JP7204640B2 - 糖尿病に関連する神経障害の改善 - Google Patents
糖尿病に関連する神経障害の改善 Download PDFInfo
- Publication number
- JP7204640B2 JP7204640B2 JP2019513949A JP2019513949A JP7204640B2 JP 7204640 B2 JP7204640 B2 JP 7204640B2 JP 2019513949 A JP2019513949 A JP 2019513949A JP 2019513949 A JP2019513949 A JP 2019513949A JP 7204640 B2 JP7204640 B2 JP 7204640B2
- Authority
- JP
- Japan
- Prior art keywords
- diabetes
- nsi
- amino substituted
- pharmaceutically acceptable
- type
- 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.)
- Active
Links
- 206010012601 diabetes mellitus Diseases 0.000 title description 46
- 201000001119 neuropathy Diseases 0.000 title description 2
- 230000007823 neuropathy Effects 0.000 title description 2
- 208000033808 peripheral neuropathy Diseases 0.000 title description 2
- 239000000835 fiber Substances 0.000 claims description 13
- 238000012360 testing method Methods 0.000 claims description 13
- 235000005152 nicotinamide Nutrition 0.000 claims description 12
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 11
- 150000005480 nicotinamides Chemical class 0.000 claims description 11
- 230000009885 systemic effect Effects 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 208000035475 disorder Diseases 0.000 claims description 9
- 208000004454 Hyperalgesia Diseases 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 8
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 7
- 208000021731 hypoalgesia Diseases 0.000 claims description 7
- 230000036032 hypoalgesia Effects 0.000 claims description 7
- 208000034783 hypoesthesia Diseases 0.000 claims description 7
- 229960003966 nicotinamide Drugs 0.000 claims description 7
- 239000011570 nicotinamide Substances 0.000 claims description 7
- DFPAKSUCGFBDDF-UHFFFAOYSA-N nicotinic acid amide Natural products NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 7
- 230000002829 reductive effect Effects 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 208000000044 Amnesia Diseases 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 230000007170 pathology Effects 0.000 claims description 5
- 230000007830 nerve conduction Effects 0.000 claims description 4
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002467 phosphate group Chemical class [H]OP(=O)(O[H])O[*] 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 1
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 30
- DYTOQURYRYYNOR-UHFFFAOYSA-N nsi-189 Chemical compound CC(C)CCNC1=NC=CC=C1C(=O)N1CCN(CC=2C=CC=CC=2)CC1 DYTOQURYRYYNOR-UHFFFAOYSA-N 0.000 description 17
- 150000001875 compounds Chemical class 0.000 description 16
- 102000004877 Insulin Human genes 0.000 description 15
- 108090001061 Insulin Proteins 0.000 description 15
- 229940125396 insulin Drugs 0.000 description 15
- 241000699670 Mus sp. Species 0.000 description 14
- 229940079593 drug Drugs 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 238000009472 formulation Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 230000001953 sensory effect Effects 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- 201000001421 hyperglycemia Diseases 0.000 description 5
- 230000002238 attenuated effect Effects 0.000 description 4
- 210000004045 bowman membrane Anatomy 0.000 description 4
- 210000005036 nerve Anatomy 0.000 description 4
- 230000001681 protective effect Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 230000015654 memory Effects 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 230000003442 weekly effect Effects 0.000 description 3
- 102000017011 Glycated Hemoglobin A Human genes 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 206010053552 allodynia Diseases 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 108091005995 glycated hemoglobin Proteins 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000007787 long-term memory Effects 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- 208000031091 Amnestic disease Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010021518 Impaired gastric emptying Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 230000006986 amnesia Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000003683 corneal stroma Anatomy 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000004452 decreased vision Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 208000001288 gastroparesis Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 231100000875 loss of motor control Toxicity 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 230000007514 neuronal growth Effects 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 230000001151 other effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 230000007425 progressive decline Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 230000031070 response to heat Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- -1 sec-amyl Chemical group 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 208000037921 secondary disease Diseases 0.000 description 1
- 230000006403 short-term memory Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 210000003901 trigeminal nerve Anatomy 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- 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
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Description
本出願は、2016年9月12日に出願された米国仮特許出願第62/393,514号からの優先権を主張するものである。当該出願の開示内容は、その全体が参照により本明細書に組み込まれる。
本発明は、糖尿病に関連する非全身性障害(non-systemic deficits)を改善する化合物を用いて、糖尿病患者を治療することに関する。さらに特定すると、本発明は、この目的のために、2-アミノ置換ニコチンアミドを使用することに関する。
今回、ある種の2-アミノ置換ニコチンアミドが、I型糖尿病とII型糖尿病の両方の続発性障害の様々な様相を予防または治療するのに特に有用であることが見出された。
I型糖尿病モデルに対する試験化合物の効果
雌の成体Swiss Websterマウス(20~25グラム)を試験に使用した。それらを65~82°Fおよび相対湿度30~70%の室内に維持し、12時間の明/暗サイクルで蛍光灯を用いて照らした。動物をケージあたり2~3匹で飼育し、固形飼料と水道水を自由に摂取できるようにした。一晩の絶食後に、2日間連続してストレプトゾトシン(STZ)を注射(0.9%無菌食塩水で90mg/kgを腹腔内(ip)投与)することにより糖尿病を誘発させた。4日後に、尾穿刺(tail prick)によって得られた血液のサンプルについて、ストリップ操作型反射率計を用いて高血糖を確認した。試験期間中は動物を毎日観察し、体重を毎週測定した。
パートA(発症)
対照+ビヒクル
糖尿病+ビヒクル
糖尿病+インスリン(移植したペレットによる)
糖尿病+NSI-158
糖尿病+NSI-189
糖尿病+NSI-190
パートB(7~8週間)
対照+ビヒクル
糖尿病+ビヒクル
糖尿病+NSI-150
糖尿病+NSI-182
糖尿病+NSI-183
糖尿病+NSI-189
・体重:糖尿病発症から毎週;
・血糖値:糖尿病発症時とその後は毎月;
・MNCV(大径運動線維機能):糖尿病発症前とその後は毎月;
・手動式von Freyフィラメントによる足触覚反応閾値(大径感覚線維機能):糖尿病の発症から毎月;
・足熱反応潜時(小径感覚繊維):糖尿病の発症から毎月;
・角膜神経密度(小径感覚線維構造):糖尿病発症前とその後は毎月画像を集めた;
・バーンズ迷路の成績(学習と記憶):糖尿病10週間後と試験終了時;および
・物体認識テスト(記憶):糖尿病10週間後と試験終了時。
Jolivalt, C. G., et al., Exp. Neurol. (2010) 223:422 431;
Jolivalt, C. G., et al., Diabetes Obes. Metab. (2011) 13:990 1000;
Jolivalt, C. G., et al., Neuroscience (2012) 202:405 412;および
Chen, D. K., et al., J. Peripher. Nerv. Syst. (2013) 18:306 315。
II型糖尿病
II型糖尿病は、db/db(BKS.Cg-Dock7m+/+Leprdb/J)マウスによってモデル化された。これらのマウスを実施例1に記載したのと同様の方法で維持した。MNCVの低下、接触性アロディニアおよび熱痛覚鈍麻の漸進的発症は、NSI-189によって17~22週間の処置後にかなり逆転された。
Claims (5)
- R1がイソアミルである、請求項1に記載の2-アミノ置換ニコチンアミドまたはその薬学的に許容される塩の使用。
