e.g., methanol, ethanol or isopropanol
  • polar aprotic solvents e.g., acetone, dimethylformamide, acetonitrile, dimethylsulfoxide or hexamethylphosphoric acid triamide
  • Compounds of Formula II can also be reacted in the presence of one or more bases, for example, inorganic bases (e.g., sodium carbonate, cesium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydride, lithium hydroxide, sodium metal or mixtures thereof), organic bases (e.g., triethy
  • Compounds of Formula IV can be treated in one or more solvents, for example, polar protic solvents (e.g., methanol, ethanol, isopropanol or mixtures thereof), polar aprotic solvents (e.g., methylethylketone, acetone, dimethylformamide, dimethylacetamide, dimethylsulfoxide or mixtures thereof) or mixtures thereof.
  • polar protic solvents e.g., methanol, ethanol, isopropanol or mixtures thereof
  • polar aprotic solvents e.g., methylethylketone, acetone, dimethylformamide, dimethylacetamide, dimethylsulfoxide or mixtures thereof
  • Compounds of Formula IV can also be treated in the presence of one or more bases, for example, inorganic bases (e.g., ammonium hydroxide, hydrazine, sodium carbonate, cesium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or mixtures thereof), organic bases (e.g., triethylamine, pyridine, tributylamine, diisopropylethylamine or 4-(N-dimethylamino)pyridine or mixtures thereof)) or mixtures thereof.
  • bases for example, inorganic bases (e.g., ammonium hydroxide, hydrazine, sodium carbonate, cesium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or mixtures thereof), organic bases (e.g., triethylamine, pyridine, tributylamine, diisopropylethylamine or 4-(N-dimethylamino)pyridine or mixtures thereof)) or mixtures thereof.
  • Compounds of Formula IX can be prepared according to Scheme II. Thus, compounds of Formula II can be reacted with compounds of Formula VII (wherein X3 is a leaving group) to form compounds of Formula VIII. Compounds of Formula VIII can be treated with compounds of Formula V to form compounds of Formula IX (wherein R 7 , Rs, R 9 , W, M 1 , M 2 , X 1 , A, Y and Ri are the same as defined earlier). Compounds of Formula IX can be further converted into their pharmaceutically acceptable salts using the methods well known to one of ordinary skill in art.
  • Compounds of Formula II can be reacted in one or more solvents, for example, polar protic solvents (e.g., methanol, ethanol, isopropanol or mixtures thereof), polar aprotic solvents (e.g., methylethyl ketone, acetone, dimethylformamide, dimethylsulfoxide, acetonitrile or mixtures thereof) or mixtures thereof.
  • polar protic solvents e.g., methanol, ethanol, isopropanol or mixtures thereof
  • polar aprotic solvents e.g., methylethyl ketone, acetone, dimethylformamide, dimethylsulfoxide, acetonitrile or mixtures thereof
  • Compounds of Formula II can be reacted in the presence of one or more inorganic bases, for example, sodium carbonate, cesium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate or mixtures thereof.
  • inorganic bases for example, sodium carbonate, cesium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate or mixtures thereof.
  • Compounds of Formula VIII can be treated in one or more solvents, for example, polar protic solvents (e.g., methanol, ethanol, isopropanol or mixtures thereof), polar aprotic (e.g., dimethylsulfoxide, acetonitrile, dimethylformamide or mixtures thereof) or mixtures thereof.
  • polar protic solvents e.g., methanol, ethanol, isopropanol or mixtures thereof
  • polar aprotic e.g., dimethylsulfoxide, acetonitrile, dimethylformamide or mixtures thereof
  • Compounds of Formula VIII can be treated in the presence of one or more organic bases, for example, triethylamine, pyridine, tributylamine, diisopropylethylamine, 4-(N- dimethylamino)pyridine or mixtures thereof.
  • organic bases for example, triethylamine, pyridine, tributylamine, diisopropylethylamine, 4-(N- dimethylamino)pyridine or mixtures thereof.
  • Compounds of Formula XIV can be prepared according to Scheme III.
  • compounds of Formula V(a) can be reacted with compounds of Formula X (wherein X 4 is alkenyl or halogen and n is an integer of from 0 to 3) to form compounds of Formula XI.
  • Compounds of Formula XI can be reduced to form compounds of Formula XII.
  • Compounds of Formula XII can be treated with compounds of Formula XIII (wherein X 3 is a leaving group) to form compounds of Formula XIV (wherein Y, Mi, M 2 , Xi, A and Ri are the same as defined earlier).
