JPS6139928B2 - - Google Patents
Info
- Publication number
- JPS6139928B2 JPS6139928B2 JP13131276A JP13131276A JPS6139928B2 JP S6139928 B2 JPS6139928 B2 JP S6139928B2 JP 13131276 A JP13131276 A JP 13131276A JP 13131276 A JP13131276 A JP 13131276A JP S6139928 B2 JPS6139928 B2 JP S6139928B2
- Authority
- JP
- Japan
- Prior art keywords
- agent according
- depression
- therapeutic agent
- compound
- group
- 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
- 150000001875 compounds Chemical class 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 208000020401 Depressive disease Diseases 0.000 claims description 9
- 208000024714 major depressive disease Diseases 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 3
- 201000003104 endogenous depression Diseases 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 230000003111 delayed effect Effects 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims description 2
- 230000000737 periodic effect Effects 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 13
- 229940124597 therapeutic agent Drugs 0.000 claims 13
- 239000003795 chemical substances by application Substances 0.000 claims 4
- 239000004480 active ingredient Substances 0.000 claims 1
- 241001465754 Metazoa Species 0.000 description 5
- 230000008485 antagonism Effects 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000006194 liquid suspension Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- MKJIEFSOBYUXJB-HOCLYGCPSA-N (3S,11bS)-9,10-dimethoxy-3-isobutyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one Chemical compound C1CN2C[C@H](CC(C)C)C(=O)C[C@H]2C2=C1C=C(OC)C(OC)=C2 MKJIEFSOBYUXJB-HOCLYGCPSA-N 0.000 description 2
- 208000009132 Catalepsy Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 206010047853 Waxy flexibility Diseases 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000001373 regressive effect Effects 0.000 description 2
- 229960005333 tetrabenazine Drugs 0.000 description 2
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-M L-tartrate(1-) Chemical compound OC(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-M 0.000 description 1
- 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 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-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
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 208000012826 adjustment disease Diseases 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-M fumarate(1-) Chemical compound OC(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-M 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 208000015238 neurotic disease Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 231100000048 toxicity data Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は式
〔式中、R1はα又はβ立体配置を有し且つ次の
基：
(a) −CH2−Ａ−CN（ここでＡは直接結合又は
−Ｓ−である）、
(b) −CH2−Ｓ−ピリジル、
(c) −NH−SO2NR5R6（ここでR5及びR6はそれ
ぞれ水素又は炭素数１〜４の低級アルキルであ
る）、又は
(d)
であり、R2及びR3はおのおの水素又は一緒に
なつての結合であり、R4は水素、塩素又は臭
素であり、但し、
(i) R1が基(a)でありＡが直接結合である場合
には、R2及びR3はおのおの水素であり；
(ii) R1が基(b)である場合には、R4は水素であ
り；
(iii) R1が基(c)である場合には、R2及びR3はお
のおの水素でありR1はα立体配置を有し；
(iv) R1が基(d)である場合には、R1はβ型であ
りR2及びR3は一緒になつての結合でありR4
は臭素である。〕
の化合物の新規な用途に関する。
R3が水素である場合には環Ａ及びＢは互いに
トランスであることが理解されるべきである。
R1が基(a)である化合物のグループにおいて
は、R4は好ましくは水素又は塩素である。Ａが
直接結合である場合にはR1は有利にはα立体配
置を有するが、ＡがＳである場合にはR1は有利
にはα又はβ立体配置を有する。好ましくはＡは
直接結合である。特定の例は次の通りである：
８α−シアノメチル−６−メチルエルゴリン−
（）〔以下化合物Ａという〕
２−クロロ−８α−シアノメチル−６−メチル
エルゴリン−（）〔化合物Ｂ〕
６−メチル−８β−チオシアノメチル−エルゴ
レン〔化合物Ｃ〕
６−メチル−８α−チオシアノメチル−エルゴ
リン−（）〔化合物Ｄ〕
６−メチル−８β−チオシアノメチル−エルゴ
リン−（）〔化合物Ｅ〕
R1が基(b)である化合物のグループにおいて
は、そのピリジル基は炭素原子を好ましくは２個
介して環に結合している。特定の例は次の通りで
ある：
６−メチル−８β−2′−ピリジルチオメチル−
エルゴレン〔化合物Ｆ〕
R1が基(c)である化合物のグループにおいて
は、R5及びR6はおのおの好ましくは低級アルキ
ル、特にメチル又はエチルである。R4は好まし
くは水素である。特定の例は次の通りである：
６−メチル−８α−（Ｎ・Ｎ−ジエチルスルフ
アモイルアミノ）エルゴリン−（）〔化合物Ｇ〕
６−メチル−８α−（Ｎ・Ｎ−ジメチルスルフ
アモイルアミノ）エルゴリン−（）〔化合物Ｈ〕
R1が基(d)である化合物は次の通りである：
２−ブロモ−α−エルゴクリプチン〔化合物
Ｊ〕CB154
上記の化合物は既知である。しかしおどろくべ
きことに本化合物は抑うつ症の治療に有効である
ことが見出されたのである。この様な抑うつ症の
例は内因性抑うつ症及び外因性（反応性）抑うつ
症、特に退縮性、サイクル／周期的、分裂情緒
的、及び遅延された抑うつ症から選ばれる。抗抑
制剤作用は動物での標準テストにより確認され
る。好適な動物実験の例にはテトラベナジン拮抗
作用テストがあり、この場合マウスにおけるテト
ラベナジン誘発カタレブシーの拮抗作用が、動物
の体重１Kg当り約１〜約10mgの化合物を皮下投与
の約120分後に観察される。他のテストとしては
レセルピン拮抗作用テストがあり、この場合はつ
かねずみで５mg/Kgi.p.のレセルピンにより誘発
されるカタレプシーの拮抗作用が、レセルピン投
与の17時間後動物の体重１Kg当り約0.1〜約10mg
の化合物を皮下投与した約120分後に観察され
る。
上記の用途に対しては、投与量はもちろん投与
型式、治療方法及び使用する化合物により変わ
る。しかし、一般に動物の体重１Kg当り約0.01〜
約10mgの１日投与量で、有利には１日に２〜４回
に分割して投与するか又は持続放出形で投与する
ことにより満足すべき結果が得られる。大きな哺
乳動物に対しては１日の総投与量は約2.5〜約40
mg有利には2.5〜25mgたとえば５〜15mgの範囲で
あり、経口投与の投与形は約0.5〜約20mg、たと
えば約0.5〜約６mgの化合物を含み固体又は液体
の担体又は希釈剤を混合してなる。
本化合物は製薬上許容しうる酸付加塩の形で投
与してもよい。この様な塩の形は既知であり、対
応する遊離塩基と一般に同じ作用をもつ。塩形成
に好適な酸の例にはメタン−スルホン酸、フマル
酸、酒石酸及び塩酸が含まれる。
本化合物はそのままで又は製薬組成物として投
与される。この様な組成物は既知であり、通常の
方法でたとえば経腸投与用としては錠剤、粉末、
顆粒、カプセル、サスペンジヨン、溶液、シロツ
プ及びエリキシルに、又は非経口投与用としては
注射しうる溶液及びサスペンジヨンに処方され
る。
以下の実施例において、本発明の用途に好適な
組成物を示す。
実施例 １
２−ブロモ−α−エルゴクリブチン錠剤
経腸投与に好適な、以下の成分を含む錠剤が既
知の方法で製造される。
成 分 重 量
２−ブロモ−α−エルゴクリプチン
2.87mg
メタンスルホネート （塩基の2.5mgに相当）
ラクトース 96.18mg
とうもろこしでん粉 14.00mg
ポリビニルピロリドン 5.00mg
ステアリン酸マグネシウム 0.70mg
タルク 1.20mg
着色剤 0.05mg
120mg
上記の錠剤を臨床テストおいて内因性抑うつ症
（たとえばサイクル／周期的抑うつ症、退縮性抑
うつ症及び分裂情緒的抑うつ症）及び精神病的抑
うつ症（たとえば反応性抑うつ症）の治療に１日
に7.5〜20mgの投与量で用いた。このテストの結
果、２−ブロモ−α−エルゴクリプチンについて
は7.5〜30mgの１日投与量が投与される。
実施例 ２
２−ブロモ−α−エルゴクリプチンカプセル
経腸投与に好適な、以下の成分を含む硬質ゼラ
チンカプセルが既知の方法で製造される。このカ
プセルは抑うつ症の治療に１日に１カプセル３回
の投与量で用いられる。
The present invention is based on the formula [wherein R 1 has an α or β configuration and the following groups: (a) -CH 2 -A-CN (where A is a direct bond or -S-), (b) -CH 2 -S-pyridyl, (c) -NH- SO2NR5R6 (wherein R5 and R6 are each hydrogen or lower alkyl having 1 to 4 carbon atoms), or (d) , R 2 and R 3 are each hydrogen or a bond taken together, and R 4 is hydrogen, chlorine or bromine, provided that (i) R 1 is a group (a) and A is a direct bond; If R 1 is a group (b), then R 2 and R 3 are each hydrogen; (ii) if R 1 is a group (b), R 4 is hydrogen; (iii) if R 1 is a group (c) (iv) If R 1 is a group (d), then R 2 and R 3 are each hydrogen and R 1 has the α configuration; 2 and R 3 together are a bond and R 4
is bromine. ] Concerning a new use of the compound. It is to be understood that when R 3 is hydrogen, rings A and B are trans to each other. In the group of compounds in which R 1 is group (a), R 4 is preferably hydrogen or chlorine. If A is a direct bond, R 1 preferably has the α configuration, whereas if A is S, R 1 preferably has the α or β configuration. Preferably A is a direct bond. A specific example is: 8α-cyanomethyl-6-methylergoline-
() [hereinafter referred to as compound A] 2-chloro-8α-cyanomethyl-6-methylergoline-() [compound B] 6-methyl-8β-thiocyanomethyl-ergolene [compound C] 6-methyl-8α-thio Cyanomethyl-ergoline-() [Compound D] 6-methyl-8β-thiocyanomethyl-ergoline-() [Compound E] In the group of compounds in which R 1 is group (b), the pyridyl group is a carbon atom is preferably bonded to the ring through two bonds. A specific example is: 6-methyl-8β-2'-pyridylthiomethyl-
Ergolene [Compound F] In the group of compounds in which R 1 is group (c), R 5 and R 6 are each preferably lower alkyl, especially methyl or ethyl. R 4 is preferably hydrogen. Specific examples are: 6-Methyl-8α-(N·N-diethylsulfamoylamino)ergoline-() [Compound G] 6-Methyl-8α-(N·N-dimethylsulfamoyl Amino)ergoline-() [Compound H] The compounds in which R 1 is group (d) are as follows: 2-Bromo-α-ergocryptine [Compound J] CB154 The above compounds are known. However, surprisingly, this compound was found to be effective in treating depression. Examples of such depressions are chosen from endogenous depression and exogenous (reactive) depression, especially regressive, cyclical, schizoaffective, and delayed depression. Anti-depressant action is confirmed by standard tests in animals. An example of a suitable animal study is the tetrabenazine antagonism test, in which antagonism of tetrabenazine-induced catalepsy in mice is observed about 120 minutes after subcutaneous administration of about 1 to about 10 mg of the compound per kg of animal body weight. . Another test is the reserpine antagonism test, in which the antagonism of catalepsy induced by 5 mg/Kg. Approximately 10mg
observed approximately 120 minutes after subcutaneous administration of the compound. For the above uses, the dosage will, of course, vary depending on the mode of administration, method of treatment and compound used. However, in general, about 0.01 to 1 kg of animal weight
Satisfactory results are obtained with daily doses of about 10 mg, advantageously administered in divided doses 2 to 4 times a day or in sustained release form. For large mammals, the total daily dose is about 2.5 to about 40
mg advantageously in the range from 2.5 to 25 mg, such as from 5 to 15 mg; dosage forms for oral administration may contain from about 0.5 to about 20 mg, such as from about 0.5 to about 6 mg, of the compound in admixture with a solid or liquid carrier or diluent. Become. The compounds may be administered in the form of pharmaceutically acceptable acid addition salts. Such salt forms are known and generally have the same effect as the corresponding free base. Examples of acids suitable for salt formation include methanesulfonic acid, fumaric acid, tartaric acid and hydrochloric acid. The compounds may be administered neat or as a pharmaceutical composition. Such compositions are known and can be prepared in the usual manner, e.g. for enteral administration, as tablets, powders, etc.
