CN100334109C - 胰高血糖素样肽-1的类似物 - Google Patents

胰高血糖素样肽-1的类似物 Download PDF

Info

Publication number
CN100334109C
CN100334109C CNB998141852A CN99814185A CN100334109C CN 100334109 C CN100334109 C CN 100334109C CN B998141852 A CNB998141852 A CN B998141852A CN 99814185 A CN99814185 A CN 99814185A CN 100334109 C CN100334109 C CN 100334109C
Authority
CN
China
Prior art keywords
hglp
seq
aib
ala
pal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CNB998141852A
Other languages
English (en)
Other versions
CN1342166A (zh
Inventor
董正欣
大卫·H·科伊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BEAUFOUR IPSEN PHARMA
Tulane University
Original Assignee
Research And Applications And Scientifiques Association Inc
Tulane University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Research And Applications And Scientifiques Association Inc, Tulane University filed Critical Research And Applications And Scientifiques Association Inc
Publication of CN1342166A publication Critical patent/CN1342166A/zh
Application granted granted Critical
Publication of CN100334109C publication Critical patent/CN100334109C/zh
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575Hormones
    • C07K14/605Glucagons
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/12Drugs for disorders of the urinary system of the kidneys
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/02Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/04Anorexiants; Antiobesity agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/48Drugs for disorders of the endocrine system of the pancreatic hormones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/04Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/12Antihypertensives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Obesity (AREA)
  • Cardiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Hematology (AREA)
  • Biophysics (AREA)
  • Rheumatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Molecular Biology (AREA)
  • Toxicology (AREA)
  • Genetics & Genomics (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Zoology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biochemistry (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Emergency Medicine (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pulmonology (AREA)

