JPH03284686A - Indole derivative and antiulcer agent containing the derivative as active component - Google Patents
Indole derivative and antiulcer agent containing the derivative as active componentInfo
- Publication number
- JPH03284686A JPH03284686A JP8105290A JP8105290A JPH03284686A JP H03284686 A JPH03284686 A JP H03284686A JP 8105290 A JP8105290 A JP 8105290A JP 8105290 A JP8105290 A JP 8105290A JP H03284686 A JPH03284686 A JP H03284686A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- derivative
- acid
- active component
- 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
- 239000003699 antiulcer agent Substances 0.000 title claims abstract description 8
- 150000002475 indoles Chemical class 0.000 title claims description 8
- 239000002253 acid Substances 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 239000004480 active ingredient Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 8
- -1 lithium aluminum hydride Chemical compound 0.000 abstract description 5
- CJDRUOGAGYHKKD-RQBLFBSQSA-N 1pon08459r Chemical class CN([C@H]1[C@@]2(C[C@@]3([H])[C@@H]([C@@H](O)N42)CC)[H])C2=CC=CC=C2[C@]11C[C@@]4([H])[C@H]3[C@H]1O CJDRUOGAGYHKKD-RQBLFBSQSA-N 0.000 abstract description 3
- 239000012280 lithium aluminium hydride Substances 0.000 abstract description 3
- 239000003377 acid catalyst Substances 0.000 abstract description 2
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 abstract description 2
- 239000003960 organic solvent Substances 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 2
- 239000000463 material Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- 108091006112 ATPases Proteins 0.000 description 4
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229940126062 Compound A Drugs 0.000 description 3
- 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 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 230000027119 gastric acid secretion Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000001103 potassium chloride Substances 0.000 description 3
- 235000011164 potassium chloride Nutrition 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 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
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229960001380 cimetidine Drugs 0.000 description 2
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-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
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 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
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 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
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 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
- 239000007983 Tris buffer Substances 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 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
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 201000000079 gynecomastia Diseases 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 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
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は新規なインドール誘導体、およびその薬理学的
に許容されうる酸との付加塩、さらにそれらを有効成分
として含有する抗潰瘍薬に関する。DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to novel indole derivatives, addition salts thereof with pharmacologically acceptable acids, and antiulcer drugs containing them as active ingredients.
（従来の技術）
現在、抗潰瘍薬として使用されている薬剤には、シメチ
ジンｊ二代表される胃酸分泌抑制剤、および胃腸細胞保
護作用を持つ薬剤が多く知られており、これらは患者の
症状などに応じて用いられている。(Prior art) Many drugs currently used as anti-ulcer drugs include gastric acid secretion inhibitors, such as cimetidine, and drugs that protect gastrointestinal cells. It is used depending on the situation.
（発明が解決しようとする問題点）
しかしながらこれらの既知の薬剤には多くの副作用が報
告されている。例えば胃酸分泌抑制剤として繁用されて
いるシメチジンについては、女性化乳房、投与中止後の
潰瘍再発などの問題があって、改良が望まれている。(Problems to be Solved by the Invention) However, many side effects have been reported for these known drugs. For example, cimetidine, which is frequently used as a gastric acid secretion suppressant, has problems such as gynecomastia and recurrence of ulcers after discontinuation of administration, and improvements are desired.
（問題を解決するｔ；めの手段）
前述の通り、既知の薬剤には副作用のために使用方法が
制限されるなどの欠点があった。そこで本発明者はこれ
らの知見の上にたって鋭意研究の結果、下記のインドー
ル誘導体が著しい抗潰瘍効果を有することを見いだして
本発明を完成させるに至った。(Means for Solving the Problem) As mentioned above, known drugs have drawbacks such as limited usage due to side effects. Based on these findings, the present inventor conducted intensive research and found that the following indole derivatives have a remarkable anti-ulcer effect, thereby completing the present invention.
本発明は次の式（Ｉ）で示される新規なインドール誘導
体、およびその薬理学的に許容されうる酸との付加塩に
関するものである。The present invention relates to a novel indole derivative represented by the following formula (I) and its addition salt with a pharmacologically acceptable acid.
式中、波線で示したものはその位置での異性体を意味し
、これら異性体の全ても本発明に関するものである。In the formula, what is shown with a wavy line means an isomer at that position, and all of these isomers are also related to the present invention.
本発明の式（Ｉ）で示される化合物、およびその薬理学
的に許容されうる酸との付加塩は、胃酸分泌抑制作用を
示すことが後述の試験において示される。従ってこの式
（Ｉ）で示される化合物は、抗潰瘍薬として有用性が期
待できる。生理活性についての詳細は後記の実施例に記
載されている。The compound represented by formula (I) of the present invention and its addition salt with a pharmacologically acceptable acid are shown to exhibit gastric acid secretion suppressive action in the tests described below. Therefore, the compound represented by formula (I) can be expected to be useful as an anti-ulcer drug. Details regarding the physiological activity are described in the Examples below.
本発明の式（Ｉ）で示される化合物は、式（ＩＩ）で示
されるインドール誘導体、および式（ＩＩＩ）で示され
るアジマリン誘導体との縮合反応に際して合目的的な任
意の方法によって合成することが出来る。好適な具体例
を示せば、下記の通りである。The compound represented by the formula (I) of the present invention can be synthesized by any convenient method during the condensation reaction with the indole derivative represented by the formula (II) and the ajmaline derivative represented by the formula (III). I can do it. Preferred specific examples are as follows.
式（Ｉ［）で示される化合物と、式（ＩＩＩ）で示され
る化合物とを酸触媒下に有機溶媒中で縮合すれば式（Ｉ
）の化合物が得られる。When a compound represented by formula (I[) and a compound represented by formula (III) are condensed in an organic solvent under an acid catalyst, formula (I
) is obtained.
用いられる酸としては塩酸等の無機酸、溶媒としてはメ
タノール等のアルコール系溶剤ヲ用いることが出来る。The acid used may be an inorganic acid such as hydrochloric acid, and the solvent may be an alcoholic solvent such as methanol.
反応条件としては０〜１００°Ｃの温度範囲が用いられ
うるが、溶剤の還流温度が好ましい。精製はクロマトグ
ラフィー等の公知の方法を用いて行なうことが出来る。As reaction conditions, a temperature range of 0 to 100°C can be used, but the reflux temperature of the solvent is preferred. Purification can be performed using known methods such as chromatography.
原料の式（Ｉｔ）で示される化合物は式（ＩＶ）で示さ
れるテトラヒドロカルポリン誘導体を原料として、公知
の方法（薬学雑誌、９７（３）、３０９−３１９、天井
進一部等）で合成することが出来る。The compound represented by formula (It) as a raw material is synthesized using a tetrahydrocarpoline derivative represented by formula (IV) as a raw material by a known method (Yakugaku Zasshi, 97(3), 309-319, Tenshi Shinbu, etc.) I can do it.
一方、式（ＤＩ）で示される原料のアジマリン誘導体ハ
、天井等の方法（Ｃｈｅｍ、 Ｐｈａｒｍ、 Ｂｕ
ｌ１２１（８） １７８３〜（Ｉ９７３））で得られる
式（Ｖ）のイし金物から、公知のＮ−メチル化例え１ｆ
クロロホルメイトとの反応、つづくリチウムアルミニウ
ムハイドライドでの還元反応などＩこよって合成するこ
とが出来る。On the other hand, the raw material ajmaline derivative represented by the formula (DI) can be prepared by the method of Chem, Pharm, Bu.
1121(8) 1783-(I973)) From the metal compound of formula (V) obtained by the known N-methylation example 1f
It can be synthesized by reaction with chloroformate followed by reduction reaction with lithium aluminum hydride.
（Ｉｎ）
本発明の式（Ｉ）で示される化合物は所望によって薬理
学的に許容されうる酸との付加塩に変換することができ
、これらの酸付加塩も本発明の範囲に包含されるもので
ある。そして、酸付加塩としては、例えば塩酸、臭化水
素酸、硫酸、リン酸などの無機酸の塩類、酢酸、コハク
酸、酪酸、シュウ酸、リンゴ酸、フマール酸、マレイン
酸、ステアリン酸、くえん酸、酒石酸、乳酸などの有機
酸の塩類があげられる。(In) The compound represented by formula (I) of the present invention can be converted into an addition salt with a pharmacologically acceptable acid if desired, and these acid addition salts are also included within the scope of the present invention. It is something. Examples of acid addition salts include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; acetic acid, succinic acid, butyric acid, oxalic acid, malic acid, fumaric acid, maleic acid, stearic acid, and Examples include salts of organic acids such as acid, tartaric acid, and lactic acid.
この−線式（Ｉ）で表わされる化合物を医薬としての用
途に使用する場合には種々の投与形態の製剤とすること
が出来る。すなわちこの製剤は経口的に錠剤、糖衣錠、
硬質カプセル剤、軟質カプセル剤、溶液、エマルジョン
または懸濁液の形の液剤の形で投与することが出来る。When the compound represented by the -linear formula (I) is used for pharmaceutical purposes, it can be formulated into various dosage forms. That is, this preparation can be administered orally as tablets, sugar-coated tablets,
It can be administered in the form of hard capsules, soft capsules, solutions, emulsions or suspensions.
また非経口的投与の場合には注射溶液の形で投与される
。これらの製剤の調製に当たっては、製剤化のだめの周
知の添加剤、例えば賦形剤、安定剤、防腐剤、溶解剤、
湿潤剤、乳化剤、滑沢剤、甘味剤、着色剤、香味剤、張
度調整剤、緩衝剤、酸化防止剤などを添加して製剤化す
ることが出来る。In the case of parenteral administration, it is administered in the form of an injection solution. In preparing these formulations, well-known additives for formulation, such as excipients, stabilizers, preservatives, solubilizers,
A formulation can be prepared by adding a wetting agent, an emulsifier, a lubricant, a sweetener, a coloring agent, a flavoring agent, a tonicity adjusting agent, a buffering agent, an antioxidant, and the like.
本発明の抗潰瘍薬の投与方法、投与量に特に制限はなく
、各種製剤形態、患者の性別、疾患の程度により適宜選
択されるが、有効成分の一日あたりの投与量は好ましく
はｌ ｍｇ〜２０００ｍｐである。There are no particular restrictions on the administration method or dosage of the anti-ulcer drug of the present invention, and the dosage is appropriately selected depending on the various formulation forms, the patient's gender, and the severity of the disease, but the daily dosage of the active ingredient is preferably 1 mg. ~2000mp.
なお式（Ｉ）で示される化合物の細胞毒性（ＫＢ細胞に
対するｉｃ、。）は１．５μｇ／ｌｎＱである。Note that the cytotoxicity (ic, . against KB cells) of the compound represented by formula (I) is 1.5 μg/lnQ.
以下に本発明を実施例によってさらＩ；詳細に説明する
が、これは本発明を巣に説明するだけのものであって、
実施例の記載は何隻本発明を限定するものではない。The present invention will be further explained in detail by way of Examples below, but these are merely to explain the present invention in its entirety.
The description of the examples is not intended to limit the invention.
実施例 １
式（Ｉ）の化合物の合成
式（ＩＩ）のインドール誘導体１００＋ｙと式（Ｉ［［
）のアジマリン誘導体９４Ｘｌ１ｇを１．５％塩酸を含
むメタノール溶液１０ｍ１２に溶かし、アルゴン雰囲気
下に１．５時間還流した。反応液に水４０ＩＩＩＱを加
え、炭酸カリウムで中和し、塩化メチレンで抽出しｌ；
。Example 1 Synthesis of compound of formula (I) Indole derivative 100+y of formula (II) and formula (I[[
) was dissolved in 10 ml of methanol solution containing 1.5% hydrochloric acid and refluxed for 1.5 hours under an argon atmosphere. Add 40IIIQ of water to the reaction solution, neutralize with potassium carbonate, and extract with methylene chloride.
.
塩化メチレン層を水洗し、芒硝で乾燥してエバポレート
した。残渣はアルミナカラムで精製して、先に流出する
化合物Ａを６３１１Ｉ９、後に流出する化合物Ｂを７６
ｍｇ得た。The methylene chloride layer was washed with water, dried over sodium sulfate, and evaporated. The residue is purified with an alumina column, and the compound A that flows out first is purified by 6311I9, and the compound B that flows out later is purified by 76
I got mg.
