WO2005009471A1 - Composition pour abaisser la glycemie - Google Patents

Composition pour abaisser la glycemie Download PDF

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Publication number
WO2005009471A1
WO2005009471A1 PCT/JP2004/011129 JP2004011129W WO2005009471A1 WO 2005009471 A1 WO2005009471 A1 WO 2005009471A1 JP 2004011129 W JP2004011129 W JP 2004011129W WO 2005009471 A1 WO2005009471 A1 WO 2005009471A1
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WO
WIPO (PCT)
Prior art keywords
histamine
diabetic
receptor
blood sugar
action
Prior art date
Application number
PCT/JP2004/011129
Other languages
English (en)
Inventor
Katsuya Nagai
Saburo Aimoto
Toru Kawakami
Original Assignee
Osaka Industrial Promotion Organization
Osaka 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 Osaka Industrial Promotion Organization, Osaka University filed Critical Osaka Industrial Promotion Organization
Priority to JP2006519248A priority Critical patent/JP2007528860A/ja
Publication of WO2005009471A1 publication Critical patent/WO2005009471A1/fr

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Classifications

    • 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
    • A61K31/4164—1,3-Diazoles
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/72—Assays involving receptors, cell surface antigens or cell surface determinants for hormones
    • G01N2333/726—G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)

Definitions

  • Fig. 1 shows the NMR spectrum obtained upon dissolving the TFA salt of imidazole compound (3) [ ⁇ -Ala-His-OCH 2 -OCO-C(CH 3 ) 3 ] prepared in Manufacturing Example 1 in deuterated methanol and carrying out 400 MHz NMR measurements.
  • Fig. 2 is a graph indicating the hypoglycemic action of (R)-(-)- ⁇ -methylhistamine (MH) on the hyperglycemic response caused by intracerebral administration of 2-deoxy-D-glucose
  • FIG. 9 is a figure indicating actual electric recordings based on the results of Fig. 8.
  • preinjection indicates pre-administration (minute 0)
  • post injection indicates the measured results 30 minutes post-administration.
  • H3 agonist means (R)-(-)-a-methylhistamine.
  • Fig. 10 is a graph indicating that the renal sympathetic nerve activity is lowered based on administration of the histamine H 3 receptor agonist (R)-(-)- ⁇ -methylhistamine (MH) into the abdominal aorta, and that the decrease is inhibited by addition of a histamine H 3 receptor antagonist (thioperamide: Thiop.) (Reference Experimental Example 3).
  • histamine H 3 receptor which is present in the presynaptic membrane of histaminergic neuron cell and control the metabolic rotation of histamine neuron, deeply participate in the control (elevation and decrease) of blood sugar levels in the body, and further, that substances that exert an agonist or agonist-like action on the histamine H 3 receptor are effective for preventing or treating illnesses caused by hyperglycemia such as diabetes and complications thereof by controlling and improving the hyperglycemic state (lowering the blood sugar level of a hyperglycemic state). Furthermore, the present inventors developed novel imidazole compounds, and found the compounds improve a hyperglycemic state through histamine H 3 receptor.
  • Item 36 The use according to any of Items 29 to 35, wherein the disease caused by hyperglycemia is type II diabetes or complications thereof.
  • Item 37 A screening method for an active ingredient of a composition for lowering blood sugar comprising a step of, selecting from the test samples a substance having an action to suppress the release of histamine from the presynaptic membrane of histaminergi ⁇ neuron cell, directly or indirectly using the amount of histamine released from the presynaptic membranes as an indicator.
  • Item 38 A screening method for an active ingredient of a composition for lowering blood sugar comprising a step of, selecting from the test samples a substance having an action to suppress the release of histamine from the presynaptic membrane of histaminergi ⁇ neuron cell, directly or indirectly using the amount of histamine released from the presynaptic membranes as an indicator.
  • the screening method for active ingredients of a composition for lowering blood sugar comprising the steps of: (a) administering a test substance to test animals with hyperglycemia artificially induced, and measuring the changes of blood sugar levels before and after administration; (b) selecting a substance that has an action to improve a hyperglycemic state artificially induced (hypoglycemic action) based on the results obtained in step (b); and if necessary, (c) selecting from substances selected in step (b) a substance whose th action to improve the hyperglycemic state artificially induced is inhibited by a histamine H 3 receptor * antagonist.
  • Item 41 comprising the steps of: (a) administering a test substance to test animals with hyperglycemia artificially induced, and measuring the changes of blood sugar levels before and after administration; (b) selecting a substance that has an action to improve a hyperglycemic state artificially induced (hypoglycemic action) based on the results obtained in step (b); and if necessary, (
  • the screening method according to Item 41 comprising the steps of: (a) directly or indirectly measuring whether a test substance reacts with histamine H 3 receptor to suppress release of histamine; (b) for the substance for which the action to suppress release of histarnines has been confirmed in said step (a), directly or indirectly measuring whether that action to suppress release of histarnines is inhibited by histamine H 3 receptor antagonists; and (c) selecting a substance whose the action to suppress release of histarnines is inhibited by the histamine H 3 receptor antagonist.
  • the screening method according to Item 42 comprising a step of conducting a binding assay of the test substance with histamine H 3 receptor, and selecting a histamine H 3 receptor agonist.
  • the screening method comprising the steps of: (a) administering a test substance to test animals with hypergl ⁇ cemia artificially induced, and measuring the changes of blood sugar levels before and after administration; (b) selecting a substance that has an action to improve a hyperglycemic state artificially induced (hypoglycemic action) based on the results obtained in step (a) ; and if necessary, (c) selecting from substances selected in step (b) a substance whose the action to improve the hyperglycemic state artificially induced is inhibited by a histamine H 3 receptor antagonist.
  • Item 45 comprising the steps of: (a) administering a test substance to test animals with hypergl ⁇ cemia artificially induced, and measuring the changes of blood sugar levels before and after administration; (b) selecting a substance that has an action to improve a hyperglycemic state artificially induced (hypoglycemic action) based on the results obtained in step (a) ; and if necessary, (c) selecting from substances selected in step
  • composition to lower blood sugar of the present invention has a substance, as an active ingredient, that exerts a direct or indirect stimulus action on the histamine H 3 receptor present in the brain, particularly in the hypothalamus, and more specifically in the presynaptic membrane of the histaminergic neuron cells in the brain.
  • Pharmaceutical compositions or food compositions may be cited as suitable compositions to lower blood sugar.
  • Substance that exert a direct or indirect stimulus action on the histamine H 3 receptor (sometimes, called simply "H 3 receptor stimulant" hereinafter) may be used singly as the hypoglycemic agent, but preferably, any carriers or additives acceptable for medicines or foods may be combined as components other than the substance, and used as compositions to lower blood sugar.
  • salts examples include salts with inorganic acid (for example, hydrochloric acid, phosphoric acid, hydrobromi ⁇ acid, sulfuric acid, hydra ⁇ id), or salts with organic acids (for example, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartari ⁇ acid, citric acid, malic acid, oxalic acid, benzoic acid, methansulfonic acid, benezenesulfonic acid) .
  • the H 3 receptor stimulants targeted by the present invention also include hydrates, hydrated salts or substances having polycrystalline structures.
  • the modified form may be, for example: a substance that has a modified form that is not metabolized in the digestive tract or blood, and that becomes the H 3 receptor stimulant in the brain after passing through the blood-brain barrier; or a substance that has a modified form that easily passes through the blood- brain barrier, and that becomes the H 3 receptor stimulant in the brain after passing through the blood-brain barrier.
  • Solid dosing forms such as tablets, pills, bulk drug, powder, granules and capsules, etc.
  • liquid dosing forms such as solutions, suspensions, emulsions, syrups, and elixirs, etc.
  • external dosing forms such as patches, ointments, creams and sprays.
  • carriers to formulate these pharmaceutical preparations include fillers, diluents, binders, moisturizers, disintegrators, disintegration inhibitors, absorption promoters, lubricants, dissolution supplements, solubilizing agents, buffers, emulsifiers, and suspending agents.
  • the amount of active ingredient to be contained in the aforementioned pharmaceutical composition and the dosage thereof is not particul rly limited, and may be suitably selected in a range corresponding to the desired therapeutic effect, administration method, therapy period, age of the patient, sex, and other conditions.
  • the dosage varies depending on the dosing route, but may be suitably selected in the range of approximately 0.1 pg to 1 mg/60 kg by calculating the amount of active ingredient per dose in relation to a person weighing 60 kg. Preferably, this is approximately 0.2 pg to 200 ⁇ g/60 kg.
  • Imidazole compound (2) can then be obtained by removing the protecting groups therefrom. Note that the preparation of the 1-iodoethyl acetate can be carried out referring to the document [Y. Yoshimura et al. , J. Antibiotics, 39, 1329 (1986)].
  • imidazole compound (5) [ ⁇ -Ala-His- OCH(CH 3 )OCOOCH(CH 3 ) 2 ] and imidazole compound (6) [ ⁇ -Ala-His- OCH(CH 3 )OCOOC 6 H ] can be obtained using a similar method to imidazole compound (4) [ ⁇ -Ala-His-OCH 2 -OCO-OCH 2 CH 3 *2HCl] (Manufacturing Example 2). That is, the corresponding alkyl 1- chloroethyl carbonate and sodium iodide are reacted together to obtain the alkyl 1-iodoethyl carbonate.
  • the form of the unit of administration of the pharmaceutical composition can be variously selected as appropriate in accordance with the route of administration; such forms ca ⁇ > be broadly categorized into orally administered preparations] nasally administered preparations, vaginally administered preparations, suppositories, sublingual preparations, non-orally administered preparations (injections, drips), external preparations (patches, ointments, creams, sprays) and so on.
  • aCSF means the results when artificial cerebrospinal fluid (test sample (1)) was independently administered in the lateral ventricle of the test rats;
  • 2DG-aCSF means the results by administrating of 2DG solution (containing aCSF) (test sample (2));
  • 2DG-MH means the results by administrating of a mixed solution of 2DG solution and MH solution (including aCSF) (test sample (3));
  • 2DG-MH- Thiop means the results by administrating of a mixed solution of 2DG solution, MH solution, and thioperamide solution (including aCSF) (test sample (4)).
  • Group 2 100 ⁇ L of FMH solution (100 mg/kg/saline 100 ⁇ L) was intraperitoneally administered, and 100 ⁇ L of FMH solution (100 mg/kg/saline 100 ⁇ L) was re-administered 22 hours later. Two hours later, 20 ⁇ L of 2DG solution (40 ⁇ mol/aCSF 20 ⁇ L) was intracerebrally administered.
  • histamine Hi receptor antagonists also inhibit the hyperglycemic response caused by 2DG (provisional model of a hyperglycemic response during hypoglycemic conditions) .
  • 2DG provisional model of a hyperglycemic response during hypoglycemic conditions
  • histamine neurons and histamine Hi receptor in the brain participate in maintenance of homeostasis in the body (regulation of the autonomic nervous system) related to blood sugar levels.
  • histamine neurons have a function to stimulate sympathetic nerves and suppress the activity of the parasympathetic nerves by the release of histarnines mediated though histamine Hi receptor.
  • mice were divided in 4 groups based on the "random blood sugar level" [group 1: control group (not administered immepip); group 2: immepip 0.05 mg/kg dosing group; group 3: immepip 0.5 mg/kg dosing group; and group 4: immepip 5.0 mg/kg dosing group], and from the following day (7 weeks of age), immepip hydrobromide (TpcrisCooksonlnc. , USA) was repeatedly administered subcutaneously once per day for 7 days (dose administered 2 mL/kg) .
  • immepip hydrobromide TpcrisCooksonlnc. , USA
  • a cerebral cannula made of PE-10 (Clay Adams, Parsippany, NJ) was inserted into the right lateral cerebral ventricle (LCV)
  • a cardiac catheter comprising a Silastic tube (Dow Corning, Midland MI) and a PE-50 tube (Clay Adams, Parsippany, NJ) was inserted into the right atrium of the heart.
  • the rats were divided into three groups (group 1: 5 rats, group 2: 5 rats, group 3: 3 rats), and various samples were administered to the respective groups of rats using the method described below.
  • hypoglycemic agent agent to suppress elevated blood sugar, hypoglycemic agent
  • agent for preventing or treating any of various disorders caused by hyperglycemia diabetes, complications of diabetes
  • the present invention provides novel imidazole compounds. As shown in the Experimental Example, such an imidazole compound has an action of reducing the blood sugar level of subjects (rats in the Experimental Example) in a hyperglycemic state.

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Diabetes (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Epidemiology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des compositions qui ont pour effet d'abaisser la glycémie chez des sujets présentant une hyperglycémie, grâce à un mécanisme différent des traitements classiques du diabète, lesdites compositions étant utilisées pour abaisser la glycémie des sujets. L'invention concerne aussi des compositions permettant, grâce à ce mécanisme, de prévenir ou de traiter des maladies dues à l'hyperglycémie, spécifiquement le diabète et les complications du diabète. L'invention concerne de plus un procédé visant à abaisser la glycémie de sujets présentant une hyperglycémie, et un procédé permettant de prévenir ou de traiter des maladies dues à l'hyperglycémie grâce à l'effet hypoglycémiant de cette composition. L'invention concerne aussi un procédé de criblage du principe actif desdites compositions. Elle a également trait à de nouveaux composés d'imidazole représentés par la formule (1), qui ont pour effet d'abaisser la glycémie d'un sujet présentant une hyperglycémie et sont utiles comme principe actif d'une composition hypoglycémiante, ou comme principe actif d'une composition pouvant servir à prévenir ou à traiter des troubles dus à l'hyperglycémie, spécifiquement le diabète et les complications du diabète.
PCT/JP2004/011129 2003-07-28 2004-07-28 Composition pour abaisser la glycemie WO2005009471A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2006519248A JP2007528860A (ja) 2003-07-28 2004-07-28 血糖降下用組成物

