GB1596210A - N-(2,3-dihydro-9-ergolen-8-ylmethyl) ureas - Google Patents
N-(2,3-dihydro-9-ergolen-8-ylmethyl) ureas Download PDFInfo
- Publication number
- GB1596210A GB1596210A GB11112/78A GB1111278A GB1596210A GB 1596210 A GB1596210 A GB 1596210A GB 11112/78 A GB11112/78 A GB 11112/78A GB 1111278 A GB1111278 A GB 1111278A GB 1596210 A GB1596210 A GB 1596210A
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- GB
- United Kingdom
- Prior art keywords
- compound
- formula
- carbon atoms
- methyl
- hydrogen
- 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
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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
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- 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
A description is given of the preparation of ergolene derivatives with an action lowering blood pressure and the formula I <IMAGE> in which R1 and R2 are each hydrogen or an alkyl group with 1 to 4 carbon atoms, or else together form an alkylidene chain with a maximum of 5 carbon atoms, and their salts with acids. Corresponding compounds unsaturated in position 2,3 are reduced selectively in position 2,3 and the resulting compounds of the formula I are converted where appropriate into their acid addition salts.
Description
(54) N-(2,3, p-DIHYDRO-9-ERGOLEN-8 p-YLMETHYL) UREAS
(71) We, SANDOZ LTD., of 35 Lichtstrasse, 4002 Basle, Switzerland, a
Swiss Body Corporate, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to ergot derivatives.
The present invention provides compounds of formula I,
wherein Rl 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, Rs is alkyl of 1 to 4 carbon atoms, and
R4 is hydrogen, alkyl of 1 to 4 carbon atoms, which is unsubstituted or sub
stituted by one to 3 halogen atoms with tbe proviso that the carbon atom
does not carry any halogen atom, or alkoxymethyl of 2 to 5 carbon atoms.
Halogen means bromine and especially fluorine and chlorine. Alkyl is preferably methyl or ethyl except where otherwise stated. Alkoxy is preferably methoxy. Alkylidene is preferably tetra- or penta-methylene. When alkyl is substituted by halogen, the halogen atom is preferably on the terminal carbon atom. Preferably alkyl, when substituted by halogen, has 2 carbon atoms. R1 and R2 are preferably alkyl, R3 is preferably methyl or isopropyl. R4 is preferably hydrogen. Conveniently R1, R2 and
Rs are all methyl.
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,
wherein Rl to R, are as defined above
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 add, may be used. Suitable solvents include trifluoroacetic acid, ether, tetrahydrofuran or dioxane or mixtures thereof. The reduction may also be effected using zinc in hydrocbloric acid.
Suitable reaction temperatures may be from 0 to 400 C.
The starting materiais 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 conventional manner and vice versa.
In the following examples all temperatures are in degrees Centigrade and are uncorrected.
All ratios refer to parts by volume.
EXAMPLE 1.
1,1-dimethyl-3-[6-methyl-2,3ss-dihydro-9-ergolen-8ssi-ylmethyl] urea.
1.95 g of sodium borohydride are added portionwise to 10.5 g 1,1-dimethyl-3 [6-methyl-9-ergolen-8ss-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 ith sodium sulphate, filtered and evaporated to give a beige foam, which is chomatographed on 120 g silicagel using methylene chloride/methanol (9:1) + 0.5% concentrated NH, as eluant.
The resultant base is converted into the hydrochloride or hydrogen fumarate.
HCI salt - M.P. from 185 (decomp.); [a]D20 = + 50 Cc = 0.675 in
ethanol/water 1:1).
Hydrogen fumarate sait - M.P. from 1200 (decomp.); [e]DD20 = + 20.90
(c = 0.44 in ethanol/water 1:1).
In analogous manner to that described in Example 1 the following compounds may be produced:
Ex. No. R1 R2 R3 R4 M.P. [α]D203) CH3 CH3 CH3 CH3-' 143 -145 1) -67.5 (c =0.68) 3 CH3 CH3 CH3 CF3-CH2- from 16502) 58.20.
(c= 0.86) 1) Free base form 2) Free base form decomposition point 3) In CHCl, 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 Grcllmann rat, in the awake spcntanecus hypertonic rat, and in the awake renal hypertonic Goldblatt dog, upon administration of 0.05 to 3 mg/kg animal body weight of the compounds.
The compounds are therefore indicated for use as anti-hypertensive agents. For this use an indicated daily dose is from 0.5 to 200 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from 0.1 to 100 mg, or in sustained release form.
A particularly interesting compound is the Example 1 compound.
The compounds of formula I may be administered in pharmaceutically acceptable
acid addition salt form. Such salts possess the same order of activity ts the free base
forms.
The invention also provides a pharmaceutical composition comprising a com
pound 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.
In a group of compounds R, is methyl and R4 is hydrogen.
WHAT WE CLAIM IS:
1. A process for the production of a 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, R, 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 ,carbon does not carry
any halogen atom, or alkoxymethyl of 2 to 5 carbon atoms, which comprises selectively reducing the 2,3-position of a compound of formula II,
wherein R1 to R4 are as defined above.
2. A process for the production of a compound of formula I, as stated in claim 1, substantially as hereinbefore described with reference to any one of the Examples.
3. A compound of formula I, whenever produced by a process according to
Claims (1)
- claim 1 or 2.4. A compound of formula I, as defined in claim 1.5. A compound of claim 4, wherein R3 is methyl and R, is hydrogen.6. 1,1-Dimethyl-3- [6-methyl-2,3J3-dihydro-9-ergolen-8.P-ylmethyl] urea.7. A compound of claim 4, wherein R1, R2 and Rs are all methyl.8. A compound of claim 7, wherein R, is CH,.9. A compound of claim 7, wherein RX is CEa-CHp,-.10. A compound according to any one of claims 3 to 9 in free base form.11. A compound according to any one of claims 3 to 9 in acid addition salt form.12. A pharmaceutical composition comprising a compound according to any one of claims 3 to 11 in free base form or in pharmaceutically acceptable acid additions salt form in association with a pharmaceutical carrier or diluent.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH381477A CH628049A5 (en) | 1977-03-25 | 1977-03-25 | Process for the preparation of ergolene derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1596210A true GB1596210A (en) | 1981-08-19 |
Family
ID=4264035
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB11112/78A Expired GB1596210A (en) | 1977-03-25 | 1978-03-21 | N-(2,3-dihydro-9-ergolen-8-ylmethyl) ureas |
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) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4695635A (en) * | 1984-03-28 | 1987-09-22 | Schering Aktiengesellschaft | Process for the production of 2,3-dihydroergolines |
| 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 |
Families Citing this family (2)
| 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 |
| GB2173189B (en) * | 1985-02-21 | 1988-04-27 | Maruko Pharmaceutical Co | Ergoline derivatives and salts thereof and pharmaceutical compositions thereof |
-
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 SE SE7803040A patent/SE7803040L/en unknown
- 1978-03-16 FI FI780835A patent/FI66375C/en not_active IP Right Cessation
- 1978-03-16 DK DK119778A patent/DK147072C/en not_active IP Right Cessation
- 1978-03-21 NL NL7803031A patent/NL7803031A/en not_active Application Discontinuation
- 1978-03-21 GB GB11112/78A patent/GB1596210A/en not_active Expired
- 1978-03-22 ES ES468133A patent/ES468133A1/en not_active Expired
- 1978-03-23 BE BE186239A patent/BE865267A/en not_active IP Right Cessation
- 1978-03-23 CA CA299,678A patent/CA1105009A/en not_active Expired
- 1978-03-23 ZA ZA00781714A patent/ZA781714B/en unknown
- 1978-03-23 IT IT48557/78A patent/IT1104183B/en active
- 1978-03-23 IL IL54342A patent/IL54342A/en unknown
- 1978-03-23 AU AU34483/78A patent/AU520738B2/en not_active Expired
- 1978-03-23 AT AT0207078A patent/AT366685B/en not_active IP Right Cessation
- 1978-03-23 IE IE580/78A patent/IE46688B1/en unknown
- 1978-03-23 NZ NZ186775A patent/NZ186775A/en unknown
- 1978-03-23 PT PT67816A patent/PT67816A/en unknown
- 1978-03-24 SU SU782595601A patent/SU1053755A3/en active
- 1978-03-24 JP JP3316578A patent/JPS53119898A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4695635A (en) * | 1984-03-28 | 1987-09-22 | Schering Aktiengesellschaft | Process for the production of 2,3-dihydroergolines |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| IT7848557A0 (en) | 1978-03-23 |
| SE7803040L (en) | 1978-09-26 |
| DK147072C (en) | 1984-09-10 |
| NL7803031A (en) | 1978-09-27 |
| JPS53119898A (en) | 1978-10-19 |
| FI66375B (en) | 1984-06-29 |
| PT67816A (en) | 1978-04-01 |
| SU1053755A3 (en) | 1983-11-07 |
| AU3448378A (en) | 1979-09-27 |
| DK147072B (en) | 1984-04-02 |
| DK119778A (en) | 1978-09-26 |
| ATA207078A (en) | 1981-09-15 |
| IE46688B1 (en) | 1983-08-24 |
| ES468133A1 (en) | 1980-06-16 |
| IL54342A0 (en) | 1978-06-15 |
| FI66375C (en) | 1984-10-10 |
| IT1104183B (en) | 1985-10-21 |
| BE865267A (en) | 1978-09-25 |
| DE2810774A1 (en) | 1978-10-05 |
| AT366685B (en) | 1982-04-26 |
| CH628049A5 (en) | 1982-02-15 |
| IL54342A (en) | 1981-02-27 |
| AU520738B2 (en) | 1982-02-25 |
| NZ186775A (en) | 1980-12-19 |
| CA1105009A (en) | 1981-07-14 |
| FI780835A (en) | 1978-09-26 |
| IE780580L (en) | 1978-09-25 |
| ZA781714B (en) | 1979-11-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed [section 19, patents act 1949] | ||
| PCNP | Patent ceased through non-payment of renewal fee |