KR100671243B1 - Pentafluorobenzenesulfonamides and analogs - Google Patents
Pentafluorobenzenesulfonamides and analogsInfo
- Publication number
- KR100671243B1 KR100671243B1 KR1019980711004A KR19980711004A KR100671243B1 KR 100671243 B1 KR100671243 B1 KR 100671243B1 KR 1019980711004 A KR1019980711004 A KR 1019980711004A KR 19980711004 A KR19980711004 A KR 19980711004A KR 100671243 B1 KR100671243 B1 KR 100671243B1
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- South Korea
- Prior art keywords
- pentafluorophenylsulfonamidobenzene
- compound
- methoxy
- substituted
- hydroxy
- Prior art date
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Abstract
본 발명은 신규한 펜타플루오로페닐설폰아미드 유도체와 동족체에 관한 방법과 조성물 및 제약학적으로 활성제로서 그들의 용도를 제공하는 것이다. 조성물은 질병 상태 치료, 특히 암, 혈관 레스테노시스, 미생물 감염 및 건선에서의 약물학적 제제 또는 이러한 제제의 발전을 위한 선구 화합물로서 특정 용도가 발견된다. 조성물은 하기 일반식(Ⅰ)의 화합물을 포함한다.The present invention provides methods and compositions for novel pentafluorophenylsulfonamide derivatives and homologues and their use as pharmaceutically active agents. The compositions find particular use as pharmacological agents in the treatment of disease states, in particular cancer, vascular restenosis, microbial infections and psoriasis, or as precursor compounds for the development of such agents. The composition comprises a compound of formula (I)
Description
본 발명은 펜타플루오로벤젠설폰아미드 유도체 및 동족체 그리고 약물학적 활성제로서 이들의 용도에 관한 것이다.The present invention relates to pentafluorobenzenesulfonamide derivatives and homologues and their use as pharmacologically active agents.
인간의 많은 질병은 비정상적 또는 비제어적 세포증식의 과정으로부터 유발된다. 이러한 것 중에서 가장 보편적인 것으로는 국소조직에 침범 및 전이하는 능력, 분화의 결핍, 비정규적 성장등으로 특징지어지는 광범위한 범위의 악성세포의 일반명 즉, 암이 거론된다. 여러 가지 이환단계를 갖고 있는 이들 악성신생물은 인체내 각 조직 및 기관에 영향을 미친다. 많은 치료학적 제제가 여러형태의 암치료를 위해 지난 수십년간 개발되어 왔다. 가장 보편적으로 사용되는 항암제 유형은 DNA-알킬화제(예 : 사이클로포스파미드, 이포스파미드), 대사길항제(예 : 메토트렉세이트, 엽산길항제, 5-플루오로우라실, 피리미딘 길항제), 미세관 분열제(microtubule disruptors, 예 : 빈크리스틴, 빈브라스틴, 파크리탁셀), DNA 삽입제(DNA intercalators, 예 : 독소루비신, 다우노마이신, 시스플라틴), 호르몬 요법제 (예 : 타목시펜, 플루타미드)등이다. 이상적인 항암제는 비악성세포에 대한 이들 약물의 독성과 관련하여 광범위한 치료계수를 가지면서, 선택적으로 악성종양세포를 살멸시키는 약물이다. 이들 약물은 악성종양세포가 약물에 계속 노출된 이후에도 악성종양세포에 대한 유효성은 그대로 남아있게 된다. 불행스럽게도 현재까지의 그 어떤 화학요법제도 이상적인 약물학적 특성을 갖고 있지 못하며, 대부분 매우 좁은 치료계수를 갖고 있으며 실제적으로 화학요법제의 치사량이하의 낮은 농도에 노출된 각각의 악성 종양세포들이 이들 약물에 대하여 내성이 생기게 되며 몇몇 기타의 항암제에 대해서는 아주 빈번히 교차내성이 생기게 된다. Many diseases in humans result from a process of abnormal or uncontrolled cell proliferation. The most common of these include the common name of a broad range of malignant cells, namely cancer, characterized by the ability to invade and metastasize to local tissues, lack of differentiation, and irregular growth. These malignant neoplasms with different stages of disease affect each tissue and organ in the human body. Many therapeutic agents have been developed for decades for the treatment of many types of cancer. The most commonly used types of anticancer agents are DNA-alkylating agents (e.g. cyclophosphamides, ifosfamides), metabolic antagonists (e.g. methotrexate, folate antagonists, 5-fluorouracil, pyrimidine antagonists), microtubule fission agents ( microtubule disruptors (e.g. vincristine, vinblastine, paclitaxel), DNA intercalators (e.g. doxorubicin, daunomycin, cisplatin), hormone therapy (e.g. tamoxifen, flutamide). An ideal anticancer agent is a drug that selectively kills malignant tumor cells, with a broad therapeutic coefficient associated with the toxicity of these drugs to nonmalignant cells. These drugs remain effective against malignant tumor cells even after malignant tumor cells continue to be exposed to the drug. Unfortunately, no chemotherapeutic regimen to date has ideal pharmacologic properties, and most of the malignant tumor cells exposed to low concentrations below the lethal dose of chemotherapeutic agents are in fact most of these drugs. It is resistant to cancer and very often cross-resistant against some other anticancer drugs.
건성인설(dry scale) 및 플라크(plague)가 생기는 것을 특징으로 하는 만성적인 피부질환인 건선은 일반적으로 비정상적인 세포증식의 결과로써 여겨진다.Psoriasis, a chronic skin disease characterized by dry scales and plaques, is generally considered as a result of abnormal cell proliferation.
이 피부질환은 상피세포의 과증식 및 각질세포의 불완전한 분화의 결과로 생기는데, 건선은 흔히 두피, 팔꿈치, 무릎, 등, 엉덩이, 손톱, 눈썹 및 생식기등에서 발생하며 경증으로부터 지극히 악화된 범위에 까지 형성되어 결국에는 건선성 관절염, 농포성 건선 및 박리성 건선 피부염으로 끝나게 된다. 아직까지는 건선에 대한 치료 요법이 확립되어 있지 않다. 경증의 경우에는 종종 외용 코티코스테로이드가 사용되지만 더욱 심한 경우에는 대사길항제인 메토트렉세이트, DNA합성억제제인 하이드록시우레아 및 미세관 분열제인 콜히친 같은 항증식 제제를 사용하게 된다.This skin disease results from hyperproliferation of epithelial cells and incomplete differentiation of keratinocytes. Psoriasis often occurs in the scalp, elbows, knees, back, hips, nails, eyebrows and genital organs, and forms from mild to extremely deteriorating. Eventually you will end up with psoriatic arthritis, pustulic psoriasis and exfoliative psoriasis dermatitis. There is no established treatment regimen for psoriasis yet. In mild cases, external corticosteroids are often used, but in more severe cases, antiproliferative agents such as methotrexate, a metabolic inhibitor, hydroxyurea, a DNA synthesis inhibitor, and colchicine, a microtubule splitting agent, are used.
비정상적으로 고수준의 세포성 증식과 관련한 기타질환에는 혈관평활근 세포가 포함된 재발협착증, 내피세포, 염증성 세포 및 사구체 세포들이 포함된 염증성 질환상태, 심근세포들이 포함된 심근경생증, 신장세포들이 포함된 사구체신염, 내피세포가 포함된 이식거부반응, 특정면역세포 및 기타 감염된 세포가 포함된 HIV감염과 말라리아 같은 감염성 질환등이 포함된다. 감염성 및 기생충성 병원체 그 자체(예를들어 박테리아, 트리파노좀, 곰팡이 등)도 본 발명의 조성물과 화합물을 사용하여 선택적인 증식 조절을 하기가 쉽다.Other diseases associated with abnormally high levels of cellular proliferation include restenosis including vascular smooth muscle cells, inflammatory disease states involving endothelial cells, inflammatory and glomerular cells, cardiomyopathy with cardiomyocytes, and kidney cells. Glomerulonephritis, transplant rejection involving endothelial cells, HIV infections involving specific immune cells and other infected cells, and infectious diseases such as malaria. Infectious and parasitic pathogens themselves (eg bacteria, tripanosomes, fungi, etc.) are also susceptible to selective proliferation control using the compositions and compounds of the present invention.
따라서, 본 발명의 하나의 목적은 직접 또는 간접적으로 활성적인 분열세포에 독성이고 악성종양, 바이러스 및 세균감염, 혈관재발협착증, 염증성 질환, 자가면역질환 및 건선등의 치료에 유용한 화합물을 제공하는 것이다.Accordingly, one object of the present invention is to provide compounds which are toxic to active dividing cells, directly or indirectly, and useful for the treatment of malignancies, viral and bacterial infections, vascular restenosis, inflammatory diseases, autoimmune diseases and psoriasis. .
본 발명의 또 다른 목적은 상기 상태를 치료하기 위한 치료학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a therapeutic composition for treating the above condition.
또 다른 목적은 악성종양, 세균 또는 상피세포같은 활성적인 증식세포를 살멸하고 각종 악성종양, 감염, 염증 및 일반적인 증식상태를 치료하기 위한 방법을 제공하는 것이다.Another object is to kill active proliferative cells, such as malignancies, bacteria or epithelial cells, and to provide a method for treating various malignancies, infections, inflammations and general proliferative conditions.
또 다른 목적은 건선 및 기타 피부장애 같은 급속히 증식하는 세포의 존재로 특징지어지는 기타의 의학적 상태를 치료하기 위한 방법을 제공하는 것이다.Another object is to provide a method for treating other medical conditions characterized by the presence of rapidly proliferating cells such as psoriasis and other skin disorders.
다른 목적, 특징 및 이점은 하기 설명과 청구범위로부터 본 기술분야에 통상의 지식을 가진자에게 명백하게 될 것이다.Other objects, features and advantages will become apparent to those skilled in the art from the following description and claims.
발명의 요약Summary of the Invention
본 발명은 신규한 펜타플루오로페닐설폰아미드 유도체와 동족체 및 약물학적으로 활성제로서 그들의 용도에 관한 방법과 조성물을 제공한다. 조성물은 질병상태, 특히 악성종양, 세균 감염 및 건선의 치료에 약물학적 제제로서 또는 이러한 제제의 개발을 위한 유도 조성물로서 특정용도를 발견한다.The present invention provides methods and compositions relating to the novel pentafluorophenylsulfonamide derivatives and their analogs and their use as pharmacologically active agents. The compositions find particular use as pharmacological agents in the treatment of disease states, in particular malignancies, bacterial infections and psoriasis or as inducible compositions for the development of such agents.
한 실시예에서, 본 발명은 일반식 Ⅰ화합물의 제약학적 용도와 식Ⅰ화합물의 제약학적으로 수용가능한 조성물을 제공하거나 In one embodiment, the present invention provides a pharmaceutical use of the compound of formula I and a pharmaceutically acceptable composition of the compound of formula I
또는 이들의 생리학적으로 수용가능한 염을 제공하고, 여기에서Or physiologically acceptable salts thereof, wherein
Y는 -S(O)- 또는 -S(O)2-;Y is -S (O)-or -S (O) 2- ;
Z는 -NR1R2 또는 -OR3 , 여기에서 R1과 R2는 독립적으로Z is -NR 1 R 2 or -OR 3 , where R 1 and R 2 are independently
수소,Hydrogen,
치환 또는 비치환된 (C1-C10)알킬,Substituted or unsubstituted (C 1 -C 10 ) alkyl,
치환 또는 비치환된 (C1-C10)알콕시,Substituted or unsubstituted (C 1 -C 10 ) alkoxy,
치환 또는 비치환된 (C3-C6)알케닐,Substituted or unsubstituted (C 3 -C 6 ) alkenyl,
치환 또는 비치환된 (C2-C6)헤테로알킬,Substituted or unsubstituted (C 2 -C 6 ) heteroalkyl,
치환 또는 비치환된 (C3-C6)헤테로알케닐,Substituted or unsubstituted (C 3 -C 6 ) heteroalkenyl,
치환 또는 비치환된 (C3-C6)알키닐,Substituted or unsubstituted (C 3 -C 6 ) alkynyl,
치환 또는 비치환된 (C3-C8)사이클로알킬,Substituted or unsubstituted (C 3 -C 8 ) cycloalkyl,
치환 또는 비치환된 (C5-C7)사이클로알케닐,Substituted or unsubstituted (C 5 -C 7 ) cycloalkenyl,
치환 또는 비치환된 (C5-C7)사이클로알카디에닐,Substituted or unsubstituted (C 5 -C 7 ) cycloalkadienyl,
치환 또는 비치환된 아릴,Substituted or unsubstituted aryl,
치환 또는 비치환된 아릴옥시,Substituted or unsubstituted aryloxy,
치환 또는 비치환된 아릴-(C3-C8)사이클로알킬,Substituted or unsubstituted aryl- (C 3 -C 8 ) cycloalkyl,
치환 또는 비치환된 아릴-(C5-C7)사이클로알케닐,Substituted or unsubstituted aryl- (C 5 -C 7 ) cycloalkenyl,
치환 또는 비치환된 아릴-(C3-C8)사이클로알킬,Substituted or unsubstituted aryl- (C 3 -C 8 ) cycloalkyl,
치환 또는 비치환된 아릴-(C1-C4)알킬,Substituted or unsubstituted aryl- (C 1 -C 4 ) alkyl,
치환 또는 비치환된 아릴-(C1-C4)알콕시,Substituted or unsubstituted aryl- (C 1 -C 4 ) alkoxy,
치환 또는 비치환된 아릴-(C1-C4)헤테로알킬,A substituted or unsubstituted aryl - (C 1 -C 4) heteroalkyl,
치환 또는 비치환된 아릴-(C3-C6)알케닐,Substituted or unsubstituted aryl- (C 3 -C 6 ) alkenyl,
치환 또는 비치환된 알콕시-(C1-C4)알킬,A substituted or unsubstituted alkoxy - (C 1 -C 4) alkyl,
치환 또는 비치환된 아릴옥시-(C2-C4)헤테로알킬,Substituted or unsubstituted aryloxy- (C 2 -C 4 ) heteroalkyl,
치환 또는 비치환된 헤테로아릴,Substituted or unsubstituted heteroaryl,
치환 또는 비치환된 헤테로아릴옥시,Substituted or unsubstituted heteroaryloxy,
치환 또는 비치환된 헤테로아릴-(C1-C4)알킬,Substituted or unsubstituted heteroaryl, - (C 1 -C 4) alkyl,
치환 또는 비치환된 헤테로아릴-(C1-C4)알콕시,Substituted or unsubstituted heteroaryl, - (C 1 -C 4) alkoxy,
치환 또는 비치환된 헤테로아릴-(C1-C4)헤테로알킬,A substituted or unsubstituted heteroaryl, - (C 1 -C 4) heteroalkyl,
치환 또는 비치환된 헤테로아릴-(C3-C6)알케닐,Substituted or unsubstituted heteroaryl- (C 3 -C 6 ) alkenyl,
치환 또는 비치환된 헤테로아릴옥시-(C1-C4)알킬 및Substituted or unsubstituted heteroaryloxy - (C 1 -C 4) alkyl and
치환 또는 비치환된 헤테로아릴옥시-(C2-C4)헤테로알킬로부터 선택되고,Substituted or unsubstituted heteroaryloxy- (C 2 -C 4 ) heteroalkyl,
여기에서 R1과 R2는 하기식의 치환체를 제공하기 위해 결합기 E에 의해 결합될 수 있고,Wherein R 1 and R 2 may be bonded by a linking group E to provide a substituent of the formula
여기에서 E는 결합, (C1-C4)알킬렌 또는(C1-C4)헤테로알킬렌 및 R1, E, R2에 의해 형성된 고리를 나타내고 질소는 8개 이하의 원자를 함유하거나 바람직하게는 R1과 R2가 NR1R2의 질소원자와 5-또는 6-으로 구성된 헤테로사이클릭 고리를 형성하는 분자에 공유적으로 결합될 수 있고;Wherein E represents a ring formed by a bond, (C 1 -C 4 ) alkylene or (C 1 -C 4 ) heteroalkylene and R 1 , E, R 2 and nitrogen contains up to 8 atoms or Preferably R 1 and R 2 may be covalently bonded to a molecule forming a heterocyclic ring consisting of 5- or 6- with the nitrogen atom of NR 1 R 2 ;
여기에서 R3는 치환 또는 비치환된 아릴 또는 헤테로아릴기이다.R 3 here is a substituted or unsubstituted aryl or heteroaryl group.
알킬, 알콕시, 알케닐, 헤테로알킬, 헤테로알케닐, 알키닐, 사이클로알킬, 헤테로사이클로알킬, 사이클로알케닐 및 사이클로알카디에닐 라디칼용 치환체는 N 이 이러한 라디칼에서 탄소원자의 총수인 0-(2N+1)의 범위의 수로 독립적으로 Substituents for alkyl, alkoxy, alkenyl, heteroalkyl, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and cycloalkadienyl radicals are 0- (2N + where N is the total number of carbon atoms in these radicals Independently of the number of ranges of 1)
- H-H
- OH-OH
- O-(C1-C10)알킬- O- (C 1 -C 10) alkyl
= O= O
- NH2 NH 2
- NH-(C1-C10)알킬- NH- (C 1 -C 10) alkyl
- N[(C1-C10)알킬]2 - N [(C 1 -C 10 ) alkyl]
- SH-SH
- S-(C1-C10)알킬- S- (C 1 -C 10) alkyl
- 할로-Halo
- Si[(C1-C10)알킬]3 - Si [(C 1 -C 10 ) alkyl] 3
로부터 선택된다.Is selected from.
아릴과 헤테로아릴기용 치환체는 O-방향족 고리 시스템에서 개방원자가의 총수까지 범위의 수로 Substituents for aryl and heteroaryl groups range from the O-aromatic ring system to the total number of open atoms.
- 할로-Halo
- OH-OH
- O-R'-O-R '
- O-C(O)-R'O-C (O) -R '
- NH2 NH 2
- NHR'-NHR '
- NR'R"-NR'R "
- SH-SH
- SR'-SR '
- R'-R '
- CN-CN
- NO2 -NO 2
- CO2HCO 2 H
- CO2-R'-CO 2 -R '
- CONH2 -CONH 2
- CONH-R'-CONH-R '
- CONR'R"-CONR'R "
- O-C(O)-NH-R'O-C (O) -NH-R '
- O-C(O)-NR'R"O-C (O) -NR'R "
- NH-C(O)-R'NH-C (O) -R '
- NR"-C(O)-R'NR "-C (O) -R '
- NH-C(O)-OR'NH-C (O) -OR '
- NR"-C(O)-R'NR "-C (O) -R '
- NH-C(NH2)=NHNH-C (NH 2 ) = NH
- NR'-C(NH2)=NHNR′-C (NH 2 ) = NH
- NH-C(NH2)=NR'NH-C (NH 2 ) = NR '
- S(O)-R'S (O) -R '
- S(O)2-R'-S (O) 2 -R '
- S(O)2-NH-R'S (O) 2 -NH-R '
- S(O)2-NR'R"-S (O) 2 -NR'R "
- N3 -N 3
- CH(Ph)2 CH (Ph) 2
치환 또는 비치환된 아릴옥시Substituted or unsubstituted aryloxy
치환 또는 비치환된 아릴아미노Substituted or unsubstituted arylamino
치환 또는 비치환된 헤테로아릴아미노Substituted or unsubstituted heteroarylamino
치환 또는 비치환된 헤테로아릴옥시Substituted or unsubstituted heteroaryloxy
치환 또는 비치환된 아릴-(C1-C4)알콕시Substituted or unsubstituted aryl- (C 1 -C 4 ) alkoxy
치환 또는 비치환된 헤테로아릴-(C1-C4)알콕시Substituted or unsubstituted heteroaryl, - (C 1 -C 4) alkoxy
퍼플루오로(C1-C4)알콕시,Perfluoro (C 1 -C 4 ) alkoxy,
퍼플루오로(C1-C4)알킬,Perfluoro (C 1 -C 4 ) alkyl,
로부터 선택되고 ; Selected from;
여기에서 R'과 R" 는 독립적으로Where R 'and R "are independently
치환 또는 비치환된(C1-C10)알킬,Substituted or unsubstituted (C 1 -C 10 ) alkyl,
치환 또는 비치환된(C1-C10)헤테로알킬,Substituted or unsubstituted (C 1 -C 10 ) heteroalkyl,
치환 또는 비치환된(C2-C6)알케닐,Substituted or unsubstituted (C 2 -C 6 ) alkenyl,
치환 또는 비치환된(C2-C6)헤테로알케닐,Substituted or unsubstituted (C 2 -C 6 ) heteroalkenyl,
치환 또는 비치환된(C2-C6)알키닐,Substituted or unsubstituted (C 2 -C 6 ) alkynyl,
치환 또는 비치환된(C3-C8)사이클로알킬,Substituted or unsubstituted (C 3 -C 8 ) cycloalkyl,
치환 또는 비치환된(C3-C8)헤테로사이클로알킬,Substituted or unsubstituted (C 3 -C 8 ) heterocycloalkyl,
치환 또는 비치환된(C5-C6)사이클로알케닐,Substituted or unsubstituted (C 5 -C 6 ) cycloalkenyl,
치환 또는 비치환된(C5-C6)사이클로알카디에닐,Substituted or unsubstituted (C 5 -C 6 ) cycloalkadienyl,
치환 또는 비치환된 아릴,Substituted or unsubstituted aryl,
치환 또는 비치환된 아릴-(C1-C4)알킬,Substituted or unsubstituted aryl- (C 1 -C 4 ) alkyl,
치환 또는 비치환된 아릴-(C1-C4)헤테로알킬,A substituted or unsubstituted aryl - (C 1 -C 4) heteroalkyl,
치환 또는 비치환된 아릴-(C2-C6)알케닐,Substituted or unsubstituted aryl- (C 2 -C 6 ) alkenyl,
치환 또는 비치환된 알콕시-(C1-C4)알킬,A substituted or unsubstituted alkoxy - (C 1 -C 4) alkyl,
치환 또는 비치환된 알콕시-(C1-C4)헤테로알킬,A substituted or unsubstituted alkoxy - (C 1 -C 4) heteroalkyl,
치환 또는 비치환된 헤테로아릴,Substituted or unsubstituted heteroaryl,
치환 또는 비치환된 헤테로아릴-(C1-C4)알킬,Substituted or unsubstituted heteroaryl, - (C 1 -C 4) alkyl,
치환 또는 비치환된 헤테로아릴-(C1-C4)헤테로알킬,A substituted or unsubstituted heteroaryl, - (C 1 -C 4) heteroalkyl,
치환 또는 비치환된 헤테로아릴-(C2-C6)알케닐,Substituted or unsubstituted heteroaryl- (C 2 -C 6 ) alkenyl,
치환 또는 비치환된 헤테로아릴옥시-(C1-C4)알킬, 및Substituted or unsubstituted heteroaryloxy - (C 1 -C 4) alkyl, and
치환 또는 비치환된 헤테로아릴옥시-(C1-C4)헤테로알킬로부터 선택된다.Substituted or unsubstituted heteroaryloxy - (C 1 -C 4) is selected from heteroalkyl.
아릴 또는 헤테로아릴 고리의 인접원자에 대한 치환체 중 2개는 임의적으로 식-T-C(O)-(CH2)n-U-의 치환체로 대체될 수 있는데 여기에서 T와 U는 독립적으로 N,O 및 C로부터 선택되고 n=0-2이다. 선택적으로, 아릴 또는 헤테로아릴 고리의 인접원자에 대한 치환체중 2개는 임의적으로 식-A-(CH2)P-B-의 치환체로 대체될 수 있는데 여기에서 A와 B는 독립적으로 C, O, N, S, SO, SO2 및 SO2NR'로부터 선택되고 p=1-3이다. 이렇게 형성된 새로운 고리의 단일 결합 중 하나는 임의적으로 이중결합으로 대체될 수 있다. 선택적으로, 아릴 또는 헤테로아릴 고리의 인접원자에 대한 치환체 중 2개는 식-(CH2)q-X-(CH2)r-의 치환체로 대체되고 여기에서 q와 r은 독립적으로 1-3이고 X는 O, N, S, SO, SO2 및 SO2NR' 로부터 선택된다. SO2NR'에서 치환체 R'은 수소 또는 (C1-C6)알킬로부터 선택된다.Two of the substituents for the adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with substituents of the formula -TC (O)-(CH 2 ) n -U-, where T and U are independently N, O And C and n = 0-2. Optionally, two of the substituents for the adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with substituents of the formula -A- (CH 2 ) P -B-, wherein A and B are independently C, O , N, S, SO, SO 2 and SO 2 NR ′ and p = 1-3. One of the single bonds of the new ring thus formed may be optionally replaced with a double bond. Optionally the aryl or two of the substituents on adjacent atoms of the heteroaryl ring is formula - (CH 2) q -X- ( CH 2) r - is replaced with a substituent of where q and r are independently 1-3 And X is O, N, S, SO, SO 2 and SO 2 NR ' Is selected from. Substituent R 'in SO 2 NR' is selected from hydrogen or (C 1 -C 6 ) alkyl.
또 다른 실시예에서 본 발명은 일반식 I의 상기 설명의 화합물을 함유하는 제약학적 조성물의 사용을 위한 새로운 방법을 제공한다. 본 발명은 하나이상의 본 발명 조성물의 효과적인 제제를 환자에게 투여하는 것을 포함하는 악성종양, 세균 감염 및 건선과 같은 병리를 치료하기 위한 새로운 방법을 제공한다In another embodiment the present invention provides a new method for the use of a pharmaceutical composition containing a compound of the above description of formula (I). The present invention provides new methods for treating pathologies such as malignancies, bacterial infections and psoriasis, comprising administering to a patient an effective formulation of one or more compositions of the present invention.
또 다른 실시예에서, 본 발명은 화학적으로 안정하고 약물학적으로 활성인 일반식 Ⅰ의 조성물,In another embodiment, the present invention provides a composition of Formula I that is chemically stable and pharmacologically active,
또는 이들의 제약학적으로 수용가능한 염을 제공하는데, 여기에서 Or pharmaceutically acceptable salts thereof, wherein
Y는 -S(O)- 또는 -S(O2)-이고;Y is -S (O)-or -S (O 2 )-;
Z는 NR1R2 이고 R2 는 임의적으로 치환된 아릴 또는 헤테로아릴기이고 R1는Z is NR 1 R 2 and R 2 is an optionally substituted aryl or heteroaryl group and R 1 is
수소,Hydrogen,
치환 또는 비치환된 (C1-C10)알킬,Substituted or unsubstituted (C 1 -C 10 ) alkyl,
치환 또는 비치환된 (C1-C10)알콕시,Substituted or unsubstituted (C 1 -C 10 ) alkoxy,
치환 또는 비치환된 (C3-C6)알케닐,Substituted or unsubstituted (C 3 -C 6 ) alkenyl,
치환 또는 비치환된 (C2-C6)헤테로알킬,Substituted or unsubstituted (C 2 -C 6 ) heteroalkyl,
치환 또는 비치환된 (C3-C6)헤테로알케닐,Substituted or unsubstituted (C 3 -C 6 ) heteroalkenyl,
치환 또는 비치환된 (C3-C6)알키닐,Substituted or unsubstituted (C 3 -C 6 ) alkynyl,
치환 또는 비치환된 (C3-C8)사이클로알킬,Substituted or unsubstituted (C 3 -C 8 ) cycloalkyl,
치환 또는 비치환된 (C5-C7)사이클로알케닐,Substituted or unsubstituted (C 5 -C 7 ) cycloalkenyl,
치환 또는 비치환된 (C5-C7)사이클로알카디에닐,Substituted or unsubstituted (C 5 -C 7 ) cycloalkadienyl,
치환 또는 비치환된 아릴,Substituted or unsubstituted aryl,
치환 또는 비치환된 아릴옥시,Substituted or unsubstituted aryloxy,
치환 또는 비치환된 아릴-(C3-C8)사이클로알킬,Substituted or unsubstituted aryl- (C 3 -C 8 ) cycloalkyl,
치환 또는 비치환된 아릴-(C5-C7)사이클로알케닐,Substituted or unsubstituted aryl- (C 5 -C 7 ) cycloalkenyl,
치환 또는 비치환된 아릴옥시-(C3-C8)사이클로알킬,Substituted or unsubstituted aryloxy- (C 3 -C 8 ) cycloalkyl,
치환 또는 비치환된 아릴-(C1-C4)알킬,Substituted or unsubstituted aryl- (C 1 -C 4 ) alkyl,
치환 또는 비치환된 아릴-(C1-C4)알콕시,Substituted or unsubstituted aryl- (C 1 -C 4 ) alkoxy,
치환 또는 비치환된 아릴-(C1-C4)헤테로알킬,A substituted or unsubstituted aryl - (C 1 -C 4) heteroalkyl,
치환 또는 비치환된 아릴-(C3-C6)알케닐,Substituted or unsubstituted aryl- (C 3 -C 6 ) alkenyl,
치환 또는 비치환된 알콕시-(C1-C4)알킬,A substituted or unsubstituted alkoxy - (C 1 -C 4) alkyl,
치환 또는 비치환된 아릴옥시-(C2-C4)헤테로알킬,Substituted or unsubstituted aryloxy- (C 2 -C 4 ) heteroalkyl,
치환 또는 비치환된 헤테로아릴,Substituted or unsubstituted heteroaryl,
치환 또는 비치환된 헤테로아릴옥시,Substituted or unsubstituted heteroaryloxy,
치환 또는 비치환된 헤테로아릴-(C1-C4)알킬,Substituted or unsubstituted heteroaryl, - (C 1 -C 4) alkyl,
치환 또는 비치환된 헤테로아릴-(C1-C4)알콕시,Substituted or unsubstituted heteroaryl, - (C 1 -C 4) alkoxy,
치환 또는 비치환된 헤테로아릴-(C1-C4)헤테로알킬,A substituted or unsubstituted heteroaryl, - (C 1 -C 4) heteroalkyl,
치환 또는 비치환된 헤테로아릴-(C3-C6)알케닐,Substituted or unsubstituted heteroaryl- (C 3 -C 6 ) alkenyl,
치환 또는 비치환된 헤테로아릴옥시-(C1-C4)알킬 및Substituted or unsubstituted heteroaryloxy - (C 1 -C 4) alkyl and
치환 또는 비치환된 헤테로아릴옥시-(C2-C4)헤테로알킬로부터 선택되고,Substituted or unsubstituted heteroaryloxy- (C 2 -C 4 ) heteroalkyl,
여기에서 R1과 R2는 하기식의 치환체를 제공하기 위해 결합기 E에 의해 결합될 수 있고,Wherein R 1 and R 2 may be bonded by a linking group E to provide a substituent of the formula
여기에서 E는 결합, (C1-C4)알킬렌, 또는(C1-C4)헤테로알킬렌 및 R1, E, R2에 의해 형성된 고리를 나타내고 질소는 8개 이하의 원자를 함유하거나, 바람직하게는 R'과 R2가 NR1R2의 질소원자와 5-또는 6-으로 구성된 헤테로사이클릭 고리를 형성하는 분자에 공유적으로 결합될 수 있는데;Wherein E represents a ring formed by a bond, (C 1 -C 4 ) alkylene, or (C 1 -C 4 ) heteroalkylene and R 1 , E, R 2 and nitrogen contains up to 8 atoms Or, preferably, R 'and R 2 may be covalently bound to a molecule forming a heterocyclic ring consisting of 5- or 6- with the nitrogen atom of NR 1 R 2 ;
Y가 -S(O2)-이고, R1은 수소 또는 메틸인 경우, R2는 치환된 페닐 또는 헤테로아릴기이고 ;When Y is -S (O 2 )-and R 1 is hydrogen or methyl, R 2 is a substituted phenyl or heteroaryl group;
Y가 -S(O2)-이고, R2가 1-나프틸, 5-퀴놀릴 또는 4-피리딜로부터 선택된 고리 시스템인 경우 R1이 수소가 아니거나 R2가 수소가 아닌 최소한 하나의 치환체에 의해 치환되고 ;If Y is -S (O 2 )-and R 2 is a ring system selected from 1-naphthyl, 5-quinolyl or 4-pyridyl, then at least one of R 1 is not hydrogen or R 2 is not hydrogen; Substituted by a substituent;
Y가 -S(O2)-이고, R2는 페닐, R1이 1,2,3,4-테트라하이드로 퀴놀린시스템을 형성하기 위해 설폰아미도기와 관련하여 페닐고리의 2-위치에 -NR1R2-의 질소를 부착시키는 프로필렌유니트일 경우 그렇게 형성된 바이사이클릭 시스템에 남아있는 하나이상의 원자가는 수소가 아닌 최소한 하나의 치환체와 치환되며 ;Y is —S (O 2 ) —, R 2 is phenyl, and R 1 is —NR at the 2-position of the phenyl ring with respect to the sulfonamido group to form 1,2,3,4-tetrahydroquinoline system In the case of a propylene unit attaching nitrogen of 1 R 2- , at least one valency remaining in the bicyclic system thus formed is substituted with at least one substituent which is not hydrogen;
Y가 -S(O2)-이고, R2가 3-(1-하이드록시에틸), 3-디메틸아미노, 4-디메틸아미노, 4-페닐, 3-하이드록시, 3-하이드록시-4-디에틸아미노메틸, 3,4-메틸렌디옥시, 3,4-에틸렌디옥시, 2-(1-피롤릴), 또는 2-메톡시-4-(1-모르폴리노)로 치환된 경우 R1은 수소가 아니거나 R1이 수소일 때는 R2의 페닐고리에 남아있는 하나이상의 원자가는 수소가 아닌 치환체로 치환되고 ;Y is -S (O 2 )-, R 2 is 3- (1-hydroxyethyl), 3-dimethylamino, 4-dimethylamino, 4-phenyl, 3-hydroxy, 3-hydroxy-4- R when substituted with diethylaminomethyl, 3,4-methylenedioxy, 3,4-ethylenedioxy, 2- (1-pyrrolyl), or 2-methoxy-4- (1-morpholino) When 1 is not hydrogen or R 1 is hydrogen, at least one valency remaining in the phenyl ring of R 2 is substituted with a substituent other than hydrogen;
Y가 -S(O2)-이고 R2가 2-메틸벤조티아졸-5-일, 6-하이드록시-4-메틸-피리미딘-2-일, 3-카보메톡시피라진-2-일, 5-카보메톡시피라진-2-일, 4-카보에톡시-1-페닐피라졸-5-일, 3-메틸피라졸-5-일, 4-클로로-2-메틸티오피리미딘-6-일, 2-트리플루오로메틸-1,3,4-티아디아졸-5-일, 5,6,7,8-테트라하이드로-2-나프틸, 4-메틸티아졸-2-일, 6,7-디하이드로인단-5-일,-7-클로로-5-메틸-1,8-나프티리딘-2-일, 5,7-디메틸-1,8-나프티리딘-2-일 또는 3-시아노피라졸-4-일경우 R1이 수소와 다른 기인 조건이다.Y is -S (O 2 )-and R 2 is 2-methylbenzothiazol-5-yl, 6-hydroxy-4-methyl-pyrimidin-2-yl, 3-carbomethoxypyrazin-2-yl , 5-carbomethoxypyrazin-2-yl, 4-carboethoxy-1-phenylpyrazol-5-yl, 3-methylpyrazol-5-yl, 4-chloro-2-methylthiopyrimidine-6 -Yl, 2-trifluoromethyl-1,3,4-thiadiazol-5-yl, 5,6,7,8-tetrahydro-2-naphthyl, 4-methylthiazol-2-yl, 6,7-dihydroindan-5-yl, -7-chloro-5-methyl-1,8-naphthyridin-2-yl, 5,7-dimethyl-1,8-naphthyridin-2-yl or 3 In the case of cyanopyrazole-4-, R 1 is a condition different from that of hydrogen.
그 자체 또는 다른 치환체의 일부로서 용어 "알킬"은 다르게 언급되지 않는다면 지정된 탄소원자 수(즉, C1-C10은 1-10개의 탄소원자를 의미한다)를 갖는, 디- 및 복합-라디칼을 포함하는 직쇄 또는 가지쇄 탄화수소 라디칼을 의미하는데 메틸, 에틸, n-프로필, 이소프로필, n-부틸, t-부틸, 이소부틸, sec-부틸, n-펜틸의 동족체 및 이성질체, n-헥실, 2-메틸펜틸, 1,5-디메틸헥실, 1-메틸-4-이소프로필헥실 등을 포함한다. 그 자체 또는 또 다른 치환체의 일부로서 용어 "알킬렌"은 -CH2CH2CH2CH2-으로 예시되는 바와같이 알칸으로부터 유도된 2가 라디칼을 의미한다. "저급 알킬"은 일반적으로 6개 이하의 탄소원자를 갖는 보다 짧은 쇄 알킬이다.As used herein or as part of another substituent, the term "alkyl" includes di- and complex-radicals having the specified number of carbon atoms (ie, C 1 -C 10 means 1-10 carbon atoms) unless stated otherwise. Meaning a straight chain or branched hydrocarbon radical, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologues and isomers of n-pentyl, n-hexyl, 2- Methylpentyl, 1,5-dimethylhexyl, 1-methyl-4-isopropylhexyl, and the like. The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by -CH 2 CH 2 CH 2 CH 2- . "Lower alkyl" is generally shorter chain alkyl having up to 6 carbon atoms.
그 자체 또는 또 다른 용어와 조합하여 용어 "헤테로알킬"은 다르게 언급되지 않는다면 언급된 수의 탄소원자와 O, N 및 S로 이루어진 그룹으로부터 선택된 1개 또는 2개의 헤테로원자로 이루어진 안정한 직쇄 또는 가지쇄 라디칼을 의미하고 여기에서 질소와 황 원자는 임의적으로 산화되고 질소 헤테로원자는 임의적으로 4개의 원자로 될 수 있다. 헤테로원자는 헤테로알킬기의 나머지와 거기에 부착되고 헤테로알킬기에 있는 최말단 탄소원자에 부착된 단편의 사이를 포함하는 헤테로 알킬기의 의 어떤 위치에 위치될 수 있다. 예로는 -O-CH2-CH2-CH3, -CH2-CH2-O-CH3, -CH2-CH2-CH2-OH, CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -O-CH2-CH2-CH2-NH-CH3 및 -CH2-CH2-S(O)2-CH3를 포함한다. 2개이하의 헤테로원자는 예를들면 -CH2-NH-OCH3와 같이 연속적일 수 있다. 그 자체 또는 또 다른 치환체의 일부로서 용어 "헤테로알킬렌"은 -CH2-CH2-S-CH2-CH2와 -CH2-S-CH2-CH2-NH-로 예시되는 바와같이 헤테로알킬로부터 유도된 2가 라디칼을 의미한다.The term "heteroalkyl" by itself or in combination with another term, unless otherwise stated, is a stable straight or branched chain radical of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N and S Wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatoms may optionally be 4 atoms. The heteroatom may be located at any position of the heteroalkyl group including between the remainder of the heteroalkyl group and the fragment attached thereto and attached to the terminal carbon atom on the heteroalkyl group. Examples include -O-CH 2 -CH 2 -CH 3, -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -CH 2 -OH, CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N (CH 3 ) -CH 3 , -CH 2 -S-CH 2 -CH 3 , -CH 2 -CH 2 -S (O) -CH 3 , -O-CH 2 -CH 2 -CH 2 -NH-CH 3, and -CH 2 -CH 2 -S (O) 2 -CH 3 . Up to two heteroatoms may be continuous, for example, —CH 2 —NH—OCH 3 . The term “heteroalkylene” as such or as part of another substituent, is exemplified by —CH 2 —CH 2 —S—CH 2 —CH 2 and —CH 2 —S—CH 2 —CH 2 —NH—. Divalent radicals derived from heteroalkyl.
그 자체 또는 다른 용어와 조합하여 용어 "사이클로알킬"과 "헤테로사이클로알킬"은 다르게 언급되지 않는다면 각각 "알킬"과 "헤테로알킬"의 고리변형을 나타낸다. 사이클로알킬의 예로는 사이클로펜틸, 사이클로헥실, 사이클로헵틸 등을 포함한다. 헤테로사이클로알킬의 예로는 1-피페리디닐, 2-피페리디닐, 3-피페리디닐, 4-모르폴리닐, 3-모르폴리닐, 테트라하이드로퓨란-2-일, 테트라하이드로퓨란-3-일,테트라하이드로티엔-2-일, 테트라하이드로티엔-3-일, 1-피페라지닐, 2-피페라지닐등을 포함한다.The terms "cycloalkyl" and "heterocycloalkyl" by themselves or in combination with other terms refer to ring modifications of "alkyl" and "heteroalkyl", respectively, unless stated otherwise. Examples of cycloalkyl include cyclopentyl, cyclohexyl, cycloheptyl and the like. Examples of heterocycloalkyl include 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3- 1, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl and the like.
단독으로 또는 다른 용어와 조합하여 사용된 용어 "알케닐"은 다르게 언급되지 않는다면 언급된 수의 탄소원자를 갖는 안정한 직쇄 또는 가지쇄 모노불포화 또는 디불포화 탄화수소기를 의미한다. 예로는 비닐 프로페닐(알릴), 크로틸, 이소펜테닐, 부타디에닐, 1,3-펜타디에닐, 1,4-펜타디에닐 및 보다 높은 동족체와 이성질체를 포함한다. 알켄으로부터 유도된 2가 라디칼은 -CH=CH-CH2-로 예시된다.The term "alkenyl", used alone or in combination with other terms, refers to a stable straight or branched chain monounsaturated or diunsaturated hydrocarbon group having the stated number of carbon atoms unless stated otherwise. Examples include vinyl propenyl (allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl and higher homologues and isomers. Divalent radicals derived from alkenes are exemplified by -CH = CH-CH 2- .
그 자체 또는 다른 용어와 조합하여 사용된 용어 "헤테로알케닐"은 다르게 언급되지 않는다면 언급된 수의 탄소와 O,N 및 S로 이루어진 그룹으로부터 선택된 1개 또는 2개의 헤테로원자로 이루어진 안정한 직쇄 또는 가지쇄 모노불포화 또는 디불포화 탄화수소 라디칼을 의미하고 여기에서 질소와 황 원자는 임의적으로 산화되고 질소 헤테로원자는 임의적으로 4개의 원자로 될 수 있다. 2개 이하의 헤테로원자는 연속적으로 위치될 수 있다. 예로는 -CH=CH-O-CH3, -CH=CH-CH2-OH, -CH2-CH=NO-OCH3, -CH=CH-N(CH3)-CH3 및 -CH2-CH=CH-CH2-SH를 포함한다.The term “heteroalkenyl” used by itself or in combination with other terms, unless stated otherwise, refers to a stable straight or branched chain consisting of one or two heteroatoms selected from the group consisting of O, N and S with the stated number of carbons It refers to a monounsaturated or diunsaturated hydrocarbon radical, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatoms may optionally be 4 atoms. Up to two heteroatoms may be located consecutively. Examples are -CH = CH-O-CH 3 , -CH = CH-CH 2 -OH, -CH 2 -CH = NO-OCH 3 , -CH = CH-N (CH 3 ) -CH 3 and -CH 2 -CH = CH-CH 2 -SH.
단독 또는 다른 용어와 조합하여 사용된 용어 "알키닐"은 다르게 언급되지 않는다면 언급된 수의 탄소원자를 갖고 에티닐, 1- 및 3-프로피닐, 4-부트-1-이닐 및 보다 높은 동족체와 이성질체와 같은 1개 또는 2개의 탄소-탄소 3중 결합을 함유하는 안정한 직쇄 또는 가지쇄 탄화수소그룹을 의미한다.The term "alkynyl", used alone or in combination with other terms, unless stated otherwise, has the stated number of carbon atoms, including ethynyl, 1- and 3-propynyl, 4-but-1-ynyl and higher homologs and isomers. It refers to a stable straight or branched chain hydrocarbon group containing one or two carbon-carbon triple bonds such as:
단독 또는 다른 용어와 조합하여 사용된 용어 "알콕시"는 다르게 언급되지 않는다면 상기에 정의된 바와같이 산소원자를 거쳐 분자의 나머지에 연결된 예를들면 메톡시, 에톡시, 1-프로폭시, 2-프로폭시 및 보다 높은 동족체와 이성질체와 같은 알킬기를 의미한다.The term "alkoxy" used alone or in combination with other terms, unless defined otherwise, is connected to the remainder of the molecule via an oxygen atom as defined above, for example methoxy, ethoxy, 1-propoxy, 2-prop By alkyl and higher homologues and isomers are meant alkyl groups.
그 자체 또는 다른 치환체의 일부로서 사용된 용어 "할로" 또는 "할로겐"은 다르게 언급되지 않는다면 불소, 염소, 브롬 또는 요오드 원자를 의미한다.The term "halo" or "halogen" used as such or as part of another substituent means a fluorine, chlorine, bromine or iodine atom unless stated otherwise.
단독 또는 다른 용어와 조합하여 사용된 용어 "아릴"은 다르게 언급되지 않는다면 페닐, 1-나프틸 또는 2-나프틸기를 의미한다. 이들 고리시스템의 각각에 부착된 치환체의 최대 수는 각각 5, 7 및 7이다. 치환체는 상기에 기재된 수용가능한 치환체의 그룹으로부터 선택된다.The term "aryl" used alone or in combination with other terms means a phenyl, 1-naphthyl or 2-naphthyl group unless stated otherwise. The maximum number of substituents attached to each of these ring systems is 5, 7 and 7, respectively. Substituents are selected from the group of acceptable substituents described above.
그 자체 또는 또 다른 치환체의 일부로서 용어 "헤테로아릴"은 다르게 언급되지 않는다면 탄소원자와 N, O 및 S로 이루어진 그룹으로부터 선택된 1-4개의 헤테로 원자로 이루어진 비치환되거나 치환되고 안정한 단일-또는 바이사이클릭 헤테로사이클릭 방향족 고리 시스템을 의미하고 여기에서 질소와 황 헤테로원자는 임의적으로 산화되고 질소 원자는 임의적으로 4개의 원자로 될 수 있다. 헤테로사이클릭 시스템은 다르게 언급되지 않는다면 안정한 구조를 제공하는 어떤 헤테로원자 또는 탄소원자에 부착될 수 있다. 헤테로사이클릭 시스템은 상기에 기재된 수용가능한 방향족 치환체의 목록으로부터 독립적으로 선택된 1-4개의 치환체로 치환되거나 비치환될 수 있다. 이러한 헤테로사이클의 예로는 2-피롤릴, 3-피롤릴, 3-피라졸릴, 2-이미다졸릴, 4-이미다졸릴, 피라지닐, 2-옥사졸릴, 4-옥사졸릴, 5-옥사졸릴, 3-이속사졸릴, 4-이속사졸릴, 5-이속사졸릴, 2-티아졸릴, 4-티아졸릴, 5-티아졸릴, 2-퓨릴, 3-퓨릴, 2-티에닐, 3-티에닐, 2-피리딜, 3-피리딜, 4-피리딜, 2-피리미딜, 4-피리미딜, 5-벤조티아졸릴, 퓨리닐, 2-벤즈이미다졸릴, 5-인돌릴, 1-이소퀴놀릴, 5-이소퀴놀릴, 2-퀴녹사리닐, 5-퀴녹사리닐, 3-퀴놀릴 및 6-퀴놀릴을 포함한다.As used herein, or as part of another substituent, the term “heteroaryl”, unless stated otherwise, refers to an unsubstituted, substituted and stable single- or bicy of carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O and S By means of a click heterocyclic aromatic ring system wherein nitrogen and sulfur heteroatoms are optionally oxidized and the nitrogen atom may optionally be 4 atoms. Heterocyclic systems can be attached to any heteroatom or carbon atom that provides a stable structure unless otherwise noted. Heterocyclic systems may be unsubstituted or substituted with 1-4 substituents independently selected from the list of acceptable aromatic substituents described above. Examples of such heterocycles are 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl , 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thier Nyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1- Isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxarinyl, 3-quinolyl and 6-quinolyl.
식 Ⅰ 화합물의 제약학적으로 수용가능한 염은 식 I의 특정화합물에서 발견된 특정 치환체에 따라 상대적으로 비독성 산과 염기를 갖는 이들 화합물의 염을 포함한다. 식 I의 화합물이 상대적으로 산성 관능성을 함유할 때 염기 부가염이 순수 또는 적당한 불활성 용매에 있는 충분한 양의 소정의 염기와 중성 형태의 화합물 I을 접촉시키므로서 얻어질 수 있다. 제약학적으로 수용가능한 염기 부가염의 예로는 나트륨, 칼륨, 칼슘, 암모늄, 유기 아미노 또는 마그네슘 염 또는 유사한 염을 포함한다. 식 I의 화합물이 상대적으로 염기 관능성을 함유할 때 산 부가 염은 순수 또는 적당한 불활성 용매에 있는 충분한 양의 소정의 산, 중성형태의 화합물 I을 접촉시키므로서 얻어질 수 있다. 제약적으로 수용가능한 산부가염의 예로는 염산, 하이드로브롬산, 질산, 탄산, 모노하이드로젠 탄산, 인산, 모노하이드로젠 인산, 디하이드로젠 인산, 황산, 모노하이드로젠 황산, 옥화수소산 또는 인산 등과 같은 무기산으로부터 유도된 것들 뿐만 아니라, 아세트산, 프로피온산, 이소부틸산, 옥살산, 말렌산, 말론산, 벤조산, 호박산, 수베르산, 푸마르산,만델산, 프탈산, 벤젠설폰산, p-톨릴설폰산, 구연산, 타르타르산, 메탄 설폰산등과 같은 상대적으로 비독성 유기산으로부터 유도된 염을 포함한다. 또한 아르기네이트등과 같은 아미노산의 염과 글루콘산 또는 갈락트우론산 등과 같은 유기산의 염(예를들면, Berge, S.M 등, "제약학적염", Journal of Pharmaceutical Science, 66권 p 1-19(1977)을 참조)이 포함된다. 식 I의 어떤 특정 화합물은 화합물이 염기 또는 산 첨가염으로 전환되도록 하는 염기와 산성 관능성을 모두 함유한다.Pharmaceutically acceptable salts of compounds of formula I include salts of these compounds with relatively nontoxic acids and bases, depending on the particular substituents found on the particular compounds of formula I. When the compound of formula I contains relatively acidic functionality, base addition salts can be obtained by contacting the neutral form of compound I with a sufficient amount of the desired base in pure or suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compound of formula I contains a relatively basic functionality, acid addition salts may be obtained by contacting a sufficient amount of the desired acid, neutral form of compound I in pure or suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen carbonate, phosphoric acid, monohydrogen phosphoric acid, dihydrogen phosphoric acid, sulfuric acid, monohydrogen sulfuric acid, hydrofluoric acid or phosphoric acid, and the like. As well as those derived from acetic acid, propionic acid, isobutyl acid, oxalic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, Salts derived from relatively non-toxic organic acids such as tartaric acid, methane sulfonic acid and the like. Also, salts of amino acids such as arginate and the like, and salts of organic acids such as gluconic acid or galacturonic acid (eg, Berge, SM et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science , Vol. 66, pp. 1-19). (1977)). Certain specific compounds of formula I contain both base and acidic functionalities that allow the compounds to be converted to base or acid addition salts.
유리 염기 형태가 염을 염기 또는 산과 접촉시키고 통상적인 방법으로 모화합물을 분리하므로서 재생될 수 있다. 화합물의 모형태는 극성 용매에서의 용해도와 같은 어떤 물리적 성질에서 다양한 염 형태와 다르지만 염은 본 발명의 목적을 위해 화합물의 모 형태와 상응한다.The free base form can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. Although the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, the salt corresponds to the parent form of the compound for the purposes of the present invention.
본 발명의 어떤 화합물은 비용해 형태 뿐만 아니라 수화된 형태를 포함하는 용해 형태로 존재할 수 있다. 일반적으로, 용해된 형태는 비용해 형태에 상응하고 본 발명의 범위에 포함된다.Certain compounds of the present invention may exist in dissolved forms, including insoluble forms as well as hydrated forms. In general, the dissolved form corresponds to the insoluble form and is included within the scope of the present invention.
본 발명의 어떤 화합물은 비대칭 탄소원자(광학적 중심)를 소유하고; 라세믹, 디아스테레오머 및 개별적인 이성질체는 본 발명의 범위내에서 포함된다.Certain compounds of the present invention possess asymmetric carbon atoms (optical centers); Racemics, diastereomers and individual isomers are included within the scope of the present invention.
본 발명의 화합물은 이러한 화합물을 구성하는 하나 이상의 원자에서 부자연스런 비율의 원자 동위원소를 함유할 수 있다. 예를들면, 화합물 트리튬(3H) 또는 탄소-14(14C)와 같은 방사성 동위원소로 방사표지될 수 있다. 본 발명의 화합물의 다양한 동위원소 변형은 방사활성을 갖는지에 관계없이 본 발명의 범위에 포함된다.Compounds of the present invention may contain an unnatural proportion of atomic isotopes at one or more atoms constituting such compounds. For example, it may be radiolabeled with a radioisotope such as compound tritium ( 3 H) or carbon-14 ( 14 C). Various isotopic variations of the compounds of the invention are included within the scope of the invention whether or not they have radioactivity.
식 I의 화합물의 제약학적 조성물의 다양한 바람직한 실시예에서, Y는 S(O2)이고 Z는 NR1R2인데 여기에서 R1은 수소 또는 메틸이고 R2는 치환된 페닐, 바람직하게는 하기와 같은 모노-, 디- 또는 트리치환된 페닐이다; 소정의 화합물의 한 그룹에서, Y는 S(O2)이고 Z는 NR1R2 인데 여기에서 R1은 수소 또는 메틸이고 R2는 하기의 그룹 중 하나에 의해 파라위치에서 바람직하게 치환된 페닐기이다: 수소, 할로겐, (C1-C10)알콕시, (C1-C10)알킬, 및 [디(C1-C10)알킬]아미노로부터 독립적으로 선택된 4개 이하의 추가 치환체를 갖는 하이드록시, 아미노, (C1-C10)알콕시, (C1-C10)알킬, (C1-C10)알킬아미노 및 [디(C1-C10)알킬]아미노. 또한 바람직한 것은 R1과 R2사이에 결합기 E가 없는 식 I의 화합물이다.In various preferred embodiments of the pharmaceutical composition of the compound of formula I, Y is S (O 2 ) and Z is NR 1 R 2 , wherein R 1 is hydrogen or methyl and R 2 is substituted phenyl, preferably Mono-, di- or trisubstituted phenyl such as; In one group of certain compounds, Y is S (O 2 ) and Z is NR 1 R 2 , wherein R 1 is hydrogen or methyl and R 2 is a phenyl group preferably substituted at the para position by one of the following groups: Is: hydrogen having up to 4 additional substituents independently selected from hydrogen, halogen, (C 1 -C 10 ) alkoxy, (C 1 -C 10 ) alkyl, and [di (C 1 -C 10 ) alkyl] amino Oxy, amino, (C 1 -C 10 ) alkoxy, (C 1 -C 10 ) alkyl, (C 1 -C 10 ) alkylamino and [di (C 1 -C 10 ) alkyl] amino. Also preferred are compounds of formula I, wherein there is no bond group E between R 1 and R 2 .
본 발명의 제약적 방법의 제약적 조성물과 화합물의 예시적인 예로는 하기를 포함한다 ;Illustrative examples of pharmaceutical compositions and compounds of the pharmaceutical methods of the present invention include the following;
2-플루오로-1-메톡시-4-펜타플루오로페닐설핀아미도벤젠 ;2-fluoro-1-methoxy-4-pentafluorophenylsulfinamidobenzene;
4-디메틸아미노-1-펜타플루오로페닐설핀아미도벤젠 ;4-dimethylamino-1-pentafluorophenylsulfinamidobenzene;
4-메틸-6-메톡시-2-펜타플루오로페닐설포아미도피리미딘 ;4-methyl-6-methoxy-2-pentafluorophenylsulfoamidopyrimidine;
4,6-디메톡시-2-펜타플루오로페닐설포아미도미리미딘 ;4,6-dimethoxy-2-pentafluorophenylsulfoamidoimiridine;
2-펜타플루오로페닐설폰아미도티오펜 ;2-pentafluorophenylsulfonamidothiophene;
3-펜타플루오로페닐설폰아미도티오펜 ;3-pentafluorophenylsulfonamidothiophene;
3-펜타플루오로페닐설폰아미도피리딘 ;3-pentafluorophenylsulfonamidopyridine;
4-펜타플루오로페닐설폰아미도피리딘 ;4-pentafluorophenylsulfonamidopyridine;
4-(N,N,-디메틸아미노)-1-(N-에틸펜타플루오로페닐설폰아미도)-벤젠 ;4- (N, N, -dimethylamino) -1- (N-ethylpentafluorophenylsulfonamido) -benzene;
4-tert-부톡시-1-펜타플루오로페닐설폰아미도벤젠 ;4-tert-butoxy-1-pentafluorophenylsulfonamidobenzene;
3-tert-부톡시-1-펜타플루오로페닐설폰아미도벤젠 ;3-tert-butoxy-1-pentafluorophenylsulfonamidobenzene;
2-tert-부톡시-1-펜타플루오로페닐설폰아미도벤젠 ;2-tert-butoxy-1-pentafluorophenylsulfonamidobenzene;
4-이소프로폭시-1-펜타플루오로페닐설폰아미도벤젠 ;4-isopropoxy-1-pentafluorophenylsulfonamidobenzene;
3-이소프로폭시-1-펜타플루오로페닐설폰아미도벤젠 ;3-isopropoxy-1-pentafluorophenylsulfonamidobenzene;
2-이소프로폭시-1-펜타플루오로페닐설폰아미도벤젠 ;2-isopropoxy-1-pentafluorophenylsulfonamidobenzene;
2-메톡시-1,3-디플루오로-5-펜타플루오로페닐설폰아미도벤젠 ;2-methoxy-1,3-difluoro-5-pentafluorophenylsulfonamidobenzene;
4-사이클로프로폭시-1-펜타플루오로페닐설폰아미도벤젠;4-cyclopropoxy-1-pentafluorophenylsulfonamidobenzene;
3-플루오로-4-사이클로프로폭시-1-펜타플루오로페닐설폰아미도벤젠;3-fluoro-4-cyclopropoxy-1-pentafluorophenylsulfonamidobenzene;
3-하이드록시-4-사이클로프로폭시-1-펜타플루오로페닐설폰아미도벤젠;3-hydroxy-4-cyclopropoxy-1-pentafluorophenylsulfonamidobenzene;
1-하이드록시-2,3-메틸렌디옥시-5-펜타플루오로페닐설폰아미도벤젠;1-hydroxy-2,3-methylenedioxy-5-pentafluorophenylsulfonamidobenzene;
1-하이드록시-2,3-에틸렌디옥시-5-펜타플루오로페닐설폰아미도벤젠;1-hydroxy-2,3-ethylenedioxy-5-pentafluorophenylsulfonamidobenzene;
1-하이드록시-2,3-카보디옥시-5-펜타플루오로페닐설폰아미도벤젠;1-hydroxy-2,3-carbodioxy-5-pentafluorophenylsulfonamidobenzene;
1,3-디하이드록시-2-에톡시-5-펜타플루오로페닐설폰아미도벤젠;1,3-dihydroxy-2-ethoxy-5-pentafluorophenylsulfonamidobenzene;
1-펜타플루오로페닐설포닐인돌;1-pentafluorophenylsulfonylindole;
1-펜타플루오로페닐설포닐(2,3-디하이드로)인돌;1-pentafluorophenylsulfonyl (2,3-dihydro) indole;
1-펜타플루오로페닐설포닐(1,2-디하이드로)퀴놀린;1-pentafluorophenylsulfonyl (1,2-dihydro) quinoline;
1-펜타플루오로페닐설포닐(1,2,3,4-테트라하이드로)퀴놀린;1-pentafluorophenylsulfonyl (1,2,3,4-tetrahydro) quinoline;
3,4-디플루오로-1-펜타플루오로페닐설폰아미도벤젠;3,4-difluoro-1-pentafluorophenylsulfonamidobenzene;
4-트리플루오로메톡시-1-펜타플루오로페닐설폰아미도벤젠;4-trifluoromethoxy-1-pentafluorophenylsulfonamidobenzene;
2-클로로-5-펜타플루오로페닐설폰아미도피리딘;2-chloro-5-pentafluorophenylsulfonamidopyridine;
2-하이드록시-1-메톡시-4-[N-5-하이드록시펜트-1-일)펜타플루오로페닐-설폰아미도]벤젠;2-hydroxy-1-methoxy-4- [N-5-hydroxypent-1-yl) pentafluorophenyl-sulfonamido] benzene;
4-(1,1-디메틸)에톡시-1-펜타플루오로페닐설폰아미도벤젠;4- (1,1-dimethyl) ethoxy-1-pentafluorophenylsulfonamidobenzene;
1-브로모-3-하이드록시-4-메톡시-1-펜타플루오로페닐설폰아미도벤젠;1-bromo-3-hydroxy-4-methoxy-1-pentafluorophenylsulfonamidobenzene;
2-브로모-4-메톡시-5-하이드록시-1-펜타플루오로페닐설폰아미도벤젠;2-bromo-4-methoxy-5-hydroxy-1-pentafluorophenylsulfonamidobenzene;
1-브로모-4-플루오로-5-메톡시-2-펜타플루오로페닐설폰아미도벤젠;1-bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene;
3-클로로-1-펜타플루오로페닐설폰아미도벤젠;3-chloro-1-pentafluorophenylsulfonamidobenzene;
4-클로로-1-펜타플루오로페닐설폰아미도벤젠;4-chloro-1-pentafluorophenylsulfonamidobenzene;
3-니트로-1-펜타플루오로페닐설폰아미도벤젠;3-nitro-1-pentafluorophenylsulfonamidobenzene;
4-메톡시-1-펜타플루오로페닐설폰아미도-3-(트리플루오로메틸)벤젠;4-methoxy-1-pentafluorophenylsulfonamido-3- (trifluoromethyl) benzene;
4-메톡시-1-[N-(2-프로페닐)펜타플루오로페닐설폰아미도]벤젠;4-methoxy-1- [N- (2-propenyl) pentafluorophenylsulfonamido] benzene;
1-(N-(3-부테닐)펜타플루오로페닐설폰아미도)-4-메톡시벤젠;1- (N- (3-butenyl) pentafluorophenylsulfonamido) -4-methoxybenzene;
4-메톡시-1-(N-(4-펜테닐)펜타플루오로페닐설폰아미도)벤젠;4-methoxy-1- (N- (4-pentenyl) pentafluorophenylsulfonamido) benzene;
1-[N-(2,3-디하이드록시프로필)펜타플루오로페닐설폰아미도]-4-메톡시-벤젠;1- [N- (2,3-dihydroxypropyl) pentafluorophenylsulfonamido] -4-methoxy-benzene;
1-(N-(3,4-디하이드록시부틸)펜타플루오로페닐설폰아미도)-4-메톡시벤젠;1- (N- (3,4-dihydroxybutyl) pentafluorophenylsulfonamido) -4-methoxybenzene;
1-(N-(4,5-하이드록시펜틸)펜타플루오로페닐설폰아미도)-4-메톡시벤젠;1- (N- (4,5-hydroxypentyl) pentafluorophenylsulfonamido) -4-methoxybenzene;
1-(N-(4-하이드록시부틸)펜타플루오로페닐설폰아미도)-4-메톡시벤젠;1- (N- (4-hydroxybutyl) pentafluorophenylsulfonamido) -4-methoxybenzene;
4-메톡시-1-(N-(5-하이드록시펜틸)펜타플루오로페닐설폰아미도)-벤젠;4-methoxy-1- (N- (5-hydroxypentyl) pentafluorophenylsulfonamido) -benzene;
3-아미노-4-메톡시-1-펜타플루오로페닐설폰아미도벤젠;3-amino-4-methoxy-1-pentafluorophenylsulfonamidobenzene;
4-부톡시-1-펜타플루오로페닐설폰아미도벤젠;4-butoxy-1-pentafluorophenylsulfonamidobenzene;
1-펜타플루오로페닐설폰아미도-4-페녹시벤젠;1-pentafluorophenylsulfonamido-4-phenoxybenzene;
6-펜타플루오로페닐설폰아미도퀴놀린;6-pentafluorophenylsulfonamidoquinoline;
2,3-디하이드로-5-펜타플루오로페닐설폰아미도인돌;2,3-dihydro-5-pentafluorophenylsulfonamidoindole;
5-펜타플루오로페닐설폰아미도벤조[아]티오펜;5-pentafluorophenylsulfonamidobenzo [a] thiophene;
5-펜타플루오로페닐설폰아미도벤조[아]퓨란;5-pentafluorophenylsulfonamidobenzo [a] furan;
3-하이드록시-4-(1-프로페릴)-1-펜타플루오로페닐설폰아미도벤젠;3-hydroxy-4- (1-propyl) -1-pentafluorophenylsulfonamidobenzene;
4-벤질옥시-1-펜타플루오로페닐설폰아미도벤젠;4-benzyloxy-1-pentafluorophenylsulfonamidobenzene;
4-메틸메카캅토-1-펜타플루오로페닐설폰아미도벤젠;4-methylmecacapto-1-pentafluorophenylsulfonamidobenzene;
2-메톡시-1-펜타플루오로페닐설폰아미도벤젠;2-methoxy-1-pentafluorophenylsulfonamidobenzene;
4-알릴옥시-1-펜타플루오로페닐설폰아미도벤젠;4-allyloxy-1-pentafluorophenylsulfonamidobenzene;
1-펜타플루오로페닐설폰아미도-4-프로폭시벤젠;1-pentafluorophenylsulfonamido-4-propoxybenzene;
4-(1-메틸)에톡시-1-펜타플루오로페닐설폰아미도벤젠;4- (1-methyl) ethoxy-1-pentafluorophenylsulfonamidobenzene;
1,2-메틸렌디옥시-4-펜타플루오로페닐설폰아미도벤젠;1,2-methylenedioxy-4-pentafluorophenylsulfonamidobenzene;
1,2-디메톡시-4-펜타플루오로페닐설폰아미도벤젠;1,2-dimethoxy-4-pentafluorophenylsulfonamidobenzene;
4-(N,N-디에틸아미노)-1-펜타플루오로페닐설폰아미도벤젠;4- (N, N-diethylamino) -1-pentafluorophenylsulfonamidobenzene;
4-아미노-1-펜타플루오로페닐설폰아미도벤젠;4-amino-1-pentafluorophenylsulfonamidobenzene;
펜타플루오로페닐설폰아미도벤젠;Pentafluorophenylsulfonamidobenzene;
5-펜타플루오로페닐설폰아미도인다졸;5-pentafluorophenylsulfonamimidazole;
4-(N,N-디메틸아미노)-1-(N-메틸펜타플루오로페닐설폰아미도)-벤젠;4- (N, N-dimethylamino) -1- (N-methylpentafluorophenylsulfonamido) -benzene;
1,2-디하이드록시-4-펜타플루오로페닐설폰아미도벤젠;1,2-dihydroxy-4-pentafluorophenylsulfonamidobenzene;
3,5-디메톡시-1-펜타플루오로페닐설폰아미도벤젠;3,5-dimethoxy-1-pentafluorophenylsulfonamidobenzene;
3-에톡시-1-펜타플루오로페닐설폰아미도벤젠;3-ethoxy-1-pentafluorophenylsulfonamidobenzene;
7-하이드록시-2-펜타플루오로페닐설폰아미도나프탈렌;7-hydroxy-2-pentafluorophenylsulfonamidonaphthalene;
3-페녹시-1-펜타플루오로페닐설폰아미도벤젠;3-phenoxy-1-pentafluorophenylsulfonamidobenzene;
4-(1-모르폴리노)-1-펜타플루오로페닐설폰아미도벤젠;4- (1-morpholino) -1-pentafluorophenylsulfonamidobenzene;
5-펜타플루오로페닐설폰아미도-1,2,3-트리메톡시벤젠;5-pentafluorophenylsulfonamido-1,2,3-trimethoxybenzene;
2-하이드록시-1,3-메톡시-5-펜타플루오로페닐설폰아미도벤젠;2-hydroxy-1,3-methoxy-5-pentafluorophenylsulfonamidobenzene;
1,2-디하이드록시-3-메톡시-5-펜타플루오로페닐설폰아미도벤젠;1,2-dihydroxy-3-methoxy-5-pentafluorophenylsulfonamidobenzene;
5-펜타플루오로페닐설폰아미도-1,2,3-트리하이드록시벤젠;5-pentafluorophenylsulfonamido-1,2,3-trihydroxybenzene;
3-하이드록시-5-메톡시-1-펜타플루오로페닐설폰아미도벤젠;3-hydroxy-5-methoxy-1-pentafluorophenylsulfonamidobenzene;
3,5-디하이드록시-1-펜타플루오로페닐설폰아미도벤젠;3,5-dihydroxy-1-pentafluorophenylsulfonamidobenzene;
2-플루오로-1-메톡시-4-(N-메틸펜타플루오로페닐설폰아미도)벤젠;2-fluoro-1-methoxy-4- (N-methylpentafluorophenylsulfonamido) benzene;
4-(N,N-디메틸아미노)-1-펜타플루오로페닐설폰아미도벤젠,하이드로클로라이드;4- (N, N-dimethylamino) -1-pentafluorophenylsulfonamidobenzene, hydrochloride;
2-메톡시-5-펜타플루오로페닐설폰아미도피리딘; 및 2-methoxy-5-pentafluorophenylsulfonamidopyridine; And
2-아닐니노-3-펜타플루오로페닐설폰아미도피리딘.2-aninilino-3-pentafluorophenylsulfonamidopyridine.
본 발명 제약학적 방법의 가장 바람직한 제약학적 조성물과 화합물의 예로는 하기를 포함한다:Examples of the most preferred pharmaceutical compositions and compounds of the pharmaceutical methods of the invention include the following:
4-(N,N-디메틸아미노)-1-펜타플루오로페닐설폰아미도벤젠;4- (N, N-dimethylamino) -1-pentafluorophenylsulfonamidobenzene;
3-(N,N-디메틸아미노)-1-펜타플루오로페닐설폰아미도벤젠;3- (N, N-dimethylamino) -1-pentafluorophenylsulfonamidobenzene;
1,2-에틸렌디옥시-4-펜타플루오로페닐설폰아미도벤젠;1,2-ethylenedioxy-4-pentafluorophenylsulfonamidobenzene;
2-하이드록시-1-메톡시-4-펜타플루오로페닐설폰아미도벤젠;2-hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene;
2-플루오로-1-메톡시-4-펜타플루오로페닐설폰아미도벤젠;2-fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene;
2-하이드록시-1-메톡시-4-펜타플루오로페닐설폰아미도벤젠,소듐염;2-hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene, sodium salt;
2-하이드록시-1-메톡시-4-펜타플루오로페닐설폰아미도벤젠,포타슘염;2-hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene, potassium salt;
2-플루오로-1-메톡시-4-펜타플루오로페닐설폰아미도벤젠,소듐염;2-fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene, sodium salt;
2-플루오로-1-메톡시-4-펜타플루오로페닐설폰아미도벤젠,포타슘염;2-fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene, potassium salt;
4-메톡시-1-펜타플루오로페닐설폰아미도벤젠;4-methoxy-1-pentafluorophenylsulfonamidobenzene;
3-하이드록시-1-펜타플루오로페닐설폰아미도벤젠;3-hydroxy-1-pentafluorophenylsulfonamidobenzene;
4-하이드록시-1-펜타플루오로페닐설폰아미도벤젠;4-hydroxy-1-pentafluorophenylsulfonamidobenzene;
1,2-디메틸-4-펜타플루오로페닐설폰아미도벤젠;1,2-dimethyl-4-pentafluorophenylsulfonamidobenzene;
5-펜타플루오로페닐설폰아미도인돌;5-pentafluorophenylsulfonamidoindole;
4-에톡시-1-펜타플루오로페닐설폰아미도벤젠;4-ethoxy-1-pentafluorophenylsulfonamidobenzene;
3-메톡시-1-펜타플루오로페닐설폰아미도벤젠;3-methoxy-1-pentafluorophenylsulfonamidobenzene;
2-브로모-1-메톡시-4-펜타플루오로페닐설폰아미도벤젠;2-bromo-1-methoxy-4-pentafluorophenylsulfonamidobenzene;
2-클로로-1-메톡시-4-펜타플루오로페닐설폰아미도벤젠;2-chloro-1-methoxy-4-pentafluorophenylsulfonamidobenzene;
2-브로모-3-하이드록시-4-메톡시-1-펜타플루오로페닐설폰아미도벤젠;2-bromo-3-hydroxy-4-methoxy-1-pentafluorophenylsulfonamidobenzene;
2-브로모-4-메톡시-5-하이드록시-1-펜타플루오로페닐설폰아미도벤젠;2-bromo-4-methoxy-5-hydroxy-1-pentafluorophenylsulfonamidobenzene;
1-브로모-4-플로오로-5-메톡시-2-펜타플루오로페닐설폰아미도벤젠;1-bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene;
4-클로로-1-펜타플루오로페닐설폰아미도벤젠; 및4-chloro-1-pentafluorophenylsulfonamidobenzene; And
3-아미노-4-메톡시-1-펜타플루오로페닐설폰아미도벤젠.3-amino-4-methoxy-1-pentafluorophenylsulfonamidobenzene.
본 발명은 약물학적, 독성적, 신진대사적등과 같은 하나이상의 가치있는 생물학적 활성을 갖는 일반식 I의 특정 신규 화합물을 제공한다. 본 발명 실시예의 예시적인 화합물로는 하기를 포함한다:The present invention provides certain novel compounds of Formula I having one or more valuable biological activities, such as pharmacological, toxic, metabolic and the like. Exemplary compounds of the Examples of the present invention include the following:
2-플루오로-1-메톡시-4-펜타플루오로페닐설폰아미도벤젠;2-fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene;
4-디메틸아미노-1-펜타플루오로페닐설폰아미도벤젠;4-dimethylamino-1-pentafluorophenylsulfonamidobenzene;
4-메틸-6-메톡시-2-펜타플루오로페닐설폰아미도피리미딘;4-methyl-6-methoxy-2-pentafluorophenylsulfonamidopyrimidine;
4,6-디메톡시-2-펜타플루오로페닐설폰아미도피리미딘;4,6-dimethoxy-2-pentafluorophenylsulfonamidopyrimidine;
2-펜타플루오로페닐설폰아미도티오펜;2-pentafluorophenylsulfonamidothiophene;
3-펜타플루오로페닐설폰아미도티오펜;3-pentafluorophenylsulfonamidothiophene;
3-펜타플루오로페닐설폰아미도피리딘;3-pentafluorophenylsulfonamidopyridine;
4-펜타플루오로페닐설폰아미도피리딘;4-pentafluorophenylsulfonamidopyridine;
4-(N,N-디메틸아미노)-1-(N-에틸펜타플루오로페닐설폰아미도)벤젠;4- (N, N-dimethylamino) -1- (N-ethylpentafluorophenylsulfonamido) benzene;
4-tert-부톡시-1-펜타플루오로페닐설폰아미도벤젠;4-tert-butoxy-1-pentafluorophenylsulfonamidobenzene;
3-tert-부톡시-1-펜타플루오로페닐설폰아미도벤젠;3-tert-butoxy-1-pentafluorophenylsulfonamidobenzene;
2-tert-부톡시-1-펜타플루오로페닐설폰아미도벤젠;2-tert-butoxy-1-pentafluorophenylsulfonamidobenzene;
4-이소프로폭시-1-펜타플루오로페닐설폰아미도벤젠;4-isopropoxy-1-pentafluorophenylsulfonamidobenzene;
3-이소프로폭시-1-펜타플루오로페닐설폰아미도벤젠;3-isopropoxy-1-pentafluorophenylsulfonamidobenzene;
2-이소프로폭시-1-펜타플루오로페닐설폰아미도벤젠;2-isopropoxy-1-pentafluorophenylsulfonamidobenzene;
2-메톡시-1,3-디플루오로-5-펜타플루오로페닐설폰아미도벤젠;2-methoxy-1,3-difluoro-5-pentafluorophenylsulfonamidobenzene;
1-하이드록시-2,3-메틸렌디옥시-5-펜타플루오로페닐설폰아미도벤젠;1-hydroxy-2,3-methylenedioxy-5-pentafluorophenylsulfonamidobenzene;
1-하이드록시-2,3-에틸렌디옥시-5-펜타플루오로페닐설폰아미도벤젠;1-hydroxy-2,3-ethylenedioxy-5-pentafluorophenylsulfonamidobenzene;
1-하이드록시-2,3-카르보디옥시-5-펜타플루오로페닐설폰아미도벤젠;1-hydroxy-2,3-carbodioxy-5-pentafluorophenylsulfonamidobenzene;
1,3-디하이드록시-2-에톡시-5-펜타플루오로페닐설폰아미도벤젠;1,3-dihydroxy-2-ethoxy-5-pentafluorophenylsulfonamidobenzene;
1-펜타플루오로페닐설포닐인돌;1-pentafluorophenylsulfonylindole;
1-펜타플루오로페닐설포닐(2,3-디하이드로)인돌;1-pentafluorophenylsulfonyl (2,3-dihydro) indole;
1-펜타플루오로페닐설포닐(1,2-디하이드로)퀴놀린;1-pentafluorophenylsulfonyl (1,2-dihydro) quinoline;
1-펜타플루오로페닐설포닐(1,2,3,4-테트라하이드로)퀴놀린;1-pentafluorophenylsulfonyl (1,2,3,4-tetrahydro) quinoline;
3,4-디플루오로-1-펜타플루오로페닐설폰아미도벤젠;3,4-difluoro-1-pentafluorophenylsulfonamidobenzene;
4-트리플루오로메톡시-1-펜타플루오로페닐설폰아미도벤젠;4-trifluoromethoxy-1-pentafluorophenylsulfonamidobenzene;
2-클로로-5-펜타플루오로페닐설폰아미도피리딘;2-chloro-5-pentafluorophenylsulfonamidopyridine;
2-하이드록시-1-메톡시-4-[N-5-하이드록시펜트-1-일)펜타플루오로페닐-설포아미도]벤젠;2-hydroxy-1-methoxy-4- [N-5-hydroxypent-1-yl) pentafluorophenyl-sulfoamido] benzene;
4-(1,1-디메틸)에톡시-1-펜타플루오로페닐설폰아미도벤젠;4- (1,1-dimethyl) ethoxy-1-pentafluorophenylsulfonamidobenzene;
1-브로모-3-하이드록시-4-메톡시-1-펜타플루오로페닐설폰아미도벤젠;1-bromo-3-hydroxy-4-methoxy-1-pentafluorophenylsulfonamidobenzene;
2-브로모-4-메톡시-5-하이드록시-1-펜타플루오로페닐설폰아미도벤젠;2-bromo-4-methoxy-5-hydroxy-1-pentafluorophenylsulfonamidobenzene;
1-브로모-4-플루오로-5-메톡시-2-펜타플루오로페닐설폰아미도벤젠;1-bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene;
3-클로로-1-펜타플루오로페닐설폰아미도벤젠;3-chloro-1-pentafluorophenylsulfonamidobenzene;
4-클로로-1-펜타플루오로페닐설폰아미도벤젠;4-chloro-1-pentafluorophenylsulfonamidobenzene;
3-니트로-1-펜타플루오로페닐설폰아미도벤젠;3-nitro-1-pentafluorophenylsulfonamidobenzene;
4-메톡시-1-펜타플루오로페닐설폰아미도-3-(트리플루오로메틸)벤젠;4-methoxy-1-pentafluorophenylsulfonamido-3- (trifluoromethyl) benzene;
4-메톡시-1-[N-(2-프로페닐)펜타플루오로페닐설폰아미도]벤젠;4-methoxy-1- [N- (2-propenyl) pentafluorophenylsulfonamido] benzene;
1-(N-(3-부테닐)펜타플루오로페닐설폰아미도)-4-메톡시벤젠;1- (N- (3-butenyl) pentafluorophenylsulfonamido) -4-methoxybenzene;
4-메톡시-1-(N-(4-펜테닐)펜타플루오로페닐설폰아미도)벤젠;4-methoxy-1- (N- (4-pentenyl) pentafluorophenylsulfonamido) benzene;
1-[N-(2,3-디하이드록시프로필)펜타플루오로페닐설폰아미도]-4-메톡시-벤젠;1- [N- (2,3-dihydroxypropyl) pentafluorophenylsulfonamido] -4-methoxy-benzene;
1-(N-(3,4-디하이드록시프로필)펜타플루오로페닐설폰아미도)-4-메톡시벤젠;1- (N- (3,4-dihydroxypropyl) pentafluorophenylsulfonamido) -4-methoxybenzene;
1-(N-(4,5-디하이드록시프로필)펜타플루오로페닐설폰아미도)-4-메톡시벤젠;1- (N- (4,5-dihydroxypropyl) pentafluorophenylsulfonamido) -4-methoxybenzene;
1-(N-(4-하이드록시부틸)펜타플루오로페닐설폰아미도)-4-메톡시벤젠;1- (N- (4-hydroxybutyl) pentafluorophenylsulfonamido) -4-methoxybenzene;
4-메톡시-1-(N-(5-하이드록시펜틸)펜타플루오로페닐설폰아미도)-벤젠;4-methoxy-1- (N- (5-hydroxypentyl) pentafluorophenylsulfonamido) -benzene;
3-아미노-4-메톡시-1-펜타플루오로페닐설폰아미도벤젠;3-amino-4-methoxy-1-pentafluorophenylsulfonamidobenzene;
4-부톡시-1-펜타플루오로페닐설폰아미도벤젠;4-butoxy-1-pentafluorophenylsulfonamidobenzene;
1-펜타플루오로페닐설폰아미도-4-페녹시벤젠;1-pentafluorophenylsulfonamido-4-phenoxybenzene;
4-벤질옥시-1-펜타플루오로페닐설폰아미도벤젠;4-benzyloxy-1-pentafluorophenylsulfonamidobenzene;
4-메틸메르캅토-1-펜타플루오로페닐설폰아미도벤젠;4-methylmercapto-1-pentafluorophenylsulfonamidobenzene;
2-메톡시-1-펜타플루오로페닐설폰아미도벤젠;2-methoxy-1-pentafluorophenylsulfonamidobenzene;
4-알릴옥시-1-펜타플루오로페닐설폰아미도벤젠;4-allyloxy-1-pentafluorophenylsulfonamidobenzene;
1-펜타플루오로페닐설폰아미도-4-프로폭시벤젠;1-pentafluorophenylsulfonamido-4-propoxybenzene;
4-(1-메틸)에톡시-1-펜타플루오로페닐설폰아미도벤젠;4- (1-methyl) ethoxy-1-pentafluorophenylsulfonamidobenzene;
1,2-메틸렌디옥시-4-펜타플루오로페닐설폰아미도벤젠;1,2-methylenedioxy-4-pentafluorophenylsulfonamidobenzene;
1,2-디메톡시-4-펜타플루오로페닐설폰아미도벤젠;1,2-dimethoxy-4-pentafluorophenylsulfonamidobenzene;
4-(N,N-디에틸아미노)-1-펜타플루오로페닐설폰아미도벤젠;4- (N, N-diethylamino) -1-pentafluorophenylsulfonamidobenzene;
4-아미노-1-펜타플루오로페닐설폰아미도벤젠;4-amino-1-pentafluorophenylsulfonamidobenzene;
펜타플루오로페닐설폰아미도벤젠;Pentafluorophenylsulfonamidobenzene;
5-펜타플루오로페닐설폰아미도벤젠;5-pentafluorophenylsulfonamidobenzene;
4-(N,N-디메틸아미노)-1-(N-메틸펜타플루오로페닐설폰아미도)-벤젠;4- (N, N-dimethylamino) -1- (N-methylpentafluorophenylsulfonamido) -benzene;
1,2-디하이드록시-4-펜타플루오로페닐설폰아미도벤젠;1,2-dihydroxy-4-pentafluorophenylsulfonamidobenzene;
3,5-디하이드록시-1-펜타플루오로페닐설폰아미도벤젠;3,5-dihydroxy-1-pentafluorophenylsulfonamidobenzene;
3-에톡시-1-펜타플루오로페닐설폰아미도벤젠;3-ethoxy-1-pentafluorophenylsulfonamidobenzene;
7-하이드록시-2-펜타플루오로페닐설폰아미도벤젠;7-hydroxy-2-pentafluorophenylsulfonamidobenzene;
3-페녹시-1-펜타플루오로페닐설폰아미도벤젠;3-phenoxy-1-pentafluorophenylsulfonamidobenzene;
4-(1-모로폴리노)-1-펜타플루오로페닐설폰아미도벤젠;4- (1-morpholino) -1-pentafluorophenylsulfonamidobenzene;
5-펜타플루오로페닐설폰아미도-1,2,3-트리메톡시벤젠;5-pentafluorophenylsulfonamido-1,2,3-trimethoxybenzene;
2-하이드록시-1,3-메톡시-5-펜타플루오로페닐설폰아미도벤젠;2-hydroxy-1,3-methoxy-5-pentafluorophenylsulfonamidobenzene;
1,2-디하이드록시-3-메톡시-5-펜타플루오로페닐설폰아미도벤젠;1,2-dihydroxy-3-methoxy-5-pentafluorophenylsulfonamidobenzene;
5-펜타플루오로페닐설폰아미도-1,2,3-트리하이드록시벤젠;5-pentafluorophenylsulfonamido-1,2,3-trihydroxybenzene;
4-사이클로프로폭시-1-펜타플루오로페닐설폰아미도벤젠;4-cyclopropoxy-1-pentafluorophenylsulfonamidobenzene;
3-플루오로-4-사이클로프로폭시-1-펜타플루오로페닐설폰아미도벤젠;3-fluoro-4-cyclopropoxy-1-pentafluorophenylsulfonamidobenzene;
6-펜타플루오로페닐설폰아미도퀴놀린;6-pentafluorophenylsulfonamidoquinoline;
2,3-디하이드로-5-펜타플루오로페닐설폰아미도인돌;2,3-dihydro-5-pentafluorophenylsulfonamidoindole;
5-펜타플루오로페닐설폰아미도벤조[아]티오펜;5-pentafluorophenylsulfonamidobenzo [a] thiophene;
5-펜타플루오로페닐설폰아미도벤조[아]퓨란;5-pentafluorophenylsulfonamidobenzo [a] furan;
3-하이드록시-4-(1-프로페닐)-1-펜타플루오로페닐설폰아미도벤젠;3-hydroxy-4- (1-propenyl) -1-pentafluorophenylsulfonamidobenzene;
3-하이드록시-5-메톡시-1-펜타플루오로페닐설폰아미도벤젠;3-hydroxy-5-methoxy-1-pentafluorophenylsulfonamidobenzene;
3,5-디하이드록시-1-펜타플루오로페닐설폰아미도벤젠;3,5-dihydroxy-1-pentafluorophenylsulfonamidobenzene;
2-플루오로-1-메톡시-4-(N-펜타플루오로페닐설폰아미도)벤젠;2-fluoro-1-methoxy-4- (N-pentafluorophenylsulfonamido) benzene;
4-(N,N-디메틸아미노)-1-펜타플루오로페닐설폰아미도벤젠, 하이드로클로라이드; 및4- (N, N-dimethylamino) -1-pentafluorophenylsulfonamidobenzene, hydrochloride; And
2-아날리노-3-펜타플루오로페닐설폰아미도피리딘.2-analino-3-pentafluorophenylsulfonamidopyridine.
본 발명의 이러한 실시예중 바람직한 화합물은 특정의 약물학적 성질을 갖는다. 본 발명의 실시예의 가장 바람직한 화합물의 예로는 하기를 포함한다:Preferred compounds in this embodiment of the invention have certain pharmacological properties. Examples of the most preferred compounds of the examples of the present invention include the following:
4-(N,N-디메틸아미노)-1-펜타플루오로페닐설폰아미도벤젠;4- (N, N-dimethylamino) -1-pentafluorophenylsulfonamidobenzene;
3-(N,N-디메틸아미노)-1-펜타플루오로페닐설폰아미도벤젠;3- (N, N-dimethylamino) -1-pentafluorophenylsulfonamidobenzene;
1,2-에틸렌디옥시-4-펜타플루오로페닐설폰아미도벤젠;1,2-ethylenedioxy-4-pentafluorophenylsulfonamidobenzene;
2-하이드록시-1-메톡시-4-펜타플루오로페닐설폰아미도벤젠;2-hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene;
2-플루오로-1-메톡시-4-펜타플루오로페닐설폰아미도벤젠;2-fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene;
2-하이드록시-1-메톡시-4-펜타플루오로페닐설폰아미도벤젠, 소듐염;2-hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene, sodium salt;
2-하이드록시-1-메톡시-4-펜타플루오로페닐설폰아미도벤젠, 포타슘염;2-hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene, potassium salt;
2-플루오로-1-메톡시-4-펜타플루오로페닐설폰아미도벤젠, 소듐염;2-fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene, sodium salt;
2-플루오로-1-메톡시-4-펜타플루오로페닐설폰아미도벤젠, 포타슘염;2-fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene, potassium salt;
4-메톡시-1-펜타플루오로페닐설폰아미도벤젠;4-methoxy-1-pentafluorophenylsulfonamidobenzene;
3-하이드록시-1-펜타플루오로페닐설폰아미도벤젠;3-hydroxy-1-pentafluorophenylsulfonamidobenzene;
4-하이드록시-1-펜타플루오로페닐설폰아미도벤젠;4-hydroxy-1-pentafluorophenylsulfonamidobenzene;
1,2-디메틸-4-펜타플루오로페닐설폰아미도벤젠;1,2-dimethyl-4-pentafluorophenylsulfonamidobenzene;
5-펜타플루오로페닐설폰아미도인돌;5-pentafluorophenylsulfonamidoindole;
4-에톡시-1-펜타플루오로페닐설폰아미도벤젠;4-ethoxy-1-pentafluorophenylsulfonamidobenzene;
3-메톡시-1-펜타플루오로페닐설폰아미도벤젠;3-methoxy-1-pentafluorophenylsulfonamidobenzene;
2-브로모-1-메톡시-4-펜타플루오로페닐설폰아미도벤젠;2-bromo-1-methoxy-4-pentafluorophenylsulfonamidobenzene;
2-클로로-1-메톡시-4-펜타플루오로페닐설폰아미도벤젠;2-chloro-1-methoxy-4-pentafluorophenylsulfonamidobenzene;
2-브로모-3-하이드록시-4-메톡시-1-펜타플루오로페닐설폰아미도벤젠;2-bromo-3-hydroxy-4-methoxy-1-pentafluorophenylsulfonamidobenzene;
2-브로모-4-메톡시-5-하이드록시-1-펜타플루오로페닐설폰아미도벤젠;2-bromo-4-methoxy-5-hydroxy-1-pentafluorophenylsulfonamidobenzene;
1-브로모-4-플루오로-5-메톡시-2-펜타플루오로페닐설폰아미도벤젠;1-bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene;
4-클로로-1-펜타플루오로페닐설폰아미도벤젠; 및4-chloro-1-pentafluorophenylsulfonamidobenzene; And
3-아미노-4-메톡시-1-펜타플루오로페닐설폰아미도벤젠.3-amino-4-methoxy-1-pentafluorophenylsulfonamidobenzene.
구성도 IConfiguration I
펜타플루오로페닐설폰아미드, 설포닉 에스테르, 설핀아미드 및 설피닉 에스테르의 합성.Synthesis of pentafluorophenylsulfonamide, sulfonic esters, sulfinamides and sulfinic esters.
구성도 ⅠConfiguration Ⅰ
구성도 ⅡDiagram II
N,N-디 치환 펜타플루오로페닐설폰아미드의 선택적인 합성.Selective Synthesis of N, N-di Substituted Pentafluorophenylsulfonamides.
구성도 ⅢConfiguration Diagram Ⅲ
페놀의 합성Synthesis of Phenolic
본 발명은 본 발명 화합물 및 조성물을 제조하는 방법을 제공한다. 한 일반적 실시예에서, 본 발명의 방법은 펜타플루오로페닐설포닐 클로라이드와 아민이 반응하여 바람직한 화합물을 형성하는 조건하에서 일반식 R1R2NH를 갖는 아민과 펜타플루오로페닐설포닐 클로라이드를 조합하고 화합물을 분리하는 것을 포함한다.The present invention provides a method of preparing the compounds and compositions of the present invention. In one general embodiment, the process of the present invention combines an amine having the general formula R 1 R 2 NH with a pentafluorophenylsulfonyl chloride under conditions such that pentafluorophenylsulfonyl chloride and amine react to form a desired compound. And separating the compound.
일반 구조 (1 또는 3)(구성도I)을 갖는 화합물은 각각 피리딘, p-디메틸아미노피리딘, 트리에틸아민, 소듐 카보네이트 또는 포타슘 카보네이트 및 펜타플루오로페닐설포닐 클로라이드 또는 펜타플루오로페닐설피닐 클로라이드와 같은 염기의 존재하에서 테트라하이드로퓨란(THF), 디메틸포름아미드(DMF), 에테르, 톨루엔 또는 벤젠과 같은 용매에 있는 적당한 출발 아민을 반응시키므로서 제조될 수 있다. 피리딘 그 자체도 용매로서 사용될 수 있다. 바람직한 용매는 피리딘과 DMF이고 바람직한 염기는 피리딘, 트리에틸아민, 및 포타슘 카보네이트이다. 이 반응은 0°- 100℃의 온도범위에서, 편리하게는 상온에서 실행될 수 있다.Compounds having the general structure (1 or 3) (Scheme I) are pyridine, p-dimethylaminopyridine, triethylamine, sodium carbonate or potassium carbonate and pentafluorophenylsulfonyl chloride or pentafluorophenylsulfinyl chloride, respectively It can be prepared by reacting a suitable starting amine in a solvent such as tetrahydrofuran (THF), dimethylformamide (DMF), ether, toluene or benzene in the presence of a base such as. Pyridine itself can also be used as a solvent. Preferred solvents are pyridine and DMF and preferred bases are pyridine, triethylamine, and potassium carbonate. This reaction can be carried out in the temperature range of 0 ° -100 ° C, conveniently at room temperature.
일반구조식(1)의 화합물은 아르곤이나 질소와 같은 활성분위기하에서, 구성 도Ⅱ에서 E로 나타낸 Cl, Br, I, MsO-, TsO-, TFAO-와 같은 잔기를 함유하는 알킬화기를 갖는 벤젠, 톨루엔, DMF또는 THF와 같은 용매에 있는 LDA, NaH, 딤실 염, 알킬 리튬, 포타슘 카보네이트와 같은 염기로 출발 설폰아미드(구성도 Ⅱ)를 처리하므로써 얻을 수 있다. 이러한 반응을 위해 바람직한 용매는 THF이고 바람직한 염기는 리튬 비스(트리메틸실릴)아미드이다. 이 반응은 0℃에서 100℃의 온도범위에서, 편리하게는 상온에서 실행될 수 있다.Compounds of the general formula (1) are benzene and toluene having an alkylation group containing residues such as Cl, Br, I, MsO-, TsO-, and TFAO- represented by E in the structural diagram II under an active atmosphere such as argon or nitrogen. It can be obtained by treating the starting sulfonamide (Schematic II) with a base such as LDA, NaH, dimsil salt, alkyl lithium, potassium carbonate in a solvent such as DMF or THF. The preferred solvent for this reaction is THF and the preferred base is lithium bis (trimethylsilyl) amide. This reaction can be carried out at a temperature ranging from 0 ° C. to 100 ° C., conveniently at room temperature.
설포닉 에스테르(2)와 설피닉 에스테르(4)를 각각 피리딘, 트리에틸아민, 소듐, 카보네이트, 포타슘 카보네이트 또는 4-디메틸아미노피리딘과 같은 염기의 존재하에서 THF,DMF, 톨루엔이나 벤젠과 같은 용매에 있는 적당한 출발 페놀을 펜타플루오로페닐설포닐 클로라이드 또는 펜타플루오로페닐설피닐 클로라이드와 반응시켜서 제조할 수 있다. 피리딘 그 자체도 용매로서 사용될 수 있다. 바람직한 용매는 피리딘과 DMF이고 바람직한 염기는 소듐 카보네이트와 포타슘 카보네이트이다. 이 반응은 0℃- 100℃의 온도범위에서, 편리하게는 상온에서 실행될 수 있다.Sulphonic esters (2) and sulfinic esters (4) are respectively dissolved in a solvent such as THF, DMF, toluene or benzene in the presence of a base such as pyridine, triethylamine, sodium, carbonate, potassium carbonate or 4-dimethylaminopyridine. Suitable starting phenols can be prepared by reacting with pentafluorophenylsulfonyl chloride or pentafluorophenylsulfinyl chloride. Pyridine itself can also be used as a solvent. Preferred solvents are pyridine and DMF and preferred bases are sodium carbonate and potassium carbonate. This reaction can be carried out in the temperature range of 0 ° C-100 ° C, conveniently at room temperature.
Ar이 방향족 기이고 x가 1-3인, 일반구조식(5)의 화합물은 불활성분위기하의 -45℃-30℃의 온도범위에서 헥산 또는 CH2Cl2와 같은 저 극성의 용매에 있는 보론 트리브로마이드와의 반응에 의해 해당 메틸 에테르(구성도 Ⅲ)로 부터 얻어질 수 있다. 바람직한 실시예에서, 반응은 약 30℃에서 CH2Cl2에서 실행된다.Compounds of the general formula (5), wherein Ar is an aromatic group and x is 1-3, are boron tribromide in a low polar solvent such as hexane or CH 2 Cl 2 in the temperature range of -45 ° C.-30 ° C. under an inert atmosphere. By reaction with the corresponding methyl ether (Schematic III). In a preferred embodiment, the reaction is carried out in CH 2 Cl 2 at about 30 ° C.
때때로, 구성도 Ⅰ-Ⅲ에 도시된 변환을 위한 기질은 주어진 반응의 조건과 즉시 조화되지 않는 관능기(예를들면, 아미노, 하이드록시 또는 카르복시)를 함유할 수 있다. 이 경우에, 이러한 기는 적당한 보호기로써 보호될 수 있고 이 보호기는 피. 지. 엠. 엇츠(P.G.M.Wuts)의 Protective Group in Organic Synthesis, 2판, John Wiley Sons, Inc., 1991년 설명된 것과 같은 잘 알려진 방법을 사용하여 원래의 관능성을 형성하도록 변환된 후 제거된다.Occasionally, the substrate for conversion shown in Schemes I-III may contain functional groups (eg, amino, hydroxy or carboxy) that do not immediately match the conditions of a given reaction. In this case, such groups can be protected with a suitable protecting group which protects. G. M. It is converted to form the original functionality and then removed using well known methods such as those described by P.G.M.Wuts Protective Group in Organic Synthesis, 2nd Edition, John Wiley Sons, Inc., 1991.
본 발명에서 초기의 출발물질로서 사용된 화합물은 상업적으로 얻어 질 수 있고 또는 선택적으로 본 기술분야에서 통상의 지식을 갖는 사람들에게 잘 알려진 표준 방법에 의해 용이하게 합성될수 있다.The compounds used as initial starting materials in the present invention can be obtained commercially or optionally can be readily synthesized by standard methods well known to those of ordinary skill in the art.
식 (I)의 몇몇 화합물은 입체이성질체로서 존재할 수 있고, 본 발명은 이러한 화합물의 모든 활성 입체이성질체 형태를 포함한다. 광학적 활성이성질체의 경우 이러한 화합물은 상기에 기술된 방법을 이용하거나 라세믹 혼합물을 분석하여 해당 광학적 활성 전구물질로부터 얻을 수 있다. 분석은 본 기술분야에서 통상의 지식을 갖고 있는 사람들에게 잘 알려진 크로마토그래피, 유도된 비대칭 염의 반복된 재결정화, 또는 유도화와 같은 다양한 기술을 이용하여 실행할 수 있다.Some compounds of formula (I) may exist as stereoisomers and the present invention includes all active stereoisomeric forms of such compounds. In the case of optically active isomers, these compounds can be obtained from the corresponding optically active precursors using the methods described above or by analyzing racemic mixtures. Assays can be performed using a variety of techniques, such as chromatography, repeated recrystallization of induced asymmetric salts, or derivatization well known to those of ordinary skill in the art.
본질적으로 산성 또는 염기성인 분자식(Ⅰ)의 화합물은 각각 다양한 무기 및 유기 염기 또는 산을 갖는 다양한 염을 형성할 수 있다. 이러한 염은 포유동물에 투여하는데에 약리학적으로 수용가능해야 한다. 본 발명 산성 화합물의 염은 수성 또는 적당한 유기 용매에 있는 선택된 무기 또는 유기 염기의 적당한 몰랄 양으로 산 화합물을 처리하고 용매를 증발시켜 염을 얻으므로서 쉽게 제조된다. 본 발명 염기성 화합물의 산 부가 염은 바람직한 무기 또는 유기산으로 처리하고 이어서 용매증발 및 분리에 의해 유사하게 얻을 수 있다.The compounds of formula (I), which are essentially acidic or basic, can form various salts with various inorganic and organic bases or acids, respectively. Such salts must be pharmacologically acceptable for administration to a mammal. Salts of the acidic compounds of the present invention are readily prepared by treating the acid compound with an appropriate molar amount of the selected inorganic or organic base in an aqueous or suitable organic solvent and obtaining the salt by evaporating the solvent. Acid addition salts of the basic compounds of the invention can be similarly obtained by treatment with the preferred inorganic or organic acid followed by solvent evaporation and separation.
본 발명의 화합물은 다양한 방법으로 표지될 수 있다. 예를들면, 이 화합물은 방사능 동위원소로서 제공될 수 있다; 예로는 트리튬 및 14C-동위원소. 마찬가지로, 화합물은 캐리어, 라벨, 보조제, 조활성제, 안정제등과 같은 프로드러그나 작용을 제공할 수 있는 다양한 결합 화합물에 공유적으로나 비공유적으로 유익하게 결합될 수 있다. 그러므로, 필수구조적 제한을 갖는 화합물은 이와같은 결합된 화합물에 직접적으로나 간접적으로 결합된(예를들면, 링커분자를 통해서) 화합물을 함유한다.The compounds of the present invention can be labeled in a variety of ways. For example, this compound may serve as a radioisotope; Examples are tritium and 14 C-isotopes. Likewise, a compound can be beneficially covalently or non-covalently bound to various binding compounds that can provide prodrugs or actions such as carriers, labels, adjuvants, co-activators, stabilizers and the like. Therefore, compounds having essential structural limitations contain compounds that are bound directly or indirectly (eg, via linker molecules) to such bound compounds.
광범위한 증상이, 예방적 또는 치료학적으로 본 발명의 화합물 및 조성물로써 치료될 수 있다. 예를들면, 본 발명 화합물 및 조성물은 세포증식의 유용한 조절제인 것으로 밝혀졌다. 세포성장의 한계는, 생체내 또는 생체외에서, 본 발명 조성물 및 화합물 중 하나 이상을 효과적인 양으로 표적세포와 접촉시키므로서 이루어진다. 화합물은 세포성장 억제 및 세포독성을 평가하기위해 세포 및 동물 모델을 이용하여 세포 증식을 조절하는 화합물의 능력에 대해 평가될 수 있는데, 이 모델은 본 기술분야에서 알려진것이지만, 에스.에이.아메드(S.A.Ahmed)등(1994)의 J. Immunol. Methods 170:211-224의 방법에 의해, 세포 성장에 대한 화합물의 효능을 측정하는 것이 예시화 되어 있다.A wide range of symptoms can be treated prophylactically or therapeutically with the compounds and compositions of the present invention. For example, the compounds and compositions of the present invention have been found to be useful modulators of cell proliferation. Limitations of cell growth are achieved by contacting one or more of the compositions and compounds of the invention with target cells in an effective amount, either in vivo or ex vivo. Compounds can be evaluated for their ability to modulate cell proliferation using cellular and animal models to assess cell growth inhibition and cytotoxicity, which is known in the art, but is known as S.A.Med. SAAhmed et al. (1994) J. Immunol. By the method 170: 211-224, measuring the efficacy of a compound on cell growth is illustrated.
본 발명의 화합물 및 조성물로 치료받을 수 있는 상태로는 다양한 세포형태중 어떤 것이 포함될 수 있는데 카포시(Kaposi's) 육종, Wilms 종양, 림프종, 백혈병, 골수종, 흑색종, 전흉부, 난소, 폐, 등과 같은 악성종양 및 낭포성 질환, 백내장, 건선, 등과 같은 다른 질병을 포함하는 다양한 종양성 질환, 비정상적 세포 증식 및 전이성 질환을 포함하여, 바람직하지 않은 세포 성장의 어떤 상태를 포함한다. 다른 상태들로는 혈관의 평활근 세포가 포함될 경우에는 재발협착증을, 내피 세포, 염증성 세포 및 사구체 세포가 포함될 경우에는 염증성 질환상태를, 심장근육 세포가 포함될 경우에는 심근 경색증을, 신장 세포가 포함될 경우에는 사구체 신장염을, 내피세포가 포함될 경우에는 이식조직 거부반응을, 특정 면역세포 및 다른 감염된 세포등이 포함될 경우에는, HIV 감염 및 말라리아와 같은 감염성 질환을 포함한다. 감염성 및 기생충성 병원체 그 자체 (예를들면, 트리파노소머, 진균류,등)도 본 발명의 조성물 및 화합물을 사용하여 선택적 증식조절된다.Conditions that can be treated with the compounds and compositions of the present invention may include any of a variety of cell types, such as Kaposi's sarcoma, Wilms tumor, lymphoma, leukemia, myeloma, melanoma, prethoracic, ovary, lung, etc. Certain conditions of unfavorable cell growth, including malignant tumors and other neoplastic diseases including cataracts, psoriasis, and the like, abnormal cell proliferation and metastatic disease. Other conditions include restenosis with smooth muscle cells in blood vessels, inflammatory disease with endothelial, inflammatory and glomerular cells, myocardial infarction with cardiomyocytes, and glomeruli with kidney cells. Nephritis includes graft rejection if endothelial cells are included, and infectious diseases such as HIV infection and malaria if certain immune cells and other infected cells are included. Infectious and parasitic pathogens themselves (eg tripanosomers, fungi, etc.) are also selectively propagated using the compositions and compounds of the invention.
많은 본 발명 화합물이 튜블린의 β-서브유니트를 결합하여 정상적인 튜블린 기능을 방해하는 것으로 나타났다. 그러므로, 화합물은 세포골격 구조 및/또는 작용을 조절하는 제제로 제공된다. 바람직한 화합물은 비가역적으로 또는 공유적으로 결합하고, 그 결과로 콜치신과 같은 선행기술의 미세관 분열제보다 강력한 작용을 제공한다. 조성물은 본 발명 화합물과는 다른 기타의 항증식화합요법제 (마르골리스(Margolis)등.(1993) US특허 제 5,262,409 참조)와 바람직하게 조합 및/또는 사용될수 있다.Many of the compounds of the invention have been shown to bind the β-subunits of tubulin to interfere with normal tubulin function. Therefore, the compounds are provided as agents that modulate cytoskeletal structure and / or action. Preferred compounds bind irreversibly or covalently and consequently provide a stronger action than prior art microtubule fission agents such as colchicine. The composition can be preferably combined and / or used with other antiproliferative therapies (see Margolis et al. (1993) US Pat. No. 5,262,409) other than the compounds of the present invention.
추가적인 관련 문헌으로는 다음을 포함한다. 우(Woo)등(1994) WO94/08041 ;보우차드(Bouchard) 등 (1996) WO96/13494 ; 봄바르델리(Bombardelli) 등 (1996) WO96/11184 ; 보누라(Bonura)등(1992) WO92/15291.Additional related literature includes: Woo et al. (1994) WO 94/08041; Bouchard et al. (1996) WO 96/13494; Bombardelli et al. (1996) WO96 / 11184; Bonura et al. (1992) WO 92/15291.
분 석analysis
본 발명 조성물이 시험관내 및 생체내 평가에서 예를들어, 관련된 병리를 감소시키거나 또는 예방법을 제공 또는 강화시키기 위해 세포 생리학을 특정하게 조절할 수 있는 제약학적 활성을 갖는 것으로 증명되었다. 바람직한 화합물은 다양한 형태의 세포에 특이적 독성을 나타낸다. 본 발명의 특정 화합물 및 조성물은 세포성 튜블린과의 상호작용에 의해 그것의 세포독성효과를 나타낸다. 본 발명의 특정 바람직한 화합물 및 조성물의 경우, 그러한 상호작용은 공유적이고 비가역적이다. 예를들면, 이러한 바람직한 화합물의 트리티화된 형태, 예를들면 조성물 7(실시예 72)에 대한 다양한 조직 및 세포 샘플 예를들면 사람의 유방암 MCF7 세포의 노출은 튜블린으로 밝혀진 단 하나의 검출가능한 세포 단백질의 비가역적 라벨링을 가져왔다. 이 단백질은 세포골격을 구성하고 또한 세포 분열을 포함하는 세포 생리학의 많은 다른 관점에서 중요한 역할을 하는 미세세관의 주 성분이다. 본 발명의 바람직한 화합물에 의한 튜블린의 라벨링은 또한 용량-의존성임을 나타냈다. 튜블린상에 공유결합하는 위치는 β-튜블린 쇄에서 시스테인-239로서 확인된다. 동일한 Cys-239 잔기는 시험관내 또는 생체내에 제공된 β-튜블린펩티드(예를들면, Ser-234에서 Met-267)를 함유하는 있는 다양한 Cys-239로 존재할 경우에 선택적으로 공유적으로 변성된다. β-튜블린에 결합하는 이러한 화합물의 능력과 일치하는, 다양한 농도의 화합물로의 다양한 세포 및 조직형태에 대한 치료는 대부분의 세포의 세포골격에 대하여 보편적이고, 비가역적인 분열을 가져왔다.It has been demonstrated that the compositions of the present invention have pharmaceutical activity that can specifically modulate cell physiology in, for example, to reduce related pathologies or to provide or enhance prophylaxis in in vitro and in vivo evaluations. Preferred compounds show specific toxicity to various types of cells. Certain compounds and compositions of the present invention exhibit their cytotoxic effects by interaction with cellular tubulin. For certain preferred compounds and compositions of the invention, such interactions are covalent and irreversible. For example, exposure of various tissue and cell samples, such as human breast cancer MCF7 cells to the tritized form of such a preferred compound, such as composition 7 (Example 72), is the only detectable It led to irreversible labeling of cellular proteins. This protein constitutes the cytoskeleton and is a major component of microtubules that plays an important role in many other aspects of cell physiology, including cell division. The labeling of tubulin by the preferred compounds of the present invention has also been shown to be dose-dependent. The covalent position on the tubulin is identified as cysteine-239 in the β-tubulin chain. The same Cys-239 residues are selectively covalently denatured when present with various Cys-239 containing β-tubulin peptides (eg, Met- 267 in Ser-234) provided in vitro or in vivo. Treatment with various cell and tissue morphologies with various concentrations of compounds, consistent with the ability of these compounds to bind β-tubulin, has resulted in universal, irreversible division of the cytoskeleton of most cells.
특히, 루두에나(Luduena)(1993) Mol Biol of the Cell 4, 445-457에 기술된 바와같이, 튜블린은 두 폴리펩티드 즉 α 및 β로 명명된 계보를 정의한다. 더욱이, 동물은 복합 α 및 β 유전자로부터 각 α 및 β유전자폴리펩티드의 복합형태(이소타입)를 나타낸다. 많은 β 이소타입은 (인간 β 2튜블린의 보존된 시스테인, Cys-239를 함유한다 : 상류의 서열 변화때문에, Cys-239의 절대적 위치는 비록 Cys-239가 기술분야에 통상의 지식을 갖는 사람에 의해 그것의 상대적 위치까지 쉽게 확인됨에도 불구하고 변화된다. (즉, 교감서열 포함하는 것의 관계, 예를들면, 최소 8, 바람직하게 12, 보다 바람직하게 16, 가장 바람직하게는 20 잔기의 Cys-239를 함유하는, 이소타입의 교감 펩티드 부위 또는 그 단편). Cys-239에 대한 선택적 결합은 Cys-239가 단백질의 시스테인을 포함하고 있는 다른 모든 잔기와 관련하여 적어도 2, 바람직하게는 10, 보다 바람직하게 100, 가장 바람직하게는 1,000의 인자까지 우선적으로 결합되는 것을 의미한다. 특히 바람직한 실시예에서, Cys-239는 거의 독점적이고 바람직하게는 독점적으로 결합된다. 튜블린에 대한 선택적 결합 또는 튜블린의 변성은 튜블린이 모든 다른 단백질과 관련하여, 적어도 2, 바람직하게는 10, 보다 바람직하게는 100, 가장 바람직하게는 1,000의 인가까지 우선적으로 변성된다는 것을 의미한다. 특히 바람직한 실시예에서, 튜블린은 거의 독점적이고 바람직하게는 독점적으로 변성된다.In particular, as described in Luduena (1993) Mol Biol of the Cell 4, 445-457, tubulin defines a lineage designated two polypeptides, α and β. Moreover, the animal shows a complex form (isotype) of the respective α and β gene polypeptides from the complex α and β genes. Many β isotypes contain Cys-239, a conserved cysteine of human β 2 tubulin: due to upstream sequence changes, the absolute position of Cys-239 is known to those of ordinary skill in the art, even though Cys-239 Even though it is easily identified to its relative position by (ie the relationship between sympathetic sequences, eg, at least 8, preferably 12, more preferably 16, most preferably 20 residues of Cys-). Sympathetic peptide sites or fragments thereof of the isotype containing 239. The selective binding to Cys-239 is at least 2, preferably 10, greater than with respect to all other residues where Cys-239 contains the cysteine of the protein. Preferably preferentially bound up to a factor of 100, most preferably 1,000. In a particularly preferred embodiment, Cys-239 is almost exclusively and preferably exclusively bound. Selective binding or denaturation of tubulin means that the tubulin is preferentially denatured by application of at least 2, preferably 10, more preferably 100, most preferably 1,000, with respect to all other proteins. In a preferred embodiment, the tubulin is almost exclusively and preferably exclusively modified.
화합물은 시험관내에서 예를들면, 에스.에이. 아메드(S.A.Ahmed)등(1994) J. Immunol. Methods 170:211-224에 기술된 바와 같이 세포 성장을 억제하는 능력에 대해 평가될 수 있다. 부가적으로, 화합물의 항증식 효과를 평가하기 위해 설정된 동물 모델들은 본 기술분야에 알려져 있다. 예를들면, 여기에 기술된 몇몇 화합물은 면역결핍성 쥐에게 이식된 MDR 및 택솔(taxol) 및/또는 빈브라스틴내성종양을 포함하는 인간종양의 성장을 억제하는 것으로 나타났다 (제이. 라이가드(J. Rygaard)와 씨.오.포블젠(C.O.Povlsen)(1969) Acta Pathol. Microbiol. Scand 77:758-760에 의해 보고되고 비.씨.지오바넬라(B.C.Giovanella) 및 제이.포그(J.Fogh)(1985) Adv. Cancer Res. 44:69-120에 의해 검토된 것과 유사한 방법론을 사용하였을 때).The compound may be in vitro, for example, S.A. Ahmed, et al. (1994) J. Immunol. The ability to inhibit cell growth can be assessed as described in Methods 170: 211-224. In addition, animal models established to assess the antiproliferative effects of compounds are known in the art. For example, some of the compounds described herein have been shown to inhibit the growth of human tumors, including MDR and taxol and / or vinblastine-resistant tumors implanted in immunodeficient mice (J. Lygard ( J. Rygaard and C.O.Povlsen (1969) reported by Acta Pathol.Microbiol.Scand 77: 758-760, BCGiovanella and J. Pog. Fogh) (1985) using a methodology similar to that reviewed by Adv. Cancer Res. 44: 69-120).
제형화 및 투여Formulation and Administration
본 발명은 질병을 치료하거나 의료적 예방법을 제공하고, 종양의 성장을 늦추고 또는 감소시키고, 세균 감염등을 치료하기 위해 본 발명의 화합물 및 조성물을 이용하는 방법을 제공한다. 이러한 방법은 효과적인 양의 본 발명 화합물 또는 제약학적으로 수용가능한 조성물을 세포와 접촉시키거나 숙주에 투여하는 것을 일반적으로 포함한다.The present invention provides methods for using the compounds and compositions of the present invention to treat diseases or provide medical prophylaxis, to slow or reduce tumor growth, to treat bacterial infections, and the like. Such methods generally comprise contacting a cell or administering an effective amount of a compound of the invention or a pharmaceutically acceptable composition to a host.
본 발명의 조성물 및 화합물과 이들의 제약학적으로 수용가능한 염은 경구, 비경구적 또는 국부적 경로와 같은 효과적인 방법으로 투여될 수 있다. 일반적으로, 화합물은 비록 변형이 질병 표적, 환자 및 투여경로에 따라 반드시 발생할지라도, 하루에 약 2mg - 약 2,000mg까지의 투여범위로 투여된다. 바람직한 투여량은 하루에 체중 kg당 약 0.05mg/kg - 약 20mg/kg, 보다 바람직하게는 약 0.05mg/kg - 약 2mg/kg, 가장 바람직하게는 약 0.05mg/kg - 약 0.2mg의 범위로 투여된다.The compositions and compounds of the present invention and their pharmaceutically acceptable salts can be administered by effective methods such as oral, parenteral or topical routes. In general, the compounds are administered in a dosage range of about 2 mg to about 2,000 mg per day, although modifications necessarily occur depending on the disease target, patient and route of administration. Preferred dosages range from about 0.05 mg / kg to about 20 mg / kg, more preferably from about 0.05 mg / kg to about 2 mg / kg, most preferably from about 0.05 mg / kg to about 0.2 mg per kg body weight per day. Is administered.
한 실시예에서, 본 발명은 무균 식염수나 기타 매체, 물, 젤라틴, 오일등과 같은 제약학적으로 우수한 부형제와 조합된 화합물을 제공하여 제약학적으로 수용가능한 조성물을 형성한다. 조성물 및/또는 화합물은 단독 또는 알맞은 캐리어, 희석제등과 조합하여 투여될 수 있고 이와같은 투여는 단독 또는 복합용량으로 제공될 수 있다. 유용한 캐리어는 고체, 반-고체 또는 물과 비-유독성 유기용매를 포함하고 있는 액체 매체를 포함한다.In one embodiment, the present invention provides compounds in combination with pharmaceutically acceptable excipients such as sterile saline or other media, water, gelatin, oils and the like to form pharmaceutically acceptable compositions. The compositions and / or compounds may be administered alone or in combination with appropriate carriers, diluents and the like and such administrations may be provided alone or in combination. Useful carriers include solid, semi-solid or liquid media comprising water and non-toxic organic solvents.
또 다른 실시예에서, 본 발명은 수용체 숙주에 의해 본 발명 화합물로 대사적으로 전환될 수 있는 프로-드러그 형태의 화합물을 제공한다. 다양한 프로-드러그 제형화가 본 기술분야에 알려져있다.In another embodiment, the present invention provides a compound in the form of a pro-drug that can be metabolically converted into a compound of the invention by a receptor host. Various pro-drug formulations are known in the art.
조성물은 타블렛, 캡슐, 로젠지, 트로키, 하드 캔디, 파우더, 스프레이, 크림, 좌약 등을 포함하는 어떠한 제형으로도 제공될 수 있다. 이러한 조성물은 제약적으로 투약용량단위 또는 벌크형태로 다양한 용기에 투입될 수 있다. 예를들어, 투약 용량단위는 캡슐, 필등을 포함하는 여러 가지 용기에 포함될 수 있다.The composition may be provided in any formulation including tablets, capsules, lozenges, troches, hard candy, powders, sprays, creams, suppositories, and the like. Such compositions may be added to various containers in pharmaceutical dosage units or in bulk form. For example, the dosage unit may be contained in various containers including capsules, pills, and the like.
조성물은 본 발명 화합물과는 다른 기타의 항증식성 치료학 또는 예방적 제제와 함께 유익하게 조합 및/또는 이용될 수 있다. 많은 경우에서, 투여는 본 발명 조성물과 함께 이러한 제제의 효능을 강화한다. 예시적인 항증식성 제제는 사이클로포스파미드, 메토트렉세이트, 아드리아마이신, 시스플라틴, 다우노마이신, 빈크리스틴, 빈블라스틴, 비나렐빈, 파크리탁셀, 도세탁셀, 타목시펜, 플루타미드, 하이드록시우레아 및 이들의 혼합물을 포함한다.The compositions may be advantageously combined and / or used with other antiproliferative therapeutic or prophylactic agents other than the compounds of the present invention. In many cases, administration enhances the efficacy of such agents in combination with the compositions of the present invention. Exemplary antiproliferative agents include cyclophosphamide, methotrexate, adriamycin, cisplatin, daunomycin, vincristine, vinblastine, vinarelvin, paclitaxel, docetaxel, tamoxifen, flutamide, hydroxyurea and these It contains a mixture of.
화합물 및 조성물은 또한 진단 평가를 포함하는 다양한 시험관내 및 생체내 평가에서의 용도가 발견된다. 특정 평가 및 생체내 분포 연구에서, 주 화합물 및 조성물의 표시된 형태, 예를들어, 방사리간드 치환 분석시험을 이용하는 것이 바람직하다. 따라서, 본 발명은 분광적이고(예를들면 형광), 방사성일 수 있는검출 가능한 라벨을 함유하고 있는 화합물 및 조성물을 제공한다.The compounds and compositions also find use in a variety of in vitro and in vivo assays, including diagnostic assessments. In certain assessments and in vivo distribution studies, preference is given to using the indicated forms of the main compounds and compositions, eg, radioligand substitution assays. Accordingly, the present invention provides compounds and compositions containing detectable labels that can be spectroscopic (eg fluorescence) and radioactive.
하기 실시예는 제한적이 아닌 예시적인 것으로 제공된다.The following examples are provided as illustrative and not restrictive.
1H NMR 스펙트럼을 Varian Gemini 400MHz NMR 분광계상에 기록했다. 중요한 피크를 다음 순서로 표를 만들었다: 다양성(s, 단선; d, 이중선; t, 3중선; q, 4중선; m, 다중선), 헤르쯔로의 결합 상수, 프로톤수. 전자 이온화(EI)질량 스펙트럼은 Hewlett Packard 5989A 질량분광계상에 기록했다. 빠른 원자충격(FAB)질량 분광검사를 VG 분석적 ZAB 2-SE 고 전장 질량 분광계로 수행했다. 질량 분광검사 결과는 전하에 대한 질량의 비율로서 기록하고 이온의 상대적인 풍부함은 괄호에 기록했다. 1 H NMR spectra were recorded on a Varian Gemini 400 MHz NMR spectrometer. The important peaks were tabulated in the following order: diversity (s, singlet; d, doublet; t, triplet; q, quadruple; m, multiplet), binding constant to hertz, proton number. Electron ionization (EI) mass spectra were recorded on a Hewlett Packard 5989A mass spectrometer. Fast atomic shock (FAB) mass spectroscopy was performed with a VG analytical ZAB 2-SE high field mass spectrometer. Mass spectroscopy results are reported as the ratio of mass to charge and the relative abundance of ions is noted in parentheses.
실시예 1Example 1
4-(N,N-디메틸아미노)-1-펜타플루오로페닐설폰아미도벤젠. 아르곤하에서 0℃에서 피리딘(50mL)에 현탁된 N,N-디메틸-1,4-페닐디아민 디하이드로클로라이드(3g, 14.6mmol)에 펜타플루오로페닐설포닐 클로라이드(2.38㎖, 16mmol)를 적하첨가했다. 반응 혼합물을 0℃에서 30분 동안 교반했고 상온으로 따뜻하게 했다. 반응혼합물을 실온에서 3시간동안 교반했다. 혼합물의 부피를 감압하에서 10mL로 감소시켰다. 혼합물을 에틸 아세테이트로 희석하고 반응을 물로 종료시켰다. 층을 분리하고 수성층을 에틸 아세테이트로 2회 추출했다. 유기층을 조합하고 소금물로 세척하고 MgSO4로 건조시켰다. 용매를 증발시키고 잔류물을 CH2Cl2로 용출하면서 실리카상에서 크로마토그래피로 정제했다. 표제 생성물을 63％ 수율(3.4g)로 흰색 고체로서 얻었다. 1H NMR(CDCl3): 7.01(d, J=8.9Hz, 2H), 6.77(s, 1H), 6.59(d, J=8.3Hz, 2H), 2.92ppm(s, 6H). FAB m/z(상대적인 존재량): 367(100％, M+H+), 135(30％), 121(25％).C14H11F5N2O2S에 대해 계산된 분석 : C 45. 95, H 3.03, N 7.65. 발견 C 45.83, H 2.99, N 7.62.4- (N, N-dimethylamino) -1-pentafluorophenylsulfonamidobenzene. Pentafluorophenylsulfonyl chloride (2.38 mL, 16 mmol) was added dropwise to N, N-dimethyl-1,4-phenyldiamine dihydrochloride (3 g, 14.6 mmol) suspended in pyridine (50 mL) at 0 ° C. under argon. did. The reaction mixture was stirred at 0 ° C. for 30 minutes and warmed to room temperature. The reaction mixture was stirred at room temperature for 3 hours. The volume of the mixture was reduced to 10 mL under reduced pressure. The mixture was diluted with ethyl acetate and the reaction terminated with water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with brine and dried over MgSO 4 . The solvent was evaporated and the residue was purified by chromatography on silica eluting with CH 2 Cl 2 . The title product was obtained in 63% yield (3.4 g) as a white solid. 1 H NMR (CDCl 3 ): 7.01 (d, J = 8.9 Hz, 2H), 6.77 (s, 1H), 6.59 (d, J = 8.3 Hz, 2H), 2.92 ppm (s, 6H). FAB m / z (relative abundance): 367 (100%, M + H + ), 135 (30%), 121 (25%). Calculated analysis for C 14 H 11 F 5 N 2 O 2 S: C 45. 95, H 3.03, N 7.65. Found C 45.83, H 2.99, N 7.62.
실시예 2Example 2
3-(N,N-디메틸아미노)-1-펜타플루오로페닐설폰아미도벤젠.3- (N, N-dimethylamino) -1-pentafluorophenylsulfonamidobenzene.
1H NMR(CDCl3): 7.12(t, J=8Hz, 1H), 7.05(s, 1H), 6.57(s, 1H), 6.53(d, J=8Hz, 1H) 6.40(d, J=8Hz, 1H) 2.94ppm(s, 6H). FAB m/z: 366(100％, M+). 화합물을 3-(N,N-디메틸아미노)아닐린 N,N-디메틸-1,4-페닐디아민 디하이드로클로라이드를 치환하므로서 실시예1과 유사한 프로토콜에 의해 제조했다. 1 H NMR (CDCl 3 ): 7.12 (t, J = 8 Hz, 1 H), 7.05 (s, 1 H), 6.57 (s, 1 H), 6.53 (d, J = 8 Hz, 1 H) 6.40 (d, J = 8 Hz , 1H) 2.94 ppm (s, 6H). FAB m / z: 366 (100%, M + ). The compound was prepared by a protocol similar to Example 1 with 3- (N, N-dimethylamino) aniline N, N-dimethyl-1,4-phenyldiamine dihydrochloride.
실시예 3Example 3
1,2-에틸렌디옥시-4-펜타플루오로페닐설폰아미도벤젠. 1H NMR(CDCl3): 6.97(s,1H), 6.76(d, J=8.6Hz, 1H), 6.72(d, J=2.6Hz, 1H), 6.62(dd, J=8.6, 2.6Hz, 1H), 4.21ppm(s, 4H). FAB m/z: 381(100％, M+H+). C14H8F5NO4S에 대한 계산된 분석: C 44.09, H 2.12, N 3.68, S 8.39. 발견 : C 43.83, H 2.19, N 3.62, S 8.20. 화합물을 3,4-에틸렌디옥시아닐린으로 N,N-디메틸-1,4-페닐디아민 디하이드로콜로라이드를 치환하므로서 실시예 1과 유사한 프로토콜에 의해 제조했다.1,2-ethylenedioxy-4-pentafluorophenylsulfonamidobenzene. 1 H NMR (CDCl 3 ): 6.97 (s, 1H), 6.76 (d, J = 8.6 Hz, 1H), 6.72 (d, J = 2.6 Hz, 1H), 6.62 (dd, J = 8.6, 2.6 Hz, 1H), 4.21 ppm (s, 4H). FAB m / z: 381 (100%, M + H + ). Calculated analysis for C 14 H 8 F 5 NO 4 S: C 44.09, H 2.12, N 3.68, S 8.39. Found: C 43.83, H 2.19, N 3.62, S 8.20. The compound was prepared by a protocol similar to Example 1 by substituting N, N-dimethyl-1,4-phenyldiamine dihydrocollide with 3,4-ethylenedioxyaniline.
실시예 4Example 4
1,2-메틸렌디옥시-4-펜타플루오로페닐설폰아미도벤젠. 1H NMR(CDCl3): 6.85(s, 1H), 6.78(s, 1H), 6.70(d, J=8Hz, 1H), 6.57(d, J=8Hz, 1H), 5.97ppm(s, 2H). 화합물을 3,4-메틸렌디옥시아닐린으로 N,N-디메틸-1,4-페닐디아민 디하이드로클로라이드를 치환하므로서 실시예1과 유사한 프로토콜에 의해 제조했다.1,2-methylenedioxy-4-pentafluorophenylsulfonamidobenzene. 1 H NMR (CDCl 3 ): 6.85 (s, 1H), 6.78 (s, 1H), 6.70 (d, J = 8 Hz, 1H), 6.57 (d, J = 8 Hz, 1H), 5.97 ppm (s, 2H ). The compound was prepared by a protocol similar to Example 1 with the substitution of N, N-dimethyl-1,4-phenyldiamine dihydrochloride with 3,4-methylenedioxyaniline.
실시예 5Example 5
1,2-디메톡시-4-펜타플루오로페닐설폰아미도벤젠. 1H NMR(CDCl3): 6.98(s, 1H), 6.85(d, 1H), 6.74(d, 1H), 6.60(dd, 1H), 3.85(s, 3H), 3.83ppm(s, 3H), EI, m/z: 383(50, M+), 152(100). 화합물을 3,4-디메톡시아닐린으로 N,N-디메틸-1,4-페닐디아민 디하이드로클로라이드를 치환하므로서 실시예1과 유사한 프로토콜에 의해 제조했다.1,2-dimethoxy-4-pentafluorophenylsulfonamidobenzene. 1 H NMR (CDCl 3 ): 6.98 (s, 1H), 6.85 (d, 1H), 6.74 (d, 1H), 6.60 (dd, 1H), 3.85 (s, 3H), 3.83ppm (s, 3H) , EI, m / z: 383 (50, M + ), 152 (100). The compound was prepared by a protocol similar to that of Example 1, replacing N, N-dimethyl-1,4-phenyldiamine dihydrochloride with 3,4-dimethoxyaniline.
실시예 6Example 6
2-하이드록시-1-메톡시-4-펜타플루오로페닐설폰아미도벤젠. 1H NMR(CDCl3): 6.93(s, 1H), 6,7-6.8(m, 3H), 5.68(bs, 1H), 3.85ppm (s,3H). EI, m/z : 333(20,M+), 138(100). mp 118-120℃. 화합물을 3-하이드록시-4-메톡시아닐린으로 N,N-디메틸-1,4-페닐디아민 디하이드로클로라이드를 치환하므로서 실시예1과 유사한 프로토콜에 의해 제조했다.2-hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene. 1 H NMR (CDCl 3 ): 6.93 (s, 1 H), 6,7-6.8 (m, 3 H), 5.68 (bs, 1 H), 3.85 ppm (s, 3 H). EI, m / z: 333 (20, M + ), 138 (100). mp 118-120 ° C. The compound was prepared by a protocol similar to Example 1 with the substitution of N, N-dimethyl-1,4-phenyldiamine dihydrochloride with 3-hydroxy-4-methoxyaniline.
실시예 7Example 7
2-플루오로-1-메톡시-4-펜타플루오로설폰아미도벤젠. 1H NMR(DMSO) 11.15(광역 s, 1H) 7. 13(t, J = 9Hz, 1H), 7.02(dd, J = 9.5 2.5Hz, 1H), 6.94ppm(dd, J = 8.8 1.5Hz, 1H), 3.79ppm(s, 3H). EI, m/z : 371(20, M+), 140(100). C13H7HF6N1O3S1 에 대해 계산된 분석 : C 42.06, H 1.90, N 3.77, S 8.64. 발견: C 42.19, N 1.83, N 3.70, S 8.60. Mp 118-119℃. 화합물을 3-플루오로-p-아니시딘으로 N,N-디메틸-1,4-페닐디아민 디하이드로클로라이드를 치환하므로서 실시예1과 유사한 프로토콜에 의해 제조했다.2-fluoro-1-methoxy-4-pentafluorosulfonamidobenzene. 1 H NMR (DMSO) 11.15 (Wide s, 1H) 7. 13 (t, J = 9 Hz, 1H), 7.02 (dd, J = 9.5 2.5 Hz, 1H), 6.94 ppm (dd, J = 8.8 1.5 Hz, 1H), 3.79 ppm (s, 3H). EI, m / z: 371 (20, M + ), 140 (100). Calculated analysis for C 13 H 7 HF 6 N 1 O 3 S 1 : C 42.06, H 1.90, N 3.77, S 8.64. Found: C 42.19, N 1.83, N 3.70, S 8.60. Mp 118-119 ° C. The compound was prepared by a protocol similar to Example 1 with the substitution of N, N-dimethyl-1,4-phenyldiamine dihydrochloride with 3-fluoro-p-anisidine.
실시예 8Example 8
4-메톡시-1-펜타플루오로페닐설폰아미도벤젠. 1H NMR(CDCl3): 6.99(s, 1H), 6.96(d, J=4Hz, 2H), 6.88(d, J=4Hz, 2H), 3.83ppm (s, 3H). EI, m/z : 353(60,M+), 122(100). M.p. 102-103℃. 화합물을 4-메톡시아닐린으로 N,N-디메틸-1,4-페닐디아민 디하이드로클로라이드를 치환하므로서 실시예1과 유사한 프로토콜에 의해 제조했다.4-methoxy-1-pentafluorophenylsulfonamidobenzene. 1 H NMR (CDCl 3 ): 6.99 (s, 1H), 6.96 (d, J = 4 Hz, 2H), 6.88 (d, J = 4 Hz, 2H), 3.83 ppm (s, 3H). EI, m / z: 353 (60, M + ), 122 (100). Mp 102-103 ° C. The compound was prepared by a protocol similar to Example 1 with the substitution of N, N-dimethyl-1,4-phenyldiamine dihydrochloride with 4-methoxyaniline.
실시예 9Example 9
3-하이드록시-1-펜타플루오로페닐설폰아미도벤젠. 1H NMR(CD3OD): 7.15(t, J= 8.1Hz, 1H), 6.67(t, J=2.2Hz, 1H), 6.60(dd, J=1.3Hz, 7.8Hz, 1H), 6.52ppm(dd, J=2.4Hz 8.3Hz, 1H). EI, m/z: 339(80,M+), 256(50), 81(100). 화합물을 3-하이드록시아닐린으로 N,N-디메틸-1,4-페닐디아민 디하이드로클로라이드를 치환하므로서 실시예1과 유사한 프로토콜에 의해 제조했다.3-hydroxy-1-pentafluorophenylsulfonamidobenzene. 1 H NMR (CD 3 OD): 7.15 (t, J = 8.1 Hz, 1H), 6.67 (t, J = 2.2 Hz, 1H), 6.60 (dd, J = 1.3 Hz, 7.8 Hz, 1H), 6.52 ppm (dd, J = 2.4 Hz 8.3 Hz, 1H). EI, m / z: 339 (80, M + ), 256 (50), 81 (100). The compound was prepared by a protocol similar to Example 1 with the substitution of N, N-dimethyl-1,4-phenyldiamine dihydrochloride with 3-hydroxyaniline.
실시예 10Example 10
4-하이드록시-1-펜타플루오로설폰아미도벤젠. 1H NMR(CD3OD): 6.95(d, J= 8.9Hz, 2H), 6.65ppm(d, J=8.9Hz, 2H). EI, m/z:339(30,M+). 화합물을 4-하이드록시아닐린으로 N,N-디메틸-1,4-페닐디아민 디하이드로클로라이드를 치환하므로서 실시예1과 유사한 프로토콜에 의해 제조했다.4-hydroxy-1-pentafluorosulfonamidobenzene. 1 H NMR (CD 3 OD): 6.95 (d, J = 8.9 Hz, 2H), 6.65 ppm (d, J = 8.9 Hz, 2H). EI, m / z: 339 (30, M + ). The compound was prepared by a protocol similar to Example 1 with the substitution of N, N-dimethyl-1,4-phenyldiamine dihydrochloride with 4-hydroxyaniline.
실시예 11Example 11
1,2-디메틸-4-펜타플루오로페닐설폰아미도벤젠. 1H NMR(CDCl3): 7.03(d,J = 7.9Hz, 1H), 6.92(s,1H), 6.85-6.82(m,2H),2.18(s,3H), 2.16ppm(s,3H). 화합물을 3,4-디메틸아닐린으로 N,N-디메틸-1,4-페닐디아민 디하이드로클로라이드를 치환하므로서 실시예1과 유사한 프로토콜에 의해 제조했다.1,2-dimethyl-4-pentafluorophenylsulfonamidobenzene. 1 H NMR (CDCl 3 ): 7.03 (d, J = 7.9 Hz, 1H), 6.92 (s, 1H), 6.85-6.82 (m, 2H), 2.18 (s, 3H), 2.16ppm (s, 3H) . The compound was prepared by a protocol similar to Example 1 with the substitution of N, N-dimethyl-1,4-phenyldiamine dihydrochloride with 3,4-dimethylaniline.
실시예 12Example 12
4-(N,N-디에틸아미노)-1-펜타플루오로페닐설폰아미도벤젠. 1H NMR(CDCl3): 6.93(d,J = 8.8Hz, 2H), 6.78(s,1), 6.45(d, J = 8.7Hz, 2H), 3.25(dd, J = 7.0Hz, 7.3Hz, 4H), 1.10ppm(t, J = 7.2Hz, 6H). 화합물을 4-(N,N-디에틸아미노)아릴린으로 N,N-디메틸-1,4-페닐디아민 디하이드로클로라이드를 치환하므로서 실시예1과 유사한 프로토콜에 의해 제조했다.4- (N, N-diethylamino) -1-pentafluorophenylsulfonamidobenzene. 1 H NMR (CDCl 3 ): 6.93 (d, J = 8.8 Hz, 2H), 6.78 (s, 1), 6.45 (d, J = 8.7 Hz, 2H), 3.25 (dd, J = 7.0 Hz, 7.3 Hz , 4H), 1.10 ppm (t, J = 7.2 Hz, 6H). The compound was prepared by a protocol similar to Example 1 with the substitution of N, N-dimethyl-1,4-phenyldiamine dihydrochloride with 4- (N, N-diethylamino) aryline.
실시예 13Example 13
4-아미노-1-펜타플루오로페닐설폰아미도벤젠. 1H NMR(CDCl3): 6.82(d, J = 8.7Hz, 2H), 6.49ppm(d, J = 8.7Hz, 2H). EI, m/z:338(7,M+), 107(100), 80(40). 화합물을 1,4-디아미노벤젠으로 N,N-디메틸-1,4-페닐디아민 디하이드로클로라이드를 치환하므로서 실시예1과 유사한 프로토콜에 의해 제조했다.4-amino-1-pentafluorophenylsulfonamidobenzene. 1 H NMR (CDCl 3 ): 6.82 (d, J = 8.7 Hz, 2H), 6.49 ppm (d, J = 8.7 Hz, 2H). EI, m / z: 338 (7, M + ), 107 (100), 80 (40). The compound was prepared by a protocol similar to Example 1 with the substitution of N, N-dimethyl-1,4-phenyldiamine dihydrochloride with 1,4-diaminobenzene.
실시예 14Example 14
펜타플루오로페닐설폰아미도벤젠. 1H NMR(CDCl3):7.30(d, J=8Hz, 2H), 7.13-7.2(m,3H), 7.0ppm(s, 1H). EI, m/z:323(90,M+), 92(100). 화합물을 아닐린으로 N,N-디메틸-1,4-페닐디아민 디하이드로클로라이드를 치환하므로서 실시예1과 유사한 프로토콜에 의해 제조했다.Pentafluorophenylsulfonamidobenzene. 1 H NMR (CDCl 3 ): 7.30 (d, J = 8 Hz, 2H), 7.13-7.2 (m, 3H), 7.0 ppm (s, 1H). EI, m / z: 323 (90, M + ), 92 (100). The compound was prepared by a protocol similar to Example 1 with the substitution of N, N-dimethyl-1,4-phenyldiamine dihydrochloride with aniline.
실시예 15Example 15
5-펜타플루오로페닐설폰아미도인다졸. 1H NMR(CD3OD): 7.98(s, 1H), 7.69(s, 1H), 7.47(d, J=8.3Hz, 1H), 7.23ppm(d, J=8.3Hz, 1H). 화합물을 5-아미노인다졸로 N,N-디메틸-1,4-페닐디아민 디하이드로클로라이드를 치환하므로서 실시예1과 유사한 프로토콜에 의해 제조했다.5-pentafluorophenylsulfonamidoindazole. 1 H NMR (CD 3 OD): 7.98 (s, 1 H), 7.69 (s, 1 H), 7.47 (d, J = 8.3 Hz, 1H), 7.23 ppm (d, J = 8.3 Hz, 1H). The compound was prepared by a protocol similar to Example 1 with the substitution of N, N-dimethyl-1,4-phenyldiamine dihydrochloride with 5-aminoindazole.
실시예 16Example 16
5-펜타플루오로페닐설폰아미도인돌. 1H NMR(CDCl3):8.2(s,1H), 7.43(s,1H), 7.3(d, J = 8Hz, 1H), 7.22(s,1H), 6.98(d, J = 8Hz, 1H), 6.92ppm(s, 1H), 6.50ppm(s, 1H). EI, m/z: 362(M+), 131(100). 화합물을 5-아미노인돌로 N,N-디메틸-1,4-페닐디아민 디하이드로클로라이드를 치환하므로서 실시예1과 유사한 프로토콜에 의해 제조했다.5-pentafluorophenylsulfonamidoindole. 1 H NMR (CDCl 3 ): 8.2 (s, 1H), 7.43 (s, 1H), 7.3 (d, J = 8Hz, 1H), 7.22 (s, 1H), 6.98 (d, J = 8Hz, 1H) , 6.92 ppm (s, 1H), 6.50 ppm (s, 1H). EI, m / z: 362 (M + ), 131 (100). The compound was prepared by a protocol similar to Example 1 with the substitution of N, N-dimethyl-1,4-phenyldiamine dihydrochloride with 5-aminoindole.
실시예 17Example 17
4-(N,N-디메틸아미노)-1-(N-메틸펜타플루오로페닐설폰아미도)벤젠. 4-(N,N-디메틸아미노)-1-(펜타플루오로페닐설폰아미도)벤젠(100mg, 0.273mmol)을 건조한 THF(2.5㎖)에 용해시키고 시스템에 실온에서 N2하에서 리튬 비스(트리메틸실릴)아미드(0.274㎖) 1M용액을 첨가했다. 반응 혼합물을 10분동안 교반하고 MeI(65mg, 0.028㎖)를 첨가했다. 반응 혼합물을 밤새 교반하고 용매를 감압하에서 증발시키고 조생성물을 60％수율(62mg)로 흰색 고체로서 생성물을 제공하기 위해 분리상으로 실리카를 사용하고 20％ EtoAc/Hex(v/v)로 용출시켜 HPLC로 정제했다. EI m/z:380(35,M+), 149(100). 1H NMR(CD3OD) 7.05(d, J=8Hz, 2H), 6.68(d, J=8Hz, 2H), 3.33(s, 3H) 2.93(s, 6H). C15H13F5SO2N2에 대해 계산된 분석 : C 47.37, H 3.45, N 7.37. 발견 : C 47.37, H 3.49, N 7.324- (N, N-dimethylamino) -1- (N-methylpentafluorophenylsulfonamido) benzene. 4- (N, N-dimethylamino) -1- (pentafluorophenylsulfonamido) benzene (100 mg, 0.273 mmol) was dissolved in dry THF (2.5 mL) and lithium bis (trimethyl) under N 2 at room temperature in the system. Silyl) amide (0.274 mL) 1 M solution was added. The reaction mixture was stirred for 10 minutes and MeI (65 mg, 0.028 mL) was added. The reaction mixture was stirred overnight and the solvent was evaporated under reduced pressure and the crude product was eluted with 20% EtoAc / Hex (v / v) using silica as a separate phase to give the product as a white solid in 60% yield (62 mg). Purified by HPLC. EI m / z: 380 (35, M + ), 149 (100). 1 H NMR (CD 3 OD) 7.05 (d, J = 8 Hz, 2H), 6.68 (d, J = 8 Hz, 2H), 3.33 (s, 3H) 2.93 (s, 6H). Anal calculated for C 15 H 13 F 5 SO 2 N 2 : C 47.37, H 3.45, N 7.37. Found: C 47.37, H 3.49, N 7.32
실시예 18Example 18
1,2-디하이드록시-4-펜타플루오로페닐설폰아미도벤젠.1,2-dihydroxy-4-pentafluorophenylsulfonamidobenzene.
1-하이드록시-2-메톡시-4-펜타플루오로페닐설폰아미도벤젠(250mg, 0.678mmol)을 0℃에서 질소하에서 건조한 CH2Cl2(5㎖)에서 현탁시켰다. 혼합물에 CH2Cl2 (0.746mmol, 1.1eq)안에 있는 1M용액으로서 BBr3을 첨가시켰다. 혼합물을 상온으로 따뜻하게 하고 밤새 교반했다. 반응 혼합물을 얼음(75㎖)상에서 붓고 30㎖부의 CH2Cl2로 3번 추출했다. 유기층을 MgSO4로 건조시키고 용매를 증발시켰다. 조생성물을 41％수율(98mg)로 흰색 고체로서 생성물을 제공하기 위해 30％(v/v)EtOAc/Hex로 용출시키면서 실리카 상에서 크로마토그래피로 정제했다. 1H NMR(DMSO): 10.63(s,1H), 9.15(s,1H), 8.91(s,1H), 6.61(d, J = 9Hz, 1H), 6.58(d, J = 3Hz,1H), 6.39ppm(dd, J = 9Hz 3Hz, 1H)1-hydroxy-2-methoxy-4-pentafluorophenylsulfonamidobenzene (250 mg, 0.678 mmol) was suspended in CH 2 Cl 2 (5 mL) dried under nitrogen at 0 ° C. To the mixture was added BBr 3 as 1M solution in CH 2 Cl 2 (0.746 mmol, 1.1 eq). The mixture was warmed to room temperature and stirred overnight. The reaction mixture was poured onto ice (75 mL) and extracted three times with 30 mL part CH 2 Cl 2 . The organic layer was dried over MgSO 4 and the solvent was evaporated. The crude product was purified by chromatography on silica eluting with 30% (v / v) EtOAc / Hex to give the product as a white solid in 41% yield (98 mg). 1 H NMR (DMSO): 10.63 (s, 1 H), 9.15 (s, 1 H), 8.91 (s, 1 H), 6.61 (d, J = 9 Hz, 1 H), 6.58 (d, J = 3 Hz, 1 H), 6.39 ppm (dd, J = 9 Hz 3 Hz, 1H)
실시예 19Example 19
4-에톡시-1-펜타플루오로설폰아미도벤젠. 25℃에서 디메틸포름아미드(3.65㎖)에 있는 p-페네티딘(0.100g, 0.729mmol)과 교반된 용액에 펜타플루오로페닐 설포닐 클로라이드(0.135㎖, 0.911mmol)와 소듐 카보네이트(0.116g, 1.09mmol)를 첨가시키고 반응 혼합물을 18시간동안 교반했다. 반응 혼합물을 에틸 아세테이트(50㎖)로 희석하고 20％ 암모늄 클로라이드(2×20㎖)와 포화 염화 나트륨(2×20㎖)으로 세척했다. 유기층을 건조시키고(소듐 설파이드), 에틸아세테이트를 불그레한 갈색 오일을 생성하기 위해 감압하에서 제거했다. 칼럼 크로마토그래피(3:1 에틸아세테이트/헥산)은 표제 화합물 (0.222g, 83％)을 생성했다. 1H NMR (CDCl3) 7.08(d, J=9Hz, 2H), 7.04(s, 1H), 6.80(d, J=9Hz, 2H), 3.96(q, J=7Hz, 2H), 1,37ppm(t, J=7Hz, 2H). IR(neat)3000-3600, 1750㎝-1. EI m/z:367(M+), 154, 136.4-ethoxy-1-pentafluorosulfonamidobenzene. In a stirred solution with p-phenetidine (0.100 g, 0.729 mmol) in dimethylformamide (3.65 mL) at 25 ° C., pentafluorophenyl sulfonyl chloride (0.135 mL, 0.911 mmol) and sodium carbonate (0.116 g, 1.09 mmol) was added and the reaction mixture was stirred for 18 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with 20% ammonium chloride (2 x 20 mL) and saturated sodium chloride (2 x 20 mL). The organic layer was dried (sodium sulfide) and ethyl acetate was removed under reduced pressure to yield a reddish brown oil. Column chromatography (3: 1 ethyl acetate / hexanes) gave the title compound (0.222 g, 83%). 1 H NMR (CDCl 3 ) 7.08 (d, J = 9 Hz, 2H), 7.04 (s, 1H), 6.80 (d, J = 9 Hz, 2H), 3.96 (q, J = 7 Hz, 2H), 1,37 ppm (t, J = 7 Hz, 2H). IR (neat) 3000-3600, 1750 cm -1 . EI m / z: 367 (M + ), 154, 136.
실시예 20-26의 화합물을 적당한 아민으로 p-페네티딘을 치환하므로서 실시예 19와 유사한 프로토콜에 의해 제조했다. The compounds of Examples 20-26 were prepared by a protocol similar to Example 19 with the substitution of p-phenetidine with a suitable amine.
실시예 20Example 20
3,5-디메톡시-1-펜타플루오로페닐설폰아미도벤젠. 화합물을 3,5-디메톡시아닐린으로 p-페네티딘을 치환하므로서 실시예 19와 유사한 프로토콜에 의해 제조했다. 1H NMR (CDCl3) 6.91(s, 1H), 6.32(s, 2H), 6.25(s, 1H), 3.72ppm(s, 6H).3,5-dimethoxy-1-pentafluorophenylsulfonamidobenzene. The compound was prepared by a protocol similar to Example 19 with the substitution of p-phenetidine with 3,5-dimethoxyaniline. 1 H NMR (CDCl 3 ) 6.91 (s, 1H), 6.32 (s, 2H), 6.25 (s, 1H), 3.72 ppm (s, 6H).
실시예 21Example 21
3-에톡시-1-펜타플루오로페닐설폰아미도벤젠. 화합물을 3-에톡시아닐린으로 p-페네티딘을 치환하므로서 실시예 19와 유사한 프로토콜에 의해 제조했다. 1H NMR(CDCl3) 7.35(t, J=8Hz, 1H), 7.21(s, 1H), 6.92(s, 1H), 6.86(d, J=8Hz, 1H), 6.83(d, J=8Hz, 1H), 4.15(q, J=6Hz, 2H), 1.56ppm(t, J=6Hz, 3H).3-ethoxy-1-pentafluorophenylsulfonamidobenzene. The compound was prepared by a protocol similar to Example 19 with the substitution of p-phenetidine with 3-ethoxyaniline. 1 H NMR (CDCl 3 ) 7.35 (t, J = 8Hz, 1H), 7.21 (s, 1H), 6.92 (s, 1H), 6.86 (d, J = 8Hz, 1H), 6.83 (d, J = 8Hz , 1H), 4.15 (q, J = 6 Hz, 2H), 1.56 ppm (t, J = 6 Hz, 3H).
실시예 22Example 22
7-하이드록시-2-펜타플루오로페닐설폰아미도나프탈렌. 화합물을 2-아미노-7-하이드록시나프탈렌으로 p-페네티딘을 치환하므로서 실시예 19와 유사한 프로토콜에 의해 제조했다. 1H NMR(CDCl3) 8.15(t, J=8Hz, 1H), 7.55(d, J=8Hz, 1H), 7.44(s, 1H), 7.42(d, J=8Hz, 1H), 7.40(s, 1H), 6.88ppm(q, J=8Hz, 1H).7-hydroxy-2-pentafluorophenylsulfonamidonaphthalene. The compound was prepared by a protocol similar to Example 19 with the substitution of p-phenetidine with 2-amino-7-hydroxynaphthalene. 1 H NMR (CDCl 3 ) 8.15 (t, J = 8 Hz, 1H), 7.55 (d, J = 8 Hz, 1H), 7.44 (s, 1H), 7.42 (d, J = 8 Hz, 1H), 7.40 (s , 1H), 6.88 ppm (q, J = 8 Hz, 1H).
실시예 23Example 23
3-페녹시-1-펜타플루오로페닐설폰아미도벤젠. 화합물을 3-페녹시아닐린으로 p-페네티딘을 치환하므로서 실시예 19와 유사한 프로토콜에 의해 제조했다. 1H NMR(CDCl3) 7.34(t, J=8Hz, 2H), 7.26(t, J=8Hz, 1H), 7.16(t, J=8Hz, 1H), 6.94(d, J=8Hz, 2H), 6.86(d, J=8Hz, 1H), 6.82(d, J=8Hz, 1H), 6.74(s, 1H).3-phenoxy-1-pentafluorophenylsulfonamidobenzene. The compound was prepared by a protocol similar to Example 19 with the substitution of p-phenetidine with 3-phenoxyaniline. 1 H NMR (CDCl 3 ) 7.34 (t, J = 8 Hz, 2H), 7.26 (t, J = 8 Hz, 1H), 7.16 (t, J = 8 Hz, 1H), 6.94 (d, J = 8 Hz, 2H) , 6.86 (d, J = 8 Hz, 1H), 6.82 (d, J = 8 Hz, 1H), 6.74 (s, 1H).
실시예 24Example 24
3-메톡시-1-펜타플루오로페닐설폰아미도벤젠. 화합물을 3-메톡시아닐린으로 p-페네티딘을 치환하므로서 실시예 19와 유사한 프로토콜에 의해 제조했다. 1H NMR(CDCl3) 7.20(d, J=8Hz, 1H,), 6.95(s, 1H), 6.78(d, J=8Hz, 1H), 6.70(t, J=8Hz, 1H), 3.79ppm(s, 1H).3-methoxy-1-pentafluorophenylsulfonamidobenzene. The compound was prepared by a protocol similar to Example 19 with the substitution of p-phenetidine with 3-methoxyaniline. 1 H NMR (CDCl 3 ) 7.20 (d, J = 8 Hz, 1H,) 6.95 (s, 1H), 6.78 (d, J = 8 Hz, 1H), 6.70 (t, J = 8 Hz, 1H), 3.79 ppm (s, 1 H).
실시예 25Example 25
4-(1-모르폴리노)-1-펜타플루오로페닐설폰아미도벤젠. 화합물을 4-(1-모르폴리노)아닐린으로 p-페네티딘을 치환하므로서 실시예 19와 유사한 프로토콜에 의해 제조했다. 1H NMR(CDCl3) 7.09(d, J=8Hz, 2H), 6.85(d, J=8Hz, 2H), 3.85(t, J=8Hz, 4H), 3.15ppm(t, J=8Hz, 4H).4- (1-morpholino) -1-pentafluorophenylsulfonamidobenzene. The compound was prepared by a protocol similar to Example 19 with the substitution of p-phenetidine with 4- (1-morpholino) aniline. 1 H NMR (CDCl 3 ) 7.09 (d, J = 8 Hz, 2H), 6.85 (d, J = 8 Hz, 2H), 3.85 (t, J = 8 Hz, 4H), 3.15 ppm (t, J = 8 Hz, 4H ).
실시예 26Example 26
5-펜타플루오로페닐설폰아미도-1,2,3-트리메톡시벤젠. 화합물을 3,4,5-트리메톡시아닐린으로 p-페네티딘을 치환하므로서 실시예 19와 유사한 프로토콜에 의해 제조했다. 1H NMR(CDCl3) 8.14(s, 1H), 6.46(s, 2H), 3.69(s, 6H), 3.59(s, 3H).5-pentafluorophenylsulfonamido-1,2,3-trimethoxybenzene. The compound was prepared by a protocol similar to Example 19 with the substitution of p-phenetidine with 3,4,5-trimethoxyaniline. 1 H NMR (CDCl 3 ) 8.14 (s, 1H), 6.46 (s, 2H), 3.69 (s, 6H), 3.59 (s, 3H).
실시예 27Example 27
1,3-디메톡시-2-하이드로시-5-펜타플루오로페닐설폰아미도벤젠.1,3-dimethoxy-2-hydrocy-5-pentafluorophenylsulfonamidobenzene.
1,2-디하이드록시-3-메톡시-5-펜타플루오로페닐설폰아미도벤젠.1,2-dihydroxy-3-methoxy-5-pentafluorophenylsulfonamidobenzene.
5-펜타플루오로페닐설폰아미도-1,2,3-트리하이드록시벤젠.5-pentafluorophenylsulfonamido-1,2,3-trihydroxybenzene.
1,2,3-메톡시-5-펜타플루오로페닐설폰아미도벤젠(269㎎, 0.65mmol)을 0℃에서 질소하에서 건조한 CH2Cl2(5㎖)에서 분산시켰다. 혼합물에 CH2Cl2(3.26mmol, 5eq.)에 있는 1M 용액으로서 BBr2를 첨가했다. 혼합물을 상온으로 따뜻하게하고 밤새 교반했다. 반응 혼합물을 얼음(75㎖)상에 붓고 30㎖부의 CH2Cl2로 3번 추출했다. 유기층을 MgSO4로 건조시키고 증발시켜 3개의 생성물을 제공하기 위해 잔류물을 30％(v/v)EtOAc/Hex로 용출시키면서 실리카 상에서 크로마토그래프했다. 실시예 28과 29의 화합물을 실시예 20의 생성물로 시작하여 이것을 BBr3로 처리하는 상기 기술된 것과 유사한 방법으로 제조했다.1,2,3-methoxy-5-pentafluorophenylsulfonamidobenzene (269 mg, 0.65 mmol) was dispersed in CH 2 Cl 2 (5 mL), dried at 0 ° C. under nitrogen. To the mixture was added BBr 2 as a 1M solution in CH 2 Cl 2 (3.26 mmol, 5eq.). The mixture was warmed to room temperature and stirred overnight. The reaction mixture was poured onto ice (75 mL) and extracted three times with 30 mL part CH 2 Cl 2 . The organic layer was dried over MgSO 4 and evaporated to chromatograph the residue on silica, eluting with 30% (v / v) EtOAc / Hex. The compounds of Examples 28 and 29 were prepared in a similar manner as described above starting with the product of Example 20 and treating it with BBr 3 .
1,3-디메톡시-2-하이드록시-5-펜타플루오로페닐설폰아미도벤젠. 1H NMR(CDCl3) 10.85(s, 1H), 8.31(s, 1H), 6.41(s, 2H), 3.66ppm(s, 6H).1,3-dimethoxy-2-hydroxy-5-pentafluorophenylsulfonamidobenzene. 1 H NMR (CDCl 3 ) 10.85 (s, 1H), 8.31 (s, 1H), 6.41 (s, 2H), 3.66 ppm (s, 6H).
1,2-디하이드록시-3-메톡시-5-펜타플루오로페닐설폰아미도벤젠. 1H NMR(CDCl3) 10.73(s, 1H), 8.31(s, 1H), 6.27(s, 1H), 6.26(s, 1H), 3.66ppm(s, 3H).1,2-dihydroxy-3-methoxy-5-pentafluorophenylsulfonamidobenzene. 1 H NMR (CDCl 3 ) 10.73 (s, 1H), 8.31 (s, 1H), 6.27 (s, 1H), 6.26 (s, 1H), 3.66 ppm (s, 3H).
5-펜타플루오로페닐설폰아미도-1,2,3-트리하이드록시벤젠. 1H NMR(CDCl3) 11.0(s, 1H), 9.03(s, 2H), 8.06(s, 1H), 6.13ppm(s, 2H).5-pentafluorophenylsulfonamido-1,2,3-trihydroxybenzene. 1 H NMR (CDCl 3 ) 11.0 (s, 1H), 9.03 (s, 2H), 8.06 (s, 1H), 6.13 ppm (s, 2H).
실시예 28Example 28
3-하이드록시-5-메톡시-1-펜타플루오로페닐설폰아미도벤젠. 1H NMR(CDCl3) 11.2(s, 1H), 9.63(s, 1H), 6.23(s, 1H), 6.21(s, 1H), 6.08(s, 1H), 3.63ppm(s, 3H).3-hydroxy-5-methoxy-1-pentafluorophenylsulfonamidobenzene. 1 H NMR (CDCl 3 ) 11.2 (s, 1H), 9.63 (s, 1H), 6.23 (s, 1H), 6.21 (s, 1H), 6.08 (s, 1H), 3.63ppm (s, 3H).
실시예 29Example 29
3,5-디하이드록시-1-펜타플루오로페닐설폰아미도벤젠. 1H NMR(CDCl3) 7.15(s, 1H), 6.25(s, 2H), 6.15(s, 1H), 5.31(s, 2H).3,5-dihydroxy-1-pentafluorophenylsulfonamidobenzene. 1 H NMR (CDCl 3 ) 7.15 (s, 1 H), 6.25 (s, 2H), 6.15 (s, 1H), 5.31 (s, 2H).
실시예 30Example 30
2-플루오로-1-메톡시-4-(N-메틸펜타플루오로페닐설폰아미도)벤젠. 적당한 비치환된 설폰아미드(실시예 7의 생성물)로 4-(N,N-디메틸아미노)-1-펜타플루오로페닐설폰아미도벤젠을 치환하는 실시예 18의 과정과 유사한 과정을 사용하여 제조된 것. 1H NMR(CDCl3): 6.97-6.94(m, 2H), 6.89(t, J=9Hz, 1H), 3.87(s, 3H), 3.35ppm(t, J=1Hz). EI m/z : 385(20, M+), 154(100). C14H9F6NO3의 계산된 분석: 발견: C 43.64, H 2.35, N 3.64.2-fluoro-1-methoxy-4- (N-methylpentafluorophenylsulfonamido) benzene. Prepared using a procedure similar to that of Example 18, in which 4- (N, N-dimethylamino) -1-pentafluorophenylsulfonamidobenzene is substituted with a suitable unsubstituted sulfonamide (product of Example 7). Thing. 1 H NMR (CDCl 3 ): 6.97-6.94 (m, 2H), 6.89 (t, J = 9 Hz, 1H), 3.87 (s, 3H), 3.35 ppm (t, J = 1 Hz). EI m / z: 385 (20, M + ), 154 (100). Calculated analysis of C 14 H 9 F 6 NO 3 : found: C 43.64, H 2.35, N 3.64.
실시예 31Example 31
2-브로모-1-메톡시-4-펜타플루오토페닐설폰아미도벤젠. 1H NMR(CDCl3): 7.35(d, J=3Hz, 1H), 7.15(dd, J=9Hz, 3Hz, 1H), 6.97(s, 1H), 6.81(d, J=9Hz, 1H), 3.88ppm(s, 3H). EI m/z: 433(35, M+), 202(100). 화합물을 3-브로모-4-메톡시아닐린으로 N,N-디메틸-1,4-페닐디아민 디하이드로클로라이드를 치환하므로서 실시예 1과 유사한 프로토콜에 의해 제조했다.2-bromo-1-methoxy-4-pentafluorotophenylsulfonamidobenzene. 1 H NMR (CDCl 3 ): 7.35 (d, J = 3 Hz, 1 H), 7.15 (dd, J = 9 Hz, 3 Hz, 1 H), 6.97 (s, 1 H), 6.81 (d, J = 9 Hz, 1 H), 3.88 ppm (s, 3 H). EI m / z: 433 (35, M + ), 202 (100). The compound was prepared by a protocol similar to Example 1 with the substitution of N, N-dimethyl-1,4-phenyldiamine dihydrochloride with 3-bromo-4-methoxyaniline.
실시예 32Example 32
2-클로로-1-메톡시-4-펜타플루오로페닐설폰아미도벤젠. 1H NMR(CDCl3): 7.19(d, J=3Hz, 1H), 7.08(dd, J=9Hz, 3Hz, 1H), 7.01(s, 1H), 6.84(d, J=9Hz, 1H), 3.85ppm(s, 3H). EI m/z(상대적인 존재량): 387(10, M+), 156(100). 화합물을 3-클로로-4-메톡시아닐린으로 N,N-디메틸-1,4-페닐디아민 디하이드로클로라이드를 치환하므로서 실시예 1과 유사한 프로토콜에 의해 제조했다.2-chloro-1-methoxy-4-pentafluorophenylsulfonamidobenzene. 1 H NMR (CDCl 3 ): 7.19 (d, J = 3 Hz, 1 H), 7.08 (dd, J = 9 Hz, 3 Hz, 1 H), 7.01 (s, 1 H), 6.84 (d, J = 9 Hz, 1 H), 3.85 ppm (s, 3 H). EI m / z (relative abundance): 387 (10, M + ), 156 (100). The compound was prepared by a protocol similar to Example 1 with the substitution of N, N-dimethyl-1,4-phenyldiamine dihydrochloride with 3-chloro-4-methoxyaniline.
실시예 33Example 33
4-(N,N-디메틸아미노)-1-펜타플루오로페닐설폰아미도벤젠 하이드로클로라이드. 4-(N,N-디메틸아미노)-1-펜타플루오로페닐설폰아미도벤젠 (2g, 5.5mmol)을 상온에서 질소하에서 15㎖의 디에틸 에테르에 용해시켰다. 기체 HCl을 반응혼합물내로 5분동안 거품을 일게했다. 혼합물을 여과하고 흰색고체(1.89g, 86％ 수율)로서의 생성물을 제공하기위해 결과로 생긴 고체를 15㎖부의 차가운 디에틸 에테르로 2번 세척했다. 1H NMR(CD3OD): 7.62(dd, J=9.0Hz, 1.6Hz, 2H), 7.44(dd, J=9.0Hz, 1.6Hz, 2H), 3.28ppm(s, 6H). FAB m/z: 367(100％, M+H+), 135(90％), 121(45％). C14H13ClF5N2O2S의 계산된 분석: C 41.79, H 3.01, N 6.97, S 7.95. 발견: C 41.71; H 3.05; N 7.01; S 7.96.4- (N, N-dimethylamino) -1-pentafluorophenylsulfonamidobenzene hydrochloride. 4- (N, N-dimethylamino) -1-pentafluorophenylsulfonamidobenzene (2 g, 5.5 mmol) was dissolved in 15 mL of diethyl ether at room temperature under nitrogen. Gas HCl was bubbled into the reaction mixture for 5 minutes. The resulting solid was washed twice with 15 ml of cold diethyl ether to afford the product as a white solid (1.89 g, 86% yield). 1 H NMR (CD 3 OD): 7.62 (dd, J = 9.0 Hz, 1.6 Hz, 2H), 7.44 (dd, J = 9.0 Hz, 1.6 Hz, 2H), 3.28 ppm (s, 6H). FAB m / z: 367 (100%, M + H + ), 135 (90%), 121 (45%). Calculated analysis of C 14 H 13 ClF 5 N 2 O 2 S: C 41.79, H 3.01, N 6.97, S 7.95. Found: C 41.71; H 3.05; N 7.01; S 7.96.
실시예 34Example 34
3,4-디플루오로-1-펜타플루오로페닐설폰아미도벤젠. 화합물을 3,4-디플루오로아닐린으로 N,N-디메틸-1,4-페닐디아민 디하이드로클로라이드를 치환하므로서 실시예1과 유사한 방법으로 제조했다. 1H NMR(CDCl3) 7.13(m, 3H), 6.91ppm(m, 1H). EI, m/z(상대적인 존재량) : 359(20), 128(100). C13H4F7NO2S의 계산된 분석: C 40.12, H 1.12, N 3.90. 발견: C 40.23, H 1.17, N 3.89.3,4-difluoro-1-pentafluorophenylsulfonamidobenzene. The compound was prepared in a similar manner to Example 1 by substituting N, N-dimethyl-1,4-phenyldiamine dihydrochloride with 3,4-difluoroaniline. 1 H NMR (CDCl 3 ) 7.13 (m, 3H), 6.91 ppm (m, 1H). EI, m / z (relative abundance): 359 (20), 128 (100). Calculated analysis of C 13 H 4 F 7 NO 2 S: C 40.12, H 1.12, N 3.90. Found: C 40.23, H 1.17, N 3.89.
실시예 35Example 35
4-트리플루오로메톡시-1-펜타플루오로페닐설폰아미도벤젠. 화합물을 4-(트리플루오로메톡시)아닐린으로 N,N-디메틸-1,4-페닐디아민 디하이드로클로라이드를 치환하므로서 실시예1과 유사한 방법으로 제조했다. 1H NMR(CDCl3) 7.18ppm(m, 4H). EI, m/z(상대적인 존재량): 407(20), 176(100). C13H5F8NO3S의 계산된 분석: C 38.34, H 1.24, N 3.44. 발견: C 38.33, H 1.30, N 3.43.4-trifluoromethoxy-1-pentafluorophenylsulfonamidobenzene. The compound was prepared in a similar manner as in Example 1 by replacing N, N-dimethyl-1,4-phenyldiamine dihydrochloride with 4- (trifluoromethoxy) aniline. 1 H NMR (CDCl 3 ) 7.18 ppm (m, 4H). EI, m / z (relative abundance): 407 (20), 176 (100). Calculated analysis of C 13 H 5 F 8 NO 3 S: C 38.34, H 1.24, N 3.44. Found: C 38.33, H 1.30, N 3.43.
실시예 36Example 36
2-클로로-5-펜타플루오로페닐설폰아미도피리딘. 화합물을 5-아미노-2-클로로피리딘으로 N,N-디메틸-1,4-페닐디아민 디하이드로클로라이드를 치환하므로서 실시예 1과 유사한 방법으로 제조했다. H NMR(DMSO-d6): 8.18(d, J=2.68Hz, 1H), 7.64(dd, J=8.75, 2.89Hz, 1H), 7.50ppm(d, J=8.75Hz, 1H). EI m/z 358(20,M+), 127(100). C11H4ClF5N2O2S의 계산된 분석: C 36.83, H 1.12, N 7.81, S 8.94, Cl 9.90. 발견:C 37.00, H 1.16, N 7.78, S 8.98, Cl 10.01. M.P.=144-145℃를 갖는 흰색 결정.2-chloro-5-pentafluorophenylsulfonamidopyridine. The compound was prepared in a similar manner to Example 1 by substituting N, N-dimethyl-1,4-phenyldiamine dihydrochloride with 5-amino-2-chloropyridine. H NMR (DMSO-d 6 ): 8.18 (d, J = 2.68 Hz, 1H), 7.64 (dd, J = 8.75, 2.89 Hz, 1H), 7.50 ppm (d, J = 8.75 Hz, 1H). EI m / z 358 (20, M + ), 127 (100). Calculated analysis of C 11 H 4 ClF 5 N 2 O 2 S: C 36.83, H 1.12, N 7.81, S 8.94, Cl 9.90. Found: C 37.00, H 1.16, N 7.78, S 8.98, Cl 10.01. White crystals with MP = 144-145 ° C.
실시예 37Example 37
2-하이드록시-1-메톡시-4-(N-(5-하이드록시펜틸)-펜타플루오로페닐설폰아미도) 벤젠. N-(5-하이드록시펜틸)-2-하이드록시-1-메톡시-4-아미노벤젠을 MeOH에 있는 NaBH4를 갖는 글루타릭 디알데히드로 5-아미노-2-메톡시 페놀의 환원성 아민화에 의해 제조했다. 2-하이드록시-1-메톡시-4-(N-(5-하이드록시펜틸)-펜타플루오로페닐설폰아미도)벤젠을 N-(5-하이드록시펜틸)-2-하이드록시-1-메톡시-4-아미노벤젠으로 N,N-디메틸-1,4-페닐디아민 디하이드로클로라이드를 치환하므로서 실시예 1과 유사한 방법으로 제조했다. 1H NMR(CDCl3): 6.78(d, J=8.6Hz, 1H), 6.71(dd, J=8.59, 2.48Hz, 1H), 6.63(d, J=2.48Hz,1H), 3.88(s, 3H), 3.7(t, J=6.8Hz, 2H), 3.6(t, J=6.39Hz, 2H), 1.5ppm(m, 6H). C18H18F5NO5S의 계산된 분석: C 47.47, H 3.98, N 3.08, S 7.04. 발견: C 47.47, H 4.04, N 3.11, S 6.97. M.P.=118°를 갖는 흰색 결정.2-hydroxy-1-methoxy-4- (N- (5-hydroxypentyl) -pentafluorophenylsulfonamido) benzene. Reducing N- (5-hydroxypentyl) -2-hydroxy-1-methoxy-4-aminobenzene with Glutaric Dialdehyde 5-amino-2-methoxy Phenol with NaBH 4 in MeOH Manufactured by folk painting. 2-hydroxy-1-methoxy-4- (N- (5-hydroxypentyl) -pentafluorophenylsulfonamido) benzene to N- (5-hydroxypentyl) -2-hydroxy-1- Prepared in a similar manner to Example 1 by substituting N, N-dimethyl-1,4-phenyldiamine dihydrochloride with methoxy-4-aminobenzene. 1 H NMR (CDCl 3 ): 6.78 (d, J = 8.6 Hz, 1H), 6.71 (dd, J = 8.59, 2.48 Hz, 1H), 6.63 (d, J = 2.48 Hz, 1H), 3.88 (s, 3H), 3.7 (t, J = 6.8 Hz, 2H), 3.6 (t, J = 6.39 Hz, 2H), 1.5 ppm (m, 6H). Calculated analysis of C 18 H 18 F 5 NO 5 S: C 47.47, H 3.98, N 3.08, S 7.04. Found: C 47.47, H 4.04, N 3.11, S 6.97. White crystals with MP = 118 °.
실시예 38Example 38
4-(1,1-디메틸)에톡시-1-펜타플루오로페닐설폰아미도벤젠.4- (1,1-dimethyl) ethoxy-1-pentafluorophenylsulfonamidobenzene.
화합물을 4-t-부톡시아닐린으로 3-클로로아닐린을 치환하므로서 실시예 46과 유사한 방법으로 제조했다. 4-t-부톡시 아닐린을 데이(Day)의 방법 (J. Med. Chem. 1975, 18, 1065)에 의해 제조했다. 1H NMR(CDCl3): d 7.07(m, 2), 6.92(m, 2), 6.88(m, 1), 1.31(s, 9). MS(EI): m/z 395(1, M+), 339(28), 108(100). C16H14F5NO3S의 계산된 분석: C 48.61; H, 3.57; N, 3.54; S, 8.11. 발견: C, 48.53; H, 3.60; N, 3.50; S, 8.02.The compound was prepared in a similar manner to Example 46 by replacing 3-chloroaniline with 4-t-butoxyaniline. 4-t-butoxy aniline was prepared by the method of Day (J. Med. Chem. 1975, 18, 1065). 1 H NMR (CDCl 3 ): d 7.07 (m, 2), 6.92 (m, 2), 6.88 (m, 1), 1.31 (s, 9). MS (EI): m / z 395 (1, M + ), 339 (28), 108 (100). Calculated analysis of C 16 H 14 F 5 NO 3 S: C 48.61; H, 3.57; N, 3.54; S, 8.11. Found: C, 48.53; H, 3. 60; N, 3.50; S, 8.02.
실시예 39Example 39
1-브로모-3-하이드록시-4-메톡시-1-펜타플루오로페닐설폰아미도벤젠. 화합물을 디클로로메탄에 있는 N-브로모석신이미드로 실시예 6의 화합물의 브롬화에 의해 제조했다. 1H NMR(CDCl3): 7.28(br s, 1H), 7.21(d, J=9Hz, 1H), 6.80(d, J=9Hz, 1H), 6.05(s, 1H), 3.89ppm(s, 3H). EI, m/z(상대적인 존재량): 449(25), 447(25), 218(100), 216(100). C13H8BrF5NO4S의 계산된 분석: C 34.84, H 1.57; N, 3.13; S 7.15. 발견: C, 34.75; H, 1.60; N, 3.07; S, 7.08.1-bromo-3-hydroxy-4-methoxy-1-pentafluorophenylsulfonamidobenzene. The compound was prepared by bromination of the compound of Example 6 with N-bromosuccinimide in dichloromethane. 1 H NMR (CDCl 3 ): 7.28 (br s, 1H), 7.21 (d, J = 9 Hz, 1H), 6.80 (d, J = 9 Hz, 1H), 6.05 (s, 1H), 3.89 ppm (s, 3H). EI, m / z (relative abundance): 449 (25), 447 (25), 218 (100), 216 (100). Calculated analysis of C 13 H 8 BrF 5 NO 4 S: C 34.84, H 1.57; N, 3.13; S 7.15. Found: C, 34.75; H, 1. 60; N, 3.07; S, 7.08.
실시예 40Example 40
1-브로모-4-메톡시-5-하이드록시-1-펜타플루오로페닐설폰아미도벤젠. 화합물을 디클로로메탄에 있는 N-브로모석신이미드로 실시예 6의 화합물의 브롬화에 의해 제조했다. 1H NMR(CDCl3): 7.28(s, 1H), 7.16(br s, 1H), 6.91(s, 1H), 3.85ppm(s, 3H). EI, m/z(상대적인 존재량): 449(25), 447(25), 218(100), 216(100). C13H8BrF5NO4S의 계산된 분석: C 34.84, H 1.57; N 3.13; S 7.15. 발견: C 34.84, H 1.57, N 3.05, S 7.06.1-bromo-4-methoxy-5-hydroxy-1-pentafluorophenylsulfonamidobenzene. The compound was prepared by bromination of the compound of Example 6 with N-bromosuccinimide in dichloromethane. 1 H NMR (CDCl 3 ): 7.28 (s, 1 H), 7.16 (br s, 1 H), 6.91 (s, 1 H), 3.85 ppm (s, 3 H). EI, m / z (relative abundance): 449 (25), 447 (25), 218 (100), 216 (100). Calculated analysis of C 13 H 8 BrF 5 NO 4 S: C 34.84, H 1.57; N 3.13; S 7.15. Found: C 34.84, H 1.57, N 3.05, S 7.06.
