TWI695830B - 化合物及其調節血紅素之用途 - Google Patents
化合物及其調節血紅素之用途 Download PDFInfo
- Publication number
- TWI695830B TWI695830B TW103109178A TW103109178A TWI695830B TW I695830 B TWI695830 B TW I695830B TW 103109178 A TW103109178 A TW 103109178A TW 103109178 A TW103109178 A TW 103109178A TW I695830 B TWI695830 B TW I695830B
- Authority
- TW
- Taiwan
- Prior art keywords
- alkyl
- group
- optionally substituted
- mmol
- aryl
- Prior art date
Links
- 0 C*(C)*C(*N)ICCI Chemical compound C*(C)*C(*N)ICCI 0.000 description 10
- TWOOAJJERQIUND-ZDUSSCGKSA-N Oc1c(C=O)c(OC[C@H](CCC2)N2C(c2ncccc2)=O)ccc1 Chemical compound Oc1c(C=O)c(OC[C@H](CCC2)N2C(c2ncccc2)=O)ccc1 TWOOAJJERQIUND-ZDUSSCGKSA-N 0.000 description 2
- LAEUDKTWJROGLP-AWEZNQCLSA-N Oc1cccc(OC[C@H](CCC2)N2C(c2cccnc2)=O)c1C=O Chemical compound Oc1cccc(OC[C@H](CCC2)N2C(c2cccnc2)=O)c1C=O LAEUDKTWJROGLP-AWEZNQCLSA-N 0.000 description 2
- OOJXQJBUZQUBHS-OLLQRSAISA-N C/C=C\C(\S(/N1[C@H](COc2c(C=O)c(O)ccc2)CCC1)=[O]\C=O)=C/N=C Chemical compound C/C=C\C(\S(/N1[C@H](COc2c(C=O)c(O)ccc2)CCC1)=[O]\C=O)=C/N=C OOJXQJBUZQUBHS-OLLQRSAISA-N 0.000 description 1
- UXKRQWMPDCGRKY-AWEZNQCLSA-N CC(C)[n]1nccc1C(N1[C@H](COc2c(C=O)c(O)ccc2)CCC1)=O Chemical compound CC(C)[n]1nccc1C(N1[C@H](COc2c(C=O)c(O)ccc2)CCC1)=O UXKRQWMPDCGRKY-AWEZNQCLSA-N 0.000 description 1
- JLFHXNINERBPLZ-HNNXBMFYSA-N Cc1ncccc1C(N1[C@H](COc2c(C=O)c(O)ccc2)CCCC1)=O Chemical compound Cc1ncccc1C(N1[C@H](COc2c(C=O)c(O)ccc2)CCCC1)=O JLFHXNINERBPLZ-HNNXBMFYSA-N 0.000 description 1
- ZKNPQOCDLSUMCM-ATNAJCNCSA-N OC(CC=C1)C(C=O)=C1OC[C@H](CCCC1)N1C(c1ccccc1)=O Chemical compound OC(CC=C1)C(C=O)=C1OC[C@H](CCCC1)N1C(c1ccccc1)=O ZKNPQOCDLSUMCM-ATNAJCNCSA-N 0.000 description 1
- AOMVIQXGKMTHAH-HNNXBMFYSA-N Oc1cccc(OC[C@H](CCC2)N2C(c2ccccc2)=O)c1C=O Chemical compound Oc1cccc(OC[C@H](CCC2)N2C(c2ccccc2)=O)c1C=O AOMVIQXGKMTHAH-HNNXBMFYSA-N 0.000 description 1
- USYDBTWWZXXXES-AWEZNQCLSA-N Oc1cccc(OC[C@H](CCC2)N2C(c2ccncc2)=O)c1C=O Chemical compound Oc1cccc(OC[C@H](CCC2)N2C(c2ccncc2)=O)c1C=O USYDBTWWZXXXES-AWEZNQCLSA-N 0.000 description 1
- NYDZWFBXOVCAIM-AWEZNQCLSA-N Oc1cccc(OC[C@H](CCC2)N2S(c2ccccc2)(=O)=O)c1C=O Chemical compound Oc1cccc(OC[C@H](CCC2)N2S(c2ccccc2)(=O)=O)c1C=O NYDZWFBXOVCAIM-AWEZNQCLSA-N 0.000 description 1
- DIXJEEIWNGTEBR-HNNXBMFYSA-N Oc1cccc(OC[C@H](CCCC2)N2C(c2cccnc2)=O)c1C=O Chemical compound Oc1cccc(OC[C@H](CCCC2)N2C(c2cccnc2)=O)c1C=O DIXJEEIWNGTEBR-HNNXBMFYSA-N 0.000 description 1
- SXAADVVBQKBOHZ-HNNXBMFYSA-N Oc1cccc(OC[C@H](COCC2)N2C(c2ccccc2)=O)c1C=O Chemical compound Oc1cccc(OC[C@H](COCC2)N2C(c2ccccc2)=O)c1C=O SXAADVVBQKBOHZ-HNNXBMFYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/48—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Dermatology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pyrrole Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Pyridine Compounds (AREA)
- Pyrane Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
本發明提供適用作血紅素之調節劑的化合物及醫藥組合物,其製備之方法及中間物,及其用於治療由血紅素介導之病症及可因組織及/或細胞氧化而受益之病症的方法。
Description
本發明提供適用作血紅素之異位調節劑的化合物及醫藥組合物,其製備之方法及中間物,及其用於治療由血紅素介導之病症及可因組織及/或細胞氧化而受益之病症的方法。
鐮狀細胞病為一種紅血球病症,其尤其在具有非洲及地中海血統者中發現。鐮狀細胞病之原理存在於鐮狀血紅素(HbS)中,相對於血紅素(Hb)之普通肽序列其含有點突變。
血紅素(Hb)自肺輸送氧分子至身體之各種組織及器官。血紅素經由構形變化結合且釋放氧。鐮狀血紅素(HbS)含有點突變,其中麩胺酸經纈胺酸置換,從而使得HbS變得易於聚合而賦予含HbS紅血球其特徵性鐮刀形狀。鐮狀細胞亦比正常紅血球堅硬且其可撓性缺乏可造成血管阻塞。US 7,160,910揭示作為血紅素之異位調節劑的化合物。然而,需要可治療由Hb或異常Hb(諸如HbS)介導之病症的其他治療劑。
本發明大體上係關於適用作血紅素之異位調節劑的化合物及醫藥組合物。在一些態樣中,本發明係關於治療由血紅素介導之病症及可因組織及/或細胞氧化而受益之病症的方法。
或其互變異構體,或其各自醫藥學上可接受之鹽或其醫藥學上可接受之鹽,其中L1為一鍵或為NR70、O、S或(CR71R72)d;其中各R70、R71及R72獨立地為氫或C1-C6烷基;d為1、2或3;L2為C=O或SO2;各Y及Z獨立地為CR10R11、O、S、SO、SO2或NR10;各R10及R11獨立地為氫或視情況經1-3個鹵基、OH或C1-C6烷氧基取代之C1-C3烷基,或CR10R11為C=O,其限制條件為若Y及Z中之一者為O、S、SO、SO2,則另一者不為CO,且Y及Z均不為雜原子或其氧化形式;其中Y相對於-L1L2R3經α或β取代;其中Z及-CV1V2H連接於環C上之相鄰原子;V1及V2獨立地為C1-C6烷氧基;或V1及V2與其所連接之碳原子一起形成下式之環:
其中各V3及V4獨立地為O、S或NH,其限制條件為當V3及V4中之
一者為S時,另一者為NH,且其限制條件為V3及V4均不為NH;q為1或2;各V5獨立地為C1-C6烷基或CO2R60,其中各R60獨立地為C1-C6烷基或氫;t為0、1、2或4;或CV1V2為C=V,其中V為O、NOR80或NNR81R82;R80為視情況經取代之C1-C6烷基;R81及R82獨立地選自由以下組成之群:氫;視情況經取代之C1-C6烷基、COR83及CO2R84;R83為氫或視情況經取代之C1-C6烷基;且R84為視情況經取代之C1-C6烷基。
且R3、B及C如下所定義。
在一種情況下,R3為C1-C6烷基、C3-C8環烷基、C1-C6烷氧基、C3-C8環烷氧基或-NR1R2;各R1及R2獨立地為氫、C1-C6烷基、C3-C8環烷基、C6-C10芳基、4-10員雜環或5-10員雜芳基,其各自含有至多5個環雜原子,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群,其中各烷基、環烷基、雜環、芳基或雜芳基視情況經取代,或R1及R2與其所連接之氮原子一起形成視情況經取代之4-7員雜環;環B為視情況經取代之C6-C10芳基、具有1-3個氮原子或N之氧化形式的視情況經取代之5-10員雜芳基或含有至多5個環雜原子之視情況經取代之4-10員雜環,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群;且環C為視情況經取代之C6-C10芳基或含有1-3個氮原子或N之氧化形式的視情況經取代之5-10員雜芳基,其中某些較佳取代基包括OH、鹵基、C1-C6烷氧基、C3-C6環烷氧基或O-R,其中R為前藥部分,其中該C1-C6烷氧基視情況經1-5個鹵基取代。
在另一情況下,R3為C6-C10芳基或5-10員雜芳基,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群,其中該芳基或雜芳基各自視情況經1-4個C1-C6烷基取代;環B為含有至多5個環雜原子之視情況經取代之4-10員雜環,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群;環C為C6-C10芳基或含有至多5個環雜原子之5-10員雜芳基,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群,其各自視情況經1-4個如下基團取代:鹵基、側氧基、-OR19、C1-C6烷基及/或C1-C6烷氧基,其中該C1-C6烷基視情況經1-5個鹵基、C1-C6烷氧基及/或含有至多5個環雜原子之4-10員雜環取代,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群,其中某些較佳取代基包括OH、鹵基、C1-C6烷氧基、C3-C6環烷氧基或O-R,其中R為前藥部分,其中該C1-C6烷氧基視情況經1-5個鹵基取代;且R19為氫或前藥部分R。
或其互變異構體,或其各自醫藥學上可接受之鹽,其中R3為C1-C6烷基、C3-C8環烷基、C1-C6烷氧基、C3-C8環烷氧基或-NR1R2;
各R1及R2獨立地為氫、C1-C6烷基、C3-C8環烷基、C6-C10芳基、4-10員雜環或5-10員雜芳基,其各自含有至多5個環雜原子,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群,其中各烷基、環烷基、雜環、芳基或雜芳基視情況經取代,或R1及R2與其所連接之氮原子一起形成視情況經取代之4-7員雜環;L為一鍵或為NR70、O、S或(CR71R72)d;其中各R70、R71及R72獨立地為氫或C1-C6烷基;d為1、2或3;環B為視情況經取代之C6-C10芳基、具有1-3個氮原子或N之氧化形式的視情況經取代之5-10員雜芳基或含有至多5個環雜原子之視情況經取代之4-10員雜環,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群;各Y及Z獨立地為CR10R11、O、S、SO、SO2或NR10;各R10及R11獨立地為氫或視情況經1-3個鹵基、OH或C1-C6烷氧基取代之C1-C3烷基,或CR10R11為C=O,其限制條件為若Y及Z中之一者為O、S、SO、SO2,則另一者不為CO,且Y及Z均不為雜原子或其氧化形式;其中Y相對於-LCOR3經α或β取代;環C為視情況經取代之C6-C10芳基或含有1-3個氮原子或N之氧化形式的視情況經取代之5-10員雜芳基;其中Z及-CV1V2H連接於環C上之相鄰原子;V1及V2獨立地為C1-C6烷氧基;或V1及V2與其所連接之碳原子一起形成下式之環:
其中各V3及V4獨立地為O、S或NH,其限制條件為當V3及V4中之
一者為S時,另一者為NH,且其限制條件為V3及V4均不為NH;q為1或2;各V5獨立地為C1-C6烷基或CO2R60,其中各R60獨立地為C1-C6烷基或氫;t為0、1、2或4;或CV1V2為C=V,其中V為O、NOR80或NNR81R82;R4為OH、鹵基、C1-C6烷氧基、C3-C6環烷氧基或O-R,其中R為前藥部分,其中該C1-C6烷氧基視情況經1-5個鹵基取代;R80為視情況經取代之C1-C6烷基;R81及R82獨立地選自由以下組成之群:氫;視情況經取代之C1-C6烷基、COR83及CO2R84;R83為氫或視情況經取代之C1-C6烷基;且R84為視情況經取代之C1-C6烷基。
其中R3為C6-C10芳基或5-10員雜芳基,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群,其中該芳基或雜芳基各自視情況經1-4個C1-C6烷基取代;L1為一鍵或為NR70、O、S或(CR71R72)d;其中各R70、R71及R72獨立地為氫或C1-C6烷基;d為1、2或3;
L2為C=O或SO2;環B為含有至多5個環雜原子之視情況經取代之4-10員雜環,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群;各Y及Z獨立地為(CR10R11)e、O、S、SO、SO2或NR10;e為1至4,較佳為1;各R10及R11獨立地為氫或視情況經1-3個鹵基、OH或C1-C6烷氧基取代之C1-C3烷基,或CR10R11為C=O,其限制條件為若Y及Z中之一者為O、S、SO、SO2,則另一者不為CO,且Y及Z均不為雜原子或其氧化形式;其中Y相對於-L1L2R3經α或β取代;環C為C6-C10芳基或含有至多5個環雜原子之5-10員雜芳基,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群,其各自視情況經1-4個如下基團取代:鹵基、側氧基、-OR2、C1-C6烷基及/或C1-C6烷氧基,其中該C1-C6烷基視情況經1-5個鹵基、C1-C6烷氧基及/或含有至多5個環雜原子之4-10員雜環取代,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群;R2為氫或前藥部分R;且其中Z及-CV1V2H連接於環C上之相鄰原子;V1及V2獨立地為C1-C6烷氧基;或V1及V2與其所連接之碳原子一起形成下式之環:
其中各V3及V4獨立地為O、S或NH,其限制條件為當V3及V4中之一者為S時,另一者為NH,且其限制條件為V3及V4均不為NH;q為1或2;各V5獨立地為C1-C6烷基或CO2R60,其中各R60獨立地為C1-C6烷基或氫;t為0、1、2或4;或CV1V2為C=V,其中V為O、NOR80或
NNR81R82;R80為視情況經取代之C1-C6烷基;R81及R82獨立地選自由以下組成之群:氫;視情況經取代之C1-C6烷基、COR83及CO2R84;R83為氫或視情況經取代之C1-C6烷基;且R84為視情況經取代之C1-C6烷基。
在一個實施例中,環b經由氮原子連接於L1或L2。在另一實施例中,R3經由氮原子連接於L2。
在本發明之其他態樣中,提供一種組合物,其包含任何本文所述化合物及至少一種醫藥學上可接受之賦形劑。
在本發明之其他態樣中,提供一種提高個體之血紅素S之氧親和力的方法,該方法包括為有需要之個體投與治療有效量之任何本文所述化合物或組合物。
在本發明之其他態樣中,提供一種治療與鐮狀細胞貧血有關之缺氧的方法,該方法包括為有需要之個體投與治療有效量之任何本文所述化合物或組合物。
除非上下文另外明確規定,否則必須注意如本文及隨附申請專利範圍中所用之單數形式「一(a)」、「一(an)」及「該(the)」包括複數指示物。由此,例如,提及「溶劑」包括複數種該等溶劑。
如本文所用之術語「包含(comprising)」或「包含(comprise)」欲意謂組合物及方法包括所述要素,但不排除其他要素。出於所述目的,「基本上由...組成(Consisting essentially of)」在用於定義組合物
及方法時應意謂排除對組合具有任何必需顯著性之其他要素。由此,基本上由如本文所定義之要素組成的組合物或製程不排除不會實質上影響本發明所主張之基本及新穎特徵的其他物質或步驟。「由...組成(Consisting of)」應意謂排除超過痕量的具有其他成分及大量方法步驟的要素。由各此等轉換術語定義之實施例屬於本發明之範疇。
除非另外指明,否則本說明書及申請專利範圍中所用之表示成分數量、反應條件等之所有數字應理解為在所有情況下均由術語「約」修飾。因此,除非相反地指明,否則以下說明書及隨附申請專利範圍中所述之數值參數為近似值。各數值參數至少應根據所報導之有效數位之數字且藉由應用一般捨入技術來分析。術語「約」在用於數字標識(例如溫度、時間、量及濃度,包括範圍)前時表明近似值,其可變化(+)或(-)10%、5%或1%。
如本文所用之Cm-Cn(諸如C1-C12、C1-C8或C1-C6)在用於基團前時指此基團含有m至n個碳原子。
術語「烷氧基」指-O-烷基。環烷氧基係指-O-環烷基。
術語「烷基」指具有1至30個碳原子(亦即C1-C30烷基)或1至22個碳原子(C1-C22烷基)、1至8個碳原子(亦即C1-C8烷基)或1至4個碳原子之單價飽和脂族烴基。此術語包括例如直鏈及分支鏈烴基,諸如甲基(CH3-)、乙基(CH3CH2-)、正丙基(CH3CH2CH2-)、異丙基((CH3)2CH-)、正丁基(CH3CH2CH2CH2-)、異丁基((CH3)2CHCH2-)、第二丁基((CH3)(CH3CH2)CH-)、第三丁基((CH3)3C-)、正戊基(CH3CH2CH2CH2CH2-)及新戊基((CH3)3CCH2-)。
術語「-CO2H酯」指在-CO2H基團與醇、較佳脂族醇之間形成的酯。較佳實例包括-CO2RE,其中RE為視情況經胺基取代之烷基或芳基。
術語「對掌性部分」指具有對掌性之部分。該部分可具有一或多個不對稱中心。較佳地,對掌性部分經對映異構性增濃,且更佳為單一對映異構體。對掌性部分之非限制性實例包括對掌性羧酸、對掌性胺、對掌性胺基酸(諸如天然存在之胺基酸)、對掌性醇(包括對掌性類固醇)及其類似物。
術語「環烷基」指具有3-12個環碳原子之單價、較佳飽和烴基單、雙或三環。環烷基較佳指飽和烴基環,如本文所用,其亦包括含有1-2個碳-碳雙鍵之環。環烷基之非限制性實例包括環丙基、環丁基、環戊基、環己基、環庚基、金剛烷基及其類似基團。縮合環可能或可能不為非芳族烴基環,其限制條件為連接點位於環烷基碳原子處。舉例而言且非限制性地,以下為環烷基:
術語「鹵基」指F、Cl、Br及/或I。
術語「雜芳基」指具有2-16個環碳原子及1-8個較佳選自N、O、S及P以及N、S及P之氧化形式的環雜原子的單價芳族單、雙或三環,其限制條件為該環含有至少5個環原子。雜芳基之非限制性實例包括呋喃、咪唑、噁二唑、噁唑、吡啶、喹啉及其類似基團。縮合環可能或可能不為含有雜原子之芳族環,其限制條件為連接點為雜芳基原子。舉例而言且非限制性地,以下為雜芳基:
術語「雜環基」或雜環指含有2-12個環碳原子及1-8個較佳選自N、O、S及P以及N、S及P之氧化形式的環雜原子的非芳族單、雙或三環,其限制條件為該環含有至少3個環原子。雜環基較佳指飽和環系統,其亦包括含有1-3個雙鍵之環系統,其限制條件為該環為非芳族。雜環基之非限制性實例包括氮雜內酯、噁唑啉、哌啶基、哌嗪基、吡咯啶基、四氫呋喃基及四氫哌喃基。縮合環可能含有或可能不含非芳族含雜原子環,其限制條件為連接點為雜環基。舉例而言且非限制性地,以下為雜環基:
術語「水解」指使RH-O-CO-、RH-O-CS-或RH-O-SO2-部分斷裂成RH-OH,較佳藉由跨過斷裂之鍵添加水達成。水解使用熟習此項技術者熟知之各種方法進行,其非限制性實例包括酸性及鹼性水解。
術語「側氧基(oxo)」指C=O基團,且指用C=O基團取代2個偕位氫原子。
術語「視情況經取代」指經取代或未經取代之基團。該基團可經一或多個取代基(諸如1、2、3、4或5個取代基)取代。取代基較佳選自由以下組成之群:側氧基、鹵基、-CN、NO2、-N2+、-CO2R100、-OR100、-SR100、-SOR100、-SO2R100、-NR101R102、-CONR101R102、-SO2NR101R102、C1-C6烷基、C1-C6烷氧基、-CR100=C(R100)2、-CCR100、C3-C10環烷基、C3-C10雜環基、C6-C12芳基及C2-C12雜芳基,其中各R100獨立地為氫或C1-C8烷基;C3-C12環烷基;C3-C10雜環基;C6-C12芳基;或C2-C12雜芳基;其中各烷基、環烷
基、雜環基、芳基或雜芳基視情況經1-3個鹵基、1-3個C1-C6烷基、1-3個C1-C6鹵烷基或1-3個C1-C6烷氧基取代。取代基較佳選自由以下組成之群:氯、氟、-OCH3、甲基、乙基、異丙基、環丙基、乙烯基、乙炔基、-CO2H、-CO2CH3、-OCF3、-CF3及-OCHF2。
R101及R102獨立地為氫;C1-C8烷基,其視情況經以下取代:-CO2H或其酯、C1-C6烷氧基、側氧基、-CR103=C(R103)2、-CCR、C3-C10環烷基、C3-C10雜環基、C6-C12芳基或C2-C12雜芳基,其中各R103獨立地為氫或C1-C8烷基;C3-C12環烷基;C3-C10雜環基;C6-C12芳基;或C2-C12雜芳基;其中各環烷基、雜環基、芳基或雜芳基視情況經1-3個烷基或1-3個鹵基取代,或R101及R102與其所連接之氮原子一起形成5-7員雜環。
術語「醫藥學上可接受」指對於活體內、較佳人類投與安全且無毒。
術語「醫藥學上可接受之鹽」指在醫藥學上可接受的鹽。
術語「鹽」指酸與鹼之間形成之離子型化合物。當本文所提供之化合物含有酸性官能基時,該等鹽包括(但不限於)鹼金屬、鹼土金屬及銨鹽類。如本文所用之銨鹽包括含有質子化氮鹼及烷基化氮鹼之鹽。適用於醫藥學上可接受之鹽的例示性且非限制性陽離子包括Na、K、Rb、Cs、NH4、Ca、Ba、咪唑鎓及銨陽離子(基於天然存在之胺基酸)。當本文所用之化合物含有鹼性官能基時,該等鹽包括(但不限於)有機酸(諸如羧酸及磺酸)及無機酸(諸如鹵化氫、硫酸、磷酸及其類似物)之鹽。適用於醫藥學上可接受之鹽的例示性且非限制性陰離子包括草酸根、順丁烯二酸根、乙酸根、丙酸根、丁二酸根、酒石酸根、氯離子、硫酸根、硫酸氫根、單、二及三鹼價磷酸根、甲磺酸根、甲苯磺酸根及其類似陰離子。
如本文所用之術語「治療(treat)」、「治療(treating)」或「治療
(treatment)」包括緩和、減輕或改善疾病或病狀或其一或多種症狀,預防其他症狀,改善或預防症狀之基本代謝原因,抑制疾病或病狀,例如阻止或抑制疾病或病狀之發展,緩解疾病或病狀,使疾病或病狀消退,緩解由該疾病或病狀所致之病狀或抑制疾病或病狀之症狀,且意欲包括預防。該等術語亦包括緩解疾病或病狀,例如使臨床症狀消退。該等術語進一步包括達成治療效益及/或預防效益。治療效益意謂根除或改善所治療之基本病症。亦可在根除或改善一或多種與基本病症有關之生理學症狀以使得在個體中觀察到改良但個體仍患有該基本病症之情況下達成治療效益。對於預防效益,將組合物投與具有產生特定疾病之風險的個體或通報疾病之一或多種生理學症狀之個體,即使尚未進行此疾病之診斷。
術語「預防(preventing)」或「預防(prevention)」指降低罹患疾病或病症之風險(亦即使疾病之至少一種臨床症狀不會在可能暴露於或易感染該疾病但尚未經歷或顯示該疾病之症狀的個體中產生)。該等術語進一步包括使臨床症狀不會在例如:具有罹患該疾病或病症之風險的個體中產生,從而實質上避免疾病或病症之發作。
術語「有效量」指藉由鼻內投與本文所述化合物或組合物而有效治療病狀或病症的量。在一些實施例中,本文所述之組合物或劑型中之任一者的有效量為本文所述之組合物或劑型中之任一者用於治療有需要之個體的由血紅素介導之病症或可因組織及/或細胞氧化而受益之病症的量。
如本文所用之術語「載劑」指有助於將化合物併入細胞(例如紅血球)或組織中之相對無毒化合物或藥劑。
如本文所用之「前藥」為投與後代謝或轉化為關於至少一種特性之活性或更具活性形式的化合物。為製備前藥,可化學修飾醫藥學活性化合物以使其活性降低或無活性,但該化學修飾使得化合物之活
性形式可藉由代謝或其他生物過程產生。相對於藥物,前藥可具有改變之代謝穩定性或輸送特徵、較少副作用或較低毒性。舉例而言,參見參考文獻Nogrady,1985,Medicinal Chemistry A Biochemical Approach,Oxford University Press,New York,第388-392頁。前藥亦可使用非藥物之化合物製備。
或其互變異構體,或其各自醫藥學上可接受之鹽或其醫藥學上可接受之鹽,其中L1為一鍵或為NR70、O、S或(CR71R72)d;其中各R70、R71及R72獨立地為氫或C1-C6烷基;d為1、2或3;L2為C=O或SO2;各Y及Z獨立地為CR10R11、O、S、SO、SO2或NR10;各R10及R11獨立地為氫或視情況經1-3個鹵基、OH或C1-C6烷氧基取代之C1-C3烷基,或CR10R11為C=O,其限制條件為若Y及Z中之一者為O、S、SO、SO2,則另一者不為CO,且Y及Z均不為雜原子或其氧化形式;其中Y相對於-L1L2R3經α或β取代;其中Z及-CV1V2H連接於環C上之相鄰原子;
V1及V2獨立地為C1-C6烷氧基;或V1及V2與其所連接之碳原子一起形成下式之環:
其中各V3及V4獨立地為O、S或NH,其限制條件為當V3及V4中之一者為S時,另一者為NH,且其限制條件為V3及V4均不為NH;q為1或2;各V5獨立地為C1-C6烷基或CO2R60,其中各R60獨立地為C1-C6烷基或氫;t為0、1、2或4;或CV1V2為C=V,其中V為O、NOR80或NNR81R82;R4為OH、鹵基、C1-C6烷氧基、C3-C6環烷氧基或O-R,其中R為前藥部分,其中該C1-C6烷氧基視情況經1-5個鹵基取代;R80為視情況經取代之C1-C6烷基;R81及R82獨立地選自由以下組成之群:氫;視情況經取代之C1-C6烷基、COR83及CO2R84;R83為氫或視情況經取代之C1-C6烷基;且R84為視情況經取代之C1-C6烷基。
且R3、B及C如下所定義。
在一種情況下,R3為C1-C6烷基、C3-C8環烷基、C1-C6烷氧基、C3-C8環烷氧基或-NR1R2;各R1及R2獨立地為氫、C1-C6烷基、C3-C8環烷基、C6-C10芳基、4-10員雜環或5-10員雜芳基,其各自含有至多5個環雜原子,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群,其中各烷基、環烷基、雜環、芳基或雜芳基視情況經取代,或R1及R2與其所連接之氮原子一起形成視情況經取代之4-7員雜環;
環B為視情況經取代之C6-C10芳基、具有1-3個氮原子或N之氧化形式的視情況經取代之5-10員雜芳基或含有至多5個環雜原子之視情況經取代之4-10員雜環,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群;且環C為視情況經取代之C6-C10芳基或含有1-3個氮原子或N之氧化形式的視情況經取代之5-10員雜芳基;在另一情況下,R3為C6-C10芳基或5-10員雜芳基,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群,其中該芳基或雜芳基各自視情況經1-4個C1-C6烷基取代;環B為含有至多5個環雜原子之視情況經取代之4-10員雜環,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群;環C為C6-C10芳基或含有至多5個環雜原子之5-10員雜芳基,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群,其各自視情況經1-4個如下基團取代:鹵基、側氧基、-OR19、C1-C6烷基及/或C1-C6烷氧基,其中該C1-C6烷基視情況經1-5個鹵基、C1-C6烷氧基及/或含有至多5個環雜原子之4-10員雜環取代,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群;且R19為氫或前藥部分R。
在某些實施例中,L1為一鍵。
在某些實施例中,L2為C=O。在某些實施例中,L2為SO2。
在一個實施例中,環C為視情況經1-4個如下基團取代之苯基:鹵基、側氧基、-OR2、C1-C6烷基及/或C1-C6烷氧基。
或其互變異構體,或其各自醫藥學上可接受之鹽或其醫藥學上可接受之鹽,其中R3為C1-C6烷基、C3-C8環烷基、C1-C6烷氧基、C3-C8環烷氧基或-NR1R2;各R1及R2獨立地為氫、C1-C6烷基、C3-C8環烷基、C6-C10芳基、4-10員雜環或5-10員雜芳基,其各自含有至多5個環雜原子,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群,其中各烷基、環烷基、雜環、芳基或雜芳基視情況經取代,或R1及R2與其所連接之氮原子一起形成視情況經取代之4-7員雜環;L1為一鍵或為NR70、O、S或(CR71R72)d;其中各R70、R71及R72獨立地為氫或C1-C6烷基;d為1、2或3;環B為視情況經取代之C6-C10芳基、具有1-3個氮原子或N之氧化形式的視情況經取代之5-10員雜芳基或含有至多5個環雜原子之視情況經取代之4-10員雜環,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群;各Y及Z獨立地為CR10R11、O、S、SO、SO2或NR10;各R10及R11獨立地為氫或視情況經1-3個鹵基、OH或C1-C6烷氧基取代之C1-C3烷基,或CR10R11為C=O,其限制條件為若Y及Z中之一者為O、S、SO、
SO2,則另一者不為CO,且Y及Z均不為雜原子或其氧化形式;其中Y相對於-LCOR3經α或β取代;環C為視情況經取代之C6-C10芳基或含有1-3個氮原子或N之氧化形式的視情況經取代之5-10員雜芳基;其中Z及-CV1V2H連接於環C上之相鄰原子;V1及V2獨立地為C1-C6烷氧基;或V1及V2與其所連接之碳原子一起形成下式之環:
其中各V3及V4獨立地為O、S或NH,其限制條件為當V3及V4中之一者為S時,另一者為NH,且其限制條件為V3及V4均不為NH;q為1或2;各V5獨立地為C1-C6烷基或CO2R60,其中各R60獨立地為C1-C6烷基或氫;t為0、1、2或4;或CV1V2為C=V,其中V為O、NOR80或NNR81R82;R4為OH、鹵基、C1-C6烷氧基、C3-C6環烷氧基或O-R,其中R為前藥部分,其中該C1-C6烷氧基視情況經1-5個鹵基取代;R80為視情況經取代之C1-C6烷基;R81及R82獨立地選自由以下組成之群:氫;視情況經取代之C1-C6烷基、COR83及CO2R84;R83為氫或視情況經取代之C1-C6烷基;且R84為視情況經取代之C1-C6烷基。
在某些實施例中,t為0。在某些實施例中,t為1。在某些實施例中,t為2。在某些實施例中,t為3。
如本文所用之R60可為氫,其限制條件為COOR60不連接於氮原子。
較佳地,在某些實施例中,Y及Z均不為雜原子或含有雜原子之部分。較佳地,Y及Z中之一者為亞甲基或經取代之亞甲基且另一者為雜原子或含有雜原子之部分。更佳地,Y為伸烷基,且Z為雜原子或含有雜原子之部分,其更佳為氧。
其中各V3及V4獨立地為O、S或NH,其限制條件為當V3及V4中之一者為S時,另一者為NH,且其限制條件為V3及V4均不為NH;q為1或2;各V5獨立地為C1-C6烷基或CO2R60,其中各R60獨立地為C1-C6烷基或氫;t為0、1、2或4;或CV1V2為C=V,其中V為O。
其中Y-Z為-CH2O-或-CH2CH2-,且其餘取代基如本文所定義。
在一些實施例中,R4及-CHO連接於環C上之相鄰原子。
在本發明之某些態樣中,式(II)化合物具有式(IIIA):
其中環B為視情況經取代之C6-C10芳基、具有1-3個氮原子或N之氧化形式的視情況經取代之5-10員雜芳基;R5為氫、C1-C6烷基或前藥部分R;R6為鹵基、C1-C6烷基、C3-C6環烷基、C1-C6烷氧基、C3-C6環烷氧基,其中該C1-C6烷基視情況經1-5個鹵基取代;且p為0、1、2或3。
在一些實施例中,化合物具有式IIIB、IIIC或IIID:
其中
、及為如本文所定義之視情況經取代之4-10員雜環;R5為氫、C1-C6烷基或前藥部分;R6為鹵基、C1-C6烷基、C1-C6烷氧基,其中該C1-C6烷基視情況經1-5個鹵基取代;且p為0、1、2或3。
在一些實施例中,環B經1-3個如下基團取代:鹵基、C1-C6烷基、COR15或COOR15;且R15為C1-C6烷基、C3-C6環烷基、C6-C10芳基、含有至多5個環雜原子之5-10員雜芳基或4-10員雜環,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群,其中該烷基、芳基、雜芳基或雜環基視情況經取代。
或其互變異構體,或其各自醫藥學上可接受之鹽,其中R3為C6-C10芳基或5-10員雜芳基,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群,其中該芳基或雜芳基各自視情況經1-4個C1-C6烷基取代;L1為一鍵或為NR70、O、S或(CR71R72)d;其中各R70、R71及R72獨立地為氫或C1-C6烷基;d為1、2或3;L2為C=O或SO2;環B為含有至多5個環雜原子之視情況經取代之4-10員雜環,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群;各Y及Z獨立地為CR10R11、O、S、SO、SO2或NR10;各R10及R11獨立地為氫或視情況經1-3個鹵基、OH或C1-C6烷氧基取代之C1-C3烷基,或CR10R11為C=O,其限制條件為若Y及Z中之一者為O、S、SO、SO2,則另一者不為CO,且Y及Z均不為雜原子或其氧化形式;其中Y相對於-L1L2R1經α或β取代;環C為C6-C10芳基或含有至多5個環雜原子之5-10員雜芳基,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群,其各自視情況經1-4個如下基團取代:鹵基、側氧基、-OR19、C1-C6烷基及/或C1-C6烷氧基,其中該C1-C6烷基視情況經1-5個鹵基、C1-C6烷氧基及/
或含有至多5個環雜原子之4-10員雜環取代,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群;R19為氫或前藥部分R;且其中Z及-CV1V2H連接於環C上之相鄰原子;V1及V2獨立地為C1-C6烷氧基;或V1及V2與其所連接之碳原子一起形成下式之環:
其中各V3及V4獨立地為O、S或NH,其限制條件為當V3及V4中之一者為S時,另一者為NH,且其限制條件為V3及V4均不為NH;q為1或2;各V5獨立地為C1-C6烷基或CO2R60,其中各R60獨立地為C1-C6烷基或氫;t為0、1、2或4;或CV1V2為C=V,其中V為O、NOR80或NNR81R82;R80為視情況經取代之C1-C6烷基;R81及R82獨立地選自由以下組成之群:氫;視情況經取代之C1-C6烷基、COR83及CO2R84;R83為氫或視情況經取代之C1-C6烷基;且R84為視情況經取代之C1-C6烷基。
在某些實施例中,Z為CH2、O、S、SO、SO2或NH。在某些實施例中,Z為O、S、S或SO2。Z較佳為O,且其中其餘變數如本文所定義。
在某些實施例中,Y為CR10R11、O、S、SO、SO2或NR10;其中各R10及R11獨立地為氫或C1-C3烷基。在某些實施例中,Y為CR10R11,其中各R10及R11獨立地為氫或C1-C3烷基。Y較佳為CH2,且其中其餘變數如本文所定義。
在某些實施例中,t為0。在某些實施例中,t為1。在某些實施例中,t為2。在某些實施例中,t為3。
CV1V2較佳為C=V,其中V為O,且其中其餘變數如本文所定義。
或其互變異構體,或其各自醫藥學上可接受之鹽,其中R3為C6-C10芳基或5-10員雜芳基,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群,其中該芳基或雜芳基各自視情況經1-4個C1-C6烷基取代;L1為一鍵或為NR70、O、S或(CR71R72)d;其中各R70、R71及R72獨立地為氫或C1-C6烷基;d為1、2或3;L2為C=O或SO2;環B為含有至多5個環雜原子之視情況經取代之4-10員雜環,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群;Z為O、S、SO或SO2;環C為C6-C10芳基或含有至多5個環雜原子之5-10員雜芳基,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群,其各自視情況經1-4個如下基團取代:鹵基、側氧基、-OR19、C1-C6烷基及/或
C1-C6烷氧基,其中該C1-C6烷基視情況經1-5個鹵基、C1-C6烷氧基及/或含有至多5個環雜原子之4-10員雜環取代,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群;且R19為氫或前藥部分R。
或其互變異構體,或其各自醫藥學上可接受之鹽,其中R3為C6-C10芳基或5-10員雜芳基,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群,其中該芳基或雜芳基各自視情況經1-4個C1-C6烷基取代;L1為一鍵或為NR70、O、S或(CR71R72)d;其中各R70、R71及R72獨立地為氫或C1-C6烷基;d為1、2或3;L2為C=O或SO2;環B為含有至多5個環雜原子之視情況經取代之4-10員雜環,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群;R4為-OR19或C1-C6烷氧基;且R19為氫或前藥部分R。
在一個實施例中,R4為-OH。
在某些實施例中,R3為視情況經取代之苯基。在其他實施例中,R3為視情況經取代之吡啶。在某些實施例中,R3為視情況經取代之吡唑。
在一個實施例中,環B為含有選自N、S或O之雜原子的5-6員雜環。在一個實施例中,環B為含有N作為雜原子之5-6員雜環。
在某些實施例中,L1為一鍵。
在某些實施例中,L2為C=O。在某些實施例中,L2為SO2。
在一個實施例中,環C為視情況經1-4個如下基團取代之苯基:鹵基、側氧基、-OR2、C1-C6烷基及/或C1-C6烷氧基。
在一些實施例中,化合物選自由以下組成之群:
或其N氧化物,其中
為單鍵或雙鍵;各P及Q獨立地選自CHR17、NCOR15、NCO2R15;N-O、O、S、SO及SO2;各R1及R2獨立地為氫、C1-C6烷基、C6-C10芳基、含有至多5個環雜原子之5-10員雜芳基或4-10員雜環,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群,其中該烷基、芳基、雜芳基或雜環基視情況經取代,R1及R2可一起形成3-7員環、較佳具有1-2個雜原子之4-7員環;R15為C1-C6烷基、C6-C10芳基、含有至多5個環雜原子之5-10員雜
芳基或4-10員雜環,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群,其中該烷基、芳基、雜芳基或雜環基視情況經取代;R17為C1-C6烷基、C6-C10芳基、含有至多5個環雜原子之5-10員雜芳基或4-10員雜環,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群,其中該烷基、芳基、雜芳基或雜環基視情況經取代;且r為0、1或2。
或其N氧化物,或其各自醫藥學上可接受之鹽。
或其N氧化物,或其各自醫藥學上可接受之鹽。
本文所提供之化合物包括實例部分中之化合物。
在一個態樣中,R為氫、含磷酸酯或二磷酸酯部分或另一前體部分或前藥部分。前藥部分較佳賦予活性部分(其中R為氫)之至少2倍、更佳4倍溶解性及/或生物利用率,且更佳在活體內水解。前體部分如本文在結構及官能性上進行定義。
在一個實施例中,R為-COR90、CO2R91或CONR92R93,其中R90及R91獨立地為C1-C6烷基、C3-C8環烷基、各自含有至少1個鹼性氮部分之4-9員雜環或5-10員雜芳基;且R92及R93獨立地為C1-C6烷基;C3-C8環烷基、各自含有至少1個鹼性氮部分之4-9員雜環或5-10員雜芳基;或R92及R93與其所鍵結之氮原子一起形成經至少1個胺基、C1-C6烷基胺基或二C1-C6烷基胺基取代之4-9員雜環。
在某些實施例中,R為-C(O)R31、C(O)OR31或CON(R13)2,各R31獨立地為C1-C6烷基;C3-C8環烷基、含有至少1個鹼性氮部分之4-9員雜環或5-10員雜芳基;且各R13獨立地為C1-C6烷基;C3-C8環烷基、含有至少1個鹼性氮部分之4-9員雜環或5-10員雜芳基;或2個R13與其所鍵結之氮原子一起形成經至少1個胺基、C1-C6烷基胺基或二C1-C6烷基胺基取代之4-9員雜環。
在一個態樣中,R為C(O)OR31、C(S)OR31、C(O)SR31或COR31,其中R31如本文所定義。
在一個實施例中,R31為式(CR32R33)eNR34R35之基團,其中各R32及R33獨立地為H、C1-C8烷基、C3-C9雜環基、C3-C8環烷基、C6-C10芳基、C3-C9雜芳基,或R32及R33與其所鍵結之碳原子一起
形成C3-C8環烷基、C6-C10芳基、C3-C9雜環基或C3-C9雜芳基環系統,或2個相鄰R32部分或2個相鄰R33部分與其所鍵結之碳原子一起形成C3-C8環烷基、C6-C10芳基、C3-C9雜環基或C3-C9雜芳基環系統;各R34及R35為C1-C8烷基、C3-C9雜環基、C3-C8環烷基,或R34及R35與其所鍵結之氮原子一起形成C3-C8環烷基或C3-C9雜環基環系統;各雜環及雜芳基環系統視情況經C1-C3烷基、-OH、胺基及羧基取代;且e為1至4之整數。
在一些次佳實施例中,R34及R35可為氫。
在一個實施例中,下標e較佳為2,且各R32及R33較佳獨立地選自基團H、CH3及如下成員,其中R32及R33連接在一起形成環丙基、環丁基、環戊基、環己基或1,1-二側氧基-六氫-1△6-硫哌喃-4-基或四氫哌喃-4-基。
關於前藥基團,較佳實施例為NR34R35為嗎啉基之化合物。
其中各R32及R33獨立地為H、C1-C8烷基,或視情況,若兩者均存在於同一取代基上,則可連接在一起形成C3-C8環烷基、C6-C10芳基、C3-C9雜環基或C3-C9雜芳基環系統。
在此實施例中,各R32及R33較佳獨立地為H、CH3,或連接在一起形成環丙基、環丁基、環戊基、環己基、1,1-二側氧基-六氫-1λ6-硫哌喃-4-基或四氫哌喃-4-基。
在一較佳實施例中,前藥部分與活性分子之其餘部分的鍵足夠穩定以使前藥之血清半衰期為約8至約24小時。
在本發明之一實施例中,前藥部分包含pKa接近7.5之生理學pH的三級胺。出於此目的,pKa在7.5之1個單位內的任何胺為適合替代性胺。該胺可由嗎啉基之胺提供。此6.5至8.5之pKa範圍使得高濃度之基本中性胺可存在於微鹼性小腸中。胺前藥之基本中性形式具有親脂性且經由小腸壁吸收至血液中。吸收至血流中後,前藥部分由天然存在於血清中之酯酶裂解而釋放活性化合物。
其N氧化物,或其各自醫藥學上可接受之鹽。
其中R36為低碳烷基(例如C1-C6烷基)。
其中X1、Y1及X2如本文所定義。
在一個實施例中,X1選自由O、S及NR37組成之群,其中R37為氫或C1-C6烷基;Y1為-C(R38)2或糖部分,其中各R38獨立地為氫或C1-C6烷基、C3-C8環烷基、C3-C9雜環基、C6-C10芳基或C3-C9雜芳基;X2選自由以下組成之群:鹵素、C1-C6烷氧基、二醯基甘油、胺
基、C1-C6烷基胺基、C1-C6二烷基胺基、C1-C6烷基硫基、PEG部分、膽汁酸部分、糖部分、胺基酸部分、二肽或三肽、PEG羧酸及-U-V,其中U為或S;且V選自由以下組成之群:C1-C6烷基、C3-C8環烷基、C3-C9雜環基、C6-C10芳基、C3-C9雜芳基、C(W2)X3、PO(X3)2及SO2X3;其中W2為或NR39其中R39為氫或C1-C6烷基、C3-C8環烷基、C3-C9雜環基、C6-C10芳基或C3-C9雜芳基;且各X3獨立地為胺基、羥基、巰基、C1-C6烷基、雜烷基、環烷基、雜環基、芳基或雜芳基、C1-C6烷氧基、C1-C6烷基胺基、C1-C6二烷基胺基、C1-C6烷基硫基、基於膽汁酸之烷氧基、糖部分、PEG部分及-O-CH2-CH(OR40)CH2X4R40,其中:X4選自由O、S、S=O及SO2組成之群;且各R40獨立地為C10-C22烷基、C3-C8環烷基、C3-C9雜環基、C6-C10芳基或C3-C9雜芳基、C1-C8伸烷基或C1-C8伸雜烷基。
各雜環及雜芳基環系統視情況經C1-C3烷基、-OH、胺基及羧基取代。
在一個實施例中,本發明使用以下Y1基團:CH2、CHMe、CH(異丙基)、CH(第三丁基)、C(Me)2、C(Et)2、C(異丙基)2及C(丙基)2。
-OMe、-OEt、-O-異丙基、O-異丁基、O-第三丁基、-O-COMe、-O-C(=O)(異丙基)、-O-C(=O)(異丁基)、-O-C(=O)(第三丁基)、-O-C(=O)-NMe2、-O-C(=O)-NHMe、-O-C(=O)-NH2、-O-C(=O)-N(H)-CH(R41)-CO2Et,其中R41為側鏈C1-C6烷基或選自必需胺基酸中所存在之側鏈基團的C3-C9雜環基;-O-P(=O)(OMe)2、-O-P(=O)(O-異丙基)2及-O-P(=O)(O-異丁基)2。各雜環視情況經一或多個、較佳1-3個C1-C3烷基、-OH、胺基及/或羧基取代。
其中X3獨立地為C1-C6烷基、C3-C8環烷基、C3-C9雜環基、C6-C10芳基或C3-C9雜芳基;且R42獨立地為氫或C1-C6烷基、C3-C8環烷基、C3-C9雜環基、C6-C10芳基或C3-C9雜芳基。
各雜環視情況經一或多個、較佳1-3個C1-C3烷基、-OH、胺基及/或羧基取代。
其中各X3獨立地為胺基、羥基、巰基、C1-C6烷基、C3-C8環烷基、C3-C9雜環基、C6-C10芳基或C3-C9雜芳基、C1-C6烷氧基、C1-C6烷基胺基、C1-C6二烷基胺基、C1-C6烷基硫基、基於膽汁酸之烷氧基、糖部分、PEG部分及-O-CH2-CH(OR40)CH2X4R40,其中:X4選自由O、S、S=O及SO2組成之群;且各R40獨立地為C10-C22烷基、C3-C8環烷基、C3-C9雜環基、C6-C10芳基或C3-C9雜芳基、C1-C8伸烷基或C1-C8伸雜烷基;且R42獨立地為氫或C1-C6烷基、C3-C8環烷基、C3-C9雜環基、C6-C10芳基或C3-C9雜芳基。
在一些實施例中,R42獨立地為氫或C1-C6烷基、C3-C8環烷基、C3-C9雜環基、C6-C10芳基或C3-C9雜芳基;且各X3獨立地為C1-C6烷基、C3-C8環烷基、C3-C9雜環基、C6-C10芳基或C3-C9雜芳基、C1-C6烷氧基、C1-C6烷基胺基、C1-C6二烷基胺基或C1-C6烷基硫基。
其中R46為(CH2)n,n=2-4,R47為(CH2)n,n=1-3且R49為或NMe。
在一個態樣中,R為-C(R200R201)O(R202R203)P(O)OR204NR205R206,
其中各R200、R201、R202、R203、R204、R205及R206獨立地為H、C1-C8烷基、C3-C9雜環基、C3-C8環烷基、C6-C10芳基、C3-C9雜芳基,其中各烷基、雜環基、環烷基、芳基及雜芳基視情況經取代。
在一些實施例中,R為-CH(R201)OCH2P(O)OR204NHR206,其中R201為C1-C8烷基,R204為苯基,其視情況經取代。在一個實施例中,R206為-CHR207C(O)OR208,其中R207選自由天然存在胺基酸側鏈及其CO2H酯組成之群,且R208為C1-C8烷基。在一個實施例中,R206為C1-C6烷基,其視情況經1-3個CO2H、SH、NH2、C6-C10芳基及C2-C10雜芳基取代。
其中Y1為-C(R38)2,其中各R38獨立地為氫或C1-C6烷基、C3-C8環烷基、C3-C9雜環基、C6-C10芳基或C3-C9雜芳基。
可用於或適用於製備本發明化合物之各種聚乙二醇(PEG)部分及其相關合成方法描述於美國專利第6,608,076號;第6,395,266號;第6,194,580號;第6,153,655號;第6,127,355號;第6,111,107號;第5,965,566號;第5,880,131號;第5,840,900號;第6,011,042號;及第5,681,567號中。
其中R50為-OH或氫;R51為-OH或氫;W為-CH(CH3)W1;其中W1為經取代之C1-C8烷基,其含有在生理學pH下視情況帶負電之部分,該部分選自由以下組成之群:CO2H、SO3H、SO2H、-P(O)(OR52)(OH)、-OP(O)(OR52)(OH)及OSO3H,其中R52為C1-C6烷基、C3-C8環烷基、C3-C9雜環基、C6-C10芳基或C3-C9雜芳基。
各雜環及/或雜芳基環系統視情況經一或多個、較佳1-3個C1-C3烷基、-OH、胺基及/或羧基取代。
其中R53為H或C1-C6烷基。
在另一態樣中,R為SO3H。
在另一態樣中,R包含可裂解連接基團,其中術語「可裂解連接基團」指在活體內具有短半衰期之連接基團。化合物中連接基團Z分解釋放或產生活性化合物。在一個實施例中,可裂解連接基團之半衰期小於十小時。在一個實施例中,可裂解連接基團之半衰期小於一小時。在一個實施例中,可裂解連接基團之半衰期為一分鐘至十五分鐘。在一個實施例中,可裂解連接基團具有至少一個具有如下結構之連接基:C*-C(=X*)X*-C*,其中C*為經取代或未經取代之亞甲基,且X*為S或O。在一個實施例中,可裂解連接基團具有至少一個C*-C(=O)O-C*連接基。在一個實施例中,可裂解連接基團具有至少一個C*-C(=O)S-C*連接基。在一個實施例中,可裂解連接基團具有至少一個-C(=O)N*-C*-SO2-N*-連接基,其中N*為-NH-或C1-C6烷基胺基。在一個實施例中,可裂解連接基團由酯酶水解。
在一個實施例中,連接基團為自犧牲連接基團,諸如Firestone之美國專利公開案2002/0147138;PCT申請案第US05/08161號及PCT公開案第2004/087075號中所揭示。在另一實施例中,連接基團為酶之受質。一般參見Rooseboom等人,2004,Pharmacol.Rev.56:53-102。
在本發明之另一態樣中,提供一種組合物,其包含任何本文所述化合物及至少一種醫藥學上可接受之賦形劑。
在另一態樣中,本發明提供一種組合物,其包含任何本文所述化合物及醫藥學上可接受之賦形劑。
該等組合物可經調配以用於不同投藥途徑。儘管適用於經口傳遞之組合物可能最常使用,但亦可使用其他途徑,包括經皮、靜脈內、動脈內、經肺、經直腸、經鼻、經陰道、經舌、肌肉內、腹膜內、皮內、顱內及皮下途徑。用於投與任何本文所述化合物之適合劑型包括錠劑、膠囊、丸劑、粉末、氣霧劑、栓劑、非經腸藥劑及口服液(包括懸浮液、溶液及乳液)。亦可例如以經皮貼片形式使用持續釋放劑型。所有劑型均可使用此項技術中之標準方法製備(參見例如Remington's Pharmaceutical Sciences,第16版,A.Oslo編輯,Easton Pa.1980)。
醫藥學上可接受之賦形劑無毒,輔助投藥且不會不利地影響本發明化合物之治療效益。該等賦形劑可為熟習此項技術者一般可獲得之任何固體、液體、半固體或氣體賦形劑(用在氣霧劑組合物情況下)。本發明之醫藥組合物藉由習知方式使用此項技術中已知之方法製備。
本文所揭示之組合物可與醫藥製劑中常用之任何媒劑及賦形劑結合使用,例如滑石、阿拉伯膠、乳糖、澱粉、硬脂酸鎂、可可脂、水性或非水性溶劑、油類、烷烴衍生物、二醇類,等。著色劑及調味
劑亦可添加於製劑中,尤其用於經口投與之製劑中。溶液可使用水或生理學上相容之有機溶劑(諸如乙醇、1,2-丙二醇、聚乙二醇、二甲亞碸、脂肪醇、三酸甘油酯、甘油之偏酯及其類似物)製備。
固體醫藥賦形劑包括澱粉、纖維素、羥基丙基纖維素、滑石、葡萄糖、乳糖、蔗糖、明膠、麥芽、稻米、麵粉、白堊、矽膠、硬脂酸鎂、硬脂酸鈉、單硬脂酸甘油酯、氯化鈉、脫脂奶粉及其類似物。液體及半固體賦形劑可選自甘油、丙二醇、水、乙醇及各種油,包括彼等源於石油、動物、植物或合成之油,例如花生油、大豆油、礦物油、芝麻油等。在某些實施例中,本文所提供之組合物包含α-生育酚、阿拉伯膠及/或羥基丙基纖維素中之一或多者。
在一個實施例中,本發明提供持續釋放調配物,諸如包含有效量之本文所提供化合物之藥物儲槽或貼片。在另一實施例中,貼片進一步在α-生育酚存在下以各別或組合方式包含阿拉伯膠或羥基丙基纖維素。羥基丙基纖維素較佳具有10,000至100,000之平均MW。在一更佳實施例中,羥基丙基纖維素具有5,000至50,000之平均MW。
本發明之化合物及醫藥組合物可以單獨使用或與其他化合物組合使用。當與另一藥劑一起投與時,共同投藥法可為使兩者之藥理學作用在患者中同時表現之任何方式。由此,共同投藥法無需使用單一醫藥組合物、相同劑型或甚至相同投藥途徑投與本發明化合物與另一藥劑,或無需精確同時地投與兩種藥劑。然而,共同投藥法最方便採用相同劑型及相同投藥途徑實質上同時完成。顯然,該投藥法最宜藉由在本發明之新穎醫藥組合物中同時傳遞兩種活性成分進行。
在本發明之態樣中,提供一種提高組織及/或細胞氧化之方法,該方法包括為有需要之個體投與治療有效量之任何本文所述化合物或組合物。
在本發明之態樣中,提供一種提高個體之血紅素S之氧親和力的方法,該方法包括為有需要之個體投與治療有效量之任何本文所述化合物或組合物。
在本發明之態樣中,提供治療與缺氧有關之病狀的方法,該方法包括為有需要之個體投與治療有效量之任何本文所述化合物或組合物。
在本發明之其他態樣中,提供一種治療與鐮狀細胞貧血有關之缺氧的方法,該方法包括為有需要之個體投與治療有效量之任何本文所述化合物或組合物。
在本發明之其他態樣中,提供治療鐮狀細胞病之方法,該方法包括為有需要之個體投與治療有效量之任何本文所述化合物或組合物。在本發明之其他態樣中,提供一種治療癌症、肺病、中風、高原病、潰瘍、褥瘡、阿茲海默氏病(Alzheimer's disease)、急性呼吸病症候群及創傷之方法,該方法包括為有需要之個體投與治療有效量之任何本文所述化合物或組合物。
亦提供製備本文所述化合物之某些方法。該等反應較佳在熟習此項技術者在閱讀本發明後顯然了解之合適惰性溶劑中執行足夠時間期,直到由薄層層析、1H-NMR等所觀察確保反應實質上已完成。若需要加速反應,則可如熟習此項技術者所熟知加熱反應混合物。如熟習此項技術者在閱讀本發明後顯然了解,最終及中間化合物必要時藉由相關技術已知方法純化,諸如結晶、沈澱、管柱層析及其類似方法。
下文以流程展示合成式(I)化合物之說明性及非限制性方法。
L、R3及R70如本文所述;A5及B5獨立地為NR14、O、S、S(O)x、NBoC、CH2、CHR14、C(R14)2,其限制條件為當A5與B5均存在於環中時,其均不為CH2、CHR14、C(R14)2,且若僅單個A5或B5存在於環中,則該A5或B5不為CH2、CHR14、C(R14)2;R14為C1-C6烷基、COR15或COOR15;其中R15為視情況經取代之C1-C6烷基、視情況經取代之C6-C10芳基、含有至多5固環雜原子之視情況經取代之5-10員雜芳基或含有至多5個環雜原子之視情況經取代之4-10員雜環,其中該雜原子選自由O、N、S、及N與S之氧化形式組成之群;X及X5各表示離去基且獨立地選自Cl、Br及I。
X6表示CR、N、O、S(O)x;其中x為0、1或2;Y5表示選自Cl、F、Br、I、OSO2R17及OSO2Ar之離去基;R71為C1-C6烷基;Ar為視情況經1-3個鹵基及/或C1-C4烷基取代之苯基;n為0、1或2。
若流程中使用已用於上文結構中之變數,則上下文將使該變數所指明確。
自經取代之亞甲基醇(1)及羥基(雜)芳基醛衍生物(3a/3b)製備芳氧基/雜芳基醚類似物(4a/4b)的通用方法A。在氮氣下攪拌羥基(雜)芳基醛衍生物(3a/3b)(0.1-2mmol)與經取代之亞甲基醇(1)(0.8至1.2eq)及PPh3(1-1.5eq)於無水THF(1-10mL)中之混合物直至完全溶解。在冰浴上冷卻溶液至0℃且經1-20分鐘之時間期逐滴添加DIAD或DEAD(1.1eq)於THF或甲苯中之溶液。經過90分鐘時,停止使用冰浴冷卻且在室溫下攪拌混合物2-48小時。攪拌混合物10分鐘,隨後經由二氧化矽填料過濾。用乙酸乙酯(2-20mL)洗滌二氧化矽。蒸發經合併之濾液且高真空下乾燥殘餘物。藉由製備型HPLC或急驟矽膠層析純化殘餘物。
自經取代之二鹵甲烷(2)及羥基(雜)芳基醛衍生物(3a/3b)製備芳氧基/雜芳基醚類似物(4a/4b)的通用方法B。在室溫下或加熱至120℃下,在氮氣氛圍下攪拌羥基(雜)芳基醛衍生物(3a/3b)(0.1-2mmol,1-4eq.)、經取代之二氯甲烷或二溴甲烷(2)(1eq)及K2CO3(2-5eq)(亦可添加催化量之NaI或Bu4NI)於DMF或乙腈(1至10mL)中之混合物0.5-8小時。在操作法A中,向反應混合物中添加水,收集沈澱之產物,用
水洗滌,隨後進行製備型HPLC或急驟矽膠層析純化。在操作法B(針對不沈澱之產物)中,在0℃下添加稀鹽酸或NH4Cl水溶液以調整pH值至約7,使反應混合物分配於乙酸乙酯或二氯甲烷與氯化鈉水溶液之間且分離有機層,乾燥且在真空下移除溶劑,得到粗產物,藉由自動矽膠管柱層析使用適當溶劑混合物(例如乙酸乙酯/己烷)純化。
製備經取代之二氯甲烷(2a)之通用方法C。在0℃或室溫下向經取代之亞甲基醇(1)(0.1至2mmol)於DCM(1-10mL)中之溶液中逐滴添加SOCl2(2eq至5eq)。在室溫下攪拌反應混合物10分鐘至6小時或直至判定反應完成為止(LC/MS)。經旋轉蒸發儀濃縮反應混合物至乾。將粗製氯化物殘餘物懸浮於甲苯中,音波處理且濃縮至乾。重複該製程三次且在真空下乾燥,得到通常呈灰白色固體狀之經取代之二氯甲烷(2),其不經進一步純化即用於下一步驟。或者,隨後添加1N Na2CO3水溶液,得到pH值約8之溶液。用DCM(3×10-50mL)萃取混合物,經硫酸鈉乾燥且濃縮,得到粗製之經取代之二氯甲烷(2a),隨後藉由矽膠管柱層析(0-100%乙酸乙酯-己烷)純化。
製備經取代之二溴甲烷(2b)的通用方法D。在0℃或室溫下向經取代之亞甲基醇(1)(0.1至2mmol)於DCM(1-10mL)中之溶液中逐滴添加Ph3P Br2(2eq至5eq)。在室溫下攪拌反應混合物10分鐘至2小時或直至判定反應完成為止(LC/MS)。經旋轉蒸發儀濃縮反應混合物至乾。藉由矽膠管柱層析(0-100%乙酸乙酯-己烷)純化殘餘物,得到純溴化物2b。
製備雜環亞甲基衍生物9、10、12及13之通用方法E。藉由LAH或DIBAL使雜環己烯羧酸酯8之酯基還原,得到相應醇9-OH(步驟4)。使醇9-OH與亞硫醯氯、Ph3PBr2(或CBr4-Ph3P或PBr3)或烷基/芳基磺醯氯進一步反應,得到相應10-X氯化物、溴化物或磺酸酯(步驟5)。
或者,在鈀催化之氫化條件下使雜環己烯羧酸酯8之雙鍵還原,得到順-雜環己烷順-11羧酸酯(步驟6)。藉由LAH或DIBAL使順-11之酯基還原,產生順-醇順-12-OH(步驟8)。可藉由與亞硫醯氯或Ph3PBr2或磺醯氯(諸如甲磺醯氯或甲苯磺醯氯)反應使醇順-12-OH轉化為其氯化物、溴化物或磺酸酯(諸如甲磺酸酯、甲苯磺酸酯)順-13-X(步驟9)。亦可藉由用醇鹽(例如乙醇鹽)溶液處理使順-環己烷羧酸酯順-11異構成熱力學更穩定反式導構體反-11。類似地,藉由施用步驟8及步
驟9之類似於相應順式異構體之條件使反-11酯轉化為反-12醇及反-13-X鹵化物。
藉由通用方法A或B使(雜)環亞甲基衍生物9、10、12及13與羥基(雜)芳基醛衍生物(3a/3b)偶合,得到相應芳氧基/雜芳基醚類似物(4c及4d)。
製備雜環亞甲基衍生物18、19、20及21之通用方法F。藉由在有機鹼(諸如許尼希氏鹼(Hunig's base))存在下用三氟甲磺酸化試劑(例如三氟甲磺酸酐)處理將酮酯14轉化為三氟甲磺酸酯中間物15(步驟1)。使三氟甲磺酸酯15與酸或酯鈴木偶合,得到雜環己烯羧酸酯16(步驟2)。隨後藉由LAH或DIBAL使酯基還原,得到相應醇18(步驟3)。使
