CN117255786A - 黑皮质素受体激动剂化合物的晶型vii及其制备方法 - Google Patents
黑皮质素受体激动剂化合物的晶型vii及其制备方法 Download PDFInfo
- Publication number
- CN117255786A CN117255786A CN202280032151.8A CN202280032151A CN117255786A CN 117255786 A CN117255786 A CN 117255786A CN 202280032151 A CN202280032151 A CN 202280032151A CN 117255786 A CN117255786 A CN 117255786A
- Authority
- CN
- China
- Prior art keywords
- form vii
- compound
- vii according
- preparing
- amine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 60
- 238000004519 manufacturing process Methods 0.000 title claims description 15
- 239000000336 melanocortin receptor agonist Substances 0.000 title description 3
- 229940117029 Melanocortin receptor agonist Drugs 0.000 title description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims description 27
- -1 tertiary amine compound Chemical class 0.000 claims description 27
- 238000002425 crystallisation Methods 0.000 claims description 23
- 230000008025 crystallization Effects 0.000 claims description 22
- 239000013078 crystal Substances 0.000 claims description 20
- 239000011259 mixed solution Substances 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 102000001796 Melanocortin 4 receptors Human genes 0.000 claims description 12
- 108010021436 Type 4 Melanocortin Receptor Proteins 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- 208000008589 Obesity Diseases 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 235000020824 obesity Nutrition 0.000 claims description 8
- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 7
- 206010061218 Inflammation Diseases 0.000 claims description 7
- 206010012601 diabetes mellitus Diseases 0.000 claims description 7
- 201000001881 impotence Diseases 0.000 claims description 7
- 230000004054 inflammatory process Effects 0.000 claims description 7
- 239000012453 solvate Substances 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 238000001704 evaporation Methods 0.000 claims description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 6
- GZVUWANWWQXKQR-UHFFFAOYSA-N 2-methylpropanamide;hydrochloride Chemical compound Cl.CC(C)C(N)=O GZVUWANWWQXKQR-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- SRLHDBRENZFCIN-UHFFFAOYSA-N n,n-di(butan-2-yl)butan-2-amine Chemical compound CCC(C)N(C(C)CC)C(C)CC SRLHDBRENZFCIN-UHFFFAOYSA-N 0.000 claims description 2
- GNVRJGIVDSQCOP-UHFFFAOYSA-N n-ethyl-n-methylethanamine Chemical compound CCN(C)CC GNVRJGIVDSQCOP-UHFFFAOYSA-N 0.000 claims description 2
- SMBYUOXUISCLCF-UHFFFAOYSA-N n-ethyl-n-methylpropan-1-amine Chemical compound CCCN(C)CC SMBYUOXUISCLCF-UHFFFAOYSA-N 0.000 claims description 2
- UTLDDSNRFHWERZ-UHFFFAOYSA-N n-ethyl-n-methylpropan-2-amine Chemical compound CCN(C)C(C)C UTLDDSNRFHWERZ-UHFFFAOYSA-N 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims 1
- 229910002651 NO3 Inorganic materials 0.000 claims 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims 1
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- RKBCYCFRFCNLTO-UHFFFAOYSA-N triisopropylamine Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 claims 1
- 238000002441 X-ray diffraction Methods 0.000 abstract description 11
- 239000000126 substance Substances 0.000 abstract description 5
- 238000001757 thermogravimetry curve Methods 0.000 abstract description 2
- 238000001938 differential scanning calorimetry curve Methods 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 27
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 19
- 238000002411 thermogravimetry Methods 0.000 description 16
- 230000000694 effects Effects 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 101000978418 Homo sapiens Melanocortin receptor 4 Proteins 0.000 description 11
- 102100023724 Melanocortin receptor 4 Human genes 0.000 description 11
- 238000000113 differential scanning calorimetry Methods 0.000 description 11
- 229940047889 isobutyramide Drugs 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 10
- 239000000556 agonist Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 102000004378 Melanocortin Receptors Human genes 0.000 description 9
- 108090000950 Melanocortin Receptors Proteins 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 102100027467 Pro-opiomelanocortin Human genes 0.000 description 8
- 230000009471 action Effects 0.000 description 7
- 235000019789 appetite Nutrition 0.000 description 7
- 230000036528 appetite Effects 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- 239000005556 hormone Substances 0.000 description 7
- 229940088597 hormone Drugs 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 230000004580 weight loss Effects 0.000 description 6
- 102000016267 Leptin Human genes 0.000 description 5
- 108010092277 Leptin Proteins 0.000 description 5
- 230000037149 energy metabolism Effects 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 108010069820 Pro-Opiomelanocortin Proteins 0.000 description 4
- 239000000683 Pro-Opiomelanocortin Substances 0.000 description 4
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Chemical compound OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 206010061428 decreased appetite Diseases 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- WHNFPRLDDSXQCL-UAZQEYIDSA-N α-msh Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(N)=O)NC(=O)[C@H](CO)NC(C)=O)C1=CC=C(O)C=C1 WHNFPRLDDSXQCL-UAZQEYIDSA-N 0.000 description 4
- IOLQYMRFIIVPMQ-YUMQZZPRSA-N 1-o-tert-butyl 2-o-methyl (2s,4s)-4-aminopyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C IOLQYMRFIIVPMQ-YUMQZZPRSA-N 0.000 description 3
- BJQMWOSPZUZYNW-YUMQZZPRSA-N 1-o-tert-butyl 2-o-methyl (2s,4s)-4-azidopyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C BJQMWOSPZUZYNW-YUMQZZPRSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 108010008364 Melanocortins Proteins 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 210000000577 adipose tissue Anatomy 0.000 description 3
- 239000000883 anti-obesity agent Substances 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000007972 injectable composition Substances 0.000 description 3
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 3
- 229940039781 leptin Drugs 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000002865 melanocortin Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000002858 neurotransmitter agent Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-M prolinate Chemical compound [O-]C(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-M 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- ORTUTLYEGOSCRP-ATNXLWBUSA-N (2s)-2-acetamido-n-[(3s,6s,13e)-14-[[(2s)-2-[[(2s)-2-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(2,3-dihydro-1h-indol-3-yl)propanoyl]amino]-3-(4h-imidazol-4-ylmethyl)-2,5,8,15-tetraoxo-1,4,9-triazacyclop Chemical compound C([C@H]1C(=O)NC(=O)\C(NC(=O)[C@H](CC2C3=CC=CC=C3NC2)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](N)CC=2C=C3C=CC=CC3=CC=2)=C/CCCNC(=O)C[C@@H](C(N1)=O)NC(=O)[C@@H](NC(C)=O)CCCC)C1C=NC=N1 ORTUTLYEGOSCRP-ATNXLWBUSA-N 0.000 description 2
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 2
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 2
- WVDGSSCWFMSRHN-UHFFFAOYSA-N 1-o-tert-butyl 2-o-methyl pyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)C1CCCN1C(=O)OC(C)(C)C WVDGSSCWFMSRHN-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- VGVHNLRUAMRIEW-UHFFFAOYSA-N 4-methylcyclohexan-1-one Chemical compound CC1CCC(=O)CC1 VGVHNLRUAMRIEW-UHFFFAOYSA-N 0.000 description 2
- 239000000275 Adrenocorticotropic Hormone Substances 0.000 description 2
- 102000006822 Agouti Signaling Protein Human genes 0.000 description 2
- 108010072151 Agouti Signaling Protein Proteins 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 101800000414 Corticotropin Proteins 0.000 description 2
- 241000484025 Cuniculus Species 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 2
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 101001047090 Homo sapiens Potassium voltage-gated channel subfamily H member 2 Proteins 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 2
- 101710151321 Melanostatin Proteins 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 102400000064 Neuropeptide Y Human genes 0.000 description 2
- 108090000189 Neuropeptides Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000012641 Pigmentation disease Diseases 0.000 description 2
- 102100022807 Potassium voltage-gated channel subfamily H member 2 Human genes 0.000 description 2
- 108010021820 SHU 9119 Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000008484 agonism Effects 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 235000021407 appetite control Nutrition 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 2
- 229960000258 corticotropin Drugs 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 229960002464 fluoxetine Drugs 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 210000003016 hypothalamus Anatomy 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- HQEIPVHJHZTMDP-UHFFFAOYSA-N methyl pyrrolidin-1-ium-2-carboxylate;chloride Chemical compound Cl.COC(=O)C1CCCN1 HQEIPVHJHZTMDP-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000003880 negative regulation of appetite Effects 0.000 description 2
- URPYMXQQVHTUDU-OFGSCBOVSA-N nucleopeptide y Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 URPYMXQQVHTUDU-OFGSCBOVSA-N 0.000 description 2
- 239000006186 oral dosage form Substances 0.000 description 2
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 2
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 2
- 229960004425 sibutramine Drugs 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 1
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- ZHCVEFJHHJZOCR-QWHCGFSZSA-N (3s,4r)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid Chemical compound C1N(C(C)(C)C)C[C@@H](C(O)=O)[C@@H]1C1=CC=C(Cl)C=C1 ZHCVEFJHHJZOCR-QWHCGFSZSA-N 0.000 description 1
- UOAQYJHCQPXLOP-VHSXEESVSA-N (3s,4r)-4-(4-chlorophenyl)pyrrolidin-1-ium-3-carboxylate Chemical compound OC(=O)[C@@H]1CNC[C@H]1C1=CC=C(Cl)C=C1 UOAQYJHCQPXLOP-VHSXEESVSA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- 229940035437 1,3-propanediol Drugs 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- QXGDJXLJHBZELB-BDAKNGLRSA-N 1-o-tert-butyl 2-o-methyl (2s,4r)-4-methylsulfonyloxypyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C QXGDJXLJHBZELB-BDAKNGLRSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 241000699725 Acomys Species 0.000 description 1
- 102100022455 Adrenocorticotropic hormone receptor Human genes 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000016623 Fragaria vesca Nutrition 0.000 description 1
- 240000009088 Fragaria x ananassa Species 0.000 description 1
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 101000678419 Homo sapiens Adrenocorticotropic hormone receptor Proteins 0.000 description 1
- 101000978431 Homo sapiens Melanocortin receptor 3 Proteins 0.000 description 1
- 101001134060 Homo sapiens Melanocyte-stimulating hormone receptor Proteins 0.000 description 1
- 206010062767 Hypophysitis Diseases 0.000 description 1
- 229940126661 MC4 antagonist Drugs 0.000 description 1
- 101150110867 MC4R gene Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- ZPXSCAKFGYXMGA-UHFFFAOYSA-N Mazindol Chemical compound N12CCN=C2C2=CC=CC=C2C1(O)C1=CC=C(Cl)C=C1 ZPXSCAKFGYXMGA-UHFFFAOYSA-N 0.000 description 1
- 102000030612 Melanocortin 5 receptor Human genes 0.000 description 1
- 108010088565 Melanocortin 5 receptor Proteins 0.000 description 1
- 102100023726 Melanocortin receptor 3 Human genes 0.000 description 1
- 108010007013 Melanocyte-Stimulating Hormones Proteins 0.000 description 1
- 101800001751 Melanocyte-stimulating hormone alpha Proteins 0.000 description 1
- 102100034216 Melanocyte-stimulating hormone receptor Human genes 0.000 description 1
- XOBKSJJDNFUZPF-UHFFFAOYSA-N Methoxyethane Chemical compound CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 241001284373 Spinus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 244000290333 Vanilla fragrans Species 0.000 description 1
- 235000009499 Vanilla fragrans Nutrition 0.000 description 1
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940125710 antiobesity agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000002830 appetite depressant Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 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
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- 229960004592 isopropanol Drugs 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 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
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960000299 mazindol Drugs 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- MQWCXKGKQLNYQG-UHFFFAOYSA-N methyl cyclohexan-4-ol Natural products CC1CCC(O)CC1 MQWCXKGKQLNYQG-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- BPGXUIVWLQTVLZ-OFGSCBOVSA-N neuropeptide y(npy) Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 BPGXUIVWLQTVLZ-OFGSCBOVSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- YZYFLRZVCOOMPS-UHFFFAOYSA-N oxolane;trimethylphosphane Chemical compound CP(C)C.C1CCOC1 YZYFLRZVCOOMPS-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- DLRJIFUOBPOJNS-UHFFFAOYSA-N phenetole Chemical compound CCOC1=CC=CC=C1 DLRJIFUOBPOJNS-UHFFFAOYSA-N 0.000 description 1
- 229960003562 phentermine Drugs 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 230000019612 pigmentation Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 210000003635 pituitary gland Anatomy 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000166 polytrimethylene carbonate 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
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- OAWXZFGKDDFTGS-UHFFFAOYSA-N pyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)C1CCCN1C(O)=O OAWXZFGKDDFTGS-UHFFFAOYSA-N 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003900 secondary neuron Anatomy 0.000 description 1
- 239000003762 serotonin receptor affecting agent Substances 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000004927 skin cell Anatomy 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000002352 surface water Substances 0.000 description 1
- 230000002459 sustained effect Effects 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
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 238000004260 weight control Methods 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- 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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Reproductive Health (AREA)
- Child & Adolescent Psychology (AREA)
- Gynecology & Obstetrics (AREA)
- Emergency Medicine (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及一种由化学式1表示的化合物的晶型VII、其制备方法以及包含其的药物组合物。根据本发明的由化学式1表示的化合物的晶型VII可以通过XRD图案、DSC曲线和/或TGA曲线进行表征。
Description
技术领域
相关申请的交叉引用
本发明基于2021年5月6日提交的韩国专利申请号10-2021-0058702要求优先权权益,该韩国专利申请的全部公开内容作为本说明书的一部分并入。
技术领域
本发明涉及一种对黑皮质素受体表现出优异的激动剂活性的新型化合物的晶型VII、其制备方法以及包含其的药物组合物。
背景技术
瘦素蛋白是一种由脂肪细胞分泌的激素,其分泌量随着体脂含量的增加而增加。它调节下丘脑产生的各种神经肽的功能,从而调节各种体内功能,包括食欲、体脂含量和能量代谢(Schwartz等人,Nature 404,661-671(2000))。控制食欲和体重的瘦素蛋白信号转导是通过调节许多下游因子来进行,其中最具代表性的是黑皮质素、刺鼠相关肽(AgRP)和神经肽Y(NPY)激素。
当体内热量过多导致血液中瘦素浓度增加时,来自垂体腺的阿黑皮素原(POMC)蛋白激素的分泌增加,AgRP和NPY的产生减少。小肽激素α-黑素细胞刺激激素(MSH)由POMC神经元产生。该激素是次级神经元的黑皮质素-4受体(MC4R)的激动剂,最终导致食欲下降。同时,当瘦素浓度因热量不足而降低时,MC4R拮抗剂AgRP的表达增加,NPY的表达也增加,最终增强食欲。即,根据瘦素的变化,α-MSH激素和AgRP激素充当MC4R的激动剂和拮抗剂,因此参与食欲控制。
除MC4R以外,α-MSH激素还结合三种MCR亚型以诱导各种生理反应。迄今已经鉴定了五种MCR亚型。其中,MC1R主要在皮肤细胞中表达并参与调节黑色素沉着(皮肤色素沉着)。MC2R主要在肾上腺中表达,已知参与糖皮质激素的产生。其配体只有来源于POMC的促肾上腺皮质激素(ACTH)。主要在中枢神经系统中表达的MC3R和MC4R参与调节食欲、能量代谢和体脂储存效率,而在各种组织中表达的MC5R已知调节外分泌功能(Wikberg等人,PharmRes 42(5)393-420(2000))。特别地,激活MC4R受体诱导食欲下降和能量代谢增加,因此具有有效减轻体重的效果。因此,它已经被证明是抗肥胖药物开发的主要作用点(综述:Wikberg,Eur.J.Pharmacol 375,295-310(1999));Wikberg等人,Pharm Res 42(5)393-420(2000);Douglas等人,Eur J Pharm 450,93-109(2002);O'Rahilly等人,Nature Med 10,351-352(2004))。
MC4R在控制食欲和体重中的作用已通过在刺鼠蛋白异常表达动物模型(agouti小鼠)中的实验得到了初步证明。在agouti小鼠的情况下,发现由于基因突变之故,刺鼠蛋白在中枢神经系统中以高浓度表达,并在下丘脑中充当MC4R的拮抗剂,从而导致肥胖(Yen,TT等人,FASEB J.8,479-488(1994);Lu D.等人,Nature 371,799-802(1994))。随后的研究结果表明,与实际刺鼠蛋白类似的刺鼠相关肽(AgRP)在下丘脑神经中表达,已知这些肽是MC4R拮抗剂并参与控制食欲(Shutter等人,Genes Dev.,11,593-602(1997);Ollman等人,Science 278,135-138(1997))。
对动物脑内施用体内MC4R激动剂α-MSH产生了降低食欲的效果。当用MC4R拮抗剂SHU9119(肽)或HS014(肽)处理所述动物时,观察到食欲再次增加(Kask等人,Biochem.Biophys.Res.Comm.245,90-93(1998))。此外,在使用美拉诺坦II(MTII,Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2)及其类似激动剂HP228的动物研究中,在脑内、腹膜内或皮下施用后,发现了抑制食欲、减轻体重和增加能量代谢等功效。(Thiele T.E.等人,AmJ Physiol 274(1Pt 2),R248-54(1998);Lee M.D.等人,FASEB J 12,A552(1998);MurphyB.等人,J Appl Physiol 89,273-82(2000))。相比之下,向动物施用代表性SHU9119表现出显著且持续的采食量和体重增加,从而提供了MCR激动剂可能是抗肥胖剂的药理学证据。施用MTII后明显表现出来的食欲降低效果在MC4R敲除(KO)小鼠中没有观察到。该实验结果再次证明食欲降低效果主要通过激活MC4R来实现(Marsh等人,Nat Genet 21,119-122(1999))。
作用于中枢神经系统的食欲抑制剂是迄今开发的抗肥胖药物中的主要类型。其中,大部分是调节神经递质作用的药物。实例包括去甲肾上腺素剂(芬特明(phentermine)和马吲哚(mazindol))、血清素能剂、氟西汀(fluoxetine)和西布曲明(sibutramine)等。然而,除了食欲抑制以外,神经递质调节剂还通过许多亚型受体对各种生理作用具有广泛影响。因此,所述调节剂缺乏对每一种亚型的选择性,因此主要缺点是它们在长期施用时会伴随各种副作用。
同时,黑皮质素激动剂是神经肽,而不是神经递质。鉴于在MC4R基因KO小鼠中,除能量代谢外的所有功能都正常,因此黑皮质素激动剂作为作用点的优势在于它们仅会通过食欲抑制来诱导体重减轻,而不会影响其它生理功能。特别地,该受体是G蛋白偶联受体(GPCR),属于迄今开发的新药作用点中最成功的类别。因此,所述作用点与现有作用点有很大的不同,因为它相对容易确保对亚型受体的选择性。
作为利用黑皮质素受体作为作用点的实例,国际公开第WO 2008/007930号和第WO2010/056022号公开了作为黑皮质素受体激动剂的化合物。
此外,本发明的发明人已经进行了广泛的研究,并发明了一种具有优异的激动剂活性的下式1的新化合物,所述化合物对黑皮质素受体,特别是黑皮质素-4受体(MC4R)具有选择性;以及一种制备所述化合物的方法(申请号KR 10-2019-0141649(于2019年11月7日提交)):
[式1]
(其中R1是C2-C5烷基。)。
同时,药物活性成分的晶体结构往往会影响药物的化学稳定性。不同的结晶条件和储存条件可以导致化合物的晶体结构发生变化,有时还会伴随产生其它形式的晶型。通常,无定形药物产品不具有规则的晶体结构,而且往往存在其它缺点,如产品稳定性差、粒径较小、过滤困难、容易结块和流动性差。因此,有必要改善产品的各种物理性能。因此,对于单一化合物,有必要研究具有高纯度和良好化学稳定性的晶体结构。
[现有技术文献]
[专利文献]
(专利文献1)国际专利申请公开号WO 2008/007930
(专利文献2)国际专利申请公开号WO 2010/056022
发明内容
技术问题
本发明的一个方面提供了一种具有优异的激动剂活性且对黑皮质素受体,特别是黑皮质素-4受体(MC4R)具有选择性的新型化合物的稳定晶型,以及其制备方法。
本发明的另一个方面提供了一种包含所述新型化合物的稳定晶型的药物组合物。
技术解决方案
根据本发明的一个方面,
提供了一种下式1化合物、其药学上可接受的盐或溶剂化物的晶型VII,
其中X射线粉末衍射图案具有3个以上或5个以上选自具有以下衍射角(2θ值)的峰的特征峰:8.24±0.2°、10.24±0.2°、10.68±0.2°、13.54±0.2°、16.04±0.2°和19.50±0.2°,
[式1]
其中
R1是C2-C5烷基。
由于式1化合物可以具有不对称的碳中心和不对称的轴或不对称的平面,因此它可以作为顺式或反式异构体、R或S异构体、外消旋体、非对映体混合物和单个非对映体存在,所有这些都在式1化合物的范围内。
在本说明书中,除非另有规定,否则为了方便起见,使用式1化合物来包括所有的式1化合物、其药学上可接受的盐、异构体和溶剂化物。
在根据本发明的一个实施方式中,在式1中,R1是C2至C5烷基。在根据本发明的另一个实施方式中,在式1中,R1是直链或支链C2至C5烷基,例如乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
在根据本发明的另一个实施方式中,在式1中,R1是C2或C3烷基。在根据本发明的另一个实施方式中,在式1中,R1是直链或支链C2或C3烷基,例如乙基、正丙基或异丙基。
在根据本发明的一个实施方式中,药学上可接受的盐包括但不限于由下列酸形成的酸加成盐:无机酸,如盐酸、硫酸、硝酸、磷酸、氢溴酸和氢碘酸;有机羧酸,如酒石酸、甲酸、柠檬酸、乙酸、三氯乙酸、三氟乙酸、葡萄糖酸、苯甲酸、乳酸、富马酸和马来酸;或磺酸,如甲磺酸、苯磺酸、对甲苯磺酸或萘磺酸。
在根据本发明的一个实施方式中,溶剂化物可以包括水合物;或与选自甲醇、乙醇、2-丙醇、1,2-丙二醇、1,3-丙二醇、正丁醇、1,4-丁二醇、叔丁醇、乙酸、丙酮、乙酸丁酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸叔丁酯、乙酸异丁酯、甲基乙基酮、2-戊酮、四氢呋喃、乙腈、三氯甲烷、甲苯、二甲基醚、二乙基醚、甲基乙基醚、甲基苯基醚、乙基苯基醚、二苯基醚以及其中两种以上的混合物的有机溶剂的溶剂化物。
在根据本发明的一个实施方式中,晶型VII可以是式1化合物的药学上可接受的盐的晶型。
式1化合物的药学上可接受的盐可以是下式2的盐酸盐化合物:
[式2]
其中R2是C2-C5烷基。
在根据本发明的另一个实施方式中,式1化合物的药学上可接受的盐可以是下式3的N-((3S,5S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-5-(吗啉-4-羰基)吡咯烷-3-基)-N-((1s,4R)-4-甲基环己基)异丁酰胺盐酸盐:
[式3]
在根据本发明的另一个实施方式中,晶型VII可以是式1化合物的药学上可接受的盐的溶剂化物(具体为水合物)的晶型。
更具体地,晶型VII可以是式1化合物的盐酸盐的晶型。
在根据本发明的一个实施方式中,晶型VII可以是下式4化合物的晶型。
[式4]
如通过X射线粉末衍射(XRD)所分析,根据本发明的晶型VII显示了包括选自8.24±0.2°、10.24±0.2°、10.68±0.2°、13.54±0.2°、16.04±0.2°和19.50±0.2°的3个以上、5个以上或所有峰的特征峰。
在根据本发明的一个实施方式中,晶型VII可以具有图4所示的XRD图案。
在根据本发明的晶型VII的差示扫描量热(DSC)曲线中,吸热峰出现在165℃至175℃。
在根据本发明的一个实施方式中,晶型VII可以具有图5所示的DSC曲线。
当加热到200℃以下的温度时,例如,在165℃至175℃的温度下,根据本发明的晶型VII在热重分析(TGA)曲线中可以具有10%以下,例如0.1%至10%、0.1%至5%、0.1%至3%或1%至3%的重量损失。
在根据本发明的一个实施方式中,晶型VII可以具有图6所示的TGA曲线。
在本说明书中,X射线衍射(XRD)分析示出了通过PXRD(Cu Kα辐射日本理学株式会社(Rigaku),Miniflex 600,日本)得到的结果。
差示扫描量热(DSC)分析示出了通过DSC(Q2000,TA仪器公司,美国)得到的结果。
热重分析(TGA)示出了通过TGA(TGA8000,珀金埃尔默公司(PerkinElmer),美国)得到的结果。
与粗式1化合物、无定形式1化合物或式1化合物的其它晶型相比,晶型VII可以具有更高的纯度,并且可以在物理和化学上更稳定。
此外,式1化合物的晶型VII对黑皮质素-4受体的激动能力和对疾病例如肥胖症、糖尿病、炎症、勃起功能障碍的预防或治疗效果可以比已知的黑皮质素-4受体激动剂更优异。然而,本发明的效果不限于此。
在另一个方面,本发明提供了一种制备晶型VII的方法,所述方法包括以下步骤:通过将所述式1化合物溶解在含有叔胺化合物的结晶溶剂中来制备混合溶液;以及通过从所述混合溶液蒸发所述结晶溶剂而由所述混合溶液得到晶体。
首先,将由式1表示的化合物溶解在含有胺化合物的结晶溶剂中。
用于制备晶型VII的式1化合物可以是式1化合物、其盐、其异构体或其溶剂化物。
式1化合物可以通过申请号KR 10-2019-0141649(2019年11月7日提交)的说明书中所述的制备方法来获得。
应使用含有叔胺化合物的结晶溶剂。‘叔胺化合物’是指被三个独立的取代基取代的胺化合物。在本文中,各个取代基可以独立地选自C1至C10烷基基团。
叔胺化合物可以包括但不限于三甲胺、三乙胺、三丙胺、三异丙胺、三丁胺、三仲丁胺、N,N-二甲基乙胺、N-乙基-N-甲基乙胺、N-乙基-N-甲基丙-1-胺、N-乙基-N-甲基丙-2-胺、N,N-二甲基丙-1-胺、N,N-二甲基丙-2-胺、N,N,2-三甲基丙-1-胺、N,N-二甲基丁-2-胺或其混合物。
在根据本发明的一个实施方式中,叔胺化合物可以包括三乙胺。
在根据本发明的另一个实施方式中,除了叔胺化合物以外,结晶溶剂还可以包括使叔胺化合物的溶解度优异的溶剂。
在根据本发明的另一个实施方式中,结晶溶剂可以是叔胺化合物与水的混合物。
在根据本发明的另一个实施方式中,可以使用体积比为90至99:1至10,具体为95:5的叔胺化合物与水作为结晶溶剂。
在根据本发明的另一个实施方式中,结晶溶剂可以是三乙胺与水以95:5的体积比混合的混合溶剂。
结晶溶剂可以按足以完全溶解式1化合物的量使用。例如,式1化合物已溶解在其中的混合溶液的浓度可以为10g/mL至200mg/mL、50mg/mL至150mg/mL、80mg/mL至120mg/mL或100mg/mL。
接下来,通过从混合溶液中蒸发结晶溶剂来得到晶体。
在本发明中,可以通过已知的溶剂蒸发结晶方法由混合溶液得到晶体。
在根据本发明的一个实施方式中,当从混合溶液中蒸发结晶溶剂时,混合溶液可能变成过饱和溶液,因此晶体可以沉淀。
在根据本发明的另一个实施方式中,在蒸发结晶溶剂的过程中,可以在保持混合溶液的温度的同时蒸发溶剂。
在根据本发明的另一个实施方式中,可以在室温下蒸发混合溶液中的结晶溶剂。
在根据本发明的另一个实施方式中,可以在大气压和室温下蒸发混合溶液中的结晶溶剂。
根据本发明,当通过蒸发结晶溶剂使晶体从混合溶液中沉淀时,所述方法还可以包括对沉淀的晶体进行干燥的步骤。
在根据本发明的一个实施方式中,当从已变成过饱和溶液的混合溶液产生的晶体的量不再增加时,可以对所得到的晶体进行干燥。然而,本发明不限于此。
在根据本发明的另一个实施方式中,可以通过将所得到的晶体放在100℃至200℃的温度下来进行干燥。然而,本发明不限于此。
在根据本发明的另一个实施方式中,可以通过将所得到的晶体放在170℃的热板上来进行干燥。然而,本发明不限于此。
与粗式1化合物、无定形式1化合物或式1的任何其它晶型相比,如上得到的晶型VII可以具有更高的纯度,并且可以在物理上和化学上更稳定。然而,本发明的效果不限于此。
在另一个方面,本发明提供了一种药物组合物,所述药物组合物包含:(i)所述晶型VII;以及(ii)药学上可接受的载体。
根据本发明的晶型VII对黑皮质素受体,特别是黑皮质素-4受体(MC4R)表现出优异的激动作用。因此,本发明可以提供一种用于激动黑皮质素受体的药物组合物,所述组合物含有上述晶型VII作为活性成分。具体地,所述药物组合物可以是用于激动黑皮质素-4受体的功能的组合物。
此外,由于所述药物组合物可以表现出预防或治疗肥胖症、糖尿病、炎症和勃起功能障碍的优异效果,因此它可以是用于预防或治疗肥胖症、糖尿病、炎症或勃起功能障碍的组合物。然而,本发明的用途不限于所述疾病。
如本文所用,“载体”是指有助于将化合物引入细胞或组织中的化合物。
当出于临床目的施用本发明的晶型VII时,以单次剂量或以分次剂量施用于宿主的总日剂量可以优选在0.01至10mg/kg体重的范围内。然而,个别患者的具体剂量水平可以取决于所使用的具体化合物、患者的体重、性别、健康状况、饮食、药物的施用时间、施用方法、排泄率、药物组合、疾病的严重程度等而变化。
本发明的晶型VII可以按需要通过任何途径施用。例如,本发明的无定形化合物可以肠胃外或口服施用。
本发明的药物组合物可以为各种口服剂型,如片剂、丸剂、粉剂、胶囊、颗粒剂、糖浆或乳剂,或肠胃外剂型,如用于肌肉内、静脉内或皮下施用的注射制剂。
注射制剂可以根据已知的技术使用合适的分散剂、润湿剂、悬浮剂或赋形剂来制备。
可用于本发明的药物制剂的赋形剂包括但不限于甜味剂、粘合剂、增溶剂、增溶试剂、润湿剂、乳化剂、等渗剂、吸附剂、崩解剂、抗氧化剂、防腐剂、润滑剂、填充剂、芳香剂等。例如,作为赋形剂,可以使用乳糖、葡萄糖、蔗糖、甘露醇、山梨醇、纤维素、甘氨酸、二氧化硅、硅酸镁铝、淀粉、明胶、黄芪胶、海藻酸、海藻酸钠、甲基纤维素、羧甲基纤维素钠、水、乙醇、聚乙二醇、聚乙烯吡咯烷酮、氯化钠、氯化钙、橙香精、草莓香精、香草调味剂等。
当本发明的药物组合物为口服剂型时,使用的载体的实例可以包括但不限于纤维素、硅酸钙、玉米淀粉、乳糖、蔗糖、葡萄糖、磷酸钙、硬脂酸、硬脂酸镁、硬脂酸钙、明胶、滑石等。
当本发明的药物组合物是可注射制剂形式时,载体的实例可以包括但不限于水、盐水、葡萄糖水溶液、糖样水溶液、醇、二醇、醚、油、脂肪酸、脂肪酸酯、甘油酯等。
在另一个方面,提供了一种如上所述的晶型VII以用于激动黑皮质素受体,特别是黑皮质素-4受体(MC4R)的功能。
在一个实施方式中,提供了一种如上所述的晶型VII以用于治疗或预防肥胖症、糖尿病、炎症或勃起功能障碍。
在另一个方面,提供了一种激动黑皮质素受体,特别是黑皮质素-4受体(MC4R)的功能的方法,所述方法包括向受试者施用上述晶型VII的步骤。
在另一个方面,提供了一种治疗肥胖症、糖尿病、炎症或勃起功能障碍的方法,所述方法包括向受试者施用上述晶型VII的步骤。
有益效果
根据本发明的晶型VII对黑皮质素受体,特别是黑皮质素-4受体(MC4R)表现出优异的激动作用,因此可有效地用于预防或治疗肥胖症、糖尿病、炎症和勃起功能障碍。
根据本发明的晶型VII对黑皮质素-4受体表现出中靶效应,从而表现出体重减轻和饮食减少效果而不影响焦虑和抑郁。此外,它可以在没有任何安全问题如人类ether-a-go-go相关基因(hERG)抑制或诱变等副作用的情况下施用。
此外,根据本发明的晶型VII的纯度、收率、物理和化学稳定性比粗式1化合物、无定形式1化合物或式1的任何其它晶型更加优异。
具体地,所述晶型VII的溶解度、储存稳定性和生产稳定性可以优于式1化合物、无定形式1化合物或式1的任何其它晶型。
附图说明
图1是制备例4的XRD结果的图。
图2是制备例4的DSC结果的图。
图3是制备例4的TGA结果的图。
图4是实施例1的XRD结果的图。
图5是实施例1的DSC结果的图。
图6是实施例1的TGA结果的图。
具体实施方式
下文将通过制备例和实施例更详细地描述本发明。然而,这些实施例仅说明本发明,本发明的范围不限于此。
制备例1:(2S,4S)-4-(N-((1s,4R)-4-甲基环己基)异丁酰胺基)吡咯烷-2-甲酸甲酯盐酸盐的制备
通过以下步骤A、步骤B、步骤C、步骤D和步骤E得到标题化合物。
步骤A:(2S,4S)-4-叠氮基吡咯烷-1,2-二甲酸1-(叔丁基)酯2-甲酯的制备
在氮气下将(2S,4R)-4-((甲基磺酰基)氧基)吡咯烷-1,2-二甲酸1-(叔丁基)酯2-甲酯(48.5g,150mmol)溶解在N,N'-二甲基甲酰胺(250ml)中,并加入叠氮化钠(19.5g,300ml)。在80℃搅拌16小时后,减压浓缩反应溶剂,加入水,用乙酸乙酯萃取两次。有机层用氯化钠水溶液和水进行洗涤,经无水硫酸镁干燥,并过滤。减压浓缩滤液,得到粗(2S,4S)-4-叠氮基吡咯烷-1,2-二甲酸1-(叔丁基)酯2-甲酯(39.59g,98%),未进行纯化便用于下一步。
MS[M+H]=271(M+1)
1H NMR(400MHz,CD3OD)δ4.43-4.37(m,1H),4.35-4.27(br,1H),3.77(s,1.8H),3.76(s,1.2H),3.73-3.66(m,1H),3.44-3.38(m,1H),2.63-2.49(m,1H),2.19-2.11(m,1H),1.50(s,4.5H),1.44(s,4.5H)
步骤B:(2S,4S)-4-氨基吡咯烷-1,2-二甲酸1-(叔丁基)酯2-甲酯的制备
将上述步骤A得到的(2S,4S)-4-叠氮基吡咯烷-1,2-二甲酸1-(叔丁基)酯2-甲酯(24.59g,91.0mmol)溶解在四氢呋喃(180ml)中,并在0℃缓慢加入1M三甲基膦四氢溶液(109.2ml,109.2mmol)。将混合物在相同温度下搅拌1小时,然后在室温下搅拌3小时。减压浓缩反应溶剂后,加入二氯甲烷(100ml)和水(150ml),并将混合物搅拌约30分钟。进行层分离并用二氯甲烷再次萃取,有机层经无水硫酸镁干燥并过滤。减压浓缩滤液,得到粗(2S,4S)-4-氨基吡咯烷-1,2-二甲酸1-(叔丁基)酯2-甲酯(20.62g,93%),未进行纯化便用于下一步。
MS[M+H]=245(M+1)
1H NMR(400MHz,CD3OD)δ4.27(m,1H),3.77(s,1.8H),3.76(s,1.2H),3.75-3.67(m,1H),3.50-3.42(m,1H),3.22-3.17(m,1H),2.58-2.47(m,1H),1.82-1.71(m,1H),1.48(s,4.5H),1.42(s,4.5H)
步骤C:(2S,4S)-4-(((1s,4R)-4-甲基环己基)氨基)吡咯烷-1,2-二甲酸1-(叔丁
基)酯2-甲酯的制备
将上述步骤B得到的(2S,4S)-4-氨基吡咯烷-1,2-二甲酸1-(叔丁基)酯2-甲酯(20.62g,84.4mmol)溶解在二氯乙烷(150ml)中,并加入4-甲基环己酮(9.5ml,101.3mmol)。在0℃加入三乙酰氧基硼氢化钠(26.8g,126.6mmol),将混合物在室温下搅拌16小时。减压浓缩反应溶剂,加入水,用乙酸乙酯萃取两次。有机层用氯化钠水溶液进行洗涤,经无水硫酸镁干燥并过滤。减压浓缩滤液,并通过柱色谱法进行纯化,得到(2S,4S)-4-(((1s,4R)-4-甲基环己基)氨基)吡咯烷-1,2-二甲酸1-(叔丁基)酯2-甲酯(22.9g,80%)。
MS[M+H]=341(M+1)
1H NMR(400MHz,CD3OD)δ4.26(m,1H),3.76(s,1.8H),3.75(s,1.2H),3.78-3.71(m,1H),3.49-3.40(m,1H),3.22-3.16(m,1H),2.69-2.60(br,1H),2.58-2.46(m,1H),1.87-1.77(m,1H),1.73-1.63(m,1H),1.62-1.35(m,8H),1.48(s,4.5H),1.42(s,4.5H),0.96(d,3H)
步骤D:(2S,4S)-4-(N-((1s,4R)-4-甲基环己基)异丁酰胺基)吡咯烷-1,2-二甲酸
1-(叔丁基)酯2-甲酯的制备
将上述步骤C得到的(2S,4S)-4-(((1s,4R)-4-甲基环己基)氨基)吡咯烷-1,2-二甲酸1-(叔丁基)酯2-甲酯(37.29g,109.5mmol)溶解在二氯甲烷(500ml)中,加入三乙胺(61.1ml,438.1mmol),然后在0℃缓慢加入异丁酰氯(11.7ml,219mmol)。将混合物在室温下搅拌16小时后,减压浓缩反应溶剂,加入碳酸氢钠水溶液,用乙酸乙酯萃取两次。有机层用氯化钠水溶液和水进行洗涤,经无水硫酸镁干燥,并过滤。减压浓缩滤液,并通过柱色谱法进行纯化,得到(2S,4S)-4-(N-((1s,4R)-4-甲基环己基)异丁酰胺基)吡咯烷-1,2-二甲酸1-(叔丁基)酯2-甲酯(38.79g,86%)。
MS[M+H]=411(M+1)
1H NMR(400MHz,CD3OD)δ4.27(m,1H),3.76(s,1.8H),3.75(s,1.2H),3.78-3.72(m,1H),3.50-3.41(m,1H),3.33-3.14(m,1H),2.69-2.60(m,2H),2.57-2.43(m,1H),1.87-1.79(m,1H),1.70-1.61(m,1H),1.60-1.32(m,8H),1.47(s,4.5H),1.41(s,4.5H),1.10(dd,6H),0.99(d,3H)
步骤E:(2S,4S)-4-(N-((1s,4R)-4-甲基环己基)异丁酰胺基)吡咯烷-2-甲酸甲酯
盐酸盐的制备
将上述步骤D得到的(2S,4S)-4-(N-((1s,4R)-4-甲基环己基)异丁酰胺基)吡咯烷-1,2-二甲酸1-(叔丁基)酯2-甲酯(34.0g,82.8mmol)溶解在二氯甲烷(200ml)中,在0℃加入4N盐酸在1,4-二烷溶液中的溶液(82.8ml,331.3mmol)。将混合物在室温下搅拌6小时后,减压浓缩反应溶剂,得到粗物质(28.7g,99%),未进行纯化便用于下一步。
MS[M+H]=311(M+1)
制备例2:(3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-甲酸的制备
根据国际专利公开号WO 2004/092126所述的方法得到标题化合物。
MS[M+H]=282(M+1)
1H NMR(400MHz,CD3OD)δ7.43-7.33(m,4H),3.90-3.69(m,3H),3.59(dd,J=11.2,10.0Hz,1H),3.29(dd,J=11.2,11.2Hz,1H),3.18-3.09(m,1H),1.44(s,9H)
制备例3:N-((3S,5S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-5-(吗啉-4-羰基)吡咯烷-3-基)-N-((1s,4R)-4-甲基环己基)异丁酰胺的制备
通过以下步骤A、步骤B和步骤C得到标题化合物。
步骤A:(2S,4S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-4-(N-
((1s,4R)-4-甲基环己基)异丁酰胺基)吡咯烷-2-甲酸甲酯的制备
将制备例1得到的(2S,4S)-4-(N-((1s,4R)-4-甲基环己基)异丁酰胺基)吡咯烷-2-甲酸甲酯盐酸盐(28.7g,82.73mmol)、制备例2得到的(3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-甲酸(24.5g,86.87mmol)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(22.2g,115.83mmol)和1-羟基苯并三唑水合物(15.7g,115.83mmol)溶解在N,N'-二甲基甲酰胺(400ml)中,缓慢加入N,N'-二异丙基乙胺(72.0ml,413.66mmol)。将混合物在室温下搅拌16小时,减压浓缩反应溶剂,加入0.5N氢氧化钠水溶液,然后用乙酸乙酯萃取两次。有机层用氯化钠水溶液和水洗涤两次,经无水硫酸镁干燥,并过滤。减压浓缩滤液,并通过柱色谱法进行纯化,得到(2S,4S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-4-(N-((1s,4R)-4-甲基环己基)异丁酰胺基)吡咯烷-2-甲酸甲酯(41.19g,87%)。
MS[M+H]=575(M+1)
步骤B:(2S,4S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-4-(N-
((1s,4R)-4-甲基环己基)异丁酰胺基)吡咯烷-2-甲酸的制备
将上述步骤A得到的(2S,4S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-4-(N-((1s,4R)-4-甲基环己基)异丁酰胺基)吡咯烷-2-甲酸甲酯(39.4g,68.62mmol)溶解在甲醇(450ml)中,然后加入6N氢氧化钠水溶液(57.2ml,343.09mmol)。将混合物在室温下搅拌16小时,用6N盐酸水溶液将pH调节至约5,然后减压浓缩反应溶液。将浓缩物溶解在二氯甲烷中,然后通过滤纸滤出不溶性固体。减压浓缩滤液,得到粗标题化合物(38.4g,99%),未进行纯化便用于下一步。
MS[M+H]=561(M+1)
步骤C:N-((3S,5S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-5-
(吗啉-4-羰基)吡咯烷-3-基)-N-((1s,4R)-4-甲基环己基)异丁酰胺的制备
将上述步骤B得到的(2S,4S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-4-(N-((1s,4R)-4-甲基环己基)异丁酰胺基)吡咯烷-2-甲酸(38.4g,68.60mmol)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(18.4g,96.04mmol)和1-羟基苯并三唑水合物(13.0g,96.04mmol)溶解在N,N'-二甲基甲酰胺(200ml)中,然后依次缓慢加入吗啉(5.9ml,68.80mmol)和N,N'-二异丙基乙胺(59.7ml,343.02mmol)。将混合物在室温下搅拌16小时,减压浓缩反应溶液,加入0.5N氢氧化钠水溶液,然后用乙酸乙酯萃取两次。有机层用氯化钠水溶液和水洗涤两次,经无水硫酸镁干燥,并过滤。减压浓缩滤液,并通过柱色谱法进行纯化,得到N-((3S,5S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-5-(吗啉-4-羰基)吡咯烷-3-基)-N-((1s,4R)-4-甲基环己基)异丁酰胺(37.05g,86%)。
MS[M+H]=630(M+1)
制备例4:N-((3S,5S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-5-(吗啉-4-羰基)吡咯烷-3-基)-N-((1s,4R)-4-甲基环己基)异丁酰胺盐酸盐的无定形化合物的制备
基于1g上述制备例3制备的化合物(MC70),在25℃下使用19mL MBTE来溶解所述化合物(MC70)。溶解完成后,加入1mL庚烷,然后将混合物冷却到-5℃至0℃。达到设定温度后,滴加1当量4MHCl/EtOAc,将混合物搅拌约90分钟并过滤,得到标题化合物(MC71)。
(收率:约90%)
制备例4的化合物的XRD(图1)、DSC(图2)和TGA(图3)分析结果分别示于图1至图3中。分析结果证实了它是无定形化合物。XRD、DSC和TGA分析方法各自如下面的实施例1的实验例所述。
实施例1
N-((3S,5S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-5-(吗啉-4-羰基)吡咯烷-3-基)-N-((1s,4R)-4-甲基环己基)异丁酰胺盐酸盐的晶型VII的制备
将100mg上面制备的制备例4的化合物(MC71)溶解在950μL三乙胺和50μL水中,然后在室温下蒸发溶剂,直到形成晶体。随后,将所形成的晶体在170℃的热板上进行干燥,以得到标题晶型VII。
比较例1
在室温下将1g上面制备的制备例4的化合物(MC71)溶解在1mL EtOAc中。溶解完成后,用电子搅拌器将混合物搅拌约43小时,但并未得到与实施例1相同的晶体。
实验例1.XRD评价
对于粉末XRD衍射图案,使用PXRD(Cu Kα辐射日本理学株式会社,Miniflex 600,日本),将管电压和管电流分别设为45kV和15mA,然后以0.02°/s的扫描速率和4°/min的步进速度测量3°至40°范围内的布拉格角(2θ)。
所得到的晶型VII的XRD测量结果示于图4中。
如图4所示的光谱中所证实,根据本发明的晶型VII表现出了在8.24°、10.24°、10.68°、13.54°、16.04°和19.50°处的特征峰(2θ)。XRD的具体值示于下表1中。
[表1]
2θ | 相对强度(I/I0) |
8.24 | 630 |
10.24 | 1361 |
10.68 | 853 |
13.54 | 706 |
16.04 | 1481 |
19.50 | 1077 |
实验例2.差示扫描量热(DSC)
使用DSC(Q2000,TA仪器公司,美国)测量脱溶剂化温度、瞬时温度和熔融温度。在以50ml/min的速率进行氮气吹扫的情况下,以10℃/min的速率扫描30℃至300℃。
所得到的晶型VII的DSC测量结果示于图5中。
如图5可见,对于晶型VII,观察到在约168.2℃处的吸热峰。温度值有±5℃的误差。
实验例3.热重分析(TGA)
通过热重分析(TGA8000,珀金埃尔默公司,美国)进行挥发物含量分析,包括表面水和溶剂化物。称5mg样品到开放的铝坩埚中,并进行TGA。将样品以10℃/min的速率从30℃加热至300℃。在测量过程中,以20mL/min的速率向仪器内部引入氮气以阻挡氧气和其它气体流入。
所得到的晶型VII的TGA测量结果示于图6中。
如图6可见,对于晶型VII,在165℃至175℃的温度下观察到约1.33%的重量损失。在约250℃之后,由于分解而发生重量损失。温度值有±5℃的误差。
Claims (14)
1.一种下式1化合物、其药学上可接受的盐或其溶剂化物的晶型VII,
其中X射线粉末衍射图案具有3个以上选自具有以下衍射角(2θ值)的峰的特征峰:8.24±0.2°、10.24±0.2°、10.68±0.2°、13.54±0.2°、16.04±0.2°和19.50±0.2°,
[式1]
其中
R1是C2-C5烷基。
2.根据权利要求1所述的晶型VII,其中R1是C2-C4烷基。
3.根据权利要求1所述的晶型VII,其中所述式1化合物的药学上可接受的盐选自:所述化合物的盐酸盐、硫酸盐、硝酸盐、磷酸盐、氢溴酸盐和氢碘酸盐。
4.根据权利要求1所述的晶型VII,所述晶型是N-((3S,5S)-1-((3S,4R)-1-(叔丁基)-4-(4-氯苯基)吡咯烷-3-羰基)-5-(吗啉-4-羰基)吡咯烷-3-基)-N-((1s,4R)-4-甲基环己基)异丁酰胺盐酸盐的晶型。
5.一种制备根据权利要求1至4中任一项所述的晶型VII的方法,所述方法包括以下步骤:
通过将所述式1化合物溶解在含有叔胺化合物的结晶溶剂中来制备混合溶液;以及
通过从所述混合溶液蒸发所述结晶溶剂而由所述混合溶液得到晶体。
6.根据权利要求5所述的制备晶型VII的方法,其中所述叔胺化合物包括三甲胺、三乙胺、三丙胺、三异丙胺、三丁胺、三仲丁胺、N,N-二甲基乙胺、N-乙基-N-甲基乙胺、N-乙基-N-甲基丙-1-胺、N-乙基-N-甲基丙-2-胺、N,N-二甲基丙-1-胺、N,N-二甲基丙-2-胺、N,N,2-三甲基丙-1-胺、N,N-二甲基丁-2-胺或其混合物。
7.根据权利要求5所述的制备晶型VII的方法,其中在保持所述混合溶液的温度的同时蒸发所述溶剂。
8.根据权利要求5所述的制备晶型VII的方法,其中在室温下蒸发所述混合溶液中的结晶溶剂。
9.根据权利要求5所述的制备晶型VII的方法,其中所述结晶溶剂还包括水。
10.根据权利要求9所述的制备晶型VII的方法,其中使用体积比为90至99:1至10的所述叔胺化合物与水作为所述结晶溶剂。
11.根据权利要求5所述的制备晶型VII的方法,所述方法还包括通过蒸发所述结晶溶剂来干燥所得到的晶体的步骤。
12.一种药物组合物,所述药物组合物包含根据权利要求1至4中任一项所述的晶型VII和药学上可接受的载体。
13.一种用于激动黑皮质素-4受体的功能的药物组合物,所述组合物包含根据权利要求1至4中任一项所述的晶型VII和药学上可接受的载体。
14.根据权利要求13所述的药物组合物,所述药物组合物用于预防或治疗肥胖症、糖尿病、炎症或勃起功能障碍。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2021-0058702 | 2021-05-06 | ||
KR20210058702 | 2021-05-06 | ||
PCT/KR2022/006479 WO2022235105A1 (ko) | 2021-05-06 | 2022-05-06 | 멜라노코르틴 수용체 작용제 화합물의 결정형 ⅶ 및 이의 제조방법 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117255786A true CN117255786A (zh) | 2023-12-19 |
Family
ID=83932334
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202280032151.8A Pending CN117255786A (zh) | 2021-05-06 | 2022-05-06 | 黑皮质素受体激动剂化合物的晶型vii及其制备方法 |
Country Status (10)
Country | Link |
---|---|
US (1) | US20240239783A1 (zh) |
EP (1) | EP4317150A1 (zh) |
JP (1) | JP2024518056A (zh) |
KR (1) | KR20220151570A (zh) |
CN (1) | CN117255786A (zh) |
AU (1) | AU2022269993A1 (zh) |
BR (1) | BR112023022863A2 (zh) |
CA (1) | CA3217201A1 (zh) |
MX (1) | MX2023013042A (zh) |
WO (1) | WO2022235105A1 (zh) |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4754030A (en) * | 1985-02-01 | 1988-06-28 | Bristol-Myers Company | Cefbuperazone crystalline triethylamine salt |
AR044510A1 (es) | 2003-04-14 | 2005-09-14 | Merck & Co Inc | Procedimiento e intermedios para preparar acidos carboxilicos de pirrolidina |
TWI332501B (en) | 2006-07-14 | 2010-11-01 | Lg Life Sciences Ltd | Melanocortin receptor agonists |
UA99555C2 (en) * | 2008-11-12 | 2012-08-27 | Элджи Лайф Саенсез Лтд. | Melanocortin receptor agonists |
EP3580194A4 (en) | 2017-02-08 | 2020-12-30 | Tilray, Inc. | LOW PRESSURE RADIANT ENERGY CANNABIS TREATMENT METHODS AND APPARATUS |
ES2970510T3 (es) * | 2019-11-07 | 2024-05-29 | Lg Chemical Ltd | Agonistas del receptor de melanocortina-4 |
JP7419029B2 (ja) | 2019-11-14 | 2024-01-22 | 大塚電子株式会社 | 光学測定装置のリニアリティ補正方法、光学測定方法及び光学測定装置 |
-
2022
- 2022-05-06 CN CN202280032151.8A patent/CN117255786A/zh active Pending
- 2022-05-06 US US18/558,148 patent/US20240239783A1/en active Pending
- 2022-05-06 AU AU2022269993A patent/AU2022269993A1/en active Pending
- 2022-05-06 EP EP22799148.6A patent/EP4317150A1/en active Pending
- 2022-05-06 WO PCT/KR2022/006479 patent/WO2022235105A1/ko active Application Filing
- 2022-05-06 JP JP2023568098A patent/JP2024518056A/ja active Pending
- 2022-05-06 CA CA3217201A patent/CA3217201A1/en active Pending
- 2022-05-06 BR BR112023022863A patent/BR112023022863A2/pt unknown
- 2022-05-06 KR KR1020220055895A patent/KR20220151570A/ko not_active Application Discontinuation
- 2022-05-06 MX MX2023013042A patent/MX2023013042A/es unknown
Also Published As
Publication number | Publication date |
---|---|
CA3217201A1 (en) | 2022-11-10 |
AU2022269993A1 (en) | 2023-11-02 |
KR20220151570A (ko) | 2022-11-15 |
MX2023013042A (es) | 2023-11-15 |
WO2022235105A1 (ko) | 2022-11-10 |
US20240239783A1 (en) | 2024-07-18 |
EP4317150A1 (en) | 2024-02-07 |
BR112023022863A2 (pt) | 2024-01-23 |
JP2024518056A (ja) | 2024-04-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP4219475A1 (en) | Crystal form iv of melanocortin receptor agonist compound, and preparation method therefor | |
TWI823169B (zh) | 黑皮質素受體促效劑化合物的晶形ⅲ及其製備方法 | |
US20230399321A1 (en) | Crystalline form ii of melanocortin receptor agonist compound and preparation method therefor | |
EP4219472A1 (en) | Crystalline form i of melanocortin receptor agonist compound, and method for preparing same | |
US20240043407A1 (en) | Crystalline form i of melanocortin receptor agonist compound and method for preparing same | |
EP4249482A1 (en) | Amorphous melanocortin receptor agonist and method for preparing same | |
EP4219471A1 (en) | Amorphous melanocortin-4 receptor agonist | |
CN116648249A (zh) | 黑皮质素受体激动剂化合物的结晶形式ii及其制备方法 | |
CN117255786A (zh) | 黑皮质素受体激动剂化合物的晶型vii及其制备方法 | |
CN117242064A (zh) | 黑皮质素受体激动剂化合物的晶型v及其制备方法 | |
US20240051919A1 (en) | Crystalline form iii of melanocortin receptor agonist compound and preparation method therefor | |
EP4317151A1 (en) | Crystal form iv of organic acid salts of melanocortin receptor agonist compound, and preparation method thereof | |
CN117242063A (zh) | 黑皮质素受体激动剂化合物与香兰素的共晶及其制备方法 | |
CN117255787A (zh) | 黑皮质素受体激动剂化合物的硫酸盐晶体及其制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |