KR20020015306A - 충동 자제 이상 치료를 위한 설파메이트 유도체의 용도 - Google Patents
충동 자제 이상 치료를 위한 설파메이트 유도체의 용도 Download PDFInfo
- Publication number
- KR20020015306A KR20020015306A KR1020017010767A KR20017010767A KR20020015306A KR 20020015306 A KR20020015306 A KR 20020015306A KR 1020017010767 A KR1020017010767 A KR 1020017010767A KR 20017010767 A KR20017010767 A KR 20017010767A KR 20020015306 A KR20020015306 A KR 20020015306A
- Authority
- KR
- South Korea
- Prior art keywords
- hydrochloride
- beta
- methylethylidene
- sulfonyl
- compound
- Prior art date
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Landscapes
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Abstract
충동 자제 이상(ICD)은 억제할 수 없는 충동에 반응하여 실행되는 유해 행동을 특징으로 한다. ICD의 근본적인 특징은 충동, 욕구, 또는 유혹을 뿌리치지 못하고 개인이나 타인에 유해한 행동을 실행하는 것이다. 본 발명은 X가 CH2또는 산소이고, R1, R2, R3, R4및 R5가 본원에서 정의한 바와 같은 화학식 1의 설파메이트류를 사용하는 ICD의 치료 또는 예방법을 포함한다. 또한, 화학식 1의 화합물을 함유하는 약학 조성물 및 이의 용법과 본 발명의 일부를 이루는 중간체가 또한 개시된다.
화학식 1
Description
간질, 녹내장, 소화성 궤양 및 남성 불임 분야에서 유용한 약학적 활성을 지닌 설파메이트 유도체가 US 특허 No. 4,075,351, 4,513,006, 4,591,601, 4,792,569, 및 5,760,007에 개시되어 있다. 이들 화합물 중 하나로 토피라메이트로서 알려진 2,3:4,5-비스-O-(1-메틸에틸리덴)-베타-D-프럭토피라노스 설파메이트가 인간 간질의 임상 시험에서 단순 및 복합 부분 발작과 2차 일반 발작에서 보조 치료제로서 또는 단일 치료제로서 효과적인 것으로 증명되었으며 2차 일반 발작을 동반하거나 동반하지 않는 단순 및 복합 부분 발작 간질의 치료용으로 현재 시판되고 있다.
탐식 이상(binge eating disorder, BED)은 탐식의 불연속 기간을 특징으로하고 이 기간 동안에는 다량의 음식이 소정의 불연속 기간에 소비되고 식욕에 대한 자제감이 부재한다. 신경성 식욕 항진증(bulimia nervosa)이 있는 개인은 뇌파 그래프에 이상이 있고 항-간질제 페니토인에 반응하여 감소된 탐식을 보이는 것으로 보고되었다. 또한, 간질 환자에서의 통제된 시험에서, 토피라메이트는 탐식과는 관련이 없는 식욕 억제 및 체중 감소와 연관이 있었다.
탐식 이상은 억제할 수 없는 충동에 반응하여 실행된 유해 행동을 특징으로 하는 충동 자제 이상(ICD)으로서 광범위하게 정의되는 정신 이상의 대 분류의 부분집합이다. ICD가 강박성 이상과 관련이 있거나 일종의 강박성 이상일 수 있음이 제안되었다. 또한, ICD가 기분 이상과 관련이 있거나 주된 우울증과 적어도 하나의 공통적인 생리학적 이상을 공유하는 이상의 가정된 계통의 이상인 일종의 정서 범위 이상일 수 있음이 가설로 제시되었다. 정신 이상의 진단 및 통계학적 매뉴얼(DSM-IV)에서, ICD의 근본적인 특징은 개인 또는 타인에 유해한 행동을 실행하려는 충동, 욕구, 또는 유혹을 뿌리치지 못한다는 점이다. 대부분의 ICD의 경우, 개인은 행동에 옮기기 전에 긴장감이나 각성감의 증가를 느끼며, 이어서 행동을 범할 때 희열, 만족감, 또는 해방감을 경험한다. 행동에 옮긴 후에는, 후회나 죄책감이 들 수도 있고 들지 않을 수도 있다. ICD는 간헐적인 폭발성 이상(IED), 도벽, 병적인 도박, 방화벽, 발모광, 및 달리 규정되지 않은(NOD) ICD를 포함하는, 어느 곳에도 분류되지 않는 ICD인 나머지 범주에 수록되어 있다. ICD NOS의 예로는 강박성 구매 또는 쇼핑, 반복성 자기-절단, 비-성도착성 섹스 중독, 중증의 손톱 물어 뜯기, 강박성 피부 찌르기, 충동성이 특징인 인격 장애, 주의력 결핍/활동 항진 이상, 탐식을 특징으로 하는 식욕 이상, 및 물질 사용 이상이 있다.
발명의 요약
본 발명의 목적은 충동 자제 이상 치료를 위한 설파메이트 유도체의 용도를 설명하는 것이다.
본 발명은 화학식 1의 화합물, 화학식 1의 화합물 하나 이상을 함유하는 약학 조성물, 또는 관련 증후 및 증상의 치료를 위한 안전 ·유효량의 하나 이상의 추가의 약제 외에 화학식 1의 화합물 하나 이상을 함유하는 약학 조성물을 사용하는 충동 자제 이상의 치료 또는 예방 방법을 포함한다.
본 출원은 1999년 2월 24일자로 출원된 McElroy의 US 임시 출원 No. 60/121,339에 기초한다.
본 발명은 일반적으로 정신 이상 치료용 약제의 용도에 관한 것이다. 좀더 구체적으로 말해서, 본 발명은 설파메이트 유도체를 투여함에 의한 충동 자제 이상(ICD)의 치료 및 예방 방법을 기술한다.
본 발명에서 사용되는 설파메이트는 화학식 1로 표시된다.
상기식에서,
X는 CH2또는 산소이고;
R1은 수소 또는 알킬이며;
R2, R3, R4및 R5는 독립적으로 수소 또는 저급 알킬이며, X가 CH2일 때, R4와 R5는 벤젠 환을 형성하기 위하여 결합된 알켄 그룹일 수 있으며, X가 산소일 때, R2와 R3및/또는 R4와 R5는 함께 화학식 2의 메틸렌디옥시 그룹일 수 있으며;
R6및 R7은 동일하거나 상이하고 수소, 저급 알킬이거나 알킬이며 결합하여 사이클로펜틸 또는 사이클로헥실 환을 형성한다.
R1은 특히 수소 또는 탄소수 약 1 내지 4의 알킬, 예를 들면 메틸, 에틸 및 이소-프로필이다. 본 명세서 전반에 걸쳐서 알킬은 직쇄 및 측쇄 알킬을 포함한다. R2, R3, R4, R5, R6및 R7에 대한 알킬 그룹은 탄소수가 약 1 내지 3개이며 메틸, 에틸, 이소-프로필 및 n-프로필을 포함한다. X가 CH2일 때, R4와 R5는 결합하여 6원 X-함유 환에 융합된 벤젠 환을 형성할 수 있고, 즉 R4와 R5는 알카트리에닐 그룹 =C-CH=CH-CH=로 정의된다.
화학식 1 화합물의 특정 그룹은 X가 산소이고 R2와 R3및 R4와 R5모두가 함께 화학식 2의 메틸렌디옥시 그룹이며, R6및 R7은 모두 산소, 모두 알킬이거나 결합하여 스피로 사이클로펜틸 또는 사이클로헥실 환을 형성하며, 특히 R6와 R7은 모두 메틸과 같은 알킬인 화합물이다. 화합물의 제 2 그룹은 X가 CH2이고 R4와 R5가 결합하여 벤젠 환을 형성하는 화합물이다. 화학식 1 화합물의 제 3 그룹은 R2와 R3모두가 수소인 화합물이다.
화학식 1의 화합물은 본원에서 전부 참조로 인용되는, US 특허 No. 4,075,351, 4,513,006, 4,591,601, 4,792,569, 5,242,942, 5,387,700에 개시된 공정에 의해 제조될 수 있다.
화학식 1의 화합물은 다양한 개개의 이성체 및 이의 라세미체를 포함한다. ICD 치료를 위해, 화학식 1의 화합물은 평균 성인의 경우, 경구 투여시 약 15 내지 1400 mg 범위의 1일 용량으로 사용된다.