醇18與亞硫醯氯、Ph3PBr2(或CBr4-Ph3P或PBr3)或烷基/芳基磺醯氯進一步反應,得到相應19氯化物、溴化物或磺酸酯(步驟4)。
或者,在鈀催化之氫化條件下使16之雙鍵還原,得到飽和雜環類似物17(步驟5)。藉由LAH或DIBAL使17之酯基還原,產生醇20(步驟7)。可藉由與亞硫醯氯或Ph3PBr2或磺醯氯(諸如甲磺醯氯或甲苯磺醯氯)反應使醇20轉化為其氯化物、溴化物或磺酸酯(諸如甲磺酸酯、甲苯磺酸酯)21(步驟8)。
藉由通用方法A或B使(雜)環亞甲基衍生物18、19、20及21與羥基(雜)芳基醛衍生物(3a/3b)偶合,得到相應芳氧基/雜芳氧基醚類似物(4e及4f)。
可根據本文所述之反應工序製備對掌性吡咯啶亞甲基衍生物25及26。經由使烯烴22與由甲醛及胺基酸23烯烴於原位產生之氮次甲基內鎓鹽1,3-偶極環加成得到吡咯啶酯24(步驟1)。隨後藉由本文所述之類似方法實現酯還原為醇24且進一步轉化為25。若使用對掌性助劑基團(諸如對掌性噁唑啶酮衍生物22a),則亦可獲得光活性吡咯啶衍生物25及26。藉由通用方法A或B使25及26與羥基(雜)芳基醛衍生物(3a/3b)偶合,得到相應芳氧基/雜芳氧基醚類似物(4)。
本文描述與四氫噻吩(亦即20及21,A=S)之通用合成方法的區別。亦描述此類類似物之不同合成方法。
藉由施用布赫瓦爾德/哈特維希胺化條件(Buchwald/Hartwig amination condition)合成具有C-N鍵之其他雜環類似物(化合物5)。諸多環胺(1)可購得(例如1a、1b、1c、1d及1e)。
式-CONHR95及-CONHOR95之經保護醯胺可根據熟習此項技術者已知之方法轉化(例如水解)為相應醯胺。
可經由通用合成流程1合成結構4之化合物。使羧酸衍生物1還原,得到羥基甲基類似物2,其可經由銅介導之N-芳基化反應(CuI,Ar-I,鹼(諸如N,N-二甲基乙二胺)及磷酸鉀,加熱)進行N-衍生,得到關鍵羥基甲基中間物3。經由典型光延條件(Mitsunobu condition)使用三苯基膦或聚合物支撐之三苯基膦使3與酚醛4偶合,得到所要醛類似物5。A1為如本文所定義之雜原子或烴基部分。
通用方法步驟1-使羧酸衍生物1還原成甲基醇2:在0℃下向羧酸1(1-10mmol)於MeOH或EtOH(2-10mL)中之懸浮液中添加SOCl2(1.5eq)。在室溫下攪拌1-12小時後,將其濃縮以移除所有溶劑,在高真空下乾燥,得到相應甲酯或乙酯。將該酯溶解於MeOH或EtOH(5-30mL)中,在0℃下向此溶液中添加NaBH4(1-4eq),使混合物升溫至室溫且再攪拌1-24小時。用飽和NH4Cl淬滅混合物,濾出不溶物且濃縮濾液,得到粗產物,藉由急驟矽膠層析純化,得到相應羥基亞甲基化合物2。
通用方法步驟2-N-烷基化(1a至1b):可首先烷基化羧酸酯1a(R1=H),隨後還原,得到N-烷基羥基亞甲基類似物1b(R1=烷基)。在典型程序中,首先將羧酸酯1a(1-10mmol)溶解於DMF(2-20mL)中;隨後向其中添加鹼(諸如NaH或Cs2CO3(1-1.2eq)),繼而添加烷基鹵化物(例如BnBr)(0.9-1.5eq)。使反應在室溫下進行或在40至115℃下加熱0.5至24小時。在操作法A中,向反應混合物中添加水,收集沈澱之產物,用水洗滌,隨後進行製備型HPLC或急驟矽膠層析純化。在操作法B(針對不沈澱之產物)中,在0℃下添加稀鹽酸或NH4Cl水溶液以調整pH值至約7,使反應混合物分配於乙酸乙酯或二氯甲烷與氯化鈉水溶液之間且分離有機層,乾燥且在真空下移除溶劑,得到粗產物,藉由自動矽膠管柱層析使用適當溶劑混合物(例如乙酸乙酯/己烷)純化。
通用方法步驟3-由2a進行銅介導之N-芳基化產生2c:對於環胺(X
=H,H),向羥基亞甲基化合物2a(1-10mmol)及芳基/雜碘化物(1-1.5eq)於iPrOH(0.5-10mL)中之溶液中添加乙二醇(1.3eq)及CuI(6.7mol%),繼而添加K3PO4(1.3eq),隨後脫氣且在88℃下加熱6-24小時。
或者,對於內醯胺(X=O),向羥基亞甲基化合物2a(1-10mmol)及芳基/雜碘化物(1-1.5eq)於二噁烷(2-20mL)中之溶液中添加CuI(0.17eq)、N,N-二甲基乙二胺(0.17eq)、K3PO4(1.7eq),隨後脫氣且在100℃下加熱6-48小時。
兩種程序之操作法:冷卻反應混合物至室溫,用EtOAc及水稀釋混合物,分離有機層且用EtOAc萃取水層,合併有機層,用鹽水洗滌,乾燥且濃縮,得到粗產物,藉由急驟矽膠層析純化,得到N-芳基/雜芳基化合物2c。
通用方法C-光延條件 在氮氣下攪拌羥基(雜)芳基醛衍生物(4)(0.1-2mmol)與經取代之亞甲基醇(3)(0.8至1.2eq)及(聚合物支撐之)PPh3(1-1.5eq)於無水THF(1-10mL)中之混合物直至完全溶解。在冰浴上冷卻溶液至0℃且經1-20分鐘之時間期逐滴添加DIAD或DEAD(1.1eq)於THF或甲苯中之溶液。經過90分鐘時,停止使用冰浴冷卻且在室溫下攪拌混合物2-48小時。經由二氧化矽填料過濾混合物。用乙酸乙酯(2-20mL)洗滌二氧化矽。蒸發經合併之濾液且高真空下乾燥殘餘物。藉由製備型HPLC或急驟矽膠層析純化殘餘物。
結構5之化合物可經由通用合成流程1合成。使羧酸衍生物1還原,得到羥基甲基類似物2,其可經由簡單的烷基鹵化物(鹼,R1X,加熱)N-烷基化或由芳基鹵化物(ArX)經由銅介導之N-芳基化反應(CuI,Ar-I,鹼(諸如N,N-二甲基乙二胺)及磷酸鉀,加熱),得到關鍵羥基甲基中間物3。經由典型光延條件使用三苯基膦或聚合物支撐之三苯基膦使3與酚醛4偶合,得到所要醛類似物5。A1為如本文所定義之雜原子或烴基部分。
通用方法步驟1-使羧酸衍生物1還原成甲基醇2:在0℃下向羧酸1(1-10mmol)於MeOH或EtOH(2-10mL)中之懸浮液中添加SOCl2(1.5eq)。在室溫下攪拌1-12小時後,將其濃縮以移除所有溶劑,在高真空下乾燥,得到相應甲酯或乙酯。將該酯溶解於MeOH或EtOH(5-30mL)中,在0℃下向此溶液中添加NaBH4(1-4eq),使混合物升溫至室溫且再攪拌1-24小時。用飽和NH4Cl淬滅混合物,濾出不溶物且濃縮濾液,得到粗產物,藉由急驟矽膠層析純化,得到相應羥基亞甲基化合物2。
通用方法步驟2-銅介導之N-芳基化:對於環胺(X=H,H),向羥基亞甲基化合物2(1-10mmol)及芳基/雜碘化物(1-1.5eq)於iPrOH(0.5-10mL)中之溶液中添加乙二醇(1.3eq)及CuI(6.7mol%),繼而添加K3PO4(1.3eq),隨後脫氣且在88℃下加熱6-24小時。
或者,對於內醯胺(X=O),向羥基亞甲基化合物2(1-10mmol)及芳基/雜碘化物(1-1.5eq)於二噁烷(2-20mL)中之溶液中添加CuI(0.17eq)、N,N-二甲基乙二胺(0.17eq)、K3PO4(1.7eq),隨後脫氣且在100℃下加熱6-48小時。
兩種程序之操作法:冷卻反應混合物至室溫,用EtOAc及水稀釋混合物,分離有機層且用EtOAc萃取水層,合併有機層,用鹽水洗滌,乾燥且濃縮,得到粗產物,藉由急驟矽膠層析純化,得到N-芳基/雜芳基化合物3。
通用方法步驟2b-N-烷基化:可首先烷基化羧酸酯1,隨後還原,得到N-烷基羥基亞甲基類似物3。在典型程序中,首先將羧酸酯1(1-10mmol)溶解於DMF(2-20mL)中;隨後向其中添加鹼(諸如NaH或Cs2CO3(1-1.2eq)),繼而添加烷基鹵化物(例如BnBr)(0.9-1.5eq)。使反應在室溫下進行或在40至115℃下加熱0.5至24小時。在操作法A中,向反應混合物中添加水,收集沈澱之產物,用水洗滌,隨後進行製備型HPLC或急驟矽膠層析純化。在操作法B(針對不沈澱之產物)中,在0℃下添加稀鹽酸或NH4Cl水溶液以調整pH值至約7,使反應混合物分配於乙酸乙酯或二氯甲烷與氯化鈉水溶液之間且分離有機層,乾燥且在真空下移除溶劑,得到粗產物,藉由自動矽膠管柱層析使用適當溶劑混合物(例如乙酸乙酯/己烷)純化。
通用方法C-光延條件 在氮氣下攪拌羥基(雜)芳基醛衍生物(4)(0.1-2mmol)與經取代之亞甲基醇(3)(0.8至1.2eq)及(聚合物支撐之)PPh3(1-1.5eq)於無水THF(1-10mL)中之混合物直至完全溶解。在冰浴上冷卻溶液至0℃且經1-20分鐘之時間期逐滴添加DIAD或DEAD(1.1eq)於THF或甲苯中之溶液。經過90分鐘時,停止使用冰浴冷卻且在室溫下攪拌混合物2-48小時。經由二氧化矽填料過濾混合物。用乙酸乙酯(2-20mL)洗滌二氧化矽。蒸發經合併之濾液且高真
空下乾燥殘餘物。藉由製備型HPLC或急驟矽膠層析純化殘餘物。
以帶有三級胺之游離羧酸為起始物來合成酯前藥。在非質子性溶劑中活化游離酸以進行酯形成,隨後在惰性鹼(諸如三乙胺)存在下與游離醇基反應,得到酯前藥。羧酸之活化條件包括在非質子性溶劑中,視情況在催化量之二甲基甲醯胺存在下使用乙二醯氯或亞硫醯氯形成醯基氯,繼而蒸發。非質子性溶劑之實例包括(但不限於)二氯甲烷、四氫呋喃及其類似物。或者,可藉由使用試劑(諸如BOP(苯并三唑-1-基氧基參(二甲基胺基)鏻六氟磷酸鹽)及其類似物(參見Nagy等人,1993,Proc.Natl.Acad.Sci.USA 90:6373-6376))於原位進行活化,繼而與游離醇反應。酯產物分離可藉由如下操作實行:對於弱酸性水溶液,用有機溶劑(諸如乙酸乙酯或二氯甲烷)萃取;繼而使用鹼處理酸性水相,使其呈鹼性;繼而用有機溶劑(例如乙酸乙酯或二氯甲烷)萃取;蒸發有機溶劑層;且自溶劑(諸如乙醇)再結晶。視情況,可用酸(諸如HCl或乙酸)酸化溶劑,得到其醫藥學上可接受之鹽。或者,可使粗反應物通過帶有質子化形式之磺酸基團的離子交換柱,用去離子水洗滌且用氨水溶離;繼而蒸發。
帶有三級胺之適合游離酸可購得,諸如2-(N-嗎啉基)-丙酸、N,N-二甲基-β-丙胺酸及其類似物。非市售酸可以簡單方式經由標準文獻程序合成。
碳酸酯及胺基甲酸酯前藥可以類似方法製備。舉例而言,可使用活化劑(諸如光氣或羰基二咪唑)活化胺基醇及二胺,得到經活化碳酸酯,其又可與醇及/或本文所用化合物上之酚羥基反應,得到碳酸酯及胺基甲酸酯前藥。
可用於或適用於製備本發明化合物之各種保護基及其相關合成方法可修改自參考文獻Testa等人,Hydrolysis in Drug and Prodrug
Metabolism,2003年6月,Wiley-VCH,Zurich,419-534及Beaumont等人,Curr.Drug Metab.2003,4:461-85。
本文藉由修改來自參考文獻Sobolev等人,2002,J.Org.Chem.67:401-410之方法提供一種合成醯氧基甲基型前藥的方法。
R51為C1-C6烷基。
本文藉由修改來自Mantyla等人,2004,J.Med.Chem.47:188-195之方法提供一種合成膦醯氧基甲基型前藥的方法。
本文提供一種合成烷氧基甲基型前藥之方法
R52為C1-C6烷基、C3-C8環烷基、C3-C9雜環基、C6-C10芳基或C3-C9雜芳基。
以下實例出於說明本發明之各種實施例之目的而提供且不欲以任何方式限制本發明。本發明之實例以及本文所述之方法目前表示較佳實施例,為例示性的且不欲限制本發明之範疇。熟習此項技術者應能設想涵蓋在由申請專利範圍之範疇所界定之本發明精神內的其中之變化及其他用途。
在以下實例以及整個申請案中,以下縮寫具有以下含義。若未定義,則術語具有其普遍接受之含義。
℃=攝氏度
RT=室溫
min=分鐘
h=小時
μL=微升
mL=毫升
mmol=毫莫耳
eq=當量
mg=毫克
ppm=百萬分率
atm=大氣壓
MS=質譜
LC-MS=液相層析-質譜
HPLC=高效液相層析
NMR=核磁共振
Sat./sat.=飽和
MeOH=甲醇
EtOH=乙醇
EtOAc=乙酸乙酯
Et3N=三乙胺
Ac2O=乙酸酐
Na(OAc)3BH=三乙醯氧基硼氫化鈉
PBr3=三溴化磷
Ph3P=三苯基膦
Ph3PBr2=三苯基膦二溴化物
CBr4四溴甲烷
DMF=N,N-二甲基甲醯胺
DCM=二氯甲烷
LAH/LiAlH4=氫化鋰鋁
THF=四氫呋喃
DIBAL=氫化二異丁基鋁
DIAD=偶氮二甲酸二異丙酯
DEAD=偶氮二甲酸二乙酯
DIPEA=N,N-二異丙基乙胺
Pd(dppf)Cl2=[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)錯合物
以下代表性B環及C環中間物可藉由熟習此項技術者通常已知之方法併入本發明化合物中。
製備5-羥基-2-(2-甲氧基乙氧基)異菸鹼醛。
在0-5℃下向6-(苯甲氧基)吡啶-3-醇(2.0g,10mmol,1eq.)於DMF(20mL)中之溶液中逐份添加NaH(60%,於礦物油中;0.6g,15mmol,1.5eq.)。完成添加後,在0-5℃下持續攪拌混合物15分鐘,添加氯甲基甲醚(0.88g,11mmol,1.1eq.),在0-5℃下再攪拌20分鐘,且用NH4Cl(飽和)溶液淬滅。用EtOAc(3×20mL)萃取水層且用水及鹽水洗滌經合併之有機層,經Na2SO4乾燥,濃縮且使用25% EtOAc/己烷作為溶離劑進行矽膠純化,得到呈無色油狀之2-(苯甲氧基)-5-(甲氧基甲氧基)吡啶(2.1g,87%)。MS(ESI)m/z 246.1[M+H]+。
向2-(苯甲氧基)-5-(甲氧基甲氧基)吡啶(1.8g,8.71mol)於EtOH中之溶液中添加Pd/C(1.0g)。向混合物中饋入H2(15psi),在室溫下攪拌45分鐘,過濾且濃縮,得到呈淺黃色固體狀之5-(甲氧基甲氧基)吡啶-2-醇(1.35g,定量產量)。MS(ESI)m/z 156.1[M+H]+。
向5-(甲氧基甲氧基)吡啶-2-醇(1.35g,8.71mmol,1eq.)與K2CO3(6.01g,43.6mmol,5.0eq.)於DMF(30.0mL)中之混合物中添加1-溴-2-甲氧基乙烷(3.61g,26.1mmol,3eq.)。在60℃下加熱混合物2小時,冷卻,過濾,濃縮且使用EtOAc與己烷之混合物作為溶離劑進行矽膠純化,得到呈無色油狀之2-(2-甲氧基乙氧基)-5-(甲氧基甲氧基)吡啶(500mg,27%)。1H NMR(400MHz,CDCl3)δ 7.94(d,J=3.0Hz,1H),7.35(ddd,J=8.9,3.0,1.0Hz,1H),6.76(dd,J=8.9,1.0Hz,1H),5.11(s,2H),4.48-4.40(m,2H),3.79-3.71(m,2H),3.50(s,3H),3.45(s,3H)。MS(ESI)m/z 214.1[M+H]+。
在-40℃下向2-(2-甲氧基乙氧基)-5-(甲氧基甲氧基)吡啶(1.34g,6.3mol,1eq.)與二異丙胺(17.5μL,0.13mmol,0.02eq.)於THF(50mL)中之混合物中添加甲基鋰(1.6M/THF,7mL,11.3mol,1.8eq.)。完成添加後,使混合物升溫至0℃,在0℃下持續攪拌3小時,冷卻降至-40℃且緩慢添加DMF(0.83mL,11.3mol,1.8eq.)。隨後在-40℃下攪拌混合物1小時,用HCl(12N,12mL)與THF(28mL)之混合物淬滅,升溫至室溫且添加水(20mL)。用固體K2CO3調整混合物之pH值至pH 8-9。用EtOAc(30mL)萃取水層兩次。經Na2SO4乾燥經合
併之有機層,濃縮且使用EtOAc與己烷之混合物作為溶離劑進行矽膠純化,得到呈淺黃色油狀之2-(2-甲氧基乙氧基)-5-(甲氧基甲氧基)異菸鹼醛與2-(2-甲氧基乙氧基)-5-(甲氧基甲氧基)菸鹼醛之混合物(5/1,1.27g,83.6%)。1H NMR(400MHz,CDCl3)δ 10.45(s,1H),8.23(s,1H),7.16(s,1H),5.27(s,2H),4.46(dd,J=5.4,3.9Hz,2H),4.14(q,J=7.1Hz,1H),3.77-3.71(m,2H),3.56(s,3H),3.46(s,3H)及1H NMR(400MHz,CDCl3)δ 10.41(s,1H),8.18(d,J=3.2Hz,1H),7.85(d,J=3.1Hz,1H),5.16(s,2H),4.64-4.57(m,2H),3.85-3.79(m,J=5.4,4.0Hz,2H),3.50(s,3H),3.46(s,3H);MS(ESI)m/z 242.1[M+H]+。
向2-甲氧基-5-(甲氧基甲氧基)異菸鹼醛(1.27g,5.29mol)於THF(5mL)中之溶液中添加HCl(3N,4mL)。在50℃下攪拌反應物1小時,冷卻至室溫且用水(5mL)稀釋。用固體K2CO3中和混合物至pH 7-8且用EtOAc(100mL)萃取水層兩次。經Na2SO4乾燥經合併之有機層,濃縮且使用EtOAc與己烷之混合物進行矽膠純化,得到5-羥基-2-(2-甲氧基乙氧基)異菸鹼醛(630mg,60%)及5-羥基-2-(2-甲氧基乙氧基)菸鹼醛(120mg,11%)。5-羥基-2-(2-甲氧基乙氧基)異菸鹼醛之資料:1H NMR(400MHz,CDCl3)δ 9.98(s,1H),9.50(s,1H),8.07(s,1H),7.02(s,1H),4.51-4.39(m,2H),3.81-3.72(m,2H),3.47(s,3H)。LRMS(M+H+)m/z 198.1。5-羥基-2-(2-甲氧基乙氧基)菸鹼醛之資料:1H NMR(400MHz,CDCl3)δ 10.3(s,1H),7.99(d,J=3.2Hz,1H),
7.58(d,J=3.2Hz,1H),7.18-7.07(br,1H),4.54(dd,J=5.4,3.7Hz,2H),3.84(dd,J=5.4,3.7Hz,2H),3.49(s,3H);MS(ESI)m/z 198.1[M+H]+。
製備2,6-二羥基苯甲醛。
向3000-mL三頸圓底燒瓶中置放AlCl3(240g,1.80mol,3.00當量)於二氯甲烷(1200mL)中之溶液。在0℃下向反應混合物中逐滴添加2,6-二甲氧基苯甲醛(100g,601.78mmol,1.00eq)於二氯甲烷(800ml)中之溶液。在室溫下攪拌所得溶液隔夜,隨後用200mL稀鹽酸(2M)淬滅。用2×200mL二氯甲烷萃取所得溶液。在真空下濃縮經合併之有機層。將殘餘物施用於用乙酸乙酯/石油醚(1:200-1:50)作為溶離劑之矽膠管柱上,得到40g(48%)呈黃色固體狀之2,6-二羥基苯甲醛。
1HNMR(300MHz,DMSO-d 6 )δ 11.25(s,2H),10.25(s,1H),7.36(m,1H),6.36(d,J=8.4Hz 2H);MS(ESI)m/z 139[M+H]+。
製備5-羥基-2-甲氧基異菸鹼醛。
步驟1:在0-5℃下向6-甲氧基吡啶-3-醇(20g,0.16mol)於DMF(200mL)中之溶液中逐滴添加NaH(60%,於礦物油中;9.6g,0.24mol)。完成添加後,在0-5℃下持續攪拌混合物15分鐘,繼而添加氯甲基甲醚。在0-5℃下再攪拌混合物20分鐘且用NH4Cl(飽和)水溶液淬滅。用EtOAc(3×100mL)萃取水層且用水及鹽水洗滌經合併之有機層,經Na2SO4乾燥且在減壓下濃縮。用25% EtOAc/己烷作為溶離劑
對殘餘物進行矽膠純化,得到呈無色油狀之2-甲氧基-5-(甲氧基甲氧基)吡啶(24.1g,89.3%)。1H NMR(400MHz;CDCl3)7.97(d,1 H),7.35(dd,1 H),6.70(d,1 H),5.12(s,2 H),3.91(s,3 H),3.51(s,3 H);MS(ESI)m/z 170.1[M+H]+。
步驟2:在-40℃下向2-甲氧基-5-(甲氧基甲氧基)吡啶(30g,0.178mol)與二異丙胺(507μL,3.6mmol)於THF(500mL)中之混合物中添加甲基鋰(1.6M/THF,200mL,0.32mol)。完成添加後,使混合物升溫至0℃且在0℃下持續攪拌3小時。隨後將反應混合物冷卻降至-40℃,繼而緩慢添加DMF(24.7mL,0.32mol)。隨後在-40℃下攪拌混合物1小時且用HCl(12N,120mL)與THF(280mL)之混合物淬滅。添加水(200mL)且用固體K2CO3調整混合物之pH值至pH 8-9。用EtOAc(300mL)萃取混合物兩次。合併有機層,經Na2SO4乾燥且濃縮,得到呈棕色固體狀之2-甲氧基-5-(甲氧基甲氧基)異菸鹼醛(33.5g,95.7%),其不經進一步純化即用於下一步驟。1H NMR(400MHz;CD3OD)7.90(s,1 H),6.92(s,1 H),5.64(s,1 H),5.20(s,2 H),3.84(s,3 H),3.48(s,3 H);MS(ESI)m/z 198.1[M+H]+。
步驟3:向2-甲氧基-5-(甲氧基甲氧基)異菸鹼醛(33.5g,0.17mol)於THF(150mL)中之溶液中添加HCl(3N,250mL)。在50℃下攪拌反應物1小時,冷卻至室溫且用水(500mL)稀釋。用固體K2CO3中和混合物至pH 7-8。收集淺黃色固體,用水洗滌且在真空烘箱(40℃)中乾燥隔夜,得到5-羥基-2-甲氧基異菸鹼醛(17.9g,74.6%)。1H NMR(400MHz;DMSO)δ=10.31(s,1 H),8.03(s,1 H),6.89(s,1 H),3.80(s,3 H);MS(ESI)m/z 154.0[M+H]+。
(S)-2-((1-苯甲醯基吡咯啉-2-基)甲氧基)-6-羥基苯甲醛
GBT915-(S)-2-((1-苯甲醯基吡咯啶-2-基)甲氧基)-6-羥基苯甲醛。
步驟1:在0℃下向(S)-吡咯啶-2-基甲醇(700mg,6.92mmol)及DIPEA(1.20mL,6.92mmol)於DCM(12ml)中之溶液中添加苯甲醯氯(0.80mL,6.92mmol),30分鐘後,再用DCM稀釋且用飽和NaHCO3、鹽水洗滌,經MgSO4乾燥,濃縮,得到粗產物,藉由管柱(EtOAc 0-100%)純化,得到(S)-(2-(羥基甲基)吡咯啶-1-基)(苯基)甲酮(1.2g)。
步驟2:在室溫下向(S)-(2-(羥基甲基)吡咯啶-1-基)(苯基)甲酮(100mg,0.49mmol)及2,6-二羥基苯甲醛(90mg,0.64mmol)於THF(1mL)中之溶液中添加PPh3(190mg,0.73mmol)及DIAD(0.15mL,0.73mmol),30分鐘後,濃縮且藉由管柱(己烷/EtOAc=100:0至1:1)純化殘餘物,得到(S)-2-((1-苯甲醯基吡咯啶-2-基)甲氧基)-6-羥基苯甲醛(65mg)。1H NMR(400MHz,氯仿-d)δ 11.90(s,1H),10.40(s,1H),7.51-7.31(m,6H),6.53(t,J=9.2Hz,2H),4.65(s,1H),4.38(d,J=6.1Hz,2H),3.51(t,J=6.8Hz,2H),2.29-1.90(m,2H),1.79(d,J=36.4Hz,1H),1.31-1.18(m,1H)。C19H19NO4之MS實驗值:326.5。
(S)-2-((1-苯甲醯基哌啶-2-基)甲氧基)-6-羥基苯甲醛
GBT952-(S)-2-((1-苯甲醯基哌啶-2-基)甲氧基)-6-羥基苯甲醛
步驟1:在室溫下向(S)-哌啶-2-基甲醇鹽酸鹽(0.11g,0.70mmol)於DCM(2mL)中之懸浮液中添加DIPEA(0.27mL,1.54mmol)及苯甲醯氯(0.08mL,0.70mmol),攪拌30分鐘後,用DCM稀釋且用飽和NH4Cl、鹽水洗滌,經MgSO4乾燥且濃縮,得到粗產物,藉由管柱(己烷/EtOAc=0:100)純化,得到(S)-(2-(羥基甲基)哌啶-1-基)(苯基)甲酮(84mg)。
步驟2:在0℃下向2,6-二羥基苯甲醛(110mg,0.80mmol)及(S)-(2-(羥基甲基)哌啶-1-基)(苯基)甲酮(0.23g,1.04mmol)於THF(1.5mL)中之溶液中添加PPh3(310mg,1.20mmol)及DIAD(0.23mL,1.20mmol),隨後使其升溫至室溫且攪拌1小時。濃縮混合物且藉由管柱(己烷/EtOAc=60:40)純化殘餘物,得到(S)-2-((1-苯甲醯基哌啶-2-基)甲氧基)-6-羥基苯甲醛(62mg)。1H NMR(400MHz,氯仿-d)δ 11.98(s,1H),10.29(s,1H),7.45-7.28(m,5H),6.58-6.50(m,2H),6.40(dt,J=8.1,0.8Hz,1H),4.32(t,J=8.5Hz,1H),4.18(s,1H),3.04(s,1H),1.94-1.76(m,3H),1.73-1.58(m,3H),1.26(dt,J=7.0,3.1Hz,2H)。C20H21NO4之MS實驗值:340.2。
(S)-2-羥基-6-((1-菸鹼醯基吡咯啶-2-基)甲氧基)苯甲醛
GBT961-(S)-2-羥基-6-((1-菸鹼醯基吡咯啶-2-基)甲氧基)苯甲醛
步驟1:在0℃下向(S)-吡咯啶-2-基甲醇(500mg,4.94mmol)於DCM(10mL)中之溶液中依序添加DIPEA(1.89mL,10.87mmol)及菸鹼基氯(0.92g,5.19mmol),攪拌30分鐘後,用DCM稀釋,用飽和NaHCO3水溶液、鹽水洗滌,乾燥且濃縮,得到粗產物,藉由管柱(DCM/MeOH=100:0至80:20)純化,得到(S)-(2-(羥基甲基)吡咯啶-1-基)(吡啶-3-基)甲酮(900mg)。
步驟2:在0℃下向(S)-(2-(羥基甲基)吡咯啶-1-基)(吡啶-3-基)甲酮(150mg,0.73mmol)及2,6-二羥基苯甲醛(0.13g,0.91mmol)於THF(1.5mL)中之溶液中添加PPh3(0.29g,1.1mmol)及DIAD(0.21mL,1.1mmol)且在室溫下攪拌2小時,隨後濃縮,藉由管柱(己烷/EtOAc=100:0至40:60至DCM/MeOH=100:0至90:10)純化所得殘餘物,得到產物之混合物,藉由製備型HPLC進一步純化,得到(S)-2-羥基-6-((1-菸鹼醯基吡咯啶-2-基)甲氧基)苯甲醛(68mg)。1H NMR(400MHz,氯仿-d)δ 11.90(s,1H),10.40(s,1H),8.78-8.72(m,1H),8.68(dd,J=4.9,1.7Hz,1H),7.82(dt,J=7.9,2.0Hz,1H),7.40(t,J=8.3Hz,1H),7.36(ddd,J=7.9,4.9,0.9Hz,1H),6.53(dd,J=8.5,4.9Hz,
2H),4.66(d,J=11.1Hz,1H),4.38(d,J=5.8Hz,2H),3.54(t,J=7.6Hz,2H),2.26(dtd,J=12.8,7.6,5.3Hz,1H),2.19-2.10(m,1H),2.10-1.98(m,1H),1.88(dt,J=12.5,7.8Hz,1H)。C18H18N2O4之MS實驗值:327.4。
(S)-2-羥基-6-((1-異菸鹼醯基吡咯啶-2-基)甲氧基)苯甲醛
GBT962-(S)-2-羥基-6-((1-異菸鹼醯基吡咯啶-2-基)甲氧基)苯甲醛
步驟1:在0℃下向(S)-吡咯啶-2-基甲醇(500mg,4.94mmol)於DCM(10mL)中之溶液中依序添加DIPEA(1.89mL,10.87mmol)及菸鹼基氯(0.88g,4.94mmol),攪拌30分鐘後,用DCM稀釋,用飽和NaHCO3水溶液、鹽水洗滌,乾燥且濃縮,得到粗產物,藉由管柱(DCM/MeOH=100:0至80:20)純化,得到(S)-(2-(羥基甲基)吡咯啶-1-基)(吡啶-4-基)甲酮(900mg)。
步驟2:在0℃下向(S)-(2-(羥基甲基)吡咯啶-1-基)(吡啶-3-基)甲酮(150mg,0.73mmol)及2,6-二羥基苯甲醛(0.13g,0.91mmol)於THF(1.5mL)中之溶液中添加PPh3(0.29g,1.1mmol)及DIAD(0.21mL,1.1mmol)且在室溫下攪拌2小時,隨後濃縮,藉由管柱(己烷/
EtOAc=100:0至40:60至DCM/MeOH=100:0至90:10)純化所得殘餘物,得到產物之混合物,藉由製備型HPLC進一步純化,得到(S)-2-羥基-6-((1-異菸鹼醯基吡咯啶-2-基)甲氧基)苯甲醛(36mg)。1H NMR(400MHz,氯仿-d)δ 11.88(s,1H),10.38(s,1H),8.72-8.63(m,2H),7.39(t,J=8.4Hz,1H),7.35-7.24(m,2H),6.52(t,J=8.6Hz,2H),4.63(dq,J=8.4,5.1Hz,1H),4.42-4.29(m,2H),3.46(hept,J=6.3,5.4Hz,2H),2.24(dtd,J=13.3,7.7,5.5Hz,1H),2.13(dq,J=13.0,6.8Hz,1H),2.03(dt,J=12.4,6.3Hz,1H),1.95-1.79(m,1H)。C18H18N2O4之MS實驗值:327.4。
(S)-2-羥基-6-((1-吡啶甲醯基吡咯啶-2-基)甲氧基)苯甲醛
GBT979-(S)-2-羥基-6-((1-吡啶甲醯基吡咯啶-2-基)甲氧基)苯甲醛
步驟1:在0℃下向(S)-吡咯啶-2-基甲醇(500mg,4.94mmol)於DCM(10mL)中之溶液中依序添加DIPEA(1.89mL,10.87mmol)及異菸鹼基氯(0.88g,4.94mmol),攪拌30分鐘後,用DCM稀釋,用飽和NaHCO3水溶液、鹽水洗滌,乾燥且濃縮,得到粗產物,藉由管柱(DCM/MeOH=100:0至80:20)純化,得到(S)-(2-(羥基甲基)吡咯啶-1-基)(吡啶-2-基)甲酮(900mg)。
步驟2:在室溫下向(S)-(2-(羥基甲基)吡咯啶-1-基)(吡啶-2-基)甲酮(100mg,0.48mmol)及2,6-二羥基苯甲醛(0.08g,0.6mmol)於THF(5mL)中之溶液中添加PPh3(聚合物支撐,600mg,0.72mmol)及DIAD(0.15mL,0.72mmol)。在室溫下攪拌3小時後,用AcCN稀釋混合物,濾出不溶物,濃縮濾液,得到粗產物,藉由製備型HPLC純化,得到(S)-2-羥基-6-((1-吡啶甲醯基吡咯啶-2-基)甲氧基)苯甲醛(15mg)。1H NMR(400MHz,氯仿-d)δ 11.92(s,1H),10.39(d,J=0.6Hz,1H),8.55(ddt,J=40.7,4.9,1.1Hz,1H),7.89-7.74(m,2H),7.40(t,J=8.4Hz,1H),7.37-7.23(m,1H),6.60-6.46(m,2H),4.76-4.65(m,1H),4.48(dd,J=9.5,3.3Hz,1H),4.32-4.18(m,1H),3.99-3.81(m,1H),3.81-3.67(m,1H),2.25-1.83(m,4H)。C18H18N2O4之MS實驗值:327.3。
(S)-2-羥基-6-((1-(1-異丙基-1H-吡唑-5-羰基)吡咯啶-2-基)甲氧基)苯甲醛
GBT1064-(S)-2-羥基-6-((1-(1-異丙基-1H-吡唑-5-羰基)吡咯啶-2-基)甲氧基)苯甲醛
步驟1:向(S)-吡咯啶-2-基甲醇(100mg,1mmol)及1-異丙基-1H-吡唑-5-甲酸(0.15g,1mmol)於DMF(2mL)中之溶液中添加
