Patent Application: US-52622400-A

Abstract:
this invention relates to a series of arylsubstituted piperazines , of formula i pharmaceutical compositions containing them and intermediates used in their manufacture . the compounds of the invention selectively inhibit binding to the α - 1a adrenergic receptor , a receptor which has been implicated in benign prostatic hyperplasia . as such the compounds are potentially useful in the treatment of this and other disease .

Description:
the terms used in describing the invention are commonly used and known to those skilled in the art . “ hbss ” refers to hank &# 39 ; s balanced salt solution . “ independently ” means that when there are more than one substituent , the substitutents may be different . the term “ alkyl ” refers to straight , cyclic and branched - chain alkyl groups and “ alkoxy ” refers o - alkyl where alkyl is as known α1 - ar antagonists defined supra . “ lda ” refers to lithium diiopropylamide , and “ bop ” refers to bezotriazole - 1 - yl - oxy - tris -( dimethylamino )- phoxphoniumhexafluorophosphate . “ boc ” refers to t - butoxycarbonyl , “ pybrop ” refers to bromo - tris - pyrrolidino - phosphonium hexafluorophosphate , “ cbz ” refers to benzyloxycarbonyl , and “ ts ” refers to toluenesulfonyl . “ dcc ” refers to 1 , 3 - dicyclohexylcarbodiimide , “ dmap ” refers to 4 - n ′ n - dimethylaminopyridine , “ edci ” refers to 1 -( 3 - dimethylamionpropyl )- 3 - ethylcarbodiimide hydrochloride , and “ hobt ” refers to 1 - hydroxybenzotriazole hydrate . the symbol “ ph ” refers to phenyl and “ pht ” refers to phthalimido . the term “ effective dose ” refers to an amount of a compound of formula i which binds to an / or antagonizes the activity of the α - 1 a adrenergic receptor . in addition , the term “ effective dose ” refers to an amount of a compound of formula i which reduces the symptoms of diseases associated with the α - 1 a adrenergic receptor . the compounds of the invention may be prepared by the following schemes , where some schemes produce more than one embodiment of the invention . in those cases , the choice of scheme is a matter of discretion which is within the capabilities of those of synthetic chemists . compounds of formula i where r 1 is phenyl , r 2 is hydrogen , r 3 is oxygen , a is ( ch 2 ) 3 and m is 4 , may be prepared as illustrated by scheme 1 . in this scheme , the molecules of formula i are prepared in a convergent synthesis where two halves of the molecule are assembled and ultimately coupled together . the starting material for one half is a mono n - substituted piperazine of type 1 a . treatment of 1 a with a mild base such as k 2 co 3 and an alkylating agent , such as acrylonitrile in an inert solvent such as meoh at room temperature for 2 - 24 hours gives the nitrile 1 b . this intermediate may be hydrogenated using rainy nickel as a catalyst to give the propylamine intermediate 1 c . the other half of the molecule is assembled using compounds of type 1c as starting materials . ε - caprolactam is treated with a strong base such as nah , in an inert solvent at 0 ° c . for about 30 minutes . the formed anion is treated with an alkylating agent such as t - butylbromoacetate in an inert solvent such as acetonitrile at room temperature for two hours to 2 days to give the ester 1 e . hydrolysis of 1e with an acid such as trifluoroacetic acid at room temperature over 2 - 16 hours gives the acid 1f . treatment of the amine 1c and the acid 1f with a peptide coupling agent such as bop and a suitable amine such as dmap at room temperature over 1 - 16 hours gives a compound of formula i , 1 g . other coupling agents may be substituted for bop . such agents include but are not limited to , pybrop , edci , hobt and the like . suitable dmap replacements include but are not limited to n - methylmorpholine , imidazole , dabco and the like . scheme 1 may be used to prepare compounds aside from 1 g . to prepare compounds where m is 1 - 5 , known lactams of the appropriate ring size such as 2 - azacyclooctanone , replace c - caprolactam in scheme 1 . to prepare compounds where r 1 is other than phenoxy , 1a is replaced with known phenyl piperazine derivatives such as n -( 2 - t - butoxyphenyl )- piperazine . to prepare compounds where a is ( ch 2 ) n and n is 1 - 6 , acrylonitrile may be replaced with alkylating agents such as 4 - chlorobutyronitrile . alternatively , intermediate 1c may be prepared by another route as illustrated in scheme 2 . piperazine derivative 1a is treated with a mild