본 발명의 약학 조성물 제조를 위해, 화학식 1의 하나 이상의 설파메이트 화합물이 통상적인 제약학적 배합 기술에 따라 약학적 담체와 균질 혼합되며, 이러한 담체는 투여, 예를 들면 경구 투여, 좌제, 또는 비경구 투여에 소망되는 제형에 따라 광범위한 형태를 취할 수 있다. 경구 투약형 조성물의 제조시, 통상적인 약학 매질이 사용될 수 있다. 따라서, 예를 들면, 현탁액, 엘릭서 및 용액과 같은 액체 경구용제의 경우, 적당한 담체 및 첨가제는 물, 글리콜, 오일, 알콜, 향미제, 보존제, 착색제 등을 포함하고; 예를 들면, 분말, 캡슐 및 정제와 같은 고형 경구용제의 경우, 적당한 담체 및 첨가제는 전분, 당, 희석제, 입상화제, 윤활제, 결합제, 붕해제 등을 포함한다. 투여의 용이성 때문에, 정제와 캡슐이 가장 유리한 경구 투약 단위형을 대표하며, 이 경우에는 고형 약학 담체가 명백히 사용된다. 필요에 따라, 정제는 표준 기술로 당의를 입히거나 장용피를 입힐 수 있다. 좌제가 제조될 수도 있으며, 이 경우에는 코코아 버터가 담체로 사용될 수 있다. 비경구용제의 경우, 담체는 통상적으로 멸균수를 포함하겠지만, 예를 들면, 용해를 돕기 위한 목적으로 또는 보존을 위해 타 성분이 포함될 수도 있다. 주사용 현탁액도 제조될 수 있으며, 이 경우에는 적당한 액체 담체, 현탁제 등이 사용될 수 있다. 토피라메이트는 현재 활성 성분 25 mg, 100 mg 또는 200 mg을 함유하는 둥근 정제 형태로 경구 투여용으로 이용가능하다. 정제는 하기 불활성 성분을 함유한다: 함수 락토스, 예비 겔화 전분, 미세결정상 셀룰로스, 나트륨 전분 글리콜레이트, 마그네슘 스테아레이트, 정제수, 카노바 왁스, 하이드록시프로필 메틸셀룰로스, 티타늄 디옥사이드, 폴리에틸렌 글리콜, 합성 철 옥사이드, 및 폴리소르베이트 80.
본원에서의 약학 조성물은 투약 단위, 예를 들면 정제, 캡슐, 분말 주사, 티스푼, 좌제 등 당, 활성 성분 약 5 내지 약 1000 mg을 함유할 것이다.
ICD 치료에서 화학식 1 화합물의 활성은 기분 이상 치료에서 토피라메이트 효능 평가를 수행한 임상 연구에서 처음으로 입증되었다. 동시적으로 탐식 이상이 있는 여러 명의 환자에서 탐식의 현저한 감소와 동시에 체중 감소가 보고되었다.
화학식 1 화합물의 구체적인 예는 다음과 같다:
2,3:4,5-비스-O-(1-메틸에틸리덴)-베타-D-프럭토피라노스 설파메이트;
2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 설파메이트;
2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-L-프럭토피라노스 설파메이트;
2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 메틸설파메이트;
2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 부틸설파메이트;
2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 에틸설파메이트;
2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 옥틸설파메이트;
2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 2-프로페닐설파메이트;
2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 페닐메틸설파메이트;
2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 사이클로프로필설파메이트;
2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 사이클로부틸설파메이트;
2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 (2,2,2-트리플루오로에틸)설파메이트;
2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 디메틸설파메이트;
2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 디에틸설파메이트;
2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 아지도설페이트;
(S)-2,3-O-(1-메틸에틸리덴)-4,5-O-설피닐-베타-D-프럭토피라노스 설파메이트;
(R)-2,3-O-(1-메틸에틸리덴)-4,5-O-설피닐-베타-D-프럭토피라노스 설파메이트;
2,3-O-(1-에틸프로필리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 설파메이트;
2,3-O-(1-메틸에틸리덴)-4,5-O-[N-(4-메틸벤젠설포닐)이미도설피닐]-베타-D-프럭토피라노스 설파메이트;
2,3-O-(1-메틸에틸리덴)-4,5-O-[N-(4-메틸벤젠설포닐)이미도설포닐]-베타-D-프럭토피라노스 설파메이트;
2,3-O-(사이클로헥실리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 설파메이트;
(S)-4,5-O-[N-(1,1-디메틸에톡시카보닐)이미도설피닐]-2,3-O-(1-메틸에틸리덴)-베타-D-프럭토피라노스 설파메이트;
및 이들의 약학적으로 허용되는 염.
본 발명의 범위 안에는 다양한 개개 아노머, 부분입체이성체와 에난티오머 및 이들의 혼합물이 포함된다. 이러한 화합물은 화학식 1의 정의 안에 포함된다. 또한, 본 발명의 화합물은 약학적으로 허용되는 염, 예를 들면: 나트륨 및 칼륨 같은 알칼리 금속 염; 암모늄 염; 모노알킬암모늄 염; 디알킬암모늄 염; 트리알킬암모늄 염; 테트라알킬암모늄 염; 및 트로메타민 염도 포함한다. 화학식 1 화합물의 수화물 및 타 용매화물도 본 발명의 범위 안에 포함된다.
화학식 1 화합물의 약학적으로 허용되는 염은 화학식 1의 설파메이트를 적당한 염기와 반응시킨 다음 염을 회수함으로써 제조될 수 있다.
설파메이트 유도체는 1종 이상의 타 약제 화합물과 병행해서 사용될 수 있고 약제가 ICD 및/또는 동반 질병의 치료에도 유효한 용도가 있는 한은 본 발명의 방법에 따라 사용될 수 있다. 약제는 하기 카테고리와 특정 예를 포함한다. 카테고리는 특정 예에 의해 한정되지 않는다. 당업자는 또한, 본 발명에 쓰임이 있는 약제를 용이하게 확인할 수 있을 것이다. 당업자는 카테고리 안에 들어 오고 본 발명에 따라 유용한 다수의 다른 화합물도 인식할 것이다.
아드레날린 작동제: 아드레날론; 아미데프린 메실레이트; 아프라클로니딘 하이드로클로라이드; 브리모니딘 타르트레이트; 다피프라졸 하이드로클로라이드; 데테레놀 하이드로클로라이드; 디피베프린; 도파민 하이드로클로라이드; 에페드린 설페이트; 에피네프린; 에피네프린 비타르트레이트; 에피네프릴 보레이트; 에스프로퀸 하이드로클로라이드; 에타페드린 하이드로클로라이드; 하이드록시암페타민 하이드로브로마이드; 레보노르데프린; 메펜테르민 설페이트; 메타라미놀 비타르트레이트; 메티졸린 하이드로클로라이드; 나파졸린 하이드로클로라이드; 노르에피네프린 비타르트레이트; 옥시도파민; 옥시메타졸린 하이드로클로라이드; 페닐에프린 하이드로클로라이드; 페닐프로파놀아민 하이드로클로라이드; 페닐프로파놀아민 폴리스티렉스; 프레날테롤 하이드로클로라이드; 프로필헥세드린; 슈도에페드린 하이드로클로라이드; 테트라하이드로졸린 하이드로클로라이드; 트라마졸린 하이드로클로라이드; 자일로메타졸린 하이드로클로라이드.
부신피질 스테로이드: 시프로시노나이드; 데스옥시코티코스테론 아세테이트; 데스옥시코티코스테론 피발레이트; 덱사메타손 아세테이트; 플루드로코티손 아세테이트; 플루목소나이드; 하이드로코티손 헤미석시네이트; 메틸프레드니솔론 헤미석시네이트; 나플로코트; 프로시노나이드; 티모베손 아세테이트; 티프레단.
부신피질 억제제: 아미노글루테티마이드; 트릴로스탄.
알콜 억제제: 디설피람.
알도스테론 길항제: 칸레노에이트 칼륨; 칸레논; 디시레논; 멕스레노에이트 칼륨; 프로레노에이트 칼륨; 스피로노락톤.
아미노산: 알라닌; 아스파트산; 시스테인 하이드로클로라이드; 시스틴; 히스티딘; 이소루이신; 루이신; 라이신; 라이신 아세테이트; 라이신 하이드로클로라이드; 메티오닌; 페닐알라닌; 프롤린; 세린; 트레오닌; 트립토판; 타이로신; 발린.
강장제: 모다피닐.
진통제: 아세트아미노펜; 알펜타닐 하이드로클로라이드; 아미노벤조에이트 칼륨; 아미노벤조에이트 나트륨; 아니독심; 아닐레리딘; 아닐레리딘 하이드로클로라이드; 아닐로팜 하이드로클로라이드; 아니롤락; 안티피린; 아스피린; 베녹사프로펜; 벤지다민 하이드로클로라이드; 비시파딘 하이드로클로라이드; 브리펜타닐 하이드로클로라이드; 브로마돌린 말리에이트; 브롬페낙 나트륨; 부프레노르핀 하이드로클로라이드; 부타세틴; 부틱시레이트; 부토르파놀; 부토르파놀 타르트레이트; 카바마제핀; 카바스피린 칼슘; 카비펜 하이드로클로라이드; 카펜타닐 시트레이트; 시프레파돌 석시네이트; 시라마돌; 시라마돌 하이드로클로라이드; 클로닉세릴; 클로닉신; 코데인; 코데인 포스페이트; 코데인 설페이트; 코노르폰 하이드로클로라이드; 사이클라조신; 덱스옥사드롤 하이드로클로라이드; 덱스페메돌락; 데조신; 디플루니살; 디하이드로코데인 비타르트레이트; 디메파단; 디피론; 독스피코민 하이드로클로라이드; 드리니덴; 에나돌린 하이드로클로라이드; 에피리졸; 에르고타민 타르트레이트; 에톡사젠 하이드로클로라이드; 에토페나메이트; 유게놀; 페노프로펜; 페노프로펜 칼슘; 펜타닐 시트레이트; 플록타페닌; 플루페니살; 플루닉신; 플루닉신 메글루민; 플루피르틴 말리에이트; 플루프로쿠아존; 플루라돌린 하이드로클로라이드; 플루르비프로펜; 하이드로모르폰 하이드로클로라이드; 이부페낙; 인도프로펜; 케타조신; 케톨파놀; 케토롤락 트로메타민; 레티마이드 하이드로클로라이드; 레보메타딜 아세테이트; 레보메타딜 아세테이트 하이드로클로라이드; 레보난트라돌 하이드로클로라이드; 레보르파놀 타르트레이트; 로페미졸 하이드로클로라이드; 로펜타닐 옥살레이트; 로르시나돌; 로목시캄; 마그네슘 살리실레이트; 메페남산; 메나비탄 하이드로클로라이드; 메페리딘 하이드로클로라이드; 멥타지놀 하이드로클로라이드; 메타돈 하이드로클로라이드; 메타딜 아세테이트; 메토폴린; 메토트리메프라진; 메트케파미드 아세테이트; 밈반 하이드로클로라이드; 미르펜타닐 하이드로클로라이드; 몰리나존; 모르핀 설페이트; 목사조신; 나비탄 하이드로클로라이드; 날부핀 하이드로클로라이드; 날멕손 하이드로클로라이드; 나목시레이트; 난트라돌 하이드로클로라이드; 나프록센; 나프록센 나트륨; 나프록솔; 네포팜 하이드로클로라이드;넥세리딘 하이드로클로라이드; 노라시메타돌 하이드로클로라이드; 옥펜타닐 하이드로클로라이드; 옥타자마이드; 올바닐; 옥세토론 푸마레이트; 옥시코돈; 옥시코돈 하이드로클로라이드; 옥시코돈 테레프탈레이트; 옥시모르폰 하이드로클로라이드; 페메돌락; 펜타모르폰; 펜타조신; 펜타조신 하이드로클로라이드; 펜타조신 락테이트; 펜타조피리딘 하이드로클로라이드; 페니라미돌 하이드로클로라이드; 피세나돌 하이드로클로라이드; 피나돌린; 피르페니돈; 피록시캄 올라민; 프라바돌린 말리에이트; 프로딜리딘 하이드로클로라이드; 프로파돌 하이드로클로라이드; 프로피람 푸마레이트; 프로폭시펜 하이드로클로라이드; 프로폭시펜 납실레이트; 프록사졸; 프록사졸 시트레이트; 프록소르판 타르트레이트; 피롤리펜 하이드로클로라이드; 레미펜타닐 하이드로클로라이드; 살콜렉스; 살레타마이드 말리에이트; 살리실라마이드; 살리실레이트 메글루민; 살살레이트; 나트륨 살리실레이트; 스피라돌린 메실레이트; 수펜타닐; 수펜타닐 시트레이트; 탈메타신; 탈니플루메이트; 탈로살레이트; 타자돌렌 석시네이트; 테부펠론; 테트리다민; 티푸락 나트륨; 틸리딘 하이드로클로라이드; 티오피낙; 토나조신 메실레이트; 트라마돌 하이드로클로라이드; 트레펜타닐 하이드로클로라이드; 트롤아민; 베라돌린 하이드로클로라이드; 베릴로팜 하이드로클로라이드; 볼라조신; 조르파놀 메실레이트; 자일라진 하이드로클로라이드; 제나조신 메실레이트; 조메피락 나트륨; 주캅사이신.
덱스펜플루라민을 포함한 식욕 감퇴제 화합물.
식욕 부진제: 아미노렉스; 암페클로랄; 클로르펜테르민 하이드로클로라이드; 클로미노렉스; 클로르테르민 하이드로클로라이드; 디에틸프로피온 하이드로클로라이드; 펜플루라민 하이드로클로라이드; 페니소렉스; 플루도렉스; 플루미노렉스; 레밤페타민 석시네이트; 마진돌; 메페노렉스 하이드로클로라이드; 펜메트라진 하이드로클로라이드; 펜테르민; 시부트라민 하이드로클로라이드.
항-불안제: 아다탄세린 하이드로클로라이드; 알피뎀; 비노스피론 메실레이트; 브레타제닐; 글레만세린; 입사피론 하이드로클로라이드; 미리세트론 말리에이트; 오시나플론; 온단세트론 하이드로클로라이드; 파나디플론; 판코프라이드; 파진아클론; 세라자핀 하이드로클로라이드; 탄도스피론 시트레이트; 잘로스피론 하이드로클로라이드.
항울제: 아다탄세린 하이드로클로라이드; 아디나졸람; 아디나졸람 메실레이트; 알라프로클레이트; 알레타민 하이드로클로라이드; 아메달린 하이드로클로라이드; 아미트립틸린 하이드로클로라이드; 아목사핀; 아프타자핀 말리에이트; 아잘록산 푸마레이트; 아제핀돌; 아지프라민 하이드로클로라이드; 비페나몰 하이드로클로라이드; 부프로피온 하이드로클로라이드; 부타세틴; 부트립틸린 하이드로클로라이드; 카록사존; 카르타졸레이트; 시클라진돌; 시독세핀 하이드로클로라이드; 실로바민 메실레이트; 클로다존 하이드로클로라이드; 클로미프라민 하이드로클로라이드; 코티닌 푸마레이트; 사이클린돌; 사이펜아민 하이드로클로라이드; 사이프롤리돌 하이드로클로라이드; 사이프록시마이드; 달레달린 토실레이트; 다폭세틴 하이드로클로라이드; 다자드롤 말리에이트; 다제피닐 하이드로클로라이드; 데시프라민 하이드로클로라이드; 덱사미솔; 덱시마펜; 디벤제핀 하이드로클로라이드; 디옥사드롤 하이드로클로라이드; 도티에핀 하이드로클로라이드; 독세핀 하이드로클로라이드; 둘록세틴 하이드로클로라이드; 에클라나민 말리에이트; 엔시프레이트; 에토페리돈 하이드로클로라이드; 판트리돈 하이드로클로라이드; 페메토졸 하이드로클로라이드; 펜메트라마이드; 페졸아민 푸마레이트; 플루오트라센 하이드로클로라이드; 플루옥세틴; 플루옥세틴 하이드로클로라이드; 플루파록산 하이드로클로라이드; 감펙신; 구아녹시펜 설페이트; 이마펜 하이드로클로라이드; 이밀록산 하이드로클로라이드; 이미프라민 하이드로클로라이드; 인델록사진 하이드로클로라이드; 인트립틸린 하이드로클로라이드; 이프린돌; 이소카복사지드; 켑티프라민 푸마레이트; 로페프라민 하이드로클로라이드; 로르탈아민; 마프로틸린; 마프로틸린 하이드로클로라이드; 메리트라센 하이드로클로라이드; 밀라세마이드 하이드로클로라이드; 미나프린 하이드로클로라이드; 미르타자핀; 모클로베마이드; 모달린 설페이트; 나팍타딘 하이드로클로라이드; 나파메졸 하이드로클로라이드; 네파조돈 하이드로클로라이드; 니속세틴; 니트라퓨담 하이드로클로라이드; 노미펜신 말리에이트; 노르트립틸린 하이드로클로라이드; 옥트립틸린 포스페이트; 오피프라몰 하이드로클로라이드; 옥사프로틸린 하이드로클로라이드; 옥시페르틴; 파록세틴; 페넬진 설페이트; 피란다민 하이드로클로라이드; 피조틸린; 프리데핀 하이드로클로라이드; 프롤린탄 하이드로클로라이드; 프로트립틸린 하이드로클로라이드; 퀴파진 말리에이트; 롤리시프린; 세프록세틴 하이드로클로라이드; 세르트랄린 하이드로클로라이드; 시부트라민 하이드로클로라이드; 설피라이드; 수리토졸; 타메트랄린 하이드로클로라이드; 탐프라민 푸마레이트; 탄다민 하이드로클로라이드; 티아제심 하이드로클로라이드; 토잘리논; 토목세틴 하이드로클로라이드; 트라조돈 하이드로클로라이드; 트레벤조민 하이드로클로라이드; 트리미프라민; 트리미프라민 말리에이트; 벤라팍신 하이드로클로라이드; 빌록사진 하이드로클로라이드; 지멜딘 하이드로클로라이드; 조메타핀.
항-고혈압제: 알푸조신 하이드로클로라이드; 알리파마이드; 알티아자이드; 아미퀸신 하이드로클로라이드; 암로디핀 베실레이트; 암로디핀 말리에이트; 아나리타이드 아세테이트; 아티프로신 말리에이트; 벨포스딜; 베미트라딘; 벤다칼올 메실레이트; 벤드로플루메티아자이드; 벤즈티아자이드; 베탁솔올 하이드로클로라이드; 베타니딘 설페이트; 베반톨올 하이드로클로라이드; 비클로딜 하이드로클로라이드; 비소프롤올; 비소프롤올 푸마레이트; 부신돌올 하이드로클로라이드; 부피코마이드; 부티아자이드; 캔독사트릴; 캔독사트릴라트; 캅토프릴; 카르베딜올; 세로나프릴; 클로로티아자이드 나트륨; 시클레타닌; 실라자프릴; 클로니딘; 클로니딘 하이드로클로라이드; 클로파마이드; 사이클로펜티아자이드; 사이클로티아자이드; 다로디핀; 데브리소퀸 설페이트; 델라프릴 하이드로클로라이드; 디아파마이드; 디아족사이드; 딜레발올 하이드로클로라이드; 딜티아젬 말레이트; 디테키렌; 독사조신 메실레이트; 에카도트릴; 에날라프릴 말리에이트; 에날라프릴라트; 에날키렌; 엔드랄라진 메실레이트; 에피티아자이드; 에프로사르탄; 에프로사르탄 메실레이트; 페놀도팜 메실레이트; 플라보딜올 말리에이트; 플로르디핀; 플로세퀴난; 포시노프릴 나트륨; 포시노프릴라트; 구아나벤즈; 구아나벤즈 아세테이트; 구아나클린 설페이트; 구아나드렐 설페이트; 구안시딘; 구안티딘 모노설페이트; 구안티딘 설페이트; 구안파신 하이드로클로라이드; 구안이소퀸 설페이트; 구아노클로르 설페이트; 구아녹틴 하이드로클로라이드; 구아녹사벤즈; 구아녹산 설페이트; 구아녹시펜 설페이트; 하이드랄라진 하이드로클로라이드; 하이드랄라진 폴리스티렉스; 하이드로플루메티아자이드; 인다크리논; 인다파마이드; 인돌아프리프 하이드로클로라이드; 인도라민; 인도라민 하이드로클로라이드; 인도레네이트 하이드로클로라이드; 라시디핀; 레니퀸신; 레브크로마칼림; 리시노프릴; 로펙시딘 하이드로클로라이드; 로사르탄 칼륨; 로술라진 하이드로클로라이드; 메부타메이트; 메카밀라민 하이드로클로라이드; 메드록살올; 메드록살올 하이드로클로라이드; 메탈티아자이드; 메티클로티아자이드; 메틸도파; 메틸도페이트 하이드로클로라이드; 메티프라놀올; 메톨라존; 메토프롤올 푸마레이트; 메토프롤올 석시네이트; 메티로신; 미녹시딜; 모나테필 말리에이트; 무졸리민; 네비볼올; 니트렌디핀; 오포르닌; 파르길린 하이드로클로라이드; 파족사이드; 펠란세린 하이드로클로라이드; 페린도프릴 에르부민; 페녹시벤자민 하이드로클로라이드; 피나시딜; 피보프릴; 폴리티아자이드; 프라조신 하이드로클로라이드; 프리미돌올; 프리지딜올 하이드로클로라이드; 퀴나프릴 하이드로클로라이드; 퀴나프릴라트; 퀴나조신 하이드로클로라이드; 퀴넬로란 하이드로클로라이드; 퀸피롤 하이드로클로라이드; 퀴누클리움 브로마이드; 라미프릴; 라우울피아 세르펜티나; 레세르핀; 사프리사르탄 칼륨; 사랄라신 아세테이트; 나트륨 니트로프루사이드; 설피날올 하이드로클로라이드; 타소사르탄; 텔루디핀 하이드로클로라이드; 테모카프릴 하이드로클로라이드; 테라조신 하이드로클로라이드; 테를라키렌; 티아메니딘; 티아메니딘 하이드로클로라이드; 티크리나펜; 티나비놀; 티오다조신; 티펜토신 하이드로클로라이드; 트리클로르메티아자이드; 트리마조신 하이드로클로라이드; 트리메타판 캄실레이트; 트리목사민 하이드로클로라이드; 트리파마이드; 지파마이드; 잔키렌하이드로클로라이드; 조페노프릴라트 아르기닌.
소염제: 알클로페낙; 알클로메타손 디프로피오네이트; 알게스톤 아세토나이드; 알파 아밀라제; 암시나팔; 암시나파이드; 암페낙 나트륨; 아미프릴로스 하이드로클로라이드; 아나킨라; 아니롤락; 아니트라자펜; 아파존; 발살라자이드 이나트륨; 벤다작; 베녹사프로펜; 벤지다민 하이드로클로라이드; 브로멜라인즈; 브로페라몰; 부데소나이드; 카르프로펜; 시클로프로펜; 신타존; 클리프로펜; 클로베타솔 프로피오네이트; 클로베타손 부티레이트; 클로피락; 클로티카손 프로피오네이트; 코르메타손 아세테이트; 코르토독손; 데플라자코르트; 데소나이드; 데속시메타손; 덱사메타손 디프로피오네이트; 디클로페낙 칼륨; 디클로페낙 나트륨; 디플로라손 디아세테이트; 디플루미돈 나트륨; 디플루니살; 디플루프레드네이트; 디프탈론; 디메틸 설폭사이드; 드로시노나이드; 엔드리손; 엔리모맙; 에놀리캄 나트륨; 에피리졸; 에토돌락; 에토페나메이트; 펠비낙; 페나몰; 펜부펜; 펜클로페낙; 펜클로락; 펜도살; 펜피팔론; 펜티아작; 플라잘론; 플루아자코르트; 플루페남 산; 플루미졸; 플루니솔라이드 아세테이트; 플루닉신; 플루닉신 메글루민; 플루오코르틴 부틸; 플루오로메톨론 아세테이트; 플루쿠아존; 플루르비프로펜; 플루레토펜; 플루티카손 프로피오네이트; 푸라프로펜; 푸로부펜; 할시노나이드; 할로베타솔 프로피오네이트; 할로프레돈 아세테이트; 이부페낙; 이부프로펜; 이부프로펜 알루미늄; 이부프로펜 피코놀; 일로니답; 인도메타신; 인도메타신 나트륨; 인도프로펜; 인독솔; 인트라졸; 이소플루프레돈 아세테이트; 이속세팍; 이속시캄; 케토프로펜; 로페미졸 하이드로클로라이드; 로르녹시캄; 로테프레드놀 에타보네이트; 메클로페나메이트 나트륨;메클로페남 산; 메클로리손 디부티레이트; 메페남 산; 메살라민; 메세클라존; 메틸프레드니솔론 술레프타네이트; 모미플루메이트; 나부메톤; 나프록센; 나프록센 나트륨; 나프록솔; 니마존; 올살라진 나트륨; 오르코테인; 오르파녹신; 옥사프로진; 옥시펜부타존; 파라닐린 하이드로클로라이드; 펜토산 폴리설페이트 나트륨; 펜부타존 나트륨 글리세레이트; 피르페니돈; 피록시캄; 피록시캄 시나메이트; 피록시캄 올라민; 피르프로펜; 프레드나제이트; 프리펠론; 프로돌 산; 프로쿠아존; 프록사졸; 프록사졸 시트레이트; 리멕솔론; 로마자리트; 살콜렉스; 살나세딘; 살살레이트; 산귀나리움 클로라이드; 세클라존; 세르메타신; 수독시캄; 술린닥; 수프로펜; 탈메타신; 탈니플루메이트; 탈로살레이트; 테부펠론; 테니답; 테니답 나트륨; 테녹시캄; 테시캄; 테시마이드; 테트리다민; 티오피낙; 틱소코르톨 피발레이트; 톨메틴; 톨메틴 나트륨; 트리클로나이드; 트리플루미데이트; 지도메타신; 조메피락 나트륨.
항-오심제: 부클리진 하이드로클로라이드; 사이클리진 락테이트; 나복테이트 하이드로클로라이드.
항-호중구감소증제: 필그라스팀; 레노그라스팀; 몰그라모스팀; 레그라모스팀; 사르그라모스팀.
항-강박제: 플루복사민 말리에이트.
항-파킨슨제: 벤즈트로핀 메실레이트; 비페리덴; 비페리덴 하이드로클로라이드; 비페리덴 락테이트; 카르만타딘; 실라도파 하이드로클로라이드; 도파만틴; 에토프로파진 하이드로클로라이드; 라자베마이드; 레보도파; 로메트랄린 하이드로클로라이드; 모페길린 하이드로클로라이드; 낙사골라이드 하이드로클로라이드; 파렙타이드 설페이트; 프로사이클리딘 하이드로클로라이드; 퀴네토란 하이드로클로라이드; 로피니롤 하이드로클로라이드; 셀레길린 하이드로클로라이드; 톨카폰; 트리헥시페니딜 하이드로클로라이드. 항-연동제: 디페녹시마이드 하이드로클로라이드; 디페녹신; 디페녹실레이트 하이드로클로라이드; 플루페라마이드; 리다미딘 하이드로클로라이드; 로페라마이드 하이드로클로라이드; 말레타머; 누페녹솔; 파레고릭.
항-정신병제: 아세토페나진 말리에이트; 알렌테몰 하이드로브로마이드; 알페르틴; 아자페론; 바텔라핀 말리에이트; 벤페리돌; 벤진도피린 하이드로클로라이드; 브로프븍신; 브롬페리돌; 브롬페리돌 데카노에이트; 부타클라몰 하이드로클로라이드; 부타페라진; 부타페라진 말리에이트; 카르페나진 말리에이트; 카르보트롤린 하이드로클로라이드; 클로르프로마진; 클로르프로마진 하이드로클로라이드; 클로르프로틱센; 신페렌; 신트리아마이드; 클로마크란 포스페이트; 클로펜틱솔; 클로피모자이드; 클로피파잔 메실레이트; 클로로페론 하이드로클로라이드; 클로티아핀; 클로틱사마이드 말리에이트; 클로자핀; 사이클로페나진 하이드로클로라이드; 드로페리돌; 에타졸레이트 하이드로클로라이드; 페니마이드; 플루신돌; 플루메자핀; 플루페나진 데카노에이트; 플루페나진 에난테이트; 플루페나진 하이드로클로라이드; 플루스피페론; 플루스피릴렌; 플루트롤린; 게보트롤린 하이드로클로라이드; 할로페마이드; 할로페리돌; 할로페리돌 데카노에이트; 일로페리돈; 이미돌린 하이드로클로라이드; 렌페론; 마자페르틴 석시네이트; 메소리다진; 메소리다진 베실레이트; 메티아핀; 밀렌페론; 밀리페르틴; 몰린돈 하이드로클로라이드; 나라놀 하이드로클로라이드; 네플루모자이드 하이드로클로라이드; 오카페리돈; 올란자핀; 옥시페로마이드; 펜플루리돌; 펜티아핀 말리에이트; 페르페나진; 피모자이드; 피녹세핀 하이드로클로라이드; 피팜페론; 피페라세타진; 피포티아진 팔니이테이트; 피퀸돈 하이드로클로라이드; 프로클로르페라진 에디실레이트; 프로클로르페라진 말리에이트; 프로마진 하이드로클로라이드; 레목시프라이드; 레목시프라이드 하이드로클로라이드; 림카졸 하이드로클로라이드; 세페리돌 하이드로클로라이드; 세르틴돌; 세토페론; 스피페론; 티오리다진; 티오리다진 하이드로클로라이드; 티오틱센; 티오틱센 하이드로클로라이드; 티오페리돈 하이드로클로라이드; 티오스피론 하이드로클로라이드; 트리플루오페라진 하이드로클로라이드; 트리플루페리돌; 트리플루프로마진; 트리플루프로마진 하이드로클로라이드; 지프라시돈 하이드로클로라이드.
식욕 억제제: 덱스펜플루라민 하이드로클로라이드; 펜디메트라진 타르트레이트; 펜테르민 하이드로클로라이드.
혈당 조절제: 인간 인슐린; 글루카곤; 톨라자마이드; 톨부타마이드; 클로로프로파마이드; 아세토헥사마이드 및 글리피자이드.
탄산 탈수효소 억제제: 아세타졸아마이드; 아세타졸아마이드 나트륨, 디클로르펜아마이드; 도르졸아마이드 하이드로클로라이드; 메타졸아마이드; 세졸아마이드 하이드로클로라이드.
심기능 억제제: 아세카이나이드 하이드로클로라이드; 아세틸콜린 클로라이드; 악티소마이드; 아데노신; 아미오다론; 아프린딘; 아프린딘 하이드로클로라이드; 아르틸라이드 푸마레이트; 아지밀라이드 디하이드로클로라이드; 비디소마이드;부카이나이드 말리에이트; 부크로마론; 부토프로진 하이드로클로라이드; 카포베네이트 나트륨; 카포벤 산; 시펜린; 시펜린 석시네이트; 클로필리움 포스페이트; 디소부타마이드; 디소피라마이드; 디소피라마이드 포스페이트; 도페틸라이드; 드로불린; 에디폴론 아세테이트; 에밀리움 토실레이트; 엔카이나이드 하이드로클로라이드; 플레카이나이드 아세테이트; 이부틸라이드 푸마레이트; 인데카이나이드 하이드로클로라이드; 이파질라이드 푸마레이트; 로라즈민 하이드로클로라이드; 로르카이나이드 하이드로클로라이드; 메오벤틴 설페이트; 멕실레틴 하이드로클로라이드; 모데카이나이드; 모리시진; 옥시라마이드; 피르메놀 하이드로클로라이드; 피롤아자마이드; 프라놀리움 클로라이드; 프로카인아마이드 하이드로클로라이드; 프로파페논 하이드로클로라이드; 피리놀린; 퀸도니움 브로마이드; 퀴니딘 글루코네이트; 퀴니딘 설페이트; 레카이남 하이드로클로라이드; 레카이남 토실레이트; 리소틸라이드 하이드로클로라이드; 로피토인 하이드로클로라이드; 세마틸라이드 하이드로클로라이드; 수리카이나이드 말리에이트; 토카이나이드; 토카이나이드 하이드로클로라이드; 트랜스카이나이드.
강심제: 악토디긴; 암리논; 베모라단; 부토파민; 카르바제란; 카르사트린 석시네이트; 데슬라노사이드; 디지탈리스; 디지톡신; 디곡신; 도부타민; 도부타민 하이드로클로라이드; 도부타민 락토비오네이트; 도부타민 타르트레이트; 에녹시몬; 이마조단 하이드로클로라이드; 인돌리단; 이소마졸 하이드로클로라이드; 레브도부타민 락토비오네이트; 릭사지논 설페이트; 메도리논; 밀리논; 펠리논 하이드로클로라이드; 피모벤단; 피록시몬; 프리녹소단; 프로실라리딘; 쿠아지논; 타졸올 하이드로클로라이드; 베스나리논.
심혈관제: 도펙사민; 도펙사민 하이드로클로라이드.
담즙분비물질: 디하이드로콜 산; 펜시부티롤; 하이메크로몬; 피프로졸린; 신칼라이드; 토캄필.
콜린작동제: 아세클리딘; 베타네콜 클로라이드; 카르바콜; 데메카리움 브로마이드; 덱스판테놀; 에코티오페이트 아이오다이드; 이소플루로페이트; 메타콜린 클로라이드; 네오스티그민 브로마이드; 네오스티그민 메틸설페이트; 파이소스티그민; 파이소스티그민 살리실레이트; 파이소스티그민 설페이트; 필로카르핀; 필로카르핀 하이드로클로라이드; 필로카르핀 니트레이트; 피리도스티그민 브로마이드.
콜린작동 효능제: 자노멜린; 자노멜린 타르트레이트.
콜린에스테라제 탈활제: 오비독심 클로라이드; 프랄리독심 클로라이드; 프랄리독심 아이오다이드; 프랄리독심 메실레이트.
항-콕시듐제: 아르프리노시드; 나라신; 셈두라마이신; 셈두라마이신 나트륨.
인식작용 보조제: 에르골로이드 메실레이트; 피라세탐; 프라미라세탐 하이드로클로라이드; 프라미라세탐 설페이트; 타크린 하이드로클로라이드.
인식작용 증강제: 베시피르딘 하이드로클로라이드; 리노피르딘; 시보피르딘.
호르몬; 디에틸스틸베스트롤; 프로게스테론; 17 하이드록시 프로게스테론; 메드록시프로게스테론; 노르게스트렐; 노레티노드렐; 에스트라디올; 메게스트롤(Megace); 노레틴드론; 레보노르게스트렐; 에틴디올; 에티닐 에스트라디올; 메스트라놀; 에스트론; 에퀼린; 17 알파 디하이드로에퀼린; 에퀼레닌; 17 알파디하이드로에퀼레닌; 17 알파 에스트라디올; 17 베타 에스트라디올; 류프롤라이드(lupron); 글루카곤; 테스톨락톤; 클로미펜; 한 메모포살 고나도트로핀; 인간 융모막 고나도트로핀; 우로폴리트로핀; 브로모크립틴; 고나도렐린; 황체 형성 호므론 방출 호르몬 및 동족체; 고나도트로핀; 다나졸; 테스토스테론; 디하이드로에피안드로스테론; 안드로스텐디온; 디하이드로에스토스테론; 릴랙신; 옥시토신; 바소프레신; 폴리쿨로스타틴; 여포 조절 단백질; 고나독트리닌; 난모세포 성숙 억제자; 인슐린 성장 인자; 여포 자극 호르몬; 황체 형성 호르몬; 타목시펜; 코르티코렐린 오바인 트리프투테이트; 코신트로핀; 메토게스트; 뇌하수체 제제(후엽); 세락타이드 아세테이트; 소말라포르; 소마트렘; 소마트로핀; 소메노포르; 소미도보브.
기억 보조제: 디목사민 하이드로클로라이드; 리바미놀.
정신 기능 증강제: 아니라세탐.
기분 조절제: 펜가빈.
신경 안정제: 듀오페론 푸마레이트; 리스페리돈.
신경보호제: 디조실핀 말리에이트.
향정신제: 미나프린.
이완제: 아디페닌 하이드로클로라이드; 알쿠로니움 클로라이드; 아미노필린; 아주몰렌 나트륨; 바클로펜; 벤족타민 하이드로클로라이드; 카리소프로돌; 클로르페네신 카바메이트; 클로르족사존; 신플루마이드; 시나메드린; 클로다놀렌; 사이클로벤자프린 하이드로클로라이드; 단트롤렌; 단트롤렌 나트륨; 페날아마이드; 페니리폴 하이드로클로라이드; 페톡실레이트 하이드로클로라이드; 플라복세이트 하이드로클로라이드; 플레타제팜; 플루메트라마이드; 플루라제팜 하이드로클로라이드; 헥사플루오레니움 브로마이드; 이소밀아민 하이드로클로라이드; 로르바메이트; 메베베린 하이드로클로라이드; 메수프린 하이드로클로라이드; 메탁살론; 메토카바몰; 메틱센 하이드로클로라이드; 나포민 말레이트; 넬레자프린 말리에이트; 파파베린 하이드로클로라이드; 피폭솔란 하이드로클로라이드; 퀸크톨레이트; 리토드린; 리토드린 하이드로클로라이드; 롤로딘; 테오필린 나트륨 글리시네이트; 티펜아밀 하이드로클로라이드; 질로밤.
진정제-수면제: 알로바르비탈; 알로니미드; 알프라졸람; 아모바르비탈 나트륨; 벤타제팜; 브로티졸람; 부타바르비탈; 부타바르비탈 나트륨; 부탈비탈; 카푸라이드; 카르보클로랄; 클로랄 베타인; 클로랄 하이드레이트; 클로르디아제폭사이드 하이드로클로라이드; 클로페리돈 하이드로클로라이드; 클로레테이트; 사이프라제팜; 덱스클라몰 하이드로클로라이드; 디아제팜; 디클로랄페나존; 에스타졸람; 에트클로르바이놀; 에토미데이트; 페노밤; 플루니트라제팜; 포사제팜; 글루테티마이드; 할라제팜; 로르메타제팜; 메클로쿠알론; 메프로바메이트; 메타쿠알론; 미다플루르; 파르알데하이드; 펜토바르비탈; 펜토바르비탈 나트륨; 페를라핀; 프라제팜; 쿠아제팜; 레클라제팜; 롤레타마이드; 세코바르비탈; 세코바르비탈 나트륨; 수프로클론; 탈리도마이드; 트라카졸레이트; 트레피팜 말리에이트; 트리아졸람; 트리세타마이드; 트리클로포스 나트륨; 트리메토진; 울다제팜; 잘레플론; 졸라제팜 하이드로클로라이드; 졸피뎀 타르트레이트.
세로토닌 길항제: 알탄세린 타르트레이트; 아메세르가이드; 케탄세린; 리탄세린.
세로토닌 억제제: 시난세린 하이드로클로라이드; 펜클로닌; 포나진 메실레이트; 자일릴아미딘 토실레이트.
세로토닌 수용체 길항제: 트로판세린 하이드로클로라이드.
자극제: 암포넬 산; 암페타민 설페이트; 암피진 설페이트; 아르부타민 하이드로클로라이드; 아자본; 카페인; 세룰레타이드; 세룰레타이드 디에틸아민; 시사프라이드; 다조프라이드 푸마레이트; 덱스트로암페타민; 덱스트로암페타민 설페이트; 디플루아닌 하이드로클로라이드; 디메플린 하이드로클로라이드; 독사프람 하이드로클로라이드; 에트립타민 아세테이트; 에타미반; 펜에틸린 하이드로클로라이드; 플루바닐레이트 하이드로클로라이드; 플루로틸; 히스타민 포스페이트; 인드릴린 하이드로클로라이드; 메펙사마이드; 메탐페타민 하이드로클로라이드; 메틸페니데이트 하이드로클로라이드; 페몰린; 피로발레론 하이드로클로라이드; 자모테롤; 자모테롤 푸마레이트.
상승작용제: 프로아디펜 하이드로클로라이드.
갑상선 호르몬: 레보티록신 나트륨; 리오티로닌 나트륨; 리오트릭스.
갑상선 억제제: 메티마졸; 프로피이티오우라실.
타이로미멕틱: 타이로메단 하이드로클로라이드.
뇌 허혈제; 덱스트로르판 하이드로클로라이드.
혈관수축제: 안지오텐신 아마이드; 펠리프레신; 메틸세르가이드; 메틸세르가이드 말리에이트.
혈관확장제: 알프로스타딜; 아자클로르진 하이드로클로라이드; 바메탄 설페이트; 베프리딜 하이드로클로라이드; 부테리진; 세티에딜 시트레이트; 크로모나르 하이드로클로라이드; 클로니트레이트; 딜티아젬 하이드로클로라이드; 디피리다몰; 드로프레닐아민; 에리트리틸 테트라니트레이트; 펠로디핀; 플루나리진 하이드로클로라이드; 포스테딜; 헥소벤딘; 이노시톨 니아시네이트; 이프록사민 하이드로클로라이드; 이소소르바이드 디니트레이트; 이소소르바이드 모노니트레이트; 이속스수프린 하이드로클로라이드; 리도플라진; 메페니딜; 메페니딜 푸마레이트; 미베프라딜 디하이드로클로라이드; 미오플라진 하이드로클로라이드; 믹시딘; 나프로닐 옥살레이트; 니카르디핀 하이드로클로라이드; 니세르골린; 니코란딜; 니코티닐 알콜; 니페디핀; 니모디핀; 니솔디핀; 옥스페니신; 옥스프레놀올 하이드로클로라이드; 펜타에리트리톨 테트라니트레이트; 펜톡시필린; 펜트리니트롤; 페르헥실린 말리에이트; 핀돌올; 피르시도민; 프레닐아민; 프로파틸 니트레이트; 술록티딜; 테로딜린 하이드로클로라이드; 티프로피딜 하이드로클로라이드; 톨라졸린 하이드로클로라이드; 잔티놀 니아시네이트.
구체적으로, 토피라메이트는 하기를 포함한 특정 증후 및 이상의 치료를 위해 다른 약제와 병행하여 투여될 수 있다;
I. 세로토닌 재흡수 억제제(예를 들면, 시탈로프람(셀렉사 CELEXA), 클로미프라민(아나프라닐 ANAFRANIL)), 플루옥세틴(프로작 PROZAC), 플루복사민(루복스 LUVOX), 벤라팍신(에펙소르 EFFEXOR), 기타 항울제(예를 들면, 부프로피온(웰부트린 WELLBUTRIN) 네파조돈(세르존 SERZONE), 트리사이클릭(예를 들면, 노르프라민 NORPRAMIN 및 파멜로르 PAMELOR), 트라조돈(데시렐 DESYREL), 물질 P 길항제), 정신자극제(예를 들면, d-암페타민, 펜테르민; 및 시부트라민(메리디아 MERIDIA)) 및 오를리스타트에 의한 탐식(탐식 이상, 신경성 다식증, 탐식을 수반하는 신경성 식욕부진)의 치료.
II. 시부트라민(메리디아 MERIDIA); 정신자극제(예를 들면, d-암페타민, 펜테르민) 및 오를리스타트에 의한 과체중/비만 증상의 치료.
III. 부프로피온(자이반 ZYBAN), 세로토닌 재흡수 억제제, 니코틴 패치와 껌, 기타 항울제에 의한 니코틴 중독/금연의 치료.
IV. 날트렉손(레비아 REVIA), 세로토닌 재흡수 억제제, 및 기타 항울제에 의한 알콜 남용/의존성(알콜중독)의 치료.
V. 세로토닌 재흡수 억제제, 리튬, 발프로 산 또는 디발프로엑스 나트륨(예를 들면, 데파켄 DEPAKENE 또는 데파코트 DEPAKOTE), 기타 항울제, 날트렉손, 부정형 항-정신병제(예를 들면, 올란자핀(자이프렉사 ZYPREXA), 퀘티아핀(세로퀘 SEROQUEL), 리스페리돈(리스페르달 RISPERDAL), 지프라시돈) 및 기타 기분 안정제(예를 들면, 카바마제핀)에 의한 기타 충동 자제 이상(행동 중독)의 치료.
VI. 세로토닌 재흡수 억제제, 리튬, 디발프로엑스 나트륨/발프로 산, 항-안드로겐제(예를 들면, 메드록시프로게스테론, 고나도트로핀-방출 호르몬(GnRH) 효능제), 기타 항울제, 및 기타 기분 안정제(예를 들면, 카바마제핀)에 의한 성적도착/섹스 중독의 치료.
투여시, 본 발명의 제형은 약학적으로 허용되는 양으로 및 약학적으로 허용되는 조성물로 적용된다. 이러한 제제는 일상적으로, 염, 완충제, 방부제, 상용성 담체, 및 임의로 타 치료 성분을 함유할 수 있다. 약제에 사용될 경우에 염은 약학적으로 허용될 수 있어야 하지만, 비-약학적 허용 염도 이의 약학적으로 허용되는 염의 제조에 편리하게 사용될 수 있으며 본 발명의 범위로부터 배제되지 않는다. 이러한 약리학적 및 약학적으로 허용되는 염에는 하기의 산으로부터 제조된 것들이 포함되며 이에 국한되지 않는다: 염산, 브롬산, 황산, 질산, 인산, 말레산, 아세트산, 살리실산, p-톨루엔 설폰산, 타르타르산, 시트르산, 메탄 설폰산, 포름산, 말론산, 석신산, 나프탈렌-2-설폰산, 및 벤젠 설폰산. 또한, 약학적으로 허용되는 염은 나트륨, 칼륨 또는 칼슘 염과 같이 알칼리 금속 또는 알칼리 토 염으로서 제조될 수 있다.
적당한 완충제로는 아세트산 및 염(1-2% W/V); 시트르산 및 염(1-3% W/V); 붕산 및 염(0.5-2.5% W/V); 및 인산 및 염(0.8-2% W/V)이 포함된다. 적당한 방부제로는 벤즈알코늄 클로라이드(0.003-0.03% W/V); 클로로부탄올(0.3-0.9% W/V); 파라벤(0.01-0.25% W/V) 및 티메로살(0.004-0.02% W/V)이 포함된다.
본 발명에서, 설파마이드 유도체는 안전 유효량으로 투여된다. 유효량이란 치료될 특정 증상의 발병을 지연, 진행을 억제, 발병 또는 진행을 함께 중단시키거나 진단하는 데 필요한 양을 의미한다. 일반적으로, ICD 치료 유효량은 현장에서 특정 ICD의 포유동물 증상 억제에 필요한 양이 될 것이다. 환자에 투여시, 유효량은 물론, 치료되는 특정 증상; 증상의 중증도; 연령, 물리적 조건, 크기 및 체중을포함한 개개 환자의 변수; 동시 치료; 치료 횟수; 및 투여 방식에 좌우될 것이다. 이러한 요인은 당업자에 잘 알려져 있으며 일상적인 실험만으로도 어드레싱될 수 있다. 일반적으로는, 최소 용량, 즉 증후의 적당한 경감을 제공하는 최저 안전 용량을 사용함이 바람직하다.
용량은 목적하는 약제 수준을 국소적으로 또는 전신적으로 달성하도록 적절히 조정될 수 있다. 일반적으로, 활성 화합물의 1일 경구 용량은 약 0.01 mg/kg/일 내지 2000 mg/kg/일이 될 것이다. 1일 약 1 내지 1000 mg/cm3범위의 IV 용량이 효과적일 것으로 예상된다. 그러한 용량에서 환자의 반응이 불충분한 경우에, 한층 더 높은 용량(또는 상이하고 더욱 국소 집중된 전달 경로에 의한 유효한 더 높은 용량)이 환자의 내약성이 허용하는 범위까지 사용될 수 있다. 예를 들면, 24시간에 걸친 연속적인 IV 투약 또는 1일 다중 용량이 화합물의 적당한 전신 수준 달성을 위해 고려된다.
다양한 투여 경로가 이용될 수 있다. 선택된 특정 양식은 물론, 선택된 특정 약제, 치료될 질환 상태의 중증도 및 치료 효능에 요구되는 용량에 따라 좌우될 것이다. 일반적으로 말해서, 본 발명의 방법은 임상적으로 용인될 수 없는 부작용을 일으킴이 없이 활성 화합물의 유효 수준을 생성하는 임의 양식을 의미하는 의학적으로 허용되는 임의의 투여 양식을 이용하여 실행될 수 있다. 이러한 투여 양식으로는 경구, 직장, 설하, 국소, 비내, 경피 또는 비경구 경로가 포함된다. "비경구"란 용어는 피하, 정맥내, 근육내, 또는 주입을 포함한다. 정맥내 경로가 바람직하다.
조성물은 편의상 단위 용량형으로 제공될 수 있으며 제약업계에 잘 알려져 있는 임의 방법으로 제조할 수 있다. 일반적으로, 조성물은 화합물을 액체 담체, 미분 고체 담체, 또는 양자 모두와 균일하고 균질하게 회합시킨 다음, 필요에 따라 산물을 조형함으로써 제조된다.
경구 투여에 적당한 조성물은 각각이 일정량의 활성 화합물을 함유하는 캡슐, 캐세이, 정제, 또는 로젠지와 같은 개별 단위로서 제공될 수 있다. 다른 조성물로는 시럽, 엘릭서, 또는 에멀션과 같이 수성 액체 또는 비-수성 액체 중의 현탁액이 포함된다.
다른 전달 시스템으로는 시간-방출, 지연 방출 또는 지속 방출 전달 시스템이 포함될 수 있다. 이러한 시스템은 본 발명의 활성 화합물의 반복 투여를 피할 수 있어, 환자와 의사에게 편리함을 증가시킨다. 여러 종류의 방출 전달 시스템이 이용가능하고 당업자에 공지되어 있다. 이러한 것들로는 폴리락트산 및 폴리글리콜산, 폴리무수물 및 폴리카프로락톤과 같은 중합체계 시스템; 콜레스테롤과 같은 스테롤, 콜레스테롤 에스테르 및 지방산 또는 중성 지방, 예를 들면 모노-, 디- 및 트리글리세라이드를 포함하는 지질인 비-중합체 시스템; 하이드로겔 방출 시스템; 실라스틱 시스템; 펩타이드계 시스템; 왁스 코팅, 통상의 결합제와 부형제를 사용하는 압축 정제, 부분 융합 이식물 등이 포함된다. 또한, 펌프계 하드웨어 전달 시스템이 사용될 수 있으며, 이 중 일부는 이식용으로 적응된다.
장기 지속 방출 이식물도 사용될 수 있다. 본원에서 사용되는 "장기" 방출이란 용어는 이식물이 적어도 30일, 바람직하게는 60일간 활성 성분의 치료 수준을 전달하도록 작제되고 배치됨을 의미한다. 장기 지속 방출 이식물은 당업자에 잘 알려져 있으며 전술한 방출 시스템 일부가 포함된다.
실시예에서, 환자는 25 mg/qHS에서 시작하는 오픈-라벨 토피라메이트로 처리되며 용량은 최대 1200 mg까지 반응이 보일 때까지 환자에 의해 용인됨에 따라 25 mg 증분으로 환자에 의해 증가된다.
Pt Pt ID 토피라메이트 최대 용량 반응# 개시 사유 (mg/일) |
1 LJM BD 1200 BD의 차도(BED) BED의 차도(비만) 107 lbs 감소2 CEJ BD 150 BD의 온화한 개선BED BED의 중간 정도의 감소과체중 5 lbs 감소진정작용, 인식의 둔화에 기인한 중단3 JAC BD 1200 BD의 중간 정도의 개선BED BED의 차도비만 50.5 lbs 감소4 JEB BD 900 BD의 중간 정도의 개선BED BED의 현저한 개선과체중 30.5 lbs 감소5 KCW BED 100 1차 시도: BED의 반응 없음비만 GI 통증에 기인한 중단강박성 구매((BD, 차도) 1002차 시도: BD의 악화BED의 차도11 lbs 감소강박성 구매의 차도6 JB BED 100 BED의 반응 없음과체중 체중 변화 없음 |
기호표: BD=양극성 이상; BED=탐식 이상; Pt=환자; D/C=토피라메이트 처리 중단; Cont.=토피라메이트 처리 지속; GI=위장 |
Pt. Pt.ID 토피라메이트 최대 용량 반응# 개시 사유 (mg/일) |
1 BAA BD 700 BD의 반응 없음비만 9 lbs(293-284) 감소(BED, 차도)2 HTB BD 300 BD의 차도과식 과식의 차도과체중 16 lbs(248-232) 감소차도에 있어서 중단된 2°질환3 ADJ BD 400 BD의 중간 정도의 개선과식 과식의 중간 정도의 개선과체중 7 lbs(239-232) 감소4 TK BD 350 BD의 반응 없음과식 과식의 온화한 개선과체중 5 lbs(238-233) 감소5 JCJ BD 1. 250 1차 시도: BD의 악화과식 2. 200 과식의 온화한 감소과체중 7 lbs(152-145)의 감소2차 시도: BD의 온화한 개선과식의 온화한 감소1 lb(154-155 lbs) 증가6 KDC 과식 800 BD의 악화과체중 9 lbs(208-199 lbs) 감소(BD, 차도)7 NLR BD 300 BD의 악화과체중 46 lbs(196-150 lbs) 감소식욕 부진에 기인한 중단8 PR BD 700 BD의 중간 정도의 개선과식 과식의 현저한 개선과체중 19 lbs(185-166) 감소G.I. 통증에 기인한 중단 |
기호표: Pt.=환자; BD=양극성 이상; BED=탐식 이상; D/C=토피라메이트 처리 중단; Cont.=토피라메이트 처리 지속; GI=위장 |
Claims (14)
- 충동 자제 이상 치료 유효량의 화학식 1 화합물을 그러한 증상을 앓고 있는 포유동물에 투여하는 단계를 포함하는, 충동 자제 이상의 치료방법.화학식 1화학식 2상기식에서,X는 CH2또는 산소이고;R1은 수소 또는 알킬이며;R2, R3, R4및 R5는 독립적으로 수소 또는 저급 알킬이며, X가 CH2일 때, R4와 R5는 벤젠 환을 형성하기 위하여 결합된 알켄 그룹일 수 있으며, X가 산소일 때, R2와 R3및/또는 R4와 R5는 함께 화학식 2의 메틸렌디옥시 그룹일 수 있으며;R6및 R7은 동일하거나 상이하고 수소, 저급 알킬이거나 알킬이며 결합하여 사이클로펜틸 또는 사이클로헥실 환을 형성한다.
- 제 1 항에 있어서, 화합물이2,3:4,5-비스-O-(1-메틸에틸리덴)-베타-D-프럭토피라노스 설파메이트;2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 설파메이트;2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-L-프럭토피라노스 설파메이트;2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 메틸설파메이트;2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 부틸설파메이트;2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 에틸설파메이트;2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 옥틸설파메이트;2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 2-프로페닐설파메이트;2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 페닐메틸설파메이트;2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 사이클로프로필설파메이트;2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 사이클로부틸설파메이트;2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 (2,2,2-트리플루오로에틸)설파메이트;2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 디메틸설파메이트;2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 디에틸설파메이트;2,3-O-(1-메틸에틸리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 아지도설페이트;(S)-2,3-O-(1-메틸에틸리덴)-4,5-O-설피닐-베타-D-프럭토피라노스 설파메이트;(R)-2,3-O-(1-메틸에틸리덴)-4,5-O-설피닐-베타-D-프럭토피라노스 설파메이트;2,3-O-(1-에틸프로필리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 설파메이트;2,3-O-(1-메틸에틸리덴)-4,5-O-[N-(4-메틸벤젠설포닐)이미도설피닐]-베타-D-프럭토피라노스 설파메이트;2,3-O-(1-메틸에틸리덴)-4,5-O-[N-(4-메틸벤젠설포닐)이미도설포닐]-베타-D-프럭토피라노스 설파메이트;2,3-O-(사이클로헥실리덴)-4,5-O-설포닐-베타-D-프럭토피라노스 설파메이트;(S)-4,5-O-[N-(1,1-디메틸에톡시카보닐)이미도설피닐]-2,3-O-(1-메틸에틸리덴)-베타-D-프럭토피라노스 설파메이트;및 이들의 약학적으로 허용되는 염으로 이루어진 그룹 중에서 선택되는 방법.
- 제 1 항에 있어서, 화합물이 (1R,2R,3S,4S)-(1,2:3,4-디-O-메틸에틸리덴사이클로헥산-1,2,3,4-테트라올-4-일)메틸 설파메이트 및 (1R,2S,3S,4S)-(3,4-O-메틸에틸리덴-1,2-O-설피닐사이클로헥산 1,2,3,4-테트라올-4-일)메틸 설파메이트로 이루어진 그룹 중에서 선택되는 방법.
- 제 1 항에 있어서, 화학식 1의 화합물이 토피라메이트인 방법.
- 제 1 항에 있어서, 치료 유효량이 1일 약 15 내지 약 2000 mg인 방법.
- 제 1 항에 있어서, 치료 유효량이 1일 약 25 내지 약 750 mg인 방법.
- 제 1 항에 있어서, 충동 자제 이상이 간헐적인 폭발성 이상(IED), 도벽, 병적인 도박, 방화벽, 발모광, 강박성 구매 또는 쇼핑, 반복성 자기-절단, 비-성도착성 섹스 중독, 중증의 손톱 물어 뜯기, 강박성 피부 찌르기, 충동성이 특징인 인격 장애, 주의력 결핍/활동 항진 이상, 탐식을 특징으로 하는 식욕 이상, 및 물질 사용 이상으로 이루어진 그룹 중에서 선택되는 방법.
- 제 1 항에 있어서, 화합물이 아드레날린 작동제, 부신피질 스테로이드, 부신피질 억제제, 알도스테론 길항제, 아미노산, 강장제, 진통제, 식욕 감퇴제 화합물, 식욕 부진제, 항-불안제, 항울제, 항-고혈압제, 소염제, 항-오심제, 항-호중구감소증제, 항-강박제, 항-파킨슨제, 항-정신병제, 식욕 억제제, 혈당 조절제, 탄산 탈수효소 억제제, 강심제, 심혈관제, 담즙분비물질, 콜린작동제, 콜린작동 효능제, 콜린에스테라제 탈활제, 인식작용 보조제, 인식작용 증강제, 호르몬, 기억 보조제, 정신 기능 증강제, 기분 조절제, 신경이완제, 신경보호제, 향정신제, 이완제, 진정제-수면제, 세로토닌 길항제, 세로토닌 억제제, 세로토닌 수용체 길항제, 자극제, 갑상선 호르몬, 갑상선 억제제, 타이로미멕틱, 뇌 허혈제, 혈관수축제, 및 혈관확장제로 이루어진 그룹 중에서 선택된 1종 이상의 타 약제 화합물과 병행하여 사용되는 방법.
- 제 1 항에 있어서, 충동 자제 이상이 식욕 이상이고 화합물이 세로토닌 재흡수 억제제, 항울제, 정신자극제, 및 오를리스타트로 이루어진 그룹 중에서 선택된 1종 이상의 타 약제 화합물과 병행하여 사용되는 방법.
- 제 1 항에 있어서, 충동 자제 이상이 과체중/비만증이고 화합물이 시부트라민, 정신자극제, 및 오를리스타트로 이루어진 그룹 중에서 선택된 1종 이상의 타 약제 화합물과 병행하여 사용되는 방법.
- 제 1 항에 있어서, 충동 자제 질환이 니코틴 중독증이고 화합물이 부프로피온, 세로토닌 재흡수 억제제, 니코틴, 및 항울제로 이루어진 그룹 중에서 선택된 1종 이상의 타 약제 화합물과 병행하여 사용되는 방법.
- 제 1 항에 있어서, 충동 자제 이상이 알콜 남용/의존증이고 화합물이 날트렉손, 세로토닌 재흡수 억제제, 및 다른 항울제로 이루어진 그룹 중에서 선택된 1종 이상의 타 약제 화합물과 병행하여 사용되는 방법.
- 제 1 항에 있어서, 충동 자제 이상이 행동 중독증이고 화합물이 세로토닌 재흡수 억제제, 리튬, 발프로 산 또는 디발프로엑스 나트륨, 다른 항울제, 날트렉손, 부정형 항-정신병제, 및 다른 기분 안정제로 이루어진 그룹 중에서 선택된 1종 이상의 타 약제 화합물과 병행하여 사용되는 방법.
- 제 1 항에 있어서, 충동 자제 이상이 성도착증/섹스 중독증이고 화합물이 세로토닌 재흡수 억제제, 리튬, 디발프로엑스 나트륨/발프로 산, 항-안드로겐제, 다른 항울제, 및 다른 기분 안정제로 이루어진 그룹 중에서 선택된 1종 이상의 타 약제 화합물과 병행하여 사용되는 방법.
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- 2000-02-18 EP EP00914630A patent/EP1158973B1/en not_active Expired - Lifetime
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ZA200106675B (en) | 2002-05-17 |
JP2002537326A (ja) | 2002-11-05 |
EP1158973A2 (en) | 2001-12-05 |
AU3599400A (en) | 2000-09-14 |
DE60019904D1 (de) | 2005-06-09 |
MXPA01008537A (es) | 2005-02-17 |
CA2364949A1 (en) | 2000-08-31 |
ES2238999T3 (es) | 2005-09-16 |
US20010023254A1 (en) | 2001-09-20 |
KR100697485B1 (ko) | 2007-03-20 |
IL144884A (en) | 2006-12-10 |
AU779248B2 (en) | 2005-01-13 |
DE60019904T2 (de) | 2006-05-04 |
EP1158973B1 (en) | 2005-05-04 |
DK1158973T3 (da) | 2005-05-30 |
HUP0200469A3 (en) | 2003-03-28 |
ATE294577T1 (de) | 2005-05-15 |
BR0008477A (pt) | 2002-01-22 |
CZ20013061A3 (cs) | 2002-06-12 |
PT1158973E (pt) | 2005-07-29 |
CN1360500A (zh) | 2002-07-24 |
HUP0200469A2 (hu) | 2002-05-29 |
NO20014104L (no) | 2001-10-16 |
NO20014104D0 (no) | 2001-08-23 |
WO2000050020A3 (en) | 2000-12-21 |
US6323236B2 (en) | 2001-11-27 |
WO2000050020A2 (en) | 2000-08-31 |
NZ513643A (en) | 2005-04-29 |
CN100548290C (zh) | 2009-10-14 |
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