CA2773353C - Oligomer-calcimimetic conjugates and related compounds - Google Patents
Oligomer-calcimimetic conjugates and related compounds Download PDFInfo
- Publication number
- CA2773353C CA2773353C CA2773353A CA2773353A CA2773353C CA 2773353 C CA2773353 C CA 2773353C CA 2773353 A CA2773353 A CA 2773353A CA 2773353 A CA2773353 A CA 2773353A CA 2773353 C CA2773353 C CA 2773353C
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- CA
- Canada
- Prior art keywords
- compound
- daltons
- lower alkyl
- oligomer
- cinacalcet
- 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.)
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- 150000001875 compounds Chemical class 0.000 title claims description 158
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 29
- 229920000642 polymer Polymers 0.000 claims abstract description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 112
- 239000000203 mixture Substances 0.000 claims description 71
- -1 2-ethylpropyl Chemical group 0.000 claims description 66
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 61
- 239000000178 monomer Substances 0.000 claims description 38
- 125000006850 spacer group Chemical group 0.000 claims description 30
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 28
- 229920001427 mPEG Polymers 0.000 claims description 27
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 11
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 11
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 11
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 11
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 208000020832 chronic kidney disease Diseases 0.000 claims description 7
- 125000000539 amino acid group Chemical group 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 claims description 2
- 125000005917 3-methylpentyl group Chemical group 0.000 claims description 2
- 201000002980 Hyperparathyroidism Diseases 0.000 claims description 2
- 208000000821 Parathyroid Neoplasms Diseases 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 208000022831 chronic renal failure syndrome Diseases 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229920000233 poly(alkylene oxides) Polymers 0.000 claims 4
- 229960003315 cinacalcet Drugs 0.000 abstract description 135
- 230000002092 calcimimetic effect Effects 0.000 abstract description 79
- VDHAWDNDOKGFTD-MRXNPFEDSA-N cinacalcet Chemical compound N([C@H](C)C=1C2=CC=CC=C2C=CC=1)CCCC1=CC=CC(C(F)(F)F)=C1 VDHAWDNDOKGFTD-MRXNPFEDSA-N 0.000 abstract description 74
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 141
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 81
- 239000000562 conjugate Substances 0.000 description 66
- 239000003153 chemical reaction reagent Substances 0.000 description 64
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 46
- 150000003384 small molecules Chemical class 0.000 description 37
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 32
- 230000015572 biosynthetic process Effects 0.000 description 31
- 125000004432 carbon atom Chemical group C* 0.000 description 31
- 125000000524 functional group Chemical group 0.000 description 30
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 29
- 150000001408 amides Chemical class 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 27
- 241000700159 Rattus Species 0.000 description 25
- 238000003786 synthesis reaction Methods 0.000 description 25
- 125000003277 amino group Chemical group 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- 238000013459 approach Methods 0.000 description 20
- 150000003335 secondary amines Chemical class 0.000 description 20
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 19
- 239000011541 reaction mixture Substances 0.000 description 19
- 235000002639 sodium chloride Nutrition 0.000 description 19
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- 230000000694 effects Effects 0.000 description 17
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 150000003839 salts Chemical class 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 15
- 238000000034 method Methods 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 239000002253 acid Substances 0.000 description 12
- 125000001246 bromo group Chemical group Br* 0.000 description 12
- 229940126586 small molecule drug Drugs 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 229940024606 amino acid Drugs 0.000 description 11
- 150000001413 amino acids Chemical class 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 11
- 230000002902 bimodal effect Effects 0.000 description 11
- 125000001309 chloro group Chemical group Cl* 0.000 description 11
- 125000004093 cyano group Chemical group *C#N 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 10
- 150000001299 aldehydes Chemical group 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
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- 210000004027 cell Anatomy 0.000 description 10
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 10
- 238000009826 distribution Methods 0.000 description 10
- 239000012528 membrane Substances 0.000 description 10
- 210000004379 membrane Anatomy 0.000 description 10
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 10
- OAOSXODRWGDDCV-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine;4-methylbenzenesulfonic acid Chemical compound CN(C)C1=CC=NC=C1.CC1=CC=C(S(O)(=O)=O)C=C1 OAOSXODRWGDDCV-UHFFFAOYSA-N 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- 229910001868 water Inorganic materials 0.000 description 10
- 102000013830 Calcium-Sensing Receptors Human genes 0.000 description 9
- 108010050543 Calcium-Sensing Receptors Proteins 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 230000008685 targeting Effects 0.000 description 9
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 8
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 230000004888 barrier function Effects 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
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- 230000007062 hydrolysis Effects 0.000 description 8
- 238000006460 hydrolysis reaction Methods 0.000 description 8
- 239000012535 impurity Substances 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 238000006467 substitution reaction Methods 0.000 description 8
- 238000011282 treatment Methods 0.000 description 8
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 7
- 239000007832 Na2SO4 Substances 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 239000011575 calcium Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000021615 conjugation Effects 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
- 125000005647 linker group Chemical group 0.000 description 6
- 239000012038 nucleophile Substances 0.000 description 6
- 239000000829 suppository Substances 0.000 description 6
- 108010010803 Gelatin Proteins 0.000 description 5
- 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 5
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- 125000003368 amide group Chemical group 0.000 description 5
- 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 5
- 239000000872 buffer Substances 0.000 description 5
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- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 4
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical group C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
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- LUYAMNYBNTVQJG-UHFFFAOYSA-N 1-chloro-2-(2-chloroethylsulfonyl)ethane Chemical compound ClCCS(=O)(=O)CCCl LUYAMNYBNTVQJG-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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| US24693109P | 2009-09-29 | 2009-09-29 | |
| US61/246,931 | 2009-09-29 | ||
| PCT/US2010/050761 WO2011056325A2 (en) | 2009-09-29 | 2010-09-29 | Oligomer-calcimimetic conjugates and related compounds |
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| CA2773353A1 CA2773353A1 (en) | 2011-05-12 |
| CA2773353C true CA2773353C (en) | 2018-02-27 |
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| JP2020105072A (ja) * | 2017-03-24 | 2020-07-09 | 協和キリン株式会社 | ポリエチレングリコール誘導体 |
| US20220040318A1 (en) * | 2018-09-28 | 2022-02-10 | Seikagaku Corporation | Primary amine compound or secondary amine compound-acidic polysaccharide conjugate and production method therefor |
| WO2022052471A1 (zh) * | 2020-09-10 | 2022-03-17 | 陕西麦科奥特科技有限公司 | 双特异性融合多肽化合物 |
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| US6011068A (en) | 1991-08-23 | 2000-01-04 | Nps Pharmaceuticals, Inc. | Calcium receptor-active molecules |
| CZ290670B6 (cs) | 1994-10-21 | 2002-09-11 | Nps Pharmaceuticals, Inc. | Sloučeniny modulující receptory anorganických iontů a farmaceutický prostředek, který je obsahuje |
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| US5648541A (en) | 1995-09-28 | 1997-07-15 | Nps Pharmaceuticals, Inc. | Chiral reductions of imines leading to the syntheses of optically active amines |
| US6835802B2 (en) | 2001-06-04 | 2004-12-28 | Nobex Corporation | Methods of synthesizing substantially monodispersed mixtures of polymers having polyethylene glycol moieties |
| CN1925875A (zh) * | 2003-12-16 | 2007-03-07 | 尼克塔治疗亚拉巴马公司 | 化学改性的小分子 |
| US7250533B2 (en) | 2005-05-16 | 2007-07-31 | Teva Pharmaceutical Industries Ltd | Process for preparing Cinacalcet hydrochloride |
| BRPI0611872B8 (pt) | 2005-06-16 | 2021-05-25 | Nektar Therapeutics | reagente polimérico, conjugado, método para preparação de um conjugado e composição farmacêutica |
| WO2007062147A1 (en) | 2005-11-22 | 2007-05-31 | Teva Pharmaceutical Industries Ltd. | Crystal forms of cinacalcet hci and processes for their preparation |
| KR20080011320A (ko) | 2006-04-27 | 2008-02-01 | 테바 파마슈티컬 인더스트리즈 리미티드 | 시나칼셋 염기의 제조 방법 |
| US8093299B2 (en) * | 2007-03-30 | 2012-01-10 | Amgen Inc. | Methods of treating bowel disorders |
| US11033631B2 (en) * | 2008-06-09 | 2021-06-15 | Nektar Therapeutics | Methods of treating CYP2D6 alternative metabolizers |
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|---|---|
| KR20120090961A (ko) | 2012-08-17 |
| CA2773353A1 (en) | 2011-05-12 |
| JP2013505966A (ja) | 2013-02-21 |
| CN102573921B (zh) | 2015-11-25 |
| AU2010315805A1 (en) | 2012-03-15 |
| AU2010315805B2 (en) | 2015-09-17 |
| WO2011056325A3 (en) | 2011-09-29 |
| IL218869A0 (en) | 2012-06-28 |
| MX2012003775A (es) | 2012-06-12 |
| JP5792175B2 (ja) | 2015-10-07 |
| IL218869A (en) | 2016-12-29 |
| MX341690B (es) | 2016-08-29 |
| CN102573921A (zh) | 2012-07-11 |
| EP2482855B1 (en) | 2017-12-27 |
| EP2482855A2 (en) | 2012-08-08 |
| WO2011056325A2 (en) | 2011-05-12 |
| KR101828613B1 (ko) | 2018-02-12 |
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