CA2025744A1 - 13-bromo-and 13,14-dibromoergolines, their production and use in medicinal agents - Google Patents
13-bromo-and 13,14-dibromoergolines, their production and use in medicinal agentsInfo
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- CA2025744A1 CA2025744A1 CA002025744A CA2025744A CA2025744A1 CA 2025744 A1 CA2025744 A1 CA 2025744A1 CA 002025744 A CA002025744 A CA 002025744A CA 2025744 A CA2025744 A CA 2025744A CA 2025744 A1 CA2025744 A1 CA 2025744A1
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- alkyl
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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
- C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8
- C07D457/06—Lysergic acid amides
-
- 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
-
- 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
-
- 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
- C07D457/02—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hydrocarbon or substituted hydrocarbon radicals, attached in position 8
-
- 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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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Abstract of the Disclosure The disclosure relates to compounds of Formula I
I
as well as their production and use in medicinal agents, and to intermediate products for the preparation of the compounds.
I
as well as their production and use in medicinal agents, and to intermediate products for the preparation of the compounds.
Description
c ~ ¦ f~
13-BROMO- AND 13,14-DIBROMOERGOLINES, THEIR
PRODUCTION AND USE IN MEDICINAL AGENTS
Backqround of the Inventio_ The invention relates to 13-bromo- and 13,14-dibromoergolines, their production and use in medicinalagents, as well as to intermediate products for their preparation.
It is known from DE-A-3,824,661.9, which corresponds to U.S. Serial No. 07/380,352, that longer-chain hydrocarbon residues in the 6-position enhance the dopamine-agonistic activity of ergolines. This effect is surprisingly also retained in ergolines brominated in the 13-position or in the 13- and 14-positions At the same time, the metabolic stability of the compounds is improved, thus attaining increased bioavailability.
Summary of the Invention The invention relates to compounds of Formula I
R B
wherein :
-R2 is C16-alkyl, C26-alkenyl or CH2-O-C1~-alkyl, R4 is hydrogen or bromine, R6 is C26-alkyl, C36-alkenyl or C35-cycloalkyl-Cl 2-alkyl, R8 is ~-NII-CX-R3, ~-NH-So2-NR5R7~ CH2-Y, B-CO-NH-optionally substituted phenyl, B-Co-NR9-co-NHR
wherein X is oxygen or sulfur, R3 is hydrogen, C16-alkyl, -O-(CH2) n N(CH3)2 or -N(C14-alkyl)2 or Cl4-alkoxy-substituted cl~6-alkYl, Rs and R7 each means hydrogen or C14-alkyl, Y is hydro~en, OH, O-C16-acyl, CN, SCH3 or CONH2, R9 and R10 each means C14-alkyl or -(CH2)n-N(CH3)2, and n stands for l, 2, 3 or 4, and C8---C9 ~ means a single or double bond wherein, if R8 is CH3, CH20H or CH2-O-C16-aCYl, C8 = C9 means a double bond and if R8 is CH2-CN, CH2-SCH3 or CH2-CONH2, C~___C9 iS a single bond and R8 is in the B-position.
The acid addition salts of compounds of Formula I
are also included in the compounds provided.
The invention also relates to methods of producing compounds of Formula I by (a) brominating compounds of Formula II, (b) substituting, in the 2-position, compounds of Formula III or (c) alkylating or alkenylating compounds of Formula IV. The intermediates of Formula III are also provided. Formulas II-IV are defined in the discussion which follows.
The invention also relates to pharmaceutical preparations which comprise a compound of Formula I, or an acid addition salt thereof, and a pharmaceutically compatible vehicle.
c~ c - ~ y l ~
Methods for treating Parkinson's disease and providing dopamine agonistic activity in a host are also provided wherein compounds of Formula I or acid addition salts thereof, are adminlstered to a host.
S The terms used herein to deEine substituents of Formula I have the following exemplary meanings. Alkyl means in each case a straight-chain or branched alkyl residue, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, 2,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, l-ethylbutyl, isopentyl, isoheptyl, 1-methyl-l-ethylpropyl.
In cases where R2 and R6 means an alkenyl residue, the latter preferably contains only one double bond, wherein the double bond in residue R6 cannot be proximate to the nitrogen atom. Examples of suitable alkenyl residues are: vinyl, l-propenyl, 2-propenyl, 1-methyl~2-propenyl, l-butenyl, methallyl.
Suitable C16-acyl groups are derived from aliphatic carboxylic acids, e.g., alkanoyl, such as, for example, formic acid, acetic acid, propionic acid, butyric acid, caproic acid.
The substituent of the phenyl residue, such as that of R8, can be in the o-, m- or p-position; suitable are Cl4-alkyl or -alkoxy, e.g., methyl, methoxy, or halogen, such as fluorine, chlorine, bromine or iodine.
The residues R9 and R10 are preferably different.
Hydrocarbons of up to 4 carbon atoms are to be considered preferred embodiments for R6 and R2.
The compounds of this invention can occur as E-isomers or Z-isomers or, if a chiral center is present in residue R2, as diastereomers and as mixtures thereof. The isomers and isomer mixtures are also encompassed by the present invention. The physiologically compatible acid addition salts are derived from the known inorganic and organic acids, such as, for example, hydrochloric acid, r ~
sulfuric acid, hydrobromic acid~ citric acid, maleie acid, fumaric acid, tartaric acid, etc.
The compounds o~ this invention as well as their acid addition salts exhibit, in particular, central dopaminergic effectiveness and therefore can be used as medieinal agents.
The dopamine-agonistie aetivity was determined with the aid of the method of automat:ie reeording of stereotypies in rats, diselosed by Horowski (Arzneim.
lo Forseh. 12:2281_22~6, 1978): Direetly after intraperitoneal administration of the test eompound and, respeetively, the vehiele, male Wistar rats (90-120 g) are plaeed singly into restraining cages of aerylie glass. By way of an eleetrodynamie reeording system mounted in front of the animal's head, the number of eontaets with a steel beaker with a eentral metal rod, as a eonsequenee of stereotypie ehewing, lieking and gnawing motions, is reeorded for a period of 60 minutes. The average values + S.E.M. of the number of eontaets during 60 minutes are ealculated for the various treatment groups, each encompassing 12 animals, and the signifieanee of the differenees among the average values of the various doses of test eompound as eompared with the vehiele-treated eontrol group is determined with the aid of simple varianee analysis in conjunction with the Dunnett test.
The results are set out in the table below.
T A B L E
Triggcring of Stereotypies in Rats Aftcr Intraperitoneal Treatment lith Vehicle and, Respcctivcly Various Doses of Ergoline Urea Derivatives (x: p ~ 0.05, xx: p < 0.01, Variance Analysis/Dunnett Test versus Control; n = Number of Animals) .. . . . ........... .. . . ... ...
Stereotypies (Counts per 60 Minutes) (Avera~e Value ~ S.E.M.) Dose of Test compound (3(13-bromo-6-n-ethyl-2-methyl-ergolinyl)1,1-diethvl urea (mqtk~ body ~ei~ht) n Control 0.025 0.1 0.39 1.56 6.25 4 U 12 2137 ~ ô49 1945 ~ 472 2470 ~ 548 7499 ~1342xx 8066 ~ 1248xx 7381 ~ 1336xx Since the compounds of this invention are distinguished especially by their dopamine-agonistic activity without the occurrence of strong ~-adrenergic effects, they are particularly well suited for the treatment of Parkinson's disease. The compounds of this invention can be administered at dosages of from 0.00001 to 0.1 mg/kg of host, per day, preferably from 0.001 to 0.1 mg/kg of host per day, analogously to the known agent Bromocryptin.