실시예 41Example 41
1-브로모-4-플루오로-5-메톡시-2-펜타플루오로페닐설폰아미도벤젠. 화합물을 브롬 수로 실시예 7의 화합물의 브롬화에 의해 제조했다. 1H NMR(CDCl3): 7.49(d, J=11.72Hz, 1H), 7.21(s, 1H), 7.04(d, J=8.2Hz, 1H), 3.84ppm(s, 3H). EI: m/z 449(20, M+), 451(20), 228(100), 230(100). C13H6BrF6NO3S의 계산된 분석: C 34.69; H 1.34; N, 3.11; S, 7.12, Br 17.75. 발견: C 34.76, H 1.29, N 3.05, S 7.12, Br 17.68. M.P.=109℃를 갖는 흰색 결정.1-bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene. The compound was prepared by bromination of the compound of Example 7 with bromine number. 1 H NMR (CDCl 3 ): 7.49 (d, J = 11.72 Hz, 1H), 7.21 (s, 1H), 7.04 (d, J = 8.2 Hz, 1H), 3.84 ppm (s, 3H). EI: m / z 449 (20, M + ), 451 (20), 228 (100), 230 (100). Calculated analysis of C 13 H 6 BrF 6 NO 3 S: C 34.69; H 1.34; N, 3.11; S, 7.12, Br 17.75. Found: C 34.76, H 1.29, N 3.05, S 7.12, Br 17.68. White crystals with MP = 109 ° C.
실시예 42Example 42
2-하이드록시-1-메톡시-4-펜타플루오로페닐설폰아미도벤젠. 화합물을 평형몰랄양의 1N NaOH(aq)로 실시예 6의 화합물을 처리하므로서 제조했다. 화합물을 동결 건조한 후 잔류물을 에틸 아세테이트/에테르로부터 재결정화했다. 1H NMR(DMSO) 8.40(s, 1H), 6.57(d, J=9Hz, 1H), 6.39(d, J=2Hz, 1H), 6.24(dd, J=9, 2Hz, 1H), 3.62ppm(s, 3H). C13H7F5NaO4S의 계산된 분석: C 39.91, H 1.80, N 3.58, Na 5.88, S 8.19. 발견: C 39.79, H 1.86, N 3.50, Na 5.78, S 8.07.2-hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene. The compound was prepared by treating the compound of Example 6 with an equimolar molar amount of 1N NaOH (aq) . The compound was lyophilized and the residue was recrystallized from ethyl acetate / ether. 1 H NMR (DMSO) 8.40 (s, 1H), 6.57 (d, J = 9Hz, 1H), 6.39 (d, J = 2Hz, 1H), 6.24 (dd, J = 9, 2Hz, 1H), 3.62ppm (s, 3 H). Calculated analysis of C 13 H 7 F 5 NaO 4 S: C 39.91, H 1.80, N 3.58, Na 5.88, S 8.19. Found: C 39.79, H 1.86, N 3.50, Na 5.78, S 8.07.
실시예 43Example 43
2-하이드록시-1-메틸-4-펜타플루오로페닐설폰아미도벤젠 포타슘 염. 화합물을 1N KOH로 1N NaOH를 치환하므로서 실시예 42와 유사한 방법으로 제조했다. 1H NMR(DMSO) 8.30(br s, 1H), 6.55(d, J=9Hz, 1H), 6.36(d, J=2Hz, 1H), 6.25(dd, J=9, 2Hz, 1H), 3.61ppm(s, 3H). C13H7F5KNO4S의 계산된 분석: C 38.33, H 1.73, N 3.44, S 7.87. 발견: C 38.09, H 1.79, N 3.39, S 7.97.2-hydroxy-1-methyl-4-pentafluorophenylsulfonamidobenzene potassium salt. The compound was prepared by a method similar to Example 42 by replacing 1N NaOH with 1N KOH. 1 H NMR (DMSO) 8.30 (br s, 1 H), 6.55 (d, J = 9 Hz, 1 H), 6.36 (d, J = 2 Hz, 1 H), 6.25 (dd, J = 9, 2 Hz, 1 H), 3.61 ppm (s, 3H). Calculated analysis of C 13 H 7 F 5 KNO 4 S: C 38.33, H 1.73, N 3.44, S 7.87. Found: C 38.09, H 1.79, N 3.39, S 7.97.
구성도 ⅣConfiguration Ⅳ
구성도 ⅣConfiguration Ⅳ
실시예 44Example 44
2-플루오로-1-메톡시-4-펜타플루오로페닐설폰아미도벤젠 포타슘 염. 화합물을 실시예 7로 실시예 6의 화합물을 치환하므로서 실시예 43과 유사한 방법으로 제조했다. 1H NMR(DMSO): 6.80(t, J=10Hz, 1H), 6.72(dd, J=9, 2Hz, 1H), 6.54(dd, J=9, 2Hz,1H), 3.68ppm(s, 3H). C13H6F6KNO3S의 계산된 분석: C 38.15, H 1.48, N 3.42, S 7.83. 발견: C 38.09, H 1.51, N 3.35, S 7.73. M.P.=202-205℃.2-fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene potassium salt. The compound was prepared in a similar manner to Example 43 by substituting the compound of Example 6 for Example 7. 1 H NMR (DMSO): 6.80 (t, J = 10 Hz, 1H), 6.72 (dd, J = 9, 2 Hz, 1H), 6.54 (dd, J = 9, 2 Hz, 1H), 3.68 ppm (s, 3H ). Calculated analysis of C 13 H 6 F 6 KNO 3 S: C 38.15, H 1.48, N 3.42, S 7.83. Found: C 38.09, H 1.51, N 3.35, S 7.73. MP = 202-205 ° C.
실시예 45Example 45
2-플루오로-1-메톡시-4-펜타플루오로페닐설폰아미도벤젠 소듐 염. 화합물을 1N NaOH로 1N KOH를 치환하므로서 실시예 44와 유사한 방법으로 제조했다. 1H NMR(DMSO) 6.80(t, J=10Hz, 1H), 6.71(dd, J=9, 2Hz, 1H), 6.53(dd, J=9, 2Hz, 1H), 3.69ppm(s, 3H). C13H6F6KNO3NNaO3S의 계산된 분석:C 39.71, H 1.54, N 3.56, Na 5.85, S 8.15. 발견: C 39.56, H 1.62, N 3.49, Na 5.88, S 8.08. M.P.>250℃.2-fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene sodium salt. The compound was prepared by a method similar to Example 44 by replacing 1N KOH with 1N NaOH. 1 H NMR (DMSO) 6.80 (t, J = 10 Hz, 1H), 6.71 (dd, J = 9, 2 Hz, 1H), 6.53 (dd, J = 9, 2 Hz, 1H), 3.69 ppm (s, 3H) . Calculated analysis of C 13 H 6 F 6 KNO 3 NNaO 3 S: C 39.71, H 1.54, N 3.56, Na 5.85, S 8.15. Found: C 39.56, H 1.62, N 3.49, Na 5.88, S 8.08. MP> 250 ° C.
실시예 46Example 46
3-클로로-1-펜타플루오로페닐설폰아미도벤젠. MeOH(4㎖)에 있는 펜타플루오로페닐설포닐 클로라이드 (0.15㎖, 1.00mmol)의 용액에 3-클로로아닐린(260㎎, 2.04mmol)을 첨가시켰다. 실온에서 1시간 동안 교반시킨 후 반응혼합물을 감압하에서 농축시키고 잔류물을 EtOAc에서 취하고 실리카겔의 충전물을 통해 여과시켰다. 여과액을 크로마토그래프시 256㎎(74％)의 생성물이 제공되는 노란색 오일을 제공하기 위해 농축했다. 1H NMR(CDCl3): d 7.28-7.24(m, 1H), 7.21-7.17(m, 2H), 7.10-7.08(m, 1H), 7.07(s, 1H). MS(EI) : m/z 357(42, M+), 258(76), 126(87), 99(100). C12H5ClF5NO2S의 계산된 분석: C, 40.30; H 1.41; N, 3.92; S, 8.96. 발견: C, 40.18; H, 1.35; N, 3.84; S, 8.90.3-chloro-1-pentafluorophenylsulfonamidobenzene. To a solution of pentafluorophenylsulfonyl chloride (0.15 mL, 1.00 mmol) in MeOH (4 mL) was added 3-chloroaniline (260 mg, 2.04 mmol). After stirring for 1 hour at room temperature the reaction mixture was concentrated under reduced pressure and the residue was taken up in EtOAc and filtered through a charge of silica gel. The filtrate was concentrated to give a yellow oil which gave 256 mg (74%) of product on chromatograph. 1 H NMR (CDCl 3 ): d 7.28-7.24 (m, 1 H), 7.21-7.17 (m, 2 H), 7.10-7.08 (m, 1 H), 7.07 (s, 1 H). MS (EI): m / z 357 (42, M + ), 258 (76), 126 (87), 99 (100). Calculated analysis of C 12 H 5 ClF 5 NO 2 S: C, 40.30; H 1.41; N, 3.92; S, 8.96. Found: C, 40.18; H, 1. 35; N, 3.84; S, 8.90.
실시예 47Example 47
4-클로로-1-펜타플루오로페닐설폰아미도벤젠. 화합물을 4-클로로아닐린으로 3-클로로아닐린을 치환하므로서 실시예 46에 기술된 방법과 유사 한 방법으로 제조했다. 1H NMR(CDCl3): d 7.30(m, 2H), 7.20(m, 1H), 7.14(m, 2H). MS(EI): m/z 357(27, M+), 258(38), 126(100), 99(85). C12H5ClF5NO2S의 계산된 분석: C, 40.30; H 1.41; N, 3.92; S, 8.96. 발견: C, 40.19; H, 1.37; N, 3.87; S, 8.88.4-chloro-1-pentafluorophenylsulfonamidobenzene. The compound was prepared by a method analogous to that described in Example 46 by substituting 3-chloroaniline with 4-chloroaniline. 1 H NMR (CDCl 3 ): d 7.30 (m, 2 H), 7.20 (m, 1 H), 7.14 (m, 2 H). MS (EI): m / z 357 (27, M + ), 258 (38), 126 (100), 99 (85). Calculated analysis of C 12 H 5 ClF 5 NO 2 S: C, 40.30; H 1.41; N, 3.92; S, 8.96. Found: C, 40.19; H, 1.37; N, 3.87; S, 8.88.
실시예 48Example 48
3-니트로-1-펜타플루오로페닐설폰아미도벤젠. 화합물을 3-니트로아닐린으로 3-클로로아닐린을 치환하므로서 실시예 46에 기술된 방법과 유사한 방법으로 제조했다. 1H NMR(CDCl3): d 8.14(s, 1H), 8.06-8.03(m, 2H), 7.66-7.63(m, 1H), 7.55(m, 1H). MS(EI): m/z 368(54, M+), 137(70), 91(100). C12H5F5N2O4S의 계산된 분석: C, 39.14; H 1.37; N, 7.61; S, 8.71. 발견: C, 39.39; H, 1.45; N, 7.46; S, 8.58.3-nitro-1-pentafluorophenylsulfonamidobenzene. The compound was prepared by a method analogous to that described in Example 46 by substituting 3-chloroaniline with 3-nitroaniline. 1 H NMR (CDCl 3 ): d 8.14 (s, 1H), 8.06-8.03 (m, 2H), 7.66-7.63 (m, 1H), 7.55 (m, 1H). MS (EI): m / z 368 (54, M + ), 137 (70), 91 (100). Calculated analysis of C 12 H 5 F 5 N 2 O 4 S: C, 39.14; H 1.37; N, 7.61; S, 8.71. Found: C, 39.39; H, 1. 45; N, 7.46; S, 8.58.
실시예 49Example 49
4-메톡시-1-펜타플루오로페닐설폰아미도-3-트리플루오로메틸벤젠. 화합물을 해당하는 니트로 화합물의 수소화에 의해 얻어진 4-메톡시-3-트리플루오로메틸아닐린으로 3-클로로아닐린을 치환하므로서 실시예 46에 기술된 방법과 유사한 방법으로 제조했다. 흰색 고체, mp 121-123℃. 1H NMR(CDCl3): d 7.43-7.37(m, 2H), 6.96(d, J=8.8, 1H), 3.88(s, 3H). MS(EI): m/z 421(16, M+), 190(100). C14H7F8NO3S의 계산된 분석: C, 39.92, H, 1.67; N, 3.32; S, 7.61. 발견: C, 40.17; H, 1.68; N, 3.28; S, 7.67.4-methoxy-1-pentafluorophenylsulfonamido-3-trifluoromethylbenzene. The compound was prepared in a similar manner to that described in Example 46 by substituting 3-chloroaniline with 4-methoxy-3-trifluoromethylaniline obtained by hydrogenation of the corresponding nitro compound. White solid, mp 121-123 ° C. 1 H NMR (CDCl 3 ): d 7.43-7.37 (m, 2H), 6.96 (d, J = 8.8, 1H), 3.88 (s, 3H). MS (EI): m / z 421 (16, M + ), 190 (100). Calculated analysis of C 14 H 7 F 8 NO 3 S: C, 39.92, H, 1.67; N, 3. 32; S, 7.61. Found: C, 40.17; H, 1.68; N, 3.28; S, 7.67.
실시예 50Example 50
4-메톡시-1-(N-(2-프로페닐)펜타플루오로페닐설폰아미도)벤젠. THF(3㎖)에 있는 4-메톡시-1-펜타플루오로설폰아미도벤젠(448㎎, 1.27mmol)의 용액에 트리펜닐포스핀(333㎎, 1.27mmol)과 아릴알콜(0.09㎖, 1.27mmol)을 첨가했다. 디에틸아조디카르복실레이트 (0.20㎖, 1.27mmol)을 첨가하고 혼합물을 실온에서 교반했다. 1시간 후, 반응 혼합물을 포화된 NaCl(10㎖)상에 붓고 CH2Cl2(3×10㎖)로 추출했다. 결합된 유기 추출물을 포화된 NaHCO3(10㎖)로 세척하고 건조시켰다(MgSO4). 순간 크로마토그래피(25:25:1/헥산:CH2Cl2:EtOAc)에 의한 농축은 흰색 고체이고 mp 59-60℃로서 451㎎(90％)의 생성물을 제공했다. 1H NMR(CDCl3): d 7.06(m, 2H), 6.85(m, 2H), 5.79(m, 1H), 5.15(s, 1H), 5.11(m, 1H), 4,37(d, J=6.3, 2H), 3.80(s, 3H). MS(EI): m/z 393(33, M+), 162(100), 134(66). C16H11F5NO3S의 계산된 분석: C, 48.98; H 2.83; N, 3.57; S, 8.17. 발견: C, 49.13; H, 3.15: N, 3.63; S, 8.15.4-methoxy-1- (N- (2-propenyl) pentafluorophenylsulfonamido) benzene. Trifenylphosphine (333 mg, 1.27 mmol) and aryl alcohol (0.09 mL, 1.27) in a solution of 4-methoxy-1-pentafluorosulfonamidobenzene (448 mg, 1.27 mmol) in THF (3 mL) mmol) was added. Diethylazodicarboxylate (0.20 mL, 1.27 mmol) was added and the mixture was stirred at room temperature. After 1 h, the reaction mixture was poured onto saturated NaCl (10 mL) and extracted with CH 2 Cl 2 (3 × 10 mL). The combined organic extracts were washed with saturated NaHCO 3 (10 mL) and dried (MgSO 4 ). Concentration by flash chromatography (25: 25: 1 / hexanes: CH 2 Cl 2 : EtOAc) gave a white solid which was 451 mg (90%) as mp 59-60 ° C. 1 H NMR (CDCl 3 ): d 7.06 (m, 2H), 6.85 (m, 2H), 5.79 (m, 1H), 5.15 (s, 1H), 5.11 (m, 1H), 4,37 (d, J = 6.3, 2H), 3.80 (s, 3H). MS (EI): m / z 393 (33, M + ), 162 (100), 134 (66). Calculated analysis of C 16 H 11 F 5 NO 3 S: C, 48.98; H 2.83; N, 3.57; S, 8.17. Found: C, 49.13; H, 3.15: N, 3.63; S, 8.15.
실시예 51Example 51
1-(N-(3-부테닐)펜타플루오로페닐설폰아미도)-4-메톡시벤젠. 화합물을 3-부텐-1-올로 아릴알콜을 치환하므로서 실시예 50에 기술된 방법과 유사한 방법으로 제조했다. 흰색 고체, mp 64-66℃. 1H NMR(CDCl3): d 7.08(m, 2H), 6.86(m, 2H), 5.74(m, 1H), 5.10-5.04(m, 2H), 3.83(m, 2H), 3.81(s, 3H), 2.25(q, J=6.9, 2H). MS(EI): m/z 407(13, M+), 366(24), 135(100). C17H14F5NO3S의 계산된 분석: C, 50.13; H, 3.46; N, 3.44; S, 7.87. 발견: C, 50.25; H, 3.51: N, 3.43; S, 7.81.1- (N- (3-butenyl) pentafluorophenylsulfonamido) -4-methoxybenzene. The compound was prepared by a method analogous to that described in Example 50 by substituting arylalcohol with 3-butene-1-ol. White solid, mp 64-66 ° C. 1 H NMR (CDCl 3 ): d 7.08 (m, 2H), 6.86 (m, 2H), 5.74 (m, 1H), 5.10-5.04 (m, 2H), 3.83 (m, 2H), 3.81 (s, 3H), 2.25 (q, J = 6.9, 2H). MS (EI): m / z 407 (13, M < + & gt ; ), 366 (24), 135 (100). Calculated analysis of C 17 H 14 F 5 NO 3 S: C, 50.13; H, 3. 46; N, 3.44; S, 7.87. Found: C, 50.25; H, 3.51: N, 3.43; S, 7.81.
실시예 52Example 52
4-메톡시-1-(N-(4-펜테닐)펜타플루오로페닐설폰아미도)벤젠. 화합물을 4-펜텐-1-올로 아릴알콜을 치환하므로서 실시예 50에 기술된 방법과 유사한 방법으로 제조했다. 저용융 반고체. 1H NMR(CDCl3): d 7.08(m, 2H), 6.87(m, 2H), 5.74(m, 1H), 5.02-4.96(m, 2H), 3.81(s, 3H), 3.76(t, J=7.04, 2H), 2.11(q, J=6.9, 2H), 1.60(펜테트, J=7.3, 2H). MS(EI): m/z 421(30, M+), 190(100). C18H16F5NO3S의 계산된 분석: C, 51.31; H 3.83; N, 3.32; S, 7.61. 발견: C, 51.44; H, 3.89; N, 3.38; S, 7.54.4-methoxy-1- (N- (4-pentenyl) pentafluorophenylsulfonamido) benzene. The compound was prepared by a method similar to the method described in Example 50 by substituting arylalcohol with 4-penten-l-ol. Low melt semisolid. 1 H NMR (CDCl 3 ): d 7.08 (m, 2H), 6.87 (m, 2H), 5.74 (m, 1H), 5.02-4.96 (m, 2H), 3.81 (s, 3H), 3.76 (t, J = 7.04, 2H), 2.11 (q, J = 6.9, 2H), 1.60 (pentet, J = 7.3, 2H). MS (EI): m / z 421 (30, M + ), 190 (100). Calculated analysis of C 18 H 16 F 5 NO 3 S: C, 51.31; H 3.83; N, 3. 32; S, 7.61. Found: C, 51.44; H, 3.89; N, 3.38; S, 7.54.
실시예 53Example 53
1-(N-(2,3-디하이드록시프로필)펜타플루오로페닐설폰아미도)-4-메톡시벤젠. 실온에서 아세톤:물 (8:1, 1㎖)에 있는 4-메톡시-1-(N-(2-프로페닐)펜타플루오로페닐설폰아미도)벤젠의 용액에 N-메틸포르폴린 N-옥사이드 (34.0㎎, 0.29mmol) OsO4(H2O 에 있는 0.10㎖의 0.16M 용액, 1.60×10-2mmol). 실온에서 18시간동안 교반한 후 반응 혼합물을 포화된 NaHSO3(5㎖)로 처리하고 실온에서 교반했다. 1시간 후, 반응 혼합물을 포화된 NaHSO3(5㎖)상에 붓고 CH2Cl(3×10㎖)로 추출했다. 결합된 유기 추출물을 건조하고 (MgSO4) 농축시켰다. 순간 크로마토그래피(1:1, 1:2/헥산: EtOAc)는 흰색고체, mp 130-131℃로서 90㎎(83％)의 생성물을 제공했다. 1H NMR(CDCl3): d 7.11(m, 2H), 6.85(m, 2H), 3.78(s, 3H), 3.90-3.65(m, 5H). C16H13F5NO5S의 계산된 분석: C, 45.08; H, 3.07; N, 3.29; S, 7.52. 발견: C, 45.09; H, 3.33; N, 3.27; S, 7.46.1- (N- (2,3-dihydroxypropyl) pentafluorophenylsulfonamido) -4-methoxybenzene. N-methylphospholine N- in a solution of 4-methoxy-1- (N- (2-propenyl) pentafluorophenylsulfonamido) benzene in acetone: water (8: 1, 1 mL) at room temperature Oxide (34.0 mg, 0.29 mmol) OsO 4 (0.10 mL 0.16M solution in H 2 O, 1.60 × 10 −2 mmol). After stirring for 18 hours at room temperature the reaction mixture was treated with saturated NaHSO 3 (5 mL) and stirred at room temperature. After 1 h, the reaction mixture was poured onto saturated NaHSO 3 (5 mL) and extracted with CH 2 Cl (3 × 10 mL). The combined organic extracts were dried (MgSO 4 ) and concentrated. Flash chromatography (1: 1, 1: 2 / hexanes: EtOAc) gave 90 mg (83%) of the product as a white solid, mp 130-131 ° C. 1 H NMR (CDCl 3 ): d 7.11 (m, 2H), 6.85 (m, 2H), 3.78 (s, 3H), 3.90-3.65 (m, 5H). Calculated analysis of C 16 H 13 F 5 NO 5 S: C, 45.08; H, 3.07; N, 3.29; S, 7.52. Found: C, 45.09; H, 3.33; N, 3.27; S, 7.46.
실시예 54Example 54
1-(N-(3,4-디하이드록시부틸)펜타플루오로페닐설폰아미도)-4-메톡시벤젠. 화합물을 1-(N-(3-부테닐)펜타플루오로페닐설폰아미도)-4-메톡시벤젠으로 4-메톡시-1-(N-(2-프로페닐)펜타플루오로페닐설폰아미도)벤젠을 치환하므로서 실시예 53에 기술된 방법과 유사한 방법으로 제조했다. 흰색 고체, mp 126-128℃. 1H NMR(CDCl3): d 7.10(m, 2H), 6.88(m, 2H), 4.13(m, 1H), 3.96(m, 1H), 3.81(s, 3H), 3.78-3.73(m, 1H), 3.64(dd, 1, J=2.9, 10.7, 1H), 3.47(dd, J=7.3, 11.2;1H), 2.67(bs, 1H), 1.92(bs, 1H), 1.62(m, 2H).1- (N- (3,4-dihydroxybutyl) pentafluorophenylsulfonamido) -4-methoxybenzene. The compound was substituted with 1- (N- (3-butenyl) pentafluorophenylsulfonamido) -4-methoxybenzene 4-methoxy-1- (N- (2-propenyl) pentafluorophenylsulfonami It was prepared by a method similar to the method described in Example 53 by substituting benzene. White solid, mp 126-128 ° C. 1 H NMR (CDCl 3 ): d 7.10 (m, 2H), 6.88 (m, 2H), 4.13 (m, 1H), 3.96 (m, 1H), 3.81 (s, 3H), 3.78-3.73 (m, 1H), 3.64 (dd, 1, J = 2.9, 10.7, 1H), 3.47 (dd, J = 7.3, 11.2; 1H), 2.67 (bs, 1H), 1.92 (bs, 1H), 1.62 (m, 2H ).
실시예 55Example 55
1-(N-(4,5-디하이드록시페닐)펜타플루오로페닐설폰아미도)-4-메톡시벤젠. 화합물을 4-메톡시-1-(N-(4-펜테닐)펜타플루오로페닐설폰아미도)벤젠으로 4-메톡시-1-(N-(2-프로페닐)펜타플루오로페닐설폰아미도)벤젠을 치환하므로서 실시예 53에 기술된 방법과 유사한 방법으로 제조했다. 흰색 고체, mp 116-118℃. 1H NMR(CDCl3): d 7.07(m, 2H), 6.86(m, 2H), 3.80(s, 3H), 3.78(m, 2H), 3.71-3.62(m, 2H), 3.43(dd, J=7.5, 10.8; 1H), 1.90(bs, 2H), 1.66-1.49(m, 4H). C18H18F5NO5S의 계산된 분석: C, 47.48; H, 3.98; N, 3.08; S, 7.04. 발견: C, 47.58; H, 3.95; N, 3.06; S, 6.95.1- (N- (4,5-dihydroxyphenyl) pentafluorophenylsulfonamido) -4-methoxybenzene. The compound was converted to 4-methoxy-1- (N- (4-pentenyl) pentafluorophenylsulfonamido) benzene 4-methoxy-1- (N- (2-propenyl) pentafluorophenylsulfonami It was prepared by a method similar to the method described in Example 53 by substituting benzene. White solid, mp 116-118 ° C. 1 H NMR (CDCl 3 ): d 7.07 (m, 2H), 6.86 (m, 2H), 3.80 (s, 3H), 3.78 (m, 2H), 3.71-3.62 (m, 2H), 3.43 (dd, J = 7.5, 10.8; 1H), 1.90 (bs, 2H), 1.66-1.49 (m, 4H). Calculated analysis of C 18 H 18 F 5 NO 5 S: C, 47.48; H, 3.98; N, 3.08; S, 7.04. Found: C, 47.58; H, 3.95; N, 3.06; S, 6.95.
실시예 56Example 56
1-(N-(4-하이드록시부틸)펜타플루오로페닐설폰아미도)-4-메톡시벤젠. -78℃에서 THF(6.5㎖)에 있는 1-(N-(3-부테닐)펜타플루오로페닐설폰아미도)-4-메톡시벤젠(410㎎, 1.01mmol)의 용액에 BH3.THF(THF에 있는 1.00㎖의 1M용액, 1.00mmol)를 첨가시켰다. -78℃에서 1시간, 0℃에서 1시간 교반한 후, 반응 혼합물을 H2O(20㎖)와 소듐 퍼보레이트(513㎎, 5.14mmol)로 처리했다. 실온에서 2시간동안 교반 후 혼합물을 H2O(20㎖)상에 붓고 CH2Cl2(3×15㎖)로 추출했다. 결합된 유기 추출물을 포화된 NaCl(20㎖)로 세척하고 건조시켰다(MgSO4). 크로마토그래피(2:1/헥산:EtOAc)에 의한 농축은 흰색 고체, mp 88-90℃로서 270㎎(64％)의 생성물을 제공했다. 1H NMR(CDCl3): d 7.08(m, 2H), 6.85(m, 2H), 3.80(s, 3H), 3.77(m, 2H), 3.64(t, J=6.0; 2H), 1.63-1.55(m, 5H), 1.50(bs, 1H). C17H16F5NO4S의 계산된 분석: C, 48.00; H, 3.79; N, 3.29; S, 7.54. 발견: C, 48.08; H, 3.76; N, 3.34; S, 7.46.1- (N- (4-hydroxybutyl) pentafluorophenylsulfonamido) -4-methoxybenzene. BH 3 .THF in a solution of 1- (N- (3-butenyl) pentafluorophenylsulfonamido) -4-methoxybenzene (410 mg, 1.01 mmol) in THF (6.5 mL) at -78 ° C. (1.00 mL of 1 M solution in THF, 1.00 mmol) was added. After stirring at −78 ° C. for 1 hour and at 0 ° C. for 1 hour, the reaction mixture was treated with H 2 O (20 mL) and sodium perborate (513 mg, 5.14 mmol). After stirring for 2 hours at room temperature the mixture was poured onto H 2 O (20 mL) and extracted with CH 2 Cl 2 (3 × 15 mL). The combined organic extracts were washed with saturated NaCl (20 mL) and dried (MgSO 4 ). Concentration by chromatography (2: 1 / hexanes: EtOAc) gave 270 mg (64%) of the product as a white solid, mp 88-90 ° C. 1 H NMR (CDCl 3 ): d 7.08 (m, 2H), 6.85 (m, 2H), 3.80 (s, 3H), 3.77 (m, 2H), 3.64 (t, J = 6.0; 2H), 1.63- 1.55 (m, 5 H), 1.50 (bs, 1 H). Calculated analysis of C 17 H 16 F 5 NO 4 S: C, 48.00; H, 3.79; N, 3.29; S, 7.54. Found: C, 48.08; H, 3.76; N, 3.34; S, 7.46.
실시예 57Example 57
4-메톡시-1-(N-(5-하이드록시펜틸)펜티플루오로페닐설폰아미도)벤젠. 화합물을 4-메톡시-1-(N-(4-펜테닐)펜타플루오로페닐설폰아미도)벤젠으로 1-(N-(3-부테닐)펜타플루오로페닐설폰아미도)-4-메톡시벤젠을 치환하므로서 실시예 58에 기술된 방법과 유사한 방법으로 제조했다. 흰색 고체, mp 96-97℃. 1H NMR(CDCl3): d 7.08(m, 2H), 6.86(m, 2H), 3.81(s, 3H), 3.76(t, J=6.8, 2H), 3.62(t, J=6.4; 2H), 1.58-1.43(m, 6H). C18H18F5NO4S의 계산된 분석: C, 49.20; H, 4.13; N, 3.19; S, 7.30. 발견: C, 49.11; H, 4.09 ; N, 3.14; S, 7.19.4-methoxy-1- (N- (5-hydroxypentyl) pentifluorophenylsulfonamido) benzene. The compound was converted to 4-methoxy-1- (N- (4-pentenyl) pentafluorophenylsulfonamido) benzene 1- (N- (3-butenyl) pentafluorophenylsulfonamido) -4- Prepared in a similar manner to the method described in Example 58 by substituting methoxybenzene. White solid, mp 96-97 ° C. 1 H NMR (CDCl 3 ): d 7.08 (m, 2H), 6.86 (m, 2H), 3.81 (s, 3H), 3.76 (t, J = 6.8, 2H), 3.62 (t, J = 6.4; 2H ), 1.58-1.43 (m, 6 H). Calculated analysis of C 18 H 18 F 5 NO 4 S: C, 49.20; H, 4.13; N, 3.19; S, 7.30. Found: C, 49.11; H, 4.09; N, 3.14; S, 7.19.
실시예 58Example 58
4-메톡시-3-니트로-1-펜타플루오로페닐설폰아미도벤젠. 화합물을 노리스(Norris)의 방법(Aust. J. Chem. 1971, 24, 1449)에 의해 제조된 4-메톡시-3-니트로아닐린으로 3-클로로아닐린을 치환하므로서 실시예 46과 유사한 방법으로 제조했다. 오렌지빛 노랑색 고체, mp 95-97℃. 1H NMR(CDCl3): d 7.64(d, J=2.7; 1H), 7.51(dd, J=2.7, 9.0; 1H), 7.09(s, 1H), 7.09(d, J=9.0; 1H), 3.95(s, 3H). C13H7F5N2O5S의 계산된 분석: C, 39.21; H, 1.77; N, 7.03; S, 8.05. 발견: C, 39.19; H, 1.73; N, 6.97; S, 7.95.4-methoxy-3-nitro-1-pentafluorophenylsulfonamidobenzene. Compounds were prepared in a similar manner to Example 46 by substituting 3-chloroaniline with 4-methoxy-3-nitroaniline prepared by the method of Norris (Aust. J. Chem. 1971, 24, 1449). did. Orange yellow solid, mp 95-97 ° C. 1 H NMR (CDCl 3 ): d 7.64 (d, J = 2.7; 1H), 7.51 (dd, J = 2.7, 9.0; 1H), 7.09 (s, 1H), 7.09 (d, J = 9.0; 1H) , 3.95 (s, 3 H). Calculated analysis of C 13 H 7 F 5 N 2 O 5 S: C, 39.21; H, 1.77; N, 7.03; S, 8.05. Found: C, 39.19; H, 1.73; N, 6.97; S, 7.95.
실시예 59Example 59
3-아미노-4-메톡시-1-펜타플루오로페닐설폰아미도벤젠. 에탄올(10㎖)에 있는 4-메톡시-3-니트로-1-펜타플루오로페닐설폰아미도벤젠(627㎎, 1.58mmol)의 용액에 10％ Pd/C(51㎎)을 첨가했다. 결과로 생기 혼합물을 1대기압에서 수소가스 분위기하에서 교반했다. 14시간 후, 혼합물을 셀리트 패드를 통과시키고 고체 잔류물을 제공하기 위해 여과액을 농축시켰다. 실리카겔 크로마토그래피(2:1, 1:1/헥산: EtOAc)는 흰색 고체, mp 142-143℃로서 542㎎(93％)의 생성물을 생성했다. 1H NMR(DMSO-d6): 10.64(s, 1), 6.68(d, J=8.4; 1H), 6.44(d, J=2.1; 1H), 6.30(d, J=2.1, 8.4; 1H), 4.88(bs, 2H), 3.69(s, 3H). C13H9F5N2O3S의 계산된 분석: C, 42.40; H, 2.46; N, 7.61; S, 8.71. 발견: C, 42.29; H, 2.36; N, 7.52; S, 8.60.3-amino-4-methoxy-1-pentafluorophenylsulfonamidobenzene. To a solution of 4-methoxy-3-nitro-1-pentafluorophenylsulfonamidobenzene (627 mg, 1.58 mmol) in ethanol (10 mL) was added 10% Pd / C (51 mg). The resulting mixture was stirred at 1 atmosphere under hydrogen gas atmosphere. After 14 hours, the mixture was passed through a pad of celite and the filtrate was concentrated to provide a solid residue. Silicagel chromatography (2: 1, 1: 1 / hexanes: EtOAc) yielded 542 mg (93%) of the product as a white solid, mp 142-143 ° C. 1 H NMR (DMSO-d 6 ): 10.64 (s, 1), 6.68 (d, J = 8.4; 1H), 6.44 (d, J = 2.1; 1H), 6.30 (d, J = 2.1, 8.4; 1H ), 4.88 (bs, 2 H), 3.69 (s, 3 H). Calculated analysis of C 13 H 9 F 5 N 2 O 3 S: C, 42.40; H, 2. 46; N, 7.61; S, 8.71. Found: C, 42.29; H, 2. 36; N, 7.52; S, 8.60.
실시예 60Example 60
4-부톡시-1-펜타플루오로페닐설폰아미도벤젠. 메탄올(4㎖)에 있는 펜타플루오로페닐설포닐 클로라이드(203㎎, 0.763mmol)의 용액에 4-부톡시아닐린(0.26㎖, 1.53mmol)을 첨가했다. 실온에서 1시간동안 교반후, 반응 혼합물을 1M HCl(15㎖)상에 붓고 CH2Cl2(3×10㎖)로 추출했다. 결합된 유기 추출물을 포화된 NaCl(10㎖)로 세척하고 건조시켰다(MgSO4). 순간 크로마토그래피(25:25:1/헥산: CH2Cl2: EtOAc)에 의한 농축은 189㎎(63％)의 생성물을 제공했다. 1H NMR(CDCl3): d 7.07(m, 2H), 6.86(s, 1H), 6.80(m, 2H), 3.89(t, J=6.5; 2H). 1.73(m, 2H), 1.46(m, 2H), 0.95(t, J=7.5; 2H). MS(EI): m/z 395(30, M+), 164(35), 108(100). C16H14F5NO3S의 계산된 분석: C, 48.61; H, 3.57; N, 3.54; S, 8.11. 발견: C, 48.54; H, 3.53; N, 3.50; S, 8.02.4-butoxy-1-pentafluorophenylsulfonamidobenzene. To a solution of pentafluorophenylsulfonyl chloride (203 mg, 0.763 mmol) in methanol (4 mL) was added 4-butoxyaniline (0.26 mL, 1.53 mmol). After stirring for 1 hour at room temperature, the reaction mixture was poured onto 1M HCl (15 mL) and extracted with CH 2 Cl 2 (3 × 10 mL). The combined organic extracts were washed with saturated NaCl (10 mL) and dried (MgSO 4 ). Concentration by flash chromatography (25: 25: 1 / hexanes: CH 2 Cl 2 : EtOAc) gave 189 mg (63%) of product. 1 H NMR (CDCl 3 ): d 7.07 (m, 2H), 6.86 (s, 1H), 6.80 (m, 2H), 3.89 (t, J = 6.5; 2H). 1.73 (m, 2H), 1.46 (m, 2H), 0.95 (t, J = 7.5; 2H). MS (EI): m / z 395 (30, M + ), 164 (35), 108 (100). Calculated analysis of C 16 H 14 F 5 NO 3 S: C, 48.61; H, 3.57; N, 3.54; S, 8.11. Found: C, 48.54; H, 3.53; N, 3.50; S, 8.02.
실시예 61Example 61
1-펜타플루오로페닐설폰아미도-4-페녹시벤젠. 화합물을 4-페녹시아닐린으로 4-부톡시아닐린을 치환하므로서 실시예 60에 기술된 방법과 유사한 방법으로 제조했다. 1H NMR(CDCl3): 7.36-7.30(m, 2H), 7.15-7.10(m, 3H), 6.99(s, 1H), 6.98-6.90(m, 4H). MS(EI): m/z 415(32, M+), 184(100), 77(66). C18H10F5NO3S의 계산된 분석: C, 52.05; H, 2.43; N, 3.27; S, 7.72. 발견: C, 51.78; H, 2.45; N, 3.25; S, 7.53.1-pentafluorophenylsulfonamido-4-phenoxybenzene. The compound was prepared by a method analogous to that described in Example 60, replacing 4-butoxyaniline with 4-phenoxyaniline. 1 H NMR (CDCl 3 ): 7.36-7.30 (m, 2H), 7.15-7.10 (m, 3H), 6.99 (s, 1H), 6.98-6.90 (m, 4H). MS (EI): m / z 415 (32, M + ), 184 (100), 77 (66). Calculated analysis of C 18 H 10 F 5 NO 3 S: C, 52.05; H, 2. 43; N, 3.27; S, 7.72. Found: C, 51.78; H, 2. 45; N, 3.25; S, 7.53.
실시예 62Example 62
4-벤질옥시-1-펜타플루오로페닐설폰아미도벤젠. 화합물을 4-벤질옥시아닐린으로 4-부톡시아닐린을 치환하므로서 실시예 60에 기술된 방법과 유사한 방법으로 제조했다. 4-벤질옥시아닐린을 수성 NaOH와의 처리에 의해 상업적으로 입수가능한 염화수소염으로부터 얻었다. 1H NMR(CDCl3): 7.38-7.37(m, 4H), 7.36-7.32(m, 1H), 7.10-7.08(m, 2H), 7.91-7.88(m, 2H), 6.78(s, 1H), 5.01(s, 1H). MS(EI): m/z 429(19, M+), 91(100). C19H12F5NO3S의 계산된 분석: C, 53.14; H, 2.82; N, 3.26; S, 7.45. 발견: C, 53.07; H, 2.78; N, 3.21; S, 7.35.4-benzyloxy-1-pentafluorophenylsulfonamidobenzene. The compound was prepared by a method analogous to that described in Example 60, replacing 4-butoxyaniline with 4-benzyloxyaniline. 4-benzyloxyaniline was obtained from a commercially available hydrogen chloride salt by treatment with aqueous NaOH. 1 H NMR (CDCl 3 ): 7.38-7.37 (m, 4H), 7.36-7.32 (m, 1H), 7.10-7.08 (m, 2H), 7.91-7.88 (m, 2H), 6.78 (s, 1H) , 5.01 (s, 1 H). MS (EI): m / z 429 (19, M + ), 91 (100). Calculated analysis of C 19 H 12 F 5 NO 3 S: C, 53.14; H, 2. 82; N, 3.26; S, 7.45. Found: C, 53.07; H, 2.78; N, 3.21; S, 7.35.
실시예 63Example 63
4-메틸메르캅토-1-펜타플루오로페닐설폰아미도벤젠. 화합물을 4-(메틸메르캅토)아닐린으로 4-부톡시아닐린을 치환하므로서 실시예 60에 기술된 방법과 유사한 방법으로 제조했다. 1H NMR(CDCl3): 7.17(m, 2H), 7.09(m, 2H), 6.89(m, 1H), 2.44(s, 3H). MS(EI): m/z 369(24, M+), 138(100), 77(66). C13H8F5NO2S2의 계산된 분석: C, 42.28; H, 2.18; N, 3.79; S, 17.36. 발견: C, 42.20; H, 2.21; N, 3.72; S, 17.28.4-methylmercapto-1-pentafluorophenylsulfonamidobenzene. The compound was prepared by a method analogous to that described in Example 60 by replacing 4-butoxyaniline with 4- (methylmercapto) aniline. 1 H NMR (CDCl 3 ): 7.17 (m, 2H), 7.09 (m, 2H), 6.89 (m, 1H), 2.44 (s, 3H). MS (EI): m / z 369 (24, M + ), 138 (100), 77 (66). Calculated analysis of C 13 H 8 F 5 NO 2 S 2 : C, 42.28; H, 2.18; N, 3.79; S, 17.36. Found: C, 42.20; H, 2. 21; N, 3.72; S, 17.28.
실시예 64Example 64
2-메톡시-1-펜타플루오로페닐설폰아미도벤젠. 화합물을 o-아니시딘으로 4-부톡시아닐린을 치환하므로서 실시예 60에 기술된 방법과 유사한 방법으로 제조했다. 1H NMR(CDCl3): d 7.54(dd, J=1.5, 8.0; 1H), 7.13(dt, J=1.5, 8.0; 1H), 6.94(dt, J=1.2, 8.0; 1H), 6.84(dd, J=1.2, 8.0; 1H), 3.79(s, 3H). MS(EI): m/z 353(82, M+), 122(100), 94(95). C13H8F5NO3S의 계산된 분석: C, 44.19; H, 2.28; N, 3.97; S, 9.06. 발견: C, 44.10; H, 2.26; N, 3.92; S, 9.03.2-methoxy-1-pentafluorophenylsulfonamidobenzene. The compound was prepared by a method analogous to that described in Example 60, replacing 4-butoxyaniline with o-anisidine. 1 H NMR (CDCl 3 ): d 7.54 (dd, J = 1.5, 8.0; 1H), 7.13 (dt, J = 1.5, 8.0; 1H), 6.94 (dt, J = 1.2, 8.0; 1H), 6.84 ( dd, J = 1.2, 8.0; 1H), 3.79 (s, 3H). MS (EI): m / z 353 (82, M + ), 122 (100), 94 (95). Calculated analysis of C 13 H 8 F 5 NO 3 S: C, 44.19; H, 2. 28; N, 3.97; S, 9.06. Found: C, 44.10; H, 2. 26; N, 3.92; S, 9.03.
실시예 65Example 65
4-알릴옥시-1-펜타플루오로페닐설폰아미도벤젠. 화합물을 4-알릴옥시아닐린으로 4-부톡시아닐린을 치환하므로서 실시예 60에 기술된 방법과 유사한 방법으로 제조했다. 4-알릴옥시아닐린을 부테라의 방법(J. Med. Chem. 1991, 34, 3212)에 의해 제조했다. 1H NMR(CDCl3): 7.08(m, 2H), 6.87(m, 1H), 6.82(m, 2H), 6.04-5.94(m, 1H), 5.39-5.34(m, 1H), 5.29-5.25(m, 1H) 4.48-4.46(m, 2H). MS(EI): m/z 379(11, M+), 148(32), 41(100). C15H10F5NO3S의 계산된 분석: C, 47.50; H, 2.66; N, 3.96; S, 8.45. 발견: C, 47.53; H, 2.68; N, 3.62; S, 8.37.4-allyloxy-1-pentafluorophenylsulfonamidobenzene. The compound was prepared by a method analogous to that described in Example 60 by replacing 4-butoxyaniline with 4-allyloxyaniline. 4-allyloxyaniline was prepared by Butera's method (J. Med. Chem. 1991, 34, 3212). 1 H NMR (CDCl 3 ): 7.08 (m, 2H), 6.87 (m, 1H), 6.82 (m, 2H), 6.04-5.94 (m, 1H), 5.39-5.34 (m, 1H), 5.29-5.25 (m, 1 H) 4.48-4.46 (m, 2 H). MS (EI): m / z 379 (11, M + ), 148 (32), 41 (100). Calculated analysis of C 15 H 10 F 5 NO 3 S: C, 47.50; H, 2. 66; N, 3.96; S, 8.45. Found: C, 47.53; H, 2.68; N, 3.62; S, 8.37.
실시예 66Example 66
1-펜타플루오로페닐설폰아미도-4-프로폭시벤젠. 화합물을 4-프로폭시아닐린으로 4-부톡시아닐린을 치환하므로서 실시예 60에 기술된 방법과 유사한 방법으로 제조했다. 4-프로폭시아닐린을 4-아릴옥시니트로벤젠의 촉매 수소화에 의해 얻었다. 4-아릴옥시니트로벤젠을 부테라의 방법 (J. Med. Chem. 1991, 34, 3212)에 의해 제조했다. 1H NMR(CDCl3): 7.09(m, 2H), 6.82(m, 2H), 6.78(m, 1H), 3.87(t, J=6.5; 2H), 1.78(m, 2H), 1.02(t, J=7.4;3H). MS(EI): m/z 381(20, M+), 150(40), 108(100). C15H12F5NO3S의 계산된 분석: C, 47.25; H, 3.17; N, 3.67; S, 8.41. 발견: C, 47.01; H, 3.20; N, 3.61; S, 8.31.1-pentafluorophenylsulfonamido-4-propoxybenzene. The compound was prepared by a method analogous to that described in Example 60, replacing 4-butoxyaniline with 4-propoxyaniline. 4-propoxyaniline was obtained by catalytic hydrogenation of 4-aryloxynitrobenzene. 4-aryloxynitrobenzene was prepared by Butera's method (J. Med. Chem. 1991, 34, 3212). 1 H NMR (CDCl 3 ): 7.09 (m, 2H), 6.82 (m, 2H), 6.78 (m, 1H), 3.87 (t, J = 6.5; 2H), 1.78 (m, 2H), 1.02 (t , J = 7.4; 3H). MS (EI): m / z 381 (20, M + ), 150 (40), 108 (100). Calculated analysis of C 15 H 12 F 5 NO 3 S: C, 47.25; H, 3.17; N, 3.67; S, 8.41. Found: C, 47.01; H, 3. 20; N, 3.61; S, 8.31.
실시예 67Example 67
4-(1-메틸)에톡시-1-펜타플루오로페닐설폰아미도벤젠. 화합물을 4-이소프로폭시아닐린으로 4-부톡시아닐린을 치환하므로서 실시예 60에 기술된 방법과 유사한 방법으로 제조했다. 4-이소프로폭시아닐린을 데이의 방법(J. Med. Chem. 1975, 18, 1065)과 유사하게 4-플루오로니트로벤젠으로부터 제조했다. 1H NMR(CDCl3): 7.08(m, 2H), 7.00(s, 1H), 6.81(m, 2H), 4.48(헵테트(heptet), J=6.1; 1H), 1.30(d, J=6.04; 6H). MS(EI): m/z 381(7, M+), 339(8), 108(100). C15H12F5NO3S의 계산된 분석: C, 47.25; H, 3.17; N, 3.67; S, 8.41. 발견: C, 47.08; H, 3.18; N, 3.60; S, 8.34.4- (1-methyl) ethoxy-1-pentafluorophenylsulfonamidobenzene. The compound was prepared by a method similar to the method described in Example 60, by replacing 4-butoxyaniline with 4-isopropoxyaniline. 4-isopropoxyaniline was prepared from 4-fluoronitrobenzene similar to Day's method (J. Med. Chem. 1975, 18, 1065). 1 H NMR (CDCl 3 ): 7.08 (m, 2H), 7.00 (s, 1H), 6.81 (m, 2H), 4.48 (heptet, J = 6.1; 1H), 1.30 (d, J = 6.04; 6H). MS (EI): m / z 381 (7, M < + & gt ; ), 339 (8), 108 (100). Calculated analysis of C 15 H 12 F 5 NO 3 S: C, 47.25; H, 3.17; N, 3.67; S, 8.41. Found: C, 47.08; H, 3.18; N, 3.60; S, 8.34.
실시예 68Example 68
1-펜타플루오로페닐설포닐옥시벤젠. 25℃에서 디메틸포름아미드(3.65㎖)에 있는 페놀(0.068g, 0.729mmol)의 교반된 용액에 펜타플루오로페닐 설포닐클로라이드(0.135㎖, 0.911mmol)와 소듐 카보네이트(0.116g, 1.09mmol)을 첨가하고 반응 혼합물을 18시간동안 교반했다. 반응 혼합물을 에틸 아세테이트(50㎖)로 희석시키고 20％ 암모늄 클로라이트(2×20㎖)와 포화된 염화나트륨(2×20㎖)으로 세척했다. 유기층을 건조시키고(소듐 설파이드) 에틸 아세테이트를 진공하에서 제거시켰다. 칼럼 크로마토그래피(3/1 에틸 아세테이트/헥산)는 표제 화합물을 생성한다. 1-pentafluorophenylsulfonyloxybenzene. To a stirred solution of phenol (0.068 g, 0.729 mmol) in dimethylformamide (3.65 mL) at 25 ° C. was added pentafluorophenyl sulfonylchloride (0.135 mL, 0.911 mmol) and sodium carbonate (0.116 g, 1.09 mmol). Was added and the reaction mixture was stirred for 18 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with 20% ammonium chlorite (2 × 20 mL) and saturated sodium chloride (2 × 20 mL). The organic layer was dried (sodium sulfide) and ethyl acetate was removed in vacuo. Column chromatography (3/1 ethyl acetate / hexanes) yields the title compound.
실시예 69Example 69
1-펜타플루오로페닐설포닐인돌. 25℃에서 디메틸포름아미드(3.65㎖)에 있는 인돌 (0.085g, 0.729mmol)의 교반된 용액에 펜타플루오로페닐 설포닐 클로라이드 (0.135㎖, 0.911mmol)와 소듐 카보네이트(0.116g, 1.09mmol)을 첨가하고 반응 혼합물을 18시간동안 교반했다. 반응 혼합물을 에틸 아세테이트(50㎖)로 희석시키고 20％ 암모늄 클로라이드(2×20㎖)와 포화된 염화나트륨(2×20㎖)으로 세척했다. 유기층을 건조시키고(소듐 설파이트), 에틸 아세테이트를 진공하에서 제거했다. 칼럼 크로마토그래피(3/1 에틸 아세테이트/헥산)는 표제 화합물을 생성한다.1-pentafluorophenylsulfonylindole. To a stirred solution of indole (0.085 g, 0.729 mmol) in dimethylformamide (3.65 mL) at 25 ° C. was added pentafluorophenyl sulfonyl chloride (0.135 mL, 0.911 mmol) and sodium carbonate (0.116 g, 1.09 mmol). Was added and the reaction mixture was stirred for 18 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with 20% ammonium chloride (2 x 20 mL) and saturated sodium chloride (2 x 20 mL). The organic layer was dried (sodium sulfite) and ethyl acetate was removed in vacuo. Column chromatography (3/1 ethyl acetate / hexanes) yields the title compound.
실시예 70Example 70
2-플루오로-1-메톡시-4-펜타플루오로페닐설핀아미도벤젠. 0℃에서 아르곤하에서 피리딘(1.84g, 23.3mmol)을 갖는 THF(50㎖)에 분산된 3-플루오로-p-아니시딘(3g,21.2mmol)에 펜타플루오로페닐설피닐 클로라이드(5.3g, 21.2mmol)을 적하첨가했다. 반응 혼합물을 0℃에서 30분간 교반하고 상온으로 따뜻하게 했다. 반응 혼합물을 실온에서 교반하고 TLC를 행했다. 반응이 완료된 후 반응 혼합물을 에틸 아세테이트로 희석하고 반응을 물로 완료시켰다. 층을 분리하고 수성 층을 에틸 아세테이트로 2번 추출했다. 유기층을 조합하고 소금물과 Na2SO4로 건조시켰다. 용매를 증발시키고 표제 생성물을 제공하기 위해 잔류물을 실리카상에서 크로마토그래피에 의해 정제했다.2-fluoro-1-methoxy-4-pentafluorophenylsulfinamidobenzene. Pentafluorophenylsulfinyl chloride (5.3 g, 21.2 mmol) was added dropwise. The reaction mixture was stirred at 0 ° C. for 30 minutes and warmed to room temperature. The reaction mixture was stirred at room temperature and TLC was performed. After the reaction was completed the reaction mixture was diluted with ethyl acetate and the reaction completed with water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined and dried over brine and Na 2 SO 4 . The residue was purified by chromatography on silica to evaporate the solvent and provide the title product.
실시예 71Example 71
2-아닐리노-3-펜타플루오로페닐설폰아미도피리딘. 실온에서 피리딘(9㎖)에 있는 펜타플루오로페닐설포닐 클로라이드(863㎎, 3.24mmol)의 용액에 3-아미노-2-아닐리노피리딘(600㎎, 3.24mmol)을 첨가했다. 실온에서 밤새 교반 후 반응 혼합물을 감압하에서 농축하고 잔류물을 1M HCl(50㎖)와 CH2Cl2(50㎖) 사이에 분할했다. 오렌지색 고체로서 377㎎(28％)의 생성물을 제공하기 위해 MPLC에 의해 정제된 오일을 제공하기 위해 유기 추출물을 건조하고 농축시켰다. 1H NMR(CDCl3): 8.50(bs, 1H), 7.80(d, J=5.1, 1H), 7.61(d, J=8.0, 1H), 7.32(t, J=8.0, 2H), 7.25(d, J=8.0, 2H), 7.11(t, J=7.3, 1H), 6.80(dd, J=5.6, 7.7, 1H), 4.20(bs, 1H). MS(FAB): m/z 438(M+Na), 416(M+H).2-anilino-3-pentafluorophenylsulfonamidopyridine. To a solution of pentafluorophenylsulfonyl chloride (863 mg, 3.24 mmol) in pyridine (9 mL) at room temperature was added 3-amino-2-anilinopyridine (600 mg, 3.24 mmol). After stirring at room temperature overnight the reaction mixture was concentrated under reduced pressure and the residue partitioned between 1M HCl (50 mL) and CH 2 Cl 2 (50 mL). The organic extract was dried and concentrated to give an oil purified by MPLC to give 377 mg (28%) of the product as an orange solid. 1 H NMR (CDCl 3 ): 8.50 (bs, 1H), 7.80 (d, J = 5.1, 1H), 7.61 (d, J = 8.0, 1H), 7.32 (t, J = 8.0, 2H), 7.25 ( d, J = 8.0, 2H), 7.11 (t, J = 7.3, 1H), 6.80 (dd, J = 5.6, 7.7, 1H), 4.20 (bs, 1H). MS (FAB): m / z 438 (M + Na), 416 (M + H).
실시예 72Example 72
4-[3H]-1=플루오로-2-메톡시-5-펜타플루오로설폰아미도벤젠. 에틸 아세테이트(2㎖)에 있는 1-브로모-4-플루오로-5-메톡시-2-펜타플루오로페닐설폰아미도벤젠(27.8㎎, 0.058mmol; 실시예 41에서 제조됨) 용액을 숯위에서 100㎎의 10％ 팔라듐으로 처리했다. 반응 용기에서 공기를 없애고 트리튬 가스로 대체했다. 실온에서 2시간 교반 후 촉매를 여과하고 용매를 증발시키고 조생성물을 용출액으로서 디클로로메탄을 사용하여 예비 박막 크로마토그래피(TLC)에 의해 정제했다. 샘플 순도는 Microsorb 실리카(250×4.6㎜)5㎜ 칼럼과 이동상으로서 15％ 에틸 아세테이트/헥산을 사용하여 HPLC에 의해 특징되었다. 물질 용출을 254㎚에서 UV 검출기와 Beta Ram 검출기를 사용하여 검출했다. 이 물질의 화학적 순도는 100％로 측정되었고 방사화학 순도는 99.3％였다. 이 물질의 특이적 활성도는 Ci/mmol이었다.4- [ 3 H] -1 = fluoro-2-methoxy-5-pentafluorosulfonamidobenzene. A solution of 1-bromo-4-fluoro-5-methoxy-2-pentafluorophenylsulfonamidobenzene (27.8 mg, 0.058 mmol; prepared in Example 41) in ethyl acetate (2 mL) was charcoal. Treatment with 100 mg of 10% palladium in the stomach. Air was removed from the reaction vessel and replaced with tritium gas. After stirring for 2 hours at room temperature the catalyst was filtered off, the solvent was evaporated and the crude product was purified by preparative thin layer chromatography (TLC) using dichloromethane as eluent. Sample purity was characterized by HPLC using a Microsorb silica (250 × 4.6 mm) 5 mm column and 15% ethyl acetate / hexanes as mobile phase. Material elution was detected at 254 nm using a UV detector and a Beta Ram detector. The chemical purity of this material was determined to be 100% and the radiochemical purity was 99.3%. The specific activity of this material was Ci / mmol.
실시예 73Example 73
시험관내에서 HeLa 세포, 잠재적인 치료제의 세포독성을 평가하기 위해 일반적으로 사용되는 사람 경부암종으로부터 유도된 영구 세포주의 성장을 억제하는 능력에 대해 화합물을 평가했다. 하기 데이터는 본 발명의 선택된 실시예의 세포독성을 반영한다. 주어진 값들은 HeLa 세포 배양에 의한 Alamar Blue(캘리포니아, 카멜리오, Biosource International)의 50％ 흡수에 의해 억제되도록 요구된 시험 화합물의 농도를 나타내고 이는 직접적으로 배양균에서 세포 대사의 전체 수준과 서로 관련되고 일반적으로 세포 성장의 적당한 마커로서 수용된다. 시험을 S. A. Ahmed et al. (1994) J. Immunol. Methods 170:211-224의 방법에 따라 수행했다. 하기 선택된 실시예는 0.05μM이하에서 10μM범위의 I(50값을 갖는 본 평가에서 유력한 세포독성 활성도를 나타낸다.Compounds were evaluated for their ability to inhibit the growth of permanent cell lines derived from human cervical carcinomas commonly used to assess the cytotoxicity of HeLa cells, potential therapeutics in vitro. The data below reflects the cytotoxicity of selected embodiments of the invention. The values given indicate the concentration of test compound required to be inhibited by 50% uptake of Alamar Blue (California, Camellio, Biosource International) by HeLa cell culture and correlated directly with the total level of cell metabolism in the culture. It is generally accepted as a suitable marker of cell growth. Tests were performed by S. A. Ahmed et al. (1994) J. Immunol. It was carried out according to the method of Methods 170: 211-224. The examples selected below show potent cytotoxic activity in this assessment with I (50 values in the range of 10 μM below 0.05 μM.
본 명세서에 인용된 모든 공보 및 특허 출원은 각각의 공보 또는 특허 출원이 참고로 도입되도록 명확하고 개별적으로 표시된 바와같이 참고로 여기에 도입된다. 본 발명은 이해를 명확하게 하기 위해 설명과 실시예에 의해 상세하게 기술되었지만 본 발명을 고려할 때 어떤 변화와 변경이 첨부된 청구범위의 정신 또는 범위에서 벗어나지 않고 이루어질 수 있음이 본 기술분야에 통상의 지식을 가진 자들에게 명백할 것이다.All publications and patent applications cited herein are hereby incorporated by reference as if expressly and individually indicated that each publication or patent application is incorporated by reference. Although the present invention has been described in detail by the description and examples for clarity of understanding, it is common in the art that certain changes and modifications may be made therein without departing from the spirit or scope of the appended claims when considering the invention. It will be apparent to those who have knowledge.
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