Analogs of 3,5-dihydroxypentanoate for bone formation 机翻标题: 暂无翻译,请尝试点击翻译按钮。

公开号/公开日
WO2016130181 A1 2016-08-18 [WO2016130181] / 2016-08-18
申请号/申请日
2015WO-US54692 / 2015-10-08
发明人
CHEN HUI-TING;HSIEH KUANG-CHAN;KAO CHAI-LIN;CHANG JE-KEN;HO MEI-LING;
申请人
HUANG ALICE;KAOHSIUNG MEDICAL UNIVERSITY;
主分类号
IPC分类号
A01N-037/00A61K-031/497A61K-038/00A61P-019/08
摘要
(WO2016130181) A method for treating low bone mineral density associated with osteopenia, osteoporosis, and other diseases is disclosed.  The method comprises administrating a composition comprising a 3,5-dihydroxypentanoic acid derivative according to Formula I to a mammal.  A compound of 3,5-dihydroxypentanoic acid derivative having a structure according to Formula I or Formula II is also disclosed.
机翻摘要
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地址
代理人
代理机构
;
优先权号
2015TW-0104625 2015-02-11
主权利要求
(WO2016130181) CLAIMS WHAT IS CLAIMED IS: 1. A method for treating low bone mineral density associated with osteopenia, osteoporosis, and other diseases, comprising: administrating a composition comprising a 3,5-dihydroxypentanoic acid derivative according to Formula I to a mammal, Formula I wherein X is one of nitrogen and carbon; R is one of hydrogen and Ci-C4alkyl group; Ra is one group selected from the following groups: (al) a Ci-Cio alkyl group, (a2) a substituted Ci-Cio alkyl group, (a3) a C3-C8cycloalkyl group, (a4) a substituted C3-C8cycloalkyl group, (a5) a phenylamino group, (a6) a substituted phenylamino group, (a7) a Q-Qo phenyl alkylamino group, (a8) a substituted Q-Qo phenyl alkylamino group, (a9) a bisphosphonate, (alO) tetracycline, (al l) an amino acid, (al2) an acidic oligopeptide, (al3) a bone-targeting peptide and (a 14) a bone affinity peptide, U-Lys(U)-Lys(U)-Gly-OH, wherein U is one selected from the group consisting of -Lys, -Lys-(Asp-NHAc)j, -NHAc, -Lys-(Asp-)k-NHAc and (Asp-NHAc)j, wherein J is 1 or 2, and K is an integer, 1≤K≤20; Rb is one selected from the group consisting of hydrogen, a substituted group, an acetyl group and an imaging moiety; The bond between Rf and Rh are single- or a double bond; Rh is one selected from the group consisting of compounds represented by Formulae (A), (B), (C), (D), (E) and (F),  Formula C) Formula (D)  Formula (E) Formula (F) Rk is a C1-C5 alkyl group; Rm is one of C1-C5 alkyl groups and a hydroxyl group; and Rn is one of C1-C5 alkyl groups and a hydroxyl group. 2. The method as claimed in Claim 1, wherein Ra is (a2) a substituted C1-C10alkyl group, and the substituted group is one selected from the group consisting of a C1-C10alkyl group, a Ci-Ci0alkoxy group, a C1-C5 alkoxycarbonyl group, a C C5acyloxyl group, a C3-C8cycloalkyl group, a phenyl group and a substituted phenyl group. 3. The method as claimed in Claim 1, wherein Ra is one selected from the group consisting of (a4) a substituted cycloalkyl group with C3-C8, (a6) a substituted phenylamino group and (a8) a substituted phenyl alkylamino group with Q-Qo, and the substituted group is one selected from the group consisting of an alkyl group with C C5, fluorine, chlorine, bromine, iodine, furan, a six-member aromatic ring with at least one oxygen atom, pyrrole and pyridine. 4. The method as claimed in Claim 1, wherein Ra is (a 12) acidic oligopeptides and is one selected from the group consisting of -Lys-(Asp)m-Lys-PEG, Aspmand Glun, wherein m and n are both integers from 1 to 10, inclusive, each Asp residue is one of D-Asp and L-Asp, and each Glu residue is one of D-Glu and L-Glu. 5. The method as claimed in Claim 1, wherein Ra is (al3) bone-targeting peptide which is one selected from the group consisting of Thr-Met-Arg-Asn-Pro-Ile-Thr-Ser-Leu-Ile-Ser-Val (SEQ ID NO: 1), Leu-Leu-Ala-Asp-Thr-Thr-His-His-Arg-Pro-Trp-Thr-Gly-Gly-Gly-Ser (SEQ ID NO: 2), Lys-Glu-Ile-Pro-Pro-Ile-Pro-Leu-Leu-Ala-Pro-Ser-Gly-Gly-Gly-Ser (SEQ ID NO: 3), Asn-Asn-Val-Ser-Gln-Lys-Trp-Gln-Gln-Arg-Leu-Ile-Gly-Gly-Gly-Ser (SEQ ID NO: 4), Asn-Ser-Met-Ile-Ala-His-Asn-Lys-Thr-Arg-Met-His-Gly-Gly-Gly-Ser (SEQ ID NO: 5), Gly-Ile-His-Val-Pro-Trp-Met-Pro-Pro-Val-Ala-Phe-Gly-Gly-Gly-Ser (SEQ ID NO: 6), Gln-Arg-Ser-T -Thr-Leu-Asp-Ser-Ala-Leu-Ser-Met-Gly-Gly-Glu-Ser (SEQ ID NO: 7), Ser-Gly-His-Gln-Leu-Leu-Leu-Asn-Lys-Met-Pro-Asn-Gly-Gly-Gly-Ser (SEQ ID NO: 8), Ser-Ser-Thr-Leu-Lys-Thr-Phe-Phe-Gly-Phe-Pro-Asp-Gly-Gly-Gly-Ser (SEQ ID NO: 9), Asp-Ser-Ser-Asn-Pro-Ile-Phe-Trp-Arg-Pro-Ser-Ser-Gly-Gly-Gly-Ser (SEQ ID NO: 10), Asn-Thr-Ser-His-Leu-Arg-Val-Lys-Leu-Pro-Thr-Pro-Gly-Gly-Gly-Ser (SEQ ID NO: 11), Ser-Gly-His-Gln-Leu-Leu-Leu-Asn-Lys-Met-Pro-Asn-Gly-Gly-Gly-Ser (SEQ ID NO: 12), Ala-Thr-T -Ser-His-His-Leu-Ser-Ser-Ala-Gly-Leu-Gly-Gly-Gly-Ser (SEQ ID NO: 13), Ser-Tyr-Ser-Gln-Met-Asp-Pro-Pro-Arg-Ser-Leu-Pro-Gly-Gly-Gly-Ser (SEQ ID NO: 14), Thr-Met-Arg-Asn-Pro-Ile-Thr-Ser-Leu-Ile-Ser-Val (SEQ ID NO: 15), Leu-Leu- Ala-Asp-Thr-Thr-His-His-Arg-Pro-Trp-Thr (SEQ ID NO: 16), Lys-Glu-Ile-Pro-Pro-Ile-Pro-Leu-Leu-Ala-Pro-Ser (SEQ ID NO: 17), Asn-Asn-Val-Ser-Gln-Lys-T -Gln-Gln-Arg-Leu-Ile (SEQ ID NO: 18), Asn-Ser-Met-Ile-Ala-His-Asn-Lys-Thr-Arg-Met-His (SEQ ID NO: 19), Gly-Ile-His-Val-Pro^-Met-Pro-Pro-Val-Ala-Phe (SEQ ID NO: 20), Gln-Arg-Ser^-Thr-Leu-Asp-Ser-Ala-Leu-Ser-Met (SEQ ID NO: 21), Ser-Gly-His-Gln-Leu-Leu-Leu-Asn-Lys-Met-Pro-Asn (SEQ ID NO: 22), Ser-Ser-Thr-Leu-Lys-Thr-Phe-Phe-Gly-Phe-Pro-Asp (SEQ ID NO: 23), Asp-Ser-Ser-Asn-Pro-Ile-Phe^-Arg-Pro-Ser-Ser (SEQ ID NO: 24), Asn-Tyr-Ser-His-Leu-Arg-Val-Lys-Leu-Pro-Thr-Pro (SEQ ID NO: 25), Ser-Gly-His-Gln-Leu-Leu-Leu-Asn-Lys-Met-Pro-Asn (SEQ ID NO: 26), Ala-Thr^-Ser-His-His-Leu-Ser-Ser-Ala-Gly-Leu (SEQ ID NO: 27), and Ser-Tyr-Ser-Gln-Met-Asp-Pro-Pro-Arg-Ser-Leu-Pro-Gly-Gly-Gly-Ser (SEQ ID NO: 28). 