JPS627167B2 - - Google Patents
Info
- Publication number
- JPS627167B2 JPS627167B2 JP53041355A JP4135578A JPS627167B2 JP S627167 B2 JPS627167 B2 JP S627167B2 JP 53041355 A JP53041355 A JP 53041355A JP 4135578 A JP4135578 A JP 4135578A JP S627167 B2 JPS627167 B2 JP S627167B2
- Authority
- JP
- Japan
- Prior art keywords
- dihydroergocristine
- dihydro
- oxohexyl
- purine
- dimethyl
- 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.)
- Expired
Links
- 229960004318 dihydroergocristine Drugs 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 12
- SPXACGZWWVIDGR-SPZWACKZSA-N dihydroergocristine mesylate Chemical compound CS(O)(=O)=O.C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](C(N21)=O)(NC(=O)[C@H]1CN(C)[C@H]2[C@@H](C=3C=CC=C4NC=C(C=34)C2)C1)C(C)C)C1=CC=CC=C1 SPXACGZWWVIDGR-SPZWACKZSA-N 0.000 claims description 8
- 150000007522 mineralic acids Chemical class 0.000 claims description 6
- 150000007524 organic acids Chemical class 0.000 claims description 6
- XBEDAMVJWVPVDS-UHFFFAOYSA-N 1,3-dimethyl-7-(5-oxohexyl)purine-2,6-dione Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2CCCCC(=O)C XBEDAMVJWVPVDS-UHFFFAOYSA-N 0.000 claims description 5
- 239000008280 blood Substances 0.000 claims description 5
- 210000004369 blood Anatomy 0.000 claims description 5
- 239000008298 dragée Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- FAIAJSOSTNJZCI-UHFFFAOYSA-N purine-2,6-dione Chemical compound O=C1NC(=O)C2=NC=NC2=N1 FAIAJSOSTNJZCI-UHFFFAOYSA-N 0.000 claims description 4
- 239000012752 auxiliary agent Substances 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- LIMAOLZSWRJOMG-HJPBWRTMSA-N dihydroergocristine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](C(N21)=O)(NC(=O)[C@H]1CN(C)[C@H]2[C@@H](C3=CC=CC4=NC=C([C]34)C2)C1)C(C)C)C1=CC=CC=C1 LIMAOLZSWRJOMG-HJPBWRTMSA-N 0.000 claims 4
- 210000004051 gastric juice Anatomy 0.000 claims 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical group CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims 1
- 210000002820 sympathetic nervous system Anatomy 0.000 claims 1
- DEQITUUQPICUMR-HJPBWRTMSA-N dihydroergocristine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](C(N21)=O)(NC(=O)[C@H]1CN(C)[C@H]2[C@@H](C=3C=CC=C4NC=C(C=34)C2)C1)C(C)C)C1=CC=CC=C1 DEQITUUQPICUMR-HJPBWRTMSA-N 0.000 description 23
- 241001465754 Metazoa Species 0.000 description 9
- 239000008194 pharmaceutical composition Substances 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000007940 sugar coated tablet Substances 0.000 description 2
- 230000002889 sympathetic effect Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000000472 traumatic effect Effects 0.000 description 2
- 229910052722 tritium Inorganic materials 0.000 description 2
- 230000000304 vasodilatating effect Effects 0.000 description 2
- -1 1,3-dimethyl-3,4-dihydro-7- (5'-oxohexyl)-1H-purine-2,6- Dione Chemical compound 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000551547 Dione <red algae> Species 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- ZAGRKAFMISFKIO-UHFFFAOYSA-N Isolysergic acid Natural products C1=CC(C2=CC(CN(C2C2)C)C(O)=O)=C3C2=CNC3=C1 ZAGRKAFMISFKIO-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010046996 Varicose vein Diseases 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 206010003230 arteritis Diseases 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- PBUNVLRHZGSROC-VTIMJTGVSA-N dihydro-alpha-ergocryptine Chemical compound C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)CC(C)C)C(C)C)=C3C2=CNC3=C1 PBUNVLRHZGSROC-VTIMJTGVSA-N 0.000 description 1
- SEALOBQTUQIVGU-QNIJNHAOSA-N dihydroergocornine Chemical class C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)C(C)C)C(C)C)=C3C2=CNC3=C1 SEALOBQTUQIVGU-QNIJNHAOSA-N 0.000 description 1
- 229960002032 dihydroergocryptine Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- OWEUDBYTKOYTAD-MKTPKCENSA-N ergocristine Chemical group C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](C(N21)=O)(NC(=O)[C@@H]1C=C2C3=CC=CC4=NC=C([C]34)C[C@H]2N(C)C1)C(C)C)C1=CC=CC=C1 OWEUDBYTKOYTAD-MKTPKCENSA-N 0.000 description 1
- WECZKEGDCUZFPL-BCOWQPNKSA-N ergocristine methanesulfonate Chemical compound CS(O)(=O)=O.C([C@@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](C(N21)=O)(NC(=O)[C@@H]1C=C2C=3C=CC=C4NC=C(C=34)C[C@H]2N(C)C1)C(C)C)C1=CC=CC=C1 WECZKEGDCUZFPL-BCOWQPNKSA-N 0.000 description 1
- HEFIYUQVAZFDEE-UHFFFAOYSA-N ergocristinine Natural products N12C(=O)C(C(C)C)(NC(=O)C3C=C4C=5C=CC=C6NC=C(C=56)CC4N(C)C3)OC2(O)C2CCCN2C(=O)C1CC1=CC=CC=C1 HEFIYUQVAZFDEE-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- ZAGRKAFMISFKIO-QMTHXVAHSA-N lysergic acid Chemical compound C1=CC(C2=C[C@H](CN([C@@H]2C2)C)C(O)=O)=C3C2=CNC3=C1 ZAGRKAFMISFKIO-QMTHXVAHSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 230000003836 peripheral circulation Effects 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 208000001297 phlebitis Diseases 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 229940065721 systemic for obstructive airway disease xanthines Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 208000027185 varicose disease Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000003422 vasoregulatory effect Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
Classifications
-
- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明の主題は、２種の知られた活性成分、即
ち１・３−ジメチル−３・４−ジヒドロ−７−
（5′−オキソヘキシル）−1H−プリン−２・６−
ジオンとジヒドロエルゴクリスチン（ここで、ジ
ヒドロとはリゼルグ酸の９・10位のジヒドロ誘導
体を意味する）又はその塩の１種との組合せを活
性成分として含む新規な持続性の薬剤組成物にあ
る。
１・３−ジメチル−３・４−ジヒドロ−７−
（5′−オキソヘキシル）−1H−プリン−２・６−
ジオンは１種のキサンチンである。これは、その
有益な血管拡張性のために、ヘミツシエ・フエル
ケ・アルバート社により1965年９月２日に出願さ
れ、第4791M号として発行されたフランス国医薬
特別特許において、特に薬剤として示されてい
る。
さらに、ジヒドロエルゴクリスチン及びその塩
は、多くの文献において薬剤として示されてい
る。ジヒドロエルゴクリスチンは、その血管調整
性（例えば血管拡張性、血圧降下作用など）のた
めに、並びに脳の交換神経制御中枢を調整する性
質のために、メタンスルホン酸塩の形でジヒドロ
エルゴコルニン及びジヒドロエルゴクリプチンと
組合せて特に人の治療に用いられる。例えば、
M.M.Janot編「Collection de Piecis de
Pharmaie（G.Valette著“Piecis de
Pharmacodynamie”p.328−332）」（1972年、パ
リ市マソン社発行）；
「Chemical Reviews」Vol.47、p.214−216
（1950）；
「Arzneim.Forsch.」17(1)、p.6−９（1967）
に記載されている。
また、ある種のキサンチンをジヒドロエルゴク
リスチンと組合せることも知られている。例え
ば、「Journal of Pharmaceutical Sciences」
Vol.59、No.３、March 1970、p.384−386に記載
の組合せがあげられる。
しかしながら、本発明者の知る限りでは、１・
３−ジメチル−３・７−ジヒドロ−７−（5′−オ
キソヘキシル）−1H−プリン−２・６−ジオンと
ジヒドロエルゴクリスチン又はその塩との組合せ
は今日まで決して実施されたことはなかつた。こ
こに、このような組合せがジヒドロエルゴクリス
チンの高い血中濃度を数時間にわたつて保持させ
ることが見出された。しかして、本発明の主題を
なすジヒドロエルゴクリスチンを基にしたこの組
成物の血管調整性並びに脳の交換神経制御中枢調
整性が持続性であり且つできるだけ一定のレベル
にあることを示すことができる。
この結果は、治療患者が事実長期間にわたつて
連続した治療を往々にして必要とするために、特
に有益である。
したがつて、本発明の主題は、１・３−ジメチ
ル−３・７−ジヒドロ−７−（5′−オキソヘキシ
ル）−1H−プリン−２・６−ジオンとジヒドロエ
ルゴクリスチン又はその製薬上許容できる無機酸
若しくは有機酸との付加塩とを含有することを特
徴とする新規な持続性薬剤組成物にある。
製薬上許容できる無機酸若しくは有機酸との付
加塩は、例えば、塩酸、臭化水素酸、よう化水素
酸、硫酸、りん酸、酢酸、安息香酸、マレイン
酸、フマル酸、こはく酸、酒石酸、くえん酸、グ
リオキシル酸、アスパラギン酸、メタン又はエタ
ンスルホン酸のようなアルカンスルホン酸、ベン
ゼン又はｐ−トルエンスルホン酸のようなアリー
ルスルホン酸及びアリールカルボン酸により形成
された塩であつてよい。
本発明の主題をなす薬剤組成物の中でも、ジヒ
ドロエルゴクリスチンの付加塩がメタンスルホン
酸塩であることを特徴とする前記のような組成物
が特にあげられる。
また、本発明の主題をなす薬剤組成物の中で
も、好ましくは、ジヒドロエルゴクリスチン又は
その製薬上許容できる無機酸若しくは有機酸との
付加塩の１重量部につき50〜150重量部の１・３
−ジメチル−３・７−ジヒドロ−７−（5′−オキ
ソヘキシル）−1H−プリン−２・６−ジオンを含
有することを特徴とする前記の組成物があげられ
る。
後者の中でも、特に、ジヒドロエルゴクリスチ
ン又はその製薬上許容できる無機酸若しくは有機
酸との付加塩の約１重量部につき100重量部の
１・３−ジメチル−３・７−ジヒドロ−７−
（5′−オキソヘキシル）−1H−プリン−２・６−
ジオンを含有する組成物、特に、ジヒドロエルゴ
クリスチンメタンスルホン酸塩１重量部につき
100重量部の１・３−ジメチル−３・７−ジヒド
ロ−７−（5′−オキソヘキシル）−1H−プリン−
２・６−ジオンを含有することを特徴とする組成
物があげられる。
本発明の主題をなす薬剤組成物は、ジヒドロエ
ルゴクリスチンと実質的に同一の薬効を示し、し
たがつて同一の用途に、例えば、アテローム性動
脈硬化症や老人の脳の機能性障害の治療に、動脈
炎、静脈炎、静脈瘤及びこれらの続発症のような
末梢循環障害の治療に、頭蓋外傷性障害及びその
続発症の治療に、並びに非外傷性起因の激しく且
存続性の頭痛の治療に用いることができる。有効
薬用量は、用いる化合物、治療患者及び病気によ
つて変り得るが、例えば、経口で１日当り１回又
は２回の投与で、メタンスルホン酸塩の形で0.5
〜1.5mgのジヒドロエルゴクリスチンにつき50〜
150mgの１・３−ジメチル−３・７−ジヒドロ−
７−（5′−オキソヘキシル）−1H−プリン−２・
６−ジオンである。
好ましくは、80mgの１・３−ジメチル−３・７
−ジヒドロ−７−（5′−オキソヘキシル）−1H−
プリン−２・６−ジオンと0.8mgのジヒドロエル
ゴクリスチンメタンスルホン酸塩を含有する組成
物が経口で１日当り１又は２回の割合で投与され
る。
本発明の主題をなす薬剤組成物は、消化器経路
で又は非経口的に投与することができる。
これらの薬剤組成物は、例えば固体又は液体で
あつてよく、人の医薬に一般に使用されている製
薬形態、例えば錠剤又は糖衣錠、ゼラチンカプセ
ル、顆粒、坐薬及び注射用調合剤として提供でき
る。それらは通常の方法で製造される。活性成分
は、これらの製薬組成物に一般に使用されている
補助剤、例えばタルク、アラビアゴム、ラクトー
ス、でん粉、ステアリン酸マグネシウム、ココア
バター、水性又は非水性ビヒクル、動物又は植物
起源の脂肪物質、パラフイン誘導体、グリコー
ル、各種の湿潤、分散又は乳化剤及び（又は）保
存剤中に配合することができる。
以下に本発明の実施例を示すが、これは本発明
を何ら制限するものではない。
例 １
下記の処方に相当する圧縮錠剤を調製した。
１・３−ジメチル−３・７−ジヒドロ−７−
（5′−オキソヘキシル）−1H−プリン−２・６−
ジオン ……100mg
ジヒドロエルゴクリスチンメタンスルホン酸塩
……１mg
補助剤
……１個300ｇまでの錠剤とするに十分な量
（補助剤の詳細：タルク、でん粉、ステアリン酸
マグネシウム）
例 ２
下記の処方に相当する胃耐性の糖衣錠剤を調製
した。
１・３−ジメチル−３・７−ジヒドロ−７−
（5′−オキソヘキシル）−1H−プリン−２・６−
ジオン ……80mg
ジヒドロエルゴクリスチンメタンスルホン酸塩
……0.8mg
補助剤
……１個250ｇまでの糖衣錠とするに十分な量
（補助剤の詳細：ラクトース、タルク、でん粉、
ステアリン酸マグネシウム、サツカロース、
セルロースアセチル−フタレート）
薬理運動学的研究
本発明の主題をなす組合せの薬理運動学的研究
をラツトにおいて、一方ではトリチウム化ジヒド
ロエルゴクリスチン（メタンスルホン酸塩の形
で）の溶液を、他方ではトリチウム化ジヒドロエ
ルゴクリスチン（メタンスルホン酸塩の形で）と
１・３−ジメチル−３・７−ジヒドロ−７−
（5′−オキソヘキシル）−1H−プリン−２・６−
ジオン（１／100の重量比で）との溶液を投与し
た後に血中の放射能の変化を測定することによつ
て行なつた。
トリチウム化ジヒドロエルゴクリスチンメタン
スルホン酸塩（DHEC3H9、10）は、接触水素化
により製造した。用いた方法は、Cousse氏他に
より1972年に報告されたもので、エルゴクリスチ
ンの９・10位置を大気圧下に選択的に還元するこ
とからなつている。クロマトグラフイーによる精
製後に得られた生成物は、5Ci／mMの最終比放
射能を持つている。
次いで、一方ではトリチウム化ジヒドロエルゴ
クリスチン（メタンスルホン酸塩）の溶液を、そ
して他方ではトリチウム化ジヒドロクリスチン
（メタンスルホン酸塩）と１・３−ジメチル−
３・７−ジヒドロ−７−（5′−オキソヘキシル）−
1H−プリン−２・６−ジオン（１／100の重量比
で）との溶液を調製した。
得られた溶液は、0.0466mg／mlのジヒドロエル
ゴクリスチン濃度及び400μCi／mlの比放射能を
有した。
実験を開始する48時間前からかごの中で順応さ
せたSprague Dawley種のラツトには、被検溶液
を胃内経路で投与する前の12時間は飼料を与えな
かつた。ラツトには水は任意に飲ませた。
次いで、動物にナトリウムペントバルビタール
を体重100ｇ当り0.1mlの割合で５％溶液として腹
腔内注射することにより麻酔させた。ループ状の
カテーテルを頚動脈の高さで側路を形成するよう
な形で挿入した。血液試料を比較的短時間でとれ
るようにその回路に蠕動ポンプを入れた。
対照バツチの動物には一匹当り0.0233mg量のト
リチウム化ジヒドロエルゴクリスチンを与えた。
処理バツチの動物には一匹当り0.0233mg量のトリ
チウム化ジヒドロエルゴクリスチンと、2.33mg量
の１・３−ジメチル−３・７−ジヒドロ−７−
（5′−オキソヘキシル）−1H−プリン−２・６−
ジオンを与えた。
「Intertechnique」型液体シンチレーシヨンス
ペクトロメータを用いてトリチウムの放射能を評
価した。以下に示す結果は、全摂取放射能に対す
る検査試料のトリチウムの放射能の比として表わ
される。
The subject of the present invention is the use of two known active ingredients, namely 1,3-dimethyl-3,4-dihydro-7-
(5'-oxohexyl)-1H-purine-2,6-
Novel long-acting pharmaceutical compositions comprising as active ingredients a combination of a dione and dihydroergocristine (herein dihydro means a dihydro derivative at position 9 and 10 of lysergic acid) or one of its salts. . 1,3-dimethyl-3,4-dihydro-7-
(5'-oxohexyl)-1H-purine-2,6-
Dione is a type of xanthine. Due to its beneficial vasodilatory properties, it is specifically indicated as a drug in the French Pharmaceutical Special Patent filed on September 2, 1965 by Hemitsier Fuerke Albert and issued as No. 4791M. There is. Furthermore, dihydroergocristine and its salts have been indicated as drugs in many publications. Dihydroergocristine is a derivative of dihydroergocornine in the form of methanesulfonate due to its vasoregulatory properties (e.g. vasodilatory, antihypertensive effects, etc.) as well as its properties to modulate the sympathetic control centers of the brain. and in combination with dihydroergocriptine for the treatment of humans. For example, MMJanot edited “Collection of Pieces de
Pharmaie (by G. Valette “Piecis de
"Pharmacodynamie"p.328-332)" (1972, published by Masson, Paris); "Chemical Reviews" Vol.47, p.214-216
(1950); “Arzneim.Forsch.” 17 (1), p.6-9 (1967)
It is described in. It is also known to combine certain xanthines with dihydroergocristine. For example, "Journal of Pharmaceutical Sciences"
Examples include the combinations described in Vol. 59, No. 3, March 1970, p. 384-386. However, to the best of the inventor's knowledge, 1.
The combination of 3-dimethyl-3,7-dihydro-7-(5'-oxohexyl)-1H-purine-2,6-dione with dihydroergocristine or its salts has never been practiced to date. . It has now been found that such a combination allows high blood concentrations of dihydroergocristine to be maintained for several hours. It can thus be shown that the vascular regulatory properties as well as the sympathetic central regulatory properties of this composition based on dihydroergocristine, which is the subject of the present invention, are long-lasting and at a level that is as constant as possible. . This result is particularly beneficial since treated patients often require continuous treatment over an extended period of time. The subject of the invention is therefore a combination of 1,3-dimethyl-3,7-dihydro-7-(5'-oxohexyl)-1H-purine-2,6-dione and dihydroergocristine or its pharmaceutically acceptable A novel long-acting pharmaceutical composition characterized by containing an addition salt with an inorganic acid or an organic acid. Addition salts with pharmaceutically acceptable inorganic or organic acids include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, acetic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, They may be salts formed with alkanesulfonic acids such as citric acid, glyoxylic acid, aspartic acid, methane or ethanesulfonic acid, arylsulfonic acids and arylcarboxylic acids such as benzene or p-toluenesulfonic acid. Among the pharmaceutical compositions that form the subject of the invention, mention may be made in particular of compositions as described above, characterized in that the addition salt of dihydroergocristine is a methanesulfonate. Also, among the pharmaceutical compositions that form the subject of the present invention, preferably 1.3 parts by weight of 50 to 150 parts by weight per 1 part by weight of dihydroergocristine or its addition salt with a pharmaceutically acceptable inorganic or organic acid.
-Dimethyl-3,7-dihydro-7-(5'-oxohexyl)-1H-purine-2,6-dione. Among the latter, in particular, 100 parts by weight of 1,3-dimethyl-3,7-dihydro-7- for about 1 part by weight of dihydroergocristine or its addition salt with a pharmaceutically acceptable inorganic or organic acid.
(5'-oxohexyl)-1H-purine-2,6-
per part by weight of compositions containing diones, in particular dihydroergocristine methanesulfonate
100 parts by weight of 1,3-dimethyl-3,7-dihydro-7-(5'-oxohexyl)-1H-purine-
Examples include compositions characterized by containing 2,6-dione. The pharmaceutical composition that forms the subject of the invention exhibits substantially the same medicinal efficacy as dihydroergocristine and therefore has the same uses, for example in the treatment of atherosclerosis and functional disorders of the brain in the elderly. , for the treatment of peripheral circulation disorders such as arteritis, phlebitis, varicose veins and their sequelae, for the treatment of cranial traumatic disorders and their sequelae, and for the treatment of severe and persistent headaches of non-traumatic origin. It can be used for. The effective dosage may vary depending on the compound used, the patient being treated and the disease, but for example, 0.5 in the form of methanesulfonate, administered orally once or twice per day.
~50 per ~1.5mg dihydroergocristine
150 mg of 1,3-dimethyl-3,7-dihydro-
7-(5'-oxohexyl)-1H-purine-2.
6-dione. Preferably 80 mg of 1,3-dimethyl-3,7
-dihydro-7-(5'-oxohexyl)-1H-
A composition containing purine-2,6-dione and 0.8 mg of dihydroergocristine methanesulfonate is administered orally once or twice per day. The pharmaceutical composition that is the subject of the invention can be administered by the gastrointestinal route or parenterally. These pharmaceutical compositions may be, for example, solid or liquid and may be presented in pharmaceutical forms commonly used in human medicine, such as tablets or dragees, gelatin capsules, granules, suppositories and injectable preparations. They are manufactured in the usual manner. The active ingredients may be supplemented with the adjuvants commonly used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin. It can be incorporated into derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives. Examples of the present invention are shown below, but these are not intended to limit the present invention in any way. Example 1 Compressed tablets were prepared corresponding to the following formulation. 1,3-dimethyl-3,7-dihydro-7-
(5'-oxohexyl)-1H-purine-2,6-
Dione...100mg dihydroergocristine methanesulfonate
...1 mg Auxiliary agent ...Enough amount to make one tablet up to 300 g (Details of adjuvants: talc, starch, magnesium stearate) Example 2 Stomach-resistant sugar-coated tablets corresponding to the following formulation were prepared. 1,3-dimethyl-3,7-dihydro-7-
(5'-oxohexyl)-1H-purine-2,6-
Dione...80mg dihydroergocristine methanesulfonate
...0.8mg Auxiliary agent ...Enough amount to make sugar-coated tablets up to 250g each (Details of adjuvants: lactose, talc, starch,
Magnesium stearate, satucalose,
Pharmacokinetic studies of the combination that forms the subject of the present invention were carried out in rats using a solution of tritiated dihydroergocristine (in the form of methanesulfonate) on the one hand and tritiated dihydroergocristine on the other hand. dihydroergocristine (in the form of methanesulfonate) and 1,3-dimethyl-3,7-dihydro-7-
(5'-oxohexyl)-1H-purine-2,6-
This was done by measuring the change in radioactivity in the blood after administering a solution with dione (in a weight ratio of 1/100). Tritiated dihydroergocristine methanesulfonate (DHEC 3 H9,10) was prepared by catalytic hydrogenation. The method used was described by Cousse et al. in 1972 and consists of selectively reducing the 9 and 10 positions of ergocristine to atmospheric pressure. The product obtained after chromatographic purification has a final specific activity of 5 Ci/mM. Then, on the one hand, a solution of tritiated dihydroergocristine (methane sulfonate) and on the other hand a solution of tritiated dihydrocristine (methane sulfonate) and 1,3-dimethyl-
3,7-dihydro-7-(5'-oxohexyl)-
A solution with 1H-purine-2,6-dione (in a weight ratio of 1/100) was prepared. The resulting solution had a dihydroergocristine concentration of 0.0466 mg/ml and a specific radioactivity of 400 μCi/ml. Sprague Dawley rats, which had been acclimated in cages for 48 hours before the start of the experiment, were deprived of food for 12 hours before being administered the test solution by intragastric route. Rats were allowed to drink water ad libitum. The animals were then anesthetized by intraperitoneal injection of sodium pentobarbital as a 5% solution at a rate of 0.1 ml/100 g body weight. A loop-shaped catheter was inserted at the level of the carotid artery to form a side channel. A peristaltic pump was included in the circuit to allow blood samples to be taken in a relatively short period of time. Control batches of animals received tritiated dihydroergocristine in an amount of 0.0233 mg per animal.
Treatment batches of animals received tritiated dihydroergocristine in an amount of 0.0233 mg per animal and 1,3-dimethyl-3,7-dihydro-7- in an amount of 2.33 mg per animal.
(5'-oxohexyl)-1H-purine-2,6-
Gave Zeon. The radioactivity of tritium was evaluated using an "Intertechnique" type liquid scintillation spectrometer. The results shown below are expressed as the ratio of the tritium radioactivity of the test sample to the total ingested radioactivity.
【表】
得られた結果は、１・３−ジメチル−３・７−
ジヒドロ−７−（5′−オキソヘキシル）−1H−プ
リン−２・６−ジオンとジヒドロエルゴクリスチ
ンメタンスルホン酸塩との組合せで処理されたバ
ツチの動物におけるジヒドロエルゴクリスチンの
血中濃度が、ジヒドロエルゴクリスチンメタンス
ルホン酸塩のみを与えられた対照バツチの動物の
それよりも非常に高く且つ非常に長時間にわたる
ことを示している。[Table] The results obtained are 1,3-dimethyl-3,7-
The blood concentration of dihydroergocristine in batches of animals treated with the combination of dihydro-7-(5'-oxohexyl)-1H-purine-2,6-dione and dihydroergocristine methanesulfonate was significantly lower than that of dihydroergocristine. It is shown to be much higher and for a much longer duration than that of control batches of animals receiving ergocristine methanesulfonate alone.
Claims (1)
（5′−オキソヘキシル）−1H−プリン−２・６−
ジオンとジヒドロエルゴクリスチン又はその製薬
上許容できる無機酸若しくは有機酸との付加塩を
含有することを特徴とする高いジヒドロエルゴク
リスチン血中濃度を持続する血管調整性又は交感
神経制御中枢調整性薬剤組成物。 ２ ジヒドロエルゴクリスチンの付加塩がメタン
スルホン酸塩であることを特徴とする特許請求の
範囲第１項記載の組成物。 ３ ジヒドロエルゴクリスチン又はその製薬上許
容できる無機酸若しくは有機酸との付加塩の１重
量部につき50〜150重量部の１・３−ジメチル−
３・７−ジヒドロ−７−（5′−オキソヘキシル）−
1H−プリン−２・６−ジオンを含有することを
特徴とする特許請求の範囲第１又は２項記載の組
成物。 ４ ジヒドロエルゴクリスチン又はその製薬上許
容できる無機酸若しくは有機酸との付加塩の１重
量部につき100重量部の１・３−ジメチル−３・
７−ジヒドロ−７−（5′−オキソヘキシル）−1H
−プリン−２・６−ジオンを含有することを特徴
とする特許請求の範囲第１〜３項のいずれかに記
載の組成物。 ５ ジヒドロエルゴクリスチンメタンスルホン酸
塩の１重量部につき100重量部の１・３−ジメチ
ル−３・７−ジヒドロ−７−（5′−オキソヘキシ
ル）−1H−プリン−２・６−ジオンを含有するこ
とを特徴とする特許請求の範囲第１〜４項のいず
れかに記載の組成物。 ６ 下記の処方 １・３−ジメチル−３・７−ジヒドロ−７−
（5′−オキソヘキシル）−1H−プリン−２・６−
ジオン ……80mg ジヒドロエルゴクリスチンメタンスルホン酸塩
……0.8mg 補助剤
……１個250mgまでの糖衣錠とするに十分な量 に相当することを特徴とする耐胃液性の糖衣錠の
形態にある特許請求の範囲第１〜６項のいずれか
に記載の組成物。[Claims] 1 1,3-dimethyl-3,7-dihydro-7-
(5'-oxohexyl)-1H-purine-2,6-
A vasomodulatory or sympathetic nervous system regulating drug composition that maintains a high blood concentration of dihydroergocristine, characterized by containing a dione and dihydroergocristine, or an addition salt thereof with a pharmaceutically acceptable inorganic or organic acid. thing. 2. The composition according to claim 1, wherein the addition salt of dihydroergocristine is methanesulfonate. 3. 50 to 150 parts by weight of 1,3-dimethyl- per part by weight of dihydroergocristine or its addition salt with a pharmaceutically acceptable inorganic or organic acid.
3,7-dihydro-7-(5'-oxohexyl)-
The composition according to claim 1 or 2, characterized in that it contains 1H-purine-2,6-dione. 4 100 parts by weight of 1,3-dimethyl-3.
7-dihydro-7-(5'-oxohexyl)-1H
- The composition according to any one of claims 1 to 3, characterized in that it contains purine-2,6-dione. 5 Contains 100 parts by weight of 1,3-dimethyl-3,7-dihydro-7-(5'-oxohexyl)-1H-purine-2,6-dione per part by weight of dihydroergocristine methanesulfonate. The composition according to any one of claims 1 to 4, characterized in that: 6 The following formulation 1,3-dimethyl-3,7-dihydro-7-
(5'-oxohexyl)-1H-purine-2,6-
Dione...80mg dihydroergocristine methanesulfonate
...0.8mg auxiliary agent ...any one of claims 1 to 6 which is in the form of a gastric juice-resistant dragee-coated tablet characterized in that it corresponds to an amount sufficient to make a dragee-coated tablet of up to 250mg each. Compositions as described.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7710906A FR2387035A1 (en) | 1977-04-12 | 1977-04-12 | NEW MEDICINAL PRODUCT INTENDED IN PARTICULAR FOR THE TREATMENT OF FUNCTIONAL CEREBRAL DISORDERS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS53130440A JPS53130440A (en) | 1978-11-14 |
| JPS627167B2 true JPS627167B2 (en) | 1987-02-16 |
Family
ID=9189287
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4135578A Granted JPS53130440A (en) | 1977-04-12 | 1978-04-10 | Novel pharmaceutical composition having obuect to treat especially functional disorder of brain |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JPS53130440A (en) |
| BE (1) | BE865891A (en) |
| DE (1) | DE2815878C2 (en) |
| FR (1) | FR2387035A1 (en) |
| GB (1) | GB1556851A (en) |
| GR (1) | GR72116B (en) |
| IL (1) | IL54462A0 (en) |
| IT (1) | IT1102581B (en) |
| NL (1) | NL7803895A (en) |
| PT (1) | PT67885B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4511557A (en) * | 1981-08-24 | 1985-04-16 | Gauri Kailash Kumar | Pharmaceutical composition |
| FI81258C (en) * | 1982-02-01 | 1990-10-10 | Sandoz Ag | FOERFARANDE FOER FRAMSTAELLNING AV EN PHARMACEUTISK KOMPOSITION FOER NASAL ADMINISTRATION. |
| GB8418430D0 (en) * | 1984-07-19 | 1984-08-22 | Beecham Wuelfing Gmbh & Co Kg | Treatment |
| GB8621869D0 (en) * | 1986-09-11 | 1986-10-15 | Beecham Group Plc | Treatment |
-
1977
- 1977-04-12 FR FR7710906A patent/FR2387035A1/en active Granted
-
1978
- 1978-04-06 IL IL54462A patent/IL54462A0/en unknown
- 1978-04-10 JP JP4135578A patent/JPS53130440A/en active Granted
- 1978-04-11 GR GR55954A patent/GR72116B/el unknown
- 1978-04-11 GB GB14173/78A patent/GB1556851A/en not_active Expired
- 1978-04-11 PT PT67885A patent/PT67885B/en unknown
- 1978-04-11 IT IT48852/78A patent/IT1102581B/en active
- 1978-04-11 BE BE186726A patent/BE865891A/en not_active IP Right Cessation
- 1978-04-12 DE DE2815878A patent/DE2815878C2/en not_active Expired
- 1978-04-12 NL NL7803895A patent/NL7803895A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| BE865891A (en) | 1978-10-11 |
| FR2387035B1 (en) | 1980-03-21 |
| IT7848852A0 (en) | 1978-04-11 |
| GR72116B (en) | 1983-09-15 |
| DE2815878A1 (en) | 1978-10-19 |
| GB1556851A (en) | 1979-11-28 |
| FR2387035A1 (en) | 1978-11-10 |
| PT67885B (en) | 1980-04-07 |
| IL54462A0 (en) | 1978-07-31 |
| DE2815878C2 (en) | 1986-10-09 |
| IT1102581B (en) | 1985-10-07 |
| JPS53130440A (en) | 1978-11-14 |
| NL7803895A (en) | 1978-10-16 |
| PT67885A (en) | 1978-05-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0920438B1 (en) | N6 heterocyclic substituted adenosine derivatives | |
| CA2289847A1 (en) | The use of 1,2,4-triazolo[1,5-c]pyrimidine heterocyclic analogues for the preparation of medicaments useful for the treatment of cerebrovascular disturbances | |
| KR20020031331A (en) | Methods of Treatment of Mitochondrial Disorders | |
| AU2019277382A1 (en) | Methods for increasing sepiapterin plasma exposure | |
| JPH085787B2 (en) | Dementia and cerebrovascular disorder prophylactic / therapeutic agent and platelet aggregation inhibitor | |
| JPH01153689A (en) | Antiparkinsonian ergoline derivative | |
| US4189469A (en) | Pharmaceutical compositions | |
| JPS6253932A (en) | Vasodilatory and antianoxia | |
| JPS627167B2 (en) | ||
| JPH039089B2 (en) | ||
| Koysooko et al. | Effect of ethanol on theophylline absorption in humans | |
| DE3525390C2 (en) | ||
| GB1600639A (en) | Medicament preparation having resorption properties and method of producing the same | |
| WO1990011080A1 (en) | Drug for improving brain function | |
| EP0071563B1 (en) | Trans-dihyldrolisuride antipsychotic | |
| JP3388778B2 (en) | Cerebrovascular dementia improving agent | |
| US5525605A (en) | Remedy for inflammatory intestinal diseases | |
| CA1094454A (en) | Treatment for scabies | |
| NL8200491A (en) | 17, 18-DEHYDROAPOVINCAMINOL-3'4 ', 5'-TRIMETHOXYBENZOATE, ITS ACID ADDITION SALTS, INTERMEDIATES, AND METHODS FOR PREPARING THESE COMPOUNDS. | |
| US4711891A (en) | Use of terguride as a geriatric agent | |
| JP3993646B2 (en) | Novel uses of β-naphthoquinone derivatives and their salts | |
| KR20010029658A (en) | Agent for enhancing cerebral acetylcholine release | |
| ES2532479T3 (en) | Agents for the treatment of migraine | |
| GB2195532A (en) | Therapeutic agent for treatment of disorders associated with cerebral ischemia | |
| JP2009143929A (en) | Preventive or treating agent for sleep disorder |