IE46688B1 - N-(2,3 -dihydro-9-ergolen-8 -yl methyl)ureas - Google Patents
N-(2,3 -dihydro-9-ergolen-8 -yl methyl)ureasInfo
- Publication number
- IE46688B1 IE46688B1 IE580/78A IE58078A IE46688B1 IE 46688 B1 IE46688 B1 IE 46688B1 IE 580/78 A IE580/78 A IE 580/78A IE 58078 A IE58078 A IE 58078A IE 46688 B1 IE46688 B1 IE 46688B1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- formula
- carbon atoms
- alkyl
- hydrogen
- Prior art date
Links
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title claims description 6
- 235000013877 carbamide Nutrition 0.000 title 1
- 150000003672 ureas Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000001118 alkylidene group Chemical group 0.000 claims abstract description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 239000012458 free base Substances 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- 239000004202 carbamide Substances 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 125000004849 alkoxymethyl group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000008024 pharmaceutical diluent Substances 0.000 claims 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 claims description 2
- 150000007513 acids Chemical class 0.000 abstract 1
- 230000036772 blood pressure Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-M fumarate(1-) Chemical compound OC(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-M 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960003133 ergot alkaloid Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- -1 sodium borohydride Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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
A description is given of the preparation of ergolene derivatives with an action lowering blood pressure and the formula I 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
This‘invention relates to ergot derivatives.
* I The present invention provides compounds of formula I, ' I wherein Rj and R2 are independently hydrogen 5 or alkyl of 1 to 4 carbon ’atoms, or are together an alkylidene chain of 2 to 5 carbon atoms, Rg is alkyl of 1 to 4 carbon iatoms, and R^ is hydrogen, alkyl of 1 td atoms, which is unsubstituted or substituted by one to 3 halogen atoms with the proviso that the α-carbon atom does not carry any halogen atom, or alkoxymethyl of carbon to 5 carbon atoms. -4-6688 -3-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 penta5 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, and R2 are preferably alkyl, Rg is preferably methyl or isopropyl. R^ is preferably hydrogen. In a group of compounds Rg is methyl and R^ is 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, wherein R. to R, are as defined above. 1 4 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 trifluoroacetic acid, ether, tetrahydrofuran or dioxane or mixtures thereof. The reduction may also be effected using zinc in hydrochloric acid.
Suitable reaction temperatures may be 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 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. ·' ό υ ο 8 EXAMPLE 1: 1,l-dimethyl-3-[6-methy1-2, 3S-dihydro-9ergolen-8_0-y Ime thyl]urea 1.95 g of sodium borohydride are added portionwise to 10.5 g 1,1-dimethy1-3-[6-methy1-95 ergolen-8p-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 : 1) + 0.5 % concentrated NH^ as eluant.
The resultant base is converted into the hydrochloride or hydrogen fumarate.
HCl salt - M.P. from 185 ° (decomp.); [a]Q = + 50 ° (c = 0.675 in ethanol/water 1:1).
Hydrogen fumarate salt - M.P. from 120 ° (decomp.); [a)^ =+20.9° (c = 0.44 in ethanol/water 1:1).
In analogous manner to that described in Example 1 the following compounds may be produced: 4 ο ϋ 3 8 ro Ο CN Q Ί? L—1 - 67.5 ° (c = 0.68) KO CO © · CN O CO || in 1 0 1 ft 3 - 145 ol) om 165 °2> • fi* μ a H ΜΗ fi· ro ffl CN ffl 0 , CT ft ' Di u 0 (0 co ffl co ffl ft 0 0 CN ro ffl co ffl ft U 0 rfi co ffl co ffl P5 u u Ex.No. CN co 4J C •fi Ο ft β Ο •fi -Ρ •fi (0 Ο ί υ ο Ό Β 0 0 MH Φ 0) m (0 ro rt rt lfi X} Λ 0 ffl Φ GJ 0 GJ GJ μ μ β ft ft H rfi CN CO »6688 - 7 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 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. 6 6 8 8 The compounds of formula X may be ' I administered in pharmaceutically acceptable acid addition salt form. Such salts possess the same order of activity as the free base forms.
The invention also provides 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.
Claims (12)
1. A process for the production of a compound of formula X, Wherein R^ and Rg are independently hydrogen or alkyl of 1 to 4 carbon atoms, ’ ' or are together an alkylidene chain of 2 to 5 carbon atoms, Rg is alkyl of 1 to 4 carbon atoms, and R^ 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 α-carbon atom does not carry any halogen atom, or alkoxymethyl of
2. To 5 carbon atoms, - 10 which comprises selectively reducing the 2,3 position of a compound of formula II, wherein Rg to R^ are as defined above. I 5 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 claim 1 or 2. I 10 .
4. A compound of formula I, as defined in claim 1. - 11 '
5. A compound of claim 4, wherein is methyl and r‘ 4 is hydrogen.
6. *A compound of claim 4, which is 1,1-dimethy1-3-[6-methy1-2,3p-dihydro-9-ergolen-8pylmethyl]urea.
7. A compound of claim 4, wherein Rg, R 2 and R g are all methyl.
8. A compound of claim 7, wherein R^ is CH 3 .
9. A compound of claim 7, wherein R^ is cf 3 -ch 2 -.
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 addition 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 (2)
| Publication Number | Publication Date |
|---|---|
| IE780580L IE780580L (en) | 1978-09-25 |
| IE46688B1 true IE46688B1 (en) | 1983-08-24 |
Family
ID=4264035
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE580/78A IE46688B1 (en) | 1977-03-25 | 1978-03-23 | N-(2,3 -dihydro-9-ergolen-8 -yl methyl)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) |
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 |
| CA1105009A (en) | 1981-07-14 |
| SU1053755A3 (en) | 1983-11-07 |
| 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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