WO2003026582A2 - Method of preparing phenoxy alkanoic, alkenoic, and alkynoic acids and salts thereof via a dicarboxylate intermediate - Google Patents
Method of preparing phenoxy alkanoic, alkenoic, and alkynoic acids and salts thereof via a dicarboxylate intermediate Download PDFInfo
- Publication number
- WO2003026582A2 WO2003026582A2 PCT/US2002/030671 US0230671W WO03026582A2 WO 2003026582 A2 WO2003026582 A2 WO 2003026582A2 US 0230671 W US0230671 W US 0230671W WO 03026582 A2 WO03026582 A2 WO 03026582A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- alkenyl
- independently
- containing compound
- phenoxy
- Prior art date
Links
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 title claims abstract description 61
- 238000000034 method Methods 0.000 title claims abstract description 60
- 239000002253 acid Substances 0.000 title claims abstract description 26
- 150000003839 salts Chemical class 0.000 title abstract description 39
- 150000007513 acids Chemical class 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 83
- 239000013543 active substance Substances 0.000 claims abstract description 62
- -1 phenoxy dicarboxylic acids Chemical class 0.000 claims abstract description 36
- 239000000203 mixture Substances 0.000 claims abstract description 32
- 241001465754 Metazoa Species 0.000 claims abstract description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
- 125000003342 alkenyl group Chemical group 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- 239000002168 alkylating agent Substances 0.000 claims description 20
- 229940100198 alkylating agent Drugs 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 16
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 239000001301 oxygen Substances 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- 239000011593 sulfur Substances 0.000 claims description 14
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 14
- 229920002554 vinyl polymer Polymers 0.000 claims description 14
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 12
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 11
- 125000002947 alkylene group Chemical group 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 230000002152 alkylating effect Effects 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 125000004450 alkenylene group Chemical group 0.000 claims description 8
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 7
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 7
- 125000004419 alkynylene group Chemical group 0.000 claims description 7
- 230000000911 decarboxylating effect Effects 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 6
- 230000003301 hydrolyzing effect Effects 0.000 claims description 6
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 5
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 5
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 5
- 229910019142 PO4 Inorganic materials 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 5
- 239000004202 carbamide Substances 0.000 claims description 5
- 150000004820 halides Chemical class 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 5
- 239000010452 phosphate Substances 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- 229940113088 dimethylacetamide Drugs 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- 150000003738 xylenes Chemical group 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 3
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000003086 colorant Substances 0.000 claims description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 2
- 239000007884 disintegrant Substances 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000004014 plasticizer Substances 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims 3
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 claims 3
- 125000004642 (C1-C12) alkoxy group Chemical group 0.000 claims 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 235000002639 sodium chloride Nutrition 0.000 description 39
- 229940124447 delivery agent Drugs 0.000 description 25
- 239000000543 intermediate Substances 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 16
- 238000006114 decarboxylation reaction Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 230000007062 hydrolysis Effects 0.000 description 10
- 238000006460 hydrolysis reaction Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 150000001413 amino acids Chemical class 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 8
- 108090000765 processed proteins & peptides Proteins 0.000 description 8
- 150000007942 carboxylates Chemical group 0.000 description 7
- 102000004196 processed proteins & peptides Human genes 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- 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 description 6
- 239000007787 solid Substances 0.000 description 6
- 159000000000 sodium salts Chemical class 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 4
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 description 4
- 229940088710 antibiotic agent Drugs 0.000 description 4
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- UBTQVPMVWAEGAC-UHFFFAOYSA-N ethyl 8-bromooctanoate Chemical compound CCOC(=O)CCCCCCCBr UBTQVPMVWAEGAC-UHFFFAOYSA-N 0.000 description 4
- 239000000122 growth hormone Substances 0.000 description 4
- 229920000669 heparin Polymers 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 102000003982 Parathyroid hormone Human genes 0.000 description 3
- 108090000445 Parathyroid hormone Proteins 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical group 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
- UEOSPPIPGYKPTO-UHFFFAOYSA-N diethyl 2-(6-bromohexyl)propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)CCCCCCBr UEOSPPIPGYKPTO-UHFFFAOYSA-N 0.000 description 3
- 239000002532 enzyme inhibitor Substances 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 229960002897 heparin Drugs 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 239000003055 low molecular weight heparin Substances 0.000 description 3
- 229940127215 low-molecular weight heparin Drugs 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 229960001319 parathyroid hormone Drugs 0.000 description 3
- 239000000199 parathyroid hormone Substances 0.000 description 3
- 229920001308 poly(aminoacid) Polymers 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- CNPVJWYWYZMPDS-UHFFFAOYSA-N 2-methyldecane Chemical compound CCCCCCCCC(C)C CNPVJWYWYZMPDS-UHFFFAOYSA-N 0.000 description 2
- 108010039627 Aprotinin Proteins 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- 0 C*(C)Oc(cc1)ccc1O Chemical compound C*(C)Oc(cc1)ccc1O 0.000 description 2
- 102000055006 Calcitonin Human genes 0.000 description 2
- 108060001064 Calcitonin Proteins 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 102000003951 Erythropoietin Human genes 0.000 description 2
- 108090000394 Erythropoietin Proteins 0.000 description 2
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical class NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 229910052788 barium Inorganic materials 0.000 description 2
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 2
- 229960004015 calcitonin Drugs 0.000 description 2
- 229960003773 calcitonin (salmon synthetic) Drugs 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- IMZMKUWMOSJXDT-UHFFFAOYSA-N cromoglycic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C(O)=O)O2 IMZMKUWMOSJXDT-UHFFFAOYSA-N 0.000 description 2
- 229960000958 deferoxamine Drugs 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 229940105423 erythropoietin Drugs 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
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- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006068 taste-masking agent Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940019375 tiludronate Drugs 0.000 description 1
- 229940108519 trasylol Drugs 0.000 description 1
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical class [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
- C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
Definitions
- the present invention relates to a method of preparing a phenoxy alkanoic, alkenoic, or alkynoic acid or a salt thereof from a phenoxy containing compound via a dicarboxylate intermediate.