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US49063603P 2003-07-28 2003-07-28
US60/490,636 2003-07-28
US55461904P 2004-03-19 2004-03-19
US60/554,619 2004-03-19

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8829041B2 (en) 2006-06-23 2014-09-09 Abbvie Inc. Cyclopropyl amine derivatives
US8853390B2 (en) 2010-09-16 2014-10-07 Abbvie Inc. Processes for preparing 1,2-substituted cyclopropyl derivatives
US8932201B2 (en) 2006-07-25 2015-01-13 Ams Research Corporation Surgical articles and methods for treating pelvic conditions
US9108948B2 (en) 2006-06-23 2015-08-18 Abbvie Inc. Cyclopropyl amine derivatives
US9186353B2 (en) 2009-04-27 2015-11-17 Abbvie Inc. Treatment of osteoarthritis pain
CN106365998A (zh) * 2016-08-19 2017-02-01 陕西思尔生物科技有限公司 一种特戊酸碘甲酯的制备方法
WO2023285790A1 (fr) * 2021-07-15 2023-01-19 Nottingham Trent University Analogues de carnosine destinés à être utilisés dans le traitement de troubles métaboliques

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101858113B1 (ko) 2016-11-28 2018-05-15 건국대학교 글로컬산학협력단 실리비닌을 유효성분으로 함유하는 케토시스 예방 및 치료용 약학 조성물.