base and known phthalimido derivatives such as n -( 4 - bromobutyl ) phthalimide to give intermediate 2a . treatment of 2a with a hydrazine such as n - methyl hydrazine in a suitable solvent such as meoh or etoh at reflux , gives intermediates of type 1c . alternatively , piperazine 1a is treated with a mild base and an n - boc protected amine such as n - tert - butoxycarbonyl - 4 - bromobutylamine to give the corresponding boc protected amine . this amine can be deprotected by treatment with an acid such as tfa to give intermediates of type 1c . to prepare compounds where r 2 is other than hydrogen , scheme 3 may be used . treatment of compounds of type 1 g with a strong base such as nah , followed by an alkylating agent such as benzyl bromide gives compounds of type 3a in 1 - 5 hours at temperatures from about 0 - 35 ° c . compounds where r 4 is oxygen , c 1 - 5 alkyl , formyl , carboxy , c 1 - 5 alkylcarbonyl , c 1 - 5 alkoxycarbonyl , phenylc 1 - 5 alkoxy , substituted phenylc 1 - 5 alkoxy , and amide may be synthesized by scheme 4 . for example to prepare compounds where r 4 is ethoxycarbonyl , m is 2 , and r 3 is carbonyl , treat ethyl - 2 - pyrrolidone - 5 - carboxylate with a strong base such as nah , in an inert solvent at 0 ° c . for about 30 minutes . the formed anion is treated with an alkylating agent such as t - butylbromoacetate in an inert solvent such as acetonitrile at room temperature for two hours to 2 days to give the ester 4a . acidic hydrolysis of 4a with trifluoroacetic acid at room temperature over 2 - 16 hours gives the acid 4b . coupling of the acid 4b and the intermediate amine 1c with a peptide coupling agent such as prybop gives a compound of formula i , 4c . the ethyl ester of compound 4c may be treated with a variety of agents to give derivatives such as amides , carboxylic acids , aldehydes etc , where the reagents and reaction conditions are within the knowledge of those skilled in the art . although the claimed compounds are useful as modulators of α1 - ar , some compounds are either preferred or particularly preferred . the preferred compounds of the invention include : the particularly preferred “ r 2 ” s are hydrogen , c 2 - 5 alkenyl and c 2 - 5 alkynyl . the particularly preferred “ a ” s are ( ch 2 ), where n is 2 - 4 . the particularly preferred compounds of formula ii include compounds where a is 2 or 3 , r 1 is c 2 - 6 alkyl , and r 7 is hydrogen . the particularly preferred compounds of formula iii include compounds where m is 3 . the compounds of formula i may be used in pharmaceutical compositions to treat patients with disorders related to modulating the activity of the α1 adrenergic receptor . the preferred route is oral administration , however compounds of the invention may be administered by other methods , including but not limited to intravenous infusion . oral doses range from about 0 . 01 - 100 mg / kg daily . the preferred oral dosage range is from about 0 . 05 - 1 . 0 mg / kg daily . infusion doses can range from about 0 . 001 - 100 mg / kg / min of inhibitor , with a pharmaceutical carrier over a period ranging from several minutes to several days . the pharmaceutical compositions can be prepared using conventional pharmaceutical excipients and compounding techniques . oral dosage forms may be elixers , syrups , capsules tablets and the like . where the typical solid carrier is an inert substance such as lactose , starch , glucose , methyl cellulose , magnesium sterate , dicalcium phosphate , mannitol and the like ; and typical liquid oral excipients include ethanol , glycerol , water and the like . all excipients may be mixed as needed with disintegrants , diluents , granulating agents , lubricants , binders and the like using conventional techniques known to those skilled in the art of preparing dosage forms . parenteral dosage forms may be prepared using pharmaceutically acceptable carriers or diluents , including but not limited to water or another sterile carrier . typically the compounds of formula i are isolated and used as free bases , however the compounds may be isolated and used as their pharmaceutically acceptable salts . examples of such salts include but are not limited to hydrobromic , hydroiodic , hydrochloric , perchloric , sulfuric , maleic , fumaric , malic , tartatic , citric , benzoic , mandelic , methanesulfonic , hydroethanesulfonic , benzenesulfonic , oxalic , pamoic , 2 - naphthalenesulfonic , p - toluenesulfonic , cyclohexanesulfamic and saccharinic . in order to illustrate the invention the following examples are included . these examples do not limit the invention . they are meant only to suggest a method of practicing the invention . those skilled in the art may find other methods of practicing the invention , which will be readily apparent to them . however those methods are deemed to be within the scope of this invention . n -( 2 - bromoethyl ) phthalimide ( 7 . 6 g , 30 mmol ) and k 2 co 3 ( 6 . 2 g , 45 mmol ) were added to a solution of n - 1 -( 2 - isopropoxyphenyl ) piperazine ( 6 . 6 g , 30 mmol ) in acetonitrile ( 100 ml ) and the resulting mixture was heated at reflux for 2 days . the mixture was concentrated in vacuo and purified by column chromatography on silica gel using etoac / hexanes ( 30 : 70 ) as an eluent gave the title compound as a solid : ms m / z 394 ( mh + ). a solution of compound 1 ( 7 . 5 g , 19 mmol ) in etoh ( 70 ml ) was stirred for 10 minutes at room temperature . methylhydrazine ( 20 ml ) was added and the mixture was heated at reflux for 2 . 5 hours . the mixture was cooled to room temperature and the resulting solid precipitate was removed by filtration . the filtrate was concentrated in vacuo yielded the title compound as solid which was used without purification : ms m / z 264 ( mh + ). 95 % sodium hydride ( 1 . 67 g , 66 mmol ) was added to a stirred solution of δ - valerolactam ( 5 . 95 g , 60 mmol ) in toluene ( 100 ml ) at 0 ° c . and the resulting suspension was stirred for 1 hours . t - butylbromoacetate ( 8 . 86 ml , 60 mmol ) was added dropwise and the reaction mixture was warmed to room temperature and stirred for 10 hours . saturated nh 4 cl aq was added and the resulting organic layer was washed with successive portions of brine and h 2 o . the combined organic layers were dried ( na 2 so 4 ) and concentrated in vacuo to give compound 3 as an oil . trifluoroacetic acid ( 15 ml ) was added to a stirred solution of compound 2 ( 12 . 93 g , 61 mmol ) in methylene chloride ( 30 ml ) under n 2 . this mixture was stirred for 4 hours and concentrated in vacuo to give the title compound as a solid : ms m / z 158 ( mh + ). a solution of compound 2 ( 3 . 61 g , 23 mmol ) in methylene chloride ( 10 ml ) was added to a solution of compound 4 ( 5 . 0 g , 19 mmol ) in methylene chloride ( 10 ml ). pybrop ( 10 . 72 g , 23 mmol ), dmap ( 3 . 85 g , 31 mmol ) and n - methylmorpholine ( 2 . 53 ml , 23 mmol ) were added and the mixture was stirred at room temperature under n 2 for 10 hours . the resulting mixture was washed with one portion of aqueous sodium bicarbonate , brine and h 2 o . the combined organic layer was dried ( na 2 so 4 ) and concentrated in vacuo . the residue was purified by mplc on silica gel using etoac / meoh / triethylamine ( 90 : 5 : 5 ) as an eluent to give the title compound as an oil : ms m / z 403 ( mh + ). treatment of the isolated compound with an equimolar portion of citric acid in ethyl acetate gave the citrate salt of the title compound as a solid . sodium hydride ( 95 % tech . 10 . 6 mg , 0 . 44 mmol ) was added to a stirred solution of compound 5 ( 140 . 5 mg , 0 . 35 mmol ) in thf ( 5 ml ) at 0 ° c . and the resulting suspension was stirred for 30 minutes . methyl iodide ( 0 . 37 mmol ) was added dropwise and the mixture was stirred overnight at room temperature . the residue was concentrated in vacuo , dissolved in ethyl acetate and washed with successive portions of aqueous , sat . ammonium chloride solution , brine and water . the combined organic layer was dried ( na 2 so 4 ) and concentrated in vacuo to give the title compound as a solid : ms m / z 417 ( mh + ). biological activity and selectivity of compounds of the invention was demonstrated by the following in vitro assays . the first assay tested the ability of compounds of formula i to bind to membrane bound receptors α1 a - ar , α1 b - ar and α1 d - ar . the dna sequences of the three cloned human α1 - ar subtypes have been published . furthermore , the cloned cdnas have been expressed both transiently in cos cells and stably in a variety of mammalian cell lines ( hela , lm ( tk -), cho , rat - 1 fibroblast ) and have been shown to retain radioligand binding activity and the ability to couple to phosphoinositide hydrolysis . we used published dna sequence information to design primers for use in rt - pcr amplification of each subtype to obtain cloned cdnas . human poly a + rna was obtained from commercially available sources and included hippocampus and prostate samples , sources which have been cited in the literature . for the primary screen a radio ligand binding assay was used which employed membrane preparations from cells expressing the individual cloned receptor cdnas . radiolabeled ligands with binding activity on all three subtypes ( non - selective ) are commercially available ([ 125i ]- heat , [ 3h ]- prazosin ). each α1 receptor subtype was cloned from poly a + rna by the standard method of reverse transcription - polymerase chain reaction ( rt - pcr ). the following sources of polya + rna were used for the cloning of the α1 receptor subtypes : α1 a - ar , human hippocampus and prostate , α1 b - ar , human hippocampus , α1 d - ar , human hippocampus . the resulting cdnas were cloned into the pcdna3 mammalian expression vector ( invitrogen corp ., san diego calif .). each dna was sequenced for verification and to detect any possible mutations introduced during the amplification process . any deviation in sequence from the published consensus for each receptor subtype was corrected by site - directed mutagenesis . the three α1 - ar subtypes ( a , b , d ) were transfected into cos cells using a standard deae - dextran procedure with a chloroquine shock . in this procedure , each tissue culture dish ( 100 mm ) was inoculated with 3 . 5 × 10 6 cells and transfected with 10 μg of dna . approximately 72 hours post - transfection , the cells were harvested and cos membranes were prepared . transfected cos cells from 25 plates ( 100 mm ) were scraped and suspended in 15 ml of te buffer ( 50 mm tris - hcl , 5 mm edta , ph7 . 4 ). the suspension was disrupted with a homogenizer . it was then centrifuged at 1000 × g for 10 minutes at 4 ° c . the supernatant was centrifuged at 34 , 500 × g for 20 minutes at 4 ° c . the pellet was resuspended in 5 ml tne buffer ( 50 mm tris - hcl , 5 mm edta , 150 mm nacl , ph7 . 4 ). the resulting membrane preparation was aliquoted and stored at − 70 ° c . the protein concentration was determined following membrane solubilization with tritonx - 100 . the ability of each compound to bind to each of the α1 - ar subtypes was assessed in a receptor binding assay . [ 125i ]- heat , a non - selective α1 - ar ligand , was used as the radiolabeled ligand . each well of a 96 - well plate received : 140 μl tne , 25 μl [ 125i ]- heat diluted in tne ( 50 , 000 cpm ; final concentration 50 pm ), 10 μl test compound diluted in dmso ( final concentration 1 pm - 10 em ), 25 ml cos cell membrane preparation expressing one of the three α1 - ar subtypes ( 0 . 05 - 0 . 2 mg membrane protein ). the plate was incubated for 1 hour at room temperature and the reaction mixtures were filtered through a packard gf / c unifilter filter plate . the filter plate was dried for 1 hour in a vacuum oven . scintillation fluid ( 25 ml ) was added to each well , and the filter plate was counted in a packard topcount scintillation counter . data was analyzed using graphpad prism software . tables a & amp ; b list the ic 50 values expressed in nanomolar concentration for select compounds of the invention in all receptor subtypes . the antagonist activity of select compounds of formula i was demonstrated by the following screen . binding of an agonist to α1 - ars causes the activation of plc through g - protein coupled mechanisms ( minneman and esbenshade , 1994 ). plc catalyzes the hydrolysis of phosphatidyl inositol 4 , 5 - bisphosphate ( pip2 ) generating two second messenger molecules , inositol 1 , 4 , 5 - triphosphate ( ip3 ) and diacylglycerol ( dag ) and ultimately resulting in mobilization of intracellular calcium stores . hits from the primary screening assay that showed selectivity in inhibiting radioligand binding to the α1 a - ar were evaluated for the ability to antagonize the mobilization of cytosolic calcium in cell lines stably expressing individual receptor subtypes . preparation of stable cell lines expressing each receptor subtype : the alpha 1 adrenergic receptor subtypes ( a , b , d ) in the pcdna3 vector were transfected into hek 293s ( human embryonic kidney ) cells to form stable receptor - expressing cell lines . transfection was performed using dmrie - c ( gibcobrl ) cationic lipid reagent mixed with 2 - 3 ug of dna and reduced serum opti - mem 1 medium ( gibcobrl ). cells in 100 mm tissue culture plates were overlayed with the lipid - dna complex and incubated at 37 ° c ., 5 % co 2 for 5 - 6 hours . serum - containing growth medium was then added and cells were incubated for an additional 48 hours . following this incubation , each plate was split 1 : 5 into selection medium containing 250 , 300 or 350 ug / ml of g418 ( geneticin ) antibiotic . plates were fed every 4 days with the appropriate selection medium . after approximately 3 weeks , colonies were picked for each subtype from the 300 ug / ml g418 selection plates . colonies were expanded and frozen . twelve cell lines of each subtype were screened for alpha 1 adrenergic receptor binding using a whole cell receptor binding assay . positive cultures were subsequently analyzed by the calcium mobilization assay . hek 293s cells expressing human α1 a - ar were lifted with trypsin and washed once with hbss . the cell pellet was resuspended in hbss with 0 . 05 % bsa to 1 - 5 × 10 6 cells / ml . a 5 mm fluo - 3 solution ( in ⅔ vol . dmso and ⅓ vol pluronic acid ) was added to the cell suspension , giving a final fluo - 3 concentration of 5 μm . cells were then incubated with gentle rocking at room temperature for 1 hr in the dark . after incubation , the cells were washed 3 × with hbss and resuspended in hbss with 1 . 25 mm cacl 2 to 0 . 7 × 10 6 cell / ml . cell aliquots ( 100 μl ) were pippetted into each well of a 96 - well microplate . calcium mobilization was induced with norepinephrine ( 10 um ) at room temperature . two minutes prior to assay , antagonists were added to cells utilizing a 96 - well pipettor . afterward , the agonist was added and fluorescent signal was monitored for 2 - 3 minutes using flipr ( molecular devices , usa ). compound 5 inhibited the mobilization of cytosolic calcium at an ic 50 of 99 μm . the antagonist activity and the selectivity of compounds of the invention for prostate tissues over aortic tissues as well as their antagonists was demonstrated as follows . the contractile responses of rat prostatic tissue and rat aorta tissues were examined in the presence and absence of antagonist compounds . as an indication of the selectivity of antagonism , test compound effects on vascular smooth muscle contractility ( α1 b - ar and α1 d - ar ) were compared to the effects on prostatic smooth muscle ( α1 a - ar ). strips of prostatic tissue and aortic rings were obtained from long evans derived male rats weighing 275 grams and sacrificed by cervical dislocation . the prostate tissue was placed under 1 gram tension in a 10 ml bath containing phosphate buffered saline ph 7 . 4 at 32 ° c . and isometric tension was measured with force transducers . the aortic tissue was placed under 2 grams tension in a 10 ml bath containing phosphate buffered saline ph 7 . 4 at 37 ° c . the ability of test compound to reduce the norepinephrine - induced contractile response by 50 % ( ic 50 ) was determined . compound 5 inhibited the contractile response in aortic tissue with an ic 50 of 31 . 9 μm and in prostate tissue with an ic 50 of 1 . 3 μm . select compounds of the invention were tested for their ability to antagonize phenylephrine ( pe ) induced increases in intraurethral pressure in dogs . the selectivity of these compounds was demonstrated by comparing their effect upon pe induced increases in mean arterial pressure ( map ) in the dog . male beagle dogs were anesthetized and catheterized to measure intraurethral pressure ( iup ) in the prostatic urethra . mean arterial pressure ( map ) was measured using a catheter placed in the femoral artery . dogs were initially administered six i . v . bolus doses ( 1 to ≦ 32 mg / kg ) of phenylephrine ( pe ) to establish a control agonist dose - response curve . iup and map were recorded following each dose until the iup returned to baseline . the dogs then were given an i . v . bolus dose of the antagonist compound , followed by i . v . pe challenges of ascending doses , as in the control agonist dose - response curve . iup and map measurements following each pe challenge were recorded . the antagonist compound was tested over a dose range of 3 to 300 ug / kg in half - log increments . the interval between antagonist doses was at least 45 minutes and three experiments were performed per dose level for each test compound . fig1 and 2 illustrates the mean percentage reductions in iup and map for compounds 5 and 12 respectively . breslin d , fields d w , chou t - c , marion d n , kane m , vaughan e d , and felsen d ( 1993 ) medical management of benign prostatic hyperplasia : a canine model comparing the in vivo efficacy of alpha - 1 adrenergic antagonists in the prostate . j . urol . 149 : 395 - 399 . bruno j f , whittaker j , song j , and berelowitz m . 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