Patent Application: US-201414770477-A

Abstract:
the present invention discloses pridoinolobenzazepine derivatives of formula 1 , wherein x is — o —, — s —, — so —, or — so 2 —. y is a single bond or a double bond . a and b are independently — n —; and ‘ n ’ varies from 0 to 3 . r 1 to r 9 are various electron donating , electron withdrawing , hydrophilic , or lipophilic groups selected to optimize the physicochemical and biological properties of compounds of formula i .

Description:
the present invention relates to pentacyclic compounds of formula i , wherein x is — chr 10 —, — o —, — nr 11 —, — s —, — so —, or — so 2 —; a and b are independently —( ch 2 ) n —, and subscript ‘ n ’ varies from 0 to 3 ; r 1 is selected from the group consisting of hydrogen , c 1 - c 10 alkyl , c 1 - c 10 hydroxyalkyl , c 5 - c 10 aryl unsubstituted or substituted with electron donating groups ( edg ) or electron withdrawing groups ( ewg ), c 1 - c 15 aroylalkyl , and c 1 - c 10 alkoxycarbonylalkyl , c 1 - c 10 carbamoylalkyl , c 5 - c 10 arylalkyl unsubstituted or substituted with edg or ewg ; r 2 to r 11 are independently selected from the group consisting of hydrogen , c 1 - c 10 alkyl , hydroxyl , c 1 - c 10 alkoxyl , — nr 12 r 13 , c 1 - c 10 hydroxyalkyl , halogen , trihaloalkyl , cyano , carboxyl , c 1 - c 10 acyl , c 1 - c 10 alkoxyalkyl ; c 1 - c 10 alkoxycarbonyl ; c 5 - c 10 aryl unsubstituted or substituted with edg or ewg , and c 5 - c 10 arylalkyl unsubstituted or substituted with edg or ewg ; and r 12 and r 13 are independently hydrogen or c 1 - c 10 alkyl , and r 12 and r 13 may optionally be tethered together from a ring . the phrase , ‘ electron donating group ( edg )’ and ‘ electron withdrawing group ( ewg )’ are well understood in the art . edg comprises alkyl , hydroxyl , alkoxyl , amino , acyloxy , acylamino , mercapto , alkylthio , and the like . ewg comprises halogen , acyl , nitro , cyano , carboxyl , alkoxycarbonyl , and the like . the first embodiment of the present invention is represented by formula i , wherein x is — chr 10 —; y is a single bond or a double bond ; a and b are —( ch 2 ) n —, and ‘ n ’ is 1 or 2 ; r 1 is selected from the group consisting of hydrogen , c 1 - c 10 alkyl , c 1 - c 10 hydroxyalkyl , c 5 - c 10 aryl unsubstituted or substituted with electron donating or electron withdrawing groups , c 1 - c 15 aroylalkyl , and c 1 - c 10 alkoxycarbonylalkyl , c 5 - c 10 arylalkyl unsubstituted or substituted with edg or ewg ; r 2 to r 11 are independently selected from the group consisting of hydrogen , c 1 - c 10 alkyl , hydroxyl , c 1 - c 10 alkoxyl , — nr 12 r 13 , c 1 - c 10 hydroxyalkyl , halogen , trihaloalkyl , cyano , carboxyl , c 1 - c 10 acyl , c 1 - c 10 alkoxyalkyl ; c 1 - c 10 alkoxycarbonyl ; c 5 - c 10 aryl unsubstituted or substituted with edg or ewg , and c 5 - c 10 arylalkyl unsubstituted or substituted with edg or ewg ; and r 12 and r 13 are independently hydrogen or c 1 - c 10 alkyl , and r 12 and r 13 may optionally be tethered together from a ring . x is — o —; y is a single bond or a double bond ; a and b are —( ch 2 ) n —, and ‘ n ’ is 1 or 2 ; r 1 is selected from the group consisting of hydrogen , c 1 - c 10 alkyl , c 1 - c 10 hydroxyalkyl , c 5 - c 10 aryl unsubstituted or substituted with electron donating or electron withdrawing groups , c 1 - c 15 aroylalkyl , and c 1 - c 10 alkoxycarbonylalkyl , c 5 - c 10 arylalkyl unsubstituted or substituted with edg or ewg ; r 2 to r 11 are independently selected from the group consisting of hydrogen , c 1 - c 10 alkyl , hydroxyl , c 1 - c 10 alkoxyl , — nr 12 r 13 , c 1 - c 10 hydroxyalkyl , halogen , trihaloalkyl , cyano , carboxyl , c 1 - c 10 acyl , c 1 - c 10 alkoxyalkyl ; c 1 - c 10 alkoxycarbonyl ; c 5 - c 10 aryl unsubstituted or substituted with edg or ewg , and c 5 - c 10 arylalkyl unsubstituted or substituted with edg or ewg ; and r 12 and r 13 are independently hydrogen or c 1 - c 10 alkyl , and r 12 and r 13 may optionally be tethered together from a ring . x is — s —; y is a single bond or a double bond ; a and b are —( ch 2 ) n —, and ‘ n ’ is 1 or 2 ; r 1 is selected from the group consisting of hydrogen , c 1 - c 10 alkyl , c 1 - c 10 hydroxyalkyl , c 5 - c 10 aryl unsubstituted or substituted with electron donating or electron withdrawing groups , c 1 - c 15 aroylalkyl , and c 1 - c 10 alkoxycarbonylalkyl , c 5 - c 10 arylalkyl unsubstituted or substituted with edg or ewg ; r 2 to r 11 are independently selected from the group consisting of hydrogen , c 1 - c 10 alkyl , hydroxyl , c 1 - c 10 alkoxyl , — nr 12 r 13 , c 1 - c 10 hydroxyalkyl , halogen , trihaloalkyl , cyano , carboxyl , c 1 - c 10 acyl , c 1 - c 10 alkoxyalkyl ; c 1 - c 10 alkoxycarbonyl ; c 5 - c 10 aryl unsubstituted or substituted with edg or ewg , and c 5 - c 10 arylalkyl unsubstituted or substituted with edg or ewg ; and r 12 and r 13 are independently hydrogen or c 1 - c 10 alkyl , and r 12 and r 13 may optionally be tethered together from a ring . x is — nr 11 —; y is a single bond or a double bond ; a and b are —( ch 2 ) n —, and ‘ n ’ is 1 or 2 ; r 1 is selected from the group consisting of hydrogen , c 1 - c 10 alkyl , c 1 - c 10 hydroxyalkyl , c 5 - c 10 aryl unsubstituted or substituted with electron donating or electron withdrawing groups , c 1 - c 15 aroylalkyl , and c 1 - c 10 alkoxycarbonylalkyl , c 5 - c 10 arylalkyl unsubstituted or substituted with edg or ewg ; r 2 to r 11 are independently selected from the group consisting of hydrogen , c 1 - c 10 alkyl , hydroxyl , c 1 - c 10 alkoxyl , — nr 12 r 13 , c 1 - c 10 hydroxyalkyl , halogen , trihaloalkyl , cyano , carboxyl , c 1 - c 10 acyl , c 1 - c 10 alkoxyalkyl ; c 1 - c 10 alkoxycarbonyl ; c 5 - c 10 aryl unsubstituted or substituted with edg or ewg , and c 5 - c 10 arylalkyl unsubstituted or substituted with edg or ewg ; and r 12 and r 13 are independently hydrogen or c 1 - c 10 alkyl , and r 12 and r 13 may optionally be tethered together from a ring . x is — chr 10 —; y is a single bond or a double bond ; a is — ch 2 —; b is — ch 2 ch 2 —; r 1 is hydrogen , c 1 - c 10 alkyl , c 5 - c 10 arylalkyl ; or c 1 - c 15 aroylalkyl ; and each of r 2 , r 3 , r 4 , r 5 , r 6 , r 7 , r 8 , r 9 , and r 10 is hydrogen . x is — o —; y is a single bond or a double bond ; a is — ch 2 —; b is — ch 2 ch 2 —; r 1 is hydrogen , c 1 - c 10 alkyl , c 5 - c 10 arylalkyl ; or c 1 - c 15 aroylalkyl ; and each of r 2 , r 3 , r 4 , r 5 , r 6 , r 7 , r 8 , r 9 , and r 10 is hydrogen . x is — s —; y is a single bond or a double bond ; a is — ch 2 —; b is — ch 2 ch 2 —; r 1 is hydrogen , c 1 - c 10 alkyl , c 5 - c 10 arylalkyl ; or c 1 - c 15 aroylalkyl ; and each of r 2 , r 3 , r 4 , r 5 , r 6 , r 7 , r 8 , r 9 , and r 10 is hydrogen . x is — nr 11 —; y is a single bond or a double bond ; a is — ch 2 —; b is — ch 2 ch 2 —; r 1 is hydrogen , c 1 - c 10 alkyl , c 5 - c 10 arylalkyl ; or c 1 - c 15 aroylalkyl ; each of r 2 , r 3 , r 4 , r 5 , r 6 , r 7 , r 8 , and r 10 is hydrogen ; and r 11 is hydrogen or c 1 - c 10 alkyl . the compounds belonging to formula i can be synthesized by the well - known fisher indole synthesis starting from known tricyclic dibenzazepines , dibenzoxazepines , and dibenzothiazepines ( 7a , b ) [ 14 , 15 ] as outlined in fig2 . stereospecific reduction of the double bond in b | c ring junction can be accomplished by nabh 3 cn / tfa or with bh 3 to give the cis - and trans - reduced compounds 11a , b and 12a , b respectively . compounds of the present invention may exist as a single stereoisomer or as mixture of enantiomers and diastereomers whenever chiral centers are present . individual enantiomers can be isolated by resolution methods or by chromatography using chiral columns , and the diastereomers can be separated by standard purification methods such as fractional crystallization or chromatography . as is well known in the pharmaceutical industry , the compounds of the present invention represented by formula i , commonly referred to as ‘ active pharmaceutical ingredient ( api )’ or ‘ drug substance ’, can be prepared as a pharmaceutically acceptable formulation . in particular , the drug substance can be formulated as a salt , ester , or other derivative , and can be formulated with pharmaceutically acceptable buffers , diluents , carriers , adjuvants , preservatives , and excipients . the phrase “ pharmaceutically acceptable ” means those formulations which are , within the scope of sound medical judgment , suitable for use in contact with the tissues of humans and animals without undue toxicity , irritation , allergic response and the like , and are commensurate with a reasonable benefit / risk ratio . pharmaceutically acceptable salts include , but are not limited to acetate , adipate , citrate , tartarate , benzoate , phosphate , glutamate , gluconate , fumarate , maleate , succinate , oxalate , chloride , bromide , hydrochloride , sodium , potassium , calcium , magnesium , ammonium , and the like . the formulation technology for manufacture of the drug product is well - known in the art , and are described in “ remington , the science and practice of pharmacy ” [ 16 ], incorporated herein by reference in its entirety . the final formulated product , commonly referred to as ‘ drug product ,’ may be administered enterally , parenterally , or topically . enteral route includes oral , rectal , topical , buccal , ophthalmic , and vaginal administration . parenteral route includes intravenous , intramuscular , intraperitoneal , intrasternal , and subcutaneous injection or infusion . the drug product may be delivered in solid , liquid , or vapor forms , or can be delivered through a catheter for local delivery at a target . also , it may be administered alone or in combination with other drugs if medically necessary . formulations for oral administration include capsules ( soft or hard ), tablets , pills , powders , and granules . such formulations may comprise the api along with at least one inert , pharmaceutically acceptable ingredients selected from the following : ( a ) buffering agents such as sodium citrate or dicalcium phosphate ; ( b ) fillers or extenders such as starches , lactose , sucrose , glucose , mannitol , and silicic acid ; ( c ) binders such as carboxymethylcellulose , alginates , gelatin , polyvinylpyrrolidone , sucrose and acacia ; ( d ) humectants such as glycerol ; ( e ) disintegrating agents such as agar - agar , calcium carbonate , potato or tapioca starch , alginic acid , certain silicates and sodium carbonate ; ( f ) solution retarding agents such as paraffin ; ( g ) absorption accelerators such as quaternary ammonium compounds ; ( h ) wetting agents such as cetyl alcohol and glycerol monostearate ; ( i ) absorbents such as kaolin and bentonite clay and ( j ) lubricants such as talc , calcium stearate , magnesium stearate , solid polyethylene glycols , sodium lauryl sulfate . and mixtures thereof ; ( k ) coatings and shells such as enteric coatings , flavoring agents , and the like . liquid dosage forms for oral administration include pharmaceutically acceptable emulsions , solutions , suspensions , syrups and elixirs . in addition to the api , the liquid dosage forms may contain inert diluents , solubilizing agents , wetting agents , emulsifying and suspending agents , sweetening , flavoring , and perfuming agents used in the art . compositions suitable for parenteral injection may comprise physiologically acceptable , sterile aqueous or nonaqueous isotonic solutions , dispersions , suspensions or emulsions , and sterile powders for reconstitution into sterile injectable solutions or dispersions . the compositions may also optionally contain adjuvants such as preserving ; wetting ; emulsifying ; dispensing , and antimicrobial agents . examples of suitable carriers , diluents , solvents , vehicles , or adjuvants include water ; ethanol ; polyols such as propyleneglycol , polyethyleneglycol , glycerol , and the like ; vegetable oils such as cottonseed , groundnut , corn , germ , olive , castor and sesame oils , and the like ; organic esters such as ethyl oleate and suitable mixtures thereof ; phenol , parabens , sorbic acid , and the like . injectable formulations may also be suspensions that contain suspending agents such as ethoxylated isostearyl alcohols , polyoxyethylene sorbitol and sorbitan esters , microcrystalline cellulose , aluminum metahydroxide , bentonite , agar - agar and tragacanth , or mixtures of these substances , and the like . prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption , for example , aluminum monostearate and gelatin . proper fluidity can be maintained , for example , by the use of coating materials such as lecithin , by the maintenance of the required particle size in the case of dispersions , and by the use of surfactants . in some cases , in order to prolong the effect of the drug , it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection . this can be accomplished by the use of a liquid suspension . the rate of absorption of the drug then depends upon its rate of dissolution which , in turn , may depend upon crystal size and crystalline form . alternatively , delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle . injectable depot forms are made by forming microencapsulated matrices of the drug in biodegradable polymers . depending upon the ratio of drug to polymer and the nature of the particular polymer employed , these compositions release the active ingredient ( s ) only , or preferentially , in a certain part of the intestinal tract , optionally , in a delayed manner . thus , the rate of drug release and the site of delivery can be controlled . examples of embedding compositions include , but are not limited to polylactide - polyglycolide poly ( orthoesters ), and poly ( anhydrides ), and waxes . the technology pertaining to controlled release formulations are described in “ design of controlled release drug delivery systems ,” [ 17 ] incorporated herein by reference in its entirety . formulations for topical administration include powders , sprays , ointments and inhalants . these formulations include the api along with suitable non - irritating excipients or carriers such as cocoa butter , polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound . compounds of the present invention can also be administered in the form of liposomes . any non - toxic , physiologically acceptable and metabolizable lipid capable of forming liposomes can be used . the present compositions in liposome form can contain , in addition to a compound of the present invention , stabilizers , preservatives , excipients and the like . the preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines ( lecithins ) used separately or together . methods to form liposomes are known in the art and are described in “ liposomes ,” [ 18 ], which is incorporated herein by reference in its entirety . the compounds of the present invention can also be administered to a patient in the form of pharmaceutically acceptable ‘ prodrugs .’ prodrugs are generally used to enhance the bioavailabilty , solubility , in vivo stability , or any combination thereof of the api . they are typically prepared by linking the api covalently to a biodegradable functional group such as a phosphate that will be cleaved enzymatically or hydrolytically in blood , stomach , or gi tract to release the api . a detailed discussion of the prodrug technology is described in “ prodrugs : design and clinical applications ,” [ 19 ] incorporated herein by reference . the dosage levels of api in the drug product can be varied so as to achieve the desired therapeutic response for a particular patient . the phrase “ therapeutically effective amount ” of the compound of the invention means a sufficient amount of the compound to treat disorders , at a reasonable benefit / risk ratio applicable to any medical treatment . it will be understood , however , that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment . the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated , the severity of the disorder ; activity of the specific compound employed ; the specific composition employed , age , body weight , general health , sex , diet of the patient ; the time of administration , route of administration , and rate of excretion of the specific compound employed , and the duration of the treatment . the total daily dose of the compounds of this invention administered may range from about 0 . 0001 to about 1000 mg / kg / day . for purposes of oral administration , more preferable doses can be in the range from about 0 . 001 to about 5 mg / kg / day . if desired , the effective daily dose can be divided into multiple doses for optimal therapeutic effect . the following examples illustrate specific embodiments and utilities of the invention , and are not meant to limit the invention . as would be apparent to skilled artisans , various modifications in the composition , operation , and method are possible , and are contemplated herein without departing from the concept and scope of the invention as defined in the claims . synthesis of compound of formula i , wherein x is chr 10 , y is a double bond , r 1 is ch 1 , and r 2 to r 10 are hydrogens ( 13a ) ( ddd - 029 ) dibenz [ b , e ] azepine ( 1 . 95 g , 10 mmol ) in ethanol ( 25 ml ), and acetic acid ( 10 ml ) was gently stirred and heated to dissolved all the solids . thereafter , the solution was cooled to ambient temperature and treated with a concentrated , aqueous solution of nano 2 ( 1 . 03 g , 15 mmol ) in water ( 5 ml ) added dropwise over a period of 5 minutes . the reaction was stirred at ambient temperature for 30 minures and treated with water ( 30 ml ). the solid was collected by filtration , washed with water , and dried to give 1 . 9 g ( 89 %) of the n - nitroso compound . the material was used as such for the next step . a stirring mixture of nitroso compound from step 1 ( 336 mg , 1 . 5 mmol ) and n - methyl - 4 - piperidone hydrochloride ( 270 mg , 1 . 8 mmol ) in ethanol ( 4 . 5 ml ) and acetic acid ( 1 . 5 ml ) was treated with zinc dust ( 393 mg , 6 . 0 mmol ) added in three equal portions allowing 5 - 10 minutes between the additions . the reaction was then stirred at ambient temperature for 2 hours . the reaction mixture was cooled to about 0 - 5 ° c ., diluted and carefully treated with 10 % naoh ( 2 ml ). the reaction mixture was extracted with dichloromethane ( 3 × 30 ml ). the combined organic layers were washed with brine , dried over anhydrous sodium sulfate , filtered , and the filtrate evaporated in vacuo . the crude material was purified by flash chromatography ( silica gel , gradient elution , 0 - 10 % methanol / chloroform over 90 minutes ) to furnish 200 mg ( 43 %) of the hydrazone . a suspension of the hydrazone from step 2 ( 400 mg , 1 . 3 mmol ) in toluene ( 3 ml ) was treated with 1 m solution of hydrogen chloride in diethyl ether ( 2 . 6 ml , 2 . 6 mmol ) and p - toluenesulfonic acid ( 300 mg , 1 . 6 mmol ), and the entire mixture was heated under reflux for 2 hours . the reaction mixture was cooled to ambient temperature , treated with 10 % naoh ( 4 ml ), and extracted with dichloromethane ( 3 × 30 ml ). the combined organic layers were washed with brine , dried over anhydrous sodium sulfate , filtered , and the filtrate evaporated in vacuo . the crude product was purified by flash chromatography ( silica gel , gradient elution , 0 - 10 % methanol / chloroform over 90 minutes ) to give 140 mg ( 37 %) of the desired product 13a . hrms ( esi ) m / z calcd . for c 20 h 21 n 2 ( m + h ) + 289 . 1699 . found , 289 . 1698 . synthesis of compound of formula i , wherein x is o , y is a double bond , r 1 is ch 3 , and r 2 to r 9 are hydrogens 13b ( ddd - 024 ) to a well stirred solution of compound dibenz [ b , e ] oxazepine ( 6 . 98 g , 32 . 7 mmol ) in thf ( 30 ml ) and acoh ( 9 ml ), a concentrated solution of nano 2 ( 7 . 03 g , 101 . 9 mmol ) in water ( 12 ml ) was added dropwise at ambient temperature . the reaction was stirred at ambient temperature for 20 min and treated with water ( 100 ml ). the product was filtered , washed with water , and dried to give 7 . 67 g ( 97 %) of the nitroso compound . to a stirred solution of nitroso compound from step 1 ( 14 . 6 g , 61 . 1 mmol ) and n - methyl 4 - pyridone ( 9 . 04 g , 79 . 9 mmol ) in ethanol ( 150 ml ) and acetic acid ( 20 ml ) at 55 ° c ., was added zinc dust ( 12 . 0 g , 183 . 5 mmol ) in three equal portions allowing 10 mins between the additions . the reaction was stirred for another 5 minutes and filtered hot . the solid washed with ethanol , and the resultant solution was heated to reflux for 30 minutes , and thereafter the solvent was removed in vacuo . the residue was treated with 8 ml of acetic acid , and heated to reflux for about 16 hours . the solvent was removed in vacuo , and the residue was dissolved in methylene chloride ( 500 ml ). the solid impurity was removed by filtration , and the filtrate was washed with 10 % naoh solution . the combined organic layer was washed with water and brine , dried over anhydrous sodium sulfate , filtered and the filtrate taken to dryness in vacuo . the crude product was purified by flash chromatography on silica gel using 0 - 5 % meoh / chloroform as the eluent to give 3 . 0 g ( 16 %) of the desired product 13b . hrms ( esi ) m / z calcd . for c 19 h 19 n 2 o ( m + h ) + 291 . 1492 . found , 291 . 1484 . synthesis of compound of formula i , wherein x is o , y is a single bond with cis - fused b | c rings , r 1 is ch 3 , and r 2 to r 9 are hydrogens 14a , b ( ddd - 030 ) a stirrerd cold solution of compound 13b from example 2 ( 2 mmol ) in trifluoroacetic acid ( 6 . 5 ml ) at − 5 ° c ., was carefully treated with solid sodium cyanoborohydride ( 0 . 125 g , 2 . 4 mmol ). the reaction mixture was then stirred at ambient temperature for 3 h , treated with 6n hcl solution , and heated under reflux for 30 minutes . the solution was cooled to ambient temperature , and excess trifluoroacetic acid is removed in vacuo . the residue was rendered alkaline with 25 % naoh solution ( 12 ml ), and the solution was extracted with chloroform . the combined organic layers are washed with water and brine , and dried over anhydrous sodium sulfate , filtered , and the filtrate evaporated in vacuo . the crude compound was purified by flash column chromatography on silica gel using 0 - 5 % meoh / chloroform gradient elution . hrms ( esi ) m / z calcd . for c 19 h 21 n 2 o ( m + h ) + 293 . 1648 . found , 293 . 1647 . synthesis of compound of formula i , wherein x is o , y is a single bond with trans - fused b | c rings , r 1 is ch 3 , and r 2 to r 9 are hydrogens 15a , b ( ddd - 031 ) the compound 13b from example 2 ( 1 mmol ) was treated with borane - thf ( 10 ml , 1 . 0 m ) at ambient temperature , and the mixture is heated under reflux for 1 hour by which time the reaction mixture became clear . after cooling to ambient temperature , the solution was treated with water to quench excess reagent borane reagent . the solvents were removed under reduced pressure , and the residue was treated with conc . hcl ( 7 ml ). the mixture was heated to reflux for 3 hours and evaporated to dryness in vacuo , and treated with 10 % naoh solution ( 10 ml ). the product was then extracted with etoac , washed with water and brine , dried over anhydrous sodium sulfate , filtered , and the filtrate evaporated to dryness under reduced pressure . the crude product was purified by flash chromatography on silica gel using 0 - 5 % meoh / chloroform gradient elution . hrms ( esi ) m / z calcd . for c 19 h 21 n 2 o ( m + h ) + 293 . 1648 . found , 293 . 1647 . the receptor binding data of compounds 6a , 13a , and 13b are given in table 1 . as can be clearly noted , the receptor binding profiles between 13a , and 13b are substantially different from each other as well as from the prior art compound 6a . most noteworthy is the fact that neither of the two compounds 13a and 13b binds significantly to any of the dopamine receptors . compound 13a displays strong binding to 5 - ht 1d , 5 - ht 2b , and h 1 , and moderate binding at 5 - ht 1a , 5 - ht 6 , and 5 - ht 7 . compound 13b binds strongly to 5 - ht 1a ; and moderate binding to 5 - ht 1d , ht 2c , binding 5 - ht 6 , 5 - ht 7 , and σ 1 . it is noteworthy that 13a and 13b differ strongly in their binding affinities to σ 1 and σ 2 receptors , which suggests that 13a and 13b may be useful for the treatment of cancer and pain respectively [ 21 , 22 ]. ddd - 024 was initially tested for effects on the reinstatement of meth seeking in a small pilot group of rats with a history of chronic meth self - administration . rats self - administered meth ( 0 . 02 mg / 50 μl bolus ; approximately 0 . 06 mg / kg ) for two weeks , followed by daily extinction sessions , whereby responding did not result in reinforcement . rats received a vehicle ( 10 % dmso ) or ddd - 024 ( 10 mg / kg ) injection ( i . p .) just before each reinstatement session , which consisted of a meth priming injection ( 1 mg / kg , i . p .) and presentation of meth - associated cues ( tone and light ) upon each lever press . results : ddd - 024 significantly reduced the number of lever presses , reflecting attenuation of meth seeking behavior ( fig3 ). in this in vivo study , locomotor activity was measured in a circular corridor with four infrared beams placed at every 90 ° ( imetronic , france ). counts were incremented by consecutive interruption of two adjacent beams ( i . e . mice moving through one - quarter of the corridor ). ddd - 024 was tested in mdma - induced motor behavior at 5 , 10 and 20 mg / kg , ip , in mice ( 129sv / pas background , 8 week old , charles river laboratories ). the animals were injected with vehicle and individually placed in the activity box for 30 min during 3 days consecutively for habituation before experiments . mice received vehicle or ddd - 024 ( 5 - 20 mg / kg , i . p .) injection 30 min before mdma injection ( 10 mg / kg ). results : ddd - 024 completely blocked the increase in motor activity elicited by mdma at 20 mg / kg , i p . in mice and partially at 10 mg / kg reflecting attenuation of mdma - seeking behavior ( fig4 ). ddd - 024 was tested in the forced swim test using three groups of rats ( n = 10 each for vehicle , positive control ( imipramine ), and ddd - 024 . each subject in the control group received 10 mg / kg of imipramine , and those in the test group received 5 , 10 , and 20 mg / kg of ddd - 024 ( i . p .). after 1 hour , the rats were individually placed in a 500 ml container of water ( 22 ° c .) filled to a height of 10 cm . rats were observed for immobility and time taken for immobility was recorded , as well as recording performance on video . immobility is the measure of the absence of active , escape - oriented behaviors such as swimming , jumping , rearing , sniffing , or diving . results : ddd - 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