HUT50468A - Process for producing 2-substituted ergoline derivatives - Google Patents

Abstract

2-Substituted ergolines of the formula I <IMAGE> in which C9...C10 is a single or double bond, X is oxygen or sulphur, R<2> is C1-10-alkyl, optionally halogen-substituted C2-10-alkenyl, CH2YR<3>, CR<12)<OR<4>)R<5>, CH2, CHR<9>, COR<10> or COR<12> in which Y denotes oxygen or sulphur, R<3> denotes hydrogen, C1-4-alkyl, phenyl, C2-5-acyl or phenyl-C1-4-alkyl, R<4> denotes hydrogen or C2-5-acyl, R<5> denotes hydrogen or C1-9-alkyl, R<9> denotes COCH3 or COO-C1-4-alkyl, R<10> denotes C1-4-alkyl or O-C1-4-alkyl, R<12> denotes C1-9-alkyl and R<6> is C2-10-alkyl, C3-10-alkenyl or C4-10-cycloalkylalkyl, and their acid addition salts, isomers and isomer mixtures are described, and their use as medicaments.

Description

The present invention relates to 2-substituted ergolinyl urea derivatives of the formula (I) and to pharmaceutical compositions containing them, wherein the bond between the carbon atoms 2 and 3 and the positions 9 and 10 is single or double,

X is oxygen or sulfur,

C1-6 alkyl, optionally halo-substituted C2-6 alkenyl group, CR 12 (OR 4) R 5 _f -CH 2 OH, CH2 O (Ci-C4) alkyl, CH2 O (2-5C) alkanoyl , -CH2O- (C1-C4) -alkylphenyl, -CH2S- (C1-C4) -alkyl, -C (O) r12 where **

hydrogen,

R ^{5 is C} 1 -C ⁵ alkyl and R 2 is hydrogen or C 1 -C 5 alkyl; C 2 -C 5 alkyl, C 3 -C 5 alkenyl, or C 4 -C 5 cycloalkylalkyl; and their acid addition salts and stereoisomers.

The compounds have central dopaminergic activity and are useful in the treatment of Parkinson's disease.

__ THE • · ♦ · ♦ · · • · · · · · · · · · · · . · ··; ..... ... ...... ......... * · · · «i '' '«MWsséb PATENT OFFICE DALSINAS 1 0 (533-73 5046 8-- k KOZz £ f £. l.xi R ^; -Ι.  Λ

Co 1-3> {11.

Process for the preparation of 2-substituted ergoline derivatives »JXUG-A7 - (^)

SCHER1NG AKTIENGESELLSCHAFT, \ ΈΕΗ1ιΙΝ BERGKAMEN V F (the latter in the Federal Republic of Germany)

; ΙΧτ 'π' '.

Inventors: dr.BRUMBY Thomas, wages-dr.SAUER Gerhard, Berlin dr.HEINDL Josef, Berlin dr.TURNÉÉ Jonathan, Berlin KÜHNE Gerhard, Boriin- bJ <- G dr.WECHTEL Helmut / Berlin MV $

Filed in: 1989 · Of. 30 ·

Union Priority: 1988 · Q7 · 15 * (p 38 24 661.9)

Federal Republic of Germany

The present invention relates to a process for the preparation of 2-substituted ergolinyl-kerbsmid 8-derivatives and pharmaceutical compositions containing them, and to processes for the preparation of intermediates.

2-Substituted ergoline urea Bzármazékok known from EP-A-16 O 842 and EP-A-250 557 and function relatively well, according to which apomorphine-antagonistic activity and / or <* ₂ "on the basis ^ROCE Ptor blocking effect of the described 2 -Essubstituted derivatives are mainly used as neuro-leptics · Surprisingly, it has been found that longer hydrocarbon groups can be substituted by 2-substituted ergolinyl urea

By introducing it at position 6, the dopamine antagonistic effect is shifted towards the dopamine agonist effect, and at the same time the metabolic stability of the compounds remains unchanged or is improved ·

The compounds of the invention are of formula I; wherein the bond between the carbon atoms 2 and 5 and the positions 8 and 10 is single or double, X is oxygen or sulfur,

C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl substituted with halogen;

CH ₂ IK ⁵ , CR ¹² (OR ⁴ ) R ⁵ , GH ₂ CHR ⁹ - SOR ¹⁰ or GOR ¹² , wherein

Y is oxygen, or a 'sulfur atom, a hydrogen atom, C1-4 alkyl, phenyl, C2-5 acyl, or phenyl (Cl-C4) alkyl, ^R4 is hydrogen or C2-5 acil5 9, R 1- C 9 alk alk alkyl, RHCOGH ^ or C00- (l l lalkyl, RalkO C R4 szén alkyl or O- (C 0 (412) alkyl, R 'hydrogen or C 1-9

alkyl; and

R 1 -C 2 -C 10 alkyl, C 3 -C 10 alkenyl * or C 3 -C 7 cycloalkyl (C 1 -C 3) * alkyl, including acid addition salts, isomers and mixtures thereof;

If the carbon atoms at positions 9 and 10 are connected by a single bond, the hydrogen at position 10 is ee and

The bond between the 2 and 3 carbon atoms is a single bond at the 3-position of the hydrogen atom. · The compounds of formula I may exist as E or Z isomers or, when the R group contains a chiral center, as diastereomers or as mixtures thereof.

Alkyl is in each case a linear or branched alkyl group is understood, for example ₉ Methyl ethyl, prop11-, isopropyl, - bút11-, of isobutyl, sec-bút11-, tert-butyl, pentyl, hexyl, heptyl -, octyl, nonyl, l, 2-dimethyl-heptyl «, decyl, 2,2-dimethylpropyl, _{2-t-butyl-3-methyl-butyl} and the like ·

In each case, the alkenyl group is e.g. vinyl,

Denotes 1-propenyl, 2-propenyl, 3-methyl-2-propenyl, 1-butenyl or methyl *

The alkenyl group R may be monosubstituted or monovalently substituted with halogen atoms such as fluorine, chlorine *, bromine or iodine, of which fluorine * and chlorine are preferred * • ·

Acyl groups include aliphatic carboxylic acids such as acetic acid, propionic acid, butyric acid, caproic acid, trimethylacetic acid, or the like.

When R is a cycloalkylalkyl group such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl and the like ·

The alkyl, alkenyl and cycloalkylalkyl groups preferably contain up to 4 carbon atoms C Ί P. The groups R ³ and R together do not contain more than 10, preferably up to carbon atoms.

Physiologically acceptable acid addition salts include the known inorganic and may be derived from organic acids, such as hydrochloric acid, sulfuric acid, brómhidrogénből, citric, maiéinsavból, fumaric acid or tartaric _the vból.

The compounds of formula I and their pharmaceutically acceptable acid addition salts are pharmaceutically active, in particular having a central dopaminergic action, and are therefore useful as medicaments. Because of their outstanding dopamine agonist activity, the compounds of the present invention are particularly useful in the treatment of Parkinson's disease,

The compounds of the present invention are formulated for use as a pharmaceutical in a pharmaceutical composition suitable for enteral or parenteral administration, in addition to the active ingredient, pharmaceutical, organic or inorganic inert carriers such as water, gelatin, acacia, lactose,

containing starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols and the like · The pharmaceutical compositions may be in solid form, e.g. containing preservatives, stabilizers, wetting agents or emulsifiers for controlling osmotic pressure, containing salts or buffers ·

The compounds of the present invention may be prepared by methods that are self-assayed.

a) a compound of the formula II in which the bond between the carbon atoms R 1, X and 9 and 10 is as defined above and both R * and R are a C 1-6 alkyl group or a 5-6 membered saturated carbon atom together with the nitrogen atom; to form a heterocycle which may optionally be interrupted by an oxygen atom - to the aldehyde of formula la, wherein the bond between r 1 X and the 9 and 10 carbon atoms has the meaning given above

b) a quaternary salt of the formula Ha in which formula

7 8

The bond between R, R, R and the 9 and 10 carbon atoms has the same meaning as defined above - a ve * p of formula I

is reacted with a methyl group or with a nucleophilic anion and optionally in a compound of formula I thus obtained, wherein R is CHgO-benzyl moiety, the benzyl group is cleaved and the CHgOH group thus obtained is · · · · · · · · ·. .

