CA2049016A1 - 2,13-disubstituted ergolines, their production and use in pharmaceutical agents - Google Patents
2,13-disubstituted ergolines, their production and use in pharmaceutical agentsInfo
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- CA2049016A1 CA2049016A1 CA002049016A CA2049016A CA2049016A1 CA 2049016 A1 CA2049016 A1 CA 2049016A1 CA 002049016 A CA002049016 A CA 002049016A CA 2049016 A CA2049016 A CA 2049016A CA 2049016 A1 CA2049016 A1 CA 2049016A1
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- 8alpha
- ergolinyl
- diethyl
- propyl
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- 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
- C07D457/10—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hetero atoms directly attached in position 8
- C07D457/12—Nitrogen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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Abstract
Abstract Compounds of formula I and their acid addition salts I
in which R2, R6, R13 and X have the meanings mentioned in the application, are described as well as the process for their production and pharmaceutical agents containing these compounds.
in which R2, R6, R13 and X have the meanings mentioned in the application, are described as well as the process for their production and pharmaceutical agents containing these compounds.
Description
2~9~
2,13-Disubstituted Ergolines, their Production and Use in Pharmaceutical Agents The invention relates to new 2,13-disubstituted ergo~ines, their production and use in pharmaceutical agents, as well as intermediate products for their produc:tion.
13-Substituted ergolines, which exhibit affinity for central dopamine receptors, are known from EP-A-220 129. The new 2,13-disubstituted ergolines show a greater affinity for the dopamine receptor with improved metabolic stability and thus an increase of action.
The invention relates to compounds of formula I and their acid addition salts NH - CX- N ( C H
R 1 3 ~;\ i ~ N - R 6 1~ ,J~ ,1 in which R2 is halogen, Cl_6alkyl or -S-CI_4alkyl, R6 is Cl_6alkyl, C3_6alkenyl or C3 5cycloalkyl-CI-2alkyl, X is oxygen or sulfur, 2 ~
Rl3 is chlorine, iodine, -s-~14alkyl, Cl_6alkyl, C2 6 alkenyl, 1,3-dithiolan-2-yl, -Co-R3 or -CR4RSoH and R3, R4 and RS
eaeh mean hydrogen or Cl 5alkyl.
The physiologieally compatible acid addition salts are derived from the known inorganic and organie aeids, such as, for example, hydrochlorie aeid, sulfuric acid, hydrobromic acid, citric aeid, maleie aeid, fumarie aeid, tartaric acid, i.a.
Halogen contains in partieular ehlorine, bromine and iodine.
By alkyl is understood respeetively a straight-chain or branched alkyl radical, sueh as, for example, methyl, ëthyl, n-propyl, isopropyl, n-butyl, isobutyl, see-butyl, tert-butyl, pentyl, hexyl, 2,2-dimethylpropyl, 2-methylbutyl, isopentyl, i.a.
If R6 or Rl3 means an alkenyl radical, the radical can be straight-ehain or branehed and eontains preferably only one double bond, and the double bond in R6 cannot be adjacent to the nitrogen atom. For example, vinyl, l-propenyl, 2-propenyl, 1-methyl-2-propenyl, l-butenyl, methallyl, are suitable as alkenyl radieals.
If R6 means a cyelo-alkyl-alkyl group, radicals with up to 5 earbon atoms, for example, cyclopropylmethyl, cyclopropylethyl and eyelobutylmethyl, are preferred.
If R2, R6 and Rl3 mean alkyl or alkenyl radicals, those with up to 4 earbon atoms are to be eonsidered as preferred.
The eompounds of formula I ean oeeur as E or Z isomers or, if a ehiral eenter is present in radieal R2 or Rl3, as 2 ~ 6 diastereomers and as their mixtures. The isomers and mixtures of isomers are also encompassed by this invention.
The compounds of formula I as well as their acid addition salts are usable as pharmaceutical agents because of their affinity for central dopamine receptors. Depending on the type of substituents in 2-, 13- and 6-position, they are dopaminergic agonistically, antagonistically or partially agonistically effective and are suitable, for example, for treatment of Par]cinson's disease, hyperprolactinemia, positive or negative `
symptoms and signs in schizophrenia or emesis.
The dopaminergic agonistic effect is determined, for example, with the help of the method, described by Horowski, of the automatic registration of stereotypes in rats (Arzneim.
Forsch. [Research on Pharmaceutical Agents~ 12, 2281-2286, 1978~:
immediately after intraperitoneal test substance or vehicle administration, male Wistar rats (90-120 g) are placed individually in restrictive cages made from acrylic glass. By an electrodynamic recording system fastened in front of the head of the animals, the number of contacts on a steel beaker with a central metal rod as a result of the stereotyped chewing, licking and gnawing movements is registered for 60 minutes. The mean values +SEM of the number of contacts over 60 minutes are calculated for the various treatment groups, each of which consists of 12 animals, and the significance of the differences between the mean values of the various test substance doses in comparison with the vehicle-treated control group is determined 1 2 0 4 9 Q ~ 6 with the help of simple analysis o~ variance in connection with the Dunnett test. The results are exp].ained in table 1.
' ~ ~
.. .
2 ~ 6 -X X X
2,13-Disubstituted Ergolines, their Production and Use in Pharmaceutical Agents The invention relates to new 2,13-disubstituted ergo~ines, their production and use in pharmaceutical agents, as well as intermediate products for their produc:tion.
13-Substituted ergolines, which exhibit affinity for central dopamine receptors, are known from EP-A-220 129. The new 2,13-disubstituted ergolines show a greater affinity for the dopamine receptor with improved metabolic stability and thus an increase of action.
The invention relates to compounds of formula I and their acid addition salts NH - CX- N ( C H
R 1 3 ~;\ i ~ N - R 6 1~ ,J~ ,1 in which R2 is halogen, Cl_6alkyl or -S-CI_4alkyl, R6 is Cl_6alkyl, C3_6alkenyl or C3 5cycloalkyl-CI-2alkyl, X is oxygen or sulfur, 2 ~
Rl3 is chlorine, iodine, -s-~14alkyl, Cl_6alkyl, C2 6 alkenyl, 1,3-dithiolan-2-yl, -Co-R3 or -CR4RSoH and R3, R4 and RS
eaeh mean hydrogen or Cl 5alkyl.
The physiologieally compatible acid addition salts are derived from the known inorganic and organie aeids, such as, for example, hydrochlorie aeid, sulfuric acid, hydrobromic acid, citric aeid, maleie aeid, fumarie aeid, tartaric acid, i.a.
Halogen contains in partieular ehlorine, bromine and iodine.
By alkyl is understood respeetively a straight-chain or branched alkyl radical, sueh as, for example, methyl, ëthyl, n-propyl, isopropyl, n-butyl, isobutyl, see-butyl, tert-butyl, pentyl, hexyl, 2,2-dimethylpropyl, 2-methylbutyl, isopentyl, i.a.
If R6 or Rl3 means an alkenyl radical, the radical can be straight-ehain or branehed and eontains preferably only one double bond, and the double bond in R6 cannot be adjacent to the nitrogen atom. For example, vinyl, l-propenyl, 2-propenyl, 1-methyl-2-propenyl, l-butenyl, methallyl, are suitable as alkenyl radieals.
If R6 means a cyelo-alkyl-alkyl group, radicals with up to 5 earbon atoms, for example, cyclopropylmethyl, cyclopropylethyl and eyelobutylmethyl, are preferred.
If R2, R6 and Rl3 mean alkyl or alkenyl radicals, those with up to 4 earbon atoms are to be eonsidered as preferred.
The eompounds of formula I ean oeeur as E or Z isomers or, if a ehiral eenter is present in radieal R2 or Rl3, as 2 ~ 6 diastereomers and as their mixtures. The isomers and mixtures of isomers are also encompassed by this invention.
The compounds of formula I as well as their acid addition salts are usable as pharmaceutical agents because of their affinity for central dopamine receptors. Depending on the type of substituents in 2-, 13- and 6-position, they are dopaminergic agonistically, antagonistically or partially agonistically effective and are suitable, for example, for treatment of Par]cinson's disease, hyperprolactinemia, positive or negative `
symptoms and signs in schizophrenia or emesis.
The dopaminergic agonistic effect is determined, for example, with the help of the method, described by Horowski, of the automatic registration of stereotypes in rats (Arzneim.
Forsch. [Research on Pharmaceutical Agents~ 12, 2281-2286, 1978~:
immediately after intraperitoneal test substance or vehicle administration, male Wistar rats (90-120 g) are placed individually in restrictive cages made from acrylic glass. By an electrodynamic recording system fastened in front of the head of the animals, the number of contacts on a steel beaker with a central metal rod as a result of the stereotyped chewing, licking and gnawing movements is registered for 60 minutes. The mean values +SEM of the number of contacts over 60 minutes are calculated for the various treatment groups, each of which consists of 12 animals, and the significance of the differences between the mean values of the various test substance doses in comparison with the vehicle-treated control group is determined 1 2 0 4 9 Q ~ 6 with the help of simple analysis o~ variance in connection with the Dunnett test. The results are exp].ained in table 1.
' ~ ~
.. .
2 ~ 6 -X X X
3 s I ~ I +l +l +~ I
ul 3 ~ i3 i3 ~D r r 13 3 ~ 3 1 r x cx 3 ~ a) .i ~1 1 '-I I I coco . ~ h ~
a 3 o ~ 3 u~ 3 ^ ~ -~ 1 3 r - O ,C h 3 2 ~ j 3 x x x 13 o Q) U~ ~D I I xx X I ~ a ~
3 ~ ~ I 0 3 ~ ~D ~ 3 h O O I ~ ~ I + l + l + l ~ j 3 ~ r 3 ~ ~ Po~
m 1 ~ x ~: I o u~ j I r r r. I o~
~ ~ U I ~ ~I I U) N _ I S-l I
u~ I .~ Ql I - I + I + I + I i I ~ ~
3 j ~ E ~ j jN ~ ao I ~ ~
ao ~ r j N
~ ~ ~ ~ ~ 3 j j ~ ~ o N~r a~o7 N ~ ~r .
~ ~ ~J I I + I + I + 1 3 o I r r j ~O ~ _ ' ~ ~',, ~
~ -~ 8 i I I a ~ I . o ~r X ~ I o I O N ao I ~ :~
h I ~ I -- _ S S ~-~
S~ o ~ I ~ I + I + I + I
U j ~D ~ ~ 3 1 I s ~
N N O I ,~ ~ C0 1~1 3 3 , ,, h -.~ .
~ 0 ~ 6 Since the compounds according to the invention are distinguished in particular by dopaminergie acJonistie aetion, they are suitable in particular for treatment of Parkinson's disease.
To use the compounds according to the invention as pharmaeeutieal agents, the eompounds are brought into the form o~
a pharmaeeutieal preparation, whieh, in addition to the aetive ingredient for enteral or parenteral administration, eontains suitable pharmaeeutical, organic or inorganic inert vehieles, such as, for example, water, gelatin, gum arabic, laetose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glyeols, ete. The pharmaceutical preparations ean be present in solid form, for example, as tablets, coated tablets, suppositories, capsules, or in liquid form, for example, as solutions, suspensions or emulsions. Optionally, they also eontain auxiliary agents, such as preservatives, stabilizers, wetting agents or emulsifiers, salts to change the osmotic pressure or buffers.
The eompounds according to the invention are introdueed in a dose of 0.001 to 10 mg of active substance in a physiologieally eompatible vehicle. The use of the compounds aecording to the invention takes place in a dose of 0.00001 to 0.1 mg/kg/day, preferably 0.001 to 0.1 mg/kg/day analogously to the known agent bromoeryptine.
2 ~ 6 The production of the compounds of formula I according to the invention can also be performed according to methods known in the art.
For example, compounds of formula I are attained, by a) compounds of formula II
CX N(c2H5)2 in which R2, R6 and X have the above-named meaning, being reacted in the presence of an acid with an electrophilic agent or b) compounds of formula III
NH-CX-NIC H I
R //\ /~ /
` / \ ~ III
H-N R
in which R-, R13 and X have the above-named meaning, being alkylated or alkenylated to compounds with R6 in the above-named meaning and then optionally 2~9~ ~
alpha) compounds with Rl3 = -co-R3 with R3 in the above-named meaning being redueed to compounds with Rl3 = -C~SOH and the latter optionally being dehydrated to eompounds with Rl3 = C2_6alkenyl or redueed to eompounds with Rl3 = Cl_6alkyl or beta) eompounds with Rl3 = 1,3-dithiolan-2-yl being eonverted to compounds with Rl3 = -CHO or CH3 or gamma) urea being converted to thiourea or delta) the isomers being separated or the acid addition salts being formed.
The eleetrophilie substitution in 13-posi~ion aeeording to proeess a) is performed in the presenee of an aeid at temperatures of 0C to 20C and is generally eompleted after l to 24 hours.
Inorganic aeids, such as phosphorie aeid, sulfurie aeid, organie aeids, sueh as trifluoroacetic aeid, methanesulfonie aeid, aeetic acid, and Lewis aeids, sueh as aluminum ehloride, titanium chloride, dimethylaluminum chloride, tin(IV) chloride, boron fluoride, i.a., can be used as acids, and the organic aeid ean be used as solvent or inert aprotic solvents, sueh as ehlorinated hydroearbons, such as dichloromethane, ehloroform, tetraehloroethane or nitrobenzene, are added.
Suitable eleetrophiles are, for example: acyl ehlorides, sueh as aeetyl ehloride, propionyl chloride; halogenation agents, sueh as N-ehlorosuccinimide, N-iodosuccinimide, triehloroisoeyanurie acid; dimethyl-methylthio-sulfonium tetrafluoroborate; dichloromethyl alkyl ether; chloroformie aeid 2 ~
alkyl ester; formie acid alkyl ester and ethanedithiol or dithiolane, i.a.
The substitution in 6-position according to process b) ean be performed, for exa~ple, according to A. Cerny et al. C'oll.
Czech. Chem. Comm. 49, 2828 (198~) or according to the process described in EP-21206, by the 6-H compound of formula II being reaeted with the eorresponding R6 halides (bromides, chlorides, iodides). The reaetion suitably takes place in an inert solvent such as ethanol, dimethylformamide, acetonitrile or nitromethane in the presence of bases such as DBU, alkali hydroxides~or alkali carbonates.
Compounds of formula I with Rl3 meaning a -CoR3 group can be reduced to alcohol aeeording to the usual processes, such as, for example, with lithium aluminum hydride or lithium tri-tert-butoxyalanate in an aprotie solvent, sueh as eyelie or acyelie ethers, for example, tetrahydrofuran, dioxane, diethyl ether.
l-Hydroxy-alkylated substituents Rl3 can also be produced by Grignardation or lithium alkylation. The Grignardation ean take place with the usual Grignard reagents, such as alkyl magnesium halides in an aprotie solvent, such as cyclic and aeyelie ethers at temperatures of -70C to 20C. The reaetion with alkyl lithium takes plaee under analogous eonditions.
The subsequent dehydration for the double bond ean be performed in the usual way, sueh as, for example, with sulfonates or aeetates in polar solvents, such as ethers in the presence of a base and optionally with heating.
' C 2 ~ 6 The reduction of the alcohols to 13-alkyl derivatives can take place, for example, by reaction with NaBH4 in acetic acid or by reduction with lithium in ammonia.
To introduce the 13-CH3 group, it: can be advantageous, before the reduction of the 13-CH2-OH radical, to este~ify this radical with acids, such as pivalic acid, acetic acid, benzoic acid and then to reduce it according to the known processes as described in German patent application P 4020341.7.
If Rl3 means a dithiolane radical, it can be converted to the 13-formyl derivative, for example, by aqueous SiO2 treatment and subsequent reaction with sulfuryl chloride in aprotic solvents, such as chlorinated hydrocarbons. The 13-methyl derivative can be produced by reaction with Raney nickel at room temperature in protic solvents such as alcohols.
The conversion of the urea derivatives to the thioureas can take ~lace, for example, according to the process described in EP-A-217730 by reaction with phosphorus oxychloride and a thiolation agent.
The mixture of isomers can be separated according to the usual methods, such as, for example, crystallization, chromatography or salt formation in the diastereomers or E/Z
isomers.
The compounds of formula I are isolated either as free bases or in the form of their physioloyically compatible acid addition salts.
2D49~ 6 For the formation of salts, a compound of formula I is dissolved, for exa~ple, in a little alcohol or methylene chloride and mixed with a concentrated solution of the desired acid.
The introduction of the substituents in 6-position can take place before or after substitution in 13-position. The invention also comprises the compounds of formu:La IV, which represent valuable intermediate products for the production of pharmacologically effective compounds. The reduction of 6-cyano-ergoline to the 6-H compound takes place, for example, according to A. Cerny et al. Coll. Czech. Chem. Comm. 49, 2828 (1984). The conversion of the intermediate products to the active substance takes place according to the method described in process variant b).
In so far as the production of the initial compounds is not described, these compounds are known or can be produced analogously to known compounds or to the processes described here.
The following examples are to explain the process according to the invention.
12 2~
Example 1 1 1-Diethyl-3-[13-(1 3-dithiolan-2-yl)-2,6-dimethyl-8alPha-erqolinyl1-urea 5.31 g of 1,1-diethyl-3-(2,6-dimethyl-8alpha-ergolinyl)-urea (15 mmol) is dissolved in 150 ml of chloroform and 50 ml of formic acid ethyl ester, 2.8 ml of ethanedithiol (33 mmol) and 60 ml of a 1 molar solution of titanium tetrachloride in dichloromethane ~60 mmol) are added and stirred for 20 hours at room temperature. Then, it is mixed with 40 ml of methanol and 300 ml of water, made alkaline with 30 ml of 25% ammonia solution and shaken out with dichloromethane. The organic phases are dried with sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel with dichloromethane/methanol. 4~14 g of substance, which crystallizes from ethyl acetate, is isolated, [C~ ]D = ~4 (0 5%
in chloroform).
Analogously, there are produced:
1,1-Diethyl-3-[13-(1,3-dithiolan-2-yl)-2-methyl-6-propyl-8alpha-ergolinyl]-urea from 1,1-diethyl-3-(2-methyl-6-propyl-8alpha-ergolinyl)-urea, in 38% yield.
1,1-diethyl-3-[13-(1,3-dithiolan-2-yl)-2-ethyl-6-propyl-8alpha-ergolinyl]-urea from 1,1-diethyl-3-(2-ethyl-6-propyl-8alpha-ergolinyl)-urea, in 28% yield.
20~ 9~ ~
Example 2 8alpha-f3 3-DiethYlureido)-2 6-dimethyl-erqoline-13-carbaldehyde 3.26 g of 1,1-diethyl-3-[13-(1,3-dithiolan-2-yl)-2,6-dimethyl-8alpha-ergolinyl]-urea ~7.1 mmol) is dissolved in 35 ml of chloroform and mixed with 5.3 g of silica gel and 5.7 ml of water. Then, the solution of 1.37 ml of sulfuryl chloride (17 mmol) is instilled in 35 ml of chloroform within 10 minutes and stirred for 1 hour at room temperature. After adding 8.5 g of potassium carbonate, it is stirred for 15 minutes, some ethanol and saturated common salt solution are added and shaken out with dichloromethane. The organic phases are dried and concentrated by evaporation, the residue is chromatographed on silica gel with ethyl acetate/methanol, yield 1.45 g. This substance is crystallized from ethyl acetate/diisopropyl ether, yield 1.09 g (40% of theory), [ C~]D = -9 (0.5% in chloroform).