HATU(0.38g,1mmol),隨後攪拌混合物直至結束,用水稀釋且用EtOAc萃取,乾燥有機層且濃縮,得到粗產物,藉由管柱(100% EtOAc)純化,得到(S)-(2-(羥基甲基)吡咯啶-1-基)(1-異丙基-1H-吡唑-5-基)甲酮(120mg)。
步驟2:在0℃下向(S)-(2-(羥基甲基)吡咯啶-1-基)(1-異丙基-1H-吡唑-5-基)甲酮(120mg,0.51mmol)及2,6-二羥基苯甲醛(0.09g,0.66mmol)於THF(4mL)中之溶液中添加PPh3(聚合物支撐,640mg,0.77mmol)及DIAD(0.16mL,0.77mmol)。在室溫下攪拌1小時後,用AcCN稀釋,濾出不溶物且濃縮濾液,得到粗產物,藉由製備型HPLC純化,得到(S)-2-羥基-6-((1-(1-異丙基-1H-吡唑-5-羰基)吡咯啶-2-基)甲氧基)苯甲醛(46mg)。1H NMR(400MHz,氯仿-d)δ 11.90(s,1H),10.37(s,1H),7.55(d,J=2.0Hz,1H),7.41(t,J=8.4Hz,1H),6.54(d,J=8.5Hz,1H),6.48(d,J=8.3Hz,1H),6.37(d,J=2.0Hz,1H),5.03-4.94(m,1H),4.65(s,1H),4.37(d,J=5.4Hz,2H),3.67(s,1H),3.60-3.45(m,1H),2.25(dd,J=13.1,6.1Hz,1H),2.11(ddt,J=30.4,12.0,6.4Hz,2H),1.93(s,1H),1.53(d,J=6.6Hz,3H),1.46(d,J=6.7Hz,3H)。C19H23N3O4之MS(M+H)實驗值:358.3。
(S)-2-羥基-6-((1-菸鹼醯基哌啶-2-基)甲氧基)苯甲醛
GBT1118-(S)-2-羥基-6-((1-菸鹼醯基哌啶-2-基)甲氧基)苯甲醛
步驟1及2:向(S)-2-(羥基甲基)哌啶-1-甲酸第三丁酯之固體樣品(215mg,1.02mmol)中添加4N HCl之二噁烷溶液(1mL)。攪拌30分鐘後濃縮,得到(S)-哌啶-2-基甲醇鹽酸鹽。在0℃下向(S)-哌啶-2-基甲醇鹽酸鹽於DCM(3mL)中之懸浮液中添加DIPEA(0.39mL,2.24mmol)及菸鹼基氯(0.2g,1.12mmol)。攪拌30分鐘後,用DCM稀釋,用飽和NaHCO3水溶液、鹽水洗滌,乾燥且濃縮,得到粗產物,藉由管柱(DCM/MeOH=90:10)純化,得到(S)-(2-(羥基甲基)哌啶-1-基)(吡啶-3-基)甲酮(130mg)。
步驟3:在0℃下向(S)-(2-(羥基甲基)哌啶-1-基)(吡啶-3-基)甲酮(130mg,0.59mmol)及2,6-二羥基苯甲醛(0.11g,0.77mmol)於THF(4mL)中之溶液中添加PPh3(聚合物支撐,0.74g,0.89mmol)且在室溫下攪拌2小時,隨後濃縮,藉由製備型HPLC純化所得殘餘物,得到產物之混合物,藉由製備型HPLC進一步純化,得到(S)-2-羥基-6-((1-菸鹼醯基哌啶-2-基)甲氧基)苯甲醛(30mg)。1H NMR(400MHz,氯仿-d)δ 11.95(s,1H),10.29(s,1H),8.66(dd,J=4.9,1.7Hz,1H),8.65-8.62(m,1H),7.73(dt,J=7.8,2.0Hz,1H),7.41(d,J=8.4Hz,1H),7.37(ddd,J=7.8,4.9,0.9Hz,1H),6.59-6.54(m,1H),6.40(d,J=7.0Hz,1H),4.39-4.30(m,2H),4.19(s,2H),3.15(s,1H),1.97-1.78(m,4H),1.72-1.56(m,2H)。C19H20N2O4之MS實驗值:341.3。
(S)-2-羥基-6-((1-(6-甲基菸鹼醯基)哌啶-2-基)甲氧基)苯甲醛
GBT1579-(S)-2-羥基-6-((1-(6-甲基菸鹼醯基)哌啶-2-基)甲氧基)苯甲醛
步驟1及2:在0℃下向6-甲基菸鹼酸(270mg,2mmol)於DCM(5mL)中之懸浮液中添加乙二醯氯(0.34mL,4mmol),繼而添加一滴DMF,在室溫下攪拌2小時後,濃縮溶液,得到粗酸氯化物。
在0℃下向上述粗酸氯化物之DCM溶液(4mL)中添加(S)-哌啶-2-基甲醇鹽酸鹽(300mg,1.98mmol)及DIPEA(1.04mL,5.94mmol),在室溫下攪拌2小時後,再添加DIPEA以驅使反應完成。用DCM稀釋反應物,用飽和NaHCO3、鹽水洗滌,乾燥且濃縮,得到粗產物,藉由管柱(DCM/MeOH=90:10)純化,得到所要(S)-(2-(羥基甲基)哌啶-1-基)(6-甲基吡啶-3-基)甲酮(100mg)。
步驟3:在0℃下向(S)-(2-(羥基甲基)哌啶-1-基)(6-甲基吡啶-3-基)甲酮(100mg,0.43mmol)及2,6-二羥基苯甲醛(80mg,0.56mmol)於THF(2.5mL)中之溶液中添加聚合物支撐之三苯基膦(435mg,0.52mmol)及DIAD(0.11mL,0.52mmol),在室溫下攪拌4小時後,過濾溶液,濃縮濾液且藉由製備型HPLC純化,得到(S)-2-羥基-6-((1-(6-甲基菸鹼醯基)哌啶-2-基)甲氧基)苯甲醛(29mg)。1H NMR(400MHz,氯仿-d)δ 11.95(s,1H),10.28(s,1H),8.53(d,J=2.2Hz,1H),7.62(dd,J
=8.0,2.3Hz,1H),7.39(t,J=8.4Hz,1H),7.21(d,J=8.0Hz,1H),6.55(dd,J=8.5,0.8Hz,1H),6.40(s,1H),4.33(t,J=8.6Hz,2H),4.19(s,1H),3.09(s,2H),2.59(s,3H),1.73(m,6H)。C20H22N2O4之MS(M+H)實驗值:355.3。
(S)-2-羥基-6-((1-(2-甲基菸鹼醯基)哌啶-2-基)甲氧基)苯甲醛
GBT1580-(S)-2-羥基-6-((1-(2-甲基菸鹼醯基)哌啶-2-基)甲氧基)苯甲醛
步驟1及2:在0℃下向2-甲基菸鹼酸(300mg,2.19mmol)於DCM(5mL)中之懸浮液中添加乙二醯氯(0.28mL,3.3mmol)且在室溫下再攪拌2小時,隨後濃縮溶液,得到粗酸氯化物。
在0℃下向酸氯化物之DCM溶液(5mL)中添加(S)-哌啶-2-基甲醇鹽酸鹽(250mg,1.65mmol)及三乙胺(0.69mL,4.95mmol)且在室溫下進一步攪拌30分鐘,再用DCM稀釋溶液且用飽和NaHCO3及鹽水洗滌有機層,乾燥且濃縮,得到粗產物,藉由管柱(DCM/MeOH=95:5)純化,得到(S)-(2-(羥基甲基)哌啶-1-基)(2-甲基吡啶-3-基)甲酮(200mg)。
步驟3:在0℃下向(S)-(2-(羥基甲基)哌啶-1-基)(2-甲基吡啶-3-基)
甲酮(180mg,0.77mmol)及2,6-二羥基苯甲醛(140mg,1.0mmol)於THF(5mL)中之溶液中添加聚合物支撐之三苯基膦(1.0g,1.16mmol)及DIAD(0.21mL,1.08mmol),在室溫下攪拌15小時後,過濾溶液,濃縮濾液且藉由製備型HPLC純化,得到(S)-2-羥基-6-((1-(2-甲基菸鹼醯基)哌啶-2-基)甲氧基)苯甲醛(129mg)。1H NMR(400MHz,氯仿-d)δ 11.99(s,1H),10.40(s,1H),8.53(m,1H),7.42(t,J=8.4Hz,1H),7.32(m,1H),7.20(m,1H),6.56(d,J=8.4Hz,1H),6.47(d,J=8.3Hz,1H),5.39(s,1H),4.38(t,J=8.8Hz,1H),4.21(dd,J=9.5,6.6Hz,1H),3.36(d,J=13.5Hz,1H),3.14(m,1H),2.52(s,3H),2.10-1.35(m,6H)。C20H22N2O4之MS(M+H)實驗值:355.3。
(S)-2-((4-苯甲醯基嗎啉-3-基)甲氧基)-6-羥基苯甲醛
GBT1124-(S)-2-((4-苯甲醯基嗎啉-3-基)甲氧基)-6-羥基苯甲醛
步驟1及2:向(R)-3-(羥基甲基)嗎啉-4-甲酸第三丁酯之固體樣品(150mg,0.69mmol)中添加4N HCl之二噁烷溶液(1.5mL)。攪拌30分鐘後濃縮,得到鹽酸鹽形式之(R)-(3-(羥基甲基)嗎啉基)(苯基)甲酮。在0℃下向(R)-(3-(羥基甲基)嗎啉基)(苯基)甲酮鹽酸鹽於DCM(2mL)中之懸浮液中添加DIPEA(0.36mL,2.07mmol)及苯甲醯氯(0.08mL,
0.69mmol)。攪拌30分鐘後,用DCM稀釋,用飽和NaHCO3水溶液、鹽水洗滌,乾燥且濃縮,得到粗產物,藉由管柱(100% EtOAc)純化,得到(R)-(3-(羥基甲基)嗎啉基)(苯基)甲酮(120mg)。
步驟3:在0℃下向(R)-(3-(羥基甲基)嗎啉基)(苯基)甲酮(80mg,0.36mmol)及2,6-二羥基苯甲醛(0.06g,0.47mmol)於THF(2mL)中之溶液中添加PPh3(聚合物支撐,0.45g,0.54mmol)及DIAD(0.11mL,0.54mmol)且在室溫下攪拌2小時,隨後濃縮,藉由製備型HPLC純化所得殘餘物,得到(S)-2-((4-苯甲醯基嗎啉-3-基)甲氧基)-6-羥基苯甲醛(20mg)。1H NMR(400MHz,氯仿-d)δ 11.96(s,1H),10.28(s,1H),7.50-7.35(m,7H),6.61-6.41(m,1H),4.37(s,2H),4.07(s,1H),3.89(s,1H),3.76(dd,J=12.2,3.2Hz,1H),3.55(s,2H),3.39(s,1H),1.35-1.18(m,1H)。C19H19NO5之MS實驗值:342.3。
(S)-2-羥基-6-((1-(苯基磺醯基)吡咯啶-2-基)甲氧基)苯甲醛
GBT1126-(S)-2-羥基-6-((1-(苯基磺醯基)吡咯啶-2-基)甲氧基)苯甲醛
步驟1:在0℃下向(S)-吡咯啶-2-基甲醇(500mg,4.94mmol)於DCM(10mL)中之溶液中依序添加TEA(1.04mL,7.41mmol)及苯磺醯氯(0.63mL,4.94mmol)。攪拌30分鐘後,用DCM稀釋,用飽和
NaHCO3水溶液、鹽水洗滌,乾燥且濃縮,得到粗產物,藉由管柱純化,得到(S)-(1-(苯基磺醯基)吡咯啶-2-基)甲醇。
步驟2:在0℃下向(S)-(1-(苯基磺醯基)吡咯啶-2-基)甲醇(125mg,0.54mmol)及2,6-二羥基苯甲醛(0.1g,0.7mmol)於THF(2mL)中之溶液中添加PPh3(0.21g,0.81mmol)及DIAD(0.16mL,0.81mmol)且在室溫下攪拌2小時,隨後濃縮,藉由製備型HPLC純化所得殘餘物,得到(S)-2-羥基-6-((1-(苯基磺醯基)吡咯啶-2-基)甲氧基)苯甲醛(37mg)。1H NMR(400MHz,氯仿-d)δ 11.90(d,J=0.4Hz,1H),10.28(d,J=0.6Hz,1H),7.93-7.76(m,2H),7.65-7.56(m,1H),7.56-7.47(m,2H),7.43(td,J=8.4,0.4Hz,1H),6.55(dt,J=8.5,0.7Hz,1H),6.48(dd,J=8.3,0.8Hz,1H),4.42-4.31(m,1H),4.08-3.95(m,2H),3.56-3.45(m,1H),3.20(ddd,J=10.0,8.0,7.0Hz,1H),2.03-1.83(m,2H),1.81-1.50(m,2H)。C18H19NO5S之MS實驗值:362.4。
(S)-2-羥基-6-((1-(吡啶-3-基磺醯基)吡咯啶-2-基)甲氧基)苯甲醛
GBT1128-(S)-2-羥基-6-((1-(吡啶-3-基磺醯基)吡咯啶-2-基)甲氧基)苯甲醛
步驟1:在0℃下向(S)-吡咯啶-2-基甲醇(320mg,3.16mmol)於DCM(6mL)中之溶液中依序添加TEA(0.97mL,6.95mmol)及吡啶-3-
磺醯氯(0.68g,3.16mmol)。攪拌30分鐘後,用DCM稀釋,用飽和NaHCO3水溶液、鹽水洗滌,乾燥且濃縮,得到粗產物,藉由管柱純化,得到(S)-(1-(吡啶-3-基磺醯基)吡咯啶-2-基)甲醇(66mg)。
步驟2:在0℃下向(S)-(1-(吡啶-3-基磺醯基)吡咯啶-2-基)甲醇(65mg,0.29mmol)及2,6-二羥基苯甲醛(0.06g,0.41mmol)於THF(2mL)中之溶液中添加PPh3(聚合物支撐,0.37g,0.44mmol)及DIAD(0.09mL,0.44mmol)且在室溫下攪拌2小時,隨後用AcCN稀釋,濾出不溶物,濃縮濾液,藉由製備型HPLC純化所得殘餘物,得到(S)-2-羥基-6-((1-(吡啶-3-基磺醯基)吡咯啶-2-基)甲氧基)苯甲醛(17mg)。1H NMR(400MHz,氯仿-d)δ 11.90(s,1H),10.29(d,J=0.6Hz,1H),9.08(dd,J=2.3,0.9Hz,1H),8.83(dd,J=4.9,1.6Hz,1H),8.18-8.09(m,1H),7.53-7.46(m,1H),7.44(t,J=8.4Hz,1H),6.61-6.54(m,1H),6.50-6.44(m,1H),4.40-4.31(m,1H),4.12-3.96(m,2H),3.56(ddd,J=10.5,7.1,4.2Hz,1H),3.21(dt,J=10.1,7.4Hz,1H),2.08-1.88(m,2H),1.87-1.66(m,2H)。C17H18N2O5S之MS(M+H)實驗值:363.4。
由上文應瞭解,儘管本發明之特定實施例在本文中為說明之目的而描述,但可在不背離本發明之精神及範疇之情況下進行各種修改。
在本發明之描述中,參考各種專利申請案及公開案,其中之每一者以全文引用的方式併入本文中。
Claims (13)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/815,735 US8952171B2 (en) | 2013-03-15 | 2013-03-15 | Compounds and uses thereof for the modulation of hemoglobin |
US13/815,735 | 2013-03-15 | ||
US201361905803P | 2013-11-18 | 2013-11-18 | |
US61/905,803 | 2013-11-18 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201518274A TW201518274A (zh) | 2015-05-16 |
TWI695830B true TWI695830B (zh) | 2020-06-11 |
Family
ID=51580732
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW103109178A TWI695830B (zh) | 2013-03-15 | 2014-03-13 | 化合物及其調節血紅素之用途 |
Country Status (22)
Country | Link |
---|---|
US (3) | US20160083343A1 (zh) |
EP (1) | EP2970196B1 (zh) |
JP (3) | JP6426694B2 (zh) |
KR (1) | KR102280614B1 (zh) |
CN (2) | CN112500338A (zh) |
AP (1) | AP2015008721A0 (zh) |
AU (3) | AU2014237340C1 (zh) |
BR (1) | BR112015021985B1 (zh) |
CA (1) | CA2903220C (zh) |
CL (1) | CL2015002501A1 (zh) |
EA (1) | EA034922B1 (zh) |
ES (1) | ES2852054T3 (zh) |
IL (1) | IL241060B (zh) |
MX (1) | MX2015011445A (zh) |
MY (1) | MY191087A (zh) |
PE (1) | PE20161035A1 (zh) |
SA (2) | SA515361026B1 (zh) |
SG (2) | SG10201802911RA (zh) |
TW (1) | TWI695830B (zh) |
UY (1) | UY35426A (zh) |
WO (1) | WO2014150268A1 (zh) |
ZA (1) | ZA201703791B (zh) |
Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2790358T3 (es) | 2011-12-28 | 2020-10-27 | Global Blood Therapeutics Inc | Compuestos de heteroaril aldehído sustituido y métodos para su uso en el aumento de la oxigenación tisular |
PT3738434T (pt) | 2011-12-28 | 2023-11-13 | Global Blood Therapeutics Inc | Intermediários para obter compostos de benzaldeído substituído e métodos para a sua utilização no aumento da oxigenação de tecidos |
SG10201802911RA (en) * | 2013-03-15 | 2018-05-30 | Global Blood Therapeutics Inc | Compounds and uses thereof for the modulation of hemoglobin |
US9422279B2 (en) | 2013-03-15 | 2016-08-23 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US8952171B2 (en) | 2013-03-15 | 2015-02-10 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US10266551B2 (en) | 2013-03-15 | 2019-04-23 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
CN111454200A (zh) | 2013-03-15 | 2020-07-28 | 全球血液疗法股份有限公司 | 化合物及其用于调节血红蛋白的用途 |
CA2902711C (en) | 2013-03-15 | 2021-07-06 | Global Blood Therapeutics, Inc. | Substituted pyridinyl-6-methoxy-2-hydroxybenzaldehyde derivatives and pharmaceutical compositions thereof useful for the modulation of hemoglobin |
US10100043B2 (en) | 2013-03-15 | 2018-10-16 | Global Blood Therapeutics, Inc. | Substituted aldehyde compounds and methods for their use in increasing tissue oxygenation |
US9458139B2 (en) | 2013-03-15 | 2016-10-04 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
EA201992707A1 (ru) | 2013-11-18 | 2020-06-30 | Глобал Блад Терапьютикс, Инк. | Соединения и их применения для модуляции гемоглобина |
SI3102208T1 (sl) | 2014-02-07 | 2021-07-30 | Global Blood Therapeutics, Inc. | Kristalinični polimorf proste baze 2-hidroksi-6-((2-(1-izopropil-1H-pirazol-5-IL)piridin-3-IL)metoksi)- benzaldehida |
WO2016043849A2 (en) * | 2014-07-24 | 2016-03-24 | Global Blood Therapeutics, Inc. | Compounds for treating acute respiratory distress syndrome or a negative effect thereof |
MA41841A (fr) | 2015-03-30 | 2018-02-06 | Global Blood Therapeutics Inc | Composés aldéhyde pour le traitement de la fibrose pulmonaire, de l'hypoxie, et de maladies auto-immunes et des tissus conjonctifs |
MA43373A (fr) | 2015-12-04 | 2018-10-10 | Global Blood Therapeutics Inc | Régimes posologiques pour 2-hydroxy-6-((2- (1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)méthoxy)benzaldéhyde |
TWI752307B (zh) | 2016-05-12 | 2022-01-11 | 美商全球血液治療公司 | 新穎化合物及製造化合物之方法 |
TWI778983B (zh) | 2016-10-12 | 2022-10-01 | 美商全球血液治療公司 | 包含2-羥基-6-((2-(1-異丙基-1h-吡唑-5-基)吡啶-3-基)甲氧基)-苯甲醛之片劑 |
US11014884B2 (en) | 2018-10-01 | 2021-05-25 | Global Blood Therapeutics, Inc. | Modulators of hemoglobin |
JP2022509091A (ja) | 2018-11-19 | 2022-01-20 | グローバル ブラッド セラピューティクス インコーポレイテッド | ヘモグロビンのモジュレーター |
MX2021006095A (es) | 2018-11-29 | 2021-07-06 | Pfizer | Pirazoles como moduladores de hemoglobina. |
WO2021202284A1 (en) | 2020-03-31 | 2021-10-07 | Global Blood Therapeutics, Inc. | Modulators of hemoglobin |
Family Cites Families (435)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE276479C (zh) | ||||
DE258226C (zh) | ||||
DE226590C (zh) | ||||
NL214522A (zh) | 1956-02-13 | 1900-01-01 | ||
BE787580A (fr) | 1971-08-13 | 1973-02-14 | Hoechst Ag | Procede de preparation de derives du furanne |
BE787576A (fr) | 1971-08-13 | 1973-02-14 | Hoechst Ag | Derives de benzofuranne et leur utilisation comme azureurs optiques |
GB1409865A (en) | 1973-02-13 | 1975-10-15 | Science Union & Cie | Dihydropyridines derivatives their preparation and pharmaceu tical compositions containing them |
GB1593417A (en) | 1976-12-22 | 1981-07-15 | Squibb & Sons Inc | Carbocyclic-fused pyrazolopyridine derivatives |
US4062858A (en) | 1976-12-22 | 1977-12-13 | E. R. Squibb & Sons, Inc. | Derivatives of 5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)-ones and 11(1H)-imines |
DE2964427D1 (en) | 1978-10-04 | 1983-02-03 | Ciba Geigy Ag | Process for the preparation of furanyl-benzazoles |
DE2853765A1 (de) | 1978-12-13 | 1980-06-26 | Bayer Ag | Verfahren zur herstellung von benzimidazolylbenzofuranen |
DE2904829A1 (de) | 1979-02-08 | 1980-08-14 | Bayer Ag | Verfahren zur herstellung von benzimidazolylbenzofuran |
GB2053218B (en) | 1979-06-29 | 1984-01-25 | Wellcome Found | Pharmaceutical ethers of 2,6-dihydroxybenzaldehyde |
HU190371B (en) * | 1980-12-18 | 1986-08-28 | The Wellcome Foundation Ltd,Gb | Process for producing ether-type compounds and pharmaceutical compositions containing them as active agents |
JPS5929667A (ja) | 1982-08-13 | 1984-02-16 | Otsuka Pharmaceut Co Ltd | カルボスチリル誘導体および強心剤 |
US4478834A (en) | 1983-02-11 | 1984-10-23 | Usv Pharmaceutical Corporation | Dihydropyridines and their use in the treatment of asthma |
GB8402740D0 (en) | 1984-02-02 | 1984-03-07 | Scras | Furo-(3 4-c)-pyridine derivatives |
JPS6140236A (ja) | 1984-08-02 | 1986-02-26 | Yamanouchi Pharmaceut Co Ltd | ハイドロキノン誘導体 |
DE3431004A1 (de) | 1984-08-23 | 1986-03-06 | Hoechst Ag, 6230 Frankfurt | Neue 3-pyridylverbindungen und verfahren zu ihrer herstellung |
GB8603475D0 (en) | 1986-02-12 | 1986-03-19 | Glaxo Group Ltd | Chemical compounds |
DK111387A (da) | 1986-03-05 | 1987-09-06 | Otsuka Pharma Co Ltd | Carbostyrilderivater og salte deraf, laegemiddel indeholdende saadanne derivater samt fremgangsmaade til fremstilling af derivaterne |
US4831041A (en) | 1986-11-26 | 1989-05-16 | Fujisawa Pharmaceutical Co., Ltd. | Imidazopyridine compounds and processes for preparation thereof |
EP0278686A1 (en) | 1987-02-07 | 1988-08-17 | The Wellcome Foundation Limited | Pyridopyrimidines methods for their preparation and pharmaceutical formulations thereof |
JPH07121937B2 (ja) | 1987-03-18 | 1995-12-25 | 大塚製薬株式会社 | カルボスチリル誘導体 |
JPS63258463A (ja) * | 1987-04-14 | 1988-10-25 | Kumiai Chem Ind Co Ltd | 2−フエノキシピリミジン誘導体及び除草剤 |
GB8711802D0 (en) | 1987-05-19 | 1987-06-24 | Fujisawa Pharmaceutical Co | Dithioacetal compounds |
GB8718940D0 (en) | 1987-08-11 | 1987-09-16 | Glaxo Group Ltd | Chemical compounds |
US4920131A (en) | 1987-11-03 | 1990-04-24 | Rorer Pharmaceutical Corp. | Quinoline derivatives and use thereof as antagonists of leukotriene D4 |
JP2650038B2 (ja) | 1988-01-27 | 1997-09-03 | サントリー株式会社 | ピロリチジン化合物およびその用途 |