6. The method as claimed in Claim 1, wherein Ra is (al4) U-Lys(U)-Lys(U)-Gly-OH. 7. The method as claimed in Claim 1, wherein the composition is one of a pharmaceutical composition and a food composition. 8. A derivative compound of 3,5-dihydroxypentanoic acid having a structure according to Formula I, Formula I wherein X is one of nitrogen and carbon; R is one of hydrogen and C C4alkyl group; Ra is one group selected from the following groups: (al) a C Cio alkyl group, (a2) a substituted Ci-Ci0alkyl group, (a3) a C3-C8cycloalkyl group, (a4) a substituted C3-C8cycloalkyl group, (a5) a phenylamino group, (a6) a substituted phenylamino group, (a7) a Ci-Ci0phenyl alkylamino group, (a8) a substituted Ci-Ci0phenyl alkylamino group, (a9) a bisphosphonate, (alO) tetracycline, (al l) an amino acid, (al2) an acidic oligopeptide, (al3) a bone-targeting peptide and (a 14) a bone affinity peptide, U-Lys(U)-Lys(U)-Gly-OH, wherein U is one selected from the group consisting of -Lys, -Lys-(Asp-NHAc)j, -NHAc, -Lys-(Asp-)k-NHAc and (Asp-NHAc)j, wherein J is 1 or 2, and K is an integer, 1≤K≤20; Rb is one selected from the group consisting of hydrogen, a substituted group, an acetyl group and an imaging moiety; The bond between Rf and Rh are single- or a double bond; Rh is one selected from the group consisting of compounds represented by Formulae (A), (B), (C), (D), (E) and (F),  Formula (C) Formula (D)  Formula (E) Formula (F) Rk is a C C5alkyl group; Rm is one of C C5alkyl groups and a hydroxyl group; and Rn is one of C1-C5 alkyl groups and a hydroxyl group. 9. The compound as claimed in Claim 8, wherein Ra is (a2) a substituted C1-C10alkyl group, and the substituted group is one selected from the group consisting of a C1-C10alkyl group, a Ci-Ci0alkoxy group, a C1-C5 alkoxycarbonyl group, a C1-C5 acyloxyl group, a C3-C8cycloalkyl group, a phenyl group and a substituted phenyl group. 10. The compound as claimed in Claim 8, wherein Ra is one selected from the group consisting of (a4) a substituted cycloalkyl group with C3-C8, (a6) a substituted phenylamino group and (a8) a substituted phenyl alkylamino group with C1-C10, and the substituted group is one selected from the group consisting of an alkyl group with C1-C5, fluorine, chlorine, bromine, iodine, furan, a six-member aromatic ring with at least one oxygen atom, pyrrole and pyridine. 