Citations (5)

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WO2000053596A2 (fr) * 1999-03-08 2000-09-14 Schering Corporation Composes imidazole substitues par un noyau heterocyclique a six ou sept membres renfermant deux atomes d'azote
WO2001068652A1 (fr) * 2000-03-17 2001-09-20 Novo Nordisk A/S Imidazoles condenses en tant que ligands de recepteur d'histamine h3
WO2001068651A1 (fr) * 2000-03-17 2001-09-20 Novo Nordisk A/S Imidazoles condenses comme ligands du recepteur h3 de l'histamine
EP1297830A1 (fr) * 2001-09-28 2003-04-02 Flamma Fabbrica Lombarda Ammino Acidi S.p.a. L'utilisation des acides aminés alpha ou bèta, leurs esters, ou de dipeptides de ces acides aminés avec des dérivés d'histidine, dans la prévention ou le traitement de lésions de la peau causées par l'ozone atmosphérique
WO2003059342A1 (fr) * 2002-01-11 2003-07-24 Abbott Laboratories Ligands de recepteur d'histamine-3 pour traiter des etats diabetiques

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000053596A2 (fr) * 1999-03-08 2000-09-14 Schering Corporation Composes imidazole substitues par un noyau heterocyclique a six ou sept membres renfermant deux atomes d'azote
WO2001068652A1 (fr) * 2000-03-17 2001-09-20 Novo Nordisk A/S Imidazoles condenses en tant que ligands de recepteur d'histamine h3
WO2001068651A1 (fr) * 2000-03-17 2001-09-20 Novo Nordisk A/S Imidazoles condenses comme ligands du recepteur h3 de l'histamine
EP1297830A1 (fr) * 2001-09-28 2003-04-02 Flamma Fabbrica Lombarda Ammino Acidi S.p.a. L'utilisation des acides aminés alpha ou bèta, leurs esters, ou de dipeptides de ces acides aminés avec des dérivés d'histidine, dans la prévention ou le traitement de lésions de la peau causées par l'ozone atmosphérique
WO2003059342A1 (fr) * 2002-01-11 2003-07-24 Abbott Laboratories Ligands de recepteur d'histamine-3 pour traiter des etats diabetiques

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
YAMANO TOSHIHIKO ET AL.: "Effect of L-carnosin on tbe hyperglycemia caused by intracranial injection of 2-deoxy-D-glucose in rats", NEUROSCIENCE LETTERS, vol. 313, 2001, pages 78 - 82, XP002982975 *
YOSHIMATSU HIRONOBU ET AL.: "Abnormalities in Obese Zuckers: Defective Control of Histaminergic Functions", PHYSIOLOGY & BEHAVIOR, vol. 54, no. 3, 1993, pages 487 - 491, XP002982976 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8829041B2 (en) 2006-06-23 2014-09-09 Abbvie Inc. Cyclopropyl amine derivatives
US9108948B2 (en) 2006-06-23 2015-08-18 Abbvie Inc. Cyclopropyl amine derivatives
US8932201B2 (en) 2006-07-25 2015-01-13 Ams Research Corporation Surgical articles and methods for treating pelvic conditions
US9186353B2 (en) 2009-04-27 2015-11-17 Abbvie Inc. Treatment of osteoarthritis pain
US8853390B2 (en) 2010-09-16 2014-10-07 Abbvie Inc. Processes for preparing 1,2-substituted cyclopropyl derivatives
CN106365998A (zh) * 2016-08-19 2017-02-01 陕西思尔生物科技有限公司 一种特戊酸碘甲酯的制备方法
WO2023285790A1 (fr) * 2021-07-15 2023-01-19 Nottingham Trent University Analogues de carnosine destinés à être utilisés dans le traitement de troubles métaboliques
GB2609002A (en) * 2021-07-15 2023-01-25 Univ Nottingham Trent Carnosine Analogs

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