• · · · · ♦ · »* * * · ♦ ·· ·, ···· ►. *» <* ····· ·

- 6 if desired esterified or oxidized to the aldehyde of formula Ia »

c) a compound of formula Ia wherein R, X and the carbon at the 9 and 10 positions are as defined above

a) reacting a compound of formula I with a Wittig reagent wherein R is optionally substituted with halogen

C2-C10 alkenyl, or

O is converted to a compound of formula I wherein R 4 is CH (O H) R 6 and, if desired, is converted to a compound of formula I wherein R 2 is C 2 -C 10 alkenyl or C 2 -C 10 alkyl and finally optionally converting the resulting compound of formula Ib wherein R, X, and the bond between the 9 and 10 carbon atoms are converted into CR (OH) R 1, as described above for a (r) in R f, wherein R 1 is C 1 -C 9 alkyl and, if desired, is subsequently converted to a compound of formula I wherein R 2 is C 10 -C 10 alkenyl or C 2 -C 10 alkyl, or the hydroxy group is esterified and optionally The unsaturated compounds obtained by the processes described in points 1 to 5 are reduced to a compound of formula I p

compounds wherein R is C2-C10 alkyl

d) alkylating or alkenylating a compound of formula IV wherein R 1, X and the carbon at the 9 and 10 carbon atoms are as defined above and Z is halogen or lithium, wherein R 1 to C 10 alkyl; or C2-C10 alkenyl,

I

- Ί e) a compound of formula V wherein R, X and the bond between the 9 and 10 carbon atoms are alkylated as defined above and optionally terminated by the compounds of formula I, wherein X is oxygen to form thioureas, conversion or reduction of the 2,3-double bond or formation of acid addition salts or separation of the isomers.

The oxidation of the Mannich bases of formula II according to process a) can be carried out, for example, at 0 ° C to -40 ° C in tert-butyl hypochlorite in an inert solvent such as ethers.

As a 5- to 6-membered saturated heterocycle of the formula -NR1-8

- which may be interrupted by an oxygen atom - for example, piperidine, morpholine or pyrrolidine is suitable ·

The reaction of the compounds of formula II and Ha according to process b) may be carried out, for example, as described in EP-A-250 357.

2-position, a disubstituted amino-met with a quaternary salt of sodium borohydride in 11 compounds in polar solvents such as reduced to 2-methyl compounds, alcohols, or nnkleofil anions reacting I compounds wherein R ² CHgYR ^ or CHgCHR ^ COR ^ ⁰ formula Nucleophilic exchange occurs after quaternization of the aminomethyl group with 1-4 alkyl halides such as methyl iodide in inert solvents such as alcohols, ethers or chlorinated hydrocarbons at room temperature or elevated temperature,

«« ♦

Suitable examples include mercaptides, alcohol ethoxates and hydrocarbonyl compounds such as malonate, ethyl acetic acid and ethyl acetate.

Subsequent eventual conversion of the CHgO-benzyl group to a CHgOH group, for example, the benzyl group by sodium, lithium or liquid ammonia, may be carried out in an inert solvent such as ether.

The esterification of the hydroxyl group may in each case be carried out by conventional methods such as acid anhydrides, by reaction with the appropriate aliphatic carboxylic acids and their solvents, or by acid chlorides in the presence of organic bases.

Conversion of 2-formyl compounds of formula Ia to compounds of formula I wherein R g is C 2 -C 10 alkenyl optionally substituted with haloethane may be accomplished by a Wittig reaction, for example by reacting a compound of formula Ia with a conventional Wittig reagent, for example triphenylphosphine, tetrahalomethane, alkyl triphenylphosphonium halide or haloalkyl triphenylphosphine tetrafluoroborate, optionally after the introduction of protecting groups customary for proton donors. The Wit.tig reaction can be carried out in polar solvents such as cyclic or acyclic ethers, chlorinated hydrocarbons, dimethylformamide or dimethylsulfoxide, at temperatures between -50 ° C and the reflux temperature of the reaction mixture, with strong bases such as alkali compounds and the like may be added to the reaction mixture.

When the compounds of formula I are prepared according to process variant ao), wherein R 1 is CR 3 - (CH) r 5, the reaction can be carried out, for example, by reaction with Grignard compounds or by lithium-b-alkylation. (e.g., alkyl magnesium halides, in aprotic solvents, e.g., cyclic or alicyclic ethers, at low temperatures above 70 ° C to 0 ° C) · Alkyl lithium compounds are reacted under similar conditions · The esterification of the hydroxyl group can be carried out as described above ·

Oxidation to 2-CHO of process variant b) or to 2-CO-R 6 of process variant o)

According to the procedure of R. A. Jones et al., Synthetic Communications 16, 1799/1986, for example, in banners inert solvents at room temperature.

Subsequent possible double bond formation may be carried out according to conventional dehydration processes, for example with sulfonates or acetates such as methanesulfonic acid chloride in polar solvents such as ethers, in the presence of a base, optionally with heating.

When the R substituent contains an exocyclic double bond, it can be reduced to the corresponding alkyl derivative in the usual manner. The reduction may be effected, for example, catalytically, in the presence of palladium carbon or Raney nickel at room temperature, in an aliphatic alcohol or sodium in liquid ammonia, in an inert solvent such as cyclic or acyclic ethers, in the presence of proton-providing agents such as aliphatic alcohols.

When the R group contains two 2-hydroxy groups, for example, it can be reduced to the corresponding 2-alkyl derivative by reaction with sodium borohydride in glacial acetic acid.

Process variant (d) may be carried out, for example, as described in SP-Α-ΙβΟ 842, for example by reacting 2-lithium ergoline derivatives with an electrophile reagent or 2-haloergoline derivatives in the presence of a palladium catalyst and a base.

Process variant (e) describes the 6-alkylation of ergoline derivatives substituted at the 2-position with an R group. This synthesis, for example, by A.Cerny et al., Coll. Chech. Comm. 49, 1984, by reducing 6-cyano-ergoline to 6-H and then alkylating it with the appropriate halides, or by carrying out the reaction as described in EP-21206.

The urea derivatives can be converted to the thiourea derivatives, for example, by reaction with phosphorus oxychloride and a thiolating agent according to the process described in EP-A-217 730. The reduction of the 2,3-double bond can be carried out, for example, according to the procedure described in EP-A-286 575, by reaction with organic spcillane compounds in the presence of an acid such as trifluoroacetic acid or sodium borohydride. The compounds of formula I are isolated as the free bases or their acid addition salts.

· *:

♦♦ ·· »· • ·« • ·

To form the salts, compounds of formula I are dissolved in methanol or methylene chloride and a concentrated solution of the desired acid is added.

The isomeric mixtures can be separated into the diastereomers or the E / Z isomers by conventional means such as crystallization, chromatography or salt formation.

The present invention also relates to processes for the preparation of compounds of formulas II, IIa, 1a, 1a, 1b, IV and V which are valuable intermediates for the preparation of pharmaceutically acceptable compounds.

Compounds of Formula V are prepared by coupling 2-halo-ergoline derivatives with an organometallic compound during metal catalysis. Bromine and iodine derivatives which are inorganic in solvents such as cyclic or acyclic ethers, hydrocarbons or dimethyl are preferred. -. formamide, in the presence of nickel or palladium catalyst, with an organometallic compound at a boiling point of the reaction mixture.

