CA2634055A1 - Antitussive agent - Google Patents
Antitussive agent Download PDFInfo
- Publication number
- CA2634055A1 CA2634055A1 CA002634055A CA2634055A CA2634055A1 CA 2634055 A1 CA2634055 A1 CA 2634055A1 CA 002634055 A CA002634055 A CA 002634055A CA 2634055 A CA2634055 A CA 2634055A CA 2634055 A1 CA2634055 A1 CA 2634055A1
- Authority
- CA
- Canada
- Prior art keywords
- hydrogen
- bound
- antitussive
- nr8r9
- represent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
- C07D489/08—Oxygen atom
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- 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
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
Abstract
An antitussive, which can be used for therapy or prophylaxyis of coughing, is disclosed. The antitussive comprises as an effective ingredient a morphinan derivative having a nitrogen-containing cyclic substituent or a pharmaceutically acceptable acid addition salt thereof, having a specific structure, such as the compound below [N-(17-cyclopeopylmethyl-4,5.alpha.-epoxy-3,14-dihydroxy-morphinan--6(3-yl)-3,4,5,6-tetrahydrophthalimide].
The antitussive has an excellent therapeutic or prophylactic effect against coughing and the side effects thereof are small.
The antitussive has an excellent therapeutic or prophylactic effect against coughing and the side effects thereof are small.
Claims (9)
1. An antitussive comprising as an effective ingredient a morphinan derivative having a nitrogen-containing cyclic substituent of the Formula (I):
[wherein R1 represents hydrogen, C1-C5 alkyl, C4-C7 cycloalkylalkyl, C5-C8 cycloalkenylalkyl, C6-C12 aryl, C7-C13 aralkyl, C3-C7 alkenyl, furanylalkyl (wherein the number of carbon atoms in the alkyl moiety is 1 to 5), thienylalkyl (wherein the number of carbon atoms in the alkyl moiety is 1 to 5) or pyridylalkyl (wherein the number of carbon atoms in the alkyl moiety is 1 to 5);
R2 and R3 represent independently hydrogen, hydroxy, C1-C5 alkoxy, C3-C7 alkenyloxy, C7-C13 aralkyloxy or C1-C5 alkanoyloxy;
-X- represents C2-C7 alkylene, alkenylene or alkynylene (one or more of the carbon atoms therein may be replaced by (a) nitrogen, oxygen and/or sulfur atom(s)) constituting a part of the ring structure;
Y represents valence bond, -C(=O)-, -C(=S)-, -S(O)-, -S(O2)-, -N(-R4)-, -C(=O)-N(-R4)-, or, -C(=S)- N(-R4)-;
R4 represents hydrogen or C1-C5 alkyl;
k represents an integer of 1 to 8;
R5(s) represent(s)(a) substituent(s) in the number of k on the ring structure, which independently represent(s) fluorine, chlorine, bromine, iodine, nitro, C1-C5 alkyl, C1-C5 alkylidene, C7-C13 cycloalkylalkyl, C7-C13 cycloalkylalkylidene, C6-C12 aryl, C7-C13 aralkyl, C7-C13 aralkylidene, C6-C12 aryloxy, trifluoromethyl, trifluoromethoxy, cyano, isothiocyanato, (CH2)p SR7, (CH2)p S(O)R7, (CH2,)p S(O2)R7, (CH2)p OR7, (CH2)p C(=O)R7, (CH2)p OC(=O)R7, (CH2)p CO2R7, (CH2)p S(O)NR8R9, (CH2)p S(O2)NR8R9, (CH2)p C(=O)NR8R9, (CH2)p NR8R9, (CH2)p N(R8)C(=O)R9, or (CH2)p N(R8)S(O2)R9, or among the R5s in the number of k, two R5s bound to the same carbon atom or to the same sulfur atom together represent one oxygen atom to form carbonyl or sulfoxide ( with the proviso that, in case where Y is valence bond, thus formed carbonyl does not directly bind to a nitrogen atom which is bound to morphinan skeleton), two R5s bound to the same carbon atom together represent one sulfur atom to form thiocarbonyl, four R5s bound to the same sulfur atom together represent two oxygen atoms to form sulfone, or among the R5s in the number of k, two R5s bound to adjacent carbon atoms, respectively, together form benzo, pyrido, naphtho, cyclopropano, cyclobutano, cyclopentano, cyclopenteno, cyclohexano, cyclohexeno, cycloheptano or cyclohepteno, each of the above-mentioned groups from benzo to cyclohepteno being unsubstituted or substituted with 1 or more R6s, wherein R6(s) independently represent(s) fluorine, chlorine, bromine, iodine, nitro, C1-C5 alkyl, C7-C13 aralkyl, trifluoromethyl, trifluoromethoxy, cyano, C6-C12 aryl, isothiocyanato, (CH2)p SR7, (CH2)p S(O)R7, (CH2)p S(O2)R7, (CH2)p OR7, (CH2)p C(=O)R7, (CH2)p OC(=O)R7, (CH2)p CO2R7, (CH2)p S(O)NR8R9, (CH2)p S(O2)NR8R9, (CH2)p C(=O)NR8R9, (CH2)p NR8R9, (CH2)p N(R8)C(=O)R9, or (CH2)p N(R8)S(O2)R9;
p represents an integer of 0 to 5;
R7, R8 and R9 represent independently hydrogen, C1-C5 alkyl, C3-C7 alkenyl, C6-aryl or C7-C13 aralkyl;
R10 represents hydrogen, C1-C5 alkyl, C2-C5 alkenyl, C7-C13 aralkyl, (CH2)p OR7 or (CH2)p CO2R7 (wherein p and R7 represent the same meanings as described above);
R11 and R12 are bound to form -O-, -S- or -CH2-, or R11 represents hydrogen and R12 represents hydrogen, hydroxy, C1-C5 alkoxy or C1-C5 alkanoyloxy; and R13 and R14 together represent oxo, or R13 represetnts hydrogen and R14 reprsents hydrogen, hydroxy, C1-C5 alkoxy or C1-C5 alkanoyloxy]
or a pharmaceutically acceptable acid addition salt thereof.
[wherein R1 represents hydrogen, C1-C5 alkyl, C4-C7 cycloalkylalkyl, C5-C8 cycloalkenylalkyl, C6-C12 aryl, C7-C13 aralkyl, C3-C7 alkenyl, furanylalkyl (wherein the number of carbon atoms in the alkyl moiety is 1 to 5), thienylalkyl (wherein the number of carbon atoms in the alkyl moiety is 1 to 5) or pyridylalkyl (wherein the number of carbon atoms in the alkyl moiety is 1 to 5);
R2 and R3 represent independently hydrogen, hydroxy, C1-C5 alkoxy, C3-C7 alkenyloxy, C7-C13 aralkyloxy or C1-C5 alkanoyloxy;
-X- represents C2-C7 alkylene, alkenylene or alkynylene (one or more of the carbon atoms therein may be replaced by (a) nitrogen, oxygen and/or sulfur atom(s)) constituting a part of the ring structure;
Y represents valence bond, -C(=O)-, -C(=S)-, -S(O)-, -S(O2)-, -N(-R4)-, -C(=O)-N(-R4)-, or, -C(=S)- N(-R4)-;
R4 represents hydrogen or C1-C5 alkyl;
k represents an integer of 1 to 8;