上述のようにして得られた化合物Ａ１およびＢは、式（
Ｉ）で示した波線のＣ−３位におけるエピマーであった
。Compounds A1 and B obtained as described above have the formula (
It was an epimer at the C-3 position indicated by the wavy line in I).
化合物 Ａ
［ＩＶ （ｎｍ、メタノール） ２１１．２５６．２８
８（ｓｈ）。Compound A [IV (nm, methanol) 211.256.28
8 (sh).
２９４．５
ＩＲ（ｃｍ−’ クロロホルム） ３４５０．３４１
０．１６８０゜６２０
ＭＡＳＳ （ｍ／ｚ、％） ６２０（Ｍ”、 １００％
）、 ４７５（Ｉ９）。294.5 IR (cm-' chloroform) 3450.341
0.1680゜620 MASS (m/z,%) 620(M”, 100%
), 475 (I9).
３２２（５）
ＮＭＲ（δ、ＣＤＣ（ｉｓ） ８−１２（ＩＨ）、 ７
．４２（ＩＨ，ｍ）、７．２０−６．９５（３Ｈ，ｍ）
、 ６−９２（ｌＨ，ｓ）、 ６．１８（ＩＨ，ｓ）
。322(5) NMR(δ, CDC(is) 8-12(IH), 7
．． 42 (IH, m), 7.20-6.95 (3H, m)
, 6-92 (IH, s), 6.18 (IH, s)
.
５．２０（ＩＨ，ｑ）、 ４．４０−３．９０（３Ｈ，
ｂｒ）、 ３．７７（３Ｈ，ｓ）。5.20 (IH, q), 4.40-3.90 (3H,
br), 3.77 (3H, s).
２．６０（３Ｈ，ｓ）、 １．６０（３Ｈ，ｄ）（ｆｆ
）Ｄ＋６０．３度（ｃ ＝ ０．６２５％、２６℃、
ＣＨＣｆｆ３）化合物 Ｂ
融点 ２１４〜２１７°Ｃ（アセトンから結晶化）［Ｉ
Ｖ（ｎｍ、メタノール） ２１１．２５６．５．２８７
．５（ｓｈ）。2.60 (3H, s), 1.60 (3H, d) (ff
)D+60.3 degrees (c=0.625%, 26℃,
CHCff3) Compound B Melting point 214-217°C (crystallized from acetone) [I
V (nm, methanol) 211.256.5.287
．． 5 (sh).
９４
ＩＲ（ｃｒｎ−’ クロロホルム） ３３３０．１６
６０．１６１５ＭＡＳＳ （ｍ／ｚ、 ％）６２０（
Ｍ’、１００％）、４７５（Ｉ７）。94 IR (crn-' chloroform) 3330.16
60.1615MASS (m/z, %)620(
M', 100%), 475 (I7).
３２２（５）
ＮＭＲ（δ、ＣＤＣＱｓ）８−２８（ＬＨ）、 ７．
４４（ＩＨ，ｍ）。322 (5) NMR (δ, CDCQs) 8-28 (LH), 7.
44 (IH, m).
７．２０−６．９６（３Ｈ，ｍ）、６．９２（ＩＨ，ｓ
）、６．２３（ＬＨ，ｓ）。7.20-6.96 (3H, m), 6.92 (IH, s
), 6.23 (LH,s).
５．２０（ＩＨ，ｄ）、４−４Ｏ−４−００（３Ｈ，ｂ
ｒ）、３．８１（３Ｈ，ｓ）。5.20 (IH, d), 4-4O-4-00 (3H, b
r), 3.81 (3H, s).
２．６］、（３Ｈ，、ｓ）、１．６２（３Ｈ，ｄ）Ｃｃ
ｒ ）”−１８，３度（ｃ −０，８６９％、２７℃、
ＣＨＣｃＬ３）製造例 １
式（Ｉｌｌ）の化合物の合成
式（Ｖ）の化合物２．８４ｇのピリジン溶液へ、クロル
炭酸エチル５ｇを加えて、室温で６時間撹拌した。溶媒
をエバボレート後クロロホルムを加えてアンモニア水溶
液で洗浄し、芒硝で乾燥してエバボレートした。シリカ
ゲルカラムで精製して２．８７＠の化合物（ＶＴ）を得
た。2.6], (3H,,s), 1.62(3H,d)Cc
r)”-18,3 degrees (c-0,869%, 27℃,
CHCcL3) Production Example 1 Synthesis of Compound of Formula (Ill) To a pyridine solution of 2.84 g of the compound of Formula (V) was added 5 g of ethyl chlorocarbonate, and the mixture was stirred at room temperature for 6 hours. After the solvent was evaporated, chloroform was added, washed with an aqueous ammonia solution, dried over sodium sulfate, and evaporated. Purification was performed using a silica gel column to obtain a compound (VT) of 2.87@.
ＩＲ（ｃｍ−’、ＣＨＯｆｆ、月７００ＵＶ（ｎｍ、エ
タノール） ２１４．２４４．２９１．２９６化合物（
■）２゜８６ｇの乾燥テトラヒドロフラン溶液に、水冷
下でリチウムアルミニウムハイドライド２．８６３ｇを
加え、加熱還流を４．５時間行なった。常法処理後にシ
リカゲルカラムで精製して、テトラヒドロフランとｎ−
ヘキサンの混液かも再結晶して、１．３８ｇの化合物（
［）を得た。IR (cm-', CHoff, 700 UV (nm, ethanol) 214.244.291.296 compounds (
(2) 2.863 g of lithium aluminum hydride was added to 2.86 g of dry tetrahydrofuran solution under water cooling, and heated under reflux for 4.5 hours. After treatment in a conventional manner, purification was performed using a silica gel column, and tetrahydrofuran and n-
The hexane mixture was also recrystallized to yield 1.38 g of the compound (
[) was obtained.
融点１３６〜１３８℃
ＵＶ（ｎｍ、エタノール） ２５１．２９８次に本発明
の抗潰瘍薬の効果に関して説明する。Melting point 136-138°C UV (nm, ethanol) 251.298 Next, the effects of the anti-ulcer drug of the present invention will be explained.
実施例 ２
Ｈ’／Ｋ”″ＡＴＰａｓｅ阻害活性
ブタ胃より調整したＨ”／Ｘ”ＡＴＰａｓｅを用いて以
下のようにして測定した。Example 2 H'/K"" ATPase inhibitory activity It was measured as follows using H"/X" ATPase prepared from pig stomach.
Ｈ”／Ｋ”ＡＴＰａｓｅ希釈溶液］００μｆｆ （９ン
ハ’ｙ １ トＬ。H"/K" ATPase diluted solution] 00 μff (9 liters).
て５０Ｉ１ｇ）を４ｎ＋Ａｉ塩化マグネシウム、２０ｍ
Ｍ塩化カリウムを含むＩ ＤｒｎＭパイズスートリス（
ｐＨ６−２）！１衝液４４０μβに加え、さらに０．１
％のナイジエリンのエタノール溶液５μＣを加えた。こ
こに５μ０のジメチルスルフオキシドを加えて、３７℃
で３０分間インキュベートした。ついで４ ｍＭ ＡＴ
Ｐニナトリウムを含む１０＋ｎＭパイプスートリス緩衝
液４５０μａを添加して反応を開始し、３０分後に５０
％トリクロロ酢酸１ｍｆｆを加えて反応を停止した。こ
の反応で生じた遊離燐酸量をり、 Ｌｅｂｅｌ、Ｇ。50I1g) with 4n+Ai magnesium chloride, 20m
I DrnM Paise Sutris containing M Potassium Chloride (
pH6-2)! 1 buffer solution 440 μβ and an additional 0.1
5 μC of a % Nidierin solution in ethanol was added. Add 5μ0 dimethyl sulfoxide to this and heat at 37°C.
and incubated for 30 minutes. Then 4 mM AT
The reaction was started by adding 450 μa of 10+ nM Pipes Tris buffer containing P disodium, and after 30 minutes, 50 μa
The reaction was stopped by adding 1 mff of % trichloroacetic acid. The amount of free phosphoric acid produced in this reaction was determined by Lebel, G.
Ｐｏ１ｒｉｅｒらの方法（Ａｎａｌ、 Ｂｉｏｃｈｅｍ
、 ８５．８６〜８９゜１９７８）により８００％ｍの
発色測定をおこなって、この時の吸光度の読みをＣ，と
じた。ヌリに塩化カリウムを加えない場合も同様メこ測
定して、この時の吸光度の読みをＣ２とした。The method of Poillier et al. (Anal, Biochem
, 85.86-89° 1978), and the absorbance reading at this time was labeled as C. A similar measurement was carried out when potassium chloride was not added to the starch, and the absorbance reading at this time was designated as C2.
阻害活性の測定は、上記反応においてジメチルスル７オ
キシドの代わりに２Ｑｔａｇ／ｌｎΩ濃度の阻害物質を
含むジメチルスル７オキシド溶液５μＱを加えて同様の
操作を行ない、塩化カリウムを加えた場合と加えない場
合の吸光度の読みをそれぞれＴ３、Ｔ、とした。To measure the inhibitory activity, perform the same procedure by adding 5 μQ of a dimethyl sulf 7 oxide solution containing an inhibitor at a concentration of 2 Q tag/lnΩ in place of dimethyl s 7 oxide in the above reaction, and measure the absorbance with and without the addition of potassium chloride. The readings were taken as T3 and T, respectively.
阻害物質の阻害バーセン）（Ｉ）は以下の式で計算され
る。The inhibition basis (I) of the inhibitor is calculated by the following formula:
１ ＝ （（Ｔ、 −Ｔ、）
被験化合物
化合物Ａ
化合物Ｂ
（ｃ、−Ｃ，））Ｘ １００／（Ｔ□〜７２）Ｈ’７
Ｋ”ＡＴＰａｓｅ阻害率Ｃ％）００
００1 = ((T, -T,) Test compound Compound A Compound B (c, -C,))X 100/(T□~72)H'7
K”ATPase inhibition rate C%) 00 00
Claims (1)
よびその薬理学的に許容されうる酸との付加塩。 ▲数式、化学式、表等があります▼（ I ） ２）式（ I ）で表わされるインドール誘導体、または
その薬理学的に許容されうる酸との付加塩を有効成分と
して含有する抗潰瘍薬。[Claims] 1) An indole derivative represented by the following formula (I) and an addition salt thereof with a pharmacologically acceptable acid. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) 2) An antiulcer drug containing an indole derivative represented by formula (I) or its addition salt with a pharmacologically acceptable acid as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8105290A JP2851117B2 (en) | 1990-03-30 | 1990-03-30 | Indole derivatives and anti-ulcer drugs containing them as active ingredients |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8105290A JP2851117B2 (en) | 1990-03-30 | 1990-03-30 | Indole derivatives and anti-ulcer drugs containing them as active ingredients |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH03284686A true JPH03284686A (en) | 1991-12-16 |
| JP2851117B2 JP2851117B2 (en) | 1999-01-27 |
Family
ID=13735645
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8105290A Expired - Fee Related JP2851117B2 (en) | 1990-03-30 | 1990-03-30 | Indole derivatives and anti-ulcer drugs containing them as active ingredients |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2851117B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7175854B2 (en) | 2000-12-07 | 2007-02-13 | Altana Pharma Ag | Pharmaceutical preparation comprising an active dispersed on a matrix |
| US7951397B2 (en) | 2002-02-20 | 2011-05-31 | Nycomed Gmbh | Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient |
-
1990
- 1990-03-30 JP JP8105290A patent/JP2851117B2/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7175854B2 (en) | 2000-12-07 | 2007-02-13 | Altana Pharma Ag | Pharmaceutical preparation comprising an active dispersed on a matrix |
| US7951398B2 (en) | 2000-12-07 | 2011-05-31 | Nycomed Gmbh | Pharmaceutical preparation comprising an active dispersed on a matrix |
| US7951397B2 (en) | 2002-02-20 | 2011-05-31 | Nycomed Gmbh | Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient |
| US8431154B2 (en) | 2002-02-20 | 2013-04-30 | Takeda Gmbh | Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidone as excipient |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2851117B2 (en) | 1999-01-27 |
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