  • Compounds of Formula XIV can be further converted into their pharmaceutically acceptable salts using the methods well known to one of ordinary skill in art.
  • Compounds of Formula V(a) can be reacted in one or more solvents, for example, polar protic solvents (e.g., methanol, ethanol, isopropanol or mixtures thereof), polar aprotic solvents (e.g., methylethylketone, acetone, dimethylformamide or mixtures thereof) or mixtures thereof.
  • polar protic solvents e.g., methanol, ethanol, isopropanol or mixtures thereof
  • polar aprotic solvents e.g., methylethylketone, acetone, dimethylformamide or mixtures thereof
  • Compounds of Formula V(a) can also be reacted in the presence of one or more bases, for example, inorganic bases (e.g., ammonium hydroxide, hydrazine, sodium carbonate, cesium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or mixtures thereof), organic bases (e.g., triethylamine, diisoproplyamine, pyridine, tributylamine or mixtures thereof) or mixtures thereof.
  • bases for example, inorganic bases (e.g., ammonium hydroxide, hydrazine, sodium carbonate, cesium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or mixtures thereof), organic bases (e.g., triethylamine, diisoproplyamine, pyridine, tributylamine or mixtures thereof) or mixtures thereof.
  • inorganic bases e.g., ammonium hydroxide, hydrazine, sodium carbonate, cesium carbonate, potassium carbonate
  • Compounds of Formula XI can be reduced in the presence of one or more reducing agents, for example, raney nickel/ hydrogen, palladium-carbon/hydrogen, platinum/hydrogen and ammonia in one or more polar protic solvents (e.g., methanol, ethanol, propanol, isopropanol, water or mixtures thereof), or mixtures thereof.
  • one or more reducing agents for example, raney nickel/ hydrogen, palladium-carbon/hydrogen, platinum/hydrogen and ammonia in one or more polar protic solvents (e.g., methanol, ethanol, propanol, isopropanol, water or mixtures thereof), or mixtures thereof.
  • Compounds of Formula XII can be reacted in one or more solvents, for example, chlorinated solvents (e.g., chloroform, dichloromethane, dichloroethane or mixtures thereof), aprotic polar solvents (e.g., dimethylformamide, acetonitrile, dime thylsulf oxide or mixtures thereof), protic polar solvents (e.g., methanol, ethanol, isopropanol or mixtures thereof) or mixtures thereof.
  • chlorinated solvents e.g., chloroform, dichloromethane, dichloroethane or mixtures thereof
  • aprotic polar solvents e.g., dimethylformamide, acetonitrile, dime thylsulf oxide or mixtures thereof
  • protic polar solvents e.g., methanol, ethanol, isopropanol or mixtures thereof
  • Compounds of Formula XII can also be reacted in the presence of one or more activating and coupling reagents, for example, pyridinium salts, phosphonium salts, uranium salts, active esters or carbodimides or mixtures thereof.
  • activating and coupling reagents for example, pyridinium salts, phosphonium salts, uranium salts, active esters or carbodimides or mixtures thereof.
  • Compounds of Formula XII can also be reacted in presence of one or more bases, for example, 4- dialkylaminopyridines, Hunigs base, 4-alkylmorpholine, triethylamine, 1- methylimidazole, 4-(l-pyrrolidino)pyridine or mixtures thereof.
  • Formula XX Compounds of Formula XX can be prepared according to Scheme IV. Thus, compounds of Formula XV can be reacted with compounds of Formula XVI (wherein X 2 is a leaving group) to form compounds of Formula XVII. Compounds of Formula XVII can be reacted with hydrazine hydrate to form compounds of Formula XVIII. Compounds of Formula XVIII can be finally treated with compounds of Formula XIX (wherein X 3 , is a leaving group) to form compounds of Formula XX (wherein Y, A and Ri are the same as defined earlier and n is an integer of from 1 to 5).
  • Compounds of Formula XX can be further converted into their pharmaceutically acceptable salts using the methods well known to one of ordinary skill in art.
  • Compounds of Formula XV can be reacted in one or more polar aprotic solvents, for example, methylethylketone, acetone, dimethylformamide or mixtures thereof.
  • Compounds of Formula XV can also be reacted in the presence of one or more bases, for example, inorganic bases (e.g., potassium carbonate, sodium hydrogen carbonate, sodium hydride, sodium carbonate, sodium acetate, sodium thiosulphate or mixtures thereof), organic bases (e.g., pyridine, triethylamine, diisopropylethylamine or mixtures thereof) or mixtures thereof.
  • inorganic bases e.g., potassium carbonate, sodium hydrogen carbonate, sodium hydride, sodium carbonate, sodium acetate, sodium thiosulphate or mixtures thereof
  • organic bases e.g., pyridine, triethylamine, diisopropylethylamine or mixtures thereof
  • Compounds of Formula XVII can be reacted in one or more solvents, for example, polar protic solvents (e.g., methanol, ethanol isopropanol or mixtures thereof), polar aprotic solvents (e.g., dimethylsulfoxide, acetonitrile or mixtures thereof) or mixtures thereof.
  • polar protic solvents e.g., methanol, ethanol isopropanol or mixtures thereof
  • polar aprotic solvents e.g., dimethylsulfoxide, acetonitrile or mixtures thereof
  • Compounds of Formula XVIII can be treated in one or more solvents, for example, chlorinated solvents (e.g., chloroform, dichloromethane, dichloroethane or mixtures thereof), aprotic polar solvents (e.g., dimethylformamide, acetonitrile, dimethylsulfoxide or mixtures thereof), protic polar solvents (e.g., methanol, ethanol, isopropanol or mixtures thereof) or mixtures thereof.
  • chlorinated solvents e.g., chloroform, dichloromethane, dichloroethane or mixtures thereof
  • aprotic polar solvents e.g., dimethylformamide, acetonitrile, dimethylsulfoxide or mixtures thereof
  • protic polar solvents e.g., methanol, ethanol, isopropanol or mixtures thereof
  • Compounds of Formula XVIII can be treated in the presence of activating and coupling reagents, for example, pyridinium salts, phosphonium salts, uranium salts, active esters or carbodiimides or mixtures thereof, and in the presence of one or more organic bases, for example, 4-dialkylaminopyridines, Hunig's base, 4-alkylmorpholine, triethylamine, 1-methylimidazole, 4-(l-pyrrolidino)pyridine or mixtures thereof.
  • activating and coupling reagents for example, pyridinium salts, phosphonium salts, uranium salts, active esters or carbodiimides or mixtures thereof
  • organic bases for example, 4-dialkylaminopyridines, Hunig's base, 4-alkylmorpholine, triethylamine, 1-methylimidazole, 4-(l-pyrrolidino)pyridine or mixtures thereof.
  • organic bases for example, 4-dial
  • Compounds of the present invention include, for example: 3 - ⁇ 3- [4-hydroxy-4-(2-methoxyphenyl)piperidin- 1 -yljpropyl ⁇ - 1 ,2,3 -benzotriazin-4(3H)- one (Compound No. 1) and its hydrochloride salt (Compound No. 2),
  • compositions which may be prepared by admixture of one or more compounds with apposite excipients and other assisting agents, if required, for oral, sublingual, parenteral, topical, rectal or transdermal administration.
  • the solid compositions include, but are not limited to, tablets, capsules, microcapsules, powders, granules, pills, wafers, dragees, catchets, caplets, suppositories or pastilles.
  • Tablets, capsules, or pills can be generally administered as a unit dose and may contain one or more suitable excipients, such as dispersing agents, binding agents, fillers, diluents, lubricants, disintegrants, colorants, flavoring agents, sweeteners, preservatives or mixtures thereof.
  • suitable excipients such as dispersing agents, binding agents, fillers, diluents, lubricants, disintegrants, colorants, flavoring agents, sweeteners, preservatives or mixtures thereof.
  • Tablets may be sugar coated, enteric coated or film coated by standard techniques well known in the art. Tablets having sustained action may also be prepared by methods well known in the art.
  • Capsules may be hard capsules or soft capsules of suitable size, wherein one or more compounds described herein can be mixed with inert solid diluents, for example, sodium carbonate, calcium carbonate, lactose, starch, calcium phosphate, sodium phosphate or mixtures thereof; disintegrants, for example, sodium starch glycolate, croscarmelose sodium or mixtures thereof; or mixtures thereof.
  • Dispersible powders and granules suitable for reconstitution to form a stable suspension by addition of water are provided with one or more active ingredients (i.e., compounds described herein and any additional active ingredient) with one or more dispersing agents and one or more suspending agents.
  • active ingredients i.e., compounds described herein and any additional active ingredient
  • dispersing agents i.e., dispersing agents and suspending agents.
  • Additional excipients for example, coloring agents, flavoring agents and sweetening agents may also be added.
