[go: up one dir, main page]

WO2006117760A1 - Adrenergic receptor antagonists - Google Patents

Adrenergic receptor antagonists Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
piperazin
propyl
benzotriazin
hydrochloride salt
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2006/051392
Other languages
French (fr)
Inventor
Pakala Kumara Savithru Sarma
Somesh Sharma
Sankaranarayanan Dharmarajan
Sandeep Y. Shelke
Arani Pal
Atul Kondaskar
Praful Gupta
Anita Chugh
Atul Tiwari
Kamna Nanda
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of WO2006117760A1 publication Critical patent/WO2006117760A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to α1a and/or α1b adrenergic receptor antagonists, which can be used to treat a disease or disorder mediated through α1a and/or α1b 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. The present invention also relates to processes to prepare the disclosed compounds, pharmaceutical compositions thereof, and methods of treating BPH or related symptoms thereof.

Description

ADRENERGIC RECEPTOR ANTAGONISTS
Field of the Invention
The present invention relates to αla and/or aid adrenergic receptor antagonists, which can be used to treat a disease or disorder mediated through αla and/or aid 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. The present invention also relates to processes to prepare the disclosed compounds, pharmaceutical compositions thereof, and methods of treating BPH or related symptoms thereof.
Background of the Invention
Benign prostatic hyperplasia (BPH) 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 α-1 adrenergic receptor. Currently, the most effective treatment for BPH is a surgical procedure known as transurethral resection of the prostate (TURP), which involves removing obstructing tissue (C. Chappie, Br. Med. Journal, 304: 1198-1199 (1992)). TURP is directed both to the static and dynamic components of the BPH. However, 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-α 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-α reductase, reduce the size of the prostate and improve urine flow through the prostatic urethra. Although finasteride is a potent 5-α 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.
The dynamic component of BPH has been addressed by the use of adrenergic receptor blocking agents, which act by decreasing the smooth muscle tone within the prostate gland. A variety of αla AR antagonists, for example, terazosin, doxazosin, prazosin, alfuzosin and tamulosin, have been investigated for the treatment of symptomatic bladder outlet obstruction due to BPH. However, 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 αi adrenoceptors. There are several lines of evidence suggesting that selectivity for αla adrenoceptor over αib adrenoceptor will result in relative lack of vascular side effects, thus lead to better tolerability. Mice deficient in ctn, adrenoreceptors show diminished blood pressure response to phenylephrine injection when compared to homozygous controls (decreased blood pressure response in mice deficient of αib adrenergic receptor. (Proc. Nat'l Acad. ScL USA, 94:1589-11594 (1997)). In-vivo studies in healthy subjects comparison of αia/αid selective antagonists (e.g., tamsulosin) or αla selective antagonists (e.g., urapidil) with non selective antagonists (e.g., doxazosin, prazosin, or terazosin) under a variety of experimental conditions (e.g., involving the administration of exogenous agonist or release of endogenous agonist by cold stimulation) in several vascular beds including the skin circulation in finger tips, the dorsal hand vein, or with total peripheral resistance have been reported. (Eur. J. Clin. Pharmacol, 49:371-375 (1996); N. Schmiedeberg, Arch. Pharmacol, 354:557-561 (1996); Jpn. J. Pharmacol, 80:209-215 (1999); Br. J. Clin.
Pharmacol, 47:67-74 (1999)). These studies reported that an antagonist with high affinity for (Xia or αia/αid receptors can cause some degree of vasodilation, although it is much lower than with non-subtype-selective (Xia adrenoceptor antagonists. Further, there is increased vascular ocib adrenoceptor expression in elderly patients and thus (Xia/(Xid- selective agents with selectivity over (Xib adrenoceptor subtype would be of particular importance in benign prostatic hyperplasia. Antagonism of both (Xia adrenoceptor and (Xid adrenoceptor is important to relieve lower urinary tract symptoms especially associated with BPH. Targeting (Xia adrenoceptors with antagonists is important in relaxing prostate smooth muscle and relieving bladder outlet obstruction, whereas (Xid adrenoceptor antagonism is important to target irritative symptoms. Over the past decade, there has been an intensive search for selective (Xia 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.
The synthesis of [Phenyl-4-piperazin-l]-3 alcoyl-3-3H-benzo- and thieno-triazine- 1,2,3 ones-for their application in therapeutic fields are described in US patent No. 4,552,878, FR 2,551,753 and Eur J Med Chem, 22(4): 337-345 (1987) disclose benzotriazine-l,2,3-ones-4 that are said to have antidepressant activity. United States Patent No. 6,166,009 and PCT Publication No. WO 96/31498 discloses N-substituted azaheterocyclic carboxylic acids and esters thereof and their use for hyperalgesic and/or inflammatory conditions. United States Patent Application No. US 2003/0032801 and PCT Publication No. WO 02/089810 discloses chemosensitizing agents for treating multiple resistant strains of Plasmodium falciparum. Other reports describing selective αla adrenoceptor antagonists are GB 1,280,941, WO 93/16073, US 5,185, 335, WO 01/49670, US 2003/0159706, WO 99/31058, WO 98/15548, WO 98/15546, WO 00/32193 all these patents are incorporated by reference herein in their entirety. Compounds described in US patent Nos. 6,083,950, 6,090,809, 6,410,735, 6,420,559, 6,420,366, US patent appl. 2002/0156085, WO 00/05206 and WO 02/44151have been shown to have good al-adrenergic blocking activity and selectivity. Summary of the Invention Provided are compounds having a structure of the Formula I
R1-A-X1R2R3
Formula I
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof, wherein:
Xi can be N or CR4;
R4 can be hydrogen, hydroxyl or alkyl;
A can be aryl, aryloxy, heterocyclyl, alkyl, alkoxy, cycloalkyl, NHCORio or CHR10R11; Rio and Rn can independently be alkyl, COO-alkyl, aryl or heterocyclyl;
R1, R2 and R3 independently in each occurrence can be hydrogen, halogen, C1-3 alkyl, alkoxy, alkyl, nitro, cyano, cycloalkoxy, R6 or S(0)o-2Rs;
R5 can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl; R2 and R3 together with Xi to which they are attached can form a ring of the form
Figure imgf000005_0001
which contains one or more additional heteroatom(s) selected from O, S or N;
Mi and M2 can independently be hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl, alkoxy or acyl; or Ml and M2 together can form a bridging group (C0-3); W can be N, CH or COH;
R6 can be
Figure imgf000006_0001
Y can be O, S, NR4, C=O or a bond;
R7, Rs and Rg are independently hydrogen, hydroxyl, amino, S(0)o- 2R5 or NHSO2R5;
L can be a linker; and • can be a point of attachment. Also provided are compounds selected from:
3- { 3 -[4-hydroxy-4-(2-methoxy phenyl)piperidin- 1 -yl]propyl } - 1 ,2,3 -benzotriazin- 4(3H)- one,
Methyl {4-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl] piperazin-1- yl } (phenyl)acetate,
3-(3- {4-[2-(cyclopentyloxy) phenyl]piperazin- 1 -yl Jpropyl)- 1 ,2,3-benzotriazin- 4(3H)-one,
3-{3-[4-(5-fluoro-2-isopropoxy phenyl)piperazin-l-yl]-2-methyl propyl}-l,2,3- benzotriazin-4(3H)-one, 3-(3 - { 4- [2-(cyclopentyloxy)-5-fluorophenyl]piperazin- 1 -yl } -2-methylpropyl)-
1,2,3- benzotriazin-4(3H)-one,
3- { 3 -[4-(2-ethoxyphenyl) piperazin- 1 -yl] -2-methyl propyl } - 1 ,2,3 -benzotriazin- 4(3H)- one,
3-{2-methyl-3-[4-(2-propoxy phenyl)piperazin-l-yl]propyl}-l,2,3-benzotriazin- 4(3H)- one,
3-(3 - { 4- [2-(cyclopentyloxy) phenyl]piperazin- 1 -yl } -2-methyl propyl)- 1 ,2,3 - benzotriazin-4 (3H)-one,
3-{3-[4-(2-isopropoxyphenyl) piperazin- l-yl]-2-methylpropyl} -1,2,3- benzotriazin- 4(3H)-one,
3- [3-(3 ,4-dihydroisoquinolin-2( lH)-yl)propyl] - 1 ,2,3 -benzotriazin-4(3H)-one, 3- { 5-[4-(2-methoxyphenyl) piperazin-1 -yl]pentyl }- 1 ,2,3-benzotriazin-4(3H)-one, 3 - { 5- [4-(2-ethoxyphenyl) piperazin- 1 -yl]pentyl } - 1 ,2,3 -benzotriazin-4(3H)-one,
3 - { 5- [4-(2-propoxyphenyl) piperazin- 1 -yl]pentyl } - 1 ,2,3-benzotriazin-4(3H)-one,
3- { 5-[4-(2-isopropoxyphenyl) piperazin- l-yl]pentyl } - l,2,3-benzotriazin-4(3H)- one,
3 - { 5- [4-(5-fluoro-2-isopropoxy phenyl)piperazin- 1 -yl]pentyl } - 1 ,2,3-benzotriazin- 4(3H)- one,
3-(5-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-yl} pentyl)-l,2,3- benzotriazin- 4(3H)-one, 3-{5-[4-(5-fluoro-2-methoxy phenyl)piperazin-l-yl]pentyl}-l,2,3-benzotriazin-
4(3H)- one,
3 - { 5 - [3 -(2-methoxyphenyl) imidazolidin- 1 -y l]pentyl } - 1 ,2, 3 -benzotriazin-4(3H) - one,
3-[5-(6,7-dimethoxy-3,4-dihydro isoquinolin-2(lH)-yl)pentyl]-l,2,3-benzotriazin- 4(3H)- one,
3-(3-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-yl} propyl)-l,2,3- benzotriazin- 4(3H)-one,
3-(3-{4-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-l-yl}propyl)-l,2,3- benzotriazin-4(3H)-one, 3-(5-{4-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-l-yl}pentyl)-l,2,3- benzotriazin-4(3H)-one,
3- { 5-[4-(5-fluoro-2-propoxyphenyl)piperazin- 1 -yl]pentyl } -1 ,2,3-benzotriazin- 4(3H)-one,
3 - { 5 - [4-(2-ethoxy-5 -fluorophenyl)piperazin- 1 -yl]pentyl } - 1 ,2, 3 -benzotriazin- 4(3H)-one,
3- [5-(3 ,4-dihydroisoquinolin-2( lH)-yl)pentyl] - 1 ,2,3 -benzotriazin-4(3H)-one,
3-{3-[8-hydroxy-8-(2-methoxy pheny^-S-azabicyclotS^.lJoct-S-ylJpropylJ-l^^- benzotriazin-4(3H)-one,
N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3-azabicyclo[3.1.0]hex-6- yljacetamide,
N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3-azabicyclo[3.1.0]hex-6- yljbenzamide, N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3-azabicyclo[3.1.0]hex-6-yl} tetrahydrofuran-2-carboxamide, 3-{ 3-[4-(5-fluoro-2-isopropoxy phenyl)piperazin-l-yl]-2-hydroxypropyl}-l,2,3- benzotriazin-4(3H)-one,
3-(3 - { 4- [2-(cyclopentyloxy) phenyl]piperazin- 1 -yl } -2-hydroxypropyl)- 1 ,2,3 - benzotriazin-4(3H)-one,
3- { 2-hydroxy-3-[4-(2-propoxy phenyl)piperazin- l-yl]propyl }- 1 ,2,3-benzotriazin- 4(3H)- one,
3- { 2-hydroxy-3-[4-(2-methoxy phenyl)piperazin-l -yl]propyl }- 1 ,2,3-benzotriazin- 4(3H)- one,
3- { 2-hydroxy-3 -[4-(2-isopropoxyphenyl)piperazin- 1 -yl]propyl } - 1 ,2,3 - benzotriazin- 4(3H)-one, 3- { 2-hydroxy-3-[4-(2-methoxy phenyl)piperazin-l -yl]propyl }- 1 ,2,3-benzotriazin-
4(3H)- one,
10-{ 3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-10H-phenoxazine, 10-{ 3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-10H-phenoxazine,
10- { 3- [4-(2-propoxyphenyl)piperazin- 1 -yl]propyl } - 10H-phenoxazine,
10-{ 3-[4-(2-isopropoxy phenyl) piperazin-l-yl]propyl}-10H-phenoxazine,
10-{ 3-[4-(2-fluoro-6-methoxy phenyl) piperazin-l-yl]propyl}-10H-phenoxazine,
10-{ 3-[4-(2-fluoro-6-isopropoxy phenyl)piperazin-l-yl]propyl}-10H-phenoxazine, 10-(3-{4-[2-(cyclopentyloxy)-6-fluoro phenyl]piperazin-l-yl}propyl)-10H- phenoxazine,
10-{ 3-[3-(2-methoxyphenyl) imidazolidin-l-yl]propyl}-10H-phenoxazine, 10- { 3- [4-(2-ethoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenothiazine,
10-{ 3-[4-(2-isopropoxy phenyl) piperazin-l-yl]propyl}-10H-phenothiazine,
10-{ 3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-10H-phenothiazine,
8-(2-methoxyphenyl)-3- [3-( 1 OH-phenothiazin- 10-yl)propyl] -3 -azabicyclo [3.2.1]octan- 8-ol,
10-(3-{4-[2-(cyclopentyloxy)phenyl] piperazin-1-yl} propyl) -1 OH-phenothiazine, N- { 3- [4-(2-methoxyphenyl)piperazin- 1 -yljpropyl } - 1 OH-phenothiazine- 10-carbox amide,
10- { 3- [4-(2-propoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenothiazine,
10-(3-{4-[2-(cyclopentyloxy)-5-fluoro phenyl]piperazin-l-yl}propyl)-10H- phenothiazine,
10-{ 3-[4-(5-fluoro-2-isopropoxyphenyl) piperazin-l-yl]propyl}-10H- phenothiazine,
N- { 3 -[4-(2-methoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenoxazine- 10- carboxamide, N- [2-(2-methoxyphenoxy)ethyl] - 1 OH-phenoxazine- 10-carboxamide,
10-(3-{4-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-l-yl}propyl)-10H- phenoxazine, 10-{ 3-[3-(2-ethoxyphenyl)imidazolidin-l-yl]propyl}-10H-phenothiazine,
10-{ 3-[4-(5-fluoro-2-propoxyphenyl)piperazin-l-yl]propyl}-10H-phenoxazine,
1 - [4-(5-fluoro-2-methoxyphenyl) piperazin- 1 -yl] -3 -( 10H-phenoxazin- 10- yl)propan-2-ol, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, Ν-oxides and metabolites thereof.
Also provided are compounds selected from: 3-{ 3-[4-hydroxy-4-(2-methoxy phenyl)piperidin-l-yl]propyl} -1,2,3 -benzotriazin-
4(3H)- one hydrochloride salt,
Methyl {4-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl] piperazin-1- yl}(phenyl)acetate hydrochloride salt,
3-(3-{4-[2-(cyclopentyloxy) phenyl]piperazin-l-yl}propyl)-l,2,3-benzotriazin- 4(3H)-one hydrochloride salt,
3-{3-[4-(5-fluoro-2-isopropoxy phenyl)piperazin-l-yl]-2-methyl propyl}-l,2,3- benzotriazin-4(3H)-one hydrochloride salt,
3-(3 - { 4- [2-(cyclopentyloxy)-5-fluorophenyl]piperazin- 1 -yl } -2-methylpropyl)- 1,2,3- benzotriazin-4(3H)-one hydrochloride salt, 3-{3-[4-(2-ethoxyphenyl) piperazin- l-yl]-2-methyl propyl} -1,2,3 -benzotriazin-
4(3H)- one hydrochloride salt, 3 - { 2-methyl-3 - [4-(2-propoxy phenyl)piperazin- 1 -yl] propyl } - 1 ,2, 3 -benzotriazin- 4(3H)- one hydrochloride salt, 3-(3-{4-[2-(cyclopentyloxy) phenyl]piperazin-l-yl}-2-methyl propyl)-l,2,3- benzotriazin-4 (3H)-one hydrochloride salt,