R5(s) represent(s)(a) substituent(s) in the number of k on the ring structure, which independently represent(s) fluorine, chlorine, bromine, iodine, nitro, C1-C5 alkyl, C1-C5 alkylidene, C7-C13 cycloalkylalkyl, C7-C13 cycloalkylalkylidene, C6-C12 aryl, C7-C13 aralkyl, C7-C13 aralkylidene, C6-C12 aryloxy, trifluoromethyl, trifluoromethoxy, cyano, isothiocyanato, (CH2)p SR7, (CH2)p S(O)R7, (CH2,)p S(O2)R7, (CH2)p OR7, (CH2)p C(=O)R7, (CH2)p OC(=O)R7, (CH2)p CO2R7, (CH2)p S(O)NR8R9, (CH2)p S(O2)NR8R9, (CH2)p C(=O)NR8R9, (CH2)p NR8R9, (CH2)p N(R8)C(=O)R9, or (CH2)p N(R8)S(O2)R9, or among the R5s in the number of k, two R5s bound to the same carbon atom or to the same sulfur atom together represent one oxygen atom to form carbonyl or sulfoxide ( with the proviso that, in case where Y is valence bond, thus formed carbonyl does not directly bind to a nitrogen atom which is bound to morphinan skeleton), two R5s bound to the same carbon atom together represent one sulfur atom to form thiocarbonyl, four R5s bound to the same sulfur atom together represent two oxygen atoms to form sulfone, or among the R5s in the number of k, two R5s bound to adjacent carbon atoms, respectively, together form benzo, pyrido, naphtho, cyclopropano, cyclobutano, cyclopentano, cyclopenteno, cyclohexano, cyclohexeno, cycloheptano or cyclohepteno, each of the above-mentioned groups from benzo to cyclohepteno being unsubstituted or substituted with 1 or more R6s, wherein R6(s) independently represent(s) fluorine, chlorine, bromine, iodine, nitro, C1-C5 alkyl, C7-C13 aralkyl, trifluoromethyl, trifluoromethoxy, cyano, C6-C12 aryl, isothiocyanato, (CH2)p SR7, (CH2)p S(O)R7, (CH2)p S(O2)R7, (CH2)p OR7, (CH2)p C(=O)R7, (CH2)p OC(=O)R7, (CH2)p CO2R7, (CH2)p S(O)NR8R9, (CH2)p S(O2)NR8R9, (CH2)p C(=O)NR8R9, (CH2)p NR8R9, (CH2)p N(R8)C(=O)R9, or (CH2)p N(R8)S(O2)R9;
p represents an integer of 0 to 5;
R7, R8 and R9 represent independently hydrogen, C1-C5 alkyl, C3-C7 alkenyl, C6-aryl or C7-C13 aralkyl;
R10 represents hydrogen, C1-C5 alkyl, C2-C5 alkenyl, C7-C13 aralkyl, (CH2)p OR7 or (CH2)p CO2R7 (wherein p and R7 represent the same meanings as described above);
R11 and R12 are bound to form -O-, -S- or -CH2-, or R11 represents hydrogen and R12 represents hydrogen, hydroxy, C1-C5 alkoxy or C1-C5 alkanoyloxy; and R13 and R14 together represent oxo, or R13 represetnts hydrogen and R14 reprsents hydrogen, hydroxy, C1-C5 alkoxy or C1-C5 alkanoyloxy]
or a pharmaceutically acceptable acid addition salt thereof.
2. The antitussive according to claim 1, wherein in said Formula (I), both R13 and R14 are hydrogen.
3. The antitussive comprising as the effective ingredient the morphinan derivative having the nitrogen-containing cyclic substituent or the pharmaceutically acceptable acid addition salt thereof according to claim 2, wherein in said Formula (I), R1 is hydrogen, C4-C7 cycloalkylalkyl, C5-C8 cycloalkenylalkyl, C6-C12 aryl or alkenyl;
(1) X is propenylene (-CH2-CH=CH-) and k is 2, or (2) X is -S-CH=CH-, k is 6, and four R5s bound to said sulfur atom together represent two oxygen atoms to form sulfone;
two R5s bound to adjacent carbon atoms, respectively, together form benzo or cyclohexeno, which benzo or cyclohexeno is unsubstituted or substituted with 1 or more substituents R6(s); and Y is valence bond.
(1) X is propenylene (-CH2-CH=CH-) and k is 2, or (2) X is -S-CH=CH-, k is 6, and four R5s bound to said sulfur atom together represent two oxygen atoms to form sulfone;
two R5s bound to adjacent carbon atoms, respectively, together form benzo or cyclohexeno, which benzo or cyclohexeno is unsubstituted or substituted with 1 or more substituents R6(s); and Y is valence bond.
4. The antitussive according to claim 2, wherein said Y in said Formula (I) is -C(=O)-.
5. The antitussive according to claim 4, wherein in said Formula (I), R11 and are bound to form -O-.
6. The antitussive according to claim 5, wherein in said Formula (I), R1 is hydrogen, C4-C7 cycloalkylalkyl, C6-C8 cycloalkenylalkyl, C6-C12 aryl or C3-C7 alkenyl; k is an integer of 2 to 8; and two R5s bound to adjacent carbon atoms, respectively, together form benzo, pyrido, naphtho, cyclopropano, cyclobutano, cyclopentano, cyclopenteno, cyclohexano, cyclohexeno, cycloheptano, or cyclohepteno, each of the above-mentioned groups from benzo to cyclohepteno being unsubstituted or substituted with 1 or more R6s.
7. The antitussive according to claim 6, wherein in said Formula (I), R1 is hydrogen, cyclopropylmethyl, cyclobutylmethyl or allyl; R2 and R3 are hydrogen, hydroxy, methoxy or acetoxy; -X- is vinylene; k is 2; two R5s together form benzo or cyclohexeno, which benzo or cyclohexeno is unsubstituted or substituted with 1 to 4 R6s; R6(s) is(are) independently fluorine, chlorine, bromine, iodine, nitro, methyl, ethyl, propyl, benzyl, hydroxy, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, isothiocyanato, mercapto, methylthio, methylsulfinyl, methylsulfonyl, hydroxymethyl, hydroxyethyl, methoxymethyl, ethoxymethyl, methoxyethyl, phenoxy, acetoxy, methoxycarbonyl, ethoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, sulfamoyl, dimethylsulfamoyl, dimethylcarbamoyl, dimethylamino, dimethylaminomethyl, dimethylaminoethyl, amino, acetamino, acetaminomethyl or methanesulfonamide; and R10 is hydrogen or methyl.
8. Use of said morphinan derivative having the nitrogen-containing cyclic substituent or the pharmaceutically acceptable acid addition salt thereof recited in any one of claims 1 to 7 for the production of an antitussive.
9. A method for suppressing cough, comprising administering an effective amount of said morphinan derivative having the nitrogen-containing cyclic substituent or the pharmaceutically acceptable acid addition salt thereof recited in any one of claims 1 to 7.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2005367825 | 2005-12-21 | ||
JP2005-367825 | 2005-12-21 | ||
PCT/JP2006/325023 WO2007072749A1 (en) | 2005-12-21 | 2006-12-15 | Antitussive agent |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2634055A1 true CA2634055A1 (en) | 2007-06-28 |
CA2634055C CA2634055C (en) | 2011-07-05 |
Family
ID=38188528
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA2634055A Expired - Fee Related CA2634055C (en) | 2005-12-21 | 2006-12-15 | Antitussive agent |
Country Status (10)
Country | Link |
---|---|
US (1) | US8106065B2 (en) |
EP (1) | EP1974731B1 (en) |
JP (1) | JP5163127B2 (en) |
KR (1) | KR20080081057A (en) |
CN (1) | CN101340911B (en) |
AU (1) | AU2006328765B2 (en) |
CA (1) | CA2634055C (en) |
ES (1) | ES2369571T3 (en) |
TW (1) | TW200733963A (en) |