C 1 -C 10 alkyl and C 2 -C 10 alkenyl-Me-X 4 derivatives, wherein Me is selected from the group consisting of zinc, magnesium, tin and boron, X is halogen, preferably chlorine or bromine, C 1 -C 4 alkyl or hydroxy; na 1-3 depending on the value of the metal ·

Examples of nickel catalysts are 1,3-diphenylphosphine-propane-nickel-II chloride · Palladium-luminescent catalysts include, for example, bis-tri-o-tolylphosphine-palladium-II-chloride, tetrakis-triphenylphosphine. palladium-II-chloride and 1,1 * -bl-diphenylphosphine-ferrocene-palladium-II-chloride may be used.

Further, if the starting compounds are not disclosed, they are known or may be prepared in a manner analogous to known methods or methods described herein.

The following examples illustrate the invention in greater detail.

Preparation of starting compounds

1 · General description of the Mannich reaction of 3- (6-alkyl-8 '-ergolinyl) -1,1-diethylurea derivatives mmol ergoline, 24.0 g (0.19 mol) morpholine hydrochloride, 4.5 g (0.15 mol) of paraformaldehyde and 220 ml of anhydrous dimethylformamide are added in the order indicated and the mixture is stirred in an oil bath preheated to 100 ° C for 30 minutes. The reaction solution is then poured onto ice, alkaline with 25% ammonia solution. and extracted with toluene. After drying over sodium sulfate, the toluene is removed in vacuo and the resulting crude product is dissolved in 100 ml of trifluoroacetic acid and stirred for 30 minutes at 60 ° C. The reaction mixture is poured onto ice, made alkaline by addition of 25% ammonia solution. After extraction and drying over sodium sulfate, the solvent is removed in vacuo to give a dark blue foam which is purified by chromatography.

The following compounds were prepared

1,1 d to 111- 3- (2-morpholinomethyl-6-n-propyl-8ec-ergolinyl) urea

After chromatography of the product (SiO ₂ , dichloromethane / methanol 97x3) 78-89%

Move + 1.6 ° (c 0.5, in chloroform),

1.1-diethyl 3- (2-morpholino-methyl-β-η-propyl-8cc-efgolinyl) urea, Hydrogen tartrate

Yield 84% (crystalline material)

M.p. 4-1.6 ° (c 0.5, in methanol),

1,1-Diethyl-3- (2-motroflinomethyl-6-cyclopropylmethyl-8c-ergolinyl) -urea

After production, after chromatography (SiO ₂ , dichloromethane / methanol, 99x1-97x3) t = -0.8 ° (c 0.5, in chloroform).

3- (6-Allyl-2-yolyl-folinomethyl-8o * -erololinyl) -1,1-di-5-yl-urea

After production, chromatography _(SiO2, dichloromethane / tietanol 97> 3) t 71-97% (56-59% crystalline material), ^{and 2} »4 ° ^s °» ^ »chloroform) 1 l, diet lv-3-yl - (6-Ethyl-2-morpholinomethyl-5H-pyrrolidinyl) -urea

Yield, after chromatography (SiO ₂ , methyl methane / methanol 99x1-95x5): 81 9 (46% crystalline), r-Λ + 4.0 ° (? 0.5, in chloroform),

5- (6-Cyano-9,10-dihydro-2-morpholinomethyl-6H-ergolinyl) -1,1-diethylurea

Production after chromatography of chromium (diethyl acetate / methanol 98 | 2-96: 4) l • ... j. ··, · »·· ··· ·. ,.,

(- 24% crystalline material, recrystallized from ethyl acetate), + 301.6 ° (c = 0.5, in chloroform).

2. General description of the quaternization of the Mennich compound Dissolve mmol ergoline in about 200 mL tatra * hydrofuran and add 4.0 mL (65 mmol) methyl iodide. After stirring for 17-22 hours at room temperature, the mixture, after which the product begins to precipitate after about 4 hours, is cooled in an ice bath and 100 ml of diisopropyl ether are added dropwise after> 30 minutes and the quaternary salt is filtered off at 0 ° C. The material thus obtained is used directly in further reactions.

The following compounds were prepared:

N- (6-Allyl-8o- / 3,3-diethyl-ureido / -2-ergolinylmethyl) -N- »ethyl-morpholinium iodide

Yield: 59-70%

N- (6-cyclopropylmethyl-8 * - / 3,3-diethyl-ureido / -2-ergolinyl *

-meti1) -N-methyl-moyfolinium iodide

Yield: 64-80

N- (6-ethyl-8β- [3,3-diethyl-ureido] -2-ergolinyl-net) -N-exethyl-morpholinium iodide

Yield: 87%

N- (6-cyano-9,10-didehydro-8 * - (3,3-diethyl-ureido) -2-ergolinylmethyl) -N-methyl-morpholinium iodide

Yield 82%.

··

3 · Bromination of 1,1-diethyl-3 (8 '-ergolinyl) urea

3- (2-bromo-8 «-ergolinil) -1,1-diethyl-urea

Preparation and Data in EP 56 556 ·

4,1,1-diethyl-3- (2-ethyl-8H-ergolinyl) -carbamide

3- (2-Bromo-8H -ergolinyl) -1,1-diethylurea (1.00 g, 2.47 mmol) was dissolved in toluene (10 mL), 1,1 * -bis &lt; - &gt; (Diphenylphosphine) ferrocene palladium II chloride is added and stirred for 15 minutes at room temperature. Then 5.5 ml of trlethylborane (1 molar solution in tetrahydrofuran) and 2.5 ml of a 4N potassium hydroxide solution are added to the reaction mixture and acidified with 2N hydrochloric acid, then basified to pH with concentrated ammonia and extracted with dichloromethane. The organic phases were dried over sodium sulfate and the solvent removed in vacuo to give a crude product. After recrystallization from ethyl acetate, the yield was 307 mg (35%) · ^{B +} 47.6 ° (c = 0.5, in chloroform) ·

5 Reduction of cyanide is carried out by methods known in the art. Cerny et al., Collection Gzechoslovak Chem · Commun., 1984, 49, 2828.

The following compounds were prepared from the 6-cyano derivatives: • · · · ···

·· ♦ · ··

5- (9,10-didehydro-2-methyl-8 '-ergolinil) _-l> l-diethyl karbainid,

5- (9,10-Didehydro-2-methoxy-ethyl-8H-ergolinyl) -1,1-diethyl-ceramide,

5- (9,10-didehydro-2-methylthio-8-iaetil «-ergolinil) -l, 1-diatil karbsmid,

5- (9,10-didehydro-2-hydroxymethyl-6H-ergolinyl) -1,1-diethylcarboxylic acid,

5- (9,10-Didehydro-2-ethyl-6H-ergoline) -1,1-diethyl-urea.

6-5- (6-cyano-9,10-didehydro-2-ethyl-e * -erololinyl) -1,1-diethylurea

Manufacture according to example ·

7-5- (6-Cyano-9,10-didehydro-2-methylmethyl-3 * -ergolinyl) * 1,1-diethylcarboxamide

Preparation as in Example 2 *

8. 5- (6-cyano-9,10-didehydro-2-yaethoxymethyl-8H-ergolinyl) ·

-1,1-diethyl-urea

Λ

Preparation as in Example 4 *.

· 5- (6-cyano-9,10-didehi dr o-2-hydro xyl-m l - &gt; - -golinyl) -

-1,1-diethyl karbaiaid

Reduction of the 2-formyl compound means # 5 - (6-dano-9,10-didehydro-2-hydroxyethyl - &lt; - > - eratinyl) *.

-1, l-diethyl-urea

Preparation as in Example 8 ·

11 · 5- (6-Cyano-9,10-didehydro-2-ethyl-η-ergolinyl) -1,1-diethylurea

Preparation as described in Example 15 ·

Example 1

General description of the reduction of quaternary salts with sodium borohydride

Ergoline (1.00 mmol) was dissolved in anhydrous ethanol (25 mL), powdered sodium borohydride (184.6 mg, 5.00 mmol) was added and stirred at room temperature · After the reaction was complete (TLC), the reaction mixture was poured into ice and extracted with dichloroethane. The crude product is purified by chromatography or crystallization.

The following compounds were prepared

5- (6-Diclopropyl-2-methyl-8 * -ergolinyl) -1,1-dlethylcarbamide Yield (after recrystallization from ethyl acetate / diisopropyl ether) t 61 "" 5.2 ° (c "0.5» in chloroform) )

5- (6-Allyl-2-methyl-8 * -ergplinyl) -1,1-diethyl-urea

Production after chromatography (SiO2 »dichloromethane / netan 95t5) * 67

- 18 (37 crystalline substances),

Mp -2.0 ° (c 0.5, in chloroform), 1-diethyl-3- (6-ethyl-2-methyl-8 * -ergplinyl) urea

Production after chromatography (SiO 2, dichloromethane / netanol

97%): 33% (13% crystalline), + 5.2 ° (c = 0.5, in chloroform),

3- (6-n-Propyl-2-net-8e, ^a -ergolinyl) -urea

Yield (after crystallization) ethyl acetate / diisopropyl ether; 65 £, / «« eJZjj ® + 34 ° (c = 0.5, pyridine).

Example 2

General description of the reaction of quaternary salts with sodium nethanethiolate

Ergoline (1.00 mmol) was dissolved in dichloromethane (50 mL) and sodium methane thiolate (600-800 mg, 8.56-11.14 mmol) was added. The reaction mixture was stirred at room temperature for 5-17 hours and if necessary with additional sodium methane thiolate (Thin layer chromatography) · Pour into a mixture of ice-ammonia solution and extract with dichloromethane · The extract is dried over sodium sulfate, the solvent is removed in vacuo and the resulting material is further purified by chromatography.

The following compounds were prepared: 1,1-Diethyl-3- (2-methylthiomethyl-6-n-propyl-8H-ergolinyl) -urea

Chromatography of the product (SiO 2, ethyl acetate / methanol 97: 5) t 45 (54% crystalline),? -12 ° + 12.8 ° (c * 0.5, in chloroform),

5- (6-Cyclopropyl-4-yl-ethyl-2-methyl-thiomethyl-8 * -ergolinyl) -1,1-diethyl-ceramide

Production, after chromatography (SiO ₂ , dichloromethane / methanol 975) 46% (40% crystalline), m.p. = -7 DEG -2.4 DEG (c ^B 0.5, in chloroform),

5- (6-allyl-2-methyl-io me t * -ergplinil 8-yl) -1,1-diethyl-urea Yield after kromatografáláa _(SiO2, ethyl acetate / methanol, 97t5) of 51% (42% crystalline material), * 0 → 0 ° (c 0.5, in chloroform), 1-diethyl-5- (6-ethyl-2-methyliomethyl-N-ergo-linyl) -carbamide amide Product · , after chromatography (SiO ₂ , dichloromethane / methanol 97i5) t 58% (24% crystalline), * 8.1 ° (o 0.5, in chloroform) ♦

General description of the reaction of quaternorones with sodium benzylate

Sodium 1.17 & (0.05 mol) is dissolved in 40 ml of benzyl alcohol in small portions with heating. 10 mmol of quaternary salt is dissolved in a minimum amount of benzyl alcohol (25-50 ml) and added dropwise to the room temperature cooled benzylate solution. After the addition is complete, stirring is continued for 50 minutes (TLC followed by chromatography) · The reaction solution is directly chromatographed (1.3 kg SiO ₂ , dichloromethane). Elution of benzyl alcohol with dichloromethane (approximately 10 L)

Addition of 1-3% methanol gave the product.

The following compounds were prepared:

3- (2-benzyloxy-methyl-O-n-propyl-S ^ -ei'golinil) -1,1-diethyl-urea

Yield: 93%

3- (2-Benzyloxymethyl-6-n-propyl- ^8e -ergolinyl) -1,1-diethylurea, L-hydrogen tartrate

Yield: 43% _7 _D = + 12.4 ° (c ^s 0.5, in methanol),

3- (2-Benzyloxymethyl-6-cyclopropylmethyl-5 H -ergolinyl) -1,1-diethyl-1-carbamide

Yield: 43% ($ 15 crystalline material), -7.2 ° -8.2 ° (c ^c 0.5 in chloroform),

3- (6-Allyl-2-benzyloxymethyl-O) -ergoline) -1,1-di-ethyl-urea

Yield: 73% (31 λ crystalline material),

-9.2 ° (c = 0.5, in chloroform),

3- (2-benzyloxy-methyl-6-ethyl-8 -ergolinil ^B4) -1,1-di-ethyl carbonate Baja Yield: 57%

3- (2-Benzyloxymethyl-6-ethyl-8H-ergolinyl) -1,1-diethylurea, L-hydrogen tartrate

Yield: 67%,? + 8.8 ° (c? 0.5 in methanol)?

* 21 -

··: ··· · · .. · ··: ·. ·· • ·

4t .....

General description of the reaction of quaternary salts with sodium motanolate

To a solution of sodium (230 mg, 10 mmol) in 20 mL of anhydrous methanol was added dropwise a solution of 2.0 mmol of quaternary salt in 20 mL of methanol at 0 ° C. After the addition was complete, stir for 15 minutes at 0 ° C and for 30 minutes at room temperature. The working-up is poured onto ice-ammonia solution and extracted with dichloromethane. The organic extract is dried over sodium sulfate, the solvent is removed in vacuo and the crude product is purified by recrystallization or chromatography.

The following compounds were claimed live

1,1-dlethyl-3- (2-methoxymethyl-6-n-propyl-8'-ergolinyl) -carbamate Production after chromatography (SlOg, dichloromethane / methanol 95) 5% 44% (28% crystalline) material) * soles +5 → 8 ° (c = 0.5, in chloroform),

3- (6-Olcopropylmethyl-2-methoxymethyl-8H-ergoline 11) -1,1-diphenylcarbamyl

Production, after chromatography (S10g, dichloromethane / methanol 97 µ3) 13% (8% crystalline material) * mp * 3.6 ° (0 * 5 * in chloroform),

3- (6-allyl-2-methoxymethyl-8 &gt; -ergollnyl) -1,1-dlethylcarbamyl Yield after recrystallization (ethyl acetate / dilsopropyl ether): 23% m.p. 5, in chloroform).

·· »'• e ¹ I ··

1.1- diet 11-3- (6-ethyl-2-methoxymethyl-8 '-ergolinyl) -carbamide Yield, after recrystallization (ethyl acetate / diisopropyl ether) t 36% t _{D =} -0.9 ° (o - 0.5 in chloroform).

General description of the synthesis of hydroxymethyl compounds from benzyl ether compounds

Ergoll (2.00 mol) was dissolved in dry tetrahydrofuran (25 µl) and added dropwise to 40 ml of ammonia at -70 ° C. Sodium (150-550 mg, 8-24 mmol) was added portionwise in small portions, always waiting for the previously administered sodium to not react. After the addition of methanol (thin layer chromatography), methanol was added to the reaction mixture and the cooling was stopped and after evaporation of ammonia, the residual solvent was removed in vacuo and the residue dissolved in viscose. The aqueous solution is extracted with dichloromethane, the organic phases are dried over sodium sulfate, the solvent is removed in vacuo and the crude product is purified by crystallization or chromatography.

The following compounds were set alive

1.1-diethyl-3- (2-hydroxymethyl-6-n-propyl-8H-ergolinyl) -carbamyl <tb> <sep> Production, after chromatography (96% dichloromethane / methanol) <tb>% (58% crystalline material, ethyl acetate / diisopropyl ether). elegyMin

+ 14.2 ° (o · 0.5 in chloroform),

'• e' <ee * 23 *

3- (6-Allyl-2-hydroxy-methyl-8 '-ergolinyl) -1,1-diethylcarbamyl Production, after chromatography (dichloromethane / methanol 97 (3) (% 06% crystalline, ethyl acetate / diisopropyl ether) from air), you _D · ♦ 3,4® (o 0,5 »in chloroform) ·

In addition, the IS% of the (6-allyl-2-methyl-8β -ergolinyl) -1,1-dlethylcarbamyl was isolated.