Analogously, there are produced:
8alpha-(3,3-Diethylureido)-2-methyl-6-propyl-ergoline-13-carbaldehyde from 1,1-diethyl-3-[13-(1,3-dithiolan-2-yl)-2-methyl-6-propyl-8alpha-ergolinyl]-urea, yield 51%.
8alpha-(3,3-diethylureido)-2-ethyl-6-propyl-ergoline-13-carbaldehyde from l,1-diethyl-3-[13-(1,3-dithiolan-2-yl)-2-ethyl-6-propyl-8alpha-ergolinyl]-urea, in 62% yield.
2~9~ ~ ~
Example 3 2-Bromo-8alpha-(3 3-diethylureido)-6-methYl-ergoline-13-carbaldehyde 838 mg of 3-(2-bromo-6-methyl-8alpha-ergolinyl)-1,1-diethylurea (2 mmol) is dissolved in 100 ml of dichloromethane, 1.2 g of anhydrous aluminum chloride (9 mmol) and 1.8 ml of dichloromethyl methyl ether (20 mmol) are added and stirred for 15 minutes at room temperature. The reaction mixture is mixed with ice and, after 15 minutes, with a solution of 1.5 g of tartaric acid in 50 ml of water and made alkaline with 5 ml of conc. ammonia solution. It is extracted with dichloromethane, the organic phases are dried with sodium sulfate and the solvent is distilled off. The residue is chromatographed on silica gel with dichloromethane/methanol, 406 mg (45% of theory) is isolated.
Analogously, there are produced:
2-Bromo-8alpha-(3,3-diethylureido)-6-propyl-ergoline-13-carbaldehyde from 3-(2-bromo-6-propyl-8alpha-ergolinyl)-l,1-diethylurea, yield 27%.
2-chloro-8alpha-(3,3-diethylureido)-6-methyl-ergoline-13-carbaldehyde from 3-(2-chloro-6-methyl-8alpha-ergolinyl)-1,1-diethylurea, in 37% yield.
2-chloro-8alpha-(3,3-diethylureido)-6-propyl-ergoline-13-carbaldehyde from 3-(2-chloro-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, in 32% yield.
2 ~
8alpha-(3,3-diethylureido)-2-methylthio-6-propyl-ergoline-13-carbaldehyde from 1,1-diethyl-3-(2-methylthio-6-propyl-8alpha-ergolinyl)-urea, in 42% yield.
Ex~mple 4 1 1-Diethyl-3-(2 6-dimethyl-13-hydroxymethyl-8alpha-erqolinvl)-urea 370 mg of 8alpha-(3,3-diethylureido)-2,6-dimethyl-ergoline-13-carbaldehyde (1 mmol) is disso~ved in 50 ml oE tetrahydrofuran and reduced with 200 mg of lithium aluminum hydride at room temperature for 1 hour. The mixture is cooled off in an ice bath and mixed in succession with 0.2 ml of water, 0.2 ml of 15%
sodium hydroxide solution and 0.6 ml of water, the precipitate is filtered off and the filtrate is evaporated to dryness. The residue is chromatographed on silica gel with dichloromethane/methanol. 243 mg of alcohol, which crystallizes from ethyl acetate, is isolated. Yield 166 mg (44~ of theory), [ C~]D = +6 (0.5% in chloroform).
Analogously, there are produced from the respective aldehydes:
1,1-Diethyl-3-(13-hydroxymethyl-2-methyl-6-propyl-8alpha-ergolinyl)-urea, yield 73%.
1,1-diethyl-3-(2-ethyl-13-hydroxymethyl-6-propyl-8alpha-ergolinyl)-urea, yield 43%.
3-(2-bromo-13-hydroxymethyl-6-methyl-8alpha-ergolinyl)-1,1-diethylurea, yield 51%.
20~9~
3-(2-bromo-13-hydroxymethyl-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 62%.
3-(2-chloro-13-hydroxymethyl-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 42%.
1,1-diethyl-3-(13-hydroxymethyl-2-methylthio-6-propyl-8alpha-ergolinyl)-urea, yield 34%.
Example 5 1 1-Diethyl-3-(2 6,13-trimethyl-8al~ha-erqolinyl)-urea 458 mg of 1,1-diethyl-3-[13-(1,3-dithiolan-2-yl)-2;6-dimethyl-8alpha-ergolinyl)-urea (1 mmol) is dissolved in 50 ml o~
methanol and treated with several portions of Raney nickel at room temperature until the initial material has disappeared according to thin-layer chromatography. It is filtered by kieselguhr, the solvent is concentrated by evaporation and the residue is chromatographed on silica gel with dichloromethane/methanol, the isolated substance is crystallized from methanol, yield 117 mg (31% of theory)~
Example 6 1 1-Diethyl-3-(2 6 13-trimethyl-8alpha-erqolinvl)-urea 715 mg of 1,1-diethyl-3-(2,6-dimethyl-13-hydroxymethyl-8alpha-ergolinyl)-urea (1.5 mmol) is dissolved in 10 ml of pyridine and mixed with 2 ml of trimethylacetyl chloride. Ice is added after 30 minutes of stirring at room temperature, it is 2 0 ~
stirred for another 30 minutes, made alkaline with ammonia and the mixture is cooled in an ice bath. The precipitated crystals are suctioned off, yield 785 m~, t ~ ]D = -2 (0-5% in chloroform). The mother liquor is extracted with dichloromethane, dried and concentrated by evaporation. Both fractions are dissolved together in 6 ml of tetrahydrofuran and the solution is instilled in 50 ml of condensed, anhydrous ammonia. Then, it is mixed with 160 mg of lithium and the blue solution is stirred for 30 minutes at -40C. Solid ammonium chloride, until decolorization, and 5 ml water are added in succession, the ammonia is evaporated and it is diluted with 80 ml of water. After 30 minutes of stirring in an ice bath, the precipitated crystals are suctioned off and dried in a vacuum, yield 643 mg (94% of theory), [C~ ]D = ~3 (0.5% in chloroform).
From the respective alcohol, there are analogously produced:
1,1-Diethyl-3-(2,13-dimethyl-6-propyl-8alpha-ergolinyl)-urea, yield 76%.
1,1-diethyl-3-(2-ethyl-13-methyl-6-propyl-8alpha-ergolinyl)-urea, yield 81%.
Example 7 3-(13-Acetyl-2 6-dimethyl-8alpha-ergolinyl~-1 1-diethylurea 2.4 g of anhydrous aluminum chloride and 1.3 ml of acetyl chloride are dissolved in 70 ml of dichloromethane and stirred for 15 minutes at room temperature. 708 mg of 1,1-diethyl-3-(2,6-dimethyl-8alpha-ergolinyl)-urea (2 mmol) dissolved in 30 ml ~9~
of dichloromethane is aclded to it, and stir~ed for 30 minutes at room temperature. Ice is added and after 15 minutes of stirring, a solution of 2.8 g of -tartaric acid in 80 ml of water is added.
After another lS minutes, it is made alkaline with conc. ammonia, the organic phase is separated and the water phase is extracted.
All organic phases are dried with sodium sulfate and concentrated by evaporation, the residue is chromatographed on silica gel with dichloromethane/methanol~ yield 454 mg.
Analogously, there are produced:
3-(13-Acetyl-2-methyl-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 61~.
3-(13-acetyl-2-ethyl-6-methyl-8alpha-ergolinyl3-1,1-diethylurea, yield 38%.
3-(13-acetyl-2-ethyl-6-propyl-8alpha-ergolinyl)~l,1-diethylurea, yield 58%.
3-(13-acetyl-2-bromo-6-methyl-8alpha-ergolinyl)-1,1-diethylurea, yield 67%.
3-(13-acetyl-2-bromo-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 47%.
3-(13-acetyl-2-chloro-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 71%.
3-(13-acetyl-6-methyl-2-methylthio-8alpha-ergolinyl)-1,1-diethylurea, yield 44~, ~ ~ ]D = +7 (0.5% in chloroform).
2~9~
Example 8 1 1-Diethyl-3-[2,6-dimethyl-13-(1-hydroxyethyl)-8alpha-erqolinyl]-urea 406 mg of 3-(13-acetyl-2,6-dimethyl-8alpha-ergoliny;)-1,1-diethylurea (1 mmol) is reduced in 50 ml of tetrahydrofuran with 200 mg of lithium aluminum hydride as described in example 4, worked up and crystallized from ethyl acetate, yield 216 mg (53%
of theory), ~ ~ JD = ~12 (0.1% in pyridine).
Analogously, the following alcohols are produced:
1,1-Diethyl-3-[13-(1-hydroxyethyl)-2-methyl-6-propyl-8alpha-ergolinyl]-urea, yield 75%.
1,1-diethyl-3-~2-ethyl-13-(1-hydroxyethyl)-6-propyl-8alpha-ergolinyl]-urea, yield 57%.
1,1-diethyl-3-t2-ethyl-13-(1-hydroxyethyl)-6-methyl-8alpha-ergolinyl]-urea, yield 43%.
3-[2-bromo-13-(1-hydroxyethyl)-6-methyl-8alpha-ergolinyl]-1,1-diethylurea, yield 51%.
3-[2-bromo-13-(1-hydroxyethyl)-6-propyl-8alpha-ergolinyl]-1,1-diethylurea, yield 61%.
3-[2-chloro-13-(1-hydroxyethyl)-6-propyl-8alpha-ergolinyl]-l,l-diethylurea, yield 47%.
1,1-diethyl-3-[13-(1-hydroxyethyl)-6-methyl-2-methylthio-8alpha-ergolinyl]-urea, yield 63~.
2 ~ 6 - -Example 9 1,1-Diethyl-3-(13-ethyl-2 6-dimethyl-8alpha-er~olinyl)-urea 280 mg of 1,1-diethyl-3-[2,6-dimethyl-13-tl-hydroxyethyl)-8alpha-ergolinyl)-urea (0.7 mmol) is dissolved in 14 ml of acetic acid and stirred with 700 mg of sodium borohydride (tablets) for 15 minutes at room temperature. Then, ice is added, it is stirred for another 15 minutes and made alkaline with conc.
ammonia. The suostance is extracted with dichloromethane, the organic phases are dried and concentrated by evaporation, the residue is chromatographed on silica gel with dichloromethane/methanol. The isolated substance is crystallized from ethyl acetate/hexane. Yield 176 mg (65% of theory), [~ ]D = ~5 (0.5% in chloroform~. -Analogously, the corresponding alcohols are reduced:
1,1-Diethyl-3-(13-ethyl-2-methyl-6-propyl-8alpha-ergolinyl)-urea, yield 73% of theory.
1,1-diethyl-3-(2,13-diethyl-6-methyl-8alpha-ergolinyl)-urea, yield 64% of theory.
1,1-diethyl-3-t2,13-diethyl-6-propyl-8alpha-ergolinyl)-urea, yield 47% of theory.
3-(2-bromo-13-ethyl-6-methyl-8alpha-ergolinyl)-1,1-diethylurea, yield 28%.
3-(2-bromo-13-ethyl-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 23%.
3-(2-chloro-13-ethyl-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 44%.
2~9~ 6 -- -l,1-diethyl-3-(13-ethyl-2-methylthio-6-propyl-8alpha-ergolinyl)-urea, yield 33%.
Example lO
3-r2-Bromo-6ll3-dimethyl-8alpha--erqolinyl)-l l-diethylurea From 3-(2-bromo-13-hydroxymethyl-6-methyl-8alpha-ergolinyl)-l,l-diethylurea by reduction as described in example 9, yield 43%.
Analogously, there are synthesized:
3-(2-Bromo-13-methyl-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 24%.
3-(2-chloro-13-methyl-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 45%.
l,1-diethyl-3-(13-methyl-2-methylthio-6-propyl-8alpha-ergolinyl)-urea, yield 37%.
Example 11 l.l-Diethyl-3- r 13-(1-hydroxy-1-methyl-ethyl~-2-6-dimethYl-8alpha-erqolinyl)-urea 396 mg of 3-(13-acetyl-2,6-dimethyl-8alpha-ergolinyl)-1,1-diethylurea (l mmol) is dissolved in 30 ml or dry tetrahydrofuran and the solution is cooled to -65C. 0.8 ml of a 1.6 molar solution of methyllithium in ether is added (1.3 mmol), then the solution is allowed to warm to room temperature and is stirred for another 30 minutes. It is poured on ice, made alkaline with conc. ammonia solution and extracted with ethyl acetate. The 2 ~
organic phases are dried and evaporated, the residue is chromatographed on silica gel with dichloromethane/methanol, yield 285 mg (67% of theory).
Analogously, there are produced from the 13-ace~yl compounds:
1,1-Diethyl-3-[13-(1-hydroxy-1-methyl-ethyl)-2-methyl-6-propyl-8alpha-ergolinyl]-1,1-urea, yield 54%.
3-[2-bromo-13-(1-hydroxy-1-methyl-ethyl)-6-propyl-8alpha-ergolinyl]-l,l-diethylurea, yield 73%.
3-[2-chloro-13-(1-hydroxy-1-methyl-ethyl)-6-propyl-8a]pha-ergolinyl)-l,l-diethylurea, yield 67%.
Example 12 1,1-Diethyl-3t2 6-dimethYl-13-isopropenYl-8alpha-ergolinyl) urea 208 mg of 1,1-diethyl-3-[13-(1-hydroxy-1-methyl-ethyl)-2,6-dimethyl-8alpha-ergolinyl]-urea (0.5 mmol) is dissolved in 20 ml of anhydrous tetrahydrofuran, mixed with 0.7 ml of triethylamine (5 mmol) and 0.4 ml of methanesulfonic acid chloride (5 mmol) and stirred for 30 minutes at room temperature. Ice is added to the mixture, it is made alkaline with conc. ammonia and shaken out with ethyl acetate. The residue is chromatographed on silica gel with dichloromethane/methanol, yield 99 mg (50% of theory).
Analogously, there are produced:
1,1-Diethyl-3-(13-isopropenyl-2-methyl-6-propyl-8alpha-ergolinyl)-urea, yield 34%.
2~9~-6-3-(2-bromo-13-isopropenyl-6-propyl-8alpha~ergolinyl)-1,1-diethylurea, yield 45%.
Example 13 l l-Diethvl-3-t2,6-dimethyl-13-isopropyl-8alpha-erqolinyl~ -urea 1,1-Diethyl-3- L 13-(1-hydroxy-1-methyl-1-ethyl)-2,6-dimethyl-8alpha-ergolinyl]-urea (0.5 mmol) is dissolved in 5 ml of glacial acetic acid and 0.25 g of sodium borohydride is added. ~fter 15 minutes of stirring at room temperature, ice is added, it is made alkaline with conc. ammonia and extracted with ethyl acetate.
The organic phases are dried with sodium sulfate and concantrated by evaporation, the residue is chromatographed on silica gel with dichloromethane/methanol, yield 76 mg (38% of theory).
Analogously, there are produced:
1,1-Diethyl-3-(13-isopropyl-2-methyl-6-propyl-8alpha-ergolinyl)-urea, yield 47%.
3-(2-chloro-13-isopropyl-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 33%.
Example 14 3-(2-Bromo-13-chloro-6-methyl-8alpha-ergolinvl)-1,1-diethylurea 2.1 g of 3-(2-bromo-6-methyl-8alpha-ergolinyl)-1,1-diethylurea (5 mmol) and 388 mg of trichloroisocyanuric acid (1.67 mmol) are dissolved in 100 ml of trifluoroacetic acid at 2~
2~9~1~
room temperature. After lS minutes, ice is added, it is made alkaline with conc. ammonia and shaken out with dichloromethane.
The organic phases are dried and concentrated by evaporation, the residue is chromatographed and the product crystallizes from ethyl acetate/ether, yield 480 mg (21% of theory).
Analogously, there are produced:
3-(2-Bromo-13-chloro-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 38%.
3-(2~13-dichloro-6-propyl-8alpha-ergolinyl)-1~1-diethylurea~
yield 33%.
3-(13-chloro-2-methyl-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 21%.
3-(13-chloro-2,6-dimethyl-8alpha-ergolinyl)-1,1-diethylurea, yield 28%.
3-(13-chloro-2-ethyl-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 41%.
Example 15 3-t2-Bromo-13-iodo-6-methyl-8alpha-erqolinvl)-1,1-diethylurea 42 mg of 3-(2-bromo-6-methyl-8alpha-ergolinyl)-1,1-diethylurea (0.1 mmol) is dissolved in 2 ml of trifluoroacetic acid and mixed with 22 mg of N-iodosuccinimide (0.1 mmol). After 15 minutes of stirring at room temperature, ice is added, it is made alkaline with ammonia, and shaken out with dichloromethane.
The organic phases are dried and concentrated by evaporation, the 2 ~ 6 residue is chromatographed. The pure substance crystallizes from dichloromethane, yield 9 mg (16% of theory).
Analogously, there are produced:
3-(2-Bromo-13-iodo-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 25%.
1,1-diethyl-3-(2,6-dimethyl-13-iodo-8alpha-ergolinyl)-urea, yield 17%.
1,1-diethyl-3-(13-iodo-2-methyl-6-propyl-8alpna-ergolinyl)-urea, yield 29%.
.
Example 16 1 1-Diethyl-3-(2 6-dimethyl-13-methylthio-8alpha-erqolinyl)-urea 3.54 g of 1,1-diethyl-3-(2,6-dimethyl-8alpha-ergolinyl)-urea (10 mmol) is dissolved in 200 ml of trifluoroacetic acid and mixed at intervals of 15 minutes in three portions each with 0.98 g of dimethyl-methylthio-sulfonium-tetrafluoroborate (15 mmol) at room temperature. After 15 minutes, the mixture is poured on ice, made alkaline with ammonia and shaken out with dichloromethane. The organic phases are dried with sodium sulfate and concentrated by evaporation, the residue is chromatographed on silica gel with dichloromethane/methanol/
hexane. The substance is crystallized from ethyl acetate/hexane, yield 138 mg (4% of theory).
2~
~0~9~:~6 Analogously, there is produced:
1,1-Diethyl-3-t2-methyl-13-methylthio-6-propyl-8alpha-ergolinyl)-urea, yield 13%.
Example 17 l.l-Diethyl-3-(2 6.13-trimethyl-8alpha-ergolinyl)-thiourea 0.5 Ml of freshly distilled phosphorus oxychloride (5.6 mmol) and 368 mg of 1,1-diethyl-3-(2,6-13-trimethyl-8alpha-ergolinyl)-urea (1 mmol) are dissolved in 20 ml of dichloromethane at -20C and the mixture is allowed to stir overnight at room temperature. The volatile portions are now drawn off in a vacuum, the residue is dissolved in 40 ml of acetonitrile and mixed with a solution of 0.8 g of potassium xanthate (5.6 mmol) in 80 ml of acetonitrile. It is stirred for 2 hours at room temperature, then ice and conc. ammonia solution are added and shaken out with dichloromethane. The organic phases are dried with sodium sulfate and concentrated by evaporation, the residue is chromatographed on silica gel with ethyl acetate and crystallized from ethyl acetate/diisopropyl ether, yield 43%.
Analogously, the following thioureas are produced by thiolation of the ureas:
1,1-Diethyl-3-(2,13-dimethyl-6-propyl-8alpha-ergolinyl)-thiourea, yield 42%.
1,1-diethyl-3-(13-ethyl-2-methyl-6-propyl-8alpha-ergolinyl)-thiourea, yield 56%.
2~9~16 3-~l3-chloro-2-methyl-6-propyl-8alpha~er~olinyl)~
diethyl-thiourea, yield 37%.
1,1-diethyl-3-(2-ethyl-13-methyl-6-propyl-8alpha-ergolinyl)-thiourea.
3-(2-bromo-6,13-dimethyl-8alpha-ergolinyl)-1,1-diethyl-thiourea, yield 61%.
3-(2-bromo-13-methyl-6-propyl-8alpha-ergolinyl)-1,1-diethyl-thiourea, yield 34~.
3-~2-bromo-13-iodo-6-propyl-8alpha-ergolinyl)-1,1-diethyl-thiourea, yield 23%.
3-(2-bromo-13-chloro-6-propyl-8alpha-ergolinyl)-1,1-diethyl-thiourea, yield 59%.
3-(2-chloro-13-methyl-6-propyl-8alpha-ergolinyl)-diethyl-thiourea, yield 65%.
3-(2,13-dichloro-6-propyl-8alpha-ergolinyl)-1,1-diethyl-thiourea, yield 42%.
1,1-diethyl-3-(13-methyl-2-methylthio~6-propyl-8alpha-ergolinyl)-thiourea, yield 34%.
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~ 0 ~ 6 Since the compounds according to the invention are distinguished in particular by dopaminergie acJonistie aetion, they are suitable in particular for treatment of Parkinson's disease.
To use the compounds according to the invention as pharmaeeutieal agents, the eompounds are brought into the form o~
a pharmaeeutieal preparation, whieh, in addition to the aetive ingredient for enteral or parenteral administration, eontains suitable pharmaeeutical, organic or inorganic inert vehieles, such as, for example, water, gelatin, gum arabic, laetose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glyeols, ete. The pharmaceutical preparations ean be present in solid form, for example, as tablets, coated tablets, suppositories, capsules, or in liquid form, for example, as solutions, suspensions or emulsions. Optionally, they also eontain auxiliary agents, such as preservatives, stabilizers, wetting agents or emulsifiers, salts to change the osmotic pressure or buffers.
The eompounds according to the invention are introdueed in a dose of 0.001 to 10 mg of active substance in a physiologieally eompatible vehicle. The use of the compounds aecording to the invention takes place in a dose of 0.00001 to 0.1 mg/kg/day, preferably 0.001 to 0.1 mg/kg/day analogously to the known agent bromoeryptine.
2 ~ 6 The production of the compounds of formula I according to the invention can also be performed according to methods known in the art.
For example, compounds of formula I are attained, by a) compounds of formula II
CX N(c2H5)2 in which R2, R6 and X have the above-named meaning, being reacted in the presence of an acid with an electrophilic agent or b) compounds of formula III
NH-CX-NIC H I
R //\ /~ /
` / \ ~ III
H-N R
in which R-, R13 and X have the above-named meaning, being alkylated or alkenylated to compounds with R6 in the above-named meaning and then optionally 2~9~ ~
alpha) compounds with Rl3 = -co-R3 with R3 in the above-named meaning being redueed to compounds with Rl3 = -C~SOH and the latter optionally being dehydrated to eompounds with Rl3 = C2_6alkenyl or redueed to eompounds with Rl3 = Cl_6alkyl or beta) eompounds with Rl3 = 1,3-dithiolan-2-yl being eonverted to compounds with Rl3 = -CHO or CH3 or gamma) urea being converted to thiourea or delta) the isomers being separated or the acid addition salts being formed.
The eleetrophilie substitution in 13-posi~ion aeeording to proeess a) is performed in the presenee of an aeid at temperatures of 0C to 20C and is generally eompleted after l to 24 hours.
Inorganic aeids, such as phosphorie aeid, sulfurie aeid, organie aeids, sueh as trifluoroacetic aeid, methanesulfonie aeid, aeetic acid, and Lewis aeids, sueh as aluminum ehloride, titanium chloride, dimethylaluminum chloride, tin(IV) chloride, boron fluoride, i.a., can be used as acids, and the organic aeid ean be used as solvent or inert aprotic solvents, sueh as ehlorinated hydroearbons, such as dichloromethane, ehloroform, tetraehloroethane or nitrobenzene, are added.
Suitable eleetrophiles are, for example: acyl ehlorides, sueh as aeetyl ehloride, propionyl chloride; halogenation agents, sueh as N-ehlorosuccinimide, N-iodosuccinimide, triehloroisoeyanurie acid; dimethyl-methylthio-sulfonium tetrafluoroborate; dichloromethyl alkyl ether; chloroformie aeid 2 ~
alkyl ester; formie acid alkyl ester and ethanedithiol or dithiolane, i.a.
The substitution in 6-position according to process b) ean be performed, for exa~ple, according to A. Cerny et al. C'oll.
Czech. Chem. Comm. 49, 2828 (198~) or according to the process described in EP-21206, by the 6-H compound of formula II being reaeted with the eorresponding R6 halides (bromides, chlorides, iodides). The reaetion suitably takes place in an inert solvent such as ethanol, dimethylformamide, acetonitrile or nitromethane in the presence of bases such as DBU, alkali hydroxides~or alkali carbonates.
Compounds of formula I with Rl3 meaning a -CoR3 group can be reduced to alcohol aeeording to the usual processes, such as, for example, with lithium aluminum hydride or lithium tri-tert-butoxyalanate in an aprotie solvent, sueh as eyelie or acyelie ethers, for example, tetrahydrofuran, dioxane, diethyl ether.
l-Hydroxy-alkylated substituents Rl3 can also be produced by Grignardation or lithium alkylation. The Grignardation ean take place with the usual Grignard reagents, such as alkyl magnesium halides in an aprotie solvent, such as cyclic and aeyelie ethers at temperatures of -70C to 20C. The reaetion with alkyl lithium takes plaee under analogous eonditions.
The subsequent dehydration for the double bond ean be performed in the usual way, sueh as, for example, with sulfonates or aeetates in polar solvents, such as ethers in the presence of a base and optionally with heating.
' C 2 ~ 6 The reduction of the alcohols to 13-alkyl derivatives can take place, for example, by reaction with NaBH4 in acetic acid or by reduction with lithium in ammonia.
To introduce the 13-CH3 group, it: can be advantageous, before the reduction of the 13-CH2-OH radical, to este~ify this radical with acids, such as pivalic acid, acetic acid, benzoic acid and then to reduce it according to the known processes as described in German patent application P 4020341.7.
If Rl3 means a dithiolane radical, it can be converted to the 13-formyl derivative, for example, by aqueous SiO2 treatment and subsequent reaction with sulfuryl chloride in aprotic solvents, such as chlorinated hydrocarbons. The 13-methyl derivative can be produced by reaction with Raney nickel at room temperature in protic solvents such as alcohols.
The conversion of the urea derivatives to the thioureas can take ~lace, for example, according to the process described in EP-A-217730 by reaction with phosphorus oxychloride and a thiolation agent.
The mixture of isomers can be separated according to the usual methods, such as, for example, crystallization, chromatography or salt formation in the diastereomers or E/Z
isomers.
The compounds of formula I are isolated either as free bases or in the form of their physioloyically compatible acid addition salts.
2D49~ 6 For the formation of salts, a compound of formula I is dissolved, for exa~ple, in a little alcohol or methylene chloride and mixed with a concentrated solution of the desired acid.
The introduction of the substituents in 6-position can take place before or after substitution in 13-position. The invention also comprises the compounds of formu:La IV, which represent valuable intermediate products for the production of pharmacologically effective compounds. The reduction of 6-cyano-ergoline to the 6-H compound takes place, for example, according to A. Cerny et al. Coll. Czech. Chem. Comm. 49, 2828 (1984). The conversion of the intermediate products to the active substance takes place according to the method described in process variant b).
In so far as the production of the initial compounds is not described, these compounds are known or can be produced analogously to known compounds or to the processes described here.
The following examples are to explain the process according to the invention.
12 2~
Example 1 1 1-Diethyl-3-[13-(1 3-dithiolan-2-yl)-2,6-dimethyl-8alPha-erqolinyl1-urea 5.31 g of 1,1-diethyl-3-(2,6-dimethyl-8alpha-ergolinyl)-urea (15 mmol) is dissolved in 150 ml of chloroform and 50 ml of formic acid ethyl ester, 2.8 ml of ethanedithiol (33 mmol) and 60 ml of a 1 molar solution of titanium tetrachloride in dichloromethane ~60 mmol) are added and stirred for 20 hours at room temperature. Then, it is mixed with 40 ml of methanol and 300 ml of water, made alkaline with 30 ml of 25% ammonia solution and shaken out with dichloromethane. The organic phases are dried with sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel with dichloromethane/methanol. 4~14 g of substance, which crystallizes from ethyl acetate, is isolated, [C~ ]D = ~4 (0 5%
in chloroform).
Analogously, there are produced:
1,1-Diethyl-3-[13-(1,3-dithiolan-2-yl)-2-methyl-6-propyl-8alpha-ergolinyl]-urea from 1,1-diethyl-3-(2-methyl-6-propyl-8alpha-ergolinyl)-urea, in 38% yield.
1,1-diethyl-3-[13-(1,3-dithiolan-2-yl)-2-ethyl-6-propyl-8alpha-ergolinyl]-urea from 1,1-diethyl-3-(2-ethyl-6-propyl-8alpha-ergolinyl)-urea, in 28% yield.