Abstract

本发明涉及胰高血糖素样肽-1的肽类似物、其药学上可接受的盐、用这些类似物治疗哺乳动物的方法以及其包含所述类似物的有用的药物组合物。

Description

胰高血糖素样肽-1的类似物
本发明涉及胰高血糖素样肽-1的肽类似物、其药学上可接受的盐、用这些类似物治疗哺乳动物的方法以及其包含所述类似物的有用的药物组合物。
胰高血糖素样肽-1(7-36)酰胺(GLP-1)(SEQ ID NO:1)是通过胰高血糖素前体前高血糖素的组织特异性翻译后加工在肠的L细胞中合成的(Varndell,J.M.等,《组织化学细胞化学杂志》,1985:33:1080-6)、并在进餐反应中释放到循环。GLP-1的血浆浓度从约15pmol/L空腹水平升至40pmol/L餐后峰值。已证实,对于升高血浆葡萄糖浓度,当口服给予葡萄糖时,血浆胰岛素的增加大概高于静脉内给药的三倍(Kreymann,B.等,Lancet 1987:2,1300-4)。这种胰岛素释放的饮食性增加,叫做肠促胰岛素作用,主要是体液性的,现在人们认为GLP-1是人的最有效的生理性肠促胰岛素。除了促胰岛素作用外,GLP-1还抑制胰高血糖素分泌、延迟胃排空(Wettergren A.等,《消化性疾病科学》1993:38:665-73)并可提高外周葡萄糖的利用(D’Alessio,D.A.等,《临床研究杂志》1994:93:2293-6)。
1994年,根据观察提出了GLP-1的治疗效能,即GLP-1的皮下(s/c)单剂量可使非胰岛素依赖性糖尿病(NIDDM)患者的餐后葡萄糖水平完全达到正常(Gutniak,M.K.等,《糖尿病治疗》1994:17:1039-44)。人们认为这种作用是通过增加胰岛素释放和减少胰高血糖素分泌来进行调节的。而且,已证实GLP-1的静脉内输注可延迟NIDDM患的餐后胃排空(Williams,B.等,《临床内分泌代谢杂志》1996:81:327-32)。与磺酰脲不同,GLP-1的促胰岛素作用依赖于血浆葡萄糖浓度(Holz,G.G.4th,等,《自然》1993:361:362-5)。因此,低血浆葡萄糖浓度时的GLP-1调节的胰岛素释放的减少可防止重度低血糖。这种结合作用使GLP-1具有超出其它目前用于治疗NIDDM的试剂的独特的潜在治疗优势。
许多研究表明,当给健康人使用时,GLP-1可有效地影响糖血(glycemic)水平以及胰岛素和胰高血糖素浓度(Orskov,C,《糖尿病学》(Diabetologia)35:701-711,1992;Holst,J.J.等,“GLP-1在胰高血糖素III的糖尿病治疗中的效能”,《实验药理学手册》,LefevbrePJ,Ed.Berlin,Springer Verlag,1996,p.311-326),这些作用是葡萄糖依赖性的(Kreymann,B.等,Lancet ii:1300-1304,1987;Weir,G.C.等,《糖尿病》38:338-342,1989)。而且,它对于糖尿病患者也是有效的(Gutni ak,M.,N.《英国医学杂志》226:1316-1322,1992;Nathan,D.M.等,《糖尿病治疗》15:270-276,1992),使II型糖尿病患者的血糖水平达到正常(Nauck,M.A.等,《糖尿病学)》(Diagbetologia)36:741-744,1993),和改善I型糖尿病患者的糖血(glycemic)控制(Creutzfeldt,W.O.等,《糖尿病治疗》19:580-586,1996),增加其用作治疗剂的可能性。
但是,GLP-1在代谢上是不稳定的,在体内的血浆半衰期(t1/2)仅为1-2分钟。外源性给药的GLP-1也会快速降解(Deacon,C.F.等,《糖尿病》44:1126-1131,1995)。这种代谢不稳定性限制了天然GLP-1的治疗效能。因此,需要一种较天然GLP-1更有效或代谢上更稳定的GLP-1类似物。
一方面,本发明涉及一种式(I)化合物,
(R2R3)-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-A34-A35-A36-A37-R1
(I)
其中:
A7为L-His,Ura,Paa,Pta,D-His,Tyr,3-Pal,4-Pal,Hppa,Tma-His,Amp,或删除,条件是当A7为Ura,Paa,Pta或Hppa时,则删除R2和R3
A8为Ala,D-Ala,Aib,Acc,N-Me-Ala,N-Me-D-Ala,Arg或N-Me-Gly;
A9为Glu,N-Me-Glu,N-Me-Asp或Asp;
A10为Gly,Acc,Ala,D-Ala,Phe或Aib;
A11为Thr或Ser;
A12为Phe,Acc,Aic,Aib,3-Pal,4-Pal,β-Nal,Cha,Trp或X1-Phe;
A13为Thr或Ser;
A14为Ser,Thr,Ala或Aib;
A15为Asp,Ala,D-Asp或Glu;
A16为Val,D-Val,Acc,Aib,Leu,Ile,Tle,Nle,Abu,Ala,D-Ala,Tba或Cha;
A17为Ser,Ala,D-Ala,Aib,Acc或Thr;
A18为Ser,Ala,D-Ala,Aib,Acc或Thr;
A19为Tyr,D-Tyr,Cha,Phe,3-Pal,4-Pal,Acc,β-Nal,Amp或X1-Phe;
A20为Leu,Ala,Acc,Aib,Nle,Ile,Cha,Tle,Val,Phe或X1-Phe;
A21为Glu,Ala或Asp;
A22为Gly,Acc,Ala,D-Ala,β-Ala或Aib;
A23为Gln,Asp,Ala,D-Ala,Aib,Acc,Asn或Glu;
A24为Ala,Aib,Val,Abu,Tle或Acc;
A25为Ala,Aib,Val,Abu,Tle,Acc,Lys,Arg,hArg,Orn,N-CH((CH2)nNR10R11))(O)HN-CH((CH2)e-X3)-C(O);
A26为Lys,Ala,3-Pal,4-Pal,Arg,hArg,Orn,Amp,HN-CH((CH2)nNR10R11))-C(O)或HN-CH((CH2)e-X3)-C(O);
A27为Glu,Ala,D-Ala或Asp;
A28为Phe,Ala,Pal,β-Nal,X1-Phe,Aic,Acc,Aib,Cha或Trp;
A29为Ile,Acc,Aib,Leu,Nle,Cha,Tle,Val,Abu,Ala,Tba或Phe;
A30为Ala,Aib,Acc或删除;
A31为Trp,Ala,β-Nal,3-Pal,4-Pal,Phe,Acc,Aib,Cha,Amp或删除;
A32为Leu,Ala,Acc,Aib,Nle,Ile,Cha,Tle,Phe,X1-Phe,Ala或删除;
A33为Val,Acc,Aib,Leu,Ile,Tle,Nle,Cha,Ala,Phe,Abu,X1-Phe,Tba,Gaba或删除;
A34为Lys,Arg,hArg,Orn,Amp,Gaba,HN-CH((CH2)n-NR10R11))-C(O),HN-CH((CH2)e-X3)-C(O)或删除;
A35为Gly或删除;
A36为L-或D-Arg,D-或L-Lys,D-或L-hArg,D-或L-Orn,Amp,HN-CH((CH2)n-NR10R11))-C(O),HN-CH((CH2)e-X3)-C(O)或删除;
A37为Gly或删除;
每次出现的X1分别选自(C1-C6)烷基,OH和卤素;
R1为OH,NH2,(C1-C12)烷氧基,或NH-X2-CH2-Z0,其中X2为(C1-C12)烃部分,Z0为H,OH,CO2H或CONH2
X3
Figure C9981418500071
或-C(O)-NHR12,其中每次出现的X4分别为-C(O)-,-NHC(O)-或-CH2-,其中每次出现的f分别为1-29的整数;
R2和R3各自分别选自H,(C1-C30)烷基,(C2-C30)链烯基,苯基(C1-C30)烷基,萘基(C1-C30)烷基,羟基(C1-C30)烷基,羟基(C2-C30)链烯基,羟苯基(C1-C30)烷基,和羟萘基(C1-C30)烷基;或R2和R3之一为C(O)X5,其中X5为(C1-C30)烷基,(C2-C30)链烯基,苯基(C1-C30)烷基,萘基(C1-C30)烷基,羟基(C1-C30)烷基,羟基(C2-C30)链烯基,羟苯基(C1-C30)烷基,羟萘基(C1-C30)烷基,
Figure C9981418500082
Figure C9981418500083
其中Y为H或OH,r为0-4,q为0-4;
每次出现的n分别是1-5的整数;和
每次出现的R10和R11分别是H,(C1-C30)烷基,(C1-C30)酰基,(C1-C30)烷基磺酰基,-C((NH(NH2))或
Figure C9981418500084
条件是当R10为(C1-C30)酰基,(C1-C30)烷基磺酰基,-C((NH)(NH2))或
Figure C9981418500085
R11为H或(C1-C30)烷基;以及
R12为(C1-C30)烷基;
条件是:
(i)至少一种式(I)化合物的氨基酸与hGLP-1(7-36,或-37)NH2(SEQIDNOS:1,2)或hGLP-1(7-36,或-37)OH(SEQID NOS:3,4)的天然序列不同;
(ii)式(I)化合物不是hGLP-1(7-36,或-37)NH2(SEQ ID NOS:1,2)或hGLP-1(7-36,-37)OH(SEQID NOS:3,4)的类似物,其中单个位置被Ala取代;
(iii)式(I)化合物不是[Lys26(Nε-链烷醇基)]hGLP-1(7-36,或-37)-E(SEQID NOS:5-8),[Lys34(Nε-链烷醇基)]hGLP-1(7-36,或-37)-E(SEQID NOS:9-12),[Lys26,34-双(Nε-链烷醇基)]hGLP-1(7-36,或-37)-E(SEQ IDNOS:13-16),[Arg26,Lys34(Nε-链烷醇基))hGLP-1(8-36,或-37)-E(SEQIDNOS:17-20),或[Arg26,34,Lys36(Nε-链烷醇基))hGLP-1(7-36,-37)-E,其中E为-OH或-NH2(SEQID NOS:21-24);
(iv)式(I)化合物不是Z1-hGLP-1(7-36,或-37)-OH,Z1-hGLP-1(7-36,或-37)-NH2,其中Z1选自:
(a)[Arg26](SEQID NOS:25-28),[Arg34](SEQ ID NOS:29-32),[Arg26,34](SEQ ID NOS:33-36),[Lys36](SEQ ID NOS:37-40),[Arg26,Lys36](SEQID NOS:41-44),[Arg34,Lys36](SEQID NOS:45-48),[D-Lys36],[Arg36](SEQID NOS:3,4,1,2),[D-Arg36],[Arg26,34,Lys36](SEQ ID NOS:49-52)或[Arg26,36,Lys34)(SEQ ID NOS:25-28);
(b)[Asp21](SEQID NOS:53-56);
(c)[Aib8](SEQID NOS:57-60),[D-Ala8]和[Asp9](SEQ ID NOS:61-64)中的至少一种;以及
(d)[Tyr7](SEQ ID NOS:65-68),(N-酰基-His7)(SEQ ID NOS:69-72),[N-烷基-His7],(N-酰基-D-His7)(SEQID NOS:73-76)或(N-烷基-D-His7);
(v)式(I)化合物不是(a)-(d)组所列出的取代物的任意两种的组合;以及
(vi)式(I)化合物不是(N-Me-Ala8)hGLP-1(8-36或-37)(SEQID NOS:77,78),[Glu15]hGLP-1(7-36或-37)(SEQ ID NOS:79,80),[Asp21]hGLP-1(7-36或-37)(SEQ ID NOS:53,54)或[Phe31]hGLP-1(7-36或-37)(SEQ ID NOS:81,82)。
刚才前面所述式(I)化合物的优选化合物为:其中A11为Thr;A13为Thr;A14为Ser、Aib或Ala;A17为Ser、Ala、Aib或D-Ala;A18为Ser、Ala、Aib或D-Ala;A21为Glu或Ala;A23为Gln、Glu或Ala;A27为Glu或Ala的化合物,或其药学上可接受的盐。
前面所述式(I)化合物的优选化合物为:其中A9为Glu,N-Me-Glu或N-Me-Asp;A12为Phe,Acc或Aic;A16为Val、D-Val、Acc、Aib、Ala、Tle或D-Ala;A19为Tyr、3-Pal、4-Pal或D-Tyr;A20为Leu,Acc、Cha、Ala或Tle;A24为Ala,Aib或Acc;A25为Ala,Aib,Acc,Lys,Arg,hArg,Orn,HN-CH((CH2)n-NHR10)-C(O);A28为Phe或Ala;A29为Ile、Acc或Tle;A30为Ala、Aib或删除;A31为Trp、Acc、3-Pal、4-Pal或删除;A32为Leu、Acc、Cha、Ala或删除;A33为Val、Acc、Ala、Gaba、Tle或删除的化合物,或其药学上可接受的盐。
前面所述式(I)化合物的优选化合物为:其中A8为Ala,D-Ala,Aib,A6c,A5c,N-Me-Ala,N-Me-D-Ala或N-Me-Gly;A10为Gly、Ala、D-Ala或Phe;A12为Phe,A6c或A5c;A16为Val、Ala、Tle、A6c、A5c或D-Val;A20为Leu,A6c,A5c、Cha、Ala或Tle;A22为Gly、Aib、β-Ala、L-Ala或D-ALa;A24为Ala或Aib;A29为Ile,A6c、A5c或Tle;A32为Leu,A6c,A5c、Cha、Ala或删除;A33为Val、A6c、A5c、Ala、Gaba、Tle或删除的化合物,或其药学上可接受的盐。
前面所述式(I)化合物的优选化合物为:其中R1为OH或NH2的化合物,或其药学上可接受的盐。
前面所述式(I)化合物的优选化合物或其药学上可接受的盐为:其中R2为H,R3为(C1-C30)烷基、(C2-C30)链烯基、(C1-C30)酰基、
式(I)化合物的最优选化合物为:
[D-Ala8,Ala17,22,23,27,3-Pal19,31,Gaba34]-GLP-1(7-34)NH2;[D-Ala8,23,27,3-Pal19,31]hGLP-1(7-35)-NH2;[Ala18,23,27,3-Pal19,31]hGLP-1(7-35)-NH2(SEQ ID NO:83);[Ala16,23,27,3-Pal19,31]hGLP-1(7-35)-NH2(SEQ ID NO:84);[Ala14,23,27,3-Pal19,31]hGLP-1(7-35)-NH2(SEQ ID NO:85);[Ala22,23,27,3-Pal19,31]hGLP-1(7-35)-NH2(SEQ ID NO:86);[Hppa7]hGLP-1(7-36)-NH2(SEQ ID NO:87);[Ala15,23,27,3-Pal19,31]hGLP-1(7-35)-NH2(SEQ ID NO:88);[Ala17,23,27,3-Pal19,31]hGLP-1(7-35)-NH2(SEQ ID NO:89);[Ala22,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2(SEQ ID NO:90);[Ala15,22,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2(SEQ ID NO:91);[Ala17,22,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2(SEQ ID NO:92);[Ala18,22,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2(SEQ ID NO:93);[Ala21,22,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2(SEQ ID NO:94);[Ala22,23,26,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2(SEQ ID NO:95);[Ala22,23,27,32,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2(SEQ ID NO:96);[Ala22,23,26,27,3-Pal19,31,Gaba33]hGLP-1(7-33)-NH2(SEQ ID NO:97);[Ala22,23,27,31,3-Pal19,Gaba33]hGLP-1(7-33)-NH2(SEQ ID NO:98);[Ala22,23,27,28,3-Pal19,31,Gaba33]hGLP-1(7-33)-NH2(SEQ ID NO:99);[Ala22,23,27,29,3-Pal19,31,Gaba33]hGLP-1(7-33)-NH2(SEQ ID NO:100);[Ala23,27,3-Pal19,31,Gaba33]hGLP-1(7-33)-NH2(SEQ ID NO:101);[Ala20,22,23,27,3-Pal19,31,Gaba33]hGLP-1(7-33)-NH2(SEQID NO:102);[Ala22,23,27,3-Pal19,31,Gaba33]hGLP-1(7-33)-NH2(SEQ ID NO:103);[Ala17,22,23,27,3-Pal19,31,Gaba33]hGLP-1(7-33)-NH2(SEQ ID NO:104);[D-Ala10,Ala22,23,27,3-Pal19,31,Gaba33]hGLP-1(7-33)-NH2;[D-Ala8,Ala17,23,27,3-Pal19,31]hGLP-1(7-34)-NH2;[Ala17,23,27,3-Pal19,26,31]hGLP-1(7-34)-NH2(SEQ ID NO:105);[D-Ala8,Ala17,3-Pal19,31]hGLP-1(7-34)-NH2;[Ala17,23,27,3-Pal19,31]hGLP-1(7-34)-NH2(SEQ IDNO:106);[D-Ala8,Ala17,23,27,3-Pal19,31,Tle29]hGLP-1(7-34)-NH 2;[D-Ala8,A la17,23,27,3-Pal19,31,Tle16]hGLP-1(7-34)-NH2;[D-Ala8,Ala17,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2;[D-Ala22,Ala17,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2;[Aib8,Ala17,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2(SEQ ID NO:107);[D-Ala8,Ala17,22,23,27,3-Pal19,31]hGLP-1(7-33)-NH2;[Aib8,Ala17,22,23,27,3-Pal19,31]hGLP-1(7-33)-NH2(SEQ IDNO:108);[Ala17,18,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2(SEQ ID NO:109);[Ala17,23,27,3-Pal19,31,Tle33,Gaba34]hGLP-1(7-34)-NH2(SEQ ID NO:110);[Tle16,Ala17,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2(SEQ ID NO:111);[N-Me-D-Ala8,Ala17,22,23,27,3-Pal19,31]hGLP-1(7-33)-NH2,[Aib8,Ala17,18,22,23,27,3-Pal19,31]hGLP-1(7-33)-NH2(SEQ ID NO:112);[Ala17,18,22,23,27,3-Pal19,31,Tle16,20,Gaba34]hGLP-1(7-34)-NH2(SEQ ID NO:113);[D-Ala8,Ala17,18,22,23,27,3-Pal19,31,Tle16,Gaba34]hGLP-1(7-34)-NH2;[D-Ala8,22,Ala17,18,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2;[D-Ala8,18,Ala17,22,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2;[D-Ala8,17,Ala18,22,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2;Or[D-Ala8,Ala17,18,22,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2;或其药学上可接受的盐。
式(I)化合物的另一最优选的化合物为:
[Aib8,A6c32]hGLP-1(7-36)NH2(SEQ ID NO:114);[A6c20,32]hGLP-1(7-36)-NH2(SEQID NO:115);[Aib8]hGLP-1(7-36)-NH2(SEQ ID NO:116);[(Tma-His)7]hGLP-1(7-36)-NH2(SEQ ID NO:117);[A6c8]hGLP-1(8-36)-NH2(SEQ ID NO:118);[A6c8]hGLP-1(7-36)-NH2(SEQ ID NO:119);[A6c16,20]hGLP-1(7-36)-NH2(SEQ ID NO:120);[A6c29,32]hGLP-1(7-36)-NH2(SEQ ID NO:121);[A6c20,Aib24]hGLP-1(7-36)-NH2(SEQ ID NO:122);[Aib24,A6c29,32]hGLP-1(7-36)-NH2(SEQ ID NO:123);[A6c16,29,32]hGLP-1(7-36)-NH2(SEQ ID NO:124);[Ura7]hGLP-1(7-36)-NH2(SEQ IDNO:125);[Paa7]hGLP-1(7-36)-NH2(SEQID NO:126);[Pta7]hGLP-1(7-36)-NH2(SEQ ID NO:127);[N-Me-Ala8]hGLP-1(7-36)-NH2(SEQ ID NO:128);[N-Me-Ala8]hGLP-1(8-36)-NH2;(SEQ ID NO.)[N-Me-D-Ala8]hGLP-1(7-36)-NH2;[N-Me-D-Ala8]hGLP-1(8-36)-NH2;[N-Me-Gly8]hGLP-1(7-36)-NH2(SEQ ID NO:129);[A5c8]hGLP-1(7-36)-NH2(SEQ ID NO:130);[N-Me-Glu9]hGLP-1(7-36)-NH2(SEQ IDNO:131);[A5c8,A6c20,32]hGLP-1(7-36)-NH2(SEQ ID NO:132);[Aib8,A6c32]hGLP-1(7-36)-NH2(SEQ ID NO:133);[Aib8,25]hGLP-1(7-36)-NH2(SEQ ID NO:134);[Aib8,24]hGLP-1(7-36)-NH2(SEQ ID NO:135);[Aib8,30]hGLP-1(7-36)-NH2(SEQ IDNO:136);[Aib8,Cha20]hGLP-1(7-36)-NH2(SEQ ID NO:137);[Aib8,Cha32]hGLP-1(7-36)-NH2(SEQ ID NO:138);[Aib8,Glu23]hGLP-1(7-36)-NH2(SEQ ID NO:139);[Aib8,A6c20]hGLP-1(7-36)-NH2(SEQ ID NO:140);[Aib8,A6c20,32]hGLP-1(7-36)-NH2(SEQ ID NO:141);[Aib8,22]hGLP-1(7-36)-NH2(SEQ ID NO:142);[Aib8,β-Ala22]hGLP-1(7-36)-NH2(SEQ ID NO:143);[Aib8,Lys25]hGLP-1(7-36)-NH2(SEQ IDNO:144);[Aib8,A6c12]hGLP-1(7-36)-NH2(SEQ ID NO:145);[Aib8,A6c29]hGLP-1(7-36)-NH2(SEQ ID NO:146);[Aib8,A6c33]hGLP-1(7-36)-NH 2(SEQID NO:147);[Aib8,14]hG LP-1(7-36)NH2(SEQ ID NO:148);[Aib8,18]hGLP-1(7-36)NH2(SEQ ID NO:149);or[Aib8,17]hGLP-1(7-36)NH 2(SEQ ID NO:150);或其药学上可接受的盐。另一方面,本发明提供了一种药物组合物,它包括有效量的上述式(I)化合物、或药学上可接受的盐和药学上可接受的载体或稀释剂。
还有一方面,本发明提供了一种从需要的患者的GLP-1受体中引起兴奋剂作用的方法,它包括给予上述患者有效量的上述式(I)化合物或其药学上可接受的盐。
另一方面,本发明提供了一种对需要的患者治疗其选自以下的疾病的方法,该疾病为I型糖尿病、II型糖尿病、肥胖、胰高血糖素瘤、导气管分泌性疾病、代谢性疾病、关节炎、骨质疏松、中枢神经系统疾病、再狭窄、神经变性疾病、肾脏衰竭、充血性心衰、肾病综合征、肝硬化、肺水肿、高血压和饮食摄入减少的疾病,这种方法包括给予上述患者有效量的上述式(I)化合物或其药学上可接受的盐。前面所述方法的优选是所治疗的疾病为I型糖尿病或II型糖尿病。
除了N-末端氨基酸外,本公开说明书中的所有氨基酸的缩写(如Ala)代表-NH-CH(R)-CO-的结构,其中R为氨基酸的侧链(如,Ala的CH3)。对于N-末端氨基酸,缩写代表(R2R3)-N-CH(R)-CO-的结构,其中R为氨基酸的侧链,R2和R3如上所述,除了当A7为Ura、Paa、Pta或Hppa时,由于认为Ura,Paa、Pta和Hppa是des-氨基酸,这种情况下R2和R3不存在。β-Nal、Nle、Cha、Amp、3-Pal、4-Pal和Aib分别是下列α氨基酸的缩写:β-(2-萘基)丙氨酸、正亮氨酸、环己基丙氨酸、4-氨基苯基丙氨酸、β-(3-吡啶基)丙氨酸、β-(4-吡啶基)丙氨酸和α-氨基异丁酸。其它氨基酸的定义为:Ura为尿刊酸;Pta为(4-吡啶基硫代)乙酸;Paa为反-3-(3-吡啶基)丙烯酸;Tma-His为N,N-四甲基脒基组氨酸;N-Me-Ala为N-甲基-丙氨酸;N-Me-Gly为N-甲基-甘氨酸;N-Me-Glu为N-甲基-谷氨酸;Tle为叔-丁基甘氨酸;Abu为α-氨基丁酸;Tba为叔-丁基丙氨酸;Orn为鸟氨酸;Aib为α-氨基异丁酸;β-Ala为β-丙氨酸;Gaba为γ-氨基丁酸;Ava为5-氨基戊酸;Aic为2-氨基-1,2-二氢化茚-2-羧酸。
Acc意指选自以下的氨基酸:1-氨基-1-环丙烷羧酸(A3c);1-氨基-1-环丁烷羧酸(A4c);1-氨基-1-环戊烷羧酸(A5c);1-氨基-1-环己烷羧酸(A6c);1-氨基-1-环庚烷羧酸(A7c);1-氨基-1-环辛烷羧酸(A8c);和1-氨基-1-环壬烷羧酸(A9c)。在上式中,羟烷基、羟苯基烷基和羟萘基烷基可含有1-4个羟基取代基。COX5代表-C=O·X5。C=O·X5的例子包括,但不限于,乙酰基和苯基丙酰基。
Lys(Nε-链烷醇基)意指下列结构:
Lys(Nε-烷基磺酰基)意指下列结构:
Figure C9981418500142
Lys(Nε-(2-(4-烷基-1-哌嗪)-乙酰基))意指下列结构:
Asp(1-(4-烷基-哌嗪))意指下列结构:
Figure C9981418500144
Asp(1-烷基氨基)意指下列结构:
Figure C9981418500145
前面结构中的变量n为1-30。
本文所用其它缩写的全名如下:Boc为叔丁氧基羰基,HF为氟化氢,Fm为甲酰基,Xan为呫吨基,Bzl为苄基,Tos为甲苯磺酰基,DNP为2,4-二硝基苯基,DMF为二甲基甲酰胺,DCM为二氯甲烷,HBTU为2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基六氟磷酸脲(uronium),DIEA为二异丙基乙胺,HOAc为乙酸,TFA为三氟乙酸,2CIZ为2-氯苄氧基羰基,OcHex为O-环己基。
本发明的肽在这也可表示为另一种形式,例如[A5c8]hGLP-1(7-36)NH2(SEQID NO:130)含有位于圆括号间的天然序列的取代氨基酸(如,hGLP-1中的Ala8的A5c8)。缩写GLP-1意指胰高血糖素样肽-1;hGLP-1意指人的胰高血糖素样肽-1。圆括号之间的数是指肽中的氨基酸数(例如,hGLP-1(7-36)(SEQID NO:3)是人GLP-1的肽序列的7-36氨基酸)。hGLP-1(7-37)(SEQID NO:4)的序列列在Mojsov,S.,《国际肽蛋白质研究杂志》(Int.J.Peptide Protein Res,.)40,1992,pp.333-342中。hGLP-1(7-36)NH2(SEQID NO:1)中的NH2表示肽的C-端被酰胺化。hGLP-1(7-36)(SEQID NO:2)表示C-端为游离酸。
本发明的肽可通过标准的固相肽合成法来制备,参见例如Stewart,J.M.等,《固相合成》(Pierce化学公司,第二版,1984)。上述通式的取代基R2和R3可通过本领域已知的标准方法与N-末端氨基酸的游离胺相连。例如,烷基基团,如(C1-C30)烷基,可通过还原烷基化作用连接。羟基烷基基团,如(C1-C30)羟基烷基,也可通过还原烷基化作用连接,其中游离羟基被叔丁基酯保护。酰基基团,如COE1,可通过偶联游离酸而连接,例如,E1COOH,通过在亚甲基氯化物中将完全树脂与3摩尔当量游离酸和二异丙基二亚胺碳混合1小时、而与N末端氨基酸的游离胺相连。如果游离酸包含游离羟基,例如对-羟苯基丙酸,则应该用另外3摩尔当量HOBT进行偶联。
当R1为NH-X2-CH2-CONH2时(即,Z0=CONH2),用与MBHA树脂偶联的BocHN-X2-CH2-COOH开始肽合成。如果R1为NH-X2-CH2-COOH时,(即,Z0=COOH),用与PAM树脂偶联的Boc-HN-X2-CH2-COOH开始肽合成。
以下描述了制备本发明肽的合成方法,该方法对于本领域技术人员来说是众所周知的。其它方法对于本领域技术人员来说也是已知的。
将氯离子形式的二苯甲基胺-聚苯乙烯树脂(Advanced ChemTech,Inc.,Louisville,KY)(0.9g,0.3mmole)置于计划要进行下列反应循环的高级ChemTech肽合成器200型的反应容器中:(a)二氯甲烷;(b)二氯甲烷中的33%三氟乙酸(2次,每次1分钟和15分钟);(c)二氯甲烷;(d)乙醇;(e)二氯甲烷;(f)二氯甲烷中的10%二异丙基乙基胺。
用Boc被护氨基酸和二氯甲烷中的二异丙基碳二亚胺(每一次3mmol)搅拌该中和树脂1小时,这种被护氨基酸是将要合成的肽的C末端氨基酸,然后将所得到的氨基酸树脂进行上述洗涤步骤(a)至(f)的循环。然后通过同样的方法将所需肽的其它氨基酸(3mmol)连续偶联。用下列方法将最终肽从树脂中裂解:即将其与茴香醚(5ml)、二硫苏糖醇(100mg)和无水氟化氢(35ml)在0℃混合并搅拌45分钟。在干氮气流下快速蒸发过量的氟化氢,沉淀出游离肽并用乙醚洗涤。然后将粗制肽溶解在最小体积的稀释乙酸中、在VYDAC十八烷基硅烷硅胶(10mM)柱(2.5×25cm)上洗脱、在0.1%三氟乙酸水溶液中用20-60%乙腈的线性梯度洗脱1小时以上。通过薄层层析和分析高效液相层析(1%/分钟的40-70%B,溶液B为含0.1%TFA的80%乙腈/水)检验各部分,混合得到最大纯度产品、而不是产率。从水中重复冷冻干燥该溶液得到白色绒状粉末产品。
通过HPLC分析肽产品。肽产品的酸水解液的氨基酸分析可证实肽的组分。将激光解吸MS用于测定肽的分子量。
按如下合成被护氨基酸1-[N-叔-丁氧基羰基-氨基]-1-环己烷羧酸(Boc-A6c-OH):将19.1g(0.133mol)的1-氨基-1-环己烷羧酸(AcrosOrganics,Fisher Scientific,Pittsburgh,PA)溶解在200ml二烷和100ml水中。在其中加入67ml的2N NaOH。将该溶液在冰水浴中冷却。在此溶液中加入32.0g(0.147mol)二-叔-丁基-碳酸氢盐。在室温下将反应混合物搅拌过夜。然后在减压下去除二烷。在剩余的水溶液中加入200ml乙酸乙酯。在冰水浴中冷却混合物。加入4N HCl将含水层的pH调至约3。分离有机层。用乙酸乙酯(1×100ml)提取含水层。混合两有机层并用水(2×150ml)洗涤,经无水MgSO4干燥、过滤、并在减压下浓缩至干。在乙酸乙酯/己烷中将残余物重结晶。得到9.2g纯产物。产率29%。
按与Boc-A6c-OH类似的方法合成Boc-A5c-OH。本领域普通技术人员可根据本文教导所指示的方法、按类似方式制备其它被护Acc氨基酸。
在本发明含A5c、A6c和/或Aib的肽的合成中,对于这些残余物和紧随其后的残余物,偶联时间为2小时。例如[Tma-His7]hGLP-1(7-36)NH2(SEQ IDNO:117)的合成,在最后的偶联反应中将4ml的DMF中的HBTU(2mmol)和DIEA(1.0ml)与肽-树脂的N末端游离胺反应,偶联时间约2小时。
上述缩写的全名如下:Boc为叔丁氧基羰基,HF为氟化氢,Fm为甲酰基,Xan为呫吨基,Bzl为苄基,Tos为甲苯磺酰基,DNP为2,4-二硝基苯基,DMF为二甲基甲酰胺,DCM为二氯甲烷,HBTU为2-(1 H-苯并三唑-1-基)-1,1,3,3-四甲基六氟磷酸脲(uronium),DIEA为二异丙基乙胺,HOAc为乙酸,TFA为三氟乙酸,2CIZ为2-氯苄氧基羰基,2BrZ为2-溴苄氧基羰基,OcHex为O-环己基。
上述通式的取代基R2和R3可通过本领域已知的标准方法与N-末端氨基酸的游离胺相连。例如,烷基基团,如(C1-C30)烷基,可通过还原烷基化作用连接。羟基烷基基团,如,(C1-C30)羟基烷基,也可通过还原烷基化作用连接,其中游离羟基被叔丁基酯保护。酰基基团,如,COX1,可通过偶联游离酸而连接,例如,X1COOH,通过在亚甲基氯化物中将完全树脂与3摩尔当量游离酸和二异丙基二亚胺碳混合1小时、而与N末端氨基酸的游离胺相连。如果游离酸包含游离羟基,例如对-羟苯基丙酸,则应该用另外3摩尔当量HOBT进行偶联。
根据下列方法可测定本发明化合物作为GLP-1结合化合物的活性。
细胞培养:
将表达GLP-1受体的RIN 5F大鼠胰岛瘤细胞(ATCC-#CRL-2058,美国模式培养物保藏所,Manassas,VA)在含10%胎牛血清的Dulbecco改进的Eagle培养基(DMEM)中培养,并在约37℃保持在5%CO2/95%空气的湿润大气中。
放射性配体结合:
采用Brinkman Polytron(Westbury,NY)(设为6、15秒)、通过RIN细胞在20ml冰冷的50 mM Tris-HCl中的均化制备用于放射性配体研究的膜。通过离心(39,000g/10分钟)洗涤匀浆两次,将最终的沉淀再悬浮在含2.5mM的MgCI2、0.1mg/ml杆菌肽(Sigma Chemical,St.Louis,MO)和0.1%BSA的50mM Tris-HCl中。为了测定,用含有或不含0.05ml未标记竞争试验肽的0.05nM[125I]GLP-1(7-36)(SEQID NO:151)(-2200Ci/mmol,NewEngland Nuclear,Boston,MA)培养等份部分(0.4ml)。培养100分钟(25℃)后,通过经GF/C滤纸(Brandel,Gaithersburg,MD)的快速过滤后从游离部分(free)分离出结合[125I]GLP-1(7-36)(SEQ ID NO:151),该滤纸之前在0.5%聚乙烯亚胺中浸湿。然后用5ml等份冰冷50mM Tris-HCl洗涤滤纸三次,通过γ光谱测定法(Wallac LKB,Gaithersburg,MD)计算残留在滤纸上的结合放射性。将特异性结合定义为总[125I]GLP-1(7-36)(SEQ IDNO:151)结合减去1000nM GLP1(7-36)(SEQID NO:3)中的结合(Bachem,Torrence,CA)。
本发明肽可以是药学上可接受的盐的形式。这些盐例如包括,但不限于,与有机酸(例如,醋酸、乳酸、马来酸、柠檬酸、苹果酸、抗坏血酸、琥珀酸、苯甲酸、甲磺酸、甲苯磺酸、或扑酸)形成的盐,与无机酸(例如,盐酸、硫酸、或磷酸)形成的盐,和与聚合酸(例如,鞣酸、羧甲基纤维素、聚乳酸、聚乙二醇酸、或聚乳酸-聚乙二醇酸的共聚物)形成的盐。制备本发明肽的盐的典型方法在本领域是公知的,它可通过标准的盐交换法来完成。因此,可以将本发明肽的TFA盐(采用制备HPLC、用含缓冲溶液的TFA洗脱对肽进行纯化而得到的TFA盐)转化成另一种盐,例如通过将肽溶解在少量0.25N醋酸水溶液中得到的醋酸盐。将所得到的溶液用于半制备柱(Zorbax,300 SB,C-8)。用下列溶液洗脱该柱:(1)0.1N醋酸铵水溶液洗脱0.5小时,(2)0.25N醋酸水溶液洗脱0.5小时,和(3)4ml/分钟流速的线性梯度(20%-100%溶液B,30分钟以上)(溶液A为0.25N醋酸水溶液;溶液B为80∶20的乙腈/水中的0.25N醋酸)。收集含肽的部分并冷冻至干。
如本领域技术人员所公知的,GLP-1的已知有效的用途是不同的且范围很广(参见,Todd,J.F.,等,《临床科学》,1998,95,pp.325-329;和Todd,J.F.等,《欧洲临床研究杂志》,1997,27,pp.533-536)。因此,为引起兴奋剂作用而给予本发明化合物可以产生同样效果,并可用作GLP-1。可以将GLP-1的这些不同用途总结如下,治疗:I型糖尿病、II型糖尿病、肥胖、胰高血糖素瘤、导气管分泌性疾病、代谢性疾病、关节炎、骨质疏松、中枢神经系统疾病、再狭窄、神经变性疾病。引起患者的拮抗剂作用的本发明的GLP-1类似物可用于治疗下列疾病:低血糖以及与胃切除术和小肠切除术有关的吸收障碍综合征。
因此,本发明包括其范围内的药物组合物,该组合物包括一种活性成分、至少一种式(I)化合物以及一种药学上可接受的载体或稀释剂。
本发明组合物中的活性成分的剂量可以不同;但是,活性成分的量必须能获得适当的剂型。所选择的剂量根据所需治疗效果、给药途径和治疗周期而改变。一般来说,本发明活性成分的有效量为1×10-7-200mg/kg/天,优选1×10-4-100mg/kg/天,可以单剂量给药或分成多剂量给药。
本发明化合物可以经口服、非肠道的(如,肌内、腹膜内、静脉内、或皮下注射、或植入)、鼻的、阴道的、直肠的、舌下的、或局部的给药途径进行给药,并可与药学上可接受的载体进行配制以提供适合于每一种给药途径的剂型。
口服的固体剂型包括胶囊、片剂、丸剂、粉剂和颗粒剂。在这些固体剂型中,将活性化合物与至少一种药学上可接受的惰性载体混合,该载体例如蔗糖、乳糖、或淀粉。这些剂型作为正常使用也可包括除惰性稀释剂外的其它物质,例如,润滑剂,如硬脂酸镁。在胶囊、片剂和丸剂中,这些剂型也可包括缓冲剂。片剂和丸剂可另外用肠衣制备。
口服的液体剂型包括药学上可接受的、含本领域通常使用的惰性稀释剂如水的乳剂、溶液、悬浮液、糖浆剂、酏剂。除了这些惰性稀释剂外,组合物也可包括辅助剂,例如润湿剂、乳化剂、悬浮剂、甜味剂、调味剂和香味剂。
本发明用于非肠道给药的制剂包括无菌水溶液或非水溶液、悬浮液或乳剂。非水溶剂或赋形剂例如丙二醇、聚乙二醇、植物油例如橄榄油和玉米油、明胶、可注射的有机酯例如油酸乙酯。这些剂型也可包含诸如防腐剂、润湿剂、乳化剂和分散剂之类的辅助剂。可以通过以下方法进行灭菌,例如经细菌存留过滤器过滤,在组合物中加入灭菌剂,照射组合物,或加热组合物。也可将它们制成无菌固体组合物的形式,使用前立即将其溶解在无菌水、或一些其它可注射的无菌介质中。
直肠或阴道给药的组合物优选栓剂,除了活性物质外,它可包含赋形剂,例如可可脂或栓剂蜡。
也可用本领域公知的标准赋形剂制备鼻或舌下给药的组合物。
另外,本发明化合物可以以持续释放组合物的形式给药,例如在下列专利和专利申请中所述,美国专利No.5,672,659公开了含生物活性剂和聚酯的持续释放组合物,美国专利No.5,595,760公开了含胶凝形式的生物活性剂的持续释放组合物,1997年9月9日提交的美国专利申请No.08/929,363公开了含生物活性剂和壳聚糖的聚合持续释放组合物,1996年11月1日提交的美国专利申请08/740,778公开了含生物活性剂和环糊精的持续释放组合物,1998年1月29日提交的美国专利申请09/015,394公开了含生物活性剂的可吸收持续释放组合物,1998年7月23日提交的美国专利申请No.09/12,653公开了一种在水包油过程中制备含诸如肽的治疗剂的微颗粒的方法,1998年8月10日提交的美国专利申请No.09/131,472公开了含诸如肽和磷酸化聚合物的治疗剂的复合体,1998年11月2日提交的美国专利申请No.09/184,413公开了含诸如肽和具有非可聚的内酯的聚合物的治疗剂的复合体。前面所述专利和申请的教导在此引作参考。
除非另有说明,本文所用的所有技术和科学术语的含义与本发明所属领域的普通技术人员通常理解的相同。还有,本文的所有出版物、专利申请、专利和其它参考资料在此引作参考。
下列实施例描述了制备本发明肽的合成方法,这些方法对于本领域技术人员来说是众所周知的。其它方法对于本领域技术人员来说也是公知的。这些实施例是为了举例说明、而不是以任何方式限定本发明的范围。
实施例1
[D-Ala8,Ala17,22,23,27,3-Pal19,31,Gaba34]-GLP-1(7-34)NH2
将氯离子形式的二苯甲基胺-聚苯乙烯树脂(Advanced ChemTechInc.,Louisville,KY)置于计划要进行下列反应循环的高级ChemTech肽合成器200型的反应容器中:(a)二氯甲烷;(b)二氯甲烷中的33%三氟乙酸(2次,每次1分钟和15分钟);(c)二氯甲烷;(d)乙醇;(e)二氯甲烷;(f)二氯甲烷中的10%二异丙基乙基胺。
用Boc-Gaba和二氯甲烷中的二异丙基碳二亚胺(每一次3mmol)搅拌该中和树脂1小时,然后将所得到的氨基酸树脂进行上述洗涤步骤(a)至(f)的循环。然后通过同样的方法将下列氨基酸(3mmol)连续偶联:Boc-Val,Boc-Leu,Boc-3-Pal,Boc-Ala,Boc-lle,Boc-Phe,Boc-Ala,Boc-Lys(2-Cl-Z),Boc-Ala,Glu(Bzl),Boc-Leu,Boc-3-Pal,Boc-Ser(Bzl),Boc-Ala,Boc-Val,Boc-Asp(Bzl),Boc-Ser(Bzl),Boc-Thr(Bzl),Boc-Phe,Boc-Thr(Bzl),Boc-Gly,Boc-Glu(Bzl),Boc-D-Ala,Boc-His(Bom)。
将具有完全肽序列的树脂与茴香醚(5ml)、二硫苏糖醇(100mg)和无水氟化氢(35ml)在0℃混合并搅拌45分钟。在干氮气流下快速蒸发过量的氟化氢,沉淀出游离肽并用乙醚洗涤。然后将粗制肽溶解在最小体积的稀释乙酸中、在VYDAC十八烷基硅烷硅胶(10mM)柱(2.5×25cm)上洗脱、并在0.1%三氟乙酸水溶液中用20-60%乙腈的线性梯度洗脱1小时以上。通过薄层层析和分析高效液相层析(1%/分钟的40-70%B,r.t.:14.1分钟)检验各部分,混合得到最大纯度产品、而不是产率。从水中重复冷冻干燥该溶液得到白色绒状粉末产品(49.9mg)。
通过HPLC和薄层色谱法证明该产品为均匀的。酸水解液的氨基酸分析可证实肽的组分。激光解吸MS得到分子量为2880(计算M+H 2873)。
实施例2
肽低级烷基酰胺的合成
用实施例1所述的Boc氨基酸方案将肽组合在O-苄基-聚苯乙烯树脂(通常叫做Merrifield树脂),除外用Fm(芴基甲基酯)基团保护Asp和Glu氨基酸羧基侧链。将完全肽--树脂悬浮在适当低级烷基胺(例如乙胺、丙胺、苯乙胺、1,2-乙二氨等)的稀释DMF溶液中、并于约60℃搅拌(约18小时),接着过滤、在减压下去除溶剂并用乙醚研制裂解的肽油得到固体的被护烷基胺肽。然后就其进行HF裂解以去除另外的侧链保护基团、并按实施例1所述进行HPLC纯化。
实施例3-5
大体上根据实施例1所述的方法、使用适当的保护氨基酸可合成实施例3-5的化合物,得到所述的肽:
实施例3:[Aib8,D-Ala17,Ala18,22,23,27,3-Pal19,31,Tle16,Gaba34]-GLP-1(7-34)NH2
实施例4:[Aib8,D-Ala17,Ala22,23,27,3-Pal19,31,Tle16]-GLP-1(7-33)NH2
实施例5:[Aib8,D-Ala17,Ala22,23,27,3-Pal19,31,Tle16,20]-GLP-1(7-33)NH2
实施例6-51
大体上根据实施例1所述的方法、但使用适当的保护氨基酸可制备实施例6-51的化合物,得到所述的肽。通过激光解吸MS得到MS(NA意指无法得到)。
实施例6:[D-Ala8,23,27,3-Pal19,31]hGLP-1(7-35)-NH2;MS=2971.0;计算值MW=2974.4;
实施例7:[Ala18,23,27,3-Pal19,31]hGLP-1(7-35)-NH2(SEQ ID NO:83);MS=2954.4;计算值MW=2958.4;
实施例8:[Ala16,23,27,3-Pal19,31]hGLP-1(7-35)-NH2(SEQ ID NO:84);MS=2943.0;计算值MW=2946.3;
实施例9:[Ala14,23,27,3-Pal19,31]hGLP-1(7-35)-NH2(SEQ ID NO:85);MS=2956.0;计算值MW=2958.4;
实施例10:[Ala22,23,27,3-Pal19,31]hGLP-1(7-35)-NH2(SEQ ID NO:86);MS=2981.0;计算值MW=2988.4;
实施例11:[Hppa7]hGLP-1(7-35)-NH2(SEQ ID NO:87);MS=NA
实施例12:[Ala15,23,27,3-Pal19,31]hGLP-1(7-35)-NH2(SEQ ID NO:88);MS=2928.0;计算值MW=2930.4;
实施例13:[Ala17,23,27,3-Pal19,31]hGLP-1(7-35)-NH2(SEQ ID NO:89);MS=2955.0;计算值MW=2958.4;
实施例14:[Ala22,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2(SEQ ID NO:90);MS=2896.0;计算值MW=2888.3;
实施例15:[Ala15,22,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2(SEQ ID NO:91);MS=2852.0;计算值MW=2844.3;
实施例16:[Ala17,22,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2(SEQ ID NO:92);MS=2880.0;计算值MW=2872.3;
实施例17:[Ala18,22,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2(SEQ ID NO:93);MS=2870.0;计算值MW=2872.3;
实施例18:[Ala21,22,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2(SEQ ID NO:94);MS=NA
实施例19:[Ala22,23,26,27,3-Pal19,31,Gaba37]hGLP-1(7-34)-NH2(SEQ ID NO:95);MS=2832.0;计算值MW=2831.2;
实施例20:[Ala22,23,27,32,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2(SEQ ID NO:96);MS=2855.0;计算值MW=2846.2;
实施例21:[Ala22,23,26,27,3-Pal19,31,Gaba33]hGLP-1(7-33)-NH2(SEQ ID NO:97);MS=2729.0;计算值MW=2732.0;
实施例22:[Ala22,23,27,31,3-Pal19,Gaba33]hGLP-1(7-33)-NH2(SEQ ID NO:98);MS=2711.6;计算值MW=2712.0;
实施例23:[Ala22,23,27,28,3-Pal19,31,Gaba33]hGLP-1(7-33)-NH2(SEQ ID NO:99);MS=2712.0;计算值MW=2713.0;
实施例24:[Ala22,23,27,29,3-Pal19,31,Gaba33]hGLP-1(7-33)-NH2(SEQ ID NO:100);MS=2746.9;计算值MW=2747.1;
实施例25:[Ala23,27,3-Pal19,31,Gaba33]hGLP-1(7-33)-NH2(SEQ ID NO:101);MS=2777.0;计算值MW=2775.1;
实施例26:[Ala20,22,23,27,3-Pal19,31,Gaba33]hGLP-1(7-33)-NH2(SEQ ID NO:102);MS=2742.0;计算值MW=2747.1;
实施例27:[Ala22,23,27,3-Pal19,31,Gaba33]hGLP-1(7-33)-NH2(SEQ ID NO:103);MS=2786.7;计算值MW=2789.1;
实施例28:[Ala17,22,23,27,3-Pal19,31,Gaba33]hGLP-1(7-33)-NH2(SEQ ID NO:104);MS=2771.0;计算值MW=2773.1;
实施例29:[D-Ala10,Ala22,23,27,3-Pal19,31,Gaba33]hGLP-1(7-33)-NH2;MS=2802.0;计算值MW=2803.2;
实施例30:[D-Ala8,Ala17,23,27,3-Pal19,31]hGLP-1(7-34)-NH2;MS=2905.0;计算值MW=2901.3;
实施例31:[Ala17,22,27,3-Pal19,26,31]hGLP-1(7-34)-NH2(SEQ ID NO:105);MS=2920.0;计算值MW=2921.3;
实施例32:[D-Ala8,Ala17,3-Pal19,31]hGLP-1(7-34)-NH2;MS=2908.0(Na+盐);计算值MW=2885.3;
实施例33:[Ala17,23,27,3-Pal19,31]hGLP-l(7-34)-NH2(SEQ ID NO:106);MS=2907.0;计算值MW=2901.3;
实施例34:[D-Ala8,Ala17,23,27,3-Pal19,31,Tle29]hGLP-1(7-34)-NH2;MS=2906.0;计算值MW=2901.3;
实施例35:[D-Ala8,Ala17,23,27,3-Pal19,31,Tle16]hGLP-1(7-34)-NH2;MS=2914.0;计算值MW=2915.4;
实施例36:[D-Ala8,Ala17,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2;MS=2856.8;计算值MW=2858.2;
实施例37:[D-Ala22,Ala17,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2;MS=2871.0;计算值MW=2872.3;
实施例38:[D-Ala8,Ala17,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2(SEQ IDNO:107);MS=2875.0;计算值MW=2872.3;
实施例39:[D-Ala8,Ala17,22,23,27,3-Pal19,31]hGLP-1(7-33)-NH2;MS=2786.0;计算值MW=2787.2;
实施例40:[Ala8,Ala17,22,23,27,3-Pal19,31]hGLP-1(7-33)-NH2(SEQ ID NO:108);MS=2800.0;计算值MW=2801.2;
实施例41:[Ala17,18,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2(SEQ ID NO:109);MS=2842.5;计算值MW=2842.2;
实施例42:[Ala17,23,27,3-Pal19,31,Tle33,Gaba34]hGLP-1(7-34)-NH2(SEQ IDNO:110);MS=2871.0;计算值MW=2872.3;
实施例43:[Tle16,Ala17,23,27,3-Pa19,31,Gaba34]hGLP-1(7-34)-NH2(SEQ IDNO:111);MS=2870.0;计算值MW=2872.3;
实施例44:[N-Me-D-Ala8,Ala17,22,23,27,3-Pal19,31]hGLP-1(7-33)-NH2;MS=2795.0;计算值MW=2801.2;
实施例45:[Aib8,Ala17,18,22,23,27,3-Pal19,31]hGLP-1(7-33)-NH2(SEQ ID NO:112);MS=2784.2;计算值MW=2785.2;
实施例46:[Ala17,18,22,23,27,3-Pal19,31,Tle16,20,Gaba34]hGLP-1(7-34)-NH2(SEQ IDNO:113);
MS=2871.9;计算值MW=2870.3;
实施例47:[D-Ala8,Ala17,18,22,23,27,3-Pal19,31,Tle16,Gaba34]hGLP-1(7-34)-NH2;MS=2870.0;计算值MW=2870.3;
实施例48:[D-Ala8,22,Ala17,18,22,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2;MS=2856.3;计算值MW=2856.3;
实施例49:[D-Ala8,18,Ala17,22,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2;MS=NA;
实施例50:[D-Ala8,17,Ala18,22,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2;MS=NA;
实施例51:[D-Ala8,Ala17,18,22,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2;MS=2861.6;计算值MW=2856.3。
实施例52
[Aib8,A6c32]hGLP-1(7-36)NH2(SEQ ID NO:114)
在应用生物系统(Foster City,CA)430A型肽合成器中合成标题肽,将该合成器改进以进行加速的Boc-化学固相合成。参见Schnolzer,等,《国际肽蛋白质研究杂志》40:180(1992)。使用含0.91mmol/g取代物的4-甲基二苯甲胺(MBHA)树脂(Peninsula,Belmont,CA)。使用具有下列保护侧链的Boc氨基酸(Bachem,CA,Torrance,CA;Nova Biochem.,LaJolla,CA):Boc-Ala-OH,Boc-Arg(Tos)-OH,Boc-Asp(OcHex)-OH,Boc-Tyr(2BrZ)-OH,Boc-His(DNP)-OH,Boc-Val-OH,Boc-Leu-OH,Boc-Gly-OH,Boc-Gln-OH,Boc-Ile-OH,Boc-Lys(2CIZ)-OH,Boc-Thr(Bzl)-OH,Boc-A6c-OH,Ser(Bzl)-OH,Boc-Phe-OH,Boc-Aib-OH,Boc-Glu(OcHex)-OH和Boc-Trp(Fm)-OH。在0.20mmol规模内进行合成。用100%TFA处理2×1分钟以去除Boc基团。在4ml DMF中用HBTU(2.0mmol)和DIEA(1.0ml)使Boc氨基酸(2.5mmol)预激活,并在没有前面所述的肽--树脂TFA盐的中和作用的情况下进行偶联。除了Boc-Aib-OH残基和Boc-A6c-OH残基、以及下列残基Boc-Trp(Fm)-OH和Boc-His(DNP)-OH的偶联时间为约2小时外,偶联时间均为约5分钟。
在肽链组合结束时,用DMF中的20%氢硫基乙醇/10%DIEA溶液处理树脂2×30分钟,以去除His侧链上的DNP基团。然后通过用100%TFA处理2×2分钟去除N-末端Boc基团。用DMF(1×1分钟)中的10%DIEA中和肽--树脂后,通过用15%乙醇胺/15%水/70%DMF溶液处理以去除侧链上的甲酰基基团。用DMF和DCM洗涤部分脱保护肽--树脂,并在减压下干燥。在0℃、通过在含1ml茴香醚和二硫苏糖醇(24mg)的10ml的HF中搅拌肽--树脂75分钟、以进行最终裂解。通过氮流去除HF。用乙醚(6×10ml)洗涤残余物、并用4N HOAc(6×10ml)提取。
在反相高效液相层析(HPLC)上用反相VYDACC18柱(Nest Group,Southborough,MA)纯化水提物中的肽混合物。用线性梯度(20%-50%溶液B,105分钟以上)以10ml/分钟的流速(溶液A=含0.1%TFA的水;溶液B=含0.1%TFA的乙腈)洗脱该柱。收集各部分并在分析HPLC上检测。混合含纯产物的那些部分并冷冻至干。得到92mg白色固体。根据分析HPLC分析纯度>99%。电喷射质谱学分析得到分子量为3324.2(计算分子量为3323.7)。
可以按实施例52所述的合成[Aib8,A6c32]hGLP-1(7-36)NH2(SEQ IDNO:114)的同样方法合成本发明的其它化合物,但根据所需的肽使用适当的被护氨基酸。
可按如下合成[(Naα-HEPES-His)7]hGLP-1(7-36)NH2(SEQ IDNO:152){HEPES为(4-(2-羟乙基)-1-哌嗪-乙烷磺酸)}:组合MBHA树脂(0.20mmol)上的肽长链后,用100%TFA处理肽--树脂(2×2分钟)并用DMF和DCM洗涤。然后用DMF中的10%DIEA中和该树脂2分钟。用DMF和DCM洗涤后,用DMF中的0.23mmol的2-氯-乙烷磺酰氯和0.7mmol的DIEA处理1小时。用DMF和DCM洗涤树脂、并用1.2mmol的2-羟乙基哌嗪处理约2小时。在最终肽从树脂的HF裂解之前,用DMF和DCM洗涤树脂、并用不同试剂((1)DMF中的20%氢硫基乙醇/10%DIEA和(2)15%乙醇胺/15%水/70%DMF)处理以去除上述His侧链上的DNP基团和Trp侧链上的甲酰基基团。
除了用2-溴乙酸酐代替2-氯-1-乙烷磺酰氯外,可大体上按上述制备[(Naα-HEPES-His)7]hGLP-1(7-36)NH2(SEQ ID NO:152)的方法制备[(Naα-HEPA-His)7]hGLP-1(7-36)NH2(SEQID NO:153)([(4-(2-羟乙基)-1-哌嗪乙酰基)-His)7]hGLP-1(7-36)NH2
实施例53-90和104
使用适当的被护氨基酸、大体上按实施例52所述的方法制备实施例53-90和104的化合物。
实施例53:[A6c20,32]hGLP-1(7-36)-NH2(SEQ ID NO:115);MS=3322.3;计算值MW=3321.7;
实施例54:[Aib8]hGLP-1(7-36)-NH2(SEQ ID NO:116);MS=3311.7;计算值MW=3311.7;
实施例55:[(Tma-His)7]hGLP-1(7-36)-NH2(SEQ ID NO:117);MS=3395.9;计算值MW=3396.9;
实施例56:[A6c8]hGLP-1(8-36)-NH2(SEQ ID NO:118);MS=3214.5;计算值MW=3214.7;
实施例57:[A6c8]hGLP-1(7-36)-NH2(SEQ ID NO:119);MS=3351.5;计算值MW=3351.8;
实施例58:[A6c16,20]hGLP-1(7-36)-NH2(SEQ ID NO:120);MS=3335.9;计算值MW=3335.8;
实施例59:[A6c29,32]hGLP-1(7-36)-NH2(SEQ ID NO:121);MS=3321.7;计算值MW=3321.7;
实施例60:[A6c20,Aib24]hGLP-1(7-36)-NH2(SEQ ID NO:122);MS=3323.6;计算值MW=3323.7;
实施例61:[Aib24,A6c29,32]hGLP-1(7-36)-NH2(SEQ ID NO:123);MS=3335.7;计算值MW=3335.8;
实施例62:[A6c16,29,32]hGLP-1(7-36)-NH2(SEQ ID NO:124);MS=3347.7;计算值MW=3347.8;
实施例63:[Ura7]hGLP-1(7-36)-NH2(SEQ ID NO:125);MS=3279.5;计算值MW=3280.7;
实施例64:[Paa7]hGLP-1(7-36)-NH2(SEQ ID NO:126);MS=3290.9;计算值MW=3291.8;
实施例65:[Pta7]hGLP-1(7-36)-NH2(SEQ ID NO:127);MS=3311.2;计算值MW=3311.8;
实施例66:[N-Me-Ala8]hGLP-1(7-36)-NH2(SEQ ID NO:128);MS=3311.4;计算值MW=3311.7;
实施例67:[N-Me-D-Ala8]hGLP-1(7-36)-NH2;MS=3311.6;计算值MW=3311.7;
实施例68:[N-Me-D-Ala8]hGLP-1(8-36)-NH2;MS=3174.0;计算值MW=3174.6;
实施例69:[N-Me-Gly8]hGLP-1(7-36)-NH2(SEQ ID NO:129);MS=3297.3;计算值MW=3297.7;
实施例70:[A5c8]hGLP-1(7-36)-NH2(SEQ ID NO:130);MS=3337.3;计算值MW=3337.8;
实施例71:[N-Me-Glu9]hGLP-1(7-36)-NH2(SEQ ID NO:131);MS=3311.4;计算值MW=3311.7;
实施例72:[A5c8,A6c20,32]hGLP-1(7-36)-NH2(SEQ ID NO:132);MS=3361.4;计算值MW=3361.8;
实施例73:[Aib8,A6c32]hGLP-1(7-36)-NH2(SEQ ID NO:133);MS=3323.2;计算值MW=3323.7;
实施例74:[Aib8,25]hGLP-1(7-36)-NH2(SEQ ID NO:134);MS=3325.8;计算值MW=3325.7;
实施例75:[Aib8,24]hGLP-1(7-36)-NH2(SEQ ID NO:135);MS=3325.8;计算值MW=3325.7;
实施例76:[Aib8,30]hGLP-1(7-36)-NH2(SEQ ID NO:136);MS=3326.1;计算值MW=3325.7;
实施例77:[Aib8,Cha20]hGLP-1(7-36)-NH2(SEQ ID NO:137);MS=3351.8;计算值MW=3351.8;
实施例78:[Aib8,Cha32]hGLP-1(7-36)-NH2(SEQ ID NO:138);MS=3352.0;计算值MW=3351.8;
实施例79:[Aib8,Glu23]hGLP-1(7-36)-NH2(SEQ ID NO:139);MS=3311.7;计算值MW=3312.7;
实施例80:[Aib8,A6c20]hGLP-1(7-36)-NH2(SEQ ID NO:140);MS=3323.6;计算值MW=3323.7;
实施例81:[Aib8,A6c20,32]hGLP-1(7-36)-NH2(SEQ ID NO:141);MS=3335.3;计算值MW=3335.7;
实施例82:[Aib8,22]hGLP-1(7-36)-NH2(SEQ ID NO:142);MS=3339.8;计算值MW=3339.8;
实施例83:[Aib8,β-Ala22]hGLP-1(7-36)-NH2(SEQ ID NO:143);MS=3325.6;计算值MW=3325.8;
实施例84:[Aib8,Lys25]hGLP-1(7-36)-NH2(SEQ ID NO:144);MS=3369.0;计算值MW=3368.8;
实施例85:[Aib8,A6c12]hGLP-1(7-36)-NH2(SEQ ID NO:145);MS=3289.8;计算值MW=3289.7;
实施例86:[Aib8,A6c29]hGLP-1(7-36)-NH2(SEQ ID NO:146);MS=3323.9;计算值MW=3323.7;
实施例87:[Aib8,A6c33]hGLP-1(7-36)-NH2(SEQ ID NO:147);MS=3338.0;计算值MW=3337.8;
实施例88:[Aib8,14]hGLP-1(7-36)-NH2(SEQ ID NO:148);MS=3309.8;计算值MW=3309.7;
实施例89:[Aib8,18]hGLP-1(7-36)-NH2(SEQ ID NO:149);MS=3309.7;计算值MW=3309.7;
实施例90:[Aib8,17]hGLP-1(7-36)-NH2(SEQ ID NO:150);MS=3309.4;计算值MW=3309.7;
实施例104:[Aib8,D-Arg26]hGLP-1(7-36)-NH2(SEQ ID NO:149);MS=3310.7;计算值MW=3311.73。
实施例91
[Aib8,A5c33]hGLP-1(7-36)NH2(SEQ ID NO:154)
使用适当的被护氨基酸、大体上按实施例52所述的方法制备标题化合物。
实施例92
[Ai b8,A6c32,Lys36(Nε-十四烷酰基)]hGLP-1(7-36)NH2(SEQ ID NO:155)
除了使用了用于Lys36(Nε-十四烷酰基)残基的Fmoc-Lys(Boc)-OH外,所用的Boc氨基酸与[Aib8,A6c32]hGLP-1(7-36)NH2(SEQ ID NO:114)(实施例52)合成中的相同。在摇动器中手工将第-氨基酸残基与树脂偶联。将2.5mmol的Fmoc-Lys(Boc)-OH溶解在DMF中的4ml的0.5N HBTU中。在溶液中加入1ml的DIEA。摇动混合物约2分钟。然后在溶液中加入0.2mmol MBHA树脂(取代物=0.91mmol/g)。摇动该混合物约1小时。用DMF洗涤该树脂、并用100%TFA处理2×2分钟以去除Boc保护基团。用DMF洗涤树脂。用4mlDMF中的HBTU(2.0mmol)和DIEA(1.0ml)使豆蔻酸(2.5mmol)预激活2分钟、并与Fmoc-Lys-树脂偶联。偶联时间约1小时。用DMF洗涤树脂、并用DMF中的25%哌啶处理2×20分钟、以去除Fmoc保护基团。用DMF洗涤树脂、并转移至肽合成器的反应容器中。肽合成和纯化的余下步骤与[Aib8,A6c32]hGLP-1(7-36)NH2(SEQ ID NO:114)的合成相同。
含Lys(Nε-链烷醇基)残基的本发明其它化合物的合成可以按照类似[Aib8,A6c32,Lys36(Nε-十四烷酰基]hGLP-1(7-36)NH2(SEQ ID NO:155)的合成方法进行。Fmoc-Lys(Boc)-OH氨基酸用于肽的Lys(Nε-链烷醇基)残基,而Boc-Lys(2CIZ)-OH氨基酸用于Lys残基。如果Lys(Nε-(链烷醇基)残基不在C末端,首先在肽合成器中应将正好在Lys(Nε-链烷醇基)残基之前的肽片段组合在树脂上。
实施例93-98
使用适当的氨基酸、大体上按照实施例92所述的方法制备实施例93-98化合物。
实施例93:[Aib8,A6c32,Lys36(Nε-十四烷酰基)]hGLP-1(7-36)-NH2(SEQ IDNO:155);
实施例94:[Aib8,Arg26,34,A6c32,Lys36(Nε-十四烷酰基)]hGLP-1(7-36)-NH2(SEQID NO:156);
实施例95:[Aib8,Arg26,A6c32,Lys34(Nε-十四烷酰基)]hGLP-1(7-36)-NH2(SEQID NO:157);
实施例96:[Aib8,Lys26(Nε-十四烷酰基),A6c32,Arg34]hGLP-1(7-36)-NH2(SEQID NO:158);
实施例97:[Aib8,Lys36(Nε-辛酰基)]hGLP-1(7-36)-NH2(SEQ ID NO:159);
实施例98:[Aib8,A6c20,32,Lys36(Nε-辛酰基)]hGLP-1(7-36)-NH2(SEQ IDNO:160)。
实施例99
[Aib8,Arg26,34,A6c32,Lys36(Nε-十四烷酰基)]hGLP-1(7-36)-OH(SEQ ID NO:161)
所用的Boc氨基酸与[Aib8,A6c32,Lys36(Nε-十四烷酰基)]hGLP-1(7-36)-NH2(SEQ ID NO:162)(实施例92)合成中的相同。用DMF(4ml)中的HBTU(2.0mmol)和DIEA(2.5 ml)使Fmoc-Lys(Boc)-OH(2.5mmol)预激活约2分钟。在摇动器上手工将这种氨基酸与235mg的PAM树脂(Chem-Impex,Wood Dale,IL;取代物=0.85mmol/g)偶联。偶联时间约8小时。肽合成和纯化的余下步骤与实施例52所述的相同。
含Lys(Nε-(链烷醇基)残基的hGLP-1(7-36)-OH(SEQ ID NO:3)和hGLP-1(7-37)-OH(SEQID NO:4)的合成按照类似[Aib8,Arg26,34,A6c32,Lys 36(Nε-十四烷酰基]hGLP-1(7-36)OH(SEQ ID NO:161)的合成方法进行。Fmoc-Lys(Boc)-OH氨基酸用于肽的Lys(Nε-链烷醇基)残基,而Boc-Lys(2CIZ)-OH氨基酸用于Lys残基。
实施例100-103
使用适当的氨基酸、大体上按照实施例99所述的方法制备实施例100-103化合物。
实施例100:[Aib8,Arg26,A6c32,Lys34(Nε-十四烷酰基)]hGLP-1(7-36)-OH(SEQID NO:162);
实施例101:[Aib8,Lys 26(Nε-十四烷酰基),A6c32,Arg34]hGLP-1(7-36)-OH(SEQID NO:163);
实施例102:[Aib8,Arg26,34,A6c32,Lys36(Nε-十四烷酰基)]hGLP-1(7-37)-OH(SEQ ID NO:164);
实施例103:[Aib8,Arg26,A6c32,Lys34(Nε-十四烷酰基)]hGLP-1(7-37)-OH(SEQID NO:165)。

Claims (5)

1.下列化合物或其药学上可接受的盐:
[Ala18,23,27,3-Pal19,31]hGLP-1(7-35)-NH2(SEQ ID NO:83);
[Ala17,22,23,27,3-Pal19,31,Gaba34]hGLP-1(7-34)-NH2(SEQ ID NO:92);
[D-Ala8,Ala17,23,27,3-Pal19,31]hGLP-1(7-34)-NH2
[Ala17,23,27,3-Pal19,31]hGLP-1(7-34)-NH2(SEQ ID NO:106);
[D-Ala8,Ala17,23,27,3-Pal19,31,Tle29]hGLP-1(7-34)-NH2
[D-Ala8,Ala17,23,27,3-Pal19,31,Tle16]hGLP-1(7-34)-NH2
[Aib8,A6c32]hGLP-1(7-36)NH2(SEQ ID NO:114);
[Aib8]hGLP-1(7-36)-NH2(SEQ ID NO:116);
[(Tma-His)7]hGLP-1(7-36)-NH2(SEQ ID NO:117);
[A6c8]hGLP-1(8-36)-NH2(SEQ ID NO:118);
[A6c8]hGLP-1(7-36)-NH2(SEQ ID NO:119);
[A6c16,20]hGLP-1(7-36)-NH2(SEQ ID NO:120);
[A6c29,32]hGLP-1(7-36)-NH2(SEQ ID NO:121);
[A6c20,Aib24]hGLP-1(7-36)-NH2(SEQ ID NO:122);
[Aib24,A6c29,32]hGLP-1(7-36)-NH2(SEQ ID NO:123);
[A6c16,29,32]hGLP-1(7-36)-NH2(SEQ ID NO:124);
[Ura7]hGLP-1(7-36)-NH2(SEQ ID NO:125);
[Paa7]hGLP-1(7-36)-NH2(SEQ ID NO:126);
[Pta7]hGLP-1(7-36)-NH2(SEQ ID NO:127);
[N-Me-D-Ala8]hGLP-1(7-36)-NH2
[A5c8]hGLP-1(7-36)-NH2(SEQ ID NO:130);
[N-Me-Glu9]hGLP-1(7-36)-NH2(SEQ ID NO:131);
[A5c8,A6c20,32]hGLP-1(7-36)-NH2(SEQ ID NO:132);
[Aib8,25]hGLP-1(7-36)-NH2(SEQ ID NO:134);
[Aib8,24]hGLP-1(7-36)-NH2(SEQ ID NO:135);
[Aib8,30]hGLP-1(7-36)-NH2(SEQ ID NO:136);
[Aib8,Cha20]hGLP-1(7-36)-NH2(SEQ ID NO:137);
[Aib8,Cha32]hGLP-1(7-36)-NH2(SEQ ID NO:138);
[Aib8,Glu23]hGLP-1(7-36)-NH2(SEQ ID NO:139);
[Aib8,A6c20]hGLP-1(7-36)-NH2(SEQ ID NO:140);
[Aib8,A6c20,32]hGLP-1(7-36)-NH2(SEQ ID NO:141);
[Aib8,22]hGLP-1(7-36)-NH2(SEQ ID NO:142);
[Aib8,Lys25]hGLP-1(7-36)-NH2(SEQ ID NO:144);
[Aib8,A6c12]hGLP-1(7-36)-NH2(SEQ ID NO:145);
[Aib8,A6c29]hGLP-1(7-36)-NH2(SEQ ID NO:146);
[Aib8,A6c33]hGLP-1(7-36)-NH2(SEQ ID NO:147);
[Aib8,14]hGLP-1(7-36)NH2(SEQ ID NO:148);或
[Aib8,18]hGLP-1(7-36)NH2(SEQ ID NO:149)。
2.一种药物组合物,它包括有效量的权利要求1所述的化合物、或其药学上可接受的盐和药学上可接受的载体或稀释剂。
3.权利要求1所述的化合物或其药学上可接受的盐在制备从需要的患者的GLP-1受体中引起兴奋剂作用的药剂中的应用。
4.权利要求1所述的化合物或其药学上可接受的盐在制备治疗下列疾病的药剂中的应用,其中所述疾病为I型糖尿病、II型糖尿病、肥胖、胰高血糖素瘤、导气管分泌性疾病、代谢性疾病、关节炎、骨质疏松、中枢神经系统疾病、再狭窄、神经变性疾病、肾脏衰竭、充血性心衰、肾病综合征、肝硬化、肺水肿和高血压。
5.根据权利要求4所述的应用,其中所述的疾病为I型糖尿病或II型糖尿病。
CNB998141852A 1998-12-07 1999-12-07 胰高血糖素样肽-1的类似物 Expired - Fee Related CN100334109C (zh)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US11118698P 1998-12-07 1998-12-07
US20683398A 1998-12-07 1998-12-07
US60/111,186 1998-12-07
US09/206,833 1998-12-07
PCT/US1999/028929 WO2000034332A1 (en) 1998-12-07 1999-12-07 Glp-1 analogues

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CN2007101410499A Division CN101108878B (zh) 1998-12-07 1999-12-07 胰高血糖素样肽-1的类似物

Publications (2)

Publication Number Publication Date
CN1342166A CN1342166A (zh) 2002-03-27
CN100334109C true CN100334109C (zh) 2007-08-29

Family

ID=26808707

Family Applications (2)

Application Number Title Priority Date Filing Date
CN2007101410499A Expired - Fee Related CN101108878B (zh) 1998-12-07 1999-12-07 胰高血糖素样肽-1的类似物
CNB998141852A Expired - Fee Related CN100334109C (zh) 1998-12-07 1999-12-07 胰高血糖素样肽-1的类似物

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN2007101410499A Expired - Fee Related CN101108878B (zh) 1998-12-07 1999-12-07 胰高血糖素样肽-1的类似物

Country Status (21)

Country Link
US (2) US7368427B1 (zh)
EP (2) EP1137666B9 (zh)
JP (3) JP2002538081A (zh)
KR (1) KR100458748B1 (zh)
CN (2) CN101108878B (zh)
AT (1) ATE394423T1 (zh)
AU (1) AU770609B2 (zh)
BR (1) BR9916027A (zh)
CA (1) CA2352573C (zh)
CZ (2) CZ303399B6 (zh)
DE (1) DE69938669D1 (zh)
DK (1) DK1137666T5 (zh)
ES (1) ES2302390T3 (zh)
HU (1) HUP0104579A3 (zh)
IL (2) IL143481A0 (zh)
NO (2) NO330293B1 (zh)
PL (3) PL393611A1 (zh)
PT (1) PT1137666E (zh)
RU (1) RU2208015C2 (zh)
TW (2) TWI262925B (zh)
WO (1) WO2000034332A1 (zh)