- 2-アミノ置換ニコチンアミドがリン酸塩の形態である、請求項1~請求項3のいずれか1項に記載の2-アミノ置換ニコチンアミドまたはその薬学的に許容される塩の使用。
- 前記使用が、続いて運動神経伝導速度(MNCV)の低下、接触性アロディニア、熱痛覚鈍麻、小径線維病理、および短期もしくは長期の記憶喪失の改善について前記対象者を試験することをさらに含む、請求項1~請求項4のいずれか1項に記載の2-アミノ置換ニコチンアミドまたはその薬学的に許容される塩の使用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662393514P | 2016-09-12 | 2016-09-12 | |
US62/393,514 | 2016-09-12 | ||
PCT/US2017/050312 WO2018048927A1 (en) | 2016-09-12 | 2017-09-06 | Amelioration of neural deficits associated with diabetes |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2019532046A JP2019532046A (ja) | 2019-11-07 |
JP7204640B2 true JP7204640B2 (ja) | 2023-01-16 |
Family
ID=61558945
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019513949A Active JP7204640B2 (ja) | 2016-09-12 | 2017-09-06 | 糖尿病に関連する神経障害の改善 |
Country Status (6)
Country | Link |
---|---|
US (1) | US10322115B2 (ja) |
EP (1) | EP3497082A4 (ja) |
JP (1) | JP7204640B2 (ja) |
CN (1) | CN109952291B (ja) |
CA (1) | CA3036571C (ja) |
WO (1) | WO2018048927A1 (ja) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013502462A (ja) | 2009-08-24 | 2013-01-24 | ニューラルステム, インコーポレイテッド | 神経刺激性ピペラジンの合成 |
WO2015195567A1 (en) | 2014-06-16 | 2015-12-23 | Neuralstem, Inc. | Protocols for treatment of major depressive disorder (mdd) |
JP2016500652A (ja) | 2012-10-01 | 2016-01-14 | オリオン コーポレーション | N−プロプ−2−インイルカルボキサミド誘導体およびtrpa1アンタゴニストとしてのそれらの使用 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1474395B1 (en) * | 2002-02-12 | 2007-10-17 | Smithkline Beecham Corporation | Nicotinamide derivates useful as p38 inhibitors |
WO2004053071A2 (en) * | 2002-12-09 | 2004-06-24 | Judith Kelleher-Andersson | Method for discovering neurogenic agents |
US20100004244A1 (en) * | 2006-06-27 | 2010-01-07 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Use of cb2 receptor agonists for promoting neurogenesis |
WO2009135091A1 (en) * | 2008-04-30 | 2009-11-05 | Medivation Technologies, Inc. | Use of asenapine and related compounds for the treatment of neuronal or non-neuronal diseases or conditions |
WO2015070234A2 (en) * | 2013-11-11 | 2015-05-14 | Board Of Regents Of The University Of Texas System | Neuroprotective compounds and use thereof |
TW201620876A (zh) * | 2014-03-28 | 2016-06-16 | 奧利安公司 | 新的醫藥化合物 |
-
2017
- 2017-09-06 EP EP17849467.0A patent/EP3497082A4/en active Pending
- 2017-09-06 CA CA3036571A patent/CA3036571C/en active Active
- 2017-09-06 JP JP2019513949A patent/JP7204640B2/ja active Active
- 2017-09-06 WO PCT/US2017/050312 patent/WO2018048927A1/en unknown
- 2017-09-06 CN CN201780068510.4A patent/CN109952291B/zh active Active
- 2017-09-12 US US15/702,162 patent/US10322115B2/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013502462A (ja) | 2009-08-24 | 2013-01-24 | ニューラルステム, インコーポレイテッド | 神経刺激性ピペラジンの合成 |
JP2016500652A (ja) | 2012-10-01 | 2016-01-14 | オリオン コーポレーション | N−プロプ−2−インイルカルボキサミド誘導体およびtrpa1アンタゴニストとしてのそれらの使用 |
WO2015195567A1 (en) | 2014-06-16 | 2015-12-23 | Neuralstem, Inc. | Protocols for treatment of major depressive disorder (mdd) |
Non-Patent Citations (1)
Title |
---|
J. Pharmacol. Exp. Ther.,2007年,320,458-464 |
Also Published As
Publication number | Publication date |
---|---|
CA3036571C (en) | 2023-10-03 |
CN109952291A (zh) | 2019-06-28 |
WO2018048927A1 (en) | 2018-03-15 |
JP2019532046A (ja) | 2019-11-07 |
EP3497082A1 (en) | 2019-06-19 |
CA3036571A1 (en) | 2018-03-15 |
EP3497082A4 (en) | 2020-04-29 |
CN109952291B (zh) | 2022-09-23 |
US10322115B2 (en) | 2019-06-18 |
US20180071267A1 (en) | 2018-03-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20210283108A1 (en) | Method for treating neurodegenerative diseases | |
BR112019020798A2 (pt) | métodos e composições para tratamento de danos associados ao envelhecimento usando inibidores de ccr3 | |
BRPI0710737A2 (pt) | uso de compostos pb-10 33 éteis para o tratamento de degeneraÇço macular relacionada À idade (amd), assim como referidos compostos | |
ES2936833T3 (es) | Tasimelteón para tratar síndrome de Smith-Magenis | |
JP7204640B2 (ja) | 糖尿病に関連する神経障害の改善 | |
Parchen et al. | Ophthalmic and anesthetic evaluation of topical 1% tetracaine and 0.5% proparacaine in dogs | |
JPWO2005072066A1 (ja) | 糖尿病黄斑症の予防又は治療剤 | |
JP2006510659A (ja) | バルビツール酸誘導体を使用する運動障害の治療方法 | |
TW201609640A (zh) | 吲哚基及吲哚啉基異羥肟酸於治療神經退化病症或認知缺乏之用途 | |
JP7474706B2 (ja) | 4-フェニル酪酸を含有する老視の治療または予防剤 | |
CN114845718A (zh) | 用于治疗与过度血管形成相关的眼部疾病的化合物 | |
JP2010529125A (ja) | 胃食道逆流疾患の治療に有用な組成物 | |
Rodrigues et al. | Intraocular pressure and pupil diameter in healthy cats anesthetized with isoflurane and pre-medicated with isolated acepromazine or in combination with tramadol | |
Schmidt et al. | Effects of systemic administration of 0.5% tropicamide on intraocular pressure, pupillary diameter, blood pressure, and heart rate in normal cats | |
JP2014525474A (ja) | 光過敏性てんかんの予防または治療における使用のための1h−キナゾリン−2,4−ジオンの使用 | |
JP2018052839A (ja) | 慢性疼痛治療剤 | |
US20230381144A1 (en) | Compositions and methods for treatment of pain | |
KR102161787B1 (ko) | 수면 장애의 예방 또는 치료용 약학적 조성물 | |
JPH07258083A (ja) | 近視予防・治療剤 | |
AU2022213938A1 (en) | Pathway modulator, pharmaceutical composition having same, use thereof, and therapeutic method using same | |
JP2019059675A (ja) | 糖尿病性神経障害の予防又は治療のための医薬 | |
TW202340723A (zh) | 藉由藥劑點眼而導致之近視誘導模型 | |
TW202027752A (zh) | 使用ccr-3抑制劑治療老化相關損傷之方法及組合物 | |
WO2024102458A1 (en) | Methods of using trazodone to reverse the effects of 5-ht2a receptor agonists | |
EA019584B1 (ru) | Холиновые соли янтарной кислоты для лечения депрессий, тревоги, шизофрении, нарушений сна и эпилепсии |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190614 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20200902 |
|
RD02 | Notification of acceptance of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7422 Effective date: 20200902 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20200903 |
|
RD02 | Notification of acceptance of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7422 Effective date: 20210416 |
|
RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20210421 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20210422 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210430 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210430 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20210715 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210824 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20211118 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220221 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220614 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220912 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20221213 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20221228 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7204640 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |