Analogues of neuropeptide y having proline substitution at position 34The present invention relates to novel analogues of neuropeptide Y, pharmaceutical compositions containing the same, pharmaceutical formulations containing the same, and method of treating diseases or conditions mediated by neuropeptide Y-receptor binding. More particularly, the present invention relates to novel analogues of neuropeptide Y having proline substitution at position 34 and other substitution(s) as defined herein that selectively bind to the neuropeptide Yl receptor subtype compared to the neuropeptide Y2 receptor subtype.The chemical compound of formula (i) (seq id no:2), or its officinal salt:(r 2r 3)-a 1-a 2-a 3-a 4-a 5-a 6-a 7-a 8-a 9-a 10-a 11-a 12-a 13-a 14-a 15-a 16-a 17-a 18-a 19-a 20-a 21-a 22-a 23-a 24-a 25-a 26-a 27-a 28-a 29-a 30-a 31-a 32-a 33-pro-a 35-a 36-a 37-r 1(i)wherein:a 1be tyr, (x 1, x 2, x 3, x 4, x 5) phe or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 2be pro, 3hyp, cis-3hyp, 4hyp or cis-4hyp; a 3be ser, abu, aib, ala, thr or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 4be lys, arg, harg, dab, dap, orn or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 5be pro, 3hyp, cis-3hyp, 4hyp or cis-4hyp; a 6be asp, aib, asn, gln, glu or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 7be asn, aib, gln or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 8be pro, 3hyp, cis-3hyp, 4hyp or cis-4hyp; a 9be gly, aib or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 10be glu, aib, asn, asp, gln or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 11be asp, aib, asn, gln, glu or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 12be ala, abu, aib, nva, val or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 13be pro, 3hyp, cis-3hyp, 4hyp or cis-4hyp; a 14be ala, abu, aib, nva, val or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 15be glu, aib, asn, asp, gln or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 16be asp, aib, asn, gln, glu or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 17be met, acc, aib, cha, ile, leu, hleu, nle, nva, tle, val or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 18be ala, abu, aib, nva, val or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 19be arg, harg, apc, dab, dap, lys, orn or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 20be tyr, (x 1, x 2, x 3, x 4, x 5) phe or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 21be tyr, (x 1, x 2, x 3, x 4, x 5) phe or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 22be ser, abu, aib, ala, thr or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 23be ala, abu, aib, nva, val or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 24be leu, acc, cha, ile, hleu, nle, nva, tle, val or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 25be arg, harg, dab, dap, lys, orn or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 26be his, 2pal, 3pal, 4pal or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 27be tyr, (x 1, x 2, x 3, x 4, x 5) phe or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 28be ile, acc, cha, leu, hleu, nle, nva, tle, val or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 29be asn, aib, gln or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 30be leu, acc, cha, ile, hleu, nle, nva, tle, val or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 31be ile, acc, cha, leu, hleu, nle, nva, tle, val or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 32be thr, aib, ser or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 33be