CN109180478A - Compound in diphenyl heptane class and its preparation method and application - Google Patents
Compound in diphenyl heptane class and its preparation method and application Download PDFInfo
- Publication number
- CN109180478A CN109180478A CN201811032569.0A CN201811032569A CN109180478A CN 109180478 A CN109180478 A CN 109180478A CN 201811032569 A CN201811032569 A CN 201811032569A CN 109180478 A CN109180478 A CN 109180478A
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- China
- Prior art keywords
- compound
- ethyl acetate
- reaction
- preparation
- heptyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 131
- QXDWRXCXHXYLNC-UHFFFAOYSA-N 4-phenylheptan-4-ylbenzene Chemical class C=1C=CC=CC=1C(CCC)(CCC)C1=CC=CC=C1 QXDWRXCXHXYLNC-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims description 40
- 239000003814 drug Substances 0.000 claims abstract description 24
- -1 cyclopropanecarbonyl Chemical group 0.000 claims abstract description 22
- 229940079593 drug Drugs 0.000 claims abstract description 21
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 20
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims abstract description 4
- 239000002775 capsule Substances 0.000 claims abstract description 4
- 239000000839 emulsion Substances 0.000 claims abstract description 4
- 238000002347 injection Methods 0.000 claims abstract description 4
- 239000007924 injection Substances 0.000 claims abstract description 4
- 239000006187 pill Substances 0.000 claims abstract description 4
- 239000000375 suspending agent Substances 0.000 claims abstract description 4
- 239000003826 tablet Substances 0.000 claims abstract description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 4
- 229960003444 immunosuppressant agent Drugs 0.000 claims abstract description 3
- 230000001861 immunosuppressant effect Effects 0.000 claims abstract description 3
- 239000003018 immunosuppressive agent Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 117
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 78
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 72
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 72
- 238000006243 chemical reaction Methods 0.000 claims description 58
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 42
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 37
- 239000000243 solution Substances 0.000 claims description 26
- 239000000047 product Substances 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 239000002994 raw material Substances 0.000 claims description 22
- 239000003054 catalyst Substances 0.000 claims description 21
- 238000001514 detection method Methods 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 11
- 239000001301 oxygen Substances 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 229940125904 compound 1 Drugs 0.000 claims description 8
- 229940125782 compound 2 Drugs 0.000 claims description 8
- 229940126214 compound 3 Drugs 0.000 claims description 8
- 229940125898 compound 5 Drugs 0.000 claims description 8
- 239000003480 eluent Substances 0.000 claims description 6
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 6
- 235000013305 food Nutrition 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 claims description 4
- ICXIVBYQRNOIJJ-UHFFFAOYSA-N 2-tert-butylbenzenesulfonyl chloride Chemical compound CC(C)(C)C1=CC=CC=C1S(Cl)(=O)=O ICXIVBYQRNOIJJ-UHFFFAOYSA-N 0.000 claims description 3
- WHIHIKVIWVIIER-UHFFFAOYSA-N 3-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC(Cl)=C1 WHIHIKVIWVIIER-UHFFFAOYSA-N 0.000 claims description 3
- KMMHZIBWCXYAAH-UHFFFAOYSA-N 4-bromobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C(Br)C=C1 KMMHZIBWCXYAAH-UHFFFAOYSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- 238000010828 elution Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 3
- SJGSVFXEXGQCCY-UHFFFAOYSA-N sulfuryl dichloride;trifluoromethylbenzene Chemical compound ClS(Cl)(=O)=O.FC(F)(F)C1=CC=CC=C1 SJGSVFXEXGQCCY-UHFFFAOYSA-N 0.000 claims description 3
- 238000003809 water extraction Methods 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000005303 weighing Methods 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 7
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 239000003292 glue Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 30
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 18
- 238000005481 NMR spectroscopy Methods 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 18
- 239000001257 hydrogen Substances 0.000 description 18
- 229910052739 hydrogen Inorganic materials 0.000 description 18
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 14
- 239000011734 sodium Substances 0.000 description 13
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 229960000485 methotrexate Drugs 0.000 description 10
- MZLKNWMNBXHXMA-UHFFFAOYSA-N 1-phenylheptylbenzene Chemical class C=1C=CC=CC=1C(CCCCCC)C1=CC=CC=C1 MZLKNWMNBXHXMA-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 206010042971 T-cell lymphoma Diseases 0.000 description 4
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 4
- 230000001766 physiological effect Effects 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical class CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 244000163122 Curcuma domestica Species 0.000 description 2
- 240000009138 Curcuma zedoaria Species 0.000 description 2
- 235000003405 Curcuma zedoaria Nutrition 0.000 description 2
- 244000062241 Kaempferia galanga Species 0.000 description 2
- 235000013421 Kaempferia galanga Nutrition 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical group O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000001812 curcuma zedoaria berg. rosc. Substances 0.000 description 2
- 210000005175 epidermal keratinocyte Anatomy 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000002510 keratinocyte Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 235000019509 white turmeric Nutrition 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- OTEKOJQFKOIXMU-UHFFFAOYSA-N 1,4-bis(trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=C(C(Cl)(Cl)Cl)C=C1 OTEKOJQFKOIXMU-UHFFFAOYSA-N 0.000 description 1
- GYOBZOBUOMDRRN-UHFFFAOYSA-N 2-methoxybenzenesulfonyl chloride Chemical compound COC1=CC=CC=C1S(Cl)(=O)=O GYOBZOBUOMDRRN-UHFFFAOYSA-N 0.000 description 1
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 description 1
- VQDQISMDUHBUFF-UHFFFAOYSA-N 4-phenylbutanoyl chloride Chemical compound ClC(=O)CCCC1=CC=CC=C1 VQDQISMDUHBUFF-UHFFFAOYSA-N 0.000 description 1
- GQJMIKVSYWHDMK-UHFFFAOYSA-N 7-phenylheptylbenzene Chemical compound C=1C=CC=CC=1CCCCCCCC1=CC=CC=C1 GQJMIKVSYWHDMK-UHFFFAOYSA-N 0.000 description 1
- JKURYFQIZDRYLU-UHFFFAOYSA-N C1(=CC=CC=C1)NC1=CC=CC=C1.CCCCCCC Chemical class C1(=CC=CC=C1)NC1=CC=CC=C1.CCCCCCC JKURYFQIZDRYLU-UHFFFAOYSA-N 0.000 description 1
- 235000014375 Curcuma Nutrition 0.000 description 1
- 235000003392 Curcuma domestica Nutrition 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010033733 Papule Diseases 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical class OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 241000669298 Pseudaulacaspis pentagona Species 0.000 description 1
- 244000273928 Zingiber officinale Species 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000007131 anti Alzheimer effect Effects 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002682 anti-psoriatic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 235000003373 curcuma longa Nutrition 0.000 description 1
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 210000001339 epidermal cell Anatomy 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000001185 psoriatic effect Effects 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- VNNLHYZDXIBHKZ-UHFFFAOYSA-N thiophene-2-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CS1 VNNLHYZDXIBHKZ-UHFFFAOYSA-N 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 235000013976 turmeric Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Immunology (AREA)
- Mycology (AREA)
- Polymers & Plastics (AREA)
- Food Science & Technology (AREA)
- Nutrition Science (AREA)
- Dermatology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to compound synthesis technical fields, and in particular to compound in diphenyl heptane class and its application, structural formula are as follows:Wherein, R1、R2It is cyclopropanecarbonyl base；Or R1For H, R2For cyclopropanecarbonyl base；Or R1For H, R2For a chlorobenzene formacyl；Or R1For H, R2ForOr R1, R2 areOr R1For H, R2ForR3For one of F, Br, trifluoromethyl or tert-butyl；Or R1、R2It isR3For acetamido.The compound of the present invention has psoriasis bioactivity, has therapeutic effect to some immunosuppressant diseases.The compound of the present invention is prepared into various pharmaceutically acceptable forms, such as tablet, pill, capsule, injection, suspending agent or emulsion, is being hopeful to replace the existing curing psoriasis drug in part in the future.
Description
Technical field
The present invention relates to compound synthesis technical fields, and in particular to compound in diphenyl heptane class and preparation method thereof and answers
With.
Background technique
Diarylheptanoids are the general names of a kind of native compound with 1,7- Diphenylheptane parent nucleus, can be pressed
Its structure is divided into linear and cyclic compound, is primarily present the compound that a class formation is more special in zingiberaceous plant,
Active constituent has various physiological activity, such as anti-liver is malicious, antitumor, anti-inflammatory, bilification, desinsection, anti-oxidant.Natural line
Property compound in diphenyl heptane class, structure is typical, physiological activity multiplicity and significant, becomes focus concerned by people in recent years.Bu Xianzhang
Deng by chemical modification technology, new serial hexichol is obtained after electronation and the modification of second phthaleinization to the main component of galangal
Heptane derivative, and study the physiological activity of its derivative, the results showed that before the physiological activity of derivative is better than modification.
Patent CN101003500A discloses a kind of diarylheptanoids, for from zingiberaceous plant ginger, turmeric, strongly fragrant
The new compound of gold, curcuma zedoary, two sodium sulfonate substituted diphenylamine heptane class obtained in galangal, which can be used for preparing anti-
Oxygen radical causes or the drug of physiological change related with oxygen radical or disease, as hepatinica, Anti-alzheimer's disease drug,
Treatment angiocarpy and cerebrovascular disease drug, antiaging agent, the diabetes complicated disease drug for the treatment of etc..
Patent CN101979366A provides 25 kinds of new compound in diphenyl heptane class, is all made of plant Guangxi zedoary as original
Material, is extracted and is separated with organic solvent and/or water, can prevent and treat inflammation and related with nitric oxide signal transduction
Disease.
Patent CN105732379A discloses a kind of biologically active diphenyl heptane compound (E) -3- acetoxyl group -
1,7- bis- (4- hydroxy phenyl) -6- heptene, can be extracted from plants or synthetic method is made, by thin to human T cell lymphoma
The testing in vitro of born of the same parents system HH cell Proliferation determines that it, with preferable Inhibit proliferaton effect and in dose-effect relationship, thus is suitable for
Preparation prevention and treatment psoriasis or food.
Patent CN105732380A discloses a kind of two (4- hydroxy benzenes of diphenyl heptane compound 3,5- diacetoxy -1,7-
Base) heptane, it can be made from plant extract or synthetic method, there is the life for inhibiting human T cell lymphoma cell line HH cell Proliferation
Object activity can be applied to preparation prevention and treatment psoriasis or food.
Although patent CN105732379A and CN105732380A disclose two kinds of diphenyl heptane compounds and its can be used for
Preparation prevention and treatment psoriasis or food, but the water solubility of two kinds of disclosed substances is not bad, active good enough yet, and it is prepared
Method is more many and diverse, is unfavorable on a large scale promoting the drug.Therefore, it is quite necessary to develop can the marketization for controlling
Treat the compound in diphenyl heptane class of psoriasis.
Summary of the invention
The purpose of the present invention is to provide the compound in diphenyl heptane class and preparation method thereof with psoriasis bioactivity
And application, with one or several in solving the above problems.
According to an aspect of the invention, there is provided the compound in diphenyl heptane class with psoriasis bioactivity, knot
Structure formula is as follows:
Wherein, R1、R2It is cyclopropanecarbonyl base；Or R1For H, R2For cyclopropanecarbonyl base；Or
Another purpose according to the present invention, provides the preparation method of above-mentioned compound in diphenyl heptane class,
Work as R1For H or cyclopropanecarbonyl base, R2When for cyclopropanecarbonyl base, preparation method includes the following steps:
1) two are added after weighing 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester, Cyclopropyl carbonyl chloride, triethylamine mixing
Chloromethanes as solvent,
2) dichloromethane solution is spin-dried for, obtains flaxen thick crude product,
3) by faint yellow crude product dry method upper prop obtained by step 2), first with petroleum ether: ethyl acetate=5:1 is eluted,
It is spin-dried for after collecting eluent, obtains the first product；It is further continued for again with petroleum ether: ethyl acetate=4:1 elution, after regathering eluent
It is spin-dried for, obtains the second product；Chemical equation is as follows:
Work as R1For H, R2When for chlorobenzene formacyl, preparation method includes the following steps:
Raw material 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester, catalyst of triethylamine are dissolved in methylene chloride
Or in dioxane or chloroform, m-chlorobenzoyl chloride is added dropwise under room temperature, reacts 2-24h, TLC detection reaction adds water and acetic acid second
Ethyl acetate is removed under reduced pressure after solution layering in ester extraction, and column chromatographs up to product, and chemical equation is as follows:
Work as R1For H orR2ForPreparation method includes the following steps:
Raw material 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester, catalyst of triethylamine are dissolved in methylene chloride
Or in dioxane or chloroform, arylsulfonyl chloride is added dropwise under room temperature, normal-temperature reaction 2-24h, TLC detection after the reaction was completed, add water
It is extracted with ethyl acetate, after solution layering, ethyl acetate is removed under reduced pressure, column chromatographs up to product.The reaction equation of preparation process
It is as follows:
Work as R1For H, R2ForR3When for F, preparation method includes the following steps:
Raw material 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester, catalyst of triethylamine are dissolved in methylene chloride
It is added dropwise or in dioxane or chloroform, under room temperature to fluorophenylsulfonyl chloride, normal-temperature reaction 2-24h, TLC detection after the reaction was completed, add
Ethyl acetate is removed under reduced pressure after solution layering in water and ethyl acetate extraction, and column chromatographs up to product；The reaction of preparation process
Formula is as follows:
Work as R1For H, R2ForR3When for Br, preparation method includes the following steps:
Raw material 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester, catalyst of triethylamine are dissolved in methylene chloride
Or in dioxane or chloroform, p-bromobenzenesulfonyl chloride is added dropwise under room temperature, normal-temperature reaction 2-24h, TLC detection after the reaction was completed, add
Ethyl acetate is removed under reduced pressure after solution layering in water and ethyl acetate extraction, and column chromatographs up to product；The reaction of preparation process
Formula is as follows:
Work as R1For H, R2ForR3When for trifluoromethyl, preparation method includes the following steps:
Raw material 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester, catalyst of triethylamine are dissolved in methylene chloride
It is added dropwise or in dioxane or chloroform, under room temperature to trifluoromethyl benzene sulfonyl chloride, normal-temperature reaction 2-24h, TLC detection reaction is completed
Afterwards, add water and ethyl acetate to extract, after solution layering, ethyl acetate is removed under reduced pressure, column chromatographs up to product；Preparation process
Reaction equation is as follows:
Work as R1For H, R2ForR3When for tert-butyl, preparation method includes the following steps:
Raw material 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester, catalyst of triethylamine are dissolved in methylene chloride
It is added dropwise or in dioxane or chloroform, under room temperature to t-butylbenzenesulfonyl chloride, normal-temperature reaction 2-24h, TLC detection reaction is completed
Afterwards, add water and ethyl acetate to extract, after solution layering, ethyl acetate is removed under reduced pressure, column chromatographs up to product.
When R1, R2 areR3When for acetamido, preparation method includes the following steps:
Raw material 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester, catalyst of triethylamine are dissolved in methylene chloride
Or in dioxane or chloroform, para-acetylaminobenzene sulfonyl chloride is added dropwise under room temperature, normal-temperature reaction 2-24h, TLC detection reaction is completed
Afterwards, add water and ethyl acetate to extract, after solution layering, ethyl acetate is removed under reduced pressure, column chromatographs up to product.
An also purpose according to the present invention provides above-mentioned compound in diphenyl heptane class in preparation prevention and treatment psoriasis and exempts from
Epidemic disease inhibits the application in disease medicament or food.
In some embodiments, compound in diphenyl heptane class includes at least one of following compounds 1~7, wherein
Compound 1 is 1,7- [two (cyclopropanecarbonyl phenoxyl)] heptyl -3,5- diol ester, chemical formula are as follows:
Compound 2 is 1- cyclopropanecarbonyl phenoxyl -7- (4- benzene hydroxyl) heptyl -3,5- diol ester, chemical formula are as follows:
Compound 3 chlorphenyl formvlphenoxv -7- (4- benzene hydroxyl) heptyl -3,5- diol ester, chemical formula between 1-
Are as follows:
Compound 4, structural formula are as follows:
Compound 4-1, structural formula:
Compound 5 is 1- to fluorophenylsulphonyl phenoxy group -7- (4- benzene hydroxyl) heptyl -3,5- diol ester, chemical formula are as follows:
Compound 6 is 1- brosyl phenoxyl -7- (4- benzene hydroxyl) heptyl -3,5- diol ester, chemical formula are as follows:
Compound 7 is its change of 1- (4- trifluoromethyl) benzenesulfonyl phenoxy group -7- (4- benzene hydroxyl) heptyl -3,5- diol ester
Formula are as follows:
Its structural formula of compound 8:
In some embodiments, drug contains one or more pharmaceutically acceptable carriers or excipient.
In some embodiments, drug can be tablet, pill, capsule, injection, suspending agent or emulsion.
The compound of the present invention structure is relatively simple, and synthesize path it is shorter, synthesis technology is relatively simple, yield compared with
It is high.It was proved that the compound of the present invention has psoriasis bioactivity, there is treatment to make some immunosuppressant diseases
With；Compared with the compound in diphenyl heptane class in the prior art with psoriasis bioactivity, the biology of the compound of the present invention
Activity improves a lot.The compound of the present invention is prepared into various pharmaceutically acceptable forms, such as: tablet, pill, capsule,
Injection, suspending agent or emulsion are being hopeful to replace the existing curing psoriasis drug in part in the future.
Detailed description of the invention
Fig. 1 is the high-resolution LC-MS map of compound 1；
Fig. 2 is the high-resolution LC-MS map of compound 2；
Fig. 3 is the high-resolution LC-MS map of compound 3；
Fig. 4-5 is the high-resolution LC-MS map and hydrogen nuclear magnetic resonance spectrogram of compound 4；
Fig. 6 is the high-resolution LC-MS map of compound 4-1；
Fig. 7 is the high-resolution LC-MS map of compound 5；
Fig. 8 is the high-resolution LC-MS map of compound 5-1；
Fig. 9-10 is the high-resolution LC-MS map and hydrogen nuclear magnetic resonance spectrogram of compound 6；
Figure 11-12 is the high-resolution LC-MS map and hydrogen nuclear magnetic resonance spectrogram of compound 6-1；
Figure 13-14 is the high-resolution LC-MS map and hydrogen nuclear magnetic resonance spectrogram of compound 7；
Figure 15-16 is the high-resolution LC-MS map and hydrogen nuclear magnetic resonance spectrogram of compound 7-1；
Figure 17-18 is the high-resolution LC-MS map and hydrogen nuclear magnetic resonance spectrogram of compound 8；
Figure 19-20 is the LC-MS map and hydrogen nuclear magnetic resonance spectrogram of compound 8-1；
Figure 21-22 is the LC-MS map and hydrogen nuclear magnetic resonance spectrogram of compound 9；
Figure 23-24 is the high-resolution LC-MS map and hydrogen nuclear magnetic resonance spectrogram of compound 9-1.
Specific embodiment
The invention will now be described in further detail with reference to the accompanying drawings.
1, the preparation of compound in diphenyl heptane class
Precise 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester 100mg, precise Cyclopropyl carbonyl chloride
5ml methylene chloride is added as solvent in 77.65mg, triethylamine 40.30mg.Normal-temperature reaction for 24 hours after, dichloromethane solution is revolved
It is dry, obtain flaxen thick crude product 87.62mg.The pale yellow powder dry method upper prop that will be spin-dried for first uses petroleum ether: second
Acetoacetic ester (5:1) 100ml is eluted, and is collected eluent, is obtained product 1, weight 16.2mg.Continue with petroleum ether: acetic acid second
Ester (4:1) 150ml elution, collects eluent, obtains product 2, weight 34.4mg.
Through analyzing, product 1 is compound 1, and product 2 is compound 2.Wherein, the high-resolution LC-MS spectrogram of compound 1 is such as
Shown in Fig. 1, [M+Na] of compound 1 in figure+Peak value is 559.23218, molecular weight 536.24102, and molecular formula is
C31H36O8。
The high-resolution LC-MS spectrogram of compound 2 is as shown in Fig. 2, in figure [M+Na]+Peak value is 491.20560, molecular weight
It is 468.21, molecular formula C27H32O7。
Also the hydroxyl it follows that Cyclopropyl carbonyl chloride and 1, in 7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester on phenyl ring
Substitution reaction occurs for base, and reaction equation is as follows:
2, the preparation of compound in diphenyl heptane class
By raw material 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester 200mg (0.5mmol), catalyst of triethylamine
(2mmol) is dissolved in methylene chloride or dioxane or chloroform, m-chlorobenzoyl chloride (2mmol) is added dropwise under room temperature, often
Temperature reaction 12h, TLC detection after the reaction was completed, add 20ml water and 20ml ethyl acetate (EA) to extract, after solution layering, decompression
EA is removed, column chromatographs to obtain two kinds of compounds.It is identified, it is compound 3 and compound 3-1.
Wherein, the high-resolution LC-MS spectrogram of compound 3 is as shown in figure 3, in figure [M+Na]+Peak value be 561.16681,
Its molecular weight is 538.00841, molecular formula C30H30O7Cl。
Above-mentioned reaction equation is as follows:
3, the preparation of compound in diphenyl heptane class
By raw material 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester 200mg (0.5mmol), catalyst of triethylamine
(1.5mmol) is dissolved in methylene chloride or dioxane or chloroform, and arylsulfonyl chloride (1.5mmol) is added dropwise under room temperature,
Normal-temperature reaction 16h, TLC detection after the reaction was completed, add 20ml water and 20ml EA to extract, and after solution layering, EA is removed under reduced pressure,
Column chromatographs to obtain two kinds of compounds.It is identified, it is compound 4 and compound 4-1.
Wherein, the high-resolution LC-MS spectrogram of compound 4 is as shown in figure 4, in figure [M+Na]+Peak value is 577.18805,
Molecular weight is 554.19744, molecular formula C30H34O8S；The hydrogen nuclear magnetic resonance spectrogram of compound 4 is as shown in figure 5, can be with from figure
Find out, specific data are as follows: (CDCl3, 600MHz) and δ 7.71-7.10 (2H, d, J=6.0), 7.32-7.30 (4H, 2H, d, J=
12.0), 7.02-6.99 (4H, m), 6.87 (2H, m), 6.75-6.72 (2H, m), 4.98-4.89 (3H, m), 2.57-2.45
(4H,m),2.01(3H,s),1.99(3H,s),1.60(6H,m)。
As shown in fig. 6, its molecular weight is 554.19744, molecular formula is the high-resolution LC-MS spectrogram of compound 4-1
C30H34O8S。
Above-mentioned reaction equation is as follows:
4, the preparation of compound in diphenyl heptane class
By raw material 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester 200mg (0.5mmol), catalyst of triethylamine
(0.5mmol) is dissolved in methylene chloride or dioxane or chloroform, is added dropwise under room temperature to fluorophenylsulfonyl chloride (1mmol),
Normal-temperature reaction 10h, TLC detection after the reaction was completed, add 20ml water and 20ml EA to extract, and after solution layering, EA is removed under reduced pressure,
Column chromatographs to obtain two kinds of compounds.It is identified, it is compound 5 and compound 5-1.
Wherein, the high-resolution LC-MS spectrogram of compound 5 is as shown in fig. 7, in figure [M+Na]+Peak value is 581.16333,
Molecular weight is 558.17237, molecular formula C29H31FO8S；
The LC-MS spectrogram of compound 5-1 is as shown in figure 8, in figure [M+Na]+Peak value is 739.14697, and molecular weight is
716.15615 molecular formula C35H34F2O10S2。
Above-mentioned reaction equation is as follows:
5, the preparation of compound in diphenyl heptane class
By raw material 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester 200mg (0.5mmol), catalyst of triethylamine
(1mmol) is dissolved in methylene chloride or dioxane or chloroform, and p-bromobenzenesulfonyl chloride (1.5mmol) is added dropwise under room temperature,
Normal-temperature reaction 8h, TLC detection after the reaction was completed, add 20ml water and 20ml EA to extract, and after solution layering, EA, column is removed under reduced pressure
Chromatography obtains two kinds of compounds.It is identified, it is compound 6 and compound 6-1.
Wherein, the high-resolution LC-MS spectrogram of compound 6 is as shown in figure 9, in figure [M+Na]+Peak value is 641.08, molecule
Amount is 618.09230, molecular formula C29H31BrO8S；The hydrogen nuclear magnetic resonance spectrogram of compound 6 is as shown in Figure 10, and specific data are such as
Under: (CDCl3, 600MHz) and δ 7.67 (4H, s), 7.09-7.08 (2H, d, J=6.0), 7.02-7.01 (2H, d, J=6.0),
6.89-6.88 (2H, d, J=6.0), 6.75-6.73 (2H, d, J=12.0), 5.04 (1H, s), 4.98-4.95 (2H, m),
2.60-2.52(4H,m),2.02(3H,s),2.00(3H,s),1.86-1.77(6H,m)。
The high-resolution LC-MS spectrogram of compound 6-1 is as shown in figure 11, in figure [M+Na]+Peak value is 860.98645, point
Son amount is 835.99601, molecular formula C35H34Br2O10S2；The hydrogen nuclear magnetic resonance spectrogram of compound 6-1 is as shown in figure 12.
Above-mentioned reaction equation is as follows:
6, the preparation of compound in diphenyl heptane class
By raw material 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester 200mg (0.5mmol), catalyst of triethylamine
(1.5mmol) is dissolved in methylene chloride or dioxane or chloroform, is added dropwise under room temperature to trifluoromethyl benzene sulfonyl chloride
(2mmol), reacts 6h, and TLC detection reaction adds 20ml water and 20ml EA to extract, after solution layering, EA, column layer is removed under reduced pressure
Analysis obtains two kinds of compounds.It is identified, it is compound 7 and compound 7-1.
Wherein, the high-resolution LC-MS spectrogram of compound 7 is as shown in figure 13, in figure [M+Na]+Peak value is 631.16.34,
Molecular weight is 608.16917, molecular formula C30H31F3O8S；The hydrogen nuclear magnetic resonance spectrogram of compound 7 is as shown in figure 14, specific number
According to as follows: (CDCl3, 600MHz) and δ 7.98-7.96 (2H, d, J=12.0), 7.82-7.80 (2H, d, J=12.0), 7.08-
7.07 (2H, d, J=6.0), 7.01-7.00 (2H, d, J=6.0), 6.89-6.88 (2H, d, J=6.0), 6.74-6.73 (2H,
D, J=6.0), 4.93-4.88 (2H, m), 4.81 (1H, s), 2.59-2.50 (4H, m), 2.02 (3H, s), 1.99 (3H, s),
1.95-1.1.72(6H,m)。
The high-resolution LC-MS spectrogram of compound 7-1 is as shown in figure 15, in figure [M+Na]+Peak value is 839.14099 [M+Na
]+, molecular weight 816.14976, molecular formula C37H34F6O10S2；The hydrogen nuclear magnetic resonance spectrogram of compound 7-1 such as Figure 16 institute
Show.
Above-mentioned reaction equation is as follows:
7, the preparation of compound in diphenyl heptane class
By raw material 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester 200mg (0.5mmol), catalyst of triethylamine
(1.5mmol) is dissolved in methylene chloride or dioxane or chloroform, is added dropwise under room temperature to t-butylbenzenesulfonyl chloride
(2mmol), reacts 14h, and TLC detection reaction adds 20ml water and 20ml EA to extract, after solution layering, EA, column is removed under reduced pressure
Chromatography obtains two kinds of compounds.It is identified, it is compound 8 and compound 8-1.
Wherein, the high-resolution LC-MS spectrogram of compound 8 is as shown in figure 17, in figure [M+Na]+Peak value is 619.23566,
Molecular weight is 596.24439, molecular formula C33H40O8S；The hydrogen nuclear magnetic resonance spectrogram of compound 8 is as shown in figure 18.
The high-resolution LC-MS spectrogram of compound 8-1 is as shown in figure 19, molecular weight 792.30019, and molecular formula is
C43H52O10S2；The hydrogen nuclear magnetic resonance spectrogram of compound 8-1 is as shown in figure 20.
Above-mentioned reaction equation is as follows:
8, the preparation of compound in diphenyl heptane class
By raw material 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester 200mg (0.5mmol), catalyst of triethylamine
(1.5mmol) is dissolved in methylene chloride or dioxane or chloroform, and para-acetylaminobenzene sulfonyl chloride is added dropwise under room temperature
(2mmol), reacts 10h, and TLC detection reaction adds 20ml water and 20ml EA to extract, after solution layering, EA, column is removed under reduced pressure
Chromatography obtains two kinds of compounds.It is identified, it is compound 9 and compound 9-1.
Wherein, the high-resolution LC-MS spectrogram of compound 9 and hydrogen nuclear magnetic resonance spectrogram be as shown in fig. 21-22；Compound 9-1
High-resolution LC-MS spectrogram and hydrogen nuclear magnetic resonance spectrogram respectively as shown in figure 23 and figure 24.
Above-mentioned reaction equation is as follows:
According to above-mentioned preparation method, different material and 1, (4- benzene hydroxyl) heptyl -3, the 5- diol ester of 7- bis- hair are selected respectively
Raw substitution reaction, such as uses 4-Nitrobenzenesulfonyl chloride and 1, and the reaction of (4- benzene hydroxyl) heptyl -3, the 5- diol ester of 7- bis- obtains a chemical combination
Object is analyzed as compound 14；
With to Methoxybenzenesulfonyl chloride and 1, the reaction of (4- benzene hydroxyl) heptyl -3, the 5- diol ester of 7- bis- obtains a compound,
It is analyzed as compound 12；
With 2- thiophenesulfonyl chloride and 1, the reaction of (4- benzene hydroxyl) heptyl -3, the 5- diol ester of 7- bis- obtains a compound, through dividing
Analysis is Compound Compound 13；
With 4- phenylbutyryl chloride and 1, the reaction of (4- benzene hydroxyl) heptyl -3, the 5- diol ester of 7- bis- obtains a compound, through dividing
Analysis is Compound Compound 11.Meanwhile the reaction equation of above-mentioned reaction is as follows:
By MTT experiment, above-mentioned 20 be prepared kind compound product drug activity is verified:
Psoriasis is a kind of common chronic inflammation skin disease easy to recur, characteristic is red papules or patch be covered with it is more
The layer silvery white scales of skin that peel off, and one of its pathological characters are abnormal hyperplasia of epidermal cell, researcher considers silver to be worth doing all the time
The entrance of the research of disease is the more degree proliferation and regulatory mechanism of keratinocyte.
Therefore, in order to further illustrate the present invention disclosed diphenyl heptane compound in prevention and treatment psoriasis and immunosupress
Above-mentioned 20 kinds of prepared diphenyl heptane compounds are each configured to a series of concentration by the application in disease medicament or food
For reagent object, epidermal keratinocytes cellulation system HaCaT cell and human T cell lymphoma cell line are immortalized with people using mtt assay
HH cell is research model, investigates the influence that 20 kinds of compounds of synthesis are proliferated it, to screen the potential for the treatment of psoriasis
Drug.
Wherein, biological material source is as follows in experiment: human T cell lymphoma cell line HH cell is purchased from ATCC, people's immortality
Change epidermal keratinocytes cellulation system HaCaT cell and is purchased from China typical culture collection center (CCTCC).
Compound in diphenyl heptane class 2mg is taken, 40 μ L dimethyl sulfoxides (DMSO) are added, sufficiently dissolve to obtain diphenyl heptane class
Object-DMSO solution is closed, takes 2 μ L compound in diphenyl heptane class-DMSO solution that 2mL DMEM culture medium is added and (is purchased from Gibco public affairs
Department), 100 μ g/mL mother liquid medicines are obtained, then dilute as a series of concentration such as 50,25,6.25,1.5625 for reagent object.Such as
There is 100 μ g/mL of IC50 > in fruit, then it is assumed that effect of drugs is bad, 1.5625 μ g/mL of IC50 <, then after diluting toward low concentration again
Measuring.
The anti-HaCaT cell of above-mentioned 20 kinds of compound in diphenyl heptane class and HH cell activity are detected by mtt assay, point
Do not obtain the administration of each compound for 24 hours with the IC50 value of 48h.
Meanwhile methotrexate (MTX) is a kind of effective antipsoriatic object, is at home and abroad widely used in the treatment of psoriasis,
The synthesis of cell DNA can be prevented, the proliferation of Psoriatic Epidermis keratinocyte is inhibited, is the immunosupress of cell toxicant class
Therefore agent as Experimental comparison's example, is chosen as positive control medicine.
20 kinds of compounds according to the present invention and control drug methotrexate (MTX) are for 24 hours with 48h to HaCaT cell and HH cell
IC50 testing result, specific data are as shown in table 1:
1 two ten kinds of compounds of table are for 24 hours with 48h to the IC50 of HaCaT cell and HH cell
As can be seen from Table 1, the IC50 of positive drug methotrexate (MTX) is far longer than 100 μ g/mL, for 20 chemical combination of synthesis
The anti-HaCaT cell activity of object is screened, and preferable anti-HaCaT activity is presented in compound 1, compound 4 and compound 6,
IC50 is between 14.46-69.46 μ g/mL, and compound 2, compound 3, compound 5 and compound 7 are after 48h administration, IC50
Also 100 μ g/mL are dropped to hereinafter, these compounds are superior to positive drug to the inhibiting effect of HaCaT cell, can be used as potential control
Treat the compound of psoriasis.
To in the screening of HH cell activity, the IC50 of methotrexate (MTX) is greater than 100 μ g/mL, and synthesize compound 2 in compound,
Compound 3, compound 4, compound 4-1, compound 5, compound 6, compound 7, compound 8 and compound 9 are all shown
Certain inhibitory activity, IC50 is between 8.48 to 79.21 μ g/mL, and wherein compound 1 is after being administered 48h, and IC50 is in 51.93 μ g/
ML or so, these compounds are far superior to positive drug methotrexate (MTX), can be used as the potential drug for the treatment of psoriasis.
Therefore, the application with (4- benzene hydroxyl) heptyl -3, the 5- diol ester of 1,7- bis- be raw material, by chemical synthesis process system
It is standby to obtain above-mentioned 20 kinds of compound in diphenyl heptane class, it judges, changes after analyzing this 20 kinds of compound in diphenyl heptane class activity
It closes object 1, compound 2, compound 3, compound 4, compound 4-1, compound 5, compound 6, compound 7, compound 8 and changes
Closing this ten kinds of diphenyl heptane compounds of object 9 can be preferably as the compound of potential treatment psoriasis.
In order to save length, the spectrogram that inactive compound in diphenyl heptane class is characterized prepared by the application,
Specification and the description of Figure of description part clipped and part attached drawing.
Above-described is only some embodiments of the present invention.For those of ordinary skill in the art, not
Under the premise of being detached from the invention design, various modifications and improvements can be made, these belong to protection model of the invention
It encloses.
Claims (6)
1. compound in diphenyl heptane class, which is characterized in that its structural formula is as follows:
Wherein, R1、R2It is cyclopropanecarbonyl base；Or R1For H, R2For cyclopropanecarbonyl base；Or R1For H, R2For a chlorobenzoyl
Base；
Or R1For H, R2ForOr R1、R2It is
Or R1For H, R2ForR3For one of F, Br, trifluoromethyl or tert-butyl；
Or R1、R2It isR3For acetamido.
2. the preparation method of compound in diphenyl heptane class described in claim 1, which is characterized in that
Work as R1For H or cyclopropanecarbonyl base, R2When for cyclopropanecarbonyl base, preparation method includes the following steps:
1) dichloromethane is added after weighing 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester, Cyclopropyl carbonyl chloride, triethylamine mixing
Alkane is as solvent, normal-temperature reaction 2-24h；
2) dichloromethane solution is spin-dried for, obtains flaxen thick crude product,
3) by faint yellow crude product dry method upper prop obtained by step 2), first with petroleum ether: ethyl acetate=5:1 is eluted, and is collected
It is spin-dried for after eluent, obtains the first product；Be further continued for petroleum ether: ethyl acetate=4:1 elution column regathers eluent back spin
It is dry, obtain the second product；
Work as R1For H, R2When for chlorobenzene formacyl, preparation method includes the following steps:
Raw material 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester, catalyst of triethylamine are dissolved in methylene chloride or two
In six ring of oxygen or chloroform, be added dropwise m-chlorobenzoyl chloride under room temperature, normal-temperature reaction 2-24h, TLC are detected after the reaction was completed, add water and
Ethyl acetate is removed under reduced pressure after solution layering in ethyl acetate extraction, and column chromatographs up to product；
Work as R1For H orR2ForWhen, preparation method includes the following steps:
Raw material 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester, catalyst of triethylamine are dissolved in methylene chloride or two
In six ring of oxygen or chloroform, arylsulfonyl chloride is added dropwise under room temperature, normal-temperature reaction 2-24h, TLC detection after the reaction was completed, add water and second
Ethyl acetate is removed under reduced pressure after solution layering in acetoacetic ester extraction, and column chromatographs up to product；
Work as R1For H, R2ForR3When for F, preparation method includes the following steps:
Raw material 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester, catalyst of triethylamine are dissolved in methylene chloride or two
Be added dropwise in six ring of oxygen or chloroform, under room temperature to fluorophenylsulfonyl chloride, normal-temperature reaction 2-24h, TLC is detected after the reaction was completed, add water and
Ethyl acetate is removed under reduced pressure after solution layering in ethyl acetate extraction, and column chromatographs up to product；
Work as R1For H, R2ForR3When for Br, preparation method includes the following steps:
Raw material 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester, catalyst of triethylamine are dissolved in methylene chloride or two
In six ring of oxygen or chloroform, be added dropwise p-bromobenzenesulfonyl chloride under room temperature, normal-temperature reaction 2-24h, TLC are detected after the reaction was completed, add water and
Ethyl acetate is removed under reduced pressure after solution layering in ethyl acetate extraction, and column chromatographs up to product；
Work as R1For H, R2ForR3When for trifluoromethyl, preparation method includes the following steps:
Raw material 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester, catalyst of triethylamine are dissolved in methylene chloride or two
It being added dropwise in six ring of oxygen or chloroform, under room temperature to trifluoromethyl benzene sulfonyl chloride, normal-temperature reaction 2-24h, TLC is detected after the reaction was completed,
Add water and ethyl acetate to extract, after solution layering, ethyl acetate is removed under reduced pressure, column chromatographs up to product；
Work as R1For H, R2ForR3When for tert-butyl, preparation method includes the following steps:
Raw material 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester, catalyst of triethylamine are dissolved in methylene chloride or two
It is added dropwise in six ring of oxygen or chloroform, under room temperature to t-butylbenzenesulfonyl chloride, normal-temperature reaction 2-24h, TLC detection after the reaction was completed, add
Ethyl acetate is removed under reduced pressure after solution layering in water and ethyl acetate extraction, and column chromatographs up to product；
Work as R1、R2It isR3When for acetamido, preparation method includes the following steps:
Raw material 1,7- bis- (4- benzene hydroxyl) heptyl -3,5- diol ester, catalyst of triethylamine are dissolved in methylene chloride or two
In six ring of oxygen or chloroform, it being added dropwise para-acetylaminobenzene sulfonyl chloride under room temperature, normal-temperature reaction 2-24h, TLC are detected after the reaction was completed,
Add water and ethyl acetate to extract, after solution layering, ethyl acetate is removed under reduced pressure, column chromatographs up to product.
3. compound in diphenyl heptane class described in claim 1 is in preparation prevention and treatment psoriasis and immunosuppressant disease drug or food
In application.
4. application according to claim 3, which is characterized in that the compound in diphenyl heptane class includes following ten kinds of chemical combination
At least one of object:
Compound 1, structural formula:
Compound 2, structural formula:
Compound 3, structural formula:
Compound 4, structural formula:
Compound 4-1, structural formula:
Compound 5, structural formula:
Compound 6, structural formula:
Compound 7, structural formula:
Compound 8, structural formula:
Compound 9, structural formula:
5. application according to claim 4, which is characterized in that the drug contains one or more pharmaceutically acceptable
Carrier or excipient.
6. according to the described in any item applications of claim 3~5, which is characterized in that the drug can be tablet, pill, glue
Capsule, injection, suspending agent or emulsion.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105732380A (en) * | 2014-12-08 | 2016-07-06 | 广东省中医院 | Diarylheptanoid compound and its preparation method and use |
| CN108140783A (en) * | 2015-04-29 | 2018-06-08 | 三星Sdi株式会社 | The partition board and electrochemical cell of high heat resistance and anti-flammability |
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2018
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105732380A (en) * | 2014-12-08 | 2016-07-06 | 广东省中医院 | Diarylheptanoid compound and its preparation method and use |
| CN108140783A (en) * | 2015-04-29 | 2018-06-08 | 三星Sdi株式会社 | The partition board and electrochemical cell of high heat resistance and anti-flammability |
Non-Patent Citations (3)
| Title |
|---|
| MASAYASU NOMURA等: "BIARYLHEPTANOIDS AND OTHER CONSTITUENTS FROM WOOD OF ALNUS JAPONICA", 《PHYTOCHEMISTRY》 * |
| 国家执业药师资格考试研究组: "《药学专业知识（一）》", 31 January 2017, 北京：中国医药科技出版社 * |
| 李正化: "《药物化学（第三版）》", 31 January 2000, 人民卫生出版社 * |
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