KR100863147B1 - Benzimidazoles and pharmaceutical compositions comprising the same for treating sexual dysfunction - Google Patents
Benzimidazoles and pharmaceutical compositions comprising the same for treating sexual dysfunction Download PDFInfo
- Publication number
- KR100863147B1 KR100863147B1 KR1020037011948A KR20037011948A KR100863147B1 KR 100863147 B1 KR100863147 B1 KR 100863147B1 KR 1020037011948 A KR1020037011948 A KR 1020037011948A KR 20037011948 A KR20037011948 A KR 20037011948A KR 100863147 B1 KR100863147 B1 KR 100863147B1
- Authority
- KR
- South Korea
- Prior art keywords
- methyl
- hydrogen
- benzimidazole
- group
- piperazin
- Prior art date
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- 201000001880 Sexual dysfunction Diseases 0.000 title claims abstract description 67
- 231100000872 sexual dysfunction Toxicity 0.000 title claims abstract description 67
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 29
- 150000001556 benzimidazoles Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 224
- 150000001408 amides Chemical class 0.000 claims abstract description 60
- 150000002148 esters Chemical class 0.000 claims abstract description 59
- 239000000203 mixture Substances 0.000 claims abstract description 50
- 229910052739 hydrogen Inorganic materials 0.000 claims description 256
- 239000001257 hydrogen Substances 0.000 claims description 256
- 150000002431 hydrogen Chemical class 0.000 claims description 130
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 120
- -1 cyano, formyl Chemical group 0.000 claims description 118
- 238000000034 method Methods 0.000 claims description 100
- 229910052736 halogen Inorganic materials 0.000 claims description 93
- 150000002367 halogens Chemical class 0.000 claims description 93
- 125000000217 alkyl group Chemical group 0.000 claims description 86
- 150000003839 salts Chemical class 0.000 claims description 63
- 241000124008 Mammalia Species 0.000 claims description 62
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 59
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 52
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 44
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 44
- 125000003545 alkoxy group Chemical group 0.000 claims description 32
- 125000004414 alkyl thio group Chemical group 0.000 claims description 29
- FRPJGTNLZNXQEX-UHFFFAOYSA-N 2-[[4-(2-pyridinyl)-1-piperazinyl]methyl]-1H-benzimidazole Chemical compound N=1C2=CC=CC=C2NC=1CN(CC1)CCN1C1=CC=CC=N1 FRPJGTNLZNXQEX-UHFFFAOYSA-N 0.000 claims description 26
- 125000003342 alkenyl group Chemical group 0.000 claims description 26
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 26
- 125000000304 alkynyl group Chemical group 0.000 claims description 26
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 25
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 25
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 23
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 23
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 21
- 229910052717 sulfur Inorganic materials 0.000 claims description 21
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- CBDXXUZXRDBOGH-UHFFFAOYSA-N 6-[4-(1h-benzimidazol-2-ylmethyl)piperazin-1-yl]pyridin-3-ol Chemical compound N1=CC(O)=CC=C1N1CCN(CC=2NC3=CC=CC=C3N=2)CC1 CBDXXUZXRDBOGH-UHFFFAOYSA-N 0.000 claims description 18
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 18
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 18
- DFYAIIXQJKVNLK-UHFFFAOYSA-N 2-[(4-pyridin-2-ylpiperidin-1-yl)methyl]-1h-benzimidazole Chemical compound N=1C2=CC=CC=C2NC=1CN(CC1)CCC1C1=CC=CC=N1 DFYAIIXQJKVNLK-UHFFFAOYSA-N 0.000 claims description 16
- NFCYVMDRDOBUCA-UHFFFAOYSA-N 2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl)methyl]-1h-benzimidazole Chemical compound C1CN(CC=2NC3=CC=CC=C3N=2)C(C)CN1C1=CC=CC=N1 NFCYVMDRDOBUCA-UHFFFAOYSA-N 0.000 claims description 15
- XJHRQPODSUYKOJ-UHFFFAOYSA-N 2-[(4-pyrimidin-2-ylpiperazin-1-yl)methyl]-1h-benzimidazole Chemical compound N=1C2=CC=CC=C2NC=1CN(CC1)CCN1C1=NC=CC=N1 XJHRQPODSUYKOJ-UHFFFAOYSA-N 0.000 claims description 15
- OTCBEARWFWNLRF-UHFFFAOYSA-N 2-[4-(1h-benzimidazol-2-ylmethyl)piperazin-1-yl]-1,3-thiazole Chemical compound N=1C2=CC=CC=C2NC=1CN(CC1)CCN1C1=NC=CS1 OTCBEARWFWNLRF-UHFFFAOYSA-N 0.000 claims description 15
- NFCYVMDRDOBUCA-CQSZACIVSA-N 2-[[(2r)-2-methyl-4-pyridin-2-ylpiperazin-1-yl]methyl]-1h-benzimidazole Chemical compound C([C@H](N(CC1)CC=2NC3=CC=CC=C3N=2)C)N1C1=CC=CC=N1 NFCYVMDRDOBUCA-CQSZACIVSA-N 0.000 claims description 15
- NFCYVMDRDOBUCA-AWEZNQCLSA-N 2-[[(2s)-2-methyl-4-pyridin-2-ylpiperazin-1-yl]methyl]-1h-benzimidazole Chemical compound C([C@@H](N(CC1)CC=2NC3=CC=CC=C3N=2)C)N1C1=CC=CC=N1 NFCYVMDRDOBUCA-AWEZNQCLSA-N 0.000 claims description 15
- VZEBBCOAASDUOG-UHFFFAOYSA-N 2-methylpropyl 2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]benzimidazole-1-carboxylate Chemical compound N=1C2=CC=CC=C2N(C(=O)OCC(C)C)C=1CN(CC1)CCN1C1=CC=CC=N1 VZEBBCOAASDUOG-UHFFFAOYSA-N 0.000 claims description 15
- ZSKFERSPBICNGI-UHFFFAOYSA-N 6-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1h-benzimidazole Chemical compound N=1C2=CC(F)=CC=C2NC=1CN(CC1)CCN1C1=CC=CC=N1 ZSKFERSPBICNGI-UHFFFAOYSA-N 0.000 claims description 15
- AREKWDVNONIIPS-UHFFFAOYSA-N [2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]benzimidazol-1-yl]-pyrrolidin-1-ylmethanone Chemical compound C1CN(C=2N=CC=CC=2)CCN1CC1=NC2=CC=CC=C2N1C(=O)N1CCCC1 AREKWDVNONIIPS-UHFFFAOYSA-N 0.000 claims description 15
- JBDSKBUSDDHPEB-UHFFFAOYSA-N n,n-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]benzimidazole-1-carboxamide Chemical compound N=1C2=CC=CC=C2N(C(=O)N(C)C)C=1CN(CC1)CCN1C1=CC=CC=N1 JBDSKBUSDDHPEB-UHFFFAOYSA-N 0.000 claims description 15
- UZJFFJHTJQGBFA-UHFFFAOYSA-N n-[2-[4-(1h-benzimidazol-2-ylmethyl)piperazin-1-yl]pyridin-3-yl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=CN=C1N1CCN(CC=2NC3=CC=CC=C3N=2)CC1 UZJFFJHTJQGBFA-UHFFFAOYSA-N 0.000 claims description 15
- DZNZGCABZHIRPU-UHFFFAOYSA-N 2-[(4-phenyl-3,6-dihydro-2h-pyridin-1-yl)methyl]-1h-benzimidazole Chemical compound N=1C2=CC=CC=C2NC=1CN(CC=1)CCC=1C1=CC=CC=C1 DZNZGCABZHIRPU-UHFFFAOYSA-N 0.000 claims description 14
- IRHVKGPETODEAT-UHFFFAOYSA-N 2-[(4-phenylpiperazin-1-yl)methyl]-1h-benzimidazole Chemical compound N=1C2=CC=CC=C2NC=1CN(CC1)CCN1C1=CC=CC=C1 IRHVKGPETODEAT-UHFFFAOYSA-N 0.000 claims description 14
- FXHHMDYNRLYBIP-UHFFFAOYSA-N 2-[4-(1h-benzimidazol-2-ylmethyl)piperazin-1-yl]benzonitrile Chemical compound N#CC1=CC=CC=C1N1CCN(CC=2NC3=CC=CC=C3N=2)CC1 FXHHMDYNRLYBIP-UHFFFAOYSA-N 0.000 claims description 14
- GVEYDRPQIGZJMX-UHFFFAOYSA-N 2-[4-(1h-benzimidazol-2-ylmethyl)piperazin-1-yl]phenol Chemical compound OC1=CC=CC=C1N1CCN(CC=2NC3=CC=CC=C3N=2)CC1 GVEYDRPQIGZJMX-UHFFFAOYSA-N 0.000 claims description 14
- HSEIIOCMMFLOGG-UHFFFAOYSA-N 2-[4-(1h-benzimidazol-2-ylmethyl)piperazin-1-yl]pyridine-3-carbonitrile Chemical compound N#CC1=CC=CN=C1N1CCN(CC=2NC3=CC=CC=C3N=2)CC1 HSEIIOCMMFLOGG-UHFFFAOYSA-N 0.000 claims description 14
- ATPCXZFSRSVMMW-UHFFFAOYSA-N 2-[[4-(2-chlorophenyl)piperazin-1-yl]methyl]-1h-benzimidazole Chemical compound ClC1=CC=CC=C1N1CCN(CC=2NC3=CC=CC=C3N=2)CC1 ATPCXZFSRSVMMW-UHFFFAOYSA-N 0.000 claims description 14
- STLDHJMNWBEBGX-UHFFFAOYSA-N 2-[[4-(2-ethoxyphenyl)piperazin-1-yl]methyl]-1h-benzimidazole Chemical compound CCOC1=CC=CC=C1N1CCN(CC=2NC3=CC=CC=C3N=2)CC1 STLDHJMNWBEBGX-UHFFFAOYSA-N 0.000 claims description 14
- APKCWCBYTWWSHR-UHFFFAOYSA-N 2-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]-1h-benzimidazole Chemical compound FC1=CC=CC=C1N1CCN(CC=2NC3=CC=CC=C3N=2)CC1 APKCWCBYTWWSHR-UHFFFAOYSA-N 0.000 claims description 14
- GRGYFXDAOZBGPF-UHFFFAOYSA-N 2-[[4-(2-methoxyphenyl)piperazin-1-yl]methyl]-1h-benzimidazole Chemical compound COC1=CC=CC=C1N1CCN(CC=2NC3=CC=CC=C3N=2)CC1 GRGYFXDAOZBGPF-UHFFFAOYSA-N 0.000 claims description 14
- QKKFQHBDHBMWGM-UHFFFAOYSA-N 2-[[4-(2-methoxyphenyl)piperidin-1-yl]methyl]-1h-benzimidazole Chemical compound COC1=CC=CC=C1C1CCN(CC=2NC3=CC=CC=C3N=2)CC1 QKKFQHBDHBMWGM-UHFFFAOYSA-N 0.000 claims description 14
- BZIHDTKDCIILSI-UHFFFAOYSA-N 2-[[4-(2-methylsulfanylphenyl)piperazin-1-yl]methyl]-1h-benzimidazole Chemical compound CSC1=CC=CC=C1N1CCN(CC=2NC3=CC=CC=C3N=2)CC1 BZIHDTKDCIILSI-UHFFFAOYSA-N 0.000 claims description 14
- KEGYYRUXGXROQP-UHFFFAOYSA-N 2-[[4-(2-nitrophenyl)piperazin-1-yl]methyl]-1h-benzimidazole Chemical compound [O-][N+](=O)C1=CC=CC=C1N1CCN(CC=2NC3=CC=CC=C3N=2)CC1 KEGYYRUXGXROQP-UHFFFAOYSA-N 0.000 claims description 14
- DIIMPNOBUZSQDU-UHFFFAOYSA-N 2-[[4-(3-fluoropyridin-2-yl)piperazin-1-yl]methyl]-1h-benzimidazole Chemical compound FC1=CC=CN=C1N1CCN(CC=2NC3=CC=CC=C3N=2)CC1 DIIMPNOBUZSQDU-UHFFFAOYSA-N 0.000 claims description 14
- WINMXTNEPXMBLG-UHFFFAOYSA-N 2-[[4-(3-methylpyridin-2-yl)piperazin-1-yl]methyl]-1h-benzimidazole Chemical compound CC1=CC=CN=C1N1CCN(CC=2NC3=CC=CC=C3N=2)CC1 WINMXTNEPXMBLG-UHFFFAOYSA-N 0.000 claims description 14
- QXIHXJBCHQNHHK-UHFFFAOYSA-N 4,6-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1h-benzimidazole Chemical compound N=1C2=CC(Br)=CC(Br)=C2NC=1CN(CC1)CCN1C1=CC=CC=N1 QXIHXJBCHQNHHK-UHFFFAOYSA-N 0.000 claims description 14
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- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 14
- FLKJVYVXYMFZRE-UHFFFAOYSA-N 2-[[4-(6-methylpyridin-2-yl)piperazin-1-yl]methyl]-1h-benzimidazole Chemical compound CC1=CC=CC(N2CCN(CC=3NC4=CC=CC=C4N=3)CC2)=N1 FLKJVYVXYMFZRE-UHFFFAOYSA-N 0.000 claims description 13
- 125000004122 cyclic group Chemical group 0.000 claims description 13
- 229920006395 saturated elastomer Polymers 0.000 claims description 13
- 229940095064 tartrate Drugs 0.000 claims description 13
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 12
- KMKXKQTUXKYJDN-WBPXWQEISA-N (2r,3r)-2,3-dihydroxybutanedioic acid;2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1h-benzimidazole Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.N=1C2=CC=CC=C2NC=1CN(CC1)CCN1C1=CC=CC=N1 KMKXKQTUXKYJDN-WBPXWQEISA-N 0.000 claims description 11
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
본 발명은 성 기능장애를 치료하기 위한 화학식 I'의 화합물의 용도 및 성 기능장애를 치료하기 위한 화학식 I'의 화합물을 함유하는 조성물에 관한 것이다.The present invention relates to the use of a compound of formula (I ') to treat sexual dysfunction and to a composition containing a compound of formula (I') to treat sexual dysfunction.
화학식 I'Formula I '
성 기능장애, 벤즈이미다졸, 에스테르, 아미드Sexual dysfunction, benzimidazole, esters, amides
Description
본 발명은 성 기능장애 치료용 벤즈이미다졸 및 당해 화합물을 함유하는 조성물의 용도에 관한 것이다.
The present invention relates to the use of benzimidazole and compositions containing the compound for the treatment of sexual dysfunction.
임상전 증거는 도파민(DA)이 포유동물의 음경 발기에 중요한 역할을 한다는 것을 나타낸다. 성적 자극은 포유동물의 대뇌 겉질에 이르는 감각(성욕) 정보에 의해 개시될 수 있다. 대뇌 겉질은 편도와 같은 가장자리 구조 뿐만 아니라 수관주변 회색질(PAG)과 같은 중간뇌 구조 및 시상하부와의 광범위한 신경세포 연결을 갖는다. 시상하부의 두 가지 중요한 핵은 내부 시각교차앞구역(MPOA) 및 뇌실곁핵(PVN)이다. MPOA 및 PVN 핵은 이러한 영역의 양쪽 병소가 남성 성적 거동을 완전히 제거하기 때문에 성적 거동에서 중요한 역할을 한다. PVN 및 MPOA 핵을 자극하는 incerto-시상하부 도파민 경로가 DA 제제의 조기발기 효과와 연관되었다. 아포모르핀((6aR) 5,6,6a,7-테트라하이드로-6-메틸-4H-디벤조[de,g]퀴놀린-10,11-디올), 퀸피롤 및 (-)-(3-하이드록시페닐)-N-프로필피페리딘(3-PPP)와 같은 DA 수용체 효능제의 전신 투여는 중심 DA 길항제인 할로페리돌에 의해 차단된 효과, 래트의 음경 발기를 촉진시킨다. 발기발생 효과는 말초 DA 길항제인 돔페리돈에 의해 차단될 수 없기 때문에, DA 효능제의 조기발기 효과는 중추적으로 매개된다고 간주된다[참조: Andersson K and Wagner G, Physiology of penile erection, Physiol Rev (1995) 75:191-236; deGroat W and Booth A, Neural Control of Penile Erection, in: Nervous control of urogenital system, Vol. 3, (ed. Maggi, C) (1993) p. 467-524, Hardwood Academic Publishers, Chur, Switzerland; and Moreland RB, Nakane M, Hsieh G and Brioni JD, Prospectives for Pharmacotherapy of Male Erectile Dysfunction, Curr Opinion CPNS Invest Drugs (2000) 2:283-302].Preclinical evidence indicates that dopamine (DA) plays an important role in mammalian penile erection. Sexual stimulation can be initiated by sensory (sexual desire) information leading to the mammalian cerebral cortex. The cerebral cortex has a wide range of neuronal connections with the hypothalamus and intermediate brain structures such as perianal gray matter (PAG) as well as edge structures such as tonsils. The two major nuclei of the hypothalamus are the MPOA and the ventricular nucleus (PVN). MPOA and PVN nuclei play an important role in sexual behavior because both lesions in these regions completely eliminate male sexual behavior. The incerto-hypothalamic dopamine pathway that stimulates PVN and MPOA nuclei has been associated with the early erectile effect of DA preparations. Apomorphine ((6aR) 5,6,6a, 7-tetrahydro-6-methyl-4H-dibenzo [de, g] quinoline-10,11-diol), quinpyrrole and (-)-(3-hydr Systemic administration of DA receptor agonists such as oxyphenyl) -N-propylpiperidine (3-PPP) promotes rat penile erection, an effect blocked by the central DA antagonist haloperidol. Since the erectile effect cannot be blocked by the peripheral DA antagonist domperidone, the early erectile effect of DA agonists is considered to be centrally mediated. Andersson K and Wagner G, Physiology of penile erection, Physiol Rev (1995) ) 75: 191-236; deGroat W and Booth A, Neural Control of Penile Erection, in: Nervous control of urogenital system, Vol. 3, (ed. Maggi, C) (1993) p. 467-524, Hardwood Academic Publishers, Chur, Switzerland; and Moreland RB, Nakane M, Hsieh G and Brioni JD, Prospectives for Pharmacotherapy of Male Erectile Dysfunction, Curr Opinion CPNS Invest Drugs (2000) 2: 283-302].
임상 데이터는 또한 파킨슨병 환자의 L-도파의 성적 자극 효과 및 사람의 아포모르핀의 조기발기 효과에 의해 나타나는 바와 같이, CNS의 DA 시스템이 남성 성적 거동의 조절에서 중요한 역할을 한다는 것을 나타낸다[참조: Morales A, Geaton J, Johnston B and Adams M, Oral and Topical Treatment of Erectile Dysfunction: present and future, in: Urologic Clinics of North America, (1995) Vol. 22, p. 879-886; Padma-Nathan H, Auerbach S, Lewis R, Lewand M and Perdok R , Efficacy and safety of apomorphine SL vs. placebo for male erectile dysfunction (MED), Urology (1999) 161:214 (abstract 821); and Dula E, Keating W, Siami P, Edmonds A, O'Neil J, Efficacy and safety of fixed-dose and dose-optimization regimens of sublingual apomorphine versus placebo in men with erectile dysfunction, Urology (2000) 56:130-135]. Clinical data also indicate that the DA system of the CNS plays an important role in the regulation of male sexual behavior, as indicated by the sexual stimulatory effect of L-dopa in Parkinson's disease and the early erectile effect of apomorphine in humans. Morales A, Geaton J, Johnston B and Adams M, Oral and Topical Treatment of Erectile Dysfunction: present and future, in: Urologic Clinics of North America, (1995) Vol. 22, p. 879-886; Padma-Nathan H, Auerbach S, Lewis R, Lewand M and Perdok R, Efficacy and safety of apomorphine SL vs. placebo for male erectile dysfunction (MED), Urology (1999) 161: 214 (abstract 821); and Dula E, Keating W, Siami P, Edmonds A, O'Neil J, Efficacy and safety of fixed-dose and dose-optimization regimens of sublingual apomorphine versus placebo in men with erectile dysfunction, Urology (2000) 56: 130-135 ].
DA 수용체는 세포내 GTP-결합 단백질에 커플링시켜 세포막을 가로질러 신호하는 단백질 수용체의 초집단(superfamily)에 속한다. 특정 세포내 이벤트를 유도하는 몇 가지의 G 단백질(Gs, Gq 및 Gi 포함)이 확인되었다[참조: Milligan G and Rees S, Chimaeric G proteins: their potential use in drug discovery, Trends Pharmacol Sci (1999) 20:118-124].DA receptors belong to a superfamily of protein receptors that couple across cellular membranes and signal across GTP-binding proteins. Several G proteins (including Gs, Gq and Gi) have been identified that induce specific intracellular events.Milligan G and Rees S, Chimaeric G proteins: their potential use in drug discovery, Trends Pharmacol Sci (1999) 20 : 118-124].
다섯 개의 공지된 DA 수용체가 존재하는데, 이는 두 개의 그룹, D1형 및 D2형으로 분류된다. D1형 수용체는 D1 및 D5를 포함한다. D2형 수용체는 D2, D3 및 D4를 포함한다[참조: Missale C, Nash S, Robinson S, Jaber M and Caron M, Dopamine receptors: from structure to function, Physiol Rev (1998) 78:189-225]. D1형 집단 수용체 아형은 Gs 커플링되어 아데닐레이트 사이클라제를 활성화시킬 수 있다. D2형 집단 수용체 아형은 Gi 커플링되어 세포네 칼슘 농도를 증가시키고 아데닐레이트 사이클라제를 억제한다.There are five known DA receptors, which are classified into two groups, type D 1 and type D 2 . Type 1 receptors include D 1 and D 5 . D type 2 receptors include D 2 , D 3 and D 4. Missale C, Nash S, Robinson S, Jaber M and Caron M, Dopamine receptors: from structure to function, Physiol Rev (1998) 78: 189 -225]. The D 1 type receptor subtype can be G s coupled to activate adenylate cyclase. Type 2 population receptor subtypes are Gi coupled to increase cellular calcium concentrations and inhibit adenylate cyclase.
D1형 집단 구성원은 아데닐레이트 사이클라제를 활성화시킬 수 있는 Gs 커플링된 수용체이다. D1 수용체는 mRNA 발현과 면역조직화학 연구에 의하면 CNS에서 가장 많으면서 일반적인 DA 수용체이다[참조: Vallone D, Picetti R and Borreli E, Structure and function of dopamine receptors, Neurosci Biobehav Rev (2000) 24:125-132]. 이는 줄무늬체, 측중격 핵(nucleus accumbens) 및 후각 결절 뿐만 아니라 변연계, 시상하부 및 시상에서 발견된다. D1 수용체 발현은 심장 및 신장에서 보고된 바 있으며, 이들 말초 D1 수용체의 기능은 명확해진 상태이지만, 혈류역학적 변수의 조절에 대한 이의 역할을 확인하여 왔다. D5 수용체는, D1 수용체보다 DA에 대한 친화도가 더 높은데, CNS 외부에서 발현의 증거가 나타나지 않는 CNS에 드물게 분포되어 있다.Type 1 population members are G s coupled receptors capable of activating adenylate cyclase. D 1 receptors are the most common DA receptors in the CNS according to mRNA expression and immunohistochemistry studies [Vallone D, Picetti R and Borreli E, Structure and function of dopamine receptors, Neurosci Biobehav Rev (2000) 24: 125 -132]. It is found in the limbic system, hypothalamus and thalamus, as well as in the striated body, nucleus accumbens and olfactory nodules. D 1 receptor expression has been reported in the heart and kidneys, although the function of these peripheral D 1 receptors is clear, but its role in the regulation of hemodynamic parameters has been confirmed. The D 5 receptor has a higher affinity for DA than the D 1 receptor and is rarely distributed in the CNS where no evidence of expression is seen outside the CNS.
D2형 집단 구성원은 아데닐레이트 사이클라제를 억제하고 세포내 칼슘 농도를 증가시키는 Gi 커플링된 수용체이다. D2 수용체는 D2형 수용체중 가장 많으며, 줄무늬체 및 흑색질 등의 뇌 부분 및 심장, 뇌하수체 및 신장 등의 말초 부분에 위치하고 있다. D3 수용체는 배 줄무늬체/측중격 핵 영역, 후각 결절, 치아이랑(dendate gyrus) 및 선조 피질에 명백한 군집 개체군을 갖는 칼레자 섬(islands of Callefa)에서 많이 발견된다[참조: Suzuki M, Hurd Y, Sokoloff P, Schwartz J and Sedwall G, D3 dopamine receptor mRNA is widely express in human brain, Brain Res (1998) 779:58-74].Type 2 population members are G i coupled receptors that inhibit adenylate cyclase and increase intracellular calcium concentration. D 2 receptors are the most common D 2 type receptors, and are located in the brain parts such as striated and black matter and in the peripheral parts of the heart, pituitary gland and kidney. D 3 receptors are found abundantly in the islands of Callefa, which have a clear population population in the fold stripe / lateral septal nucleus region, olfactory nodule, dendate gyrus and ancestral cortex. Suzuki M, Hurd Y, Sokoloff P, Schwartz J and Sedwall G, D 3 dopamine receptor mRNA is widely express in human brain, Brain Res (1998) 779: 58-74].
D4 수용체의 발현은 RNA 하이브리드화 및 면역조직화학적 연구에 의해 문서화되었다. 최근, D4 발현이 측후각뇌 피질(entorhinal cortex), 측중격핵, 해마 및 시상하부의 내부 시각교차앞구역에서 가장 높은 것으로 연구 결과 드러났다[참조: Primus R, Thurkauf A, Xu J, Yevich E, Mcinerney S, Shaw K, Tallman J and Gallagher D, Localization and characterization of dopamine D4 binding sites in rat and human brain by use of the novel D4 receptor-selective ligand [3H]NGD 94-1, J Pharmacol Exp Ther (1997) 282:1020-1027]. D4의 국소화는 D2 수용체가 선조체 영역에서 가장 많으므로, 뇌의 D2의 분포로부터 명백하다. 시상하부의 MPOA에의 D4 수용체의 발현은 피질과 척수 경로 사이의 통합 영역으로서의 시상하부의 역할 면에서 음경 발기를 촉진시키는 데 중요하다. 다른 DNS 영역, 시상, 시상밑 및 척수에의 D4 수용체의 참여를 제외시킬 수 없다.Expression of the D 4 receptor has been documented by RNA hybridization and immunohistochemical studies. Recently, studies have shown that D 4 expression is highest in the medial cortex, lateral septal nucleus, hippocampus and hypothalamus' internal visual cross-section. See Primus R, Thurkauf A, Xu J, Yevich E. , Mcinerney S, Shaw K, Tallman J and Gallagher D, Localization and characterization of dopamine D 4 binding sites in rat and human brain by use of the novel D 4 receptor-selective ligand [ 3 H] NGD 94-1, J Pharmacol Exp Ther (1997) 282: 1020-1027. Localization of D 4 is evident from the distribution of D 2 in the brain, since D 2 receptors are most common in the striatum. Expression of the D 4 receptor in the hypothalamus MPOA is important for promoting penile erection in terms of the role of the hypothalamus as an integration region between the cortex and the spinal cord pathway. Involvement of D 4 receptors in other DNS regions, thalamus, hypothalamus and spinal cord cannot be excluded.
미국 특허 제3,472,854호(Sterling)에는 정신안정제, 진정제, 골격근 이완제, 항아드레날린제, 저체온제, 항경련제, 저혈압제 및 심장혈관제로서 유용한 벤즈이미다졸 화합물이 기재되어 있다.US Pat. No. 3,472,854 (Sterling) describes benzimidazole compounds useful as antipsychotics, sedatives, skeletal muscle relaxants, antiadrenergics, hypothermia, anticonvulsants, hypotensives and cardiovascular agents.
슐(Sule) 등은 잠재적으로 구충 활성을 갖는 2-(N4-치환된-N1-피페라지닐)메틸-5-(또는 6)-치환된 벤즈이미다졸을 공개하였다. 특히, 당해 문헌에는 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸의 합성이 기재되어 있지만, 당해 화합물은 구충제로서 유효하다고 여겨지지는 않는다[참조: Bull. Haffkine Inst., 1978, 6(2), 62-64]Sule et al. Have disclosed 2- (N4-substituted-N1-piperazinyl) methyl-5- (or 6) -substituted benzimidazoles with potentially antiparasitic activity. In particular, this document describes the synthesis of 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, but the compound is not considered to be effective as an antiparasitic agent. : Bull. Haffkine Inst., 1978, 6 (2), 62-64]
미국 특허 제5,792,768호(Merck Sharp and Dome)에는 D4 길항제 및 유용한 항정신병제로서의 벤즈이미다졸 화합물이 기재되어 있다.US Patent No. 5,792,768 to Merck Sharp and Dome describes benzimidazole compounds as D 4 antagonists and useful antipsychotics.
미국 특허 제5,714,498호(Merck Sharp and Dome)에는 정신분열증, 우울증, 구토, 파킨슨병, 지연운동 이상증, 시상하부-뇌하수체 기능 장애, 상부 위창자 장 애, 약물 남용, 항정신병제 및 심장혈관 장애를 포함하는 도파민 시스템의 장애에 대한 D4 리간드로서의 벤즈이미다졸 화합물이 기재되어 있다.US Patent No. 5,714,498 (Merck Sharp and Dome) includes schizophrenia, depression, vomiting, Parkinson's disease, dyskinesia, hypothalamic-pituitary dysfunction, upper gastrointestinal disorder, drug abuse, antipsychotics and cardiovascular disorders. Benzimidazole compounds as D 4 ligands for disorders of the dopamine system comprising are described.
본 발명은 화학식 I의 벤즈이미다졸의 포유동물의 성 기능장애 치료 용도를 규명한다. 보다 구체적으로, 당해 화합물은 이로써 한정하려는 것은 아니지만, 남성 발기 기능장애를 포함하는 성 기능장애의 치료에 유용하다.The present invention discloses the use of benzimidazole of formula (I) for the treatment of sexual dysfunction in mammals. More specifically, the compounds are useful in the treatment of sexual dysfunction, including but not limited to male erectile dysfunction.
발명의 요약Summary of the Invention
본 발명은 화학식 I의 화합물, 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 포유동물에게 투여함을 포함하는, 포유동물, 특히 사람의 성 기능장애의 치료방법에 관 것이다.The present invention relates to a method of treating sexual dysfunction in a mammal, in particular a human, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide or prodrug thereof. Will.
위의 화학식 I에서,In Formula I above,
A는 , , , , , , , , , , , , , , , , , , , 또는 로부터 선택되고, A is , , , , , , , , , , , , , , , , , , , or Is selected from,
X는 NH, O 또는 S로부터 선택되고,X is selected from NH, O or S,
L은 CH2, CH2CH2, CH2CH2CH2 또는 CH 2CH2CH2CH2로부터 선택되고,L is selected from CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 or CH 2 CH 2 CH 2 CH 2 ,
R1, R2, R3, R4 및 R5는 각각 독립적으로 수소, 알콕시, 알케닐, 알킬, 알킬설피닐, 알킬설포닐, 알킬티오, 알키닐, 알콕시카보닐, 알킬카보닐, 알킬카보닐옥시, 카복시, 시아노, 포르밀, 할로겐, 할로알콕시, 할로알킬, 하이드록시, 하이드록시알킬, 머캅토, 니트로, -NZ1Z2, (NZ1Z2)카보닐 또는 (NZ1Z2)설포닐[여기서, Z1 및 Z2는 각각 독립적으로 수소, 알킬, 알킬카보닐, 알킬설포닐 또는 포르밀로 이루어진 그룹으로부터 선택된다]로부터 선택되고,R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkyl Carbonyloxy, carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ 1 Z 2 , (NZ 1 Z 2 ) carbonyl or (NZ 1 Z 2 ) sulfonyl, wherein Z 1 and Z 2 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl or formyl;
RA, RB, RC 및 RD는 각각 독립적으로 수소, 알콕시, 알케닐, 알킬, 알킬설피닐, 알킬설포닐, 알킬티오, 알키닐, 알콕시카보닐, 알킬카보닐, 알킬카보닐옥시, 카복시, 시아노, 포르밀, 할로겐, 할로알콕시, 할로알킬, 하이드록시, 하이드록시알킬, 머캅토, 니트로, -NZ1Z2 또는 (NZ1Z2)카보닐로부터 선택되고, R A , R B , R C and R D are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy , Carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ 1 Z 2 or (NZ 1 Z 2 ) carbonyl,
RE는 수소, 알콕시카보닐, 알킬, 알킬카보닐, 아릴카보닐, 사이클로알킬카보닐, 헤테로사이클카보닐 또는 (NZ1Z2)카보닐로부터 선택되고,R E is selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclecarbonyl or (NZ 1 Z 2 ) carbonyl,
RF는 수소 또는 알킬로부터 선택되고,R F is selected from hydrogen or alkyl,
Z는 N, C 또는 CH로부터 선택되고, Z is selected from N, C or CH,
---는, Z가 C인 경우, 결합이고, Z가 N 또는 CH인 경우, 부재한다.
--- is a bond when Z is C and absent when Z is N or CH.
당해 명세서에 인용된 모든 특허, 특허원 및 특허 문헌은 본원에서 전체적으로 참조로 인용된다.All patents, patent applications, and patent documents cited in this specification are herein incorporated by reference in their entirety.
원칙적인 양태에서, 본 발명은 화학식 I의 화합물, 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 포유동물에게 투여함을 포함하는, 포유동물, 특히 사람의 성 기능장애의 치료방법에 관한 것이다.In principle embodiments, the present invention comprises administering to a mammal a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, in a mammal, in particular in humans It relates to a method for treating a disorder.
화학식 IFormula I
위의 화학식 I에서,In Formula I above,
A는 , , , , , , , , , , , , , , , , , , , 또는 로부터 선택되고, A is , , , , , , , , , , , , , , , , , , , or Is selected from,
X는 NH, O 또는 S로부터 선택되고,X is selected from NH, O or S,
L은 CH2, CH2CH2, CH2CH2CH2 또는 CH 2CH2CH2CH2로부터 선택되고,L is selected from CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 or CH 2 CH 2 CH 2 CH 2 ,
R1, R2, R3, R4 및 R5는 각각 독립적으로 수소, 알콕시, 알케닐, 알킬, 알킬설피닐, 알킬설포닐, 알킬티오, 알키닐, 알콕시카보닐, 알킬카보닐, 알킬카보닐옥시, 카복시, 시아노, 포르밀, 할로겐, 할로알콕시, 할로알킬, 하이드록시, 하이드록시알킬, 머캅토, 니트로, -NZ1Z2 및 (NZ1Z2)카보닐 [여기서, Z1 및 Z2는 각각 독립적으로 수소, 알킬, 알킬카보닐, 알킬설포닐 및 포르밀로 이루어진 그룹으로부터 선택된다]로부터 선택되고,R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkyl Carbonyloxy, carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ 1 Z 2 and (NZ 1 Z 2 ) carbonyl [here, Z 1 and Z 2 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl and formyl],
RA, RB, RC 및 RD는 각각 독립적으로 수소, 알콕시, 알케닐, 알킬, 알킬설피닐, 알킬설포닐, 알킬티오, 알키닐, 알콕시카보닐, 알킬카보닐, 알킬카보닐옥시, 카복시, 시아노, 포르밀, 할로겐, 할로알콕시, 할로알킬, 하이드록시, 하이드록시알킬, 머캅토, 니트로, -NZ1Z2 또는 (NZ1Z2)카보닐로부터 선택되고, R A , R B , R C and R D are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy , Carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ 1 Z 2 or (NZ 1 Z 2 ) carbonyl,
RE는 수소, 알콕시카보닐, 알킬, 알킬카보닐, 아릴카보닐, 사이클로알킬카보닐, 헤테로사이클카보닐 또는 (NZ1Z2)카보닐로부터 선택되고,R E is selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclecarbonyl or (NZ 1 Z 2 ) carbonyl,
RF는 수소 또는 알킬로부터 선택되고,R F is selected from hydrogen or alkyl,
Z는 N, C 또는 CH로부터 선택되고,Z is selected from N, C or CH,
---는, Z가 C인 경우, 결합이고, Z가 N 또는 CH인 경우, 부재한다. --- is a bond when Z is C and absent when Z is N or CH.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE가 수소이고, Z가 N이고, ---이 부재하고, L 및 A가 화학식 I에서 정의한 바와 같은 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E is hydrogen, Z is N, --- is absent, L and A relates to a method of treating sexual dysfunction in a mammal in which a therapeutically effective amount of a compound of formula (I) as defined in formula (I) is administered to the mammal.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE가 수소이고, Z가 N이고, ---이 부재하고, A가 이고, L, R1, R2, R3, R4 및 R5가 화학식 I에서 정의한 바와 같은 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E is hydrogen, Z is N, --- is absent, and A is And a method for treating sexual dysfunction in a mammal in which L, R 1 , R 2 , R 3 , R 4 and R 5 are administered to the mammal a therapeutically effective amount of a compound of formula (I) as defined in formula (I). will be.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE 및 RF가 각각 수소이고, L이 CH2이고, Z가 N이고, ---이 부재하고, A가 이고, R2, R3 및 R4가 각각 수소이고, R1 및 R5이 화학식 I에서 정의한 바와 같은 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E and R F are each hydrogen, L is CH 2 , Z is N , --- is absent, and A R 2 , R 3 and R 4 are each hydrogen, and R 1 and R 5 are each a method for treating sexual dysfunction in a mammal, wherein the mammal is administered a therapeutically effective amount of a compound of formula (I) It is about.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE 및 RF가 각각 수소이고, L이 CH2이고, Z가 N이고, ---이 부재하고, A가 이고, R2, R3 및 R4가 각각 수소이며, R1 및 R5가 화학식 I에 정의된 바와 같은 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E and R F are each hydrogen, L is CH 2 , Z is N , --- is absent, and A , R 2 , R 3 and R 4 are each hydrogen, and R 1 and R 5 are each the treatment of sexual dysfunction in a mammal administering to the mammal a therapeutically effective amount of a compound of formula (I) as defined in formula (I) It is about a method.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE가 수소이고, Z가 N이고, ---이 부재하고, A가 이고, L, R1, R2, R3 및 R4가 화학식 I에서 정의한 바와 같은 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E is hydrogen, Z is N, --- is absent, and A is And L, R 1 , R 2 , R 3 and R 4 are directed to a method of treating sexual dysfunction in a mammal in which a therapeutically effective amount of a compound of formula (I) is defined in formula (I) to a mammal.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE 및 RF가 각각 수소이고, L이 CH2이고, Z가 N이고, ---이 부재하고, A가 이고, R2, R3 및 R4가 각각 수소이고, R1이 화학식 I에서 정의한 바와 같은 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다. In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E and R F are each hydrogen, L is CH 2 , Z is N , --- is absent, and A And R 2 , R 3 and R 4 are each hydrogen and R 1 is a method for the treatment of sexual dysfunction in a mammal by administering to the mammal a therapeutically effective amount of a compound of formula (I) as defined in formula (I). .
또 다른 양태에서, 본 발명은 RA, RB, RC, RD, RE 및 RF가 각각 수소이고, L이 CH2이고, Z가 N이고, ---이 부재하고, A가 이며, R1, R2, R3 및 R4가 각각 수소인 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C , R D , R E and R F are each hydrogen, L is CH 2 , Z is N, --- is absent, and A is And a method for the treatment of sexual dysfunction in a mammal by administering to the mammal a therapeutically effective amount of a compound of formula (I) wherein R 1 , R 2 , R 3 and R 4 are each hydrogen.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE가 수소이고, RF가 알킬이고, L이 CH2이고, Z가 N이고, ---이 부재하고, A가 이고, R2, R3 및 R4가 각각 수소이며, R1이 화학식 I에서 정의한 바와 같은 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E is hydrogen, R F is alkyl, L is CH 2 , and Z is N, --- is absent, and A is And R 2 , R 3 and R 4 are each hydrogen and R 1 is a method for the treatment of sexual dysfunction in a mammal by administering to the mammal a therapeutically effective amount of a compound of formula (I) as defined in formula (I). .
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE가 수소이고, RF가 알킬(여기서, 알킬은 메틸이다)이고, L이 CH2이고, Z가 N이고, ---이 부재하고, A가 이며, R1, R2, R3 및 R4가 각각 수소인 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다. In another embodiment, the present invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E is hydrogen, R F is alkyl (where alkyl is methyl), L is CH 2 , Z is N, --- is absent, and A is And a method for the treatment of sexual dysfunction in a mammal by administering to the mammal a therapeutically effective amount of a compound of formula (I) wherein R 1 , R 2 , R 3 and R 4 are each hydrogen.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE가 수소이고, Z가 N이고, ---이 부재하고, A가 이고, R1, R2, R3 및 R4가 각각 독립적으로 수소 또는 하이드록시로부터 선택되며, L이 화학식 I에서 정의한 바와 같은 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E is hydrogen, Z is N, --- is absent, and A is R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen or hydroxy and L is a mammal that administers to the mammal a therapeutically effective amount of a compound of formula (I) as defined in formula (I). The present invention relates to a method for treating sexual dysfunction.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE 및 RF가 각각 수소이고, L이 CH2이고, Z가 N이고, ---이 부재하고, A가 이고, R1, R2 및 R4가 각각 수소이며, R3이 하이드록시인 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E and R F are each hydrogen, L is CH 2 , Z is N , --- is absent, and A And R 1 , R 2 and R 4 are each hydrogen and R 3 is hydroxy, and the method relates to a method for treating sexual dysfunction in a mammal by administering to the mammal a therapeutically effective amount of the compound of formula (I).
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE가 수소이고, Z가 N이고, ---이 부재하고, A가 이며, L, R2, R3 및 R4가 화학식 I에서 정의한 바와 같은 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다. In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E is hydrogen, Z is N, --- is absent, and A is And L, R 2 , R 3 and R 4 are directed to a method of treating sexual dysfunction in a mammal in which a therapeutically effective amount of a compound of formula (I) is defined as defined in formula (I).
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE 및 RF가 각각 수소이고, L이 CH2이고, Z가 N이고, ---이 부재하고, A가 이며, R2, R3 및 R4가 각각 수소인 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E and R F are each hydrogen, L is CH 2 , Z is N , --- is absent, and A And a method for the treatment of sexual dysfunction in a mammal by administering to the mammal a therapeutically effective amount of a compound of formula (I) wherein R 2 , R 3 and R 4 are each hydrogen.
또 다른 양태에서, 본 발명은 RA, RB, RC, RD, RE 및 RF가 각각 수소이고, L이 CH2이고, Z가 N이고, ---이 부재하고, A가 이며, R2, R3 및 R4가 각각 수소인 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C , R D , R E and R F are each hydrogen, L is CH 2 , Z is N, --- is absent, and A is And a method for the treatment of sexual dysfunction in a mammal by administering to the mammal a therapeutically effective amount of a compound of formula (I) wherein R 2 , R 3 and R 4 are each hydrogen.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE가 수소이고, Z가 N이고, ---이 부재하고, A가 이며, X, L, R2 및 R3이 화학식 I에서 정의한 바와 같은 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E is hydrogen, Z is N, --- is absent, and A is And X, L, R 2 and R 3 are directed to a method of treating sexual dysfunction in a mammal in which a therapeutically effective amount of a compound of formula (I) is defined as defined in formula (I) to the mammal.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE 및 RF가 각각 수소이고, L이 CH2이고, Z가 N이고, ---이 부재하고, A가 이고, R2 및 R3이 각각 수소이며, X가 S인 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E and R F are each hydrogen, L is CH 2 , Z is N , --- is absent, and A And R 2 and R 3 are each hydrogen and X is S, the present invention relates to a method for the treatment of sexual dysfunction in a mammal by administering to said mammal a therapeutically effective amount.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 및 할로겐으로부터 선택되고, RE가 알콕시카보닐, 알킬카보닐, 알킬, 아릴카보닐, 사이클로알킬카보닐, 헤테로사이클카보닐 또는 (NZ1Z2)카보닐로부터 선택되고, Z가 N이고, ---이 부재하고, A가 이고, Z1, Z2, L, R1, R2, R3 및 R4가 화학식 I에서 정의한 바와 같은 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen and halogen, and R E is alkoxycarbonyl, alkylcarbonyl, alkyl, arylcarbonyl, cycloalkylcarbon Nyl, heterocyclecarbonyl or (NZ 1 Z 2 ) carbonyl, Z is N, --- is absent, and A is Treatment of sexual dysfunction in a mammal in which Z 1 , Z 2 , L, R 1 , R 2 , R 3 and R 4 are administered to the mammal a therapeutically effective amount of a compound of formula (I) as defined in Formula (I) It is about a method.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE가 알콕시카보닐, 알킬카보닐, (NZ1Z2)카보닐 또는 헤테로사이클카보닐(여기서, 헤테로사이클카보닐의 헤테로사이클 부분은 피롤리디닐이다)로부터 선택되고, RF가 수소이고, L이 CH2이고, Z가 N이고, ---이 부재하고, A가 이고, R2, R3 및 R4가 각각 수소이며, Z1, Z2 및 R1이 화학식 I에서 정의한 바와 같은 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E is alkoxycarbonyl, alkylcarbonyl, (NZ 1 Z 2 ) carbonyl or Heterocyclecarbonyl, wherein the heterocycle portion of the heterocyclecarbonyl is pyrrolidinyl, R F is hydrogen, L is CH 2 , Z is N, --- is absent, and A end And R 2 , R 3 and R 4 are each hydrogen and Z 1 , Z 2 and R 1 are sexual dysfunction in a mammal administering to the mammal a therapeutically effective amount of a compound of formula (I) as defined in formula (I) It relates to a method of treatment.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE가 수소이고, Z가 CH이고, ---이 부재하고, A가 이며, L, R1, R2, R3, R4 및 R5가 화학식 I에서 정의한 바와 같은 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E is hydrogen, Z is CH, --- is absent and A is A method for treating sexual dysfunction in a mammal in which L, R 1 , R 2 , R 3 , R 4 and R 5 are administered to the mammal a therapeutically effective amount of a compound of formula (I) as defined in formula (I). will be.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE 및 RF가 각각 수소이고, L이 CH2이고, ---이 부재하고, Z가 CH이고, A가 이고, R2, R3 및 R4가 각각 수소이며, R1 및 R5가 화학식 I에서 정의한 바와 같은 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E and R F are each hydrogen, L is CH 2, and Absent, Z is CH and A is R 2 , R 3 and R 4 are each hydrogen and R 1 and R 5 are each a method of treating sexual dysfunction in a mammal, wherein the mammal is administered a therapeutically effective amount of a compound of formula (I) as defined in formula (I). It is about.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE가 수소이고, Z가 CH이고, ---이 부재하고, A가 이며, L, R1, R2, R3 및 R4가 화학식 I에서 정의한 바와 같은 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E is hydrogen, Z is CH, --- is absent and A is And L, R 1 , R 2 , R 3 and R 4 are directed to a method of treating sexual dysfunction in a mammal in which a therapeutically effective amount of a compound of formula (I) is defined in formula (I) to a mammal.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE 및 RF가 각각 수소이고, L이 CH2이고, ---이 부재하고, Z가 CH이고, A가 이고, R2, R3 및 R4가 각각 수소이며, R1이 화학식 I에서 정의한 바와 같은 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E and R F are each hydrogen, L is CH 2, and Absent, Z is CH and A is And R 2 , R 3 and R 4 are each hydrogen and R 1 is a method for the treatment of sexual dysfunction in a mammal by administering to the mammal a therapeutically effective amount of a compound of formula (I) as defined in formula (I). .
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE가 수소이고, Z가 C이고, ---이 결합이고, A가 이며, L, R1, R2, R3, R4 및 R5가 화학식 I에서 정의한 바와 같은 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E is hydrogen, Z is C, --- is a bond, and A is A method for treating sexual dysfunction in a mammal in which L, R 1 , R 2 , R 3 , R 4 and R 5 are administered to the mammal a therapeutically effective amount of a compound of formula (I) as defined in formula (I). will be.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE 및 RF가 각각 수소이고, L이 CH2이고, Z가 C이고, ---이 결합이고, A가 이고, R2, R3 및 R4가 각각 수소이며, R1 및 R5이 화학식 I에서 정의한 바와 같은 화학식 I의 화합물의 치료학적 유효량을 포유동물에게 투여하는 포유동물의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E and R F are each hydrogen, L is CH 2 , Z is C , --- is a bond, and A is R 2 , R 3 and R 4 are each hydrogen, and R 1 and R 5 are each a method of treating sexual dysfunction in a mammal, wherein the mammal is administered a therapeutically effective amount of a compound of formula (I) as defined in formula (I). It is about.
또 다른 양태에서, 본 발명은In another aspect, the present invention
2-{[4-(3-메틸피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]니코티노니트릴;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile;
5,7-디브로모-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
5-플루오로-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-{[4-(1,3-티아졸-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
이소부틸 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸-1-카복실레이트;Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate;
2-[(4-피리딘-2-일피페라진-1-일)메틸]-1-(피롤리딘-1-일카보닐)-1H-벤즈이미다졸;2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole;
N,N-디메틸-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸-1-카복스아미드;N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide;
2-[(4-페닐피페라진-1-일)메틸]-1H-벤즈이미다졸;2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]벤조니트릴; 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile;
2-{[4-(2-클로로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-플루오로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-니트로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-메톡시페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
4-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]페놀;4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;
2-({4-[2-(메틸티오)페닐]피페라진-1-일}메틸)-1H-벤즈이미다졸;2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole;
2-{[4-(2-에톡시페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]페놀;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;
2-{[4-(2-메톡시페닐)피페리딘-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole;
2-[(4-피리딘-2-일피페리딘-1-일)메틸]-1H-벤즈이미다졸;2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole;
2-[(4-페닐-3,6-디하이드로피리딘-1(2H)-일)메틸]-1H-벤즈이미다졸;2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole;
2-{[4-(6-메틸피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[(2-메틸-4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-{[(2S)-2-메틸-4-피리딘-2-일피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;
2-{[(2R)-2-메틸-4-피리딘-2-일피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;
N-{2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]피리딘-3-일}메탄설폰아미드; 및N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide; And
2-{[4-(3-플루오로피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸로부터 선택된 화학식 I의 화합물, 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 사람에게 투여함을 포함하는 남성 성 기능 장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.A compound of formula (I) selected from 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, or a pharmaceutically acceptable salt, ester, A method of treating sexual dysfunction in a human, including male sexual dysfunction, comprising administering a therapeutically effective amount of an amide or prodrug to a human.
또 다른 양태에서, 본 발명은 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides a compound of the 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof A method of treating sexual dysfunction in humans, including male sexual dysfunction, comprising administering a therapeutically effective amount to a human, and female sexual dysfunction.
또 다른 양태에서, 본 발명은 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 비스((L)타르트레이트)의 치료학적 유효량을 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides a therapeutically effective amount of 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate) to a human The present invention relates to a method for treating sexual dysfunction of a person, including male sexual dysfunction, including female ham.
또 다른 양태에서, 본 발명은 2-[(4-피리미딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof The present invention relates to a method of treating sexual dysfunction in a human, including male sexual dysfunction and female sexual dysfunction comprising administering to a human a therapeutically effective amount of.
또 다른 양태에서, 본 발명은 6-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]피리딘-3-올 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol or a pharmaceutically acceptable salt, ester, amide or A method of treating sexual dysfunction in a person, including male sexual dysfunction and female sexual dysfunction, comprising administering to a human a therapeutically effective amount of a prodrug.
또 다른 양태에서, 본 발명은 화학식 I의 화합물, 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 약제학적으로 허용되는 담체와 함께 사람에게 투여함을 포함하는 남성 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the present invention provides a male comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, to a human with a pharmaceutically acceptable carrier and The present invention relates to a method for treating sexual dysfunction of a person including female sexual dysfunction.
또 다른 양태에서, 본 발명은In another aspect, the present invention
2-{[4-(3-메틸피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]니코티노니트릴;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile;
5,7-디브로모-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
5-플루오로-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-{[4-(1,3-티아졸-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
이소부틸 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸-1-카복실레이트;Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate;
2-[(4-피리딘-2-일피페라진-1-일)메틸]-1-(피롤리딘-1-일카보닐)-1H-벤즈이미다졸;2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole;
N,N-디메틸-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸-1-카복스아미드;N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide;
2-[(4-페닐피페라진-1-일)메틸]-1H-벤즈이미다졸;2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]벤조니트릴;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile;
2-{[4-(2-클로로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-플루오로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-니트로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-메톡시페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸; 2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
4-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]페놀;4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;
2-({4-[2-(메틸티오)페닐]피페라진-1-일}메틸)-1H-벤즈이미다졸;2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole;
2-{[4-(2-에톡시페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]페놀;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;
2-{[4-(2-메톡시페닐)피페리딘-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole;
2-[(4-피리딘-2-일피페리딘-1-일)메틸]-1H-벤즈이미다졸;2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole;
2-[(4-페닐-3,6-디하이드로피리딘-1(2H)-일)메틸]-1H-벤즈이미다졸;2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole;
2-{[4-(6-메틸피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[(2-메틸-4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-{[(2S)-2-메틸-4-피리딘-2-일피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;
2-{[(2R)-2-메틸-4-피리딘-2-일피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;
N-{2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]피리딘-3-일}메탄설폰아미드; 및N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide; And
2-{[4-(3-플루오로피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸로부터 선택된 화학식 I의 화합물, 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 약제학적으로 허용되는 담체와 함께 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.A compound of formula (I) selected from 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, or a pharmaceutically acceptable salt, ester, A method of treating sexual dysfunction in humans, including male and female sexual dysfunctions, comprising administering to a human a therapeutically effective amount of an amide or prodrug together with a pharmaceutically acceptable carrier.
또 다른 양태에서, 본 발명은 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭 의 치료학적 유효량을 약제학적으로 허용되는 담체와 함께 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another aspect, the present invention provides a compound of 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof. A method of treating sexual dysfunction in humans comprising male sexual dysfunction and female sexual dysfunction comprising administering to a human a therapeutically effective amount with a pharmaceutically acceptable carrier.
또 다른 양태에서, 본 발명은 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 비스((L)타르트레이트)의 치료학적 유효량을 약제학적으로 허용되는 담체와 함께 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the present invention provides a pharmaceutical composition for treating a therapeutically effective amount of 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate). A method of treating sexual dysfunction in a human, including male sexual dysfunction, comprising administering to a human with an acceptable carrier, and female sexual dysfunction.
또 다른 양태에서, 본 발명은 2-[(4-피리미딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 약제학적으로 허용되는 담체와 함께 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof A method of treating sexual dysfunction in a human, including male sexual dysfunction and female sexual dysfunction, comprising administering a therapeutically effective amount of to a human with a pharmaceutically acceptable carrier.
또 다른 양태에서, 본 발명은 6-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]피리딘-3-올 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 약제학적으로 허용되는 담체와 함께 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol or a pharmaceutically acceptable salt, ester, amide or A method of treating sexual dysfunction in a human, including male sexual dysfunction and female sexual dysfunction, comprising administering a therapeutically effective amount of a prodrug to a human with a pharmaceutically acceptable carrier.
또 다른 양태에서, 본 발명은 화학식 I의 화합물, 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 이로써 한정하려는 것은 아니지만, 실데나필 또는 바르데나필을 포함하는 포스포디에스테라제 5 억제제와 함께 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the present invention is not intended to limit the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, but includes phosphodides, including sildenafil or vardenafil. A method of treating sexual dysfunction in humans, including male sexual dysfunction, comprising administering to humans with a therapase 5 inhibitor, and female sexual dysfunction.
또 다른 양태에서, 본 발명은In another aspect, the present invention
2-{[4-(3-메틸피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]니코티노니트릴;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile;
5,7-디브로모-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
5-플루오로-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-{[4-(1,3-티아졸-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
이소부틸 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸-1-카복실레이트;Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate;
2-[(4-피리딘-2-일피페라진-1-일)메틸]-1-(피롤리딘-1-일카보닐)-1H-벤즈이미다졸;2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole;
N,N-디메틸-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸-1-카복스아미드;N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide;
2-[(4-페닐피페라진-1-일)메틸]-1H-벤즈이미다졸;2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]벤조니트릴;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile;
2-{[4-(2-클로로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-플루오로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-니트로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-메톡시페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸; 2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
4-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]페놀;4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;
2-({4-[2-(메틸티오)페닐]피페라진-1-일}메틸)-1H-벤즈이미다졸;2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole;
2-{[4-(2-에톡시페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]페놀;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;
2-{[4-(2-메톡시페닐)피페리딘-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole;
2-[(4-피리딘-2-일피페리딘-1-일)메틸]-1H-벤즈이미다졸;2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole;
2-[(4-페닐-3,6-디하이드로피리딘-1(2H)-일)메틸]-1H-벤즈이미다졸;2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole;
2-{[4-(6-메틸피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[(2-메틸-4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-{[(2S)-2-메틸-4-피리딘-2-일피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;
2-{[(2R)-2-메틸-4-피리딘-2-일피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;
N-{2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]피리딘-3-일}메탄설폰아미드; 및N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide; And
2-{[4-(3-플루오로피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸로부터 선택된 화학식 I의 화합물, 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 이로써 한정하려는 것은 아니지만, 실데나필 또는 바르데나필을 포함하는 포스포디에스테라제 5 억제제와 함께 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.A compound of formula (I) selected from 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, or a pharmaceutically acceptable salt, ester, Although not intended to limit the therapeutically effective amount of an amide or prodrug, it includes male sexual dysfunction and female sexual dysfunction, including administration to humans with phosphodiesterase 5 inhibitors including sildenafil or vardenafil The present invention relates to a method of treating sexual dysfunction of a person.
또 다른 양태에서, 본 발명은 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤 즈이미다졸 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 이로써 한정하려는 것은 아니지만, 실데나필 또는 바르데나필을 포함하는 포스포디에스테라제 5 억제제와 함께 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof It is not intended to thereby limit the therapeutically effective amount of to a sex of a person, including male sexual dysfunction and female sexual dysfunction, including administering to a human with a phosphodiesterase 5 inhibitor comprising sildenafil or vardenafil. It relates to a method of treating dysfunction.
또 다른 양태에서, 본 발명은 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 비스((L)타르트레이트)의 치료학적 유효량을 이로써 한정하려는 것은 아니지만, 실데나필 또는 바르데나필을 포함하는 포스포디에스테라제 5 억제제와 함께 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the present invention seeks to thereby limit the therapeutically effective amount of 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate) But not, to a method of treating sexual dysfunction in humans, including male and female sexual dysfunctions, comprising administering to humans with phosphodiesterase 5 inhibitors including sildenafil or vardenafil. .
또 다른 양태에서, 본 발명은 2-[(4-피리미딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 이로써 한정하려는 것은 아니지만, 실데나필 또는 바르데나필을 포함하는 포스포디에스테라제 5 억제제와 함께 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof It is not intended to thereby limit the therapeutically effective amount of to a sex of a person, including male sexual dysfunction and female sexual dysfunction, including administering to a human with a phosphodiesterase 5 inhibitor comprising sildenafil or vardenafil. It relates to a method of treating dysfunction.
또 다른 양태에서, 본 발명은 6-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]피리딘-3-올 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 이로써 한정하려는 것은 아니지만, 실데나필 또는 바르데나필을 포함하는 포스포디에스테라제 5 억제제와 함께 사람에게 투여함을 포함하 는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol or a pharmaceutically acceptable salt, ester, amide or Although not intended to limit the therapeutically effective amount of prodrugs to this, including male sexual dysfunction and female sexual dysfunction, including administration to humans with phosphodiesterase 5 inhibitors, including sildenafil or vardenafil A method of treating sexual dysfunction in humans.
또 다른 양태에서, 본 발명은 화학식 I의 화합물, 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 이로써 한정하려는 것은 아니지만, 테라조신, 프라조신 또는 탐설로신을 포함하는 아드레날린성 수용체 길항제와 함께 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the present invention is not intended to limit the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, but includes terrazocin, prazosin or tamsulosin The present invention relates to a method for treating sexual dysfunction in a human, including male and female sexual dysfunction, including administration to a human with an adrenergic receptor antagonist.
또 다른 양태에서, 본 발명은In another aspect, the present invention
2-{[4-(3-메틸피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]니코티노니트릴;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile;
5,7-디브로모-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
5-플루오로-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-{[4-(1,3-티아졸-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
이소부틸 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸-1-카복실레이트;Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate;
2-[(4-피리딘-2-일피페라진-1-일)메틸]-1-(피롤리딘-1-일카보닐)-1H-벤즈이미다졸;2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole;
N,N-디메틸-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸-1-카복스아미드;N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide;
2-[(4-페닐피페라진-1-일)메틸]-1H-벤즈이미다졸; 2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]벤조니트릴;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile;
2-{[4-(2-클로로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-플루오로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-니트로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-메톡시페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
4-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]페놀;4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;
2-({4-[2-(메틸티오)페닐]피페라진-1-일}메틸)-1H-벤즈이미다졸;2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole;
2-{[4-(2-에톡시페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]페놀;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;
2-{[4-(2-메톡시페닐)피페리딘-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole;
2-[(4-피리딘-2-일피페리딘-1-일)메틸]-1H-벤즈이미다졸;2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole;
2-[(4-페닐-3,6-디하이드로피리딘-1(2H)-일)메틸]-1H-벤즈이미다졸;2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole;
2-{[4-(6-메틸피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[(2-메틸-4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-{[(2S)-2-메틸-4-피리딘-2-일피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;
2-{[(2R)-2-메틸-4-피리딘-2-일피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;
N-{2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]피리딘-3-일}메탄설폰아미드; 및N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide; And
2-{[4-(3-플루오로피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸로부터 선택된 화학식 I의 화합물, 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미 드 또는 프로드럭의 치료학적 유효량을 이로써 한정하려는 것은 아니지만, 테라조신, 프라조신 또는 탐설로신을 포함하는 아드레날린성 수용체 길항제와 함께 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.A compound of formula (I) selected from 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, or a pharmaceutically acceptable salt, ester, It is not intended to limit the therapeutically effective amount of an amide or prodrug, but male sexual dysfunction and female sexual dysfunction, including administration to humans with an adrenergic receptor antagonist including terrazocin, prazosin or tamsulosin It relates to a method of treating sexual dysfunction of a person containing.
또 다른 양태에서, 본 발명은 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 이로써 한정하려는 것은 아니지만, 테라조신, 프라조신 또는 탐설로신을 포함하는 아드레날린성 수용체 길항제와 함께 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides a compound of the 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof Although not intended to limit the therapeutically effective amount, sexual function in humans, including male sexual dysfunction and female sexual dysfunction, including administration to humans with adrenergic receptor antagonists including terrazocin, prazosin or tamsulosin It relates to a method for treating a disorder.
또 다른 양태에서, 본 발명은 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 비스((L)타르트레이트)의 치료학적 유효량을 이로써 한정하려는 것은 아니지만, 테라조신, 프라조신 또는 탐설로신을 포함하는 아드레날린성 수용체 길항제와 함께 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the present invention seeks to thereby limit the therapeutically effective amount of 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate) But not, to a method of treating sexual dysfunction in humans, including male sexual dysfunction and female sexual dysfunction, comprising administering to a human with an adrenergic receptor antagonist comprising terrazosin, prazosin or tamsulosin .
또 다른 양태에서, 본 발명은 2-[(4-피리미딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 이로써 한정하려는 것은 아니지만, 테라조신, 프라조신 또는 탐설로신을 포함하는 아드레날린성 수용체 길항제와 함께 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof It is not intended to limit the therapeutically effective amount of to a sex of a person, including male sexual dysfunction and female sexual dysfunction, including administering to a human with an adrenergic receptor antagonist including terrazocin, prazosin or tamsulosin. It relates to a method of treating dysfunction.
또 다른 양태에서, 본 발명은 6-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]피리딘-3-올 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 이로써 한정하려는 것은 아니지만, 테라조신, 프라조신 또는 탐설로신을 포함하는 아드레날린성 수용체 길항제와 함께 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol or a pharmaceutically acceptable salt, ester, amide or Although not intended to limit the therapeutically effective amount of prodrugs to this, persons including male sexual dysfunction and female sexual dysfunction, including administration to humans with adrenergic receptor antagonists including terrazosin, prazosin or tamsulosin The present invention relates to a method for treating sexual dysfunction.
또 다른 양태에서, 본 발명은 화학식 I의 화합물, 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 이로써 한정하려는 것은 아니지만, 아포모르핀을 포함하는 도파민 효능제와 함께 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the present invention is not intended to limit the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, but in combination with a dopamine agonist comprising apomorphine. The present invention relates to a method for treating sexual dysfunction of a person, including male sexual dysfunction, including female administration.
또 다른 양태에서, 본 발명은In another aspect, the present invention
2-{[4-(3-메틸피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]니코티노니트릴;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile;
5,7-디브로모-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
5-플루오로-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-{[4-(1,3-티아졸-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
이소부틸 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸-1-카복실레이트; Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate;
2-[(4-피리딘-2-일피페라진-1-일)메틸]-1-(피롤리딘-1-일카보닐)-1H-벤즈이미다졸;2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole;
N,N-디메틸-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸-1-카복스아미드;N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide;
2-[(4-페닐피페라진-1-일)메틸]-1H-벤즈이미다졸;2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]벤조니트릴;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile;
2-{[4-(2-클로로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-플루오로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-니트로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-메톡시페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
4-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]페놀;4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;
2-({4-[2-(메틸티오)페닐]피페라진-1-일}메틸)-1H-벤즈이미다졸;2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole;
2-{[4-(2-에톡시페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]페놀;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;
2-{[4-(2-메톡시페닐)피페리딘-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole;
2-[(4-피리딘-2-일피페리딘-1-일)메틸]-1H-벤즈이미다졸;2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole;
2-[(4-페닐-3,6-디하이드로피리딘-1(2H)-일)메틸]-1H-벤즈이미다졸;2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole;
2-{[4-(6-메틸피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[(2-메틸-4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-{[(2S)-2-메틸-4-피리딘-2-일피페라진-1-일]메틸}-1H-벤즈이미다졸; 2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;
2-{[(2R)-2-메틸-4-피리딘-2-일피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;
N-{2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]피리딘-3-일}메탄설폰아미드; 및N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide; And
2-{[4-(3-플루오로피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸로부터 선택된 화학식 I의 화합물, 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 이로써 한정하려는 것은 아니지만, 아포모르핀을 포함하는 도파민 효능제와 함께 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.A compound of formula (I) selected from 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, or a pharmaceutically acceptable salt, ester, Although not intended to limit the therapeutically effective amount of an amide or prodrug, it may be possible to control sexual dysfunction in humans, including male sexual dysfunction and female sexual dysfunction, including administering to humans with a dopamine agonist comprising apomorphine. It relates to a method of treatment.
또 다른 양태에서, 본 발명은 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 이로써 한정하려는 것은 아니지만, 아포모르핀을 포함하는 도파민 효능제와 함께 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides a compound of the 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof Although not intended to limit the therapeutically effective amount thereto, the present invention relates to methods of treating sexual dysfunction in humans, including male sexual dysfunction and female sexual dysfunction, including administration to a human with a dopamine agonist comprising apomorphine. .
또 다른 양태에서, 본 발명은 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 비스((L)타르트레이트)의 치료학적 유효량을 이로써 한정하려는 것은 아니지만, 아포모르핀을 포함하는 도파민 효능제와 함께 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the present invention seeks to thereby limit the therapeutically effective amount of 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate) It is not, but it relates to a method for the treatment of sexual dysfunction in humans, including male and female sexual dysfunction, including administering to a human with a dopamine agonist comprising apomorphine.
또 다른 양태에서, 본 발명은 2-[(4-피리미딘-2-일피페라진-1-일)메틸]-1H- 벤즈이미다졸 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 이로써 한정하려는 것은 아니지만, 아포모르핀을 포함하는 도파민 효능제와 함께 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof Although not intended to limit the therapeutically effective amount of to a method for treating sexual dysfunction in humans, including male sexual dysfunction and female sexual dysfunction, including administering to a human with a dopamine agonist comprising apomorphine. will be.
또 다른 양태에서, 본 발명은 6-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]피리딘-3-올 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 이로써 한정하려는 것은 아니지만, 아포모르핀을 포함하는 도파민 효능제와 함께 사람에게 투여함을 포함하는 남성 성 기능장애 및 여성 성 기능장애를 포함하는 사람의 성 기능장애의 치료방법에 관한 것이다.In another embodiment, the invention provides 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol or a pharmaceutically acceptable salt, ester, amide or Although not intended to limit the therapeutically effective amount of prodrugs to this, methods of treating sexual dysfunction in humans, including male sexual dysfunction and female sexual dysfunction, including administering to humans with a dopamine agonist comprising apomorphine. It is about.
또 다른 양태에서, 본 발명은 화학식 I의 화합물, 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 발기 부전의 치료를 요하는 남성에게 투여함을 포함하는 남성의 발기 부전의 치료방법에 관한 것이다.In another aspect, the invention provides an erection in a male comprising administering to a man in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide or prodrug thereof The present invention relates to a method for treating dysfunction.
또 다른 양태에서, 본 발명은In another aspect, the present invention
2-{[4-(3-메틸피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]니코티노니트릴;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile;
5,7-디브로모-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
5-플루오로-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-{[4-(1,3-티아졸-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
이소부틸 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸-1-카복실 레이트;Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate;
2-[(4-피리딘-2-일피페라진-1-일)메틸]-1-(피롤리딘-1-일카보닐)-1H-벤즈이미다졸;2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole;
N,N-디메틸-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸-1-카복스아미드;N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide;
2-[(4-페닐피페라진-1-일)메틸]-1H-벤즈이미다졸;2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]벤조니트릴;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile;
2-{[4-(2-클로로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-플루오로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-니트로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-메톡시페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
4-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]페놀;4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;
2-({4-[2-(메틸티오)페닐]피페라진-1-일}메틸)-1H-벤즈이미다졸;2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole;
2-{[4-(2-에톡시페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]페놀;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;
2-{[4-(2-메톡시페닐)피페리딘-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole;
2-[(4-피리딘-2-일피페리딘-1-일)메틸]-1H-벤즈이미다졸;2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole;
2-[(4-페닐-3,6-디하이드로피리딘-1(2H)-일)메틸]-1H-벤즈이미다졸;2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole;
2-{[4-(6-메틸피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[(2-메틸-4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸; 2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-{[(2S)-2-메틸-4-피리딘-2-일피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;
2-{[(2R)-2-메틸-4-피리딘-2-일피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;
N-{2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]피리딘-3-일}메탄설폰아미드; 및N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide; And
2-{[4-(3-플루오로피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸로부터 선택된 화학식 I의 화합물, 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 발기 부전의 치료를 요하는 남성에게 투여함을 포함하는 남성의 발기 부전의 치료방법에 관한 것이다.A compound of formula (I) selected from 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, or a pharmaceutically acceptable salt, ester, A method of treating erectile dysfunction in men, comprising administering a therapeutically effective amount of an amide or prodrug to a male in need thereof.
또 다른 양태에서, 본 발명은 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 발기 부전의 치료를 요하는 남성에게 투여함을 포함하는 남성의 발기 부전의 치료방법에 관한 것이다.In another embodiment, the invention provides a compound of the 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof A method of treating erectile dysfunction in men, comprising administering a therapeutically effective amount to a man in need thereof.
또 다른 양태에서, 본 발명은 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 비스((L)타르트레이트)의 치료학적 유효량을 발기 부전의 치료를 요하는 남성에게 투여함을 포함하는 남성의 발기 부전의 치료방법에 관한 것이다.In another embodiment, the invention provides a therapeutically effective amount of 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate) of erectile dysfunction A method of treating erectile dysfunction in men, including administering to men in need thereof.
또 다른 양태에서, 본 발명은 2-[(4-피리미딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 발기 부전의 치료를 요하는 남성에게 투여함을 포함하는 남성의 발기 부전의 치료방법에 관한 것이다.In another embodiment, the invention provides 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof A method of treating erectile dysfunction in men, comprising administering a therapeutically effective amount of to a male in need thereof.
또 다른 양태에서, 본 발명은 6-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1- 일]피리딘-3-올 또는 약제학적으로 의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 발기 부전의 치료를 요하는 남성에게 투여함을 포함하는 남성의 발기 부전의 치료방법에 관한 것이다.In another embodiment, the invention provides 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol or a pharmaceutically salt, ester, amide or prodrug of A method of treating erectile dysfunction in men, comprising administering a therapeutically effective amount of to a male in need thereof.
또 다른 양태에서, 본 발명은 화학식 I의 화합물, 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 불감증, 음핵 발기 부족, 질 충혈, 성교통증 또는 질경련의 치료를 요하는 여성에게 투여함을 포함하는 여성의 불감증, 음핵 발기 부족, 질 충혈, 성교통증 또는 질경련의 치료방법에 관한 것이다.In another embodiment, the present invention provides a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, for treating insensitivity, clitoris impotence, vaginal hyperemia, dyspareunia or vaginal spasms. A method of treating insensitivity, clitoris erection, vaginal hyperemia, dyspareunia or vaginal spasm in a woman, including administration to a woman in need thereof.
또 다른 양태에서, 본 발명은In another aspect, the present invention
2-{[4-(3-메틸피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]니코티노니트릴;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile;
5,7-디브로모-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
5-플루오로-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-{[4-(1,3-티아졸-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
이소부틸 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸-1-카복실레이트;Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate;
2-[(4-피리딘-2-일피페라진-1-일)메틸]-1-(피롤리딘-1-일카보닐)-1H-벤즈이미다졸;2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole;
N,N-디메틸-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸-1-카복스아미드; N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide;
2-[(4-페닐피페라진-1-일)메틸]-1H-벤즈이미다졸;2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]벤조니트릴;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile;
2-{[4-(2-클로로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-플루오로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-니트로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-메톡시페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
4-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]페놀;4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;
2-({4-[2-(메틸티오)페닐]피페라진-1-일}메틸)-1H-벤즈이미다졸;2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole;
2-{[4-(2-에톡시페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]페놀;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;
2-{[4-(2-메톡시페닐)피페리딘-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole;
2-[(4-피리딘-2-일피페리딘-1-일)메틸]-1H-벤즈이미다졸;2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole;
2-[(4-페닐-3,6-디하이드로피리딘-1(2H)-일)메틸]-1H-벤즈이미다졸;2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole;
2-{[4-(6-메틸피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[(2-메틸-4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-{[(2S)-2-메틸-4-피리딘-2-일피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;
2-{[(2R)-2-메틸-4-피리딘-2-일피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;
N-{2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]피리딘-3-일}메탄설폰아미드; 및N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide; And
2-{[4-(3-플루오로피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸로부터 선택된 화학식 I의 화합물, 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 불감증, 음핵 발기 부족, 질 충혈, 성교통증 또는 질경련의 치료를 요하는 여성에게 투여함을 포함하는 여성의 불감증, 음핵 발기 부족, 질 충혈, 성교통증 또는 질경련의 치료방법에 관한 것이다.A compound of formula (I) selected from 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, or a pharmaceutically acceptable salt, ester, Insensitivity, clitoris erection, vaginal hyperemia, dyspareunia or vagina in women, including administering a therapeutically effective amount of an amide or prodrug to a woman in need of treatment for insensitivity, clitoris erection, vaginal hyperemia, dyspareunia or vaginal spasms It relates to a method of treating cramps.
또 다른 양태에서, 본 발명은 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 불감증, 음핵 발기 부족, 질 충혈, 성교통증 또는 질경련의 치료를 요하는 여성에게 투여함을 포함하는 여성의 불감증, 음핵 발기 부족, 질 충혈, 성교통증 또는 질경련의 치료방법에 관한 것이다.In another embodiment, the invention provides a compound of the 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof A method of treating insensitivity, clitoris erection, vaginal hyperemia, dyspareunia or vaginal spasm in a woman, comprising administering a therapeutically effective amount to a woman in need of treatment for insensitivity, lack of clitoris erection, vaginal hyperemia, dyspareunia or vaginal spasms. It is about.
또 다른 양태에서, 본 발명은 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 비스((L)타르트레이트)의 치료학적 유효량을 불감증, 음핵 발기 부족, 질 충혈, 성교통증 또는 질경련의 치료를 요하는 여성에게 투여함을 포함하는 여성의 불감증, 음핵 발기 부족, 질 충혈, 성교통증 또는 질경련의 치료방법에 관한 것이다.In another embodiment, the invention provides a therapeutically effective amount of 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate) insensitive, clitoris A method of treating insensitivity, clitoris erectile deficiency, vaginal hyperemia, dyspareunia or vaginal spasm in a woman, comprising administering to a woman in need of treatment for erectile dysfunction, vaginal hyperemia, dyspareunia or vaginal spasm.
또 다른 양태에서, 본 발명은 2-[(4-피리미딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 불감증, 음핵 발기 부족, 질 충혈, 성교통증 또는 질경련의 치료를 요하는 여성에게 투여함을 포함하는 여성의 불감증, 음핵 발기 부족, 질 충혈, 성교통증 또는 질경련의 치료방법에 관한 것이다.In another embodiment, the invention provides 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof A method of treating insensitivity, clitoris erection, vaginal hyperemia, dyspareunia or vaginal spasm in a woman comprising administering a therapeutically effective amount of to a woman in need of treatment for insensitivity, lack of clitoris erection, vaginal hyperemia, dyspareunia or vaginal cramp It is about.
또 다른 양태에서, 본 발명은 6-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]피리딘-3-올 또는 약제학적으로 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 불감증, 음핵 발기 부족, 질 충혈, 성교통증 또는 질경련의 치료를 요하는 여성에게 투여함을 포함하는 여성의 불감증, 음핵 발기 부족, 질 충혈, 성교통증 또는 질경련의 치료방법에 관한 것이다.In another embodiment, the invention provides 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol or a pharmaceutically salt, ester, amide or prodrug thereof A method of treating insensitivity, clitoris erection, vaginal hyperemia, dyspareunia or vaginal spasm in a woman comprising administering a therapeutically effective amount of to a woman in need of treatment for insensitivity, lack of clitoris erection, vaginal hyperemia, dyspareunia or vaginal spasms It is about.
또 다른 양태에서, 본 발명은 화학식 I의 화합물, 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 심장혈관 장애, 염증 장애, 주의력 결핍 과다활동 장애, 알츠하이머 병, 악물 남용, 파킨슨 병, 불안, 기분 장애 및 우울증으로부터 선택된 장애의 치료를 요하는 사람에게 투여함을 포함하는 사람의 심장혈관 장애, 염증 장애, 주의력 결핍 과다활동 장애, 알츠하이머 병, 악물 남용, 파킨슨 병, 불안, 기분 장애 및 우울증으로부터 선택된 장애의 치료방법에 관한 것이다.In another embodiment, the invention provides a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, for cardiovascular disorders, inflammatory disorders, attention deficit hyperactivity disorders, Alzheimer's disease, gross Cardiovascular disorders, inflammatory disorders, attention deficit hyperactivity disorders, Alzheimer's disease, gross abuse, Parkinson's disease in humans, including administration to a person in need of treatment of a disorder selected from abuse, Parkinson's disease, anxiety, mood disorders and depression, A method of treating disorders selected from anxiety, mood disorders and depression.
또 다른 양태에서, 본 발명은In another aspect, the present invention
2-{[4-(3-메틸피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]니코티노니트릴;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile;
5,7-디브로모-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
5-플루오로-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-{[4-(1,3-티아졸-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
이소부틸 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸-1-카복실레이트;Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate;
2-[(4-피리딘-2-일피페라진-1-일)메틸]-1-(피롤리딘-1-일카보닐)-1H-벤즈이 미다졸;2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole;
N,N-디메틸-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸-1-카복스아미드;N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide;
2-[(4-페닐피페라진-1-일)메틸]-1H-벤즈이미다졸;2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]벤조니트릴;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile;
2-{[4-(2-클로로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-플루오로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-니트로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-메톡시페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
4-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]페놀;4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;
2-({4-[2-(메틸티오)페닐]피페라진-1-일}메틸)-1H-벤즈이미다졸;2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole;
2-{[4-(2-에톡시페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]페놀;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;
2-{[4-(2-메톡시페닐)피페리딘-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole;
2-[(4-피리딘-2-일피페리딘-1-일)메틸]-1H-벤즈이미다졸;2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole;
2-[(4-페닐-3,6-디하이드로피리딘-1(2H)-일)메틸]-1H-벤즈이미다졸;2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole;
2-{[4-(6-메틸피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[(2-메틸-4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-{[(2S)-2-메틸-4-피리딘-2-일피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;
2-{[(2R)-2-메틸-4-피리딘-2-일피페라진-1-일]메틸}-1H-벤즈이미다졸; 2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole;
N-{2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]피리딘-3-일}메탄설폰아미드; 및N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide; And
2-{[4-(3-플루오로피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸로부터 선택된 화학식 I의 화합물, 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 심장혈관 장애, 염증 장애, 주의력 결핍 과다활동 장애, 알츠하이머 병, 악물 남용, 파킨슨 병, 불안, 기분 장애 및 우울증으로부터 선택된 장애의 치료를 요하는 사람에게 투여함을 포함하는 사람의 심장혈관 장애, 염증 장애, 주의력 결핍 과다활동 장애, 알츠하이머 병, 악물 남용, 파킨슨 병, 불안, 기분 장애 및 우울증으로부터 선택된 장애의 치료방법에 관한 것이다.A compound of formula (I) selected from 2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole, or a pharmaceutically acceptable salt, ester, A therapeutically effective amount of an amide or prodrug is administered to a person in need of treatment for a disorder selected from cardiovascular disorders, inflammatory disorders, attention deficit hyperactivity disorders, Alzheimer's disease, evil abuse, Parkinson's disease, anxiety, mood disorders and depression. Cardiovascular disorders, inflammatory disorders, attention deficit hyperactivity disorders, Alzheimer's disease, bad substance abuse, Parkinson's disease, anxiety, mood disorders, and depression in a person comprising.
또 다른 양태에서, 본 발명은 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 심장혈관 장애, 염증 장애, 주의력 결핍 과다활동 장애, 알츠하이머 병, 악물 남용, 파킨슨 병, 불안, 기분 장애 및 우울증으로부터 선택된 장애의 치료를 요하는 사람에게 투여함을 포함하는 사람의 심장혈관 장애, 염증 장애, 주의력 결핍 과다활동 장애, 알츠하이머 병, 악물 남용, 파킨슨 병, 불안, 기분 장애 및 우울증으로부터 선택된 장애의 치료방법에 관한 것이다.In another embodiment, the invention provides a compound of the 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof A therapeutically effective amount of the heart of a person comprising administering a therapeutically effective amount to a person in need of treatment of a disorder selected from cardiovascular disorders, inflammatory disorders, attention deficit hyperactivity disorders, Alzheimer's disease, evil abuse, Parkinson's disease, anxiety, mood disorders and depression It relates to a method for treating disorders selected from vascular disorders, inflammatory disorders, attention deficit hyperactivity disorders, Alzheimer's disease, evil abuse, Parkinson's disease, anxiety, mood disorders and depression.
또 다른 양태에서, 본 발명은 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 비스((L)타르트레이트)의 치료학적 유효량을 심장혈관 장애, 염증 장애, 주의력 결핍 과다활동 장애, 알츠하이머 병, 악물 남용, 파킨슨 병, 불안, 기분 장애 및 우울증으로부터 선택된 장애의 치료를 요하는 사람에게 투여함을 포함 하는 사람의 심장혈관 장애, 염증 장애, 주의력 결핍 과다활동 장애, 알츠하이머 병, 악물 남용, 파킨슨 병, 불안, 기분 장애 및 우울증으로부터 선택된 장애의 치료방법에 관한 것이다.In another embodiment, the invention provides a therapeutically effective amount of 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole bis ((L) tartrate) for cardiovascular disorders. Cardiovascular disorders, inflammatory disorders, attention in humans, including administration to persons in need of treatment of disorders selected from inflammatory disorders, attention deficit hyperactivity disorders, Alzheimer's disease, evil abuse, Parkinson's disease, anxiety, mood disorders and depression And a method for treating a disorder selected from deficit hyperactivity disorder, Alzheimer's disease, bad substance abuse, Parkinson's disease, anxiety, mood disorders and depression.
또 다른 양태에서, 본 발명은 2-[(4-피리미딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 심장혈관 장애, 염증 장애, 주의력 결핍 과다활동 장애, 알츠하이머 병, 악물 남용, 파킨슨 병, 불안, 기분 장애 및 우울증으로부터 선택된 장애의 치료를 요하는 사람에게 투여함을 포함하는 사람의 심장혈관 장애, 염증 장애, 주의력 결핍 과다활동 장애, 알츠하이머 병, 악물 남용, 파킨슨 병, 불안, 기분 장애 및 우울증으로부터 선택된 장애의 치료방법에 관한 것이다.In another embodiment, the invention provides 2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole or a pharmaceutically acceptable salt, ester, amide or prodrug thereof Administering a therapeutically effective amount of to a person in need thereof for treatment of a disorder selected from cardiovascular disorders, inflammatory disorders, attention deficit hyperactivity disorders, Alzheimer's disease, evil abuse, Parkinson's disease, anxiety, mood disorders and depression. Cardiovascular disorders, inflammatory disorders, attention deficit hyperactivity disorders, Alzheimer's disease, evil abuse, Parkinson's disease, anxiety, mood disorders and depression.
또 다른 양태에서, 본 발명은 6-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]피리딘-3-올 또는 약제학적으로 의 염, 에스테르, 아미드 또는 프로드럭의 치료학적 유효량을 심장혈관 장애, 염증 장애, 주의력 결핍 과다활동 장애, 알츠하이머 병, 악물 남용, 파킨슨 병, 불안, 기분 장애 및 우울증으로부터 선택된 장애의 치료를 요하는 사람에게 투여함을 포함하는 사람의 심장혈관 장애, 염증 장애, 주의력 결핍 과다활동 장애, 알츠하이머 병, 악물 남용, 파킨슨 병, 불안, 기분 장애 및 우울증으로부터 선택된 장애의 치료방법에 관한 것이다.In another embodiment, the invention provides 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol or a pharmaceutical salt, ester, amide or prodrug of Administering a therapeutically effective amount of to a person in need thereof for treatment of a disorder selected from cardiovascular disorders, inflammatory disorders, attention deficit hyperactivity disorders, Alzheimer's disease, evil abuse, Parkinson's disease, anxiety, mood disorders and depression. Cardiovascular disorders, inflammatory disorders, attention deficit hyperactivity disorders, Alzheimer's disease, evil abuse, Parkinson's disease, anxiety, mood disorders and depression.
또 다른 양태에서, 본 발명은 화학식 II의 화합물, 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭에 관한 것이다 In another aspect, the invention relates to a compound of Formula (II), or a pharmaceutically acceptable salt, ester, amide or prodrug thereof
A는 , , , , , , , , , , , , , , , , , 또는 로부터 선택되고,A is , , , , , , , , , , , , , , , , , or Is selected from,
X는 NH, O 또는 S로부터 선택되고,X is selected from NH, O or S,
L은 CH2, CH2CH2, CH2CH2CH2 또는 CH 2CH2CH2CH2로부터 선택되고,L is selected from CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 or CH 2 CH 2 CH 2 CH 2 ,
R1, R2, R3, R4 및 R5는 각각 독립적으로 수소, 알콕시, 알케닐, 알킬, 알킬설피닐, 알킬설포닐, 알킬티오, 알키닐, 알콕시카보닐, 알킬카보닐, 알킬카보닐옥시, 카복시, 시아노, 포르밀, 할로겐, 할로알콕시, 할로알킬, 하이드록시, 하이드록시알킬, 머캅토, 니트로, -NZ1Z2 및 (NZ1Z2)카보닐(여기서, Z1 및 Z2는 각각 독립적으로 수소, 알킬, 알킬카보닐, 알킬설포닐 및 포르밀로 이루어진 그룹으로부터 선택된다)로부터 선택되고,R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkyl Carbonyloxy, carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ 1 Z 2 and (NZ 1 Z 2 ) carbonyl, wherein Z 1 and Z 2 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl and formyl),
RA, RB, RC 및 RD는 각각 독립적으로 수소, 알콕시, 알케닐, 알킬, 알킬설피 닐, 알킬설포닐, 알킬티오, 알키닐, 알콕시카보닐, 알킬카보닐, 알킬카보닐옥시, 카복시, 시아노, 포르밀, 할로겐, 할로알콕시, 할로알킬, 하이드록시, 하이드록시알킬, 머캅토, 니트로, -NZ1Z2 또는 (NZ1Z2)카보닐로부터 선택되고, R A , R B , R C and R D are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy , Carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ 1 Z 2 or (NZ 1 Z 2 ) carbonyl,
RE는 수소, 알콕시카보닐, 알킬, 알킬카보닐, 아릴카보닐, 사이클로알킬카보닐, 헤테로사이클카보닐 또는 (NZ1Z2)카보닐로부터 선택되고,R E is selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclecarbonyl or (NZ 1 Z 2 ) carbonyl,
RF는 수소 및 알킬로 이루어진 그룹으로부터 선택되며,R F is selected from the group consisting of hydrogen and alkyl,
A가 이고 X가 S이면, R2 또는 R3은 수소가 아니다.A And X is S, then R 2 or R 3 is not hydrogen.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE가 수소이고, A가 이고, L, R2, R3 및 R4가 화학식 II에서 정의한 바와 같은 화학식 II의 화합물에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E is hydrogen and A is And L, R 2 , R 3 and R 4 are directed to compounds of formula II as defined in formula II.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE 및 RF가 각각 수소이고, L이 CH2이고, A가 이며, R2, R3 및 R4가 각각 수소인 화학식 II의 화합물에 관한 것이다.In another embodiment, the present invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E and R F are each hydrogen, L is CH 2 , and A is And R 2 , R 3 and R 4 are each hydrogen.
또 다른 양태에서, 본 발명은 화학식 III의 화합물, 또는 약제학적으로 허용 되는 이의 염, 에스테르, 아미드 또는 프로드럭에 관한 것이다.In another aspect, the invention relates to a compound of Formula III, or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.
위의 화학식 III에서,In Formula III above,
R1, R2, R3 및 R4는 각각 독립적으로 수소, 알킬설피닐, 알킬설포닐, 알킬설포닐아미노, 알킬티오 또는 하이드록시로부터 선택되고,R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, alkylthio or hydroxy,
L은 CH2, CH2CH2, CH2CH2CH2 또는 CH 2CH2CH2CH2로부터 선택되고,L is selected from CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 or CH 2 CH 2 CH 2 CH 2 ,
RA, RB, RC 및 RD는 각각 독립적으로 수소, 알콕시, 알케닐, 알킬, 알킬설피닐, 알킬설포닐, 알킬티오, 알키닐, 알콕시카보닐, 알킬카보닐, 알킬카보닐옥시, 카복시, 시아노, 포르밀, 할로겐, 할로알콕시, 할로알킬, 하이드록시, 하이드록시알킬, 머캅토, 니트로, -NZ1Z2 및 (NZ1Z2)카보닐(여기서, Z1 및 Z2 각각 독립적으로 수소, 알킬, 알킬카보닐, 알킬설포닐 및 포르밀로 이루어진 그룹으로부터 선택된다)로부터 선택되고,R A , R B , R C and R D are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy , Carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ 1 Z 2 and (NZ 1 Z 2 ) carbonyl, wherein Z 1 and Z is selected from 2 each are independently selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl and formyl group consisting of wheat),
RE는 수소, 알콕시카보닐, 알킬, 알킬카보닐, 아릴카보닐, 사이클로알킬카보닐, 헤테로사이클카보닐 또는 (NZ1Z2)카보닐로부터 선택되고, R E is selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclecarbonyl or (NZ 1 Z 2 ) carbonyl,
RF는 수소 및 알킬로 이루어진 그룹으로부터 선택되며,R F is selected from the group consisting of hydrogen and alkyl,
RF가 수소이면, R1, R2, R3 및 R4 중의 하나 이상은 수소가 아니다.If R F is hydrogen, at least one of R 1 , R 2 , R 3 and R 4 is not hydrogen.
또 다른 양태에서, 본 발명은 R1, R2, R3 및 R4가 각각 독립적으로 수소 또는 하이드록시로부터 선택되며, 단 R1, R2, R3 및 R4 중의 하나 이상은 하이드록시이고, RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE가 수소이며, L이 화학식 I에서 정의된 바와 같은 화학식 III의 화합물에 관한 것이다.In another embodiment, the present invention provides that R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen or hydroxy provided that at least one of R 1 , R 2 , R 3 and R 4 is hydroxy , R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E is hydrogen, and L relates to compounds of formula III as defined in formula (I).
또 다른 양태에서, 본 발명은 R1, R2 및 R4가 각각 수소이고, R3이 하이드록시이고, L이 CH2이고, RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되며, RE 및 RF가 각각 수소인 화학식 III의 화합물에 관한 것이다.In another embodiment, the invention provides that R 1 , R 2 and R 4 are each hydrogen, R 3 is hydroxy, L is CH 2 , and R A , R B , R C and R D are each independently hydrogen Or halogen, and R E and R F are each hydrogen.
또 다른 양태에서, 본 발명은 R1, R2, R3 및 R4가 각각 수소이고, L이 CH2이고, RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE가 수소이며, RF가 알킬인 화학식 III의 화합물에 관한 것이다.In another embodiment, the invention provides that R 1 , R 2 , R 3 and R 4 are each hydrogen, L is CH 2 , and R A , R B , R C and R D are each independently selected from hydrogen or halogen And R E is hydrogen and R F is alkyl.
또 다른 양태에서, 본 발명은 R1, R2, R3 및 R4가 각각 독립적으로 수소 또는 알킬설포닐아미노로부터 선택되며, 단 R1, R2, R3 또는 R4 중의 하나 이상은 알킬설포닐아미노이고, RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선 택되고, RE가 수소이며, RF가 화학식 III에서 정의된 바와 같은 화학식 III의 화합물에 관한 것이다.In another embodiment, the present invention provides that R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen or alkylsulfonylamino, provided that at least one of R 1 , R 2 , R 3 or R 4 is alkyl Sulfonylamino, R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E is hydrogen, and R F is directed to a compound of formula III as defined in formula III will be.
또 다른 양태에서, 본 발명은 R1, R3 및 R4가 각각 수소이고, R1이 알킬설포닐아미노이고, L이 CH2이고, RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되며, RE 및 RF가 각각 수소인 화학식 III의 화합물에 관한 것이다.In another embodiment, the invention provides that R 1 , R 3 and R 4 are each hydrogen, R 1 is alkylsulfonylamino, L is CH 2 , and R A , R B , R C and R D are each independent And hydrogen or halogen, wherein R E and R F are each hydrogen.
또 다른 양태에서, 본 발명은 화학식 IV의 화합물, 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭에 관한 것이다.In another aspect, the present invention relates to a compound of formula IV, or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.
위의 화학식 IV에서,In Formula IV above,
A는 , , , , , , , , , , , , , , , , , , 또는 로부터 선택되고,A is , , , , , , , , , , , , , , , , , , or Is selected from,
X는 NH, O 또는 S로부터 선택되고, X is selected from NH, O or S,
L은 CH2, CH2CH2, CH2CH2CH2 또는 CH 2CH2CH2CH2로부터 선택되고,L is selected from CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 or CH 2 CH 2 CH 2 CH 2 ,
R1, R2, R3, R4 및 R5는 각각 독립적으로 수소, 알콕시, 알케닐, 알킬, 알킬설피닐, 알킬설포닐, 알킬티오, 알키닐, 알콕시카보닐, 알킬카보닐, 알킬카보닐옥시, 카복시, 시아노, 포르밀, 할로겐, 할로알콕시, 할로알킬, 하이드록시, 하이드록시알킬, 머캅토, 니트로, -NZ1Z2 및 (NZ1Z2)카보닐(여기서, Z1 및 Z2는 각각 독립적으로 수소, 알킬, 알킬카보닐, 알킬설포닐 및 포르밀로 이루어진 그룹으로부터 선택된다)로부터 선택되고,R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkyl Carbonyloxy, carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ 1 Z 2 and (NZ 1 Z 2 ) carbonyl, wherein Z 1 and Z 2 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl and formyl),
RA, RB, RC 및 RD는 각각 독립적으로 수소, 알콕시, 알케닐, 알킬, 알킬설피닐, 알킬설포닐, 알킬티오, 알키닐, 알콕시카보닐, 알킬카보닐, 알킬카보닐옥시, 카복시, 시아노, 포르밀, 할로겐, 할로알콕시, 할로알킬, 하이드록시, 하이드록시알킬, 머캅토, 니트로, -NZ1Z2 또는 (NZ1Z2)카보닐로부터 선택되고, R A , R B , R C and R D are each independently hydrogen, alkoxy, alkenyl, alkyl, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy , Carboxy, cyano, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ 1 Z 2 or (NZ 1 Z 2 ) carbonyl,
RE는 수소, 알콕시카보닐, 알킬, 알킬카보닐, 아릴카보닐, 사이클로알킬카보닐, 헤테로사이클카보닐 또는 (NZ1Z2)카보닐로부터 선택되고,R E is selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclecarbonyl or (NZ 1 Z 2 ) carbonyl,
RF는 수소 또는 알킬로부터 선택되고,R F is selected from hydrogen or alkyl,
Z는 C 또는 CH로부터 선택되며,Z is selected from C or CH,
---는, Z가 C인 경우, 결합이고, Z가 CH인 경우, 부재한다.--- is a bond when Z is C and absent when Z is CH.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE가 수소이고, Z가 CH이고, ---가 부재하고, A가 이며, L, R1, R2, R3, R4 및 R5가 화학식 IV에서 정의한 바와 같은 화학식 IV의 화합물에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E is hydrogen, Z is CH, --- is absent and A is And L, R 1 , R 2 , R 3 , R 4 and R 5 are directed to compounds of formula IV as defined in formula IV.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE 및 RF가 각각 수소이고, L이 CH2이고, Z가 CH이고, ---가 부재하고, A가 이고, R2, R3 및 R4가 각각 수소이며, R1 및 R5가 화학식 IV에서 정의한 바와 같은 화학식 IV의 화합물에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E and R F are each hydrogen, L is CH 2 , Z is CH , --- is absent, and A R 2 , R 3 and R 4 are each hydrogen, and R 1 and R 5 are directed to compounds of formula IV as defined in formula IV.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE가 수소이고, Z가 CH이고, ---가 부재하고, A가 이며, L, R1, R2, R3 및 R4가 화학식 IV에서 정의한 바와 같은 화학식 IV의 화합물에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E is hydrogen, Z is CH, --- is absent and A is And L, R 1 , R 2 , R 3 and R 4 are directed to compounds of formula IV as defined in formula IV.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE 및 RF가 각각 수소이고, L이 CH2이고, Z가 CH이고, -- -가 부재하고, A가 이고, R2, R3 및 R4가 각각 수소이고, R1이 화학식 IV에서 정의한 바와 같은 화학식 IV의 화합물에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E and R F are each hydrogen, L is CH 2 , Z is CH ,--Is absent, and A R 2 , R 3 and R 4 are each hydrogen and R 1 relates to a compound of formula IV as defined in formula IV.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE가 수소이고, Z가 C이고, ---가 결합이고, A가 이며, L, R1, R2, R3, R4 및 R5가 화학식 IV에서 정의한 바와 같은 화학식 IV의 화합물에 관한 것이다.In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E is hydrogen, Z is C, --- is a bond, and A is And L, R 1 , R 2 , R 3 , R 4 and R 5 are directed to compounds of formula IV as defined in formula IV.
또 다른 양태에서, 본 발명은 RA, RB, RC 및 RD가 각각 독립적으로 수소 또는 할로겐으로부터 선택되고, RE 및 RF가 각각 수소이고, L이 CH2이고, Z가 C이고, ---가 결합이고, A가 이고, R2, R3 및 R4가 각각 수소이며, R1 및 R5가 화학식 IV에서 정의한 바와 같은 화학식 IV의 화합물에 관한 것이다.
In another embodiment, the invention provides that R A , R B , R C and R D are each independently selected from hydrogen or halogen, R E and R F are each hydrogen, L is CH 2 , Z is C , --- is a bond, and A is R 2 , R 3 and R 4 are each hydrogen, and R 1 and R 5 are directed to compounds of formula IV as defined in formula IV.
본 발명의 정의Definition of the present invention
당해 명세서 및 첨부된 청구항을 통하여 사용된 바와 같이, 다음 용어는 다음의 의미를 갖는다:As used throughout this specification and the appended claims, the following terms have the following meanings:
본원에 사용된 바와 같은 용어 "알케닐"은 두 개의 수소를 제거하여 형성된 하나 이상의 탄소-탄소 이중결합을 함유하는 탄소수 2 내지 10의 직쇄 또는 측쇄 탄화수소를 말한다. 알케닐의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 에테닐, 2-프로페닐, 2-메틸-2-프로페닐, 3-부테닐, 4-펜테닐, 5-헥세닐, 2-헵테닐, 2-메틸-1-헵테닐 및 3-데세닐이 포함된다.As used herein, the term "alkenyl" refers to a straight or branched chain hydrocarbon of 2 to 10 carbon atoms containing one or more carbon-carbon double bonds formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl and 3-decenyl are included.
본원에 사용된 바와 같은 용어 "알콕시"는 산소원자를 통하여 모 분자 잔기에 부착된 본원에서 정의한 바와 같은 알킬 그룹을 말한다. 알콕시의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 메톡시, 에톡시, 프로폭시, 2-프로폭시, 부톡시, 3급 부톡시, 펜틸옥시 및 헥실옥시가 포함된다.The term "alkoxy" as used herein refers to an alkyl group as defined herein attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy.
본원에 사용된 바와 같은 용어 "알콕시알콕시"는 본원에서 정의한 바와 같은 또 다른 알콕시 그룹을 통하여 모 분자 잔기에 부착된 본원에 정의한 바와 같은 알콕시 그룹을 말한다. 알콕시알콕시의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 3급 부톡시메톡시, 2-에톡시에톡시, 2-메톡시에톡시 및 메톡시메톡시가 포함된다.The term "alkoxyalkoxy" as used herein refers to an alkoxy group, as defined herein, attached to the parent molecular moiety through another alkoxy group, as defined herein. Representative examples of alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy and methoxymethoxy.
본원에 사용된 바와 같은 용어 "알콕시알킬"은 본원에서 정의한 바와 같은 알킬 그룹을 통하여 모 분자 잔기에 부착된 본원에서 정의한 바와 같은 알콕시 그룹을 말한다. 알콕시알킬의 대표적인 예로는 이들로 한정하려는 것은 아니지만 3급 부톡시메틸, 2-에톡시에틸, 2-메톡시에틸 및 메톡시메틸이 포함된다.As used herein, the term “alkoxyalkyl” refers to an alkoxy group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl and methoxymethyl.
본원에 사용된 바와 같은 용어 "알콕시카보닐"은 본원에서 정의한 바와 같은 카보닐 그룹을 통하여 모 분자 잔기에 부착된 본원에서 정의된 바와 같은 알콕시 그룹을 말한다. 알콕시카보닐의 대표적인 예로는 이들로 한정하려는 것은 아니지만 메톡시카보닐, 에톡시카보닐 및 3급 부톡시카보닐이 포함된다.The term "alkoxycarbonyl" as used herein refers to an alkoxy group, as defined herein, attached to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl.
본원에 사용된 바와 같은 용어 "알콕시카보닐알킬"은 본원에서 정의한 바와 같은 알킬 그룹을 통하여 모 분자 잔기에 부착된 본원에서 정의한 바와 같은 알콕시카보닐 그룹을 말한다. 알콕시카보닐알킬의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 3-메톡시카보닐프로필, 4-에톡시카보닐부틸 및 2-3급 부톡시카보닐에틸이 포함된다.The term "alkoxycarbonylalkyl" as used herein refers to an alkoxycarbonyl group as defined herein attached to the parent molecular moiety through an alkyl group as defined herein. Representative examples of alkoxycarbonylalkyl include, but are not limited to, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and 2-3-butoxycarbonylethyl.
본원에 사용된 바와 같은 용어 "알콕시설포닐"은 본원에서 정의한 바와 같은 설포닐 그룹을 통하여 모 분자 잔기에 부착된 본원에서 정의한 바와 같은 알콕시 그룹을 말한다. 알콕시설포닐의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 메톡시설포닐, 에톡시설포닐 및 프로폭시설포닐이 포함된다.The term "alkoxysulfonyl" as used herein refers to an alkoxy group, as defined herein, attached to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkoxysulfonyl include, but are not limited to, methoxysulfonyl, ethoxysulfonyl and propoxysulfonyl.
본원에서 사용된 바와 같은 용어 "알킬"은 탄소수 1 내지 10의 직쇄 또는 측쇄 탄화수소를 말한다. 알킬의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 메틸, 에틸, n-프로필, 이소-프로필, n-부틸, 2급 부틸, 이소-부틸, 3급 부틸, n-펜틸, 이소펜틸, 네오펜틸, n-헥실, 3-메틸헥실, 2,2-디메틸펜틸, 2,3-디메틸펜틸, n-헵틸, n-옥틸, n-노닐 및 n-데실이 포함된다.As used herein, the term "alkyl" refers to a straight or branched chain hydrocarbon of 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, secondary butyl, iso-butyl, tertiary butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
본원에 사용된 바와 같은 용어 "알킬카보닐"은 본원에서 정의한 바와 같은 카보닐 그룹을 통하여 모 분자 잔기에 부착된 본원에서 정의한 바와 같은 알킬 그룹을 말한다. 알킬카보닐의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 아세틸, 1-옥소프로필, 2,2-디메틸-1-옥소프로필, 1-옥소부틸 및 1-옥소펜틸이 포함된다.The term "alkylcarbonyl" as used herein refers to an alkyl group, as defined herein, attached to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
본원에서 사용된 바와 같은 용어 "알킬카보닐알킬"은 본원에서 정의한 바와 같은 알킬 그룹을 통하여 모 분자 잔기에 부착된 본원에서 정의한 바와 같은 알킬카보닐 그룹을 말한다. 알킬카보닐알킬의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 2-옥소프로필, 3,3-디메틸-2-옥소프로필, 3-옥소부틸 및 3-옥소펜틸이 포함된다.The term "alkylcarbonylalkyl" as used herein refers to an alkylcarbonyl group as defined herein attached to the parent molecular moiety through an alkyl group as defined herein. Representative examples of alkylcarbonylalkyl include, but are not limited to, 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl.
본원에서 사용된 바와 같은 용어 "알킬카보닐옥시"는 산소원자를 통하여 모 분자 잔기에 부착된 본원에서 정의한 바와 같은 알킬카보닐 그룹을 말한다. 알킬카보닐옥시의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 아세틸옥시, 에틸카보닐옥시 및 3급 부틸카보닐옥시가 포함된다.The term "alkylcarbonyloxy" as used herein refers to an alkylcarbonyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy and tertiary butylcarbonyloxy.
본원에서 사용된 바와 같은 용어 "알킬설피닐"은 본원에서 정의한 바와 같은 설피닐 그룹을 통하여 모 분자 잔기에 부착된 본원에서 정의한 바와 같은 알킬 그룹을 말한다. 알킬설피닐의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 메틸설피닐 및 에틸설피닐이 포함된다.The term "alkylsulfinyl" as used herein refers to an alkyl group, as defined herein, attached to the parent molecular moiety through a sulfinyl group, as defined herein. Representative examples of alkylsulfinyl include, but are not limited to, methylsulfinyl and ethylsulfinyl.
본원에서 사용된 바와 같은 용어 "알킬설포닐"은 본원에서 정의한 바와 같은 설포닐 그룹을 통하여 모 분자 잔기에 부착된 본원에서 정의한 바와 같은 알킬 그룹을 말한다. 알킬설포닐의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 메틸설포닐 및 에틸설포닐이 포함된다.The term "alkylsulfonyl" as used herein refers to an alkyl group, as defined herein, attached to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl.
본원에서 사용된 바와 같은 용어 "알킬설포닐아미노"는 NH 그룹을 통하여 모 분자 잔기에 부착된 본원에서 정의한 바와 같은 알킬설포닐 그룹을 말한다. 알킬설포닐아미노의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 메틸설포닐아미노 및 에틸설포닐아미노가 포함된다.The term "alkylsulfonylamino" as used herein refers to an alkylsulfonyl group, as defined herein, attached to the parent molecular moiety through an NH group. Representative examples of alkylsulfonylamino include, but are not limited to, methylsulfonylamino and ethylsulfonylamino.
본원에서 사용된 바와 같은 용어 "알킬티오"는 황원자를 통하여 모 분자 잔기에 부착된 본원에서 정의한 바와 같은 알킬 그룹을 말한다. 알킬티오의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 메틸설파닐, 에틸설파닐, 3급 부틸설파닐 및 헥실설파닐이 포함된다.The term "alkylthio" as used herein refers to an alkyl group as defined herein attached to the parent molecular moiety through a sulfur atom. Representative examples of alkylthio include, but are not limited to, methylsulfanyl, ethylsulfanyl, tertiary butylsulfanyl and hexylsulfanyl.
본원에서 사용된 바와 같은 용어 "알킬티오알킬"은 본원에서 정의한 바와 같은 알킬 그룹을 통하여 모 분자 잔기에 부착된 본원에서 정의한 바와 같은 알킬티오 그룹을 말한다. 알킬티오알킬의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 메틸설파닐메틸 및 2-(에틸설파닐)에틸이 포함된다.The term "alkylthioalkyl" as used herein refers to an alkylthio group as defined herein attached to the parent molecular moiety through an alkyl group as defined herein. Representative examples of alkylthioalkyls include, but are not limited to, methylsulfanylmethyl and 2- (ethylsulfanyl) ethyl.
