Field of the Invention
Provided herein are α1a and/or α1d adrenergic receptor antagonists, which can be used for safe and effective treatment of a disease or disorder mediated through α1a and/or α1d adrenergic receptors. Compounds disclosed herein can be used for the treatment of benign prostatic hyperplasia (BPH) and the related symptoms thereof, lower urinary tract symptoms (LUTS) associated with or without BPH. Processes for the preparation of the disclosed compounds, pharmaceutical compositions thereof and the methods of treating BPH and related symptoms thereof, LUTS associated with or without BPH are also provided.
Background of the Invention
Benign prostatic hyperplasia (BPH) is a condition, which develops in elderly males and refers to the benign overgrowth of the stromal and epithelial elements of the prostate with aging. The symptoms of BPH vary, but the most common ones involve changes or problems with urination, such as hesitant, interrupted, weak stream or urgency and leaking or dribbling or more frequent urination, especially at night. Consequences of BPH can involve hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection.
There are two components of BPH, static and a dynamic component. The static component is due 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 due to increased smooth muscle tone of the bladder neck and prostate itself and is regulated by a -1 adrenergic receptor.
Currently, the most effective treatment for BPH is the surgical procedure of transurethral resection of the prostate (TURP), since it removes the obstructing tissue (C. Chappie's Br. Med. Journal 304: 1198-1199, 1992). It is a treatment, which is directed to the static and dynamic components of the BPH. However this surgical treatment is associated with rates of mortality (1%) and adverse event (incontinence 2-4%) infection 5-10 %, and impotence 5-10%. A noninvasive alternative treatment is therefore highly desirable. There are some drug therapies, which address the static component of this condition. 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 a-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-a reductase reduce the size of the prostate and improve urine flow through the prostatic urethra. Although finasteride is a potent 5-a reductase inhibitor and causes a marked decrease in serum and tissue concentrations of
dihydrotestosterone, it is moderately effective in the treatment of symptomatic BPH. The effects of fmasteride 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 α1 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 hypertention, syncope, dizziness, headache etc) due to lack of selectivity of action between prostatic and vascular α1 adrenoceptor. There are several lines of evidence to suggest that selectivity for α1a adrenoceptor over α1b adrenoceptor will result in relative lack of vascular side effects, thus lead to a better tolerability. Mice deficient in α1b adrenoreceptors show diminished blood pressure response to phenylephrine injection compared to homozygous controls (Decreased blood pressure response in mice deficient of α1b adrenergic receptor. (Proc Natl Acad Sci USA 1997,94,11589-11594). In-vivo studies in healthy subjects comparison of α1a / α1d selective antagonists (for example, tamsulosin) or α1a selective antagonists (for example, urapidil) with non selective antagonists (for example,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, 1996,49, 371-375; Naunyn Schmiedeberg's Arch Pharmacol 1996, 354, 557-561; Jpn J Pharmacol 1999, 80, 209-215; Br J Clin Pharmacol 1999, 47, 67-74). These studies have reported that an antagonist with high affinity for α1a or α1a/α1d can cause some degree of vasodilation but that it is much smaller than with non-subtype-selective α1 adrenoceptor antagonist. Further, there is increased vascular α1b, adrenoceptor expression in elderly patients and thus α1a/α1d selective agents with selectivity over α1b adrenoceptor subtype would be of particular importance in benign prostatic hyperplasia, which is generally a disease of old age. Antagonism of both α1a adrenoceptor and α1d adrenoceptor is important to relieve lower urinary tract symptoms especially associated (suggestive of) with BPH. Targeting α1a adrenoceptor with antagonists is important in relaxing prostate smooth muscle and relieving bladder outlet obstruction whereas α1d adrenoceptor antagonism is important to target irritative symptoms.
Over the past decade, there has been an intensive search for selective α1a 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 disclosed in US patent No. 4,552,878. FR 2,551,753, Eur J Med Chem (1987), 22(4), 337-345, discloses benzotriazine-l,2,3-ones-4 that are said to have antidepressant activity. US 6,166,009 and WO 96/31498 discloses N-substituted azaheterocyclic carboxylic acids and esters thereof and their use for hyperalgesic and/or inflammatory conditions. US 2003/0032801 and WO 02/089810 discloses chemosensitizing agents for treating multiple resistant strains of Plasmodium falciparum. Other reports describing selective α1a 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 disclosed 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
Generally provided are alpha la and/or alpha Id adrenergic receptor antagonists, which can be used for the treatment of a disease or disorder mediated through alpha 1 a and/or alpha 1 d adrenergic receptors. Processes for the synthesis of these compounds, pharmaceutical compositions thereof, are also provided. Encompassed pharmaceutical compositions may also contain one or more pharmaceutically acceptable carriers or diluents.
Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, conjugates, or prodrugs of such compounds having the same type of activity are also provided, which can be useful for safe and effective treatment of a disease or disorder mediated through alpha la and/or alpha Id adrenergic receptors.
Pharmaceutical compositions comprising the compounds disclosed herein, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, conjugates, or prodrugs in combination with one or more pharmaceutically acceptable carriers, and optionally included excipients, are also included, which can be useful for safe and effective treatment of a disease or disorder mediated through alpha la and/or alpha Id adrenergic receptors.
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,
(Formula Removed)
Formula I and their pharmaceutically acceptable salts, esters, enantiomers, diastereomers, N-oxides,
prodrugs, metabolites, polymorphs, pharmaceutically acceptable solvates, wherein
X1 can be N or CR4 (wherein R4 can be hydrogen, hydroxyl or alkyl); A can be aryl, aryloxy, heterocyclyl, alkyl, alkoxy, cycloalkyl, NHCOR10 or CHR10R11 (wherein R10 and R11 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(O)0-2R5 (wherein R5 can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl or heterocyclyl), or R2 and R3 together with X1 to which they are attached may also form a ring of the form
(Formula Removed)
which may contain additional one or more heteroatom(s) selected from O, S or N, wherein,
M1 and M2 can independently be hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl,
alkoxy or acyl, M1 and M2 together can form a bridging group (C0-3), W can be N, CH or COH,
R6 can be (Formula Removed)

wherein, Y can be O, S, NR4, C=O or a bond, R7, R8 and R9 can be independently hydrogen, hydroxyl, amino, S(O)o-2R5 or NHSO2R5, L can be a linker, • can be point of attachment.
In another aspect, provided herein are methods for the treatment of a patient suffering from a disease or disorder mediated through alpha la and/or alpha Id adrenergic receptor, comprising administering to a patient, a therapeutically effective amount of one or more compounds or compositions disclosed herein.
In another aspect, provided herein are methods for the treatment of a patient suffering from benign prostatic hyperplasia (BPH) and related symptoms, lower urinary tract symptoms (LUTS) with or without BPH comprising administering to a patient, a therapeutically effective amount of one or more compounds or compositions disclosed herein.
LUTS may include, for example, irritative symptoms such as frequent urination, urgent urination, nocturia and unstable bladder contractions, obstructive symptoms such as hesitancy, poor stream, prolong urination, and feelings of incomplete emptying.
In another aspect, provided herein are processes for the preparation of the compounds described herein.
In yet another aspect, provided herein are methods for the treatment of a patient suffering from BPH or LUTS with or without BPH, comprising administering to a patient, a therapeutically effective amount of one or more compounds or compositions disclosed 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-HT antagonists or combination thereof.
The compounds of this invention are potent adrenergic receptor antagonists. Compounds disclosed herein have good selectivity for α1a v/s an,. Alpha la adrenergic receptors are involved in relieving the obstructive symptoms whereas α1d adrenoreceptor antagonism is associated with alleviation of irritative symptoms. The relatively low affinity at the α1b 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 α1a adrenoceptors. Compounds and compositions described herein can be administered orally, parenterally, subcutaneously, transdermally or topically.
The following definitions apply to the terms as used herein:
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, -NR11R12, -CONR11R12, -COOR12, -CONHR12, -OCOR12, -COR12, -NHSO2R12 and -SO2NHR12 wherein R11 and R12 are independently selected from hydrogen or alkyl.
The term "alkoxy" herein refers to ORa 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(R8)2, CS(R8)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, Inflate 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.
Detailed Description of the Invention
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.
Scheme I
(Scheme Removed)
The compound of Formula VI can be prepared according to Scheme I. Thus, reacting a compound of Formula II with a compound of Formula III (wherein X2 and X3 is a leaving group), to give a compound of Formula IV, which on treatment with a compound of Formula V, gives a compound of Formula VI (wherein L, R7, R8, R9, W, M1, M2, X1, A, Y and R1 are the same as defined earlier).
The reaction of a compound of Formula II with a compound of Formula III to give a compound of Formula IV can be carried out in one or more solvent(s), for example, polar protic (methanol, ethanol or isopropyl alcohol), polar aprotic solvents (acetone, dimethylformamide, acetonitrile, dimethylsulfoxide or hexamethylphosphoric acid triamide) or mixture thereof
The reaction of a compound of Formula II with a compound of Formula III to give a compound of Formula IV can be carried out in the presence of one or more bases, for example, sodium carbonate, cesium carbonate, potassium carbonate, sodium hydrogen carbonate, triethylamine, pyridine, tributylamine, diisopropylethylamine, sodium hydride, sodium-t-butoxide, 4-(N-dimethylamino)pyridine, lithium diisopropylamine, lithium hydroxide, potassiun-t-butoxide, n-butyllithium or dry liquid ammonia and sodium metal.
The reaction of a compound of Formula IV with a compound of Formula V to give a compound of Formula VI can be carried out in one or more solvent(s), for example, polar protic
solvents (methanol, ethanol or isopropyl alcohol), polar aprotic solvents (methylethylketone, acetone, dimethylformamide, dimethylacetamide or dimethylsulfoxide) or mixture thereof.
The reaction of a compound of Formula IV to give a compound of Formula VI can be carried out in the presence of one or more bases, for example, ammonium hydroxide, hydrazine, sodium carbonate, cesium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, pyridine, tributylamine, diisopropylethylamine or
4-(N-dimethylamino)pyridine.
Scheme II
(Scheme Removed)
The compound of Formula IX can be prepared according to Scheme II. Thus, reacting a compound of Formula II with a compound of Formula VII (wherein X3 is a leaving group), to give a compound of Formula VIII which on treatment with a compound of Formula V gives a compound of Formula IX (wherein R7, R8, R9, W, M1, M2, X1, A, Y and RI are the same as defined earlier).
The reaction of a compound of Formula II with a compound of Formula VII to give a compound of Formula VIII can be carried out in one or more solvent(s), for example, polar protic solvents (methanol, ethanol or isopropyl alcohol), polar aprotic solvents (methylethyl ketone, acetone, dimethylformamide, dimethylsulfoxide or acetonitrile) or mixture thereof.
The reaction of a compound of Formula II to give a compound of Formula VII can be carried out in the presence of one or more inorganic bases, for example, sodium carbonate, cesium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate.
The reaction of a compound of Formula VIII with a compound of Formula V to give a compound of Formula IX can be carried out in one or more solvent(s), for example,
polar protic solvents (methanol, ethanol or isopropyl alcohol), polar aprotic (dimethylsulfoxide, acetonitrile or dimethylformamide) or mixture thereof.
The reaction of a compound of Formula VIII to give a compound of Formula IX can be carried out in the presence of one or more organic bases, for example, triethylamine, pyridine, tributylamine, diisopropylethylamine or 4-(N-dimethylamino)pyridine.
Scheme III
(Scheme Removed)
The compound of Formula XIV can be prepared according to Scheme III. Thus, reacting a compound of Formula V(a) with a compound of Formula X (wherein X4 is alkenyl or halogen and n is an integer 0 to 3) to give a compound of Formula XI which on reduction gives a compound of Formula XII, which is finally treated with a compound of Formula XIII (wherein X3 is a leaving group) to give a compound of Formula XIV (wherein Y, M1, M2, X1, A and R1 are the same as defined earlier).
The reaction of a compound of Formula V(a) with a compound of Formula X to give a compound of Formula XI can be carried out in one or more solvent(s), for example, polar protic solvents (methanol, ethanol or isopropyl alcohol), polar aprotic solvents (methylethylketone, acetone or dimethylformamide) or mixture thereof.
The reaction of a compound of Formula V(a) to give a compound of Formula XI can be carried out in the presence of one or more bases, for example, ammonium hydroxide, hydrazine, sodium carbonate, cesium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, diisoproplyamine, pyridine or tributylamine.
The reduction of a compound of Formula XI to give a compound of Formula XII can be carried out in the presence of one or more reducing agent(s), for example, Raney nickel/
hydrogen, Palladium-carbon/hydrogen, Platinum/hydrogen and ammonia in one or more alcoholic solvents.
The reaction of a compound of Formula XII with compound of Formula XIII to give a compound of Formula XIV can be carried out in one or more solvent(s), for example, chlorinated solvents (chloroform, dichloromethane or dichloroethane), aprotic polar solvents (dimethylformamide, acetonitrile or dimethylsulfoxide), protic polar solvents (methanol, ethanol or isopropyl alcohol) or mixture thereof.
The reaction of a compound of Formula XII to give a compound of Formula XIV can be carried out in presence of activating and coupling reagents, for example, pyridinium salts, phosphonium salts, uranium salts, active esters or carbodimides.
The reaction of a compound of Formula XII to give a compound of Formula XIV can be carried out in presence of one or more bases, for example, 4-dialkylaminopyridines, Hunig's base, 4-alkylmorpholine, triethylamine, 1-methylimidazole or 4-(l-Pyrrolidino)pyridine.
Scheme IV
(Scheme Removed)
The compound of Formula XX can be prepared according to Scheme IV. Thus, reacting a compound of Formula XV with a compound of Formula XVI (wherein, X2 is a leaving group) to give a compound of Formula XVII which on reaction with hydrazine hydrate gives a compound of Formula XVIII, which is finally treated with a compound of Formula XIX (wherein X3, is a leaving group) to give a compound of Formula XX (wherein Y, A and R\ are the same as defined earlier and n is an integer 1-5).
The reaction of a compound of Formula XV with a compound of Formula XVI to give a compound of Formula XVII can be carried out in one or more polar aprotic solvent(s), for example, methylethylketone, acetone or dimethylformamide.
The reaction of a compound of Formula XV to give a compound of Formula XVII can be carried out in presence of one or more bases, for example, potassium carbonate, sodium
hydrogen carbonate, sodium hydride, pyridine, triethylamine, sodium carbonate, sodium acetate, sodium thiosulphate or diisopropylethylamine
The reaction of a compound of Formula XVII with hydrazine hydrate to give a compound of Formula XVIII can be carried out in one or more solvent(s), for example, polar protic solvents (methanol, ethanol or isopropyl alcohol), polar aprotic solvents (dimethylsulfoxide or acetonitrile) or mixture thereof.
The reaction of a compound of Formula XVIII with compound of Formula XIX to give a compound of Formula XX can be carried out in one or more solvent(s), for example, chlorinated solvents (chloroform, dichloromethane, dichloroethane), aprotic polar solvents (dimethylformamide, acetonitrile or dimethylsulfoxide), protic polar solvents ( methanol, ethanol or isopropyl alcohol) or mixture thereof.
The reaction of a compound of Formula XVIII with compound of Formula XIX to give a compound of Formula XX can be carried out in presence of activating and coupling reagents, for example, pyridinium salts, phosphonium salts, uranium salts, active esters or carbodiimides and in presence of one or more bases, for example, 4-dialkylaminopyridines, Hunig's base, 4-alkylmorpholine, triethylamine, 1-methylimidazole or 4-(l-Pyrrolidino)pyridine. Compounds of the present invention useful for such purpose are listed below:
3- {3-[4-hydroxy-4-(2-methoxyphenyl)piperidin-1 -yl]propyl} -1,2,3-benzotriazin-4(3H)-one (Compound No. 1) and its hydrochloride salt (Compound No. 2),
Methyl (4-[3-(4-oxo-l ,2,3-berizotriazm-3(4H)-yl)propyl] piperazin-l-yl}(phenyl)acetate (Compound No. 3) and its hydrochloride salt (Compound No. 4),
3 -(3 - {4- [2-(cyclopentyloxy) pheny 1] piperazin-1 -y 1} propy 1)-1,2,3 -benzotriazin-4(3H)-one (Compound No. 5) and its hydrochloride salt (Compound No. 6),
3-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]-2-methylpropyl}-l,2,3-benzotriazin-4(3H)-one (Compound No. 7) and its hydrochloride salt (Compound No. 8),
3-(3-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-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} -1,2,3 -benzotriazin-4(3H)-one (Compound No. 11) and its hydrochloride salt (Compound No. 12),
3-{2-methyl-3-[4-(2-propoxy phenyl)piperazin-l-yl]propyl}-l,2,3-benzotriazin-4(3H)-one (Compound No. 13) and its hydrochloride salt (Compound No. 14),
3-(3-{4-[2-(cyclopentyloxy) phenyl]piperazin-l-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(1H)-yl)propyl]-l,2,3-benzotriazin-4(3H)-one (Compound No. 19) and its hydrochloride salt (Compound No. 20),
3-{5-[4-(2-methoxyphenyl) piperazin-1 -yl]pentyl}-1,2,3-benzotriazin-4(3H)-one (Compound No. 21) and its hydrochloride salt (Compound No. 22),
3-{5-[4-(2-ethoxyphenyl) piperazin-l-yl]pentyl}-l,2,3-benzotriazin-4(3H)-one (Compound No. 23) and its hydrochloride salt (Compound No. 24),
3-{5-[4-(2-propoxyphenyl) piperazin-1 -yl]pentyl}-1,2,3-benzotriazin-4(3H)-one (Compound No. 25) and its hydrochloride salt (Compound No. 26),
3-{5-[4-(2-isopropoxyphenyl)piperazin-l-yl]pentyl}-l,2,3-benzotriazin-4(3H)-one (Compound No. 27) and its hydrochloride salt (Compound No. 28),
3-{5-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]pentyl}-l,2,3-benzotriazin-4(3H)-one (Compound No. 29) and its hydrochloride salt (Compound No. 30),
3-(5-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-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-methoxyphenyl)piperazin-l-yl]pentyl}-l,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(1H)-yl)pentyl]-l,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-l-yl}propyl)-l,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-l-yl}pentyl)-l,2,3-benzotriazin-4(3H)-one (Compound No. 43) and its hydrochloride salt (Compound No. 44),
3-{5-[4-(5-fluoro-2-propoxyphenyl)piperazin-l-yl]pentyl}-l,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(1H)-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-methoxyphenyl)-3-azabicyclo[3.2.1]oct-3-yl]propyl}-l,2,3-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-yl}acetamide (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-yl}benzamide (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-hydroxypropyl} -1,2,3-benzotriazin-4(3H)-one (Compound No. 59) and its hydrochloride salt (Compound No. 60),
3-(3-{4-[2-(cyclopentyloxy) phenyl]piperazin-l -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-l-yl]propyl}-l,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-methoxyphenyl)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-l-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 phenyljpiperazin-1 -yl}propyl)-10H-phenoxazine (Compound No. 83) and its hydrochloride salt (Compound No. 84),
10-{3-[3-(2-methoxyphenyl) imidazolidin-1-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-1-yl] propyl}-10H-phenothiazine (Compound No. 89) and its hydrochloride salt (Compound No. 90),
10-{3-[4-(2-methoxyphenyl)piperazin-l-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-(cyclopentyloxy)phenyl] piperazin-1 -yl}propyl)-10H-phenothiazine (Compound No. 95) and its hydrochloride salt (Compound No. 96),
N-{3-[4-(2-methoxyphenyl)piperazin-1 -yl]propyl}-10H-phenothiazine-10-carbox amide (Compound No. 97) and its hydrochloride salt (Compound No. 98),
10-{3-[4-(2-propoxyphenyl)piperazin-l-yl]propyl}-10H-phenothiazine (Compound No. 99) and its hydrochloride salt (Compound No. 100),
10-(3- {4-[2-(cyclopentyloxy)-5-fluoro phenyl]piperazin-1 -yl}propyl)-10H-phenothiazine (Compound No. 101) and its hydrochloride salt (Compound No. 102),
10-{3-[4-(5-fluoro-2-isopropoxyphenyl) piperazin-1 -yl]propyl}-10H-phenothiazine (Compound No. 103) and its hydrochloride salt (Compound No. 104),
N- {3 - [4-(2-methoxyphenyl)piperazin-1 -yl]propyl} -10H-phenoxazine-10-carboxamide (Compound No. 105) and its hydrochloride salt (Compound No. 106),
N-[2-(2-methoxyphenoxy)ethyl]-10H-phenoxazine-l 0-carboxamide (Compound No. 107) and its hydrochloride salt (Compound No. 108),
10-(3- {4-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1 -yl}propyl)-10H-phenoxazine (Compound No. 109) and its hydrochloride salt (Compound No. 110),
10-{3-[3-(2-ethoxyphenyl)imidazolidin-l-yl]propyl}-10H-phenothiazine (Compound No. 111) and its hydrochloride salt (Compound No. 112),
10-{3-[4-(5-fluoro-2-propoxyphenyl)piperazin-1-yl]propyl} -10H-phenoxazine (Compound No. 113) and its hydrochloride salt (Compound No. 114),
1 -[4-(5-fluoro-2-methoxyphenyl) piperazin-1 -yl]-3-(l0H-phenoxazin-10-yl)propan-2-ol (Compound No. 115) and its hydrochloride salt (Compound No. 116),
and their pharmaceutically acceptable salts, esters, enantiomers, diastereomers, N-oxides, prodrugs, metabolites, polymorphs, pharmaceutically acceptable solvates,
In the above schemes, where the base, solvents, etc., are mentioned, it is to be understood that other bases, solvents, etc., known to those skilled in the art may be used. Similarly, the reaction temperature and duration may be adjusted according to the desired needs.
Compounds of this invention may be administered with or without an excipient. The present invention also provides the compositions which may be prepared by admixture of compounds with apposite excipients and other assisting agents, if required, for oral, sublingual, parenteral, topical, rectal or transdermal administration.
The solid compositions include tablets, capsules, microcapsules, powders, granules, pills, wafers, dragees, catchets, caplets, suppositories and pastilles.
Tablets, capsules, pills are generally administered as a unit dose and may contain suitable excipients such as dispersing agents, binding agents, fillers, diluents, lubricants, disintegrants, colorants, flavoring agents, sweetners or preservatives.
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 the compound is mixed with inert solid diluent, for example, sodium carbonate, calcium carbonate, lactose, starch, calcium phosphate or sodium phosphate; disintegrants, for example, sodium starch glycolate or croscarmelose sodium.
Dispersible powders and granules suitable for reconstitution to form a stable suspension by addition of water are provided with the active ingredient with a dispersing and a suspending agent. Additional excipients, for example, coloring agents, flavoring agents and sweetening agents may also be added.
Suppositories for rectal administration may include carbondioxide releasing laxative suppositories, dosage form for topical or transdermal administration of a compound of the present invention includes ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, spot-on or patches. The active compound is admixed under sterile condition with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
Liquid form preparation for oral administration includes pharmaceutically acceptable emulsions, microemulsions, solutions, aqueous or oily suspensions, syrups, sprays and elixirs.
For liquid form preparation, the active compound is 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 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 are water for injection, Ringer's solution and isotonic sodium chloride. Ophthalmic formulations, eardrops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
The pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be packaged preparation, 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.
Examples set forth below demonstrate the general synthetic procedure for the preparation of representative compounds. The examples are provided to illustrate particular aspect of the disclosure and do not constrain the scope of the present invention as defined by the claims.
Experimental Details 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-methoxvphenyl)-3-azabicyclo[3.2.1]octan-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 25-30°C 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. Tetrahydrofuran layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was concentrated to get the title product. Yield: 76%
Step 2: Preparation of 8-(2-methoxvphenvl)-3-azabicvclo[3.2.1]octan-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°C and under 50 psi pressure for about 5 hours. Filtered through a bed of celite and concentrated to get the required product. Yield: 90% The following compound is prepared similarly: 1. 4-(2-methoxyphenyl)piperidin-4-ol
b) Preparation of Methyl phenyl(piperazin-l-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 120-130°C for about 16 hours. Reaction mixture was concentrated under vacuum. The residue was basified with 10% sodium hydroxide solution and extracted with dichloromethane. The combined 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 get the titled product. Yield: 43%
c) Preparation of 1 -(2-methoxyphenyl)imidazolidine
Step 1: Preparation of N-(2-methoxyphenvnethane-l ,2-diamine
A solution of o-anisidine (1.0 equiv.), bromoethyl amine hydrobromide (1.5 equiv.) and potassium carbonate (0.5 equiv.) in water was refluxed for about 24 hours. Reaction mixture was cooled to 25-30°C then basified with 20% sodium hydroxide solution followed by extraction with ethyl acetate. The combined organic layer was washed with water and brine solution. The organic layer was then dried and concentrated to get the crude product which was purified on silica gel column using mixture of methanol and dichloromethane as eluent. Yield: 25% Step2: Preparation of l-(2-methoxyphenyl)imidazoIidin-2-one
A solution of N-(2-methoxyphenyl)ethane-l,2-diamine (1.0 equiv.) and N,N'-carbonyldiimidazole (1.5 equiv.) in dry tetrahydrofuran was stirred at 25-30°C for about 24 hours. Reaction mixture was concentrated under vacuum. The residue was diluted with water extracted with ethyl acetate and the combined organic layer was washed with water and brine solution. Dried and concentrated to get the crude. Purified by silica gel column chromatography using ethyl acetate in hexane as solvent. Yield: 75%.
Step3: Preparation of 1 -(2-methoxyphenyl)imidazolidine
To a solution of the above (1.0 equiv.) in toluene at -20°C under nitrogen, borane-dimethylsulfide complex (2.0 equiv.) was added dropwise and the reaction mixture was refluxed for about 18 hours. The reaction mixture was cooled to -20°C and 10% sodium bicarbonate solution was added dropwise. 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 combined organic layer was concentrated to get the required product. 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-3-benzylazabicyclo[3.1.0]hex-6-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, the bed washed well with methanol. The filtrate was concentrated to afford the product as reddish brown oil.
e) Preparation of N-3-azabicyclo[3.1.0]hex-6-yltetrahydrofuran-2-carboxamide
N-3-azabicyclo[3.1.0]hex-6-ylacetamide was taken in a mixture of ethanol and 5N sodium hydroxide solution (2:1) and refluxed overnight. It was then cooled and the solvent was then removed. The resulting product was diluted with water followed by extraction 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]piperazine
Trifluoroethanol (1 equiv.) was taken in dichloromethane, cooled to about 5-10°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 to this solvent mixture drop wise. The reaction mixture was then allowed to come to room temperature and stirred overnight at room 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 combined organic extracts were dried, concentrated to afford the product in 90 % yield. To a suspension of sodium hydride (1 equiv.) in hexamethylphosphoric triamide, cooled to about 0°C, 4-fluoro-2-nitro phenol was added portion wise and the reaction mixture was stirred for about 30 minutes. The above product (1.2 equiv.) was then added portion wise and the reaction mixture was then allowed to come to room temperature and then it was heated at about 140 °C for about 24 hours. The reaction mixture was then cooled, poured into chilled water and extracted with ethyl acetate to get the product in 38 % yield. The above product was dissolved in methanol, 10 % dry palladium-carbon was added and hydrogenated in Parr apparatus under 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 160°C. The reaction mixture was cooled to 40°C poured into hexane, filtered to get the pure product in 85 % yield. The following compounds were prepared similarly:
1 -[2-(cyclopentyloxy)phenyl]piperazine, 1 -[2-(cyclopentyloxy)-5-fluorophenyl]piperazine, 1 -(5-fluoro-2-isopropoxyphenyl)piperazine, 1 -(2-isopropoxyphenyl)piperazine, 1 -(2-ethoxyphenyl)piperazine, 1-(2-propoxyphenyl)piperazine, l-(2-methoxyphenyl)piperazine, l-(5-fluoro-2-methoxyphenyl)piperazine, 1 -(5-fluoro-2-propoxyphenyl)piperazine, 1 -(2-ethoxy-5-fluorophenyl)piperazine, 1 -[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazine, 1 -(2-fluoro-6-isopropoxyphenyl)piperazine, l-(2-fluoro-6-methoxyphenyl)piperazine The following examples illustrate the invention but do not limit it anyway
Example 1
Preparation of 3-(3-[4-hvdroxv-4-(2-methoxyphenyl)piperidin-l-vl]propyl}-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 25-30°C in 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 combined 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 get the desired product. 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 (Chem. Pharm. Bull. 2000, 48(12), 1978, 1.2 equiv.), potassium carbonate (3.0 equiv.) and potassium iodide (10 mole %) in methyl ethyl ketone was refluxed for about 12 hours. Reaction mixture was concentrated under vacuum. The residue was taken in water, extracted with ethyl acetate and the combined 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 3: Preparation of 3-{3-[4-hydroxy-4-(2-methoxy phenyl) piperidin-l-yl]propyl}-1,2,3-benzotriazin-4(3H)-one hydrochloride salt
An equimolar quantity of isopropyl alcohol 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. The solid which precipitates, was then filtered. Mass (m/z): 395 (M++l). 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), 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), 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}-1,2,3-benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 408 (M++l), 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), hygroscopic;
Compound No. 16: 3-(3-{4-[2-(cyclopentyloxy) phenyl]piperazin-l-yl}-2-methyl propyl)-1,2,3-benzotriazin-4 (3H)-one hydrochloride salt, Mass (m/z): 448 (M++l), 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), hygroscopic;
Compound No. 20: 3-[3-(3,4-dihydroisoquinolin-2(1H)-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), 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), 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), 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), hygroscopic;
Compound No. 32: 3-(5-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-yl} pentyl)-1,2,3-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), hygroscopic;
Compound No. 38: 3-[5-(6,7-dimethoxy-3,4-dihydro isoquinolin-2(1H)-yl)pentyl]-l,2,3-benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 409 (M++l), hygroscopic;
Compound No. 40: 3-(3-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-yl} propyl)-1,2,3-benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 452 (M++l), 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: 137-138°C;
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: 161-162°C;
Compound No. 50: 3-[5-(3,4-dihydroisoquinolin-2(1H)-yl)pentyl]-l,2,3-benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 349.3 (M++l), M.P: 134-135°C;
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), 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), 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++NH4+), 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), hygroscopic;
Example 2
Preparation of 3-{3-[4-(5-fluoro-2-isopropoxy phenyl)piperazin-l-yl]-2-hvdroxypropyl}- 1,2,3-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. Reaction mixture was concentrated under vacuum; the residue was taken in water and extracted with ethyl acetate. The combined 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 get the title compound. Yield: 75%
Step2: Preparation of 3-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-1 -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.), l-(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 get the title product. 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. The solid which precipitates, was then filtered. Mass (m/z): 442 (M++l), hygroscopic. The following compounds were prepared similarly
Compound No. 62: 3-(3-{4-[2-(cyclopentyloxy) phenyl]piperazin-l-yl}-2-hydroxypropyl)-1,2,3-benzotriazin-4(3H)-one hydrochloride salt, Mass (m/z): 450 (M++l), 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), 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), 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), 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), hygroscopic;
General Procedure Preparation of 10-(3-chloropropyl)-10H-phenoxazine
A dry two-necked 250ml 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 (FeCl3) 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 Na2SO4 concentrated in vacuo, to get the desired product. 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 portion wise, 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 the 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-[4-(2-methoxvphenyl)piperazin-1 -yl]propyl)-10H-phenoxazine hvdrochloride 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.), 1-(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. Reaction mixture was concentrated under vacuum. The residue was taken in water, extracted with ethyl acetate and the combined 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. The solid which precipitates, was then filtered. Mass (m/z): 416 (M++l), M.P: 220-225°C; The following compounds were prepared similarly
Compound No. 74: 10-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-10H-phenoxazine hydrochloride salt, Mass (m/z): 430 (M++l), hygroscopic;
Compound No. 76: 10-{3-[4-(2-propoxyphenyl)piperazin-l-yl]propyl}-10H-phenoxazine hydrochloride salt, Mass (m/z): 444 (M++l), hygroscopic;
Compound No. 78: 10-{3-[4-(2-isopropoxy phenyl) piperazin-l-yl]propyl}-10H-phenoxazine hydrochloride salt, Mass (m/z): 444 (M"*"+l), 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), 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), hygroscopic;
Compound No. 84: 10-(3-{4-[2-(cyclopentyloxy)-6-fluoro phenyl]piperazin-l-yl}propyl)-10H-phenoxazine hydrochloride salt, Mass (m/z): 488 (M++l), hygroscopic;
Compound No. 86: 10-{3-[3-(2-methoxyphenyl) imidazolidin-l-yl]propyl}-10H-phenoxazine hydrochloride salt, Mass (m/z): 404 (M++l), hygroscopic;
Example 4
Preparation of 10- {3-[4-(2-ethoxyphenvl)piperazin-1 -yl]propyl} -10H-phenothiazine hydrochloride salt (Compound No. 44)
Step 1: Preparation of 10-{3-[4-(2-ethoxyphenyl)piperazin-l-yl]propyl}-10H-phenothiazine
The titled compound was prepared by according to the procedure as described in Example 3 using 10-(3-chloropropyl)-10H-phenothiazine in place of 10-(3-chloropropyl)-10H-phenoxazine.
Step2: 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. The solid, which precipitates, was then filtered. Mass (m/z): 445 (M++l), M.P: 196-198°C 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), hygroscopic;
Compound No. 92: 10-{3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-10H-phenothiazine hydrochloride salt, Mass (m/z): 432 (M++l), M.P: 190-195 °C;
Compound No. 94: 8-(2-methoxyphenyl)-3-[3-(10//-phenothiazin-10-yl)propyl]-3-azabicyclo [3.2.1]octan-8-ol hydrochloride salt, Mass (m/z): 472 (M++l), 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: 210-212°C;
Compound No. 100: 10-{3-[4-(2-propoxyphenyl)piperazin-l-yl]propyl}-10H-phenothiazine hydrochloride salt, Mass (m/z): 460 (M++l), M.P: 185-190°C;
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), 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), hygroscopic;
Compound No. 110: 10-(3-{4-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-l-yI}propyl)-10H-phenoxazine hydrochloride salt, Mass (m/z): 502 (M++l), M.P: 90-95 °C;
Compound No. 112: 10-{3-[3-(2-ethoxyphenyl)imidazolidin-l-yl]propyl}-10H-phenothiazine hydrochloride salt, Mass (m/z): 420 (M++3), M.P: 80-85 °C;
Compound No. 114: 10-{3-[4-(5-fluoro-2-propoxyphenyl)piperazin-l-yl]propyl}-10H-phenoxazine hydrochloride salt, Mass (m/z): 462 (M++l), M.P: 164-165 °C;
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 °C;
Example 5
Preparation of N-(3-[4-(2-methoxyphenyl')piperazin-l-yl]propyl}-10H-phenothiazine-10-carboxamide hydrochloride salt
Stepl: Preparation of N-{3-[4-(2-methoxyphenyl)piperazin-l-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 10H-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 dichloromthane. 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} -10H-phenothiazine-10-carboxamide The solid which precipitates, was then filtered. Mass (m/z): 475 (M++l), M.P: 189.7-190.9°C 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), M.P: 204-206 °C;
Compound No. 108: Ar-[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-Ib adrenoceptors. The affinity of different compounds for and α1a 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-Ib 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 O.lmg/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 HC1 5 mM, EDTA 5 mM, pH 7.4) using polytron homogenizer. The homogenate was centrifuged at 40, OOOg for 20min at 4°C. The pellet thus obtained was resuspended in assay buffer (Tris HC1 5 mM, EDTA 5 mM, pH 7.4) and were stored at -70 °C until the time of assay.
Competition radioligand binding to the cloned subtypes of α1-adrenoceptors was performed using [3H] prazosin as the radioligand '. The membrane homogenates (5-10 µg protein) were incubated in 250µ1 of assay buffer (Tris HC1 50 mM, EDTA 5 mM, pH 7.4) at 24-25 °C for 1 hour. Non-specific binding was determined in the presence of 10µMterazosin. The incubation was terminated by vacuum filtration over GF/B fiber filters. The filters were then washed with ice-cold 50 mM Tris HC1 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+L/Kd) where L is the concentration of [3H] prazosin used in the particular experiment.
Results: The affinity of compounds (expressed as Ki) at human recombinant alpha-la adrenoceptors lies between lnM->2000nM whereas the affinity (expressed as Ki) at human recombinant alpha-lb adrenoceptors lies in the range of 7nM->1000 nM.
Reference: Michel, M. C., Griibbel, B., Taguchi, K. et al: Drugs for treatment of benign prostatic hyperplasia: affinity comparison at cloned ai-adrenoceptor subtypes and in human prostate. J Auton Pharmacol, 16: 21, 1996

WE CLAIM:
1. A compound having the structure of the Formula I
(Formula Removed)
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof, wherein:
X1 is N or CR4 (wherein R4 is hydrogen, hydroxyl or alkyl); A is aryl, aryloxy,
heterocyclyl, alkyl, alkoxy, cycloalkyl, NHCOR10 or CHR10R11 (wherein R10 and R11 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 (wherein R5 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl or
heterocyclyl), or R2 and R3 together with X1 to which they are attached form a ring of
the form (Formula Removed)

which contain additional one or more heteroatom(s) selected from O, S or N, wherein, M1 and M2 are independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl, alkoxy or acyl, M1 and M2 together form a bridging group (C0-3), W is
N, CH or COH, R6 is
(Formula Removed)
wherein, Y is O, S, NR4, C=O or a bond, R7, R8 and R9 are independently hydrogen, hydroxyl, amino, S(O)0-2R5 or NHSO2R5, L is a linker, • is the point of attachment.
2. A compound namely:
3-{3-[4-hydroxy-4-(2-methoxy phenyl)piperidin-l-yl]propyl}-l,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
Methyl {4-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl] piperazin-l-yl}(phenyl)acetate and its hydrochloride salt,
3-(3-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}propyl)-l,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-{3-[4-(5-fluoro-2-isopropoxy phenyl)piperazin-l-yl]-2-methyl propyl}-1,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-(3-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-yl}-2-methylpropyl)-l,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-{3-[4-(2-ethoxyphenyl) piperazin-1 -yl]-2-methyl propyl} -1,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-{2-methyl-3-[4-(2-propoxyphenyl)piperazin-l-yl]propyl}-l,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-(3-{4-[2-(cyclopentyloxy) phenyl]piperazin-l-yl}-2-methyl propyl)-! ,2,3-benzotriazin-4 (3H)-one and its hydrochloride salt,
3-{3-[4-(2-isopropoxyphenyl) piperazin-1 -yl]-2-methylpropyl} -1,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-[3-(3,4-dihydroisoquinolin-2(1H)-yl)propyl]-l ,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-{5-[4-(2-methoxyphenyl) piperazin-l-yl]pentyl}-l,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-{5-[4-(2-ethoxyphenyl) piperazin-l-yl]pentyl}-l,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-{5-[4-(2-propoxyphenyl) piperazin-l-yl]pentyl}-l,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-{5-[4-(2-isopropoxyphenyl)piperazin-l-yl]pentyl}-l,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3- {5-[4-(5-fluoro-2-isopropoxy phenyl)piperazin-1 -yl]pentyl} -1,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-(5-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-yl} pentyl)-l,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-{5-[4-(5-fluoro-2-methoxy phenyl)piperazin-l -yl]pentyl}-l ,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-{5-[3-(2-methoxyphenyl) imidazolidin-l-yl]pentyl}-l,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-[5-(6,7-dimethoxy-3,4-dihydro isoquinolin-2(1H)-yl)pentyl]-l,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-(3-{4-[2-(cyclopentyloxy)-5-fluorophenyl]piperazin-l-yl} propyl)-1,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-(3-{4-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-l-yl}propyl)-l,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-(5-{4-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-l-yl}pentyl)-l,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-{5-[4-(5-fluoro-2-propoxyphenyl)piperazin-l-yl]pentyl}-l,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3- {5-[4-(2-ethoxy-5-fluorophenyl)piperazin-1 -yl]pentyl} -1,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-[5-(3,4-dihydroisoquinolin-2(1H)-yl)pentyl]-l,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-{3-[8-hydroxy-8-(2-methoxyphenyl)-3-azabicyclo[3.2.1]oct-3-yl]propyl}-l,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3-azabicyclo[3.1.0]hex-6-yl}acetamide and its hydrochloride salt,
N-{3-[3-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)propyl]-3-azabicyclo[3.1.0]hex-6-yl}benzamide and its 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 and its hydrochloride salt,
3-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]-2-hydroxypropyl}-l,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-(3-{4-[2-(cyclopentyloxy)phenyl]piperazin-l-yl}-2-hydroxypropyl)-1,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-{2-hydroxy-3-[4-(2-propoxyphenyl)piperazin-l-yl]propyl}-l,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-{2-hydroxy-3-[4-(2-methoxyphenyl)piperazin-l-yl]propyl}-l,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3-{2-hydroxy-3-[4-(2-isopropoxyphenyl)piperazin-l-yl]propyl}-l,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
3 - {2-hydroxy-3 - [4-(2-methoxy phenyl)piperazin-1 -yl]propyl} -1,2,3-benzotriazin-4(3H)-one and its hydrochloride salt,
10- {3-[4-(2-methoxyphenyl)piperazin-1 -yl]propyl}-10H-phenoxazine and its hydrochloride salt,
10-{3-[4-(2-methoxyphenyl)piperazin-1 -yl]propyl}-10H-phenoxazine and its hydrochloride salt,
10-{3-[4-(2-propoxyphenyl)piperazin-1 -yl]propyl}-10H-phenoxazine and its hydrochloride salt,
10-{3-[4-(2-isopropoxy phenyl) piperazin-l-yl]propyl}-10H-phenoxazine and its hydrochloride salt,
10-{3-[4-(2-fluoro-6-methoxy phenyl) piperazin-l-yl]propyl}-10H-phenoxazine and its hydrochloride salt,
10-{3-[4-(2-fluoro-6-isopropoxy phenyl)piperazin-l-yl]propyl}-10H-phenoxazine and its hydrochloride salt,
10-(3- {4-[2-(cyclopentyloxy)-6-fluoro phenyl] piperazin-1 -yl}propyl)-l 0H-phenoxazine and its hydrochloride salt,
10-{3-[3-(2-methoxyphenyl) imidazolidin-l-yl]propyl}-10H-phenoxazine and its hydrochloride salt,
10- {3-[4-(2-ethoxyphenyl)piperazin-1 -yl]propyl} -10H-phenothiazine and its hydrochloride salt,
10-{3-[4-(2-isopropoxy phenyl) piperazin-l-yl]propyl}-10H-phenothiazine and its hydrochloride salt,
10- {3 - [4-(2-methoxyphenyl)piperazin-1 -yl] propyl} -10H-phenothiazine and its hydrochloride salt,
8-(2-methoxyphenyl)-3-[3-(10H-phenothiazin-10-yl)propyl]-3-azabicyclo [3.2.1]octan-8-ol and its hydrochloride salt,
10-(3-{4-[2-(cyclopentyloxy)phenyl] piperazin-l-yl}propyl)-10H-phenothiazine and its hydrochloride salt,
N-{3-[4-(2-methoxyphenyl)piperazin-1 -yl]propyl}-10H-phenothiazine-10-carbox amide and its hydrochloride salt,
10- {3-[4-(2-propoxyphenyl)piperazin-1 -yl]propyl}-10H-phenothiazine and its hydrochloride salt,
10-(3- {4-[2-(cyclopentyloxy)-5-fluoro phenyl] piperazin-1 -yl}propyl)-10H-phenothiazine and its hydrochloride salt,
10-{3-[4-(5-fluoro-2-isopropoxyphenyl)piperazin-l-yl]propyl}-10H-phenothiazine and its hydrochloride salt,
N- {3-[4-(2-methoxyphenyl)piperazin-1 -yl]propyl} -10H-phenoxazine-10-carboxamide and its hydrochloride salt,
N-[2-(2-methoxyphenoxy)ethyl]-10H-phenoxazine-10-carboxamide and its hydrochloride salt,
10-(3-{4-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-l-yl}propyl)-10H-phenoxazine and its hydrochloride salt,
10-{3-[3-(2-ethoxyphenyl)imidazolidin-1 -yl]propyl}-10H-phenothiazine and its hydrochloride salt,
10-{3-[4-(5-fluoro-2-propoxyphenyl)piperazin-l-yl]propyl}-10H-phenoxazineandits hydrochloride salt,
l-[4-(5-fluoro-2-methoxyphenyl)piperazin-l-yl]-3-(10H-phenoxazin-10-yl)propan-2-ol and its hydrochloride salt,
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof.
3. A pharmaceutical composition comprising a therapeutically effective amount of one or
more compounds of claim 1 together with pharmaceutically acceptable carriers,
excipients or diluents.
4. A method for treatment of a patient suffering from a disease or disorder mediated
through aia and/or α1d adrenergic receptor, comprising administering to said patient a
therapeutically effective amount of one or more compounds of claim 1 or pharmaceutical
composition of claim 3.
5. The method according to claim 5 wherein a disease or disorder is benign prostatic
hyperplasia or LUTS.
6. 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.
7. A method for the preparation of compounds of Formula VI,
(Formula Removed)
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites wherein, R, L, W, X1, M1, M2, A and R1 are the same as defined in claim 1, the method comprising:
(a) reacting a compound of Formula II with a compound of Formula III (wherein X2 and X3 is a leaving group)
(Formula Removed)
to give a compound of Formula IV
(Formula Removed)

(b) treating a compound of Formula IV with a compound of Formula V
(Formula Removed)
to give a compound of Formula VI.
8. A method for the preparation of compounds of Formula IX,
(Formula Removed)
Formula IX pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs,
prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites wherein, R, W, X1, M1, M2, A and RI are the same as defined in claim 1, the method comprising:
(a) reacting a compound of Formula II with a compound of Formula VII (wherein Xs is a
leaving group) (Formula Removed)
to give a compound of Formula VIII
(Formula Removed)
(b) treating a compound of Formula VIII with a compound of Formula V
(Formula Removed)
to give a compound of Formula IX.
9. A method for the preparation of compounds of Formula XIV,
(Formula Removed)
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites wherein,
Y, L, W, X1, M1, M2, A and R1 are the same as defined in claim 1, the method comprising:
(a) reacting a compound of Formula V(a) with a compound of Formula X (wherein X4 is
alkenyl or halogen)
(Formula Removed)
FomulaV(a) (Formula V, wherein W=N)
to give a compound of Formula XI
(Formula Removed)
(b) reducing a compound of Formula XI to give a compound of Formula XII
(Formula Removed)
(c) reacting a compound of Formula XII with a compound of Formula XIII
(Formula Removed)
to give a compound of Formula XIV 10. A method for the preparation of compounds of Formula XX,
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pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites wherein, Y, A and RI are the same as defined in claim 1 and n is an integer from 0-5 the method comprising:
(a) reacting a compound of Formula X with a compound of Formula VII
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to give a compound of Formula XVII
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(b) treating a compound of Formula XVI with a hydrazine hydrate to give a compound of
Formula XVIII
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(c) finally, treating a compound of Formula XVIII with a compound of Formula XIX
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give a compound of Formula XX.