arg, harg, dab, dap, lys, orn or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 35be arg, aic, apc, harg, dab, dap, lys, orn, nh 2phe, nh 2ch 2phe or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 36be tyr, aic, (x 1, x 2, x 3, x 4, x 5) phe or hn-ch ((ch 2) n-n (r 4r 5))-c (o); a 37be hn-ch ((ch 2) n-n (r 4r 5))-c (o) or by being deleted; r 1be oh, nh 2, (c 1-30) alkoxyl or nh-x 6-ch 2-x 7, x wherein 6be (c 1-40) alkyl or (c 2-40) alkenyl, and x wherein 7be h, oh, co 2h or c (o)-nh 2r 2and r 3be selected from independently of one another: h, (c 1-30) alkyl, (c 1-30) alkyl, (c mix 1-30) acyl group, (c 2-30) alkenyl, (c 2-30) alkynyl, aryl (c 1-30) alkyl, aryl (c 1-30) acyl group, substituted (c 1-30) alkyl, substituted (c 1-30) alkyl, substituted (c mix 2-30) acyl group, substituted (c 2-30) alkenyl, substituted (c 2-30) alkynyl, substituted aryl (c 1-30) alkyl and substituted aryl (c 1-30) acyl group; condition is to work as r 2be (c 1-30) acyl group, aryl (c 1-30) acyl group, substituted (c 2-30) acyl group or substituted aryl (c 1-30) during acyl group, r 3be h, (c 1-30) alkyl, (c 1-30) alkyl, (c mix 2-30) alkenyl, (c 2-30) alkynyl, aryl (c 1-30) alkyl, substituted (c 1-30) alkyl, substituted (c 1-30) alkyl, substituted (c mix 2-30) alkenyl, substituted (c 2-30) alkynyl or substituted aryl (c 1-30) alkyl; r 4and r 5be independently of one another: h, (c 1-40) alkyl, (c 1-40) alkyl, (c mix 1-40) acyl group, (c 2-40) alkenyl, (c 2-40) alkynyl, aryl (c 1-40) alkyl, aryl (c 1-40) acyl group, substituted (c 1-40) alkyl, substituted (c 1-40) alkyl, substituted (c mix 1-40) acyl group, substituted (c 2-40) alkenyl, substituted (c 2-40) alkynyl, substituted aryl (c 1-40) alkyl, substituted aryl (c 1-40) acyl group, (c 1-40) alkyl sulphonyl or c (nh)-nh 2, wherein work as r 4be (c 1-40) acyl group, aryl (c 1-40) acyl group, substituted (c 1-40) acyl group, substituted aryl (c 1-40) acyl group, (c 1-40) alkyl sulphonyl or c (nh)-nh 2the time, r then 5be h or (c 1-c 40) alkyl, (c 1-40) alkyl, (c mix 2-40) alkenyl, (c 2-40) alkynyl, aryl (c 1-40) alkyl, substituted (c 1-40) alkyl, substituted (c 1-40) alkyl, substituted (c mix 2-40) alkenyl, substituted (c 2-40) alkynyl or substituted aryl (c 1-40) alkyl; n is 1,2,3,4 or 5 independently of one another;x 1, x 2, x 3, x 4and x 5be independently of one another: h, f, cl, br, i, (c 1-10) alkyl, substituted (c 1-10) alkyl, aryl, substituted aryl, oh, ch 2nh 2, nh 2, no 2or cn; and condition is that this chemical com...
34번 위치에 프롤린 치환이 있는 뉴로펩타이드 Ｙ의 유사체본 발명은 신규한 뉴로펩타이드 Y 유사체, 이를 포함하는 약학 조성물, 이를 포함하는 약학 제형 및 뉴로펩타이드 Y-수용체의 결합에 의해 매개되는 질환 또는 증상의 치료 방법에 관한 것이다. 보다 상세하게는, 본 발명은 본원에서 정의된 바와 같이 34번 위치에 프롤린 치환과 그외 치환(들)이 있는, 뉴로펩타이드 Y2 수용체 서브타입과 비교하여 뉴로펩타이드 Y1 수용체 서브타입에 선택적으로 결합하는, 신규한 뉴로펩타이드 Y 유사체에 관한 것이다.식 (I)로 표시되는 화합물 (서열번호 2) 또는 그의 약제학적으로 허용가능한 염:(R2R3)-A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-Pro-A35-A36-A37-R1 (I)상기 식 (I)에서,A1은 Tyr, (X1,X2,X3,X4,X5)Phe, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A2는 Pro, 3Hyp, cis-3Hyp, 4Hyp, 또는 cis-4Hyp이고;A3는 Ser, Abu, Aib, Ala, Thr, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A4는 Lys, Arg, hArg, Dab, Dap, Orn, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A5는 Pro, 3Hyp, cis-3Hyp, 4Hyp, 또는 cis-4Hyp이고;A6는 Asp, Aib, Asn, Gln, Glu, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A7은 Asn, Aib, Gln, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A8은 Pro, 3Hyp, cis-3Hyp, 4Hyp, 또는 cis-4Hyp이고;A9은 Gly, Aib, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A10은 Glu, Aib, Asn, Asp, Gln, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A11은 Asp, Aib, Asn, Gln, Glu, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A12은 Ala, Abu, Aib, Nva, Val, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A13은 Pro, 3Hyp, cis-3Hyp, 4Hyp, 또는 cis-4Hyp이고;A14은 Ala, Abu, Aib, Nva, Val, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A15은 Glu, Aib, Asn, Asp, Gln, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A16은 Asp, Aib, Asn, Gln, Glu, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A17은 Met, Acc, Aib, Cha, Ile, Leu, hLeu, Nle, Nva, Tle, Val, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A18은 Ala, Abu, Aib, Nva, Val, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A19은 Arg, hArg, Apc, Dab, Dap, Lys, Orn, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A20은 Tyr, (X1,X2,X3,X4,X5)Phe, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A21은 Tyr, (X1,X2,X3,X4,X5)Phe, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A22는 Ser, Abu, Aib, Ala, Thr, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A23는 Ala, Abu, Aib, Nva, Val, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A24는 Leu, Acc, Cha, Ile, hLeu, Nle, Nva, Tle, Val, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A25는 Arg, hArg, Dab, Dap, Lys, Orn, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A26는 His, 2Pal, 3Pal, 4Pal, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A27은 Tyr, (X1,X2,X3,X4,X5)Phe, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A28은 Ile, Acc, Cha, Leu, hLeu, Nle, Nva, Tle, Val, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A29은 Asn, Aib, Gln, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A30는 Leu, Acc, Cha, Ile, hLeu, Nle, Nva, Tle, Val, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A31은 Ile, Acc, Cha, Leu, hLeu, Nle, Nva, Tle, Val, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A32는 Thr, Aib, Ser, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A33는 Arg, hArg, Dab, Dap, Lys, Orn, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A35는 Arg, Aic, Apc, hArg, Dab, Dap, Lys, Orn, NH2Phe, NH2CH2Phe, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A36는 Tyr, Aic, (X1,X2,X3,X4,X5)Phe, 또는 HN-CH((CH2)n-N(R4R5))-C(O)이고;A37은 HN-CH((CH2)n-N(R4R5))-C(O) 또는 생략되고;R1은 OH, NH2, (C1-30)알콕시, 또는 NH-X6-CH2-X7이되, 상기 X6는 (C1-40)알킬 또는 (C2-40)알케닐이고, 상기 X7은 H, OH, CO2H, 또는 C(O)-NH2이고;R2 및 R3는 각각 각 경우에 독립적으로, H, (C1-30)알킬, (C1-30)헤테로알킬, (C1-30)아실, (C2-30)알케닐, (C2-30)알키닐, 아릴(C1-30)알킬, 아릴(C1-30)아실, 치환된 (C1-30)알킬, 치환된 (C1-30)헤테로알킬, 치환된 (C2-30)아실, 치환된 (C2-30)알케닐, 치환된 (C2-30)알키닐, 치환된 아릴(C1-30)알킬 및 치환된 아릴(C1-30)아실로 이루어진 군으로부터 선택되되;단, R2가 (C1-30)아실, 아릴(C1-30)아실, 치환된 (C2-30)아실, 또는 치환된 아릴(C1-30)아실이면, R3는 H, (C1-30)알킬, (C1-30)헤테로알킬, (C2-30)알케닐, (C2-30)알키닐, 아릴(C1-30)알킬, 치환된 (C1-30)알킬, 치환된 (C1-30)헤테로알킬, 치환된 (C2-30)알케닐, 치환된 (C2-30)알키닐, 또는 치환된 아릴(C1-30)알킬이고;R4 및 R5는 각각 각 경우에 독립적으로, H, (C1-40)알킬, (C1-40)헤테로알킬, (C1-40)아실, (C2-40)알케닐, (C2-40)알키닐, 아릴(C1-40)알킬, 아릴(C1-40)아실, 치환된 (C1-40)알킬, 치환된 (C1-40)헤테로알킬, 치환된 (C1-40)아실, 치환된 (C2-40)알케닐, 치환된 (C2-40)알키닐, 치환된 아릴(C1-40)알킬, 치환된 아릴(C1-40)아실, (C1-40)알킬설포닐, 또는 C(NH)-NH2이되, R4가 (C1-40)아실, 아릴(C1-40)아실, 치환된 (C1-40)아실, 치환된 아릴(C1-40)아실, (C1-40)알킬설포닐, 또는 C(NH)-NH2이면, R5는 H 또는 (C1-C40)알킬, (C1-40)헤테로알킬, (C2-40)알케닐, (C2-40)알키닐, 아릴(C1-40)알킬, 치환된 (C1-40)알킬, 치환된 (C1-40)헤테로알킬, 치환된 (C2-40)알케닐, 치환된 (C2-40)알키닐, 또는 치환된 아릴(C1-40)알킬이고;n은 각 경우에 독립적으로, 1, 2, 3, 4, 또는 5이고;X1, X2, X3, X4, 및 X5는 각각 각 경우에 독립적으로, H, F, Cl, Br, I, (C1-10)알킬, 치환된 (C1-10)알킬, 아릴, 치환된 아릴, OH, CH2NH2, NH2, NO2, 또는 CN이되;단, 상기 화합물은 Arg, hArg, Lys, Orn, Dab, 또는 Dap은 아닌, HN-CH((CH2)n-N(R4R5))-C(O), Aib 및 Acc로 이루어진 군으로부터 선택되는 하나 이상의 아미노산을 포함한다.