본원에서 사용된 바와 같은 용어 "알키닐"은 한 개 이상의 탄소-탄소 삼중결합을 함유하는 탄소수 2 내지 10의 직쇄 또는 측쇄 탄화수소 그룹을 말한다. 알키닐의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 아세틸레닐, 1-프로피닐, 2-프로피닐, 3-부티닐, 2-펜티닐 및 1-부티닐이 포함된다.As used herein, the term "alkynyl" refers to a straight or branched chain hydrocarbon group of 2 to 10 carbon atoms containing one or more carbon-carbon triple bonds. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl and 1-butynyl.
본원에서 사용된 바와 같은 용어 "아릴"은 한 개 이상의 융합 환이 방향족인 모노사이클릭 환 시스템 또는 비사이클릭 또는 트리사이클릭 융합환 시스템을 말한다. 아릴의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 안트라세닐, 아줄레닐, 플루오레닐, 인다닐, 인데닐, 나프틸, 페닐 및 테트라하이드로나프틸이 포함된다.The term "aryl" as used herein refers to a monocyclic ring system or a bicyclic or tricyclic fused ring system in which one or more fused rings is aromatic. Representative examples of aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl and tetrahydronaphthyl.
본 발명의 아릴 그룹은 알케닐, 알콕시, 알콕시알콕시, 알콕시알킬, 알콕시카보닐, 알콕시카보닐알킬, 알콕시설포닐, 알킬, 알킬카보닐, 알킬카보닐알킬, 알킬카보닐옥시, 알킬티오, 알킬티오알킬, 알키닐, 카복시, 카복시알킬, 시아노, 시아노알킬, 에틸렌디옥시, 포르밀, 할로알콕시, 할로알킬, 할로겐, 하이드록시, 하이드록시알킬, 머캅토, 메틸렌디옥시, 니트로, -NZ1Z2 및 (NZ1Z2)카보닐로부터 독립적으로 선택된 1, 2, 3, 4 또는 5개의 치환체로 치환될 수 있다.The aryl groups of the present invention are alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkyl Thioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro,- Or 1, 2, 3, 4 or 5 substituents independently selected from NZ 1 Z 2 and (NZ 1 Z 2 ) carbonyl.
본원에서 사용된 바와 같은 용어 "아릴카보닐"은 본원에서 정의한 바와 같은 카보닐 그룹을 통하여 모 분자 잔기에 부착된 본원에서 정의한 바와 같은 아릴 그룹을 말한다. 아릴카보닐의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 벤조일 및 나프토일이 포함된다.The term "arylcarbonyl" as used herein refers to an aryl group as defined herein attached to the parent molecular moiety through a carbonyl group as defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl and naphthoyl.
본원에서 사용된 바와 같은 용어 "카보닐"은 -C(O)- 그룹을 말한다.The term "carbonyl" as used herein refers to a -C (O)-group.
본원에서 사용된 바와 같은 용어 "카복시"는 -CO2H 그룹을 말한다.The term "carboxy" as used herein refers to a -CO 2 H group.
본원에서 사용된 바와 같은 용어 "카복시알킬"은 본원에서 정의한 바와 같은 알킬 그룹을 통하여 모 분자 잔기에 부착된 본원에서 정의한 바와 같은 카복시 그룹을 말한다. 카복시알킬의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 카복시메틸, 2-카복시에틸 및 3-카복시프로필이 포함된다.As used herein, the term “carboxyalkyl” refers to a carboxy group as defined herein attached to a parent molecular moiety through an alkyl group as defined herein. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxyethyl and 3-carboxypropyl.
본원에서 사용된 바와 같은 용어 "시아노"는 -CN 그룹을 말한다.As used herein, the term “cyano” refers to a —CN group.
본원에서 사용된 바와 같은 용어 "시아노알킬"은 본원에서 정의한 바와 같은 알킬 그룹을 통하여 모 분자 잔기에 부착된 본원에서 정의한 바와 같은 시아노 그룹을 말한다. 시아노알킬의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 시아노메틸, 2-시아노에틸 및 3-시아노프로필이 포함된다.As used herein, the term “cyanoalkyl” refers to a cyano group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2-cyanoethyl and 3-cyanopropyl.
본원에서 사용된 바와 같은 용어 "사이클로알킬"은 탄소수 3 내지 8의 포화 사이클릭 탄화수소 그룹을 말한다. 사이클로알킬의 예로는 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헵틸 및 사이클로옥틸이 포함된다.The term "cycloalkyl" as used herein refers to a saturated cyclic hydrocarbon group having 3 to 8 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
본원에서 사용된 바와 같은 용어 "사이클로알킬카보닐"은 본원에서 정의한 바와 같은 카보닐 그룹을 통하여 모 분자 잔기에 부착된 본원에서 정의한 바와 같은 사이클로알킬 그룹을 말한다. 사이클로알킬카보닐의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 사이클로프로필카보닐, 사이클로부틸카보닐 및 사이클로헥실카보닐이 포함된다.As used herein, the term “cycloalkylcarbonyl” refers to a cycloalkyl group, as defined herein, attached to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of cycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl, cyclobutylcarbonyl, and cyclohexylcarbonyl.
본원에서 사용된 바와 같은 용어 "에틸렌디옥시"는 에틸렌디옥시 그룹의 산소원자가 5원 환을 형성하는 하나의 탄소원자를 통하여 모 분자 잔기에 결합되거나 에틸렌디옥시 그룹의 산소원자가 6원 환을 형성하는 두 개의 인접 탄소원자를 통하여 모 분자 잔기에 결합된 -O(CH2)2O- 그룹을 말한다.As used herein, the term "ethylenedioxy" refers to the attachment of the oxygen atom of the ethylenedioxy group to the parent molecular moiety through one carbon atom forming a five-membered ring, or the oxygen atom of the ethylenedioxy group to form a six-membered ring. A -O (CH 2 ) 2 O- group bonded to the parent molecular moiety through two adjacent carbon atoms.
본원에서 사용된 바와 같은 용어 "포르밀"은 -C(O)H 그룹을 말한다.The term "formyl" as used herein refers to a -C (O) H group.
본원에서 사용된 바와 같은 용어 "할로" 또는 "할로겐"은 -Cl, -Br, -I 또는 -F를 말한다.The term "halo" or "halogen" as used herein refers to -Cl, -Br, -I or -F.
본원에서 사용된 바와 같은 용어 "할로알콕시"는 본원에서 정의한 바와 같은 알콕시 그룹을 통하여 모 분자 잔기에 부착된 본원에서 정의한 바와 같은 하나 이상의 할로겐을 말한다. 할로알콕시의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 2-플루오로-1-클로로에톡시, 클로로메톡시, 2-플루오로에톡시, 트리플루오로메톡시 및 펜타플루오로에톡시가 포함된다.The term "haloalkoxy" as used herein refers to one or more halogen as defined herein attached to the parent molecular moiety through an alkoxy group as defined herein. Representative examples of haloalkoxy include, but are not limited to, 2-fluoro-1-chloroethoxy, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy and pentafluoroethoxy.
본원에서 사용된 바와 같은 용어 "할로알킬"은 본원에서 정의한 바와 같은 알킬 그룹을 통하여 모 분자 잔기에 부착된 본원에서 정의한 바와 같은 하나 이상의 할로겐을 말한다. 할로알킬의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 클로로메틸, 2-플루오로에틸, 트리플루오로메틸, 펜타플루오로에틸 및 2-클로로-3-플루오로펜틸이 포함된다.As used herein, the term “haloalkyl” refers to one or more halogen as defined herein attached to the parent molecular moiety through an alkyl group as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl and 2-chloro-3-fluoropentyl.
본원에 사용된 바와 같은 용어 "헤테로사이클" 또는 "헤테로사이클릭"은 모노사이클릭, 비사이클릭 또는 트리사이클릭 환 시스템을 말한다. 모노사이클릭 환 시스템으로는 산소, 질소 및 황으로부터 독립적으로 선택된 헤테로원자를 함유하는 3원 또는 4원 환, 또는 헤테로원자가 질소, 산소 및 황으로부터 독립적으로 선택된 한 개, 두 개 또는 세 개의 헤테로원자를 포함하는 5원, 6원 또는 7원 환을 들 수 있다. 5원 환은 0 내지 2개의 이중결합을 갖고 6원 및 7원 환은 0 내지 3개의 이중결합을 갖는다. 모노사이클릭 환 시스템의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 아제티디닐, 아제파닐, 아지리디닐, 디아제피닐, 1,3-디옥솔라닐, 디옥사닐, 디티아닐, 푸릴, 이미다졸릴, 이미다졸리닐, 이미다졸리디닐, 이소티라졸릴, 이소티아졸리닐, 이소티아졸리디닐, 이소옥사졸릴, 이소옥사졸리닐, 이소옥사졸리디닐, 모르폴리닐, 옥사디아졸릴, 옥사디아졸리닐, 옥사디아졸리디닐, 옥사졸릴, 옥사졸리닐, 옥사졸리디닐, 피페라지닐, 피페라디닐, 피라닐, 피라지닐, 피라졸릴, 피라졸리닐, 피라졸리디닐, 피리디닐, 피리미디닐, 피리다지닐, 피롤릴, 피롤리닐, 피롤리디닐, 테트라하이드로푸라닐, 테트라하이드로티에닐, 테트라지닐, 테트라졸릴, 티아디아졸릴, 티아디아졸리닐, 티아디아졸리디닐, 티아졸릴, 티아졸리닐, 티아졸리디닐, 티에닐, 티오모르폴리닐, 1,1-디옥시도티오모르폴리닐(티오모르폴린 설폰), 티오피라닐, 트리아지닐, 트리아졸리닐 및 트리티아닐이 포함된다. 비사이클릭 환 시스템은 본원에서 정의한 바와 같은 아릴 그룹, 본원에서 정의한 바와 같은 사이클로알킬 그룹 또는 또 다른 모노사이클릭 환 시스템에 융합된 위의 모노사이클릭 환 시스템 중의 어느 하나를 들 수 있다. 비사이클릭 환 시스템의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 벤즈이미다졸릴, 벤조디옥시닐, 벤조티아졸릴, 벤조티에닐, 벤조트리아졸릴, 벤즈옥사졸릴, 벤조푸라닐, 벤조피라닐, 벤조티오피라닐, 신놀리닐, 인다졸릴, 인돌릴, 2,3-디하이드로인돌릴, 인돌리지닐, 나프티리디닐, 이소벤조푸라닐, 이소벤조티에닐, 이소인돌릴, 이소퀴놀리닐, 프탈라지닐, 피라노피리디닐, 퀴놀리닐, 퀴놀리지닐, 퀴녹살리닐, 퀴나졸리닐, 테트라하이드로이소퀴놀리닐, 테트라하이드로퀴놀리닐 및 티오피라노피리디닐이 포함된다. 트리사이클릭 환 시스템은 본원에서 정의된 바와 같은 아릴 그룹, 본원에서 정의한 바와 같은 사이클로알킬 그룹 또는 모노사이클릭 환 시스템에 융합된 위의 비사이클릭 환 시스템 중의 어느 하나를 들 수 있다. 트리사이클릭 환 시스템의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 아크리디닐, 카바졸릴, 카볼리닐, 디벤조[b,d]푸라닐, 디벤조[b,d]티에닐, 나프토[2,3-b]푸란, 나프토[2,3-b]티에닐, 페나지닐, 페노티아지닐, 페녹사지닐, 티안트레닐, 티옥산테닐 및 크산테닐이 포함된다.The term "heterocycle" or "heterocyclic" as used herein refers to a monocyclic, bicyclic or tricyclic ring system. Monocyclic ring systems include three or four membered rings containing heteroatoms independently selected from oxygen, nitrogen and sulfur, or one, two or three heteroatoms wherein heteroatoms are independently selected from nitrogen, oxygen and sulfur Five-, six- or seven-membered ring containing a. 5 membered rings have 0 to 2 double bonds and 6 and 7 membered rings have 0 to 3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepinyl, 1,3-dioxolanyl, dioxanyl, ditianyl, furyl, imida Zolyl, imidazolinyl, imidazolidinyl, isotrazolyl, isothiazolinyl, isothiazolidinyl, isoxazolyl, isoxoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolyl, oxadia Zolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperazinyl, pyranyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidinin, pyridinyl, pyrimidinyl , Pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiadiazolinyl, thiadiazolidinyl, thiazolyl, thia Zolinyl, thiazolidinyl, thienyl, thio Le morpholinyl, 1,1-oxido thiomorpholinyl (thiomorpholine sulfone), thio pyranyl, triazinyl, include not triazol Jolly carbonyl and tea tree. Bicyclic ring systems include any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein or another monocyclic ring system. Representative examples of bicyclic ring systems include, but are not limited to, benzimidazolyl, benzodioxynyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, benzofuranyl, benzopyranyl, Benzothiopyranyl, cinnolinyl, indazolyl, indolyl, 2,3-dihydroindolyl, indolinyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolinyl, isoquinolinyl Phthalazinyl, pyranopyridinyl, quinolinyl, quinolininyl, quinoxalinyl, quinazolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl and thiopyranopyridinyl. Tricyclic ring systems can include any of the above acyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or a monocyclic ring system. Representative examples of tricyclic ring systems include, but are not limited to, acridinyl, carbazolyl, carbolinyl, dibenzo [b, d] furanyl, dibenzo [b, d] thienyl, naphtho [ 2,3-b] furan, naphtho [2,3-b] thienyl, phenazinyl, phenothiazinyl, phenoxazinyl, thianthrenyl, thioxanthenyl and xanthenyl.
본 발명의 헤테로사이클은 알케닐, 알콕시, 알콕시알콕시, 알콕시알킬, 알콕 시카보닐, 알콕시카보닐알킬, 알콕시설포닐, 알킬, 알킬카보닐, 알킬카보닐알킬, 알킬카보닐옥시, 알킬티오, 알킬티오알킬, 알키닐, 카복시, 카복시알킬, 시아노, 시아노알킬, 에틸렌디옥시, 포르밀, 할로알콕시, 할로알킬, 할로겐, 하이드록시, 하이드록시알킬, 머캅토, 메틸렌디옥시, 니트로, 옥소, -NZ1Z2 및 (NZ1Z 2)카보닐로부터 독립적으로 선택된 1, 2 또는 3개의 치환체로 치환될 수 있다.Heterocycles of the invention are alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxy carbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkyl Thioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo , -NZ 1 Z 2 and (NZ 1 Z 2 ) carbonyl may be substituted with 1, 2 or 3 substituents independently selected.
본원에서 사용된 바와 같은 용어 "헤테로사이클카보닐"은 본원에서 정의한 바와 같은 카보닐 그룹을 통하여 모 분자 잔기에 부착된 본원에서 정의한 바와 같은 헤테로사이클을 말한다. 헤테로사이클카보닐의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 피리딘-3-일카보닐 및 퀴놀린-3-일카보닐이 포함된다.As used herein, the term “heterocyclecarbonyl” refers to a heterocycle as defined herein attached to the parent molecular moiety through a carbonyl group as defined herein. Representative examples of heterocyclecarbonyl include, but are not limited to, pyridin-3-ylcarbonyl and quinolin-3-ylcarbonyl.
본원에서 사용된 바와 같은 용어 "하이드록시"는 -OH 그룹을 말한다.As used herein, the term "hydroxy" refers to an -OH group.
본원에서 사용된 바와 같은 용어 "하이드록시알킬"은 본원에서 정의한 바와 같은 알킬 그룹을 통하여 모 분자 잔기에 부착된 본원에서 정의한 바와 같은 하나 이상의 하이드록시 그룹을 말한다. 하이드록시알킬의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 하이드록시메틸, 2-하이드록시에틸, 3-하이드록시프로필 2-에틸-4-하이드록시헵틸 및 2,4-디하이드록시부틸이 포함된다.As used herein, the term “hydroxyalkyl” refers to one or more hydroxy groups, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl 2-ethyl-4-hydroxyheptyl, and 2,4-dihydroxybutyl .
용어 "하이드록시 보호 그룹" 또는 "O 보호 그룹"은 합성 공정 동안 불필요한 반응에 대하여 하이드록실 그룹을 보호하는 치환체를 말한다. 하이드록시 보호 그룹의 예로는 이들로 한정하려는 것은 아니지만, 치환된 메틸 에테르, 예를 들면, 메톡시메틸, 벤질옥시메틸, 2-메톡시에톡시메틸, 2-(트리메틸실릴)-에톡시메틸, 벤 질 및 트리페닐메틸; 테트라하이드로피라닐 에테르; 치환된 에틸 에테르, 예를 들면, 2,2,2-트리클로로에틸 및 t-부틸; 실릴 에테르, 예를 들면, 트리메틸실릴, t-부틸디메틸실릴 및 t-부틸디페닐실릴; 사이클릭 아세틸 및 케탈, 예를 들면, 메틸렌 아세틸, 아세토나이드 및 벤질리덴 아세틸; 사이클릭 오르토 에스테르, 예를 들면, 메톡시메틸렌; 사이클릭 카보네이트; 및 사이클릭 보로네이트가 포함된다.The term "hydroxy protecting group" or "O protecting group" refers to a substituent that protects the hydroxyl group against unwanted reactions during the synthesis process. Examples of hydroxy protecting groups include, but are not limited to, substituted methyl ethers such as methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2- (trimethylsilyl) -ethoxymethyl, Benzyl and triphenylmethyl; Tetrahydropyranyl ethers; Substituted ethyl ethers such as 2,2,2-trichloroethyl and t-butyl; Silyl ethers such as trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; Cyclic acetyls and ketals such as methylene acetyl, acetonide and benzylidene acetyl; Cyclic ortho esters such as methoxymethylene; Cyclic carbonates; And cyclic boronates.
본원에서 사용된 바와 같은 용어 "머캅토"는 -SH 그룹을 말한다.The term "mercapto" as used herein refers to the -SH group.
본원에서 사용된 바와 같은 용어 "메틸렌디옥시"는 메틸렌디옥시의 산소원자가 두 개의 인접 탄소원자를 통하여 모 분자 잔기에 결합된 -OCH2O- 그룹을 말한다.The term "methylenedioxy" as used herein refers to an -OCH 2 O- group in which the oxygen atom of methylenedioxy is bonded to the parent molecular moiety through two adjacent carbon atoms.
본원에서 사용된 바와 같은 용어 "니트로"는 -NO2 그룹을 말한다.As used herein, the term “nitro” refers to the —NO 2 group.
본원에서 사용된 바와 같은 용어 "질소 보호 그룹"은 합성 공정 동안 불필요한 반응에 대하여 아미노 그룹을 보호하는 그룹을 말한다. 질소 보호 그룹은 카바메이트, 아미드, N-벤질 유도체 및 이민 유도체를 포함한다. 바람직한 질소 보호 그룹은 아세틸, 벤조일, 벤질, 벤질옥시카보닐(Cbz), 포르밀, 페닐설포닐, 피발로일, 3급 부톡시카보닐(Boc), 3급 부틸아세틸, 트리플루오로아세틸 및 트리페닐메틸(트리틸)이다.The term "nitrogen protecting group" as used herein refers to a group that protects an amino group against unwanted reactions during the synthesis process. Nitrogen protecting groups include carbamates, amides, N-benzyl derivatives and imine derivatives. Preferred nitrogen protecting groups are acetyl, benzoyl, benzyl, benzyloxycarbonyl (Cbz), formyl, phenylsulfonyl, pivaloyl, tert-butoxycarbonyl (Boc), tertiary butylacetyl, trifluoroacetyl and Triphenylmethyl (trityl).
본원에서 사용된 바와 같은 용어 "-NZ1Z2"는 질소원자를 통하여 모 분자 잔기에 부착된 두 개의 그룹 Z1 및 Z2를 말한다. Z1 및 Z2는 각각 독립적으로 수소, 알킬, 알킬카보닐, 알킬설포닐 및 포르밀로부터 선택된다. -NZ1Z2의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 아미노, 메틸아미노, 디메틸아미노, 아세틸아미노, (아세틸)(메틸)아미노 및 (메틸설포닐)아미노가 포함된다.The term "-NZ 1 Z 2 " as used herein refers to two groups Z 1 and Z 2 attached to the parent molecular moiety through a nitrogen atom. Z 1 and Z 2 are each independently selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl and formyl. Representative examples of -NZ 1 Z 2 include, but are not limited to, amino, methylamino, dimethylamino, acetylamino, (acetyl) (methyl) amino and (methylsulfonyl) amino.
본원에서 사용된 바와 같은 용어 "(NZ1Z2)카보닐"은 본원에서 정의한 바와 같은 카보닐 그룹을 통하여 모 분자 잔기에 부착된 본원에서 정의한 바와 같은 -NZ1Z2 그룹을 말한다. (NZ1Z2)카보닐의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 아미노카보닐, (메틸아미노)카보닐, (디메틸아미노)카보닐, ((아세틸)(메틸)아미노)카보닐 및 (에틸메틸아미노)카보닐이 포함된다.The term "(NZ 1 Z 2 ) carbonyl" as used herein refers to the group -NZ 1 Z 2 as defined herein attached to the parent molecular moiety through a carbonyl group as defined herein. Representative examples of (NZ 1 Z 2 ) carbonyl include, but are not limited to, aminocarbonyl, (methylamino) carbonyl, (dimethylamino) carbonyl, ((acetyl) (methyl) amino) carbonyl and ( Ethylmethylamino) carbonyl.
본원에서 사용된 바와 같은 용어 "(NZ1Z2)설포닐"은 본원에서 정의한 바와 같은 설포닐 그룹을 통하여 모 분자 잔기에 부착된 본원에서 정의된 바와 같은 -NZ1Z2 그룹을 말한다. (NZ1Z2)설포닐의 대표적인 예로는 이들로 한정하려는 것은 아니지만, 아미노설포닐, (메틸아미노)설포닐, (디메틸아미노)설포닐, ((아세틸)(메틸)아미노)설포닐 및 (에틸메틸아미노)설포닐이 포함된다.As used herein, the term “(NZ 1 Z 2 ) sulfonyl” refers to the group —NZ 1 Z 2 as defined herein attached to the parent molecular moiety through a sulfonyl group as defined herein. Representative examples of (NZ 1 Z 2 ) sulfonyl include, but are not limited to, aminosulfonyl, (methylamino) sulfonyl, (dimethylamino) sulfonyl, ((acetyl) (methyl) amino) sulfonyl and ( Ethylmethylamino) sulfonyl.
본원에서 사용된 바와 같은 용어 "옥소"는 =O 잔기를 말한다.The term "oxo" as used herein refers to a = 0 moiety.
본원에서 사용된 바와 같은 용어 "설피닐"은 -S(O)- 그룹을 말한다.The term "sulfinyl" as used herein refers to the group -S (O)-.
본원에서 사용된 바와 같은 용어 "설포닐"은 -S(O)2- 그룹을 말한다.The term "sulfonyl" as used herein refers to a -S (O) 2 -group.
본원에서 사용된 바와 같은 용어 "성 기능장애"는 남성 및 여성 성 기능장애를 포함하는 포유동물의 성 기능장애를 말한다.The term “sexual dysfunction” as used herein refers to sexual dysfunction of a mammal, including male and female sexual dysfunction.
본원에서 사용된 바와 같은 용어 "남성 성 기능장애"는 이들로 한정하려는 것은 아니지만, 발기 부전 및 조루증이 포함된다.The term "male dysfunction" as used herein includes, but is not limited to, erectile dysfunction and premature ejaculation.
본원에서 사용된 바와 같은 용어 "여성 성 기능장애"는 이들로 한정하려는 것은 아니지만, 여성 불감증, 음핵 발기 부족, 질 충혈, 성교통증 및 질경련이 포함된다.The term “female sexual dysfunction” as used herein includes, but is not limited to, female insensitivity, clitoris erection, vaginal hyperemia, dyspareunia, and vaginal spasms.
본 발명의 화합물은 비대칭 또는 키랄 중심이 존재하는 입체이성체로서 존재할 수 있다. 이러한 입체이성체는 키랄 탄소원자 주위의 치환체의 형태에 좌우되는 "R" 또는 "S"이다. 본원에서 사용되는 용어 "R" 및 "S"는 문헌[참조: IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30]에 정의된 바와 같은 배열이다. 본 발명은 다양한 입체이성체 및 이의 혼합물을 고려하며, 구체적으로는 본 발명의 영역 내에 포함된다. 입체이성체는 거울상이성체, 부분입체이성체 및 거울상이성체 또는 부분입체이성체의 혼합물을 포함한다. 본 발명의 화합물의 개별적인 입체이성체는 비대칭 또는 키랄 중심을 함유하는 시판중인 출발 물질로부터 합성적으로 제조되거나, 라세미체 혼합물을 제조한 다음 당해 기술분야의 숙련가에게 익히 공지된 분해로 제조할 수 있다. 이러한 분해 방법으로는 (1) 키랄 보조체에 거울상이성체의 혼합물을 결합시키고, 재결정 또는 크로마토그래피에 의해 생성되는 부분입체이성체의 혼합물을 분리하고, 보조체로부터 광학적으로 순수한 생성물을 유리시키는 방법 또는 (2) 키랄 크로마토그래피 컬럼 상에서 광학적 거울상이성체의 혼합물을 직접 분리하는 방법을 들 수 있다.The compounds of the present invention may exist as stereoisomers in which asymmetric or chiral centers exist. Such stereoisomers are "R" or "S" depending on the form of substituents around the chiral carbon atom. The terms "R" and "S" as used herein are described in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The present invention contemplates various stereoisomers and mixtures thereof and is specifically included within the scope of the present invention. Stereoisomers include enantiomers, diastereomers and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds of the present invention may be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers, or may be prepared by preparing racemic mixtures and then by degradation well known to those skilled in the art. . Such decomposition methods include (1) combining a mixture of enantiomers to a chiral adjuvant, separating a mixture of diastereomers produced by recrystallization or chromatography, and releasing the optically pure product from the adjuvant, or ( 2) a method of directly separating a mixture of optical enantiomers on a chiral chromatography column.
본 발명의 바람직한 화합물로는,As a preferable compound of this invention,
2-{[4-(3-메틸피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸; 2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]니코티노니트릴;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile;
5,7-디브로모-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
5-플루오로-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸;5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-{[4-(1,3-티아졸-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole;
이소부틸 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸-1-카복실레이트;Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate;
2-[(4-피리딘-2-일피페라진-1-일)메틸]-1-(피롤리딘-1-일카보닐)-1H-벤즈이미다졸;2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole;
N,N-디메틸-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸-1-카복스아미드;N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide;
2-[(4-페닐피페라진-1-일)메틸]-1H-벤즈이미다졸;2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]벤조니트릴;2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile;
2-{[4-(2-클로로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-플루오로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-니트로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-{[4-(2-메톡시페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
4-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]페놀;4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;
2-({4-[2-(메틸티오)페닐]피페라진-1-일}메틸)-1H-벤즈이미다졸;2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole;
2-{[4-(2-에톡시페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole;
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]페놀; 2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol;
2-{[4-(2-메톡시페닐)피페리딘-1-일]메틸}-1H-벤즈이미다졸;2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole;
2-[(4-피리딘-2-일피페리딘-1-일)메틸]-1H-벤즈이미다졸; 및 2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole; And
2-[(4-페닐-3,6-디하이드로피리딘-1(2H)-일)메틸]-1H-벤즈이미다졸; 또는 약제학적으로 허용되는 이의 염, 에스테르, 아미드 또는 프로드럭이 포함된다.2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole; Or pharmaceutically acceptable salts, esters, amides or prodrugs thereof.
본 발명의 보다 바람직한 화합물은,More preferred compound of the present invention,
6-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]피리딘-3-올 및6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol and
2-[(4-피리미딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸이다.2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole.
본 발명의 가장 바람직한 화합물은Most preferred compounds of the present invention
2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸이다.
2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole.
약어Abbreviation
다음의 반응식 및 실시예의 설명에 사용된 약어는 다음과 같다: BF3OEt2 삼불화붕소 디에틸 에테르 착체; BINAP 2,2'-비스(디페닐포스피노)-1,1'-비나프틸; Boc 3급 부톡시카보닐; nBuLi n-부틸리튬; dba 디벤질리덴아세톤; DME 디메톡시에탄; DMF N,N-디메틸포름아미드; DMSO 디메틸설폭사이드; EtOH 에탄올; MeOH 메탄올; TEA 트리에틸아민; TFA 트리플루오로아세트산; THF 테트라하이드로푸란; THP 테트라하이드로피란; TLC 박층 크로마토그래피.Abbreviations used in the description of the following schemes and examples are as follows: BF 3 OEt 2 boron trifluoride diethyl ether complex; BINAP 2,2'-bis (diphenylphosphino) -1,1'-binafyl; Boc tert-butoxycarbonyl; nBuLi n-butyllithium; dba dibenzylideneacetone; DME dimethoxyethane; DMF N, N-dimethylformamide; DMSO dimethylsulfoxide; EtOH ethanol; MeOH methanol; TEA triethylamine; TFA trifluoroacetic acid; THF tetrahydrofuran; THP tetrahydropyran; TLC thin layer chromatography.
본 발명의 화합물의 제조Preparation of Compounds of the Invention
본 발명의 화합물은 다양한 합성 경로로 제조할 수 있다. 대표적인 공정은 반응식 1 내지 5에 기재한다.The compounds of the present invention can be prepared by various synthetic routes. Representative processes are described in Schemes 1-5.
RA, RB, RC, RD, RF, A, Z 및 ---가 화학식 I에서 정의된 바와 같은 벤즈이미다졸(4)은 반응식 1에 기재된 바와 같이 제조할 수 있다. 벤젠-1,2-디아민(1)을 클로로아세트산 및 6N HCl 등의 산으로 처리하여 2-클로로메틸벤즈이미다졸(2)을 수득한다. 2-클로로메틸벤즈이미다졸(2)을 아세토니트릴 또는 N,N-디메틸포름아미드 등의 용매 중에서 트리에틸아민, 탄산칼륨 또는 탄산세슘 등의 염기의 존재하에 화합물(3)로 처리하여 벤즈이미다졸(4)을 수득한다.Benzimidazole (4), wherein R A , R B , R C , R D , R F , A, Z and --- are as defined in Formula (I) can be prepared as described in Scheme 1. Benzene-1,2-diamine (1) is treated with an acid such as chloroacetic acid and 6N HCl to give 2-chloromethylbenzimidazole (2). 2-chloromethylbenzimidazole (2) is treated with compound (3) in acetonitrile or a solvent such as N, N-dimethylformamide in the presence of a base such as triethylamine, potassium carbonate or cesium carbonate to form benzimidazole. (4) is obtained.
RA, RB, RC, RD, RF 및 A가 화학식 I에서 정의한 바와 같은 벤즈이미다졸(10)은 반응식 2에 기재한 바와 같이 제조할 수 있다. Y가 할로겐인 할로헤테로사이클(6)을 탄산세슘 등의 염기의 존재하에 (또는 염기의 부재하에) 열을 가하면서 에탄올 또는 n-부탄올 등의 용매 중에서 P가 -C(O)OC(CH3)3 또는 -C(O)OCH2Ph 등의 질소 보호 그룹인 과량의 N-보호된 피페라진(7)으로 처리하여 N-보호된 피페라진(8)을 수득할 수 있다. 또 다른 방법으로, 할로헤테로사이클(6) 및 N-보호된 피페라진을 문헌[참조: Wagaw and Buchwald, JOC 61 (1996) 7240-7241; Harris et al., JOC 64 (1999) 6019-6022; or Yang and Buchwald, J. of Organometallic Chem. 576 (1999) 125-146]에 기재된 바와 같이 전이금속 촉매로 처리하여 N-보호된 피페라진(8)을 수득할 수 있다. N-보호된 피페라진(8)은 당해 기술분야의 숙련가에게 공지된 조건을 사용하여 탈보호시킬 수 있다. 예를 들면, 산성 조건을 사용하여 메틸렌 클로라이드 중의 트리플루오로아세트산 또는 1,4-디옥산 중의 4N HCl 등의 -C(O)OC(CH3)3을 제거할 수 있다. 메탄올, 에탄올 또는 에틸 아세테이트 등의 용매 중에서 수소 1 내지 4기압하에 탄소상 팔라듐을 사용하는 등의 수소화 조건을 사용하여 -C(O)OCH2Ph를 제거할 수 있다. 탈보호된 피페라진(9)을 반응식 1에 기재된 바와 같이 처리하여 벤즈이미다졸(10)을 수득할 수 있다.Benzimidazole (10), wherein R A , R B , R C , R D , R F and A are as defined in Formula (I), can be prepared as described in Scheme 2. P is -C (O) OC (CH 3 ) in a solvent such as ethanol or n-butanol while heat is applied to haloheterocycle (6) wherein Y is halogen in the presence of a base such as cesium carbonate (or in the absence of a base). N-protected piperazine (8) can be obtained by treatment with an excess of N-protected piperazine (7), which is a nitrogen protecting group such as) 3 or -C (O) OCH 2 Ph. Alternatively, haloheterocycle (6) and N-protected piperazine are described in Wagaw and Buchwald, JOC 61 (1996) 7240-7241; Harris et al., JOC 64 (1999) 6019-6022; or Yang and Buchwald, J. of Organometallic Chem. 576 (1999) 125-146 can be treated with a transition metal catalyst to yield N-protected piperazine 8. N-protected piperazine 8 can be deprotected using conditions known to those skilled in the art. For example, acidic conditions can be used to remove -C (O) OC (CH 3 ) 3 , such as trifluoroacetic acid in methylene chloride or 4N HCl in 1,4-dioxane. -C (O) OCH 2 Ph can be removed using hydrogenation conditions such as using palladium on carbon under 1 to 4 atmospheres of hydrogen in a solvent such as methanol, ethanol or ethyl acetate. Deprotected piperazine (9) can be treated as described in Scheme 1 to obtain benzimidazole (10).
RA, RB, RC, RD, RF 및 A가 화학식 I에서 정의된 바와 같은 벤즈이미다졸(15)을 반응식 3에 기재된 바와 같이 제조할 수 있다. 3급 부틸 4-옥소피페리딘-1-카복실레이트(제조원: Aldrich)를 할로헤테로사이클(6) 및 오가노리튬 시약 또는 그리냐드 시약으로 처리하여 알콜(13)을 수득할 수 있다. 알콜(13)을 티오닐 클로라이드로 처리하여 테트라하이드로피리딘(14)을 수득할 수 있다. 테트라하이드로피리딘(14)을 반응식 1에 기재된 바와 같이 처리하여 벤즈이미다졸(15)을 수득할 수 있다.Benzimidazole (15), wherein R A , R B , R C , R D , R F and A are as defined in Formula (I), can be prepared as described in Scheme 3. Tertiary butyl 4-oxopiperidine-1-carboxylate (Aldrich) can be treated with haloheterocycle (6) and organolithium reagent or Grignard reagent to give alcohol (13). Alcohol (13) can be treated with thionyl chloride to give tetrahydropyridine (14). Tetrahydropyridine (14) can be treated as described in Scheme 1 to yield benzimidazole (15).
RA, RB, RC, RD, RF 및 A가 화학식 I에서 정의된 바와 같은 벤즈이미다졸(21)을 반응식 4에 기재된 바와 같이 제조할 수 있다. 벤질 4-옥소피리딘-1-카복실레이트(제조원: Aldrich)를 할로헤테로사이클(6) 및 오가노리튬 시약 또는 그리냐드 시약으로 처리하여 알콜(18)을 수득할 수 있다. 알콜(18)을 티오닐 클로라이드로 처리하여 테트라하이드로피리딘(19)을 수득할 수 있다. 테트라하이드로피리딘(19)을 수소 대기하에 탄소상 팔라듐 등의 전이금속 촉매로 처리하여 피페리딘(20)을 수득할 수 있다. 피페리딘(20)을 반응식 1에 기재된 바와 같이 처리하여 벤즈이미다졸(21)을 수득할 수 있다.Benzimidazole (21), wherein R A , R B , R C , R D , R F and A are as defined in Formula (I), can be prepared as described in Scheme 4. Benzyl 4-oxopyridine-l-carboxylate (Aldrich) can be treated with haloheterocycle (6) and organolithium reagent or Grignard reagent to give alcohol (18). Alcohol 18 may be treated with thionyl chloride to give tetrahydropyridine 19. Tetrahydropyridine 19 can be treated with a transition metal catalyst such as palladium on carbon under hydrogen atmosphere to give piperidine 20. Piperidine 20 may be treated as described in Scheme 1 to yield benzimidazole 21.
RA, RB, RC, RD 및 RF가 화학식 I에서 정의된 바와 같은 벤즈이미다졸(23)은 반응식 5에 기재된 바와 같이 제조할 수 있다. 5-아미노-2-클로로피리딘(제조원: Aldrich)을 문헌[참조: Lynch et at., Tetrahedron Asymmetry 9 (1998) 2791-2794 and Koch and Schnatterer, Synthesis (1990) 499-501]에 기재된 바와 같이 처리하여 6-클로로피리딘-3-일 아세테이트 및 6-클로로피리딘-3-올을 수득할 수 있다. 6-클로로피리딘-3-올 또는 6-클로로피리딘-3-일 아세테이트를 반응식 1 및 2에 기재된 바와 같이 처리하여 벤즈이미다졸(23)을 수득할 수 있다. 또 다른 방법으로, 탄산세슘 등의 염기하에 6-클로로피리딘-3-올을 DMF 중의 벤질 브로마이드 또는 베질 클로라이드 등의 하이드록시 보호 시약으로 처리하여 P'이 벤질인 하이드록시 보호된 클로로피리딘(22)을 수득할 수 있다. 하이드록시 보호된 클로로피리딘(22)을 반응식 1 및 2에 기재된 바와 같이 처리하여 벤즈이미다졸(23)을 수득한 후, 당해 기술분야의 숙련가에게 공지된 표준 탈보호 방법을 사용하여 하이드록시 보호 그룹을 탈보호시킨다. 예를 들면, 벤질 하이드록시 보호 그룹은 메탄올, 에탄올 또는 에틸 아세테이트 등의 용매 중에서 수소 대기하에 탄소상 팔라듐 등의 전이금속 촉매를 사용하여 제거할 수 있다.Benzimidazole (23), wherein R A , R B , R C , R D and R F are defined in Formula (I), can be prepared as described in Scheme 5. 5-amino-2-chloropyridine (Aldrich) was treated as described in Lynch et at., Tetrahedron Asymmetry 9 (1998) 2791-2794 and Koch and Schnatterer, Synthesis (1990) 499-501. To give 6-chloropyridin-3-yl acetate and 6-chloropyridin-3-ol. 6-chloropyridin-3-ol or 6-chloropyridin-3-yl acetate can be treated as described in Schemes 1 and 2 to yield benzimidazole 23. Alternatively, 6-chloropyridin-3-ol is treated under a base such as cesium carbonate with a hydroxy protective reagent such as benzyl bromide or benzyl chloride in DMF to allow hydroxy protected chloropyridine (22) in which P 'is benzyl. Can be obtained. The hydroxy protected chloropyridine (22) was treated as described in Schemes 1 and 2 to obtain benzimidazole (23), followed by hydroxy protecting groups using standard deprotection methods known to those skilled in the art. Deprotection. For example, the benzyl hydroxy protecting group can be removed using a transition metal catalyst such as palladium on carbon under a hydrogen atmosphere in a solvent such as methanol, ethanol or ethyl acetate.
실시예 1Example 1
2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 말레에이트2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole maleate
실시예 1AExample 1A
2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole
20℃의 수욕에서 큰 환저 플라스크 속의 신속하게 교반된 DMF(15㎖) 중의 1-(2-피리딜)피페라진(5.9g, 36mmol) 용액에 2-클로로메틸벤즈이미다졸 분말(6g, 36mmol)을 2분에 걸쳐 가한다. 트리에틸아민(7.5㎖, 1.5당량)을 가하고, TLC가 출발 물질이 완전히 소모되었음을 나타낼 때까지 반응물을 16시간 동안 교반한다. 이어서, 반응물을 트리에틸아민 5㎖로 처리한 다음, 물(70㎖)을 서서히 적가한다. 1시간 후, 침전물을 흡인 여과로 수집하고, 물 400㎖로 세척하고 건조시켜 생성물 9g을 수득한다. 고체를 비등성 n-부탄올로부터 2회 재결정화시켜 담황색(buff) 분말로서 표제 화합물 7.6g(정제된 수율 72%)을 수득한다. 융점 220-221℃. 1H NMR (d6-DMSO, 300 MHz) δ2.55 (4H, J=4.5 Hz), 3.52 (4H, J=4.5 Hz), 3.77 (s, 2H), 6.62 (1H, J=6.6, 4.5 Hz), 6.81 (1H, J=8.7 Hz), 7.14 (2H, m), 7.41-7.58 (3H, m), 8.09 (1H, J=4.5, 1.8 Hz). MS (DCI/NH3) m/z 294 (M+H)+. C17H19N5에 대한 원소분석: 이론치: C, 69.60; H, 6.53; N, 23.87. 실측치: C, 69.47; H, 6.58; N, 23.87.2-chloromethylbenzimidazole powder (6 g, 36 mmol) in a solution of 1- (2-pyridyl) piperazine (5.9 g, 36 mmol) in rapidly stirred DMF (15 mL) in a large round bottomed flask at 20 ° C. water bath. Add over 2 minutes. Triethylamine (7.5 mL, 1.5 equiv) is added and the reaction is stirred for 16 h until TLC indicates the starting material is consumed completely. The reaction is then treated with 5 ml of triethylamine and then slowly added dropwise water (70 ml). After 1 hour, the precipitate is collected by suction filtration, washed with 400 ml of water and dried to give 9 g of product. The solid is recrystallized twice from boiling n-butanol to give 7.6 g (72% purified yield) of the title compound as a buff powder. Melting point 220-221 ° C. 1 H NMR (d 6 -DMSO, 300 MHz) δ2.55 (4H, J = 4.5 Hz), 3.52 (4H, J = 4.5 Hz), 3.77 (s, 2H), 6.62 (1H, J = 6.6, 4.5 Hz), 6.81 (1H, J = 8.7 Hz), 7.14 (2H, m), 7.41-7.58 (3H, m), 8.09 (1H, J = 4.5, 1.8 Hz). MS (DCI / NH 3 ) m / z 294 (M + H) + . Elemental Analysis for C 17 H 19 N 5 : Theoretical: C, 69.60; H, 6.53; N, 23.87. Found: C, 69.47; H, 6. 58; N, 23.87.
실시예 1BExample 1B
2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 말레에이트2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole maleate
실시예 1A(1.66g)로부터의 생성물과 말레산(657㎎)을 충분한 에탄올 중에서 합하여 약하게 가열하면서 용해시킨다. 혼합물을 실온으로 냉각시키고 수득한 고체를 여과로 수집하고 에탄올로부터 결정화시켜 백색 분말로서 말레에이트 염을 수득했다. 융점 189-190℃. C17H19N5·C4H4O4에 대한 원소분석: 이론치: C, 61.60; H, 5.66; N, 17.10. 실측치: C, 61.42; H, 5.88; N, 17.12.The product from Example 1A (1.66 g) and maleic acid (657 mg) were combined in sufficient ethanol and dissolved with mild heating. The mixture was cooled to room temperature and the solid obtained was collected by filtration and crystallized from ethanol to give the maleate salt as a white powder. Melting point 189-190 ° C. Elemental Analysis for C 17 H 19 N 5 · C 4 H 4 O 4 : Theoretical: C, 61.60; H, 5. 66; N, 17.10. Found: C, 61.42; H, 5.88; N, 17.12.
실시예 2Example 2
2-[(4-피리미딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸2-[(4-pyrimidin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole
1-(2-피리딜)피페라진을 1-(2-피리미딜)피페라진으로 대체시키고, 용매로서 DMF를 CH3CN으로 대체시킴을 제외하고는, 실시예 1A의 공정에 따라 표제 화합물을 제조했다. 융점 198-200℃. 1H NMR (CD3OD, 300 MHz) δ2.60 (t, J=6 Hz, 4H), 3.86 (t, J=6 Hz, 4H), 3.85 (s, 2H), 6.58 (t, J=5 Hz, 1H), 7.23 (m, 2H), 7.52 (brm, 2H), 8.30 (d, J=5 Hz, 2H). MS (DCI/NH3) m/z 295 (M+H)+. C16H18N6·(0.25 헥산)에 대한 원소분석: 이론치: C, 66.54; H, 6.86; N, 26.60. 실측치: C, 66.41; H, 6.91; N, 26.41.The title compound was prepared according to the procedure of Example 1A, except that 1- (2-pyridyl) piperazine was replaced with 1- (2-pyrimidyl) piperazine and DMF was replaced with CH 3 CN as solvent. Manufactured. Melting point 198-200 ° C. 1 H NMR (CD 3 OD, 300 MHz) δ 2.60 (t, J = 6 Hz, 4H), 3.86 (t, J = 6 Hz, 4H), 3.85 (s, 2H), 6.58 (t, J = 5 Hz, 1H), 7.23 (m, 2H), 7.52 (brm, 2H), 8.30 (d, J = 5 Hz, 2H). MS (DCI / NH 3 ) m / z 295 (M + H) + . Elemental Analysis for C 16 H 18 N 6. (0.25 Hexane): Theoretical: C, 66.54; H, 6. 86; N, 26.60. Found: C, 66.41; H, 6.91; N, 26.41.
실시예 3Example 3
2-{[4-(6-메틸피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸2-{[4- (6-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole
1-(2-피리미딜)피페라진을 1-(6-메틸피리딘-2-일)피페라진으로 대체시킴을 제외하고는, 실시예 2의 공정에 따라 표제 화합물을 제조했다. 1H NMR (CD3OD, 300 MHz) δ2.55 (s, 3H), 2.86 (t, J=5 Hz, 4H), 3.83 (t, J=5 Hz, 4H), 4.22 (s, 2H), 6.84 (d, J=7 Hz, 1H), 7.17 (d, J=9 Hz, 1 H), 7.59 (m, 2H), 7.79 (m, 2H), 7.92 (dd, J=7, 9 Hz, 1H). MS (DCI/NH3) m/z 308 (M+H)+ The title compound was prepared according to the process of Example 2 except for replacing 1- (2-pyrimidyl) piperazine with 1- (6-methylpyridin-2-yl) piperazine. 1 H NMR (CD 3 OD, 300 MHz) δ2.55 (s, 3H), 2.86 (t, J = 5 Hz, 4H), 3.83 (t, J = 5 Hz, 4H), 4.22 (s, 2H) , 6.84 (d, J = 7 Hz, 1H), 7.17 (d, J = 9 Hz, 1H), 7.59 (m, 2H), 7.79 (m, 2H), 7.92 (dd, J = 7, 9 Hz , 1H). MS (DCI / NH 3 ) m / z 308 (M + H) +
실시예 4Example 4
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]니코티노니트릴2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] nicotinonitrile
1-(2-피리미딜)피페라진을 1-(3-시아노피리딘-2-일)피페라진으로 대체시킴을 제외하고는, 실시예 2의 공정에 따라 표제 화합물을 제조했다. 융점 208-210℃. 1H NMR (CD3OD, 300 MHz) δ2.72 (t, J=6 Hz, 4H), 3.74 (t, J=6 Hz, 4H), 3.87 (s, 2H), 6.87 (dd, J=7, 6 Hz, 1H), 7.22 (2H, m), 7.54 ( brm, 1H), 7.93 (dd, J=7, 3 Hz, 1H), 8.35 (dd, J=6, 3 Hz, 1H). MS (DCI/NH3) m/z 319 (M+H)+. C18H18N6에 대한 원소분석: 이론치: C, 67.68; H, 5.66; N, 26.22. 실측치: C, 67.91; H, 5.70; N, 26.40.The title compound was prepared according to the process of Example 2 except for replacing 1- (2-pyrimidyl) piperazine with 1- (3-cyanopyridin-2-yl) piperazine. Melting point 208-210 ° C. 1 H NMR (CD 3 OD, 300 MHz) δ2.72 (t, J = 6 Hz, 4H), 3.74 (t, J = 6 Hz, 4H), 3.87 (s, 2H), 6.87 (dd, J = 7, 6 Hz, 1H), 7.22 (2H, m), 7.54 (brm, 1H), 7.93 (dd, J = 7, 3 Hz, 1H), 8.35 (dd, J = 6, 3 Hz, 1H). MS (DCI / NH 3 ) m / z 319 (M + H) + . Elemental Analysis for C 18 H 18 N 6 : Theoretical: C, 67.68; H, 5. 66; N, 26.22. Found: C, 67.91; H, 5. 70; N, 26.40.
실시예 5 Example 5
5,7-디브로모-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸5,7-dibromo-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole
실시예 6A의 4-플루오로-1,2-페닐렌디아민을 4,6-디브로모-1,2-페닐렌디아민으로 대체시킴을 제외하고는, 실시예 6A 및 실시예 6B의 공정에 따라 표제 화합물을 제조했다. 1H NMR (CDCl3, 300 MHz) δ2.70 (t, J=6 Hz, 4H), 3.58 (t, J=6 Hz, 4H), 3.90 (s, 2H), 6.67 (m, 2H), 7.53 (m, 2H,), 7.65 (brm, 1H), 8.18 (m, 1H). MS (DCI/NH3) m/z 450, 452, 454 (M+H)+. C17H17Br2N5에 대한 원소분석: 이론치: C, 45.26; H, 3.80; N, 15.52. 실측치: C, 44.96; H, 3.87; N, 15.26.Except for replacing the 4-fluoro-1,2-phenylenediamine of Example 6A with 4,6-dibromo-1,2-phenylenediamine, the process of Examples 6A and 6B was repeated. According to the title compound. 1 H NMR (CDCl 3 , 300 MHz) δ2.70 (t, J = 6 Hz, 4H), 3.58 (t, J = 6 Hz, 4H), 3.90 (s, 2H), 6.67 (m, 2H), 7.53 (m, 2 H,), 7.65 (brm, 1 H), 8.18 (m, 1 H). MS (DCI / NH 3 ) m / z 450, 452, 454 (M + H) + . Elemental Analysis for C 17 H 17 Br 2 N 5 : Theoretical: C, 45.26; H, 3.80; N, 15.52. Found: C, 44.96; H, 3.87; N, 15.26.
실시예 6Example 6
5-플루오로-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole
실시예 6AExample 6A
5-플루오로-2-클로로메틸벤즈이미다졸5-fluoro-2-chloromethylbenzimidazole
250㎖ 환저 플라스크에 4-플루오로-1,2-페닐렌디아민(39.70mmol, 5.0g), 클로로아세트산(51.60mmol, 4.87g) 및 6N HCl(25㎖)을 가하고 혼합물을 95℃에서 12시간 동안 가열한다. 혼합물을 실온으로 냉각시키고 K2CO3으로 중화시키고, 에틸 아세테이트(5X, 500㎖)로 추출하고, 건조시키고(MgSO4), 여과하고, 감압하에 농축한다. 생성물을 SiO2 상에서 정제하고, 10% MeOH/CH2Cl2로 용출시켜 36%의 수율로 갈색 발포체(2.65g)를 수득한다. 1H NMR (CD3OD, 300MHz) δ4.87 (br s, 2H), 7.05 (td, J=3.0, 9.0 Hz, 1H), 7.27 (dd, J=3.0, 9.0 Hz, 1H), 7.51-7.55 (m, 1H). MS (DCI/NH3) m/z 185 (M+H)+.To a 250 mL round bottom flask was added 4-fluoro-1,2-phenylenediamine (39.70 mmol, 5.0 g), chloroacetic acid (51.60 mmol, 4.87 g) and 6N HCl (25 mL) and the mixture was stirred at 95 ° C for 12 h. Heat during. The mixture is cooled to rt and neutralized with K 2 CO 3 , extracted with ethyl acetate (5 ×, 500 mL), dried (MgSO 4 ), filtered and concentrated under reduced pressure. The product is purified on SiO 2 and eluted with 10% MeOH / CH 2 Cl 2 to give a brown foam (2.65 g) in 36% yield. 1 H NMR (CD 3 OD, 300 MHz) δ 4.87 (br s, 2H), 7.05 (td, J = 3.0, 9.0 Hz, 1H), 7.27 (dd, J = 3.0, 9.0 Hz, 1H), 7.51- 7.55 (m, 1 H). MS (DCI / NH 3 ) m / z 185 (M + H) + .
실시예 6BExample 6B
5-플루오로-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸5-fluoro-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole
2-클로로벤즈이미다졸을 5-플루오로-2-클로로벤즈이미다졸로 대체시킴을 제외하고는, 실시예 1A의 공정에 따라 표제 화합물을 제조한다. 1H NMR (CD3OD, 300MHz) δ2.62-2.69 (t, J=5.8Hz, 4H), 3.52-3.59 (t, J=6.0 Hz, 4H), 3.84 (s, 2H), 6.77 (dd, J=2.0, 6.0 Hz, 1H), 6.82 (d, J=9.0 Hz, 1H), 7.02 (dt, J=3.0, 9.0 Hz, 1H), 7.24 (dd, J=2.0, 9.0 Hz, 1H), 7.48-7.59 (m, 2H), 8.05-8.10 (m, 1H). MS (DCI/NH3) m/z 312 (M+H)+. C17H18N5F·0.20 MeOH에 대한 원소분석: 이론치: C, 65.01; H, 5.96; N, 22.04. 실측치: C, 64.79; H, 5.97; N, 22.17.The title compound is prepared following the procedure of Example 1A, except that 2-chlorobenzimidazole is replaced with 5-fluoro-2-chlorobenzimidazole. 1 H NMR (CD 3 OD, 300 MHz) δ 2.62-2.69 (t, J = 5.8 Hz, 4H), 3.52-3.59 (t, J = 6.0 Hz, 4H), 3.84 (s, 2H), 6.77 (dd , J = 2.0, 6.0 Hz, 1H), 6.82 (d, J = 9.0 Hz, 1H), 7.02 (dt, J = 3.0, 9.0 Hz, 1H), 7.24 (dd, J = 2.0, 9.0 Hz, 1H) , 7.48-7.59 (m, 2 H), 8.05-8.10 (m, 1 H). MS (DCI / NH 3 ) m / z 312 (M + H) + . Elemental Analysis for C 17 H 18 N 5 F · 0.20 MeOH: Theoretical: C, 65.01; H, 5.96; N, 22.04. Found: C, 64.79; H, 5.97; N, 22.17.
실시예 7Example 7
2-{[4-(1,3-티아졸-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole
실시예 7AExample 7A
1-(2-티아조일)피페라진1- (2-thiazoyl) piperazine
톨루엔 중의 3급 부틸 1-피페라진카복실레이트(2g, 10.74mmol)의 현탁액에 2-브로모티아졸(1.75g, 10.74mmol), 탄산세슘(6.65g, 20.4mmol), 라세미체 BINAP(0.2g, 0.32mmol) 및 트리스(디벤질리덴아세톤-디팔라듐)(0)(0.2g, 0.2mmol)을 가한다. 혼합물을 16시간 동안 환류 가열시키고 냉각시킨다. 반응 혼합물을 물과 에틸 아세테이트 사이에 분배한다. 유기 층을 합하고, 건조시키고(MgSO4), 감압하에 농축한다. 플래쉬 SiO2 컬럼을 사용하여 정제하여 목적하는 N-Boc 피페라진 유도체 0.45g(16%)을 황색 고체로서 제공한다. Boc-피페라진 유도체(0.45g, 1.68mmol)를 농축 HCl(8㎖)과 10분 동안 실온에서 교반한다. 반응 혼합물을 물로 희석하고, 고체 Na2CO3으로 pH 8 내지 9로 중화시키고 에틸 아세테이트로 추출한다. 유기 층을 합하고, 염수로 세척하고 건조시키고(Na2CO3) 여액을 감압하에 농축하여 황색 고체(0.33g)로서 표제 화합물을 제공하며, 이를 추가로 정제하지 않고 사용한다.2-bromothiazole (1.75 g, 10.74 mmol), cesium carbonate (6.65 g, 20.4 mmol), racemate BINAP (0.2 g) in a suspension of tertiary butyl 1-piperazinecarboxylate (2 g, 10.74 mmol) in toluene , 0.32 mmol) and tris (dibenzylideneacetone-dipalladium) (0) (0.2 g, 0.2 mmol) are added. The mixture is heated to reflux for 16 hours and cooled. The reaction mixture is partitioned between water and ethyl acetate. The organic layers are combined, dried (MgSO 4 ) and concentrated under reduced pressure. Purification using a flash SiO 2 column provides 0.45 g (16%) of the desired N-Boc piperazine derivative as a yellow solid. Boc-piperazine derivative (0.45 g, 1.68 mmol) is stirred with concentrated HCl (8 mL) for 10 minutes at room temperature. The reaction mixture is diluted with water, neutralized with solid Na 2 CO 3 to pH 8-9 and extracted with ethyl acetate. The organic layers are combined, washed with brine and dried (Na 2 CO 3 ) and the filtrate is concentrated under reduced pressure to give the title compound as a yellow solid (0.33 g) which is used without further purification.
실시예 7BExample 7B
2-{[4-(1,3-티아졸-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸2-{[4- (1,3-thiazol-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole
1-(2-피리딜)피페라진을 1-(2-티아졸릴)피페라진으로 대체시킴을 제외하고는, 표제 화합물을 실시예 1A의 공정에 따라 제조했다. 융점 203-205℃. 1H NMR (d6-DMSO, 300 MHz) δ2.58-2.62 (t, J=5.8Hz, 4H), 3.42-3.46 (t, J=6.0 Hz, 4H), 3.79 (s, 2H), 6.84 (d, J=3.0 Hz, 1H), 7.11-7.15 (m, 2H), 6.18 (d, J=3.0 Hz, 1H), 7.42-7.46 (m, 1H), 7.53-7.57 (m, 1H). MS (DCI/NH3) m/z 300 (M+H)+. C15H17N5S·0.25 H2O에 대한 원소분석: 이론치: C, 59.31; H, 5.77; N, 23.06. 실측치: C, 59.60; H, 5.97; N, 23.17The title compound was prepared following the procedure of Example 1A, except that 1- (2-pyridyl) piperazine was replaced with 1- (2-thiazolyl) piperazine. Melting point 203-205 ° C. 1 H NMR (d 6 -DMSO, 300 MHz) δ 2.58-2.62 (t, J = 5.8 Hz, 4H), 3.42-3.46 (t, J = 6.0 Hz, 4H), 3.79 (s, 2H), 6.84 (d, J = 3.0 Hz, 1H), 7.11-7.15 (m, 2H), 6.18 (d, J = 3.0 Hz, 1H), 7.42-7.46 (m, 1H), 7.53-7.57 (m, 1H). MS (DCI / NH 3 ) m / z 300 (M + H) + . Elemental Analysis for C 15 H 17 N 5 S · 0.25 H 2 O: Theoretical: C, 59.31; H, 5.77; N, 23.06. Found: C, 59.60; H, 5.97; N, 23.17
실시예 8Example 8
이소부틸 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸-1-카복실레이트Isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate
디클로로메탄(7㎖) 중의 실시예 1A의 교반된 용액(0.77g, 2.6mmol)에 이소부틸 클로로포르메이트(0.375㎖, 2.9mmol)를 가한다. 혼합물을 실온에서 16시간 동안 교반하고, 감압하에 농축하고, 잔사를 1.3% 메탄올/디클로로메탄으로 용출시켜 SiO2 상의 플래쉬 컬럼으로 정제하여 오일로서 표제 화합물 0.5g(49%)을 수득한다. 1H NMR (CDCl3, 300 MHz) δ1.10 (d, J=6 Hz, 6H), 2.22 (m, 1H), 2.86 (bm, 4H), 3.67 (bm, 4H), 4.18 (bs, 2H), 4.33 (d, J=7 Hz, 2H), 6.66 (m, 2H), 7.35 (m, 2H), 7.53 (m, 1H), 7.76 (m, 1H), 7.93 (m, 1H), 8.19 (m, 1H). MS (DCI/NH3) m/z 394 (M+H)+.To the stirred solution of Example 1A (0.77 g, 2.6 mmol) in dichloromethane (7 mL) isobutyl chloroformate (0.375 mL, 2.9 mmol) was added. The mixture is stirred at rt for 16 h, concentrated under reduced pressure and the residue is purified by flash column on SiO 2 by eluting with 1.3% methanol / dichloromethane to afford 0.5 g (49%) of the title compound as an oil. 1 H NMR (CDCl 3 , 300 MHz) δ 1.10 (d, J = 6 Hz, 6H), 2.22 (m, 1H), 2.86 (bm, 4H), 3.67 (bm, 4H), 4.18 (bs, 2H ), 4.33 (d, J = 7 Hz, 2H), 6.66 (m, 2H), 7.35 (m, 2H), 7.53 (m, 1H), 7.76 (m, 1H), 7.93 (m, 1H), 8.19 (m, 1 H). MS (DCI / NH 3 ) m / z 394 (M + H) + .
실시예 9Example 9
2-[(4-피리딘-2-일피페라진-1-일)메틸]-1-(피롤리딘-1-일카보닐)-1H-벤즈이미다졸2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole
디클로로메탄(7㎖) 중의 실시예 1A의 교반된 용액(0.66g, 2.2mmol)에 1-피롤리딘카보닐 클로라이드(0.28㎖, 2.2mmol)와 트리에틸아민(0.625㎖, 4.5mmol)을 가한다. 혼합물을 밀봉된 바이얼 속에서 17시간 동안 가열하고, 실온으로 냉각시키고, 디클로로메탄으로 희석하고, 5% NaHCO3으로 세척하고, 건조시키고, 감압하에 농축한다. 잔사를 20% 헥산/에틸 아세테이트로 용출시키는 SiO2 상의 플래쉬 컬럼으로 정제하여 표제 화합물을 0.4g(40%) 수득했다. 융점 120-121℃. 1H NMR (CDCl3, 300 MHz) δ1.79-2.10 (m, 4H), 2.70 (m, 4H), 3.13 (m, 1H), 3.35-3.78 (bm, 8H), 4.32 (m, 1H), 6.65 (m, 2H), 7.30 (m, 3H), 7.49 (m, 1H), 7.76 (m, 1H), 8.28 (m, 1H). MS (DCI/NH3) m/z 391 (M+H)+. C22H26N6O·1/2H2O에 대한 원소분석: 이론치: C, 66.14; H, 6.81; N, 21.04. 실측치: C 66.22, H 6.68, N 21.11.To the stirred solution of Example 1A (0.66 g, 2.2 mmol) in dichloromethane (7 mL) was added 1-pyrrolidinecarbonyl chloride (0.28 mL, 2.2 mmol) and triethylamine (0.625 mL, 4.5 mmol). do. The mixture is heated in a sealed vial for 17 hours, cooled to room temperature, diluted with dichloromethane, washed with 5% NaHCO 3 , dried and concentrated under reduced pressure. The residue was purified by flash column on SiO 2 eluting with 20% hexanes / ethyl acetate to afford 0.4 g (40%) of the title compound. Melting point 120-121 ° C. 1 H NMR (CDCl 3 , 300 MHz) δ 1.79-2.10 (m, 4H), 2.70 (m, 4H), 3.13 (m, 1H), 3.35-3.78 (bm, 8H), 4.32 (m, 1H) , 6.65 (m, 2H), 7.30 (m, 3H), 7.49 (m, 1H), 7.76 (m, 1H), 8.28 (m, 1H). MS (DCI / NH 3 ) m / z 391 (M + H) + . Elemental Analysis for C 22 H 26 N 6 O · ½H 2 O: Theoretical: C, 66.14; H, 6.81; N, 21.04. Found: C 66.22, H 6.68, N 21.11.
실시예 10Example 10
N,N-디메틸-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸-1-카복스아미드N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide
1-피롤리딘카보닐 클로라이드를 N,N-디메틸카바모일로 대체시킴을 제외하고는, 실시예 9의 공정에 따라 표제 화합물을 제조했다. 융점 174-176℃. 1H NMR (CDCl3, 300 MHz) δ2.68 (bm, 4H), 2.93 (bm, 3H), 3.21 (bm, 3H), 3.48 (bm, 4H), 3.71 (bm, 1H), 4.25 (bm, 1H), 6.64 (m, 2H), 7.29 (m, 3H), 7.48 (m, 1H), 7.76 (m, 1H), 8.18 (m, 1H). MS (DCI/NH3) m/z 365 (M+H)+. C20H24N6O에 대한 원소분석: 이론치: C, 65.91; H, 6.64; N, 23.06. 실측치: C 65.28, H 6.56, N 22.97.The title compound was prepared according to the process of Example 9 except for replacing 1-pyrrolidinecarbonyl chloride with N, N-dimethylcarbamoyl. Melting point 174-176 ° C. 1 H NMR (CDCl 3 , 300 MHz) δ 2.68 (bm, 4H), 2.93 (bm, 3H), 3.21 (bm, 3H), 3.48 (bm, 4H), 3.71 (bm, 1H), 4.25 (bm , 1H), 6.64 (m, 2H), 7.29 (m, 3H), 7.48 (m, 1H), 7.76 (m, 1H), 8.18 (m, 1H). MS (DCI / NH 3 ) m / z 365 (M + H) + . Elemental Analysis for C 20 H 24 N 6 O: Theoretical: C, 65.91; H, 6. 64; N, 23.06. Found: C 65.28, H 6.56, N 22.97.
실시예 11Example 11
2-[(4-페닐피페라진-1-일)메틸]-1H-벤즈이미다졸2-[(4-phenylpiperazin-1-yl) methyl] -1H-benzimidazole
1-(2-피리미딜)피페라진을 1-페닐피페라진으로 대체시킴을 제외하고는, 실시예 2의 공정에 따라 표제 화합물을 제조했다. 융점 285-260℃. 1H NMR (CD3OD, 300 MHz) δ3.01 (m, 4H), 3.39 (m, 4H), 4.28 (s, 2H), 6.97 (m, 1H), 7.08 (m, 2H), 7.31 (m, 2H), 7.57 (m, 2H), 7.78 (m, 2H). MS (DCI/NH3) m/z 393 (M+H)+. C18H20N4에 대한 원소분석: 이론치: C, 73.94; H, 6.89; N, 19.16. 실측치: C, 73.76; H, 6.99; N, 19.23.The title compound was prepared according to the process of Example 2 except for replacing 1- (2-pyrimidyl) piperazine with 1-phenylpiperazine. Melting point 285-260 ° C. 1 H NMR (CD 3 OD, 300 MHz) δ3.01 (m, 4H), 3.39 (m, 4H), 4.28 (s, 2H), 6.97 (m, 1H), 7.08 (m, 2H), 7.31 ( m, 2H), 7.57 (m, 2H), 7.78 (m, 2H). MS (DCI / NH 3 ) m / z 393 (M + H) + . Elemental Analysis for C 18 H 20 N 4 : Theoretical: C, 73.94; H, 6.89; N, 19.16. Found: C, 73.76; H, 6. 99; N, 19.23.
실시예 12Example 12
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]벤조니트릴2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] benzonitrile
1-(2-피리미딜)피페라진을 1-(2-시아노페닐)피페라진으로 대체시킴을 제외하고는, 실시예 2의 공정에 따라 표제 화합물을 제조했다. 융점 236-237℃. 1H NMR (CD3OD, 300 MHz) δ2.77 (m, 4H), 3.27 (m, 4H), 3.89 (s, 2H), 7.07 (m, 1H), 7.15 (m, 1H), 7.23 (m, 2H), 7.56 (m, 4H). MS (DCI/NH3) m/z 318 (M+H)+. C19H19N5에 대한 원소분석: 이론치: C, 71.90; H, 6.03; N, 22.07. 실측치: C, 71.76; H, 6.03; N, 22.16.The title compound was prepared according to the process of Example 2 except for replacing 1- (2-pyrimidyl) piperazine with 1- (2-cyanophenyl) piperazine. Melting point 236-237 ° C. 1 H NMR (CD 3 OD, 300 MHz) δ 2.77 (m, 4H), 3.27 (m, 4H), 3.89 (s, 2H), 7.07 (m, 1H), 7.15 (m, 1H), 7.23 ( m, 2H), 7.56 (m, 4H). MS (DCI / NH 3 ) m / z 318 (M + H) + . Elemental Analysis for C 19 H 19 N 5 : Theoretical: C, 71.90; H, 6.03; N, 22.07. Found: C, 71.76; H, 6.03; N, 22.16.
실시예 13Example 13
2-{[4-(2-클로로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸2-{[4- (2-chlorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole
1-(2-피리미딜)피페라진을 1-(2-클로로페닐)피페라진으로 대체시킴을 제외하고는, 실시예 2의 공정에 따라 표제 화합물을 제조했다. 융점 245-246℃. 1H NMR (CD3OD, 300 MHz) δ3.02 (m, 4H), 3.20 (m, 4H), 4.29 (s, 2H), 7.04 (m, 1H), 7.17 (dd, J=9, 2 Hz, 1H), 7.28 (m, 1H), 7.47 (dd, J=9, 2 Hz, 1H), 7.55 (m, 2H), 7.75 (m, 2H). MS (DCI/NH3) m/z 327 (M+H)+. C18H19ClN4에 대한 원소분석: 이론치: C, 66.15; H, 5.86; N, 17.14. 실측치: C, 66.07; H, 5.95; N, 17.15.The title compound was prepared according to the process of Example 2 except for replacing 1- (2-pyrimidyl) piperazine with 1- (2-chlorophenyl) piperazine. Melting point 245-246 ° C. 1 H NMR (CD 3 OD, 300 MHz) δ3.02 (m, 4H), 3.20 (m, 4H), 4.29 (s, 2H), 7.04 (m, 1H), 7.17 (dd, J = 9, 2 Hz, 1H), 7.28 (m, 1H), 7.47 (dd, J = 9, 2 Hz, 1H), 7.55 (m, 2H), 7.75 (m, 2H). MS (DCI / NH 3 ) m / z 327 (M + H) + . Elemental Analysis for C 18 H 19 ClN 4 : Theory: C, 66.15; H, 5. 86; N, 17.14. Found: C, 66.07; H, 5.95; N, 17.15.
실시예 14Example 14
2-{[4-(2-플루오로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸2-{[4- (2-fluorophenyl) piperazin-1-yl] methyl} -1H-benzimidazole
1-(2-피리미딜)피페라진을 1-(2-플루오로페닐)피페라진으로 대체시킴을 제외하고는, 실시예 2의 공정에 따라 표제 화합물을 제조했다. 융점 262-264℃. 1H NMR (CD3OD, 300 MHz) δ2.96 (m, 4H), 3.24 (m, 4H), 4.26 (s, 2H), 7.06 (m, 4H), 7.55 (m, 2H), 7.66 (m, 2H). MS (DCI/NH3) m/z 311 (M+H)+. C18H19FN4에 대한 원소분석: 이론치: C, 69.66; H, 6.17; N, 18.05. 실측치: C, 69.51; H, 6.19; N, 18.12.The title compound was prepared according to the process of Example 2, except that 1- (2-pyrimidyl) piperazine was replaced with 1- (2-fluorophenyl) piperazine. Melting point 262-264 ° C. 1 H NMR (CD 3 OD, 300 MHz) δ 2.96 (m, 4H), 3.24 (m, 4H), 4.26 (s, 2H), 7.06 (m, 4H), 7.55 (m, 2H), 7.66 ( m, 2H). MS (DCI / NH 3 ) m / z 311 (M + H) + . Elemental Analysis for C 18 H 19 FN 4 : Theoretical: C, 69.66; H, 6. 17; N, 18.05. Found: C, 69.51; H, 6. 19; N, 18.12.
실시예 15Example 15
2-{[4-(2-니트로페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸2-{[4- (2-nitrophenyl) piperazin-1-yl] methyl} -1H-benzimidazole
1-(2-피리미딜)피페라진을 1-(2-니트로페닐)피페라진으로 대체시킴을 제외하고는, 실시예 2의 공정에 따라 표제 화합물을 제조했다. 역상 지지체상에서 용출제로서 아세토니트릴/TFA를 사용하여 정제하여 TFA 염으로서 표제 화합물을 수득한다. 1H NMR (CD3OD, 300 MHz) δ2.89 (m, 4H), 3.20 (m, 4H), 4.22 (s, 2H), 7.17 (m, 1H), 7.24 (m, 1H), 7.57 (m, 3H), 7.77 (m, 3H). MS (DCI/NH3) m/z 338 (M+H)+.The title compound was prepared according to the process of Example 2 except for replacing 1- (2-pyrimidyl) piperazine with 1- (2-nitrophenyl) piperazine. Purification using acetonitrile / TFA as eluent on a reverse phase support affords the title compound as a TFA salt. 1 H NMR (CD 3 OD, 300 MHz) δ 2.89 (m, 4H), 3.20 (m, 4H), 4.22 (s, 2H), 7.17 (m, 1H), 7.24 (m, 1H), 7.57 ( m, 3H), 7.77 (m, 3H). MS (DCI / NH 3 ) m / z 338 (M + H) + .
실시예 16Example 16
2-{[4-(2-메톡시페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸2-{[4- (2-methoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole
1-(2-니트로페닐)피페라진을 1-(2-메톡시페닐)피페라진으로 대체시킴을 제외하고는, 실시예 15의 공정에 따라 표제 화합물을 제조했다. 1H NMR (CD3OD, 300 MHz) δ3.13 (m, 4H), 3.46 (m, 4H), 3.93 (s, 3H), 4.33 (s, 2H), 7.03 (m, 1H), 7.12 (m, 1H), 7.35 (m, 2H), 7.55 (m, 2H), 7.76 (m, 2H). MS (DCI/NH3) m/z 323 (M+H)+.The title compound was prepared according to the process of Example 15 except that 1- (2-nitrophenyl) piperazine was replaced with 1- (2-methoxyphenyl) piperazine. 1 H NMR (CD 3 OD, 300 MHz) δ3.13 (m, 4H), 3.46 (m, 4H), 3.93 (s, 3H), 4.33 (s, 2H), 7.03 (m, 1H), 7.12 ( m, 1H), 7.35 (m, 2H), 7.55 (m, 2H), 7.76 (m, 2H). MS (DCI / NH 3 ) m / z 323 (M + H) + .
실시예 17Example 17
4-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]페놀4- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol
1-(2-피리미딜)피페라진을 1-(4-하이드록시페닐)피페라진으로 대체시킴을 제외하고는, 실시예 2의 공정에 따라 표제 화합물을 제조했다. 융점 206-209℃. 1H NMR (CD3OD, 300 MHz) δ3.12 (m, 4H), 3.55 (m, 4H), 4.32 (s, 2H), 6.93 (m, 2H), 7.32 (m, 2H), 7.60 (m, 2H), 7.80 (m, 2H). MS (DCI/NH3) m/z 309 (M+H)+.The title compound was prepared according to the process of Example 2, except that 1- (2-pyrimidyl) piperazine was replaced with 1- (4-hydroxyphenyl) piperazine. Melting point 206-209 ° C. 1 H NMR (CD 3 OD, 300 MHz) δ3.12 (m, 4H), 3.55 (m, 4H), 4.32 (s, 2H), 6.93 (m, 2H), 7.32 (m, 2H), 7.60 ( m, 2H), 7.80 (m, 2H). MS (DCI / NH 3) m / z 309 (M + H) + .
실시예 18Example 18
2-({4-[2-(메틸티오)페닐]피페라진-1-일}메틸)-1H-벤즈이미다졸2-({4- [2- (methylthio) phenyl] piperazin-1-yl} methyl) -1H-benzimidazole
1-(2-피리미딜)피페라진을 1-(2-메틸티오페닐)피페라진으로 대체시킴을 제외하고는, 실시예 2의 공정에 따라 표제 화합물을 제조했다. 융점 214-216℃. 1H NMR (CDCl3, 300 MHz) δ2.14 (s, 3H), 2.77 (m, 4H), 3.07 (m, 4H), 3.94 (s, 2H), 7.06 (m, 1H), 7.12 (m, 3H), 7.25 (m, 2H), 7.59 (m, 2H). MS (DCI/NH3) m/z 339 (M+H)+. C19H22N4O·1/4 H20에 대한 원소분석: 이론치: C, 66.54; H, 6.61; N, 16.34. 실측치: C 66.23, H 6.54, N 16.36.The title compound was prepared according to the process of Example 2 except for replacing 1- (2-pyrimidyl) piperazine with 1- (2-methylthiophenyl) piperazine. Melting point 214-216 ° C. 1 H NMR (CDCl 3 , 300 MHz) δ 2.14 (s, 3H), 2.77 (m, 4H), 3.07 (m, 4H), 3.94 (s, 2H), 7.06 (m, 1H), 7.12 (m , 3H), 7.25 (m, 2H), 7.59 (m, 2H). MS (DCI / NH 3 ) m / z 339 (M + H) + . Elemental Analysis for C 19 H 22 N 4 O · 1/4 H 2 0: Theoretical: C, 66.54; H, 6. 61; N, 16.34. Found: C 66.23, H 6.54, N 16.36.
실시예 19Example 19
2-{[4-(2-에톡시페닐)피페라진-1-일]메틸}-1H-벤즈이미다졸2-{[4- (2-ethoxyphenyl) piperazin-1-yl] methyl} -1H-benzimidazole
1-(2-피리미딜)피페라진을 1-(2-에톡시페닐)피페라진으로 대체시킴을 제외하고는, 실시예 2의 공정에 따라 표제 화합물을 제조했다. 융점 95-100℃. 1H NMR (CDCl3, 300 MHz) δ1.45 (t, J=6 Hz, 3H), 2.39 (m, 4H), 3.33 (m, 4H), 4.03 (s, 2H), 4.07 (q, J=6 Hz, 2H), 6.83-7.03 (m, 3H), 7.26 (m, 3H), 7.60 (m, 2H). MS (DCI/NH3) m/z 337 (M+H)+. C20H24N4O에 대한 원소분석: 이론치: C, 71.40; H, 7.19; N, 16.65. 실측치: C 68.97, H 6.90, N 16.01.The title compound was prepared according to the process of Example 2, except that 1- (2-pyrimidyl) piperazine was replaced with 1- (2-ethoxyphenyl) piperazine. Melting point 95-100 ° C. 1 H NMR (CDCl 3 , 300 MHz) δ 1.45 (t, J = 6 Hz, 3H), 2.39 (m, 4H), 3.33 (m, 4H), 4.03 (s, 2H), 4.07 (q, J = 6 Hz, 2H), 6.83-7.03 (m, 3H), 7.26 (m, 3H), 7.60 (m, 2H). MS (DCI / NH 3 ) m / z 337 (M + H) + . Elemental Analysis for C 20 H 24 N 4 O: Theoretical: C, 71.40; H, 7. 19; N, 16.65. Found: C 68.97, H 6.90, N 16.01.
실시예 20Example 20
2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]페놀2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] phenol
1-(2-피리미딜)피페라진을 1-(2-하이드록시페닐)피페라진으로 대체시킴을 제외하고는, 실시예 2의 공정에 따라 표제 화합물을 제조했다. 융점 208-216℃. 1H NMR (CDCl3, 300 MHz) δ2.78 (m, 4H), 2.97 (m, 4H), 3.93 (s, 2H), 6.83-6.95 (m, 2H), 7.05 (m, 1H), 7.14 (dd, J=7, 2 Hz, 1H), 7.59 (m, 2H). MS (DCI/NH3) m/z 309 (M+H)+. C18H20N4O·1/2H2O에 대한 원소분석: 이론치: C, 68.12; H, 6.67; N, 17.65. 실측치: C 68.34, H 6.53, N 17.28.The title compound was prepared according to the process of Example 2 except for replacing 1- (2-pyrimidyl) piperazine with 1- (2-hydroxyphenyl) piperazine. Melting point 208-216 ° C. 1 H NMR (CDCl 3 , 300 MHz) δ 2.78 (m, 4H), 2.97 (m, 4H), 3.93 (s, 2H), 6.83-6.95 (m, 2H), 7.05 (m, 1H), 7.14 (dd, J = 7, 2 Hz, 1 H), 7.59 (m, 2 H). MS (DCI / NH 3 ) m / z 309 (M + H) + . Elemental Analysis for C 18 H 20 N 4 O · ½H 2 O: Theoretical: C, 68.12; H, 6.67; N, 17.65. Found: C 68.34, H 6.53, N 17.28.
실시예 21Example 21
2-{[4-(2-메톡시페닐)피페리딘-1-일]메틸}-1H-벤즈이미다졸2-{[4- (2-methoxyphenyl) piperidin-1-yl] methyl} -1H-benzimidazole
DMF(8㎖) 중의 4-(2-메톡시페닐)피페리딘(0.2g, 1.06mmol), 2-클로로메틸-벤즈이미다졸(186, 1.1mmol) 및 Cs2CO3 (0.36g, 0.36mmol)의 혼합물을 실온에서 18시간 동안 교반한다. 반응 혼합물을 물(30㎖)에 붓고 에틸 아세테이트(20㎖)로 추출한다. 유기 층을 염수(2×30㎖)로 세척하고 MgSO4로 건조시키고 여과하고 여액을 감압하에 농축시킨다. 잔사를 5% 메탄올로 디클로로메탄 중에서 용출시키는 플래쉬 크로마토그래피로 정제하여 표제 화합물(82㎎, 25%)을 수득한다. 1H NMR (CDCl3, 300 MHz) δ1.69 (m, 4H), 2.19 (m, 2H), 2.87(m, 1H), 2.96 (m, 2H), 3.75 (s, 2H), 3.77 (s, 3H), 6.92 (m, 2H), 7.15 (m, 4H), 7.45 (m, 1H), 7.55 (m, 1H), 12.26 (s, 1H). MS (DCI-NH3) m/z 322 (M+H)+.4- (2-methoxyphenyl) piperidine (0.2 g, 1.06 mmol), 2-chloromethyl-benzimidazole (186, 1.1 mmol) and Cs 2 CO 3 (0.36 g, 0.36 in DMF (8 mL) mmol) is stirred at rt for 18 h. The reaction mixture is poured into water (30 mL) and extracted with ethyl acetate (20 mL). The organic layer is washed with brine (2 × 30 mL), dried over MgSO 4 , filtered and the filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography, eluting with 5% methanol in dichloromethane to afford the title compound (82 mg, 25%). 1 H NMR (CDCl 3, 300 MHz) δ 1.69 (m, 4H), 2.19 (m, 2H), 2.87 (m, 1H), 2.96 (m, 2H), 3.75 (s, 2H), 3.77 (s , 3H), 6.92 (m, 2H), 7.15 (m, 4H), 7.45 (m, 1H), 7.55 (m, 1H), 12.26 (s, 1H). MS (DCI-NH 3 ) m / z 322 (M + H) + .
실시예 22Example 22
2-[(4-피리딘-2-일피페리딘-1-일)메틸]-1H-벤즈이미다졸2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole
실시예 22AExample 22A
벤질 4-하이드록시-4-피리딘-2-일피페리딘-1-카복실레이트Benzyl 4-hydroxy-4-pyridin-2-ylpiperidine-1-carboxylate
THF(20㎖) 중의 2-브로모피리딘(0.47㎖, 5mmol) 용액을 -60℃로 냉각시키고 nBuLi(헥산 중의 1.6M, 5.2㎖, 5.2mmol)로 적가 처리한다. 반응 혼합물을 -60℃에서 30분 동안 교반한 다음, THF(10㎖) 중의 벤질 4-옥소-1-피페리딘 카복실레이트(1.14g, 4.9mmol)를 반응 혼합물에 서서히 가한다. 반응 혼합물을 -60℃에서 15분 동안 교반한 다음, 포화 NH4Cl로 급냉시킨다. 냉각 욕을 제거하고 반응 혼합물을 실온으로 가온시킨다. 혼합물을 CH2Cl2로 추출하고 유기물을 건조시키고(MgSO4) 여과시키고 감압하에 여액을 농축시킨다. 잔사를 헥산:에틸 아세테이트(1:1)를 사용하여 플래쉬 크로마토그래피로 정제하여 표제 화합물 400㎎(27%)을 수득한다. 1H NMR (d6-DMSO, 300 MHz) δ1.54 (m, 4H), 2.05 (m, 4 H), 3.25 (m, 4H), 3.95 (m, 4H), 5.11 (s, 2H), 5.35 (s, 1H), 7.25 (m, 2H), 7.35 (m, 5H), 7.68 (m, 1H), 7.79 (m, 1H), 8.5 (m, 1H); MS (DCI/NH3) m/z 313 (M+H)+.A solution of 2-bromopyridine (0.47 mL, 5 mmol) in THF (20 mL) is cooled to -60 ° C and treated dropwise with nBuLi (1.6 M in hexane, 5.2 mL, 5.2 mmol). The reaction mixture is stirred at −60 ° C. for 30 minutes, then benzyl 4-oxo-1-piperidine carboxylate (1.14 g, 4.9 mmol) in THF (10 mL) is slowly added to the reaction mixture. The reaction mixture is stirred at −60 ° C. for 15 minutes and then quenched with saturated NH 4 Cl. The cooling bath is removed and the reaction mixture is allowed to warm to room temperature. The mixture is extracted with CH 2 Cl 2 and the organics are dried (MgSO 4 ), filtered and the filtrate is concentrated under reduced pressure. The residue was purified by flash chromatography using hexanes: ethyl acetate (1: 1) to give 400 mg (27%) of the title compound. 1 H NMR (d 6 -DMSO, 300 MHz) δ 1.54 (m, 4H), 2.05 (m, 4 H), 3.25 (m, 4H), 3.95 (m, 4H), 5.11 (s, 2H), 5.35 (s, 1 H), 7.25 (m, 2 H), 7.35 (m, 5 H), 7.68 (m, 1 H), 7.79 (m, 1 H), 8.5 (m, 1 H); MS (DCI / NH 3 ) m / z 313 (M + H) + .
실시예 22BExample 22B
4-(피리드-2-일)피페리딘4- (pyrid-2-yl) piperidine
티오닐 클로라이드(6㎖) 중의 실시예 22A로부터의 생성물(0.4g, 1.28mmol)을 3시간 동안 환류시키고, 실온으로 냉각시키고, 감압하에 농축한다. 잔사를 얼음 및 40% NaOH로 처리하고 CH2Cl2로 추출한다. 유기물을 분리하고 염수로 세척하고 건조시키고(Na2SO4) 여과하고 여액을 농축시켜 탈수 생성물 332㎎을 수득한다.The product from Example 22A (0.4 g, 1.28 mmol) in thionyl chloride (6 mL) was refluxed for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue is treated with ice and 40% NaOH and extracted with CH 2 Cl 2 . The organics are separated, washed with brine, dried (Na 2 SO 4 ), filtered and the filtrate is concentrated to give 332 mg of dehydration product.
이어서, 조 탈수 생성물을 60psi에서 10% Pd/C(250㎎)를 사용하여 50℃에서 40시간 동안 수소화시켜 표제 화합물(150㎎, 88%)을 수득한다. MS (DCI/NH3) m/z 163 (M+H)+.
The crude dehydration product is then hydrogenated at 60 ° C. with 10% Pd / C (250 mg) for 40 hours at 50 ° C. to afford the title compound (150 mg, 88%). MS (DCI / NH 3 ) m / z 163 (M + H) + .
실시예 22CExample 22C
2-[(4-피리딘-2-일피페리딘-1-일)메틸]-1H-벤즈이미다졸2-[(4-pyridin-2-ylpiperidin-1-yl) methyl] -1H-benzimidazole
DMF(8㎖) 중의 실시예 22B로부터의 생성물(0.6g, 0.36mmol), 2-클로로메틸-벤즈이미다졸(0.62g, 0.36mmol) 및 Cs2CO3(0.12g, 0.36mmol)을 실온에서 18시간 동안 교반한다. 반응 혼합물을 물(30㎖)에 붓고 에틸 아세테이트(20㎖)로 추출한다. 유기 층을 염수(2×30㎖)로 세척하고 MgSO4로 건조시키고 여과하고 여액을 감압하에 농축시킨다. 잔사를 5% MeOH/CH2Cl2로 용출시키는 플래쉬 크로마토그래피로 정제하여 표제 화합물(11.2㎎, 11%)을 수득한다. 1H NMR (CDCl3, 300 MHz) δ2.0 (m, 5H), 2.51 (m, 2H), 2.79 (m, 1H), 3.14 (m, 2H), 4.01 (s, 2H), 7.09 (m, 3H), 7.29 (m, 1H), 7.55 (m, 3H), 8.49 (m, 1H). MS (DCI/NH3) m/z 293 (M+H)+.Product from Example 22B (0.6 g, 0.36 mmol), 2-chloromethyl-benzimidazole (0.62 g, 0.36 mmol) and Cs 2 CO 3 (0.12 g, 0.36 mmol) in DMF (8 mL) at room temperature Stir for 18 hours. The reaction mixture is poured into water (30 mL) and extracted with ethyl acetate (20 mL). The organic layer is washed with brine (2 × 30 mL), dried over MgSO 4 , filtered and the filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography, eluting with 5% MeOH / CH 2 Cl 2 to afford the title compound (11.2 mg, 11%). 1 H NMR (CDCl 3 , 300 MHz) δ2.0 (m, 5H), 2.51 (m, 2H), 2.79 (m, 1H), 3.14 (m, 2H), 4.01 (s, 2H), 7.09 (m , 3H), 7.29 (m, 1 H), 7.55 (m, 3 H), 8.49 (m, 1 H). MS (DCI / NH 3 ) m / z 293 (M + H) + .
실시예 23Example 23
2-[(4-페닐-3,6-디하이드로피리딘-1(2H)-일)메틸]-1H-벤즈이미다졸2-[(4-phenyl-3,6-dihydropyridin-1 (2H) -yl) methyl] -1H-benzimidazole
4-(피리딘-2-일)피페리딘을 4-페닐-1,2,3,6-테트라하이드로피리딘으로 대체시킴을 제외하고는, 실시예 22C에 기재된 바와 같이 표제 화합물을 제조했다. 1H NMR (CD3OD + CDCl3 1방울 + TFA 1방울, 300 MHz) δ2.90 (m, 2H), 3.52 (t, 2H), 3.92 (m, 2H), 4.7 (s, 2H), 6.14 (m, 1H), 7.34 (m, 3H), 7.46 (m, 2H), 7.52 (m, 2H), 7.78 (m, 2H). MS (DCI/NH3) m/z 290 (M+H)+.The title compound was prepared as described in Example 22C, except the 4- (pyridin-2-yl) piperidine was replaced with 4-phenyl-1,2,3,6-tetrahydropyridine. 1 H NMR (CD 3 OD + CDCl 3 1 drop of TFA + 1 drop, 300 MHz) δ2.90 (m, 2H), 3.52 (t, 2H), 3.92 (m, 2H), 4.7 (s, 2H), 6.14 (m, 1H), 7.34 (m, 3H), 7.46 (m, 2H), 7.52 (m, 2H), 7.78 (m, 2H). MS (DCI / NH 3 ) m / z 290 (M + H) + .
실시예 24Example 24
2-[(2-메틸-4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole
실시예 24AExample 24A
3-메틸-1-피리딘-2-일피페라진 하이드로브로마이드3-methyl-1-pyridin-2-ylpiperazine hydrobromide
2-메틸피페라진(1.0g, 0.01mol, 라세미체 혼합물)과 2-브로모피리딘(10㎖, 0.1mol)을 합하고 120℃에서 16시간 동안 가열한다. 반응 혼합물을 23℃로 냉각시키고 에틸 아세테이트와 물 사이에 분배한다. 층을 분리하고, 수 층을 감압하에 농축시킨다. 잔사를 에틸 아세테이트, 디클로로메탄 및 메탄올와 함께 분쇄시켜 회백색 고체로서 표제 화합물 460㎎(수율 26%)을 수득한다. 1H NMR (300 MHz, DMSO-d6) δ1.27 (d, J=6.6 Hz, 3H), 2.90 (dd, J=10.5, 14.1 Hz, 1H), 3.10 (m, 2H), 3.40 (m, 2H), 4.32 (m, 2H), 6.77 (dd, J=4.8, 6.9 Hz, 1H), 6.98 (d, J=8.1 Hz, 1H), 7.64 (m, 1H), 8.15 (m, 1H), 8.63 (bs, 1H), 8.92 (bs, 1H); MS (APCI) m/e 178 (M+H)+.2-Methylpiperazine (1.0 g, 0.01 mol, racemic mixture) and 2-bromopyridine (10 mL, 0.1 mol) were combined and heated at 120 ° C. for 16 hours. The reaction mixture is cooled to 23 ° C. and partitioned between ethyl acetate and water. The layers are separated and the aqueous layer is concentrated under reduced pressure. The residue is triturated with ethyl acetate, dichloromethane and methanol to yield 460 mg (26% yield) of the title compound as an off-white solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 1.27 (d, J = 6.6 Hz, 3H), 2.90 (dd, J = 10.5, 14.1 Hz, 1H), 3.10 (m, 2H), 3.40 (m , 2H), 4.32 (m, 2H), 6.77 (dd, J = 4.8, 6.9 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 7.64 (m, 1H), 8.15 (m, 1H) , 8.63 (bs, 1 H), 8.92 (bs, 1 H); MS (APCI) m / e 178 (M + H) + .
실시예 24BExample 24B
2-[(2-메틸-4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸2-[(2-methyl-4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole
N,N-디메틸포름아미드(10㎖) 중의 실시예 24A로부터의 생성물(0.50g, 1.93mmol)을 N,N-디메틸포름아미드(10㎖) 중의 2-클로로메틸-1H-벤즈이미다졸(0.31g, 1.83mmol) 용액으로 서서히 처리한다. 5분 후, 혼합물을 탄산세슘(0.60mmol, 1.83mmol)으로 처리하고 냉각 욕을 제거한다. 1시간 후, 반응 혼합물을 에틸 아세테이트로 희석시키고, 물(3×) 및 염수로 세척하고, Na2SO4로 건조시키고, 여과하고, 여액을 감압하에 농축시킨다. 잔사를 플래쉬 실리카 겔(2% 메탄올/디클로로메탄) 상에서 크로마토그래피하여 표제 화합물 201㎎(수율 36%)을 수득한다. 융점 207-209℃; 1H NMR (300 MHz, DMSO-d6) δ1.18 (d, J=6.0 Hz, 3H), 2.38 (m, 1H), 2.52 (m, 1H), 2.78 (m, 2H), 3.02 (m, 1H), 3.67 (d, J=14.4 Hz, 1H), 3.97 (m, 2H), 4.08 (d, J=14.4 Hz, 1H), 6.62 (dd, J=5.1, 6.9 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 7.14 (m, 2H), 7.50 (m, 3H), 8.08 (m, 1H), 12.22 (bs, 1H); MS (ESI) m/e 308 (M+H)+; C18H21N5에 대한 원소분석: 이론치: C, 70.33; H, 6.89; N, 22.78. 실측치: C, 70.15; H, 6.92; N, 22.46.The product from Example 24A (0.50 g, 1.93 mmol) in N, N-dimethylformamide (10 mL) was added 2-chloromethyl-1H-benzimidazole (0.31 in N, N-dimethylformamide (10 mL). g, 1.83 mmol) solution slowly. After 5 minutes, the mixture is treated with cesium carbonate (0.60 mmol, 1.83 mmol) and the cooling bath is removed. After 1 h, the reaction mixture is diluted with ethyl acetate, washed with water (3 ×) and brine, dried over Na 2 SO 4 , filtered and the filtrate is concentrated under reduced pressure. The residue is chromatographed on flash silica gel (2% methanol / dichloromethane) to give 201 mg (36% yield) of the title compound. Melting point 207-209 ° C .; 1 H NMR (300 MHz, DMSO-d 6 ) δ 1.18 (d, J = 6.0 Hz, 3H), 2.38 (m, 1H), 2.52 (m, 1H), 2.78 (m, 2H), 3.02 (m , 1H), 3.67 (d, J = 14.4 Hz, 1H), 3.97 (m, 2H), 4.08 (d, J = 14.4 Hz, 1H), 6.62 (dd, J = 5.1, 6.9 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 7.14 (m, 2H), 7.50 (m, 3H), 8.08 (m, 1H), 12.22 (bs, 1H); MS (ESI) m / e 308 (M + H) + ; Elemental Analysis for C 18 H 21 N 5 : Theoretical: C, 70.33; H, 6.89; N, 22.78. Found: C, 70.15; H, 6.92; N, 22.46.
실시예 25Example 25
2-{[(2S)-2-메틸-4-피리딘-2-일피페라진-1-일]메틸}-1H-벤즈이미다졸2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole
실시예 25AExample 25A
(3S)-3-메틸-1-피리딘-2-일피페라진(3S) -3-methyl-1-pyridin-2-ylpiperazine
(S)-(+)-2-메틸피페라진(0.50g, 0.005mol, Aldrich)과 2-브로모피리딘(5㎖, 0.05mol)을 합하고 120℃에서 14시간 동안 가열한다. 반응 혼합물을 23℃로 냉각시키고 에틸 아세테이트와 물 사이에 분배한다. 층을 분리하고 수 층을 에틸 아세테이트로 2회 추출한다. 수성 상을 포화 중탄산나트륨 및 고형 탄산나트륨으로 pH 약 11이 되도록 한다. 염화나트륨을 가하고, 포화 수용액을 에틸 아세테이트(2×) 및 디클로로메탄(2×)으로 추출한다. 합한 유기 추출물을 Na2SO4로 건조시키고, 여과하고, 여액을 감압하에 농축시켜 표제 화합물 0.6g(수율 67%)을 수득한다. 1H NMR (400 MHz, DMSO-d6) δ1.02 (d, J=6.0 Hz, 3H), 2.27 (dd, J=10, 12 Hz, 1), 2.67 (m, 3H), 2.92 (m, 1H), 4.07 (m, 2H), 6.58 (dd, J=6, 8 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 7.49 (m, 1H), 8.08 (m, 1H); MS (ESI) m/e 178 (M+H)+.(S)-(+)-2-methylpiperazine (0.50 g, 0.005 mol, Aldrich) and 2-bromopyridine (5 mL, 0.05 mol) were combined and heated at 120 ° C. for 14 hours. The reaction mixture is cooled to 23 ° C. and partitioned between ethyl acetate and water. The layers are separated and the aqueous layer is extracted twice with ethyl acetate. The aqueous phase is brought to pH about 11 with saturated sodium bicarbonate and solid sodium carbonate. Sodium chloride is added and the saturated aqueous solution is extracted with ethyl acetate (2 ×) and dichloromethane (2 ×). The combined organic extracts are dried over Na 2 SO 4 , filtered and the filtrate is concentrated under reduced pressure to give 0.6 g (67% yield) of the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ1.02 (d, J = 6.0 Hz, 3H), 2.27 (dd, J = 10, 12 Hz, 1), 2.67 (m, 3H), 2.92 (m , 1H), 4.07 (m, 2H), 6.58 (dd, J = 6, 8 Hz, 1H), 6.77 (d, J = 8 Hz, 1H), 7.49 (m, 1H), 8.08 (m, 1H) ; MS (ESI) m / e 178 (M + H) + .
실시예 25BExample 25B
2-{[(2S)-2-메틸-4-피리딘-2-일피페라진-1-일]메틸}-1H-벤즈이미다졸2-{[(2S) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole
N,N-디메틸포름아미드(10㎖) 중의 실시예 25B의 생성물(0.24g, 1.33mmol)을 23℃에서 3시간 동안 교반하면서 2-클로로메틸-1H-벤즈이미다졸(0.21g, 1.27mmol) 및 탄산세슘(0.41mmol, 1.27mmol)으로 처리한다. 반응 혼합물을 에틸 아세테이트로 희석시키고 물(3×) 및 염수로 세척하고, Na2SO4로 건조시키고 여과하고 여액을 감압하에 농축시킨다. 잔사를 플래쉬 실리카 겔 상에서 크로마토그래피(메탄올 1 내지 3%/디클로로메탄 구배)시켜 담황색 고체로서 표제 화합물 178㎎(수율 46%)을 수득한다. 융점 149-151℃; 1H NMR (400 MHz, DMSO-d6) δ1.18 (d, J=6 Hz, 3H), 2.38 (m, 1H), 2.53 (m, 1H), 2.76 (dd, J=8, 11.2 Hz, 1H), 2.83 (m, 1H), 3.03 (m, 1H), 3.69 (d, J=14 Hz, 1H), 3.94 (m, 1H), 4.00 (m, 1H), 4.07 (d, J=14 Hz, 1H), 6.60 (dd, J=4.8, 6.4 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 7.13 (m, 2H), 7.60 (m, 3H), 8.08 (m, 1H), 12.22 (bs, 1H); MS (ESI) m/e 308 (M+H)+; C18H21N5에 대한 원소분석: 이론치: C, 70.33; H, 6.89; N, 22.78. 실측치: C, 70.21; H, 6.77; N, 22.62. The product of Example 25B (0.24 g, 1.33 mmol) in N, N-dimethylformamide (10 mL) was stirred at 23 ° C. for 3 hours with 2-chloromethyl-1H-benzimidazole (0.21 g, 1.27 mmol). And cesium carbonate (0.41 mmol, 1.27 mmol). The reaction mixture is diluted with ethyl acetate and washed with water (3 ×) and brine, dried over Na 2 SO 4 , filtered and the filtrate is concentrated under reduced pressure. The residue is chromatographed on flash silica gel (1-3% methanol / dichloromethane gradient) to give 178 mg (46% yield) of the title compound as a pale yellow solid. Melting point 149-151 ° C .; 1 H NMR (400 MHz, DMSO-d 6 ) δ1.18 (d, J = 6 Hz, 3H), 2.38 (m, 1H), 2.53 (m, 1H), 2.76 (dd, J = 8, 11.2 Hz , 1H), 2.83 (m, 1H), 3.03 (m, 1H), 3.69 (d, J = 14 Hz, 1H), 3.94 (m, 1H), 4.00 (m, 1H), 4.07 (d, J = 14 Hz, 1H), 6.60 (dd, J = 4.8, 6.4 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 7.13 (m, 2H), 7.60 (m, 3H), 8.08 (m, 1H), 12.22 (bs, 1H); MS (ESI) m / e 308 (M + H) + ; Elemental Analysis for C 18 H 21 N 5 : Theoretical: C, 70.33; H, 6.89; N, 22.78. Found: C, 70.21; H, 6. 77; N, 22.62.
실시예 26 Example 26
2-{[(2R)-2-메틸-4-피리딘-2-일피페라진-1-일]메틸}-1H-벤즈이미다졸2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole
실시예 26AExample 26A
(3R)-3-메틸-1-피리딘-2-일피페라진(3R) -3-methyl-1-pyridin-2-ylpiperazine
(R)-(-)-2-메틸피페라진(0.50g, 0.005mol, Aldrich)과 2-브로모피리딘(5㎖, 0.05mol)을 합하고 120℃에서 14시간 동안 가열한다. 반응 혼합물을 23℃로 냉각시키고 대용적의 에틸 아세테이트 및 물 사이에 분배한다. 층을 분리한 다음, 추가의 물을 에틸 아세테이트 용액에 가한다. 1N HCl 용액 몇 방울을 격렬하게 혼합하면서 물/에틸 아세테이트 혼합물에 가한다. 층을 분리하고 합한 수성 상을 포화 중탄산나트륨 및 고형 탄산나트륨 용액으로 pH 약 11로 염기성화시킨다. 염화나트륨을 가하고, 포화 수용액을 몇 방울의 이소프로필 알콜(5×)을 함유한 클로로포름으로 추출한다. 합한 유기 추출물을 Na2SO4로 건조시키고, 여과하고, 여액을 감압하에 농축시켜 표제 화합물 0.79g(수율 89%)을 수득한다. 1H NMR (400 MHz, DMSO-d6) δ1.02 (d, J=6.0 Hz, 3H), 2.27 (dd, J=10, 12 Hz, 1), 2.67 (m, 3H), 2.92 (m, 1H), 4.07 (m, 2H), 6.58 (dd, J=6, 8 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 7.49 (m, 1H), 8.08 (m, 1H); MS (ESI) m/e 178 (M+H)+.Combine (R)-(-)-2-methylpiperazine (0.50 g, 0.005 mol, Aldrich) and 2-bromopyridine (5 mL, 0.05 mol) and heat at 120 ° C. for 14 hours. The reaction mixture is cooled to 23 ° C. and partitioned between a large volume of ethyl acetate and water. After separating the layers, additional water is added to the ethyl acetate solution. A few drops of 1N HCl solution are added to the water / ethyl acetate mixture with vigorous mixing. The layers are separated and the combined aqueous phases are basified to pH about 11 with saturated sodium bicarbonate and solid sodium carbonate solution. Sodium chloride is added and the saturated aqueous solution is extracted with chloroform containing a few drops of isopropyl alcohol (5 ×). The combined organic extracts are dried over Na 2 S0 4 , filtered and the filtrate is concentrated under reduced pressure to yield 0.79 g (89% yield) of the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ1.02 (d, J = 6.0 Hz, 3H), 2.27 (dd, J = 10, 12 Hz, 1), 2.67 (m, 3H), 2.92 (m , 1H), 4.07 (m, 2H), 6.58 (dd, J = 6, 8 Hz, 1H), 6.77 (d, J = 8 Hz, 1H), 7.49 (m, 1H), 8.08 (m, 1H) ; MS (ESI) m / e 178 (M + H) + .
실시예 26BExample 26B
2-{[(2R)-2-메틸-4-피리딘-2-일피페라진-1-일]메틸}-1H-벤즈이미다졸2-{[(2R) -2-methyl-4-pyridin-2-ylpiperazin-1-yl] methyl} -1H-benzimidazole
실시예 26A의 생성물(0.79g, 4.43mmol) 및 N,N-디메틸포름아미드(15㎖)를 0℃에서 N,N-디메틸포름아미드(15㎖) 중의 2-클로로메틸-1H-벤즈이미다졸(0.70g, 4.21mmol) 용액으로 처리한다. 10분 후, 혼합물을 탄산세슘(1.37mmol, 4.21mmol)으로 처리하고 냉각 욕을 제거한다. 1시간 후, 반응 혼합물을 에틸 아세테이트로 희석시키고 물(3×) 및 염수로 세척하고, Na2SO4로 건조시키고, 여과하고, 여액을 감압하에 농축시킨다. 잔사를 플래쉬 실리카 겔 상에서 크로마토그래피시켜(메탄올 1 내지 3%/디클로로메탄 구배) 표제 화합물 0.50g(수율 39%)을 담황색 고체로서 수득한다. 융점 151-153℃; 1H NMR (400 MHz, DMSO-d6) δ1.18 (d, J=6 Hz, 3H), 2.38 (m, 1H), 2.53 (m, 1H), 2.76 (dd, J=8, 11.2 Hz, 1H), 2.83 (m, 1H), 3.03 (m, 1H), 3.69 (d, J=14 Hz, 1H), 3.94 (m, 1H), 4.00 (m, 1H), 4.07 (d, J=14 Hz, 1H), 6.60 (dd, J=4.8, 6.4 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 7.13 (m, 2H), 7.60 (m, 3H), 8.08 (m, 1H), 12.22 (bs, 1H); MS (ESI) m/e 308 (M+H)+; C18H21N5에 대한 원소분석: 이론치: C, 70.33; H, 6.89; N, 22.78. 실측치: C, 70.10; H, 7.03; N, 22.63.The product of Example 26A (0.79 g, 4.43 mmol) and N, N-dimethylformamide (15 mL) were 2-chloromethyl-1H-benzimidazole in N, N-dimethylformamide (15 mL) at 0 ° C. (0.70 g, 4.21 mmol) solution. After 10 minutes, the mixture is treated with cesium carbonate (1.37 mmol, 4.21 mmol) and the cooling bath is removed. After 1 h, the reaction mixture is diluted with ethyl acetate and washed with water (3 ×) and brine, dried over Na 2 SO 4 , filtered and the filtrate is concentrated under reduced pressure. The residue is chromatographed on flash silica gel (1-3% methanol / dichloromethane gradient) to yield 0.50 g (39% yield) of the title compound as a pale yellow solid. Melting point 151-153 ° C .; 1 H NMR (400 MHz, DMSO-d 6 ) δ1.18 (d, J = 6 Hz, 3H), 2.38 (m, 1H), 2.53 (m, 1H), 2.76 (dd, J = 8, 11.2 Hz , 1H), 2.83 (m, 1H), 3.03 (m, 1H), 3.69 (d, J = 14 Hz, 1H), 3.94 (m, 1H), 4.00 (m, 1H), 4.07 (d, J = 14 Hz, 1H), 6.60 (dd, J = 4.8, 6.4 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 7.13 (m, 2H), 7.60 (m, 3H), 8.08 (m, 1H), 12.22 (bs, 1H); MS (ESI) m / e 308 (M + H) + ; Elemental Analysis for C 18 H 21 N 5 : Theoretical: C, 70.33; H, 6.89; N, 22.78. Found: C, 70.10; H, 7.03; N, 22.63.
실시예 27Example 27
N-{2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]피리딘-3-일}메탄설폰아미드N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide
실시예 27AExample 27A
N-(2-클로로피리딘-3-일)메탄설폰아미드N- (2-chloropyridin-3-yl) methanesulfonamide
23℃에서 디클로로메탄(20㎖) 중의 2-클로로-피리딘-3-일아민(1.00g, 7.75mmol)을 메탄 설포닐 클로라이드(2.23g, 19.4mmol) 및 트리에틸아민(1.96g, 19.4mmol)으로 처리한다. 48시간 동안 교반한 후, 반응 혼합물을 물로 희석하고, 층을 분리하고, 수성 상을 디클로로메탄(2×)으로 추출한다. 유기 층을 합하고, MgSO4로 건조시키고, 여과하고, 여액을 감압하에 농축시킨다. 잔사를 플래쉬 실리카 겔 상에서 크로마토그래피시키고(20% 에틸 아세테이트:헥산), 감압하에 농축하고, 10% 수산화나트륨 수용액(32㎖)에 가한다. 용액을 균질해 질때까지 약 0.5시간 동안 격렬하게 교반한다. 이어서, 용액을 2N HCl로 pH 약 7까지 중화시키고, Na2SO4로 포화시키고, 에틸 아세테이트(3×)로 추출한다. 합한 추출물을 Na2SO4로 건조시키고, 여과하고, 여액을 감압하에 농축시켜 표제 화합물 1.5g(수율 93%)을 수득한다[참조: Tetrahedron Letters 38, 26, 4667-4670, 1997; Eur. J. Org. Chem. 2000, 1263-1270]. 1H NMR (300 MHz, DMSO-d6) δ3.12 (s, 3H), 7.46 (dd, J=4.5, 8.4 Hz, 1H), 7.89 (dd, J=1.5, 8.4 Hz, 1H), 8.27 (dd, J=1.5, 4.5 Hz, 1H), 9.72 (bs, 1H); MS (ESI) m/e 205 (M)-.2-chloro-pyridin-3-ylamine (1.00 g, 7.75 mmol) in dichloromethane (20 mL) at 23 ° C. was treated with methane sulfonyl chloride (2.23 g, 19.4 mmol) and triethylamine (1.96 g, 19.4 mmol). To be processed. After stirring for 48 hours, the reaction mixture is diluted with water, the layers are separated and the aqueous phase is extracted with dichloromethane (2x). The organic layers are combined, dried over MgSO 4 , filtered and the filtrate is concentrated under reduced pressure. The residue is chromatographed on flash silica gel (20% ethyl acetate: hexanes), concentrated under reduced pressure and added to 10% aqueous sodium hydroxide solution (32 mL). Stir vigorously for about 0.5 hours until the solution is homogeneous. The solution is then neutralized with 2N HCl to pH about 7, saturated with Na 2 SO 4 and extracted with ethyl acetate (3 ×). The combined extracts are dried over Na 2 S0 4 , filtered and the filtrate is concentrated under reduced pressure to yield 1.5 g (93% yield) of the title compound (Tetrahedron Letters 38, 26, 4667-4670, 1997; Eur. J. Org. Chem. 2000, 1263-1270. 1 H NMR (300 MHz, DMSO-d 6 ) δ3.12 (s, 3H), 7.46 (dd, J = 4.5, 8.4 Hz, 1H), 7.89 (dd, J = 1.5, 8.4 Hz, 1H), 8.27 (dd, J = 1.5, 4.5 Hz, 1 H), 9.72 (bs, 1 H); MS (ESI) m / e 205 (M) - .
실시예 27BExample 27B
N-(2-피페라진-1-일피리딘-3-일)메탄설폰아미드N- (2-piperazin-1-ylpyridin-3-yl) methanesulfonamide
피페라진(5.2g, 60.2mmol), 실시예 27A로부터의 생성물(1.24g, 6.02mmol) 및 n-부탄올(90㎖)을 합하고 3일 동안 환류시킨다. 반응 혼합물을 23℃로 냉각시키고, 감압하에 농축한다. 잔사를 플래쉬 실리카 겔 상에서 크로마토그래피하여(1% 아세트산을 갖는 33% 메탄올/디클로로메탄) 표제 화합물 2.0g(수율 약 88%)을 수득한다. 1H NMR (300 MHz, CD3OD) δ1.97 (s, CH3CO2H으로부터의 CH3), 3.13 (s, 3H), 3.42 (m, 8H), 7.13 (dd, J=4.5, 8.4 Hz, 1H), 7.78 (dd, J=1.5, 8.4 Hz, 1H), 8.12 (dd, J=1.5, 4.5 Hz, 1H); MS (DCI/NH3) m/e 257 (M+H)+.Piperazine (5.2 g, 60.2 mmol), the product from Example 27A (1.24 g, 6.02 mmol) and n-butanol (90 mL) were combined and refluxed for 3 days. The reaction mixture is cooled to 23 ° C. and concentrated under reduced pressure. The residue is chromatographed on flash silica gel (33% methanol / dichloromethane with 1% acetic acid) to yield 2.0 g (about 88% yield) of the title compound. 1 H NMR (300 MHz, CD 3 OD) δ1.97 (s, CH 3 from the CO 2 H CH 3), 3.13 (s, 3H), 3.42 (m, 8H), 7.13 (dd, J = 4.5, 8.4 Hz, 1H), 7.78 (dd, J = 1.5, 8.4 Hz, 1H), 8.12 (dd, J = 1.5, 4.5 Hz, 1H); MS (DCI / NH 3 ) m / e 257 (M + H) + .
실시예 27CExample 27C
N-{2-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]피리딘-3-일}메탄설폰아미드N- {2- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-yl} methanesulfonamide
실시예 27B로부터의 생성물(0.066g, 0.21mmol)과 탄산세슘(0.137g, 0.42mmol)을 23℃에서 N,N-디메틸포름아미드(2㎖) 중에서 합하고 5분 동안 교반한다. 이어서, 혼합물을 2-클로로메틸-1H-벤즈이미다졸(0.035g, 0.21mmol)로 처리한다. 1시간 후, 반응 혼합물을 감압하에 농축시킨다. 잔사를 플래쉬 실리카 겔상에서 함침시키고 플래쉬 실리카 겔 상에서 크로마토그래피시켜(10% 메탄올/디클로로메탄) 표제 화합물 22㎎(수율 27%)을 수득한다. 1H NMR (500 MHz, DMSO-d6) δ2.64 (m, 4H), 3.12 (s, 3H), 3.23 (m, 4H), 3.79 (s, 2H), 5.75 (s, 2H), 6.98 (dd, J=5, 8.5 Hz, 1H), 7.14 (m, 2H), 7.44 (bd, J=7.5 Hz, 1H), 7.57 (bd, J=7.5 Hz, 1H), 7.58 (dd, J=1, 7 Hz, 1H), 8.08 (dd, J=1, 5 Hz, 1H), 8.76 (bs, 1H); MS (ESI) m/e 387 (M+H)+.The product from Example 27B (0.066 g, 0.21 mmol) and cesium carbonate (0.137 g, 0.42 mmol) were combined in N, N-dimethylformamide (2 mL) at 23 ° C. and stirred for 5 minutes. The mixture is then treated with 2-chloromethyl-1H-benzimidazole (0.035 g, 0.21 mmol). After 1 hour, the reaction mixture is concentrated under reduced pressure. The residue is impregnated on flash silica gel and chromatographed on flash silica gel (10% methanol / dichloromethane) to give 22 mg (27% yield) of the title compound. 1 H NMR (500 MHz, DMSO-d 6 ) δ 2.64 (m, 4H), 3.12 (s, 3H), 3.23 (m, 4H), 3.79 (s, 2H), 5.75 (s, 2H), 6.98 (dd, J = 5, 8.5 Hz, 1H), 7.14 (m, 2H), 7.44 (bd, J = 7.5 Hz, 1H), 7.57 (bd, J = 7.5 Hz, 1H), 7.58 (dd, J = 1, 7 Hz, 1H), 8.08 (dd, J = 1, 5 Hz, 1H), 8.76 (bs, 1H); MS (ESI) m / e 387 (M + H) + .
실시예 28Example 28
2-{[4-(3-플루오로피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole
실시예 28AExample 28A
2-클로로-3-플루오로피리딘2-chloro-3-fluoropyridine
디에틸 에테르(130㎖) 중의 1,4-디아자비사이클로[2.2.2]옥탄(5.78g, 51.5mmol)을 -78℃에서 n-부틸리튬(32.2㎖, 51.5mmol, 헥산 중의 1.6M 용액)으로 적가 처리한다. 반응 혼합물을 -20℃로 1시간 동안 가온시킨 다음, -78℃로 재냉각시킨다. 재냉각된 혼합물을 디에틸 에테르(5㎖) 중의 3-플루오로피리딘(5.0g, 51.5mmol)으로 적가 처리한다. -78℃에서 2시간 동안 교반시킨 후, 혼합물을 테트라하이드로푸란(24㎖) 중의 헥사클로로에탄(12.2g, 51.5mmol)으로 처리한다. -78℃에서 1시간 동안 교반한 후, 반응 혼합물을 물(15㎖) 및 테트라하이드로푸란(25㎖) 용액으로 처리한다. 반응 혼합물을 0℃로 가온시키고, 30분 후, 추가의 물 및 디에틸 에테르를 혼합물에 가한다. 층을 분리하고 수성 상을 디에틸 에테르(2×)로 추출한다. 합한 에테르 층을 Na2SO4로 건조시키고, 여과하고, 여액을 감압하에 농축시킨다. 잔사를 플래쉬 실리카 겔 상에서 크로마토그래피시켜(10% 에틸 아세테이트/헥산) 표제 화합물 3.5g(수율 52%)을 수득한다. 1H NMR (300 MHz, DMSO-d6) δ7.54 (m, 1H), 7.96 (m, 1H), 8.31 (m, 1H); MS (ESI) m/e 154 (M+Na)+.1,4-diazabicyclo [2.2.2] octane (5.78 g, 51.5 mmol) in diethyl ether (130 mL) was n-butyllithium (32.2 mL, 51.5 mmol, 1.6 M solution in hexane) at −78 ° C. Drop by the deal. The reaction mixture is warmed to -20 ° C for 1 hour and then recooled to -78 ° C. The recooled mixture is treated dropwise with 3-fluoropyridine (5.0 g, 51.5 mmol) in diethyl ether (5 mL). After stirring at −78 ° C. for 2 hours, the mixture is treated with hexachloroethane (12.2 g, 51.5 mmol) in tetrahydrofuran (24 mL). After stirring at −78 ° C. for 1 hour, the reaction mixture is treated with a solution of water (15 mL) and tetrahydrofuran (25 mL). The reaction mixture is warmed to 0 ° C. and after 30 minutes additional water and diethyl ether are added to the mixture. The layers are separated and the aqueous phase is extracted with diethyl ether (2 ×). The combined ether layers are dried over Na 2 S0 4 , filtered and the filtrate is concentrated under reduced pressure. The residue is chromatographed on flash silica gel (10% ethyl acetate / hexanes) to yield 3.5 g (52% yield) of the title compound. 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.54 (m, 1H), 7.96 (m, 1H), 8.31 (m, 1H); MS (ESI) m / e 154 (M + Na) + .
실시예 28BExample 28B
1-(3-플루오로피리딘-2-일)피페라진1- (3-fluoropyridin-2-yl) piperazine
23℃에서 n-부탄올(150㎖) 중의 실시예 28A의 생성물(3.3g, 0.025mol)을 피페라진(21.5g, 0.25mol)으로 처리한 다음, 3일 동안 환류시킨다. 반응 혼합물을 23℃로 냉각시키고 감압하에 농축한다. 잔사를 물 및 에틸 아세테이트로 슬러리화시킨다. 에틸 아세테이트 용액을 분리하고, Na2SO4로 건조시키고, 여과하고, 여액을 감압하에 농축시켜 표제 화합물 3.3g(수율 73%)을 수득한다. 1H NMR (500 MHz, DMSO-d6) δ2.80 (m, 4H), 3.38 (m, 4H), 6.84 (m, 1H), 7.47 (m, 1H), 7.98 (m, 1H); MS (ESI) m/e 182 (M+H)+.The product of Example 28A (3.3 g, 0.025 mol) in n-butanol (150 mL) at 23 ° C. was treated with piperazine (21.5 g, 0.25 mol) and then refluxed for 3 days. The reaction mixture is cooled to 23 ° C. and concentrated under reduced pressure. The residue is slurried with water and ethyl acetate. The ethyl acetate solution is separated, dried over Na 2 SO 4 , filtered and the filtrate is concentrated under reduced pressure to give 3.3 g (73% yield) of the title compound. 1 H NMR (500 MHz, DMSO-d 6 ) δ 2.80 (m, 4H), 3.38 (m, 4H), 6.84 (m, 1H), 7.47 (m, 1H), 7.98 (m, 1H); MS (ESI) m / e 182 (M + H) + .
실시예 28CExample 28C
2-{[4-(3-플루오로피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸2-{[4- (3-fluoropyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole
실시예 28B의 생성물(0.50g, 2.76mmol), 2-클로로메틸-1H-벤즈이미다졸(0.48g, 2.90mmol) 및 탄산세슘(1.8g, 5.52mmol)을 23℃에서 N,N-디메틸포름아미드(28㎖) 중에서 합하고 1.25시간 동안 교반한다. 혼합물을 감압하에 농축하고 10% 메탄올/디클로로메탄으로 헹군다. 고체를 여과시키고 여액을 감압하에 농축한다. 잔사를 플래쉬 실리카 겔상에서 함침시키고 플래쉬 실리카 겔 상에서 크로마토그래피시켜(10% 메탄올/디클로로메탄) 표제 화합물 311㎎(수율 36%)을 수득한다. 융점 210-212℃; 1H NMR (300 MHz, DMSO-d6) δ2.62 (m, 4H), 3.43 (m, 4H), 3.78 (s, 2H), 6.87 (m, 1H), 7.14 (m, 2H), 7.50 (m, 3H), 8.00 (m, 1H); MS (APCI) m/e 312 (M+H)+; C17H18FN5·0.4 H2O에 대한 원소분석: 이론치: C, 64.10; H, 5.95; N, 21.98. 실측치: C, 64.16; H, 5.86; N, 21.95.The product of Example 28B (0.50 g, 2.76 mmol), 2-chloromethyl-1H-benzimidazole (0.48 g, 2.90 mmol) and cesium carbonate (1.8 g, 5.52 mmol) at 23 ° C. were N, N-dimethylform Combine in amide (28 mL) and stir for 1.25 h. The mixture is concentrated under reduced pressure and rinsed with 10% methanol / dichloromethane. The solid is filtered off and the filtrate is concentrated under reduced pressure. The residue is impregnated on flash silica gel and chromatographed on flash silica gel (10% methanol / dichloromethane) to give 311 mg (36% yield) of the title compound. Melting point 210-212 ° C .; 1 H NMR (300 MHz, DMSO-d 6 ) δ2.62 (m, 4H), 3.43 (m, 4H), 3.78 (s, 2H), 6.87 (m, 1H), 7.14 (m, 2H), 7.50 (m, 3 H), 8.00 (m, 1 H); MS (APCI) m / e 312 (M + H) + ; Elemental Analysis for C 17 H 18 FN 5 · 0.4 H 2 O: Theoretical: C, 64.10; H, 5.95; N, 21.98. Found: C, 64.16; H, 5. 86; N, 21.95.
실시예 29Example 29
6-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]피리딘-3-올6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol
실시예 29AExample 29A
5-(벤질옥시)-2-클로로피리딘5- (benzyloxy) -2-chloropyridine
DMF 8㎖ 중의 2-클로로-5-하이드록시피리딘(2.6g, 20mmol)과 탄산세슘(7.2g, 22mmol)을 벤질 브로마이드(2.6㎖)로 처리한다. 반응 생성물을 23℃에서 6시간 동안 교반한 후, 반응 혼합물을 물로 희석하고, 포화 수성 NaH2PO4로 pH 7로 조절하고, 디클로로메탄으로 추출한다. 유기 추출물을 Na2SO4로 건조시키고 여과하고 여액을 감압하에 농축시킨다. 잔사를 플래쉬 크로마토그래피로 정제하여(CH2Cl2로 용출시킴) 표제 화합물을 백색 고체(3.44g, 79%)로서 제공한다. 융점 <50℃; Rf=0.4 (CH2Cl2); MS 220 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ8.20 (d, 1H, J=2.7 Hz), 7.55 (dd, 1H, J=9, 2.7 Hz), 7.3-7.5 (m, 6H), 5.19 (s, 2H).2-chloro-5-hydroxypyridine (2.6 g, 20 mmol) and cesium carbonate (7.2 g, 22 mmol) in 8 mL of DMF were treated with benzyl bromide (2.6 mL). After the reaction product is stirred at 23 ° C. for 6 hours, the reaction mixture is diluted with water, adjusted to pH 7 with saturated aqueous NaH 2 PO 4 and extracted with dichloromethane. The organic extract is dried over Na 2 S0 4 , filtered and the filtrate is concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with CH 2 Cl 2 ) to provide the title compound as a white solid (3.44 g, 79%). Melting point <50 ° C; R f = 0.4 (CH 2 Cl 2 ); MS 220 (M + H) + ; 1 H NMR (300 MHz, DMSO-d 6 ) δ8.20 (d, 1H, J = 2.7 Hz), 7.55 (dd, 1H, J = 9, 2.7 Hz), 7.3-7.5 (m, 6H), 5.19 (s, 2H).
실시예 29BExample 29B
3급 부틸 4-[5-(벤질옥시)피리딘-2-일]피페라진-1-카복실레이트Tert-Butyl 4- [5- (benzyloxy) pyridin-2-yl] piperazin-1-carboxylate
실시예 29A로부터의 생성물(2.63g), Pd2(dba)3(0.33g), 라세미체 BINAP(0.45g), 나트륨 3급 부톡사이드(2.3g) 및 3급 부틸 피페라진-1-카복실레이트(4.46g)를 톨루엔(80㎖) 중에서 합하고, 95℃에서 3시간 동안 가열한다. 반응 혼합물을 톨루엔(50㎖)으로 처리하고 디에틸 에테르(200㎖)로 처리한다. 혼합물을 물로 세척하고 유기 상을 Na2SO4로 건조시키고 여과하고 여액을 감압하에 농축시킨다. 잔사를 1:4 에틸 아세테이트/헥산으로 용출시키는 플 래쉬 크로마토그래피로 정제시켜 표제 화합물(4.06g, 92%)을 수득한다. 융점 93-94℃; Rf=0.21 (1:4 에틸 아세테이트/헥산); MS 370 (M+H)+.
Product from Example 29A (2.63 g), Pd 2 (dba) 3 (0.33 g), racemate BINAP (0.45 g), sodium tert-butoxide (2.3 g) and tert-butyl piperazine-1-carboxyl The rate (4.46 g) is combined in toluene (80 mL) and heated at 95 ° C for 3 hours. The reaction mixture is treated with toluene (50 mL) and with diethyl ether (200 mL). The mixture is washed with water, the organic phase is dried over Na 2 SO 4 , filtered and the filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography, eluting with 1: 4 ethyl acetate / hexanes to give the title compound (4.06 g, 92%). Melting point 93-94 ° C; R f = 0.21 (1: 4 ethyl acetate / hexane); MS 370 (M + H) + .
실시예 29CExample 29C
1-[5-(벤질옥시)피리딘-2-일]피페라진1- [5- (benzyloxy) pyridin-2-yl] piperazine
실시예 29B로부터의 생성물(1.96g)을 트리플루오로아세트산(3.5㎖)으로 23℃에서 2시간 동안 교반하면서 처리한다. 혼합물을 CH2Cl2(100㎖)/n-부탄올(5㎖)과 물(400㎖)/NH4OH(5㎖) 사이에 분배한다. 유기 상을 분리하고 Na2SO4로 건조시키고 여과하고 여액을 감압하에 농축시켜 백색 분말로서 표제 화합물을 수득하며, 이는 추가로 정제하지 않고 다음 단계에서 사용한다.The product from Example 29B (1.96 g) was treated with trifluoroacetic acid (3.5 mL) at 23 ° C. for 2 hours with stirring. The mixture is partitioned between CH 2 Cl 2 (100 mL) / n-butanol (5 mL) and water (400 mL) / NH 4 OH (5 mL). The organic phase is separated, dried over Na 2 SO 4 , filtered and the filtrate is concentrated under reduced pressure to give the title compound as a white powder which is used in the next step without further purification.
실시예 29DExample 29D
2-({4-[5-(벤질옥시)피리딘-2-일]피페라진-1-일}메틸)-1H-벤즈이미다졸2-({4- [5- (benzyloxy) pyridin-2-yl] piperazin-1-yl} methyl) -1H-benzimidazole
실시예 29C로부터의 생성물과 2-클로로메틸-1H-벤조이미다졸(0.88㎎)을 합하고 DMF(7㎖)/트리에틸아민(1.5㎖)에 용해시킨다. 23℃에서 2시간 동안 교반한 후, 혼합물을 아세토니트릴(20㎖)로 처리한 다음, 24시간 동안 교반한다. 반응 혼합물을 CH2Cl2(100㎖)/n-부탄올(5㎖)과 물(800㎖)/NH4OH(5㎖) 사이에 분배한다. 유기 상을 분리하고 Na2SO4로 건조시키고 여과하고 여액을 감압하에 농축한다. 잔사를 플래쉬 크로마토그래피로 정제시켜 표제 화합물을 백색 고체(1.169g, 55%)로서 수득한다. 융점 62-64℃; Rf=0.26 (95:5 CH2Cl2:메탄올:0.1% NH4OH); MS 400 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ12.3 (bs, NH, 1H), 7.90 (d, 1H, J=3 Hz), 7.55 (m, 1H), 7.3-7.5 (m, 8H), 7.15 (m, 2H), 6.80 (d, 1H, J=9 Hz), 5.05 (s, 2H), 3.76 (s, 2H), 3.39 (t, 4H, J=5.1 Hz), 2.57 (t, 4H, J=5.1 Hz).The product from Example 29C and 2-chloromethyl-1H-benzoimidazole (0.88 mg) were combined and dissolved in DMF (7 mL) / triethylamine (1.5 mL). After stirring at 23 ° C. for 2 hours, the mixture is treated with acetonitrile (20 mL) and then stirred for 24 hours. The reaction mixture is partitioned between CH 2 Cl 2 (100 mL) / n-butanol (5 mL) and water (800 mL) / NH 4 OH (5 mL). The organic phase is separated, dried over Na 2 SO 4 , filtered and the filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography to give the title compound as a white solid (1.169 g, 55%). Melting point 62-64 ° C .; R f = 0.26 (95: 5 CH 2 Cl 2 : methanol: 0.1% NH 4 OH); MS 400 (M + H) + ; 1 H NMR (300 MHz, DMSO-d 6 ) δ12.3 (bs, NH, 1H), 7.90 (d, 1H, J = 3 Hz), 7.55 (m, 1H), 7.3-7.5 (m, 8H) , 7.15 (m, 2H), 6.80 (d, 1H, J = 9 Hz), 5.05 (s, 2H), 3.76 (s, 2H), 3.39 (t, 4H, J = 5.1 Hz), 2.57 (t, 4H, J = 5.1 Hz).
실시예 29EExample 29E
6-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]피리딘-3-올6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol
에틸 아세테이트(35㎖) 중의 실시예 29D로부터의 생성물(800㎎)을 탄소상 10% 팔라듐(85㎎)으로 수소 기체 블랭킷하에 23℃에서 TLC가 출발 물질의 소모를 나타낼 때까지 처리한다. 혼합물을 여과하고 필터 케이크를 메탄올과 CH2Cl2로 세척한다. 여액을 합하고 감압하에 농축시킨다. 잔사를 플래쉬 크로마토그래피로 정제하여(90:10:0.1 CH2Cl2:메탄올:NH4OH로 용출시킴) 순수한 표제 화합물을 백색 고체(566㎎, 92%)로서 수득한다. 융점 144-145℃; Rf=0.08; (95:5 CH2Cl2:메탄올:0.1% NH4OH); MS 310 (M+H)+; 1H NMR (300 MHz, MeOD) δ7.72 (d, 1H, J=2.7 Hz), 7.53 (m, 2H), 7.21 (m, 2H), 7.12 (dd, 1H, J=9, 3 Hz), 6.75 (d, 1H, J=9 Hz), 3.85 (s, 2H), 3.40 (t, 4H, J=5.1 Hz), 2.69 (t, 4H, J=5.1 Hz); C17H19N5O에 대한 원소분석(메탄올 1.0당량, 디클로로메탄 0.1당량): 이론치: C 62.13; H 6.68; N 20.01. 실측치: C 62.04; H 6.57; N 19.67.The product from Example 29D in ethyl acetate (35 mL) (800 mg) was treated with 10% palladium on carbon (85 mg) at 23 ° C. under a hydrogen gas blanket until TLC showed consumption of starting material. The mixture is filtered and the filter cake is washed with methanol and CH 2 Cl 2 . The filtrates are combined and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with 90: 10: 0.1 CH 2 Cl 2 : methanol: NH 4 OH) to afford the pure title compound as a white solid (566 mg, 92%). Melting point 144-145 ° C .; R f = 0.08; (95: 5 CH 2 Cl 2 : methanol: 0.1% NH 4 OH); MS 310 (M + H) + ; 1 H NMR (300 MHz, MeOD) δ7.72 (d, 1H, J = 2.7 Hz), 7.53 (m, 2H), 7.21 (m, 2H), 7.12 (dd, 1H, J = 9, 3 Hz) , 6.75 (d, 1H, J = 9 Hz), 3.85 (s, 2H), 3.40 (t, 4H, J = 5.1 Hz), 2.69 (t, 4H, J = 5.1 Hz); Elemental analysis for C 17 H 19 N 5 O (1.0 equivalent of methanol, 0.1 equivalent of dichloromethane): Theoretical: C 62.13; H 6.68; N 20.01. Found: C 62.04; H 6.57; N 19.67.
실시예 30Example 30
2-{[4-(3-메틸피리딘-2-일)피페라진-1-일]메틸}-1H-벤즈이미다졸2-{[4- (3-methylpyridin-2-yl) piperazin-1-yl] methyl} -1H-benzimidazole
1-(2-피리미딜)피페라진을 1-(3-메틸피리딘-2-일)피페라진으로 대체시킴을 제외하고는, 실시예 2의 공정에 따라 표제 화합물을 제조할 수 있다.
The title compound can be prepared according to the process of Example 2, except that 1- (2-pyrimidyl) piperazine is replaced with 1- (3-methylpyridin-2-yl) piperazine.
생체내 데이터In vivo data
래트 음경 발기 모델Rat penis erection model
위스타 래트(Wistar rat)를 주요 동물 모델로서 사용하여 생체내 음경 발기를 연구했다. 모든 실험을 적색 광으로 산광 조명의 시험실에서 오전 9시부터 오후 3시까지 수행했다. 동물의 체중을 측정하고 실험을 시작하기 전에 60분 동안 시험실에 적응시켰다. 래트를 약제 주사 후 투명한 케이지(20×30×30㎝)에 개별적으로 위치시켰다. 약제 투여 후에 60분 동안 직접 관찰하여 음경 발기 수를 기록하고, 1회 이상의 발기를 나타내는 동물 수를 발생률(%)로 나타냈다.In vivo penile erection was studied using Wistar rat as the main animal model. All experiments were performed from 9 am to 3 pm in a diffused light laboratory with red light. Animals were weighed and acclimated to the laboratory for 60 minutes before starting the experiment. Rats were individually placed in clear cages (20 × 30 × 30 cm) after drug injection. The penile erection number was recorded by direct observation for 60 minutes after drug administration, and the number of animals showing one or more erections was expressed as the percentage of occurrence.
비히클로서 염수 중의 (L)-아스코르브산(1㎎/㎖)을 사용했다. 용량당 12마리의 동물을 사용했다. 양성 대조군으로서 아포모르핀을 래트 음경 발기의 83% 발생률을 발생시키는 0.1μmol/kg의 용량으로 사용했다.As vehicle, (L) -ascorbic acid (1 mg / ml) in saline was used. Twelve animals were used per dose. As a positive control, apomorphine was used at a dose of 0.1 μmol / kg which produced 83% incidence of rat penile erection.
표 1의 데이터는 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸 0.01 내지 0.10μmol/kg의 용량을 피하 투여 후에 래트에게서 통계학적으로 현저한 음경 발기가 유도됨을 나타냈다.The data in Table 1 show statistically significant penis in rats after subcutaneous administration of 0.01 to 0.10 μmol / kg 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole Erection was induced.
염수 중의 (L)-아스코르브산(1㎎/㎖)을 비히클로서 사용했다. 용량당 12마리의 동물을 사용했다. 양성 대조군으로서 아포모르핀을 래트 음경 발기의 93% 발생률을 발생시키는 0.1μmol/kg의 용량으로 사용했다.(L) -ascorbic acid (1 mg / ml) in brine was used as the vehicle. Twelve animals were used per dose. As a positive control, apomorphine was used at a dose of 0.1 μmol / kg, resulting in 93% incidence of rat penile erection.
표 2의 데이터는 6-[4-(1H-벤즈이미다졸-2-일메틸)피페라진-1-일]피리딘-3-올 0.01 내지 0.10μmol/kg의 용량을 피하 투여 후 래트에게서 통계학적으로 현저한 음경 발기가 유도됨을 나타냈다.The data in Table 2 is statistically determined in rats after subcutaneous administration of 0.01-0.10 μmol / kg of 6- [4- (1H-benzimidazol-2-ylmethyl) piperazin-1-yl] pyridin-3-ol As a result, a significant penile erection was induced.
본 발명의 바람직한 화합물은 약 0.003 내지 약 1.0μmol/kg의 용량에서 래트의 음경 발기의 50% 이상의 발생률을 유도했다.Preferred compounds of the present invention induced at least 50% incidence of penile erection of rats at doses of about 0.003 to about 1.0 μmol / kg.
페릿의 구토 모델Ferret's Vomiting Model
수컷 피치 페릿(체중 1.0 내지 1.5kg)을 구입한다(Marshall Farms). 페릿을 실험 전에 밤새 절식시켰다. 아포모르핀 또는 본 발명의 화합물을 피하 투여하고; 동물을 관찰 케이지에 개별적으로 위치시키고 약제 유도된 구토 및 오심 신호를 약제 주입 후 90분 동안 측정했다(직접 관찰하여). 오심은 핥음, 구역질, 후퇴, 머리 묻음 및 강한 복부 그루밍(grooming) 등의 거동을 특징으로 한다. 구토는 통상적으로 이들 거동을 선행하고 토하거나 구역질하는 운동과 관련된 주기적인 복부 수축을 특징으로 한다.Male pitch ferrets (weight 1.0-1.5 kg) are purchased (Marshall Farms). Ferrets were fasted overnight before the experiment. Subcutaneous administration of apomorphine or a compound of the present invention; Animals were placed individually in the observation cage and drug-induced vomiting and nausea signals were measured 90 minutes after drug injection (directly observed). Nausea is characterized by behaviors such as licks, nausea, retreat, hair buring, and strong abdominal grooming. Vomiting is usually characterized by periodic abdominal contractions associated with exercise that precedes these behaviors and vomits or nausea.
멸균 염수를 비히클로서 사용했다. 용량당 여섯 마리의 동물을 사용했다. 표 3의 양성 대조군으로서 아포모르핀을 구토를 나타내는 페릿의 100% 발생률을 발생시키는 0.3μmol/kg의 용량으로 사용했다.Sterile saline was used as the vehicle. Six animals were used per dose. As a positive control in Table 3, apomorphine was used at a dose of 0.3 μmol / kg, generating 100% incidence of vomiting ferrets.
표 3에 나타낸 바와 같이, 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸은 피하 투여 후 페릿의 구토를 유도하지 않았다.As shown in Table 3, 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole did not induce ferret vomiting after subcutaneous administration.
아포모르핀은 이들 연구에서 양성 대조군으로서 포함시켰다. 이들 데이터는 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸이 구토를 유도하지 않고 음경 발기를 촉진시키기 때문에, 아포모르핀보다 현저한 이점을 제공함을 나타낸다.Apomorphine was included as a positive control in these studies. These data show that 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole provides significant benefits over apomorphine because it promotes penile erection without inducing vomiting. Indicates.
본 발명의 화합물, 특히 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸은 포유동물의 성 기능장애의 치료방법으로서, 이들로 한정하려는 것은 아니지만, 실데나필 또는 바르데나필을 포함하는 포스포디에스테라제 5 억제제와 배합하여 사용할 수 있다.Compounds of the present invention, in particular 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, are not intended to be limited to these methods of treatment of sexual dysfunction in mammals. And phosphodiesterase 5 inhibitors including sildenafil or vardenafil.
본 발명의 화합물, 특히 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸은 포유동물의 성 기능장애의 치료방법으로서, 이들로 한정하려는 것은 아니지만, 테라조신, 프라조신 또는 탐설로신을 포함하는 아드레날린성 수용체 길항제와 배합하여 사용할 수 있다.Compounds of the present invention, in particular 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, are not intended to be limited to these methods of treatment of sexual dysfunction in mammals. It can be used in combination with an adrenergic receptor antagonist, including terrazocin, prazosin or tamsulosin.
본 발명의 화합물, 특히 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸은 포유동물의 성 기능장애의 치료방법으로서, 이들로 한정하려는 것은 아니지만, 아포모르핀을 포함하는 도파민 효능제와 배합하여 사용할 수 있다.Compounds of the present invention, in particular 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, are not intended to be limited to these methods of treatment of sexual dysfunction in mammals. It can be used in combination with a dopamine agonist including apomorphine.
본 발명의 화합물, 특히 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸은 도파민 효능제이며, 따라서 문헌[참조: The dopamine D4 receptor: a controversial therapeutic target. N.J. Hrib. Drugs of the future 25:587-611 (2000); Dopamine and sexual behavior. M. Melis and A. Argiolas. Neuroscience and Biobehavioral Reviews 19:19-38 (1995); and Dopamine receptors: from structure to function. C. Missale, S.R. Nash, S. Robinson, M. Jabber and M. Caron. Physiological Reviews 78: 189-225 (1998)]에 기재된 바와 같이 여성 성 기능장애, 주의력 결핍 과다활동 장애, 알츠하이머 병, 약물 남용, 파킨슨 병, 불안, 정신분열증, 기분 장애 및 우울증의 치료에 유용하다.Compounds of the invention, in particular 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, are dopamine agonists and are therefore described in The dopamine D 4 receptor: a controversial therapeutic target. NJ Hrib. Drugs of the future 25: 587-611 (2000); Dopamine and sexual behavior. M. Melis and A. Argiolas. Neuroscience and Biobehavioral Reviews 19: 19-38 (1995); and Dopamine receptors: from structure to function. C. Missale, SR Nash, S. Robinson, M. Jabber and M. Caron. Physiological Reviews 78: 189-225 (1998), which are useful for the treatment of female sexual dysfunction, attention deficit hyperactivity disorder, Alzheimer's disease, drug abuse, Parkinson's disease, anxiety, schizophrenia, mood disorders and depression.
본 발명의 화합물, 특히 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸은 도파민 효능제이며, 따라서 심장혈관 장애의 치료에 유용하다. 도파민 및 도파민제는 혈압 및 심장 박동수에 약리학적으로 현저한 심장혈관성 효과를 발휘하여 심장혈관 장애의 치료에 유용할 수 있다고 보고되었고[참조: Chen FF, and Lin MT, Effects of dopamine, apomorphine gamma-hydroxybutyric acid, haloperidol, and pimozide on reflex bradycardia in rats, Journal of Pharmacology and Experimental Therapeutics (1980) 214: 427-432], 영장류의 데이터는 심장혈관 질환을 치료하는 데 대한 도파민 수용체 효능제의 잠재적인 임상적 유용성을 지지한다고 보고되어 있다[참조: Hahn, RA and MacDonald BR, Primate cardiovascular responses meditated by dopaminine receptors: effects of N,N-dipropyldopamine and LY171555, Journal of Phamacology and Experimental Therapeutics (1984) 229: 132-138].Compounds of the invention, in particular 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, are dopamine agonists and are therefore useful for the treatment of cardiovascular disorders. Dopamine and dopamine have been reported to be useful in the treatment of cardiovascular disorders by exerting pharmacologically significant cardiovascular effects on blood pressure and heart rate [Chen FF, and Lin MT, Effects of dopamine, apomorphine gamma-hydroxybutyric acid, haloperidol, and pimozide on reflex bradycardia in rats, Journal of Pharmacology and Experimental Therapeutics (1980) 214: 427-432], data from primates suggest the potential clinical utility of dopamine receptor agonists in treating cardiovascular disease. (Hahn, RA and Mac Donald BR, Primate cardiovascular responses meditated by dopaminine receptors: effects of N, N-dipropyldopamine and LY171555, Journal of Phamacology and Experimental Therapeutics (1984) 229: 132-138).
본 발명의 화합물, 특히 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸은 도파민 효능제이며, 따라서 염증의 치료에 유용하다. 도파민제는 소염 효과를 나타낼 수 있어 염증이 유해한 역할을 하는 질환의 치료에 유용할 수 있다[참조: Bendele AM, Spaethe SM, Benslay DN, and Bryant HU, Anti-inflammatory activity of pergolide, a dopamine receptor agonist, in Journal of Pharmacology of Pharmacology and Experimental Therapeutics (1991) 259: 169-175]. 도파민제는 또한 암의 치료에도 유용할 수 있다[참조: Lissoni P, Mandala M, Giani L, Malugani F, Secondino S, Zonato S, Rocco F, Gardani G, Efficacy of Bromocriptine in the Treatment of Metastatic Breast Cancer and Prostate Cancer-related Hyperprolactinemia, Neuroendocrinology Letters (2000) 21: 405-408].Compounds of the invention, in particular 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole, are dopamine agonists and are therefore useful for the treatment of inflammation. Dopamine may have an anti-inflammatory effect and may be useful in the treatment of diseases in which inflammation plays a detrimental role [Bendele AM, Spaethe SM, Benslay DN, and Bryant HU, Anti-inflammatory activity of pergolide, a dopamine receptor agonist , in Journal of Pharmacology of Pharmacology and Experimental Therapeutics (1991) 259: 169-175]. Dopamine may also be useful in the treatment of cancer. See Lissoni P, Mandala M, Giani L, Malugani F, Secondino S, Zonato S, Rocco F, Gardani G, Efficacy of Bromocriptine in the Treatment of Metastatic Breast Cancer and Prostate Cancer-related Hyperprolactinemia, Neuroendocrinology Letters (2000) 21: 405-408].
본원에서 사용된 바와 같은 용어 효능제는 하나 이상의 도파민 수용체 아형과 상호작용하고 관찰 가능한 세포내 생화학적 반응을 유도하는 화합물을 말한다. 반응은 도파민과 같은 전체 효능제에 대하여 측정된다.The term agonist as used herein refers to a compound that interacts with one or more dopamine receptor subtypes and induces observable intracellular biochemical responses. Response is measured for total agonists such as dopamine.
본원에서 사용된 바와 같은 용어 "약제학적으로 허용되는 담체"는 모든 유형의 비독성, 불활성 고형, 반고형 또는 액상 충전제, 희석제, 캡슐화 물질 또는 제형 보조제를 의미한다. 약제학적으로 허용되는 담체로서 사용할 수 있는 일부 물질의 예로는 락토스, 글루코스 및 수크로스 등의 당; 옥수수 전분 및 감자 전분 등의 전분류; 나트륨 카복시메틸 셀룰로스, 에틸 셀룰로스 및 셀룰로스 아세테이트 등의 셀룰로스 및 이의 유도체; 트라가칸트 분말; 맥아; 젤라틴; 탈크; 코코아 버터 및 좌약 왁스 등의 부형제; 땅콩유, 면실유, 잇꽃유, 참깨유, 올리브유, 옥수수유 및 대두유 등의 오일; 프로필렌 글리콜 등의 글리콜; 에틸 올레에이트 및 에틸 라우레이트 등의 에스테르; 한천; 수산화마그네슘 및 수산화알루미늄 등의 완충제; 알긴산; 비발열수; 등장 염수; 링거액; 에틸 알콜 및 인산염 완충 용액이 있으며, 기타 비독성 혼화성 윤활제, 예를 들면, 나트륨 라우릴 설페이트 및 마그네슘 스테아레이트, 및 착색제, 이형제, 피복제, 감미료, 향미제 및 방향제, 방부제 및 산화방지제 또한 제형화 업자의 판단에 따라 당해 조성물에 존재할 수 있다.The term "pharmaceutically acceptable carrier" as used herein means any type of nontoxic, inert solid, semisolid or liquid filler, diluent, encapsulating material or formulation aid. Examples of some materials that can be used as pharmaceutically acceptable carriers include sugars such as lactose, glucose and sucrose; Starches such as corn starch and potato starch; Cellulose and derivatives thereof such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; Tragacanth powder; malt; gelatin; Talc; Excipients such as cocoa butter and suppository waxes; Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; Glycols such as propylene glycol; Esters such as ethyl oleate and ethyl laurate; Agar; Buffers such as magnesium hydroxide and aluminum hydroxide; Alginic acid; Unheated water; Isotonic saline; Ringer's solution; Ethyl alcohol and phosphate buffer solutions, and other nontoxic miscible lubricants such as sodium lauryl sulfate and magnesium stearate, and colorants, release agents, coatings, sweeteners, flavoring and fragrances, preservatives and antioxidants It may be present in the composition at the discretion of the supplier.
본 발명은 하나 이상의 비독성 약제학적으로 허용되는 담체와 함께 제형화된 본 발명의 화합물을 포함하는 약제학적 조성물을 제공한다. 약제학적 조성물은 고형 또는 액상 형태의 경구 투여용, 비경구 주사용 또는 장내 투여용으로 제형화될 수 있다.The present invention provides a pharmaceutical composition comprising a compound of the present invention formulated with one or more nontoxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be formulated for oral administration, parenteral injection or enteral administration in solid or liquid form.
하나 이상의 비독성의 약제학적으로 허용되는 조성물과의 배합물로 제조되고 제형화된 하나 이상의 도파민 효능제를 포함하는 약제학적 조성물이 본 발명의 영역 내에 추가로 포함된다. 약제학적 조성물은 고형 또는 액상 형태의 경구 투여용, 비경구 주사용 또는 장애 투여용으로 제형화될 수 있다.Further included within the scope of the present invention are pharmaceutical compositions comprising one or more dopamine agonists prepared and formulated in combination with one or more nontoxic pharmaceutically acceptable compositions. The pharmaceutical composition may be formulated for oral administration, parenteral injection or disorder administration in solid or liquid form.
본 발명의 약제학적 조성물은 경구, 설하, 직장내, 비경구, 수조내, 요도내, 질내, 복막내, 국소(분말, 연고 또는 점적제), 구강내 또는 경구 또는 코용 스프레이로서 사람 및 기타 포유동물에게 투여할 수 있다. 본원에서 사용된 바와 같은 용어 "비경구"는 정맥내, 근육내, 복막내, 피하, 관절내 주사 및 주입을 포함하는 투여 형태를 말한다.The pharmaceutical compositions of the present invention are oral, sublingual, rectal, parenteral, intracranial, urethra, intravaginal, intraperitoneal, topical (powder, ointment or drops), oral or oral or nasal sprays for human and other mammals. It can be administered to the animal. The term “parenteral” as used herein refers to dosage forms including intravenous, intramuscular, intraperitoneal, subcutaneous, intraarticular injection and infusion.
사람에게 바람직한 투여는 경구 또는 설하이다.Preferred administration to humans is oral or sublingual.
본 발명의 경구 주사용 약제학적 조성물은 약제학적으로 허용되는 멸균 수용액 또는 비수용액, 분산제, 현탁제 또는 에멀션 및 멸균 주사용제 또는 분산제로 재구성하기 위한 멸균 분말을 포함한다. 적합한 수성 및 비수성 담체, 희석제, 용 매 또는 비히클의 예로는 물, 에탄올, 폴리올(프로필렌 글리콜, 폴리에틸렌 글리콜, 글리세롤 등), 이의 적합한 혼합물, 식물유(예: 올리브유) 및 에틸 올레에이트 등의 주사용 유기 에스테르가 포함된다. 예를 들면, 레시틴 등의 피막을 사용하고, 분산제의 경우 필요한 입자 크기를 유지시키고, 계면활성제를 사용함으로써 적당한 유동성을 유지시킬 수 있다.Oral injectable pharmaceutical compositions of the present invention include sterile powders for reconstitution into pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersants, suspensions or emulsions and sterile injectable solutions or dispersants. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (e.g. olive oil) and ethyl oleate, for example. Organic esters are included. For example, proper fluidity can be maintained by using a coating such as lecithin, maintaining the required particle size in the case of a dispersant, and using a surfactant.
이러한 조성물은 방부제, 습윤제, 유화제 및 분산제 등의 보조제를 함유할 수도 있다. 미생물의 작용은 다양한 항균제 및 항진균제, 예를 들면, 파라벤, 클로로부탄올, 페놀, 소르브산 등에 의해 방지할 수 있다. 등장제, 예를 들면, 당, 염화나트륨 등을 포함시키는 것이 바람직할 수도 있다. 주사용 약제학적 형태는 흡수를 지연시키는 제제, 예를 들면, 알루미늄 모노스테아레이트 및 젤라틴을 사용하여 흡수를 지연시킬 수 있다.Such compositions may contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. The action of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid and the like. It may be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Pharmaceutical forms for injection can be delayed with agents that delay absorption, such as aluminum monostearate and gelatin.
어떤 경우에는, 약제의 효과를 연장시키기 위하여, 피하 또는 근육내 주사로부터 약제의 흡수를 서서히 하는 것이 종종 바람직하다. 이는 수 용해도가 불량한 결정성 또는 무정형 물질의 액상 현탁액을 사용하여 달성할 수 있다. 그러면, 약제의 흡수율은 이의 용해 속도에 좌우되며, 이는 또한 결정 크기 및 결정 형태에 좌우될 수 있다. 또 다른 방법으로, 비경구 투여된 약제 형태의 지연된 흡수는 오일 비히클에 약제를 용해시키거나 현탁시켜 달성된다.In some cases, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection, in order to prolong the effect of the drug. This can be achieved using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
활성 화합물 외에 현탁액은 현탁제, 예를 들면, 에톡실화 이소스테아릴 알콜, 폴리옥시에틸렌 소르비톨 및 소르비탄 에스테르, 미세결정성 셀룰로스, 알루미늄 메타하이드록사이드, 벤토나이트, 한천, 트라가칸트 및 이들의 혼합물을 함유할 수 있다.In addition to the active compounds, suspensions may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth and mixtures thereof It may contain.
필요한 경우, 보다 유효한 분포를 위하여, 본 발명의 화합물은 중합체 매트릭스, 리포좀 및 미소구체 등의 서방성 또는 표적 운반 시스템으로 혼입시킬 수 있다. 이는, 예를 들면, 박테리아 보유 필터를 통하여 여과시키거나 사용 직전에 멸균수 또는 기타 멸균 주사용 매질에 용해시킬 수 있는 멸균 고형 조성물의 형태로 멸균화제를 혼입시켜 멸균화시킬 수 있다.If desired, for more effective distribution, the compounds of the present invention can be incorporated into sustained or targeted delivery systems such as polymeric matrices, liposomes and microspheres. It may be sterilized by incorporating a sterilizing agent, for example, in the form of a sterile solid composition that can be filtered through a bacterial retention filter or dissolved in sterile water or other sterile injectable media immediately prior to use.
본 발명의 화합물은 또한 필요한 경우, 위에서 주목한 바와 같은 하나 이상의 부형제와 미세 캡슐화된 형태일 수도 있다. 정제, 당의정, 캡슐, 환제 및 과립 형태의 고체 투여형은 약제학적 제형화 기술분야에 익히 공지된 장용피, 방출 조절 피막 및 기타 피막 등의 피막 및 쉘로 제조할 수 있다. 이러한 고체 투여형에서 활성 화합물은 수크로스, 락토스 또는 전분 등의 하나 이상의 불활성 희석제와 혼합할 수 있다. 이러한 투여형은 통상적으로 실시되는 바와 같이, 불활성 희석제 이외의 추가의 물질, 예를 들면, 정제화 윤활제 및, 마그네슘 스테아레이트 및 미세결정성 셀룰로스 등의 기타 정제화 보조제를 포함할 수도 있다. 캡슐, 정제 및 환제의 경우, 투여 형태는 또한 완충제를 포함할 수도 있다. 이는 불투명화제를 임의로 함유할 수 있으며, 또한 활성 성분(들)만을 또는 이를 우선적으로 지연된 방식으로 장관의 특정 부분으로 방출하는 이러한 조성물일 수도 있다. 사용될 수 있는 내장 조성물의 예로는 중합체성 물질 및 왁스가 포함된다.The compounds of the present invention may also be in microencapsulated form with one or more excipients as noted above, if necessary. Solid dosage forms in the form of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms the active compound may be mixed with one or more inert diluents such as sucrose, lactose or starch. Such dosage forms may include additional materials other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose, as is commonly practiced. In the case of capsules, tablets and pills, the dosage form may also comprise a buffer. It may optionally contain an opaque agent and may also be such a composition which releases only the active ingredient (s) or preferentially to a particular part of the intestine in a delayed manner. Examples of visceral compositions that can be used include polymeric substances and waxes.
주사 가능한 데포우 형태는 폴리락타이드-폴리글리콜라이드 등의 생분해성 중합체에 본 발명의 화합물의 미세캡슐화 매트릭스를 형성시켜 제조한다. 중합체에 대한 본 발명의 화합물의 비율 및 사용되는 특정 중합체의 특성에 따라, 본 발명의 화합물의 비율을 조절할 수 있다. 기타 생분해성 중합체의 예로는 폴리(오르토에스테르) 및 폴리(무수물)이 포함된다. 데포우 주사용 제형은 또한 생체 조직과 혼화될 수 있는 리포좀 또는 마이크로에멀션에 약제를 포획시킴으로써 제조된다.Injectable depot forms are made by forming microencapsulated matrices of the compounds of the invention in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the compound of the invention to the polymer and the nature of the particular polymer used, the ratio of the compound of the invention can be adjusted. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the agent in liposomes or microemulsions, which can be mixed with living tissue.
주사용 제형은, 예를 들면, 박테리아 보유 필터를 통하여 여과시키거나 멸균수 또는 기타 멸균 주사용 매질에 사용 직전에 용해시키거나 분산시킬 수 있는 멸균 고형 조성물 형태로 멸균화제를 혼입시켜 멸균시킬 수 있다.Injectable formulations may be sterilized, for example, by incorporation of a sterilizing agent in the form of a sterile solid composition that can be filtered through a bacterial retention filter or dissolved or dispersed immediately prior to use in sterile water or other sterile injectable media. .
주사용 제제, 예를 들면, 멸균 주사용 수성 또는 유질 현탁액은 적합한 분산제 또는 습윤화제와 현탁제를 사용하는 당해 기술분야에 공지된 방법에 따라 제형화할 수 있다. 멸균 주사용 제제는 또한 1,3-부탄디올 중의 용액과 같은 비독성의, 비경구적으로 허용되는 희석제 또는 용매 중의 멸균 주사용 액제, 현탁액 또는 에멀션일 수 있다. 사용될 수 있는 허용되는 비히클 및 용매는 물, 링거액, U.S.P. 및 염화나트륨 등장 용액일 수 있다. 또한, 멸균 비휘발성 오일이 용매 또는 현탁 매질로서 통상적으로 사용된다. 이를 위하여 합성 모노- 또는 디글리세라이드를 포함하는 어떠한 블랜드 비휘발성 오일이라도 사용될 수 있다. 또한, 올레산 등의 지방산이 주사가능물의 제조에 사용된다.Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to methods known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions or emulsions in nontoxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be employed include water, Ringer's solution, U.S.P. And sodium chloride isotonic solution. In addition, sterile, nonvolatile oils are conventionally employed as a solvent or suspending medium. Any blended nonvolatile oil can be used for this purpose including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
경구 투여용 고체 투여 형태는 캡슐, 정제, 환제, 분말 및 과립을 포함한다. 이러한 고체 투여 형태에서, 본 발명의 화합물 또는 화합물들은 하나 이상의 불활성, 약제학적으로 허용되는 부형제 또는 담체, 예를 들면, 나트륨 시트레이트 또는 인산칼슘 및/또는 a) 전분, 락토스, 수크로스, 글루코스, 만니톨 및 규산 등의 충전제 또는 증량제; b) 카복시메틸셀룰로스, 알기네이트, 젤라틴. 폴리비닐피롤리돈, 수크로스 및 아카시아 등의 결합제; c) 글리세롤 등의 보습제; d) 한천, 탄산칼슘, 감자 또는 타피오카 전분, 알긴산, 특정 규산염 및 탄산나트륨 등의 붕해제; e) 파라핀 등의 용해 지연제; f) 4급 암모늄 화합물 등의 흡수 촉진제; g) 세틸 알콜 및 글리세롤 모노스테아레이트 등의 습윤제; h) 카올린 및 벤토나이트 점토 등의 흡수제; 및 i) 탈크, 칼슘 스테아레이트, 마그네슘 스테아레이트, 고형 폴리에틸렌 글리콜, 나트륨 라우릴 설페이트 등의 윤활제 및 이들의 혼합물과 혼합한다.Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compound or compounds of the present invention may comprise one or more inert, pharmaceutically acceptable excipients or carriers such as sodium citrate or calcium phosphate and / or a) starch, lactose, sucrose, glucose, Fillers or extenders such as mannitol and silicic acid; b) carboxymethylcellulose, alginate, gelatin. Binders such as polyvinylpyrrolidone, sucrose and acacia; c) humectants, such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) dissolution retardants such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; And i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof.
유사한 유형의 고형 조성물은 락토스 또는 유당으로서 이러한 부형제 및 고분자량 폴리에틸렌 글리콜 등을 사용하여 연질 및 경질 충전된 젤라틴 캡슐의 충전제로서 사용될 수도 있다.Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using such excipients and high molecular weight polyethylene glycols and the like as lactose or lactose.
정제, 당의정, 캡슐, 환제 및 과립의 고체 투여 형태는 약제학적 제형화 기술분야에 익히 공지된 장용피 및 기타 피막 등의 피막 및 쉘로 제조할 수 있다. 이는 임의로 불투명화제를 함유할 수 있으며, 지연된 방식으로 장관의 특정 부분에 활성 성분(들)만을 또는 이를 우선적으로 방출시키는 조성물일 수도 있다. 사용될 수 있는 내장 조성물의 예는 중합체성 물질 및 왁스를 포함한다.Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric and other coatings, which are well known in the pharmaceutical formulation art. It may optionally contain an opacifying agent and may also be a composition which releases only or preferentially the active ingredient (s) to a specific part of the intestine in a delayed manner. Examples of visceral compositions that can be used include polymeric substances and waxes.
경구 투여용 액체 투여 형태는 약제학적으로 허용되는 에멀션, 마이크로에멀션, 용액, 현탁액, 시럽 및 엘릭서를 포함한다. 본 발명의 화합물 외에, 액체 투여 형태는, 예를 들면, 물 및 기타 용매, 가용화제 및 유화제, 예를 들면, 에틸 알콜, 이소프로필 알콜, 에틸 카보네이트, 에틸 아세테이트, 벤질 알콜, 벤질 벤조에이트, 프로필렌 글리콜, 1,3-부틸렌 글리콜, 디메틸포름아미드, 오일(특히 면실유, 낙화생유, 옥수수유, 발아유, 올리브유, 피마자유 및 참깨유), 글리세롤, 테트라하이드로푸르푸릴 알콜, 폴리에틸렌 글리콜 및 소르비탄의 지방산 에스테르, 및 이들의 혼합물과 같은 당해 기술 분야에 통상적으로 사용되는 불활성 희석제를 함유할 수 있다.Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the compounds of the present invention, liquid dosage forms include, for example, water and other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene Glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germinated oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan Inert diluents commonly used in the art, such as fatty acid esters, and mixtures thereof.
불활성 희석제 외에, 경구 조성물은 습윤제, 유화제 및 현탁제, 감미제, 향미제 및 방향제를 포함할 수도 있다.In addition to inert diluents, oral compositions may also include humectants, emulsifiers and suspending agents, sweetening agents, flavoring agents, and fragrances.
본 발명의 화합물의 국소 투여 또는 경피 투여용 투여 형태는 연고, 페이스트, 크림, 로션, 겔, 분말, 용액, 스프레이, 흡입제 또는 패치를 포함한다. 활성 성분은 필요할 수 있는 정도의 약제학적으로 허용되는 담체와 어떠한 필요한 방부제 또는 완충제와 멸균 조건하에 혼합된다. 안구용 제형, 귀용 드롭제, 안용 연고, 분말 및 용액 또한 본 발명의 영역 내에 속하는 것으로 고려한다.Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier to the extent necessary and any necessary preservatives or buffers. Ocular formulations, ear drops, ointments, powders and solutions are also contemplated as being within the scope of this invention.
연고, 페이스트, 크림 및 겔은 본 발명의 화합물 외에도, 동물성 및 식물성 지방, 오일, 왁스, 파라핀, 전분, 트라가간트, 셀룰로스 유도체, 폴리에틸렌 글리콜, 실리콘, 벤토나이트, 규산, 탈크 및 산화아연 등의 부형제 또는 이들의 혼합물을 함유할 수 있다.Ointments, pastes, creams and gels, in addition to the compounds of the present invention, include excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanths, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids, talc and zinc oxide Or mixtures thereof.
분말 및 스프레이는 본 발명의 화합물 외에, 락토스, 탈크, 규산, 수산화알루미늄, 규산칼슘 및 폴리아미드 분말 등의 부형제 또는 이들 물질의 혼합물을 함유할 수 있다. 스프레이는 클로로플루오로하이드로카본 등의 통상적인 추진제를 추가로 함유할 수 있다.Powders and sprays may contain, in addition to the compounds of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these materials. The spray may further contain conventional propellants such as chlorofluorohydrocarbons.
본 발명의 화합물은 무기산 또는 유기산으로부터 유도된 약제학적으로 허용되는 염의 형태로 사용될 수 있다. 용어 "약제학적으로 허용되는 염"은 안전한 의학적 판단 영역 내에서 과도한 독성, 자극, 알레르기성 반응 등이 없이 포유동물, 특히 사람의 조직과 접촉하여 사용하기에 적합하고 합당한 이익/위험 비로 균형잡힌 염을 의미한다. 약제학적으로 허용되는 염은 당해 기술분야에 익히 공지되어 있다. 예를 들면, 문헌[참조: S.M. Berge, J. Pharmaceutical Sciences, 1977, 66: 1 et seq]에 약제학적으로 허용되는 염이 상세히 기재되어 있다. 당해 염은 본 발명의 화합물을 최종적으로 분리하거나 정제하는 동안 반응계 내에서 또는 유리 염기 관능기를 적합한 유기산과 반응시켜 개별적으로 제조할 수 있다. 대표적인 산 부가염으로는 이들로 한정하려는 것은 아니지만, 아세테이트, 아디페이트, 알기네이트, 시트레이트, 아스파르테이트, 벤조에이트, 벤젠설포네이트, 비설페이트, 부티레이트, 캄포레이트, 캄포설포네이트, 디글루코네이트, 글리세로포스페이트, 헤미설페이트, 헵타노에이트, 헥사노에이트, 푸마레이트, 하이드로클로라이드, 디하이드로클로라이드, 트리하이드로클로라이드, 하이드로브로마이드, 하이드로요오다이드, 2-하이드록시에탄설포네이트(이세테오네이트), 락테이트, 말레에이트, 메탄설포네이트, 니코티네이트, 2-나프탈렌설포네이트, 옥살레이트, 파모에이트, 펙티네이트, 퍼설페이트, 3-페닐프로피오네이트, 피크레이트, 피발레이트, 프로피오네이트, 석시네이트, 설페이트, 비스(타르트레이트), 타르트레이트, (L)-타르트레이트, 비스((L) 타르트레이트), (D) 타르트레이트, 비스((L) 타르트레이트), (DL) 타르트레이트, 비스((DL) 타르트레이트), 메소-타르트레이트, 비스(메소 타르트레이트), 티오시아네이트, 포스페이트, 글루타메이트, 비카보네이트, p-톨루엔설포네이트 및 운데카노에이트가 포함된다.The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The term “pharmaceutically acceptable salts” refers to salts that are suitable for use in contact with mammals, in particular human tissues, and at a reasonable benefit / risk ratio, without the presence of excessive toxicity, irritation, allergic reactions, etc., within safe medical judgment Means. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge, J. Pharmaceutical Sciences, 1977, 66: 1 et seq, describes pharmaceutically acceptable salts in detail. The salts can be prepared separately, either in the reaction system or by reacting the free base functional groups with a suitable organic acid during the final isolation or purification of the compounds of the present invention. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate , Glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, dihydrochloride, trihydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isetheonate) , Lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, Succinate, sulfate, bis (tartrate), tartrate, (L) -tartrate, ((L) tartrate), (D) tartrate, bis ((L) tartrate), (DL) tartrate, bis ((DL) tartrate), meso-tartrate, bis (meth tartrate) , Thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate.
본 발명의 바람직한 약제학적으로 허용되는 염은 비스((D) 타르트레이트), 비스((DL) 타르트레이트), 비스(브로마이드), 비스(설페이트), 비스(포스페이트), 푸마레이트 및 트리스(하이드로클로라이드)이다.Preferred pharmaceutically acceptable salts of the present invention are bis ((D) tartrate), bis ((DL) tartrate), bis (bromide), bis (sulfate), bis (phosphate), fumarate and tris (hydro Chloride).
본 발명의 가장 바람직한 약제학적으로 허용되는 염은 비스((L) 타르트레이트)이다.The most preferred pharmaceutically acceptable salt of the present invention is bis ((L) tartrate).
본원에서 사용되는 바와 같은 용어 "약제학적으로 허용되는 프로드럭" 또는 "프로드럭"은 과도한 독성, 자극, 알레르기성 반응 등이 없이, 안전한 의학적 판단의 영역 내에서 포유동물, 특히 사람의 조직과 접촉하여 사용하기에 적합하고 합당한 이익/위험 비로 균형잡히고 이의 의도하는 용도에 대해 유효한 본 발명의 화합물의 프로드럭을 나타낸다. 본 발명의 화합물의 프로드럭은 예를 들면, 혈중 가수분해에 의해 본 발명의 화합물로 생체내 전환시킬 수 있다. 문헌[참조: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987)]에 자세히 논의되어 있다. 예를 들면, RE가 알콕시카보닐, 알킬, 알킬카보닐, 아릴카보닐, 사이클로알킬카보닐, 헤테로사이클로카보닐 또는 (NZ1Z2)카보닐로 치환된 화학식 I의 화합물은 프로드럭이다. 특히, 이소부틸 2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸-1-카복실레이트; 2-[(4-피리딘-2-일피페라진- 1-일)메틸]-1-(피롤리딘-1-일카보닐)-1H-벤즈이미다졸; 및 N,N-디메틸-2-[(4-피리딘-2-일피페라진-1-일)메틸]-1H-벤즈이미다졸-1-카복스아미드가 화학식 I의 화합물의 프로드럭의 대표적인 예이다.As used herein, the term “pharmaceutically acceptable prodrug” or “prodrug” refers to contacting a mammal, in particular a human tissue, within the scope of safe medical judgment, without excessive toxicity, irritation, allergic reactions, or the like. To show a prodrug of a compound of the invention that is suitable for use, balanced at a reasonable benefit / risk ratio and effective for its intended use. Prodrugs of the compounds of the invention can be converted in vivo to the compounds of the invention, for example, by blood hydrolysis. See T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the ACS Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987). For example, a compound of Formula I wherein R E is substituted with alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclocarbonyl or (NZ 1 Z 2 ) carbonyl is a prodrug . In particular, isobutyl 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxylate; 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1- (pyrrolidin-1-ylcarbonyl) -1H-benzimidazole; And N, N-dimethyl-2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole-1-carboxamide is a representative example of a prodrug of a compound of formula (I) to be.
본원에 사용된 바와 같은 용어 "약제학적으로 허용되는 에스테르" 또는 "에스테르"는 생체내에서 가수분해하는 본 발명의 화합물의 에스테르를 말하며, 인체에서 신속하게 파괴되어 모체 화합물 또는 이의 염을 남기는 것들을 포함한다. 본 발명의 약제학적으로 허용되는 비독성 에스테르의 예는 C1 내지 C6 알킬 에스테르 및 C5 내지 C7 사이클로알킬 에스테르를 포함하지만, C1 내지 C4 알킬 에스테르가 바람직하다. 화학식 I의 화합물의 에스테르는 통상적인 방법에 따라 제조할 수 있다.As used herein, the term “pharmaceutically acceptable ester” or “ester” refers to an ester of a compound of the invention that hydrolyzes in vivo, including those that are rapidly destroyed in the human body, leaving the parent compound or a salt thereof. do. Examples of pharmaceutically acceptable non-toxic esters of the invention include C 1 to C 6 alkyl esters and C 5 to C 7 cycloalkyl esters, although C 1 to C 4 alkyl esters are preferred. Esters of compounds of formula (I) can be prepared according to conventional methods.
본원에서 사용된 바와 같은 용어 "약제학적으로 허용되는 아미드" 또는 "아미드"는 암모니아, 1급 C1 내지 C6 알킬 아민 및 2급 C1 내지 C6 디알킬 아민으로부터 유도된 본 발명의 비독성 아미드를 말한다. 2급 아민의 경우, 아민은 하나의 질소원자를 함유하는 5원 또는 6원 헤테로사이클의 형태일 수도 있다. 암모니아, C1 내지 C3 알킬 1급 아미드 및 C1 내지 C2 디알킬 2급 아미드로부터 유도된 아미드가 바람직하다. 화학식 I의 화합물의 아미드는 통상적인 방법에 따라 제조될 수 있다.As used herein, the term "pharmaceutically acceptable amide" or "amide" is a nontoxic of the present invention derived from ammonia, primary C 1 to C 6 alkyl amines and secondary C 1 to C 6 dialkyl amines. Refers to amide. In the case of secondary amines, the amine may be in the form of a five or six membered heterocycle containing one nitrogen atom. Preferred are amides derived from ammonia, C 1 to C 3 alkyl primary amides and C 1 to C 2 dialkyl secondary amides. Amides of compounds of formula (I) may be prepared according to conventional methods.
본 발명의 화합물의 국소 투여용 투여 형태는 분말, 스프레이, 연고 및 흡입제를 포함할 수 있다. 활성 화합물은 약제학적으로 허용되는 담체 및 필요할 수 있는 임의의 방부제, 완충제 또는 추진제와 멸균 상태하에 혼합된다. 안구용 배합물, 안용 연고, 분말 및 용제 또한 본 발명의 영역 내에서 고려된다.Dosage forms for topical administration of a compound of this invention may include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers or propellants that may be required. Eye formulations, ointments, powders and solvents are also contemplated within the scope of the present invention.
본 발명의 약제학적 조성물 중의 활성 성분의 실질적 투여 수준은 특정한 환자, 조성물 및 투여 형태에 대해 목적하는 치료적 반응을 달성하기에 유효한 본 발명의 화합물 또는 화합물들의 양을 수득할 수 있도록 변화시킬 수 있다. 선택된 투여 수준은 특정한 화합물의 활성, 투여 경로, 치료 상태의 중증도 및 치료되는 환자의 상태 및 이전 병력에 좌우된다. 그러나, 본 발명의 화합물의 용량을 목적하는 치료학적 효과를 달성하는 데 필요한 것보다 낮은 수준으로 출발하고 목적하는 효과가 달성될 때까지 용량을 점차적으로 증가시키는 것은 당해 기술분야의 기술범위 내에 있다.The actual level of administration of the active ingredient in the pharmaceutical composition of the present invention can be varied to obtain an amount of the compound or compounds of the present invention effective to achieve the desired therapeutic response for a particular patient, composition and dosage form. . The dosage level chosen depends on the activity of the particular compound, the route of administration, the severity of the condition of treatment and the condition and previous history of the patient being treated. However, it is within the skill in the art to start with a dose of a compound of the present invention at a lower level than necessary to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.
본 발명은, 예를 들면, 본 발명의 화합물에 프로드럭을 투여하고 후속적으로 본 발명의 화합물로 생체내 생전환시킴으로써 화학적으로 합성되거나 형성된 본 발명의 화합물을 고려한다.The present invention contemplates a compound of the invention that has been chemically synthesized or formed, for example, by administering a prodrug to a compound of the invention and subsequently bioconverting to the compound of the invention.
위의 치료 또는 기타 치료에 사용되는 경우, 본 발명의 화합물의 치료학적 유효량은 순수한 형태로 또는 이러한 형태가 약제학적으로 허용되는 염 또는 프로드럭 형태로 존재하는 형태로 사용될 수 있다. 또 다른 방법으로, 본 발명의 화합물은 하나 이상의 약제학적으로 허용되는 부형제와 배합하여 본 발명의 화합물 또는 화합물들을 함유하는 약제학적 조성물로서 투여할 수 있다. 본 발명의 화합물의 "치료학적 유효량"이라는 구문은 성 기능장애를 어떠한 의학적 치료에 적용 가능한 합당한 이익/위험 비에서 치료하기에 충분한 본 발명의 화합물 또는 화합물들의 양을 의미한다. 그러나, 본 발명의 화합물 또는 화합물들 및 이의 조성물의 총 1일 사용량은 안전한 의학적 판단의 영역 내에서 주치의에 의해 결정된다는 것이 이해된다. 임의의 특별한 환자에 대한 특정한 치료학적 유효 용량 수준은 치료되는 성 기능장애 및 성 기능장애의 중증도; 사용되는 본 발명의 화합물 또는 화합물들의 활성도; 사용되는 특정 조성물; 환자의 연령, 체중, 일반적인 건강, 성별 및 식이; 본 발명의 화합물 또는 화합물들의 투여 시간, 투여 경로 및 배설률; 치료 기간; 본 발명의 화합물 또는 화합물들과 함께 또는 동시에 사용되는 약제; 및 의학 기술분야에 익히 공지된 인자를 포함하는 다양한 인자에 좌우된다. 예를 들면, 목적하는 치료 효과를 달성하는 데 필요한 수준보다 낮은 수준에서 효능제의 용량을 시작하고 목적하는 효과가 달성될 때까지 용량을 점차적으로 증가시키는 것은 당해 기술분야에 익히 공지되어 있다.When used in the above treatment or other treatments, the therapeutically effective amounts of the compounds of the present invention may be used in pure form or in the form in which they are present in the form of pharmaceutically acceptable salts or prodrugs. Alternatively, the compounds of the present invention may be administered in combination with one or more pharmaceutically acceptable excipients as a pharmaceutical composition containing the compound or compounds of the present invention. The phrase “therapeutically effective amount” of a compound of the present invention means that the compound or amount of compounds of the present invention is sufficient to treat sexual dysfunction at a reasonable benefit / risk ratio applicable to any medical treatment. However, it is understood that the total daily usage of a compound or compounds of the present invention and compositions thereof is determined by the attending physician within the scope of safe medical judgment. Specific therapeutically effective dose levels for any particular patient may include the severity of the sexual and sexual dysfunction being treated; The activity of the compound or compounds of the invention used; The specific composition employed; The age, body weight, general health, sex and diet of the patient; The time of administration, route of administration, and rate of excretion of the compound or compounds of the invention; Duration of treatment; Medicaments used in combination or coincidental with the compound or compounds of the present invention; And various factors including factors well known in the medical arts. For example, it is well known in the art to start a dose of agonist at a level lower than necessary to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.
사람 또는 기타 포유동물에게 투여되는 본 발명의 화합물의 총 1일 용량은 약 0.001 내지 약 30mg/kg/일의 범위일 수 있다. 경구 투여를 위하여, 보다 바람직한 용량은 약 0.01 내지 약 10mg/kg/일의 범위일 수 있다. 설하 투여를 위하여, 보다 바람직한 용량은 약 0.001 내지 약 0.15mg/kg/일의 범위일 수 있다. 필요한 경우, 유효한 1일 용량은 투여를 목적으로 하는 다중 용량으로 나눌 수 있으며, 결과적으로 단일 용량 조성물은 1일 용량을 보충하는 이러한 양 또는 이의 부분량을 함유할 수 있다.The total daily dose of a compound of the invention administered to a human or other mammal may range from about 0.001 to about 30 mg / kg / day. For oral administration, more preferred doses may range from about 0.01 to about 10 mg / kg / day. For sublingual administration, more preferred doses may range from about 0.001 mg to about 0.15 mg / kg / day. If necessary, an effective daily dose may be divided into multiple doses for the purpose of administration, and consequently a single dose composition may contain such amounts or partial amounts thereof that supplement the daily dose.
Claims (112)
Applications Claiming Priority (7)
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US80353701A | 2001-03-09 | 2001-03-09 | |
US09/803,537 | 2001-03-09 | ||
US09/874,484 | 2001-06-05 | ||
US09/874,484 US20030008878A1 (en) | 2001-03-09 | 2001-06-05 | Benzimidazoles that are useful in treating sexual dysfunction |
US10/017,939 US20020169166A1 (en) | 2001-03-09 | 2001-12-14 | Benzimidazoles that are useful in treating sexual dysfunction |
US10/017,939 | 2001-12-14 | ||
PCT/US2002/007791 WO2002088093A1 (en) | 2001-03-09 | 2002-03-06 | Benzimidazoles that are useful in treating sexual dysfunction |
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KR100863147B1 true KR100863147B1 (en) | 2008-10-13 |
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WO1994022839A1 (en) * | 1993-03-30 | 1994-10-13 | Merck Sharp & Dohme Limited | Antipsychotic benzimidazole derivatives |
EP0882718A1 (en) * | 1995-12-28 | 1998-12-09 | Fujisawa Pharmaceutical Co., Ltd. | Benzimidazole derivatives |
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- 2002-03-06 KR KR1020037011948A patent/KR100863147B1/en not_active IP Right Cessation
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1994022839A1 (en) * | 1993-03-30 | 1994-10-13 | Merck Sharp & Dohme Limited | Antipsychotic benzimidazole derivatives |
EP0882718A1 (en) * | 1995-12-28 | 1998-12-09 | Fujisawa Pharmaceutical Co., Ltd. | Benzimidazole derivatives |
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TW200510374A (en) | 2005-03-16 |
KR20040067865A (en) | 2004-07-30 |
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