It is formulated into granules, capsules, suspensions, solutions, syrups and elixirs, or for parenteral administration into injectable solutions and suspensions. The following examples demonstrate compositions suitable for use in the present invention. Example 1 2-Bromo-α-ergocributine Tablets Tablets suitable for enteral administration and containing the following ingredients are manufactured in a known manner. Ingredient weight 2-bromo-α-ergocryptine
2.87mg Methanesulfonate (equivalent to 2.5mg of base) Lactose 96.18mg Corn starch 14.00mg Polyvinylpyrrolidone 5.00mg Magnesium stearate 0.70mg Talc 1.20mg Coloring agent 0.05mg 120mg The above tablets have been tested in clinical tests to improve endogenous depression (e.g. It was used in the treatment of cyclic/periodic depression, regressive depression and schizoaffective depression) and psychotic depression (eg reactive depression) at doses of 7.5 to 20 mg per day. As a result of this test, daily doses of 7.5 to 30 mg are administered for 2-bromo-alpha-ergocriptine. Example 2 2-Bromo-α-ergocriptine Capsules Hard gelatin capsules suitable for enteral administration and containing the following ingredients are manufactured in a known manner. This capsule is used in the treatment of depression at a dosage of 1 capsule 3 times per day.
【表】
実施例 ３及び４
注射用無菌サスペンジヨン及び経口用液体サス
ペンジヨン
以下の製薬組成物が通常の技術を用いて所定量
の活性剤により処方される。注射用サスペンジヨ
ン及び経口用液体サスペンジヨンは単位投与量と
して有効な処方を示してあり、抑うつ症の治療の
ため投与される。注射用サスペンジヨンは１日に
１回の投与が好適であるが、しかし経口用液体サ
スペンジヨンはこの目的のためには好適には１日
に２〜４回投与される。TABLE Examples 3 and 4 Sterile Injectable Suspensions and Oral Liquid Suspensions The following pharmaceutical compositions are formulated using conventional techniques with predetermined amounts of active agent. Injectable suspensions and oral liquid suspensions represent effective formulations as unit doses and are administered for the treatment of depression. Injectable suspensions are preferably administered once a day, whereas oral liquid suspensions are preferably administered two to four times a day for this purpose.
【表】
実施例 ５
上記実施例１〜４における２−ブロモ−α−エ
ルゴクリプチンを、等量の上記式の特定の化合
物、即ち化合物Ａ〜Ｈのいづれか、たとえば
８α−シアノメチル−６−メチル−エルゴリン
−（）メタンスルホネート；６−メチル−８β
−チオシアノメチル−エルゴレンハイドロゼンフ
マレート；６−メチル−８β−2′−ピリジルチオ
メチルエルゴレンハイドロゼンタートレート；６
−メチル−８α−Ｎ・Ｎ−ジメチルスルフアモイ
ルアミノ−エルゴリン−（）塩酸塩
におきかえる。
薬理データ
抗抑制剤活性
上記のレセルビン拮抗作用テストで得られた
ED50値は下記の通りである。数値は皮下投与用
化合物の動物の体重１Kg当りのmg数で与えられ
る。
毒性データ
マウス及びラツトでの３日間以上にわたる急性
毒性テストにおいて得られたLD50値は下記の通
りmg/Kgで与えられる。[Table] Example 5 2-bromo-α-ergocriptine in Examples 1 to 4 above was mixed with an equivalent amount of a specific compound of the above formula, that is, any one of compounds A to H, such as 8α-cyanomethyl-6-methyl -ergoline-()methanesulfonate; 6-methyl-8β
-Thiocyanomethyl-ergolene hydrogen fumarate; 6-methyl-8β-2'-pyridylthiomethylergolene hydrogen tartrate; 6
-Methyl-8α-N.N-dimethylsulfamoylamino-ergoline-() hydrochloride. Pharmacological data Anti-inhibitory activity Obtained in the above reservin antagonism test
The ED50 values are as follows. Values are given in mg/kg of animal body weight of the compound for subcutaneous administration. Toxicity Data The LD 50 values obtained in acute toxicity tests over 3 days in mice and rats are given below in mg/Kg.
Claims (1)
基： (a) −CH2−Ａ−CN（ここで、Ａは直接結合又
は−Ｓ−である）、 (b) −CH2−Ｓ−ピリジル、 (c) −NH−SO2NR5R6（ここで、R5及びR6はそ
れぞれ独立に水素又は炭素数１〜４個の低級ア
ルキルである）、又は (d) であり、 R2及びR3は各々水素であるか又は一緒にな
つて結合を表わし、 R4は水素、塩素又は臭素であり、但し、 (i) R1が基(a)であり且つＡが直接結合である
場合には、R2及びR3は各々水素であり； (ii) R1が基(b)である場合には、R4は水素であ
り； (iii) R1が基(c)である場合には、R2及びR3は
各々水素であり且つR1はα立体配置を有
し； (iv) R1が基(d)である場合には、R1はβ立体配
置を有し、R2及びR3は一緒になつて結合を
表わし且つR4は臭素である］ の化合物を遊離塩基の形又は製薬学的に許容しう
る酸付加塩の形で有効成分として含有することを
特徴とする抑うつ症処置剤。 ２ 式においてR1が基(a)である特許請求の範
囲第１項記載の処置剤。 ３ 該化合物が６−メチル−８β−チオシアノメ
チル−エルゴレンである特許請求の範囲第２項記
載の処置剤。 ４ 基(a)においてＡが直接結合である特許請求の
範囲第２項記載の処置剤。 ５ 該化合物が８α−シアノメチル−６−メチル
エルゴリン−（）である特許請求の範囲第３項
記載の処置剤。 ６ 式においてR1が基(b)である特許請求の範
囲第１項記載の処置剤。 ７ 該化合物が６−メチル−８β−2′−ピリジル
チオメチル−エルゴレンである特許請求の範囲第
６項記載の処置剤。 ８ 式においてR1が基(c)である特許請求の範
囲第１項記載の処置剤。 ９ 該化合物が６−メチル−８α−（Ｎ・Ｎ−ジ
エチルスルフアモイルアミノ）エルゴリン−
（）である特許請求の範囲第７項記載の処置
剤。 １０ 該化合物が６−メチル−８α−（Ｎ・Ｎ−
ジメチルスルフアモイルアミノ）エルゴリン−
（）である特許請求の範囲第７項記載の処置
剤。 １１ 該化合物が２−ブロモ−α−エルゴクリプ
チンである特許請求の範囲第１項記載の処置剤。 １２ 約0.5〜約20mgの該化合物を含む単位投与
形態にある特許請求の範囲第１項記載の処置剤。 １３ 約0.5〜約６mgの該化合物を含む単位投与
形態にある特許請求の範囲第１項記載の処置剤。 １４ 抑うつ症が内因性抑うつ症である特許請求
の範囲第１項記載の処置剤。 １５ 抑うつ症が外因性抑うつ症である特許請求
の範囲第１項記載の処置剤。 １６ 抑うつ症が退縮性抑うつ症である特許請求
の範囲第１項記載の処置剤。 １７ 抑うつ症がサイクル／周期的抑うつ症であ
る特許請求の範囲第１項記載の処置剤。 １８ 抑うつ症が分裂情緒的抑うつ症である特許
請求の範囲第１項記載の処置剤。 １９ 抑うつ症が遅延された抑うつ症である特許
請求の範囲第１項記載の処置剤。[Claims] 1 formula [wherein R 1 has an α or β configuration and the following groups: (a) -CH 2 -A-CN (wherein A is a direct bond or -S-), (b) - CH 2 -S-pyridyl, (c) -NH-SO 2 NR 5 R 6 (wherein R 5 and R 6 are each independently hydrogen or lower alkyl having 1 to 4 carbon atoms), or (d ) , R 2 and R 3 are each hydrogen or together represent a bond, R 4 is hydrogen, chlorine or bromine, provided that (i) R 1 is a group (a) and A is a direct bond, R 2 and R 3 are each hydrogen; (ii) if R 1 is a group (b), R 4 is hydrogen; (iii) if R 1 is a group (c), then R 2 and R 3 are each hydrogen and R 1 has an α configuration; (iv) when R 1 is a group (d), R 1 is β steric configuration, R 2 and R 3 taken together represent a bond and R 4 is bromine] as an active ingredient in the form of a free base or in the form of a pharmaceutically acceptable acid addition salt. A depression treatment agent characterized by containing: 2. The treatment agent according to claim 1, wherein in the formula, R 1 is a group (a). 3. The therapeutic agent according to claim 2, wherein the compound is 6-methyl-8β-thiocyanomethyl-ergolene. 4. The therapeutic agent according to claim 2, wherein A in group (a) is a direct bond. 5. The therapeutic agent according to claim 3, wherein the compound is 8α-cyanomethyl-6-methylergoline-(). 6. The treatment agent according to claim 1, wherein R 1 is a group (b) in the formula. 7. The therapeutic agent according to claim 6, wherein the compound is 6-methyl-8β-2'-pyridylthiomethyl-ergolene. 8. The treatment agent according to claim 1, wherein R 1 is a group (c) in the formula. 9 The compound is 6-methyl-8α-(N·N-diethylsulfamoylamino)ergoline-
The therapeutic agent according to claim 7, which is ( ). 10 The compound is 6-methyl-8α-(N・N-
dimethylsulfamoylamino)ergoline-
The therapeutic agent according to claim 7, which is ( ). 11. The therapeutic agent according to claim 1, wherein the compound is 2-bromo-α-ergocriptine. 12. The treatment of claim 1 in unit dosage form containing about 0.5 to about 20 mg of the compound. 13. The treatment of claim 1 in a unit dosage form containing about 0.5 to about 6 mg of the compound. 14. The therapeutic agent according to claim 1, wherein the depression is endogenous depression. 15. The therapeutic agent according to claim 1, wherein the depression is exogenous depression. 16. The therapeutic agent according to claim 1, wherein the depression is involutional depression. 17. The therapeutic agent according to claim 1, wherein the depression is cycle/periodic depression. 18. The therapeutic agent according to claim 1, wherein the depression is schizoaffective depression. 19. The therapeutic agent according to claim 1, wherein the depression is delayed depression.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB4563375 | 1975-11-03 | ||
| GB4563675 | 1975-11-03 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5257332A JPS5257332A (en) | 1977-05-11 |
| JPS6139928B2 true JPS6139928B2 (en) | 1986-09-06 |
Family
ID=26265625
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13131276A Granted JPS5257332A (en) | 1975-11-03 | 1976-11-02 | Improvement in organic compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5257332A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0543464Y2 (en) * | 1990-04-20 | 1993-11-02 |
-
1976
- 1976-11-02 JP JP13131276A patent/JPS5257332A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0543464Y2 (en) * | 1990-04-20 | 1993-11-02 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5257332A (en) | 1977-05-11 |
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