JP7446465B2 - 糖尿およびそれに伴う代謝疾患の予防または治療用の薬学的組成物 - Google Patents
糖尿およびそれに伴う代謝疾患の予防または治療用の薬学的組成物 Download PDFInfo
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- JP7446465B2 JP7446465B2 JP2022554634A JP2022554634A JP7446465B2 JP 7446465 B2 JP7446465 B2 JP 7446465B2 JP 2022554634 A JP2022554634 A JP 2022554634A JP 2022554634 A JP2022554634 A JP 2022554634A JP 7446465 B2 JP7446465 B2 JP 7446465B2
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- 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
- 238000001794 hormone therapy Methods 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- 235000015243 ice cream Nutrition 0.000 description 1
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- 230000003993 interaction Effects 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 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
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
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- 244000144972 livestock Species 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
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- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
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- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 235000012149 noodles Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
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- 229940126701 oral medication Drugs 0.000 description 1
- 229940116315 oxalic acid Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 235000013550 pizza Nutrition 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000030558 renal glucose absorption Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 235000013580 sausages Nutrition 0.000 description 1
- 108010027322 single cell proteins Proteins 0.000 description 1
- 235000011888 snacks Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940121377 sodium-glucose co-transporter inhibitor Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000003765 sweetening agent Substances 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
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000004867 thiadiazoles Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
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- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- 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
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- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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- 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Plant Substances (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
一方、糖尿患者にとっては、糖尿に伴う代謝疾患が問題となっている。具体的には、糖尿に伴う肥満または脂質異常症が問題となっている。
本発明は、投与対象に投与時に血中脂質濃度の改善および体脂肪の減少効果を示す薬学的組成物を提供することを一つの目的とする。
本発明は、糖尿またはそれに伴う代謝疾患の予防または治療用途として有用に使用できる薬学的組成物を提供することを一つの目的とする。
もよい。前記アルキル基または前記ヒドロキシアルキル基は、それぞれ独立して、置換されていないか、またはハロゲン原子またはC1-C6アルコキシ基で置換されていてもよい。
前記化学式1中、前記Aは、直鎖もしくは分岐鎖のC1-C6アルキル基で置換されたオキサジアゾール基であり、前記Bは、直鎖もしくは分岐鎖のC1-C6アルキル基で置換されたピリミジン基であり、Xは、Fであってもよい。
2-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-4,5-ジヒドロオキサゾール、
(R)-2-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-4-メチル-4,5-ジヒドロオキサゾール、
(S)-2-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-4-メチル-4,5-ジヒドロオキサゾール、
(S)-2-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-5-メチル-4,5-ジヒドロオキサゾール、
(R)-2-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4
-イル)プロポキシ)-2,6-ジフルオロフェニル)-5-メチル-4,5-ジヒドロオキサゾール、
2-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-5,5-ジメチル-4,5-ジヒドロオキサゾール、
(R)-(2-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-4,5-ジヒドロオキサゾール-5-イル)メタノール、
(S)-(2-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-4,5-ジヒドロオキサゾール-5-イル)メタノール、
(R)-3-(2-(4-(3-(3,5-ジフルオロ-4-(5-メチル-4,5-ジヒドロオキサゾール-2-イル)フェノキシ)プロピル)ピペリジン-1-イル)ピリミジン-5-イル)-5-イソブチル-1,2,4-オキサジアゾール、
(R)-5-(4-(3-(3,5-ジフルオロ-4-(4-メチル-4,5-ジヒドロオキサゾール-2-イル)フェノキシ)プロピル)ピペリジン-1-イル)-3-イソプロピル-1,2,4-オキサジアゾール、
(S)-5-(4-(3-(3,5-ジフルオロ-4-(5-メチル-4,5-ジヒドロオキサゾール-2-イル)フェノキシ)プロピル)ピペリジン-1-イル)-3-イソプロピル-1,2,4-オキサジアゾール、
5-(4-(3-(4-(5,5-ジメチル-4,5-ジヒドロオキサゾール-2-イル)-3,5-ジフルオロフェノキシ)プロピル)ピペリジン-1-イル)-3-イソプロピル-1,2,4-オキサジアゾール、
3-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-5-メチル-1,2,4-オキサジアゾール、
3-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-5-プロピル-1,2,4-オキサジアゾール、
3-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-5-イソプロピル-1,2,4-オキサジアゾール、
5-(tert-ブチル)-3-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-1,2,4-オキサジアゾール、
(3-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-1,2,4-オキサジアゾール-5-イル)メタノール、
2-(3-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-1,2,4-オキサジアゾール-5-イル)エタン-1-オール、
(S)-1-(3-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-1,2,4-オキサジアゾール-5-イル)プロパン-1-オール、
(R)-1-(3-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-1,2,4-オキサジアゾール-5-イル)プロパン-2-オール、
(S)-1-(3-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-1,2,4-オキサジアゾール-5-イル)プロパン-2-オール、
2-(3-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-1,2,4-オキサジアゾール-5-イル)-2-メチルプロパン-1-オール、
3-(2,6-ジフルオロ-4-(3-(1-(5-プロピルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)フェニル)-5-イソプロピル-1,2,4-オキサジアゾール、
3-(2,6-ジフルオロ-4-(3-(1-(5-ペンチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)フェニル)-5-イソプロピル-1,2,4-オキサジアゾール、
3-(2,6-ジフルオロ-4-(3-(1-(5-(トリフルオロメチル)ピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)フェニル)-5-イソプロピル-1,2,4-オキサジアゾール、
3-(2,6-ジフルオロ-4-(3-(1-(5-メトキシピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)フェニル)-5-イソプロピル-1,2,4-オキサジアゾール、
3-(2,6-ジフルオロ-4-(3-(1-(5-イソプロポキシピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)フェニル)-5-イソプロピル-1,2,4-オキサジアゾール、
3-(4-(3-(1-(5-クロロピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-5-イソプロピル-1,2,4-オキサジアゾール、
3-(4-(3-(1-(5-ブロモピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-5-イソプロピル-1,2,4-オキサジアゾール、
3-(2,6-ジフルオロ-4-(3-(1-(5-(5-イソブチル-1,2,4-オキサジアゾール-3-イル)ピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)フェニル)-5-メチル-1,2,4-オキサジアゾール、
3-(2,6-ジフルオロ-4-(3-(1-(5-(5-イソブチル-1,2,4-オキサジアゾール-3-イル)ピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)フェニル)-5-エチル-1,2,4-オキサジアゾール、
3-(2,6-ジフルオロ-4-(3-(1-(5-(5-イソブチル-1,2,4-オキサジアゾール-3-イル)ピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)フェニル)-5-イソプロピル-1,2,4-オキサジアゾール、
5-(sec-ブチル)-3-(2,6-ジフルオロ-4-(3-(1-(5-(5-イソブチル-1,2,4-オキサジアゾール-3-イル)ピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)フェニル)-1,2,4-オキサジアゾール、
3-(2,6-ジフルオロ-4-(3-(1-(5-(5-イソブチル-1,2,4-オキサジアゾール-3-イル)ピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)フェニル)-5-(メトキシメチル)-1,2,4-オキサジアゾール、
(S)-1-(3-(2,6-ジフルオロ-4-(3-(1-(5-(5-イソブチル-1,2,4-オキサジアゾール-3-イル)ピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)フェニル)-1,2,4-オキサジアゾール-5-イル)プロパン-1-オール、
2-(3-(2,6-ジフルオロ-4-(3-(1-(5-(5-イソブチル-1,2,4-オキサジアゾール-3-イル)ピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)フェニル)-1,2,4-オキサジアゾール-5-イル)-2-メチルプロパン-1-オール、
3-(4-(3-(1-(5-クロロピラジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-5-イソプロピル-1,2,4-オキサジアゾール、
3-(2,6-ジフルオロ-4-(3-(1-(5-(トリフルオロメチル)ピリジン-2-イル)ピペリジン-4-イル)プロポキシ)フェニル)-5-イソプロピル-1,2,4-オキサジアゾール、
3-(2,6-ジフルオロ-4-(3-(1-(3-イソプロピル-1,2,4-オキサジアゾール-5-イル)ピペリジン-4-イル)プロポキシ)フェニル)-5-メチル-1,2,4-オキサジアゾール、
3-(2,6-ジフルオロ-4-(3-(1-(3-イソプロピル-1,2,4-オキサジアゾール-5-イル)ピペリジン-4-イル)プロポキシ)フェニル)-5-イソプロピル-1,2,4-オキサジアゾール、
(3-(2,6-ジフルオロ-4-(3-(1-(3-イソプロピル-1,2,4-オキサジアゾール-5-イル)ピペリジン-4-イル)プロポキシ)フェニル)-1,2,4-オキサジアゾール-5-イル)メタノール、
2-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-5-メチル-1,3,4-オキサジアゾール、
2-エチル-5-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-1,3,4-オキサジアゾール、
2-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-5-イソプロピル-1,3,4-オキサジアゾール、
5-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-N-イソプロピル-1,3,4-オキサジアゾール-2-アミン、
2-(2,6-ジフルオロ-4-(3-(1-(5-(トリフルオロメチル)ピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)フェニル)-5-メチル-1,3,4-オキサジアゾール、
2-(2,6-ジフルオロ-4-(3-(1-(5-(トリフルオロメチル)ピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)フェニル)-5-エチル-1,3,4-オキサジアゾール、
2-(2,6-ジフルオロ-4-(3-(1-(5-(トリフルオロメチル)ピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)フェニル)-5-イソプロピル-1,3,4-オキサジアゾール、
2-(4-(3-(1-(5-クロロピラジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-5-メチル-1,3,4-オキサジアゾール、
2-(4-(3-(1-(5-クロロピラジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-5-エチル-1,3,4-オキサジアゾール、
2-(4-(3-(1-(5-クロロピラジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-5-イソプロピル-1,3,4-オキサジアゾール、
5-(4-(3-(3,5-ジフルオロ-4-(5-メチル-1,3,4-オキサジアゾール-2-イル)フェノキシ)プロピル)ピペリジン-1-イル)-3-プロピル-1,2,4-オキサジアゾール、
5-(4-(3-(3,5-ジフルオロ-4-(5-エチル-1,3,4-オキサジアゾール-2-イル)フェノキシ)プロピル)ピペリジン-1-イル)-3-プロピル-1,2,4-オキサジアゾール、
5-(4-(3-(3,5-ジフルオロ-4-(5-イソプロピル-1,3,4-オキサジアゾール-2-イル)フェノキシ)プロピル)ピペリジン-1-イル)-3-プロピ
ル-1,2,4-オキサジアゾール、
5-(4-(3-(3,5-ジフルオロ-4-(5-メチル-1,3,4-オキサジアゾール-2-イル)フェノキシ)プロピル)ピペリジン-1-イル)-3-イソプロピル-1,2,4-オキサジアゾール、
5-(4-(3-(4-(5-エチル-1,3,4-オキサジアゾール-2-イル)-3,5-ジフルオロフェノキシ)プロピル)ピペリジン-1-イル)-3-イソプロピル-1,2,4-オキサジアゾール、
5-(4-(3-(3,5-ジフルオロ-4-(5-イソプロピル-1,3,4-オキサジアゾール-2-イル)フェノキシ)プロピル)ピペリジン-1-イル)-3-イソプロピル-1,2,4-オキサジアゾール、
5-(4-(3-(3,5-ジフルオロ-4-(5-メチル-1,3,4-オキサジアゾール-2-イル)フェノキシ)プロピル)ピペリジン-1-イル)-3-(2,2,2-トリフルオロエチル)-1,2,4-オキサジアゾール、
3-(4-(3-(3,5-ジフルオロ-4-(5-イソプロピル-1,3,4-オキサジアゾール-2-イル)フェノキシ)プロピル)ピペリジン-1-イル)-5-イソプロピル-1,2,4-オキサジアゾール、
2-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-5-イソプロピル-1,3,4-チアジアゾール、
2-(2,6-ジフルオロ-4-(3-(1-(5-プロピルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)フェニル)-5-イソプロピル-1,3,4-チアジアゾール、
2-(2,6-ジフルオロ-4-(3-(1-(5-ペンチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)フェニル)-5-イソプロピル-1,3,4-チアジアゾール、
2-(2,6-ジフルオロ-4-(3-(1-(5-フルオロピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)フェニル)-5-イソプロピル-1,3,4-チアジアゾール、
2-(2,6-ジフルオロ-4-(3-(1-(5-(トリフルオロメチル)ピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)フェニル)-5-イソプロピル-1,3,4-チアジアゾール、
2-(2,6-ジフルオロ-4-(3-(1-(5-(トリフルオロメチル)ピリジン-2-イル)ピペリジン-4-イル)プロポキシ)フェニル)-5-イソプロピル-1,3,4-チアジアゾール、および
4-エチル-2-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)チアゾール。
リプチンのうち少なくとも一つであってもよい。
本発明の一実施形態においては、特殊飼料を供給して高血糖、インスリン抵抗性または肥満を誘発したマウスモデルにおいて、血糖、中性脂肪および体重の測定を介して、一実施形態の薬学的組成物が糖尿および糖尿に伴う代謝疾患の治療および予防に効果があることを明らかにした。
どの滑沢剤も用いられる。
えられる動物またはヒトにおける生物学的または医学的反応を誘導する活性成分または薬学的組成物の量を意味するものであって、これは、治療される疾患または障害の症状の緩和を誘導する量を含む。本発明の有効成分に対する治療上の有効投与量および投与回数は、所望の効果に応じて変化できることは当業者に明らかなことである。
物の例としては、ブドウ糖、果糖、マルトース、スクロース、オリゴ糖、デキストリン、シクロデキストリン、キシリトール、ソルビトール、エリトロール、サッカリンまたは合成香味剤が挙げられるが、これに制限されない。本発明の食品組成物は、食品として認められる剤形であれば制限されずに多様な形態の剤形に製造されてもよい。
本発明に係る薬学的組成物を投与対象に投与時に血中脂質濃度の改善および体脂肪の減少効果を示すことができる。
したがって、本発明に係る薬学的組成物は、糖尿またはそれに伴う代謝疾患の予防または治療用途として有用に使用することができる。
ド系薬物およびα-グルコシダーゼ阻害剤の中から選択される少なくとも一つ;をさらに含んでもよい。したがって、一実施形態の薬学的組成物は、異なるメカニズムを有する2以上の薬物を併用投与し、多様なメカニズムで血糖を降下させることで、効果的に血糖を調節することができる。
(ipragliflozin)、ルセオグリフロジン(luseogliflozin)、レモグリフロジン(remogliflozin)、セルグリフロジン(sergliflozin)、ソタグリフロジンン(sotagliflozin)およびトホグリフロジン(tofogliflozin)のうち少なくとも一つを含んでもよい。
正常マウスでの1回投与有効性の評価
16時間以上絶食させたICR 7週齢の雄性マウスに、化合物1、DDPIV阻害剤としてシタグリプチンまたはエボグリプチンを単独投与するか、またはシタグリプチンおよびエボグリプチンのうち一つを化合物1と併用投与した。単独投与および併用投与のいずれも、化合物1は0.3mg/kg、シタグリプチンは10mg/kg、エボグリプチンは0.2mg/kgを経口で投与した。薬物投与から30分経過時点で、ブドウ糖溶液を2g/kg/10mlで経口で注入した。
PIV阻害剤を前処理した容器から血漿を分離し、血中の活性型GLP-1濃度を、GLP-1(Active)ELISAキット(Millipore、Cat.EGLP-35K)を用いて定量した。食後血糖に対する薬物反応評価のためには、血中ブドウ糖の注入から0、15、30、60、90、120分の時点に、尾静脈から採血した全血中の血糖を、Roche社のAccuChek Active血糖測定器を用いて測定した。時間-血糖反応曲線を得、溶媒のみを投与した対照群の時間-血糖曲線下面積と薬物投与群の時間-血糖曲線下面積との変化率を比較した。その結果を図1および図2に示した。
ICR 7週齢の雄性マウスに、高脂肪飼料(Research Diets Inc.、D12492;60% kcal fat)を3週間供給した。3週目にストレプトゾトシン(STZ)80mg/kgを腹腔注射から3週経過した時点で、体重、血糖、血中中性脂肪濃度に応じて群を分離した。具体的には、正常マウスよりも非絶食時血糖が1SD(Standard Deviation)以上、血漿中性脂肪が2SD以上に増加した個体を選別して群を分離した。分離した群に、100mg/kg/dayの化合物1と150mg/kg/dayのシタグリプチンが混合された薬物混合飼料を投与した。飼料は、10週間供給した。その後、絶食時血糖、非絶食時血糖および血漿中の中性脂肪濃度を測定した。絶食時血糖および非絶食時血糖は、尾静脈から採血した血液で、Roche社のAccuChek Active血糖測定器を用いて測定した。非絶食下で剖検後に採血した血漿で、自動血液分析装置(Konelab 20i)を用いて血漿中の中性脂肪濃度を測定した。
16時間以上絶食させたICR 7週齢の雄性マウスに、化合物1、SGLT阻害剤としてダパグリフロジンまたはインスリン分泌促進剤としてグリメピリドを単独投与するか、またはダパグリフロジンおよびグリメピリドのうち一つを化合物1と併用投与した。化合物1は3mg/kg、SGLT2阻害剤であるダパグリフロジンは0.3mg/kg、またはインスリン分泌促進剤であるグリメピリドは0.1mg/kgを単独または併用で経口で薬物投与から30分経過時点で、ブドウ糖溶液を2g/kg/10mlで経口で注
入した。食後血糖に対する薬物反応評価のためには、血中ブドウ糖の注入から0、15、30、60、90、120分の時点に、尾静脈から採血した全血中の血糖を、Roche社のAccuChek Active血糖測定器を用いて測定した。時間-血糖反応曲線を得、溶媒のみを投与した対照群の曲線下面積に対して、薬物投与群の時間-血糖曲線下面積の変化率を比較した。
インスリン抵抗性の誘発のために、6週齢の雄性のC57BL/6Jマウスに、高脂肪、高果糖、高コレステロールの特殊飼料(Research Diets Inc.、D09100301)を27週以上供給した。肥満およびインスリン抵抗性が誘発された(Diet-induced obese;DIO)マウスに、化合物1を100mg/kg/day、PPARアゴニストであるエラフィブラノールを30mg/kg/dayでそれぞれ単独または併用投与するために、薬物混合飼料を製造した。製造された薬物混合飼料をマウスに12週間供給した。薬物投与から12週の時点で剖検後に採血した血漿中の非絶食時血糖を、Roche社のAccuChek Active血糖測定器を用いて測定した。
<実施例4>GPR119リガンドとビグアナイド系薬物との併用効能の確認
4週齢の雄性のC57BL/6Jマウスに、10週間高脂肪飼料(Research Diets Inc.、D12492;60% kcal fat)を供給し、インスリン抵抗性を誘発した。2週間薬物投与に適応させた後、体重および体脂肪を基準に群分離を行った。化合物1の単独投与群には、化合物1を50mg/kgで1日に2回、メトホルミンの単独投与群には、メトホルミンを150mg/kgで1日に2回単独投与した。併用投与群には、化合物1を50mg/kg、メトホルミンを150mg/kgで併用して1日に2回ずつ3週間経口投与した。16日の投薬時点まで体重を経時的に測定した後、最後の週には、Minispec LF90II NMRスペクトロメータ(Bruker Optics、Ettlingen、Germany)を用いて体成分を順次測定した。投与から2週目に6時間絶食させた後、尾静脈から得た全血から、Roche社のAccuChek Active血糖測定器を用いて空腹時血糖を測定した。3週間の投薬後に非絶食下で剖検し、血漿中の総GLP-1濃度は、Total GLP-1 ELISA(7-36 and 9-36)アッセイキット(Alpco、43-GPTHU-E01)を用いて定量した。
それぞれ-4.0%、-4.4%の体重減少を示した。これに対し、二つの薬物を2週間併用投与した場合には、-16.3%の体重減少を示した。すなわち、二つの薬物を併用投与する場合、二つの薬物をそれぞれ単独投与した場合に比べて、薬物に対する反応性が有意に増加することが確認される。このことから、二つの薬物の併用投与による肥満の予防または治療に対する相乗効果を確認した。
16時間以上絶食させたICR 8週齢の雄性マウスに、化合物1は3mg/kg、α-グルコシダーゼ阻害剤であるボグリボースは0.02mg/kgを単独または併用で経口薬物投与から30分経過時点で、蔗糖(sucrose)溶液を2g/kg/10mlで経口で注入した。食後血糖に対する薬物反応評価のために、血中ブドウ糖の注入から0、15、30、60、90、120分の時点に、尾静脈から採血した全血中の血糖を、Roche社のAccuChek Active血糖測定器を用いて測定した。時間-血糖反応曲線を得、溶媒のみを投与した対照群の曲線下面積に対して、薬物投与群の時間-血糖曲線下面積の変化率を比較した。
Claims (5)
- 前記化学式1で表される化合物は、3-(4-(3-(1-(5-エチルピリミジン-2-イル)ピペリジン-4-イル)プロポキシ)-2,6-ジフルオロフェニル)-5-イソプロピル-1,2,4-オキサジアゾールである、請求項1に記載の薬学的組成物。
- 糖尿または、肥満および脂質異常症の中から選択される少なくとも一つの疾患の予防または治療用の薬学的製剤を製造するための、請求項1に記載の化学式1で表される化合物、その薬学的に許容可能な塩、その光学異性体、その水和物または溶媒和物、またはその混合物;および
エボグリプチン、シタグリプチン、エラフィブラノール、ダパグリフロジン、メトホルミンおよびボグリボースの中から選択される少なくとも一つ;を含む薬学的組成物の使用。
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JP2017533213A (ja) | 2014-10-27 | 2017-11-09 | ドン−ア エスティ カンパニー リミテッド | Gpr119作用活性を有する化合物、その製造方法およびこれを有効性分として含有する薬剤学的組成物 |
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UA91698C2 (ru) * | 2005-01-10 | 2010-08-25 | Арена Фармасьютікалз, Інк. | Комбинированная терапия для лечения диабета и родственных ему состояний и для лечения состояний, улучшенных увеличением уровня glp-1 крови |
CN101754961A (zh) * | 2007-04-20 | 2010-06-23 | 先灵公司 | 嘧啶酮衍生物及其使用方法 |
US20120053180A1 (en) * | 2010-08-27 | 2012-03-01 | Chemizon, A Division Of Optomagic Co., Ltd. | Cyclohexane analogues as gpr119 agonists |
WO2012145604A1 (en) * | 2011-04-22 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2016068453A1 (en) * | 2014-10-27 | 2016-05-06 | Dong-A St Co., Ltd. | Compound having gpr119 agonistic activity, method for preparing the same, and pharmaceutical composition including the same as effective component |
WO2017106112A1 (en) * | 2015-12-16 | 2017-06-22 | Merck Sharp & Dohme Corp. | Methods of preventing or treating hypoglycemia by administering a gpr119 agonist |
CA3113579A1 (en) * | 2018-09-12 | 2020-03-19 | Dong-A St Co., Ltd. | Pharmaceutical composition for preventing or treating nonalcoholic fatty liver disease, containing gpr119 ligand as active ingredient |
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JP2008526235A (ja) | 2005-01-10 | 2008-07-24 | アリーナ ファーマシューティカルズ, インコーポレイテッド | 糖尿病および糖尿病に関連する状態の治療のため、ならびに血中glp−1レベルの増加によって改善される状態の治療のための併用療法 |
JP2017517483A (ja) | 2014-04-07 | 2017-06-29 | サノフイ | エキセンジン−4に由来する二重glp−1/グルカゴン受容体アゴニスト |
JP2017533213A (ja) | 2014-10-27 | 2017-11-09 | ドン−ア エスティ カンパニー リミテッド | Gpr119作用活性を有する化合物、その製造方法およびこれを有効性分として含有する薬剤学的組成物 |
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KR20210114888A (ko) | 2021-09-24 |
AU2021235294B2 (en) | 2024-05-30 |
BR112022017942A2 (pt) | 2023-01-17 |
WO2021182877A1 (ko) | 2021-09-16 |
US20230143119A1 (en) | 2023-05-11 |
MX2022011129A (es) | 2022-10-13 |
EP4098262A4 (en) | 2024-02-28 |
KR102538048B1 (ko) | 2023-05-30 |
AU2021235294A1 (en) | 2022-09-08 |
IL295948A (en) | 2022-10-01 |
JP2023517612A (ja) | 2023-04-26 |
CN115243689A (zh) | 2022-10-25 |
EP4098262A1 (en) | 2022-12-07 |
CA3167630A1 (en) | 2021-09-16 |
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