JP7234151B2 - 脂肪酸誘導体およびこれらの使用 - Google Patents
脂肪酸誘導体およびこれらの使用 Download PDFInfo
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- JP7234151B2 JP7234151B2 JP2019572570A JP2019572570A JP7234151B2 JP 7234151 B2 JP7234151 B2 JP 7234151B2 JP 2019572570 A JP2019572570 A JP 2019572570A JP 2019572570 A JP2019572570 A JP 2019572570A JP 7234151 B2 JP7234151 B2 JP 7234151B2
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- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000002540 product ion scan Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000009430 psychological distress Effects 0.000 description 1
- 238000007388 punch biopsy Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000246 remedial effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 238000005464 sample preparation method Methods 0.000 description 1
- 235000021003 saturated fats Nutrition 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 210000000697 sensory organ Anatomy 0.000 description 1
- 230000020341 sensory perception of pain Effects 0.000 description 1
- 230000009007 sensory signaling Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000008591 skin barrier function Effects 0.000 description 1
- 238000007390 skin biopsy Methods 0.000 description 1
- 230000036620 skin dryness Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000010009 steroidogenesis Effects 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical class [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229920002994 synthetic fiber Polymers 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001839 systemic circulation Effects 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
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 125000000464 thioxo group Chemical class S=* 0.000 description 1
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- QURCVMIEKCOAJU-UHFFFAOYSA-N trans-isoferulic acid Natural products COC1=CC=C(C=CC(O)=O)C=C1O QURCVMIEKCOAJU-UHFFFAOYSA-N 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Images
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- C07D303/02—Compounds containing oxirane rings
- C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/00—Drugs for disorders of the nervous system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07C33/02—Acyclic alcohols with carbon-to-carbon double bonds
- C07C33/025—Acyclic alcohols with carbon-to-carbon double bonds with only one double bond
- C07C33/03—Acyclic alcohols with carbon-to-carbon double bonds with only one double bond in beta-position, e.g. allyl alcohol, methallyl alcohol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
- C07C49/24—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing hydroxy groups
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- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
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- C07D303/02—Compounds containing oxirane rings
- C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D303/40—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals by ester radicals
- C07D303/42—Acyclic compounds having a chain of seven or more carbon atoms, e.g. epoxidised fats
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
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Description
本特許出願は、2017年7月7日に出願された米国仮出願第62/529,846号への優先権を主張し、当該出願は、その全体が本明細書において参考として援用される。
本発明の実施形態において、例えば以下の項目が提供される。
(項目1)
による構造を有する化合物、またはその立体異性体、互変異性体、もしくは薬学的に許容される塩(式中、
Xは1~16個の炭素の長さの脂肪族であり
Zは、1~16個の炭素の長さの脂肪族であるか、または存在せず、
Yは、
から選択され、R 1 、R 2 、およびR 3 は、独立して水素または低級アルキルであり、
R 4 は、低級アルキル、ヒドロキシル、カルボキシル、またはアミンであり、
R 5 は、水素、低級アルキル、またはハロゲン化物であり、
R 6 は、ヒドロキシルまたは置換されているチオールであり、
各R 7 は、独立して、水素もしくはフッ化物であるか、または存在せず、隣接する炭素原子はアルキンを形成する)。
(項目2)
Yが、
のいずれか1つから選択され、各R 7 が独立して水素またはフッ化物である、項目1に記載の化合物。
(項目3)
Xが1~10個の炭素の長さである、先行する項目のいずれか一項に記載の化合物。
(項目4)
Xが6個の炭素の長さである、先行する項目のいずれか一項に記載の化合物。
(項目5)
Zが1~10個の炭素の長さである、先行する項目のいずれか一項に記載の化合物。
(項目6)
Zが4個の炭素の長さである、先行する項目のいずれか一項に記載の化合物。
(項目7)
XおよびZが一緒になって、8~14個の炭素の長さである、先行する項目のいずれか一項に記載の化合物。
(項目8)
XおよびZが一緒になって、10個の炭素の長さである、先行する項目のいずれか一項に記載の化合物。
(項目9)
XおよびZが、独立して、アルキル、置換アルケニル、または非置換アルケニルである、先行する項目のいずれか一項に記載の化合物。
(項目10)
XおよびZが、独立して1つまたは複数のフルオロアルケン、ジフルオロアルケン、および/またはビス-アリル性重水素置換を含む、先行する項目のいずれか一項に記載の化合物。
(項目11)
式(II)~(CII)のいずれか1つによる構造を有する、項目1に記載の化合物(式中、存在する場合、
R 1 は水素または低級アルキルであり、
R 2 は水素または低級アルキルであり、
R 3 は水素または低級アルキルであり、
R 4 は、低級アルキル、ヒドロキシル、カルボキシル、またはアミンであり、
R 5 は、水素、低級アルキル、またはハロゲン化物であり、
R 6 はヒドロキシルまたは置換チオールであり、
各R 7 は、独立して、水素もしくはフッ化物であるか、または存在せず、隣接する炭素はアルキンを形成し、
各R 8 は、独立して、水素またはフッ化物であり、
各R 9 は、独立して、水素または重水素である)。
(項目12)
各R 7 が独立して水素またはフッ化物である、項目11に記載の化合物。
(項目13)
R 1 、R 2 、R 3 、およびR 4 が独立してメチルである、先行する項目のいずれか一項に記載の化合物。
(項目14)
R 1 、R 2 、R 3 、およびR 4 がメチルである、先行する項目のいずれか一項に記載の化合物。
(項目15)
R 5 が水素である、先行する項目のいずれか一項に記載の化合物。
(項目16)
R 6 がヒドロキシルである、先行する項目のいずれか一項に記載の化合物。
(項目17)
R 6 がシステインまたはグルタチオンである、項目1から5のいずれか一項に記載の化合物。
(項目18)
化合物2、4、9~12、16~180、182~183、185~330のいずれか1つとして記載された構造を有する、先行する項目のいずれか一項に記載の化合物。
(項目19)
化合物1、3、5~8、13、15、181、または184のいずれかとして記載された構造を有さない、項目1から17のいずれか一項に記載の化合物。
(項目20)
化合物1~16のいずれか1つとして記載された構造を有さない、項目1から17のいずれか一項に記載の化合物。
(項目21)
による構造を有する、化合物、またはその立体異性体、互変異性体、もしくは薬学的に許容される塩(式中、
Xは、10~25個の炭素の長さの脂肪族であり、1つまたは複数のエポキシ、ヒドロキシル、またはカルボニル置換を含み、
R 1 は水素または低級アルキルであり、
各R 2 は、独立して、メチルまたは水素である)。
(項目22)
Xが、置換もしくは非置換のアルキル、置換もしくは非置換のヘテロアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のヘテロアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のヘテロアルキニル、置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリールである、項目21に記載の化合物。
(項目23)
各R 2 がメチルである、項目21または項目22に記載の化合物。
(項目24)
各R 2 が水素である、項目21または項目22に記載の化合物。
(項目25)
Xが1つまたは複数のビス-アリル性重水素置換を含む、項目21から24のいずれか一項に記載の化合物。
(項目26)
Xが17個の炭素の長さである、項目21から25のいずれか一項に記載の化合物。
(項目27)
のうちの1つによる構造を有する、化合物、またはその立体異性体、互変異性体、もしくは薬学的に許容される塩(式中、
R 5 は水素、低級アルキル、またはハロゲン化物であり、
各R 7 は、独立して、水素もしくはフッ化物であるか、または存在せず、隣接する炭素はアルキンを形成し、
R 10 およびR 11 は、独立して、脂肪族である)。
(項目28)
各R 7 が、独立して、水素またはフッ化物である、項目27に記載の化合物。
(項目29)
R 5 が水素である、項目27または項目28に記載の化合物。
(項目30)
R 10 がメチルである、項目27から29のいずれか一項に記載の化合物。
(項目31)
R 10 およびR 11 が、独立して置換もしくは非置換の低級アルキル、置換もしくは非置換の低級ヘテロアルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級ヘテロアルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級ヘテロアルキニル、置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリールである、項目27から30のいずれか一項に記載の化合物。
(項目32)
R 11 がメチルである、項目27から31のいずれか一項に記載の化合物。
(項目33)
化合物263~270のいずれか1つとして記載された構造を有する、項目27から32のいずれか一項に記載の化合物。
(項目34)
項目1から33のいずれか一項に記載の化合物と、薬学的に許容される担体とを含む、医薬組成物。
(項目35)
局所的、非経口、または経口投与用に製剤化される、項目34に記載の医薬組成物。
(項目36)
対象において疾患または状態を処置する方法であって、
項目34または項目35に記載の医薬組成物の治療有効量を、前記疾患もしくは状態を有する、または有する疑いがある対象に投与することを含み、
前記疾患または状態が、炎症、慢性のかゆみ、慢性疼痛、自己免疫障害、アテローム性動脈硬化症、皮膚障害、関節炎、神経変性障害、または精神疾患障害のうちの1つから選択される、方法。
(項目37)
前記医薬組成物が、前記対象の皮膚もしくは粘膜の、炎症、慢性疼痛、慢性のかゆみ、または皮膚障害の部位に局所的に投与される、項目36に記載の方法。
(項目38)
前記皮膚障害が水バリア機能障害または表皮性水分蒸散の増加を伴う状態である、項目37に記載の方法。
(項目39)
前記皮膚障害が魚鱗癬、湿疹、アトピー性皮膚炎、乾癬、および/または乾燥皮膚である、項目38に記載の方法。
(項目40)
前記医薬組成物中の前記化合物が2,2-ジメチルを含み、リノール酸の酸化誘導体である、項目36から39のいずれか一項に記載の方法。
(項目41)
前記医薬組成物中の前記化合物が、化合物31~36、38~43、および66~72のうちの1つまたは複数を含む、項目36から40のいずれか一項に記載の方法。
(項目42)
対象において疾患または状態を診断する方法であって、
前記対象から生物学的試料を得ることと、
前記生物学的試料中の化合物1~16のいずれか1つのレベルを測定することと、
正常な対照と比較して、前記化合物のいずれか1つのレベルの上昇が前記生物学的試料において検出された場合、前記疾患または状態を有する対象であると前記対象を診断することと
を含み、前記疾患または状態が、炎症、慢性のかゆみ、慢性疼痛、自己免疫障害、アテローム性動脈硬化症、皮膚障害、関節炎、神経変性障害、または精神疾患障害のうちの1つから選択される、方法。
(項目43)
正常な対照と比較して、前記化合物のいずれか1つのレベルの上昇が前記生物学的試料において検出された場合、前記対象には、多価不飽和脂肪酸を減らした食事を摂取させることをさらに含む、項目42に記載の方法。
I.用語
II.脂肪酸誘導体
追加の化合物実施形態
III.医薬組成物
IV.方法
以下の実施例は、ある特定の実施形態の特定の特徴を例示するために提供されているが、特許請求の範囲は、これらの例示された特徴に限定されるべきではない。
(実施例1)
疼痛およびかゆみの新規伝達物質を発見するために使用される系統的手法
(1)組織特異的な前駆体の存在量および生合成遺伝子の遺伝子発現プロファイルに基づく新規の脂質伝達物質を予測すること;
(2)全化学合成により、予測された化合物を合成すること;
(3)本物の標準物質および液体クロマトグラフィータンデム質量分析法(LC-MS/MS)を使用して、ラットおよびヒト組織においてこれらの伝達物質を特定および定量化すること;
(4)これらの化合物のレベルが食事および慢性の炎症性状態により変更できるか決定すること、ならびに
(5)盲検されたex vivo感覚ニューロン培養物およびin vivo挙動試験を使用して、これら新規脂質の疼痛および掻痒性活性を調査すること。生合成遺伝子およびこれらの発現を特定するためのこのアプローチおよび文献の系統的見直しにより、炎症性皮膚障害、掻痒症および侵害受容を調節することができる新規LA誘導性脂質伝達物質を特定した。
結果
前駆体の存在量および生合成の遺伝子発現プロファイルに基づき伝達物質を予測する
ヒドロキシ-エポキシ-およびケト-エポキシ-オクタデセノエートの組織特異的な分布
11-ヒドロキシ(H)-12,13-trans-エポキシ-(E)-オクタデセノエート(11H-12,13E-LA)
11-ケト(K)-12,13-trans-エポキシ-(E)-オクタデセノエート(11K-12,13E-LA)
9-ヒドロキシ(H)-12,13-trans-エポキシ-(E)-オクタデセノエート(9H-12,13E-LA)
炎症性乾癬のヒト皮膚における遊離伝達物質レベルの上昇
血清における伝達物質濃度は、皮膚または乾癬の状態と相関しなかった
新規LA誘導体は、部位選択的方式でラット感覚ニューロンを刺激する
新規伝達物質の皮内注射は、げっ歯類において疼痛およびかゆみに関連する挙動を引き起こす
新規伝達物質は、食事性LAにより調節され、血漿レベルの低減は臨床的疼痛減少と相関する
考察
新規内在性起痒物質としての9-ケト-12,13-エポキシ-オクタデセノエートの特定
ヒドロキシ-エポキシ-オクタデセノエートおよび慢性頭痛の食事による調節
材料および方法
データ分析
ラット組織収集
ラット痛覚回路組織の前駆体脂肪酸分析
ヒト痛覚回路組織の遺伝子発現
RNA-Seq分析のための組織の収集およびRNA精製
RNA-Seqカウント数データのアライメントおよび定量化
ヒドロキシ-エポキシ-およびケト-エポキシ-オクタデセノエートの全化学合成
LC-MS/MSを用いたヒドロキシ-およびケト-エポキシド-オクタデセノエートの特定および定量化
試料収集物を用いたヒト実験
乾癬および対照参加者からの皮膚生検および血清収集物
日常的な慢性頭痛(CDH)治験
LC-MS/MS分析のための固体組織の調製
LC-MS-MS分析のための血漿および血清の調製
ex vivo感覚ニューロン増感作用アッセイ(CGRP放出アッセイ)
げっ歯類挙動アッセイ
掻痒受容性(かゆみ)挙動
侵害受容性(疼痛)挙動
(実施例2)
11-ヒドロキシ-および11-ケト-trans-エポキシ-オクタデセノエート
(実施例3)
11-ヒドロキシ-および11-ケト-trans-エポキシ-オクタデセノエート
(実施例4)
13-ヒドロキシ-および13-ケト-trans-エポキシ-オクタデセノエート
(実施例5)
9-ヒドロキシ-および9-ケト-trans-エポキシ-オクタデセノエート
(実施例6)
2,2-ジメチル-13-ヒドロキシ-および2,2-ジメチル-13-ケト-trans-エポキシ-オクタデセノエート
(実施例7)
2,2-ジメチル-11-ヒドロキシ-、メチル-2,2-ジメチル-11-ケト-、およびメチル-2,2-ジメチル-11-ヒドロキシ-trans-エポキシ-オクタデセノエート
(実施例8)
2,2-ジメチル-11-ヒドロキシ-、メチル-2,2-ジメチル-11-ヒドロキシ-、メチル-2,2-ジメチル-11-ケト-trans-エポキシ-オクタデセノエート
(実施例9)
2,2-ジメチル-9-ヒドロキシ-、メチル-2,2-ジメチル-9-ケト-、メチル-2,2-ジメチル-9-ヒドロキシ-trans-エポキシ-オクタデセノエート
(実施例10)
1,5-エポキシファーマコフォア
(実施例11)
1,3-エポキシファーマコフォア
(実施例12)
7-ヒドロキシ-5,6-trans-エポキシ-(8Z)-オクタデセン酸(7H-5E-SA)
9-ヒドロキシ-5,6-trans-エポキシ-(7E)-オクタデセン酸(9H-5E-SA)
5-ヒドロキシ-8,9-trans-エポキシ-(6E)-オクタデセン酸(5H-8E-SA)
5-ヒドロキシ-8,9-trans-エポキシ-(6E)-オクタデセン酸(5H-8E-SA)
9-ヒドロキシ-5,6-trans-エポキシ-(7E,11Z)-エイコサジエン酸(9H-5E-MA)
7-ヒドロキシ-5,6-trans-エポキシ-(8Z,11Z)-エイコサジエン酸(7H-5E-MA)
9-ヒドロキシ-5,6-trans-エポキシ-(7E,11Z,14Z)-エイコサトリエン酸(9H-5E-AA)
7-ヒドロキシ-5,6-trans-エポキシ-(8Z,11Z,14Z)-エイコサトリエン酸(7H-5E-AA)
2,2-ジメチル-5,6-エポキシド中間体の合成
(実施例21)
2,2-ジメチル-4-ヒドロキシ-DHAの合成
(実施例22)
脂肪酸誘導体によるニューロン活性のモジュレーション
(実施例23)
脂肪酸誘導体によるかゆみ応答のモジュレーション
(実施例24)
脂肪酸誘導体によるコレステロール排出のモジュレーション
(実施例25)
脂肪酸誘導体によるPBMCサイトカイン分泌のモジュレーション
(実施例26)
2,2-ジメチル-4-HDHA-d10の合成
2,2-ジメチル-14-HDHAの合成
2,2-ジメチル-16,17-エポキシ-DHAの合成
2,2-ジメチル-7-HDHAの合成
2,2-ジメチル-17-HDHAの合成
11-OH-7,8-エポキシ-9,10-デヒドロアドレン酸の合成
本実施例は、例示的11-ヒドロキシおよび11-ケト-trans-エポキシ-9,10-デヒドロドコサジエノエート化合物の生成を例示する。以下は例示的な反応プロセスを例示している:
9-OH-7,8-エポキシ-10,11-デヒドロアドレン酸の合成
本実施例は、例示的な9-ヒドロキシおよび9-ケト-trans-エポキシ-10,11-デヒドロドコサジエノエート化合物の生成を例示する。以下は例示的な反応プロセスを例示している:
13-ヒドロキシ-9,10-trans-エポキシ-11,12-デヒドロ-オクタデセン酸の合成
9-ヒドロキシ-12,13-trans-エポキシ-10,11-デヒドロ-オクタデセン酸の合成
13-ヒドロキシ-9(R),10(R)-エポキシ-オクタデカ-11-エノエートの合成
(実施例36)
13-ヒドロキシ-9(S),10(S)-エポキシ-オクタデカ-11-エノエートの合成
(実施例37)
9,10,13-トリヒドロキシ-オクタデカ-11-エノエートの合成
(実施例38)
エステル化阻止のための2,2-ジメチル部分
LC-MS条件:Agilent 1100 LC
A:10mM NH4OAc、pH7.4
B:アセトニトリル+0.1%ギ酸
0~1.50分:5%B
1.50~2分:5~90%B
2~10分:90%B
10.01~15分:5%B
DAD1 254nm
DAD2 215nm
Agilent Zorbax XDB-C18 5μm C18 50×2.0mm
0.4ml/分
MSパラメーター:エレクトロスプレーイオン化を用いた、Agilent 6120
乾燥用気体流:11.0L/分
ネブライザー圧力:40psig
乾燥用気体温度:350℃
ポジティブキャピラリー電圧:4000V
ネガティブキャピラリー電圧:3000V
13-ヒドロキシ-9,10-trans-エポキシ-(11E)-オクタデセン酸2-グリセリルエステル
9,10,13-トリヒドロキシ-(11E)-オクタデセン酸2-グリセリルエステル
2,2-ジメチル-13-ヒドロキシ-9,10-trans-エポキシ-(11E)-オクタデセン酸
4-ヒドロキシ-DHAおよび4-ヒドロキシ-DHAラクトン
2-メチル-4-ヒドロキシ-DHA
2,2-ジメチル-4-ヒドロキシ-DHA
(実施例39)
リノール酸の酸化誘導体の類似体の局所投与を介した、皮膚遊離酸およびエステル化した脂質プールの選択的操作
Claims (16)
- (a)
Xは1~16個の炭素の長さのアルキル、置換アルケニル、または非置換アルケニルであり
Zは、1~16個の炭素の長さのアルキル、置換アルケニル、もしくは非置換アルケニルであるか、または存在せず、
Yは、
R1は、水素または低級アルキルであり、
R2およびR3は、低級アルキルであり、
R4は、低級アルキルであり、
R5は、水素であり、
R6は、ヒドロキシルであり、
各R7は、独立して、水素であるか、または存在せず、隣接する炭素原子はアルキンを形成する)、または
(b)
(式中、
R 1 は、水素または低級アルキルであり、
R 2 およびR 3 は、低級アルキルであり、
R 4 は、低級アルキルであり、
R 5 は、水素であり、
R 6 は、ヒドロキシルであり、
各R 7 は、独立して、水素であるか、または存在せず、隣接する炭素原子はアルキンを形成し、そして
各R9は、独立して、水素または重水素である)
による構造を有する、化合物、またはその立体異性体、互変異性体、もしくは薬学的に許容される塩。 - (i)Xが1~10個の炭素の長さである、または
(ii)Zが1~10個の炭素の長さである、または
(iii)XおよびZが一緒になって、8~14個の炭素の長さである、または
(iv)(i)、(ii)および(iii)の任意の組合せである、
請求項1または2に記載の式Iによる化合物。 - (i)Xが6個の炭素の長さである、または
(ii)Zが4個の炭素の長さである、または
(iii)XおよびZが一緒になって、10個の炭素の長さである、請求項1から3のいずれか一項に記載の式Iによる化合物。 - XおよびZが、独立して1つまたは複数のフルオロアルケン、ジフルオロアルケン、および/またはビス-アリル性重水素置換を含む、請求項1から4のいずれか一項に記載の式Iによる化合物。
- 各R7が水素である、請求項5に記載の化合物。
- R1、R2、R3、およびR4が独立してメチルである、請求項1から7のいずれか一
項に記載の式Iによる化合物。 - (i)R5が水素である、または
(ii)R6がヒドロキシルである、または
(iii)(i)および(ii)の両方である、請求項1から8のいずれか一項に記載の式Iによる化合物。 - 請求項1から10のいずれか一項に記載の化合物と、薬学的に許容される担体とを含む、医薬組成物。
- 局所的、非経口、または経口投与用に製剤化される、請求項11に記載の医薬組成物。
- 対象において疾患または状態を処置するための方法における使用のための、請求項1から9のいずれか一項に記載の化合物および薬学的に許容される担体を含む医薬組成物であって、前記方法は、
前記医薬組成物の治療有効量を、前記疾患もしくは状態を有する、または有する疑いがある対象に投与することを含み、
前記疾患または状態が、炎症、慢性のかゆみ、慢性疼痛、自己免疫障害、アテローム性動脈硬化症、皮膚障害、関節炎、神経変性障害、または精神疾患障害のうちの1つから選択される、医薬組成物。 - 前記医薬組成物が、前記対象の皮膚もしくは粘膜の、炎症、慢性疼痛、慢性のかゆみ、または皮膚障害の部位に局所的に投与される、請求項13に記載の使用のための医薬組成物。
- 前記皮膚障害が水バリア機能障害または表皮性水分蒸散の増加を伴う状態であり、特に、前記皮膚障害が、魚鱗癬、湿疹、アトピー性皮膚炎、乾癬、および/または乾燥皮膚である、請求項14に記載の使用のための医薬組成物。
- 前記医薬組成物中の前記化合物が、化合物31、32、38、39、66または67のうちの1つまたは複数を含む、請求項13から15のいずれか一項に記載の使用のための医薬組成物。
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JP2012502035A (ja) | 2008-09-04 | 2012-01-26 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ロイコトリエン産生のインドリジン阻害剤 |
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US20020037876A1 (en) * | 1998-06-25 | 2002-03-28 | Yissum Research Development Company Of Hebrew University Of Jerusalem | Carboxylic acids and derivatives thereof and pharmaceutical compositions containing them |
WO2006106438A2 (en) * | 2005-01-11 | 2006-10-12 | Evolva Sa | Modulators of ppar activity |
AU2006242914B2 (en) | 2005-05-04 | 2012-02-02 | Pronova Biopharma Norge As | New DHA derivatives and their use as medicaments |
JP6160375B2 (ja) | 2013-09-06 | 2017-07-12 | ブラザー工業株式会社 | 画像記録装置 |
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CN110869354A (zh) | 2020-03-06 |
WO2019010414A1 (en) | 2019-01-10 |
US20210139440A1 (en) | 2021-05-13 |
AU2018297192B2 (en) | 2022-02-17 |
EP3649115A1 (en) | 2020-05-13 |
US20220274940A1 (en) | 2022-09-01 |
CA3064132A1 (en) | 2019-01-10 |
KR20200027545A (ko) | 2020-03-12 |
US11555021B2 (en) | 2023-01-17 |
AU2018297192A1 (en) | 2019-12-19 |
CA3064132C (en) | 2024-06-04 |
JP2020526505A (ja) | 2020-08-31 |
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