JPH01305081A (ja) | 1988-04-04 | 1989-12-08 | E R Squibb & Sons Inc | 3―アシルアミノ―1―[[[(置換スルホニル)アミノ〕カルボニル〕アミノ〕―2―アゼチジノン類 |
US4952574A (en) | 1988-09-26 | 1990-08-28 | Riker Laboratories, Inc. | Antiarrhythmic substituted N-(2-piperidylmethyl)benzamides |
IE81170B1 (en) | 1988-10-21 | 2000-05-31 | Zeneca Ltd | Pyridine derivatives |
US5236917A (en) | 1989-05-04 | 1993-08-17 | Sterling Winthrop Inc. | Saccharin derivatives useful as proteolytic enzyme inhibitors and compositions and method of use thereof |
IT1230859B (it) | 1989-06-05 | 1991-11-08 | Corvi Camillo Spa | 2 alchinilfenoli sostituiti ad azione anti infiammatoria, procedimento per la loro preparazione e composizioni farmaceutiche che li contengono. |
WO1991009594A1 (en) | 1989-12-28 | 1991-07-11 | Virginia Commonwealth University | Sigma receptor ligands and the use thereof |
GB2244054B (en) | 1990-04-19 | 1994-04-06 | Ici Plc | Pyridine derivatives |
NZ238576A (en) | 1990-06-18 | 1994-12-22 | Merck & Co Inc | Pyridinone derivatives, preparation and pharmaceutical compositions thereof |
CA2051705A1 (en) | 1990-06-19 | 1991-12-20 | Kiyoaki Katano | Pyridine derivatives having angiotensin ii antagonism |
NL9001752A (nl) | 1990-08-02 | 1992-03-02 | Cedona Pharm Bv | Nieuwe 1,4-dihydropyridinederivaten. |
IL99731A0 (en) | 1990-10-18 | 1992-08-18 | Merck & Co Inc | Hydroxylated pyridine derivatives,their preparation and pharmaceutical compositions containing them |
JPH05301872A (ja) | 1992-04-23 | 1993-11-16 | Kumiai Chem Ind Co Ltd | ピコリン酸誘導体及び除草剤 |
US5403816A (en) | 1990-10-25 | 1995-04-04 | Kumiai Chemical Industry Co., Ltd. | Picolinic acid derivative and herbicidal composition |
WO1992013841A1 (de) | 1991-02-08 | 1992-08-20 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Komplexbildner |
JPH0641118A (ja) | 1991-05-31 | 1994-02-15 | Kumiai Chem Ind Co Ltd | ピコリン酸誘導体及び除草剤 |
US5185251A (en) | 1991-06-07 | 1993-02-09 | Merck & Co., Inc. | Microbial transformation of a substituted pyridinone using actinoplanacete sp. MA 6559 |
JPH06509069A (ja) | 1991-06-27 | 1994-10-13 | バージニア・コモンウェルス・ユニバーシティ | シグマレセプターリガンドおよびその用途 |
JP2600644B2 (ja) | 1991-08-16 | 1997-04-16 | 藤沢薬品工業株式会社 | チアゾリルベンゾフラン誘導体 |
FR2680512B1 (fr) | 1991-08-20 | 1995-01-20 | Adir | Nouveaux derives de 2,4-thiazolidinedione, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
US5202243A (en) | 1991-10-04 | 1993-04-13 | Merck & Co., Inc. | Method of hydroxylating 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methyl-2-(1H)-pyridinone by incubation with liver slices |
GB9203798D0 (en) | 1992-02-21 | 1992-04-08 | Fujisawa Pharmaceutical Co | Quinolylbenzofuran derivatives,processes for preparation thereof and pharmaceutical composition comprising the same |
EP0648209A1 (de) | 1992-07-01 | 1995-04-19 | Byk Gulden Lomberg Chemische Fabrik GmbH | Kontrastmittel für die mr diagnostik |
US5290941A (en) | 1992-10-14 | 1994-03-01 | Merck & Co., Inc. | Facile condensation of methylbenzoxazoles with aromatic aldehydes |
KR0173145B1 (ko) | 1993-04-07 | 1999-02-01 | 고바야시 유키오 | 티아졸리딘 유도체 및 이를 함유하는 약학적 조성물 |
DE4318550A1 (de) | 1993-06-04 | 1994-12-08 | Boehringer Mannheim Gmbh | Aryliden-4-oxo-2-thioxo-3- thiazolidincarbonsäuren, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel |
US5534529A (en) | 1993-06-30 | 1996-07-09 | Sankyo Company, Limited | Substituted aromatic amides and ureas derivatives having anti-hypercholesteremic activity, their preparation and their therapeutic uses |
JPH0725882A (ja) | 1993-07-07 | 1995-01-27 | Res Dev Corp Of Japan | アクロメリン酸bおよびeを製造するための中間体と、その製造方法 |
ES2132284T3 (es) | 1993-08-05 | 1999-08-16 | Hoechst Marion Roussel Inc | Derivados de carbamato de 2-(piperidin-4-il, piridin-4-il y tetrahidropiridin-4-il)-benzofurano-7, su preparacion y su uso como inhibidores de acetilcolinesterasa. |
EP0640609A1 (en) | 1993-08-24 | 1995-03-01 | Ono Pharmaceutical Co., Ltd. | Fused phenol derivatives having inhibitory activity on TXA2 synthetase, and 5-lipoxygenase and scavenging activity on oxygen species |
US5840900A (en) | 1993-10-20 | 1998-11-24 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
US5880131A (en) | 1993-10-20 | 1999-03-09 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
US5965566A (en) | 1993-10-20 | 1999-10-12 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
US5605976A (en) | 1995-05-15 | 1997-02-25 | Enzon, Inc. | Method of preparing polyalkylene oxide carboxylic acids |
AU7992594A (en) | 1993-11-19 | 1995-06-06 | Ciba-Geigy Ag | Benzothiophene derivatives possessing a methoxyimino substituent as microbicides |
EP0658559A1 (de) * | 1993-12-14 | 1995-06-21 | Chemisch Pharmazeutische Forschungsgesellschaft m.b.H. | Thienothiazinderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als 5-dipoxygenase und Cyclooxygenaseinhibitoren |
WO1995021854A1 (en) | 1994-02-14 | 1995-08-17 | Merrell Pharmaceuticals Inc. | Novel mercaptoacetylamido 1,3,4,5-tetrahydro-benzo[c]azepin-3-one disulfide derivatives useful as inhibitors of enkephalinase and ace |
TW474813B (en) | 1994-06-10 | 2002-02-01 | Geltex Pharma Inc | Alkylated composition for removing bile salts from a patient |
GB9420557D0 (en) | 1994-10-12 | 1994-11-30 | Zeneca Ltd | Aromatic compounds |
DE4442050A1 (de) | 1994-11-25 | 1996-05-30 | Hoechst Ag | Heterospiroverbindungen und ihre Verwendung als Elektrolumineszenzmaterialien |
US5650408A (en) | 1995-06-07 | 1997-07-22 | Karanewsky; Donald S. | Thiazolo benzazepine containing dual action inhibitors |
GB9511694D0 (en) | 1995-06-09 | 1995-08-02 | Fujisawa Pharmaceutical Co | Benzamide derivatives |
TW434240B (en) | 1995-06-20 | 2001-05-16 | Zeneca Ltd | Aromatic compounds, preparation thereof and pharmaceutical composition comprising same |
EP0862435A4 (en) | 1995-11-22 | 1999-02-03 | Merck & Co Inc | INHIBITORS OF FARNESYL PROTEIN TRANSFERASE |
GB9604311D0 (en) | 1996-02-29 | 1996-05-01 | Merck & Co Inc | Inhibitors of farnesyl-protein transferase |
JP3895404B2 (ja) | 1996-05-17 | 2007-03-22 | 興和株式会社 | カルコン誘導体及びこれを含有する医薬 |
WO1997041120A1 (en) | 1996-07-26 | 1997-11-06 | Dr. Reddy's Research Foundation | Thiazolidinedione compounds having antidiabetic, hypolipidaemic, antihypertensive properties, process for their preparation and pharmaceutical compositions thereof |
EP0922028A1 (en) | 1996-08-26 | 1999-06-16 | Genetics Institute, Inc. | Inhibitors of phospholipase enzymes |
US6630496B1 (en) | 1996-08-26 | 2003-10-07 | Genetics Institute Llc | Inhibitors of phospholipase enzymes |
AU4136197A (en) | 1996-09-09 | 1998-03-26 | Kyowa Hakko Kogyo Co. Ltd. | Pyrrolocarbazole derivatives |
WO1998021199A2 (en) | 1996-11-12 | 1998-05-22 | Novartis Ag | Pyrazole derivatives useful as herbicides |
US5932590A (en) | 1996-12-05 | 1999-08-03 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
US5977134A (en) | 1996-12-05 | 1999-11-02 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
US6043389A (en) | 1997-03-11 | 2000-03-28 | Mor Research Applications, Ltd. | Hydroxy and ether-containing oxyalkylene esters and uses thereof |
FR2761069A1 (fr) | 1997-03-20 | 1998-09-25 | Pf Medicament | Spiroamines derivees de dihydrobenzofuranes, leur preparation et leur application comme medicaments |
FR2761687B1 (fr) | 1997-04-08 | 2000-09-15 | Centre Nat Rech Scient | Derives de quinoleines, possedant notamment des proprietes antivirales, leurs preparations et leurs applications biologiques |
US5760232A (en) | 1997-06-16 | 1998-06-02 | Schering Corporation | Synthesis of intermediates useful in preparing bromo-substituted tricyclic compounds |
US6214817B1 (en) | 1997-06-20 | 2001-04-10 | Monsanto Company | Substituted pyridino pentaazamacrocyle complexes having superoxide dismutase activity |
US6011042A (en) | 1997-10-10 | 2000-01-04 | Enzon, Inc. | Acyl polymeric derivatives of aromatic hydroxyl-containing compounds |
EP1023270A4 (en) | 1997-10-17 | 2001-04-18 | Merck & Co Inc | INHIBITORS OF FARNESYL PROTEIN TRANSFERASE |
US6103723A (en) | 1997-10-17 | 2000-08-15 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
US6111107A (en) | 1997-11-20 | 2000-08-29 | Enzon, Inc. | High yield method for stereoselective acylation of tertiary alcohols |
BR9815170A (pt) | 1997-12-12 | 2000-10-10 | Euro Celtique S A Luxembourg | "método de obter composto aplicável no tratamento de asma em mamìferos" |
ID26123A (id) | 1998-02-25 | 2000-11-23 | Genetics Inst | Penghambat-penghambat phospholipase a2 |
JP2002506873A (ja) | 1998-03-18 | 2002-03-05 | アリアド・ファーマシューティカルズ・インコーポレイテッド | 複素環式シグナル伝達阻害剤、それを含む組成物 |
US6214879B1 (en) | 1998-03-24 | 2001-04-10 | Virginia Commonwealth University | Allosteric inhibitors of pyruvate kinase |
AU762726B2 (en) | 1998-03-31 | 2003-07-03 | Acadia Pharmaceuticals, Inc. | Compounds with activity on muscarinic receptors |
US6528529B1 (en) | 1998-03-31 | 2003-03-04 | Acadia Pharmaceuticals Inc. | Compounds with activity on muscarinic receptors |
US6153655A (en) | 1998-04-17 | 2000-11-28 | Enzon, Inc. | Terminally-branched polymeric linkers and polymeric conjugates containing the same |
GB9810860D0 (en) | 1998-05-20 | 1998-07-22 | Hoechst Schering Agrevo Gmbh | Substituted pyridine and pyrimidines, processes for their preparation and their use as pesticides |
US6232320B1 (en) | 1998-06-04 | 2001-05-15 | Abbott Laboratories | Cell adhesion-inhibiting antiinflammatory compounds |
PL345906A1 (en) | 1998-06-04 | 2002-01-14 | Abbott Lab | Cell adhesion-inhibiting antinflammatory compounds |
GB9818627D0 (en) | 1998-08-26 | 1998-10-21 | Glaxo Group Ltd | Improvements in dva vaccination |
GB9823871D0 (en) | 1998-10-30 | 1998-12-23 | Pharmacia & Upjohn Spa | 2-Amino-thiazole derivatives, process for their preparation, and their use as antitumour agents |
US20030060425A1 (en) | 1998-11-24 | 2003-03-27 | Ahlem Clarence N. | Immune modulation method using steroid compounds |
WO2000035858A1 (en) | 1998-12-14 | 2000-06-22 | F. Hoffmann-La Roche Ag | Phenylglycine derivatives |
CA2358955A1 (en) | 1998-12-31 | 2000-07-13 | Aventis Pharmaceuticals Inc. | N-carboxymethyl substituted benzolactams as inhibitors of matrix metalloproteinase |
US6544980B2 (en) | 1998-12-31 | 2003-04-08 | Aventis Pharmaceuticals Inc. | N-carboxymethyl substituted benzolactams as inhibitors of matrix metalloproteinase |
MXPA01007957A (es) | 1999-02-04 | 2002-07-30 | Millennium Pharm Inc | Receptor helicoidal acoplado a la proteina-g que une compuestos y metodos para el uso del mismo. |
MXPA01009733A (es) * | 1999-03-31 | 2002-11-04 | Basf Ag | Diamidas del acido piridin-2,3-dicarboxilico. |
JP2000302757A (ja) | 1999-04-16 | 2000-10-31 | Shiseido Co Ltd | N−置換ピペリジン誘導体 |
US6251927B1 (en) | 1999-04-20 | 2001-06-26 | Medinox, Inc. | Methods for treatment of sickle cell anemia |
KR100693771B1 (ko) | 1999-04-28 | 2007-03-12 | 사노피-아벤티스 도이칠란트 게엠베하 | Ppar 수용체 리간드로서의 트리아릴 산 유도체 및 이를 포함하는 약제학적 조성물 |
MXPA01011502A (es) | 1999-05-14 | 2003-08-20 | Boehringer Ingelheim Pharma | Compuestos de tipo profarmaco anti-tumorigenos, activados por enzimas. |
US6184228B1 (en) | 1999-05-25 | 2001-02-06 | Anadys Pharmaceuticals, Inc. | Anti-sickling agents: selection methods and effective compounds |
WO2000075145A1 (en) | 1999-06-03 | 2000-12-14 | Abbott Laboratories | Cell adhesion-inhibiting antiinflammatory compounds |
AUPQ105499A0 (en) | 1999-06-18 | 1999-07-08 | Biota Scientific Management Pty Ltd | Antiviral agents |
AU778218B2 (en) | 1999-06-28 | 2004-11-25 | Janssen Pharmaceutica N.V. | Respiratory syncytial virus replication inhibitors |
EP1217001B1 (en) | 1999-09-28 | 2005-12-07 | Eisai Co., Ltd. | Quinuclidine compounds and drugs containing the same as the active ingredient |
SE9903759D0 (sv) | 1999-10-18 | 1999-10-18 | Astra Ab | Pharmaceutically active compounds |
JP5117658B2 (ja) | 1999-11-05 | 2013-01-16 | エミスフェアー・テクノロジーズ・インク | フェノキシカルボン酸化合物及び活性剤を送達するための組成物 |
AUPQ407699A0 (en) | 1999-11-16 | 1999-12-09 | Fujisawa Pharmaceutical Co., Ltd. | Aminoalcohol derivatives |
NZ519984A (en) | 2000-01-07 | 2004-03-26 | Transform Pharmaceuticals Inc | High-throughput formation, identification, and analysis of diverse solid-forms |
AU2001230537A1 (en) | 2000-02-01 | 2001-08-14 | Daiichi Pharmaceutical Co., Ltd. | Pyridoxazine derivatives |
FR2804431A1 (fr) | 2000-02-02 | 2001-08-03 | Adir | Nouveaux derives heterocycliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
US6506755B2 (en) | 2000-02-03 | 2003-01-14 | Hoffmann-La Roche Inc. | Thiazolidinecarboxyl acids |
AUPQ585000A0 (en) | 2000-02-28 | 2000-03-16 | Fujisawa Pharmaceutical Co., Ltd. | Aminoalcohol derivatives |
BR0109107A (pt) | 2000-03-09 | 2002-12-03 | Aventis Pharma Gmbh | Usos terapêuticos de mediadores ppar |
WO2001066534A2 (en) | 2000-03-09 | 2001-09-13 | Abbott Laboratories | Cyclic and bicyclic diamino histamine-3 receptor antagonists |
US6559140B2 (en) | 2000-03-09 | 2003-05-06 | Abbott Laboratories | Cyclic and bicyclic diamino histamine-3 receptor antagonists |
AU2001245823A1 (en) | 2000-03-17 | 2001-10-03 | Corixa Corporation | Novel amphipathic aldehydes and their use as adjuvants and immunoeffectors |
AUPQ841300A0 (en) | 2000-06-27 | 2000-07-20 | Fujisawa Pharmaceutical Co., Ltd. | New aminoalcohol derivatives |
CZ303639B6 (cs) | 2000-07-14 | 2013-01-23 | F. Hoffmann-La Roche Ag | N-Oxid derivátu 4-fenylpyridinu, zpusob jeho prípravy a lécivo s jeho obsahem |
US20020142995A1 (en) | 2000-08-01 | 2002-10-03 | Nicolau Yves Claude | Ammonium salts of hemoglobin allosteric effectors, and uses thereof |
CA2419027A1 (en) | 2000-08-08 | 2002-02-14 | Ortho-Mcneil Pharmaceutical, Inc. | Bicyclic compounds as h3 receptor ligands |
US6653313B2 (en) | 2000-08-10 | 2003-11-25 | Warner-Lambert Company Llc | 1,4-dihydropyridine compounds as bradykinin antagonists |
JP4272338B2 (ja) | 2000-09-22 | 2009-06-03 | バイエル アクチェンゲゼルシャフト | ピリジン誘導体 |
AUPR034000A0 (en) | 2000-09-25 | 2000-10-19 | Fujisawa Pharmaceutical Co., Ltd. | Aminoalcohol derivatives |
IL155702A0 (en) | 2000-11-20 | 2003-11-23 | Biovitrum Ab | Piperazinylpyrazine compounds as agonist or antagonist of serotonin 5-ht2 receptor |
EP1217000A1 (en) | 2000-12-23 | 2002-06-26 | Aventis Pharma Deutschland GmbH | Inhibitors of factor Xa and factor VIIa |
JPWO2002051849A1 (ja) | 2000-12-26 | 2004-04-22 | 第一製薬株式会社 | Cdk4活性阻害剤 |
DE60139025D1 (de) | 2000-12-28 | 2009-07-30 | Takeda Pharmaceutical | Alkansäurederivate, verfahren zu deren herstellung und deren verwendung |
US20040077654A1 (en) | 2001-01-15 | 2004-04-22 | Bouillot Anne Marie Jeanne | Aryl piperidine and piperazine derivatives as inducers of ldl-receptor expression |
SE0100326D0 (sv) | 2001-02-02 | 2001-02-02 | Astrazeneca Ab | New compounds |
US20030022923A1 (en) | 2001-03-01 | 2003-01-30 | Medinox, Inc. | Methods for treatment of sickle cell anemia |
SE0101324D0 (sv) | 2001-04-12 | 2001-04-12 | Astrazeneca Ab | New process |
US6627646B2 (en) | 2001-07-17 | 2003-09-30 | Sepracor Inc. | Norastemizole polymorphs |
MXPA04000695A (es) | 2001-07-23 | 2005-08-26 | Galileo Pharmaceuticals Inc | Compuestos citoprotectores, formulaciones farmaceuticas y cosmeticas y metodos. |
JP2003075970A (ja) | 2001-08-31 | 2003-03-12 | Konica Corp | ハロゲン化銀カラー写真感光材料、カラー写真感光材料、その画像形成方法及びデジタル画像情報作製方法 |
KR100467313B1 (ko) | 2001-11-22 | 2005-01-24 | 한국전자통신연구원 | 적색 유기 전기발광 화합물 및 그 제조 방법과 전기발광소자 |
US20030187026A1 (en) | 2001-12-13 | 2003-10-02 | Qun Li | Kinase inhibitors |
BR0215240A (pt) | 2001-12-19 | 2004-10-26 | Atherogenics Inc | Derivados de calcona e seu uso no tratamento de doenças |
US20030190333A1 (en) | 2002-02-04 | 2003-10-09 | Corixa Corporation | Immunostimulant compositions comprising aminoalkyl glucosaminide phosphates and saponins |
ATE399012T1 (de) | 2002-04-03 | 2008-07-15 | Topotarget Uk Ltd | Carbaminsäurederivate enthaltend eine piperazin verknüpfung als hdac-inhibitoren |
US20040072796A1 (en) | 2002-04-18 | 2004-04-15 | Embury Stephen H. | Method and composition for preventing pain in sickle cell patients |
US6608076B1 (en) | 2002-05-16 | 2003-08-19 | Enzon, Inc. | Camptothecin derivatives and polymeric conjugates thereof |
GB0212785D0 (en) | 2002-05-31 | 2002-07-10 | Glaxo Group Ltd | Compounds |
JP2006505522A (ja) * | 2002-08-08 | 2006-02-16 | スミスクライン ビーチャム コーポレーション | チオフェン化合物 |
US7074809B2 (en) | 2002-08-09 | 2006-07-11 | Astrazeneca Ab | Compounds |
WO2004014370A2 (en) | 2002-08-09 | 2004-02-19 | Astrazeneca Ab | Oxadiazoles as modulators of metabotropic glutamate receptor-5 |
TW200420542A (en) | 2002-08-23 | 2004-10-16 | Kirin Brewery | A compound having TGF β inhibition activity and a medicinal composition containing the same |
AU2003262023A1 (en) | 2002-09-10 | 2004-04-30 | Takeda Pharmaceutical Company Limited | Five-membered heterocyclic compounds |
GB0223712D0 (en) | 2002-10-14 | 2002-11-20 | Astrazeneca Ab | Chemical intermediate |
EP1567490B1 (en) | 2002-12-04 | 2011-10-05 | Virginia Commonwealth University | Anti-sickling agents |
US6908921B2 (en) | 2002-12-13 | 2005-06-21 | Merck & Co., Inc. | Quinoxalinone derivatives as bradykinin B1 antagonists |
WO2004056727A2 (en) | 2002-12-19 | 2004-07-08 | Atherogenics, Inc. | Process of making chalcone derivatives |
EP1577317A4 (en) | 2002-12-25 | 2007-05-09 | Kissei Pharmaceutical | NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVES, MEDICINAL COMPOSITIONS COMPRISING SAID DERIVATIVES AND MEDICAL USE OF SAID DERIVATIVES |
EP1596818B1 (de) | 2003-02-24 | 2006-05-03 | Randolph Dr. Dr. Prof. Riemschneider | Kosmetische zusammensetzung mit whitening-effekt, verfahren zu ihrer herstellung und ihre verwendung |
GB0305142D0 (en) | 2003-03-06 | 2003-04-09 | Eisai London Res Lab Ltd | Synthesis |
US20040186077A1 (en) | 2003-03-17 | 2004-09-23 | Medicure International Inc. | Novel heteroaryl phosphonates as cardioprotective agents |
ZA200507752B (en) | 2003-03-28 | 2007-01-31 | Threshold Pharmaceuticals Inc | Compositions and methods for treating cancer |
EP1611902A4 (en) | 2003-04-03 | 2006-04-12 | Kyowa Hakko Kogyo Kk | MEANS FOR THE PREVENTION AND / OR TREATMENT OF NEUROPATHIC PAIN |
GB0308333D0 (en) | 2003-04-10 | 2003-05-14 | Glaxo Group Ltd | Novel compounds |
EP1613613B1 (en) | 2003-04-11 | 2021-06-02 | Genzyme Corporation | Cxcr4 chemokine receptor binding compounds |
BRPI0409949A (pt) | 2003-05-01 | 2006-04-25 | Bristol Myers Squibb Co | compostos de pirazol amida aril-substituìda úteis como inibidores de cinase |
WO2004099127A1 (en) | 2003-05-07 | 2004-11-18 | Novo Nordisk A/S | Novel compounds as kinase inhibitors |
MXPA05013224A (es) | 2003-06-12 | 2006-03-09 | Novo Nordisk As | Piridinilcarbamatos como inhibidores de lipasa sensible a hormonas. |
WO2005019220A2 (en) | 2003-08-11 | 2005-03-03 | Cellular Genomics Inc. | Substituted imidazo[1,2-a]pyrazines as modulators of kinase activity |
US7411083B2 (en) | 2003-09-25 | 2008-08-12 | Wyeth | Substituted acetic acid derivatives |
DE602004019294D1 (de) | 2003-10-01 | 2009-03-19 | Xention Ltd | Tetrahydronaphthalin- und harnstoffderivate |
US7211671B2 (en) | 2003-10-01 | 2007-05-01 | Bristol Myers Squibb Company | Substituted 1,3-dihydro-imidazol-2-one and 1,3-dihydro-imidazol-2-thione derivatives as inhibitors of matrix metalloproteinases and/or TNF-α converting enzyme (TACE) |
WO2005042491A1 (en) | 2003-10-22 | 2005-05-12 | Arena Pharmaceuticals, Inc. | Benzazepine derivatives and methods of prophylaxis or treatment of 5ht2c receptor associated diseases |
US20080027075A1 (en) | 2003-10-31 | 2008-01-31 | Lica Pharmaceuticals A/S | Quaternary Amino-Function Chalcones |
EP2314576A1 (en) | 2003-11-05 | 2011-04-27 | F.Hoffmann-La Roche Ag | Phenyl derivatives as PPAR agonists |
EP1687268A1 (en) | 2003-11-10 | 2006-08-09 | Schering Aktiengesellschaft | Benzylether amine compounds useful as ccr-5 antagonists |
CN101966183A (zh) | 2003-12-02 | 2011-02-09 | 细胞基因公司 | 用于治疗和控制血红蛋白病和贫血病的方法和组合物 |
EP1555264A1 (en) | 2004-01-15 | 2005-07-20 | Sireen AG | Five-membered heterocyclic compounds as inhibitors of SRC family protein kinase. |
US7378439B2 (en) | 2004-01-20 | 2008-05-27 | Usv, Ltd. | Process for the preparation of 4-(2-dipropylaminoethyl)-1,3-dihydro-2H-indol-2-one hydrochloride |
JP2007519735A (ja) | 2004-01-30 | 2007-07-19 | メルク エンド カムパニー インコーポレーテッド | Hivインテグラーゼ阻害剤として有用であるn−ベンジル−3,4−ジヒドロキシピリジン−2−カルボキサミド及びn−ベンジル−2,3−ジヒドロキシピリジン−4−カルボキサミド化合物 |
WO2005077373A2 (en) | 2004-02-03 | 2005-08-25 | Astrazeneca Ab | Treatment of gastro-esophageal reflux disease (gerd) |
WO2005077368A2 (en) | 2004-02-03 | 2005-08-25 | Astrazeneca Ab | Treatment of gastro-esophageal reflux disease (gerd) |
GB0403038D0 (en) | 2004-02-11 | 2004-03-17 | Novartis Ag | Organic compounds |
AU2005222398A1 (en) | 2004-03-08 | 2005-09-22 | Wyeth | Ion channel modulators |
US20070281937A1 (en) | 2004-03-08 | 2007-12-06 | Robert Zelle | Ion Channel Modulators |
EP1725554A1 (en) | 2004-03-09 | 2006-11-29 | Istituto di Richerche di Biologia Molecolare P. Angeletti S.p.A. | Hiv integrase inhibitors |
US20080132458A1 (en) | 2004-03-10 | 2008-06-05 | Threshold Pharmaceuticals, Inc. | Hypoxia-Activated Anti-Cancer Agents |
DE102004015226B3 (de) | 2004-03-24 | 2005-08-25 | Siemens Ag | Verfahren zum Plasmareinigen eines Werkstücks und zu dessen Durchführung geeignete Vorrichtung |
US7297817B2 (en) | 2004-04-13 | 2007-11-20 | Cephalon France | Thio-substituted arylmethanesulfinyl derivatives |
JP2007533730A (ja) | 2004-04-20 | 2007-11-22 | アブ サイエンス | 筋炎および筋ジストロフィーを含む炎症性筋疾患を処置するためのc−kit阻害剤の使用法 |
WO2005102318A1 (en) | 2004-04-20 | 2005-11-03 | Ab Science | Use of c-kit inhibitors for treating hiv related diseases |
CA2563752A1 (en) * | 2004-04-22 | 2005-11-03 | Allos Therapeutics, Inc. | Compositions of allosteric hemoglobin modifiers and methods of making the same |
JP2007533731A (ja) | 2004-04-23 | 2007-11-22 | アブ サイエンス | マラリア原虫関連の疾病を処置するためのc−kit阻害剤の使用法 |
JP2007533732A (ja) | 2004-04-23 | 2007-11-22 | アブ サイエンス | 線維症を処置するためのc−kit阻害剤の使用法 |
WO2005102326A2 (en) | 2004-04-23 | 2005-11-03 | Ab Science | Use of c-kit inhibitors for treating renal diseases |
CA2566104A1 (en) | 2004-05-18 | 2005-12-01 | Ab Science | Use of mast cells inhibitors for treating patients exposed to chemical or biological weapons |
WO2005115385A1 (en) | 2004-05-24 | 2005-12-08 | Ab Science | Use of c-kit inhibitors for treating acne |
WO2005115304A2 (en) | 2004-05-24 | 2005-12-08 | Ab Science | Use of c-kit inhibitors for treating fibrodysplasia |
TW200606133A (en) | 2004-06-30 | 2006-02-16 | Sankyo Co | Substituted benzene compounds |
TW200606129A (en) | 2004-07-26 | 2006-02-16 | Chugai Pharmaceutical Co Ltd | Novel cyclohexane derivative, its prodrug, its salt and diabetic therapeutic agent containing the same |
GB0420722D0 (en) | 2004-09-17 | 2004-10-20 | Addex Pharmaceuticals Sa | Novel allosteric modulators |
CA2585165A1 (en) | 2004-10-28 | 2006-05-18 | Medicure International Inc. | Dual antiplatelet/anticoagulant pyridoxine analogs |
EP1831170A4 (en) | 2004-12-14 | 2009-10-14 | Astrazeneca Ab | SUBSTITUTED AMINOPYRIDINES AND THEIR USE |
US7968574B2 (en) | 2004-12-28 | 2011-06-28 | Kinex Pharmaceuticals, Llc | Biaryl compositions and methods for modulating a kinase cascade |
JP5317257B2 (ja) | 2005-02-21 | 2013-10-16 | 塩野義製薬株式会社 | Hivインテグラーゼ阻害活性を有する2環性カルバモイルピリドン誘導体 |
CA2601871A1 (en) | 2005-03-19 | 2006-09-28 | Amorepacific Corporation | Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same |
JP4874958B2 (ja) | 2005-03-30 | 2012-02-15 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | ピリジン誘導体を含有する抗真菌剤 |
GB0506677D0 (en) | 2005-04-01 | 2005-05-11 | Btg Int Ltd | Iron modulators |
EP1879881A2 (en) | 2005-04-14 | 2008-01-23 | Bristol-Myers Squibb Company | Inhibitors of 11-beta hydroxysteroid dehydrogenase type i |
JP2006306926A (ja) | 2005-04-26 | 2006-11-09 | Fuji Photo Film Co Ltd | 液晶組成物及び液晶素子 |
DK3187225T3 (da) | 2005-04-28 | 2022-02-28 | Viiv Healthcare Co | Polycyklisk carbamoylpyridonderivat med hiv-integrasehæmmende aktivitet |
US20080280849A1 (en) | 2005-06-01 | 2008-11-13 | Herve Leh | Synergic Combinations Comprising a Quinoline Compound and Other Hiv Infection Therapeutic Agents |
MX2007015002A (es) | 2005-06-02 | 2008-02-15 | Bayer Cropscience Ag | Derivados de heteroarilo sustituidos con fenilalquilo. |
DE102005025989A1 (de) | 2005-06-07 | 2007-01-11 | Bayer Cropscience Ag | Carboxamide |
JP2006342115A (ja) | 2005-06-10 | 2006-12-21 | Shionogi & Co Ltd | Hivインテグラーゼ阻害活性を有する多環性化合物 |
WO2006137771A1 (en) | 2005-06-20 | 2006-12-28 | Astrazeneca Ab | Process for the preparation of sulfonic acid salts of oxabispidines |
AU2006264649A1 (en) * | 2005-06-30 | 2007-01-11 | Prosidion Limited | GPCR agonists |
CN100562514C (zh) * | 2005-07-22 | 2009-11-25 | 中国科学院上海药物研究所 | 一类取代丙酰胺衍生物、其制备方法和用途 |
GB0516270D0 (en) | 2005-08-08 | 2005-09-14 | Glaxo Group Ltd | Novel compounds |
ES2442865T3 (es) | 2005-09-16 | 2014-02-14 | Janssen Pharmaceutica N.V. | Procedimiento para la preparación de derivados de venzo[E][1,2,4]triazepina-2-ona |
ES2379987T3 (es) | 2005-10-11 | 2012-05-07 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Compuestos de benzofurano marcados isotópicamente como radiotrazadores para proteínas amiloidógenas |
MX2008005137A (es) | 2005-10-27 | 2008-09-29 | Shionogi & Co | Derivado de carbamoilpiridona policiclica que tiene actividad inhibidora en vih integrasa. |
WO2007061923A2 (en) | 2005-11-18 | 2007-05-31 | Takeda San Diego, Inc. | Glucokinase activators |
WO2007081630A2 (en) | 2005-12-21 | 2007-07-19 | Janssen Pharmaceutica, N.V. | Substituted pyrimidinyl kinase inhibitors |
EP1976851A2 (en) | 2006-01-17 | 2008-10-08 | Neurocrine Biosciences, Inc. | Phenoxy-substituted pyrimidines as adenosine receptor antagonists |
WO2007095495A2 (en) | 2006-02-13 | 2007-08-23 | Pharmacopeia, Inc. | Benzodiazepine gcnf modulators for stem cell modulation |
NZ570528A (en) | 2006-02-15 | 2011-09-30 | Allergan Inc | Indole-3-carboxylic acid amide, ester, thioamide and thiol ester compounds bearing aryl or heteroaryl groups having sphingosine-1-phosphate (s1p) receptor antagonist biological activity |
US8013153B2 (en) | 2006-03-23 | 2011-09-06 | Janssen Pharmaceutica, N.V. | Substituted pyrimidine kinase inhibitors |
US7351434B2 (en) | 2006-04-07 | 2008-04-01 | Academia Sinica | Therapeutic Gastrodia extracts |
RU2318818C1 (ru) | 2006-04-12 | 2008-03-10 | Общество С Ограниченной Ответственностью "Исследовательский Институт Химического Разнообразия" | Азагетероциклы, комбинаторная библиотека, фокусированная библиотека, фармацевтическая композиция и способ получения (варианты) |
CA2648207A1 (en) | 2006-04-13 | 2007-10-25 | Vertex Pharmaceuticals Incorporated | Thiophene-carboxamides useful as inhibitors of protein kinases |
JP4963863B2 (ja) | 2006-04-27 | 2012-06-27 | 株式会社Adeka | 新規化合物及び該化合物を含有してなる液晶組成物 |
EP2044038B1 (en) | 2006-06-06 | 2014-07-02 | Cornerstone Therapeutics Inc. | Novel piperazines, pharmaceutical compositions and methods of use thereof |
US7943622B2 (en) | 2006-06-06 | 2011-05-17 | Cornerstone Therapeutics, Inc. | Piperazines, pharmaceutical compositions and methods of use thereof |
WO2007141318A1 (en) | 2006-06-08 | 2007-12-13 | Speedel Experimenta Ag | 2,5-disubstituted piperidines |
GB0614586D0 (en) | 2006-07-22 | 2006-08-30 | Pliva Istrazivacki Inst D O O | Pharmaceutical Formulation |
CN101113148A (zh) | 2006-07-26 | 2008-01-30 | 中国海洋大学 | 二氧哌嗪类化合物及其制备方法和用途 |
AR063211A1 (es) | 2006-07-27 | 2009-01-14 | Amorepacific Corp | Derivados de 3-(piridin-3-il)acrilamida y 3-(piridin-3-il)propionamida, un metodo para su preparacion, una composicion farmaceutica que los comprende y su uso en la fabricacion de medicamentos para el tratamiento de enfermedades asociadas con el receptor vaniloide. |
TW200817424A (en) | 2006-08-04 | 2008-04-16 | Daiichi Sankyo Co Ltd | Benzylphenyl glucopyranoside derivatives |
TWI389895B (zh) | 2006-08-21 | 2013-03-21 | Infinity Discovery Inc | 抑制bcl蛋白質與結合夥伴間之交互作用的化合物及方法 |
JP5466006B2 (ja) | 2006-09-03 | 2014-04-09 | テックフィールズ バイオケム カンパニー リミテッド | 非常に速い皮膚浸透率を有するアセトアミノフェン及び関連化合物の正荷電水溶性プロドラッグ |
WO2008041118A2 (en) | 2006-10-04 | 2008-04-10 | Pfizer Products Inc. | Pyrido[4,3-d]pyrimidin-4(3h)-one derivatives as calcium receptor antagonists |
KR20090068345A (ko) | 2006-10-23 | 2009-06-26 | 머크 앤드 캄파니 인코포레이티드 | 글루코코르티코이드 수용체 리간드로서의 2-[1-페닐-5-하이드록시-4알파-메틸-헥사하이드로사이클로펜타[f]인다졸-5-일]에틸 페닐 유도체 |
WO2008066151A1 (en) | 2006-11-30 | 2008-06-05 | Tokyo Institute Of Technology | Novel curcumin derivative |
TW200835687A (en) | 2006-11-30 | 2008-09-01 | R Tech Ueno Ltd | Thiazole derivatives and their use as VAP-1 inhibitor |
FR2909379B1 (fr) | 2006-11-30 | 2009-01-16 | Servier Lab | Nouveaux derives heterocycliques,leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
DE102006060598A1 (de) | 2006-12-21 | 2008-06-26 | Merck Patent Gmbh | Tetrahydrobenzoisoxazole |
JP2010515750A (ja) | 2007-01-11 | 2010-05-13 | アラーガン インコーポレイテッド | スフィンゴシン−1−ホスフェート(s1p)受容体アンタゴニスト生物活性を有する6−置換インドール−3−カルボン酸アミド化合物 |
US8524917B2 (en) | 2007-01-11 | 2013-09-03 | Allergan, Inc. | 6-substituted indole-3-carboxylic acid amide compounds having sphingosine-1-phosphate (S1P) receptor antagonist biological activity |
US8557853B2 (en) | 2007-02-09 | 2013-10-15 | Allergan, Inc. | Aryl fluoroethyl ureas acting as alpha 2 adrenergic agents |
CA2677949C (en) | 2007-02-22 | 2016-02-09 | Paul Anthony Worthington | Iminipyridine derivatives and their uses as microbiocides |
TWI407960B (zh) | 2007-03-23 | 2013-09-11 | Jerini Ag | 小分子緩激肽b2受體調節劑 |
WO2008121066A1 (en) | 2007-03-30 | 2008-10-09 | Astrazeneca Ab | Novel tricyclic spiropiperidines or spiropyrrolidines and their use as modulators of chemokine receptors |
EP2149545B1 (en) | 2007-05-22 | 2016-10-05 | Sumitomo Chemical Company, Limited | Method for producing benzaldehyde compound |
EP2167464B1 (en) | 2007-05-25 | 2014-12-03 | AbbVie Deutschland GmbH & Co KG | Heterocyclic compounds as positive modulators of metabotropic glutamate receptor 2 (mglu2 receptor) |
WO2009001214A2 (en) | 2007-06-28 | 2008-12-31 | Pfizer Products Inc. | Thieno[2,3-d]pyrimidin-4(3h)-one, isoxazolo[5,4-d]pyrimidin-4(5h)-one and isothiazolo[5,4-d]pyrimidin-4(5h)-one derivatives as calcium receptor antagonists |
US20090069288A1 (en) * | 2007-07-16 | 2009-03-12 | Breinlinger Eric C | Novel therapeutic compounds |
EP2178845B1 (en) | 2007-07-17 | 2013-06-19 | F. Hoffmann-La Roche AG | Inhibitors of 11b-hydroxysteroid dehydrogenase |
US8143253B2 (en) | 2007-07-26 | 2012-03-27 | Novartis Ag | Organic compounds |
TW200918521A (en) | 2007-08-31 | 2009-05-01 | Astrazeneca Ab | Heterocyclic amides and methods of use thereof |
PE20091383A1 (es) | 2007-10-17 | 2009-10-17 | Novartis Ag | DERIVADOS DE IMIDAZO-[1,2-a]PIRIDINA COMO INHIBIDORES DE ALK-5 Y ALK-4 |
JP2009108152A (ja) | 2007-10-29 | 2009-05-21 | Sumitomo Chemical Co Ltd | 重合性化合物および光学フィルム |
AU2008333326B2 (en) | 2007-12-04 | 2013-05-30 | F. Hoffmann-La Roche Ag | Isoxazolo-pyridine derivatives |
US7776875B2 (en) | 2007-12-19 | 2010-08-17 | Hoffman-La Roche Inc. | Spiroindolinone derivatives |
JP2009149754A (ja) | 2007-12-20 | 2009-07-09 | Sumitomo Chemical Co Ltd | 重合性化合物および該重合性化合物を重合してなる光学フィルム |
JP2009203230A (ja) | 2008-01-31 | 2009-09-10 | Daiichi Sankyo Co Ltd | ベンジルフェニルグルコピラノシド誘導体を含有する医薬組成物 |
WO2009105782A1 (en) | 2008-02-21 | 2009-08-27 | Sequoia Pharmaceuticals, Inc. | Hiv protease inhibitor and cytochrome p450 inhibitor combinations |
WO2009106599A2 (en) | 2008-02-29 | 2009-09-03 | Novartis Ag | Substituted piperidines as therapeutic compounds |
US8268834B2 (en) | 2008-03-19 | 2012-09-18 | Novartis Ag | Pyrazine derivatives that inhibit phosphatidylinositol 3-kinase enzyme |
JP5219583B2 (ja) | 2008-03-31 | 2013-06-26 | 住友化学株式会社 | 組成物、光学フィルムとその製造方法、光学部材及び表示装置 |
US8633245B2 (en) | 2008-04-11 | 2014-01-21 | Institute Of Medicinal Molecular Design, Inc. | PAI-1 inhibitor |
EP2272817A4 (en) | 2008-04-11 | 2011-12-14 | Inst Med Molecular Design Inc | INHIBITOR OF PAI-1 |
MX2010011258A (es) | 2008-04-14 | 2011-06-20 | Univ Texas | Inhibidores de molecula pequeña del dominio de homologia de pleckstrin y metodos para usar los mismos. |
JP2011136906A (ja) | 2008-04-18 | 2011-07-14 | Otsuka Pharmaceut Co Ltd | 複素環化合物 |
US8119647B2 (en) | 2008-04-23 | 2012-02-21 | Glenmark Pharmaceuticals S.A. | Fused pyrimidineone compounds as TRPV3 modulators |
ES2599002T3 (es) * | 2008-05-08 | 2017-01-31 | Nova Southeastern University | Inhibidores específicos para receptores del factor de crecimiento endotelial vascular |
JP5514810B2 (ja) | 2008-06-04 | 2014-06-04 | タイメッド バイオロジクス インコーポレイテッド | ピリドキシンに由来するhivインテグラーゼ阻害剤 |
DE102008027574A1 (de) | 2008-06-10 | 2009-12-17 | Merck Patent Gmbh | Neue Pyrrolidinderivate als MetAP-2 Inhibitoren |
JP5314330B2 (ja) | 2008-06-16 | 2013-10-16 | 住友化学株式会社 | 2−(アリールオキシメチル)ベンズアルデヒドの製造方法およびその中間体 |
GB0811451D0 (en) * | 2008-06-20 | 2008-07-30 | Syngenta Participations Ag | Novel microbiocides |
EP2303859A4 (en) | 2008-06-20 | 2012-08-22 | Metabolex Inc | ARYL GPR119 AGONISTS AND USES THEREOF |
ES2711249T3 (es) | 2008-06-27 | 2019-04-30 | Celgene Car Llc | Compuestos de heteroarilo y usos de los mismos |
JP5552121B2 (ja) | 2008-09-04 | 2014-07-16 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ロイコトリエン産生のインドリジン阻害剤 |
JP5443720B2 (ja) | 2008-09-05 | 2014-03-19 | 住友化学株式会社 | 組成物、光学フィルム及びその製造方法、光学部材ならびに表示装置 |
JP2010066630A (ja) | 2008-09-12 | 2010-03-25 | Sumitomo Chemical Co Ltd | 光学フィルムの製造方法及び光学フィルム |
AR073304A1 (es) | 2008-09-22 | 2010-10-28 | Jerini Ag | Moduladores del receptor de bradiquinina b2 de molecula pequena |
WO2010039789A1 (en) | 2008-10-03 | 2010-04-08 | Schering Corporation | Spiro-imidazolone derivatives as glucagon receptor antagonists |
CN106243100B (zh) | 2008-10-10 | 2019-04-09 | Vm生物医药公司 | 治疗酒精使用障碍,疼痛和其他疾病的药物组合与方法 |
WO2010048149A2 (en) | 2008-10-20 | 2010-04-29 | Kalypsys, Inc. | Heterocyclic modulators of gpr119 for treatment of disease |
JP2012508692A (ja) | 2008-11-12 | 2012-04-12 | シェーリング コーポレイション | 脂肪酸結合タンパク質(fabp)の阻害薬 |
US8846664B2 (en) | 2008-11-12 | 2014-09-30 | Ariad Pharmaceuticals, Inc. | Pyrazinopyrazines and derivatives as kinase inhibitors |
KR20110097932A (ko) | 2008-12-08 | 2011-08-31 | 베링거 인겔하임 인터내셔날 게엠베하 | 암 치료용 화합물 |
WO2010073011A2 (en) | 2008-12-23 | 2010-07-01 | Betagenon Ab | Compounds useful as medicaments |
JP5053459B2 (ja) | 2009-01-12 | 2012-10-17 | アイカジェン, インコーポレイテッド | スルホンアミド誘導体 |
US20110319416A1 (en) | 2009-01-28 | 2011-12-29 | Emory University | Subunit Selective NMDA Receptor Antagonists For The Treatment Of Neurological Conditions |
WO2010088518A2 (en) | 2009-01-31 | 2010-08-05 | Kalypsys, Inc. | Heterocyclic modulators of gpr119 for treatment of disease |
TW201033201A (en) * | 2009-02-19 | 2010-09-16 | Hoffmann La Roche | Isoxazole-isoxazole and isoxazole-isothiazole derivatives |
KR101641385B1 (ko) | 2009-03-16 | 2016-07-20 | 스미또모 가가꾸 가부시끼가이샤 | 화합물, 광학 필름 및 광학 필름의 제조 방법 |
JP5899607B2 (ja) | 2009-03-16 | 2016-04-06 | 住友化学株式会社 | 化合物、光学フィルム及び光学フィルムの製造方法 |
WO2010108187A2 (en) | 2009-03-20 | 2010-09-23 | Brandeis University | Compounds and methods for treating mammalian gastrointestinal microbial infections |
CN102421434A (zh) | 2009-03-31 | 2012-04-18 | 利亘制药公司 | 治疗高血压和糖尿病肾病的二苯基磺酰胺内皮素和血管紧张素ii受体激动剂的口服制剂 |
EP2427190B1 (en) | 2009-05-08 | 2013-09-18 | Tetraphase Pharmaceuticals, Inc. | 8-aza tetracycline compounds |
JP2011006360A (ja) | 2009-06-26 | 2011-01-13 | Sumitomo Chemical Co Ltd | 化合物、光学フィルム及び光学フィルムの製造方法 |
JP5739334B2 (ja) | 2009-08-26 | 2015-06-24 | 武田薬品工業株式会社 | 縮合複素環誘導体およびその用途 |
US20120245344A1 (en) | 2009-08-31 | 2012-09-27 | Nippon Chemiphar Co., Ltd. | Gpr119 agonist |
WO2011032169A2 (en) | 2009-09-14 | 2011-03-17 | Phusis Therapeutics Inc. | Pharmaceutical compositions and formulations including inhibitors of the pleckstrin homology domain and methods for using same |
MX2012003170A (es) | 2009-09-21 | 2012-04-11 | Hoffmann La Roche | Compuestos heterociclicos antivirales. |
RS59599B2 (sr) | 2009-11-09 | 2023-03-31 | Wyeth Llc | Formulacije tableta neratinib maleata |
TW201139406A (en) | 2010-01-14 | 2011-11-16 | Glaxo Group Ltd | Voltage-gated sodium channel blockers |
EP2528898A2 (en) | 2010-01-25 | 2012-12-05 | Kareus Therapeutics SA | NOVEL COMPOSITIONS FOR REDUCING Aß 42 PRODUCTION AND THEIR USE IN TREATING ALZHEIMER'S DISEASE (AD) |
WO2011100324A1 (en) | 2010-02-09 | 2011-08-18 | Ironwood Pharmaceuticals Inc. | Cannabinoid receptor agonists |
WO2011100359A1 (en) | 2010-02-09 | 2011-08-18 | Ironwood Pharmaceuticals, Inc. | Cannabinoid agonists |
JP5375644B2 (ja) | 2010-02-10 | 2013-12-25 | 住友化学株式会社 | 組成物及び光学フィルム |
CA2794003A1 (en) | 2010-03-25 | 2011-09-29 | Merck Sharp & Dohme Corp. | Novel spiro imidazolones as glucagon receptor antagonists, compositions, and methods for their use |
CN102206172B (zh) | 2010-03-30 | 2015-02-25 | 中国医学科学院医药生物技术研究所 | 一组取代双芳基化合物及其制备方法和抗病毒应用 |
KR101698153B1 (ko) | 2010-04-26 | 2017-01-23 | 광주과학기술원 | P2x1 및 p2x3 수용체 길항제로 사용되는 신규한 피리딘 카르복실산계 화합물, 이의 제조방법 및 이를 포함하는 조성물 |
CN102232949A (zh) | 2010-04-27 | 2011-11-09 | 孙远 | 提高药物溶出度的组合物及其制备方法 |
TWI535442B (zh) | 2010-05-10 | 2016-06-01 | Kyowa Hakko Kirin Co Ltd | A nitrogen-containing heterocyclic compound having an action of inhibiting the production of canine erythritine |
NZ603789A (en) | 2010-05-26 | 2015-03-27 | Sunovion Pharmaceuticals Inc | Heteroaryl compounds and methods of use thereof |
JP5703594B2 (ja) | 2010-05-26 | 2015-04-22 | 住友化学株式会社 | 化合物、光学フィルム及び光学フィルムの製造方法 |
EP2593107A1 (en) | 2010-07-12 | 2013-05-22 | Merck Sharp & Dohme Corp. | Tyrosine kinase inhibitors |
US20120122928A1 (en) | 2010-08-11 | 2012-05-17 | Bayer Cropscience Ag | Heteroarylpiperidine and -Piperazine Derivatives as Fungicides |
DK2616444T3 (en) | 2010-09-14 | 2015-11-30 | Inst Biochemii I Biofizyki Pan | Compounds as modulators of a mutant CFTR protein and their use in the treatment of diseases associated with CFTR protein malfunction |
CN102116772B (zh) | 2010-09-28 | 2013-08-28 | 上海大学 | 二氢查尔酮化合物的筛选方法 |
CN103313977B (zh) | 2010-10-21 | 2015-06-03 | 拜耳知识产权有限责任公司 | 1-(杂环羰基)哌啶 |
WO2012052491A2 (en) | 2010-10-21 | 2012-04-26 | Bayer Cropscience Ag | 1-(heterocyclic carbonyl)-2-substituted pyrrolidines |
CA2817577A1 (en) | 2010-11-10 | 2012-05-18 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
AU2011350396A1 (en) | 2010-12-27 | 2013-07-11 | Takeda Pharmaceutical Company Limited | Orally disintegrating tablet |
WO2012097013A1 (en) | 2011-01-10 | 2012-07-19 | Nimbus Iris, Inc. | Irak inhibitors and uses thereof |
US20120184572A1 (en) | 2011-01-13 | 2012-07-19 | Metabolex, Inc. | Aryl gpr119 agonists and uses thereof |
EP2670245B1 (en) | 2011-02-04 | 2015-09-09 | The Scripps Research Institute | Alpha-ketoheterocycles and methods of making and using |
WO2012138981A2 (en) | 2011-04-06 | 2012-10-11 | Teva Pharmaceutical Industries Ltd. | New intermediates and processes for preparing ticagrelor |
RU2625790C2 (ru) | 2011-04-11 | 2017-07-19 | Грин Тек Ко.,Лтд. | Новое пиразольное производное |
KR20140093610A (ko) | 2011-04-21 | 2014-07-28 | 재단법인 한국파스퇴르연구소 | 소염 화합물 |
TWI478908B (zh) | 2011-07-01 | 2015-04-01 | Gilead Sciences Inc | 作為離子通道調節劑之稠合雜環化合物 |
US8791114B2 (en) | 2011-07-01 | 2014-07-29 | Merck Patent Gmbh | Dihydropyrazoles |
US8969363B2 (en) | 2011-07-19 | 2015-03-03 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
KR102022716B1 (ko) | 2011-07-29 | 2019-09-18 | 카리오팜 쎄라퓨틱스, 인코포레이티드 | 하이드라지드 함유 핵 수송 조절인자 및 이의 용도 |
MX2014001933A (es) | 2011-09-15 | 2014-03-27 | Demerx Inc | Ansolvatos de sal de noribogaina. |
US20140308260A1 (en) | 2011-10-07 | 2014-10-16 | Radiorx, Inc. | Methods and compositions comprising a nitrite-reductase promoter for treatment of medical disorders and preservation of blood products |
ES2790358T3 (es) | 2011-12-28 | 2020-10-27 | Global Blood Therapeutics Inc | Compuestos de heteroaril aldehído sustituido y métodos para su uso en el aumento de la oxigenación tisular |
PT3738434T (pt) | 2011-12-28 | 2023-11-13 | Global Blood Therapeutics Inc | Intermediários para obter compostos de benzaldeído substituído e métodos para a sua utilização no aumento da oxigenação de tecidos |
TWI589579B (zh) | 2012-01-10 | 2017-07-01 | 林伯士艾瑞斯公司 | Irak抑制劑及其用途 |
BR112014031424A2 (pt) | 2012-06-14 | 2017-06-27 | Janssen Biotech Inc | tratamento de células pluripotentes |
US9505735B2 (en) | 2012-06-21 | 2016-11-29 | Whitehead Institute For Biomedical Research | Compounds for treating infectious diseases |
JP2014005380A (ja) | 2012-06-25 | 2014-01-16 | Dic Corp | 液晶組成物 |
US9067948B2 (en) | 2012-07-11 | 2015-06-30 | Nimbus Iris, Inc. | IRAK inhibitors and uses thereof |
WO2014011911A2 (en) | 2012-07-11 | 2014-01-16 | Nimbus Iris, Inc. | Irak inhibitors and uses thereof |
WO2014011902A1 (en) | 2012-07-11 | 2014-01-16 | Nimbus Iris, Inc. | Irak inhibitors and uses thereof |
EP2878594B1 (en) | 2012-07-27 | 2018-11-28 | Sato Pharmaceutical Co., Ltd. | Difluoromethylene compound |
US9388185B2 (en) | 2012-08-10 | 2016-07-12 | Incyte Holdings Corporation | Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors |
WO2014031872A2 (en) | 2012-08-23 | 2014-02-27 | The Broad Institute, Inc. | Small molecule inhibitors for treating parasitic infections |
BR112015003729A2 (pt) | 2012-08-24 | 2018-06-05 | Univ Texas | composto de fórmula estrutural i; composição farmacêutica; método de tratamento de uma doença mediada por caminho do hif; método de tratamento de uma doença causada por proliferação anormal de células; e método para alcançar um efeito em um paciente |
US20140073634A1 (en) | 2012-08-24 | 2014-03-13 | Institute For Applied Cancer Science/The University of Texas MD Anderson Cancer Center | Heterocyclic modulators of hif activity for treatment of disease |
EP2888253A4 (en) | 2012-08-24 | 2016-01-06 | Univ Texas | HETEROCYCLIC MODULATORS OF HIF FACTOR ACTIVITY USED FOR THE TREATMENT OF DISEASES |
TW201416348A (zh) | 2012-08-29 | 2014-05-01 | Gruenenthal Chemie | 以氟甲基取代之吡咯甲醯胺 |
EP2902489B9 (en) | 2012-09-27 | 2018-02-07 | Chugai Seiyaku Kabushiki Kaisha | Fgfr3 fusion gene and pharmaceutical drug targeting same |
WO2014104384A1 (ja) | 2012-12-27 | 2014-07-03 | 住友化学株式会社 | テトラゾリノン化合物及びその用途 |
US9073946B2 (en) | 2013-01-15 | 2015-07-07 | Kineta, Inc. | Anti-viral compounds |
WO2014130856A2 (en) | 2013-02-21 | 2014-08-28 | Wayne Rothbaum | Treatment of skeletal-related disorders |
US9200005B2 (en) | 2013-03-13 | 2015-12-01 | AbbVie Deutschland GmbH & Co. KG | Inhibitor compounds of phosphodiesterase type 10A |
SG10201802911RA (en) | 2013-03-15 | 2018-05-30 | Global Blood Therapeutics Inc | Compounds and uses thereof for the modulation of hemoglobin |
US10100043B2 (en) | 2013-03-15 | 2018-10-16 | Global Blood Therapeutics, Inc. | Substituted aldehyde compounds and methods for their use in increasing tissue oxygenation |
US9422279B2 (en) | 2013-03-15 | 2016-08-23 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
WO2014150256A1 (en) | 2013-03-15 | 2014-09-25 | Global Blood Therapeutics, Inc. | Compositions and methods for the modulation of hemoglobin (s) |
CN111454200A (zh) | 2013-03-15 | 2020-07-28 | 全球血液疗法股份有限公司 | 化合物及其用于调节血红蛋白的用途 |
US20150057251A1 (en) | 2013-08-26 | 2015-02-26 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US8952171B2 (en) * | 2013-03-15 | 2015-02-10 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
MX2015011509A (es) | 2013-03-15 | 2016-05-31 | Global Blood Therapeutics Inc | Compuestos y usos de estos para la modulacion de la hemoglobina. |
US9802900B2 (en) | 2013-03-15 | 2017-10-31 | Global Blood Therapeutics, Inc. | Bicyclic heteroaryl compounds and uses thereof for the modulation of hemoglobin |
US9458139B2 (en) | 2013-03-15 | 2016-10-04 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US9604999B2 (en) | 2013-03-15 | 2017-03-28 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US10266551B2 (en) | 2013-03-15 | 2019-04-23 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US20140271591A1 (en) | 2013-03-15 | 2014-09-18 | Global Blood Therapeutics, Inc. | Compositions and methods for the modulation of hemoglobin (s) |
CA2902711C (en) | 2013-03-15 | 2021-07-06 | Global Blood Therapeutics, Inc. | Substituted pyridinyl-6-methoxy-2-hydroxybenzaldehyde derivatives and pharmaceutical compositions thereof useful for the modulation of hemoglobin |
US20140274961A1 (en) | 2013-03-15 | 2014-09-18 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
CA2902874C (en) | 2013-03-15 | 2021-04-20 | Global Blood Therapeutics, Inc. | Substituted pyridinyl-6-methoxy-benzaldehyde derivatives and pharmaceutical compositions thereof useful for the modulation of hemoglobin |
KR20140127587A (ko) | 2013-04-25 | 2014-11-04 | (주)프론트바이오 | 5원 헤테로사이클릭 유도체, 이의 제조방법 및 이를 포함하는 약제학적 조성물 |
WO2014179144A1 (en) | 2013-04-29 | 2014-11-06 | E. I. Du Pont De Nemours And Company | Fungicidal heterocyclic compounds |
EP2991963B1 (en) | 2013-04-30 | 2021-07-07 | Heinrich-Heine-Universität Düsseldorf | Inhibitors of nhr2 and/or runx1/eto-tetramerization |
WO2014194242A2 (en) | 2013-05-31 | 2014-12-04 | Nimbus Iris, Inc. | Flt3 inhibitors and uses thereof |
WO2014194201A2 (en) | 2013-05-31 | 2014-12-04 | Nimbus Iris, Inc. | Cdk8 inhibitors and uses thereof |
US20160206604A1 (en) | 2013-08-26 | 2016-07-21 | Global Blood Therapeutics, Inc. | Formulations comprising wetting agents and compounds for the modulation of hemoglobin (s) |
US20160207904A1 (en) | 2013-08-27 | 2016-07-21 | Global Blood Therapeutics, Inc. | Crystalline 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde ansolvate salts |
WO2015031285A1 (en) | 2013-08-27 | 2015-03-05 | Global Blood Therapeutics, Inc. | Crystalline 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde ansolvate salts |
KR101628288B1 (ko) | 2013-09-30 | 2016-06-08 | 주식회사 엘지화학 | 음성 광학 분산도를 갖는 광학 소자 제조용 조성물 및 이로부터 제조된 광학 이방체 |
WO2015051230A1 (en) | 2013-10-04 | 2015-04-09 | Drexel University | Novel compositions useful for inhibiting hiv-1 infection and methods using same |
US9663718B2 (en) | 2013-10-21 | 2017-05-30 | Merck Patent Gmbh | Method of preparing a birefringent polymer film |
US20150141465A1 (en) | 2013-11-18 | 2015-05-21 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
EA201992707A1 (ru) | 2013-11-18 | 2020-06-30 | Глобал Блад Терапьютикс, Инк. | Соединения и их применения для модуляции гемоглобина |
CN103936659B (zh) | 2013-12-12 | 2016-06-22 | 石家庄诚志永华显示材料有限公司 | 含有碳桥联咔唑结构单元的化合物及其制备方法与应用 |
CN103936658B (zh) | 2013-12-12 | 2016-01-13 | 石家庄诚志永华显示材料有限公司 | 含有咔唑结构单元的化合物及其制备方法与应用 |
EP2883934B1 (en) | 2013-12-16 | 2019-11-13 | Merck Patent GmbH | Liquid-crystalline medium |
US9248199B2 (en) | 2014-01-29 | 2016-02-02 | Global Blood Therapeutics, Inc. | 1:1 adducts of sickle hemoglobin |
SI3102208T1 (sl) | 2014-02-07 | 2021-07-30 | Global Blood Therapeutics, Inc. | Kristalinični polimorf proste baze 2-hidroksi-6-((2-(1-izopropil-1H-pirazol-5-IL)piridin-3-IL)metoksi)- benzaldehida |
ES2726648T3 (es) | 2014-02-25 | 2019-10-08 | Univ Texas | Sales de moduladores heterocíclicos de la actividad del HIF para el tratamiento de enfermedades |
SG11201607183PA (en) | 2014-03-06 | 2016-10-28 | Shanghai Haiyan Pharmaceutical Technology Co Ltd | Piperidine derivatives as orexin receptor antagonist |
US20150258106A1 (en) | 2014-03-13 | 2015-09-17 | Demerx, Inc. | Methods for acute and long-term treatment of substance abuse |
US20150258105A1 (en) | 2014-03-13 | 2015-09-17 | Demerx, Inc. | Methods for acute and long-term treatment of alcohol dependence |
US20150258104A1 (en) | 2014-03-13 | 2015-09-17 | Demerx, Inc. | Use of noribogaine for the treatment of pain |
TWI648282B (zh) | 2014-03-27 | 2019-01-21 | 印度商托仁特生技有限公司 | 新熔合咪唑苯并噻唑化合物 |
WO2015193263A1 (en) | 2014-06-17 | 2015-12-23 | Chiesi Farmaceutici S.P.A. | Indolizine derivatives as phoshoinositide 3-kinases inhibitors |
WO2016043849A2 (en) | 2014-07-24 | 2016-03-24 | Global Blood Therapeutics, Inc. | Compounds for treating acute respiratory distress syndrome or a negative effect thereof |
JP6896614B2 (ja) | 2014-07-28 | 2021-06-30 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングMerck Patent Gesellschaft mit beschraenkter Haftung | ホメオトロピック配向を有する液晶媒体 |
EP2985334B1 (en) | 2014-08-15 | 2018-06-20 | Merck Patent GmbH | Liquid-crystalline medium |
EP3201292B1 (en) | 2014-09-30 | 2018-08-01 | Transitions Optical, Inc. | Ultraviolet light absorbers |
AU2015330906A1 (en) | 2014-10-07 | 2017-04-27 | Sage Therapeutics, Inc. | Neuroactive compounds and methods of use thereof |
WO2016077541A1 (en) | 2014-11-12 | 2016-05-19 | The Trustees Of The University Of Pennsylvania | Novel anti-infective compounds and methods using same |
ES2867174T3 (es) | 2014-11-26 | 2021-10-20 | Demerx Inc | Métodos y composiciones para potenciar la acción de analgésicos opioides mediante el uso de alcaloides de iboga |
CN107613965A (zh) | 2015-02-19 | 2018-01-19 | 普渡制药公司 | 用于减少胃排空的方法和组合物 |
US10647679B2 (en) | 2015-03-15 | 2020-05-12 | Emory University | N-methyl-D-aspartate receptor (NMDAR) potentiators, pharmaceutical compositions, and uses related thereto |
WO2016153951A1 (en) | 2015-03-20 | 2016-09-29 | Deuterx, Llc | 5-deutero-thiazolidinyldione compounds and methods of treating medical disorders using same |
MA41841A (fr) | 2015-03-30 | 2018-02-06 | Global Blood Therapeutics Inc | Composés aldéhyde pour le traitement de la fibrose pulmonaire, de l'hypoxie, et de maladies auto-immunes et des tissus conjonctifs |
CN104876912B (zh) | 2015-04-08 | 2017-07-21 | 苏州云轩医药科技有限公司 | Wnt信号通路抑制剂及其应用 |
WO2017004133A1 (en) | 2015-06-29 | 2017-01-05 | Nimbus Iris, Inc. | Irak inhibitors and uses thereof |
WO2017004134A1 (en) | 2015-06-29 | 2017-01-05 | Nimbus Iris, Inc. | Irak inhibitors and uses thereof |
WO2017039318A1 (en) | 2015-09-01 | 2017-03-09 | Kainos Medicine, Inc. | Benzimidazole derivatives for dna methylation inhibitors |
WO2017040982A1 (en) | 2015-09-02 | 2017-03-09 | The Regents Of The University Of California | Her3 ligands and uses thereof |
WO2017040963A1 (en) | 2015-09-03 | 2017-03-09 | Forma Therapeutics, Inc. | [6,6] fused bicyclic hdac8 inhibitors |
MA43373A (fr) | 2015-12-04 | 2018-10-10 | Global Blood Therapeutics Inc | Régimes posologiques pour 2-hydroxy-6-((2- (1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)méthoxy)benzaldéhyde |
ES2947636T3 (es) | 2016-03-16 | 2023-08-14 | Kura Oncology Inc | Derivados de tieno[2,3-d]pirimidina sustituida como inhibidores de menina-MLL y métodos de uso |
WO2017184531A1 (en) | 2016-04-18 | 2017-10-26 | Demerx, Inc. | Treatment of movement-related disorders using noribogaine |
TWI752307B (zh) | 2016-05-12 | 2022-01-11 | 美商全球血液治療公司 | 新穎化合物及製造化合物之方法 |
EP3484858A4 (en) | 2016-06-21 | 2020-02-26 | The University of Melbourne | HIV LATENCY ACTIVATORS |
WO2017223514A1 (en) | 2016-06-24 | 2017-12-28 | Saint Louis University | Lxr inverse agonists for treatment of cancer |
TWI778983B (zh) | 2016-10-12 | 2022-10-01 | 美商全球血液治療公司 | 包含2-羥基-6-((2-(1-異丙基-1h-吡唑-5-基)吡啶-3-基)甲氧基)-苯甲醛之片劑 |
US11014884B2 (en) | 2018-10-01 | 2021-05-25 | Global Blood Therapeutics, Inc. | Modulators of hemoglobin |
JP2022509091A (ja) | 2018-11-19 | 2022-01-20 | グローバル ブラッド セラピューティクス インコーポレイテッド | ヘモグロビンのモジュレーター |
-
2014
- 2014-03-10 SG SG10201802911RA patent/SG10201802911RA/en unknown
- 2014-03-10 SG SG11201507320QA patent/SG11201507320QA/en unknown
- 2014-03-10 CN CN202010996640.8A patent/CN112500338A/zh active Pending
- 2014-03-10 CN CN201480015944.4A patent/CN105073728A/zh not_active Withdrawn
- 2014-03-10 CA CA2903220A patent/CA2903220C/en active Active
- 2014-03-10 US US14/776,726 patent/US20160083343A1/en not_active Abandoned
- 2014-03-10 ES ES14770695T patent/ES2852054T3/es active Active
- 2014-03-10 EP EP14770695.6A patent/EP2970196B1/en active Active
- 2014-03-10 JP JP2016501058A patent/JP6426694B2/ja active Active
- 2014-03-10 EA EA201591432A patent/EA034922B1/ru unknown
- 2014-03-10 AP AP2015008721A patent/AP2015008721A0/xx unknown
- 2014-03-10 MX MX2015011445A patent/MX2015011445A/es unknown
- 2014-03-10 BR BR112015021985-3A patent/BR112015021985B1/pt active IP Right Grant
- 2014-03-10 MY MYPI2015002271A patent/MY191087A/en unknown
- 2014-03-10 WO PCT/US2014/022769 patent/WO2014150268A1/en active Application Filing
- 2014-03-10 KR KR1020157024781A patent/KR102280614B1/ko active IP Right Grant
- 2014-03-10 PE PE2015001922A patent/PE20161035A1/es unknown
- 2014-03-10 AU AU2014237340A patent/AU2014237340C1/en active Active
- 2014-03-13 TW TW103109178A patent/TWI695830B/zh active
- 2014-03-13 UY UY0001035426A patent/UY35426A/es not_active Application Discontinuation
-
2015
- 2015-09-02 IL IL241060A patent/IL241060B/en unknown
- 2015-09-07 CL CL2015002501A patent/CL2015002501A1/es unknown
- 2015-09-09 SA SA515361026A patent/SA515361026B1/ar unknown
- 2015-09-09 SA SA517382253A patent/SA517382253B1/ar unknown
-
2017
- 2017-06-02 ZA ZA2017/03791A patent/ZA201703791B/en unknown
-
2018
- 2018-09-11 US US16/127,776 patent/US20190010121A1/en not_active Abandoned
- 2018-10-25 JP JP2018200506A patent/JP6690861B2/ja active Active
- 2018-11-06 AU AU2018260808A patent/AU2018260808B2/en active Active
- 2018-11-09 US US16/186,275 patent/US11053195B2/en active Active
-
2020
- 2020-04-07 JP JP2020069169A patent/JP2020105228A/ja active Pending
- 2020-06-12 AU AU2020203882A patent/AU2020203882A1/en not_active Abandoned
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI695830B (zh) | 化合物及其調節血紅素之用途 | |
TWI682926B (zh) | 化合物及其調節血紅素之用途 | |
JP6401771B2 (ja) | ヘモグロビンの修飾のための化合物及びその使用 | |
US10450269B1 (en) | Compounds and uses thereof for the modulation of hemoglobin | |
US10858317B2 (en) | Compounds and uses thereof for the modulation of hemoglobin | |
TW201518286A (zh) | 化合物及其調節血紅素之用途 | |
US10266551B2 (en) | Compounds and uses thereof for the modulation of hemoglobin | |
US9604999B2 (en) | Compounds and uses thereof for the modulation of hemoglobin | |
OA17480A (en) | Compounds and uses thereof for the modulation of hemoglobin. |