IE41427B1 - 6-methyl-8 -cyanomethylergoline i - Google Patents
6-methyl-8 -cyanomethylergoline iInfo
- Publication number
- IE41427B1 IE41427B1 IE2047/78A IE204778A IE41427B1 IE 41427 B1 IE41427 B1 IE 41427B1 IE 2047/78 A IE2047/78 A IE 2047/78A IE 204778 A IE204778 A IE 204778A IE 41427 B1 IE41427 B1 IE 41427B1
- Authority
- IE
- Ireland
- Prior art keywords
- cyanomethylergoline
- compound
- methyl
- effected
- compound according
- Prior art date
Links
- LBMFWYCMCHRLBU-PXFYRTPJSA-N 2-[(6ar,10ar)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-yl]acetonitrile Chemical compound C1=CC([C@H]2CC(CC#N)CN([C@@H]2C2)C)=C3C2=CNC3=C1 LBMFWYCMCHRLBU-PXFYRTPJSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 6
- 150000003839 salts Chemical group 0.000 claims description 6
- 239000012458 free base Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 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
- LBMFWYCMCHRLBU-SGIREYDYSA-N 2-[(6ar,9r,10ar)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-yl]acetonitrile Chemical compound C1=CC([C@H]2C[C@H](CC#N)CN([C@@H]2C2)C)=C3C2=CNC3=C1 LBMFWYCMCHRLBU-SGIREYDYSA-N 0.000 claims 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 241000700159 Rattus Species 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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
- 230000003291 dopaminomimetic effect Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 2
- 230000002085 persistent effect Effects 0.000 description 2
- 229910003446 platinum oxide Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000006748 scratching Methods 0.000 description 2
- 230000002393 scratching effect Effects 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 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
- 101100119767 Caenorhabditis elegans fat-4 gene Proteins 0.000 description 1
- 101100468762 Caenorhabditis elegans ric-3 gene Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 229920005439 Perspex® Polymers 0.000 description 1
- 102000003946 Prolactin Human genes 0.000 description 1
- 108010057464 Prolactin Proteins 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- RHGUXDUPXYFCTE-ZWNOBZJWSA-N ergoline Chemical compound C1=CC([C@@H]2[C@H](NCCC2)C2)=C3C2=CNC3=C1 RHGUXDUPXYFCTE-ZWNOBZJWSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- LLCOIQRNSJBFSN-UHFFFAOYSA-N methane;sulfurochloridic acid Chemical compound C.OS(Cl)(=O)=O LLCOIQRNSJBFSN-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 210000004681 ovum Anatomy 0.000 description 1
- DIVDFFZHCJEHGG-UHFFFAOYSA-N oxidopamine Chemical compound NCCC1=CC(O)=C(O)C=C1O DIVDFFZHCJEHGG-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229940097325 prolactin Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000003523 substantia nigra Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 238000011121 vaginal smear Methods 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
TATENT APPLICATION BY (71) SANDOZ LTD., A SWISS BODY CORPORATE, OF 35 LICHTSTRASSE, 4002, BASLE, SWITZERLAND.
Pnct I2|p 6-p’ethyl~8a-cvanoinethv3.grqoline I The present invention relates to 5-methyl-8oc -cyanomethylergoline 1 · The compound may be made by exchanging a radical Z for a cyano group in a compound of formula wherein Z is a radical capable of being exchanged in a nuclophilic substitution reaction.' The reaction may be effected in conventional manner for the production of analogous compounds. For exanple the compound may be produced as follows (all .temperatures are in degrees Centigrade and are uncorrected) 3.35 g (10 millimols) of 6-methyl~8a-mesyloxymethyl-ergoline I are dissolved in 20 cc of dimethyl formamide, and a solution of 3.25 g of potassium cyanide (50 millimols) in 4 cc of water is added.
After standing at 80° for 48 hours, the reaction solution is poured into an excess of a 2 normal sodium carbonate solution, the precipitate is filtered off, dried in the air and subsequently chromatographed on 150 g of aluminium oxide activity - 2 10 is eluted with 0f2% of methanol in methylene chloride and crystallizes from methanol (M.P. 160 to 162°, [α]2θ= -96° (o = 0.3, dimethyl formsmide).
The 6-methyl~8a~mesylj3xymethyl-ergoline I. required as starting material, may be obtained as follows: (a) 100 g ofΔ^'^-lysergic acid methyl ester are dissolved in 900 cc of dimethyl formamide while heating, dilution is effected with 1.5 litres of ι .. · I '·· ; «·· ’’ ' glacial acetic acid) and after the addition of 10 g of platinum oxide, hydrogenation is effected at +40-50° and normal pressure until the take up of hydrogen stops. The catalyst is filtered off and the filtrate is further hydrogenated under the above conditions after the addition of 5 g of platinum oxide.
Working up is effected by filtering and evaporating the filtrate to dryness. The resulting resin is dissolved in 1.5 litres of methylene chloride containing 5% of methyl alcohol, the solution is stirred well with 20 g of active charcoal, filtration is effected; after cooling well, it is slowly covered with a layer of one litre of 2 κ sodium carbonate solution and carefully shaken. The aqueous phase is again extracted twice with 500 cc of methylene - 3 chloride. After drying the organic phase over sodium sulphate and concentrating to about 1/5 of the original volume, dilution with about 500 cc of ether and scratching are effected. After standing at 0° for 2 hours, 9,10-dihydro-isolysergic acid methyl ester 1 crystallizes. Working up of the evaporation residue in accordance with known methods yields an additional amount of 9,10-dihydro-isolysergic acid methyl ester 1· After recrystallization from methylene chloride/ethyl acetate or ethanol, the ester has a M.P. of 178 to 180° , [α]2θ= -82° (c = ί. pyridine). (b) 38 g of lithium aluminium hydride are suspended in 2.5 litres of absolute tetrahydrofuran under nitrogen, cooling is effected to 0°, and a solution of 200 g of 9,10-dihydro-isolysergic acid methyl ester I in 2,5 litres of absolute tetrahydrofuran is added dropwise within 15 minutes while stirring vigorously.
The reaoticn product is subsequently diluted with 2.5 litres of absolute tetrahydrofuran and stirred for a further 30 minutes. Working up is effected by the careful successive dropwise addition of 100 cc of ethyl acetate, 100 cc of methanol and 50 cc of water. Dilution is subsequently effected with 2 litres of 30% methanol in methylene chloride and filtration is effected. The residue is again boiled 4stimes with 1 litre amounts - 4 41427 of 30% methanol in methylene chloride. After concentration and crystallization from methanol, the combined filtrates yield 9,10-dihydro-isolysergol having a M.P. of 189° to 193°. A further amount of 9,10-dihydro-isolysergol I may be isolated from the mother liquor by chromatography. (c) 100 g of 9,10-dihydro-isolysergol1 are suspended in 500 cc of absolute pyridine and 1.1 litres of absolute acetonitrile, and a solution of 80 cc of methane-sulphochloride in 200 cc of absolute acetonitrile is added ctopwise at 0° while stirring. After removing the cooling bath, the reaction mixture is stirred for a further hour at room temperature, whereby a yellowish precipitate results. Working up is effected by again cooling to 0° and adding a 2 N ammonia solution until an alkaline reaction is obtained. After scratching, 6-methyl-8cx-methane-sulphonyloxymethyl ergoline I crystallizes (m.P. 139-141°; )2θ= -54.6° (c = 1, dimethyl-formamide).
Acid addition salt forms of the compound may be made in conventional manner from the free base form ant? vice versa.
The compound exhibits pharmacological activity.
The compound exhibits prolactin secretion inhibition activity as indicated in standard tests, for example, --542437 in rats by an inhibition of ovum implantion as follows: The compound under investigation is administered to female rats 5 days after coitus and shown to be sperm positive according to the vaginal smear test.
The rats are sacrificed on day 12 and their uteri are examined by means of the Salewski reaction for proof that the nidations process has been interrupted [Arch, exp.Path.Pharm.247, 367 (1967)]. In particular, the compound also exhibits notable central dopaminergic stimulant activity, as indicated in standard tests, for example according to the principles of U.Ungerstedt Acta Physiol.Scand.Suppl. (1971) 367, 69-93, by an induction of contralateral turning in rats lesioned unilaterally in the substantia nigra by 6-hydroxydopamine and by an induction of dose dependent stereotyped sniffing, licking and biting behaviour in the rat according to the following test: Rats,18O-222g, are placed in Perspex (Registered Trads'^ark) cylinders of 30 cm diameter on a wire grid floor.
After 30 minutes to allow acclimatisation to the cage, the rats are injected with the compound under investigation. The behaviour of the rats is observed - 6 41487 for 2 minutes at 30 minute'intervals for 2 hours and then at 60 minute intervals for a total of up to 7 hours. The degree of stereotyped behaviour observed is assessed using a scoring system based on that des5 cribed by Costall, Naylor and Olley [Euro J. Pharmac. 18, 83-94 (1972)].
The scores and criteria are as follows ί 1. Intermittent sniffing 2. Persistent sniffing, occasional licking 3. Licking, occasional biting 4, Intense and persistent biting The compound is, therefore, indicated for use as a central dopaminergic stimulant agent, for example, for treating Morbus Parkinson. For this use an indi15 oated dose in from 0.5 to 100 mg, especially - 50 mg, conveniently administered in divided doses to 4 times a day in unit dosage form containing from 0.1 to 50 mg, or in sustained release form.
The compound may be administered in pharmaceuti 20 oally acceptable acid addition salt form. Such acid addition salt forms exhibit the same order of activity as the free base forms and are readily prepared in conventional manner. The present invention also provides a pharmaceutical composition comprising the compound, " in free base form or in pharmaceutically acceptable - 7 42427 acid addition salt form, in association with a pharma ceutical carrier or diluent,' Such compositions may be formulated in conventional manner, so as to be, for example, a solution or a tablet.
Claims (7)
1. A process for the production of 6-methyl8a-cyanomethylergoline by exchanging the radical Z for a cyano group in a compound of formula
2. A process for the production of 6~msthvl8a-cyanarrethylergoline substantially as hereinbefore described with reference to the Example. 10 3. 6-methyl-8cc-cyanomethylergoline whenever produced by a process according to claim 1 or 2.
3. Or 4 in acid addition salt form. - 9 =
4. 6-methyl~8a-cyanomethylergoline.
5. A compound according to any one of claims 3 or 4 in free base form. 15
6. A compound according to any one of claims 5 wherein i is a radical capable of being exchanged in a nucleophilic substitution reaction.
7. A pharmaceutical composition comprising a compound according to claim: 3 or 4 in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH998374A CH605936A5 (en) | 1974-07-19 | 1974-07-19 | 8-Alpha-(Amino-or cyanomethyl)-ergoline derivs |
| CH1103174A CH605938A5 (en) | 1974-08-13 | 1974-08-13 | 8-Alpha-(Amino-or cyanomethyl)-ergoline derivs |
| IE1596/75A IE41426B1 (en) | 1974-07-19 | 1975-07-17 | 8 -substituted ergoline i derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE41427L IE41427L (en) | 1976-01-19 |
| IE41427B1 true IE41427B1 (en) | 1980-01-02 |
Family
ID=27176349
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE2048/78A IE41428B1 (en) | 1974-07-19 | 1975-07-17 | 6-methyl-8 -n,n-dimethyl sulphamoylaminoergoline i |
| IE2047/78A IE41427B1 (en) | 1974-07-19 | 1975-07-17 | 6-methyl-8 -cyanomethylergoline i |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE2048/78A IE41428B1 (en) | 1974-07-19 | 1975-07-17 | 6-methyl-8 -n,n-dimethyl sulphamoylaminoergoline i |
Country Status (1)
| Country | Link |
|---|---|
| IE (2) | IE41428B1 (en) |
-
1975
- 1975-07-17 IE IE2048/78A patent/IE41428B1/en unknown
- 1975-07-17 IE IE2047/78A patent/IE41427B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IE41427L (en) | 1976-01-19 |
| IE41428B1 (en) | 1980-01-02 |
| IE41428L (en) | 1976-01-19 |
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