2 -imidazolines having a good affinity to the trace amine associated receptors (TAAR)The present invention relates to compounds of formula (I) wherein X-Y is -N(R2) -CH(R3)-, CH(R3)-N(R2)-, -NH-NH-, -O-CHR3-, -CHR3-O-, -S-CHR3, -CHR3-S- or -CHR3-CHR3 -; R1 is hydrogen, halogen, lower alkyl, lower alkoxy, -(CH2)o-phenyl optionally substituted by lower alkoxy, -(CH2)o-C(O)-phenyl optionally substituted by lower alkoxy, -(CH2)o-O-phenyl optionally substituted by lower alkoxy, -(CH2)o-O-phenyl, CF3, cycloalkyl, NO2, amino or hydroxy; R2 is hydrogen, lower alkyl, phenyl optionally substituted by hydroxy or benzyl; R3/R3' are independently from each other hydrogen, lower alkyl or benzyl; Ar is phenyl, naphthyl, benzofuranyl or benzo [1,3] dioxolyl; n is 1, 2, 3 or 4; o is 0, 1, 2, 3 and to their pharmaceutically active salts, It has been found that the compounds of formula (I) have a good affinity to the trace amine associated receptors (TAARs), especially for TAAR1. The compounds may be used for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.Formula i compoundwherein:x-y is-n (r 2)-ch (r 3)-, ch (r 3)-n (r 2)-,-nh-nh-,-o-chr 3-,-chr 3-o-,-s-chr 3,-chr 3-s-or-chr 3-chr 3'-; r 1be hydrogen, halogen, low alkyl group, lower alkoxy-(ch 2) o-, the optional phenyl that is replaced by lower alkoxy ,-(ch 2) othe phenyl that-c (o)-optional is replaced by lower alkoxy ,-(ch 2) othe optional phenyl that is replaced by lower alkoxy of-o-, -(ch 2) o-o-phenyl, cf 3, cycloalkyl, no 2, amino or hydroxyl; r 2be hydrogen, low alkyl group, the optional phenyl that is replaced by hydroxyl, or benzyl; r 3/ r 3' be hydrogen, low alkyl group or benzyl independently of one another; ar is phenyl, naphthyl, benzofuryl or benzo [1, a 3] dioxa cyclopentenyl;n is 0,1,2,3 or 4;o is 1,2,3;and their pharmaceutically active salt, except the following compound:(4-chloro-phenyl)-(4,5-dihydro-1h-imidazoles-2-ylmethyl)-amine(3-chloro-phenyl)-(4,5-dihydro-1h-imidazoles-2-ylmethyl)-amine(4,5-dihydro-1h-imidazoles-2-ylmethyl)-ethyl-phenyl-amine3-[(4,5-dihydro-1h-imidazoles-2-ylmethyl)-p-methylphenyl-amino]-phenol benzyl-(4,5-dihydro-1h-imidazoles-2-ylmethyl)-phenyl-amine2-(4-benzyl-phenoxymethyl)-4,5-dihydro-1h-imidazoles2-(4-styroyl-phenoxymethyl)-4,5-dihydro-1h-imidazoles2-(2,3,6-trimethylammonium-phenoxymethyl)-4,5-dihydro-1h-imidazoles2-(2,6-two chloro-phenoxymethyls)-4,5-dihydro-1h-imidazoles2-(2-chloro-phenoxymethyl)-4,5-dihydro-1h-imidazoles2-(xenyl-2-base oxygen ylmethyl)-4,5-dihydro-1h-imidazoles2-(2,3-two chloro-phenoxymethyls)-4,5-dihydro-1h-imidazoles2-(xenyl-4-base oxygen ylmethyl)-4,5-dihydro-1h-imidazoles2-(2-methoxyl group-phenoxymethyl)-4,5-dihydro-1h-imidazoles2-(naphthalene-2-base oxygen ylmethyl)-4,5-dihydro-1h-imidazoles2-(4-chloro-phenoxymethyl)-4,5-dihydro-1h-imidazoles2-(3-trifluoromethyl-phenoxymethyl)-4,5-dihydro-1h-imidazoles2-(2,4-two chloro-phenoxymethyls)-4,5-dihydro-1h-imidazoles2-[1-(2-benzyloxy-phenoxy group)-2-phenyl-ethyl]-4,5-dihydro-1h-imidazoles2-(2-cyclopropyl-phenoxymethyl)-4,5-dihydro-1h-imidazoles2-[1-(2,6-two chloro-phenoxy groups)-ethyl]-4,5-dihydro-1h-imidazoles2-(3-chloro-phenoxymethyl)-4,5-dihydro-1h-imidazoles2-phenoxymethyl-4,5-dihydro-1h-imidazoles2-styroyl-4,5-dihydro-1h-imidazolesn-(3-chloro-2-methyl-phenyl)-n '-(4,5-dihydro-1h-imidazoles-2-yl)-hydrazine benzyl-(4,5-dihydro-1h-imidazoles-2-yl)-amine2-(3,4-two chloro-phenyl sulfenyl methyl)-4,5-dihydro-1h-imidazoles2-(2,4-two chloro-dibenzylsulfide bases)-4,5-dihydro-1h-imidazoles2-(3-chloro-4-propoxy--benzyl sulfenyl)-4,5-dihydro-1h-imidazoles2-(3-nitro-4-propoxy--benzyl sulfenyl)-4,5-dihydro-1h-imidazoles2-benzyl sulfenyl-4,5-dihydro-1h-imidazoles2-(2-chloro-6-fluoro-benzyl sulfenyl)-4,5-dihydro-1h-imidazoles2-(3-chloro-4-oxyethyl group-benzyl sulfenyl)-4,5-dihydro-1h-imidazoles2-(2,6-two chloro-dibenzylsulfide bases)-4,5-dihydro-1h-imidazoles2-(3,4-two chloro-dibenzylsulfide bases)-4,5-dihydro-1h-imidazoles.
미량 아민 결합 수용체(ＴＡＡＲ)에 대한 양호한 친화도를 갖는 2-이미다졸린본 발명은 하기 화학식 1의 화합물 또는 이의 약학적인 활성 염에 관한 것이다: 화학식 1  상기 식에서, X-Y는 -N(R2)-CH(R3)-, -CH(R3)-N(R2)-, -NH-NH-, -O-CHR3-, -CHR3-O-, -S-CHR3-, -CHR3-S- 또는 -CHR3-CHR3'-이고; R1은 수소, 할로겐, 저급 알킬, 저급 알콕시, 저급 알콕시로 선택적으로 치환된 -(CH2)o-페닐, 저급 알콕시로 선택적으로 치환된 -(CH2)o-C(O)-페닐, 저급 알콕시로 선택적으로 치환된 -(CH2)o-O-페닐, -(CH2)o-O-페닐, CF3, 사이클로알킬, NO2, 아미노 또는 하이드록시이고; R2는 수소, 저급 알킬, 하이드록시로 선택적으로 치환된 페닐, 또는 벤질이고; R3 및 R3'는 서로 독립적으로 수소, 저급 알킬 또는 벤질이고; Ar은 페닐, 나프틸, 벤조푸란일 또는 벤조[1,3]다이옥솔릴이고; n은 1, 2, 3 또는 4이고; o는 0, 1, 2 또는 3이다. 화학식 1의 화합물이 미량 아민 결합 수용체(TAAR), 특히 TAAR1에 대한 양호한 친화도를 갖음이 밝혀졌다. 상기 화합물은 우울증, 불안 장애, 양극성 장애, 주의력 결핍 과다행동 장애(ADHD), 스트레스-관련 질환, 정신병적 장애, 예컨대 정신분열증, 신경학적 질병, 예컨대 파킨슨병, 신경퇴행성 질환, 예컨대 알츠하이머병, 간질, 편두통, 고혈압, 물질 남용 또는 대사 장애, 예컨대 섭식 장애, 당뇨병, 당뇨병 합병증, 비만, 이상지질혈증, 에너지 소비 또는 동화의 장애, 체온 항상성의 장애 또는 기능이상, 수면 또는 일주기 리듬의 장애, 또는 심혈관 질환의 치료에 사용될 수 있다.하기 화학식 1의 화합물 또는 이의 약학적으로 허용되는 염:화학식 1[이미지]상기 식에서,X-Y는 -N(R2)-CH(R3)-, -CH(R3)-N(R2)-, -NH-NH-, -O-CHR3-, -CHR3-O-, -S-CHR3-, -CHR3-S- 또는 -CHR3-CHR3'-이고;R1은 수소, 할로겐, 저급 알킬, 저급 알콕시, 저급 알콕시로 선택적으로 치환된 -(CH2)o-페닐, 저급 알콕시로 선택적으로 치환된 -(CH2)o-C(O)-페닐, 저급 알콕시로 선택적으로 치환된 -(CH2)o-O-페닐, -(CH2)o-O-페닐, CF3, 사이클로알킬, NO2, 아미노 또는 하이드록시이고;R2는 수소, 저급 알킬, 하이드록시로 선택적으로 치환된 페닐, 또는 벤질이고;R3 및 R3'는 서로 독립적으로 수소, 저급 알킬 또는 벤질이고; Ar은 페닐, 나프틸, 벤조푸란일 또는 벤조[1,3]다이옥솔릴이고; n은 0, 1, 2, 3 또는 4이고;o는 0, 1, 2 또는 3이되;하기 화합물은 제외된다:(4-클로로-페닐)-(4,5-다이하이드로-1H-이미다졸-2-일메틸)-아민;(3-클로로-페닐)-(4,5-다이하이드로-1H-이미다졸-2-일메틸)-아민;(4,5-다이하이드로-1H-이미다졸-2-일메틸)-에틸-페닐-아민;3-[(4,5-다이하이드로-1H-이미다졸-2-일메틸)-p-톨릴-아미노]-페놀;벤질-(4,5-다이하이드로-1H-이미다졸-2-일메틸)-페닐-아민;2-(4-벤질-페녹시메틸)-4,5-다이하이드로-1H-이미다졸;2-(4-펜에틸-페녹시메틸)-4,5-다이하이드로-1H-이미다졸;2-(2,3,6-트라이메틸-페녹시메틸)-4,5-다이하이드로-1H-이미다졸;2-(2,6-다이클로로-페녹시메틸)-4,5-다이하이드로-1H-이미다졸;2-(2-클로로-페녹시메틸)-4,5-다이하이드로-1H-이미다졸;2-(바이페닐-2-일옥시메틸)-4,5-다이하이드로-1H-이미다졸;2-(2,3-다이클로로-페녹시메틸)-4,5-다이하이드로-1H-이미다졸;2-(바이페닐-4-일옥시메틸)-4,5-다이하이드로-1H-이미다졸;2-(2-메톡시-페녹시메틸)-4,5-다이하이드로-1H-이미다졸;2-(나프탈렌-2-일옥시메틸)-4,5-다이하이드로-1H-이미다졸;2-(4-클로로-페녹시메틸)-4,5-다이하이드로-1H-이미다졸;2-(3-트라이플루오로메틸-페녹시메틸)-4,5-다이하이드로-1H-이미다졸;2-(2,4-다이클로로-페녹시메틸)-4,5-다이하이드로-1H-이미다졸;2-[1-(2-벤질옥시-페녹시)-2-페닐-에틸]-4,5-다이하이드로-1H-이미다졸;2-(2-사이클로프로필-페녹시메틸)-4,5-다이하이드로-1H-이미다졸;2-[1-(2,6-다이클로로-페녹시)-에틸]-4,5-다이하이드로-1H-이미다졸;2-(3-클로로-페녹시메틸)-4,5-다이하이드로-1H-이미다졸;2-페녹시메틸-4,5-다이하이드로-1H-이미다졸;2-펜에틸-4,5-다이하이드로-1H-이미다졸;N-(3-클로로-2-메틸-페닐)-N'-(4,5-다이하이드로-1H-이미다졸-2-일)-하이드라진;벤질-(4,5-다이하이드로-1H-이미다졸-2-일)-아민;2-(3,4-다이클로로-페닐설판일메틸)-4,5-다이하이드로-1H-이미다졸;2-(2,4-다이클로로-벤질설판일)-4,5-다이하이드로-1H-이미다졸;2-(3-클로로-4-프로폭시-벤질설판일)-4,5-다이하이드로-1H-이미다졸;2-(3-나이트로-4-프로폭시-벤질설판일)-4,5-다이하이드로-1H-이미다졸;2-벤질설판일-4,5-다이하이드로-1H-이미다졸;2-(2-클로로-6-플루오로-벤질설판일)-4,5-다이하이드로-1H-이미다졸;2-(3-클로로-4-에톡시-벤질설판일)-4,5-다이하이드로-1H-이미다졸;2-(2,6-다이클로로-벤질설판일)-4,5-다이하이드로-1H-이미다졸; 및2-(3,4-다이클로로-벤질설판일)-4,5-다이하이드로-1H-이미다졸.