3-{3-[4-(2-isopropoxyphenyl) piperazin-l-yl]-2-methylpropyl} -1,2,3- benzotriazin- 4(3H)-one hydrochloride salt,
3- [3-(3 ,4-dihydroisoquinolin-2( lH)-yl)propyl] - 1 ,2,3 -benzotriazin-4(3H)-one hydrochloride salt,
3 - { 5- [4-(2-methoxyphenyl) piperazin- 1 -yl]pentyl } - 1 ,2,3 -benzotriazin-4(3H)-one hydrochloride salt,
3- { 5-[4-(2-ethoxyphenyl) piperazin- 1 -yl]pentyl } -1 ,2,3-benzotriazin-4(3H)-one hydrochloride salt, 3 - { 5- [4-(2-propoxyphenyl) piperazin- 1 -yl]pentyl } - 1 ,2,3 -benzotriazin-4(3H)-one hydrochloride salt,
3-{5-[4-(2-isopropoxyphenyl) piperazin-l-yl]pentyl}-l,2,3-benzotriazin-4(3H)-one hydrochloride salt,
3- { 5-[4-(5-fluoro-2-isopropoxy phenyl)piperazin- l-yl]pentyl }- 1 ,2,3-benzotriazin- 4(3H)- one hydrochloride salt,
3-(5-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-yl} pentyl)-l,2,3- benzotriazin- 4(3H)-one hydrochloride salt,
3-{5-[4-(5-fluoro-2-methoxy phenyl)piperazin-l-yl]pentyl}-l,2,3-benzotriazin- 4(3H)- one hydrochloride salt, 3-{5-[3-(2-methoxyphenyl) imidazolidin-l-yl]pentyl}-l,2,3-benzotriazin-4(3H)- one hydrochloride salt,
3-[5-(6,7-dimethoxy-3,4-dihydro isoquinolin-2(lH)-yl)pentyl]-l,2,3-benzotriazin- 4(3H)- one hydrochloride salt,
3-(3-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-yl} propyl)-l,2,3- benzotriazin- 4(3H)-one hydrochloride salt,
3-(3-{4-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-l-yl}propyl)-l,2,3- benzotriazin-4(3H)-one hydrochloride salt,
3-(5-{4-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-l-yl}pentyl)-l,2,3- benzotriazin-4(3H)-one hydrochloride salt, 3- { 5-[4-(5-fluoro-2-propoxyphenyl)piperazin- 1 -yl]pentyl } -1 ,2,3-benzotriazin- 4(3H)-one hydrochloride salt, 3 - { 5 - [4-(2-ethoxy-5 -fluorophenyl)piperazin- 1 -yl]pentyl } - 1 ,2, 3 -benzotriazin-
4(3H)-one hydrochloride salt,
3- [5-(3 ,4-dihydroisoquinolin-2( lH)-yl)pentyl] - 1 ,2,3 -benzotriazin-4(3H)-one hydrochloride salt,
3-{3-[8-hydroxy-8-(2-methoxy phenyrj-S-azabicycloP^.lJoct-S-ylJpropylJ-l^S- benzotriazin-4(3H)-one hydrochloride salt,
N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3-azabicyclo[3.1.0]hex-6- yljacetamide hydrochloride salt,
N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3-azabicyclo[3.1.0]hex-6- yljbenzamide hydrochloride salt, N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3-azabicyclo[3.1.0]hex-6-yl} tetrahydrofuran-2-carboxamide hydrochloride salt,
3 - { 3 - [4-(5-fluoro-2-isopropoxy phenyl)piperazin- 1 -yl] -2-hydroxypropyl } - 1 ,2, 3 - benzotriazin-4(3H)-one hydrochloride salt,
3-(3 - { 4- [2-(cyclopentyloxy) phenyl]piperazin- 1 -yl } -2-hydroxypropyl)- 1 ,2,3 - benzotriazin-4(3H)-one hydrochloride salt,
3- { 2-hydroxy-3-[4-(2-propoxy phenyl)piperazin- l-yl]propyl }- 1 ,2,3-benzotriazin- 4(3H)- one hydrochloride salt,
3- { 2-hydroxy-3-[4-(2-methoxy phenyl)piperazin-l -yl]propyl }- 1 ,2,3-benzotriazin- 4(3H)- one hydrochloride salt, 3- { 2-hydroxy-3 -[4-(2-isopropoxyphenyl)piperazin- 1 -yl]propyl } - 1 ,2,3 - benzotriazin- 4(3H)-one hydrochloride salt,
3- { 2-hydroxy-3-[4-(2-methoxy phenyl)piperazin-l -yl]propyl }- 1 ,2,3-benzotriazin- 4(3H)- one hydrochloride salt,
10-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-10H-phenoxazine hydrochloride salt,
10- { 3- [4-(2-ethoxyphenyl)piperazin- 1 -yl]propyl } - 10H-phenoxazine hydrochloride salt,
10- { 3- [4-(2-propoxyphenyl)piperazin- 1 -yl]propyl } - 10H-phenoxazine hydrochloride salt, 10-{ 3-[4-(2-isopropoxy phenyl) piperazin-l-yl]propyl}-10H-phenoxazine hydrochloride salt, 10-{3-[4-(2-fluoro-6-methoxy phenyl) piperazin-l-yl]propyl}-10H- phenoxazinehydrochloride salt,
10-{3-[4-(2-fluoro-6-isopropoxy phenyl)piperazin-l-yl]propyl}-10H- phenoxazinehydrochloride salt,
10-(3-{4-[2-(cyclopentyloxy)-6-fluoro phenyl]piperazin-l-yl}propyl)-10H- phenoxazine hydrochloride salt,
10-{ 3-[3-(2-methoxyphenyl) imidazolidin-l-yl]propyl}-10H-phenoxazine hydrochloride salt,
10- { 3- [4-(2-ethoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenothiazine hydrochloride salt, 10-{ 3-[4-(2-isopropoxy phenyl) piperazin-l-yl]propyl}-10H-phenothiazine hydrochloride salt,
10-{ 3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-10H-phenothiazine hydrochloride salt,
8-(2-methoxyphenyl)-3- [3-( 1 OH-phenothiazin- 10-yl)propyl] -3 -azabicyclo [3.2.1]octan- 8-ol hydrochloride salt,
10-(3-{4-[2-(cyclopentyloxy)phenyl] piperazin-1-yl} propyl) -1 OH-phenothiazine hydrochloride salt,
N- { 3 - [4-(2-methoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenothiazine- 10-carbox amide hydrochloride salt, 10- { 3- [4-(2-propoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenothiazine hydrochloride salt,
10-(3-{4-[2-(cyclopentyloxy)-5-fluoro phenyl]piperazin-l-yl}propyl)-10H- phenothiazine hydrochloride salt,
10-{3-[4-(5-fluoro-2-isopropoxyphenyl) piperazin-l-yl]propyl}-10H- phenothiazine hydrochloride salt,
N- { 3 -[4-(2-methoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenoxazine- 10- carboxamide hydrochloride salt,
N- [2-(2-methoxyphenoxy)ethyl] - 1 OH-phenoxazine- 10-carboxamide hydrochloride salt, 10-(3-{4-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-l-yl}propyl)-10H- phenoxazine hydrochloride salt,
10-{3-[3-(2-ethoxyphenyl)imidazolidin-l-yl]propyl}-10H-phenothiazine hydrochloride salt,
10-{3-[4-(5-fluoro-2-propoxyphenyl)piperazin-l-yl]propyl}-10H-phenoxazine hydrochloride salt, 1 - [4-(5-fluoro-2-methoxyphenyl) piperazin- 1 -yl] -3 -( 10H-phenoxazin- 10- yl)propan-2-ol hydrochloride salt.
In another aspect, provided are pharmaceutical compositions comprising therapeutically effective amounts of one or more compounds having the structure of the Formula I
R1-A-X1R2R3
Formula I
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof, together with one or more pharmaceutically acceptable carriers, excipients or diluents, wherein:
Xi can be N or CR4; R4 can be hydrogen, hydroxyl or alkyl;
A can be aryl, aryloxy, heterocyclyl, alkyl, alkoxy, cycloalkyl, NΗCORio or CΗRioRn;
Rio and Rn can independently be alkyl, COO-alkyl, aryl or heterocyclyl;
R1, R2 and R3 independently in each occurrence can be hydrogen, halogen, C1-3 alkyl, alkoxy, alkyl, nitro, cyano, cycloalkoxy, R6 or S(0)o-2Rs;
R5 can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl; R2 and R3 together with Xi to which they are attached can form a ring of the form
Figure imgf000014_0001
which contains one or more additional heteroatom(s) selected from O, S or N;
Mi and M2 can independently be hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl, alkoxy or acyl; or Ml and M2 together form a bridging group (C0-3);
W can be N, CH or COH; R6 can be
Figure imgf000014_0002
Y can be O, S, NR4, C=O or a bond; R7, R8 and R9 can independently be hydrogen, hydroxyl, amino,
S(O)0_2R5 or NHSO2R5;
L can be a linker; and
• can be a point of attachment.
In another aspect, provided are methods for treating a disease or disorder mediated through αla and/or aid 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
R1-A-X1R2R3
Formula I
or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof, or a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds having the structure of the Formula I, wherein
Xi can be N or CR4;
R4 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;
R1, R2 and R3 independently in each occurrence can be hydrogen, halogen, C1-3 alkyl, alkoxy, alkyl, nitro, cyano, cycloalkoxy, R6 or S(0)o-2Rs; R5 can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl;
R2 and R3 together with Xi to which they are attached can form a ring of the form
Figure imgf000015_0001
which contains one or more additional heteroatom(s) selected from O, S or N;
Mi and M2 can independently be hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl, alkoxy or acyl; or Ml and M2 together form a bridging group (C0-3);
W can be N, CH or COH; R6 can be
Figure imgf000015_0002
Y can be O, S, NR4, C=O or a bond;
R7, Rs and R9 can independently be hydrogen, hydroxyl, amino,
Figure imgf000016_0001
L can be a linker; and • can be a point of attachment
The methods can also include one or more of the following embodiments. For example, the disease or disorder can be benign prostatic hyperplasia or lower urinary tract symptoms. In another example, the compounds described herein can cause minimal fall or no fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia. In another aspect, provided are methods for preparing compounds of Formula VI,
R — L — W ^1-A-R1
M2
Formula VI
or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof, comprising the steps of: (a) reacting the compound of Formula II
R-H
Formula II
with a compound of Formula III (wherein X2 and X3 are leaving groups)
X2 — L — X3 Formula III to form a compound of Formula IV
R — L — X3
Formula IV
(b) treating the compound of Formula IV with a compound of Formula V
Figure imgf000017_0001
Formula V
to form a compound of Formula VI, wherein,
Xi can be N or CR4; R4 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,
Figure imgf000017_0002
R5 can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl; R6 can be
Figure imgf000017_0003
Mi and M2 can independently be hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl, alkoxy or acyl; or Ml and M2 together form a bridging group (C0-3);
W can be N, CH or COH; R can be
Figure imgf000018_0001
Y can be O, S, NR4, C=O or a bond;
R7, Rs and R9 can independently be hydrogen, hydroxyl, amino, S(0)o-2Rs or NHSO2R5; and
L can be a linker. In another aspect, provided are methods for preparing compound of Formula IX,
Figure imgf000018_0002
Formula IX
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof, comprising the steps of:
(a) reacting the compound of Formula II
R — H
Formula II
with a compound of Formula VII (wherein X3 is a leaving group)
o
X3
Formula VII to form a compound of Formula VIII
Figure imgf000019_0001
Foπnula VHI (b) treating the compound of Formula VIII with a compound of Formula V
Figure imgf000019_0002
Formula V
to form a compound of Formula IX, wherein,
Xi can be N or CR4;
R4 can eb hydrogen, hydroxyl or alkyl;
A can be aryl, aryloxy, heterocyclyl, alkyl, alkoxy, cycloalkyl, NHCORi0 or CHRi0Rn; Ri0 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 θr S(0)o_2R5;
R5 can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl; and R6 can be
Figure imgf000019_0003
Mi and M2 can independently be hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl, alkoxy or acyl; or Ml and M2 together form a bridging group (Co-3);
W can be N, CH or COH; R can be
Figure imgf000020_0001
Y can be O, S, NR4, C=O or a bond; and
R7, Rs and R9 can independently be hydrogen, hydroxyl, amino, S(0)o-2Rs or NHSO2R5
In yet another aspect, provided are methods for preparing compounds of Formula XIV,
A-R1
Figure imgf000020_0002
Formula XTV
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof, comprising the steps of:
(a) reacting the compound of Formula V(a) with a compound of Formula X
(wherein X4 is alkenyl or halogen)
H — N ^1-A — R1 X4 (CH2)S CN
Formula X
M2
Formula V (a)
(Formula V, wherein W=N) to form a compound of Formula XI
R1-A-X1 T|J—(CH2)H CN
M2 Formula XI
(b) reducing the compound of Formula XI to form a compound of Formula XII
R1 A — X1 IjT (CH2)J CH2-NH2 XM M2
Formula XTT
(c) reacting the compound of Formula XII with a compound of Formula XIII
Figure imgf000021_0001
Formula Xm to form a compound of Formula XIV, wherein,
Xi can be N or CR4; R4 can be hydrogen, hydroxyl or alkyl;
A can be aryl, aryloxy, heterocyclyl, alkyl, alkoxy, cycloalkyl, NHCORio or CHR10R11;
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,
Figure imgf000021_0002
R5 can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl; R6 can be
Figure imgf000022_0001
Mi and M2 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
Y can be O, S, NR4, C=O or a bond; In another aspect, provided are methods for preparing compounds of Formula XX,
Figure imgf000022_0002
Formula XX
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof, comprising the steps of:
(a) reacting the compound of Formula X
R1 — A— OH
Formula XV
with a compound of Formula VII
Figure imgf000022_0003
Formula XVI to form a compound of Formula XVII
Figure imgf000023_0001
Fomiula XVII
(b) treating the compound of Formula XVII with a hydrazine hydrate to form a compound of Formula XVIII, and
Fromula XVHI
(c) treating the compound of Formula XVIII with a compound of Formula XIX
Figure imgf000023_0002
Formula Xm
to form a compound of Formula XX, wherein, 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, Ci_3 alkyl, alkoxy, alkyl, nitro, cyano, cycloalkoxy,
Figure imgf000023_0003
R5 can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl;
R6 can be
Figure imgf000023_0004
Y can be O, S, NR4, C=O or a bond; and n can be an integer of from 0 to 5.
Detailed Description of the Invention
The present invention provides αla 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. The present invention also provides for processes for the synthesis of such compounds. Also provided herein are pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxide of such compounds. Also provided are 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. Other aspect and properties of this matter will be set forth in description which follows, and will be apparent from the description or may be learnt by the practice thereof. In one aspect, provided herein are compounds having the structure of Formula I,
Figure imgf000024_0001
Formula I
pharmaceutically acceptable salts, esters, enantiomers, diastereomers, N-oxides, prodrugs, metabolites, polymorphs or pharmaceutically acceptable solvates thereof, wherein: Xi can be N or CR4, wherein
R4 can be hydrogen, hydroxyl or alkyl;
A can be aryl, aryloxy, heterocyclyl, alkyl, alkoxy, cycloalkyl, NHCORio or CHRi0Ri i, wherein
Ri0 and Rn can be independently alkyl, COO-alkyl, aryl or heterocyclyl; R1, R2 and R3 independently in each occurrence can be hydrogen, halogen, C1-3 alkyl, alkoxy, alkyl, nitro, cyano, cycloalkoxy, R6 or S(0)o-2Rs, wherein R5 can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl; and R2 and R3 together with Xi to which they are attached may also form a ring of the form
Figure imgf000025_0001
which may contain additional one or more heteroatom(s) selected from O, S or N, wherein
Mi and M2 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; and
Figure imgf000025_0002
wherein
Y can be O, S, NR4, C=O or a bond;
R7, Rs and R9 can be independently hydrogen, hydroxyl, amino, S(0)o-2Rs or NHSO2R5;
L can be a linker; and • can be point of attachment.
In another aspect, provided herein are compounds selected from:
3 - { 3- [4-hydroxy-4-(2-methoxy phenyl)piperidin- 1 -yl]propyl } - 1 ,2,3 -benzotriazin-4(3H)- one,
Methyl {4-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl] piperazin-l-yl}(phenyl)acetate, 3-(3-{4-[2-(cyclopentyloxy) phenyl]piperazin-l-yl}propyl)-l,2,3-benzotriazin-4(3H)-one,
3-{ 3-[4-(5-fluoro-2-isopropoxy phenyl)piperazin-l-yl]-2-methyl propyl }- 1,2,3 - benzotriazin-4(3H)-one, 3-(3- { 4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin- 1 -yl } -2-methylpropyl)-l ,2,3- benzotriazin-4(3H)-one, 3-{3-[4-(2-ethoxyphenyl) piperazin-l-yl]-2-methyl propyl}-l,2,3-benzotriazin-4(3H)-one,
3 - { 2-methyl-3 - [4-(2-propoxy phenyl)piperazin- 1 -yl]propyl } - 1 ,2,3 -benzotriazin-4(3H)- one, 3-(3-{4-[2-(cyclopentyloxy) phenyl]piperazin-l-yl} -2 -methyl propyl)-l,2,3-benzotriazin-4 (3H)-one,
3-{ 3-[4-(2-isopropoxyphenyl) piperazin-l-yl]-2-methylpropyl} -l,2,3-benzotriazin-4(3H)- one,
3 - [3 -(3 ,4-dihydroisoquinolin-2( IH) -yl)propyl] -1,2,3 -benzotriazin-4(3H) -one,
3 - { 5- [4-(2-methoxyphenyl) piperazin- 1 -yl]pentyl } - 1 ,2,3 -benzotriazin-4(3H)-one, 3- { 5- [4-(2-ethoxyphenyl) piperazin- 1 -yl]pentyl } - 1 ,2,3 -benzotriazin-4(3H)-one, 3 - { 5- [4-(2-propoxyphenyl) piperazin- 1 -yl]pentyl } - 1 ,2,3-benzotriazin-4(3H)-one,
3 - { 5- [4-(2-isopropoxyphenyl) piperazin- 1 -yl]pentyl } - 1 ,2,3-benzotriazin-4(3H)-one,
3 - { 5- [4-(5-fluoro-2-isopropoxy phenyl)piperazin- 1 -yl]pentyl } - 1 ,2,3 -benzotriazin-4(3H)- one,
3-(5-{ 4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin- 1 -yl } pentyl)- 1 ,2,3-benzotriazin- 4(3H)-one,
3 - { 5- [4-(5-fluoro-2-methoxy phenyl)piperazin- 1 -yl]pentyl } - 1 ,2,3 -benzotriazin-4(3H)-one,
3- { 5- [3-(2-methoxyphenyl) imidazolidin- 1 -yl]pentyl } - 1 ,2,3 -benzotriazin-4(3H)-one,
3-[5-(6,7-dimethoxy-3,4-dihydro isoquinolin-2(lH)-yl)pentyl]-l,2,3-benzotriazin-4(3H)- one,
3-(3-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-yl} propyl)-l,2,3-benzotriazin- 4(3H)-one,
3 -(3- { 4- [5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin- 1 -yl Jpropyl)- 1 ,2,3 - benzotriazin-4(3H)-one, 3 -(5- { 4- [5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin- 1 -yl jpentyl)- 1 ,2,3- benzotriazin-4(3H)-one,
3 - { 5- [4-(5-fluoro-2-propoxyphenyl)piperazin- 1 -yl]pentyl } - 1 ,2,3-benzotriazin-4(3H)-one, 3 - { 5- [4-(2-ethoxy-5-fluorophenyl)piperazin- 1 -yl]pentyl } - 1 ,2,3 -benzotriazin-4(3H)-one,
3-[5-(3,4-dihydroisoquinolin-2(lH)-yl)pentyl]-l,2,3-benzotriazin-4(3H)-one,
3-{3-[8-hydroxy-8-(2-methoxy pheny^-S-azabicyclofS^.lJoct-S-yllpropylJ-l^^- benzotriazin-4(3H)-one,
N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3-azabicyclo[3.1.0]hex-6- yljacetamide,
N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3-azabicyclo[3.1.0]hex-6- yljbenzamide, N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3-azabicyclo[3.1.0]hex-6-yl} tetrahydrofuran-2-carboxamide,
3 - { 3- [4-(5-fluoro-2-isopropoxy phenyl)piperazin- 1 -yl] -2-hydroxypropyl } - 1 ,2,3- benzotriazin-4(3H)-one, 3 -(3- { 4- [2-(cyclopentyloxy) phenyl]piperazin- 1 -yl } -2-hydroxypropyl)- 1 ,2,3 -benzotriazin- 4(3H)-one,
3 - { 2-hydroxy-3 - [4-(2-propoxy phenyl)piperazin- 1 -yl]propyl } - 1 ,2,3 -benzotriazin-4(3H)- one,
3 - { 2-hydroxy-3 - [4-(2-methoxy phenyl)piperazin- 1 -yl]propyl } - 1 ,2,3 -benzotriazin-4(3H)- one,
3-{2-hydroxy-3-[4-(2-isopropoxyphenyl)piperazin-l-yl]propyl}-l,2,3-benzotriazin-4(3H)- one,
3 - { 2-hydroxy-3 - [4-(2-methoxy phenyl)piperazin- 1 -yl]propyl } - 1 ,2,3 -benzotriazin-4(3H)- one, 10- { 3 - [4-(2-methoxyphenyl)piperazin- 1 -yl]propyl } - 10H-phenoxazine, 10- { 3 - [4-(2-methoxyphenyl)piperazin- 1 -yl]propyl } - 10H-phenoxazine,
10- { 3 - [4-(2-propoxyphenyl)piperazin- 1 -yl]propyl } - 10H-phenoxazine,
10- { 3 - [4-(2-isopropoxy phenyl) piperazin- 1 -yl]propyl } - 10H-phenoxazine,
10- { 3 - [4-(2-fluoro-6-methoxy phenyl) piperazin- 1 -yl]propyl } - 10H-phenoxazine, 10- { 3 - [4-(2-fluoro-6-isopropoxy phenyl)piperazin- 1 -yl]propyl } - 10H-phenoxazine,
10-(3 - { 4-[2-(cyclopentyloxy)-6-fluoro phenyl]piperazin- 1 -yl } propyl)- 10H-phenoxazine, 10- { 3 - [3-(2-methoxyphenyl) imidazolidin- 1 -yl]propyl } - 10H-phenoxazine, 10- { 3 - [4-(2-ethoxyphenyl)piperazin- 1 -yl]propyl } - 10H-phenothiazine,
10- { 3 - [4-(2-isopropoxy phenyl) piperazin- 1 -yl]propyl } - 1 OH-phenothiazine,
10- { 3 - [4-(2-methoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenothiazine,
8-(2-methoxyphenyl)-3-[3-(10H-phenothiazin-10-yl)propyl]-3-azabicyclo [3.2.1]octan-8- ol,
10-(3 - { 4- [2-(cy clopentyloxy)phenyl] piperazin- 1 -yl } propyl) - 1 OH-phenothiazine, N- { 3- [4-(2-methoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenothiazine- 10-carbox amide, 10- { 3 - [4-(2-propoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenothiazine,
10-(3 - { 4-[2-(cyclopentyloxy)-5-fluoro phenyl]piperazin- 1 -yl } propyl)- 1 OH-phenothiazine,
10- { 3 - [4-(5-fluoro-2-isopropoxyphenyl) piperazin- 1 -yl]propyl } - 1 OH-phenothiazine,
N- { 3 - [4-(2-methoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenoxazine- 10-carboxamide,
N-[2-(2-methoxyphenoxy)ethyl]-10H-phenoxazine-10-carboxamide, 10-(3-{4-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-l-yl}propyl)-10H- phenoxazine, 10- { 3 - [3-(2-ethoxyphenyl)imidazolidin- 1 -yl]propyl } - 10H-phenothiazine,
10- { 3 - [4-(5-fluoro-2-propoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenoxazine, l-[4-(5-fluoro-2-methoxyphenyl) piperazin-l-yl]-3-(10H-phenoxazin-10-yl)propan-2-ol, a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, polymorph, prodrug, stereoisomer, tautomeric form, Ν-oxide or metabolite thereof. In another aspect, provided herein are compounds selected from:
3 - { 3- [4-hydroxy-4-(2-methoxy phenyl)piperidin- 1 -yl]propyl } - 1 ,2,3 -benzotriazin-4(3H)- one hydrochloride salt,
Methyl { 4-[3 -(4-oxo- 1 ,2,3 -benzotriazin-3 (4H)-yl)propyl] piperazin- 1 -yl } (phenyl)acetate hydrochloride salt,
3-(3-{4-[2-(cyclopentyloxy) phenyl]piperazin-l-yl}propyl)-l,2,3-benzotriazin-4(3H)-one hydrochloride salt, 3-{3-[4-(5-fluoro-2-isopropoxy phenyl)piperazin-l-yl]-2-methyl propyl }- 1,2,3 - benzotriazin-4(3H)-one hydrochloride salt, 3-(3- { 4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin- 1 -yl } -2-methylpropyl)-l ,2,3- benzotriazin-4(3H)-one hydrochloride salt,
3-{ 3-[4-(2-ethoxyphenyl) piperazin-l-yl]-2-methyl propyl}-l,2,3-benzotriazin-4(3H)-one hydrochloride salt,
3 - { 2-methyl-3 - [4-(2-propoxy phenyl)piperazin- 1 -yl]propyl } - 1 ,2,3 -benzotriazin-4(3H)-one hydrochloride salt, 3-(3-{4-[2-(cyclopentyloxy) phenyl]piperazin-l-yl} -2 -methyl propyl)-l,2,3-benzotriazin-4 (3H)-one hydrochloride salt,
3-{ 3-[4-(2-isopropoxyphenyl) piperazin-l-yl]-2-methylpropyl} -l,2,3-benzotriazin-4(3H)- one hydrochloride salt,
3 - [3 -(3 ,4-dihydroisoquinolin-2( IH) -yl)propyl] -1,2,3 -benzotriazin-4(3H) -one hydrochloride salt,
3 - { 5- [4-(2-methoxyphenyl) piperazin- 1 -yl]pentyl } - 1 ,2,3 -benzotriazin-4(3H)-one hydrochloride salt,
3 - { 5- [4-(2-ethoxyphenyl) piperazin- 1 -yl]pentyl } - 1 ,2,3 -benzotriazin-4(3H)-one hydrochloride salt,
3 - { 5- [4-(2-propoxyphenyl) piperazin- 1 -yl]pentyl } - 1 ,2,3-benzotriazin-4(3H)-one hydrochloride salt,
3 - { 5- [4-(2-isopropoxyphenyl) piperazin- 1 -yl]pentyl } - 1 ,2,3-benzotriazin-4(3H)-one hydrochloride salt, 3- { 5- [4-(5-fluoro-2-isopropoxy phenyl)piperazin- 1 -yl]pentyl } - 1 ,2,3 -benzotriazin-4(3H)- one hydrochloride salt,
3-(5-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-yl} pentyl)-l,2,3-benzotriazin- 4(3H)-one hydrochloride salt,
3 - { 5- [4-(5-fluoro-2-methoxy phenyl)piperazin- 1 -yl]pentyl } - 1 ,2,3 -benzotriazin-4(3H)-one hydrochloride salt,
3- { 5- [3-(2-methoxyphenyl) imidazolidin- 1 -yl]pentyl } - 1 ,2,3 -benzotriazin-4(3H)-one hydrochloride salt,
3-[5-(6,7-dimethoxy-3,4-dihydro isoquinolin-2(lH)-yl)pentyl]-l,2,3-benzotriazin-4(3H)- one hydrochloride salt, 3-(3-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-yl} propyl)-l,2,3-benzotriazin- 4(3H)-one hydrochloride salt, 3 -(3- { 4- [5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin- 1 -yl Jpropyl)- 1 ,2,3 - benzotriazin-4(3H)-one hydrochloride salt,
3 -(5- { 4- [5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin- 1 -yl jpentyl)- 1 ,2,3- benzotriazin-4(3H)-one hydrochloride salt,
3 - { 5- [4-(5-fluoro-2-propoxyphenyl)piperazin- 1 -yl]pentyl } - 1 ,2,3-benzotriazin-4(3H)-one hydrochloride salt, 3 - { 5- [4-(2-ethoxy-5-fluorophenyl)piperazin- 1 -yl]pentyl } - 1 ,2,3 -benzotriazin-4(3H)-one hydrochloride salt,
3-[5-(3,4-dihydroisoquinolin-2(lH)-yl)pentyl]-l,2,3-benzotriazin-4(3H)-one hydrochloride salt,
3-{3-[8-hydroxy-8-(2-methoxy pheny^-S-azabicycloP^.ljoct-S-yllpropylJ-l^S- benzotriazin-4(3H)-one hydrochloride salt,
N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3-azabicyclo[3.1.0]hex-6- yljacetamide hydrochloride salt,
N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3-azabicyclo[3.1.0]hex-6- yljbenzamide hydrochloride salt, N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3-azabicyclo[3.1.0]hex-6-yl} tetrahydrofuran-2-carboxamide hydrochloride salt,
3 - { 3 - [4-(5-fluoro-2-isopropoxy phenyl)piperazin- 1 -yl] -2-hydroxypropy 1 } - 1 ,2, 3 - benzotriazin-4(3H)-one hydrochloride salt,
3 -(3- { 4- [2-(cyclopentyloxy) phenyl]piperazin- 1 -yl } -2-hydroxypropyl)- 1 ,2,3 -benzotriazin- 4(3H)-one hydrochloride salt,
3 - { 2-hydroxy-3 - [4-(2-propoxy phenyl)piperazin- 1 -yl]propyl } - 1 ,2,3 -benzotriazin-4(3H)- one hydrochloride salt,
3 - { 2-hydroxy-3 - [4-(2-methoxy phenyl)piperazin- 1 -yl]propyl } - 1 ,2,3 -benzotriazin-4(3H)- one hydrochloride salt, 3-{2-hydroxy-3-[4-(2-isopropoxyphenyl)piperazin-l-yl]propyl}-l,2,3-benzotriazin-4(3H)- one hydrochloride salt,
3 - { 2-hydroxy-3 - [4-(2-methoxy phenyl)piperazin- 1 -yl]propyl } - 1 ,2,3 -benzotriazin-4(3H)- one hydrochloride salt,
10- { 3 - [4-(2-methoxyphenyl)piperazin- 1 -yl]propyl } - 10H-phenoxazine hydrochloride salt,
10- { 3 - [4-(2-methoxyphenyl)piperazin- 1 -yl]propyl } - 10H-phenoxazine hydrochloride salt, 10- { 3 - [4-(2-propoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenoxazine hydrochloride salt,
10-{3-[4-(2-isopropoxy phenyl) piperazin-l-yl]propyl}-10H-phenoxazine hydrochloride salt,
10- { 3 - [4-(2-fluoro-6-methoxy phenyl) piperazin- 1 -yl]propyl } - 1 OH-phenoxazine hydrochloride salt, 10- { 3 - [4-(2-fluoro-6-isopropoxy phenyl)piperazin- 1 -yl]propyl } - 1 OH-phenoxazine hydrochloride salt,
10-(3 - { 4-[2-(cyclopentyloxy)-6-fluoro phenyl]piperazin- 1 -yl } propyl)- 1 OH-phenoxazine hydrochloride salt,
10- { 3 - [3-(2-methoxyphenyl) imidazolidin- 1 -yl]propyl } - 1 OH-phenoxazine hydrochloride salt,
10- { 3 - [4-(2-ethoxyphenyl)piperazin- 1 -yl]propyl } - 10H-phenothiazine hydrochloride salt,
10-{3-[4-(2-isopropoxy phenyl) piperazin- l-yl]propyl}-10H-phenothiazine hydrochloride salt,
10- { 3 - [4-(2-methoxyphenyl)piperazin- 1 -yl]propyl } - 10H-phenothiazine hydrochloride salt,
8-(2-methoxyphenyl)-3-[3-(10H-phenothiazin-10-yl)propyl]-3-azabicyclo [3.2.1]octan-8- ol hydrochloride salt,
10-(3 - { 4- [2-(cy clopentyloxy)phenyl] piperazin- 1 -yl } propyl) - 1 OH-phenothiazine hydrochloride salt,
N- { 3- [4-(2-methoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenothiazine- 10-carbox amide hydrochloride salt, 10- { 3 - [4-(2-propoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenothiazine hydrochloride salt,
10-(3 - { 4-[2-(cyclopentyloxy)-5-fluoro phenyl]piperazin- 1 -yl } propyl)- 1 OH-phenothiazine hydrochloride salt, 10- { 3 - [4-(5-fluoro-2-isopropoxyphenyl) piperazin- 1 -yl]propyl } - 1 OH-phenothiazine hydrochloride salt,
N- { 3 - [4-(2-methoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenoxazine- 10-carboxamide hydrochloride salt,
N-[2-(2-methoxyphenoxy)ethyl]-10H-phenoxazine-10-carboxamide hydrochloride salt,
10-(3-{4-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-l-yl}propyl)-10H- phenoxazine hydrochloride salt, 10- { 3 - [3-(2-ethoxyphenyl)imidazolidin- 1 -yl]propyl } - 10H-phenothiazine hydrochloride salt,
10- { 3 - [4-(5-fluoro-2-propoxyphenyl)piperazin- 1 -yl]propyl } - 10H-phenoxazine hydrochloride salt, or l-[4-(5-fluoro-2-methoxyphenyl) piperazin-l-yl]-3-(10H-phenoxazin-10-yl)propan-2-ol hydrochloride salt.
In another aspect, provided herein are pharmaceutical compositions comprising therapeutically effective amounts of one or more compounds described herein together with one or more pharmaceutically acceptable carriers, excipients or diluents.