- the phenoxy alkanoic, alkenoic, and alkynoic acids and salts thereof prepared by this method are suitable for use in compositions for delivering active agents via oral or other routes of administration to animals.
- the present invention relates to phenoxy dicarboxylic acids and their salts for delivering active agents, such as biologically or chemically active agents, to a target.
- the present invention relates to a method of preparing a phenoxy alkanoic, alkenoic, or alkynoic acid or a salt thereof from a phenoxy containing compound via a dicarboxylated phenoxy containing intermediate.
- the present invention includes a dicarboxylated intermediate having the formula
- R 1 , R 2 , R 3 , and R 4 are independently H, -OH, halogen, C C 4 alkyl, C 2 -C 4 alkenyl, C r C 4 alkoxy, -C(O)R 12 , -NO 2 , -NR 9 R 10 , or -NVR 10 R 13 (R 14 ) " ;
- R 5 is H, -OH, -NO 2 , halogen, -CF 3 , -R 15 R 16 , -NW R 17 (R 18 ) ⁇ amide, C ⁇ -C ⁇ alkoxy, C 1 - 2 alkyl, C 2 -C ⁇ 2 alkenyl, carbamate, carbonate, urea, or -C(O)R 19 ;
- R 7 is a linear or branched, C ⁇ -C 2 o alkylene, C 2 -C 2 o alkenylene, or C2-C20 alkynylene;
- R 7 is optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 alkenyl, oxygen, nitrogen, sulfur, halogen, -OH, C 1 -C 4 alkoxy, aryl, heteraryl, or vinyl;
- R 7 is optionally interrupted with aryl, heteroaryl, vinyl, oxygen, nitrogen, or sulfur;
- R 8 and R 11 are independently C 1 -C 4 alkyl or C1-C 4 haloalkyl
- R 9 , R 10 , and R 13 are independently H or C1-C10 alkyl
- R 12 is H, C1-C4 alkyl, C 2 -C 4 alkenyl, or -NH 2 ;
- R 14 and R 18 are independently a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate;
- R 15 , R 16 , and R 17 are independently H, C1-C10 alkyl, C 1 -C 10 alkyl substituted with - COOH, C 2 -Ci 2 alkenyl, C 2 -C ⁇ 2 alkenyl substituted with -COOH, -C(O)R 20 ;
- R 19 is -H, C ⁇ -C 6 alkyl, or C 2 -C ⁇ 2 alkenyl
- R 20 is -OH, C1-C10 alkyl, or C 2 -C ⁇ 2 alkenyl.
- R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, hydroxy, halogen, and C 1 -C 4 alkoxy;
- R 7 is a linear or branched, C 1 -C 20 alkylene, C 2 -C 2 o alkenylene, or C 2 -C 2 o alkynylene;
- R 7 is optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 alkenyl, oxygen, nitrogen, sulfur, halogen, -OH, C 1 -C 4 alkoxy, aryl, heteraryl, or vinyl;
- R 7 is optionally interrupted with aryl, heteroaryl, vinyl, oxygen, nitrogen, or sulfur; and
- R 8 and R 11 are independently C 1 -C 4 alkyl or C 1 -C 4 haloalkyl.
- R 1 , R 2 , R 3 , R 4 , and R 5 are selected from hydrogen, hydroxy, halogen, methoxy and ethoxy.
- R 7 is a C 7 -Ci 2 alkylene and, more preferably, is a linear C 7 -C ⁇ 2 alkylene.
- the dicarboxylated intermediate may be prepared by alkylating a phenoxy containing compound with a dicarboxylate alkylating agent.
- the phenoxy alkanoic, alkenoic, or alkynoic acid is prepared by hydrolyzing the dicarboxylated intermediate
- the phenoxy alkanoic, alkenoic, or alkynoic acid is prepared by decarboxylating the dicarboxylated intermediate.
- the dicarboxylated intermediate can be hydrolyzed before or after being decarboxylated.
- the dicarboxylated intermediate is hydrolyzed before undergoing decarboxylation.
- the phenoxy alkanoic, alkenoic, and alkynoic acids and salts thereof prepared by this method are suitable for use in compositions for delivering active agents via oral or other routes of administration to animals.
- alkylating agents disclosed in the prior art such as ethyl 8-bromo- octanoate as disclosed in International Publication No. WO 01/32596, which is hereby incorporated by reference, are prepared from the dicarboxylate alkylating agents of the present invention.
- the process for converting the dicarboxylate compounds to the alkylating agents of the prior art is often expensive and time consuming.
- ethyl 8-bromo-octanoate is prepared from 2-(6-bromohexyl)malonic acid diethyl ester by a multi-step process which includes an expensive distillation step.
- the process of the present invention reduces the number of synthetic steps required to prepare alkylated salicylamides and, therefore, reduces their manufacturing cost and time.
- R 1 , R 2 , R 3 , R 4 , R 5 , and R 7 are defined as above, facilitate the delivery of active agents.
- R is -(CH 2 ) n -, where n is 4 to 10 and more preferably 7 to 9.
- delivery agents and “delivery agent compounds” as used herein refer to the dicarboxylic compounds of the present invention and phenoxy alkanoic, alkenoic, and alkynoic acids and salts thereof prepared by the method of the present invention.
- One embodiment is a composition comprising at least one of the delivery agent compounds and at least one active agent. These compositions deliver active agents to biological systems in increased or improved bioavailability of the active agent compared to administration of the active agent without the delivery agent compound.
- the dosage unit may be in the form of a liquid or a solid, such as a tablet, capsule or particle, including a powder or sachet.
- Another embodiment is a method for administering an active agent to an animal in need of the active agent, by administering a composition comprising at least one of the delivery agent compounds and the active agent to the animal.
- Preferred routes of administration include the oral, intracolonic and pulmonary routes.
- Yet another embodiment is a method of treating a disease or for achieving a desired physiological effect in an animal by administering the composition of the present invention.
- Yet another embodiment is a method of preparing a composition of the present invention by mixing at least one delivery agent compound and at least one active agent.
- alkyl alkenyl
- alkynyl alkynyl
- alkylene alkenylene
- alkynylene alkynylene
- substituted refers to compounds substituted with one or more of C 1 -C 4 alkyl, C 2 -C 4 alkenyl, and C 2 -C 4 alkynyl.
- phenoxy refers to a moiety which contains a phenyl group bound to an oxygen atom.
- the phenyl group may be substituted or unsubstituted.
- the oxygen atom of the phenoxy group of the phenoxy containing compound is bound to a leaving group.
- Suitable phenoxy containing compounds include, but are not limited to, compounds having the formula
- R , R , R , R , and R are defined as above;
- R is a leaving group (e.g., H).
- An example of a suitable phenoxy containing compound is 1,4-dihydroxybenzene.
- the phenoxy containing compound is alkylated with a dicarboxylate alkylating agent to form the dicarboxylated intermediate.
- Suitable dicarboxylate alkylating agents include, but are not limited to, those having the formula
- R 7 is a linear or branched, C ⁇ -C 2 o alkylene, C 2 -C 2 o alkenylene, or C 2 -C 2 o alkynylene;
- R 7 is optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 alkenyl, oxygen, nitrogen, sulfur, halogen, -OH, C 1 -C 4 alkoxy, aryl, heteraryl, or vinyl; R 7 is optionally interrupted with aryl, heteroaryl, vinyl, oxygen, nitrogen, or sulfur;
- R 8 and R 11 are independently C ⁇ -C 4 alkyl or C ⁇ -C 4 haloalkyl
- X is a suitable leaving group.
- Suitable leaving groups include, but are not limited to, halogens and alcohols. Two preferred leaving groups are chlorine and bromine.
- R 8 and R 11 are independently C ⁇ -C 4 alkyl.
- R and R are the same.
- R is preferably C 4 -C ⁇ 2 alkylene and more preferably C -C 9 alkylene.
- a preferred dicarboxylate alkylating agent has the formula
- R 21 and R 22 are independently C ⁇ -C 4 alkyl
- X is a suitable leaving group; and n is an integer from 2 to 12. Preferably, n ranges from 3 to 10, more preferably from 4 to 8, and most preferably from 6 to 8.
- dicarboxylate alkylating agents include 2-(6-bromohexyl)- malonic acid diethyl ester and 2-(8-bromooctyl)malonic acid diethyl ester, which are available from Allied Signal, Inc. of Morristown, NJ.
- alkylating agents disclosed in the prior art such as ethyl 8-bromo- octanoate as disclosed in International Publication No. WO 01/32596, are prepared from the dicarboxylate alkylating agents of the present invention.
- the process for converting the dicarboxylate compounds to the alkylating agents of the prior art is often expensive and time consuming.
- ethyl 8-bromo-octanoate is prepared from 2-(6- bromohexyl)malonic acid diethyl ester by a multi-step process which includes an expensive distillation step.
- the process of the present invention reduces the number of synthetic steps required to prepare alkylated salicylamides and, therefore, reduces their manufacturing cost and time.
- the reaction between the dicarboxylate alkylating agent and the phenoxy containing compound is preferably carried out in the presence of a slight molar excess of phenoxy containing compound relative to dicarboxylate alkylating agent.
- the molar ratio of phenoxy containing compound to dicarboxylate alkylating agent ranges from about 1:1 to about 1:0.5, preferably from about 1 :0.99 to about 1 :0.8, and most preferably about 1 :0.95.
