CA2471436A1 - Non-sedating barbituric acid derivatives - Google Patents
Non-sedating barbituric acid derivatives Download PDFInfo
- Publication number
- CA2471436A1 CA2471436A1 CA002471436A CA2471436A CA2471436A1 CA 2471436 A1 CA2471436 A1 CA 2471436A1 CA 002471436 A CA002471436 A CA 002471436A CA 2471436 A CA2471436 A CA 2471436A CA 2471436 A1 CA2471436 A1 CA 2471436A1
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- Prior art keywords
- lower alkyl
- phenyl
- benzyl
- group
- substituted
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
- C07D239/62—Barbituric acids
- C07D239/64—Salts of organic bases; Organic double compounds
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K31/515—Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
Abstract
The present invention relates to novel non-sedating barbituric acid derivatives, pharmaceutical compositions containing them and methods of neuroprotection in cases of cerebral ischemia, head trauma and other acute neurologic injuries, and prevention of resulting neuronal damage. The invention also relates to the use of non-sedating barbituric acid derivatives given in a manner and dosage effective to produce blood levels and brain levels of these drugs and/or their active metabolites sufficient to provide a therapeutic effect.
Claims (34)
1. A method of protecting a mammal from neurological damage, comprising administering to said mammal a dose of a non-sedative barbiturate, having the structure which is sufficient to provide a neuroprotective effect, said non-sedative barbiturate being non-sedative and non-hypnotic, at said dose, wherein R1 and R2 may be the same or different and are independently hydrogen;
lower alkyl, optionally substituted by lower cycloalkyl, acyl, acyloxy, aryl, aryloxy, lower alkoxy, thioalkyl or thioaryl, amino, alkylamino, dialkylamino, or one or more halogen atoms;
phenyl;
CH2XR5, wherein X is S or O and R5 is lower alkyl, aryl, alkylaryl, or benzyl;
C(O)XR6, wherein X is as defined above and R6 is lower alkyl or aryl;
CXR7, wherein X is as defined above and R7 is hydrogen, lower alkyl or aryl; and CH(XR8)2, wherein X is as defined above and R8 is a lower alkyl group, with the proviso that at least one of R1 and R2 is not hydrogen; and wherein R3 and R4 may be the same or different and are independently hydrogen;
aryl optionally containing one or more heteroatoms selected from the group consisting of N, S, and O;
lower acyloxy;
phenyl;
phenyl substituted with a halogen, lower alkyl group, lower acyl group or derivative thereof or acetamide;
benzyl; benzyl substituted on the ring by one or more halogens, lower alkyl groups or both; cycloalkyl, which optionally contains one or more heteroatoms selected from the group consisting of N, O, and S;
lower alkyl; or lower alkyl substituted with an aromatic moiety;
provided that at least one of R3 and R4 is an aromatic ring or an aromatic ring containing moiety, and salts thereof.
lower alkyl, optionally substituted by lower cycloalkyl, acyl, acyloxy, aryl, aryloxy, lower alkoxy, thioalkyl or thioaryl, amino, alkylamino, dialkylamino, or one or more halogen atoms;
phenyl;
CH2XR5, wherein X is S or O and R5 is lower alkyl, aryl, alkylaryl, or benzyl;
C(O)XR6, wherein X is as defined above and R6 is lower alkyl or aryl;
CXR7, wherein X is as defined above and R7 is hydrogen, lower alkyl or aryl; and CH(XR8)2, wherein X is as defined above and R8 is a lower alkyl group, with the proviso that at least one of R1 and R2 is not hydrogen; and wherein R3 and R4 may be the same or different and are independently hydrogen;
aryl optionally containing one or more heteroatoms selected from the group consisting of N, S, and O;
lower acyloxy;
phenyl;
phenyl substituted with a halogen, lower alkyl group, lower acyl group or derivative thereof or acetamide;
benzyl; benzyl substituted on the ring by one or more halogens, lower alkyl groups or both; cycloalkyl, which optionally contains one or more heteroatoms selected from the group consisting of N, O, and S;
lower alkyl; or lower alkyl substituted with an aromatic moiety;
provided that at least one of R3 and R4 is an aromatic ring or an aromatic ring containing moiety, and salts thereof.
2. The method of claim 1, with the proviso that when R1 and/or R2 is methoxymethyl, R3 and R4 are not both phenyl, are not both phenyl substituted by lower alkyl, and are not both phenyl substituted by halogen; and when one of R3 and R4 is phenyl or benzyl, the other of R3 and R4 is not ethyl; and when at least one of R1 and R2 is benzyl, then when one of R3 and R4 is phenyl, the other of R3 and R4 is not allyl; and when one of R1 and R2 is methyl and the other is hydrogen, then when one of R3 and R4 is phenyl, the other of R3 and R4 is not unsubstituted lower alkyl; and when R1 = R2 = Ra, where Ra is alkoxymethyl or (acyloxy)methyl, then when one of R3 and R4 is 1-phenylethyl, the other of R3 and R4 is not propionyloxy; and the compound is other than a) 1-methyl-5-(1-phenylethyl)-5-propionyloxy-barbituric acid, b) 1,3-diphenyl-5,5-(dibenzyl) barbituric acid, c) 1,3,5-triphenyl barbituric acid, and d) 5-benzyl-1,3-dimethyl barbituric acid.
3. The method of claim 1, wherein either (a) at least one of R1 and R2 is lower alkyl substituted by lower cycloalkyl, acyl, acyloxy, aryl, aryloxy, thioalkyl or thioaryl, amino, alkylamino, dialkylamino, or one or more halogen atoms;
phenyl;
CH2SR5, wherein R5 is lower alkyl, aryl, alkylaryl, or benzyl;
C(S)XR6, wherein X is S or O and R6 is lower alkyl or aryl;
CSR7, wherein R7 is hydrogen, lower alkyl, or aryl; and CH(SR8)2, wherein R8 is a lower alkyl group; or (b) at least one of R3 and R4 is lower acyloxy;
phenyl substituted with a lower acyl group or derivative thereof or acetamide; and cycloalkyl of which the ring optionally contains one or more heteroatoms selected from the group consisting of N, O, and S.
phenyl;
CH2SR5, wherein R5 is lower alkyl, aryl, alkylaryl, or benzyl;
C(S)XR6, wherein X is S or O and R6 is lower alkyl or aryl;
CSR7, wherein R7 is hydrogen, lower alkyl, or aryl; and CH(SR8)2, wherein R8 is a lower alkyl group; or (b) at least one of R3 and R4 is lower acyloxy;
phenyl substituted with a lower acyl group or derivative thereof or acetamide; and cycloalkyl of which the ring optionally contains one or more heteroatoms selected from the group consisting of N, O, and S.
4. The method of claim 3, with the proviso that when R1 and/or R2 is methoxymethyl, R3 and R4 are not both phenyl, are not both phenyl substituted by lower alkyl, and are not both phenyl substituted by halogen; and when one of R3 and R4 is phenyl or benzyl, the other of R3 and R4 is not ethyl; and when at least one of R1 and R2 is benzyl, then when one of R3 and R4 is phenyl, the other of R3 and R4 is not allyl; and when R1 = R2 = Ra, where Ra is alkoxymethyl or (acyloxy)methyl, then when one of R3 and R4 is 1-phenylethyl, the other of R3 and R4 is not propionyloxy; and the compound is other than a) 1-methyl-5-(1-phenylethyl)-5-propionyloxy-barbituric acid, b) 1,3-diphenyl-5,5-(dibenzyl) barbituric acid, and c) 1,3,5-triphenyl barbituric acid.
5. The method of claim 1, wherein R1 and R2 are the same or different and selected from the group consisting of hydrogen, butyl, benzyl, thiophenylmethyl, cyclopropylmethyl, 3,3,3-trifluoropropyl, benzyloxymethyl, and alkoxymethyl.
6. The method of claim 2, wherein at least one of R1 and R2 is methoxymethyl.
7. The method of claim 1, wherein R3 and R4 are both aromatic rings or aromatic ring containing moieties.
8. The method of claim 1, wherein R3 and R4 are the same or different and are independently phenyl; phenyl substituted with a halogen or lower alkyl group;
cycloalkyl, which optionally contains one or more heteroatoms selected from the group consisting of N, O, or S; benzyl; benzyl substituted on the ring by one or more halogens, lower alkyl groups or both; lower alkyl; or lower alkyl substituted with an aromatic moiety, provided that at least one of R3 and R4 is phenyl or substituted phenyl.
cycloalkyl, which optionally contains one or more heteroatoms selected from the group consisting of N, O, or S; benzyl; benzyl substituted on the ring by one or more halogens, lower alkyl groups or both; lower alkyl; or lower alkyl substituted with an aromatic moiety, provided that at least one of R3 and R4 is phenyl or substituted phenyl.
9. The method of claim 1, wherein at least one of R3 and R4 are selected from the group consisting of phenyl, benzyl, fluorophenyl and tolyl.
10. The method of claim 1, wherein at least one of R3 and R4 is selected from the group consisting of
11. The method of claim 1, wherein said administered dose is greater than about 25 mg/kg body weight.
12. The method of claim 1, wherein said non-sedative barbiturate is administered in a dose sufficient to produce a blood concentration of at least p,g/ml of said non-sedative barbiturate or an active metabolite thereof.
13. The method of claim 12, wherein said blood concentration of said non-sedative barbiturate or active metabolite thereof is at least 30 µg/ml for at least 12 hours after said administering.
14. The method of claim 1, wherein said non-sedative barbiturate is administered in a dose greater than twice the anticonvulsant doseage.
15. The method of claim 1, wherein said non-sedative barbiturate is administered orally or intravenously.
16. The method of claim 1, wherein said non-sedative barbiturate is administered prophylactically before evident neuronal damage or therapeutically after onset of neuronal damage.
17. The method of claim 1, wherein said non-sedative barbiturate is administered in conjunction with cardiac surgery or carotid endarterectomy.
18. The method of claim 1, wherein said neuroprotective effect diminishes, or protects the subject from, neuronal damage caused by atrial fibrillation, a transient ischemic attack (TIA), cerebral ischemia, bacterial endocarditis, stroke, head trauma, subarachnoid hemorrhage, or other acute neurologic injury.
19. The method of claim 1, wherein said non-sedative barbiturate is administered to protect said mammal which has or is at risk for atrial fibrillation, a transient ischemic attack (TIA), cerebral ischemia, bacterial endocarditis, stroke, head trauma, subarachnoid hemorrhage, or other acute neurologic injury.
20. A pharmaceutical composition, comprising as active material a non-sedative barbiturate, together with a pharmaceutically acceptable carrier, the composition being non-sedative and non-hypnotic when administered at a dose which is neuroprotective, the barbiturate having the structure wherein R1 and R2 may be the same or different and are independently hydrogen;
lower alkyl, optionally substituted by lower cycloalkyl, acyl, acyloxy, aryl, aryloxy, lower alkoxy, thioalkyl or thioaryl, amino, alkylamino, dialkylamino, or one or more halogen atoms;
phenyl;
CH2XR5, wherein X is S or O and R5 is lower alkyl, aryl, alkylaryl, or benzyl;
C(O)XR6, wherein X is as defined above and R6 is lower alkyl or aryl;
CXR7, wherein X is as defined above and R7 is hydrogen, lower alkyl or aryl; and CH(XR8)2, wherein X is as defined above and R8 is a lower alkyl group, with the proviso that at least one of R1 and R2 is not hydrogen; and wherein R3 and R4 may be the same or different and are independently hydrogen;
aryl optionally containing one or more heteroatoms selected from the group consisting of N, S, and O;
lower acyloxy;
phenyl;
phenyl substituted with a halogen, lower alkyl group, lower acyl group or derivative thereof or acetamid;
benzyl; benzyl substituted on the ring by one or more halogens, lower alkyl groups or both; cycloalkyl, which optionally contains one or more heteroatoms selected from the group consisting of N, O, and S;
lower alkyl; or lower alkyl substituted with an aromatic moiety;
provided that at least one of R3 and R4 is an aromatic ring or an aromatic ring containing moiety, and salts thereof, with the proviso that:
when R1 and/or R2 is methoxymethyl, R3 and R4 are not both phenyl, are not both phenyl substituted by lower alkyl, and are not both phenyl substituted by halogen; and when one of R3 and R4 is phenyl or benzyl, the other of R3 and R4 is not ethyl; and when at least one of R1 and R2 is benzyl, then when one of R3 and R4 is phenyl, the other of R3 and R4 is not allyl; and when one of R1 and R2 is methyl and the other is hydrogen, then when one of R3 and R4 is phenyl, the other of R3 and R4 is not unsubstituted lower alkyl; and when R1 = R2 = R a, where R a is alkoxymethyl or (acyloxy)methyl, then when one of R3 and R4 is 1-phenylethyl, the other of R3 and R4 is not propionyloxy; and the compound is other than a) 1-methyl-5-(1-phenylethyl)-5-propionyloxy-barbituric acid, b) 1,3-diphenyl-5,5-(dibenzyl) barbituric acid, c) 1,3,5-triphenyl barbituric acid, and d) 5-benzyl-1,3-dimethyl barbituric acid.
lower alkyl, optionally substituted by lower cycloalkyl, acyl, acyloxy, aryl, aryloxy, lower alkoxy, thioalkyl or thioaryl, amino, alkylamino, dialkylamino, or one or more halogen atoms;
phenyl;
CH2XR5, wherein X is S or O and R5 is lower alkyl, aryl, alkylaryl, or benzyl;
C(O)XR6, wherein X is as defined above and R6 is lower alkyl or aryl;
CXR7, wherein X is as defined above and R7 is hydrogen, lower alkyl or aryl; and CH(XR8)2, wherein X is as defined above and R8 is a lower alkyl group, with the proviso that at least one of R1 and R2 is not hydrogen; and wherein R3 and R4 may be the same or different and are independently hydrogen;
aryl optionally containing one or more heteroatoms selected from the group consisting of N, S, and O;
lower acyloxy;
phenyl;
phenyl substituted with a halogen, lower alkyl group, lower acyl group or derivative thereof or acetamid;
benzyl; benzyl substituted on the ring by one or more halogens, lower alkyl groups or both; cycloalkyl, which optionally contains one or more heteroatoms selected from the group consisting of N, O, and S;
lower alkyl; or lower alkyl substituted with an aromatic moiety;
provided that at least one of R3 and R4 is an aromatic ring or an aromatic ring containing moiety, and salts thereof, with the proviso that:
when R1 and/or R2 is methoxymethyl, R3 and R4 are not both phenyl, are not both phenyl substituted by lower alkyl, and are not both phenyl substituted by halogen; and when one of R3 and R4 is phenyl or benzyl, the other of R3 and R4 is not ethyl; and when at least one of R1 and R2 is benzyl, then when one of R3 and R4 is phenyl, the other of R3 and R4 is not allyl; and when one of R1 and R2 is methyl and the other is hydrogen, then when one of R3 and R4 is phenyl, the other of R3 and R4 is not unsubstituted lower alkyl; and when R1 = R2 = R a, where R a is alkoxymethyl or (acyloxy)methyl, then when one of R3 and R4 is 1-phenylethyl, the other of R3 and R4 is not propionyloxy; and the compound is other than a) 1-methyl-5-(1-phenylethyl)-5-propionyloxy-barbituric acid, b) 1,3-diphenyl-5,5-(dibenzyl) barbituric acid, c) 1,3,5-triphenyl barbituric acid, and d) 5-benzyl-1,3-dimethyl barbituric acid.
21. The composition of claim 20, wherein either (a) at least one of R1 and R2 is lower alkyl substituted by lower cycloalkyl, acyl, acyloxy, aryl, aryloxy, thioalkyl or thioaryl, amino, alkylamino, dialkylamino, or one or more halogen atoms;
phenyl;
CH2SR5, wherein R5 is lower alkyl, aryl, alkylaryl, or benzyl;
C(S)XR6, wherein X is S or O and R6 is lower alkyl or aryl;
CSR7, wherein R7 is hydrogen, lower alkyl, or aryl; and CH(SR8)2, wherein R8 is a lower alkyl group; or (b) at least one of R3 and R4 is lower acyloxy;
phenyl substituted with a lower acyl group or derivative thereof or acetamide; and cycloalkyl of which the ring optionally contains one or more heteroatoms selected from the group consisting of N, O, and S.
phenyl;
CH2SR5, wherein R5 is lower alkyl, aryl, alkylaryl, or benzyl;
C(S)XR6, wherein X is S or O and R6 is lower alkyl or aryl;
CSR7, wherein R7 is hydrogen, lower alkyl, or aryl; and CH(SR8)2, wherein R8 is a lower alkyl group; or (b) at least one of R3 and R4 is lower acyloxy;
phenyl substituted with a lower acyl group or derivative thereof or acetamide; and cycloalkyl of which the ring optionally contains one or more heteroatoms selected from the group consisting of N, O, and S.
22. The pharmaceutical composition of claim 20, wherein R1 and R2 are the same or different and selected from the group consisting of hydrogen, butyl, benzyl, thiophenylmethyl, cyclopropylmethyl, 3,3,3-trifluoropropyl, benzyloxymethyl, and alkoxymethyl.
23. The pharmaceutical composition of claim 20, wherein at least one of R1 and R2 is methoxymethyl.
24. The pharmaceutical composition of claim 20, wherein R3 and R4 are both aromatic rings or aromatic ring containing moieties.
25. The pharmaceutical composition of claim 20, wherein R3 and R4 are the same or different and are independently phenyl; phenyl substituted with a halogen or lower alkyl group; cycloalkyl, which optionally contains one or more heteroatoms selected from the group consisting of N, O or S; benzyl; benzyl substituted on the ring by one or more halogens, lower alkyl groups or both;
lower alkyl; or lower alkyl substituted with an aromatic moiety, provided that at least one of R3 and R4 is phenyl or substituted phenyl.
lower alkyl; or lower alkyl substituted with an aromatic moiety, provided that at least one of R3 and R4 is phenyl or substituted phenyl.
26. The pharmaceutical composition of claim 20, wherein at least one of R3 and R4 are selected from the group consisting of phenyl, benzyl, fluorophenyl and tolyl.
27. The pharmaceutical composition of claim 20, wherein at least one of R3 and R4 is selected from the group consisting of
28. The pharmaceutical composition of claim 20, wherein said dose is greater than about 25 mg/kg body weight.
29. The pharmaceutical composition of claim 20, wherein said dose is sufficient to produce a blood concentration of at least 30 µg/ml of said non-sedative barbiturate or an active metabolite thereof.
30. The pharmaceutical composition of claim 29, wherein said blood concentration of said non-sedative barbiturate or active metabolite thereof is at least 30 µg/ml for at least 12 hours after said administering.
31. The pharmaceutical composition of claim 20, wherein said administered dose is greater than twice an anticonvulsant doseage.
32. A method of treating a neurological disorder comprising administering a composition according to claim 20.
33. A method of providing neuroprotection comprising (a) identifying a mammal in need of cerebral neuroprotection;
(b) selecting a pharmaceutical composition according to claim 20; and (c) administering to said mammal an effective neuroprotective dose of said pharmaceutical composition, thereby providing said neuroprotection.
(b) selecting a pharmaceutical composition according to claim 20; and (c) administering to said mammal an effective neuroprotective dose of said pharmaceutical composition, thereby providing said neuroprotection.
34. The method of claim 33, wherein either (a) at least one of R1 and R2 is lower alkyl substituted by lower cycloalkyl, acyl, acyloxy, aryl, aryloxy, thioalkyl or thioaryl, amino, alkylamino, dialkylamino, or one or more halogen atoms;
phenyl;
CH2SR5, wherein R5 is lower alkyl, aryl, alkylaryl, or benzyl;
C(S)XR6, wherein X is S or O and R6 is lower alkyl or aryl;
CSR7, wherein R7 is hydrogen, lower alkyl, or aryl; and CH(SR8)2, wherein R8 is a lower alkyl group; or (b) at least one of R3 and R4 is lower acyloxy;
phenyl substituted with a lower acyl group or derivative thereof or acetamide; and cycloalkyl of which the ring optionally contains one or more heteroatoms selected from the group consisting of N, O, and S.
phenyl;
CH2SR5, wherein R5 is lower alkyl, aryl, alkylaryl, or benzyl;
C(S)XR6, wherein X is S or O and R6 is lower alkyl or aryl;
CSR7, wherein R7 is hydrogen, lower alkyl, or aryl; and CH(SR8)2, wherein R8 is a lower alkyl group; or (b) at least one of R3 and R4 is lower acyloxy;
phenyl substituted with a lower acyl group or derivative thereof or acetamide; and cycloalkyl of which the ring optionally contains one or more heteroatoms selected from the group consisting of N, O, and S.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US35227302P | 2002-01-30 | 2002-01-30 | |
| US60/352,273 | 2002-01-30 | ||
| PCT/US2003/002638 WO2003063872A1 (en) | 2002-01-30 | 2003-01-30 | Non-sedating barbituric acid derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2471436A1 true CA2471436A1 (en) | 2003-08-07 |
| CA2471436C CA2471436C (en) | 2011-10-11 |
Family
ID=27663075
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2471436A Expired - Fee Related CA2471436C (en) | 2002-01-30 | 2003-01-30 | Non-sedating barbituric acid derivatives |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1485101A4 (en) |
| JP (1) | JP2005516052A (en) |
| CN (2) | CN1291720C (en) |
| CA (1) | CA2471436C (en) |
| IL (1) | IL163168A (en) |
| WO (1) | WO2003063872A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6756379B2 (en) | 2001-07-26 | 2004-06-29 | Taro Pharmaceutical Industries Ltd. | Non-sedating barbiturate compounds as neuroprotective agents |
| US7683071B2 (en) | 2000-07-26 | 2010-03-23 | Taro Pharmaceuticals Industries Ltd. | Composition and method for improved bioavailability and enhanced brain delivery of 5,5-diphenyl barbituric acid |
| JP4739760B2 (en) | 2002-12-11 | 2011-08-03 | タロー・ファーマシューティカル・インダストリーズ・リミテッド | Method for treating movement disorders using barbituric acid derivatives |
| EP1625848A1 (en) * | 2004-08-10 | 2006-02-15 | Taro Pharmaceuticals North America, Inc. | Composition and method for enhanced delivery of 5,5-diphenyl barbituric acid |
| JP2015092251A (en) * | 2010-10-07 | 2015-05-14 | 富士フイルム株式会社 | Polarizing plate protective film, polarizing plate and liquid crystal display device |
| GB201115937D0 (en) | 2011-09-14 | 2011-10-26 | Univ Aberdeen | 18F-labelled compounds for use as positron emission imaging agents |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE946804C (en) * | 1952-02-28 | 1956-08-09 | Emanuel Merck Ohg | Process for the production of sulfur-containing extracts of barbituric acid |
| DE1103339B (en) * | 1959-02-04 | 1961-03-30 | Chemische Werke Radebeul Veb | Process for the preparation of 5-position crotylated, basic substituted barbituric acid derivatives |
| DE1100639B (en) * | 1959-03-24 | 1961-03-02 | Chemische Werke Radebeul Veb | Process for the preparation of basic substituted barbituric acid derivatives |
| US3711607A (en) * | 1971-03-17 | 1973-01-16 | Kendall & Co | N,n -dihalomethyl phenobarbital for the treatment of convulsions |
| US3900475A (en) * | 1972-06-26 | 1975-08-19 | Kendall & Co | Certain phenobarbital salts |
| IL69722A (en) * | 1983-09-14 | 1986-09-30 | Taro Pharma Ind | Oxopyrimidine derivatives and pharmaceutical compositions containing them |
| US4833148A (en) * | 1987-04-09 | 1989-05-23 | Washington University | Method of using alkenyl- or alkynyl-substituted thiobarbiturates to reduce neurotoxic injury |
| US5474990A (en) * | 1989-10-20 | 1995-12-12 | Olney; John W. | Barbiturates as safening agents in conjunction with NMDA antagonists |
| US6093820A (en) * | 1997-10-02 | 2000-07-25 | Taro Pharmaceutical Industries Ltd. | Method and reagents for N-alkylating ureides |
| CA2306170A1 (en) * | 2000-04-18 | 2001-10-18 | Kenneth Curry | Novel amino, carboxy derivatives of barbituric acid |
| DE60132337T2 (en) * | 2000-07-26 | 2009-02-12 | Taro Pharmaceutical Industries Ltd. | NON-SEDANT BARBITURATE COMPOUNDS AS NEUROPROTECTIVE ACTIVE SUBSTANCES |
-
2003
- 2003-01-30 JP JP2003563562A patent/JP2005516052A/en active Pending
- 2003-01-30 WO PCT/US2003/002638 patent/WO2003063872A1/en active Application Filing
- 2003-01-30 EP EP03735068A patent/EP1485101A4/en not_active Withdrawn
- 2003-01-30 CN CNB038029898A patent/CN1291720C/en not_active Expired - Fee Related
- 2003-01-30 CA CA2471436A patent/CA2471436C/en not_active Expired - Fee Related
- 2003-01-30 CN CNA2006100902858A patent/CN1896084A/en active Pending
-
2004
- 2004-07-22 IL IL163168A patent/IL163168A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| EP1485101A4 (en) | 2006-04-12 |
| CN1291720C (en) | 2006-12-27 |
| CN1896084A (en) | 2007-01-17 |
| JP2005516052A (en) | 2005-06-02 |
| IL163168A (en) | 2012-01-31 |
| CA2471436C (en) | 2011-10-11 |
| CN1625401A (en) | 2005-06-08 |
| WO2003063872A1 (en) | 2003-08-07 |
| EP1485101A1 (en) | 2004-12-15 |
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