DD295848A5 - 13-BROM AND 13,14-DIBROM-ERGOLINE, THEIR PREPARATION AND THEIR ADMINISTRATION - Google Patents

Abstract

Compounds of the formula I <IMAGE> and their preparation and use in pharmaceutical compositions and intermediates for the preparation of the compounds are described.

Description

N-H

H-N

wherein R ² , R ⁸ and C ₈ -Cg have the abovementioned meaning, alkylated or alkenylated and, if desired, subsequently a carbonyl group and / or the acid addition salts

 5. Compounds of the formula III

III

H-N

characterized in that R, R and C ₈ -C _{9 have} the above meaning.

The invention relates to 13-bromo and 13,14-dibromo ergoline, their preparation and use in medicaments and intermediates for the preparation thereof.

It is known from DE-A-824661.9 that longer chain hydrocarbon radicals in 6-position increase the dopamine agonistic activity of ergolines. Surprisingly, this mode of action is also retained in ergolines brominated in position 13 or 13 and 14. At the same time, the metabolic stability of the compounds is improved and thus increased bioavailability is achieved.

The invention relates to compounds of the formula I.

NO

R ³ R ⁵

'R

wherein

R ^{2 is} Ce-alkyl, C ₂ _6-alkenyl or CHj-OC ^ -alkyl,

R ^{4 is} hydrogen or bromine

R ^{6 is} C ₂ _6 alkyl, Cj-s alkenyl or C ^ cycloalkyl Cv

R ⁸ α-NH-CX-R ³ , 0 -NH-SO ₂ -NR ⁵ R ⁷ , CH ₂ -Y, β-CO-NH-gg. substituted phenyl, β-CO-NR ⁹ -CO-NHR ¹⁰ in which

X oxygen or sulfur,

Hydrogen, optionally substituted by C ₁ ^ -AIkOXy substituted C ^ -AIkyl.-CMCH ^ n-NfCHshoder-NfCW

and R ^{7 are} each hydrogen or C ₁ - ^ -alkyl, Y is hydrogen, OH, O-C ₆ -alkyl, CN, SCH ₃ or CONH ₂ and R ⁹ and R ^{10 are} each C 1-4 -alkyl or - (CH ₂ ) n N ( CH ₃ ) 2 and η is 1,2,3 or 4 and C ₈ -C _{9 represents} a single or double bond, where if R ^{8 is} CH ₃ , CH ₂ OH or CH ₂ -OC ₁ ^ -ACyI, C ₈ -Cg is a double bond and if R ^{8 is} CH ₂ -CN, CH ₂ -SCH ₃ or CH ₂ -CONH ₂ , C ₈ -C _{9 is} a single bond and R ^{8 is} ß-permanently, as well as their acid addition salts.

Alkyl is in each case a straight-chain or branched alkyl radical, for example methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec. Butyl, tert. Butyl, pentyl, hexyl, heptyl, 2,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, 1-ethylbutyl, isopentyl, isoheptyl, i-methyl-ethyl-propyl.

If R ² or R ^{6 is} an alkenyl radical, this preferably contains only one double bond, it being possible for the double bond in the radical R ⁶ not to be adjacent to the nitrogen atom. Suitable alkenyl radicals are, for example: vinyl, 1-propenyl, 2-propenyl, i-methyl-2-propenyl, 1-butenyl, methallyl.

Suitable C 1-6 acyl groups are aliphatic carboxylic acids such as, for example, formic acid, acetic acid, propionic acid, butyric acid, caproic acid.

The substituent of the phenyl radical can be in the o-, m- or p-position, where C 1 -C 4 -alkyl, C ₁ -C 4 -alkoxy or halogen, such as fluorine, chlorine, bromine or iodine, are suitable

The radicals R ⁹ and R ¹⁰ are preferably alternating.

Preferred embodiments of R ⁶ and R ² are hydrocarbons having up to 4C atoms. The compounds of formula I can exist as E or Z isomers or, if a chiral center is present in the radical R ² , as diastereomers and as mixtures thereof. The isomers and mixtures of isomers are also encompassed by the present invention. The physiologically acceptable acid addition salts are derived from the known inorganic and organic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, citric acid, maleic acid, fumaric acid, tartaric acid and others

In particular, the compounds of the formula I and their acid addition salts have central dopaminergic activity and can therefore be used as medicaments.