11. The compound as claimed in Claim 8, wherein Ra is (al2) acidic oligopeptides and is one selected from the group consisting of••I .ys--( As ):,,-·! .ys-Pi -X.L Aspmand GIun, wherein m and n are both integers from 1 to 10, inclusive, each Asp residue is one of D-Asp and L-Asp, and each Glu residue is one of D-Glu and L-Glu. 12. The compound as claimed in Claim 8, wherein Ra is (a 13) bone-targeting peptide which is one selected from the group consisting of Thr-Met-Arg-Asn-Pro-Ile-Thr-Ser-Leu-Ile-Ser-Val (SEQ ID NO: 1), Leu-Leu-Ala-Asp-Thr-Thr-His-His-Arg-Pro-Trp-Thr-Gly-Gly-Gly-Ser (SEQ ID NO: 2), Lys-Glu-Ile-Pro-Pro-Ile-Pro-Leu-Leu-Ala-Pro-Ser-Gly-Gly-Gly-Ser (SEQ ID NO: 3), Asn-Asn-Val-Ser-Gln-Lys-Trp-Gln-Gln-Arg-Leu-Ile-Gly-Gly-Gly-Ser (SEQ ID NO: 4), Asn-Ser-Met-Ile-Ala-His-Asn-Lys-Thr-Arg-Met-His-Gly-Gly-Gly-Ser (SEQ ID NO: 5), Gly-Ile-His-Val-Pro-Trp-Met-Pro-Pro-Val-Ala-Phe-Gly-Gly-Gly-Ser (SEQ ID NO: 6), Gln-Arg-Ser-T -Thr-Leu-Asp-Ser-Ala-Leu-Ser-Met-Gly-Gly-Glu-Ser (SEQ ID NO: 7), Ser-Gly-His-Gln-Leu-Leu-Leu-Asn-Lys-Met-Pro-Asn-Gly-Gly-Gly-Ser (SEQ ID NO: 8), Ser-Ser-Thr-Leu-Lys-Thr-Phe-Phe-Gly-Phe-Pro-Asp-Gly-Gly-Gly-Ser (SEQ ID NO: 9), Asp-Ser-Ser-Asn-Pro-Ile-Phe-Trp-Arg-Pro-Ser-Ser-Gly-Gly-Gly-Ser (SEQ ID NO: 10), Asn-Thr-Ser-His-Leu-Arg-Val-Lys-Leu-Pro-Thr-Pro-Gly-Gly-Gly-Ser (SEQ ID NO: 11), Ser-Gly-His-Gln-Leu-Leu-Leu-Asn-Lys-Met-Pro-Asn-Gly-Gly-Gly-Ser (SEQ ID NO: 12), Ala-Thr-T -Ser-His-His-Leu-Ser-Ser-Ala-Gly-Leu-Gly-Gly-Gly-Ser (SEQ ID NO: 13), Ser-Tyr-Ser-Gln-Met-Asp-Pro-Pro-Arg-Ser-Leu-Pro-Gly-Gly-Gly-Ser (SEQ ID NO: 14), Thr-Met-Arg-Asn-Pro-Ile-Thr-Ser-Leu-Ile-Ser-Val (SEQ ID NO: 15), Leu-Leu- Ala-Asp-Thr-Thr-His-His-Arg-Pro-Trp-Thr (SEQ ID NO: 16), Lys-Glu-Ile-Pro-Pro-Ile-Pro-Leu-Leu-Ala-Pro-Ser (SEQ ID NO: 17), Asn-Asn-Val-Ser-Gln-Lys-T -Gln-Gln-Arg-Leu-Ile (SEQ ID NO: 18), Asn-Ser-Met-Ile-Ala-His-Asn-Lys-Thr-Arg-Met-His (SEQ ID NO: 19), Gly-Ile-His-Val-Pro^-Met-Pro-Pro-Val-Ala-Phe (SEQ ID NO: 20), Gln-Arg-Ser^-Thr-Leu-Asp-Ser-Ala-Leu-Ser-Met (SEQ ID NO: 21), Ser-Gly-His-Gln-Leu-Leu-Leu-Asn-Lys-Met-Pro-Asn (SEQ ID NO: 22), Ser-Ser-Thr-Leu-Lys-Thr-Phe-Phe-Gly-Phe-Pro-Asp (SEQ ID NO: 23), Asp-Ser-Ser-Asn-Pro-Ile-Phe^-Arg-Pro-Ser-Ser (SEQ ID NO: 24), Asn-Tyr-Ser-His-Leu-Arg-Val-Lys-Leu-Pro-Thr-Pro (SEQ ID NO: 25), Ser-Gly-His-Gln-Leu-Leu-Leu-Asn-Lys-Met-Pro-Asn (SEQ ID NO: 26), Ala-Thr^-Ser-His-His-Leu-Ser-Ser-Ala-Gly-Leu (SEQ ID NO: 27), and Ser-Tyr-Ser-Gln-Met-Asp-Pro-Pro-Arg-Ser-Leu-Pro-Gly-Gly-Gly-Ser (SEQ ID NO: 28). 13. The compound as claimed in Claim 8, wherein Ra is (al4) U-Lys(U)-Lys(U)-Gly-OH. 14. A compound having a structure according to Formula II, Formula II  wherein Rt is one selected from the group consisting of a Ci-Cio alkyl group, a hydroxyl group, a Ci-Cio alkylamino group, -NH-(Ci-Ci0)alkyl-Rz, -NH-(Ci-C5)alkyl-0-(Ci-C5)alkyl-Rz, -NH-amino group; and Rz is one selected from the group consisting of a C Cio unsaturated alkyl group, a hydroxyl group, an amino group, furan, a six-membered aromatic ring with at least one oxygen atom, pyrrole and pyridine.
法律状态
(WO2016130181) LEGAL DETAILS FOR WO2016130181  Actual or expected expiration date=2018-08-11    Legal state=ALIVE    Status=PENDING     Event publication date=2015-10-08  Event code=WO/APP  Event indicator=Pos  Event type=Examination events  Application details  Application country=WO WOUS2015054692  Application date=2015-10-08  Standardized application number=2015WO-US54692     Event publication date=2016-08-18  Event code=WO/A1  Event type=Examination events  Published application with search report  Publication country=WO  Publication number=WO2016130181  Publication stage Code=A1  Publication date=2016-08-18  Standardized publication number=WO2016130181  LEGAL DETAILS FOR DESIGNATED STATE DE  Actual or expected expiration date=2017-08-12    Legal state=DEAD    Status=LAPSED   Corresponding cc:  Designated or member state=DE     Event publication date=2017-08-12  Event code=WO/NENP  Event type=Event indicating Not In Force  Non-entry into the national phase in: Corresponding cc:  Designated or member state=DE  LEGAL DETAILS FOR DESIGNATED STATE EP3256131  Actual or expected expiration date=2035-10-08    Legal state=ALIVE    Status=PENDING   Corresponding cc:  Designated or member state=EP Corresponding appl: EP15882260  Application date in the designated or member state=2015-10-08   Application number in the designated or member state=2015EP-0882260 Corresponding cc:  Designated or member state=EP Corresponding pat: EP3256131  Publication stage code in the designated or member state=A1  Publication date in the designated or member state=2017-12-20   Publication number in the designated or member state=EP3256131    Event publication date=2016-10-26  Event code=WO/121  Event type=Designated states  EP: The EPO has been informed by wipo that ep was designated in this application Corresponding cc:  Designated or member state=EP     Event publication date=2017-09-11  Event code=WO/REEP  Event indicator=Pos  Event type=Entry into national phase  Request for entry into the European phase Corresponding cc:  Designated or member state=EP  LEGAL DETAILS FOR DESIGNATED STATE JP  Actual or expected expiration date=2017-12-08    Legal state=DEAD    Status=LAPSED   Corresponding cc:  Designated or member state=JP Corresponding appl: JP2017542015    Event publication date=2017-08-10  Event code=WO/ENP  Event type=Entry into national phase  Entry into the national phase in: Corresponding cc:  Designated or member state=JP     Event publication date=2017-12-08  Event code=WO/NENP  Event type=Event indicating Not In Force  Non-entry into the national phase in: Corresponding cc:  Designated or member state=JP
专利类型码
A1
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