20~ 9~ ~
Example 2 8alpha-f3 3-DiethYlureido)-2 6-dimethyl-erqoline-13-carbaldehyde 3.26 g of 1,1-diethyl-3-[13-(1,3-dithiolan-2-yl)-2,6-dimethyl-8alpha-ergolinyl]-urea ~7.1 mmol) is dissolved in 35 ml of chloroform and mixed with 5.3 g of silica gel and 5.7 ml of water. Then, the solution of 1.37 ml of sulfuryl chloride (17 mmol) is instilled in 35 ml of chloroform within 10 minutes and stirred for 1 hour at room temperature. After adding 8.5 g of potassium carbonate, it is stirred for 15 minutes, some ethanol and saturated common salt solution are added and shaken out with dichloromethane. The organic phases are dried and concentrated by evaporation, the residue is chromatographed on silica gel with ethyl acetate/methanol, yield 1.45 g. This substance is crystallized from ethyl acetate/diisopropyl ether, yield 1.09 g (40% of theory), [ C~]D = -9 (0.5% in chloroform).
Analogously, there are produced:
8alpha-(3,3-Diethylureido)-2-methyl-6-propyl-ergoline-13-carbaldehyde from 1,1-diethyl-3-[13-(1,3-dithiolan-2-yl)-2-methyl-6-propyl-8alpha-ergolinyl]-urea, yield 51%.
8alpha-(3,3-diethylureido)-2-ethyl-6-propyl-ergoline-13-carbaldehyde from l,1-diethyl-3-[13-(1,3-dithiolan-2-yl)-2-ethyl-6-propyl-8alpha-ergolinyl]-urea, in 62% yield.
2~9~ ~ ~
Example 3 2-Bromo-8alpha-(3 3-diethylureido)-6-methYl-ergoline-13-carbaldehyde 838 mg of 3-(2-bromo-6-methyl-8alpha-ergolinyl)-1,1-diethylurea (2 mmol) is dissolved in 100 ml of dichloromethane, 1.2 g of anhydrous aluminum chloride (9 mmol) and 1.8 ml of dichloromethyl methyl ether (20 mmol) are added and stirred for 15 minutes at room temperature. The reaction mixture is mixed with ice and, after 15 minutes, with a solution of 1.5 g of tartaric acid in 50 ml of water and made alkaline with 5 ml of conc. ammonia solution. It is extracted with dichloromethane, the organic phases are dried with sodium sulfate and the solvent is distilled off. The residue is chromatographed on silica gel with dichloromethane/methanol, 406 mg (45% of theory) is isolated.
Analogously, there are produced:
2-Bromo-8alpha-(3,3-diethylureido)-6-propyl-ergoline-13-carbaldehyde from 3-(2-bromo-6-propyl-8alpha-ergolinyl)-l,1-diethylurea, yield 27%.
2-chloro-8alpha-(3,3-diethylureido)-6-methyl-ergoline-13-carbaldehyde from 3-(2-chloro-6-methyl-8alpha-ergolinyl)-1,1-diethylurea, in 37% yield.
2-chloro-8alpha-(3,3-diethylureido)-6-propyl-ergoline-13-carbaldehyde from 3-(2-chloro-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, in 32% yield.
2 ~
8alpha-(3,3-diethylureido)-2-methylthio-6-propyl-ergoline-13-carbaldehyde from 1,1-diethyl-3-(2-methylthio-6-propyl-8alpha-ergolinyl)-urea, in 42% yield.
Ex~mple 4 1 1-Diethyl-3-(2 6-dimethyl-13-hydroxymethyl-8alpha-erqolinvl)-urea 370 mg of 8alpha-(3,3-diethylureido)-2,6-dimethyl-ergoline-13-carbaldehyde (1 mmol) is disso~ved in 50 ml oE tetrahydrofuran and reduced with 200 mg of lithium aluminum hydride at room temperature for 1 hour. The mixture is cooled off in an ice bath and mixed in succession with 0.2 ml of water, 0.2 ml of 15%
sodium hydroxide solution and 0.6 ml of water, the precipitate is filtered off and the filtrate is evaporated to dryness. The residue is chromatographed on silica gel with dichloromethane/methanol. 243 mg of alcohol, which crystallizes from ethyl acetate, is isolated. Yield 166 mg (44~ of theory), [ C~]D = +6 (0.5% in chloroform).
Analogously, there are produced from the respective aldehydes:
1,1-Diethyl-3-(13-hydroxymethyl-2-methyl-6-propyl-8alpha-ergolinyl)-urea, yield 73%.
1,1-diethyl-3-(2-ethyl-13-hydroxymethyl-6-propyl-8alpha-ergolinyl)-urea, yield 43%.
3-(2-bromo-13-hydroxymethyl-6-methyl-8alpha-ergolinyl)-1,1-diethylurea, yield 51%.
20~9~
3-(2-bromo-13-hydroxymethyl-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 62%.
3-(2-chloro-13-hydroxymethyl-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 42%.
1,1-diethyl-3-(13-hydroxymethyl-2-methylthio-6-propyl-8alpha-ergolinyl)-urea, yield 34%.
Example 5 1 1-Diethyl-3-(2 6,13-trimethyl-8al~ha-erqolinyl)-urea 458 mg of 1,1-diethyl-3-[13-(1,3-dithiolan-2-yl)-2;6-dimethyl-8alpha-ergolinyl)-urea (1 mmol) is dissolved in 50 ml o~
methanol and treated with several portions of Raney nickel at room temperature until the initial material has disappeared according to thin-layer chromatography. It is filtered by kieselguhr, the solvent is concentrated by evaporation and the residue is chromatographed on silica gel with dichloromethane/methanol, the isolated substance is crystallized from methanol, yield 117 mg (31% of theory)~
Example 6 1 1-Diethyl-3-(2 6 13-trimethyl-8alpha-erqolinvl)-urea 715 mg of 1,1-diethyl-3-(2,6-dimethyl-13-hydroxymethyl-8alpha-ergolinyl)-urea (1.5 mmol) is dissolved in 10 ml of pyridine and mixed with 2 ml of trimethylacetyl chloride. Ice is added after 30 minutes of stirring at room temperature, it is 2 0 ~
stirred for another 30 minutes, made alkaline with ammonia and the mixture is cooled in an ice bath. The precipitated crystals are suctioned off, yield 785 m~, t ~ ]D = -2 (0-5% in chloroform). The mother liquor is extracted with dichloromethane, dried and concentrated by evaporation. Both fractions are dissolved together in 6 ml of tetrahydrofuran and the solution is instilled in 50 ml of condensed, anhydrous ammonia. Then, it is mixed with 160 mg of lithium and the blue solution is stirred for 30 minutes at -40C. Solid ammonium chloride, until decolorization, and 5 ml water are added in succession, the ammonia is evaporated and it is diluted with 80 ml of water. After 30 minutes of stirring in an ice bath, the precipitated crystals are suctioned off and dried in a vacuum, yield 643 mg (94% of theory), [C~ ]D = ~3 (0.5% in chloroform).
From the respective alcohol, there are analogously produced:
1,1-Diethyl-3-(2,13-dimethyl-6-propyl-8alpha-ergolinyl)-urea, yield 76%.
1,1-diethyl-3-(2-ethyl-13-methyl-6-propyl-8alpha-ergolinyl)-urea, yield 81%.
Example 7 3-(13-Acetyl-2 6-dimethyl-8alpha-ergolinyl~-1 1-diethylurea 2.4 g of anhydrous aluminum chloride and 1.3 ml of acetyl chloride are dissolved in 70 ml of dichloromethane and stirred for 15 minutes at room temperature. 708 mg of 1,1-diethyl-3-(2,6-dimethyl-8alpha-ergolinyl)-urea (2 mmol) dissolved in 30 ml ~9~
of dichloromethane is aclded to it, and stir~ed for 30 minutes at room temperature. Ice is added and after 15 minutes of stirring, a solution of 2.8 g of -tartaric acid in 80 ml of water is added.
After another lS minutes, it is made alkaline with conc. ammonia, the organic phase is separated and the water phase is extracted.
All organic phases are dried with sodium sulfate and concentrated by evaporation, the residue is chromatographed on silica gel with dichloromethane/methanol~ yield 454 mg.
Analogously, there are produced:
3-(13-Acetyl-2-methyl-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 61~.
3-(13-acetyl-2-ethyl-6-methyl-8alpha-ergolinyl3-1,1-diethylurea, yield 38%.
3-(13-acetyl-2-ethyl-6-propyl-8alpha-ergolinyl)~l,1-diethylurea, yield 58%.
3-(13-acetyl-2-bromo-6-methyl-8alpha-ergolinyl)-1,1-diethylurea, yield 67%.
3-(13-acetyl-2-bromo-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 47%.
3-(13-acetyl-2-chloro-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 71%.
3-(13-acetyl-6-methyl-2-methylthio-8alpha-ergolinyl)-1,1-diethylurea, yield 44~, ~ ~ ]D = +7 (0.5% in chloroform).
2~9~
Example 8 1 1-Diethyl-3-[2,6-dimethyl-13-(1-hydroxyethyl)-8alpha-erqolinyl]-urea 406 mg of 3-(13-acetyl-2,6-dimethyl-8alpha-ergoliny;)-1,1-diethylurea (1 mmol) is reduced in 50 ml of tetrahydrofuran with 200 mg of lithium aluminum hydride as described in example 4, worked up and crystallized from ethyl acetate, yield 216 mg (53%
of theory), ~ ~ JD = ~12 (0.1% in pyridine).
Analogously, the following alcohols are produced:
1,1-Diethyl-3-[13-(1-hydroxyethyl)-2-methyl-6-propyl-8alpha-ergolinyl]-urea, yield 75%.
1,1-diethyl-3-~2-ethyl-13-(1-hydroxyethyl)-6-propyl-8alpha-ergolinyl]-urea, yield 57%.
1,1-diethyl-3-t2-ethyl-13-(1-hydroxyethyl)-6-methyl-8alpha-ergolinyl]-urea, yield 43%.
3-[2-bromo-13-(1-hydroxyethyl)-6-methyl-8alpha-ergolinyl]-1,1-diethylurea, yield 51%.
3-[2-bromo-13-(1-hydroxyethyl)-6-propyl-8alpha-ergolinyl]-1,1-diethylurea, yield 61%.
3-[2-chloro-13-(1-hydroxyethyl)-6-propyl-8alpha-ergolinyl]-l,l-diethylurea, yield 47%.
1,1-diethyl-3-[13-(1-hydroxyethyl)-6-methyl-2-methylthio-8alpha-ergolinyl]-urea, yield 63~.
2 ~ 6 - -Example 9 1,1-Diethyl-3-(13-ethyl-2 6-dimethyl-8alpha-er~olinyl)-urea 280 mg of 1,1-diethyl-3-[2,6-dimethyl-13-tl-hydroxyethyl)-8alpha-ergolinyl)-urea (0.7 mmol) is dissolved in 14 ml of acetic acid and stirred with 700 mg of sodium borohydride (tablets) for 15 minutes at room temperature. Then, ice is added, it is stirred for another 15 minutes and made alkaline with conc.
ammonia. The suostance is extracted with dichloromethane, the organic phases are dried and concentrated by evaporation, the residue is chromatographed on silica gel with dichloromethane/methanol. The isolated substance is crystallized from ethyl acetate/hexane. Yield 176 mg (65% of theory), [~ ]D = ~5 (0.5% in chloroform~. -Analogously, the corresponding alcohols are reduced:
1,1-Diethyl-3-(13-ethyl-2-methyl-6-propyl-8alpha-ergolinyl)-urea, yield 73% of theory.
1,1-diethyl-3-(2,13-diethyl-6-methyl-8alpha-ergolinyl)-urea, yield 64% of theory.
1,1-diethyl-3-t2,13-diethyl-6-propyl-8alpha-ergolinyl)-urea, yield 47% of theory.
3-(2-bromo-13-ethyl-6-methyl-8alpha-ergolinyl)-1,1-diethylurea, yield 28%.
3-(2-bromo-13-ethyl-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 23%.
3-(2-chloro-13-ethyl-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 44%.
2~9~ 6 -- -l,1-diethyl-3-(13-ethyl-2-methylthio-6-propyl-8alpha-ergolinyl)-urea, yield 33%.
Example lO
3-r2-Bromo-6ll3-dimethyl-8alpha--erqolinyl)-l l-diethylurea From 3-(2-bromo-13-hydroxymethyl-6-methyl-8alpha-ergolinyl)-l,l-diethylurea by reduction as described in example 9, yield 43%.
Analogously, there are synthesized:
3-(2-Bromo-13-methyl-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 24%.
3-(2-chloro-13-methyl-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 45%.
l,1-diethyl-3-(13-methyl-2-methylthio-6-propyl-8alpha-ergolinyl)-urea, yield 37%.
Example 11 l.l-Diethyl-3- r 13-(1-hydroxy-1-methyl-ethyl~-2-6-dimethYl-8alpha-erqolinyl)-urea 396 mg of 3-(13-acetyl-2,6-dimethyl-8alpha-ergolinyl)-1,1-diethylurea (l mmol) is dissolved in 30 ml or dry tetrahydrofuran and the solution is cooled to -65C. 0.8 ml of a 1.6 molar solution of methyllithium in ether is added (1.3 mmol), then the solution is allowed to warm to room temperature and is stirred for another 30 minutes. It is poured on ice, made alkaline with conc. ammonia solution and extracted with ethyl acetate. The 2 ~
organic phases are dried and evaporated, the residue is chromatographed on silica gel with dichloromethane/methanol, yield 285 mg (67% of theory).
Analogously, there are produced from the 13-ace~yl compounds:
1,1-Diethyl-3-[13-(1-hydroxy-1-methyl-ethyl)-2-methyl-6-propyl-8alpha-ergolinyl]-1,1-urea, yield 54%.
3-[2-bromo-13-(1-hydroxy-1-methyl-ethyl)-6-propyl-8alpha-ergolinyl]-l,l-diethylurea, yield 73%.
3-[2-chloro-13-(1-hydroxy-1-methyl-ethyl)-6-propyl-8a]pha-ergolinyl)-l,l-diethylurea, yield 67%.
Example 12 1,1-Diethyl-3t2 6-dimethYl-13-isopropenYl-8alpha-ergolinyl) urea 208 mg of 1,1-diethyl-3-[13-(1-hydroxy-1-methyl-ethyl)-2,6-dimethyl-8alpha-ergolinyl]-urea (0.5 mmol) is dissolved in 20 ml of anhydrous tetrahydrofuran, mixed with 0.7 ml of triethylamine (5 mmol) and 0.4 ml of methanesulfonic acid chloride (5 mmol) and stirred for 30 minutes at room temperature. Ice is added to the mixture, it is made alkaline with conc. ammonia and shaken out with ethyl acetate. The residue is chromatographed on silica gel with dichloromethane/methanol, yield 99 mg (50% of theory).
Analogously, there are produced:
1,1-Diethyl-3-(13-isopropenyl-2-methyl-6-propyl-8alpha-ergolinyl)-urea, yield 34%.
2~9~-6-3-(2-bromo-13-isopropenyl-6-propyl-8alpha~ergolinyl)-1,1-diethylurea, yield 45%.
Example 13 l l-Diethvl-3-t2,6-dimethyl-13-isopropyl-8alpha-erqolinyl~ -urea 1,1-Diethyl-3- L 13-(1-hydroxy-1-methyl-1-ethyl)-2,6-dimethyl-8alpha-ergolinyl]-urea (0.5 mmol) is dissolved in 5 ml of glacial acetic acid and 0.25 g of sodium borohydride is added. ~fter 15 minutes of stirring at room temperature, ice is added, it is made alkaline with conc. ammonia and extracted with ethyl acetate.
The organic phases are dried with sodium sulfate and concantrated by evaporation, the residue is chromatographed on silica gel with dichloromethane/methanol, yield 76 mg (38% of theory).
Analogously, there are produced:
1,1-Diethyl-3-(13-isopropyl-2-methyl-6-propyl-8alpha-ergolinyl)-urea, yield 47%.
3-(2-chloro-13-isopropyl-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 33%.
Example 14 3-(2-Bromo-13-chloro-6-methyl-8alpha-ergolinvl)-1,1-diethylurea 2.1 g of 3-(2-bromo-6-methyl-8alpha-ergolinyl)-1,1-diethylurea (5 mmol) and 388 mg of trichloroisocyanuric acid (1.67 mmol) are dissolved in 100 ml of trifluoroacetic acid at 2~
2~9~1~
room temperature. After lS minutes, ice is added, it is made alkaline with conc. ammonia and shaken out with dichloromethane.
The organic phases are dried and concentrated by evaporation, the residue is chromatographed and the product crystallizes from ethyl acetate/ether, yield 480 mg (21% of theory).
Analogously, there are produced:
3-(2-Bromo-13-chloro-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 38%.
3-(2~13-dichloro-6-propyl-8alpha-ergolinyl)-1~1-diethylurea~
yield 33%.
3-(13-chloro-2-methyl-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 21%.
3-(13-chloro-2,6-dimethyl-8alpha-ergolinyl)-1,1-diethylurea, yield 28%.
3-(13-chloro-2-ethyl-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 41%.
Example 15 3-t2-Bromo-13-iodo-6-methyl-8alpha-erqolinvl)-1,1-diethylurea 42 mg of 3-(2-bromo-6-methyl-8alpha-ergolinyl)-1,1-diethylurea (0.1 mmol) is dissolved in 2 ml of trifluoroacetic acid and mixed with 22 mg of N-iodosuccinimide (0.1 mmol). After 15 minutes of stirring at room temperature, ice is added, it is made alkaline with ammonia, and shaken out with dichloromethane.
The organic phases are dried and concentrated by evaporation, the 2 ~ 6 residue is chromatographed. The pure substance crystallizes from dichloromethane, yield 9 mg (16% of theory).
Analogously, there are produced:
3-(2-Bromo-13-iodo-6-propyl-8alpha-ergolinyl)-1,1-diethylurea, yield 25%.
1,1-diethyl-3-(2,6-dimethyl-13-iodo-8alpha-ergolinyl)-urea, yield 17%.
1,1-diethyl-3-(13-iodo-2-methyl-6-propyl-8alpna-ergolinyl)-urea, yield 29%.
.
Example 16 1 1-Diethyl-3-(2 6-dimethyl-13-methylthio-8alpha-erqolinyl)-urea 3.54 g of 1,1-diethyl-3-(2,6-dimethyl-8alpha-ergolinyl)-urea (10 mmol) is dissolved in 200 ml of trifluoroacetic acid and mixed at intervals of 15 minutes in three portions each with 0.98 g of dimethyl-methylthio-sulfonium-tetrafluoroborate (15 mmol) at room temperature. After 15 minutes, the mixture is poured on ice, made alkaline with ammonia and shaken out with dichloromethane. The organic phases are dried with sodium sulfate and concentrated by evaporation, the residue is chromatographed on silica gel with dichloromethane/methanol/
hexane. The substance is crystallized from ethyl acetate/hexane, yield 138 mg (4% of theory).
2~
~0~9~:~6 Analogously, there is produced:
1,1-Diethyl-3-t2-methyl-13-methylthio-6-propyl-8alpha-ergolinyl)-urea, yield 13%.
Example 17 l.l-Diethyl-3-(2 6.13-trimethyl-8alpha-ergolinyl)-thiourea 0.5 Ml of freshly distilled phosphorus oxychloride (5.6 mmol) and 368 mg of 1,1-diethyl-3-(2,6-13-trimethyl-8alpha-ergolinyl)-urea (1 mmol) are dissolved in 20 ml of dichloromethane at -20C and the mixture is allowed to stir overnight at room temperature. The volatile portions are now drawn off in a vacuum, the residue is dissolved in 40 ml of acetonitrile and mixed with a solution of 0.8 g of potassium xanthate (5.6 mmol) in 80 ml of acetonitrile. It is stirred for 2 hours at room temperature, then ice and conc. ammonia solution are added and shaken out with dichloromethane. The organic phases are dried with sodium sulfate and concentrated by evaporation, the residue is chromatographed on silica gel with ethyl acetate and crystallized from ethyl acetate/diisopropyl ether, yield 43%.
Analogously, the following thioureas are produced by thiolation of the ureas:
1,1-Diethyl-3-(2,13-dimethyl-6-propyl-8alpha-ergolinyl)-thiourea, yield 42%.
1,1-diethyl-3-(13-ethyl-2-methyl-6-propyl-8alpha-ergolinyl)-thiourea, yield 56%.
2~9~16 3-~l3-chloro-2-methyl-6-propyl-8alpha~er~olinyl)~
diethyl-thiourea, yield 37%.
1,1-diethyl-3-(2-ethyl-13-methyl-6-propyl-8alpha-ergolinyl)-thiourea.
3-(2-bromo-6,13-dimethyl-8alpha-ergolinyl)-1,1-diethyl-thiourea, yield 61%.
3-(2-bromo-13-methyl-6-propyl-8alpha-ergolinyl)-1,1-diethyl-thiourea, yield 34~.
3-~2-bromo-13-iodo-6-propyl-8alpha-ergolinyl)-1,1-diethyl-thiourea, yield 23%.
3-(2-bromo-13-chloro-6-propyl-8alpha-ergolinyl)-1,1-diethyl-thiourea, yield 59%.
3-(2-chloro-13-methyl-6-propyl-8alpha-ergolinyl)-diethyl-thiourea, yield 65%.
3-(2,13-dichloro-6-propyl-8alpha-ergolinyl)-1,1-diethyl-thiourea, yield 42%.
1,1-diethyl-3-(13-methyl-2-methylthio~6-propyl-8alpha-ergolinyl)-thiourea, yield 34%.
Claims (5)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Compounds of formula I and their acid addition salts I
in which R2 is halogen, C1-6alkyl or -S-C1-4alkyl, R6 is C1-6alkyl, C3-6alkenyl or C3-5cycloalkyl-C1-2alkyl, X is oxygen or sulfur, R13 is chlorine, iodine, -S-C1-4alkyl, C1-6alkyl, C2-6alkenyl, 1,3-dithiolan-2-yl, -Co-R3 or -CR4R5OH and R3, R4 and R5 each mean hydrogen or C1-5alkyl.
in which R2 is halogen, C1-6alkyl or -S-C1-4alkyl, R6 is C1-6alkyl, C3-6alkenyl or C3-5cycloalkyl-C1-2alkyl, X is oxygen or sulfur, R13 is chlorine, iodine, -S-C1-4alkyl, C1-6alkyl, C2-6alkenyl, 1,3-dithiolan-2-yl, -Co-R3 or -CR4R5OH and R3, R4 and R5 each mean hydrogen or C1-5alkyl.
2. 1,1-Diethyl-3-(2,6,13-trimethyl-8alpha-ergolinyl)-urea 1,1-diethyl-3-(2,13-dimethyl-6-propyl-8alpha-ergolinyl)-urea 1,1-diethyl-3-(13-ethyl-2,6-dimethyl-8alpha-ergolinyl)-urea 1,1-diethyl-3-(13-ethyl-2-methyl-6-propyl-8alpha-ergolinyl)-urea 1,1-diethyl-3-(2,6-dimethyl-13-isopropyl-8alpha-ergolinyl)-urea 3-(13-acetyl-2-methyl-6-propyl-8alpha-ergolinyl)-1,1-diethylurea 8alpha-(3,3-diethylureido)-2-methyl-6-propyl-ergoline-13-carbaldehyde 3-(2-bromo-13-chloro-6-methyl-8alpha-ergolinyl)-1,1-diethylurea 3-(2-bromo-13-chloro-6-propyl-8alpha-ergolinyl)-1,1-diethylurea 1,1-diethyl-3-(2,6-dimethyl-13-methylthio-8alpha-ergolinyl)-urea 1,1-diethyl-3-(2,13-dimethyl-6-propyl-8alpha-ergolinyl)-thiourea
3. Pharmaceutical agents based on compounds according to claims 1 and 2.
4. Process for the production of the compounds according to claim 1, characterized in that a) compounds of formula II
II
in which R2, R6 and X have the above-named meaning, are reacted in the presence of an acid with an electrophilic agent or b) compounds of formula III
III
in which R2, R13 and X have the above-named meaning, are alkylated or alkenylated to compounds with R6 in the above-named meaning and then optionally alpha) compounds with R13 = -CO-R3 with R3 in the above-named meaning are reduced to compounds with R13 = -CR4R5OH and the latter optionally are dehydrated to compounds with R13 = C2-6alkenyl or reduced to compounds with R13 = C1-6alkyl or beta) compounds with R13 = 1,3-dithiolan-2-yl are converted to compounds with R13 = -CHO or CH3 or gamma) urea is converted to thiourea or delta) the isomers are separated or the acid addition salts are formed.
II
in which R2, R6 and X have the above-named meaning, are reacted in the presence of an acid with an electrophilic agent or b) compounds of formula III
III
in which R2, R13 and X have the above-named meaning, are alkylated or alkenylated to compounds with R6 in the above-named meaning and then optionally alpha) compounds with R13 = -CO-R3 with R3 in the above-named meaning are reduced to compounds with R13 = -CR4R5OH and the latter optionally are dehydrated to compounds with R13 = C2-6alkenyl or reduced to compounds with R13 = C1-6alkyl or beta) compounds with R13 = 1,3-dithiolan-2-yl are converted to compounds with R13 = -CHO or CH3 or gamma) urea is converted to thiourea or delta) the isomers are separated or the acid addition salts are formed.
5. Compounds of formula IV
IV
in which R2, R13 and X have the above-named meaning.
IV
in which R2, R13 and X have the above-named meaning.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4001323A DE4001323A1 (en) | 1990-01-15 | 1990-01-15 | 2,13-DISUBSTITUTED ERGOLINE, THEIR PRODUCTION AND USE IN MEDICINAL PRODUCTS |
| DEP4001323.5 | 1990-01-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2049016A1 true CA2049016A1 (en) | 1991-07-16 |
Family
ID=6398304
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002049016A Abandoned CA2049016A1 (en) | 1990-01-15 | 1991-01-15 | 2,13-disubstituted ergolines, their production and use in pharmaceutical agents |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0463139B1 (en) |
| JP (1) | JPH04504425A (en) |
| AT (1) | ATE124945T1 (en) |
| CA (1) | CA2049016A1 (en) |
| CZ (1) | CZ279777B6 (en) |
| DE (2) | DE4001323A1 (en) |
| DK (1) | DK0463139T3 (en) |
| ES (1) | ES2076517T3 (en) |
| HU (1) | HUT58093A (en) |
| WO (1) | WO1991010663A1 (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3587860D1 (en) * | 1984-04-09 | 1994-07-28 | Schering Ag | 2-Substituted ergoline derivatives, process for their preparation and their use as medicines. |
| DE3533675A1 (en) * | 1985-09-19 | 1987-03-26 | Schering Ag | NEW 12- AND 13-BROMINE ERGOL DERIVATIVES |
| DE3533672A1 (en) * | 1985-09-19 | 1987-03-26 | Schering Ag | NEW 12- AND 13-SUBSTITUTED ERGOL DERIVATIVES |
| DE3806374A1 (en) * | 1988-02-25 | 1989-09-07 | Schering Ag | NEW ERGOLIN DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS |
-
1990
- 1990-01-15 DE DE4001323A patent/DE4001323A1/en not_active Withdrawn
-
1991
- 1991-01-15 AT AT91902179T patent/ATE124945T1/en not_active IP Right Cessation
- 1991-01-15 JP JP3502370A patent/JPH04504425A/en active Pending
- 1991-01-15 ES ES91902179T patent/ES2076517T3/en not_active Expired - Lifetime
- 1991-01-15 CA CA002049016A patent/CA2049016A1/en not_active Abandoned
- 1991-01-15 WO PCT/DE1991/000039 patent/WO1991010663A1/en active IP Right Grant
- 1991-01-15 DE DE59105961T patent/DE59105961D1/en not_active Expired - Fee Related
- 1991-01-15 CZ CS9177A patent/CZ279777B6/en unknown
- 1991-01-15 EP EP91902179A patent/EP0463139B1/en not_active Expired - Lifetime
- 1991-01-15 HU HU912908A patent/HUT58093A/en unknown
- 1991-01-15 DK DK91902179.0T patent/DK0463139T3/en active
Also Published As
| Publication number | Publication date |
|---|---|
| CS9100077A2 (en) | 1991-10-15 |
| EP0463139A1 (en) | 1992-01-02 |
| HUT58093A (en) | 1992-01-28 |
| WO1991010663A1 (en) | 1991-07-25 |
| DE4001323A1 (en) | 1991-07-18 |
| EP0463139B1 (en) | 1995-07-12 |
| JPH04504425A (en) | 1992-08-06 |
| ATE124945T1 (en) | 1995-07-15 |
| DK0463139T3 (en) | 1995-11-06 |
| CZ279777B6 (en) | 1995-06-14 |
| DE59105961D1 (en) | 1995-08-17 |
| ES2076517T3 (en) | 1995-11-01 |
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