- the alkylating reaction is preferably performed in the presence of a suitable base, such as pyridine, picoline, tetramethylguanidine, triethylamine, diisopropylethylamine, sodium or potassium bicarbonate, sodium or potassium carbonate, or any combination of any of the foregoing.
- a suitable base such as pyridine, picoline, tetramethylguanidine, triethylamine, diisopropylethylamine, sodium or potassium bicarbonate, sodium or potassium carbonate, or any combination of any of the foregoing.
- the base is sodium carbonate.
- the reaction is performed in the presence of a slight molar excess of base relative to the phenoxy containing compound.
- the reaction may be carried out in solvents including, but not limited to, dimethylacetamide (DM AC); dimethylformamide (DMF); ketones, such as acetone, methylethylketone, and methylisobutylketone; and any combination of any of the foregoing.
- solvents including, but not limited to, dimethylacetamide (DM AC); dimethylformamide (DMF); ketones, such as acetone, methylethylketone, and methylisobutylketone; and any combination of any of the foregoing.
- the solvent is non-aqueous.
- the alkylating reaction is generally performed at a temperature of from about 40 to about 80° C.
- the reaction is preferably performed at a temperature of from about 60 to about 80° C and most preferably at about 70° C.
- the reaction is typically performed at atmospheric pressure to full vacuum and preferably from about 22 to about 24" Hg of vacuum.
- the reaction mixture prior and during the reaction preferably contains less than 5%, more preferably less than 3%, and most preferably less than 1% by weight of water, based upon 100% total weight of reaction mixture.
- the reaction is generally performed for a time sufficient to ensure the complete reaction of the alkylating agent. The reaction duration may vary depending on the starting materials. Generally, the reaction is allowed to run for a time sufficient so that at least about 90% and preferably at least about 99% of the limiting reagent, i.e., the dicarboxylate alkylating agent, has been consumed, but is stopped before significant side reaction product builds up . This reduces or eliminates the need for purification of the final product. According to one embodiment, the reaction is performed for from about 2 to about 18 hours, more preferably from about 3 to about 5 hours, and most preferably about 4 hours.
- the dicarboxylated intermediate has the formula
- R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 and R 11 are defined as above.
- the dicarboxylated intermediate is then, optionally, hydrolyzed and decarboxylated to yield the phenoxy alkanoic, alkenoic, or alkynoic acid or salt thereof.
- the hydrolysis step may be performed before or after the decarboxylation.
- the decarboxylation is performed after hydrolysis.
- this process entails the removal of one of the carboxylate moieties.
- the carboxylate moiety or moieties of the alkylated phenoxy containing compound maybe hydrolyzed to form a carboxylic acid moiety or carboxylic acid moieties or carboxylate salt.
- One of the carboxylate groups may be removed and the remaining carboxylate group may be hydrolyzed by acidic, basic and/or neutral hydrolysis as known in the art.
- Neutral hydrolysis may be performed, for example, with super-heated water at a temperature of from about 100 to about 250° C.
- the phenoxy alkanoic, alkenoic, or alkynoic acid or carboxylate derivative thereof may be further reacted to modify the end group of the alkylating moiety, i.e., R or R 11 .
- the end group -CN or -C(O)O-CH 2 -CH 3 may be modified to -COOH or a salt thereof. This may be accomplished by methods known in the art, such as neutralization and acidic, basic, and neutral hydrolysis.
- the prepared dicarboxylate intermediate may be decarboxylated.
- the decarboxylation step is performed either before or after the optional hydrolysis step.
- decarboxylation is performed after the deprotecting and deactivating steps and optional hydrolysis step.
- the decarboxylation step removes one of the carboxylate moieties from the dicarboxylated intermediate (i.e. one of the two carboxyl groups at the end of the chain R ).
- Decarboxylation can be performed by any method known in the art, such as acidic hydrolysis. Acidic hydrolysis may be performed, for example, with aqueous hydrochloric acid or aqueous trifluoroacetic acid.
- acidic hydrolysis may be performed with aqueous hydrochloric acid in acetone at a temperature of from about 25 to about 65° C.
- acidic hydrolysis is performed at apH of about 3.5 to 4.5 and preferably at about 4.
- the reaction may be performed in the presence of acetone.
- Decarboxylation can also be performed by heating the dicarboxylated intermediate in a high boiling point organic solvent, such as xylenes, toluene, heptane, dimethyl acetamide (DMA or DMAC), dimethyl formamide (DMF), methyl sulfoxide, isoparaffms ⁇ e.g.
- the organic solvent preferably has a boiling point of at least 110° C and more preferably of at least 140° C.
- the decarboxylation reaction is preferably performed at a temperature ranging from about 120 to about 160° C, more preferably from about 140 to about 160° C, and most preferably from about 145 to about 165° C.
- the temperature at which the reaction is performed should be sufficient to remove one of the carboxylate groups at the end of the chain R 7 .
- any water in the reaction mixture is removed prior to heating.
- Water may be removed from a reaction mixture containing the free acid of the dicarboxylated intermediate (which is formed if the dicarboxylated intermediate is hydrolyzed as described in the "Hydrolysis" section above) as follows.
- the free acid is mixed with an organic solvent in which it is soluble, such as xylenes.
- the aqueous layer is then extracted, which in this case is the lower layer, leaving the free acid in xylenes.
- the reaction mixture may then be heated to decarboxylate the free acid of the dicarboxylated intermediate.
- the reaction mixture prior and during the decarboxylation reaction preferably contains less than 5%, more preferably less than 3%, and most preferably less than 1% by weight of water, based upon 100% total weight of reaction mixture.
- the decarboxylation step may also be performed neat ⁇ i.e. without a solvent) by heating the dicarboxylated intermediate (or free acid thereof) to a temperature ranging from about 140 to about 200° C.
- the hydrolyzing and decarboxylating steps maybe performed at a temperature of from about 20 to about 200 °C.
- Suitable solvents for the alkylated phenoxy containing compound in the decarboxylating and hydrolyzing steps include, but are not limited to, organic solvents, such as ethanol, dimethylacetamide (DMAC), dimethylformamide (DMF), ketones ⁇ e.g. acetone, methylethylketone, and methylisobutylketone), and any combination of any of the foregoing.
- organic solvents such as ethanol, dimethylacetamide (DMAC), dimethylformamide (DMF), ketones ⁇ e.g. acetone, methylethylketone, and methylisobutylketone
- Salts of the alkylated phenoxy containing compound may be formed by any method known in the art.
- the acid form of the alkylated phenoxy containing compound i.e., where the alkylated phenoxy containing compound has a -COOH moiety, may be converted into the corresponding sodium salt by reacting it with sodium hydroxide.
- Suitable salts include, but are not limited to, organic and inorganic salts, for example alkali-metal salts, such as sodium, potassium and lithium; alkaline-earth metal salts, such as magnesium, calcium or barium; ammonium salts; basic amino acids, such as lysine or arginine; and organic amines, such as dimethylamine or pyridine.
- Sodium salts include, but are not limited to, mono-, di-, and other multi-valent sodium salts.
- a preferred salt is the disodium salt.
- the salts may also be solvates, including ethanol solvates, and hydrates.
- solvate as used herein includes, but is not limited to, a molecular or ionic complex of molecules or ions of a solvent, such as ethanol, with ions or molecules of the compounds of the present invention.
- the present method maybe used to prepare phenoxy alkanoic, alkenoic, and alkynoic acids and salts thereof having the formula
- R 1 , R 2 , R 3 , R 4 , R 5 , and R 7 are defined as above.
- the alkylated phenoxy containing compounds of the present invention may be isolated and/or purified by methods known in the art.
- the alkylated phenoxy containing compounds may be purified by recrystallization or fractionation on one or more chromatographic supports. Fractionation may be performed on suitable chromatographic supports, such as silica gel or alumina, using solvent mixtures such as acetic acid/butanol/water as the mobile phase; reverse phase column supports using trifluoroacetic acid/acetonitrile mixtures as the mobile phase; and ion exchange chromatography using water as the mobile phase.
- the alkylated phenoxy containing compounds may also be purified to remove impurities, such as inorganic salts, by extraction with a lower alcohol, such as methanol, butanol, or isopropanol.
- the method of the present invention uses readily available and inexpensive starting materials and provides a cost-effective method for preparing and isolating alkylated phenoxy containing compounds.
- the method is simple to perform and is amenable to industrial scale- up for commercial production.
- the dicarboxylate delivery agent compounds of the present invention include the free acids of the dicarboxylated intermediates of the present invention ⁇ i.e. when R and R are hydrogen) and salts thereof.
- Suitable salts include, but are not limited to, organic and inorganic salts, for example alkali-metal salts, such as sodium, potassium and lithium; alkaline-earth metal salts, such as magnesium, calcium or barium; ammonium salts; basic amino acids, such as lysine or arginine; and organic amines, such as dimethylamine or pyridine.
- the salts are sodium salts.
- the salts may be mono- or multi-valent salts, such as monosodium salts, di-sodium salts, and trisodium salts.
- the salts may also be solvates, including ethanol solvates, and hydrates.
- the delivery agent compounds may be in the form of the free amine or salts thereof.
- Suitable salts include, but are not limited to, organic and inorganic salts, for example hydrochlori.de salts, acetate or citrate.
- Salts of the delivery agent compounds of the present invention maybe prepared by methods known in the art.
- sodium salts may be prepared by dissolving the delivery agent compound in ethanol and adding aqueous sodium hydroxide, hi addition, poly amino acids and peptides comprising one or more of these compounds may be used.
- An amino acid is any carboxylic acid having at least one free amine group and includes naturally occurring and synthetic amino acids.
- Poly amino acids are either peptides (which are two or more amino acids j oined by a peptide bond) or are two or more amino acids linked by a bond formed by other groups which can be linked by, e.g., an ester or an anhydride linkage.
- Peptides can vary in length from dipeptides with two amino acids to polypeptides with several hundred amino acids. One or more of the amino acids or peptide units may be acylated or sulfonated.
- Active agents suitable for use in the present invention include biologically active agents and chemically active agents, including, but not limited to, pesticides, pharmacological agents, and therapeutic agents.
- biologically or chemically active agents suitable for use in the present invention include, but are not limited to, proteins; polypeptides; peptides; hormones; polysaccharides, and particularly mixtures of muco-polysaccharides; carbohydrates; lipids; small polar organic molecules (t.e.
- polar organic molecules having a molecular weight of 500 daltons or less
- other organic compounds and particularly compounds which by themselves do not pass (or which pass only a fraction of the administered dose) through the gastrointestinal mucosa and/or are susceptible to chemical cleavage by acids and enzymes in the gastro-intestinal tract; or any combination thereof.
- growth hormones including human growth hormones (hGH), recombinant human growth hormones (rhGH), bovine growth ho ⁇ nones, and porcine growth ho ⁇ nones; growth hormone releasing hormones; growth hormone releasing factor, interferons, including ⁇ , ⁇ and ⁇ , interleukin-1 ; interleukin-2; insulin, including porcine, bovine, human, and human recombinant, optionally having counter ions including zinc, sodium, calcium and ammonium; insulin-like growth factor, including IGF-1 ; heparin, including unfractionated heparin, heparinoids, demiatans, chondroitins, low molecular weight heparin, very low molecular weight heparin and ultra low molecular weight heparin; calcitonin, including salmon, eel, porcine and human; erythropoietin; atrial
- Non-limiting examples of antibiotics include gram-positive acting, bacteriocidal, lipopeptidal and cyclic peptidal antibiotics, such as daptomycin and analogs thereof.
- a preferred active agent is calcitonin and more preferably salmon calcitonin.
- composition of the present invention comprises one or more delivery agent compounds of the present invention, and one or more active agents.
- one or more of the delivery agent compounds, or salts of these compounds, or poly amino acids or peptides of which these compounds or salts form one or more of the units thereof, may be used as a delivery agent by mixing with the active agent prior to administration to fonn an administration composition.
- the administration compositions maybe in the form of a liquid.
- the solution medium maybe water (for example, for salmon calcitonin, parathyroid hormone, and erythropoietin), 25% aqueous propylene glycol (for example, for heparin) and phosphate buffer (for example, for rhGH).
- Other dosing vehicles include polyethylene glycol.
- Dosing solutions may be prepared by mixing a solution of the delivery agent compound with a solution of the active agent, just prior to administration. Alternately, a solution of the delivery agent compound (or active agent) may be mixed with the solid form of the active agent (or delivery agent compound). The delivery agent compound and the active agent may also be mixed as dry powders. The delivery agent compound and the active agent can also be admixed during the manufacturing process.
- the dosing solutions may optionally contain additives such as phosphate buffer salts, citric acid, glycols, or other dispersing agents. Stabilizing additives maybe incorporated into the solution, preferably at a concentration ranging between about 0.1 and 20% (w/v).
- the administration compositions may alternately be in the form of a solid, such as a tablet, capsule or particle, such as a powder or sachet.
- Solid dosage forms may be prepared by mixing the solid form of the compound with the solid form of the active agent.
- a solid may be obtained from a solution of compound and active agent by methods known in the art, such as freeze-drying (lyophihzation), precipitation, crystallization and solid dispersion.
- the administration compositions of the present invention may also include one or more enzyme inhibitors.
- enzyme inhibitors include, but are not limited to, compounds such as actinonin or epiactinonin and derivatives thereof.
- Other enzyme inhibitors include, but are not limited to, aprotinin (Trasylol) and Bowman-Birk inhibitor.
- the amount of active agent used in an administration composition of the present invention is an amount effective to accomplish the purpose of the particular active agent for the target indication.
- the amount of active agent in the compositions typically is a pharmacologically, biologically, therapeutically, or chemically effective amount. However, the amount can be less than that amount when the composition is used in a dosage unit form because the dosage unit form may contain a plurality of delivery agent compound/active agent compositions or may contain a divided pharmacologically, biologically, therapeutically, or chemically effective amount.
- the total effective amount can then be administered in cumulative units containing, in total, an effective amount of the active agent.
- compositions of the invention may deliver active agents more efficiently than compositions containing the active agent alone, lower amounts of biologically or chemically active agents than those used in prior dosage unit forms or delivery systems can be administered to the subject, while still achieving the same blood levels and/or therapeutic effects.
- the presently disclosed delivery agent compounds facilitate the delivery of biologically and chemically active agents, particularly in oral, intranasal, sublingual, intraduodenal, subcutaneous, buccal, intracolonic, rectal, vaginal, mucosal, pulmonary, transdermal, intradermal, parenteral, intravenous, intramuscular and ocular systems, as well as traversing the blood-brain barrier.
- Dosage unit forms can also include any one or combination of excipients, diluents, disintegrants, lubricants, plasticizers, colorants, flavorants, taste-masking agents, sugars, sweeteners, salts, and dosing vehicles, including, but not limited to, water, 1 ,2-propane diol, ethanol, olive oil, and any combination thereof.
- the delivery agent compounds and compositions of the subject invention are useful for administering biologically or chemically active agents to any animals, including but not limited to birds such as chickens; mammals, such as rodents, cows, pigs, dogs, cats, primates, and particularly humans; and insects.
- the system is particularly advantageous for delivering chemically or biologically active agents that would otherwise be destroyed or rendered less effective by conditions encountered before the active agent reaches its target zone (i.e. the area in which the active agent of the delivery composition is to be released) and within the body of the animal to which they are administered.
- target zone i.e. the area in which the active agent of the delivery composition is to be released
- the compounds and compositions of the present invention are useful in orally administering active agents, especially those that are not ordinarily orally deliverable, or those for which improved delivery is desired.
- compositions comprising the delivery agent compounds and active agents have utility in the delivery of active agents to biological systems and in an increased or improved bioavailability of the active agent compared to administration of the active agent without the delivery agent. Delivery can be improved by delivering more active agent over a period of time, or in delivering active agent in a particular time period (such as to effect quicker or delayed delivery), or in delivering the active agent at a specific time, or over a period of time (such as sustained delivery).
- Another embodiment of the present invention is a method for the treatment or prevention of a disease or for achieving a desired physiological effect, such as those listed in the table below, in an animal by administering the composition of the present invention.
- Specific indications for active agents can be found in the Physicians' Desk Reference (54 th Ed., 2000, Medical Economics Company, Inc., Montvale, NJ), which is herein incorporated by reference.
- the active agents in the table below include their analogs, fragments, mimetics, and polyethylene glycol-modified derivatives.
- one embodiment of the present invention is a method for treating a patient suffering from or susceptible to diabetes by administering insulin and at least one of the delivery agent compounds of the present invention.
- the active agent present in the composition or dosage unit form is taken up into the circulation.
- the bioavailability of the agent is readily assessed by measuring a known pharmacological activity in blood, e.g. , an increase in blood clotting time caused by heparin, or a decrease in circulating calcium levels caused by calcitonin- Alternately, the circulating levels of the active agent itself can be measured directly.
- Example 1 A disodium salt of a phenoxy carboxylic acid compound can be prepared by l ⁇ e procedure shown in the flow chart below.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2003530221A JP2005528322A (en) | 2001-09-26 | 2002-09-26 | Process for the preparation of phenoxyalkanoic acids, alkenoic acids and alkynic acids and their salts via dicarboxylate intermediates |
US10/489,727 US7411084B2 (en) | 2001-09-26 | 2002-09-26 | Method of preparing phenoxy alkanoic, alkenoic, and alkynoic acids and salts thereof via a dicarboxylate intermediate |
ES02776011T ES2400683T3 (en) | 2001-09-26 | 2002-09-26 | Method of preparing phenoi-alkanoic acids and salts thereof by means of a dicarboxylate intermediate |
CA2460782A CA2460782C (en) | 2001-09-26 | 2002-09-26 | Method of preparing phenoxy alkanoic, alkenoic, and alkynoic acids and salts thereof via a dicarboxylate intermediate |
EP02776011A EP1448509B1 (en) | 2001-09-26 | 2002-09-26 | Method of preparing phenoxy alkanoic acids and salts thereof via a dicarboxylate intermediate |
AU2002341856A AU2002341856A1 (en) | 2001-09-26 | 2002-09-26 | Method of preparing phenoxy alkanoic, alkenoic, and alkynoic acids and salts thereof via a dicarboxylate intermediate |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US32565701P | 2001-09-26 | 2001-09-26 | |
US60/325,657 | 2001-09-26 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2003026582A2 true WO2003026582A2 (en) | 2003-04-03 |
WO2003026582A3 WO2003026582A3 (en) | 2003-10-16 |
Family
ID=23268830
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2002/030671 WO2003026582A2 (en) | 2001-09-26 | 2002-09-26 | Method of preparing phenoxy alkanoic, alkenoic, and alkynoic acids and salts thereof via a dicarboxylate intermediate |
Country Status (8)
Country | Link |
---|---|
US (1) | US7411084B2 (en) |
EP (1) | EP1448509B1 (en) |
JP (1) | JP2005528322A (en) |
CN (1) | CN100516020C (en) |
AU (1) | AU2002341856A1 (en) |
CA (1) | CA2460782C (en) |
ES (1) | ES2400683T3 (en) |
WO (1) | WO2003026582A2 (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6960355B2 (en) | 1996-03-29 | 2005-11-01 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
WO2005112937A1 (en) | 2004-05-19 | 2005-12-01 | Emisphere Technologies, Inc. | Acyclovir formulations |
WO2006072070A2 (en) | 2004-12-29 | 2006-07-06 | Emisphere Technologies, Inc. | Pharmaceutical formulations of gallium salts |
EP2279732A2 (en) | 2004-05-14 | 2011-02-02 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
WO2011017346A2 (en) | 2009-08-03 | 2011-02-10 | Emisphere Technologies, Inc. | Fast-acting naproxen composition with reduced gastrointestinal effects |
US8110547B2 (en) | 2005-01-12 | 2012-02-07 | Emisphere Technologies, Inc. | Compositions for buccal delivery of parathyroid hormone |
US8975227B2 (en) | 2005-07-15 | 2015-03-10 | Emisphere Technologies, Inc. | Intraoral dosage forms of glucagon |
US9498487B2 (en) * | 2004-05-19 | 2016-11-22 | Emisphere Technologies, Inc. | Topical cromolyn formulations |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8927015B2 (en) | 2006-04-12 | 2015-01-06 | Emisphere Technologies, Inc. | Formulations for delivering insulin |
US9364502B2 (en) | 2006-06-28 | 2016-06-14 | Emisphere Technologies, Inc. | Gallium nitrate formulations |
CA2662853C (en) | 2006-08-31 | 2016-07-26 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
CN103086871B (en) * | 2013-02-02 | 2014-12-10 | 刘珍明 | Preparation method of dicarboxylic acid with branch at alpha position for aluminum electrolytic capacitor electrolyte |
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US4337267A (en) * | 1980-08-25 | 1982-06-29 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Phenalkoxyalkyl- and phenoxyalkyl-substituted oxiranecarboxylic acids, their use and medicaments containing them |
HU196886B (en) * | 1985-10-01 | 1989-02-28 | Mta Koezponti Kemiai Kutato In | Herbicides containing as active substance 4-chlor-aryloxiacetil or 4-chlor-aryloxi-propionil-malonic-acid-esther derivatives and process for production of active substance |
US5192785A (en) * | 1989-09-03 | 1993-03-09 | A. H. Robins Company, Incorporated | Sulfamates as antiglaucoma agents |
US5025031A (en) * | 1989-11-30 | 1991-06-18 | A. H. Robins Co., Inc. | Aryl and aryloxyalkyl sulfamate esters useful as anticonvulsants |
DE4012405C1 (en) * | 1990-04-19 | 1991-08-14 | Forschungszentrum Juelich Gmbh, 5170 Juelich, De | Radioisotope labelled oxiranyl carboxylic acid derivs. prodn. - by nucleophilic replacement of corresp. bromo or iodo substits. with radioactive alkali halide(s) in polar medium |
US5747537A (en) * | 1995-09-05 | 1998-05-05 | Washington University | Method of inhibiting parasitic activity |
FR2749583B1 (en) * | 1996-06-07 | 1998-08-21 | Lipha | NOVEL SUBSTITUTED THIAZOLIDINE -2,4- DIONE DERIVATIVES, PROCESSES FOR OBTAINING SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME |
DE19623608A1 (en) * | 1996-06-13 | 1997-12-18 | Basf Ag | Process for the production of epoxides from olefins and hydrogen peroxide or hydroperoxides |
DE19943636A1 (en) * | 1999-09-13 | 2001-03-15 | Bayer Ag | Novel dicarboxylic acid derivatives with pharmaceutical properties |
AU2622301A (en) * | 1999-11-05 | 2001-05-14 | Emisphere Technologies, Inc. | Phenyl amine carboxylic acid compounds and compositions for delivering active agents |
-
2002
- 2002-09-26 JP JP2003530221A patent/JP2005528322A/en not_active Withdrawn
- 2002-09-26 WO PCT/US2002/030671 patent/WO2003026582A2/en active Application Filing
- 2002-09-26 CN CNB028211073A patent/CN100516020C/en not_active Expired - Fee Related
- 2002-09-26 ES ES02776011T patent/ES2400683T3/en not_active Expired - Lifetime
- 2002-09-26 CA CA2460782A patent/CA2460782C/en not_active Expired - Lifetime
- 2002-09-26 AU AU2002341856A patent/AU2002341856A1/en not_active Abandoned
- 2002-09-26 US US10/489,727 patent/US7411084B2/en not_active Expired - Lifetime
- 2002-09-26 EP EP02776011A patent/EP1448509B1/en not_active Expired - Lifetime
Non-Patent Citations (2)
Title |
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None |
See also references of EP1448509A4 |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6960355B2 (en) | 1996-03-29 | 2005-11-01 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
EP2279732A2 (en) | 2004-05-14 | 2011-02-02 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
WO2005112937A1 (en) | 2004-05-19 | 2005-12-01 | Emisphere Technologies, Inc. | Acyclovir formulations |
US9498487B2 (en) * | 2004-05-19 | 2016-11-22 | Emisphere Technologies, Inc. | Topical cromolyn formulations |
WO2006072070A2 (en) | 2004-12-29 | 2006-07-06 | Emisphere Technologies, Inc. | Pharmaceutical formulations of gallium salts |
US8110547B2 (en) | 2005-01-12 | 2012-02-07 | Emisphere Technologies, Inc. | Compositions for buccal delivery of parathyroid hormone |
US8975227B2 (en) | 2005-07-15 | 2015-03-10 | Emisphere Technologies, Inc. | Intraoral dosage forms of glucagon |
WO2011017346A2 (en) | 2009-08-03 | 2011-02-10 | Emisphere Technologies, Inc. | Fast-acting naproxen composition with reduced gastrointestinal effects |
Also Published As
Publication number | Publication date |
---|---|
US7411084B2 (en) | 2008-08-12 |
JP2005528322A (en) | 2005-09-22 |
EP1448509B1 (en) | 2012-12-19 |
EP1448509A2 (en) | 2004-08-25 |
EP1448509A4 (en) | 2006-02-08 |
WO2003026582A3 (en) | 2003-10-16 |
AU2002341856A1 (en) | 2003-04-07 |
ES2400683T3 (en) | 2013-04-11 |
CN100516020C (en) | 2009-07-22 |
CA2460782C (en) | 2011-11-08 |
CN1639106A (en) | 2005-07-13 |
US20040171865A1 (en) | 2004-09-02 |
CA2460782A1 (en) | 2003-04-03 |
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