  • Suppositories for rectal administration may include carbon dioxide releasing laxative suppositories.
  • Dosage forms for topical or transdermal administration of one or more compounds described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, spot-on or patches.
  • the active compound can be admixed under sterile condition with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Liquid form preparations for oral administration include, for example, pharmaceutically acceptable emulsions, microemulsions, solutions, aqueous or oily suspensions, syrups, sprays or elixirs.
  • active ingredients can be mixed with water or other solvent, solubilizing agents, cosolvents, buffers, emulsifiers, for example, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils, for example, cottonseed, groundnut, corn, germ, olive, castor and sesame oil), glycerol, and fatty acid esters of sorbitan and mixture thereof; suspending agents, for example, sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose or carboxymethylcellolose and preservatives, for example, methyl or propyl p-hydroxybenzoate and sorbic acid.
  • the spray composition can contains suitable propellants.
  • Injectable preparations for example, sterile aqueous or non-aqueous injections, injectable depot forms, aqueous suspensions or emulsions may be formulated according to the art using parenterally dispersing or wetting and suspending agent.
  • acceptable vehicles and solvents include, for example, water for injection, Ringer's solution and isotonic sodium chloride.
  • Ophthalmic formulations, eardrops, eye ointments, powders and solutions are also provided herein.
  • compositions can be in unit dosage form. In such form, preparations can be subdivided into unit doses containing appropriate quantities of the active ingredient(s).
  • Unit dosage forms can be packaged preparations, the package containing discrete capsules, powders, in vials or ampoules, and ointments capsule, sachet, tablet, gel, cream itself or it can be the appropriate number of any of these packaged forms. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.
  • Step 2 Preparation of 8-(2-methoxyphenyl)-3-azabicvclor3.2.11octan-8-ol
  • a solution of 3-benzyl-8-(2-methoxyphenyl)-3-azabicyclo[3.2.1]octan-8-ol and palladium-carbon (10% by weight) in methanol was hydrogenated at about 25-30 0 C and under 50 psi pressure for about 5 hours.
  • the reaction mixture was filtered through a bed of celite and concentrated to form 8-(2-methoxyphenyl)-3-azabicyclo[3.2.1]octan-8-ol. Yield: 90% l,4-(2-methoxyphenyl)piperidin-4-ol was prepared similarly.
  • b) Preparation of Methyl phenyl ⁇ iperazin- 1 -yl)acetate
  • N-S-azabicycloP.l.OJhex- ⁇ -ylacetamide was taken in a mixture of ethanol and 5 ⁇ sodium hydroxide solution (2:1) and refluxed overnight. The reaction mixture was then cooled and the solvent was removed. The resulting product was diluted with water and extracted with dichloromethane. The solvent was then removed to afford the crude product as white solid, which was purified on silica gel column.
  • Trifluoroethanol (1 equiv.) was taken in dichloromethane, cooled to about 5-10 0 C and stirred for about 15 minutes. Triethylamine was added to this mixture and again stirred for about 10 minutes. Methanesulphonylchloride (1.5 equiv.) in dichloromethane was the added dropwise to the solvent mixture. The reaction mixture was then allowed to come to room temperature and stirred overnight at this temperature. The reaction mixture was poured into 5% sodium bicarbonate solution and stirred for about 15 minutes. The dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane. The organic extract was dried, concentrated to afford the product in 90 % yield.
  • Example 1 illustrates the invention but do not limit it any way.
  • Example 1 illustrates the invention but do not limit it any way.
  • Step 2 Preparation of 3- ⁇ 3-[4-hydroxy-4-(2-methoxy phenyl) piperidin-l-yl]propyl ⁇ - l,2,3-benzotriazin-4(3H)-one
  • Step 3 Preparation of 3- ⁇ 3-[4-hydroxy-4-(2-methoxy phenyl) piperidin-l-yl]propyl ⁇ - l,2,3-benzotriazin-4(3H)-one hydrochloride salt
  • Step 2 Preparation of 3- ⁇ 3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]-2- hydroxypropyl ⁇ -1 ,2,3-benzotriazin-4(3H)-one A solution of 3-(oxiran-2-ylmethyl)-l,2,3-benzotriazin-4(3H)-one (1.0 equiv.), 1-
  • Step 3 Preparation of 3- ⁇ 3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]-2- hydroxypropyl ⁇ -l,2,3-benzotriazin-4(3H)-one hydrochloride salt
  • Step 1 Preparation of 10- ⁇ 3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl ⁇ -10H- phenoxazine
  • the reaction mixture was concentrated under vacuum.
  • the residue was taken in water, extracted with ethyl acetate and the organic layer was washed with water.
  • the aqueous layer was dried with anhydrous sodium sulfate and then concentrated.
  • the residue was purified by silica gel column chromatography using mixture of methanol and dichloromethane as eluent.
  • Step 2 Preparation of 10- ⁇ 3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl ⁇ -10H- phenoxazine hydrochloride salt An equimolar quantity of isopropyl alcohol and hydrochloric acid was added to 10-
  • Step 1 Preparation of 10- ⁇ 3-[4-(2-ethoxyphenyl)piperazin-l-yl]propyl ⁇ -10H- phenothiazine
  • the titled compound was prepared according to the procedure as described in
  • Example 3 using 10-(3-chloropropyl)-10H-phenothiazine in place of 10-(3-chloropropyl)- 1 OH-phenoxazine .
  • Step 2 Preparation of 10- ⁇ 3-[4-(2-ethoxyphenyl)piperazin-l-yl]propyl ⁇ -10H- phenothiazine hydrochloride salt An equimolar quantity of isopropyl alcohol and hydrochloric acid was added to 10-
  • Step 1 Preparation of N- ⁇ 3- [4-(2-methoxyphenyl)piperazin- 1 -yl]propyl ⁇ - 10H- phenothiazine-10-carboxamide
  • Step 2 Preparation of N- ⁇ 3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl ⁇ -10H- phenothiazine-10-carboxamide hydrochloride salt
  • Receptor binding assays were performed using recombinant cells expressing human alpha-la and alpha-lb adrenoceptors. The affinity of different compounds for ⁇ la and ctn, adrenoceptor subtypes was evaluated by studying their ability to displace specific [ 3 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°C in DMEM medium supplemented with 10%heat inactivated fetal calf serum, ImM glutamine, 100U/ml penicillin and 0.1mg/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 polytron homogenizer. The homogenate was centrifuged at 40, 00Og for 20min at 4°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.
  • buffer Tris HCl 5 mM, EDTA 5 mM, pH 7.4
  • Ki IC 50 /(1+IVKd) where L is the concentration of [ 3 H] prazosin used in the particular experiment.
  • results of the human recombinant assays of the compounds described herein are as follows: a) The compounds described herein exhibited ⁇ la Ki (nM) values of between about 0.5 nM to about 2500 nM, between about 0.5 nM to about 166 nM, between about 0.5 nM to about 89 nM, and even between about 0.5 nM to about 70 nM. b) The compounds described herein exhibited (Xib Ki (nM) values of between about 5 nM to about 1333 nM, between about 5 nM to about 759 nM, and even between about 5 nM to about 100 nM.

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Abstract

La présente invention concerne des antagonistes des récepteurs adrénergiques la et/ou a^ qui peuvent s'utiliser pour le traitement d'une maladie ou d'un trouble induit par les dits récepteurs adrénergiques. Les composés et compositions de l'invention conviennent pour le traitement de l'hyperplasie bénigne de la prostate (BPH) et symptômes connexes. De tels composés peuvent d'utiliser également pour le traitement de symptômes en rapport avec les voies urinaires inférieures pouvant être ou ne pas être associés à une hyperplasie bénigne de la prostate. De plus, l'invention concerne des procédés de fabrication de ces composés et compositions pharmaceutiques ainsi que des méthodes de traitement de l'hyperplasie bénigne de la prostate et symptômes connexes.
PCT/IB2006/051392 2005-05-03 2006-05-03 Antagonistes de recepteurs adrenergiques WO2006117760A1 (fr)

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US9187439B2 (en) 2011-09-21 2015-11-17 Inception Orion, Inc. Tricyclic compounds useful as neurogenic and neuroprotective agents
JP2015536921A (ja) * 2012-10-11 2015-12-24 サザン リサーチ インスティテュート アミノアルキルピペラジンの尿素及びアミド誘導体並びにその使用

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9187439B2 (en) 2011-09-21 2015-11-17 Inception Orion, Inc. Tricyclic compounds useful as neurogenic and neuroprotective agents
JP2015536921A (ja) * 2012-10-11 2015-12-24 サザン リサーチ インスティテュート アミノアルキルピペラジンの尿素及びアミド誘導体並びにその使用
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AU2013329097B2 (en) * 2012-10-11 2018-10-18 Southern Research Institute Urea and amide derivatives of aminoalkylpiperazines and use thereof

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