In order to utilize the compounds of this invention as medicinal agents, they are brought into the form of a pharmaceutical preparation containing, besides the active agent, pharmaceutical organic or inorganic, inert vehicles suitable for enteral or parenteral administration, such as, for example, water, gelatin, gum arabic, lactose, amylose, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. The compounds are administered at a dosage within the range of 0.001 to 10 mg~with a pharmaceutically compatible vehicle. The pharmaceutical preparations can be present in solid form, e.g., as tablets, dragees, suppositories, capsules, or in the liquid form, e.g., as solutions, suspensions or emulsions. Optionally, they contain moreover auxiliary materials, such as preservatives, stabilizers, surfactants or emulsifiers, salts for varying osmotic pressure, or buffers.
The compounds of this invention can be produced pursuant to methods known per se.
For example, compounds of this invention can be obtained by (a) brominating a compound of Formula II
f~ J, H
N
H-- R~
wherein R6, R8, ~a___C9 have the above meanin~s and R2 is C1.6--alXyl; or (b) substltuting, in the 2-position, a compound o~
Formulz~ III or its quaternary salt R ~
r ~ ~N -~
wherein R6, ~8 and CB ~=C9 ha~e the above me~ning~; or tc) alkylating or alkenyla~ ng a compound of Formula IV
. . .
;J ~ !i i ', 'Y, H ~:~
D r ~ "N-11 wherein R2, R8 and C~ C9 have the above meanings, and, if desired, subsequently thiolating a carbonyl group and/or forming the acid addition salts.
The compounds of Formula II are brominated according to method (a) in a strongly acidic solution, for example in trifluoroacetic acid or glacial acetic acid. Suitable brominating agents are elemental bromine, pyridine hydrobromide perbromide, or pyrrolidone hydroperbromide;
optionally, chlorinated hydrocarbons, such as chloroform, methylene chloride or ethers, such as tetrahydrofuran, dioxane and isopropyl ether can be added as solvents.
The bromination is conducted at temperatures of -20C to 80C, preferably at room temperature, and is finished after about 15 minutes up to one hour.
When adding molar amounts of brominating reagent, 13-bromo derivatives are mainly obtained; with the use of 2 moles of brominating reagent, 13,14-dibromo derivatives are isolated.
Introduction of the substituents in the 6- or 2-position can take place prior to or after bromination.
In accordance with method (b), the substituent R2 is introduced in accordance with the procedure described in German Patent Application P 38 24 661.9. In this process, the Mannich base of Formula III is substituted in nucleophilic fashion or is oxidized to the 2-formyl derivative which is subsequently reacted in a Wittig reaction to the desired compound of Formula I.
'J
The nucleophilic exchange takes place optionally after quaternization of the aminomethyl group in an inert solvent, such as alcohols, polar aprotic solvents, ethers, or chlorinated hydrocarbons at room temperature 5 or elevated temperature; alcoholates can be utilized as nucleophilic anions which can be subsequently converted into the CH2-OH group, if desired. For preparing the 2-methyl derivative, the quaternary salt can be reduced in polar solvents, such as alcohols, with sodium borohydride.
Oxidation to a 2-CHO compound can take place analogously to the process described in R.A. Jones et al., Synthe-tic Communications 16:1799 (1986) with pyrolusite or tert~butyl hypochlorite in inert solvents at room temperature. Conversion of the 2-formyl compounds to compounds of Formula I wherein RZ means an alkenyl residue can take place in a Wittig reaction, such as, for example, with alkyl triphenylphosphonium halogenide in polar solvents, such as cyclic and acyclic ethers, chlorinated hydrocarbons, dimethylformamide or dimethyl sulfoxide at temperatures of -50C up to the boiling temperature of the reaction mixture; for producing the ylene, strong bases are added, such as alkali alcoholates, lithium organyl, and others.
If the substituent R2 contains a hydroxy group, the latter can be reduced, e.g., by reaction with NaBII4 in glacial acetic acid to the corresponding 2-alkyl derivative, or it can be dehydrated with introduction of a double bond.
The production of substituents R2 hydroxylated in the l-position can be conducted, for example, by Grignardization or lithium alkylation of the 2-aldehydes or ketones. Grignardization can take place with the customary Grignard reagents, such as alkyl magnesium halides in an aprotic solvent, such as cyclic and acyclic C~' . ~, .; ,~ . i:!
ethers at low temperatures (-70C to 0C). The reaction with alkyllithium takes place under analogous conditions.
Substitution in the 6-position according to method (c) can be performed, for example, in accordance with the process described in ~. Cerny et al., Coll. Czech. Chem.
Comm. 49:2828 (1984) or the procedure disclosed in EP-21,206, by reacting the 6H compound of Formula IV with the corresponding R6-halogenides (bromides, chlorides, iodides). Suitably, the reaction is carried out in an inert solvent, such as dimethyl sulfoxide, dimethylformamide, acetonitrile or nitromethane in the presence of bases, such as alkali hydroxides or carbonates.
Conversion of the amides and urea dsrivatives into the thioamides and thiourea derivatives can take place, for example, according to the procedure disclosed in EP-A-217,730 by reaction with phosphorus oxychloride and thiolating agent, or with Lawesson's reagent (2,~-bis(4-methoxyphenyl-1,3-dithiophosphetane-2,4-disulfide)) according to Fieser and Fieser, "Reagents for Org.
Synth." IX, 49. The compounds of Formula I are isolated either as the free bases or in the form of their physiologically compatible acid addition salts.
For the formation of salts, a compound of Formula I
is dissolved, for example, in a small amount of methanol or methylene chloride and combined with a concentrated solution of the desired acid.
The isomer mixtures can be separated according to the usual methods, such as, for example, crystallization, chromatography or salt formation, into the diastereomers and/or trans/cis isomers.
The invention also encompasses the compounds of Formula III representing valuable intermediates for the preparation of pharmacologically effective compounds.
The conversion of the intermediate products takes place according to the methods described hereinabove.
6 ~ ' 7 ~ r The starting compounds are either known or can be prepared analogously to known compounds or analogous to methods described herein. For example, the bromination of the starting compounds can be effected in accordance with the process described in E:P-A-217,734, and the 2-morpholinomethyl group can be introduced pursuant to the method disclosed in DE-A-3,824,661.9.
The examples set forth below are to explain the process of this invention.
Without further elaboration, ik is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight.
The entire disclosures of all applications, patents and publications, cited above and below, and of corresponding application Federal Republic of Germany P 39 31 819.2, filed September 20, 1989, are hereby incorporated by reference.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
,. ..
.
12 ~ ~ J^~;d ~ ,~
Example 1 3-(13-Bromo-2-me-thyl-6-n-propyl-8~-ergolinyl)-l,l-diethylurea ____________________________________ _________ 382 mg of 1,1-diethyl-3-(2-methyl-6-n-propyl-8~-ergolinyl)urea (1 mmol) is dissolved in 20 ml of trifluoroacetic acid and, at room temperature, 1 ml of a l-molar solution of bromine in dichloromethane is added dropwise. The mixture is stirred for 30 minutes, then combined with ice, made alkaline with concen-trated ammonia solution, 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); after crystallization from ethyl acetate, 146 mg ~31~ of theory~, [~]D = -11 (0.5% in chloroform).
Analogously, the following 13-bromo derivatives are prepared from the respective starting compounds:
3-(13-bromo-2-ethyl-6-n-propyl-8a-ergolinyl)-1,1-diethylurea, yield 42%;
3-(13-bromo-6-ethyl-2-methyl-8~-ergolinyl~-1,1-diethylurea, yield 26%, [~]D = -17 (0.5% in chloroform);
N-(13-bromo-2-me-thyl-6-n-propyl-8~-ergolinyl)formamide, yield 47%;
N-(13-bromo-2-ethyl-6-n-propyl-8~-ergolinyl)formamide, yield 35%;
N-(13-bromo-2-methyl-6-n-propyl-8~-ergolinyl)-2-methyl-propionamide, yield 28%, [~]D = +13 (0.5% in chloroform);
- :L3 - ~3 i., ~ 7 . ~
N-(13-bromo-2-methyl-6-n~propyl-~-ergolinyl)-2-methyl-2-ethylbutyrylamide, yield 47%;
N-(13-bromo-2-methyl-6-n-propyl-8~-ergolinyl)methoxy-acetamide, yield 32~, [~]D = ~~7 (0-5% in chloroform);
N-(13-bromo-6-ethyl-2-methyl-8~-ergolinyl)formamide, yield 48~;
3-(13-bromo-2-methyl-6-n-propyl-8a-ergolinyl)-1,1-diethylthiourea, yield 14%, [~]D = -~20 (0.5% in chloroform);
10 (13-bromo-2-methyl-6-n-propyl-8~-ergolinylamino)-(dimethylamino)sulfone, yield 41%;
13-bromo-2-methyl-8~-methylthiomethyl-6-n-propylergoline, yield 16%, [~]D = -46 (0.1% in chloroform);
13-bromo-6-cyclopropylmethyl-2-methyl-8~-methylthio-15 methylergoline, yield 49%, [a]D = -68 (0.1% in chloroform);
13-bromo-6-ethyl-2-methyl-8~-methylthiomethylergoline, yield 29%;
13-bromo-6-cyclopropylmethyl-2-ethyl-8~-methylthio-20 methylergoline, yield 31%, 1~]D = -60 (0.1% in chloroform);
13-bromo-2-ethyl-8~-methylthiomethyl-6-n-propylergoline, yield 42%, [~]D = ~57 (0.1% in chloroform);
(13-bromo-2-methyl-6-n-propyl-8~-ergolinyl)aceto-25 nitrile, yield 65%, [~]D = -42 (0.5% in chloroform~;
(13-bromo-6-ethyl-2-methyl-8~-ergolinyl)acetonitrile, yield 47%;
f~/ ~ ~ J _ i (13-bromo-2-ethyl-6-n-propyl-8~-ergolinyl)acetonitrile, yield 40%, [a]D = -40 (0.5% in chloroform);
(13-bromo-2-methyl-6-n-propyl-8~-ergolinyl)acetamide, yield 36~o, [a]D = -47 (0.5~i in pyridine);
(13-bromo-6-ethyl-2-me-thyl-8f~i-ergolinyl)acetamide, yield 52%;
(13-bromo-2-ethyl-6-n-propyl-8~-ergolinyl)acetamide, yield 20%, [a]D = -28 (O.l~i in pyridine);
13-bromo-2-methyl-6-n-propyl-8~-ergolinecarboxylic acid (4-fluoroanilide), yield 45%, [a]D = -102 (0.1% in pyridine);
13-bromo-8,9-didehydro-2,8-dimethyl-6-n-propylergoline, yield 38%, [a]D = -51 (O.l~i in chloroform);
13-bromo-8,9-didehydro-6-ethyl-2,8-dimethylergoline, lS yield 11%, [a]D = -36 (0.1% in chloroform);
13-bromo-8,9-didehydro-2,6-diethyl-8-methylergoline, yield 19%;
13-bromo-8,9-didehydro-8-hydroxymethyl-2-methyl-6-n-propylergoline, yield 43%, [a]D = -51 (0.1% in pyridine);
13-bromo-8,9-didehydro-6-ethyl-8-hydroxymethyl-2-methylergoline, yield 37%.
-- 1 5 -- f~ J J ,J) ~
Example 2 3-(13,14-Dibromo-2-methyl-6-n-propyl-8~-ergolinyl)-l,l-diethylurea ____________________________._______ _______________ 382 mg of 1,1-diethyl-3-12-me-thyl-6-n-propyl-8~-ergolinyl)urea (1 mmol) is dissolved in 20 ml of trifluoroacetic acid and, at room temperature, 2 ml of a l-molar solution of bromine in dichloromethane is added dropwise. The mixture is stirred for 30 minutes, then combined with ice, made alkaline with concentrated ammonia solution, 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%, [~]D = -14 (0.5% in chloroform).
The following compounds are prepared analogously:
3-(13,14-dibromo-6-ethyl-2-methyl-8~-ergolinyl)-l,l-diethylurea, yield 49%~ [~]D = ~ (0-5% in chloroform);
N-(13,14-dibromo-6-ethyl-2-methyl-8~-ergolinyl)form-amide, yield 63%;
N-(13,14-dibromo-2-methyl-6-n-propyl-8~-ergolinyl)-methoxyacetamide, yield 67%, [~]D = +2 (0.5% in chloroform);
13,14-dibromo-6-ethyl-2-methyl-8~-methylthiomethyl-ergoline, yield 54%;
13,14-dibromo-2-methyl-6-n-propyl-8~-methylthiomethyl-6-n-propylergoline, yield 36%;
~ .
- 16 - ~ 3 ,~
6-cyclopropylmethyl-13,1~-dibromo-2-ethyl-8~-methylthiomethylergoline, yield 62~;
(13,14-dibromo-6-ethyl-2-methyl-8~-ergolinyl)acet-amide, yield 43%;
13,14-dibromo-8,9-didehydro-2,8-dimethyl-6-n-propyl-ergoline, yield 51%.
Example 3 3-(13-Bromo-6-n-propyl-2-vinyl-8~-ergolinyl)-l,l-diethylurea ________ __ _________________________________ By heating to 100 C, 4.47 g of 3-(13-bromo-6-n-propyl-8~-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 anhydrous dimethylformamide. After 30 minutes, the mixture is cooled, poured on ice, made alkaline with concentrated ammonia solution, and extracted with toluene. The organic phases are dried with sodium sulfate and evaporated, the residue is dissolved in 30 ml of trifluoroacetic acid and heated for 30 minutes to 60 C. This reaction mixture is again poured on ice, gently made alkaline with concentrated ammonia solution, and extracted by sha~ing with dichloromethane. The organic phases are dried as above and concentrated by evaporation, the residue is chromatographed on silica gel with dichloromethane/methanol, thus obtaining 3.11 g of oily 3-(13-bromo-2-morpholinomethyl-6-n-propyl-8~-ergolinyl)-1,1-diethylurea (57~ of theory).
This crude produc-t is dissolved in 150 ml of tetra-hydrofuran, the solution is cooled -to -40 C, combined with 3 ml of triethylamine, and then a solution of 1 ml of tert-butyl hypochlorite in 15 ml of tetrahydrofuran is quickly added dropwise. After 30 minutes of agita-tion, the mixture is poured on ice, made alkaline with .
.