In another aspect, 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.
In another aspect, provided herein are methods for treating benign prostatic hyperplasia (BPΗ) and related symptoms, lower urinary tract symptoms (LUTS) with or without BPΗ comprising administering to a patient in need thereof therapeutically effective amounts of one or more compounds or compositions described herein. In an embodiment, 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). In another aspect, provided herein are methods for treating BPΗ or LUTS with or without BPΗ 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-ΗT antagonists or combination thereof.
In yet another aspect, provided are processes for preparing compounds described herein. The compounds of this invention are potent adrenergic receptor antagonists. Compounds described herein have good selectivity for αla v/s αib. 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 (Xib 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 αla adrenoceptors. Compounds and compositions described herein can be administered orally, parenterally, subcutaneously, transdermally or topically or any other suitable route. The term "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.
The term "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.
The term "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. The term "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.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "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.
The term "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. The term "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. Examples of 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, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, thiazolyl, and thienyl, and the like.
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, -NRnRi2, -CONRHRI2, -COORI2, -CONHRi2, -OCORi2, -CORi2, - NHSO2Ri2 and -SO2NHRi2 wherein Rn and Ri2 are independently selected from hydrogen or alkyl.
The term "alkoxy" herein refers to 0Ra wherein Ra can be alkyl, alkenyl or alkynyl.
The term "cycloalkoxy" herein refers to ORb wherein Rb can be cycloalkyl.
The term 'linker' refers to CON(Rs)2, CS(Rs)2, [wherein R8 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.
The term "leaving group" refers to any group that leaves the molecule during substitution, elimination and addition-elimination reactions. Illustrative examples of 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. The term "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.
The term "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.
The term "pharmaceutically acceptable 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.
The term "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.
The term "pharmaceutically acceptable 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. In general, such 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.
Conventional procedure for the selection and preparation of suitable prodrug derivatives are described, for example, in "design of prodrugs", ed. H Bundgaard and, Elsevier, 1985. Enantiomers and Diastereomers are as defined by the IUPAC 1974 Recommendations for Section E.
Scheme I
R-H + X2 — L — X3 R — L-X3 Formula II Formula III Formula IV
V
Figure imgf000036_0001
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 X2 and X3 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, R7, Rs, R9, W, Mi, M2, 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 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., triethylamine, pyridine, tributylamine, diisopropylethylamine, sodium-?-butoxide, 4-(N-dimethylamino)pyridine, lithium diisopropylamine, potassium-?-butoxide, n-butyllithium or dry liquid ammonia or mixtures thereof) or mixtures thereof.
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.
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.
Scheme π
O O
R — H
X^ R>
Formu
Figure imgf000038_0001
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 R7, Rs, R9, W, M1, M2, X1, 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.
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.
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.
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.
Scherre m
M1
H — N X1-A — R1 X4 (CH2)S CN R1-A-X1 N-(CH2)- -CN
Formula X
M2 M2
Formula V (a) Formula XI
Figure imgf000039_0001
Formula XTV
Compounds of Formula XIV can be prepared according to Scheme III. Thus, compounds of Formula V(a) can be reacted with compounds of Formula X (wherein X4 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 X3 is a leaving group) to form compounds of Formula XIV (wherein Y, Mi, M2, 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. 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.
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. 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. 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. 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.
Scheme IV
Figure imgf000040_0001
Figure imgf000040_0002
Formula XVII
Figure imgf000040_0003
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 X2 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 X3, 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.
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.
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.
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. In the above schemes, where the base, solvents, etc., are indicated, other bases, solvents, etc., known to those skilled in the art may be used. Similarly, reaction temperatures and durations may be adjusted accordingly.
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),
Methyl { 4- [3-(4-oxo- 1 ,2, 3-benzotriazin-3 (4H)-yl)propyl] piperazin- 1 -yl } (phenyl)acetate (Compound No. 3) and its hydrochloride salt (Compound No. 4),
3-(3-{4-[2-(cyclopentyloxy) phenyl]piperazin-l-yl}propyl)-l,2,3-benzotriazin-4(3H)-one (Compound No. 5) and its hydrochloride salt (Compound No. 6),
3- { 3 - [4-(5-fluoro-2-isopropoxy phenyl)piperazin- 1 -yl] -2-methyl propyl } - 1 ,2,3 - benzotriazin-4(3H)-one (Compound No. 7) and its hydrochloride salt (Compound No. 8),
3-(3- { 4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin- 1 -yl } -2-methylpropyl)-l ,2,3- benzotriazin-4(3H)-one (Compound No. 9) and its hydrochloride salt (Compound No. 10), 3-{3-[4-(2-ethoxyphenyl) piperazin- 1-yl] -2-methyl propyl}-l,2,3-benzotriazin-4(3H)-one (Compound No. 11) and its hydrochloride salt (Compound No. 12),
3 - { 2-methyl-3 - [4-(2-propoxy phenyl)piperazin- 1 -yl]propyl } - 1 ,2,3 -benzotriazin-4(3H)-one (Compound No. 13) and its hydrochloride salt (Compound No. 14),
3 -(3- { 4- [2-(cyclopentyloxy) phenyl]piperazin- 1 -yl } -2-methyl propyl)- 1 ,2,3 -benzotriazin-4 (3H)-one (Compound No. 15) and its hydrochloride salt (Compound No. 16),
3-{ 3-[4-(2-isopropoxyphenyl) piperazin- l-yl]-2-methylpropyl} -l,2,3-benzotriazin-4(3H)- one (Compound No. 17) and its hydrochloride salt (Compound No. 18),
3 - [3 -(3 ,4-dihydroisoquinolin-2( IH) -yl)propyl] -1,2,3 -benzotriazin-4(3H) -one (Compound No. 19) and its hydrochloride salt (Compound No. 20), 3 - { 5- [4-(2-methoxyphenyl) piperazin- 1 -yljpentyl } - 1 ,2,3 -benzotriazin-4(3H)-one (Compound No. 21) and its hydrochloride salt (Compound No. 22),
3 - { 5- [4-(2-ethoxyphenyl) piperazin- 1 -yljpentyl } - 1 ,2,3 -benzotriazin-4(3H)-one (Compound No. 23) and its hydrochloride salt (Compound No. 24),
3 - { 5- [4-(2-propoxyphenyl) piperazin- 1 -yljpentyl } - 1 ,2,3-benzotriazin-4(3H)-one (Compound No. 25) and its hydrochloride salt (Compound No. 26),
3 - { 5- [4-(2-isopropoxyphenyl) piperazin- 1 -yljpentyl } - 1 ,2,3-benzotriazin-4(3H)-one (Compound No. 27) and its hydrochloride salt (Compound No. 28), 3 - { 5- [4-(5-fluoro-2-isopropoxy phenyl)piperazin- 1 -yl]pentyl } - 1 ,2,3 -benzotriazin-4(3H)- one (Compound No. 29) and its hydrochloride salt (Compound No. 30), 3-(5- { 4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin- 1 -yl } pentyl)- 1,2,3-benzotriazin- 4(3H)-one (Compound No. 31) and its hydrochloride salt (Compound No. 32),
3 - { 5- [4-(5-fluoro-2-methoxy phenyl)piperazin- 1 -yl]pentyl } - 1 ,2,3 -benzotriazin-4(3H)-one (Compound No. 33) and its hydrochloride salt (Compound No. 34),
3 - { 5- [3 -(2-methoxyphenyl) imidazolidin- 1 -yl] pentyl } - 1 ,2,3-benzotriazin-4(3H)-one (Compound No. 35) and its hydrochloride salt (Compound No. 36),
3- [5-(6,7-dimethoxy-3 ,4-dihydro isoquinolin-2( lH)-yl)pentyl] - 1 ,2,3 -benzotriazin-4(3H)- one (Compound No. 37) and its hydrochloride salt (Compound No. 38),
3-(3-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-yl} propyl)-l,2,3-benzotriazin- 4(3H)-one (Compound No. 39) and its hydrochloride salt (Compound No. 40), 3 -(3- { 4- [5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin- 1 -yl jpropyl)- 1 ,2,3 - benzotriazin-4(3H)-one (Compound No. 41) and its hydrochloride salt (Compound No. 42),
3-(5- { 4- [5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin- 1 -yl Jpentyl)- 1 ,2,3- benzotriazin-4(3H)-one (Compound No. 43) and its hydrochloride salt (Compound No. 44),
3 - { 5- [4-(5-fluoro-2-propoxyphenyl) piperazin- 1 -yl]pentyl } - 1 ,2,3 -benzotriazin-4(3H)-one (Compound No. 45) and its hydrochloride salt (Compound No. 46),
3 - { 5- [4-(2-ethoxy-5-fluorophenyl)piperazin- 1 -yl]pentyl } - 1 ,2,3 -benzotriazin-4(3H)-one (Compound No. 47) and its hydrochloride salt (Compound No. 48),
3-[5-(3,4-dihydroisoquinolin-2(lH)-yl)pentyl]-l,2,3-benzotriazin-4(3H)-one (Compound No. 49) and its hydrochloride salt (Compound No. 50),
3-{3-[8-hydroxy-8-(2-methoxy pheny^-S-azabicycloP^.ljoct-S-yllpropylJ-l^S- benzotriazin-4(3H)-one (Compound No. 51) and its hydrochloride salt (Compound No. 52),
N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3-azabicyclo[3.1.0]hex-6- yljacetamide (Compound No. 53) and its hydrochloride salt (Compound No. 54),
N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3-azabicyclo[3.1.0]hex-6- yljbenzamide (Compound No. 55) and its hydrochloride salt (Compound No. 56), N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3-azabicyclo[3.1.0]hex-6-yl} tetrahydro- furan-2-carboxamide (Compound No. 57) and its hydrochloride salt (Compound No. 58), 3 - { 3 - [4-(5 -fluoro-2-isopropoxy phenyl)piperazin- 1 -yl] -2-hydroxypropy 1 } - 1 ,2, 3 - benzotriazin-4(3H)-one (Compound No. 59) and its hydrochloride salt (Compound No. 60),
3 -(3- { 4- [2-(cyclopentyloxy) phenyl]piperazin- 1 -yl } -2-hydroxypropyl)- 1 ,2,3 -benzotriazin- 4(3H)-one (Compound No. 61) and its hydrochloride salt (Compound No. 62),
3 - { 2-hydroxy-3 - [4-(2-propoxy phenyl)piperazin- 1 -yl]propyl } - 1 ,2,3 -benzotriazin-4(3H)- one (Compound No. 63) and its hydrochloride salt (Compound No. 64), 3- { 2-hydroxy-3 - [4-(2-methoxy phenyl)piperazin- 1 -yl]propyl } - 1 ,2,3 -benzotriazin-4(3H)- one (Compound No. 65) and its hydrochloride salt (Compound No. 66),
3 - { 2-hydroxy-3 - [4-(2-isopropoxyphenyl)piperazin- 1 -yl]propyl } - 1 ,2,3 -benzotriazin-4(3H)- one (Compound No. 67) and its hydrochloride salt (Compound No. 68),
3 - { 2-hydroxy-3 - [4-(2-methoxy phenyl)piperazin- 1 -yl]propyl } - 1 ,2,3 -benzotriazin-4(3H)- one (Compound No. 69) and its hydrochloride salt (Compound No. 70),
10-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-10H-phenoxazine (Compound No. 71) and its hydrochloride salt (Compound No. 72),
10-{3-[4-(2-ethoxyphenyl)piperazin-l-yl]propyl}-10H-phenoxazine (Compound No. 73) and its hydrochloride salt (Compound No. 74), 10-{3-[4-(2-propoxyphenyl)piperazin-l-yl]propyl}-10H-phenoxazine (Compound No. 75) and its hydrochloride salt (Compound No. 76),
10-{3-[4-(2-isopropoxy phenyl) piperazin-l-yl]propyl}-10H-phenoxazine (Compound No. 77) and its hydrochloride salt (Compound No. 78),
10- { 3 - [4-(2-fluoro-6-methoxy phenyl) piperazin- 1 -yl]propyl } - 10H-phenoxazine (Compound No. 79) and its hydrochloride salt (Compound No. 80),
10- { 3 - [4-(2-fluoro-6-isopropoxy phenyl)piperazin- 1 -yl]propyl } - 10H-phenoxazine (Compound No. 81) and its hydrochloride salt (Compound No. 82),
10-(3 - { 4-[2-(cyclopentyloxy)-6-fluoro phenyl]piperazin- 1 -yl } propyl)- 10H-phenoxazine (Compound No. 83) and its hydrochloride salt (Compound No. 84), 10-{3-[3-(2-methoxyphenyl) imidazolidin-l-yl]propyl}-10H-phenoxazine (Compound No. 85) and its hydrochloride salt (Compound No. 86), 10-{3-[4-(2-ethoxyphenyl)piperazin-l-yl]propyl}-10H-phenothiazine (Compound No. 87) and its hydrochloride salt (Compound No. 88),
10-{3-[4-(2-isopropoxy phenyl) piperazin-l-yl]propyl}-10H-phenothiazine (Compound No. 89) and its hydrochloride salt (Compound No. 90),
10- { 3 - [4-(2-methoxyphenyl)piperazin- 1 -yl]propyl } - 10H-phenothiazine (Compound No. 91) and its hydrochloride salt (Compound No. 92), 8-(2-methoxyphenyl)-3-[3-(10H-phenothiazin-10-yl)propyl]-3-azabicyclo [3.2.1]octan-8- ol (Compound No. 93) and its hydrochloride salt (Compound No. 94),
10-(3 - { 4- [2-(cy clopentyloxy)phenyl] piperazin- 1 -yl } propyl) - 1 OH-phenothiazine (Compound No. 95) and its hydrochloride salt (Compound No. 96),
N- { 3- [4-(2-methoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenothiazine- 10-carbox amide (Compound No. 97) and its hydrochloride salt (Compound No. 98),
10- { 3 - [4-(2-propoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenothiazine (Compound No. 99) and its hydrochloride salt (Compound No. 100),