The dopamine agonist activity was determined by means of the Horowski method of automatically stereotyping stereotypes on rats (Arzneim. Forsch. 12, 2281-2286, 1978): Immediately after intraperitoneal test substance. Vehicle delivery, male Wistra rats (90-12Og) are individually placed in forced pens made of acrylic glass. An electrodynamic pickup system mounted in front of the head of the animals registers the number of contacts on a steel can with a central metal rod as a result of stereotypical chewing, licking and nudging movements for 60 minutes. The mean ± SEM of the number of contacts during 60 minutes for the different treatment groups, each of 12 animals, is calculated and the significance of the differences between the means of the different test substance doses compared to the vehicle-treated control group using the simple analysis of variance in Determined connection with the Dunnett test

 The results are set forth in the table below.

table

Retrieval of stereotypies in rats for 60 minutes after intraperitoneal treatment with vehicle or different doses of ergoline-urea derivatives

η control Stereotypes (counts per 60 minutes) (mean ± S.F.M.) test substance dose (mg / kg) 6.25 R ⁶ 12 2137 ± 849 0.025 0.1 0.39 1.56 7381 ± 1336 " CH ₂ CH ₃ 1943 ± 472 2470 ± 548 7499 ± 1342 "8066 ± 1248 **

(*: p <0.05, * *: ρ <0.01, analysis of variance / Dunnett test vs. control, n: number of animals)

Since the compounds according to the invention are distinguished, in particular, by dopamine agonistic action, without strong a-adrenergic effects occurring, they are particularly suitable for the treatment of Parkinson's disease.

For use of the compounds according to the invention as medicaments, these are brought into the form of a pharmaceutical preparation which, in addition to the active substance for enteral or parenteral administration, is suitable for pharmaceutical, organic or inorganic inert carrier materials, such as, for example, water, gelatine, gum arabic, lactose, starch, Magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. contains. The pharmaceutical preparations may be in solid form, for example as tablets, dragees, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions. If appropriate, they also contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, salts for varying the osmotic pressure or buffers.

The compounds according to the invention are introduced in a dose of 0.001 to 10 mg of active substance into a physiologically acceptable carrier. The application of the compounds according to the invention is carried out in a dose of 0.00001 to 0.1 mg / kg / day, preferably 0.001 to 0.1 mg / kg / day analogous to the known agent bromocryptine.

The preparation of the compounds of the formula I according to the invention can be carried out by methods known per se.

For example, compounds of the formula I according to claim 1 are obtained by reacting

a) a compound of formula II

,8th

NO

H-N

wherein R ⁶ , R ⁸ and C ₈ -C _{9 have} the above meaning and R ^{2 is} C 1 -C 4 alkyl, brominated or

b) a compound of formula III or its quaternary salt

R ⁸

III

H-N-

wherein

R ⁶ , R ⁸ and C ₈ -C _{9 have} the abovementioned meaning, substituted in the 2-position or c) a compound of the formula IV

N-H

IV

H-N

wherein R ² , R ⁸ and Cg-Cg have the above meaning, alkylated or alkenylated and, if desired, subsequently a carbonyl group is thiolated and / or forms the acid addition salts.

The compounds of the formula II are brominated according to process a) in a strongly acidic solution, for example in trifluoroacetic acid or glacial acetic acid. Suitable brominating agent is elemental bromine, pyridine hydrobromide perbromide or pyrrolidone hydro-perbromide, optionally chlorinated hydrocarbons such as chloroform, methylene chloride or ethers such as tetrahydrofuran, dioxane and isopropyl ether may be added as a solvent. The bromination is carried out at temperatures of -20 ° C to 80 ⁰ C, preferably at room temperature, and is complete after about 15 minutes to 1 hour. If molar amounts of bromination reagent are added, the result is mainly 13-bromo derivatives; when using 2 moles of bromination reagent 13,14-dibromo derivatives are isolated.