25~ str~ J~ all~lllollia~ ancl extracted l)y shalcincJ with ethyl acetate. lrlle orgallic pil~lses are dried wi-th sodium sulfate and the solvent removecl by c1istillation;
the resicl~le is crude 3-(13-bromo-2-formyl-6-n-propyl-8~-ergolinyl)-1,1-diethylurea, yield 2.0 g.
10 g of methyltriphenylphospllonium bromide (2~ mmol) is s~ls~)ellded in 100 m] oE anhydrous tetra-hydrofuran, cooled to -70 C, and 3.45 g of potassium tert-buty]ate is added. ~fter L5 minutes of agitation, a solution of -the crude product in 50 ml of anhydrous tetrahydrofuran is added dropwise and the mixture is allowed to warm up to 0 C wi-thin three hours. Then the mixture is combined with satura-ted sodium chloride solution and extracted with ethyl acetate. The organic phases are dried and evapora-ted, the residue is chroma'.ographed on silica gel with dichloromethane/meth-anol. Yield: 1.52 g. Crystalliza-tion Erom ethyl acetate/diisorpopyl ether yields 1.03 g of the final product (21% of theory).
From 3-(13-bromo-6-ethyl-8~-ergolinyl)-1,1-diethylurea, 3-(13-bromo-6-ethyl-2-vinyl-8a-ergolinyl)-l,l-diethylurea is analogously produced in a 27% yield.
r~
From the foregoing description, one skllled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
13-BROMO- AND 13,14-DIBROMOERGOLINES, THEIR
PRODUCTION AND USE IN MEDICINAL AGENTS
Backqround of the Inventio_ The invention relates to 13-bromo- and 13,14-dibromoergolines, their production and use in medicinalagents, as well as to intermediate products for their preparation.
It is known from DE-A-3,824,661.9, which corresponds to U.S. Serial No. 07/380,352, that longer-chain hydrocarbon residues in the 6-position enhance the dopamine-agonistic activity of ergolines. This effect is surprisingly also retained in ergolines brominated in the 13-position or in the 13- and 14-positions At the same time, the metabolic stability of the compounds is improved, thus attaining increased bioavailability.
Summary of the Invention The invention relates to compounds of Formula I
R B
wherein :
-R2 is C16-alkyl, C26-alkenyl or CH2-O-C1~-alkyl, R4 is hydrogen or bromine, R6 is C26-alkyl, C36-alkenyl or C35-cycloalkyl-Cl 2-alkyl, R8 is ~-NII-CX-R3, ~-NH-So2-NR5R7~ CH2-Y, B-CO-NH-optionally substituted phenyl, B-Co-NR9-co-NHR
wherein X is oxygen or sulfur, R3 is hydrogen, C16-alkyl, -O-(CH2) n N(CH3)2 or -N(C14-alkyl)2 or Cl4-alkoxy-substituted cl~6-alkYl, Rs and R7 each means hydrogen or C14-alkyl, Y is hydro~en, OH, O-C16-acyl, CN, SCH3 or CONH2, R9 and R10 each means C14-alkyl or -(CH2)n-N(CH3)2, and n stands for l, 2, 3 or 4, and C8---C9 ~ means a single or double bond wherein, if R8 is CH3, CH20H or CH2-O-C16-aCYl, C8 = C9 means a double bond and if R8 is CH2-CN, CH2-SCH3 or CH2-CONH2, C~___C9 iS a single bond and R8 is in the B-position.
The acid addition salts of compounds of Formula I
are also included in the compounds provided.
The invention also relates to methods of producing compounds of Formula I by (a) brominating compounds of Formula II, (b) substituting, in the 2-position, compounds of Formula III or (c) alkylating or alkenylating compounds of Formula IV. The intermediates of Formula III are also provided. Formulas II-IV are defined in the discussion which follows.
The invention also relates to pharmaceutical preparations which comprise a compound of Formula I, or an acid addition salt thereof, and a pharmaceutically compatible vehicle.
c~ c - ~ y l ~
Methods for treating Parkinson's disease and providing dopamine agonistic activity in a host are also provided wherein compounds of Formula I or acid addition salts thereof, are adminlstered to a host.
S The terms used herein to deEine substituents of Formula I have the following exemplary meanings. Alkyl means in each case a straight-chain or branched alkyl residue, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, 2,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, l-ethylbutyl, isopentyl, isoheptyl, 1-methyl-l-ethylpropyl.
In cases where R2 and R6 means an alkenyl residue, the latter preferably contains only one double bond, wherein the double bond in residue R6 cannot be proximate to the nitrogen atom. Examples of suitable alkenyl residues are: vinyl, l-propenyl, 2-propenyl, 1-methyl~2-propenyl, l-butenyl, methallyl.
Suitable C16-acyl groups are derived from aliphatic carboxylic acids, e.g., alkanoyl, such as, for example, formic acid, acetic acid, propionic acid, butyric acid, caproic acid.
The substituent of the phenyl residue, such as that of R8, can be in the o-, m- or p-position; suitable are Cl4-alkyl or -alkoxy, e.g., methyl, methoxy, or halogen, such as fluorine, chlorine, bromine or iodine.
The residues R9 and R10 are preferably different.
Hydrocarbons of up to 4 carbon atoms are to be considered preferred embodiments for R6 and R2.
The compounds of this invention can occur as E-isomers or Z-isomers or, if a chiral center is present in residue R2, as diastereomers and as mixtures thereof. The isomers and isomer mixtures are also encompassed by the present invention. The physiologically compatible acid addition salts are derived from the known inorganic and organic acids, such as, for example, hydrochloric acid, r ~
sulfuric acid, hydrobromic acid~ citric acid, maleie acid, fumaric acid, tartaric acid, etc.
The compounds o~ this invention as well as their acid addition salts exhibit, in particular, central dopaminergic effectiveness and therefore can be used as medieinal agents.
The dopamine-agonistie aetivity was determined with the aid of the method of automat:ie reeording of stereotypies in rats, diselosed by Horowski (Arzneim.
lo Forseh. 12:2281_22~6, 1978): Direetly after intraperitoneal administration of the test eompound and, respeetively, the vehiele, male Wistar rats (90-120 g) are plaeed singly into restraining cages of aerylie glass. By way of an eleetrodynamie reeording system mounted in front of the animal's head, the number of eontaets with a steel beaker with a eentral metal rod, as a eonsequenee of stereotypie ehewing, lieking and gnawing motions, is reeorded for a period of 60 minutes. The average values + S.E.M. of the number of eontaets during 60 minutes are ealculated for the various treatment groups, each encompassing 12 animals, and the signifieanee of the differenees among the average values of the various doses of test eompound as eompared with the vehiele-treated eontrol group is determined with the aid of simple varianee analysis in conjunction with the Dunnett test.
The results are set out in the table below.
T A B L E
Triggcring of Stereotypies in Rats Aftcr Intraperitoneal Treatment lith Vehicle and, Respcctivcly Various Doses of Ergoline Urea Derivatives (x: p ~ 0.05, xx: p < 0.01, Variance Analysis/Dunnett Test versus Control; n = Number of Animals) .. . . . ........... .. . . ... ...
Stereotypies (Counts per 60 Minutes) (Avera~e Value ~ S.E.M.) Dose of Test compound (3(13-bromo-6-n-ethyl-2-methyl-ergolinyl)1,1-diethvl urea (mqtk~ body ~ei~ht) n Control 0.025 0.1 0.39 1.56 6.25 4 U 12 2137 ~ ô49 1945 ~ 472 2470 ~ 548 7499 ~1342xx 8066 ~ 1248xx 7381 ~ 1336xx Since the compounds of this invention are distinguished especially by their dopamine-agonistic activity without the occurrence of strong ~-adrenergic effects, they are particularly well suited for the treatment of Parkinson's disease. The compounds of this invention can be administered at dosages of from 0.00001 to 0.1 mg/kg of host, per day, preferably from 0.001 to 0.1 mg/kg of host per day, analogously to the known agent Bromocryptin.
In order to utilize the compounds of this invention as medicinal agents, they are brought into the form of a pharmaceutical preparation containing, besides the active agent, pharmaceutical organic or inorganic, inert vehicles suitable for enteral or parenteral administration, such as, for example, water, gelatin, gum arabic, lactose, amylose, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. The compounds are administered at a dosage within the range of 0.001 to 10 mg~with a pharmaceutically compatible vehicle. The pharmaceutical preparations can be present in solid form, e.g., as tablets, dragees, suppositories, capsules, or in the liquid form, e.g., as solutions, suspensions or emulsions. Optionally, they contain moreover auxiliary materials, such as preservatives, stabilizers, surfactants or emulsifiers, salts for varying osmotic pressure, or buffers.
The compounds of this invention can be produced pursuant to methods known per se.
For example, compounds of this invention can be obtained by (a) brominating a compound of Formula II
f~ J, H
N
H-- R~
wherein R6, R8, ~a___C9 have the above meanin~s and R2 is C1.6--alXyl; or (b) substltuting, in the 2-position, a compound o~
Formulz~ III or its quaternary salt R ~
r ~ ~N -~
wherein R6, ~8 and CB ~=C9 ha~e the above me~ning~; or tc) alkylating or alkenyla~ ng a compound of Formula IV
. . .
;J ~ !i i ', 'Y, H ~:~
D r ~ "N-11 wherein R2, R8 and C~ C9 have the above meanings, and, if desired, subsequently thiolating a carbonyl group and/or forming the acid addition salts.
The compounds of Formula II are brominated according to method (a) in a strongly acidic solution, for example in trifluoroacetic acid or glacial acetic acid. Suitable brominating agents are elemental bromine, pyridine hydrobromide perbromide, or pyrrolidone hydroperbromide;
optionally, chlorinated hydrocarbons, such as chloroform, methylene chloride or ethers, such as tetrahydrofuran, dioxane and isopropyl ether can be added as solvents.
The bromination is conducted at temperatures of -20C to 80C, preferably at room temperature, and is finished after about 15 minutes up to one hour.
When adding molar amounts of brominating reagent, 13-bromo derivatives are mainly obtained; with the use of 2 moles of brominating reagent, 13,14-dibromo derivatives are isolated.
Introduction of the substituents in the 6- or 2-position can take place prior to or after bromination.
In accordance with method (b), the substituent R2 is introduced in accordance with the procedure described in German Patent Application P 38 24 661.9. In this process, the Mannich base of Formula III is substituted in nucleophilic fashion or is oxidized to the 2-formyl derivative which is subsequently reacted in a Wittig reaction to the desired compound of Formula I.
'J
The nucleophilic exchange takes place optionally after quaternization of the aminomethyl group in an inert solvent, such as alcohols, polar aprotic solvents, ethers, or chlorinated hydrocarbons at room temperature 5 or elevated temperature; alcoholates can be utilized as nucleophilic anions which can be subsequently converted into the CH2-OH group, if desired. For preparing the 2-methyl derivative, the quaternary salt can be reduced in polar solvents, such as alcohols, with sodium borohydride.
Oxidation to a 2-CHO compound can take place analogously to the process described in R.A. Jones et al., Synthe-tic Communications 16:1799 (1986) with pyrolusite or tert~butyl hypochlorite in inert solvents at room temperature. Conversion of the 2-formyl compounds to compounds of Formula I wherein RZ means an alkenyl residue can take place in a Wittig reaction, such as, for example, with alkyl triphenylphosphonium halogenide in polar solvents, such as cyclic and acyclic ethers, chlorinated hydrocarbons, dimethylformamide or dimethyl sulfoxide at temperatures of -50C up to the boiling temperature of the reaction mixture; for producing the ylene, strong bases are added, such as alkali alcoholates, lithium organyl, and others.
If the substituent R2 contains a hydroxy group, the latter can be reduced, e.g., by reaction with NaBII4 in glacial acetic acid to the corresponding 2-alkyl derivative, or it can be dehydrated with introduction of a double bond.
The production of substituents R2 hydroxylated in the l-position can be conducted, for example, by Grignardization or lithium alkylation of the 2-aldehydes or ketones. Grignardization can take place with the customary Grignard reagents, such as alkyl magnesium halides in an aprotic solvent, such as cyclic and acyclic C~' . ~, .; ,~ . i:!
ethers at low temperatures (-70C to 0C). The reaction with alkyllithium takes place under analogous conditions.
Substitution in the 6-position according to method (c) can be performed, for example, in accordance with the process described in ~. Cerny et al., Coll. Czech. Chem.
Comm. 49:2828 (1984) or the procedure disclosed in EP-21,206, by reacting the 6H compound of Formula IV with the corresponding R6-halogenides (bromides, chlorides, iodides). Suitably, the reaction is carried out in an inert solvent, such as dimethyl sulfoxide, dimethylformamide, acetonitrile or nitromethane in the presence of bases, such as alkali hydroxides or carbonates.
Conversion of the amides and urea dsrivatives into the thioamides and thiourea derivatives can take place, for example, according to the procedure disclosed in EP-A-217,730 by reaction with phosphorus oxychloride and thiolating agent, or with Lawesson's reagent (2,~-bis(4-methoxyphenyl-1,3-dithiophosphetane-2,4-disulfide)) according to Fieser and Fieser, "Reagents for Org.
Synth." IX, 49. The compounds of Formula I are isolated either as the free bases or in the form of their physiologically compatible acid addition salts.
For the formation of salts, a compound of Formula I
is dissolved, for example, in a small amount of methanol or methylene chloride and combined with a concentrated solution of the desired acid.
The isomer mixtures can be separated according to the usual methods, such as, for example, crystallization, chromatography or salt formation, into the diastereomers and/or trans/cis isomers.
The invention also encompasses the compounds of Formula III representing valuable intermediates for the preparation of pharmacologically effective compounds.
The conversion of the intermediate products takes place according to the methods described hereinabove.
6 ~ ' 7 ~ r The starting compounds are either known or can be prepared analogously to known compounds or analogous to methods described herein. For example, the bromination of the starting compounds can be effected in accordance with the process described in E:P-A-217,734, and the 2-morpholinomethyl group can be introduced pursuant to the method disclosed in DE-A-3,824,661.9.
The examples set forth below are to explain the process of this invention.
Without further elaboration, ik is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight.
The entire disclosures of all applications, patents and publications, cited above and below, and of corresponding application Federal Republic of Germany P 39 31 819.2, filed September 20, 1989, are hereby incorporated by reference.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
,. ..
.
12 ~ ~ J^~;d ~ ,~
Example 1 3-(13-Bromo-2-me-thyl-6-n-propyl-8~-ergolinyl)-l,l-diethylurea ____________________________________ _________ 382 mg of 1,1-diethyl-3-(2-methyl-6-n-propyl-8~-ergolinyl)urea (1 mmol) is dissolved in 20 ml of trifluoroacetic acid and, at room temperature, 1 ml of a l-molar solution of bromine in dichloromethane is added dropwise. The mixture is stirred for 30 minutes, then combined with ice, made alkaline with concen-trated ammonia solution, 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); after crystallization from ethyl acetate, 146 mg ~31~ of theory~, [~]D = -11 (0.5% in chloroform).
Analogously, the following 13-bromo derivatives are prepared from the respective starting compounds:
3-(13-bromo-2-ethyl-6-n-propyl-8a-ergolinyl)-1,1-diethylurea, yield 42%;
3-(13-bromo-6-ethyl-2-methyl-8~-ergolinyl~-1,1-diethylurea, yield 26%, [~]D = -17 (0.5% in chloroform);
N-(13-bromo-2-me-thyl-6-n-propyl-8~-ergolinyl)formamide, yield 47%;
N-(13-bromo-2-ethyl-6-n-propyl-8~-ergolinyl)formamide, yield 35%;
N-(13-bromo-2-methyl-6-n-propyl-8~-ergolinyl)-2-methyl-propionamide, yield 28%, [~]D = +13 (0.5% in chloroform);
- :L3 - ~3 i., ~ 7 . ~
N-(13-bromo-2-methyl-6-n~propyl-~-ergolinyl)-2-methyl-2-ethylbutyrylamide, yield 47%;
N-(13-bromo-2-methyl-6-n-propyl-8~-ergolinyl)methoxy-acetamide, yield 32~, [~]D = ~~7 (0-5% in chloroform);
N-(13-bromo-6-ethyl-2-methyl-8~-ergolinyl)formamide, yield 48~;
3-(13-bromo-2-methyl-6-n-propyl-8a-ergolinyl)-1,1-diethylthiourea, yield 14%, [~]D = -~20 (0.5% in chloroform);
10 (13-bromo-2-methyl-6-n-propyl-8~-ergolinylamino)-(dimethylamino)sulfone, yield 41%;
13-bromo-2-methyl-8~-methylthiomethyl-6-n-propylergoline, yield 16%, [~]D = -46 (0.1% in chloroform);
13-bromo-6-cyclopropylmethyl-2-methyl-8~-methylthio-15 methylergoline, yield 49%, [a]D = -68 (0.1% in chloroform);
13-bromo-6-ethyl-2-methyl-8~-methylthiomethylergoline, yield 29%;
13-bromo-6-cyclopropylmethyl-2-ethyl-8~-methylthio-20 methylergoline, yield 31%, 1~]D = -60 (0.1% in chloroform);
13-bromo-2-ethyl-8~-methylthiomethyl-6-n-propylergoline, yield 42%, [~]D = ~57 (0.1% in chloroform);
(13-bromo-2-methyl-6-n-propyl-8~-ergolinyl)aceto-25 nitrile, yield 65%, [~]D = -42 (0.5% in chloroform~;
(13-bromo-6-ethyl-2-methyl-8~-ergolinyl)acetonitrile, yield 47%;
f~/ ~ ~ J _ i (13-bromo-2-ethyl-6-n-propyl-8~-ergolinyl)acetonitrile, yield 40%, [a]D = -40 (0.5% in chloroform);
(13-bromo-2-methyl-6-n-propyl-8~-ergolinyl)acetamide, yield 36~o, [a]D = -47 (0.5~i in pyridine);
(13-bromo-6-ethyl-2-me-thyl-8f~i-ergolinyl)acetamide, yield 52%;
(13-bromo-2-ethyl-6-n-propyl-8~-ergolinyl)acetamide, yield 20%, [a]D = -28 (O.l~i in pyridine);
13-bromo-2-methyl-6-n-propyl-8~-ergolinecarboxylic acid (4-fluoroanilide), yield 45%, [a]D = -102 (0.1% in pyridine);
13-bromo-8,9-didehydro-2,8-dimethyl-6-n-propylergoline, yield 38%, [a]D = -51 (O.l~i in chloroform);
13-bromo-8,9-didehydro-6-ethyl-2,8-dimethylergoline, lS yield 11%, [a]D = -36 (0.1% in chloroform);
13-bromo-8,9-didehydro-2,6-diethyl-8-methylergoline, yield 19%;
13-bromo-8,9-didehydro-8-hydroxymethyl-2-methyl-6-n-propylergoline, yield 43%, [a]D = -51 (0.1% in pyridine);
13-bromo-8,9-didehydro-6-ethyl-8-hydroxymethyl-2-methylergoline, yield 37%.
-- 1 5 -- f~ J J ,J) ~
Example 2 3-(13,14-Dibromo-2-methyl-6-n-propyl-8~-ergolinyl)-l,l-diethylurea ____________________________._______ _______________ 382 mg of 1,1-diethyl-3-12-me-thyl-6-n-propyl-8~-ergolinyl)urea (1 mmol) is dissolved in 20 ml of trifluoroacetic acid and, at room temperature, 2 ml of a l-molar solution of bromine in dichloromethane is added dropwise. The mixture is stirred for 30 minutes, then combined with ice, made alkaline with concentrated ammonia solution, 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%, [~]D = -14 (0.5% in chloroform).
The following compounds are prepared analogously:
3-(13,14-dibromo-6-ethyl-2-methyl-8~-ergolinyl)-l,l-diethylurea, yield 49%~ [~]D = ~ (0-5% in chloroform);
N-(13,14-dibromo-6-ethyl-2-methyl-8~-ergolinyl)form-amide, yield 63%;
N-(13,14-dibromo-2-methyl-6-n-propyl-8~-ergolinyl)-methoxyacetamide, yield 67%, [~]D = +2 (0.5% in chloroform);
13,14-dibromo-6-ethyl-2-methyl-8~-methylthiomethyl-ergoline, yield 54%;
13,14-dibromo-2-methyl-6-n-propyl-8~-methylthiomethyl-6-n-propylergoline, yield 36%;
~ .
- 16 - ~ 3 ,~
6-cyclopropylmethyl-13,1~-dibromo-2-ethyl-8~-methylthiomethylergoline, yield 62~;
(13,14-dibromo-6-ethyl-2-methyl-8~-ergolinyl)acet-amide, yield 43%;
13,14-dibromo-8,9-didehydro-2,8-dimethyl-6-n-propyl-ergoline, yield 51%.
Example 3 3-(13-Bromo-6-n-propyl-2-vinyl-8~-ergolinyl)-l,l-diethylurea ________ __ _________________________________ By heating to 100 C, 4.47 g of 3-(13-bromo-6-n-propyl-8~-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 anhydrous dimethylformamide. After 30 minutes, the mixture is cooled, poured on ice, made alkaline with concentrated ammonia solution, and extracted with toluene. The organic phases are dried with sodium sulfate and evaporated, the residue is dissolved in 30 ml of trifluoroacetic acid and heated for 30 minutes to 60 C. This reaction mixture is again poured on ice, gently made alkaline with concentrated ammonia solution, and extracted by sha~ing with dichloromethane. The organic phases are dried as above and concentrated by evaporation, the residue is chromatographed on silica gel with dichloromethane/methanol, thus obtaining 3.11 g of oily 3-(13-bromo-2-morpholinomethyl-6-n-propyl-8~-ergolinyl)-1,1-diethylurea (57~ of theory).
This crude produc-t is dissolved in 150 ml of tetra-hydrofuran, the solution is cooled -to -40 C, combined with 3 ml of triethylamine, and then a solution of 1 ml of tert-butyl hypochlorite in 15 ml of tetrahydrofuran is quickly added dropwise. After 30 minutes of agita-tion, the mixture is poured on ice, made alkaline with .
.
25~ str~ J~ all~lllollia~ ancl extracted l)y shalcincJ with ethyl acetate. lrlle orgallic pil~lses are dried wi-th sodium sulfate and the solvent removecl by c1istillation;
the resicl~le is crude 3-(13-bromo-2-formyl-6-n-propyl-8~-ergolinyl)-1,1-diethylurea, yield 2.0 g.
10 g of methyltriphenylphospllonium bromide (2~ mmol) is s~ls~)ellded in 100 m] oE anhydrous tetra-hydrofuran, cooled to -70 C, and 3.45 g of potassium tert-buty]ate is added. ~fter L5 minutes of agitation, a solution of -the crude product in 50 ml of anhydrous tetrahydrofuran is added dropwise and the mixture is allowed to warm up to 0 C wi-thin three hours. Then the mixture is combined with satura-ted sodium chloride solution and extracted with ethyl acetate. The organic phases are dried and evapora-ted, the residue is chroma'.ographed on silica gel with dichloromethane/meth-anol. Yield: 1.52 g. Crystalliza-tion Erom ethyl acetate/diisorpopyl ether yields 1.03 g of the final product (21% of theory).
From 3-(13-bromo-6-ethyl-8~-ergolinyl)-1,1-diethylurea, 3-(13-bromo-6-ethyl-2-vinyl-8a-ergolinyl)-l,l-diethylurea is analogously produced in a 27% yield.
r~
From the foregoing description, one skllled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
Claims (15)
1. A compound of Formula I
I
wherein R2 is C1-6-alkyl, C2-6-alkenyl or CH2-O-C1-4-alkyl, R4 is hydrogen or bromine, R6 is C2-6-alkyl, C3-6-alkenyl or C3-5-cycloalkyl-C1-2-alkyl, R8 is .alpha.-NH-CX-R3, .alpha.-NH-SO2-NR5R7, CH2-Y, .beta.-CO-NH-phenyl (substituted or unsubstituted), or .beta.-CO-NR9-CO-NHR10 wherein X is oxygen or sulfur, R3 is hydrogen, C1-6-alkyl, -O-(CH2) n-N(CH3)2, -N(C1-4-alkyl)2 or C1-4-alkoxy substituted C1-6-alkyl, R5 and R7 each independently means hydrogen or C1-4-alkyl, Y is hydrogen, OH, O-C1-6-alkanoyl, CN, SCH3 or CONH2, R9 and R10 each independently means C1-4-alkyl or -(CH2)n-N(CH3)2, and n stands for 1, 2, 3 or 4, and means a single or double bond wherein, if R8 is CH3, CH2OH or CH2-O-C1-6 acyl, is a double bond and if R8 is CH2-CN, CH2-SCH3 or CH2-CONH2, is a single bond and R8 is in the .beta.-position, or a pharmaceutically acceptable acid addition salt thereof.
I
wherein R2 is C1-6-alkyl, C2-6-alkenyl or CH2-O-C1-4-alkyl, R4 is hydrogen or bromine, R6 is C2-6-alkyl, C3-6-alkenyl or C3-5-cycloalkyl-C1-2-alkyl, R8 is .alpha.-NH-CX-R3, .alpha.-NH-SO2-NR5R7, CH2-Y, .beta.-CO-NH-phenyl (substituted or unsubstituted), or .beta.-CO-NR9-CO-NHR10 wherein X is oxygen or sulfur, R3 is hydrogen, C1-6-alkyl, -O-(CH2) n-N(CH3)2, -N(C1-4-alkyl)2 or C1-4-alkoxy substituted C1-6-alkyl, R5 and R7 each independently means hydrogen or C1-4-alkyl, Y is hydrogen, OH, O-C1-6-alkanoyl, CN, SCH3 or CONH2, R9 and R10 each independently means C1-4-alkyl or -(CH2)n-N(CH3)2, and n stands for 1, 2, 3 or 4, and means a single or double bond wherein, if R8 is CH3, CH2OH or CH2-O-C1-6 acyl, is a double bond and if R8 is CH2-CN, CH2-SCH3 or CH2-CONH2, is a single bond and R8 is in the .beta.-position, or a pharmaceutically acceptable acid addition salt thereof.
2. 3-(13-Bromo-2-methyl-6-n-propyl-8.alpha.-ergolinyl)-1,1-diethylurea;
3-(13-bromo-6-ethyl-2-methyl-8.alpha.-ergolinyl)-1,1-diethylurea;
3-(13-bromo-2-methyl-6-n-propyl-8.alpha.-ergolinyl)-1,1-diethylthiourea;
3-(13,14-dibromo-2-methyl-6-n-propyl-8.alpha.-ergolinyl)-1,1-diethylurea; or 3-(13-bromo-6-n-propyl-2-vinyl-8.alpha.-ergolinyl)-1,1-diethylurea, each a compound of claim 1.
3. A compound as in claim 1, wherein R2 is C1-6-alkyl or C2-6-alkenyl.
3-(13-bromo-2-methyl-6-n-propyl-8.alpha.-ergolinyl)-1,1-diethylthiourea;
3-(13,14-dibromo-2-methyl-6-n-propyl-8.alpha.-ergolinyl)-1,1-diethylurea; or 3-(13-bromo-6-n-propyl-2-vinyl-8.alpha.-ergolinyl)-1,1-diethylurea, each a compound of claim 1.
3. A compound as in claim 1, wherein R2 is C1-6-alkyl or C2-6-alkenyl.
4. A compound as in claim 1, wherein R4 is bromine.
5. A compound as in claim 1, where R6 is C2-6-alkyl or C3-6-alkenyl.
6. A compound as in claim 1, wherein R8 is .alpha.-NH-CX-R3 and X is oxygen and R3 is hydrogen, C1-6-alkyl or -N(C1-4-alkyl)2.
7. A compound of claim 1, wherein R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, 2,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, 1-ethylbutyl, isopentyl, isoheptyl, 1-methyl-1-ethylpropyl vinyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-butyl or methallyl and R6 is cyclopropyl methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, 2,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, 1-ethylbutyl, isopentyl, isoheptyl, 1-methyl-1-ethylpropyl vinyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-butyl or methallyl.
8. A pharmaceutical preparation which comprises a compound of claim 1 and a pharmaceutically compatible vehicle.
9. A pharmaceutical preparation which comprises a compound of claim 2 and a pharmaceutically compatible vehicle.
10. A method for providing dopamine agonistic aetivity in a host which comprises administering to a host of a compound of claim 1.
11. A method of treating Parkinson's disease which comprises administering to a host afflicted with such a disease, a compound of claim 1.
12. A process for the production of the compounds of Formula I of claim 1 by brominating a compound of Formula II
II
wherein R6, R8 and are as defined in claim 1 and R2 is C1-6-alkyl.
II
wherein R6, R8 and are as defined in claim 1 and R2 is C1-6-alkyl.
13. A process for the production of the compounds of formula I of claim 1 by substituting, in the 2-position, a compound of formula III or its quaternary salt III
with a C1-6-alkyl, C2-6-alkenyl or CH2-O-O-C1-4-alkyl group, wherein R6, R8 and are as defined in claim 1.
with a C1-6-alkyl, C2-6-alkenyl or CH2-O-O-C1-4-alkyl group, wherein R6, R8 and are as defined in claim 1.
14. A process for the production of compounds of formula I of claim 1 by alkylating or alkenylating a compound of Formula IV
IV
with a C2-6-alkyl group, C3-6-alkenyl group or C3-5 cycloalkyl-C1-2-alkyl group, wherein R2, R8 and are as defined in claim 1.
IV
with a C2-6-alkyl group, C3-6-alkenyl group or C3-5 cycloalkyl-C1-2-alkyl group, wherein R2, R8 and are as defined in claim 1.
15. A compound of formula III or its quaternary salt III
wherein R6 is C2-6-alkyl, C3-6-alkenyl or C3-5-cycloalkyl-C1-2-alkyl:
R8 is .alpha.-NH-CO-R3, .alpha.-NH-CS-R3, .alpha.-NH-SO2-N-NR5R7, CH2-Y, .beta.-CO-NH-phenyl(substituted or unsubstituted), or .beta.-CO-NR2CO-NHR10, wherein R3 is hydrogen, C1-6-alkyl, -O-(CH2)n-N(CH3)2 or -N(C1-4-alkyl)2 or C1-4-alkoxy-substituted C-6-alkyl, R5 and R7 each independently means hydrogen or C1-4-alkyl, Y is hydrogen, OH, O-C1-6-acyl, CN, SCH3 or CONH2, R9 and R10 each independently means C1-4 alkyl, or -(CH2)n-N(CH3)2, and n stands for 1, 2, 3 or 4 and means single or double bond wherein, if R8 is CH3, CH2OH or CH2-O-C1-6-acyl, is a double bond and, if R8 is CH2-CN, CH2-SCH3 or CH2-CONH2, is a single bond and R8 is in the .beta.-position.
wherein R6 is C2-6-alkyl, C3-6-alkenyl or C3-5-cycloalkyl-C1-2-alkyl:
R8 is .alpha.-NH-CO-R3, .alpha.-NH-CS-R3, .alpha.-NH-SO2-N-NR5R7, CH2-Y, .beta.-CO-NH-phenyl(substituted or unsubstituted), or .beta.-CO-NR2CO-NHR10, wherein R3 is hydrogen, C1-6-alkyl, -O-(CH2)n-N(CH3)2 or -N(C1-4-alkyl)2 or C1-4-alkoxy-substituted C-6-alkyl, R5 and R7 each independently means hydrogen or C1-4-alkyl, Y is hydrogen, OH, O-C1-6-acyl, CN, SCH3 or CONH2, R9 and R10 each independently means C1-4 alkyl, or -(CH2)n-N(CH3)2, and n stands for 1, 2, 3 or 4 and means single or double bond wherein, if R8 is CH3, CH2OH or CH2-O-C1-6-acyl, is a double bond and, if R8 is CH2-CN, CH2-SCH3 or CH2-CONH2, is a single bond and R8 is in the .beta.-position.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3931819A DE3931819A1 (en) | 1989-09-20 | 1989-09-20 | 13-BROM AND 13, 14-DIBROM-ERGOLINE, THEIR PRODUCTION AND USE IN MEDICINAL PRODUCTS |
| DEP3931819.2 | 1989-09-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2025744A1 true CA2025744A1 (en) | 1991-03-21 |
Family
ID=6390055
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002025744A Abandoned CA2025744A1 (en) | 1989-09-20 | 1990-09-19 | 13-bromo-and 13,14-dibromoergolines, their production and use in medicinal agents |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0418990B1 (en) |
| JP (1) | JPH03120277A (en) |
| AT (1) | ATE97130T1 (en) |
| CA (1) | CA2025744A1 (en) |
| CZ (1) | CZ278319B6 (en) |
| DD (1) | DD295848A5 (en) |
| DE (2) | DE3931819A1 (en) |
| DK (1) | DK0418990T3 (en) |
| ES (1) | ES2062313T3 (en) |
| HU (1) | HU206346B (en) |
| IE (1) | IE65416B1 (en) |
| PT (1) | PT95350A (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4123587A1 (en) * | 1991-07-12 | 1993-01-14 | Schering Ag | 2,14-DISUBSTITUTED ERGOLINE, THEIR PRODUCTION AND USE IN MEDICINAL PRODUCTS |
| US9676776B2 (en) | 2015-01-20 | 2017-06-13 | Xoc Pharmaceuticals, Inc. | Isoergoline compounds and uses thereof |
| EP3253753A4 (en) | 2015-01-20 | 2018-06-27 | Xoc Pharmaceuticals, Inc | Ergoline compounds and uses thereof |
| AU2018275873A1 (en) | 2017-06-01 | 2019-12-19 | Xoc Pharmaceuticals, Inc. | Ergoline derivatives for use in medicine |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1413068A (en) * | 1972-06-22 | 1975-11-05 | Farmaceutici Italia | Bromoergolines |
| DE2802023A1 (en) * | 1977-01-28 | 1978-08-03 | Sandoz Ag | NEW ERGOT DERIVATIVES, THEIR PRODUCTION AND USE |
| GB2074566B (en) * | 1980-04-03 | 1983-11-02 | Erba Farmitalia | Ergoline derivatives |
| DE3533675A1 (en) * | 1985-09-19 | 1987-03-26 | Schering Ag | NEW 12- AND 13-BROMINE ERGOL DERIVATIVES |
| DE3730124A1 (en) * | 1987-09-08 | 1989-03-16 | Eich Eckart | NEW FESTUCLAVIN AND PYROCLAVIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT |
-
1989
- 1989-09-20 DE DE3931819A patent/DE3931819A1/en not_active Withdrawn
-
1990
- 1990-09-13 DE DE90250235T patent/DE59003446D1/en not_active Expired - Lifetime
- 1990-09-13 AT AT90250235T patent/ATE97130T1/en not_active IP Right Cessation
- 1990-09-13 DK DK90250235.0T patent/DK0418990T3/en active
- 1990-09-13 EP EP90250235A patent/EP0418990B1/en not_active Expired - Lifetime
- 1990-09-13 ES ES90250235T patent/ES2062313T3/en not_active Expired - Lifetime
- 1990-09-18 IE IE336990A patent/IE65416B1/en not_active IP Right Cessation
- 1990-09-19 CA CA002025744A patent/CA2025744A1/en not_active Abandoned
- 1990-09-19 PT PT95350A patent/PT95350A/en not_active Application Discontinuation
- 1990-09-19 DD DD90344101A patent/DD295848A5/en not_active IP Right Cessation
- 1990-09-19 HU HU905969A patent/HU206346B/en not_active IP Right Cessation
- 1990-09-20 JP JP2249012A patent/JPH03120277A/en active Pending
- 1990-09-20 CZ CS904582A patent/CZ278319B6/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CZ278319B6 (en) | 1993-11-17 |
| ES2062313T3 (en) | 1994-12-16 |
| DE59003446D1 (en) | 1993-12-16 |
| ATE97130T1 (en) | 1993-11-15 |
| IE65416B1 (en) | 1995-10-18 |
| PT95350A (en) | 1991-05-22 |
| DE3931819A1 (en) | 1991-03-28 |
| EP0418990A3 (en) | 1991-07-03 |
| HUT54682A (en) | 1991-03-28 |
| EP0418990A2 (en) | 1991-03-27 |
| EP0418990B1 (en) | 1993-11-10 |
| CZ458290A3 (en) | 1993-04-14 |
| DK0418990T3 (en) | 1994-03-14 |
| IE903369A1 (en) | 1991-04-10 |
| HU206346B (en) | 1992-10-28 |
| JPH03120277A (en) | 1991-05-22 |
| DD295848A5 (en) | 1991-11-14 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |