AU2017256803B2 - Dipeptidyl peptidase-4 inhibitors for topical eye treatment of retinal neurodegenerative diseases - Google Patents

Dipeptidyl peptidase-4 inhibitors for topical eye treatment of retinal neurodegenerative diseases Download PDF

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AU2017256803B2
AU2017256803B2 AU2017256803A AU2017256803A AU2017256803B2 AU 2017256803 B2 AU2017256803 B2 AU 2017256803B2 AU 2017256803 A AU2017256803 A AU 2017256803A AU 2017256803 A AU2017256803 A AU 2017256803A AU 2017256803 B2 AU2017256803 B2 AU 2017256803B2
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topical
veterinary
inhibitor
pharmaceutically
dipeptidyl peptidase
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AU2017256803A1 (en
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Cristina HERNÁNDEZ PASCUAL
Rafael SIMÓ CANONGE
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Fundacio Institut de Recerca Hospital Universitari Vall dHebron
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Fundacio Institut de Recerca Hospital Universitari Vall dHebron
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • 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
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/08—Solutions
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Endocrinology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
AU2017256803A 2016-04-29 2017-04-28 Dipeptidyl peptidase-4 inhibitors for topical eye treatment of retinal neurodegenerative diseases Active AU2017256803B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP16382190 2016-04-29
EP16382190.3 2016-04-29
PCT/EP2017/060234 WO2017186934A1 (en) 2016-04-29 2017-04-28 Dipeptidyl peptidase-4 inhibitors for topical eye treatment of retinal neurodegenerative diseases

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AU2017256803A1 AU2017256803A1 (en) 2018-12-06
AU2017256803B2 true AU2017256803B2 (en) 2022-12-01

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US (2) US11013738B2 (https=)
EP (1) EP3448388B1 (https=)
JP (1) JP7068706B2 (https=)
KR (1) KR102411574B1 (https=)
CN (1) CN109152776B (https=)
AU (1) AU2017256803B2 (https=)
BR (1) BR112018072127A2 (https=)
CA (1) CA3022152C (https=)
DK (1) DK3448388T3 (https=)
ES (1) ES2863701T3 (https=)
IL (1) IL262526B (https=)
MX (1) MX383599B (https=)
RU (1) RU2744878C2 (https=)
WO (1) WO2017186934A1 (https=)

Families Citing this family (5)

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Publication number Priority date Publication date Assignee Title
JP7068706B2 (ja) * 2016-04-29 2022-05-17 フンダシオ オスピタル ウニベルシタリ バル デブロン－インスティテュート デ レセルカ 網膜神経変性疾患の眼局所治療のためのジペプチジルペプチダーゼ－４阻害剤
RU2727898C1 (ru) * 2020-02-25 2020-07-24 Общество с ограниченной ответственностью «Необиотек» Фармацевтическая композиция на основе действующего вещества, ингибитора дипептидилпептидазы-4, для предупреждения развития и лечения сахарного диабета 2 типа
CN111166870A (zh) * 2020-03-18 2020-05-19 复旦大学附属眼耳鼻喉科医院 艾塞那肽在制备滴眼治疗眼部缺血疾病、改善眼部血液循环的药物中的应用
GB202014740D0 (en) * 2020-09-18 2020-11-04 Invex Therapeutics Ltd Method of reducing intraocular pressure
WO2026078034A1 (en) 2024-10-09 2026-04-16 Fundació Hospital Universitari Vall D'hebron - Institut De Recerca Sitagliptin for use in retinal diseases with neovascularization

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080221200A1 (en) * 2005-09-30 2008-09-11 Malcolm Allison Combination of Organic Compounds
US20140371243A1 (en) * 2013-06-14 2014-12-18 Boehringer Ingelheim International Gmbh Medical use of a dpp-4 inhibitor

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19616486C5 (de) * 1996-04-25 2016-06-30 Royalty Pharma Collection Trust Verfahren zur Senkung des Blutglukosespiegels in Säugern
US7560597B2 (en) * 2007-03-08 2009-07-14 The University Court Of The University Of Aberdeen 2′,4′-dichloro-biphenyl-4-yl-hydroxy-ketones and related compounds and their use as therapeutic agents
WO2009084024A2 (en) * 2007-11-02 2009-07-09 Glenmark Generics Limited A process for the preparation of r-sit agliptin and its pharmaceutically acceptable salts thereof
US20100330177A1 (en) * 2008-02-05 2010-12-30 Merck Sharp & Dohme Corp. Pharmaceutical compositions of a combination of metformin and a dipeptidyl peptidase-iv inhibitor
EP2251028A1 (en) * 2009-05-12 2010-11-17 Biocompatibles Uk Ltd. Treatment of eye diseases using encapsulated cells encoding and secreting an anti-angiogenic factor and/or a neuroprotective factor
CN101921270A (zh) * 2009-06-16 2010-12-22 海南德泽药物研究有限公司 一种芒果苷小檗碱盐及其制备方法与用途
TWI469785B (zh) * 2012-04-25 2015-01-21 Inovobiologic Inc 用於治療代謝性疾病之膳食纖維組成物
JP6368722B2 (ja) * 2013-03-01 2018-08-01 フンダシオ オスピタル ウニベルシタリ バル デブロン−インスティテュート デ レセルカ 網膜神経変性疾患の、特に、初期の糖尿病性網膜症及び神経変性が本質的な役割を果たす他の網膜疾患における局所治療における使用のためのペプチド
JP7068706B2 (ja) * 2016-04-29 2022-05-17 フンダシオ オスピタル ウニベルシタリ バル デブロン－インスティテュート デ レセルカ 網膜神経変性疾患の眼局所治療のためのジペプチジルペプチダーゼ－４阻害剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080221200A1 (en) * 2005-09-30 2008-09-11 Malcolm Allison Combination of Organic Compounds
US20140371243A1 (en) * 2013-06-14 2014-12-18 Boehringer Ingelheim International Gmbh Medical use of a dpp-4 inhibitor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Pandit, Rahul S., et al., "Retinal and lens protective effet of sitagliptin in streptozotocin induced type-1 diabetic wistar rats", Biomedicine & Aging Pathology Jun. 2013, 3 pp. 65-73. *

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CN109152776A (zh) 2019-01-04
JP7068706B2 (ja) 2022-05-17
RU2018140127A3 (https=) 2020-07-02
WO2017186934A1 (en) 2017-11-02
US11918577B2 (en) 2024-03-05
EP3448388B1 (en) 2020-11-18
MX383599B (es) 2025-03-14
BR112018072127A2 (pt) 2019-03-19
IL262526B (en) 2022-05-01
KR102411574B1 (ko) 2022-06-21
CA3022152A1 (en) 2017-11-02
EP3448388A1 (en) 2019-03-06
RU2018140127A (ru) 2020-05-29
US11013738B2 (en) 2021-05-25
JP2019519479A (ja) 2019-07-11
CA3022152C (en) 2024-10-29
ES2863701T3 (es) 2021-10-11
KR20190003575A (ko) 2019-01-09
DK3448388T3 (da) 2021-02-08
US20210315890A1 (en) 2021-10-14
CN109152776B (zh) 2022-04-29
IL262526A (en) 2018-12-31
US20190134030A1 (en) 2019-05-09
AU2017256803A1 (en) 2018-12-06
RU2744878C2 (ru) 2021-03-16

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