1,1-Dlethyl-3- (6-ethyl-2-hydroxymethyl-8 &gt; -ergolyl) -urea Production after chromatography (dichloromethane / methanol 97 (3 6s 90 90) 10% 69% 06% crystalline material ethyl acetate / diisopropyl ether (Airborne), re _{D =} 9.8 ° (c · 0.5, in chloroform),

Production of 3- (6-cyclopropyl-Biethyl-2 * -hydroxy-n-methyl-8 '-ergolln-yl) -1,1-dlethyl-urea, after chromatography (dichloromethane / methanol 95 (5) (%, 27% crystalline) ethyl acetate / diisopropyl ether mixture * Ml).

again) -0.4 ° (o = 0.5 in chloroform) ·

General description of the acetylation of 2-hydroxymethyl-ergoline derivatives

Dissolve 1.00 omol ergol in 10 ml glacial acetic acid · Then add acetic anhydride (0.05 mole) and anhydrous sodium lumacetate (0.8 g, 0.01 mole) and stir overnight at room temperature. to add ice, stir for 30 minutes and then mix with ammonia. The reaction mixture was extracted with dichloromethane, dried over sodium sulfate, the solvent was removed in vacuo and the resulting crude product was chromatographed or crystallized.

The following compounds were claimed live

3- (2-Acetoxymethyl-6-n-propyl-8ec-ergolinyl) -1,1-diethyl-co

After production, crystallization (from ethyl acetate / dl / isopropyl ether) t 34% bull = + 3.2 ° («0.5 in chloroform),

3- (2-acetoxy-met11-6 oiklopropil-methyl-8 ** - ergolinll) -l, 1-diethyl-phenylurea

Yield 69% after crystallization (from ethyl acetate / diisopropyl ether)

C = J _D · -5.6 ° (o-0.5 in chloroform) *

3 * (2-aoethoxymethyl-6-yl-8 '-ergolinyl) -1,1-diethylcarbamyl Production, after chromatography (dichloromethane / methanol 95x5) 69% (48% crystalline from otylacotate) * teu _D · -2 * 3® (o «0 * 5 * in chloroform),

3- (2-aoethoxymethyl-9,10-didehydro-6-n-propyl-8 '-ergolinate) -1,1-diethylurea.

7 '

3- (2-aoethoxymethyl-6-allyl-8e-ergolinyl) -1,1-diethylurea

213 * 6 g (0 * 54 mmol)> (6-allyl-2-hydroxymethyl-8 '-ergolinyl) -1,1-diethylurea are dissolved in 5 ml of pyridine and ml (ο, 11 mol) of acetic anhydride are added. The reaction mixture is stirred for 2 hours at room temperature, then poured onto ice, stirred for 1 hour and worked up as described above.

Yield, 64% after recrystallization (from ethyl acetate / diisopropyl ether),

Cm3 _{d D} -7.2 ° (o · 0.5 in chloroform) ·

8A. JL * lte

General description of the methyl lithium roablock derivative of 2 * formyl * rgoline derivatives

Ergoll (5.00 mmol) was dissolved in anhydrous tetrahydrofuran (150 mL) and cooled to -65 ° C. Then 10 x 15 omol of methyl lithium (1.6 M in ether) was added in 5 x 7 portions. after adding allow to thaw and stir for 30 minutes at room temperature · Re * akoi <

Thin layer chromatography was carried out by pouring the reaction mixture onto ice, adjusting the pH to alkaline with 25% ammonia solution, and extracting with ethyl acetate.

The following compounds were prepared: 1,1 * diethyl-3-t- (1-hydroxyethyl) -6-n-propyl-8e-ergoline} -j-urea (diastereomeric mixture).

After production, chromatography (ethyl acetate / methanol 4713 - 95i5) t 66% (78% based on the reagents used), · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· · ♦ ··· ··· · · ·

- 26 ·

3- (6-Allyl-2- (1-hydroxy-ethyl-ergolinyl) -1,1-diothylcarbamyl

After production, after chromatography (dichloromethane / methanol, 973) 1 * (diastereomeric mixture), the less polar cluster isomer obtained in the purity of the chromatography and recrystallized from ethyl acetate · The above data refer to the nasal isomer ·)

[Α] D = -42.8 ° (o = 0.5 in chloroform),

1.1-Dlethyl-3- (6-ethyl-2- (1-hydroxyethyl) -8 '-ergolinyl) -urea (diastereomeric mixture)

After production, after chromatography (ethyl acetate / methanol 95 5 to 90 10) 74% (67% crystalline from ethyl acetate / dl / isopropyl ether).

(-) - 3- [6-Olclopropylmethyl-2- (1-hydroxyethyl) -8a-ergollinyl] -1,1-dimethylurea base · -13.6 ° («0.5) chloroform), (apolar isomer) and (+) - 3- (6-cycloprepylmethyl) -2- (1-hydroxyethyl) -8H-ergolinyl / -1,1-diethylcarbamyl

Caljj + 16.7 ° (o - 0.5, polar isomer in chloroform) ·

Total yield after chromatography (ethyl acetate / methanol 97i3 & 95ι5) ι 58% (66% based on input) ·

1.1- die 111-3- (2- (1-hydroxyethyl) -6-n-propyl-8 '-ergollinyl) urea

After chromatography (dichloromethane / methanol 98t2) 1% (47% crystalline, recrystallized from ethyl acetate), · 4-23.0 ° (o 0.5 in chloroform) ·

S, t

Reactions with Grignard Roagons

a) 1.28 g (3.2 mmol) of 1,1-diethyl-3- (6-n-propyl-2-formyl-8e-ergolinyl) urea with 20 mmol of ethylmagnesium bromide (10 mL, 2 mol) in ether · The crude product was first chromatographed on 2 interconnected 0-mark latex columns (Merek) (eluting with otyl acetate / methanol 9713), where the more polar isomer was clearly separated ·

Production 36% ·

1,1-Dlethyl * 3- (2-1-hydroxy-n-propyl / -6-n-propyl-8®-ergolinyl) urea + 26.1 ° (c = 0.5, in chloroform, polar isomer) ) ·

The resulting mixture fractions were chromatographed once more (dichloromethane / methanol 98t2) to give the pure non-polar isomer in 18% yield.

1,1-diethyl-3- (2- (1-hydroxy-n-propyl) -6-n-propyl-8eB-ergolinyl) -carboxamide lupus = 4-6.2 ° (c = 0.5, in chloroform, apolar polar isomer) · In addition, 21% blend fractions and 11% adducts were obtained · Total yield 74% (82% based on input) ·

b) 1.70 g (4.3 mmol) of 1,1-diethyl-3- (6-n-propyl-2-formyl-8'-ergoline-1D-urea) in 43 mmol of n-pentylmagnesium bromide (10 mL, 2 mol) , ethereal solution) react as above · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 28th

1,1-Diethyl-3- (2- / 1-hydroxy-n-hexyl / -6-n-propyl-8-ergolinyl) urea (diastereomeric mixture)

After chromatography (dichloromethane / methanol 97i3), the yield is 25%.

General Description of the Preparation of 2-Alkenyl Derivatives from 2-Hydroxyalkyl Compounds

Ergoline (1.00 omol) was dissolved in tetrahydrofuran (40 mL) of analytical grade and triethylamine (1.4 mL, 10 mmol) was added. Methanesulfonic acid chloride (0.8 mL, 10 mmol) was added to titanium and stirred for a further 30 minutes at room temperature (5 min. Examined by TLC). The reaction mixture is poured onto ice, the pH is made alkaline with 25% aqueous ammonia solution and extracted with ethyl acetate. The crude product obtained after evaporation of the solvent is chromatographed.

The following compounds were claimed live

1,1-Diethyl-3- (6-n-propyl-2-vinyl-8 &gt; -ergolinyl) -urea Yield: 47% (11% crystalline material, ethyl acetate) after chromatography (dichloromethane / methanol 97-3). dilisopropylether from the mixture), travel +44 0 0 ° (c 0,5 0.5 kl in chloroform),

1,1-Diethyl 11-3- (6-ethyl-2-vinyl-8eB-ergolinyl) -urea Production after chromatography (ethyl acetate / methanol 97t3)% (24% crystalline from ethyl acetate / diisopropyl ether), _T · +34 »2 ° (o 0.5» in chloroform), ί,.

X 6-Allyl-2-vinyl-8-ergolinyl) -1,1-dlethylurea Production after chromatography (alumina / ethyl acetate) 53%, (31% crystalline material, ethyl acetate / diisopropyl ether yield), Cedjj « + 3.3 ° («0.5, in chloroform,

3- (6-Cyclopropylmethyl-2-vinyl-8®-ergolinyl) -1,1-diethylurea

Production, after chromatography (alumina / ethyl acetate) 46%, (24% crystalline material, ethyl acetate / diisopropyl ether),

Εβύρ ·-20,3 ⁰ (o 0.5, in chloroform),

1, l-diethyl-3- (2-isopropenyl-6-n-propyl-8a-ergoIinil3 karbaald yield, _after the crystallization (ethyl acetate / diizopropiletiléter) i 46 *

Eeu _D * 4-79.0 ° (o · 0.5 in chloroform) ·

UuJÁldS

Preparation of 2-alkenylergoline derivatives by Wittig reaction

To a suspension of 5.35 g (14 mmol) of fluorophilyl triphenylphosphine tetrafluoroborate in ² x 120 ml of anhydrous dioxane was added potassium tert-butanolate (1.58 g, 14 mmol) in three portions over 2 · After stirring for 30 minutes at room temperature, a solution of 560 mg (1.4 mmol) of 1,1-diethyl-3- (2-formyl-6-n-propyl-8H-eraolinyl) urea in 15 ml of dioxane is added dropwise. After 30 minutes (Thin "layer chromatography), the reaction was poured onto ice ²⁵ Burton, D, J« Wlemers, DM, J. Fluorine Chem. 27, 85/1984 / · and solid oitromsav addition the pH was adjusted to 3. It is then extracted with ethyl acetate and the organic phase is washed with 2N nitric acid. The combined aqueous phases were basified to pH alkaline by cooling with 25% ammonia solution and extracted with dichloromethane. The organic layers were washed with brine, dried over magnesium sulfate and the solvent removed in vacuo. Chromatography (finished column C, Merek, diisopropylether / methanol, 95) yields 279 g (4β%) of the fluorovinyl compound (total yield). Crystallization of each fraction yielded pure isomers.

(E) -1,1-diethyl-3- (2- (2-fluoroethylenyl) -6-n-propyl-8ec-ergolinyl) urea and (Z) -1,1-diethyl-3- (2- (2-Fluoro-ethylenyl) -6-n-propyl-8E-ergolinyl) * urea.

1,1-dlet 11-3- (9,10-didehydro-6-n-propyl-2-vinyl-8 H-ergolinyl) v-urea

Production 59%,

Ced _D + 355 ° (? 0.5, in chloroform).

• · · • · · · · ······ · ·········

- 31 Reduction of 2-alkenyl ergoline derivatives

To about 15 mL of ammonia was added 345 mg (15 »1) of sodium at -65 ° C and stirred at this temperature for 5 minutes. A solution of ergoline (1.00 mmol) in anhydrous tetrahydrofuran (25 mL) was added dropwise to the reaction mixture while the dark blue solution disappeared after half addition. After 15 minutes, 0.2 to 0.2 mL of ethanol was added three times over 5 minutes and then stirred at -65 ° C for 10 minutes. The reaction is quenched by addition of 15 ml of alcohol and 15 ml of water.

The following compound pouch was made live with 3- (6-allyl-2-ethyl-8E-ergolinyl) -1,1-diethylurea Production, after chromatography (dichloromethane / methanol 9812 and 97.3), t , ethyl acetate / dil isopropyl ether),

Ced _D + 2.9 ° (c 0.5, in chloroform),

1,1-die 111-3- (2,6-diethyl-8-ergolinyl) -urea Production, after chromatography (ethyl acetate / methanol 97-3) »85%, (40% crystalline material, from ethyl acetate), Caelp * + 6.2 ° (c 0.5, in chloroform).

• · · · ·> 2 ▲ 2-hydroxyalkyl-orgoline-price reducing agent

Ergoline (2.00 µl) was dissolved in 25 µl of glacial acetic acid and 1.0 g (26.4 today) of sodium maleic anhydride (half tablet) was added under argon. After the completion of the roacool (thin layer chromatography), the reaction mixture was poured into ice, made alkaline by addition of 25% ammonia solution under cooling, and extracted with dichloromethane. 3- (6-Cyclopropylmethyl-2-ethyl-8 * -ergolinyl) -1,1-diethylurea Prepared after chromatography (ethyl acetate / methane 970) $ 65% (96% crystalline otyl acetate / diisopropyl ether). ?

-0.8 (c 0.5, in chloroform),

1.1-diethyl-3- [2,6-di-n-propyl] - * - ergolinyl] -carbanide Production, after chromatography (otyl acetate / netanal 9715) ι% 9 (99% crystalline from ethyl acetate / diisopropyl ether), · * 14.4® («0.5 in chloroform),

1.1-Diethyl 11-5- (2-n-hexyl-6-n-propyl-1 H-ergolinyl) urea, after chromatography (ethyl acetate / nethanol 9515) 1% (69% crystalline from ethyl acetate / hexane) , - “* 14» 4 * (a · 0.5, in chloroform)?

·· ·· · • ♦ · · · · 9 · · · · · · · · · · · · · · · · · · · 4, 1-diet 11-3 {2-lsopr © pil-6-n-propyl-8 * -ergolinyl) -urea By reaction with ▲ sodium borohydride a mixture of the desired compound and 1,1-diethyl 11-3- (2-ia-propenyl-6-n-propyl-8H -ergoline-D-urea) is obtained. * as described in the example, it is re-reduced with the Na / NH 4 reducing reagent *

Térnélés, after crystallization (otilacetátból) of 28% »^" \ 7 _d * · 17.6 ° (p 0.5, chloroform) g

14 », EXAMPLE

2-alkyl-ergDlin derivatives N-alkylation

The reaction is carried out according to methods known in the literature

The following compounds were prepared

1,1-Diethyl 11-3 (2-ethyl-n-propyl-**-ergBlinyl) -carboxamide Production, after chromatography 64% (54% crystalline material tert-butyl methyl ether) / hexane mixture int / _r * 42.8® (≤ 0.5, in pyridine),

3- (9,10-Didehydro-2-ethyl-6-n-propyl-8H-ergolinyl) -1,1-diethylurea

Yield 65 * 284® (o = 0 ^ 5 in chloroform) f

3- (6-Allyl-9,10-didehydro-2-methyl-8 * -ergDlinyl) -1,1-diethylurea

Production 55

ZX7 © * 506® (c «0.5 in chloroform), '*> 12-21 206 ······ · · · · · · · · · · · · · · ····· «· •• ·· ♦ · ··· ···

- 34 3- (6-cyclopropyl-mot 11-9,10-didhydro-2-methyl-8'-ergolinyl) -1,1-distylurea

Tofmolé ·: 42 <»· * 235 ° (in 0.5» chloroform) »·

3- (9,10-didsh.hydro-6-ethyl-2-ethyl-N, N * -ergolinyl) -1,1-diethyl-torxole: 69 * 54 * (o 0.3 in chloroform),

3- (9,10-Dodhydro-2-mst oxymethyl-6-n-propyl-1 H -rgolinyl) -1,1-distylurea

Products ·: 26

ZT * (7j) ^β + 260 ° (c «0.5 in chloroform)

3- (9,10-dídshidro mstiltio-2-methyl-6-n-propyl-o «-srgolinil) -1,1-Distil urea

Product ·: in the form of 50 hydrogen tartrates *

3- (9,10-Didhydro-2-hydroxymethyl-6-n-propyl-e * -orgolinyl) -1,1-distylurea »

3- (9,10-didshidro-2-Atil-6-n-propyl-8 * -ergolínil) -1,1-Distil-karbsmid

Termi ·: 38 9 *

Γ-Λ - («» in 0.5f chloroform) n

15 · Example ▲ General Description of Brown Oxidation of 2-Hydroxyalkyl-Orgoline Derivatives Dissolve mmol srgoline in 20 ml of analytical grade dichlormstene and 865 xg (10 mmol) of tannin (MnOg-activated ^ ^^ AWoxe · and tmiyxty Coxxuaiox · »1799/1986 / ^

Merek) · Stir the reaction mixture overnight at 0 ° C, filter through alumina / alumite, wash with dichloromethane and otyl acetate

The pure product is obtained by digesting the crystal or by chromatography;

The following compounds were prepared

5- (6-Allyl-2-fornyl-8 * -orolinyl) -1,1-dimethylurea Production after chromatography (dichloromethane / methanol 9715) 1%, (65% crystalline material, ethyl acetate / diisopropyl ether) ), + 21.5 («0.5, in chloroform) φ

5- (6-Cyclopropylmethyl-2-formyl-8 * -ergolinyl) -1,1-distylurea

Production, after recrystallization 70% (otilaoethane / diisopropyl ether straight away),?

J-q ·. + 27.0 ° (o 0.5 »'in chlorine of myo), ·

5- (2-Aaethyl-6-n-propyl-ε-ergplinyl) -1,1-di-ethyl urea Yield 88% (57% crystalline material, from stylate acetate),? 7? + 20, -5 ° (o 0.5, in chloroform)!

General description of the oxidation of Mennich dung bees with tert-butyl hypochlorite

Ergoline (10.0 mmol) was dissolved in THF (160 mL), cooled to -40 ° C and triethylamine (1.6-5.2 mL, 11.5-25.0 mmol) was added. ml ········································································································································ · (12.5 moles) of a solution of tert-butyl hypochlorite in 25 µl of tetrahydrofuran is slowly added dropwise to the reaction mixture after 5 minutes. 50 minutes after the thin layer (electron chromatography), the reaction mixture is poured onto ice, the pH is made alkaline with 25% amane solution and extracted with ethyl acetate. The solvent was removed in vacuo and the crude fractions were purified by chromatography

The following compounds were claimed live

1.1- Diode 11-5 (2-formyl-6-n-propyl-e * -ergolinyl) urea Product, after chromatography / ethyl acetate / 98x2-95t5) 56-64

After chromatography on 5- (6-allyl-2-phenylmethyl) -1'-diethylcarbamyl-1,1-diethylcarbamyl (ethyl acetate / methanol 9T5) 52-65

5- (6-Cyclopropylmethyl-2-formyl-8 * -ergolinyl) -1,1-diethylurea

Production after filtration through Akt .III aluminone oxide (ethyl acetate)

1.1- Diethyl- (6- (1H-2-fornyl-8 * -srginyl) carban Ad After chromatography (dichloromethane / methanol 97t5): 28-62% (crystallized from ethyl acetate / diisopropyl ether), * -7 © * + 45 ^ 8® (c «0.5, in chloroform), · · · · · · · · · · · · · · · · · · · · · · · · · · · · 9 ···· 9 9

9999 99 99 · 99 • 57 5- (6-Cyano-9,10-didehydro-2-formyl-8 * -ergolinyl) -1,1-diothyl-

-urea

Tarmalist 6? &

▲ General description of the preparation of thiourea compounds from the urea wedge «1 in dichloromethane at -20 ° C successively

Dissolve 0.15 µl of freshly distilled phosphorus oxychloride (1.4 mmol) and 0.25 mmol ergolinyl urea * at room temperature overnight, remove volatiles completely in vacuo, and dissolve the residue in ml of acetonitrile. solution of ethyl xanthogenate in 20 ml aoetonitrile f

After stirring for 2 hours at room temperature, ice and concentrated ammonia solution are added to the reaction mixture. It is extracted with dichloromethane, the organic phases are dried over sodium sulfate, chromatographed with ethyl acetate and then with ethyl acetate / diisopropyl ether.

The following compounds were prepared

5- (9,10-Didehydro-2-ethyl-6-d-propyl-8 * -ergolinyl) -diethyl

thiourea

Yield: 15 · * 575 · (0.25% in chloroform), · · · · · · · ··················································································

- 38 3- (9,10-didhydro-2-eeotyl-6-n-propyl-8 * -sigolinyl) -diode11-tlcarbamide

39% production,

Z “L7d · + 419® (0.5 in chloroform)?

1,1-di st 11-3- (2,6-di-n-propyl-8 ° * -srgollnyl) -thiocarbamld.

/ ·· _7 _d "+ 91 ° (0.25% in chloroform) _r, l was diethyl 3- (2-methyl-6-n-propyl-8" -srgDlinil) thiourea

Yield: 61%, +49 (0.5%, in chloroform)

, 1-Diethyl-5- (9,10-didehydro-2- 5β-dihydro-2E-ethyl-6-n-propyl-8 * -ergolinyl) -carbamide

3- (9,10-Didehydro-2-ethyl-6-n-propyl-e * -ergo-phenyl) -1,1-diethyl-urea (2.3 mmol) (880 mg) was dissolved in trifluoroacetic acid (50 mL) and three equal portions at room temperature. At 5 dust intervals in Outes, 1.48 ml of triothylethylsilane are added. After stirring over 60 powders, first ice, then with cooling, 25% smmenia solution was made hero and the alkaline solution was extracted with dichloromethane. The slurry phases were dried and evaporated to a sheep. After chromatography on production, 578 mg of ethyl acetate / diisepropyl ether was recrystallized from 106 mg / theoretical Z 12 -7d * 204® (0-5 S in chloroform).

• · · · · · · · · · · ································································································ This

1,1-Diethyl-3- (2 ', 3' B-dihydro-2-methyl-6-n-propyl-8 * -ergelinyl) -

-karbanid

Terms 65

1,1-Diethyl-3- (2,3e-dihydro-6-ethyl-2-ethyl-8H-arolinyl) -carbanes

Yields 34 ° to 50 ° (° to 5% in chloroform),

1,1-Diethyl-3- (2,3B-dihydro-2,6-di-n-propyl-8H-ergolinyl) -

-urea

Terms 33

C * J - ⁺ 5 ° (0.5%, in chloroform),

1.1- die 111-3- (2,3B-Dihydro-6-ethyl-2-methyl-11 &gt; -ergo-linyl) -

-tlokarbamid

Claims (4)

1 · Exit Compounds of Formula I - single or double bond between moles of carbon atoms 2 and 5 and 9 and 10 X is oxygen or sulfur / p R 1-10 alkyl group optionally substituted with 2-10 halogens asénatomoo alkeniloooport / CHgXB ⁵ / OB ¹² (OR ⁴⁾ R ⁵ / ^ CO ^ -OHB OOR ^{12 -COR10} or a group wherein Y is O or B, B is hydrogen, C 1-4 alkyl, phenyl, C 2 -C 5 lower alkyl or phenyl (C 1 -C 4) alkyl, B ^{4 is} hydrogen or C 2 -C 5 acyl, C 1 -C 9 alkylene; / B® COCH ^ 000- or (1-4C) alkyl / ^R10 C 1-4 alkyl or 0- (C 1-4) alkyl group * / R ² is hydrogen or C1-9 alkyl dzénatomos * group/ R @ 2 is a C2-C10 alkyl, C3-C10 alkenyl * or C4-C10 cycloalkyl derivative, and its acid addition salts, isomeric good and isomorologyol, characterized in that: a) a compound of Formula II - wherein R @ 4, X and the carbon atoms at positions 9 and 10 are as defined above, and R @ 1 and R @ are both alkyl atoms of 1-6 carbon atoms or with nitrogen; Denotes a 6-membered saturated heterocyclic group * which may be optionally interrupted by oxygenation of the brain to form an aldehyde of formula la, wherein B ⁶ , X and the bond between the 9 and 10 carbon atoms have the meanings given above b) reducing the quatemeric compound of formula II, wherein B $, b \ B% X and the bond between 9 and 10 carbon atoms have the same meaning as previously defined, to a compound of formula I wherein R ^{2 is} methyl pendant or reacting it with a nucleophilic anion in the case of a compound of formula I thus obtained, where B is a dgO-bonsilyl ring, the benzyl ring is cleaved and the CHgOH group thus obtained is optionally sterilized or oxidized to the aldehyde of formula Ia. o) brain of the formula Ia *) reacting with a Wittig reagent to form a compound of formula I wherein R ² is an optionally substituted C 2 -C 10 alkenyl tube powder, or 8) Converting CH (0H) B ^ to a compound of formula X and optionally, if appropriate, to a compound of formula X wherein R ^{2 is} C 2 -C 10 alkenyl or C 2 -C 10 alkyl, or the hydroxyl group is oxidized to the stereo or ketone and desired in which case the compound of formula Ib thus obtained is then obtained, wherein R ⁶ , X, R ⁶ and the carbon atoms 9 and 10 are bonded to a compound of formula CB ^ ² (0H) B ^ as defined above in point 8). converted, where B ^ ² • ·· · · · · · · · · • r "·" ₉ * _99Λ · · · · ··· ···· »·· *" 4 "" - 42 C 1 -C 9 alkyl and, in the case of cyano, then Is converted to a compound of formula I wherein R ^{2 is} esterified with C 2 -C 10 alkenyl or C 2 -C 10 azene atoms or * hydroxy groups and optionally reduced to compounds of formula X or B) to form a compound of formula X, wherein R ^{2 has from 2 to} 10 carbon atoms in the alkyl moiety; d) a compound of formula XV wherein R 1, X and a 9 and 10 carbon atoms as defined kostí bond előzőéiben present TeAu * and * Z is a halogen tom or a lithium compound of the general formula of alkenyl or alkyl and X, R ² C1-10 alkyl or C2-10 Bzénatomos omos alkenílosöpört? e) a compound of Formula V of the brain wherein R ² , X and 9 and The 10-carbon bond is alkylated at the 6-position as defined above, and finally compounds x of the formula x containing an oxygen atom as X in any one of processes a-e) are treated with the thiourea compound. It is converted to the eluted forms or the 2,5-bond double bond is reduced or the acid addition salts are formed or the isomers are separated. The process according to claim 1, which is - (6-cyclopropylthioethyl-2-motile-B * -ergDlinyl) -1,1-dimethylurea 5- (6-Allyl-2-methyl-8 H -erginyl) -1,1-diethylurea 1.1-Distyl-9- (6-ethyl-2-methyl-8 * -ergolinyl) * carboxamide | 1,1-diethyl-3- (2-methyl-6-n-propyl-8 * -orollnyl) urea | · ♦ ·· ·· 9 «· ··> ····« • 999 999 9 9 999 .. ·. · ···· · · 1,1-Diethyl-3- (2-methylamethyl-6-n-propyl-8H-ergolinyl) urea} 3- (9,10-Didehydro-2-methylthiomethyl - (-? - n -propyl-O-ergolinyl) -1,1-diethylurea) 2- (6-Allyl-2-yl-ethyl-8 * -ergolinyl) -1,1-diethyl-urea} 1,1-Diethyl-3- (6-ethyl-2-ethyl-thio-methyl-8 * -ergolinyl) -urea} 3- (2-Banyloxymethyl-6-n-propyl-8 H -orgolinyl) -1,1-diethylurea 1,1-Diethyl-3- (2-motoxyethyl-6-n-propyl-8H-arolinyl) «urea} 3- (9,10-Didehydro-2-methyl-oxy-methyl-6-n-propyl-e * -ergolinyl) -1,1-diethyl-urea | 3- (6-Allyl-2-methoxy-methyl-8H-ergolinyl) -1,1-diethyl-urea} 1,1-dimethyl-5- (6-ethyl-2-methoxymethyl-1-8 * ergolinyl) urea} 1.1-Diethyl-J- (2-hydroxy-methyl-6-n-propyl-Θ-ergolinyl) - «urea} 3- (9,10-Dideo-Dro-2-methyl-6-n-propyl-8 * -epholinyl) -1,1-diethylurea} 3- (9,10-Didehydro-2-ethyl-6-n-propyl-O-ergolinyl) -1,1-diethylurea} 3- (9,10-Didehydro-6-ethyl-2-methyl-8H-ergolinyl) -1,1-diethyl-urea} 1.1-Diethyl-3- (2-methyl-6-n-propyl-8 * -ergolinyl) -thiourea} 1.1-Diethyl-3- (2,2'-dihydro-6-ethyl-2-methyl-8 * -er golinyl) -thiourea} 1.1- dlet 11-3- (2-aoethoxymethyl-6-n-propyl-8e * -argolinyl) -carbamld} 1,1-Diethyl-3- (2-A-hydroxyethyl) -6-n-propyl-O-argolinyl) urea} 1,1-Diatyl-5- (6-atyl-2-vinyl-8H-ergolinyl) <4carbamide | 1,1-Diethyl-5- (9,10-didehydro-6-n-propyl-2 * vl-8 * -arolinyl) urea} 1,1-dle <11-5- (6-eicopropylmethyl-2-vinyl - &gt; - * ergolixyl) urea} 1.1-Diethyl 11-5- (6-n-propyl-2-vinyl-8 * -argolinyl) -urea | 1,1-Diethyl-3- (2-ethyl-6-n-propyl-&gt; -? - erlinyl) urea} 1,1-Diethyl-5- (9,10-didehydro-2-methyl-6-n-propyl-8 '-ergollmyl) -thiourea} 1,1-Diethyl-5- (9,10-dihydro-2H, 5e-dlhydro-2A-methyl-6-n-propyl-8 * -ergolinyl) -urea} 1,1-diethyl-3- (2 _R 5 R © dihydro-2-methyl-6-n-propyl-O * -ergolinil) urea} 1,1-diethyl-3- (2,5'-dihydro-2,6-di-n-propyl-8'-ergolinyl) - urea} (1) -1, l-diethyl-3- (2- / 2-fluoro-etilonil / 6-n-propyl-8 ^| * -ergollall) urea} (Z) -1,1-DIAT 11-5- (2- / 2-Fluoro-ethyl-N-6-n-propyl-8H-allergenyl) -carbamyl} 5- (6-Alloy-2-ethyl-8 * -ergplinyl) -1,1-diethylurea} 1,1-Diethyl-5- (2,6-dlethyl-8 * -ergplinyl) -urea} * 3- (6-Cyclopropylmethyl-2-ethyl-2H-ergolinyl) -1,1-diethylcarbamide 1,1-diethyl-3- (2/6-di-n-propyl-8e * -ergolinyl) -carbamyl and 1.1-Diethyl-3- (2-n-hexyl-6-yl-propyl-e * -ergolinyl) -urea, characterized by the use of appropriately substituted starting materials * A process for the preparation of a pharmaceutical composition, characterized in that the compounds of the formula I according to claims 1 or 2 - wherein Between 2 and 5 and the carbon atoms at position 9 and 10 bonds / X / B ² EO fi · 1 ** as defined in claim meanings - gyégyássatilag acceptable excipients and / or things to add dosage forms together with customary excipients · Processes for the preparation of compounds of the formulas II, Ha, Ia / Ib / IV and V having the meaning given in claims Η ² , H ⁵ , B ⁶ / Η ⁷ / B® / B ¹² / X and Z as 1 «