Families Citing this family (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1495198A (zh) 1998-12-07 2004-05-12 �о���Ӧ�ÿ�ѧЭ��ɷ����޹�˾ 胰高血糖素样肽-1的类似物
PT1137666E (pt) * 1998-12-07 2008-06-02 Sod Conseils Rech Applic Análogos de glp-1
BR0113178A (pt) * 2000-08-02 2004-04-06 Theratechnologies Inc Peptìdeos biológicos modificados com potência aumentada
US7371721B2 (en) 2000-09-18 2008-05-13 Sanos Bioscience A/S Use of GLP-2 and related compounds for the treatment, prevention, diagnosis, and prognosis of bone-related disorders and calcium homeostasis related syndromes
US7186683B2 (en) 2000-09-18 2007-03-06 Sanos Bioscience A/S Use of GLP for the treatment, prevention, diagnosis, and prognosis of bone-related and nutrition-related disorders
DK1326630T3 (da) * 2000-09-18 2008-09-15 Sanos Bioscience As Anvendelse af GLP-2-peptider
WO2002034285A2 (en) 2000-10-20 2002-05-02 Coolidge Thomas R Treatment of hibernating myocardium and diabetic cardiomyopathy with a glp-1 peptide
CA2430934C (en) 2000-12-01 2011-06-21 Takeda Chemical Industries, Ltd. A method of producing sustained-release preparations of a bioactive substance using high-pressure gas
DE60228972D1 (de) * 2001-07-31 2008-10-30 Us Gov Health & Human Serv Glp 1 exendin 4 peptidanaloga und deren verwendungen
AU2012202081B2 (en) * 2001-07-31 2014-09-25 The Government Of The United States Of America As Represented By The Secretary, Department Of Health And Human Services GLP-1 Exendin-4 peptide analogs and uses thereof
US7238671B2 (en) 2001-10-18 2007-07-03 Bristol-Myers Squibb Company Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions
IL160917A0 (en) * 2001-10-18 2004-08-31 Bristol Myers Squibb Co Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions
WO2004009616A2 (en) * 2002-07-23 2004-01-29 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Ghrelin analogs
EP1583549A4 (en) * 2003-01-17 2006-10-04 Sod Conseils Rech Applic YY PEPTIDE ANALOGS
CN1750842A (zh) * 2003-02-19 2006-03-22 研究及应用科学协会股份有限公司 Glp-1的类似物
KR20060013369A (ko) * 2003-03-28 2006-02-09 독립행정법인농업생물자원연구소 재조합 단백질이 다량 생산되는 식물 저장 기관의 생산방법 및 신규 재조합 단백질
US7094800B2 (en) 2003-07-25 2006-08-22 Sanofi-Aventis Deutschland Gmbh Cyanopyrrolidides, process for their preparation and their use as medicaments
US7008957B2 (en) 2003-07-25 2006-03-07 Sanofi-Aventis Deutschland Gmbh Bicyclic cyanoheterocycles, process for their preparation and their use as medicaments
US7094794B2 (en) 2003-07-28 2006-08-22 Sanofi-Aventis Deutschland Gmbh Substituted thiazole-benzoisothiazole dioxide derivatives, process for their preparation and their use
DE10335092B3 (de) 2003-08-01 2005-02-03 Aventis Pharma Deutschland Gmbh Substituierte Benzoylureido-o-benzoylamide, Verfahren zu deren Herstellung und deren Verwendung
ES2393335T3 (es) 2003-12-16 2012-12-20 Ipsen Pharma Análogos de GLP-1
CA2550695A1 (en) * 2003-12-16 2005-06-30 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R Glp-1 pharmaceutical compositions
BRPI0506694A (pt) * 2004-01-08 2007-05-02 Theratechnologies Inc análogos de peptìdeo-1 semelhante ao glucagon com longa duração de ação
TW200611704A (en) * 2004-07-02 2006-04-16 Bristol Myers Squibb Co Human glucagon-like-peptide-1 modulators and their use in the treatment of diabetes and related conditions
US7534763B2 (en) 2004-07-02 2009-05-19 Bristol-Myers Squibb Company Sustained release GLP-1 receptor modulators
PT1891105E (pt) * 2005-06-13 2012-06-27 Imp Innovations Ltd Análogos de oxintomodulina e seus efeitos sobre o comportamento da alimentação
WO2007051987A1 (en) * 2005-11-01 2007-05-10 Activotec Spp Limited Insulinotropic compounds and uses thereof
US8293869B2 (en) 2005-12-16 2012-10-23 Nektar Therapeutics Polymer conjugates of GLP-1
MX2008013304A (es) 2006-04-20 2008-10-27 Amgen Inc Compuestos de peptido 1 tipo glucagon.
US20100022457A1 (en) 2006-05-26 2010-01-28 Bristol-Myers Squibb Company Sustained release glp-1 receptor modulators
ES2628063T3 (es) * 2007-01-05 2017-08-01 Indiana University Research And Technology Corporation Análogos de glucagón que muestran una mayor solubilidad en tampones de pH fisiológicos
JP2010538069A (ja) * 2007-09-07 2010-12-09 イプセン ファルマ ソシエテ パール アクシオン サンプリフィエ エキセンディン−4およびエキセンディン−3の類似体
CA2727161A1 (en) * 2008-06-17 2009-12-23 Indiana University Research And Technology Corporation Glucagon analogs exhibiting enhanced solubility and stability physiological ph buffers
RU2011131714A (ru) * 2008-12-29 2013-02-10 Панацеа Биотек Лтд. Аналоги glp-1 и их использования
CA2796894A1 (en) * 2010-06-24 2011-12-29 Indiana University Research And Technology Corporation Amide based glucagon superfamily peptide prodrugs
WO2012054861A1 (en) 2010-10-22 2012-04-26 Nektar Therapeutics Glp-1 polymer conjugates having a releasable linkage
WO2012054822A1 (en) 2010-10-22 2012-04-26 Nektar Therapeutics Pharmacologically active polymer-glp-1 conjugates
PT2713722T (pt) 2011-05-31 2017-06-27 Receptos Llc Novos estabilizadores e moduladores do receptor glp-1
AU2012352349B2 (en) 2011-12-12 2017-08-17 Receptos Llc Carboxylic acid derivatives comprising four cycles acting as GLP-1 receptor modulators for therapy of diseases such as diabetes
CN102584982B (zh) * 2012-02-10 2014-02-05 深圳翰宇药业股份有限公司 一种纯化固相合成利拉鲁肽粗肽的方法
WO2014010586A1 (ja) 2012-07-10 2014-01-16 武田薬品工業株式会社 注射用製剤
PE20151770A1 (es) * 2013-05-28 2015-12-11 Takeda Pharmaceutical Compuesto peptidico
CN103285379A (zh) * 2013-06-09 2013-09-11 南方医科大学 Glp-1用于制备预防与治疗2型糖尿病大血管并发症的药物的用途
EP3008056B8 (en) 2013-06-11 2021-03-03 Receptos Llc Novel glp-1 receptor modulators
CN112457301A (zh) 2014-07-25 2021-03-09 赛尔基因第二国际有限公司 新的glp-1受体调节剂
JP2018012644A (ja) * 2014-11-26 2018-01-25 武田薬品工業株式会社 ペプチド化合物
WO2016094729A1 (en) 2014-12-10 2016-06-16 Celgene International Ii Sarl Glp-1 receptor modulators
SG10202103552XA (en) 2015-03-09 2021-05-28 Intekrin Therapeutics Inc Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
UA127495C2 (uk) 2015-12-23 2023-09-13 Амджен Інк. Виділений антигензв'язуючий білок, який специфічно зв'язується з поліпептидом рецептора шлункового інгібіторного пептиду (gipr) людини, та фармацевтична композиція, яка його містить
PL3393496T3 (pl) 2015-12-23 2024-04-22 The Johns Hopkins University Długo działający agonista glp-1r jako terapia stanów neurologicznych i neurodegeneracyjnych
WO2017204219A1 (ja) 2016-05-24 2017-11-30 武田薬品工業株式会社 ペプチド化合物
WO2017210241A1 (en) * 2016-06-02 2017-12-07 Indiana University Research And Technology Corporation Aqueously soluble & chemically stable glucagon peptides
JOP20190177A1 (ar) 2017-01-17 2019-07-16 Amgen Inc طريقة لعلاج أو تحسين اضطرابات أيضية باستخدام مساعدات مستقبل glp-1 مقترنة بمناهضات لمستقبل ببتيد مثبط معوي (gipr)
AU2018249822A1 (en) 2017-04-03 2019-10-31 Coherus Biosciences Inc. PPArgamma agonist for treatment of progressive supranuclear palsy
CN109942696A (zh) * 2017-12-21 2019-06-28 中国药科大学 长效化胰高血糖素样肽-1(glp-1)类似物及其应用
CN116970062B (zh) * 2022-04-29 2024-04-09 南京知和医药科技有限公司 一种超长效glp-1多肽衍生物及其制备方法和用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5545618A (en) * 1990-01-24 1996-08-13 Buckley; Douglas I. GLP-1 analogs useful for diabetes treatment
CN1131674A (zh) * 1995-03-21 1996-09-25 伊莱利利公司 高血糖素样胰岛素营养复合物,组合物及其方法

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1539498A (en) 1925-05-26 And fifteen
ATE164852T1 (de) * 1990-01-24 1998-04-15 Douglas I Buckley Glp-1-analoga verwendbar in der diabetesbehandlung
DK36392D0 (da) * 1992-03-19 1992-03-19 Novo Nordisk As Anvendelse af kemisk forbindelse
AU671117B2 (en) * 1992-06-15 1996-08-15 Scios Inc. Glucagon-like peptide and insulinotropin derivatives
US5672659A (en) 1993-01-06 1997-09-30 Kinerton Limited Ionic molecular conjugates of biodegradable polyesters and bioactive polypeptides
US5595760A (en) 1994-09-02 1997-01-21 Delab Sustained release of peptides from pharmaceutical compositions
US5512549A (en) * 1994-10-18 1996-04-30 Eli Lilly And Company Glucagon-like insulinotropic peptide analogs, compositions, and methods of use
US5665702A (en) 1995-06-06 1997-09-09 Biomeasure Incorporated Ionic molecular conjugates of N-acylated derivatives of poly(2-amino-2-deoxy-D-glucose) and polypeptides
AU2263197A (en) * 1996-02-06 1997-08-28 Eli Lilly And Company Diabetes therapy
US6458924B2 (en) 1996-08-30 2002-10-01 Novo Nordisk A/S Derivatives of GLP-1 analogs
DE122009000079I2 (de) 1996-08-30 2011-06-16 Novo Nordisk As Novo Alle Glp-1 derivate
US5916883A (en) 1996-11-01 1999-06-29 Poly-Med, Inc. Acylated cyclodextrin derivatives
UA65549C2 (uk) 1996-11-05 2004-04-15 Елі Ліллі Енд Компані Спосіб регулювання ожиріння шляхом периферійного введення аналогів та похідних glp-1 (варіанти) та фармацевтична композиція
WO1998043658A1 (en) * 1997-03-31 1998-10-08 Eli Lilly And Company Glucagon-like peptide-1 analogs
EP1056774A1 (en) 1998-02-27 2000-12-06 Novo Nordisk A/S N-terminally truncated glp-1 derivatives
FR2777283B1 (fr) 1998-04-10 2000-11-24 Adir Nouveaux composes peptidiques analogues du glucagon-peptide- 1 (7-37), leur procede de preparation et les compositions pharmaceutiques qui les contiennent
US6720407B1 (en) 1998-08-28 2004-04-13 Eli Lilly And Company Method for administering insulinotropic peptides
CN1495198A (zh) 1998-12-07 2004-05-12 �о���Ӧ�ÿ�ѧЭ��ɷ����޹�˾ 胰高血糖素样肽-1的类似物
PT1137666E (pt) * 1998-12-07 2008-06-02 Sod Conseils Rech Applic Análogos de glp-1
AU1269501A (en) 1999-11-12 2001-05-30 Novo Nordisk A/S Use of glp-1 agonists for the inhibition of beta cell degeneration

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5545618A (en) * 1990-01-24 1996-08-13 Buckley; Douglas I. GLP-1 analogs useful for diabetes treatment
CN1131674A (zh) * 1995-03-21 1996-09-25 伊莱利利公司 高血糖素样胰岛素营养复合物,组合物及其方法

Also Published As

Publication number Publication date
JP2010001301A (ja) 2010-01-07
BR9916027A (pt) 2001-08-28
EP1137666B1 (en) 2008-05-07
US7368427B1 (en) 2008-05-06
TWI262925B (en) 2006-10-01
AU1751200A (en) 2000-06-26
KR20010102953A (ko) 2001-11-17
IL143481A (en) 2010-02-17
IL143481A0 (en) 2002-04-21
PL393611A1 (pl) 2011-05-09
TW200628489A (en) 2006-08-16
EP1137666A1 (en) 2001-10-04
WO2000034332A1 (en) 2000-06-15
ATE394423T1 (de) 2008-05-15
HUP0104579A2 (hu) 2002-04-29
PL208751B1 (pl) 2011-06-30
CZ20011895A3 (cs) 2001-12-12
ES2302390T3 (es) 2008-07-01
NO20100307L (no) 2001-08-06
US20090149378A1 (en) 2009-06-11
CN101108878B (zh) 2012-08-29
NO330293B1 (no) 2011-03-21
DE69938669D1 (de) 2008-06-19
CZ303399B6 (cs) 2012-08-29
RU2208015C2 (ru) 2003-07-10
NO20012787L (no) 2001-08-06
KR100458748B1 (ko) 2004-12-03
EP1992641A2 (en) 2008-11-19
CA2352573A1 (en) 2000-06-15
EP1137666B9 (en) 2009-04-01
CA2352573C (en) 2012-04-10
PT1137666E (pt) 2008-06-02
DK1137666T3 (da) 2008-09-08
DK1137666T5 (da) 2009-10-05
NO20012787D0 (no) 2001-06-06
CZ303120B6 (cs) 2012-04-11
EP1992641A3 (en) 2009-07-29
TWI339208B (en) 2011-03-21
HUP0104579A3 (en) 2002-05-28
CN1342166A (zh) 2002-03-27
PL205713B1 (pl) 2010-05-31
AU770609B2 (en) 2004-02-26
CN101108878A (zh) 2008-01-23
JP2002538081A (ja) 2002-11-12
JP2006077022A (ja) 2006-03-23

Similar Documents

Publication Publication Date Title
CN100334109C (zh) 胰高血糖素样肽-1的类似物
CN100540566C (zh) 胰高血糖素样肽-1的类似物
JP2007536214A (ja) Glp−1類似体
CN1935839B (zh) 胰高血糖素样肽-1的类似物
MXPA01005763A (en) Glp-1 analogues
AU2003271325A1 (en) GLP-1 Analogues

Legal Events

Date Code Title Description
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C06 Publication
PB01 Publication
C14 Grant of patent or utility model
GR01 Patent grant
C56 Change in the name or address of the patentee

Owner name: IPSEN MEDICINE CO.,LTD.

Free format text: FORMER NAME: SOD CONSEILS RECH APPLIC

CP03 Change of name, title or address

Address after: Paris, FRA

Co-patentee after: Tulane Educational Fund Management Committee

Patentee after: Beaufour Ipsen Pharma

Address before: Paris, FRA

Co-patentee before: Tulane Educational Fund Management Committee

Patentee before: Association of research and Applied Sciences Limited by Share Ltd

C56 Change in the name or address of the patentee
CP03 Change of name, title or address

Address after: France 92650 - Boulogne Billancourt, Georges Plantagenet pier No. 65

Co-patentee after: Tulane Educational Fund Management Committee

Patentee after: Beaufour Ipsen Pharma

Address before: Paris, FRA

Co-patentee before: Tulane Educational Fund Management Committee

Patentee before: Beaufour Ipsen Pharma

C17 Cessation of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20070829

Termination date: 20121207