IL305510A - A dry powder preparation of terprostinil and its prodrug that will additionally contain (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobiotyl]-2,5-dictopiperazine (FDKP) - Google Patents
A dry powder preparation of terprostinil and its prodrug that will additionally contain (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobiotyl]-2,5-dictopiperazine (FDKP)Info
- Publication number
- IL305510A IL305510A IL305510A IL30551023A IL305510A IL 305510 A IL305510 A IL 305510A IL 305510 A IL305510 A IL 305510A IL 30551023 A IL30551023 A IL 30551023A IL 305510 A IL305510 A IL 305510A
- Authority
- IL
- Israel
- Prior art keywords
- substituted
- treprostinil
- salt
- dry powder
- alkyl
- Prior art date
Links
- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical group C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 title claims description 196
- 229960005032 treprostinil Drugs 0.000 title claims description 188
- 229940002612 prodrug Drugs 0.000 title claims description 67
- 239000000651 prodrug Substances 0.000 title claims description 67
- 239000000203 mixture Substances 0.000 title claims description 63
- 239000000843 powder Substances 0.000 title claims description 40
- -1 fumaryl 2,5-diketopiperazine Chemical compound 0.000 claims description 136
- 125000000623 heterocyclic group Chemical group 0.000 claims description 133
- 125000001072 heteroaryl group Chemical group 0.000 claims description 112
- 125000003107 substituted aryl group Chemical group 0.000 claims description 54
- 125000000217 alkyl group Chemical group 0.000 claims description 53
- 150000003839 salts Chemical class 0.000 claims description 53
- 238000009472 formulation Methods 0.000 claims description 51
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 48
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 48
- 125000001424 substituent group Chemical group 0.000 claims description 46
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 40
- 238000000034 method Methods 0.000 claims description 23
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 22
- 235000001014 amino acid Nutrition 0.000 claims description 14
- 150000008545 L-lysines Chemical class 0.000 claims description 13
- 150000001413 amino acids Chemical class 0.000 claims description 13
- 239000004475 Arginine Substances 0.000 claims description 12
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 12
- 235000009697 arginine Nutrition 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- 230000009257 reactivity Effects 0.000 claims description 11
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 8
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 8
- 239000004472 Lysine Substances 0.000 claims description 8
- 235000018977 lysine Nutrition 0.000 claims description 8
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 7
- 229910052700 potassium Inorganic materials 0.000 claims description 7
- 239000011591 potassium Substances 0.000 claims description 7
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 5
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 4
- 150000008535 L-arginines Chemical class 0.000 claims description 4
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 claims description 4
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 claims description 4
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 2
- RHWRWEUCEXUUAV-ZSESPEEFSA-N 2-[[(1r,2r,3as,9as)-2-hydroxy-1-[(3s)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1h-cyclopenta[g]naphthalen-5-yl]oxy]acetic acid;2-(2-hydroxyethylamino)ethanol Chemical compound OCCNCCO.C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 RHWRWEUCEXUUAV-ZSESPEEFSA-N 0.000 claims description 2
- NGUUMHKSNSFLOS-UHFFFAOYSA-N 2-methoxyethyl hydrogen carbonate Chemical compound COCCOC(O)=O NGUUMHKSNSFLOS-UHFFFAOYSA-N 0.000 claims description 2
- RVQCCDLSVZDZQC-FHNDMYTFSA-N CC(O)=O.CC(O)=O.OC(=O)[C@@H](N)CCCNC(N)=N Chemical compound CC(O)=O.CC(O)=O.OC(=O)[C@@H](N)CCCNC(N)=N RVQCCDLSVZDZQC-FHNDMYTFSA-N 0.000 claims description 2
- XZSBLWHLGQWNQO-UHFFFAOYSA-M COC(OC([O-])=O)=O.[K+] Chemical compound COC(OC([O-])=O)=O.[K+] XZSBLWHLGQWNQO-UHFFFAOYSA-M 0.000 claims description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- 239000007983 Tris buffer Substances 0.000 claims description 2
- RBZGBEYLWFFHKN-XRIGFGBMSA-N acetic acid;(2s)-2,6-diaminohexanoic acid Chemical compound CC(O)=O.CC(O)=O.NCCCC[C@H](N)C(O)=O RBZGBEYLWFFHKN-XRIGFGBMSA-N 0.000 claims description 2
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 claims description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims description 2
- 229960001231 choline Drugs 0.000 claims description 2
- LFQRKUIOSYPVFY-UHFFFAOYSA-L dipotassium diacetate Chemical compound [K+].[K+].CC([O-])=O.CC([O-])=O LFQRKUIOSYPVFY-UHFFFAOYSA-L 0.000 claims description 2
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 2
- 235000019371 penicillin G benzathine Nutrition 0.000 claims description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 2
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 claims description 2
- 229960004919 procaine Drugs 0.000 claims description 2
- 229960000281 trometamol Drugs 0.000 claims description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 description 88
- 125000003118 aryl group Chemical group 0.000 description 62
- 125000000753 cycloalkyl group Chemical group 0.000 description 49
- 125000000547 substituted alkyl group Chemical group 0.000 description 39
- 125000000304 alkynyl group Chemical group 0.000 description 37
- 125000003342 alkenyl group Chemical group 0.000 description 36
- 125000005017 substituted alkenyl group Chemical group 0.000 description 34
- 125000004426 substituted alkynyl group Chemical group 0.000 description 34
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 31
- 125000004104 aryloxy group Chemical group 0.000 description 24
- 125000004432 carbon atom Chemical group C* 0.000 description 24
- 229910052739 hydrogen Inorganic materials 0.000 description 24
- 239000001257 hydrogen Substances 0.000 description 23
- 125000004414 alkyl thio group Chemical group 0.000 description 22
- 125000005110 aryl thio group Chemical group 0.000 description 22
- 125000004465 cycloalkenyloxy group Chemical group 0.000 description 22
- 125000005366 cycloalkylthio group Chemical group 0.000 description 22
- 125000005553 heteroaryloxy group Chemical group 0.000 description 22
- 125000005368 heteroarylthio group Chemical group 0.000 description 22
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 22
- 125000004468 heterocyclylthio group Chemical group 0.000 description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 17
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000012535 impurity Substances 0.000 description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 14
- 150000003573 thiols Chemical class 0.000 description 14
- 125000002252 acyl group Chemical group 0.000 description 13
- 125000003545 alkoxy group Chemical group 0.000 description 13
- 125000004093 cyano group Chemical group *C#N 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- 125000004442 acylamino group Chemical group 0.000 description 12
- 125000004423 acyloxy group Chemical group 0.000 description 12
- 229940024606 amino acid Drugs 0.000 description 12
- 125000005843 halogen group Chemical group 0.000 description 12
- 239000004615 ingredient Substances 0.000 description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 12
- 125000005415 substituted alkoxy group Chemical group 0.000 description 12
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 125000004682 aminothiocarbonyl group Chemical group NC(=S)* 0.000 description 11
- 125000000000 cycloalkoxy group Chemical group 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 11
- 125000005338 substituted cycloalkoxy group Chemical group 0.000 description 11
- 125000003441 thioacyl group Chemical group 0.000 description 11
- 229910006069 SO3H Inorganic materials 0.000 description 10
- 125000002947 alkylene group Chemical group 0.000 description 10
- 229960003121 arginine Drugs 0.000 description 10
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 125000004419 alkynylene group Chemical group 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- 229960003646 lysine Drugs 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 238000006467 substitution reaction Methods 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 125000001183 hydrocarbyl group Chemical group 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 125000004450 alkenylene group Chemical group 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- ZQMIGQNCOMNODD-UHFFFAOYSA-N diacetyl peroxide Chemical compound CC(=O)OOC(C)=O ZQMIGQNCOMNODD-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 229940112141 dry powder inhaler Drugs 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 125000004043 oxo group Chemical group O=* 0.000 description 4
- 229910052717 sulfur Chemical group 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 125000000732 arylene group Chemical group 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- 150000001721 carbon 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
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 125000004404 heteroalkyl group Chemical group 0.000 description 3
- 125000005549 heteroarylene group Chemical group 0.000 description 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 125000003003 spiro group Chemical group 0.000 description 3
- 239000011593 sulfur Chemical group 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 2
- 125000006694 (C2-C10) heterocyclyl group Chemical group 0.000 description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- ASSKVPFEZFQQNQ-UHFFFAOYSA-N 2-benzoxazolinone Chemical compound C1=CC=C2OC(O)=NC2=C1 ASSKVPFEZFQQNQ-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
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- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
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- 239000003053 toxin Substances 0.000 description 1
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Classifications
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
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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
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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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- A61K47/50—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
- 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
- A61K47/54—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 compound
- A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
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- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Otolaryngology (AREA)
- Pulmonology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US202163156110P | 2021-03-03 | 2021-03-03 | |
| PCT/US2022/018505 WO2022187352A1 (en) | 2021-03-03 | 2022-03-02 | A dry powder composition of trestinil and its prodrug thereof and further comprising comprising (e)-3,6-bis[4-(n-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine (fdkp) |
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| IL305510A true IL305510A (en) | 2023-10-01 |
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| IL305510A IL305510A (en) | 2021-03-03 | 2022-03-02 | A dry powder preparation of terprostinil and its prodrug that will additionally contain (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobiotyl]-2,5-dictopiperazine (FDKP) |
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| CN121241041A (zh) * | 2023-01-19 | 2025-12-30 | 联合治疗公司 | 曲前列尼尔类似物及相关制备和使用方法 |
| EP4680223A1 (en) * | 2023-03-17 | 2026-01-21 | Insmed Incorporated | Spray dried treprostinil formulation |
| WO2025174856A1 (en) * | 2024-02-12 | 2025-08-21 | Mannkind Corporation | Process for making a composition for pulmonary inhalation |
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| US2485614A (en) | 1946-08-29 | 1949-10-25 | Chicago Bridge & Iron Co | Stabilizing and guide apparatus for lifter roofs |
| US3037116A (en) | 1957-07-26 | 1962-05-29 | Weber Georges | Apparatus for irradiating liquids |
| US3035516A (en) | 1958-08-18 | 1962-05-22 | Lee Brothers Company | Stencil device |
| US3646509A (en) | 1969-08-08 | 1972-02-29 | Texas Instruments Inc | Method for field stacking seismic data and system using write after read bulk data storage |
| US4306075A (en) | 1980-03-28 | 1981-12-15 | The Upjohn Company | Composition and process |
| US4547016A (en) | 1984-08-13 | 1985-10-15 | Eeco Incorporated | Quick release mounting |
| GB8814438D0 (en) | 1988-06-17 | 1988-07-20 | Wellcome Found | Compounds for use in medicine |
| IT1231076B (it) | 1989-09-28 | 1991-11-12 | Pirelli Cavi Spa | Procedimento per la realizzazione di gruppo di connessione separabile per fibre ottiche riunite a nastro e gruppo di connessione con esso realizzato. |
| GB9011588D0 (en) | 1990-05-24 | 1990-07-11 | Wellcome Found | Prostaglandin analogues for use in medicine |
| US6441245B1 (en) | 1997-10-24 | 2002-08-27 | United Therapeutics Corporation | Process for stereoselective synthesis of prostacyclin derivatives |
| ES2214753T3 (es) | 1997-11-14 | 2004-09-16 | United Therapeutics Corporation | Uso de 9-desoxi-2',9-alfa-metano-3-oxa-4,5,6-trinor-3,7-(1',3'-interfenilen)-13,14-dihidro-prostaglandina f1 para tratar la enfermedad vascular periferica. |
| US6521212B1 (en) | 1999-03-18 | 2003-02-18 | United Therapeutics Corporation | Method for treating peripheral vascular disease by administering benzindene prostaglandins by inhalation |
| KR20020012169A (ko) | 1999-03-31 | 2002-02-15 | 유나이티드 쎄러퓨틱스 코포레이션 | 프로스타글란딘 화합물, 조성물 및 말초혈관질병 및폐고혈압증의 치료방법 |
| US7464706B2 (en) | 1999-07-23 | 2008-12-16 | Mannkind Corporation | Unit dose cartridge and dry powder inhaler |
| US7305986B1 (en) | 1999-07-23 | 2007-12-11 | Mannkind Corporation | Unit dose capsules for use in a dry powder inhaler |
| US6700025B2 (en) | 2001-01-05 | 2004-03-02 | United Therapeutics Corporation | Process for stereoselective synthesis of prostacyclin derivatives |
| US6803386B2 (en) | 2002-01-16 | 2004-10-12 | United Therapeutics Corporation | Prostacyclin derivative containing compositions and methods of using the same for the treatment of cancer |
| US6756117B1 (en) | 2002-12-20 | 2004-06-29 | The United States Of America As Represented By The United States Department Of Energy | Photonic polymer-blend structures and method for making |
| CN102697790A (zh) | 2003-05-22 | 2012-10-03 | 联合治疗公司 | 化合物和释放前列环素类似物的方法 |
| US20090124697A1 (en) | 2003-12-16 | 2009-05-14 | United Therapeutics Corporation | Inhalation formulations of treprostinil |
| US7199157B2 (en) | 2003-12-16 | 2007-04-03 | United Therapeutics Corporation | Use of treprostinil to improve kidney functions |
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-
2022
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- 2022-03-02 KR KR1020237033199A patent/KR20240012354A/ko active Pending
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| US20220280430A1 (en) | 2022-09-08 |
| JP2024510930A (ja) | 2024-03-12 |
| AU2022229367A1 (en) | 2023-09-14 |
| US12168071B2 (en) | 2024-12-17 |
| EP4301372A1 (en) | 2024-01-10 |
| US20250064743A1 (en) | 2025-02-27 |
| WO2022187352A1 (en) | 2022-09-09 |
| KR20240012354A (ko) | 2024-01-29 |
| CA3209987A1 (en) | 2022-09-09 |
| CN117479946A (zh) | 2024-01-30 |
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