WO (1) | WO2007072749A1 (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101965187B (en) | 2007-05-21 | 2012-11-21 | 东丽株式会社 | Crystalline micropowder particles |
WO2014091295A1 (en) | 2012-12-14 | 2014-06-19 | Purdue Pharma L.P. | Pyridonemorphinan analogs and biological activity on opioid receptors |
TW201434836A (en) | 2012-12-14 | 2014-09-16 | Purdue Pharma Lp | Nitrogen containing morphinan derivatives and the use thereof |
WO2014102593A1 (en) | 2012-12-28 | 2014-07-03 | Purdue Pharma L.P. | Substituted morphinans and the use thereof |
EP2941430B1 (en) | 2012-12-28 | 2017-04-26 | Purdue Pharma LP | 7,8-cyclicmorphinan analogs |
WO2015097546A1 (en) | 2013-12-26 | 2015-07-02 | Purdue Pharma L.P. | Propellane-based compounds and their use as opioid receptor modulators |
EP3681506A4 (en) | 2017-09-12 | 2021-09-22 | Yang Ye | Solid forms of stemospironine and its salts |
AU2019229892A1 (en) | 2018-03-08 | 2020-09-03 | University Of Kansas | Treatment of demyelinating diseases |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3108041A (en) * | 1960-05-11 | 1963-10-22 | Endo Lab | Antitussive compositions |
JPS4118823B1 (en) * | 1964-02-03 | 1966-10-31 | ||
WO1995003308A1 (en) | 1993-07-23 | 1995-02-02 | Toray Industries, Inc. | Morphinan derivative and medicinal use |
EP0897726B1 (en) | 1996-11-25 | 2007-04-11 | Toray Industries, Inc. | Antipruritic agent |
AU2003272944B2 (en) * | 2002-10-09 | 2009-11-12 | Toray Industries, Inc. | Remedies or preventives for urinary frequency or urinary incontinence and morphinan derivatives having nitrogen-containing heterocyclic group |
US7718664B2 (en) * | 2004-03-30 | 2010-05-18 | Toray Industries, Inc. | Anti-itching agent |
AR053098A1 (en) | 2004-11-04 | 2007-04-25 | Toray Industries | ANALGESICO DERIVADO DE MORFINANO |
-
2006
- 2006-12-15 AU AU2006328765A patent/AU2006328765B2/en not_active Ceased
- 2006-12-15 EP EP06834766A patent/EP1974731B1/en not_active Not-in-force
- 2006-12-15 CA CA2634055A patent/CA2634055C/en not_active Expired - Fee Related
- 2006-12-15 KR KR1020087017850A patent/KR20080081057A/en active IP Right Grant
- 2006-12-15 CN CN2006800483797A patent/CN101340911B/en not_active Expired - Fee Related
- 2006-12-15 WO PCT/JP2006/325023 patent/WO2007072749A1/en active Application Filing
- 2006-12-15 ES ES06834766T patent/ES2369571T3/en active Active
- 2006-12-15 US US12/158,100 patent/US8106065B2/en not_active Expired - Fee Related
- 2006-12-15 JP JP2007551062A patent/JP5163127B2/en not_active Expired - Fee Related
- 2006-12-19 TW TW095147632A patent/TW200733963A/en unknown
Also Published As
Publication number | Publication date |
---|---|
CN101340911A (en) | 2009-01-07 |
EP1974731A4 (en) | 2009-05-20 |
US8106065B2 (en) | 2012-01-31 |
AU2006328765A1 (en) | 2007-06-28 |
EP1974731A1 (en) | 2008-10-01 |
ES2369571T3 (en) | 2011-12-02 |
JPWO2007072749A1 (en) | 2009-05-28 |
JP5163127B2 (en) | 2013-03-13 |
AU2006328765B2 (en) | 2012-01-12 |
WO2007072749A1 (en) | 2007-06-28 |
KR20080081057A (en) | 2008-09-05 |
TW200733963A (en) | 2007-09-16 |
CN101340911B (en) | 2013-01-02 |
EP1974731B1 (en) | 2011-07-13 |
US20090176818A1 (en) | 2009-07-09 |
CA2634055C (en) | 2011-07-05 |
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EEER | Examination request | ||
MKLA | Lapsed |
Effective date: 20191216 |