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藥學碩士學位論文 4-MethylsulfonylaminophenylTRPV1 Antagonists 에서 One-carbon 이연장된 유사체들의구조활성연구 SAR on One-carbon HomolongatedAnalogues of4-methylsulfonylaminophenyltrpv1 Antagonists 2012 年 8 月 서울大學校大學院 制藥學科藥品化學專攻 李浩斌
4-MethlysulfonylaminophenylTRPV1Antagonists 에서 One-carbon 이연장된유사체들의구조활성연구 SAR on One-carbon HomolongatedAnaloguesof 4-MethylsulfonylaminophenylTRPV1Antagonists 指導敎授李智雨 이論文을藥學碩士學位論文으로提出함 2012 年 08 月 서울大學校大學院 藥學科藥品化學專攻 李浩斌 李浩斌의藥學碩士學位論文을認准함 2012 年 08 月 委員長 ( 印 ) 副委員長 ( 印 ) 委員 ( 印 )
요약 ( 국문초록 ) Transientreceptorpotentialvaniloid1(TRPV1) 은비선택적양이온채널로, 주로말초신경의유해수용체와중추신경계에분포하며신경손상에의한만성통증에중요한역할을하고있다.TRPV1 은외인성인자 (vaniloid,capsai cin,resiniferatoxin 등 ) 와내인성인자 (arachidonicacid metabolite,ananda mide 등 ) 그리고열과 ph 와같은물리, 화학적자극에의해활성화되며통증의전달과조절에주된역할을하는것으로알려져있다. 본연구실에서합성하는 TRPV1 antagonist 는 A,B,C region 으로나누어구조의골격을설정하였다.A-region 은 Phenyl 계,Aryl-Ring 계,Aryl-Aryl 계등을도입하여다양하게변화를준다.B-region 은 acetamide,propanamide,ur ea 를도입하며 C-region 은 pyridine,piperidine 에여러가지치환기를도입한형태이다. 본연구실의선행연구에의해서 2-[3-Fluoro-4-(Methylsulfonylamino)phen yl]propanamide 계화합물들이 TRPV1 에강력한길항효과와높은진통효과를보임을알수있었다.(Ki, (ant)human [CAP]:35nM). 이로부터합성된 4-Methyl sulfonylaminophenylpropanamide 유도체를토대로 A-region 의 elongated car bon 구조인 4-Methylsulfonylaminomethylphenyl 유도체를합성하였다. 이러한구조적변화를통하여 4-Methylsulfonylaminophenyl 기가체내대사에의해 Aniline 구조로변화됨에따라나타나는독성을개선하고자하였다. 그리고 B-region 으로 propanamide 와 urea 를갖는 38 종의화합물을합성하여 recepto r에대한 bioactivity(ki, (ant)human [CAP]/(nM ) 측정하여그결과를살펴보고자했다. 그결과,A-region 에 sulfamide 치환기를가지는 propanamidetype 의 H BL-321(Ki, (ant)human [CAP]:1.7nM) 화합물이선도물질보다좋은활성을보였다. 주요어 :TRPV1 길항제, 진통제, 구조활성연구학번 :201023665 - i -
목 차 Ⅰ. 서론 1 1. 통증과진통 1 1-1 통증이란무엇인가 1 1-2 새로운진통제개발의필요성 2 2.TRPV1 4 2-1TRPV1 이란? 4 2-2TRPV1agonist 5 2-3TRPV1antagonist 7 Ⅱ. 본론 9 1. 선행연구와약물의디자인 9 2. 합성과정 11 2-1A-region 의합성 11 2-2C-region 의합성 15 2-3B-region 의합성 15 3. 구조활성관계 17 3-1 구조활성연구 17 Ⅲ. 결론 25 Ⅳ.Experimentaldata 26 Ⅴ.References 46 Abstract 51 - ii -
I. 서론 1. 통증과진통 1-1. 통증이란무엇인가. 통증 (pain) 은 실질적혹은잠재적조직손상혹은그런손상과연관된감각적이고정서적인불쾌한경험 으로정의된다. 일차적으로는조직손상을막기위한생체내방어기전중하나지만통증자극이과다해지면삶의질을떨어뜨릴뿐만아니라영구적인신경손상에의한만성통증질환으로발전할수도있으며심하면사망에이를수도있다. 통증은피부, 내부기관혹은중추신경계 (CS), 외부의말초 (periphery) 에서시작된다. 발끝을계단에부딪히거나뜨거운난로에손이닿으면신경세포는뜨거운온도, 물리적인압력또는외상이나염증으로인해발생하는화학물질과같은위험한자극에반응하여통증수용체 (ociceptor) 에게신호를보낸다. 통증수용체는두개의가지를가지고있다. 하나는말초에뻗어있는감지기능체 (sensation-detecting branch) 이고, 다른하나는척수까지뻗어있는신경다발이다. 척추밖의구조에존재하는통증수용체의세포는두팔사이에끼어있는모양으로되어있다. 말초에뻗어있는통증수용체의특화된감지분자가피부나신체기관에서유해한물질을만나면척수후각 (dors alhorn) 이라고명명된척수의특정부위로신호를전송한다. 그곳에서통증수용체는신경전달물질 (neurotransmiter) 이라고불리는신호분자 (sig naling molecules) 를방출하여척수후각의신경을활성화시키고, 이신경은뇌로긴급메시지를전달한다. 비록통증수용체가때때로통증인지뉴런이라고불리기는하지만사실은잠재적인위험한자극을알려주는역할을할뿐이다. 통증을인지하고비명을지르게하는것은뇌의역할이다. 모든통증이다나쁜것만은아니다. 예를들어염좌나찰과상과같은경미한신체손상으로인한순간적인통증은우리신체에대한방어기제로작용한다. 이런고통을반복하지않도록해주고, 이통증은시간의흐름에 - 1 -
따라저절로소실된다. 환자와의사모두에게고통을주는통증은시간이흘러도사라지지않으며처치가곤란한통증이다. 많은임상예에서볼수있듯이상처와염증으로인해지속되는통증이정말문제가된다. 만성관절염으로인한통증그리고암에서관찰되는광범위한신체손상과염증으로인한고통이이런예가될수있다. 다른예로는신경세포자체가손상을입어통증이지속되는신경병증성통증 (neuropathicpain) 을들수있다. 구체적인예로는다발성경화증 (multipl esclerosis), 뇌졸중또는척수손상으로인한신경병증성통증을들수있다. 또다른예로말초신경의손상으로인한신경병증성통증도있다. 팔이나다리를절단한뒤에도그곳에서통증을느끼는환지통 (phantom limb pain), 헤르페스에감염된뒤계속해서피부에불타는듯한통증을느끼는헤르페스후신경병증 (postherpeticneuralgia) 등이대표적인예라고할수있다. 원인이해소된뒤에도이런종류의통증이지속되는경우, 이자체가신경시스템의병이므로통증전문가의처치를필요로하다. 1-2. 새로운진통제개발의필요성몸의이상여부를알리는신호로서중요한역할을하는통증은다양한요인에의하여발생하며, 말초신경을통하여중추신경계와뇌에통증신경신호가전달되면서자각된다. 이러한통증이인체가참을수있는한계를초과하게되고, 그빈도가잦아지면서오랜기간지속된다면통증자체를질병으로인식할수있다. 통증은발생기간에따라만성통증과급성통증으로나눌수있으며, 각각의특징은다음과같다. 급성통증은일반적으로외부의물리적인충격이나열, 화학적인자극에의하여세포가손상되었을때발생하며, 통증을일시적으로일으킨다. 이러한급성통증은비교적세포의손상이크지않고신경손상이없는경우에발생한다. 이에반하여만성통증은외부의자극이나바이러스감염, 암세포에의한장기침해등으로신경이손상되었을경우에발생하며, 장기간통증이지속적으로발생한다. 현재이러한병적인급만성통증을제거하기위하여 - 2 -
크게세가지분류의진통제가사용된다. 첫번째는 ibuprofen,aspirin,indomethacin,diclofenac,piroxicam 등의비스테로이드성소염진통제 (on SteroidalAnti-Inflammatory drugs,said S) 는 COX 저해작용이있는대부분의약물은산성화합물로서주작용은국소염증에서의 Prostaglandin 에서의산생억제에의한진통, 항부종작용, 해열작용이다. 조직에손상이있을때그부위에여러종류의세포들이 Prostagl andin 이라는화학물질을내뿜는다. 이물질은통증수용체의반응역치값을떨어뜨려통증을인지하게한다.SAIDS 는세포들이통증을유발하는 Prostaglandin 을만드는데쓰이는효소인 cyclooxygenase 의활성을차단하여통증을인지하지못하게만든다. 하지만다른부위에서도 Prostaglandin 을억제하기때문에위통, 설사, 위궤양등을유발하는부작용을가지고있기때문에장기복용이나용량을크게늘리지못한다. 이런위장관계부작용을없애기위해여개발된 celecoxib 등의 COX-2inhibitor 는효능도좋고위장관계부작용도거의없지만최근심장마비와뇌졸중같은심혈관계질환을유발한다는것이밝혀지면서문제가되고있다. 두번째는 codein 이나fentanyl 등의마약성진통제이다.Opioid receptor 에작용하여진통효과를나타내는데한계효과는없으나의존성, 위장관기능저하로인한변비, 호흡억제, 내성등의심각한문제를일으킨다. 세번재로는진통보조제로사용되고있는것들이다.Amitryptiline,ortryp tiline 등의 TCA( 삼환계항우울제 ) 가 SAIDs 제와함께사용되기도하는데이역시진정작용, 변비, 기립성저혈압, 녹내장등의부작용이나타난다. 최근분자수준에서의통증의발생및전달기정에대한연구가활발해짐에따라신경섬유에존재하는통증관련이온채널에대한연구가증가하고있으며통증치료기전으로서의중요성이대두되고있다. 그중, 대단히매력적으로보이는것이캡사이신수용체이다. 대부분의통증수용체의표면에존재하는이온통로는고추의매운맛의성분인캡사이신은물론뜨거운열과양이온에반응한다. 캡사이신,proton 및섭씨 43 도이상의온도등의조건이충족되면통증수용체의이온통로는나트륨이온과칼슘이온이토증수용체로들어올수잇게통로를열어준다. 즉, - 3 -
