WO2024028744A1 - Traitement de l'anémie aplasique (aa) - Google Patents
Traitement de l'anémie aplasique (aa) Download PDFInfo
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- WO2024028744A1 WO2024028744A1 PCT/IB2023/057752 IB2023057752W WO2024028744A1 WO 2024028744 A1 WO2024028744 A1 WO 2024028744A1 IB 2023057752 W IB2023057752 W IB 2023057752W WO 2024028744 A1 WO2024028744 A1 WO 2024028744A1
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- WIPO (PCT)
- Prior art keywords
- subject
- pharmaceutically acceptable
- acceptable salts
- formula
- amount
- Prior art date
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- 208000032467 Aplastic anaemia Diseases 0.000 title claims abstract description 60
- 238000011282 treatment Methods 0.000 title claims abstract description 20
- 108010041111 Thrombopoietin Proteins 0.000 claims abstract description 169
- 102000036693 Thrombopoietin Human genes 0.000 claims abstract description 168
- 229940044601 receptor agonist Drugs 0.000 claims abstract description 84
- 239000000018 receptor agonist Substances 0.000 claims abstract description 84
- 208000007502 anemia Diseases 0.000 claims abstract description 49
- 239000000203 mixture Substances 0.000 claims abstract description 23
- 102000004079 Prolyl Hydroxylases Human genes 0.000 claims abstract description 9
- 108010043005 Prolyl Hydroxylases Proteins 0.000 claims abstract description 9
- 239000003112 inhibitor Substances 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims description 199
- 150000001875 compounds Chemical class 0.000 claims description 144
- -1 amines salts Chemical class 0.000 claims description 51
- 108010017584 romiplostim Proteins 0.000 claims description 51
- 229960004262 romiplostim Drugs 0.000 claims description 50
- WUWDLXZGHZSWQZ-WQLSENKSSA-N semaxanib Chemical group N1C(C)=CC(C)=C1\C=C/1C2=CC=CC=C2NC\1=O WUWDLXZGHZSWQZ-WQLSENKSSA-N 0.000 claims description 50
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 40
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 40
- 229960001069 eltrombopag Drugs 0.000 claims description 39
- XDXWLKQMMKQXPV-QYQHSDTDSA-N eltrombopag Chemical compound CC1=NN(C=2C=C(C)C(C)=CC=2)C(=O)\C1=N/NC(C=1O)=CC=CC=1C1=CC=CC(C(O)=O)=C1 XDXWLKQMMKQXPV-QYQHSDTDSA-N 0.000 claims description 37
- 239000008194 pharmaceutical composition Substances 0.000 claims description 34
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 30
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 30
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 30
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 30
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 30
- OFZJKCQENFPZBH-UHFFFAOYSA-N 1-[3-chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)-1,3-thiazol-2-yl]carbamoyl]pyridin-2-yl]piperidine-4-carboxylic acid Chemical compound C1CC(C(=O)O)CCN1C1=NC=C(C(=O)NC=2SC(=C(C=3SC=C(Cl)C=3)N=2)N2CCN(CC2)C2CCCCC2)C=C1Cl OFZJKCQENFPZBH-UHFFFAOYSA-N 0.000 claims description 29
- 229950011007 avatrombopag Drugs 0.000 claims description 29
- 229950009491 lusutrombopag Drugs 0.000 claims description 29
- NOZIJMHMKORZBA-KJCUYJGMSA-N lusutrombopag Chemical compound CCCCCCO[C@@H](C)C1=CC=CC(C=2N=C(NC(=O)C=3C=C(Cl)C(\C=C(/C)C(O)=O)=C(Cl)C=3)SC=2)=C1OC NOZIJMHMKORZBA-KJCUYJGMSA-N 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 25
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 22
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims description 22
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 20
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 20
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 20
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 20
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 20
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 20
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 20
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 20
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 20
- QYPPJABKJHAVHS-UHFFFAOYSA-N agmatine Chemical compound NCCCCNC(N)=N QYPPJABKJHAVHS-UHFFFAOYSA-N 0.000 claims description 20
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 claims description 20
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 claims description 20
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 claims description 20
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 claims description 20
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 claims description 20
- 229910052751 metal Inorganic materials 0.000 claims description 20
- 239000002184 metal Substances 0.000 claims description 20
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 20
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 claims description 20
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 20
- 239000004471 Glycine Substances 0.000 claims description 16
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 claims description 14
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 13
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 12
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 12
- 241001465754 Metazoa Species 0.000 claims description 12
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052700 potassium Inorganic materials 0.000 claims description 12
- 239000011591 potassium Substances 0.000 claims description 12
- 229910052708 sodium Inorganic materials 0.000 claims description 12
- 239000011734 sodium Substances 0.000 claims description 12
- 229960001231 choline Drugs 0.000 claims description 11
- 229910052742 iron Inorganic materials 0.000 claims description 11
- PINPOEWMCLFRRB-LURJTMIESA-N (1s)-1-(4-chlorophenyl)ethanamine Chemical compound C[C@H](N)C1=CC=C(Cl)C=C1 PINPOEWMCLFRRB-LURJTMIESA-N 0.000 claims description 10
- JTDGKQNNPKXKII-ZETCQYMHSA-N (1s)-1-(4-methoxyphenyl)ethanamine Chemical compound COC1=CC=C([C@H](C)N)C=C1 JTDGKQNNPKXKII-ZETCQYMHSA-N 0.000 claims description 10
- DXSUORGKJZADET-YFKPBYRVSA-N (2s)-3,3-dimethylbutan-2-amine Chemical compound C[C@H](N)C(C)(C)C DXSUORGKJZADET-YFKPBYRVSA-N 0.000 claims description 10
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 claims description 10
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 claims description 10
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims description 10
- GXVUZYLYWKWJIM-UHFFFAOYSA-N 2-(2-aminoethoxy)ethanamine Chemical compound NCCOCCN GXVUZYLYWKWJIM-UHFFFAOYSA-N 0.000 claims description 10
- JBIJLHTVPXGSAM-UHFFFAOYSA-N 2-naphthylamine Chemical compound C1=CC=CC2=CC(N)=CC=C21 JBIJLHTVPXGSAM-UHFFFAOYSA-N 0.000 claims description 10
- HVLUYXIJZLDNIS-UHFFFAOYSA-N 2-thiophen-2-ylethanamine Chemical compound NCCC1=CC=CS1 HVLUYXIJZLDNIS-UHFFFAOYSA-N 0.000 claims description 10
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 claims description 10
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- 239000004475 Arginine Substances 0.000 claims description 10
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical group [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 10
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 10
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 claims description 10
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims description 10
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 10
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 10
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 10
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 10
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 10
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 10
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- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 10
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- 239000004472 Lysine Substances 0.000 claims description 10
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 10
- BAVYZALUXZFZLV-UHFFFAOYSA-O Methylammonium ion Chemical compound [NH3+]C BAVYZALUXZFZLV-UHFFFAOYSA-O 0.000 claims description 10
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 10
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 10
- XTUVJUMINZSXGF-UHFFFAOYSA-N N-methylcyclohexylamine Chemical compound CNC1CCCCC1 XTUVJUMINZSXGF-UHFFFAOYSA-N 0.000 claims description 10
- PAMIQIKDUOTOBW-UHFFFAOYSA-N N-methylcyclohexylamine Natural products CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 10
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- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 claims description 10
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- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 10
- 239000004473 Threonine Substances 0.000 claims description 10
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 10
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 10
- 235000004279 alanine Nutrition 0.000 claims description 10
- 229910052782 aluminium Inorganic materials 0.000 claims description 10
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 10
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 10
- 229960003805 amantadine Drugs 0.000 claims description 10
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 10
- 229910052788 barium Inorganic materials 0.000 claims description 10
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 claims description 10
- UPABQMWFWCMOFV-UHFFFAOYSA-N benethamine Chemical compound C=1C=CC=CC=1CNCCC1=CC=CC=C1 UPABQMWFWCMOFV-UHFFFAOYSA-N 0.000 claims description 10
- 229960003237 betaine Drugs 0.000 claims description 10
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 10
- 229910052793 cadmium Inorganic materials 0.000 claims description 10
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 claims description 10
- 229910052792 caesium Inorganic materials 0.000 claims description 10
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 claims description 10
- 229910052791 calcium Inorganic materials 0.000 claims description 10
- 239000011575 calcium Substances 0.000 claims description 10
- 239000004202 carbamide Substances 0.000 claims description 10
- 229910017052 cobalt Inorganic materials 0.000 claims description 10
- 239000010941 cobalt Substances 0.000 claims description 10
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 10
- 229910052802 copper Inorganic materials 0.000 claims description 10
- 239000010949 copper Substances 0.000 claims description 10
- VXVVUHQULXCUPF-UHFFFAOYSA-N cycloheptanamine Chemical compound NC1CCCCCC1 VXVVUHQULXCUPF-UHFFFAOYSA-N 0.000 claims description 10
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- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 10
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- XBRDBODLCHKXHI-UHFFFAOYSA-N epolamine Chemical compound OCCN1CCCC1 XBRDBODLCHKXHI-UHFFFAOYSA-N 0.000 claims description 10
- 229950008932 epolamine Drugs 0.000 claims description 10
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- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 claims description 10
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 10
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- 239000011133 lead Substances 0.000 claims description 10
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- 229910052749 magnesium Inorganic materials 0.000 claims description 10
- 239000011777 magnesium Substances 0.000 claims description 10
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 claims description 10
- 229960003194 meglumine Drugs 0.000 claims description 10
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- 229960003105 metformin Drugs 0.000 claims description 10
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 10
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 10
- HVAAHUDGWQAAOJ-UHFFFAOYSA-N n-benzylethanamine Chemical compound CCNCC1=CC=CC=C1 HVAAHUDGWQAAOJ-UHFFFAOYSA-N 0.000 claims description 10
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 claims description 10
- XHFGWHUWQXTGAT-UHFFFAOYSA-N n-methylpropan-2-amine Chemical compound CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 claims description 10
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 claims description 10
- 229960004919 procaine Drugs 0.000 claims description 10
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 claims description 10
- 229910052709 silver Inorganic materials 0.000 claims description 10
- 239000004332 silver Substances 0.000 claims description 10
- 229910052712 strontium Inorganic materials 0.000 claims description 10
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 claims description 10
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 10
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Classifications
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4704—2-Quinolinones, e.g. carbostyril
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K31/515—Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
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- 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
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- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention describes a combination of a suitable prolyl hydroxylase inhibitors with a suitable thrombopoietin (TPO) receptor agonist for the treatment of Aplastic anemia (AA).
- TPO thrombopoietin
- the invention also describes the preparation of such combination and its compositions.
- Aplastic anemia is a rare disorder characterized by suppression of bone marrow function resulting in progressive pancytopenia. 1 The most common cause of AA is immune system attacking the stem cells in bone marrow. Radiation and chemotherapy treatments are the other factors that can injure bone marrow and affect blood cell production. It is diagnosed with values have to lower than 10 g/dl for hemoglobin, 1.5 x 10 9 /L for neutrophils and 50 x 10 9 /L for a platelets. Megakaryocytes pattern may be useful in distinguishing myelodysplasia (MDS) from AA since they are often reduced/absent in AA whereas small or aberrant megakaryocytes are more typical of MDS.
- MDS myelodysplasia
- thrombopoietin mimetic TPO agonist
- TPO thrombopoietin receptor agonist
- c-Mpl thrombopoietin receptor agonist
- 6 thrombopoietin (TPO) receptor agonist are intravenous peptibody Romiplostim, oral small molecules y
- Eltrombopag bisethanolamine chemical name 3'-(2-(l-(3,4-dimethylphenyl)-3-methyl-5-oxo- 1 ,5-dihydro-4H-pyrazol-4-ylidene)hydrazineyl)-2'-hydroxy-[l, l'-biphenyl]-3-carboxylic acid 2- hydroxy-N,N,N-trimethylethan-l-aminium (1: 1).
- Eltrombopag is a small-molecule, non-peptide thrombopoietin (TPO) receptor agonist that has been shown to stimulate the proliferation and differentiation of megakaryocytes, the bone marrow cells that give rise to blood platelets in pre-clinical research and clinical trials.
- TPO non-peptide thrombopoietin
- Eltrombopag bisethanolamine is the active ingredient of the marketed drug Promacta® (US) or Revolade® (EU) indicated in the treatment of chronic immune thrombocytopenia (CIT) in patients who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. It is also indicated for thrombocytopenia in patients with chronic hepatitis C and in severe aplastic anaemia.
- Eltrombopag is disclosed in US Patent No. 7,160,870.
- Eltrombopag bisethanolamine salt is disclosed in US Patent No. 7,547,719.
- Eltrombopag tromethamine salt is disclosed in International Patent Publication No. W020170042839. Crystalline forms of Eltrombopag choline are disclosed in International Patent Publication No. W020190071111 and US Patent No. 11,072,586.
- Romiplostim is an active ingredient of the marketed drug Nplate. It is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Romiplostim disclosed in US Patent No. 9,145,450 and W02000/24770.
- the small molecule hypoxia-inducible factor stabilizer compound Desidustat (compound of formula (la)), inhibits the prolyl hydroxylase and has demonstrated hematinic potential by combined effects on endogenous erythropoietin release and efficient iron utilization. It also o enhances erythroid maturation by suppressing hepcidin-ferroportin axis.
- W02004108681 and W02008002576 covers the prolyl hydroxylase inhibitors named Roxadustat and Vadadustat respectively.
- W02014102818 discloses compounds of the following general formula
- formula (la) and its pharmaceutically acceptable salts are effective in the treatment of aplastic anemia when combine with a suitable TPO receptor agonist improve two lineage of hematopoietic precursor cells for the benefit of patients. Also, such combination with cyclosporine will be useful.
- Embodiments of the invention describes a combination of a suitable prolyl hydroxylase inhibitor or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist.
- TPO thrombopoietin
- the present invention describes a combination of the compound of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist.
- the present invention provides a combination of the compound of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist for the treatment of Aplastic anemia (AA).
- TPO thrombopoietin
- a pharmaceutical composition comprising, the compound of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist along with at least one a suitable pharmaceutically acceptable carrier, diluents, vehicle or excipient for the treatment of Aplastic anemia (AA).
- AA Aplastic anemia
- present invention provides use of combination of the compound of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist for the treatment of Aplastic anemia (AA).
- TPO thrombopoietin
- the present invention provides a method of treating Aplastic anemia (AA) using the compound of formula (la) or its pharmaceutically acceptable salts.
- the present invention provides a combination of the compound of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist optionally with cyclosporine.
- TPO thrombopoietin
- Figure 1 The effect of formula (la), Romiplostim and their combination on white blood cells (A) and Platelets (B) in busulphan-induced aplastic anemia in Balb/c mice.
- Figure 2 The effect of formula (la) and their combination with Romiplostim on white blood cells (A) and Platelets (B) in cyclophosphamide-induced aplastic anemia in C57 mice.
- the present invention describes a combination of a suitable prolyl hydroxylase inhibitors with a suitable thrombopoietin (TPO) receptor agonist for the treatment of Aplastic anemia (AA).
- TPO thrombopoietin
- the invention also describes the preparation of such combination and its compositions.
- treatment refers to slowing, stopping, or delaying the progression of the disease or clinical symptoms in a patient, as evidenced by a decrease or elimination of a clinical or diagnostic symptom of the disease, disorder or condition.
- subject refer to a human and animal.
- effective amount in the context of the administration of the amount of the drug substance sufficient to have the desired effect.
- pharmaceutically acceptable use embraces both human and veterinary use.
- the compound of formula (la) is Desidustat. Combination of a suitable prolyl hydroxylase inhibitors with a suitable thrombopoietin (TPO) receptor agonist
- the present invention describes a combination of a suitable prolyl hydroxylase inhibitors and suitable thrombopoietin (TPO) receptor agonist.
- a suitable prolyl hydroxylase inhibitor is selected from Roxadustat, Vadadustat, Daprodustat, Molidustat, Enardustat and the compound of formula (la) or its pharmaceutically acceptable salts.
- a suitable thrombopoietin (TPO) receptor agonist is Romiplostim or its pharmaceutically acceptable salts, Eltrombopag or its pharmaceutically acceptable salts, Avatrombopag or its pharmaceutically acceptable salts and Lusutrombopag or its pharmaceutically acceptable salts.
- present invention provides a combination of compound of formula (la) or its pharmaceutically acceptable salts with a suitable thrombopoietin (TPO) receptor agonist, wherein formula (la) is represented by:
- the pharmaceutical acceptable salts of the compound of formula (la) may be selected from suitable inorganic metal salts or organic amines salts.
- the inorganic metal salt may be selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium and the like.
- Organic amines salt is selected from methylamine, dimethylamine, ethylamine, diethyl amine, n- propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t- butyl amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine, benzene-methanamine,
- a suitable thrombopoietin (TPO) receptor agonist is Romiplostim or its pharmaceutically acceptable salts, Eltrombopag or its pharmaceutically acceptable salts, Avatrombopag or its pharmaceutically acceptable salts and Lusutrombopag or its pharmaceutically acceptable salts.
- Combination as described above can be administered as oral, rectal, topical, nasal, pulmonary, ocular, intestinals or parenteral.
- an effective amount, e.g., dose, of combination compound or drug can readily be determined by routine experimentation, as can an effective and convenient route of administration and an appropriate formulation.
- Various formulations and drug delivery systems are available in the art. (See, e.g., Gennaro, ed. (2000) Remington's Pharmaceutical Sciences,; and Hardman, Limbird, and Gilman, eds. (2001) The Pharmacological Basis of Therapeutics, supra.)
- a suitable routes of administration may, for example, include oral, rectal, topical, nasal, pulmonary, ocular, intestinal, and parenteral administration.
- Primary routes for parenteral administration include intravenous, intramuscular, and subcutaneous administration.
- Secondary routes of administration include intraperitoneal, intra-arterial, intra-articular, intracardiac, intracisternal, intradermal, intralesional, intraocular, intrapleural, intrathecal, intrauterine, and intraventricular administration.
- the indication to be treated, along with the physical, chemical, and biological properties of the drug, dictate the type of formulation and the route of administration to be used, as well as whether local or systemic delivery would be preferred.
- the compound of formula (la) or its pharmaceutically acceptable salts for oral administration to a subject at a dose in the range of 1 mg to 500 mg or in the range of 50 mg to 450 mg or in the range of 100 mg to 400 mg or in the range of 150 mg to 350 mg or in the range of 200 mg to 300 mg or in the range of 1 mg to 50 mg or in the range of 1 mg to 25 mg to the subject.
- the compound of formula (la) or a pharmaceutically acceptable salts for oral administration to a subject to provide the compound of formula (la) or a pharmaceutically acceptable salts at a dose of 1 mg to 150 mg.
- the compound of formula (la) or its pharmaceutically acceptable salts for oral administration to a subject at a dose in the range of 1 mg to 2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 25 mg to 30 mg or 30 mg to 35 mg or 35 mg to 40 mg or
- Eltrombopag is administered orally to a subject in an amount of about 1 mg to about 500 mg.
- Avatrombopag is administered orally to a subject in an amount of about 1 mg to 100 mg.
- Lusutrombopag is administered orally to a subject in an amount of about 1 mg to 100 mg.
- Eltrombopag is administered orally to a subject in an amount of about 12.5 mg, 25 mg, 50 mg, 75 mg and 100 mg.
- Avatrombopag is administered orally to a subject in an amount of about 20 mg.
- Lusutrombopag is administered orally to a subject in an amount of about 3 mg.
- the compound of formula (la) or its pharmaceutically acceptable salts for parenteral administration to a subject at a dose in the range of 1 mg to 2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 27.5 mg to 30 mg or 30 mg to 32.5 mg or 32.5 mg to 35 mg or 35 mg to 37.5 mg or 37.5 mg to 40 mg or 40 mg to 42.5 mg or 42.5 mg to 45 mg or 45 mg to 47.5 mg or 47.5 mg to 50 mg.
- Romiplostim is administered parenterally to a subject in an amount of about 1 pg to about 500 pg, about 50 pg to about 450 pg, about 100 pg to about 400 pg, about 150 pg to about 350 pg, about 200 pg to about 300 pg.
- Romiplostim is administered parenterally to a subject in an amount of about 125 pg, 250 pg and 500 pg. In a further embodiment.
- combination of compounds of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist can be further characterized according to the dose of compound administered to a subject, where subject is animal or human.
- compounds of formula (la) or its pharmaceutically acceptable salts and the a suitable thrombopoietin (TPO) receptor agonist are administered as one composition. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist are administered separately. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist are administered consecutively. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and the a suitable thrombopoietin (TPO) receptor agonist are administered simultaneously. Method of treating Aplastic anemia (AA) in combination of compound of formula (la) or its pharmaceutically acceptable salts with a suitable thrombopoietin (TPO) receptor agonist
- the present invention provides a method of treating Aplastic anemia (AA) in a subject, comprising administering a combination of compound of formula (la) or its pharmaceutically acceptable salts with a suitable thrombopoietin (TPO) receptor agonist.
- AA Aplastic anemia
- TPO thrombopoietin
- the pharmaceutical acceptable salts of the compound of formula (la) may be selected from a suitable inorganic metal salts or organic amines salts.
- the inorganic metal salt may be selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium and the like.
- Organic amines salt is selected from methylamine, dimethylamine, ethylamine, diethyl amine, n- propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t- butyl amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine, benzene-methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl benzylamine, 4- methoxybenzylamine,
- a suitable thrombopoietin (TPO) receptor agonist is Romiplostim or its pharmaceutically acceptable salts, Eltrombopag or its pharmaceutically acceptable salts, Avatrombopag or its pharmaceutically acceptable salts and Lusutrombopag or its pharmaceutically acceptable salts.
- Combination as described above can be administered as oral, rectal, topical, nasal, pulmonary, ocular, intestinal or parenteral.
- the compound of formula (la) or its pharmaceutically acceptable salts for oral administration to a subject at a dose in the range of 1 mg to 500 mg or in the range of 50 mg to 450 mg or in the range of 100 mg to 400 mg or in the range of 150 mg to 350 mg or in the range of 200 mg to 300 mg or in the range of 1 mg to 50 mg or in the range of 1 mg to 25 mg to the subject.
- the compound of formula (la) or a pharmaceutically acceptable salts for oral administration to a subject to provide the compound of formula (la) or a pharmaceutically acceptable salts at a dose of 1 mg to 150 mg.
- the compound of formula (la) or its pharmaceutically acceptable salts for oral administration to a subject at a dose in the range of 1 mg to 2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 25 mg to 30 mg or 30 mg to 35 mg or 35 mg to 40 mg or 40 mg to 45 mg or 45 mg to 50 mg or 50 mg to 55 mg or 55 mg to 60 mg or 60 mg to 65 mg or 65 mg to 70 mg or 70 mg to 75 mg or 75 mg to 80 mg or 80 mg to 85 mg or 85 mg to 90 mg or 90 mg to 95 mg or 95 mg to 100 mg.
- Eltrombopag is administered orally to a subject in an amount of about 1 mg to about 500 mg.
- Avatrombopag is administered orally to a subject in an amount of about 1 mg to 100 mg.
- Lusutrombopag is administered orally to a subject in an amount of about 1 mg to 100 mg.
- Eltrombopag is administered orally to a subject in an amount of about 12.5 mg, 25 mg, 50 mg, 75 mg and 100 mg.
- Avatrombopag is administered orally to a subject in an amount of about 20 mg.
- Lusutrombopag is administered orally to a subject in an amount of about 3 mg.
- Romiplostim is administered parenterally to a subject in an amount of about 1 pg to about 500 pg, about 50 pg to about 450 pg, about 100 pg to about 400 pg, about 150 pg to about 350 pg, about 200 pg to about 300 pg.
- Romiplostim is administered parenterally to a subject in an amount of about 125 pg, 250 pg and 500 pg. In a further embodiment.
- combination of compounds of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist can be further characterized according to the dose of compound administered to a subject, where subject is animal or human.
- compounds of formula (la) or its pharmaceutically acceptable salts and the a suitable thrombopoietin (TPO) receptor agonist are administered as one composition. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist are administered separately. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist are administered consecutively. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and the a suitable thrombopoietin (TPO) receptor agonist are administered simultaneously. Pharmaceutical composition of compound of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist for use in treating Aplastic anemia (AA)
- present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising compound of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist optionally with one or more pharmaceutically acceptable excipients for use in treating Aplastic anemia (AA).
- TPO thrombopoietin
- the pharmaceutical acceptable salts of the compound of formula (la) may be selected from suitable inorganic metal salts or organic amines salts.
- the inorganic metal salt may be selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium and the like.
- Organic amines salt is selected from methylamine, dimethylamine, ethylamine, diethyl amine, n- propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t- butyl amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine, benzene-methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl benzylamine, 4- methoxybenzylamine,
- a suitable thrombopoietin (TPO) receptor agonist is Romiplostim or its pharmaceutically acceptable salts, Eltrombopag or its pharmaceutically acceptable salts, Avatrombopag or its pharmaceutically acceptable salts and Lusutrombopag or its pharmaceutically acceptable salts.
- the pharmaceutical composition as mentioned in above embodiment may be in form of oral, rectal, topical, nasal, pulmonary, ocular, intestinal, or parenteral.
- the pharmaceutical composition is in the oral form.
- compositions as described above or anywhere in the specification may be in the form of tablet, capsule and oral liquids.
- the pharmaceutically acceptable excipients are selected at least one from diluent, binders, disintegrating agents, lubricating agents, glidant agent, sweetener, pH modifier, suspending agent or viscosity modifying agent, flavouring agent and optionally coating redimix.
- Diluents include, but are not limited to lactose monohydrate, lactose, microcrystalline cellulose, polymethacrylates selected from Eudragit, potassium chloride, sulfobutylether b-cyclodextrin, sodium chloride, spray dried lactose, and preferably sulfobutyl ether b-cyclodextrin combinations thereof and other such materials known to those of ordinary skill in the art.
- Binders include, but are not limited to hypromellose 3 Cps, carbomers selected from carbopol, gellan, gum Arabic, hydrogenated vegetable oil, polymethacrylates selected from Eudragit, xanthan, lactose and Zein combinations thereof and other such materials known to those of ordinary skill in the art.
- Disintegrating agents include, but are not limited to, croscarmellose Sodium, bicarbonate salt, chitin, gellan gum, polacrillin potassium and docusate Sodium combinations thereof and other such materials known to those of ordinary skill in the art.
- Glidant agents include, but are not limited to, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.
- Lubricant agents include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, glycerin behenate, hydrogenated vegetable oil, sodium stearyl fumarate and myristic Acid suitable combinations thereof and other such materials known to those of ordinary skill in the art.
- a suitable pH modifying agents which maintain the pH of the formulation according to the present invention include, but are not limited to Citric acid and other similar excipients and their suitable combinations and other materials known to those of ordinary skill in the art.
- Suspending agents or viscosity agent according to the present invention include, but are not limited to microcrystalline cellulose and carboxymethylcellulose sodium (Avicel CL 611) and other similar excipients and their suitable combinations and other materials known to those of ordinary skill in the art.
- Sweetener is selected from Sucrose and all such materials known to those of ordinary skill in the art.
- Flavouring agent is selected from cherry flavour, orange flavour, mango flavour and all such fruit flavour known to those of ordinary skill in the art.
- Coating redimix is selected from Opadry Pink all such materials known to those of ordinary skill in the art.
- the compound of formula (la) or its pharmaceutically acceptable salts for oral administration to a subject at a dose in the range of 1 mg to 500 mg or in the range of 50 mg to 450 mg or in the range of 100 mg to 400 mg or in the range of 150 mg to 350 mg or in the range of 200 mg to 300 mg or in the range of 1 mg to 50 mg or in the range of 1 mg to 25 mg to the subject.
- the compound of formula (la) or a pharmaceutically acceptable salts for oral administration to a subject to provide the compound of formula (la) or a pharmaceutically acceptable salts at a dose of 1 mg to 150 mg.
- the compound of formula (la) or its pharmaceutically acceptable salts for oral administration to a subject at a dose in the range of 1 mg to 2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 25 mg to 30 mg or 30 mg to 35 mg or 35 mg to 40 mg or 40 mg to 45 mg or 45 mg to 50 mg or 50 mg to 55 mg or 55 mg to 60 mg or 60 mg to 65 mg or 65 mg to 70 mg or 70 mg to 75 mg or 75 mg to 80 mg or 80 mg to 85 mg or 85 mg to 90 mg or 90 mg to 95 mg or 95 mg to 100 mg.
- Table 1 Stable oral pharmaceutical composition of formula (la)
- TPO thrombopoietin
- Eltrombopag is administered orally to a subject in an amount of about 1 mg to about 500 mg.
- Avatrombopag is administered orally to a subject in an amount of about 1 mg to 100 mg.
- Lusutrombopag is administered orally to a subject in an amount of about 1 mg to 100 mg.
- Eltrombopag is administered orally to a subject in an amount of about 12.5 mg, 25 mg, 50 mg, 75 mg and 100 mg.
- Avatrombopag is administered orally to a subject in an amount of about 20 mg.
- Lusutrombopag is administered orally to a subject in an amount of about 3 mg.
- compounds of formula (la) or its pharmaceutically acceptable salts can be further characterized according to the dose of compound administered to a subject, where subject is animal or human.
- compounds of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist are administered as one composition.
- compounds of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist are administered separately.
- compounds of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist are administered consecutively.
- compounds of formula (la) or its pharmaceutically acceptable salts and the a suitable thrombopoietin (TPO) receptor agonist are administered simultaneously.
- composition of combination of compound of formula (la) or its pharmaceutically acceptable salts and Romiplostim is in parenteral form.
- composition of combination of compound of formula (la) or its pharmaceutically acceptable salts and Romiplostim can be administered via parenteral rout.
- parenteral formulation of compound of formula (la) or its pharmaceutically acceptable salts can be prepared as method known in art.
- AA Aplastic anemia
- the pharmaceutically acceptable excipients are selected at least one from dextrose in water, captisol in water, microemulsion and cosolvent or emulsifying agent with pH adjustment for use in treating Aplastic anemia (AA).
- Cosolvent or emulsifying agent is selected from CaptexTM 300, SolutolTM Hl 5, Propylene glycol, PhospholiponTM 90G, SolutolTM HS15, dimethylacetamide with ethanol, PEG400 and N- methylpyrrolidone.
- TPO thrombopoietin
- AA Aplastic anemia
- the pharmaceutical composition as described above is in parenteral form.
- a suitable thrombopoietin (TPO) receptor agonist is Romiplostim or its pharmaceutically acceptable salts.
- the pharmaceutically acceptable excipients are selected at least one from a buffer, a bulking agent, a stabilizing agent and a surfactant for the treatment of Aplastic Anemia (AA).
- AA Aplastic Anemia
- Buffer is selected from glycine, histidine, glutamate, succinate, phosphate, acetate and aspartate.
- Bulking agent is selected from mannitol, glycine, sucrose, dextran, polyvinylpyrolidone, carboxymethylcellulose, lactose, sorbitol, trehalose or xylitol.
- the stabilizing agent is selected from sucrose, trehalose, mannose, maltose, lactose, glucose, raffinose, cellobiose, gentiobiose, isomaltose, arabinose, glucosamine, fructose, mannitol, sorbitol, glycine, arginine HCL, poly-hydroxy compounds, including polysaccharides such as dextran, starch, hydroxyethyl starch, cyclodextrins, N-methylpyrollidene, cellulose and hyaluronic acid, sodium chloride.
- the surfactant is selected from sodium lauryl sulfate, dioctyl sodium sulfosuccinate, dioctyl sodium sulfonate, chenodeoxycholic acid, N-lauroylsarcosine sodium salt, lithium dodecyl sulfate, 1 -octanesulfonic acid sodium salt, sodium cholate hydrate, sodium deoxycholate, glycodeoxycholic acid sodium salt, benzalkonium chloride or benzethonium chloride, cetylpyridinium chloride monohydrate, hexadecyltrimethylammonium bromide, CHAPS, CHAPSO, SB3-10, SB3-12, digitonin, Triton X-100, Triton X-114, lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 40, 50 and 60, glycerol monostearate, polysorbate 20, 40, 60, 65 and 80
- Romiplostim is administered parenterally to a subject in an amount of about 1 pg to about 500 pg, about 50 pg to about 450 pg, about 100 pg to about 400 pg, about 150 pg to about 350 pg, about 200 pg to about 300 pg.
- Romiplostim is administered parenterally to a subject in an amount of about 125 pg, 250 pg and 500 pg.
- compounds of formula (la) or its pharmaceutically acceptable salts can be further characterized according to the dose of compound administered to a subject, where subject is animal or human.
- compounds of formula (la) or its pharmaceutically acceptable salts and Romiplostim are administered as one composition. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and Romiplostim are administered separately. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and Romiplostim are administered consecutively. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and Romiplostim are administered simultaneously.
- Parenteral formulation can be administered by Subcutaneous, Intramuscular, Intravenous and Intrathecal.
- present invention provides use of combination of compound of formula (la) or its pharmaceutically acceptable salts with a suitable thrombopoietin (TPO) receptor agonist for treating Aplastic anemia (AA).
- the pharmaceutical acceptable salts of the compound of formula (la) may be selected from a suitable inorganic metal salts or organic amines salts.
- the inorganic metal salt may be selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium and the like.
- Organic amines salt is selected from methylamine, dimethylamine, ethylamine, diethyl amine, n- propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t- butyl amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine, benzene-methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl benzylamine, 4- methoxybenzylamine,
- a suitable thrombopoietin (TPO) receptor agonist is Romiplostim or its pharmaceutically acceptable salts, Eltrombopag or its pharmaceutically acceptable salts, Avatrombopag or its pharmaceutically acceptable salts and Lusutrombopag or its pharmaceutically acceptable salts. Combination as described above can be administered as oral, rectal, topical, nasal, pulmonary, ocular, intestinal, or parenteral.
- the compound of formula (la) or its pharmaceutically acceptable salts for oral administration to a subject at a dose in the range of 1 mg to 500 mg or in the range of 50 mg to 450 mg or in the range of 100 mg to 400 mg or in the range of 150 mg to 350 mg or in the range of 200 mg to 300 mg or in the range of 1 mg to 50 mg or in the range of 1 mg to 25 mg to the subject.
- the compound of formula (la) or a pharmaceutically acceptable salts for oral administration to a subject to provide the compound of formula (la) or a pharmaceutically acceptable salts at a dose of 1 mg to 150 mg.
- the compound of formula (la) or its pharmaceutically acceptable salts for oral administration to a subject at a dose in the range of 1 mg to 2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 25 mg to 30 mg or 30 mg to 35 mg or 35 mg to 40 mg or 40 mg to 45 mg or 45 mg to 50 mg or 50 mg to 55 mg or 55 mg to 60 mg or 60 mg to 65 mg or 65 mg to 70 mg or 70 mg to 75 mg or 75 mg to 80 mg or 80 mg to 85 mg or 85 mg to 90 mg or 90 mg to 95 mg or 95 mg to 100 mg.
- Eltrombopag is administered orally to a subject in an amount of about 1 mg to about 500 mg.
- Avatrombopag is administered orally to a subject in an amount of about 1 mg to 100 mg.
- Lusutrombopag is administered orally to a subject in an amount of about 1 mg to 100 mg.
- Eltrombopag is administered orally to a subject in an amount of about 12.5 mg, 25 mg, 50 mg, 75 mg and 100 mg.
- Avatrombopag is administered orally to a subject in an amount of about 20 mg.
- Lusutrombopag is administered orally to a subject in an amount of about 3 mg.
- Romiplostim is administered parenterally to a subject in an amount of about 1 pg to about 500 pg, about 50 pg to about 450 pg, about 100 pg to about 400 pg, about 150 pg to about 350 pg, about 200 pg to about 300 pg.
- Romiplostim is administered parenterally to a subject in an amount of about 125 pg, 250 pg and 500 pg. In a further embodiment.
- combination of compounds of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist can be further characterized according to the dose of compound administered to a subject, where subject is animal or human.
- compounds of formula (la) or its pharmaceutically acceptable salts and the a suitable thrombopoietin (TPO) receptor agonist are administered as one composition. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist are administered separately. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist are administered consecutively. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and the a suitable thrombopoietin (TPO) receptor agonist are administered simultaneously.
- the present invention provides a method of treating Aplastic anemia (AA) in a subject, comprising administering an effective amount of compound of formula (la) or its pharmaceutically acceptable salts.
- the pharmaceutical acceptable salts of the compound of formula (la) may be selected from a suitable inorganic metal salts or organic amines salts.
- the inorganic metal salt may be selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium and the like.
- Organic amines salt is selected from methylamine, dimethylamine, ethylamine, diethyl amine, n- propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t- butyl amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine, benzene-methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl benzylamine, 4- methoxybenzylamine,
- the compound of formula (la) or its pharmaceutically acceptable salts for administration to a subject at a dose in the range of 1 mg to 500 mg or in the range of 50 mg to 450 mg or in the range of 100 mg to 400 mg or in the range of 150 mg to 350 mg or in the range of 200 mg to 300 mg or in the range of 1 mg to 50 mg or in the range of 1 mg to 25 mg to the subject.
- the compound of formula (la) or a pharmaceutically acceptable salts for administration to a subject to provide the compound of formula (la) or a pharmaceutically acceptable salts at a dose of 1 mg to 150 mg.
- the compound of formula (la) or its pharmaceutically acceptable salts for administration to a subject at a dose in the range of 1 mg to 2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 25 mg to 30 mg or 30 mg to 35 mg or 35 mg to 40 mg or 40 mg to 45 mg or 45 mg to 50 mg or 50 mg to 55 mg or 55 mg to 60 mg or 60 mg to 65 mg or 65 mg to 70 mg or 70 mg to 75 mg or 75 mg to 80 mg or 80 mg to 85 mg or 85 mg to 90 mg or 90 mg to 95 mg or 95 mg to 100 mg.
- compounds of formula (la) or its pharmaceutically acceptable salts can be further characterized according to the dose of compound administered to a subject, where subject is animal or human.
- composition of formula (la) or its pharmaceutically acceptable salts can be prepared as anywhere disclosed in the specification.
- a suitable thrombopoietin (TPO) receptor agonist is Eltrombopag or its pharmaceutically acceptable salts, Romiplostim or its pharmaceutically acceptable salts, Avatrombopag or its pharmaceutically acceptable salts and Lusutrombopag or its pharmaceutically acceptable salts.
- the pharmaceutical acceptable salts of the compound of formula (la) may be selected from a suitable inorganic metal salt or organic amines salts.
- the inorganic metal salt may be selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium and the like.
- Organic amines salt is selected from methylamine, dimethylamine, ethylamine, diethyl amine, n- propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t- butyl amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine, benzene-methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl benzylamine, 4- methoxybenzylamine,
- present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising compound of formula (la) or its pharmaceutically acceptable salts and a suitable thrombopoietin (TPO) receptor agonist optionally with cyclosporine.
- TPO thrombopoietin
- compositions, dosage form and rout of administration as described above or anywhere in the specification.
- the compound of formula (la) may be prepared by any of the methods known in the art including those processes disclosed in the prior art such as those mentioned elsewhere in the specification.
- Romiplostim may be prepared by any of the methods known in the art including those processes disclosed in the prior art such as those mentioned elsewhere in the specification.
- TPO thrombopoietin
- Example 1 Effect of formula (la), Romiplostim and its combination on busulphan-induced aplastic anemia in Balb/c mice
- Aplastic anemia (AA) was induced in BALB/c mice by administration of busulphan (BU).
- BU was dissolved in acetone at concentrations of 5-10 mg/mL.
- deionized water was added to the BU-acetone solution and the solution was given by intraperitoneal (ip) injection at dose of 9 mg/kg.
- Control mice were given vehicle at the same dose volume.
- 9 Compound of formula (la) (15 mg/kg, PO, daily) and Romiplostim (50 pg/kg, SC, once a week) combination were administered.
- mice were be dosed with vehicle or BU on 10 occasions over a period of 21 days (days 1, 3, 6, 8, 10, 13, 15, 17, 19 and 21). Between 1 to 127 days after the final BU dose, mice from each group were autopsied for blood. 9
- Example 2 Effect of formula (la) and its combination with Romiplostim on cyclophosphamide-induced aplastic anemia in C57 mice
- Aplastic anemia was induced in C57 mice by administration of cyclophosphamide.
- Cyclophosphamide was dissolved in deionized water at concentrations of 20 mg/mL. Immediately before administration, deionized water was added to the stock solution and the solution was given by intraperitoneal (ip) injection at dose of 100 mg/kg. Mice were dosed with vehicle or cyclophosphamide for 4 days. Control mice were given vehicle at the same dose volume. 10 Compound of formula (la) (15 mg/kg, PO, daily) and Romiplostim (30 pg/kg, SC, once a week) combination were administered.
- WBC cyclophosphamide-induced aplastic anemia
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Abstract
La présente invention concerne une combinaison associant un inhibiteur de prolyl hydroxylase approprié et un agoniste du récepteur de la thrombopoïétine (TPO) approprié pour le traitement de l'anémie aplasique (AA). L'invention concerne également la préparation d'une telle combinaison et des compositions de celle-ci.
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WO2014102818A1 (fr) * | 2012-12-24 | 2014-07-03 | Cadila Healthcare Limited | Dérivés inédits de quinolone |
WO2020085467A1 (fr) * | 2018-10-26 | 2020-04-30 | 協和キリン株式会社 | Composition pharmaceutique destinée au traitement de l'anémie aplasique |
WO2022155352A1 (fr) * | 2021-01-13 | 2022-07-21 | Dyve Biosciences, Inc. | Formulations d'agents pénétrants transdermiques pour l'administration de médicaments |
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WO2014102818A1 (fr) * | 2012-12-24 | 2014-07-03 | Cadila Healthcare Limited | Dérivés inédits de quinolone |
WO2020085467A1 (fr) * | 2018-10-26 | 2020-04-30 | 協和キリン株式会社 | Composition pharmaceutique destinée au traitement de l'anémie aplasique |
WO2022155352A1 (fr) * | 2021-01-13 | 2022-07-21 | Dyve Biosciences, Inc. | Formulations d'agents pénétrants transdermiques pour l'administration de médicaments |
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