The introduction of the substituents in the 6- or in the 2-position can take place before or after the bromination. According to process b), the substituent R ^{2 is introduced} by the process described in German Patent Application P 3824661.9. In this case, the Mannich base of the formula III is nucleophilically substituted or oxidized to form the 2-formyl derivative, which is subsequently reacted in a Wittig reaction to give the desired compound of the formula I.

The nucleophilic exchange is carried out optionally after quaternization of the aminomethyl group in an inert solvent such as alcohols, polar, aprotic solvents, ethers or chlorinated hydrocarbons at room temperature or elevated temperature, where as nucleophilic anions alkoxides can be used, the desired case then in the CHy-OH group can be transferred. To prepare the 2-methyl derivative, the quaternary salt can be reduced in polar solvents such as alcohols with sodium borohydride.

The oxidation to a 2-CHO compound can be carried out analogously to that described in RAJones et al. Synthetic Communications 16,1799 (1986) described method with brownstone or tert. Butyl hypochlorite in inert solvents at room temperature. Conversion of the 2-formyl compounds to compounds of the formula I in which R ^{2 is} an alkenyl radical can be carried out in a Wittigtion, such as with alkyl-triphenylphosphonium halide in polar solvents such as cyclic and acyclic ethers, chlorinated hydrocarbons, dimethylformamide or dimethyl sulfoxide Temperatures of -50 ⁰ C to the boiling temperature of the reaction mixture, wherein for the production of Ylens strong bases such as alkali metal, lithium organyl, etc. are added.

If the substituent R ^{2 contains} a hydroxyl group, this can be reduced, for example by reaction with Na BH ₄ in glacial acetic acid, to the corresponding 2-alkyl derivative or dehydrated with the introduction of a double bond. The representation of substituents R ² hydroxylated in the 1-position can be carried out, for example, by Grignardization or lithium alkylation of the 2-aldehydes or ketones. The Grignardization can be carried out with the usual Grignard reagents such as alkylmagnesium halides in an aprotic solvent such as cyclic and acyclic ethers at low temperatures (-70 ⁰ C to 0 ° C). The reaction with alkyl lithium takes place under analogous conditions.

The substitution in the 6-position according to the method с) can, for example, according to A. Cerny et al. Coll. Czech. Chem. Comm. 49 2828

(1984) or according to the method described in EP-21206, by reacting the 6H-compound of formula IV with the corresponding R ⁶ -halides (bromides, chlorides, iodides). Conveniently, the reaction takes place in an inert solvent such as dimethyl sulfoxide, dimethylformamide, acetonitrile or nitromethane in the presence of bases such as alkali metal hydroxides or carbonates.

The conversion of the amides and urea derivatives into the thioamides and thiourea derivatives can be carried out, for example, by the process described in EP-A-217730 by reaction with phosphorus oxychloride and a thiolating agent or with Lawesson's reagent according to Fieser and Fieser Reagents for Org. Synth. IX, 49. The compounds of formula I are isolated either as free bases or in the form of their physiologically acceptable acid addition salts.

To form salts, a compound of the formula I is dissolved, for example, in a little methanol or methylene chloride and treated with a concentrated solution of the desired acid.

The isomer mixtures can be separated into the diastereomers or E / Z isomers by customary methods such as, for example, crystallization, chromatography or salt formation.

The invention also includes the compounds of formula III, which are valuable intermediates for the preparation of pharmacologically active compounds. The conversion of the intermediates is carried out according to the methods described above.

Unless the preparation of the starting compounds is described, they are known or can be prepared analogously to known compounds or processes described herein. For example, the bromination of the starting compounds can be carried out by the process described in EP-A-217734 and the 2-morpholinomethyl group can be introduced by the method described in DE-A-3824661.9.

The following examples are intended to illustrate the process according to the invention.

example 1

3- (13-bromo-2-methyl-6-n-propyl-8a-ergolinyl) -1,1-diethyl-urea

382 mg of 1,1-diethyl-3- (2-methyl-6-n-propyl-8a-ergolinyl) urea (1 mmol) are dissolved in 20 ml of trifluoroacetic acid and 1 ml of a 1 molar solution of bromine in dichloromethane is added dropwise at room temperature , It is stirred for 30 minutes, then mixed with ice, made with conc. Ammonia solution alkaline and extracted with dichloromethane. The organic phases are dried with sodium sulfate and evaporated. The residue is chromatographed on silica gel with dichloromethane / methanol 95: 5. Yield 259 mg (56% of theory) by crystallization from Essigester 146 mg (31% of theory), [a] _D = -11 ⁰ C (0.5% in chloroform).

The following 13-bromo derivatives are prepared in an analogous manner from the starting compounds in question: 3- (13-bromo-2-ethyl-6-n-propyl-8a-ergolinyl) -1,1-diethylurea yield 42% 3- (13-bromo-6-ethyl-2-methyl-8a-ergolinyl) -1,1-diethyl-urea yield 26%, [α] _D = -17 ° C (0.5% in chloroform) N - (13-bromo-2-methyl-6-n-propyl-8a-ergolinyl) -formamide Yield 47% N- (13-bromo-2-ethyl-6-n-propyl-8a-ergolinyl) -formamide Yield 35%

N- (13-bromo-2-methyl-6-n-propyl-8a-ergolinyl) -2-methyl-propionamide 28% yield, [a] ₀ = + 13 ° C (0.5% in chloroform) N - (13-Bromo-2-methyl-6-n-propyl-8a-ergolinyl) -2-ethyl-butyrylamide Yield 47% N-Fis-Bromo-methyl-en-propyl-EA-ergoliny O-methoxyacetamide Yield 32%, [α] _D = + 7 ⁰ C (0.5% in chloroform) N- (13-bromo-6-ethyl-2-methyl-8a-ergolinyl) -formamide Yield 48%

3- (13-bromo-2-methyl-6-n-propyl-8a-ergolinyl) -1,1-diethyl-thiourea yield 14%, [a] _D = +20 ⁰ C (0.5% in chloroform ) (13-Bromo-2-methyl-6-n-propyl-8a-ergolinylamino) - (dimethylamino) sulfone Yield 41% 13-Bromo-2-methyl-8β-methylthiomethyl-6-n-propyl-ergoline - Yield 16%, Ia] ₀ = -46 ° C (0.1% in chloroform) IS-Bromo-e-cyclopropylmethyl ^ -methyl-eß-methylthiomethyl-ergoline Yield 49%, [afo = -68 ° C (0 , 1% in chloroform) IS-bromo-e-ethyl-methyl-eß-methyrthiomethyl-ergoline Yield 29%

IS-bromo-e-cyclopropylmethyl ^ -ethyl-Eβ-methylthiomethyl-ergoline Yield 31%, [α] _D = -60 ° C (0.1% in chloroform) 13-bromo-2-ethyl-8β-methylthiomethyl- 6-n-propyl-ergoline-Ausbeute42%, [a] ₀ = -57 ° C (0.1% in chloroform) (13-bromo-2-methyl-6-n-propyl-8ss ergolinyl) -acetonitril- Yield 65%, [ab = -42 ° C (0.5% in chloroform) (13-bromo-6-ethyl-2-methyl-8β-ergolinyl) -acetonitrile] Yield 47%

(IS-bromo ^ -ethyl-en-propyl-ESS-ergolinyO-acetonitrile yield 40%, Ia] ₀ = ⁰ -4o C (0.5% in chloroform) (13-bromo-2-methyl-6-n -propyl-8β-ergolinyl) -acetamide Yield 36%, [ab = -47 ° C (0.5% in pyridine) (IS-bromo-e-ethyl-methyl-eß-ergolinyl-D-acetamide Yield 52%.

(13-bromo-2-ethyl-6-n-propyl-8β-ergolinyl) -acetamide yield 20%, [α] _D = -28 ° C (0.1% in pyridine) 13-bromo-2-methyl- 6-n-propyl-8ss ergolincarbonsäure- (4-fluoroanilide) - yield 45%, [a] _D = -102 ⁰ C (0.1% in pyridine) IS-bromo-e ^ e ^ didehydro-dimethyl- ene-propyl-ergoline yield 38%, [a] _D = -51 "C (0.1% in chloroform) IS-bromo-e ^ -didehydro-e-ethyl-e-dimethyl-ergoline yield 11%, [α] _D = -36 ° C (0.1% in chloroform) 13-bromo-8,9-didehydro-2,6-diethyl-8-methyl-ergoline - Yield 19%

1 S-bromo-eS-didehydro-e-hydroxymethyl ^ -methyl-en-propyl-ergoline - yield 43%, [a] _D = -51 ⁰ C (0.1% in pyridine) 13-bromo-8,9 -Didehydro-6-ethyl-8-hydroxymethyl-2-methyl-ergoline - Yield 37%

Example 2

3- (13,14-dibromo-2-methyl-6-n-propyl-8a-ergolinyl) -1,1-diethyl-urea

Dissolve 382 mg of 1,1-diethyl-3- (2-methyl-6-n-propyl-8a-ergolinyl) urea (1 mmol) in 20 ml of trifluoroacetic acid and added dropwise at room temperature, 2 ml of a 1 molar solution of bromine in dichloromethane , It is stirred for 30 minutes, then mixed with ice, made with conc. Ammonia solution alkaline and extracted with dichloromethane. The organic phases are dried with sodium sulfate and evaporated. The residue is chromatographed on silica gel with dichloromethane / methanol 95: 5, yield 56%, Ia] ₀ = -14 ° C (0.5% in chloroform)

Analog are shown:

a-iiS.I ^ dibromo-e-ethyl-methyl-ea-ergolyldD-ii-diethyl-urea yield 49%, [a] _D = ± 0 ° C (0.5% in chloroform) N- (13, 14-dibromo-6-ethyl-2-methyl-8a-ergolinyl) -formamide Yield 63%

N-dS.M-dibromo ^ -methyl-en-propyl-ea-ergolinyl-methoxyacetamide yield 67%, [a] _D = + 2 ⁰ C (0.5% in chloroform), M-dibromo-e- ethyl--methyl-ε-methylthiomethyl-ergoline yield 54% 1 S.IA-dibromo-methyl-ene-propyl-ε-methylthiomethyl-en-propyl-ergoline. Yield 36% e-cyclopropylmethyl-IS.M-dibromo Y-ethyl-eß-methylthiomethyl-ergolinyl-yield 62% (IS. ^ - dibromo-e-ethyl-methyl-eß-ergolinyl-O-acetamide - yield 43%

IS.M-dibromo-e ^ -didehydro-e-dimethyl-e-n-propyl-ergoline Yield 51%

Example 3

3- (13-Bromo-6-n-propyl-2-vinyl-8a-ergolinyl) -1,1-diethylamine

4.47 g of 3- (13-bromo-6-n-propyl-8a-ergolinyl) -1,1-diethylurea (10 mmol), 8 g of morpholine hydrochloride (63 mmol) and 1.5 g of paraformaldehyde (50 mmol) are dissolved in 70 ml of dry Dimethylformamide by heating to 100 ⁰ C. After 30 minutes, cooled, poured the mixture on ice, makes with conc. Ammonia solution alkaline and extracted with toluene. The organic phases are dried with sodium sulfate and evaporated, the residue dissolved in 30 ml of trifluoroacetic acid and heated to 60 ⁰ C for 30 minutes. This reaction mixture is poured again on ice, making careful with conc. Alkaline ammonia solution and shake out with dichloromethane. The organic phases are dried as above and evaporated, the residue on silica gel with dichloromethane / methanol chromatographies. This gives 3.11 g of oily 3- (13-bromo-2-morpholinomethyl-6-n-propyl-8a-ergolinyl) -1,1-diethylurea (57% of theory). This crude product is dissolved in 150 ml of tetrahydrofuran, the solution was cooled to -40 ⁰ C, treated with 3 ml of triethylamine and then the solution of 1 ml of tert-butyl hypochlorite in 15 ml of tetrahydrofuran was added dropwise rapidly. After stirring for 30 minutes, the mixture is poured on ice, made alkaline with 25% ammonia and shaken out with ethyl acetate. The organic phases are dried with sodium sulfate and the solvent is distilled off, the residue is crude 3- (13-bromo-2-formyl-6-n-propyl-8a-ergolinyl) -1,1-diethyl-urea, yield 2.0 g ,

10g Methylthriphenylphosphoniumbromid (28mmol) are suspended in 100 ml of anhydrous tetrahydrofuran, cooled to -70 ⁰ C., and 3,45g of potassium tert-butylate. After stirring for 15 minutes, the solution of the crude product is added dropwise in 50 ml of anhydrous tetrahydrofuran and the mixture is allowed to warm to 0 ° C. in three hours. The organic phases are dried and evaporated, the residue is chromatographed on silica gel with dichloromethane / methanol, yield 1.52 g. By crystallization from ethyl acetate / diisopropyl ether 1.03 g of the final product are obtained (21% of theory). From 3- (13-bromo-6-ethyl-8a-ergolinyl) -1,1-diethyl-urea is analogous to the 3- (13-bromo-6-ethyl-2-vinyl-8a-ergolinyl) -1,1 -diethylurea in 27% yield.

Claims (4)

claims: 1. Compounds of the formula I NO H-N characterized in that R ^{2 is} de-alkyl, Сг-6-alkenyl or CHr-OC ^ -alkyl, R ^{4 is} hydrogen or bromine R ⁶ Cz-e-alkyl, C ^ -alkenyl or С ^ -СусІоаІкуІ-С ^ гу R ⁸ α-NH-CX-R ³ , 0 -NH-SO ₂ -NR ⁵ R ⁷ , CH ₂ -Y, β-CO-NH-gg. substituted phenyl, β-CO-NR ⁹ -CO-NHR ¹⁰ in which Oxygen or sulfur, hydrogen, C ₁ -C 4 alkyl optionally substituted by C 1 -C 4 -alkyl, -O- (CH ₂ ) _n -N (CH ₃ ) ₂ or -N (C ₁ -C 4 -alkyl) ₂ , and R ⁷ each Is hydrogen or C 1-4 -alkyl, hydrogen, OH, C 1-6 -acyl, CN, SCH ₃ or CONH ₂ and R ^{10 are} each C 1-4 -alkyl or - (CH ₂ ) _n -N (CH ₃ ) ₂ and η is 1 , 2,3 or 4 and C ₈ -C _{9 represents} a single or double bond, wherein when R ^{8 is} CH ₃ , CH ₂ OH or CH ₂ -OC ₁ -O-ACyI, C ₈ -C _{9 is} a double bond and if R ^{8 is} CH ₂ -CN, CH ₂ -SCH _{3 is} OdOrCH ₂ -CONH ₂ , C ₈ -C _{9 is} a single bond and R ^{8 is 8} , and their acid addition salts. 2. 3- (13-bromo-2-methyl-6-n-propyl-8a-ergolinyl) -l, 1-diethylurea 3- (13-bromo-6-ethyl-2-methyl-8a-ergolinyl) -1,1-diethylurea 3- {13-bromo-2-methyl-6-n-propyl-8a-ergolinyl) -1,1-diethyl-thiourea 3- (13,14-dibromo-2-methyl) 6-n-propyl-8a-ergolinyl) -1,1-diethylurea 3- (13-bromo-6-n-propyl) -2-vinyl-8a-ergolinyl) -1,1-diethylurea 3. Medicaments based on the compounds according to claim 1 and 4. A process for the preparation of the compounds according to claim 1, characterized in that a) a compound of formula II NO H-N wherein R ⁶ , R ⁸ and C ₈ -C _{9 have} the above meaning and R ^{2 is} C 1 -C 4 alkyl, brominated or b) a compound of formula III or its quaternary salts , 6 wherein H-N NO r ~ \ * 0 \ _J R, R and C ₈ -C _{9 have} the above meaning, substituted in the 2-position or c) a compound of formula IV