매운맛, 뜨거운온도그리고염증반응이있을때통증신호가발생한다는뜻이다. 따라서통증수용체의표면에존재하는캡사이신수용체를차단하는물질이있다면염증으로인한통증을차단할수있게된다. 실제로실험실의동물모델에서는캡사이신수용체차단물질즉, 캡사이신길항제 (antagonist) 가뼈조직으로전이되어조직에손상을입힌종양 (tumor) 주위의강한산으로인한심각한통증을완화하는효과가관찰되었다. 그렇기때문에오늘날많은제약회사들이캡사이신길항제개발에피나는경쟁을하고있다. 2.TRPV1 2-1.TRPV1 이란? Capsaicin( 고추의주요성분 ) 은신경말단의통각수용체 (nociceptor) 를자극하여활성화시킴으로써초기에통증을유발시키나즉시탈감작 (desensitiz ation) 상태를지속하여 capsaicin 뿐만아니라다른화학물질의자극및열에도반응하지않게된다. 이러한 capsaicin 의통증유발및진통작용은 cap saicin 과 vaniloidreceptor1 과의결합에의해매개되며, 최근 vaniloidrece ptor1 이 cloing 됨으로써구조와물리화학적특징이 TRP(transientreceptor potential)chnneltrpv1(transientreceptorpotentialvaniloidreceptor1) 으로명명되었다.(Caterina,1997) TRPV1 은통각자극의분자매개체로서 unmyelinatedpain-sensing nerve fiber 인 C-fiber 와 smala-deltafiber 에주로발현하는수용체이다.TRPV 1은리간드에의해개폐되고 a+,ca2+ 등에투과성이있는비선택적인양이온채널이다. 구조적으로세포내에아미노말단과카르복실말단을가지고있고 6개의 transmembranesegments 로구성되어있으며 5번과 6번 segment 사이에 hydrophobicpore 부분을가지고있다. TRPV1 은 capsaicin 및 Resiniferatoxin 과같은 vaniloid 화합물뿐만아니라 proton(low PH), 열,anandamide 와같은내인성리간드및 lipoxygenase 생산물인 12-HPETE 에의해활성화되며,bradykinin 에의해서도간접적으 - 4 -
로활성화된다. Fig.1TRPV1 의구조및기전 TRPV1 은통증및진통작용의매개체로서 TRPV1 의효능제및길항제가모두동물모델에서항염및진통효과를나타내며최근이에대한보고가급증하면서더불어새로운진통제개발에대한연구및특허가증가하고있는추세이다. 2-2.TRPV1agonist TRPV1 은두가지작용모드를가지고있는데, 내인성통증유발물질의경쟁적저해로인해작용을나타내는 antagonist 와는달리,agonist 는탈감작 (desensitization) 현상으로진통작용을나타낸다. 즉, 초기에는수용체를활성화하여양이온채널을열어줌으로써칼슘이온을강하게유입, 효능제로서작용하지만, 세포막내부의칼슘이온의농도가증가함에따라수용체의감도가떨어져효능제의효과가차단되는탈감작에의해작용하게되는것이다. TRPV1 의 agonist 로는지금까지 capsaicin 류,resiniferatoxin 류,endo-van iloid 류, 천연 aldehyde 계화합물인 isoveleral,polygodial,scutigeral 등이알려져있다. - 5 -
Figure2.TRPV1agonists 의구조 Capsaicinoid O H Capsaicin Topical analgesic cream OCH 3 OH X OCH 3 H H H O 2 SDZ-249, 482 (X=S) SDZ-249, 665 (X=O) O H OCH 3 O H 2 O H OCH 3 OH DA-5018 Clinical trial as tropical analgesic cream onivamide Endovanilloids O H OH HOO O OH Anandamide 12-HPETE Resiniferatoxin H O O O H O OH Resiniferatoxin Afferon Clinical trial as analgesics for diabetic neuropathy & urinary urge incontinence O OH O OCH 3 현재상품으로이용되고있는진통제중 capsaicin 은 Zostrix(Genderm 사 ) - 6 -
라는상품명으로관절염이나근육통의크림제제로사용되고있으며,caps aicin 유도체로는 orvatis 사의 SDZ 249-482 와국내에서는동아제약의 D A-5018 이있으며, 외용제로서임상실험중에있다. 이들은 capsaicin 자체가가진진통효력과독성문제해결에많은어려움을겪고있다고알려져있다. 2-3.TRPV1antagonist 현재 capsaicin 은여러가지임상적용도로쓰이고있으나, 무엇보다도실제적인문제점으로지적되고있는것은효력이낮아임상적으로만족할만한결과를얻을수없다는것이다. TRPV1 과관련된연구에서는 1991 년최초로 competitivevaniloidantago nist 인 capsazepine 이개발되면서연구에활기를띄기시작하여, 지난몇년간혁명적인발전을거듭하고있다. 이물질은기니피그의 TRPV1 에있어서 capsaicin, 열,proton 에의한활성을차단효과지님으로염증성통증에있어 TRPV1 의효용성에대해평가하는데큰영향을주었다아래의그림 Fig.5 은대표적인 TRPV1antagonist 들의개발현항에대한그림으로서대체적으로분자량 500 이내이며, 가운데 linker 를두고 Aroma ticgroup 이존재하는형태를가지고있다. 특히 PurduePharma 사의 BCTC 화합물은현재개발한화합물중가장약효가좋은것으로알려져있으나물성이좋지않아 PK 에서낮은흡수율을보이는것으로알려져있다. - 7 -
Figure3. 알려진 TRPV1antagonists 의구조 Cl F 3 C H O A-425619 AMG9810 H O H H AMG0347 O F F F OH O O F F F Capsazepine CF 3 JJ-17203212 JYL1421 H H H S Cl O S H O OH OH CF 3 F HSO 2 Me O O O C 1 AMG2674 F F F Compound 26 F F F H H O SB-705498 H O H Br BCTC Cl - 8 -
Ⅱ. 본론 1. 선행연구와약물의디자인 TRPV1antagonist 의개발은 TRPV1agonist 로잘알려진 Capsaicin 의구조적특성연구를기본으로하여발전해왔다.Capsaicin 은 TRPV1receptor 의 vaniloidbindingpocket 을구성하는 Arg114,Glu761,TM3bindingsite 와 hydrophobicinteraction 을형성한다. Fig 4.PharmacophoreofCapsaicin Capsaicin 의 pharmacophore 은크게 A,B,C-region 로나누어그특징을구분지어보면,A-region 은 aromaticring,b-region 은 ester 또는 amidelinker 그리고 C-region 에는 liphophilic 한 aliphaticgroup 을 pharmacophore 로가진다. 선행연구에서 capsaicin 의 phenolichydroxide 와 amidemoiety 를제거했을때,potency 가감소했음이보고되어두구조가 capsaicin 과 TRPV1rece ptor 와의반응에필수요소로간주되었다. 특히 phenolgroup 은 phasei 대사가잘일어나는것으로알려져있다.PhaseI 또는 conjugating enzymes 은극성을가지는작은체내의분자들과결합을하여약물을빠르게체내로배출시킨다.PhaseI 는 glucuronidation,sulfation,glutathione,acetylation,met hylation 등등이있고, 이와같은반응이일어나면약물의 halflife 를짧게하여, 약물이약효를낼수있는충분한시간을갖지못하게한다. 이와같은약점을보완하기위하여 A-region phenol 구조의 bioisostericreplacement 를하고자하였다.Phenol 의 OH 는 Hydrogenbondingdonor 로써 bindingsiteso 에있는다른단백질 ( 아미노산 ) 과중요한수소결합을하여약효에책을지는것으로판단되어,phenol 과 pka 가유사한 alkylsulfonamide 그룹 (pka= 약 - 9 -
10) 을디자인하였다.Alkylsulfonamide 는 phenol 과비슷한거리와각도로수소결합을할것으로예상하였다. 또한다양한 alkylsulfonamide 를디자인하여구조활성관계를연구하였다. 그중에서 methanesulfonamide 그룹이가장좋은활성을나타내었다. 그러나대사가일어남에따라 methanesulfon 그룹이떨어지면서생성되는아닐린구조가독성을나타내는것으로확인되었다. 이러한것들을종합하여본연구실에서는 A-region 에 alkylsulfonamide 보다하나의 carbon 이연장된구조를디자인하여도입하였으며,B-region 에는 propanamide 와 urea 를도입하였고,C-region 에는선행연구에의해도출된다양한구조를도입하여합성을진행하고, 이화합물에대한구조-활성관계를연구하고자하였다. - 10 -
2. 합성과정 B-region linker 를중심으로좌우로나누어 A-region 과 C-region 을각각 합성한후, 두화합물을 coupling 하는방식으로진행하였다. 2-1.A-region 의합성 A-region 은 4-Alkylsulfonylaminomethylphenyl 구조를기본으로하여 methansulfonylgroup,ethansulfonylgroup,sulfamidegroup 을 benzyl 의 4 번위치또는 pyridine 의 6번위치에도입하였으며, 치환기의 para- 위치에 B-regionlinker 를갖는화합물을합성하였다. 2-1-1.2-(4-(methylsulfonamidomethyl)phenyl)propanoicacid 의합성 A-region 에 4-methanesulfonaminomehtyl 을가지며,B-region 에 propionic acid 를가지는 2-(4-(methylsulfonamidomethyl)phenyl)propanoicacid 의합성법을 scheme1. 에나타내었다. Scheme1.2-(4-(methylsulfonamidomethyl)phenyl)propanoicacid 의 합성법 Commercialy available 한 4-bromobenzylamine 을시작물질로하여 mesyl group 을도입한후,ickelcatalysedcross-coupling 을하여 propionicacid 를도입하였다. 이를 Hydrolysis 하여 carboxylicacid 형태의 key 중간체를 - 11 -
합성하였다. 2-1-2.2-(4-(methylsulfonamidomethyl)pyridine)propanoicacid 의합성 A-region 에 4-methanesulfonaminomehtyl 을가지며,B-region 에 propionic acid 를가지는 2-(4-(methylsulfonamidomethyl)pyridine)propanoic acid 의합성법을 scheme2. 에나타내었다. Scheme2.2-(4-(methylsulfonamidomethyl)phenyl)propanoicacid 의합성법 commercialy available 한 6-Chloro-3-pyridineaceticacid 를 esterification 한후,cyanation 을하였다. 이어서 ah 를이용하여 alpha-methylation 한후 hy drolysis 를하여 carboxylicacid 형태의중간체를합성하였다. 그런다음 ED C amidecoupling 을하여 C-region 을도입한후에 reduction 과 bocprotectio n을하나의 step 으로진행하였으며,TFA 를이용하여 boc 을 deprotection 하였다. 그후 mesylation 을하여최종화합물을합성하였다. 2-1-3.2-(4-(sulfamidemethyl)phenyl)propanoicacid 의합성 A-region 에 4-sulfamidemehtyl 을가지며,B-region 에 propionicacid 를가지는 2-(4-(sulfamidemethyl)phenyl)propanoic acid 의합성법을 scheme 3. 에나타내었다. - 12 -
Scheme3.2-(4-(methylsulfonamidomethyl)phenyl)propanoicacid 의 합성 Scheme 3-1.(tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4 H)-yl)sulfonyl)amide 의합성법 commercialyavailable 한 chlorosulfonylisocyanate 을 DMAP 과 tert-butyla lcohol 과함께반응시켜 sulfamidegroup 을도입하기위한안정한중간체를합성하였다. 2-1-4.phenyl(4-(methylsulfonamidomethyl)phenyl)carbamate 의합성 A-region 에 4-methanesulfonylaminomethyl 을가지며,B-region 에 carbam ate 를가지는 (4-(methylsulfonamidomethyl)phenyl)carbamate 의합성법을 scheme4. 에나타내었다. - 13 -
Scheme4.(4-(methylsulfonamidomethyl)phenyl)carbamate 의합성법 commercialyavailable 한 4-nitrobenzylalcohol 을 mesylation 하여좋은 leavi nggroup 을만든후에 phthalimide 를도입하였다. 이후에 GabrielReaction 을하고,mesylgroup 을도입하고 paladium reduction 을하였다. 마지막으로 ca rbamate 를 keyintermediate 을합성하였다. 2-1-5.phenyl(4-(ethylsulfonamidomethyl)phenyl)carbamate 의합성 A-region 에 4-ethanesulfonylaminomethyl 을가지며,B-region 에 carbamat e를가지는 (4-(ethylsulfonamidomethyl)phenyl)carbamate 의합성법을 sche me4. 에나타내었다. - 14 -
Scheme5.(4-(ethylsulfonamidomethyl)phenyl)carbamate 의합성법 Scheme4. 와동일하게반응을진행하였으나 methanesulfonylchloride 대신 ethanesulfonylchloride 를이용하여 ethanesulfonylgroup 을도입하였다. 2-2.C-region 의합성본연구실에서도출해낸 TRPV1antagonist 의 C-region 은 aromaticring 에 h ydrogen bonding acceptor 을포함하는 liphophilic 한부분이다. 본실험실에서는크게 Pyridinering 과 Pyrazolering 을 core 로가지는다양한 amine 을합성하였다. 2-3.B-region 의합성 B-region 은 propanamidelinker 와 urealinker 두가지를합성하였다.porpan amide linker 는앞서합성한각각의 A-region 의 acid 와 C-region 의 amine 을 EDC amide-coupling 반응을통해서합성하였고,urea linker 는좋은 leaving group 을가지고있는 A-region 의 amine 과 C-region 의 amine 을 urea-couplin g반응으로합성하였다. 2-3-1.PropanamideLinker 의합성 Commercialyavailable 한 aceticacid 류및합성한 propionicacid 류의 A-reg ion 과 C-region 의 amine 을 1-(3-Dimethylaminopropyl)-3-ethyl-carbodimide hydro- chloride(edc) 와 1-Hydroxybenzotriazole(HOBt) 을이용하여 Acetonit ril 용매하에실온에서 6-12 시간교반시켜 amidecoupling 을실시하였다. 반응후,extraction,column chromatography 등의 purification 과정을거쳐서최종화합물을얻었다 (Scheme6). Scheme6.EDCI-amidecouplingforsynthesisofamidelinker - 15 -
2-3-2.UreaLinker 의합성 A-region 으로좋은 leavinggroup 을가지고있는 carbamate 화합물과 C-reg ion 의 amine 을 TEA 또는 4-Dimethylaminopyridine(DMAP) 을이용하여 Acet onitril 용매에녹인후, 60-80 에서 6-12 시간교반시켜 coupling 하였다. 반응후,extraction,column chromatography 등의 purification 과정을거쳐서최종화합물을얻었다 (Shceme7). Scheme7.UreacouplingforsynthesisofUrealinker - 16 -
3. 구조활성관계 3-1 구조활성연구합성된화합물들은생물학적효능검색의일환으로 TRPV1 에대한기질의 50% 를 inhibition 하는 IC 50 값과그것의농도를측정한후 Capsaicin 의농도에따라보정한값,Ki 를측정하였다. 세포는 TRPV1 의 cda 가감염되어테트라사이클린의투여여부에따라발현을조절할수있는중국햄스터난소세포 (CHO cel) 와 dorsalrootganglia 세포를사용하였으며 3H RTX 를이용한 competitionbindingassay 는이전에발표된논문 (s zalasietal.pharmacol.exp.ther.,262,p883-888,1992) 를근거로하여확인하기위하여 TRPV1 과발현하는 CHO 세포를테트라사이클린 on/ofsyste m을이용하여 45Ca 2+ 흡입량실험을수행하였다 3-1-1PropanamideB-region 을가지는유도체선도물질인HCR-477 화합물을토대로 A-region 에 alkylsulfonylaminometh yl 기를가지고,B-region 에 propanamide 를도입하여합성하여총 19 종의유도체를합성하였고, 각화합물의구조활성연구는앞서설명된방법으로진행되었다. - 17 -
Table1.SAR ofhavingpropanamidforb-linker Code C-region A&B-region Ki(ant) human [CAP] [nm] 1 10.9 F 3 C 2 19.6 3 66.2 4 81.3 5 9.3 6 18.5-18 -
7 22.2 8 82.5 9 56.1 10 pag (37.6) 11 pag (7.3) Cl 12 pag (17.6) - 19 -
13 pag (76) 14 pag (42.6) 15 1.7 16 7 F 3 C 17 37.6 18 E 19 60.9-20 -
B-region 에 propanamide 를가지고 A-region 에 4-alkylsulfonylaminometh yl 을가지는화합물의활성측정한결과,pyridinetype 의화합물은활성이좋지않음을확인할수있었다. 또한 methanesulfonylaminomethylphenyl type 의화합물은 C-region 에 tert-butylpyrazole 을가지는경우 partialago nism 을보였으며 Sulfamidegroup 을가지는화합물이비교적좋은화성을나타내는것으로나타났다. 그중에서도 15 번 (HBL-321) 화합물이 Ki(CAP) =1.7nM 로가장좋은활성을나타내었다. 3-1-2UreaB-region 을가지는 Indazole 유도체선도물질인 ABT-102 화합물을기본골격으로하여 A-region 에 4-isomer 와 5-isomerindazole 구조를도입하고 B-region 에 urealinker 를도입하여총 79 종의유도체를합성하였고, 각화합물의구조활성연구는앞서설명된방법으로진행되었다. Table2.SAR ofhavingureaforb-linker Code C-region A&B-region Ki(ant) human [CAP] [nm] 20 3.6 F 3 C 21 26.1 22 28.1-21 -
23 30.9 24 9.8 25 33 26 24.2 27 3.5 28 10.8 Cl 29 11.6-22 -
30 7.5 F 3 C 31 58.4 32 E 33 22.7 34 23.4 35 53.5 36 57.5-23 -
37 pag (16.1) Cl 38 67 B-region 에 urea 를가지고 A-region 에 4-alkylsulfonylaminomethyl 기를가지는화합물의활성측정결과 methanesulfonly group 을가지는화합물이 ethanesulfonylgroup 을가지는화합물보다활성이비교적좋게나타나는것을확인할수있었다. 그러나특별히좋은활성을나타내는화합물은없었다. Table3.SAR ofhaving4-methylpiperidineamineatc-region Code C-region A&B-region Ki(ant) human [CAP] [nm] 15 1.7 20 3.6-24 -
30 7.5 1 10.9 18 E C-region 을 4-methylpiperidine amine 으로고정하고 A,B-region 을활성이높은순에서낮은순으로정리해보았다. 그결과 A-region 에 sulfamidegro up 을가지는화합물이가장활성이좋게나타나며,B-region 에 propanamide 가있는화합물보다 Urea 가있는화합물이활성이좋게나타남을관찰할수있었다. Ⅲ. 결론 본연구실의선행연구에의해 A-region 에 4-methanesulfonamidogroup 을가지는 HCR-477 화합물이좋은활성을가짐을알수있었다. 하지만이화합물은신체내대사에의해 demesylationdl 일어나 aniline 형태가되면서독성을나타내는것으로확인되었다. 따라서이독성문제를해결하기위하여 4- methanesulfonulamine 기보다하나의 carbona 이연장된화합물들을 design 하여그활성을살펴보았다. 그중 HBL-321 화합물이 TRPV1 길항효과가 Ki(ant)=1.7nM 로비교적좋은결과를나타내었다. - 25 -
Figure7.StructureofHBL-321 선도물질의화학구조에서 structuremodification 을통하여 druglibrary 를구 축하였으며, 이를토대로독성을해결하는동시에좋은활성을나타내는화 합물을합성할수있었다. Ⅳ. Experimental data CommercialreagentsthatweremainlyAldrichorTCIproductwereused withoutfurtherpurification.meltingpointweredeterminedbypackingthe sampleintoopencapilaryusingbuchib-540meltingpointapparatus.i folowedstandarddistilationmethodinanhydrousreactionconditions. AnalyticalTLC analysiswasperformedonmercksilicagel60f254glass plates.1h MR spectrawererecordedat300mhzand400mhzonaje LJM-LA 300,andchemicalshiftswereexpressedonppm(δ)relativeto internal(ch3)4sias0.00ppm.gc MasspectrawereobtainedonaJEOL JMS-700 -(4-bromobenzyl)methanesulfonamide(A-1) 4-Bromobenzylaminewasdissolvedinpyridineand1.9equivalentsofMs Clwasaddedtothesoltionat0 o C.Themixturewasstirredfor1hat0 o C. Then,themixturewasquenchedwith1 HClandextractedwithEA.Dr yingwithmgso 4 andevaporationoftheethylacetateandpurifiedbysilica - 26 -
-gelcolumnchromatographygavethecompoundinpureform. Ethyl2-(4-(methylsulfonamidomethyl)phenyl)propanoate(A-2) Toasolutionof-(4-Bromo-benzyl)-methanesulfonamide)inDMF,Mn, ibr 2 bipy,ethyl-2-chloropropionatewasadded.anditwasfolowedbya dditionoftfa.themixturewasstirredfor60hat65 o C.Thereactionmi xturewasquenchedbyc-hcl.andthenitwasextractedwithdiethyleth er,driedwithmgso 4 andevaporationoftheethylacetateandpurifiedby silica-gelcolumnchromatographygavethecompoundinpureform. Generalprocedureforcarboxylicacidcompound 2-(4-(methylsulfonamidomethyl)phenyl)propanoicacid(A-3) Toasolutionofethyl2-(4-(methylsulfonamidomethyl)phenyl)propanoatei nthfandwaterco-solvent,sodium hydroxidewasaddedatroom tempe rature.andthemixturewasstiredforovernightandthenitwasdiluted withsmalamountofwaterandacidifywith1 HCl.Thenitwasextract edwithea,driedwithmgso 4 andevaporationoftheethylacetateandpu rifiedbysilica-gelcolumnchromatographygavethecompoundinpurefor m. Generalcoupling procedureofpropanamidecompound(a-4) C-regionaminewasaddedtothesynthesizedcarboxylicacidcompounddi ssolvedinacetonirileandedci,hobtandtea wasaddedandthemixt urewasalowedtoreactfor15hatroom temperature.thereactionwas quenchedbywaterandorganiccompoundwasextractedwithethylacetat e.thecombinedextractsweredriedovermgso 4,andsolventwasremov edunderreducedpressureafterfilteration.theproductwaspurifiedwith silica-gelcolumnchromatographyusingpropereluentssystem depending onproductspolaritiesandtheidentitiesofcompoundswereanalyzedby MR. - 27 -
-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)me thyl)-2-(4-(methylsulfonamidomethyl)phenyl)propanamide(1) 78%,whitesolid,m.p.:113-117 o C 1 H MR (300MHz,CDCl 3 )δ 7.45(d,2H,J=7.50Hz),7.32(m,5H)7.18 (d,1h,j=7.68hz),6.13(m,1h),4.59(m,1h),4.44(d,2h,j=5.85hz), 4.30(d,2H,J=6.21Hz),3.63(q,1H,J=7.14Hz),3.33(m,2H),2.92(s, 3H),2.79(m,2H),1.70(m,2H),1.50(m,4H),1.21(m,2H),0.87(d,2H,J =7.35Hz) Mass(FAB)m/z513(M+H) 2-(4-(methylsulfonamidomethyl)phenyl)--((2-(pyrrolidin-1-yl)-6- (trifluoromethyl)pyridin-3-yl)methyl)propanamide(2) 61%,whitesolid,m.p.:130-133 o C 1 H MR (300MHz,CDCl 3 )δ 7.29-7.36(m,5H),6.92(d,1H,J=7.5Hz), 5.76(bs,1H),4.49(bs,1H,H),4.44(t,2H,J=4.95Hz),4.29(s,2H),3.5 8(m,1H),3.41(m,4H),1.52(d,3H,J=7.14Hz) Mass(FAB)m/z485(M+H) 2-(4-(methylsulfonamidomethyl)phenyl)--((2-(m-tolyl)-6-(trifluo romethyl)pyridin-3-yl)methyl)propanamide(3) 69%,whitesolid,60-65 o C 1 H MR (300MHz,CDCl 3 )δ 7.76(d,1H,J=8.07Hz),7.58(d,1H,J= 8.07Hz),7.32-7.12(m,8H),5.54(bt,1H),4.63(bt,1H),4.45(d,2H,J=6.2 4Hz),4.30(d,2H,J=6.21Hz),3.51(q,1H,J=7.14Hz,),2.91(s,3H), 2.38(s,3H),1.48(d,3H,J=7.14Hz) Mass(FAB)m/z506[M+H] -((1-(3-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methy - 28 -
l)-2-(4-(methylsulfonamidomethyl)phenyl)propanamide(4) 56%,whitesolid,m.p:65-70 o C 1 H MR (300MHz,CDCl 3 )δ 7.44(q,1H,J=6.03Hz),7.34(d,2H,J= 8.04Hz),7.26-7.10(m,5H),6.35(s,1H),5.59(bt,1H),4.60(bt,1H),4.46 (m,2h,j=5.49hz),4.32(d,2h,j=6.24hz),3.54(q,1h,j=7.14hz), 2.94(s,3H),1.49(d,1H,J=7.14Hz) Mass(FAB)m/z499[M+H] -((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methy l)-2-(4-(methylsulfonamidomethyl)phenyl)propanamide(5) 84%,whitesolid,m.p.:165-167 o C 1 H MR (300MHz,CDCl 3 )δ 7.51-7.22(m,8H),6.35(s,1H),5.56(bt,1 H),4.59-4.42(m,3H),4.32(d,2H,J=6.06Hz),3.54(q,1H,J=7.14Hz), 2.94(s,3H),1.49(d,3H,J=7.14Hz) Mass(FAB)m/z515[M+H] 2-(4-(methylsulfonamidomethyl)phenyl)--((1-(m-tolyl)-3-(trifluo romethyl)-1h-pyrazol-5-yl)methyl)propanamide(6) 85%,whitesolid,m.p.:150-156 o C 1 H MR (300MHz,CDCl 3 )δ 7.36-7.31(m,3H),7.24-7.22(d,3H),7.18(s, 1H),7.12(d,1H,J=7.89Hz),6.33(s,1H),5.54(bt,1H),4.58(bt,1H),4.4 4(m,2H),4.31(d,2H,J=6.03Hz),3.52(q,1H,J=7.14Hz),2.93(s,3 H),2.39(s,3H),1.48(d,3H,J=7.14Hz) Mass(FAB)m/z495[M+H] -((1-(3-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)met hyl)-2-(4-(methylsulfonamidomethyl)phenyl)propanamide(7) 87%,whitesolid,m.p.:73-79 o C - 29 -
1 H MR (300MHz,CDCl 3 )δ 7.37-7.30(m,3H),7.22(d,2H,J=8.07Hz), 6.98(d,1H),6.90(d,1H),6.88(d,1H,J=1.65Hz),6.35(s,1H),5.56(bt, 1H),4.67(brt,1H),4.44(m,2H),4.31(d,2H,J=6.03Hz),3.83(s,3H),3.5 2(q,1H,J=7.14Hz),2.93(s,3H),1.47(d,3H,J=7.14Hz) Mass(FAB)m/z511[M+H] -((1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methy l)-2-(4-(methylsulfonamidomethyl)phenyl)propanamide(8) 59%,whitesolid,m.p.:60-65 o C 1 H MR(300MHz,CD 3 OD)δ 7.45(m,2H),7.33(d,2H,J=8.25Hz),7.27-7.19(m,4H),6.50(s,1H),4.36(q,J=12.45Hz,2H),4.22(s,2H),3.58(q, 1H,J=7.14Hz),2.83(s,3H),1.37(d,3H,J=7.14Hz) Mass(FAB)m/z500[M+H] -((1-(3,4-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)me thyl)-2-(4-(methylsulfonamidomethyl)phenyl)propanamide(9) 64%,whitesolid,m.p.:65 o C 1 H MR (300MHz,CDCl 3 )δ 7.34(d,2H,J=7.86Hz),7.30-7.20(m,4H), 7.14(m,1H),6.35(s,1H),5.62(bt,1H),4.61(bt,1H),4.44(m,2H),4.32 (d,2h,j=6.24hz),3.53(q,1h,j=7.14hz),2.94(s,3h), 1.49(d,J= 7.14Hz,3H) Mass(FAB)m/z517[M+H] -((3-(tert-butyl)-1-(3-fluorophenyl)-1H-pyrazol-5-yl)methyl)-2- (4-(methylsulfonamidomethyl)phenyl)propanamide(10) 68%,whitesolid,m.p.:160-168 o C 1 H MR (300MHz,CDCl 3 )δ 7.37-7.30(m,3H),7.23(d,2H,J=8.25Hz), 7.13-7.00(m,3H),6.02(s,1H),5.46(brt,1H),4.53(brt,1H),4.46(m,2H), 4.31(d,2H,J=6.03Hz),3.51(q,1H,J=7.14Hz),2.92(s,3H),1.48(d, - 30 -
3H,J=7.14Hz),1.28(s,9H) Mass(FAB)m/z487[M+H] -((3-(tert-butyl)-1-(m-tolyl)-1H-pyrazol-5-yl)methyl)-2-(4-(me thylsulfonamidomethyl)phenyl)propanamide(12) 93%,whitesolid,m.p.:61-68 o C 1 H MR (300MHz,CDCl 3 )δ 7.31(d,2H,J=8.04Hz),7.24(t,3H),7.15 (s,2h),7.10(t,1h,j=8.04hz),5.98(s,1h),5.45(brt,1h),4.56(br,1h), 4.43(d,2H,J=5.49Hz),4.30(d,2H,J=6.03Hz),3.49(q,1H,J=7.14 Hz),2.91(s,3H),2.36(s,3H),1.46(d,3H,J=7.14Hz),1.29(s,9H) Mass(FAB)m/z483[M+H] -((3-(tert-butyl)-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2- (4-(methylsulfonamidomethyl)phenyl)propanamide(11) 87%,whitesolid,m.p.:70-80 o C 1 H MR (300MHz,CDCl 3 )δ 7.38-7.21(m,8H),6.01(s,1H),5.45(brt,1 H), 4.54 (brt,1h), 4.46(m,2H),4.31(d,2H,J=6.24Hz),3.51(q,1H, J=7.14Hz),2.92(s,3H),1.48(d,3H,J=7.14Hz),1.28(s,9H) Mass(FAB)m/z503[M+H] -((3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)methyl)-2- (4-(methylsulfonamidomethyl)phenyl)propanamide(13) 87%,whitesolid,m.p.:190-193 o C 1 H MR(300MHz,CDCl 3 )δ 7.35-7.21(m,6H),7.06(t,2H,J=8.61Hz), 6.00(s,1H),5.44(brt,1H),4.56(brt,1H),4.41(t,2H,J=4.95Hz),4.31(d, 2H,J=6.03Hz),3.49(q,1H,J=7.14Hz),2.93(s,3H),1.47(d,3H,J= 7.14Hz,3H),1.28(s,9H) Mass(FAB)m/z487[M+H] - 31 -
-((3-(tert-butyl)-1-(3,4-difluorophenyl)-1H-pyrazol-5-yl)methyl) -2-(4-(methylsulfonamidomethyl)phenyl)propanamide(14) 70%,whitesolid,m.p.:180-183 o C 1 H MR (300MHz,CDCl 3 )δ 7.32(d,2H,J=8.04Hz),7.24-7.08(m,5H), 6.02(s,1H),5.46(brt,1H),4.58(brt,1H),4.44(m,2H),4.31(d,2H, J= 6.21Hz),3.50(q,1H,J=7.14Hz),2.93(s,3H),1.47(d,3H,J=7.14Hz), 1.28(s,9H) Mass(FAB)m/z505[M+H] Ethyl2-(4-bromophenyl)acetate(B-1) Toastirredsolutionof4-Bromophenylaceticacidinethanolwereaddeds ulfuricacidthereactionmixturewasrefluxedforovernightandcooledto room temperature.thesolventwasevaporated.theresiduewasdissolved withetoa andneutralizedwithahco 3.Theorganiclayerwaswashed withwatertwotimes,thendried(mgso 4 )andfiltered.thefiltrateremove dinvacuo.thecrudewaspurifiedbycolumn-chromatography. Ethyl2-(4-cyanophenyl)acetate(B-2) To a stirred solution ofethyl2-(4-bromophenyl)acetateinanhydrous DMF wereaddedzinccyanideandtetrakis(triphenylphosphine)paladium T hereactionmixturewasrefluxedforovernightthencooledtoroom tempe rature.themixturewasfilteredusingcelitepadandthefiltratewasevap orated.theresiduewasdilutedwithetoacandwashedwithwaterand brine.theorganiclayerwasdried(mgso 4 )andfiltered.thefilteratewas concentratedunderreducedpressuretogetthecrude.thecrudewaspurif iedbycolumn-chromatography. Ethyl2-(4-cyanophenyl)propanoate(B-3) Toastirredsolutionofethyl2-(4-cyanophenyl)acetateinanhydrousDMF - 32 -
wereadded60% ah andiodomethanewereaddedafter10minwithan icebath.thereactionmixturewasstiredfor1h,quenchedwithwateran dextractedwithetoacwhichiswashedwithwaterandbrine.theorgan iclayerwasdried withmgso 4 andfiltered.thefilteratewasconcentrate dunderreducedpressure.theresiduewaspurifiedbycolumn-chromatog raphy. 2-(4-cyanophenyl)propanoicacid(B-4) (GeneralProcedureforcarboxylicacidcompound) Folow theprocedurea-3 Generalcoupling procedureofpropanamidecompound(b-5) Folow theprocedurea-4 Generalprocedurefornitrilreduction(B-6) Toastirredsolutionofcoupledcompoundinethanolwascooledto0 Can daddedicl 2 6H 2 O andstirredmorethen15mins.sodiumborohydride( abh 4 )wasthenaddedinsmalportions.thereactionwasexothermicand efervescent.theresultingreactionmixturewasalowedtowarm toroom temperatureandstirredfor2h.themixturewasfilteredusingcelitepad. Thefiltratewasconcentratedbyevaporation. Theresiduewasdissolved inetoacandwashedwithwaterandbrine,butwhenitdoesnotseparate easily,smalamountof1hclandahco 3 (sat.)wasused.theorganicl ayerwasdried(mgso 4 )andfiltered.thefiltratewasconcentratedagain byevaporation.thecrudewaspurifiedbycolumn-chromatography. Generalprocedureforintroducing thesulfamide-bocgroup(b-7) i)procedureoftheintermediatesynthesis Chlorosulfonylisocyanatewasdropwisetoacooledsolutionoft-butylalc - 33 -
oholindichloromethane.,-dimethylpyridin-4-amine(dmap)wasadded after10minandthereactionmixturewasstiredatambienttemperature for1h.thereactionmixturewaswashedwithwaterseveraltimes,dried withmgso 4,filteredandconcentrated.Thecrudewaspurifiedbycolumn chromatography. i)generalprocedureforintroducingthesulfamide-bocgroup Toastiredsolutionof reductedcompoundindichloromethane, theinter mediate(synthesizedati)andtriethylaminewasaddedandstiredforover nightatroom temperature.themixturewasdilutedwithdichloromethane andwashwithwater,brine,dried(mgso 4 )andfiltered.thefilteratewas evaporatedandtheresiduewaspurifiedbycolumn-chromatography. Generalprocedurefordeprotection ofboc(b-8) Thestirredsolutionofprotectedsulfamidecompoundindichloromethane wascooledbyicebathandtrifluoroaceticacidwasadded.thereactionmi xturewasstirredforovernight.themixturewasdilutedwithmcandthe nwashedwithahco 3,brine,dried(MgSO 4 )andfiltered.thefilteratew asevaporatedandpurifiedbycolumn-chromatography. -((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)me thyl)-2-(4-((sulfamoylamino)methyl)phenyl)propanamide(15) 86%,whitesolid,m.p.:74-79 o C 1 H MR (300MHz,CDCl 3 )δ 7.45(d,1H,J=7.8Hz),7.29-7.34(m,4H) 7.18(d,1H,J=7.5Hz),6.16(bs,1H),4.55(s,2H),4.45(d,2H,J=5.7H z),4.28(d,2h,j=6.0hz),3.60(m,1h,ch),3.28(t,2h,j=14.4hz),2.80 (m,2h),1.70(m,2h),1.54(d,3h,j=7.2hz),1.20(m,2h),0.96(d,3h, J=6.6Hz) Mass(FAB)m/z514[M+H] - 34 -
2-(4-((sulfamoylamino)methyl)phenyl)--((2-(m-tolyl)-6-(trifluoro methyl)pyridin-3-yl)methyl)propanamide.(16) 80%,whitesolid,m.p.:87-97 o C 1 H MR (300MHz,CDCl 3 )δ 7.76(d,1H,J=7.86Hz),7.58(s,1H,J= 7.86Hz),7.27-7.32(m,3H),7.10-7.24(m,5H),5.59(bs,1H),4.69(bs,1H), 4.58(s,2H),4.44(d,2H,J=6.03Hz),4.26(d,2H,J=6.21Hz),3.50(m, 1H),2.38(s,3H),1.46(d,3H,J=7.14Hz) Mass(FAB)m/z507[M+H] -((2-(pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2- (4-((sulfamoylamino)methyl)phenyl)propanamide(17) 76% whitesolid,m.p.:63-75 o C 1 H MR (300MHz,CDCl 3 )δ 7.28-7.36(m,5H),6.92(d,1H,J=7.68Hz),5. 65(bs,1H),4.61(bs,1H),4.44(t,2H,J=4.77Hz,8.79Hz),4.28(d,2H, J=6.21Hz),3.57(m,1H),3.40(m,4H),1.84(m,4H),1.52(d,3H,J=7.14 Hz) Mass(FAB)m/z486[M+H] Ethyl2-(6-chloropyridin-3-yl)acetate(C-1) Folow theprocedureb-1,using2-(6-chloropyridin-3-yl)aceticacidasthe startingmaterial. Ethyl2-(6-cyanopyridin-3-yl)acetate(C-2) Folow theprocedureb-2,usingtheproductofc-1asthestartingmateri al. Ethyl2-(6-cyanopyridin-3-yl)propanoate(C-3) Folow theprocedureb-2,usingtheproductofc-2asthestartingmateri al. - 35 -
2-(6-cyanopyridin-3-yl)propanoicacid(C-4) Folow theprocedurea-3,usingtheproductofc-3asthestartingmateri al. Generalcoupling procedureofpropanamidecompound(c-5) Folow theprocedurea-4,usingtheproductofc-4asthestartingmateri al. Generalprocedurefornitrilreductionandbocprotection(1step)(C- 6) ToastirredsolutionofcoupledcompoundinMethanolwascooledto0 C andaddedboc 2 O,iCl 2 6H 2 0andaBH 4 thenstirredfor1hat0 o C.Afte r1haddeddeta tothemixtureandstirredatroom temperaturefor1h. TLC showedcompleteconsumptionofstartingmaterial.thereactionmixt urewasdilutedwithwaterandextractedwithea.theorganicpartwas washedwithwaterandbrine.theorganiclayerwasdriedovermgso 4 a ndconcentratedunderreducedpressure.thecrudewaspurifiedbycolum n-chromatography. Generalprocedurefordeprotection ofboc(c-7) Folow theprocedureb-8,usingtheproductofc-6asthestartingmateri al. ProcedureforMesylation afterthecoupling.(c-8) ToasolutionofdeprotectedcompoudinMC wasaddedmethanesulfonylc hlorideandtea at0oc.thereactionmixturewasstirredfor30min.tlc showedcompleteconsumptionofstartingmaterial.themixturewasextra ctedwithea andwashedwithwaterandbrine.theextractwasdriedov - 36 -
ermgso4andconcentratedunderreducedpressure.thecrudewaspurifi edbycolumn-chromatographytogivethefinalcompound. -((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)me thyl)-2-(6-(methylsulfonamidomethyl)pyridin-3-yl)propanamide (1 8) 52%,whitesolid,m.p.:131-139 o C 1 H MR(300MHz,CDCl 3 )δ 8.45(s,1H,Ar-H),7.68(d,1H,J=8.00Hz), 7.47(d,1H,J=7.68Hz),7.27(d,1H,J=7.64Hz),7.19(d,1H,J=7.64 Hz),6.33(bs,1H),5.49(bs,1H),4.46(t,2H,J=6.96Hz),4.41(d,2H,J= 5.32Hz),3.56(m,1H),3.30(m,2H),2.81(m,2H),1.71(t,2H,J=10.84 Hz),1.55(s,3H),1.20(m,3H),0.96(d,3H,J=6.48Hz) Mass(FAB)m/z514[M+H] -((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methy l)-2-(6-(methylsulfonamidomethyl)pyridin-3-yl)propanamide(19) 51%,whitesolid,m.p.:101-104 o C 1 H MR (300MHz,CDCl 3 )δ 8.42(s,1H),7.64(dd,1H,J=2.22Hz,8.07 Hz),7.43(m,3H),7.32(m,2H),6.46(s,1H),5.79(bs,1H),5.59(bs,1H), 4.51(d,2H,J=5.67Hz),4.43(d,2H,J=5.31Hz),3.53(m,1H),2.96(s, 3H),1.49(d,3H,J=6.96Hz) Mass(FAB)m/z517[M+H] 4-nitrobenzylmethanesulfonate(D-1) Toasolutionof4-nitrobenzylalcoholinToluenewasslowlyaddedMetha ne-sulfonylchlorideatroom temperature.thereactionmixturewasheated to80 o Cfor4h.TLCshowedcompleteconsumptionofstartingmaterial.T hereactionmixturewascooledtoroom temperature.themixturewasext ractedwithea andwashedwithwaterandbrine.theextractwasdried overmgso 4 andconcentratedunderreducedpressure.thecrudewaspuri - 37 -
fiedbycolumn-chromatography. 2-(4-nitrobenzyl)isoindoline-1,3-dione(D-2) A solutionof4-nitrobenzylmethanesulfonateindmfwasaddedpotassiu m phthalimideandstiredatroom temperatureforovernight.tlcshowed completeconsumptionofstartingmaterial.themixturewasextractedwit hea andwashedwithwaterandbrine.theextractwasdriedovermgs O 4 andconcentratedunderreducedpressure.thecrudewaspurifiedbycr ystalization. (4-nitrophenyl)methanamine(D-3) 2-(4-nitrobenzyl)isoindoline-1,3-dionewasdissolvedinTHF.Tothesolut ionhydrazinemonohydrateandp-toluenesulfonicacidmonohydratewasad ded.itwasrefluxed for6h.tlc showedcompleteconsumptionofstartin gmaterial.themixturewasextractedwithea andwashedwithwatera ndbrine.theextractwasdriedovermgso 4 andconcentratedunderredu cedpressure.thecrudewaspurifiedbycolumn-chromatography. -(4-nitrobenzyl)methanesulfonamide(D-4) (4-nitrophenyl)methanaminewasdissolvedinpyridine.Thereactionmixtu rewasaddedmethane-sulfonylchlorideandstirredfor1hatroom tempera ture.tlcshowedcompleteconsumptionofstartingmaterial.themixture wasdilutedwith1 HClandextractedwithEA.Theextractwasdriedo vermgso 4 andconcentratedunderreducedpressure.thecrudewaspurif iedbycolumn-chromatography. -(4-aminobenzyl)methanesulfonamide(D-5) -(4-nitrobenzyl)methanesulfonamidewasdissolvedinMeOH andthf.1 0% Pd/C wasaddedtoit.theresultingmixturewasstiredatroom temp - 38 -
eratureforovernightunderh 2 gas.tlc showedcompleteconsumptionof startingmaterial.themixturewasfilteredthroughcelitebedandthefilte ratewasconcentratedunderreducedpressure.thecrudewaspurifiedby column-chromatography. GeneralprocedureforCarbamatecompound(D-6) phenyl(4-(methylsulfonamidomethyl)phenyl)carbamate -(4-aminobenzyl)methanesulfonamidewasdissolvedinCH 3 C andth F.Thereactionmixturewasaddedpyridineandphenylchloroformateand stiredatroom temperaturefor3hunder 2 gas.tlcshowedcompleteco nsumptionofstartingmaterial.thereactionmixturewasdilutedwithwat erandextractedwithea.theorganicpartwaswashedwithwaterand brine.theorganiclayerwasdriedovermgso 4 andconcentratedunderre ducedpressure.thecrudewaspurifiedbycolumn-chromatography. Generalcoupling procedureofureacompound(d-7) ToasolutionofcarbamatecompoundinCH 3 C wasaddeddmap(andc -regionamineatroom temperature.thereactionmixturewasheatedto5 0 o C forovernight(about12 15h).TLC showedcompleteconsumptionof startingmaterial.thereactionmixturewasdilutedwithwaterandextract edwithea.theorganicpartwaswashedwithwaterandbrine.theorg aniclayerwasdriedovermgso 4 andconcentratedunderreducedpressure.thecrudewaspurifiedbycolumn-chromatography. -(4-(3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3 -yl)methyl)ureido)benzyl)methanesulfonamide(20) 96%,whitesolid,m.p.:145-157 o C 1 H MR (300MHz,DMSO)11.03(s,1H),8.77(s,1H),7.78(d,1H,J= 7.86Hz),7.46(d,2H,J=4.77Hz),7.37(d,2H,J=8.61Hz),7.19(d,2H, - 39 -
J=8.61Hz),6.74(t,1H),4.31(d,2H,J=5.31Hz),4.05(d,2H,J=6.24 Hz),3.38(m,2H),2.80(s,3H),2.78(m,2H),1.73(d,2H,J=12.18Hz), 1.55(br,1H),1.28(m,6H),0.97(d,3H,J=6.42Hz) Mass(FAB)m/z500[M+H] -(4-(3-((2-(pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)meth yl)ureido)benzyl)methanesulfonamide(21) 70%,whitesolid,m.p.:134-139 o C 1 H MR(300MHz,CD 3 OD)δ 7.65(d,1H,J=7.32Hz),7.32(m,4H),7.01 (d,1h,j=7.5hz),4.48(s,2h),4.17(s,2h),3.58(m,4h),2.81(s,3h), 1.96(m,4H) Mass(FAB)m/z472[M+H] -(4-(3-((2-butoxy-6-(trifluoromethyl)pyridin-3-yl)methyl)ureido) benzyl)methanesulfonamide(22) 87%,whitesolid,m.p.:139-141 o C 1 H MR (300MHz,CD 3 OD)δ 7.77(d,1H,J=7.5Hz),7.25-7.38(m,5H), 4.23(t,2H,J=6.57Hz),4.39(s,2H),4.17(s,2H),2.81(s,3H),1.80(m, 2H),1.51(m,2H),0.99(t,3H,J=4.82Hz) Mass(FAB)m/z476[M+H] -(4-(3-((2-isopropoxy-6-(trifluoromethyl)pyridin-3-yl)methyl)ure ido)benzyl)methanesulfonamide(23) 72%,whitesolid,m.p.:153-158 o C 1 H MR (300MHz,CD 3 OD)δ 7.75(d,1H,J =7.32Hz),7.25-7.38(m, 5H),5.40(m,1H),4.36(s,2H),4.17(s,2H),2.81(s,3H),1.39(d,6H,J= 6.24Hz) Mass(FAB)m/z462[M+H] -(4-(3-((2-(m-tolyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)ureid - 40 -
o)benzyl)methanesulfonamide(24) 56%,whitesolid,m.p.:71-84 o C 1 H MR (300MHz,CD 3 OD)δ 8.10(d,1H,J=7.50Hz),7.77(d,1H,J= 8.07Hz),7.25-7.43(m,8H),4.45(s,2H),4,17(s,2H),2.81(s,3H),2.43(s, 3H) Mass(FAB)m/z493[M+H] -(4-(3-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-y l)methyl)ureido)benzyl)methanesulfonamide(25) 78%,whitesolid,m.p.:95-106 o C 1 H MR (300MHz,CD 3 OD)7.24-7.64(m,8H)6.75(s,1H),4.46(s,2H), 4.17(s,2H),2.81(s,3H) Mass(FAB)m/z503[M+H] -(4-(3-((1-(m-tolyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methy l)ureido)benzyl)methanesulfonamide(26) 94%,whitesolid,m.p.:161-163 o C 1 H MR(300MHz,CD 3 OD)δ 7.25-7.48(m,8H),6.73(s,1H),4.43(s,2H), 4.17(s,2H),2.81(s,3H),2.43(s,3H) Mass(FAB)m/z483[M+H] -(4-(3-((1-(3-isopropylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5 -yl)methyl)ureido)benzyl)methanesulfonamide(27) 86%,whitesolid,m.p.:140-159 o C 1 H MR(300MHz,CD 3 OD)δ 7.25-7.51(m,8H),6.74(s,1H).4.43(s,2H), 4.17(s,2H),3.02(m,1H),2.81(s,3H),1.29(d,6H,J=6.78Hz) Mass(FAB)m/z511[M+H] -(4-(3-((3-(tert-butyl)-1-(3-chlorophenyl)-1H-pyrazol-5-yl)met hyl)ureido)benzyl)methanesulfonamide(28) - 41 -
75%,whitesolid,m.p.:130-140 o C 1 H MR (400MHz,CDCl 3 )δ 7.43(s,1H),7.30(m,2H),7.12(q,4H),6.89 (s,1h),6.24(s,1h),5.28(d,1h),4.92(t,1h),4.39(d,2h),4.15(d,2h), 4.09(q,1H),2.85(s,3H),1.28(s,9H) Mass(FAB)m/z490[M+H] -(4-(3-((3-(tert-butyl)-1-(m-tolyl)-1H-pyrazol-5-yl)methyl)urei do)benzyl)methanesulfonamide(29) 96%,whitesolid,m.p.:137-163 o C 1 H MR(300MHz,CD 3 OD)δ 7.24-7.42(m,8H),6.33(s,1H).4.37(s,2H), 4.17(s,2H),2.81(s,3H),2.41(s,3H),1.32(s,9H) Mass(FAB)m/z470[M+H] 4-nitrobenzylmethanesulfonate(E-1) Folow theprocedured-1 2-(4-nitrobenzyl)isoindoline-1,3-dione(E-2) Folow theprocedured-2 (4-nitrophenyl)methanamine(E-3) Folow theprocedured-3 -(4-nitrobenzyl)ethanesulfonamide(E-4) Folow theprocedured-4,usingethansulfonylchloridethenmethansulfon ylchloride -(4-aminobenzyl)ethanesulfonamide(E-5) Folow theprocedured-5-42 -
phenyl(4-(ethylsulfonamidomethyl)phenyl)carbamate(e-6) Folow theprocedured-6(generalprocedureforcarbamatecompound) Generalcoupling procedureofureacompound(e-7) Folow theprocedured-7(generalcouplingprocedureforureacompound) -(4-(3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3 -yl)methyl)ureido)benzyl)ethanesulfonamide(30) 44%,whitesolid,m.p.:144-151 o C 1 H MR (300MHz,CD 3 OD)δ 7.80(d,1H,J=7.5Hz),7.26-7.39(m,5H), 4.45(s,2H),4.15(s,2H),3.45(d,2H,J=12.8Hz),2.90(m,2H),2.85(m, 2H),1.76(d,2H,J=13.0Hz),1.58(m,1H),1.41(m,2H),1.24(t,3H,J= 7.32Hz),1.01(d,3H,J=6.24Hz) Mass(FAB)m/z515[M+H] -(4-(3-((2-(pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)meth yl)ureido)benzyl)ethanesulfonamide(31) 83%,whitesolid,m.p.:175 o C 1 H MR(300MHz,CD 3 OD)δ 7.65(d,1H,J=7.52Hz),7.25-7.36(dd,4H, J=8.44Hz,27.15Hz),7.01(d,1H,J=7.56Hz),4.48(s,2H),4.15(s,2H), 3.58(t,4H,J=6.6Hz,13.1Hz),2.90(m,2H),1.97(m,4H),1.24(m,2H) Mass(FAB)m/z486[M+H] -(4-(3-((2-butoxy-6-(trifluoromethyl)pyridin-3-yl)methyl)ureido) benzyl)ethanesulfonamide(32) 74%,whitesolid,m.p.:137-144 o C 1 H MR (300MHz,CD 3 OD)δ 7.77(d,1H,J=7.5Hz),7.25-7.37(m,5H), 4.43(t,2H,J=6.39Hz),4.39(s,2H),4.15(s,2H),2.91(m,2H),1.81(m, 2H),1.51(m,2H),1.24(t,3H,J=7.32Hz),0.99(t,3H,J=7.32Hz) Mass(FAB)m/z490[M+H] - 43 -
-(4-(3-((2-isopropoxy-6-(trifluoromethyl)pyridin-3-yl)methyl)ure ido)benzyl)ethanesulfonamide(33) 69%,whitesolid,m.p.:161-168 o C 1 H MR (300MHz,CD 3 OD)δ 7.75(d,1H,J=7.5Hz),7.25-7.36(m,5H), 5.39(m,1H),4.35(s,2H),4.15(s,2H),2.90(m,2H),1.39(s,3H),1.38(s, 3H),1.23(t,3H,J=7.3Hz) Mass(FAB)m/z475[M+H] -(4-(3-((2-(m-tolyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)ureid o)benzyl)ethanesulfonamide(34) 45%,whitesolid,m.p.:64-89 o C 1 H MR (300MHz,CD 3 OD)δ 8.10(d,1H,J=8.07Hz),7.78(d,1H,J= 8.22Hz),7.24-7.43(m,8H),4.45(s,2H),4,15(s,2H),2.87-2.94(q,2H,J =7.32Hz),2.43(s,3H),2.23(t,3H,J=7.32Hz) Mass(FAB)m/z507[M+H] -(4-(3-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-y l)methyl)ureido)benzyl)ethanesulfonamide(35) 88%,whitesolid,m.p.:146-150 o C 1 H MR (300MHz,CD 3 OD)δ 7.64(m,1H),7.51-7.57(m,3H),7.24-7.33 (m,4h),6.76(s,1h),4.47(s,2h),4.15(s,2h),2.90(m,2h),1.25(t,3h, J=7.32Hz) Mass(FAB)m/z517[M+H] -(4-(3-((1-(m-tolyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methy l)ureido)benzyl)ethanesulfonamide(36) 93%,whitesolid,m.p.:146-150 o C 1 H MR(300MHz,CD 3 OD)δ 7.24-7.48(m,8H),6.37(s,1H),4.43(s,2H), 4.15(s,2H),2.91(m,2H),2.43(s,3H),1.24(t,3H,J=7.32Hz) Mass(FAB)m/z497[M+H] - 44 -
-(4-(3-((3-(tert-butyl)-1-(3-chlorophenyl)-1H-pyrazol-5-yl)met hyl)ureido)benzyl)ethanesulfonamide(37) 67%,whitesolid,m.p.:169-182 o C 1 H MR(300MHz,CD 3 OD)δ 7.24-7.54(m,8H),6.36(s,1H),4.41(s,2H), 4.15(s,2H),2.90(m,2H),1.31(s,9H),1.24(t,3H,J=4.41Hz) Mass(FAB)m/z505[M+H] -(4-(3-((3-(tert-butyl)-1-(m-tolyl)-1H-pyrazol-5-yl)methyl)urei do)benzyl)ethanesulfonamide(38) 83%,whitesolid,m.p.:154-156 o C 1 H MR(300MHz,CD 3 OD)δ 7.24-7.42(m,8H),6.32(s,1H),4.46(s,2H), 4.15(s,2H),2.90(m,2H),2.40(s,3H),1.31(s,9H),1.24(t,3H,J=7.32 Hz) Mass(FAB)m/z484[M+H] - 45 -
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Abstract SAR on One-carbon HomolongatedAnalogues of4-methylsulfonylaminophenyltrpv1 Antagonistsn Hobin Lee ColegeofPharmacy,Medicinalchemisty TheGraduateSchool SeoulationalUniversity ThevaniloidreceptorTRPV1isahomotetrameric,nonselectivecation channelexpressedonperiperal sensoryneuronsandinthecentralnerv oussystem abundantly expressedinnociceptors.itisactivatedby awi devariety ofexogenousandendogenousphysicalsuch ascapsaisin,aic d,andheat. TRPV1isconsideredasahighly validatedpaintagetconsidering gre atefectsofagonistandantagonist;trpv1agonistscausedesensitizati onoftrpv1channelswhichrelievespainbehaviorsinpreclinicalspeci es,andantagonistsrelievepainbehaviorsinrodentmodelsofinflammat ion,osteoarthritis,andcancer. BlokadeofTRPV1activationby selectiveantagonistsisunderinvesti gationinanatempttoidentify novelagentsforpaintreatment.thede signandsynthesisofaseriesofnoveltrpv1antagonistswithavarie ty ofdiferent4-methanesulfonylaminomethylphenylderivativesaredes - 51 -
cribed,andtheevaluationofthetoxicityandthestructure-activityrelat ionshipsofanumberofthesecompoundsisreported. Keywords:TRPV1antagonist,analgesic,structureactivityrelationship Studentumber:2010-23665 - 52 -