EP0000355A1 - Indolderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel. - Google Patents
Indolderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel. Download PDFInfo
- Publication number
- EP0000355A1 EP0000355A1 EP78100274A EP78100274A EP0000355A1 EP 0000355 A1 EP0000355 A1 EP 0000355A1 EP 78100274 A EP78100274 A EP 78100274A EP 78100274 A EP78100274 A EP 78100274A EP 0000355 A1 EP0000355 A1 EP 0000355A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- hydrogen
- compound
- formula
- alkoxy
- 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
- 0 CCC1(C)C=CC(C(*)=C(*)*2)=C2C=C1 Chemical compound CCC1(C)C=CC(C(*)=C(*)*2)=C2C=C1 0.000 description 6
- ZXKBVCUVSLFOSC-UHFFFAOYSA-N C1C2C1COC2 Chemical compound C1C2C1COC2 ZXKBVCUVSLFOSC-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- 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
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D209/16—Tryptamines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Definitions
- the present invention relates to new indole derivates, processes for their preparation, and pharmaceutical compositions containing them.
- Any alkyl, alkoxy or alkylthio radical contains preferably two carbon atoms, especially one carbon atom.
- Halogen means fluorine, chlorine, bromine or iodine, especially chlorine.
- A is 1,4-cyclohexylidene
- this may be cis or trans-l,4-cyclohexylidene.
- A is optionally substituted trimethylene, this is preferably either unsubstituted or monosubstituted, conveniently at the middle carbon atom.
- R 1 and R 2 are chosen from hydrogen or alkyl, these are preferably alkyl.
- A is optionally substituted trimethylene or 1,4-cyclohexylidene.
- A is optionally substituted trimethylene.
- R 3 When R 3 is or contains a dialkylamino radical, the alkyl groups are preferably the same.
- R 3 is an optionally substituted phenyl or phenylamino radical, the substituents are conveniently identical. Conveniently these radicals are unsubstituted or monosubstituted preferably in the para position.
- R 3 is a heterocycle, conveniently this contains one heteroatom chosen from nitrogen, oxygen or sulphur and optionally a second nitrogen atom, e.g. thienyl, furyl, pyrrolyl, pyridyl or pyrazinyl. Conveniently the heterocycle is bound to X by a ring carbon atom adjacent to a heteroatom.
- R 3 is preferably unsubstituted phenyl.
- R 4 and R 5 are conveniently hydrogen.
- X is conveniently -CO-.
- the present invention provides a process for the production of a compound of formula I as defined above, which comprises
- Process a) may be effected in conventional manner for the production of amides or thio-amides from amines.
- acylating agent a compound of formula V wherein X is as defined above, R 3 ' has the same signification as R 3 but is other than amino, alkylamino and optionally substituted phenylamino and Z is chlorine or bromine.
- the reaction may be effected conveniently in a solvent such as pyridine and at temperatures from O to 25°.
- R 3 is amino, alkylamino or optionally substituted phenylamino
- a compound of formula VI wherein X is as defined above and R 6 is imino, alkylimino or optionally substituted phenylimino.
- the reaction may be effected conveniently in a solvent such as dimethylformamide and at temperatures from 5 to 25°.
- a compound of formula VI wherein R 6 is imino may be prepared in situ from potassium or sodium cyanate or thiocyanate, by treatment with acid , for example hydrochloric acid.
- Process b) may be effected in conventional manner for a condensation reaction to produce a secondary or tertiary amine.
- Y is conveniently chlorine, bromine, iodine, tosyloxy or mesyloxy.
- the reaction may be conveniently effected in acetone or dimethylformamide. Suitable reaction temperatures are from 20 to 150°.
- the compounds of formula I may be isolated from the reaction mixture and purified in known manner.
- the free base forms may be converted into acid addition salt forms in the usual manner and vice versa.
- Suitable acids for salt formation are hydrochloric acid, oxalic acid, fumaric acid naphthalene-2-sulphonic acid and naphthalene-l,5-disulphonic acid.
- the starting material of formula II may be produced from a compound of formula III and a compound of formula VII wherein A, R 1 and R 2 are as defined above, in analogous manner to process b).
- the conditions should be chosen to avoid the formation of the undesired corresponding compound produced by condensation at the nitrogen atom bearing the R 1 substituent.
- the amine may be used in protected form of formula VIII wherein R 7 is a protecting group, such as benzyl or benzyloxy, which may be removed from the resulting product, e.g. by hydrogenolysis.
- a starting material of formula IIa wherein A I is or and wherein R 8 is (C 1-4 )alkyl and n, R 2 , R 4 and R 5 are as defined above, may alternatively be produced by reducing a compound of formula IX wherein B is -CH(R 8 )-CH 2 - or -CH 2 -CH(R 8 )-and n, R 2 , R 4 , R 5 and R 8 are as defined above, e.g. by hydrogenation in the presence of Raney-nickel.
- Any starting material of formula II wherein R 1 and/or R 2 is hydrogen may be converted into a corresponding compound wherein R 1 and R 2 are both alkyl, or R 1 is alkyl and R 2 is hydrogen under appropriate selective alkylation conditions.
- the starting material of formula IV may be produced by acylating an amine of formula VII in analogous manner to process a). If desired, one nitrogen atom of an unsymmetrical amine may be protected to facilitate production of the desired product.
- a starting material of formula IVa wherein X, R 2 and R 3 are as defined above and A II together with R 1 and the nitrogen atom to which R 1 is bound, form a 4-piperidyl radical may alternatively be produced by acylating 4-piperidone with a compound of formula V or VI and condensing the resulting compound of formula X wherein X and R 3 are as defined above, with a compound of formula XI wherein R 2 is as defined above, under simultaneous reduction, e.g. with hydrogen in presence of a catalyst.
- the starting material may be obtained as follows :
- the starting material may be obtained as follows:
- the compounds of formula I exhibit pharmacological activity in animals.
- the compounds exhibit anti-hypertensive activity, as indicated by standard tests, e.g. in the awake renal hypertonic Grollman rat upon administration of 1 to 50 mg/kg animal body weight of the compounds, and in the awake renal hypertonic Goldblatt dog upon administration of 1 to 10 mg/kg animal body weight of the compounds.
- an indicated daily dose is from about lO to about 2000 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about2,5 to about 1000 mg, or in sustained release form.
- a particularly interesting compound is the
- the compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form. Such salts exhibit the same order of activity as the free base forms.
- the invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula I, in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.
- a suitable pharmaceutical form is a capsule.
- A is trimethylene
- R 1 is hydrogen or (C 1-5 )alkyl
- R 2 is hydrogen or (C 1-5 )alkyl
- R 3 is phenyl or benzyl unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, (C 1-4 )alkyl, (C 1-4 )alkoxy or di-(C 1-4 )alkylamino; (C3-6)cycloalkyl; or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur
- R 4 is hydrogen, chlorine, bromine or (C 1-4 )alkyl
- R 5 is hydrogen, (C 1-4 )alkyl, (C 1-4 )alkoxy, or (C 1-4 )alkylthio
- X is -CO-.
- n 2
- A is trimethylene and R 1 is hydrogen or (C 1-5 ) alkyl, or A together with R 1 and the nitrogen atom to which R 1 is bound form a 4-piperidyl radical
- R 2 is hydrogen or (C 1-5 )alkyl
- R 3 is (C 1-4 )alkyl; phenyl unsubstituted or mono-, di- or trisubstituted independently by halogen, (C 1-4 )alkyl or (C 1-4 )alkoxy; (C 3-6 )cycloalkyl; or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur
- R 4 is hydrogen, chlorine, bromine or (C 1-4 )alkyl
- R S is hydrogen, (C 1-4 )alkyl or (C 1-4 )alkoxy
- X is -CO- or -CS.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH8589/77 | 1977-07-12 | ||
CH858977 | 1977-07-12 | ||
CH300878 | 1978-03-20 | ||
CH3008/78 | 1978-03-20 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0000355A1 true EP0000355A1 (de) | 1979-01-24 |
EP0000355B1 EP0000355B1 (de) | 1982-01-06 |
Family
ID=25691930
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP78100274A Expired EP0000355B1 (de) | 1977-07-12 | 1978-06-29 | Indolderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel. |
Country Status (14)
Country | Link |
---|---|
EP (1) | EP0000355B1 (de) |
JP (1) | JPS5436259A (de) |
AU (1) | AU521641B2 (de) |
CA (1) | CA1114381A (de) |
DE (1) | DE2861502D1 (de) |
DK (1) | DK300978A (de) |
ES (1) | ES471593A1 (de) |
FI (1) | FI782138A (de) |
IE (1) | IE47209B1 (de) |
IL (1) | IL55116A (de) |
IT (1) | IT7850140A0 (de) |
NZ (1) | NZ187813A (de) |
PH (1) | PH14993A (de) |
PT (1) | PT68270A (de) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0003901A2 (de) * | 1978-02-24 | 1979-09-05 | Pfizer Limited | 3-(Imidazol-1-ylalkyl) indole als selektive Thromboxansynthetase Hemmungsmittel, pharmazeutische Zusammensetzungen die diese enthalten und Verfahren zu ihrer Herstellung |
US4634713A (en) * | 1982-05-28 | 1987-01-06 | Ciba-Geigy Corporation | Antihypertensive 3-(ureidocyclohexyleneamino)propane-1,2-diol derivatives |
GB2223012A (en) * | 1988-09-21 | 1990-03-28 | Kotobuki Seiyaku Co Ltd | Thiophene derivatives |
EP0376819A1 (de) * | 1988-12-22 | 1990-07-04 | Roussel-Uclaf | Acylierte Polyamine, Verfahren zu ihrer Herstellung und ihre Verwendung als Fungizide |
WO1994022826A1 (en) * | 1993-04-07 | 1994-10-13 | Otsuka Pharmaceutical Co., Ltd. | Peripheral vasodilating agent containing n-acylated 4-amino piperidine derivatives as active ingredients |
US8445516B2 (en) | 2004-01-29 | 2013-05-21 | Otsuka Pharmaceutical Co., Ltd. | Pharmaceutical composition for promoting angiogenesis |
EP3852215A1 (de) * | 2020-01-15 | 2021-07-21 | Solaredge Technologies Ltd. | Fotovoltaikanlage mit mehreren leistungsstufen |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115433164B (zh) * | 2022-09-14 | 2023-12-12 | 南京师范大学 | 烟酰胺衍生物及其制备方法和在抗衰老延长寿命中的应用 |
-
1978
- 1978-06-12 PH PH21359A patent/PH14993A/en unknown
- 1978-06-29 DE DE7878100274T patent/DE2861502D1/de not_active Expired
- 1978-06-29 EP EP78100274A patent/EP0000355B1/de not_active Expired
- 1978-07-03 IT IT7850140A patent/IT7850140A0/it unknown
- 1978-07-03 FI FI782138A patent/FI782138A/fi not_active Application Discontinuation
- 1978-07-03 DK DK783009A patent/DK300978A/da not_active Application Discontinuation
- 1978-07-10 IL IL55116A patent/IL55116A/xx unknown
- 1978-07-10 PT PT68270A patent/PT68270A/pt unknown
- 1978-07-10 ES ES471593A patent/ES471593A1/es not_active Expired
- 1978-07-10 NZ NZ187813A patent/NZ187813A/xx unknown
- 1978-07-10 IE IE1382/78A patent/IE47209B1/en unknown
- 1978-07-11 JP JP8363778A patent/JPS5436259A/ja active Pending
- 1978-07-11 CA CA307,174A patent/CA1114381A/en not_active Expired
- 1978-07-11 AU AU37939/78A patent/AU521641B2/en not_active Expired
Non-Patent Citations (1)
Title |
---|
CHEMICAL ABSTRACT (1974) vol. 81, 105181k & Khim-Farm. Zk. 1974 8(6)-7-11. * |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0003901A2 (de) * | 1978-02-24 | 1979-09-05 | Pfizer Limited | 3-(Imidazol-1-ylalkyl) indole als selektive Thromboxansynthetase Hemmungsmittel, pharmazeutische Zusammensetzungen die diese enthalten und Verfahren zu ihrer Herstellung |
EP0003901A3 (en) * | 1978-02-24 | 1979-09-19 | Pfizer Limited | 3-(imidazol-1-ylalkyl)indoles as selective inhibitors of thromboxane synthetase,pharmaceutical compositions thereof, and methods for preparing them |
US4634713A (en) * | 1982-05-28 | 1987-01-06 | Ciba-Geigy Corporation | Antihypertensive 3-(ureidocyclohexyleneamino)propane-1,2-diol derivatives |
GB2223012B (en) * | 1988-09-21 | 1992-04-29 | Kotobuki Seiyaku Co Ltd | Diamine derivatives,and method of manufacturing the same |
GB2223012A (en) * | 1988-09-21 | 1990-03-28 | Kotobuki Seiyaku Co Ltd | Thiophene derivatives |
EP0376819A1 (de) * | 1988-12-22 | 1990-07-04 | Roussel-Uclaf | Acylierte Polyamine, Verfahren zu ihrer Herstellung und ihre Verwendung als Fungizide |
FR2642422A1 (fr) * | 1988-12-22 | 1990-08-03 | Roussel Uclaf | Nouvelles polyamines acylees, leur procede de preparation et leur application comme fongicides |
WO1994022826A1 (en) * | 1993-04-07 | 1994-10-13 | Otsuka Pharmaceutical Co., Ltd. | Peripheral vasodilating agent containing n-acylated 4-amino piperidine derivatives as active ingredients |
US5656642A (en) * | 1993-04-07 | 1997-08-12 | Otsuka Pharmaceutical Co., Ltd. | Peripheral vasodilating agent containing piperidine derivative as active ingredient |
US5760058A (en) * | 1993-04-07 | 1998-06-02 | Otsuka Pharmaceutical Co., Ltd. | Peripheral vasodilating agent containing piperidine derivative as active ingredient |
CN1052224C (zh) * | 1993-04-07 | 2000-05-10 | 大塚制药株式会社 | 哌啶衍生物、含有它的外周血管舒张剂及其应用 |
US8445516B2 (en) | 2004-01-29 | 2013-05-21 | Otsuka Pharmaceutical Co., Ltd. | Pharmaceutical composition for promoting angiogenesis |
EP3852215A1 (de) * | 2020-01-15 | 2021-07-21 | Solaredge Technologies Ltd. | Fotovoltaikanlage mit mehreren leistungsstufen |
US11764679B2 (en) | 2020-01-15 | 2023-09-19 | Solaredge Technologies Ltd. | Power device |
Also Published As
Publication number | Publication date |
---|---|
FI782138A (fi) | 1979-01-13 |
JPS5436259A (en) | 1979-03-16 |
DE2861502D1 (en) | 1982-02-25 |
IE781382L (en) | 1979-01-12 |
AU521641B2 (en) | 1982-04-22 |
EP0000355B1 (de) | 1982-01-06 |
ES471593A1 (es) | 1979-10-01 |
IL55116A (en) | 1982-02-28 |
IT7850140A0 (it) | 1978-07-03 |
DK300978A (da) | 1979-01-13 |
PH14993A (en) | 1982-03-22 |
IE47209B1 (en) | 1984-01-11 |
AU3793978A (en) | 1980-01-17 |
PT68270A (en) | 1978-08-01 |
CA1114381A (en) | 1981-12-15 |
NZ187813A (en) | 1981-03-16 |
IL55116A0 (en) | 1978-09-29 |
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