10-(3 - { 4-[2-(cyclopentyloxy)-5-fluoro phenyl]piperazin- 1 -yl } propyl)- 1 OH-phenothiazine (Compound No. 101) and its hydrochloride salt (Compound No. 102),
10- { 3 - [4-(5-fluoro-2-isopropoxyphenyl) piperazin- 1 -yl]propyl } - 1 OH-phenothiazine (Compound No. 103) and its hydrochloride salt (Compound No. 104),
N- { 3 - [4-(2-methoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenoxazine- 10-carboxamide (Compound No. 105) and its hydrochloride salt (Compound No. 106), N-[2-(2-methoxyphenoxy)ethyl]-10H-phenoxazine-10-carboxamide (Compound No. 107) and its hydrochloride salt (Compound No. 108),
10-(3-{4-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-l-yl}propyl)-10H- phenoxazine (Compound No. 109) and its hydrochloride salt (Compound No. 110),
10- { 3 - [3-(2-ethoxyphenyl)imidazolidin- 1 -yl]propyl } - 1 OH-phenothiazine (Compound No. Il l) and its hydrochloride salt (Compound No. 112),
10-{3-[4-(5-fluoro-2-propoxyphenyl)piperazin-l-yl]propyl}-10H-phenoxazine (Compound No. 113) and its hydrochloride salt (Compound No. 114), l-[4-(5-fluoro-2-methoxyphenyl) piperazin-l-yl]-3-(10H-phenoxazin-10-yl)propan-2-ol (Compound No. 115) and its hydrochloride salt (Compound No. 116), pharmaceutically acceptable salts, esters, enantiomers, diastereomers, N-oxides, prodrugs, metabolites, polymorphs or pharmaceutically acceptable solvates thereof. Compounds described herein may be administered with or without an excipient. The present invention also provides 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.
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. 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.
For liquid form preparations, 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. Among the acceptable vehicles and solvents that may be employed 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.
Pharmaceutical preparations 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. Examples General Procedure Preparation of a compound of Formula V a) Preparation of 8-(2-methoxyphenyl)-3-azabicyclo[3.2.1]octan-8-ol Step 1: Preparation of 3-benzyl-8-(2-methoxyphenyl)-3-azabicvclor3.2.11octan-8-ol
A solution of 2-methoxy phenyl magnesium bromide (1.3 equiv.) in tetrahydrofuran was added to a solution of 3-benzyl-3-azabicyclo[3.2.1]octan-8-one (1.0 equiv.) in tetrahydrofuran at about 25-300C under nitrogen atmosphere. The reaction mixture was stirred for about 12 hours at the same temperature and quenched by addition of saturated ammonium chloride solution. The tetrahydrofuran layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was concentrated to form 3-benzyl-8-(2-methoxyphenyl)-3-azabicyclo[3.2.1]octan-8-ol. Yield: 76%
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 25-300C 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 phenylφiperazin- 1 -yl)acetate
A solution of methyl ester of (S)-phenyl glycine (1.0 equiv.), bis-(2-chloroethyl) amine hydrochloride (2.0 equiv.) and triethylamine (3.0 equiv.) in n-butanol was heated at about 120-1300C for about 16 hours. The reaction mixture was concentrated under vacuum. The residue was basified with 10% sodium hydroxide solution and extracted with dichloromethane. The dichloromethane layer was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography using methanol and dichloromethane mixture as eluent to form Methyl phenyl(piperazin-l- yl)acetate. Yield: 43% c) Preparation of l-(2-methoxyphenyl)imidazolidine Step 1: Preparation of N-(2-methoxyphenyl)ethane-l,2-diamine
A solution of oanisidine (1.0 equiv.), bromoethyl amine hydrobromide (1.5 equiv.) and potassium carbonate (0.5 equiv.) in water was refluxed for about 24 hours. The reaction mixture was cooled to about 25-300C then basified with 20% sodium hydroxide solution followed by extraction with ethyl acetate. The organic layer was washed with water and brine solution. The organic layer was then dried and concentrated to form a crude product which was purified on silica gel column using mixture of methanol and dichloromethane as eluent. Yield: 25% Step 2: Preparation of l-(2-methoxyphenyl)imidazolidin-2-one
A solution of N-(2-methoxyphenyl)ethane-l,2-diamine (1.0 equiv.) and Ν,Ν'- carbonyldiimidazole (1.5 equiv.) in dry tetrahydrofuran was stirred at about 25-300C for about 24 hours. The reaction mixture was concentrated under vacuum. The residue was diluted with water, extracted with ethyl acetate and the organic layer was washed with water and brine solution. The organic layer was then dried and concentrated to form a crude product, which was purified by silica gel column chromatography using ethyl acetate in hexane as solvent to yield the title compound. Yield: 75%.
Step 3: Preparation of l-(2-methoxyphenyl)imidazolidine
Borane-dimethylsulfide complex (2.0 equiv.) was added dropwise to a solution of l-(2-methoxyphenyl)imidazolidin-2-one (1.0 equiv.) in toluene at about -200C under nitrogen and the reaction mixture was refluxed for about 18 hours. The reaction mixture was cooled to about -200C and 10% sodium bicarbonate solution was added dropwise. The reaction mixture was refluxed for about 2 hours. The reaction mixture was cooled and the organic layer was then separated. Aqueous layer was extracted with ethyl acetate. The organic layer was concentrated to form l-(2-methoxyphenyl)imidazolidine. Yield: 90%.
The following compound was prepared similarly: 1 -(2-ethoxyphenyl)imidazolidine d) Preparation of N-3-azabicyclo[3.1.0]hex-6-ylacetamide N-S-benzylazabicycloP.l.OJhex-ό-ylacetamide (1.0 equiv.) was taken in methanol, palladium-carbon (10% dry, 1 equiv.) was added to it and the reaction was subjected to hydrogenation in the Parr apparatus under about 50 psi pressure for about 6 hours. The reaction mixture was then filtered through a bed of celite and the bed washed well with methanol. The filtrate was concentrated to form N-3-azabicyclo[3.1.0]hex-6-ylacetamide as a reddish brown oil. e) Preparation of N-S-azabicycloP.l.OJhex-o-yltetrahydrofuran^-carboxamide
N-S-azabicycloP.l.OJhex-ό-ylacetamide was taken in a mixture of ethanol and 5Ν 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.
The following compound was prepared similarly: N-3-azabicyclo[3.1.0]hex-6-ylbenzamide f) Preparation of l-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl] Diperazines
Trifluoroethanol (1 equiv.) was taken in dichloromethane, cooled to about 5-100C 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. To a suspension of sodium hydride (1 equiv.) in hexamethylphosphoric triamide, cooled to about 00C, 4-fluoro-2-nitro phenol was added portionwise and the reaction mixture was stirred for about 30 minutes. The above product (1.2 equiv.) was then added portionwise, the reaction mixture was allowed to come to room temperature and then heated at about 140 0C for about 24 hours. The reaction mixture was cooled, poured into chilled water and extracted with ethyl acetate to form a product in 38 % yield. The above product was dissolved in methanol, 10 % dry palladium-carbon was added and hydrogenated in Parr apparatus under about 50-60 psi pressure. The reaction mixture was filtered through a bed of celite, the bed washed well with methanol, filtrate concentrated to afford the product in 94 % yield. Equimolar quantities of the above compound and Bis-(2- chloroethyl)amine hydrochloride were heated in a mixture of 1,2-dichlorobenzene and n- hexanol (10: 1) for about 42 hours at about 1600C. The reaction mixture was cooled to about 400C poured into hexane, filtered to form l-[5-fluoro-2-(2,2,2- trifluoroethoxy)pheny I] D iperazines. Yield: 85 %
The following compounds were prepared similarly: l-[2-(cyclopentyloxy)pheny I] D iperazines, l-[2-(cyclopentyloxy)-5- fluorophenyl] Diperazines, l-(5-fluoro-2-isopropoxyphenyl)Diperazines, l-(2- isopropoxyphenyl) Diperazines, 1 -(2 -ethoxypheny 1) □ iperazines, l-(2- propoxyphenyl) Diperazines, l-(2-methoxyphenyl) Diperazines, l-(5-fluoro-2- methoxyphenyl) Diperazines, l-(5-fluoro-2-propoxyphenyl) □ iperazines, l-(2-ethoxy-5- fluorophenyl)D iperazines, l-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl] □ iperazines, l-(2- fluoro-6-isopropoxyphenyl) D iperazines, 1 -(2-fluoro-6-methoxyphenyl) D iperazines
The following examples illustrate the invention but do not limit it any way. Example 1:
Preparation of 3-{3-r4-hydroxy-4-(2-methoxy phenyl)piperidin-l-yllpropyl|-l,2,3- benzotriazin-4(3H)-one hydrochloride salt (Compound No. 2)
Step 1: Preparation of 3-(3-bromopropyl)-l,2,3-benzotriazin-4(3H)-one
A solution of 1, 2, 3-benzotriazin-4(3H)-one (commercially available, 1.0 equiv.), 1,3-dibromopropane (commercially available, 6.0 equiv.) and potassium carbonate (2.0 equiv.) in acetone was stirred at about 25-300C for about 24 hours. The solvent was removed under vacuum and the residue was taken in water. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with water. The aqueous layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified on silica gel column using mixture of ethyl acetate and hexane as eluent to form 3-(3-bromopropyl)-l,2,3-benzotriazin-4(3H)-one. Yield: 70%. Step 2: Preparation of 3-{3-[4-hydroxy-4-(2-methoxy phenyl) piperidin-l-yl]propyl}- l,2,3-benzotriazin-4(3H)-one
A solution of 3-(3-bromopropyl)-l, 2, 3-benzotriazin-4(3H)-one (1.0 equiv.), 4-(2- methoxyphenyl)piperidin-4-ol (prepared as described in Chem. Pharm. Bull. 48(12), 1978, (2000) 1.2 equiv.), potassium carbonate (3.0 equiv.) and potassium iodide (10 mole %) in methyl ethyl ketone was refluxed for about 12 hours. 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 concentrated. The residue was purified by silica gel column chromatography using mixture of methanol and dichloromethane as eluent.
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
An equimolar quantity of isopropanol and hydrochloric acid was added to 3-{3-[4- hydroxy-4-(2-methoxy phenyl) piperidin-l-yl]propyl}-l,2,3-benzotriazin-4(3H)-one. A solid precipitated and was then filtered. Mass (m/z): 395 (M++l); IR (cm 1): 1672.5.
The following compounds were prepared similarly.
Compound No. 4: Methyl{4-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl] piperazin-1- yl} (phenyl)acetate hydrochloride salt, Mass (m/z): 422 (M++l); IR (cm 1): 1742, 1684, hygroscopic;
Compound No. 6: 3-(3-{4-[2-(cyclopentyloxy) phenyl]piperazin-l-yl}propyl)-l,2,3- benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 434 (M++l); IR (cm 1): 1685, hygroscopic; Compound No. 8: 3-{3-[4-(5-fluoro-2-isopropoxy phenyl)piperazin-l-yl]-2-methyl propyl }-l, 2,3 -benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 440 (M++l), hygroscopic;
Compound No. 10: 3-(3-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-yl}-2- methylpropyl)-l,2,3-benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 466 (M++l), hygroscopic;
Compound No. 12: 3-{3-[4-(2-ethoxyphenyl) piperazin-l-yl]-2-methyl propyl}-l,2,3- benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 408 (M++l); IR (cm 1): 1636, hygroscopic; Compound No. 14: 3-{2-methyl-3-[4-(2-propoxy phenyl)piperazin-l-yl]propyl}- 1,2,3- benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 422 (M++l); IR (cm 1): 2933, 1684, hygroscopic; Compound No. 16: 3-(3-{4-[2-(cyclopentyloxy) phenyl]piperazin-l-yl}-2-methyl propyl)- l,2,3-benzotriazin-4 (3H)-one hydrochloride salt, Mass (m/z): 448 (M++l); IR (cm 1): 1686, hygroscopic;
Compound No. 18: 3-{3-[4-(2-isopropoxyphenyl) piperazin-l-yl]-2-methylpropyl} -1,2,3- benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 422 (M++l); IR (cm 1): 1685, hygroscopic;
Compound No. 20: 3-[3-(3,4-dihydroisoquinolin-2(lH)-yl)propyl]-l,2,3-benzotriazin- 4(3H)-one hydrochloride salt, Mass (m/z): 321 (M++l), hygroscopic;
Compound No. 22: 3-{5-[4-(2-methoxyphenyl) piperazin-l-yl]pentyl}-l,2,3-benzotriazin- 4(3H)-one hydrochloride salt, Mass (m/z): 408 (M++l); IR (cm 1): 1683, hygroscopic;
Compound No. 24: 3-{5-[4-(2-ethoxyphenyl) piperazin-l-yl]pentyl} -1,2,3 -benzotriazin- 4(3H)-one hydrochloride salt, Mass (m/z): 422 (M++l); IR (cm 1): 1685, hygroscopic;
Compound No. 26: 3-{5-[4-(2-propoxyphenyl) piperazin-l-yl]pentyl}-l,2,3-benzotriazin- 4(3H)-one hydrochloride salt, Mass (m/z): 436 (M++l); IR (cm 1): 1685, hygroscopic; Compound No. 28: 3-{5-[4-(2-isopropoxyphenyl) piperazin-l-yl]pentyl}-l,2,3- benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 436 (M++l), hygroscopic;
Compound No. 30: 3-{5-[4-(5-fluoro-2-isopropoxy phenyl)piperazin-l-yl]pentyl}-l,2,3- benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 454 (M++l); IR (cm 1): 1687, hygroscopic;
Compound No. 32: 3-(5-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-yl} pentyl)- l,2,3-benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 480 (M++l), hygroscopic;
Compound No. 34: 3-{5-[4-(5-fluoro-2-methoxy phenyl)piperazin-l-yl]pentyl}-l,2,3- benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 426 (M++l), hygroscopic;
Compound No. 36: 3-{5-[3-(2-methoxyphenyl) imidazolidin-l-yl]pentyl}-l,2,3- benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 396 (M++2); IR (cm 1): 1685, hygroscopic;
Compound No. 38: 3-[5-(6,7-dimethoxy-3,4-dihydro isoquinolin-2(lH)-yl)penty I]- 1,2,3 - benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 409 (M++l) ; IR (cm 1): 1681, hygroscopic; Compound No. 40: 3-(3-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-yl} prqpyl)- 1l,,22,,33 --bbeennzzoottririaazziinn--44(3H)-one hydrochloride salt, Mass (m/z): 452 (M++l) ; IR (cm 1): 1684, hygroscopic; Compound No. 42: 3-(3-{4-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-l- yl}propyl)-l,2,3-benzotriazin-4(3H)-one hydrochloride salt, Mass: m/z 466 (M++l), hygroscopic; Compound No. 44: 3-(5-{4-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-l- yl}pentyl)-l,2,3-benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 494.2 (M++l), M.P: 137-1380C;
Compound No. 46: 3-{5-[4-(5-fluoro-2-propoxyphenyl)piperazin-l-yl]pentyl}-l,2,3- benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 454.3 (M++l), M.P: 122°-123°C;
Compound No. 48: 3-{5-[4-(2-ethoxy-5-fluorophenyl)piperazin-l-yl]pentyl}-l,2,3- benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 440.3 (M++l), M.P: 161-1620C; Compound No. 50: 3-[5-(3,4-dihydroisoquinolin-2(lH)-yl)pentyl]-l,2,3-benzotriazin- 4(3H)-one hydrochloride salt, Mass (m/z): 349.3 (M++l), M.P: 134-1350C;
Compound No. 52: 3-{3-[8-hydroxy-8-(2-methoxy phenyl)-3-azabicyclo[3.2.1]oct-3- yl]propyl}-l,2,3-benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 421 (M++l) ; IR (cm 1): 1678, hygroscopic;
Compound No. 54: N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3- azabicyclo[3.1.0] hex-6-yl} acetamide hydrochloride salt, Mass (m/z): 328 (M++l) ; IR (cm 1): 1680, hygroscopic;
Compound No. 56: N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3- azabicyclo[3.1.0] hex-6-yl} benzamide hydrochloride salt, Mass (m/z): 408 (M+-I-NH4 +); IR (cm 1): 1685, hygroscopic; Compound No. 58: N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3- azabicyclo[3.1.0]hex-6-yl} tetrahydrofuran-2-carboxamide hydrochloride salt, Mass (m/z): 384 (M++l) ; IR (cm 1): 1690, 1647, hygroscopic;
Example 2: Preparation of 3-{3-r4-(5-fluoro-2-isopropoxy phenyl )piperazin-l-yll -2-hydroxypropyl }- l,2,3-benzotriazin-4(3H)-one hydrochloride salt (Compound No. 60)
Step 1: Preparation of 3-(oxiran-2-ylmethyl)-l,2,3-benzotriazin-4(3H)-one
A solution of l,2,3-benzotriazin-4(3H)-one (commercially available, 1.0 equiv.), 2- chloromethyl-oxirane (4.0 equiv.) and potassium carbonate (4.0 equiv.) in methyl ethyl ketone was refluxed for about 16 hours. The reaction mixture was concentrated under vacuum; the residue was taken in water and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography using mixture of ethyl acetate and hexane as eluent to form 3- (oxiran-2-ylmethyl)-l,2,3-benzotriazin-4(3H)-one. Yield: 75%
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-
(5-fluoro-2-isopropoxyphenyl)piperazine (commercially available, 1.0 equiv.) and triethylamine (1.5 equiv.) in ethanol was refluxed for about 16 hours. The reaction mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography using mixture of methanol and dichloromethane as eluent to form 3-{3- [4-(5-fluoro-2-isopropoxyphenyl)piperazin- 1 -yl] -2-hydroxypropyl } - 1 ,2,3 -benzotriazin- 4(3H)-one. Yield: 95%
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
An equimolar quantity of isopropyl alcohol and hydrochloric acid was added to 3- {3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]-2-hydroxypropyl}-l,2,3-benzotriazin- 4(3H)-one.
A solid precipitated and was then filtered. Mass (m/z): 442 (M++l) ; IR (cm 1): 2924, 1679, hygroscopic.
The following compounds were prepared similarly, Compound No. 62: 3-(3-{4-[2-(cyclopentyloxy) phenyl]piperazin-l-yl}-2- hydroxypropyl)-l,2,3-benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 450 (M++ 1) ; IR (cm 1): 2362, 1662, hygroscopic;
Compound No. 64: 3-{2-hydroxy-3-[4-(2-propoxy phenyl)piperazin-l-yl]propyl}-l,2,3- benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 424 (M++l) ; IR (cm 1): 2924, 2684, hygroscopic;
Compound No. 66: 3-{2-hydroxy-3-[4-(2-methoxy phenyl)piperazin-l-yl]propyl}-l,2,3- benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 410 (M++l) ; IR (cm ): 2924, 1666, hygroscopic;
Compound No. 68: 3-{2-hydroxy-3-[4-(2-isopropoxyphenyl)piperazin-l-yl]propyl}-l,2,3- benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 424 (M++l) ; IR (cm 1): 2925, 1678, hygroscopic; Compound No. 70: 3-{2-hydroxy-3-[4-(2-methoxy phenyl)piperazin-l-yl]propyl}-l,2,3- benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 396 (M++l) ; IR (cm 1): 2368, 1675, hygroscopic;
General Procedure Preparation of 10-(3-chloropropyl)-10H-phenoxazine
A dry two-necked 250 ml round bottom flask containing about 75 ml of dry liquid ammonia and fitted with a stirring bar ammonia condenser and calcium chloride guard tube was charged with phenoxazine (3.5g). Initially few sodium pieces were added carefully then Ferric chloride in catalytic amount was added. This was followed by further addition of sodium pieces, after stirring for about 1 hour, bromochloropropane was added drop wise. The reaction mixture was then allowed to come to room temperature slowly overnight. To the residue, water was added and extracted with ether. Ether extract was washed with water, and brine, dried over anhydrous sodium sulfate, concentrated in vacuo to form 10-(3-chloropropyl)-10H-phenoxazine Yield: 4.7g Preparation of 10-(3-chloropropyl)-10H-phenothiazine
In a 100 ml dry round bottom flask fitted with a stirring bar was placed phenothiazine (5.0 g) and dimethylformamide in cold condition, to this was added sodium hydride portionwise, then the reaction mixture was stirred overnight at room temperature. To this l-bromo-3-chloropropane was added drop wise and stirred for about 12 hours at room temperature. The reaction mixture was then quenched with saturated ammonium chloride solution. The solvent was then evaporated under vacuum, the residue was partitioned between water and ethyl acetate. Ethyl acetate extract was washed with brine solution and concentrated under vacuum. The residue was purified by column chromatography. Yield: 2.3 g Example 3:
Preparation of 10-{ 3-r4-(2-methoxyphenyl)piperazin-l-vHpropyl|-10H-phenoxazine hydrochloride salt (Compound No. 72)
Step 1: Preparation of 10-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-10H- phenoxazine A solution of 10-(3-chloropropyl)-10H-phenoxazine (1.0 equiv.), l-(2- ethoxyphenyl)- piperazine (1.2 equiv.), potassium carbonate (3.0 equiv.) and potassium iodide (10 mole %) in methyl ethyl ketone was refluxed for about 12 hours. 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-
{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-10H-phenoxazine. A solid precipitated and was then filtered. Mass (m/z): 416 (M++l) ; IR (cm 1): 3424, 1490; M.P: 220-2250C;
The following compounds were prepared similarly
Compound No. 74: 10-{3-[4-(2-ethoxyphenyl)piperazin-l-yl]propyl}-10H-phenoxazine hydrochloride salt, Mass (m/z): 430 (M++l) ; IR (cm 1): 2411, 1491, hygroscopic;
Compound No. 76: 10-{3-[4-(2-propoxyphenyl)piperazin-l-yl]propyl}-10H-phenoxazine hydrochloride salt, Mass (m/z): 444 (M++l) ; IR (cm 1): 1491, 1270, hygroscopic; Compound No. 78: 10-{3-[4-(2-isopropoxy phenyl) piperazin-l-yl]propyl}-10H- phenoxazine hydrochloride salt, Mass (m/z): 444 (M++l) ; IR (cm 1): 3396, 1491, hygroscopic;
Compound No. 80: 10-{3-[4-(2-fluoro-6-methoxy phenyl) piperazin-l-yl]propyl}-10H- phenoxazine hydrochloride salt, Mass (m/z): 434 (M++l) ; IR (cm 1): 3396, 1491, hygroscopic;
Compound No. 82: 10-{3-[4-(2-fluoro-6-isopropoxy phenyl)piperazin-l-yl]propyl}-10H- phenoxazine hydrochloride salt, Mass (m/z): 462 (M++l) ; IR (cm 1): 3382, 1492, hygroscopic;
Compound No. 84: 10-(3-{4-[2-(cyclopentyloxy)-6-fluoro phenyl]piperazin-l-yl}propyl)-
1 100HH--pphheennooxxaazine hydrochloride salt, Mass (m/z): 488 (M++l) ; IR (cm 1): 2447, 1491, hygroscopic;
Compound No. 86: 10-{3-[3-(2-methoxyphenyl) imidazolidin-l-yl]propyl}-10H- phenoxazine hydrochloride salt, Mass (m/z): 404 (M++ 1), hygroscopic;
Example 4: Preparation of 10-{ 3-r4-(2-ethoxyphenyl)piperazin-l-yllpropyl|-10H-phenothiazine hydrochloride salt (Compound No. 88)
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-
{3-[4-(2-ethoxyphenyl)piperazin-l-yl]propyl}-10H-phenothiazine. A solid precipitated and was then filtered. Mass (m/z): 445 (M++l) ; IR (cm 1): 3421, 1461, M.P: 196-1980C
The following compounds were prepared similarly:
Compound No. 90: 10-{3-[4-(2-isopropoxy phenyl) piperazin-l-yl]propyl}-10H- phenothiazine hydrochloride salt, Mass (m/z): 459 (M++l) ; IR (cm 1): 3422, 1462, hygroscopic;
Compound No. 92: 10-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-10H- phenothiazine hydrochloride salt, Mass (m/z): 432 (M++l) ; IR (cm 1): 3437, 1460, M.P: 190-195 0C;
Compound No. 94: 8-(2-methoxyphenyl)-3-[3-(10H-phenothiazin-10-yl)propyl]-3- azabicyclo [3.2.1]octan-8-ol hydrochloride salt, Mass (m/z): 472 (M++l) ; IR (cm 1): 2934, 1657, M.P:189-190°C;
Compound No. 96: 10-(3-{4-[2-(cyclopentyloxy)phenyl] piperazin-l-yl}propyl)-10H- phenothiazine hydrochloride salt, Mass (m/z): 559 (M++l), M.P: 210-2120C;
Compound No. 100: 10-{3-[4-(2-propoxyphenyl)piperazin-l-yl]propyl}-10H- phenothiazine hydrochloride salt, Mass (m/z): 460 (M++l) ; IR (cm 1): 3439, 1459, M.P: 185-19O0C;
Compound No. 102: 10-(3-{4-[2-(cyclopentyloxy)-5-fluoro phenyl]piperazin-l- yl}propyl)-10H-phenothiazine hydrochloride salt, Mass (m/z): 503 (M++l) ; IR (cm 1): 3445, 1460, hygroscopic;
Compound No. 104: 10-{3-[4-(5-fluoro-2-isopropoxyphenyl) piperazin-l-yl]propyl}-10H- phenothiazine hydrochloride salt, Mass (m/z): 478 (M++l) ; IR (cm 1): 3450, 1459, hygroscopic; Compound No. 110: 10-(3-{4-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-l- yl}propyl)-10H-phenoxazine hydrochloride salt, Mass (m/z): 502 (M++l) ; IR (cm 1): 3413, 2936, M.P: 90-95 0C; Compound No. 112: 10-{3-[3-(2-ethoxyphenyl)imidazolidin-l-yl]propyl}-10H- phenothiazine hydrochloride salt, Mass (m/z): 420 (M++3) ; IR (cm 1): 3399, 2922, M.P: 80-85 0C;
Compound No. 114: 10-{3-[4-(5-fluoro-2-propoxyphenyl)piperazin-l-yl]propyl}-10H- phenoxazine hydrochloride salt, Mass (m/z): 462 (M++l) ; IR (cm 1): 3409, 2935, M.P: 164-165 0C;
Compound No. 116: l-[4-(5-fluoro-2-methoxyphenyl) piperazin-l-yl]-3-(10H- phenoxazin-10-yl)propan-2-ol hydrochloride salt hydrochloride salt, Mass (m/z): 450 (M++l), M.P: 223-225 0C;
Example 5:
Preparation of N- { 3 - r4-(2-methoxyphenyl)piperazin- 1 - yllpropyl I - 1 OH-phenothiazine- 10- carboxamide hydrochloride salt (Compound No. 98)
Step 1 : Preparation of N- { 3- [4-(2-methoxyphenyl)piperazin- 1 -yl]propyl } - 10H- phenothiazine-10-carboxamide
In a dry 10 ml round bottom flask fitted with a stirring bar and guard tube, was placed, 3-[4-(2-methoxyphenyl)piperazin-l-yl]propan-l-amine, dichloromethane, 4- dimethylamino- pyridine and triethylamine, the resulting solution was cooled in an ice cold bath. To it was added 1 OH-phenothiazine- 10-carbonyl chloride in portions. The reaction mixture was then stirred at room temperature for about 18 hours. The reaction mixture was quenched with saturated sodium carbonate solution. The aqueous layer was extracted in dichloromethane. The combined dichloromethane layer was washed with water and saturated brine solution, then was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Step 2: Preparation of N-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-10H- phenothiazine-10-carboxamide hydrochloride salt
An equimolar quantity of isopropyl alcohol and hydrochloric acid was added to N- { 3 -[4-(2-methoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenothiazine- 10-carboxamide A solid precipitated and was then filtered. Mass (m/z): 475 (M++l) ; IR (cm 1): 1674, 2927, M.P: 189.7-190.90C
The following compounds were prepared similarly:
Compound No. 106: N-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-10H- phenoxazine-10-carboxamide hydrochloride salt, Mass (m/z): 458 (M++l) ; IR (cm 1): 1258, 1455, M.P: 204-206 0C;
Compound No. 108: N-[2-(2-methoxyphenoxy)ethyl]-10H-phenoxazine-10-carboxamide hydrochloride salt, Mass (m/z): 376 (M++l), hygroscopic
Pharmacological testing
Receptor Binding Assay: Receptor binding assays were performed using recombinant cells expressing human alpha-la and alpha-lb adrenoceptors. The affinity of different compounds for αla and ctn, adrenoceptor subtypes was evaluated by studying their ability to displace specific [3H] 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%CO2 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 (3μg/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 -700C until the time of assay.
Competition radioligand binding to the cloned subtypes of (Xi -adrenoceptors was performed using [3H] prazosin as the radioligand \ The membrane homogenates (5-10 μg protein) were incubated in 250 μl of assay buffer (Tris HCl 50 mM, EDTA 5 mM, pH 7.4) at 24-25 0C for 1 hour. Non-specific binding was determined in the presence of lOμMterazosin. 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 IC50 and Kd were estimated by using the non-linear curve -fitting program using Graph pad prism software. The value of inhibition constant Ki was calculated from competitive binding studies by using Cheng and Prusoff equation (Cheng and Prusoff, Biochem Pharmacol, 1973, 22:3099-3108), Ki = IC50 /(1+IVKd) where L is the concentration of [3H] prazosin used in the particular experiment.
Reference: Michel, M. C, Grϋbbel, B., Taguchi, K. et al: Drugs for treatment of benign prostatic hyperplasia: affinity comparison at cloned (Xi-adrenoceptor subtypes and in human prostate. J Auton Pharmacol, 16: 21, 1996
Results: The results of the human recombinant assays of the compounds described herein are as follows: a) The compounds described herein exhibited αla 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.

Claims

We claim: 1. A compound having the structure of the Formula I
R1-A-X1R2R3
Formula I
a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, polymorph, prodrug, stereoisomer, tautomeric form, N-oxide or metabolitesthereof, wherein: Xi is N or CR4; R4 is hydrogen, hydroxyl or alkyl; A is aryl, aryloxy, heterocyclyl, alkyl, alkoxy, cycloalkyl, NHCORio or CHRi0Ri i; Ri0 and Rn are independently alkyl, COO-alkyl, aryl or heterocyclyl; R1, R2 and R3 independently in each occurrence are hydrogen, halogen, C1-3 alkyl, alkoxy, alkyl, nitro, cyano, cycloalkoxy, R6 or S(O)0^R5; R5 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl; R2 and R3 together with Xi to which they are attached also form a ring of the form
M1
M2
which contains one or more additional heteroatom(s) selected from O, S or N; Mi and M2 are independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl, alkoxy or acyl; or Ml and M2 together form a bridging group (Co_3); W is N, CH or COH; Re is
Figure imgf000063_0001
Y is O, S, NR4, C=O or a bond; R7, R8 and Rg are independently hydrogen, hydroxyl, amino, S(0)o- 2Rs or NHSO2R5; L is a linker; and • is a point of attachment. 2. A compound selected from: 3- { 3 -[4-hydroxy-4-(2-methoxy phenyl)piperidin- 1 -yl]propyl } - 1 ,2,3 -benzotriazin- 4(3H)- one, Methyl {4-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl] piperazin-1- yl } (phenyl)acetate, 3-(3-{4-[2-(cyclopentyloxy) phenyl]piperazin-l-yl}propyl)-l,2,3-benzotriazin- 4(3H)-one, 3-{3-[4-(5-fluoro-2-isopropoxy phenyl)piperazin-l-yl]-2-methyl propyl}-l,2,3- benzotriazin-4(3H)-one, 3-(3 - { 4- [2-(cyclopentyloxy)-5-fluorophenyl]piperazin- 1 -yl } -2-methylpropyl)- 1,2,3- benzotriazin-4(3H)-one, 3-{3-[4-(2-ethoxyphenyl) piperazin-l-yl]-2-methyl propyl} -1,2,3 -benzotriazin- 4(3H)- one, 3-{2-methyl-3-[4-(2-propoxy phenyl)piperazin-l-yl]propyl}-l,2,3-benzotriazin- 4(3H)- one, 3-(3-{4-[2-(cyclopentyloxy) phenyl]piperazin-l-yl}-2-methyl propyl)-l,2,3- benzotriazin-4 (3H)-one, 3-{3-[4-(2-isopropoxyphenyl) piperazin-l-yl]-2-methylpropyl} -1,2,3- benzotriazin- 4(3H)-one, 3- [3-(3 ,4-dihydroisoquinolin-2( lH)-yl)propyl] - 1 ,2,3 -benzotriazin-4(3H)-one, 3- { 5-[4-(2-methoxyphenyl) piperazin-1 -yl]pentyl }- 1 ,2,3-benzotriazin-4(3H)-one, 3- { 5-[4-(2-ethoxyphenyl) piperazin-1 -yl]pentyl } -1 ,2,3-benzotriazin-4(3H)-one, 3- { 5-[4-(2-propoxyphenyl) piperazin- l-yl]pentyl } -1 ,2,3-benzotriazin-4(3H)-one, 3- { 5-[4-(2-isopropoxyphenyl) piperazin- l-yl]pentyl } - l,2,3-benzotriazin-4(3H)- one, 3- { 5-[4-(5-fluoro-2-isopropoxy phenyl)piperazin- l-yl]pentyl }- 1 ,2,3-benzotriazin- 4(3H)- one, 3-(5-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-yl} pentyl)-l,2,3- benzotriazin- 4(3H)-one, 3-{5-[4-(5-fluoro-2-methoxy phenyl)piperazin-l-yl]pentyl}-l,2,3-benzotriazin- 4(3H)- one, 3 - { 5 - [3 -(2-methoxyphenyl) imidazolidin- 1 -y l]pentyl } - 1 ,2, 3 -benzotriazin-4(3H) - one, 3-[5-(6,7-dimethoxy-3,4-dihydro isoquinolin-2(lH)-yl)pentyl]-l,2,3-benzotriazin- 4(3H)- one, 3-(3-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-yl} propyl)-l,2,3- benzotriazin- 4(3H)-one, 3-(3-{4-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-l-yl}propyl)-l,2,3- benzotriazin-4(3H)-one, 3-(5-{4-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-l-yl}pentyl)-l,2,3- benzotriazin-4(3H)-one, 3- { 5-[4-(5-fluoro-2-propoxyphenyl)piperazin- 1 -yl]pentyl } -1 ,2,3-benzotriazin- 4(3H)-one, 3 - { 5 - [4-(2-ethoxy-5 -fluorophenyl)piperazin- 1 -yl]pentyl } - 1 ,2, 3 -benzotriazin- 4(3H)-one, 3- [5-(3 ,4-dihydroisoquinolin-2( lH)-yl)pentyl] - 1 ,2,3 -benzotriazin-4(3H)-one, 3-{3-[8-hydroxy-8-(2-methoxy pheny^-S-azabicyclotS^.lJoct-S-ylJpropylJ-l^^- benzotriazin-4(3H)-one, N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3-azabicyclo[3.1.0]hex-6- yljacetamide, 78 N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3-azabicyclo[3.1.0]hex-6-
79 yljbenzamide, 80
81 N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3-azabicyclo[3.1.0]hex-6-yl}
82 tetrahydrofuran-2-carboxamide, 83
84 3 - { 3 - [4-(5-fluoro-2-isopropoxy phenyl)piperazin- 1 -yl] -2-hydroxypropyl } - 1 ,2, 3 -
85 benzotriazin-4(3H)-one, 86
87 3-(3 - { 4- [2-(cyclopentyloxy) phenyl]piperazin- 1 -yl } -2-hydroxypropyl)- 1 ,2,3 -
88 benzotriazin-4(3H)-one, 89
90 3- { 2-hydroxy-3-[4-(2-propoxy phenyl)piperazin- l-yl]propyl }- 1 ,2,3-benzotriazin-
91 4(3H)- one, 92
93 3- { 2-hydroxy-3-[4-(2-methoxy phenyl)piperazin-l -yl]propyl }- 1 ,2,3-benzotriazin-
94 4(3H)- one, 95
96 3- { 2-hydroxy-3 -[4-(2-isopropoxyphenyl)piperazin- 1 -yl]propyl } - 1 ,2,3 -
97 benzotriazin- 4(3H)-one, 98
99 3- { 2-hydroxy-3-[4-(2-methoxy phenyl)piperazin-l -yl]propyl }- 1 ,2,3-benzotriazin-
100 4(3H)- one, 101
102 10-{ 3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-10H-phenoxazine,
103
104 10-{ 3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-10H-phenoxazine,
105
106 10- { 3- [4-(2-propoxyphenyl)piperazin- 1 -yl]propyl } - 10H-phenoxazine,
107
108 10-{ 3-[4-(2-isopropoxy phenyl) piperazin-l-yl]propyl}-10H-phenoxazine,
109
110 10-{3-[4-(2-fluoro-6-methoxy phenyl) piperazin-l-yl]propyl}-10H-phenoxazine,
111
112 10-{3-[4-(2-fluoro-6-isopropoxy phenyl)piperazin-l-yl]propyl}-10H-phenoxazine,
113
114 10-(3-{4-[2-(cyclopentyloxy)-6-fluoro phenyl]piperazin-l-yl}propyl)-10H-
115 phenoxazine, 116
117 10-{ 3-[3-(2-methoxyphenyl) imidazolidin-l-yl]propyl}-10H-phenoxazine,
118
119 10- { 3- [4-(2-ethoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenothiazine,
120
121 10-{3-[4-(2-isopropoxy phenyl) piperazin-l-yl]propyl}-10H-phenothiazine,
122
123 10-{ 3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-10H-phenothiazine,
124
125 8-(2-methoxyphenyl)-3- [3-( 1 OH-phenothiazin- 10-yl)propyl] -3 -azabicyclo
126 [3.2.1]octan- 8-ol,
127 128 10-(3-{4-[2-(cyclopentyloxy)phenyl] piperazin-1-yl} propyl) -10H-phenothiazine, 129
130 N- { 3 -[4-(2-methoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenothiazine- 10-carbox
131 amide,
132
133 10- { 3- [4-(2-propoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenothiazine,
134
135 10-(3 - { 4-[2-(cyclopentyloxy)-5-fluoro phenyl]piperazin- 1 -yl } propyl)- 1 OH-phenothiazine,
136
137 10-{ 3-[4-(5-fluoro-2-isopropoxyphenyl) piperazin-l-yl]propyl}-10H-
138 phenothiazine, 139
140 N- { 3 -[4-(2-methoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenoxazine- 10-
141 carboxamide,
142
143 N- [2-(2-methoxyphenoxy)ethyl] - 1 OH-phenoxazine- 10-carboxamide,
144
145 10-(3-{4-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-l-yl}propyl)-10H-
146 phenoxazine, 147
148 10-{ 3-[3-(2-ethoxyphenyl)imidazolidin-l-yl]propyl}-10H-phenothiazine,
149
150 10-{ 3-[4-(5-fluoro-2-propoxyphenyl)piperazin-l-yl]propyl}-10H-phenoxazine,
151
152 1 - [4-(5-fluoro-2-methoxyphenyl) piperazin- 1 -yl] -3 -( 10H-phenoxazin-
153 10-yl)propan-2-ol, 154
155 pharmaceutically acceptable salts, pharmaceutically acceptable solvates,
156 polymorphs, prodrugs, stereoisomers, tautomeric forms, Ν-oxides and metabolites
157 thereof.
3. A compound selected from: 3- { 3 -[4-hydroxy-4-(2-methoxy phenyl)piperidin- 1 -yl]propyl } - 1 ,2,3 -benzotriazin- 4(3H)- one hydrochloride salt, Methyl {4-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl] piperazin-1- yl}(phenyl)acetate hydrochloride salt, 3-(3-{4-[2-(cyclopentyloxy) phenyl]piperazin-l-yl}propyl)-l,2,3-benzotriazin- 4(3H)-one hydrochloride salt, 3-{3-[4-(5-fluoro-2-isopropoxy phenyl)piperazin-l-yl]-2-methyl propyl}-l,2,3- benzotriazin-4(3H)-one hydrochloride salt, 3-(3 - { 4- [2-(cyclopentyloxy)-5-fluorophenyl]piperazin- 1 -yl } -2-methylpropyl)- 1,2,3- benzotriazin-4(3H)-one hydrochloride salt, 3-{3-[4-(2-ethoxyphenyl) piperazin-l-yl]-2-methyl propyl} -1,2,3 -benzotriazin- 4(3H)- one hydrochloride salt, 3-{2-methyl-3-[4-(2-propoxy phenyl)piperazin-l-yl]propyl}-l,2,3-benzotriazin- 4(3H)- one hydrochloride salt, 3-(3-{4-[2-(cyclopentyloxy) phenyl]piperazin-l-yl}-2-methyl propyl)-l,2,3- benzotriazin-4 (3H)-one hydrochloride salt, 3-{3-[4-(2-isopropoxyphenyl) piperazin-l-yl]-2-methylpropyl} -1,2,3- benzotriazin- 4(3H)-one hydrochloride salt, 3- [3-(3 ,4-dihydroisoquinolin-2( lH)-yl)propyl] - 1 ,2,3 -benzotriazin-4(3H)-one hydrochloride salt, 3- { 5-[4-(2-methoxyphenyl) piperazin-1 -yljpentyl }- 1 ,2,3-benzotriazin-4(3H)-one hydrochloride salt, 3- { 5-[4-(2-ethoxyphenyl) piperazin- 1 -yljpentyl } -1 ,2,3-benzotriazin-4(3H)- onehydrochloride salt, 3- { 5-[4-(2-propoxyphenyl) piperazin- l-yl]pentyl } -1 ,2,3-benzotriazin-4(3H)- onehydrochloride salt, 3-{5-[4-(2-isopropoxyphenyl) piperazin- l-yl]pentyl}-l, 2,3 -benzotriazin-4(3H)-one hydrochloride salt, 3- { 5-[4-(5-fluoro-2-isopropoxy phenyl)piperazin- l-yl]pentyl }- 1 ,2,3-benzotriazin- 4(3H)- one hydrochloride salt, 3-(5-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-yl} pentyl)-l,2,3- benzotriazin- 4(3H)-one hydrochloride salt, 3-{5-[4-(5-fluoro-2-methoxy phenyl)piperazin-l-yl]pentyl}-l,2,3-benzotriazin- 4(3H)- one hydrochloride salt, 3-{5-[3-(2-methoxyphenyl) imidazolidin-l-yl]pentyl}-l,2,3-benzotriazin-4(3H)- one hydrochloride salt, 3-[5-(6,7-dimethoxy-3,4-dihydro isoquinolin-2(lH)-yl)pentyl]-l,2,3-benzotriazin- 4(3H)- one hydrochloride salt, 3-(3-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-yl} propyl)-l,2,3- benzotriazin-4(3H)-one hydrochloride salt, 3-(3-{4-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-l-yl}propyl)-l,2,3- benzotriazin-4(3H)-one hydrochloride salt, 3-(5-{4-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-l-yl}pentyl)-l,2,3- benzotriazin-4(3H)-one hydrochloride salt, 3- { 5-[4-(5-fluoro-2-propoxyphenyl)piperazin- 1 -yl]pentyl } -1 ,2,3-benzotriazin 4(3H)-one hydrochloride salt, 3 - { 5 - [4-(2-ethoxy-5 -fluorophenyl)piperazin- 1 -yl]pentyl } - 1 ,2, 3 -benzotriazin- 4(3H)-one hydrochloride salt, 3- [5-(3 ,4-dihydroisoquinolin-2( lH)-yl)pentyl] - 1 ,2,3 -benzotriazin-4(3H)-one hydrochloride salt, 3-{3-[8-hydroxy-8-(2-methoxy phenyl)-3-azabicyclo[3.2.1]oct-3-yl]propyl}-l,2,3- benzotriazin-4(3H)-one hydrochloride salt, N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3-azabicyclo[3.1.0]hex-6- yljacetamide hydrochloride salt, N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3-azabicyclo[3.1.0]hex-6- yljbenzamide hydrochloride salt, N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3-azabicyclo[3.1.0]hex-6-yl} tetrahydrofuran-2-carboxamide hydrochloride salt, 3 - { 3 - [4-(5-fluoro-2-isopropoxy phenyl)piperazin- 1 -yl] -2-hydroxypropyl } - 1 ,2, 3 - benzotriazin-4(3H)-one hydrochloride salt, 3-(3 - { 4- [2-(cyclopentyloxy) phenyl]piperazin- 1 -yl } -2-hydroxypropyl)- 1 ,2,3 - benzotriazin-4(3H)-one hydrochloride salt, 95 3- { 2-hydroxy-3-[4-(2-propoxy phenyl)piperazin- l-yl]propyl }- 1 ,2,3-benzotriazin-
96 4(3H)-one hydrochloride salt, 97
98 3- { 2-hydroxy-3-[4-(2-methoxy phenyl)piperazin-l -yl]propyl }- 1 ,2,3-benzotriazin-
99 4(3H)-one hydrochloride salt, 100
101 3- { 2-hydroxy-3 -[4-(2-isopropoxyphenyl)piperazin- 1 -yl]propyl } - 1 ,2,3 -
102 benzotriazin-4(3H)-one hydrochloride salt, 103
104 3- { 2-hydroxy-3-[4-(2-methoxy phenyl)piperazin-l -yl]propyl }- 1 ,2,3-benzotriazin-
105 4(3H)-one hydrochloride salt, 106
107 10-{ 3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-10H-phenoxazine
108 hydrochloride salt, 109
110 10- { 3- [4-(2-ethoxyphenyl)piperazin- 1 -yl]propyl } - 10H-phenoxazine hydrochloride
111 salt,
112
113 10- { 3- [4-(2-propoxyphenyl)piperazin- 1 -yl]propyl } - 10H-phenoxazine
114 hydrochloride salt, 115
116 10-{3-[4-(2-isopropoxy phenyl) piperazin-l-yl]propyl}-10H-phenoxazine
117 hydrochloride salt, 118
119 10-{ 3-[4-(2-fluoro-6-methoxy phenyl) piperazin-l-yl]propyl}-10H-phenoxazine
120 hydrochloride salt, 121
122 10-{ 3-[4-(2-fluoro-6-isopropoxy phenyl)piperazin-l-yl]propyl}-10H-phenoxazine
123 hydrochloride salt, 124
125 10-(3-{4-[2-(cyclopentyloxy)-6-fluoro phenyl]piperazin-l-yl}propyl)-10H-
126 phenoxazine hydrochloride salt, 127
128 10-{ 3-[3-(2-methoxyphenyl) imidazolidin-l-yl]propyl}-10H-phenoxazine
129 hydrochloride salt, 130
131 10- { 3- [4-(2-ethoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenothiazine
132 hydrochloride salt, 133
134 10-{ 3-[4-(2-isopropoxy phenyl) piperazin-l-yl]propyl}-10H-phenothiazine
135 hydrochloride salt, 136
137 10-{ 3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-10H-phenothiazine
138 hydrochloride salt, 139
140 8-(2-methoxyphenyl)-3- [3-( 1 OH-phenothiazin- 10-yl)propyl] -3 -azabicyclo
141 [3.2.1]octan- 8-ol hydrochloride salt, 142
143 10-(3-{4-[2-(cyclopentyloxy)phenyl] piperazin- 1-yl} propyl) -1 OH-
144 phenothiazinehydrochloride salt, 145
146 N- { 3 - [4-(2-methoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenothiazine- 10-carbox
147 amide hydrochloride salt, 148
149 10- { 3- [4-(2-propoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenothiazine
150 hydrochloride salt, 151
152 10-(3-{4-[2-(cyclopentyloxy)-5-fluoro phenyl]piperazin-l-yl}propyl)-10H-
153 phenothiazine hydrochloride salt, 154
155 10-{ 3-[4-(5-fluoro-2-isopropoxyphenyl) piperazin-l-yl]propyl}-10H-
156 phenothiazine hydrochloride salt, 157
158 N- { 3 -[4-(2-methoxyphenyl)piperazin- 1 -yl]propyl } - 1 OH-phenoxazine- 10-
159 carboxamide hydrochloride salt, 160
161 N- [2-(2-methoxyphenoxy)ethyl] - 1 OH-phenoxazine- 10-carboxamide hydrochloride
162 salt, 163
164 10-(3-{4-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-l-yl}propyl)-10H-
165 phenoxazine hydrochloride salt, 166
167 10-{ 3-[3-(2-ethoxyphenyl)imidazolidin-l-yl]propyl}-10H-phenothiazine
168 hydrochloride salt, 169
170 10-{ 3-[4-(5-fluoro-2-propoxyphenyl)piperazin-l-yl]propyl}-10H-phenoxazine
171 hydrochloride salt, 172
173 1 - [4-(5-fluoro-2-methoxyphenyl) piperazin- 1 -yl] -3 -( 10H-phenoxazin- 10-
174 yl)propan-2-ol hydrochloride salt.
1 4. A pharmaceutical composition comprising a therapeutically effective amount of 2 one or more compounds having the structure of the Formula I
R1-A-X1R2R3
Formula I
4 a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,
5 polymorph, prodrug, stereoisomer, tautomeric form, Ν-oxide or metabolite thereof,
6 together with one or more pharmaceutically acceptable carriers, excipients or
7 diluents, wherein:
8 Xi is Ν or CR4; R4 is hydrogen, hydroxyl or alkyl;
A is aryl, aryloxy, heterocyclyl, alkyl, alkoxy, cycloalkyl, NHCORio or CHRi0Ri i; Ri0 and Rn are independently alkyl, COO-alkyl, aryl or heterocyclyl;
R1, R2 and R3 independently in each occurrence are hydrogen, halogen, C1-3 alkyl, alkoxy, alkyl, nitro, cyano, cycloalkoxy, R6 or S(O)0-2R5;
R5 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl; R2 and R3 together with Xi to which they are attached also form a ring of the form
Figure imgf000071_0001
which contains one or more additional heteroatom(s) selected from O, S or N;
Mi and M2 are independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl, alkoxy or acyl; or Ml and M2 together form a bridging group
(Co_3);
W is N, CH or COH; R6 is
Figure imgf000071_0002
Y is O, S, NR4, C=O or a bond;
R7, Rs and R9 are independently hydrogen, hydroxyl, amino, S(O)0. 2R5 or NHSO2R5;
L is a linker; and
• is a point of attachment.
5. A method for treating a disease or disorder mediated through αla and/or aw adrenergic receptors, comprising administering to a patient in need thereof a therapeutically effective amount of one or more compound having the structure of the Formula I
R1-A-X1R2R3
Formula I
a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, polymorph, prodrug, stereoisomer, tautomeric form, N-oxide or metabolite thereof, or a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds having the structure of the Formula I, wherein Xi is N or CR4; R4 is hydrogen, hydroxyl or alkyl; A is aryl, aryloxy, heterocyclyl, alkyl, alkoxy, cycloalkyl, NHCORio or CHRi0Ri i; Ri0 and Rn are independently alkyl, COO-alkyl, aryl or heterocyclyl; R1, R2 and R3 independently in each occurrence are hydrogen, halogen, C1-3 alkyl, alkoxy, alkyl, nitro, cyano, cycloalkoxy, R6 or S(O)0^R5; R5 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl; R2 and R3 together with Xi to which they are attached also form a ring of the form
Figure imgf000072_0001
which contains one or more additional heteroatom(s) selected from O, S or N; Mi and M2 are independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl, alkoxy or acyl; or Ml and M2 together form a bridging group (Co_3); W is N, CH or COH; Re is
Figure imgf000073_0001
Y is O, S, NR4, C=O or a bond; R7, R8 and Rg are independently hydrogen, hydroxyl, amino, S(0)o- 2Rs or NHSO2R5; L is a linker; and • is a point of attachment 6. The method according to claim 5, wherein a disease or disorder is benign prostatic hyperplasia or lower urinary tract symptoms. 7. The method according to claim 5, wherein compound causes minimal fall or no fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia. 8. A method for preparing a compound of Formula VI,
Figure imgf000073_0002
Formula VI
a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, polymorph, prodrug, stereoisomer, tautomeric form, N-oxide or metabolite thereof, comprising the steps of: (a) reacting the compound of Formula II
R-H
Formula II
with a compound of Formula III (wherein X2 and X3 are leaving groups) X2 — L — X3
Formula III to form a compound of Formula IV
R — L — X3
Formula IV (b) treating the compound of Formula IV with a compound of Formula V
Figure imgf000074_0001
Formula V
to form a compound of Formula VI, wherein, Xi is N or CR4; R4 is hydrogen, hydroxyl or alkyl; A is aryl, aryloxy, heterocyclyl, alkyl, alkoxy, cycloalkyl, NHCORi0 or CHRi0Rn; Ri0 and Rn are independently alkyl, COO-alkyl, aryl or heterocyclyl; Ri is hydrogen, halogen, C1-3 alkyl, alkoxy, alkyl, nitro, cyano, cycloalkoxy, R6 or S(0)o_2R5; R5 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl; R6 is
Figure imgf000074_0002
Mi and M2 are independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl, alkoxy or acyl; or Ml and M2 together form a bridging group (Co_3); W is N, CH or COH; R is
Figure imgf000075_0001
Y is O, S, NR4, C=O or a bond;
R7, Rs and Rg are independently hydrogen, hydroxyl, amino, S(0)o-2Rs or NHSO2R5; and
L is a linker. A method for preparing a compound of Formula IX,
Figure imgf000075_0002
Formula IX
a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, polymorph, prodrug, stereoisomer, tautomeric form, N-oxide or metabolite thereof, comprising the steps of:
(a) reacting the compound of Formula II
R-H
Formula II
with a compound of Formula VII (wherein X3 is a leaving group)
o
X3
Formula VII to form a compound of Formula VIII
Figure imgf000076_0001
Formula Vm (b) treating the compound of Formula VIII with a compound of Formula V
Figure imgf000076_0002
Formula V
to form a compound of Formula IX, wherein,
Xi is N or CR4
R4 is hydrogen, hydroxyl or alkyl;
A is aryl, aryloxy, heterocyclyl, alkyl, alkoxy, cycloalkyl, NHCORi0 or CHRi0Rn; Ri0 and Rn are independently alkyl, COO-alkyl, aryl or heterocyclyl;
Ri is hydrogen, halogen, C1-3 alkyl, alkoxy, alkyl, nitro, cyano, cycloalkoxy, R6 or S(0)o_2R5;
R5 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl; and R6 is
Figure imgf000076_0003
Mi and M2 are independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl, alkoxy or acyl; or Ml and M2 together form a bridging group (Co-3);
W is N, CH or COH;
Figure imgf000077_0001
Y is O, S, NR4, C=O or a bond; and
R7, Rs and Rg are independently hydrogen, hydroxyl, amino, S(0)o-2Rs or NHSO2R5
10. A method for preparing a compound of Formula XIV,
A-R1
Figure imgf000077_0002
Formula XTV
a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, polymorph, prodrug, stereoisomer, tautomeric form, N-oxide or metabolite thereof, comprising the steps of:
(a) reacting the compound of Formula V(a) with a compound of Formula X (wherein X4 is alkenyl or halogen)
Figure imgf000077_0003
Formula V (a) (Formula V, wherein W=N)
to form a compound of Formula XI
CN
Figure imgf000077_0004
Formula XI (b) reducing the compound of Formula XI to form a compound of Formula XII
R1 A — X1 IjT (CH2); CH2-NH2
M2 Formula Xπ
(c) reacting the compound of Formula XII with a compound of Formula XIII
Figure imgf000078_0001
Formula Xm to form a compound of Formula XIV, wherein, Xi is N or CR4;
R4 is hydrogen, hydroxyl or alkyl; A is aryl, aryloxy, heterocyclyl, alkyl, alkoxy, cycloalkyl, NHCORio or CHRi0Ri i;
Ri0 and Rn are independently alkyl, COO-alkyl, aryl or heterocyclyl;
Ri is hydrogen, halogen, C1-3 alkyl, alkoxy, alkyl, nitro, cyano, cycloalkoxy, R6 or S(0)o_2R5;
R5 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl; Re is
Figure imgf000078_0002
Mi and M2 are independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl, alkoxy or acyl; or Ml and M2 together form a bridging group (Co-3); and
Y is O, S, NR4, C=O or a bond;
11. A method for preparing a compound of Formula XX,
Figure imgf000079_0001
a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, polymorph, prodrug, stereoisomer, tautomeric form, N-oxide or metabolite thereof, comprising the steps of: (a) reacting the compound of Formula X
R1 — A — OH
Formula XV
with a compound of Formula VII
Figure imgf000079_0002
to form a compound of Formula XVII
Figure imgf000079_0003
Formula XVII (b) treating the compound of Formula XVII with a hydrazine hydrate to form a compound of Formula XVIII, and
Figure imgf000079_0004
Fromula XVHI (c) treating the compound of Formula XVIII with a compound of Formula XIX
Formula Xm to form a compound of Formula XX, wherein, A is aryl, aryloxy, heterocyclyl, alkyl, alkoxy, cycloalkyl, NHCORio or CHRi0Ri i;
Ri0 and Rn are independently alkyl, COO-alkyl, aryl or heterocyclyl;
Ri is hydrogen, halogen, C1-3 alkyl, alkoxy, alkyl, nitro, cyano, cycloalkoxy, R6 or S(0)o_2R5;
R5 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl;
Re is
Figure imgf000080_0002
Y is O, S, NR4, C=O or a bond; and n is an integer of from 0 to 5.
PCT/IB2006/051392 2005-05-03 2006-05-03 Adrenergic receptor antagonists Ceased WO2006117760A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1099DE2005 2005-05-03
IN1099/DEL/2005 2005-05-03

Publications (1)

Publication Number Publication Date
WO2006117760A1 true WO2006117760A1 (en) 2006-11-09

Family

ID=36843288

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2006/051392 Ceased WO2006117760A1 (en) 2005-05-03 2006-05-03 Adrenergic receptor antagonists

Country Status (1)

Country Link
WO (1) WO2006117760A1 (en)

Cited By (2)

* 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 (en) * 2012-10-11 2015-12-24 サザン リサーチ インスティテュート Urea and amide derivatives of aminoalkylpiperazines and uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1280941A (en) * 1969-05-22 1972-07-12 Cassella Farbwerke Mainkur Ag New basically substituted 1,2,3-benzotriazine-4(3h)-one derivatives and processes for the production thereof
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 (en) * 2000-11-30 2002-06-06 Ranbaxy Laboratories Limited 1,4-disubstituted piperazine derivatives useful as uro-selective $g(a)1-adrenoceptor blockers

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1280941A (en) * 1969-05-22 1972-07-12 Cassella Farbwerke Mainkur Ag New basically substituted 1,2,3-benzotriazine-4(3h)-one derivatives and processes for the production thereof
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 (en) * 2000-11-30 2002-06-06 Ranbaxy Laboratories Limited 1,4-disubstituted piperazine derivatives useful as uro-selective $g(a)1-adrenoceptor blockers

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CALIENDO G ET AL: "Synthesis by microwave irradiation and binding properties of novel 5-HT1A receptor ligands", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, FR, vol. 36, no. 11-12, November 2001 (2001-11-01), pages 873 - 886, XP004400908, ISSN: 0223-5234 *
CALIENDO G ET AL: "Synthesis of new 1,2,3-benzotriazin-4-one-arylpiperazine derivatives as 5-HT(1A) serotonin receptor ligands", BIOORGANIC AND MEDICINAL CHEMISTRY 2000 UNITED KINGDOM, vol. 8, no. 3, 2000, pages 533 - 538, XP002396680, ISSN: 0968-0896 *
FERRAND G ET AL: "Synthesis of new 1,2,3-triazin-4-ones as potential anti-depressants", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 1987 FRANCE, vol. 22, no. 4, 1987, pages 337 - 345, XP002396679, ISSN: 0223-5234 *
ROMEO G ET AL: "Novel antagonists for [alpha]1-adrenoceptor subtypes", EXPERT OPINION ON THERAPEUTIC PATENTS 2004 UNITED KINGDOM, vol. 14, no. 5, 2004, pages 619 - 637, XP002396678, ISSN: 1354-3776 *

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 (en) * 2012-10-11 2015-12-24 サザン リサーチ インスティテュート Urea and amide derivatives of aminoalkylpiperazines and uses thereof
US9969743B2 (en) 2012-10-11 2018-05-15 Southern Research Institute Urea and amide derivatives of aminoalkylpiperazines and use thereof
AU2013329097B2 (en) * 2012-10-11 2018-10-18 Southern Research Institute Urea and amide derivatives of aminoalkylpiperazines and use thereof

Similar Documents

Publication Publication Date Title
US7378431B2 (en) Amide derivatives as NMDA receptor antagonists
JP4211394B2 (en) Propane-1,3-dione derivatives
US9622991B2 (en) Hematopoietic growth factor mimetic small molecule compounds and their uses
ES2443127T3 (en) New tricyclic derivatives or pharmaceutically acceptable salts thereof, their manufacturing process and pharmaceutical compositions containing them
CN112912376A (en) Proteolytic targeted chimeric (PROTAC) compounds with E3 ubiquitin ligase binding activity and targeting alpha-synuclein for the treatment of neurodegenerative diseases
JP2009525333A (en) Amide compounds and their use as pharmaceuticals
SK6912002A3 (en) Tyrosine kinase inhibitors, pharmaceutical composition containing them and their use
KR20100044816A (en) Phthalazinone derivatives as inhibitors of parp-1
WO1999061426A1 (en) Heterocyclic compounds and methods to treat cardiac failure and other disorders
SK1022004A3 (en) Piperidine derivatives as NMDA receptor antagonists
JP2008538749A (en) NPY antagonists, preparation and use
TW200536578A (en) Therapeutic compounds
KR20070089908A (en) Indole Acetic Acid and its Uses Showing CrtH2 Receptor Antagonism
KR20080094962A (en) Amide derivatives or salts thereof
JP2009179616A (en) 3-Naphthylpyrazole compounds
US6340685B1 (en) Compounds and methods to treat cardiac failure and other disorders
US20100190826A1 (en) Benzimidazole derivative
SK116394A3 (en) Substituted phenylcarbamates and ureas
JP5466154B2 (en) Urotensin II receptor antagonist
KR20080105092A (en) Pyrrole derivatives or salts thereof
WO2006117760A1 (en) Adrenergic receptor antagonists
JP2574348B2 (en) Novel condensed diazepinone, method for producing the same and pharmaceutical composition containing the same
CN101208328B (en) Heteroaryl-substituted amides comprising a saturated linker group, and their use as pharmaceuticals
US6458821B1 (en) N-substituted azabicycloheptane derivatives, production and use thereof
WO2006051374A2 (en) Arylpiperazines useful as adrenergic receptor antagonists

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

NENP Non-entry into the national phase

Ref country code: RU

WWW Wipo information: withdrawn in national office

Country of ref document: RU

122 Ep: pct application non-entry in european phase

Ref document number: 06744863

Country of ref document: EP

Kind code of ref document: A1