Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/575—Hormones
  • C07K14/605—Glucagons
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/26—Glucagons
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/575—Hormones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

• Y is hydrogen, hydroxyl, fluorine, (Ci-C 6 ) alkyl.
• Z is nitrogen, carbon, oxygen, sulphur.
• Ri is hydrogen, (C!-C 6 ) alkyl, (Ci-C 6 )alkoxy.
• X is hydrogen, fluorine, trifluoromethyl.
• Ri is hydrogen, (Ci-C 6 ) alkyl, (Ci-C 6 )alkoxy.
• Xaai 6 is a naturally or non-naturally occurring amino acid selected from the group consisting of valine, lysine and leucine; wherein one or more of the carbon atoms of said amino acid is optionally substituted with one or more alkyl groups. Or Xaai6 is lysine linked with T-U.
• Y is hydrogen, (Ci-C ) alkyl.
• Xaaig is a naturally or non-naturally occurring amino acid selected from the group consisting of serine, serine, arginine and lysine; wherein one or more of the carbon atoms of said amino acid is optionally substituted with one or more alkyl groups
• U is a fatty acid with length of 8 to 20 carbon
• R 2 is hydrogen, (Ci-C 6 ) alkyl, (Ci-C 6 )alkoxy.
• Z is nitrogen, carbon, oxygen, sulphur.
• n 1,2,3,4,5,6,7,8,9,10,1 1,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27;
• T is selected from the group consisting of
• k is selected from the group of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and m is selected from 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10
• Xaa 7 is a natural or non natural amino acid selected from the group consisting of L-His, D- histidine, desamino-histidine, 2-amino-histidine, ⁇ -hydroxy-histidine, homohistidine, a- fluoromethyl-histidine, and a-methyl-histidine;
• N-8 26 [y- -glutamyl(N-a-hexadecanoyl)]-[Q-linker-a8-9,Arg34]GLP-l -(7-37)-peptide ⁇ N-E 26 -[y- -glutamyl(N-a-hexadecanoyl)]-[Q-linker-b8-9,Arg34]GLP-l-(7-37)-peptide
• the compounds of the invention may have one or more asymmetric centers, such as A- linker in Formula I. Such compounds may be present in one or more stereo isomeric forms. These compounds can be, for example, racemates, optically active forms, or enantiomerically enriched mixtures of stereoisomers. Where desired, the single enantiomers, i. e. , optically active forms, can be obtained by known procedures, e. g. , by asymmetric synthesis, by synthesis from optically active starting materials, or by resolution of the racemates.
• a peptide fragment of the invention may be synthesized by solid phase methodology utilizing a Applied Biosystems 430 peptide synthesizer (Applied Biosystems, Inc., 850 Lincoln Centre Drive, Foster City, CA 94404) and synthesis cycles supplied by Applied Biosystems.
• Boc protected amino acids and other reagents are commercially available from Applied Biosystems and other chemical venders. Sequential Boc chemistry using double couple protocols are applied to the starting p-methyl benzhydryl amine resins for the production of C- terminal carboxamides.
• the corresponding PAM resin can be used.
• Asp, Gin and Arg are coupled using preformed hydroxyl benzotriazole esters.
• Nonaethylene glycol monododecyl ether N- Nonanoyl-N-methylglucamine, N-Nonanoyl-N- methylglucamine, Octaethylene glycol monodecyl ether, Octaethylene glycol monododecyl ether, Octaethylene glycol monohexadecyl ether, Octaethylene glycol monooctadecyl ether,
• alkyl- polyglucosides are alkyl glucosides such n-decyl ⁇ -D- glucopyranoside, decyl ⁇ -D- maltopyranoside, dodecyl ⁇ -D-glucopyranoside, n-dodecyl ⁇ -D- maltoside, n-dodecyl ⁇ -D- maltoside, n-dodecyl ⁇ -D-maltoside, tetradecyl ⁇ -D-glucopyranoside, decyl ⁇ -D-maltoside, hexadecyl ⁇ -D-maltoside, decyl ⁇ -D-maltotrioside, dodecyl ⁇ -D- maltotrioside, tetradecyl ⁇ -D- maltotrioside, hexadecyl ⁇ -D-maltotrioside, n-dodecyl-s
• compositions of the invention may further be compounded in, or attached to, for example through covalent, hydrophobic and electrostatic interactions, a drug carrier, drug delivery system and advanced drug delivery system in order to further enhance stability of the compound of the present invention, increase bioavailability, increase solubility, decrease adverse effects, achieve chronotherapy well known to those skilled in the art, and increase patient compliance or any combination thereof.
• the formulation could be aerosolized by any known aerosolisation technology, such as nebulisation, to achieve a MMAD of aerosol particles less than 10 ⁇ , more preferably between 1 -5 ⁇ , and most preferably between 1 -3 ⁇ .
• the preferred particle size is based on the most effective size for delivery of drug to the deep lung, where protein is optimally absorbed (cf . Edwards DA, Ben-Jebria A, Langer A, Recent advances in pulmonary drug delivery using large, porous inhaled particles. J Appl Physiol 84(2) (1998) 379-385).
• the modified GLP-1 analogs of the invention find multiple uses including use as a treatment for diabetes, a sedative, a treatment of nervous system disorders, use to induce an anxiolytic effect on the CNS, use to activate the CNS, use for post surgery treatment and as a treatment for insulin resistance.
• intracerebroventriculary orally, subcutaneously, intramuscularly, or intravenously.
• Such methods are useful to treat or ameliorate nervous system conditions such as anxiety, movement disorder, aggression, psychosis, seizures, panic attacks, hysteria and sleep disorders.
• the perfusate is a modified Kreba-Ringer bicarbonate buffer with 4%dextran T70 and 0.2% bovine serum albumin (fraction V), and is bubbled with 95% 0 2 and 5% C0 2 .
• a nonpulsatile flow, 4-channel roller bearing pump (Buchler polystatic, Buchler Instruments
• Boc tert butyloxycarbonyl
• OtBu tert butyl ester
• tBu tert butyl
• Tit triphenylmethyl
• Pmc 2,2,5, 7,8-Pentamethyl-chroman-6-sulfonyl
• the required polymer-bonded peptide fragment can also be prepared by using Fmoc protected.
• the selective deprotection of the Lys (Aloe) group was performed manually and accomplished by treating the resin with a solution of 3 eq.

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• 2010
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