CA1105009A - Ergot derivatives - Google Patents
Ergot derivativesInfo
- Publication number
- CA1105009A CA1105009A CA299,678A CA299678A CA1105009A CA 1105009 A CA1105009 A CA 1105009A CA 299678 A CA299678 A CA 299678A CA 1105009 A CA1105009 A CA 1105009A
- Authority
- CA
- Canada
- Prior art keywords
- carbon atoms
- compound
- alkyl
- formula
- acid addition
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/02—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hydrocarbon or substituted hydrocarbon radicals, attached in position 8
-
- 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
ERGOT DERIVATIVES
Abstract of the Disclosure:
Compounds of formula I, I
wherein R1 and R2 are independently hydrogen or alkyl of 1 to 4 carbon atoms, or are together an alkylidene chain of 2 to 5 carbon atoms, R3 is alkyl of 1 to 4 carbon atoms, and R4 is hydrogen, alkyl of 1 to 4 carbon atoms, which is unsubstituted or substituted by one to 3 halogen atoms with the proviso that the .alpha.-carbon atom does not carry any halogen atom, or alkoxymethyl of 2 to 5 carbon atoms, are useful anti-hypertensive agents.
Abstract of the Disclosure:
Compounds of formula I, I
wherein R1 and R2 are independently hydrogen or alkyl of 1 to 4 carbon atoms, or are together an alkylidene chain of 2 to 5 carbon atoms, R3 is alkyl of 1 to 4 carbon atoms, and R4 is hydrogen, alkyl of 1 to 4 carbon atoms, which is unsubstituted or substituted by one to 3 halogen atoms with the proviso that the .alpha.-carbon atom does not carry any halogen atom, or alkoxymethyl of 2 to 5 carbon atoms, are useful anti-hypertensive agents.
Description
P9 C as e 10 0 - 4 7 81 ERGOT DERIVATIVES
The present invention provides compounds of formula I, ,~;~N~I-C -N
~r~ I
R" - N _ wherein Rl ~nd R2 are independently hydrogen or alkyl of 1 to 4 carbon atoms, ; or are together an alkylidene chain of 2 to 5 carbon atoms, R3 is alkyl of 1 to 4 carbon atoms, and R~ ls hydrogen, alkyl of 1 to 4 carbon atoms, whi.ch is unsubstituted or : substit.uted by one to 3 halogen atoms ~ith the proviso that the ~ carbon atom does not carry any halo~en atom, or alkoxymethyl of
The present invention provides compounds of formula I, ,~;~N~I-C -N
~r~ I
R" - N _ wherein Rl ~nd R2 are independently hydrogen or alkyl of 1 to 4 carbon atoms, ; or are together an alkylidene chain of 2 to 5 carbon atoms, R3 is alkyl of 1 to 4 carbon atoms, and R~ ls hydrogen, alkyl of 1 to 4 carbon atoms, whi.ch is unsubstituted or : substit.uted by one to 3 halogen atoms ~ith the proviso that the ~ carbon atom does not carry any halo~en atom, or alkoxymethyl of
2 to 5 carbon atoms, and pharmaceutically ; . .
acceptable acid addition salts of said compounds.
.
~ ( Halogen means bromine and especially fluorine and chlorine. Alkyl is preferably me-thyl or ethyl except where otherwise stated. Alkoxy is preferably methoxy. Alkylidene is preferably tetra- or penta-5 methylene. When alkyl is substituted by halogen,the halogen atom ls prefera~ly on the terminal carbon atom, Preferably alkyl, when substituted by halogen, has 2 carbon atoms. Rl and R2 are preferably al~yl, R3 is preferably methyl or isopropyl. R4 is preferably hydrogen~
.
The present invention also provides a process for the production of a compound of formula I
as defined above, which comprises selectively reducing the 2,3 position of a compound of formula II, CH -NH~C-N
~ 2 ; ~ ~ 3 II
R
.
wherein Rl to R4 are as defined above; and,where desired, preparing a pharmaceutically acceptable acid addition salt of the resultant compound of formula I.
.
. :
:
s~
acceptable acid addition salts of said compounds.
.
~ ( Halogen means bromine and especially fluorine and chlorine. Alkyl is preferably me-thyl or ethyl except where otherwise stated. Alkoxy is preferably methoxy. Alkylidene is preferably tetra- or penta-5 methylene. When alkyl is substituted by halogen,the halogen atom ls prefera~ly on the terminal carbon atom, Preferably alkyl, when substituted by halogen, has 2 carbon atoms. Rl and R2 are preferably al~yl, R3 is preferably methyl or isopropyl. R4 is preferably hydrogen~
.
The present invention also provides a process for the production of a compound of formula I
as defined above, which comprises selectively reducing the 2,3 position of a compound of formula II, CH -NH~C-N
~ 2 ; ~ ~ 3 II
R
.
wherein Rl to R4 are as defined above; and,where desired, preparing a pharmaceutically acceptable acid addition salt of the resultant compound of formula I.
.
. :
:
s~
- 3 ~ 100-4781 The process may be effected in conventional manner for the reduction of the 2,3 double bond in an ergot alkaloid. A complex hydride such as sodium borohydride, e.g. in the presence of trifluoroacetic acid, may be used. Suitable solvents include trifluoro-acetic acid, ethex, tetrahydrofuran or dioxane or mixtures thereof. The reduction may also be effected using zinc in hydrochloric acid.
Suita~le reaction temperatures may he from 0 to 40 C. :
The starting materials are either known or may be made in conventional manner~
Free base forms of the compounds of formula I
may be converted into acid addition salt forms, e.g.
the hydrochloride or hydrogen fumarate, in conventlonal manner and vice versa.
In the following examples all temp~ratures are in degrees Centigrade and are uncorrected.
All ratios refer to parts by volume.
' ~; .
:~ :
....
, :
Suita~le reaction temperatures may he from 0 to 40 C. :
The starting materials are either known or may be made in conventional manner~
Free base forms of the compounds of formula I
may be converted into acid addition salt forms, e.g.
the hydrochloride or hydrogen fumarate, in conventlonal manner and vice versa.
In the following examples all temp~ratures are in degrees Centigrade and are uncorrected.
All ratios refer to parts by volume.
' ~; .
:~ :
....
, :
- 4 - 100-4781 EXAMPLE _ 1,1-dimethyl-3-[6-met~yl-2,3~dihydro-9-- .e~
1.95 g of sodium borohydride are added portionwise to 10.5 g l,l-dimethyl 3-[6-methyl-9-S ergolen-8~ylmethyl],urea in 115 ml trifluoroacetic acid. The mixture is stirred for 20 minutes and poured onto ice/water. Solid potassium carbonate is added to the mixture, which is vigorously stirred, until a pH
of 8 is reached. The mixture is extracted three times with methylene chloride. The combined organic phases are dried with sodium sulphate, filtered and evaporated to give a beige foam, which is chromatographed ; on 120 g silicagel using methylene chloride/methanol (9 ~ 0.5 ~ concentrated NH3 as eluant.
The resultant base is converted into the hydrochloride or hydxogen fumarate.
HCl salt - M.P. from 185 (decomp.); [~]D0 =
50 (c = 0.675 in ethanol/water 1 ~
Hydrogen fumarake salt M.P. from 120 (decomp.); [~20 - ~ 20.9 (c = 0.44 in ethanol/water 1 : 1).
Xn analogous manner to that describ~d in Example 1 the following compounds may be produced:
.
~$~
1.95 g of sodium borohydride are added portionwise to 10.5 g l,l-dimethyl 3-[6-methyl-9-S ergolen-8~ylmethyl],urea in 115 ml trifluoroacetic acid. The mixture is stirred for 20 minutes and poured onto ice/water. Solid potassium carbonate is added to the mixture, which is vigorously stirred, until a pH
of 8 is reached. The mixture is extracted three times with methylene chloride. The combined organic phases are dried with sodium sulphate, filtered and evaporated to give a beige foam, which is chromatographed ; on 120 g silicagel using methylene chloride/methanol (9 ~ 0.5 ~ concentrated NH3 as eluant.
The resultant base is converted into the hydrochloride or hydxogen fumarate.
HCl salt - M.P. from 185 (decomp.); [~]D0 =
50 (c = 0.675 in ethanol/water 1 ~
Hydrogen fumarake salt M.P. from 120 (decomp.); [~20 - ~ 20.9 (c = 0.44 in ethanol/water 1 : 1).
Xn analogous manner to that describ~d in Example 1 the following compounds may be produced:
.
~$~
- 5 - 100-~1781 r-T~ ~
~0 u~ O ~ O
C`3 ~ ,~ ,, c~ ,, r~m ~ _ .
~ :I~' ~
. . . .
~ .~.. ...~.. ~ ~ ~
a) a~ ~
~; . ... ...... t~ t~, H
X
' :~
`:~
- . .-. , . . - .
~0 u~ O ~ O
C`3 ~ ,~ ,, c~ ,, r~m ~ _ .
~ :I~' ~
. . . .
~ .~.. ...~.. ~ ~ ~
a) a~ ~
~; . ... ...... t~ t~, H
X
' :~
`:~
- . .-. , . . - .
- 6 - 100-4781 The compounds of formula I exhibit pharmacological activity. In particular, the compounds exhibit anti-hypertensive activity, as indicated by standard tests, e.g. in the awake renal hypertonic Grollman rat, in the awake spontaneous hypertonic rat, and in the awake renal hypertonic Goldblatt dog, upon administration of 0.05 to 3 mg/kg animal body weight of the compoundsO
The compounds are therefore indicated for use as anti-hypertensive agents. For this use an indicated daily dose is from about 0.5 to about 200 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.1 to about lO0 mg, or in sustained release form.
A particularly interesting compound is the Example l compound.
-' ,' :
The compounds are therefore indicated for use as anti-hypertensive agents. For this use an indicated daily dose is from about 0.5 to about 200 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.1 to about lO0 mg, or in sustained release form.
A particularly interesting compound is the Example l compound.
-' ,' :
- 7 - 100-4781 The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form. Such salts possess the same order of activity as the fr~e base forms.
The invention also provides a pharmaceutical composition comprising a compound of formula I, in free base or pharmaceutically acceptable acid addition salt ~orm, ln association with a pharmaceutical carrier or dlluent~ A suitable pharmaceutical form i9 a capsule. ... .
- In a group of compounds R3 .is methyl and :
R~ is hydrogen.
.
; ~ :
, .
.
.
::
,:
The invention also provides a pharmaceutical composition comprising a compound of formula I, in free base or pharmaceutically acceptable acid addition salt ~orm, ln association with a pharmaceutical carrier or dlluent~ A suitable pharmaceutical form i9 a capsule. ... .
- In a group of compounds R3 .is methyl and :
R~ is hydrogen.
.
; ~ :
, .
.
.
::
,:
Claims (4)
1. A process for the production of a compound of formula I, I
wherein R1 and R2 are independently hydrogen or alkyl of 1 to 4 carbon atoms, or are together an alkylidene chain of 2 to 5 carbon atoms, R3 is alkyl of 1 to 4 carbon atoms, and R4 is hydrogen, alkyl of 1 to 4 carbon atoms, which is unsubstituted or substituted by one to 3 halogen atoms with the proviso that the .alpha.-carbon atom does not carry any halogen atom, or alkoxymethyl of 2 to 5 carbon atoms, or a pharmaceutically acceptable acid addition salt thereof, .
which comprises selectively reducing the 2,3 position of a compound of formula II, II
wherein R1 to R4 are as defined above; and where desired, preparing a pharmaceutically acceptable acid addition salt of the resultant compound of formula I.
wherein R1 and R2 are independently hydrogen or alkyl of 1 to 4 carbon atoms, or are together an alkylidene chain of 2 to 5 carbon atoms, R3 is alkyl of 1 to 4 carbon atoms, and R4 is hydrogen, alkyl of 1 to 4 carbon atoms, which is unsubstituted or substituted by one to 3 halogen atoms with the proviso that the .alpha.-carbon atom does not carry any halogen atom, or alkoxymethyl of 2 to 5 carbon atoms, or a pharmaceutically acceptable acid addition salt thereof, .
which comprises selectively reducing the 2,3 position of a compound of formula II, II
wherein R1 to R4 are as defined above; and where desired, preparing a pharmaceutically acceptable acid addition salt of the resultant compound of formula I.
2. A compound of formula I, as defined in Claim 1 or a pharmaceutically acceptable acid addition salt thereof, whenever produced by a process according to Claim 1.
3. A process which comprises reacting 1,1-dimethyl-3-[6-methyl-9-ergolen-8.beta. -yl-methyl] urea with sodium boro-hydride in the presence of trifluoroacetic acid, thereby to produce the compound 1,1-dimethyl-3-[6-methyl-2,3.beta.-dihydro-9-ergolen-8 .beta.-ylmethyl] urea; and where desired, forming a pharmaceutically acceptable acid addition salt of said compound so produced.
4. 1,1-dimethyl-3-[6-methyl-2,3 .beta.-dihydro-9-ergolen-8 .beta.-ylmethyl]urea, or a pharmaceutically acceptable acid addition salt thereof, whenever produced by the process of Claim 3, or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH381477A CH628049A5 (en) | 1977-03-25 | 1977-03-25 | Process for the preparation of ergolene derivatives |
| CH3814/77 | 1977-03-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1105009A true CA1105009A (en) | 1981-07-14 |
Family
ID=4264035
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA299,678A Expired CA1105009A (en) | 1977-03-25 | 1978-03-23 | Ergot derivatives |
Country Status (20)
| Country | Link |
|---|---|
| JP (1) | JPS53119898A (en) |
| AT (1) | AT366685B (en) |
| AU (1) | AU520738B2 (en) |
| BE (1) | BE865267A (en) |
| CA (1) | CA1105009A (en) |
| CH (1) | CH628049A5 (en) |
| DE (1) | DE2810774A1 (en) |
| DK (1) | DK147072C (en) |
| ES (1) | ES468133A1 (en) |
| FI (1) | FI66375C (en) |
| GB (1) | GB1596210A (en) |
| IE (1) | IE46688B1 (en) |
| IL (1) | IL54342A (en) |
| IT (1) | IT1104183B (en) |
| NL (1) | NL7803031A (en) |
| NZ (1) | NZ186775A (en) |
| PT (1) | PT67816A (en) |
| SE (1) | SE7803040L (en) |
| SU (1) | SU1053755A3 (en) |
| ZA (1) | ZA781714B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3205169A1 (en) * | 1981-02-24 | 1982-10-14 | Sandoz-Patent-GmbH, 7850 Lörrach | NEW ERGOL DERIVATIVES, THEIR PRODUCTION AND THEIR PHARMACEUTICAL COMPOSITIONS |
| DE3411981A1 (en) * | 1984-03-28 | 1985-10-10 | Schering AG, Berlin und Bergkamen, 1000 Berlin | METHOD FOR PRODUCING 2.3-DIHYDROERGOLINES |
| GB2173189B (en) * | 1985-02-21 | 1988-04-27 | Maruko Pharmaceutical Co | Ergoline derivatives and salts thereof and pharmaceutical compositions thereof |
| US4798834A (en) * | 1987-08-31 | 1989-01-17 | Eli Lilly And Company | Optionally substituted (3β-9,10-didehydro-2,3-dihydro ergoline as serotonergic function enhancement |
-
1977
- 1977-03-25 CH CH381477A patent/CH628049A5/en not_active IP Right Cessation
-
1978
- 1978-03-13 DE DE19782810774 patent/DE2810774A1/en not_active Withdrawn
- 1978-03-16 FI FI780835A patent/FI66375C/en not_active IP Right Cessation
- 1978-03-16 SE SE7803040A patent/SE7803040L/en unknown
- 1978-03-16 DK DK119778A patent/DK147072C/en not_active IP Right Cessation
- 1978-03-21 GB GB11112/78A patent/GB1596210A/en not_active Expired
- 1978-03-21 NL NL7803031A patent/NL7803031A/en not_active Application Discontinuation
- 1978-03-22 ES ES468133A patent/ES468133A1/en not_active Expired
- 1978-03-23 IE IE580/78A patent/IE46688B1/en unknown
- 1978-03-23 ZA ZA00781714A patent/ZA781714B/en unknown
- 1978-03-23 AU AU34483/78A patent/AU520738B2/en not_active Expired
- 1978-03-23 CA CA299,678A patent/CA1105009A/en not_active Expired
- 1978-03-23 IT IT48557/78A patent/IT1104183B/en active
- 1978-03-23 AT AT0207078A patent/AT366685B/en not_active IP Right Cessation
- 1978-03-23 BE BE186239A patent/BE865267A/en not_active IP Right Cessation
- 1978-03-23 NZ NZ186775A patent/NZ186775A/en unknown
- 1978-03-23 PT PT67816A patent/PT67816A/en unknown
- 1978-03-23 IL IL54342A patent/IL54342A/en unknown
- 1978-03-24 SU SU782595601A patent/SU1053755A3/en active
- 1978-03-24 JP JP3316578A patent/JPS53119898A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| AT366685B (en) | 1982-04-26 |
| IL54342A (en) | 1981-02-27 |
| ES468133A1 (en) | 1980-06-16 |
| BE865267A (en) | 1978-09-25 |
| JPS53119898A (en) | 1978-10-19 |
| GB1596210A (en) | 1981-08-19 |
| FI780835A (en) | 1978-09-26 |
| AU3448378A (en) | 1979-09-27 |
| FI66375B (en) | 1984-06-29 |
| DK119778A (en) | 1978-09-26 |
| IL54342A0 (en) | 1978-06-15 |
| DE2810774A1 (en) | 1978-10-05 |
| AU520738B2 (en) | 1982-02-25 |
| IT1104183B (en) | 1985-10-21 |
| FI66375C (en) | 1984-10-10 |
| IE780580L (en) | 1978-09-25 |
| NZ186775A (en) | 1980-12-19 |
| PT67816A (en) | 1978-04-01 |
| NL7803031A (en) | 1978-09-27 |
| SE7803040L (en) | 1978-09-26 |
| SU1053755A3 (en) | 1983-11-07 |
| IE46688B1 (en) | 1983-08-24 |
| IT7848557A0 (en) | 1978-03-23 |
| DK147072C (en) | 1984-09-10 |
| DK147072B (en) | 1984-04-02 |
| ZA781714B (en) | 1979-11-28 |
| ATA207078A (en) | 1981-09-15 |
| CH628049A5 (en) | 1982-02-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |