DE1470217A1 - New compounds from the class of D-6-methyl- (and-1,6-dimethyl-) - 8-amino-methyl-ergoline I and process for their preparation - Google Patents

Description

PROF, DR. DR. J, REITSTÖTTER DR.-ING. WOLFRAM BUNTE

D - Bf'Otl MÖNCHEN 15 HAYHNSTBASSE S. FERNW F OBIlI S3 Λ7 \ Z

Soc. Farmaceutici Italia

P 14 7o 217. 1 Munich, 1 ?. June 1969 M / 617 ² *

New compounds from the class of D-6-methyl- (and -1, 6-dimethyl-) - 8-amino-methyl-ergoline I and process for their preparation.

The invention relates to new compounds from the class of D-6-methyl- (and 1,6-dimethyl-) - 8-aminomethyl-ergolines I. and "a process for their preparation. The novel compounds have the following structural formula

N-CH ₃ '"

wherein R ¹ is hydrogen or a methyl radical and R is a residue of an organic carbon or sulfonic acid of the aliphatic, cycloaliphatic, aromatic and heterocyclic series documents (Art. 7 § \ Abs. 2 no. l clause 3 of the Änderungte "·· v. 4.9.

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with not more than 10 carbon atoms. The molecule of said acids can optionally have a substituent of Halogen group, a free or alkylated amino group, or a nitro, hydroxy, alkoxy, thioether and sulfone group wear.

The products of the new invention have both "in vivo" properties as well as 'in vitro' a high labor-stimulating, anti-therapeutic, adrenolytic, hypotensive and sedative activity and a very low toxicity.

The method according to the invention is based on the acylation of dihydro-D-lysergamine and or 1-methyl-dihydro-D-lysergamine, which are obtained by reducing the dihydro-D-lysergamine and 1-methyl-dihydro-D-lysergamide became. The reduction of the dihydro lysergic acid amides and D-or 1-methyl-dihydro-D- _t lysergic acid amides is carried out by a reducing agent, which Ψ is capable of converting the amide into an amino group. Lithium aluminum hydride is very suitable for this. The reaction begins at room temperature, but it is preferably carried out to the end in the heat. It is carried out in the presence of a solvent which is resistant to reducing agents and which belongs to the ether group, such as ethyl ether, propyl ether, tetrahydrofuran, ethylene glycol dimethyl ether and the like.

The dihydro-D-lysergamine (or 1-methyl-dihydro-D-lysergamixi) , is obtained as a free base in crystalline form by concentrating the reaction mixture and subsequent cooling isolated.

90985 0 / U70

" ³ " H70217

Eic corresponding Ιί-Acyldcrivnto been duroh Unoetaon deo Dihydro-D-lyaersanine (dew. Deo l-nnttoyl-dihydro-D-lyoercamine) with an acyl ion monol such as the anhydride or the chloride oinor organic carboxyl or sulphonic acid represent aliphatiochen, sykloalix-hotlachen, aromatic lind Hottroayklioohen Eoito · □ it is not less than 10 KoUlonotoffetomen, GOgebonsnfallo In Presence of oinco tort · Aa4.n0 such as pyridine, diethylaniline and Triilthylaiflin, herceotolltf dae molecule of beoagton acids know gocobonon cases a subotituent of the halogen group, tin free "or" ttllcylerte amlnogrupp "or" r a hit ro-, hydroxy-, Alky-ρ A lic οχ / -γ Thiouther- or 8i & £ on £ ruppt carry »

fypieohe Boieplelt the Aoylderirate ηαοα the present Sr * the invention eind the Derirpte the following 8üureni Bealfeäure "Triste thy leesigeüurof Propionoüure * ButtereUure, Valeri" neüure, Beptanoäure _t üktaneiiure, Bekanetlure _{(Zyklopentenf} Z / klopenthylproitonaäure, Bomettineüure, Selioyl-Toluylcüuro, 2-IÄetliOxybenaoooüure, Mothylthiooalloyl

PhonyIpropioniäure, Aunox / e8aisoUttro _f α -Phenoxypropionetxir «, '5. Chlore oelgsäuroi I-DlUthy 1 amine eelt ^ iüxxre,

Thimothyl «esic acid, cX -phenoxybiAttereuure, Butoxykohlenettur» »laobutoxykohlenoäur ·, Itboxykonleneäure, Propoxykolü.en» liure _# '-iDCpropoxykohlenaiiur ·, 1-ithyl-enthratyläure, 1,1-DiaattoaaUlfole »Katharina / UattaaUlfole -a- ·

likotinattur ·, Ieoni «J» tin-pyridine-3-sulfonic acid _t

S09850 / U70

BATH ORIGINAL

Lutidinsiure, Pyridin-J-oooisoäuro »picolinic acid» Pyridin-3-ioobuttoraaure, Piporidin - ^ - oarbonsäura, 3-Athyl-> piperidin-4 ~ oanijnäure, Indole-3-O8sisa: iurG , Imidazol - ^ - eeeifisäuro <-, PyraBina .ure, Pipcrusin-1-ooaigaiure »Piperazine-2-diaethylamineUthyl-1-oarboxylic acid» Pyriaidin-4-oarboxylic acid »Pyrimidine-5-bromo-2H3carbonaauro»? yrialdin- »5-amine-2-aothyl-4-Oarbon» Uurt _# Puran-3-ao-tljyl-2-carboiiaäuro »Puran-Z-oarbonaäure» Fyren «2» 6 <«dic bonoliurc, Thiophene-3-Oarbonoäiire, Thiophene-294-oulfoneÄuro, Ioooxoso 1-3-Oarbonoüure _t leooxa * ol-5- * Eilh-3-iaothgrl-4-oa3rt) on-β auro _f H-Uor pho lino α alga äuro _f Thiooorpholln-3 _e 5-dioerboneUurt ThiGiol-2-oorbonaUure, Thia «ol-4-attigrl- 2-oirbonic acid, thiaaol-2-onyne-4-oarbonaUur ·, thieaol ^ -hydroxy - ^ - oerboneaure, thiasol-2-e »eieeäiir · and the analogs ·

You Brzeugniooe des Yerfonrona naoh der nouen Brfinduns oind forbloe odor celb colored xrlatoll powder «you one in the Usual organic solvents and acids wniaon a high vehenanrosonde »entiontoraxainiooh ·, edrenolyti ^ hypoteniivc, boruliigonde Aktitrltttt and a far lower toxicity (bia su XO aal lower) in the Tergleioh au den

. More well-known products on · Bei · Koneohen can · on oral, intrsauekulUrea »aubknteaas and intraYenöee» sweep

^: ; dansereioht «earth and auoh in the inner modes» in «earth aie

f '■■ ■ ■ "

! applied (Hieran ·, Kopfeonaers, nerröee Saohykardit · Stomach »

atoniei Hyptrthyreooo, Saaedow * eoh * Xrenkheit, Srigenminu - ^% neuralgia, poripheriaohe Durohblutungoaturungen) in the ötburta-

. help and in gynecology (gynecological bleeding

t · ·

909850/1470. ^SAD

Puerperium, scraping of the uterus, miscarriage, Pregnancy toxicosis). You have also called Beruhi proven to act on the central nervous system.

In humans, the daily doses of o _f 1 to 5 of active compound will vary depending on the cases.

The therapeutic preparations commonly used contain one or more compounds of the new invention a certain amount of a solid or liquid binder.

The following examples serve to explain the new invention without, however, restricting it.

example 1 N-acetyl-dihydro-D-lysergamine

0.8oo g of dihydro-D-lysergamine are dissolved in 5 ml of pyridine Cooled -1O ° C and treated with 0.3 ml of acetyl chloride. After the mixture for 10 minutes at this temperature and then left to stand for 10 minutes at room temperature, it is now diluted with chloroform and it becomes methanol

909 850 / U70

and 5% aqueous sodium bicarbonate solution to complete Resolution added *

The chloroform layer is separated and the mother liquor is extracted twice more with chloroform.

The extracts are combined, washed with water and dried over anhydrous sodium sulfate. After

Distillation of the solvent and recrystallization from acetone-petroleum ether gives 0.700 g of N-acetyl-dihydro-D-lyeergamine; Fp 15o to 152C.

Example 2 N-propionyl-dihydro-D-lysergamine

A solution of 0.300 g of dihydro-D-lysergämLn in 2 ml of pyridine 0.3 ml of propionic anhydride are added and the reaction mass is left to stand at room temperature for 1 hour; o, 28o g of N-propionyl-dihydro-D-lys ^ r ^ aminiJ are obtained Mp 193-195 ° C

9 0 9 8 5 0/1 k 7 0

Ρ 1βρ1 1 3

Eino InJQuns ▼ <> »0.300 g dihydro-D-lyoorßnasin in 2 ml pyride in is with O ₉ J ml Dok-uioylüAureohlorid το roe tat | well, oh, UrJcriotallialcrcn from ether-Potrolütlior aohoidon 0.300 g N-Dolianoyl-

dihydro-D-lyooreanine from | Fp Dö up to 90 ⁰ C.

Ρ · 1 »ρ1β1 4

In älinliohor Woioo wio in Boiepi'l 2, raun duroh Umaotauna clay obtained 0.3CO g DiI ^ dro-D-lyoergaain in 2 ml pyridine with 0.3 nl Ioobuty * ylohlorid and naohfol ^ ondes U.-nkriotalllaiaren from Azoton-PatrolUtfcor 0.250 g HI «obutyr / l-dihyaro-D-lycor £; -aninj Pp 225 bio 22S ⁰ C.

D «! Game 5

In ühnliolier ifeiae wio in Boiopiel 2 is obtained by Unootzung tone 0.300 q Dihydro-B-lyoorgnain in 2 ml of pyridine 0.3 ml nit cyclopentyl-propionyl chloride and noohfolcendee TTxnkristdllinieron OUA Aeeton-Potrolätfaer 0.300 g B-Zyklopentylpropionyl-dihydro-D-Tp lyeorßaaini 130 tie 152 ⁰ O.

noiaplel 6

N-Suooiny 1-d ihy dr oD-ly α ornainin '

c Dihydro-D-lyoar ^ amine in 2 nl "pyridine are with 0.300 g ecologic acid hydride and 1 hour at RauatoEiporatur atohon golaoaen «Haoh addition of chloroform

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and ffeeior wira dit bereeblltbest Suoptnalon is in vorUnnttr

and dl · ttetmg wiffd alt Kohl® * ot? äs-fe% «si ί®?» kuue konatntriort. Dor entatandeno Slodereshl & g wi £ d »bfi ^ itriebt and nlt ϊοοβογ jev / ooohen. Man trhäli O _e JSO f Fp 255 at 25ü ° C

Product crystallized with olftea M © lekUl

Πβ1 »ρ1 · 1 7

In Ülmlioher V7oiso as in Boiupiol 2 one obtains by Uicootzung of ü, 270 ß dihydro-D-lyoerjasiin in 2 a & l P / ridia alt O _g l> ü ml Benaoylohlorid and naohfolconde «tJakr.istallioier®xi» us 0,100 s N- Donaoyl-dihydro-D-lyeergaifliiäi #p 296 öte 19Q

Ueiapiel 8

In the same way as in Boiopiei 2 "rh complexes cum du ^ ch of 0.300 ß dihydro-D-lyeersnmin in 2 al i ^ ridln with 0 _L 3 ml Phony 1-propionylohlorid and naolif ο Inende e UmJcrinto 1.1.1 aiaron from acetone -Petroläthor O ₈ 400 g N Pp 105 to 105 ⁰ C.

Example 9 n-Plicnoxy-aoptyl-flihydro-D-lyBcriianiiii

In ilhnliohcr Wciao v / ie in Eeiopisl 2 received buk through of 0.300 c Dlhydro-D-lyoerjamin in 2 ml P / riöin with 0 ^ 3 nl Phonoxy-ocotylchlorid and nachicl ^ onaae Oaicrio valliele ^ en from \

9 0 9 8 5 0 / U 7 0 BAD ORIGINAL

U ^'l 0217

l / eorjuainj Pp 110 bia 112 ⁰ C.
Example Io

AIA in 2 ml Pyridirt Rait 0.3 nl v-i'enosy-propionylohlorid and nochi'oljjendoe Umkrintalliaioran OUA acetone Potrolfither 0.420 g: In ahnliohor Weioo WLA in Baiajiel 2 wan duroh Uaootauns receives from 0.300 q I) ihyciro-D-lyaerßa H-.λ »Phenoagr-

Pp 100 ble 102 ⁰ C;

nelaptel 11

In a similar woioo as in Eeiapicl 2, roan is obtained by dissolving 0.300 q dihydro-D-lyaörcaiain in 2 ml pyridine old 0.300 £ j 2 _t 6-diaothoxy-bcm3oylchloride and naohfol ^ ondos Uakriotalliulcron aua Azoton-Potrolüthar 0.4CO β ! 2 _i) 6 »Diaothoxy bontJoyl-dihydro-D-lyscrgatalnj Pp 243 to 245 ⁰ C.

Example · T2

N-3,4..5-trinethoxy-bonaoyl-dihydro- <D-lyoor ^ o: riin

In uiinlichar üclao v.io in Baio ^ iel 2 orliult nan by Uaootzung of 0.300 g of dihydro-D-lyaorgainine in 2 ml of pyridine nit 0.300 g 3,4,5-2rlnutlioxy-bonaoylchloride and. naohfol ^ endee Unkriotallialeren aua Asseton 0.230 g K-3i4 »5-2rimothoxybansoyl-

Pp 228 to 230 ° $

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Ρβ1 »ρ1 · 1 13

In a similar way as in Boiopiel Z one obtains by um ootauns of 0.5GO g Diliydro-D-lyuorgaiain in 2 al pyridine with 0.300 s diethyloorbünylchlorid and subsequently β 3 Umkriatalliaierou auo Aeeton-Petroläthor 0 _e 150 g N-Dionrbonyl- dihydro-D-lyoerijttinini Fp 150 bia 152 ⁰ C.

Example I **

In uhnliohor Weiae wio in Boif3piel 2, aar obtains β dihydro-D-lyaertjassin ± _n χ _η χ by unootzung from 0.5CO

with 0.500 ml of ethyl chloro carbonate and subsequently oieron auo asetone petroleum ether 0.4-50 g of K-carbätboxy-dihydro mp 18C to 19O ⁰ C.

ο t »

Example 15

In a manner similar to that in Boiopiol Z , by substituting G, 500 q dihydro-D-ly3orßa.-ain in 3 ta! Pyridine with 0.400 ml of triutyl-Qootylohlorid and subsequentoo Umkriütnllloloren aua Azoton-Potrolüther 0.500 q If-Trinethyloootyl-Dihydro-D-lyeersaraini Pp 190 at 132 ° C,

Belapiel 16

DL-11-Ί. -Phenoxy-butyryl-dihydro-D-lyeörffDnin

In normal Woioo as in Boiepiel 2, one gets through uaoet2unß of 0.500 β dihydro-D-lyeergamine in 3 ml of pyridine

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BAD ORIG'NAL

nit 0,400 nl DL- ^ -Phenoxy-butyrylohlorid und nashfoXßend · »Uiakrintallioioren oua Asoton-PatraXathcr 0 * 550 g DIi-II-'X-PhonQxy-butyryl-tiihydro-L-lyoorßamiEjs Fp SO to 90 ⁰ Ct

Example 17

In ähnlichor üoino in Boi3piel 2 to orhült by Uncetüung from 0.500 g dihydro-D-lyoerßoraiu in 3 ul of pyridine with 0.4 to 00 β Iaopropyloliloroarbonat and na ohi ο Ige nd ^ a To "kriotulliaioron ouch Aacton-Potrollithor 0 _t β 45C Nßurbcioopropoa dihydro-D-lyöorgauiini Fp 110 tia 112 ⁰ O,

Example 18

In ulinliohor V / eiao? 7ie in Bciopiol 2 one obtains by using 0.500 β dihydro-D-Iyoortiorain in 3 ml pyridine with 0.400 β propylohlorcorbonate and subsequently Unkriatalliaieron quo Asoton-Patrolüthor 0.500 β H-Cari: opropropxy -D-lyoör ₍ ianin | Pp 173 bio 180 ⁰ Cc

neiapiel 19

In iümlioher V? Eiao wio in Boiuidol 2 orhält mon by Ua, -ootzunß of 0.5CO g of dihydro-D'lyaor ^ jain in 3 jni pyridine nit 400 β butyl chlorocarbonate and no ο hf ol / jonciee ^r Ja.krietallioiorcn oua Asoton- Potroliithor 0 _s 5 ^ 0 £ H-Carbcbutoxy-dihydroi Pp 120 to 130 ⁰ C,

90985 0 / U70

Example 2o N-carboisobutoxy-dihydro-D-lysergamine

In a manner similar to that in Example 1, conversion of 0.5oo g of dihydro-D-lysergamine in 3 ml of pyridine is obtained with 400 g of isobutyl chlorocarbonate and subsequent recrystallization from acetone petroleum ether 0.18 g of N-carboisobutoxy-dihydro-D-lysergamine; Mp 138-140 ° C.

Example 21 N-acetyl-1-methyl-dihydro-D-lysergamine

0.300 g of 1-methyl-dihydro-D-lysergamine are in 2 ml Pyridine cooled to - 10 ° C and treated with 2 ml of acetyl chloride offset. The mixture becomes Io min. At this temperature and then left to stand for 10 minutes at room temperature, whereupon chloroform and aqueous sodium bicarbonate solution can be added until completely dissolved. The chloroform layer is separated and extracted

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aqueous layer again 2 times with chloroform. The extracts are combined, washed with water and dried over anhydrous Dried sodium sulfate. After evaporation of the solvent and recrystallization of the residue from acetone petroleum ether gives 0.300 g of N-acetyl-1-methyl-dihydro-D-lysergamiri, which melts at 2o3 to 2o5 C.

Example 22 N - propionyl-1-methyl-dihydro-D-lyserganiine

In a manner similar to that in Example 1, the reaction of 0.5oo g of 1-methyl-dihydro-D-lysergamine in 3 nil gives Pyridine with 0.5 ml of propionic anhydride and the following Recrystallize from acetone petroleum ether 0.4oo g of N-propionyl-. 1-methyl-dihydro-D-lysergamine, which at 185 to 187 C melts.

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- ¹ * --- H70217

Raiapiel 23

'In Uhsilioher fioioe wio in Bninpiel 2 one obtains by Unoetson from 0.500 β l-Matiiyl-dihydro-D-lyeargaiiin in 3 ml pyridine with ü, | j ml Iaobutyrylchlorid mid nachiolgondea üiakriotalliaieron from A ao ton-Pot ro lather 0,400 g if- Iaobutyryl-1-isethyl-dihydro-D-lyoersarain; Pp 140 to 142 ⁰ O *

DeiBptel 2k

IT-CarbÜthoxy-1-üiethyl-dihv-dro-D-lyoörsninin

In a similar week as in Example 2, a total of 0 _f 5ü0 g of 1-methyl-dihydro-D-lyaorjacin in 3 nl of pyridine with 0.4 ml of xthylochlorocarbonate and stillioltfondea Umkrictallioioron auo acetone-Potroläthor 0,450 g N-carbatixyl dihydro-D-lysorsomini m.p. 130 to 152 ⁰ C.

Example 25

Aue 0.500 β l-Iiothyl-dihydro-D-lysörgomin and 0.5 DL-3 -Plionoxy-proptonylchlorid in 3 nl pyridine vuid by Ublicheo ünicriistollioieron ou3 Aceton Potrolather gets nan 0 »450 g DL-N - ^ - Phonoxy-propionyl -dihydro-IV-lyQer ^ arain; Pp 145 to 147 ⁰ O,

game 26 _f

H ^ Eanaoyl-l-nethyl-dilwdro-D-lyaorganjin

Aua 0.500 s l ~ Iio-ethyl-dihydro-D-lyeer £ aain and 0.4 nl

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SAD ORIGINAL

H70217

Bcni'.oyloblorid in 3 «1 pyridine and Uuroh Ublioheo iJnkrir.talli« olorcn receives r-nn 0.5 g Π-diinsoyl-1-nothyl-dihydro-D-lyeere- emlni Pp 2? 0 bio 222 ⁰ O.

section 27

Au3 0.500 β l-Iiothyl-dihydro-D-lyaoreamine and C, 4 ial El-OT-Phonoxy-butyr / lohlorid in 3 ml pyridine and by li'oliohce Um kriRtnllisiejron aua Aaeton receives nan 0.500 β El-H- ^ Phonoxy butyryl -1-ciotiiyl-dihydro-D-lyaorGncdni m.p. 180 to 190 ⁰ C.

PeiBpiel 28

Π-Plionöxy-ooo tyl * -l-no thyl-dihydro-D-lyeo r ijacin

From 0.500 g of l-LIothyl-dihydro-D-lyeergaain and C, 4 nl of phenoxyaoetylohlorid in 3 ml of pyridine and dui'oh Ubllchoa üakriotollieioron aua acetone petrol> ithsr orhält nan 0.150 # N-phenoxyoootyl-l-nothyl-dihydro- D-lyaersaiiini Pp 16 a bio 170 ⁰ O.

neisplel 29

In iilinlichor Weiao λΙο in Uoiupiel 2 oriiält iaan by converting 0, 'jOO g l-LIeth / i-dilViiro-D-lysorijarain in 3 al pyridine ait 0.500 β ioobutylohloronrbonat and noohfolor ^ ondoe UiV.crintilthoton 0.4 from azo 17-corboiaobutoxy-l-

^? 13Ü bio 14C ⁰ C,

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Ralapfl 3o

Zn similar üeloe "i · In fiolapi" l 2 is nan by reaction of 0.500 g of 1-methyl-dlhydro-D-lyeerganin in 3 ml Fyrldln ait U ₁ 430 · q Isopropylchloronrbonat and subsequently ·· UmltristoXlioioron quo Auoton Pctrolütker-O 45O _t S K-Oorboissopropo * yl-aethyl-dihydro-Dl> 3orgamlnt Vp 193 bio 195 ⁰ C.

BelBpiel 31

K-CarbobutOKV-l-iflothyl-dihyclro-D-lyaer / joiain

In a similar way as in Example 2 can be obtained by umeotsunc of 0.500 g of l-Uotl ^ yl-dihydro-D-lyeerccnin in 5 ml of fyrldine with 0 »500 β butylohloroarbonate and then ·« »krlstolllaieron aua Ateton-Potroläthor 0,4- 60 g of N-Oarbobutoxy-1-mothyl-dihydro-D-lyeorgazaiiij mp 125 to 127 ⁰ O.

nal «piel 32

In the same way as in Example 2, by converting 0.500 g of 1-ethyl-difeydro-D ~ l78ergarain in 3 μl of pyridine, 0.450, 5 propylohlorocarbonate and neuhfolcendee to kriotallleieren aue asetone potrolether 0.450 g of N-carbopropyloxy-1-dihydro-dihydroxy -B-Ueergaiain »7p 128 to 130 ⁰ C.

Balaplel 33

To a lube of 1 g of 1-methyl-dlhydro-B-lyetrgamine in 20 el

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tetrahydrofuran are 1.42 a Hatriuiaaßetat and under. Simultaneous cooling 0.320 ml of chloroethyl chloride bug ·· •• tst · Because the addition of chloroform and sodium hydroxide is added. Di · OhXoroformXttoung is then gawaoohen with Wosoer and the Löoungomittal is ia vacuum Yordampft. UsUcriotaXXiaieron dea RUokatandes from acetone Patroläthor gives O ₉ QOO g of product} Pp 2 ^ bia ⁰

BeisPial 3 * » _;

In iüinliohor YFoiao, as it is beaohriobon in Beiopiel 37, O _t lÖ α H-Llkthylönin-aoetyl-l-mathyl-dihydro-D-Xyaeraaain $ Pp X28 Dia 130 ⁰ O.

free spin 35

From 0.500 g of dihydro-D-lyoorsamine and 0.5 aX pyraainoylohloride in 3 ml of pyridine. and by UbXiohoa UsucriataXXiaioren • rhält iaan 0.450 g of H-pyrazinoyl-dihydro-D-lyoorgamini Pp λ

bia 232 ⁰ C (with zero setting) _λ

Example 36

-. Aua 0.500 g of dihydro-D-Xyeergoain in 5 mX pyridine and 0.5QO g aaXsaaurem liiootinylohlorid increases ügoi 0.450 β product with the Pp IQO bia 190 ⁰ O (aua Äseton).

SAD ORIGINAL 909850 / 1470-

Bai «pi« l 37

Au · 0.500 g of l-ethyl-hydro-B-lyeer ^ anln in 3 nl pyridln and 4 O ₉ ^ OO Q oalzsaurea Hiootinyl Chloride gives 0.400 g of product with the Pp XW up to 180 ⁰ O («uo Aseton ~ petroleum ether).

2 »

Aue 0.500 Q 1-ethyl-dihydro-D-lyoargonin in 3 ml pyridine "J and 0.500 ß oalaaaurea Iaoniootinylohlorid one obtains 0.450 g product} Pp 218 at 220 ⁰ O Cauo Asoton ~ petroleum ether) ·

B «l« plel 39

Aue 0.500 8 1-ethyl-dihydro-D-lyecrgainin in 3 al Pyridln and 0.500 s Pioolinylohlorld receives 0.350 β product! Pp 168 to 170 ⁰ O (also aaetone-pctrolether).

Bel »pi ·! ^ o

H-iiorpholin-aoetyl-1-nothyl-dihydro-Blyaor ^ amine

Aue 0.500 ß 1-Hothyl-dihydro-D-Iyacramin in 3 ml pyridine and 0.500 g oalzoauram N-Iiorpholinoootyl receives 0.380 product mp 163 bio 165 ⁰ O (aue Azoton).

Bctapiel

n-pyrrolidine-aootyl-1-nothyl-diliydro-D-lyoor / ronine

Aue 0.500 g of lfothyl-dihydro-D-lyoersaain in 3 μl of pyridine

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'SAD-

and 0.500 β Pyrrolidinucetylohlorid receives men 0.450 g product) 7p bia 153 155 ⁰ C (aua Aeeton-Petrolöther).

D «l« piel

Aue O ₉ SOO s Dihydro-D-lyoersßmi »and 0.500 β toeylohlorid la 5 al P / rldln obtained mn 0.450 β product ι Ip 16? bia 165 ⁰ O (from Aseton).

Xn doroolbon Vela · can be obtained other K-Aoy! Derivatives vrle Hp.Cnlorbonaoyl-dlhydro-D-lyeorßoinin (Fp 13Ö bla 140 ⁰ O) ₉ Hp.ChlorbonBoyl-l-mathyl-dihydro-D-lyaerganin (7p 223 bia 2JO ⁰ C) ₉ H-diethyl-eottyl-dihydro-D-lyoorgamine (mp 100 to 102 ⁰ O), H-oinnamoyl-dihydro-D-lyeoreanine (mp 143 to 145 ⁰ O) ₉ If-ß-Ohlor-proploayl -l-methyl-dihydro "- D-2yeorceain (9p 143 to 145 ⁰ O) ₉ H-corbonothoxy-1-methyldihydro-D-lyeoraanine (Pp 80 ble 02 ⁰ O) and the analogs.

In the following table and the relevant values of the Effect and the UCoxinitilt of some advantages *

The founding of the hearing in Vorhältnia bu those dee Brsoaetrina listed _{9 which were} conventionally not a · feotgceetst.

BATH ORIGINAL

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H70217

links

irgoaetrin

ϊ-Λο ο tyl * dihydro-D-ly00 rgoraln

J-Propiony1-dihydro-D-lyee rgattln

tl-carbethoxy-l-metbyl-dihydro-D-lyoergaiain j

relatively · stimulate labor «·

1 1 2 2.5

relasstiT · Toxlci-

0.2 0.5

0 »9

The wehtnonrecondQ activity let foetßeotelXt still be the Möthode Äitttle the Kaninoheacebärnuttor in aitu, dl · von Hothlin (Sohiveii.iled.öoohenooürift 1938, p.971). eohrio bea became · «Beoli the Bauoheobnitt is dlo uterus through« Inen 7ad «a bit an öohreibhobtl rerbundtni da · organ is wrapped in with phyeiologiacher Lueuns ffitrünkto tfett · · 1η $ · <* and old of an Iafrerotloope« rests. 3) 1 · will entapreohond den Torouohen footfioetoXit, dlo at Uodikoaenton der loreorgaäureebkümialinge boi intravenous Binepriteun ^ & w Tested connections on rabbits and Xitun oueeefUart.

Aueeerdoa have been immunized in vivo with me Antienteramine effect near the Ue t hod β oueffeiüarl »dl · von I.Doepfner and A.Oerlettl (Int.Arch.Allorey 12, 1958, 8. 09 * 97) drill rubd ·, the ouV des 50 ^ ic »n inhibition ·· «·· of 5- ^ ydroav-tryptemlÄ nervareeruXeaa« Odern ·

109160/1470

the rat paw is based · Sohlieoalioh were Yerauohe in τΙτο to the conduction of the adrenotytiaohan activity which leads to dea InhibitionoToraösea der Adrenalhypertenoloa 03 Confederation is based

Visits to the antienteraain active ingredient lat'dao Oarbüthoxyl-mothyl-dihydro-D-lyeorsonin 3 as more effective ice DiUthorl-D-lyoor2aain in vitro, and oe eisst a tdrenmlytische Virksenkeit »the rorgXeiohbar bit that of the Ergotamine is·

Besü ^ lioh the Aatieatcreuain-WirkoeaJceit is the Oarboieo «propoxy-l-nethyl ^ iajdro-D-lyaergeÄln 5 aal effectantr ala dao Dietyl-D-lyatrßaaid in vitro , and it reduces the artoriellan blood pressure boia rabbits.

N-Niootinyl-1-ethyl-dlh / dro-D-lyaorßuoin iat in the Adronolytioolion Wirfcaankoit 1.5 times atttrJcor than tartaric acid ersotanln and it ootet. arterial blood pressure boia Kaninohon down "

909850 / U7Q BAD

Claims (1)

Patent claims 1.) Ergoline derivatives of the general formula CH ₂ NHR where R ¹ denotes a V / uöserstofi'atoaj or a methyl group and R o denotes an organic carbon-odor imlfonaüure of the aliphatic, oycloaliphatic, aromatic or heterooyolic series with no more than 10 carbon atoms, the molecules of which may be a substituent of the halogen group, a free o ' the alkylated amine group or a nitro, hydroxy, alkyl, alkoxy, thioether or sulfonic group can carry. Documents in accordance with Article 7Si Aba 9098 50/1470 2 No. 1 Date 3 of the amendment «·· v. A. 9. BATH ORIGINAL 2) if-aottyl-dihydro-D-lyttrguain 3.) K-Propiony 1-dihydro-B-Iyeerganiin k .) 5-i) »icanoyl-dih; uro-t-lysergaain 3.) il-Ieobutyryi-dihydro-D-lycergomin 6 ") n-Cyclopeatyl-propionyl-dihjdro-II-lysorgamine 7.) n-3uooinyl-dihydro-D-lye # rgoxin 9.) il-phenyl-propionyl-dihydro-D-lyoergumin to.) ir-phenoxy-acctyl-dihydro-D-lyeorgeain n.)! T-Ä-rhenoxy-propionyl-dihydro-D-lyeergamine 12.). R-2 | 6 13 ·) N-J ^ 15.) N-16.) N 18.) W-Oarboiiopropoxy-dlhy4ro-1> -lyitrf "ln 19.) W-Corbopropoxy-dihydro-D-lyortaain 2o ·) "-Carbobutoxy-aihydro-P-lyeergiiain ti.) H-CurboliObutox] r-dlhydre-D-iyieriÄ.tin lt.) 9-as.) H- • OHIO / UTO 28 ·) Ilr-S-a-phenoxy-butityl-1-octhyl-dlhydro-D-xyfergoaiine 29 ff-B "n2oyl ~ l-aotbyl-dih} dro-I) -lyeergamia 3o.) K-Cartoopropoxy-1-methyl-dlhydro-D-lyiorgaaiü 31 *) N-carboleobutoxy-1-tatthyl-dihydro-D-lyaergaain 32 ") if-CarboiaopropDiy-l-methj'l-aihydro-E ^ -Iy eergaain 33.)! T-Carbobutoxy-1- ^ tbyl-dihydro-D-lyeerßumln 34.) TI-Chloroaoetyl-1-methyl-dibvdro-L-lyeergaiBin 35.) r-Ciathylaain-acetyl-1-ethyl-diliydro-D-lyeergAain 36 ·) p-Toeyl-dihydro-XJ-lyaergaxnin 37 ·) N-Pyrazinoyl-dihydro-E-lyöerßaaln 3β ·) ϊ-hieotinyl-dihydro-B-lyeergemin 39 ·) TT-Kicotinyl-1-methyl-difaydro-D-lyeergßinine ko,) . IT -Igon iootinyl-1-methyl-dlh. *, Dro-I) -lysergamine 4i _¥ ) pioolinyl-1-methyl-dibyäro-D-lyiergaain k2,) ! l -;! orpholine-acetyl-l-oi »thyl-dlhyäro-I> -iye # pgaiain S-p. Cblorbenioyl-dlhydro-P-lyaergarain 46.) »-Diethyl-acetyl-dihydro-r-lyfiergaiuia 47 ·) H-Cinnaooyl-dihydro-l ^ lya.ergaxnin 48 ·) JP-ß-chloro-proplonyl-l-m ^ thyi-dihydro-l ^ -Xyeepgaain 49.) S- BAD ORiC ^ NAi 909850/1470 5o.) Process for the production of D-ergoline derivatives of general formula CH ₀ -MIR N I R ' where R ¹ denotes a hydrogen atom or a methyl group and R denotes an organic carboxylic or sulfonic acid of the aliphatic, cycloialiphatic, aromatic or heterocyclic series with not more than 10 carbon atoms, the molecules of which may contain a substituent of the halogen group, a free or alkylated amine group or a may carry nitro, hydroxy, alkyl, alkoxy, thioether or sulfone group, characterized indicates overall that in per se known manner dihydro-D-lysergamin or "man-l-methyl-D-dihydrg lysergamin acylated with the chloride or anhydride of the acids mentioned above, optionally in the presence of a tertiary amine « 2k6 / mo 909850/147