FI62537C - FOERFARANDE FOER FRAMSTAELLNING AV 8ALFA-ERGOLIN-I-FOERENINGARMED DOPAMINERGISK OCH PROLAKTINSEKRETIONSHAEMMANDE NET - Google Patents

Description

62537

Process for the preparation of -ergoline-I compounds having dopaminergic and prolactin-inhibitory activity 5 Separated from application 752011/1975

The invention relates to novel compounds of the formula H <1, NHR 4 in which X is hydrogen, chlorine or bromine and R 1 is formyl, alkanoyl having 2 to 5 carbon atoms, alkoxycarbonyl having 2 to 5 carbon atoms, 3-5 carbon atoms mono-, di- or trihaloalkoxycarbonyl containing an alkoxy residue which cannot be substituted in the N-position relative to oxygen or a residue SO2R5 in which R5 is alkyl having 1 to 4 carbon atoms, mono-, di- or trihaloalkyl having 1 to 4 carbon atoms, phenyl, pyridyl, phenyl monosubstituted by halogen or alkoxy having 1 to 4 carbon atoms, or a group NRgR7, in which R8 and R7 each represent hydrogen or alkyl having 1 to 4 carbon atoms, in their free form or in the form of their acid addition salts.

30 X is especially hydrogen.

If the radical R4 or Rg is a halogen substituent, this is fluorine, chlorine or bromine. When the residue R4 or R1 is di- or trihalogenated, the halogen substituents of these residues are preferably the same.

Preferred radicals R 2 are methoxycarbonyl, 2,62537 ethoxycarbonyl, (2,2,2-trihaloalkoxy) carbonyl and the group SC 2 R 2.

Possible halogen substituents on the residue R 1 are, in particular, fluorine and chlorine.

When R 1 is alkyl of 1 to 4 carbon atoms or mono-, di- or trihaloalkyl of 1 to 4 carbon atoms, it preferably contains 1 or 2 carbon atoms.

If R 1 is phenyl monosubstituted by alkoxy having 1 to 4 carbon atoms, the alkoxy substituent has in particular 1 or 2 carbon atoms and preferably 1 carbon atom.

Rg is preferably methyl, phenyl, pyridyl or the group NRgR4.

When R 9 and R 2 each represent alkyl having 1 to 4 carbon atoms, they preferably contain 1 or 2 carbon atoms.

NR 9 R 8 is preferably an amino, dimethylamino, or diethylamino group.

U.S. Pat. No. 2,533,698 discloses compounds closely related to the compounds I according to the invention which have a central nervous system stimulating and analeptic effect, but which differ from the compounds I according to the invention in a 9:10 bond which is a double bond.

DK patent publication 99 025 discloses ergolyl-25 and ergolenyl and isoergolenylurea derivatives having anti-serotonin activity. The compounds according to the invention are strongly dopaminergic and inhibit prolactin secretion, as can be seen from the results of the pharmacological experiments presented below.

FI patent publication 53 127 describes N- (D-6-methyl-8-isoergolin-1-yl) -N ', N'-diethylurea, which has a similar effect to the compounds prepared according to the present invention. The compounds prepared according to the invention are considerably superior in terms of dopaminergic activity than the compounds known from FI patent publication 62537 3 53 127.

According to the invention, compounds of formula I are prepared such that a compound of formula II is 5 H 2 NH 2

flx NCH3 II

X

Wherein X is as defined above, is acylated with a reactive, functional derivative of an R 1 OH of an acid having the same meaning as above.

The reaction of the compounds of formula II to the compounds of formula I can take place in a manner analogous to known methods.

This method is the N-acylation method. For example, the following reactive functional derivatives of R 1 OH may be used to attach a residue to compounds of formula II: a mixed anhydride of formic acid and acetic acid to attach a formyl residue, an acid-corresponding halide such as an acid chloride or acid bromide to attach other residues of R 2, and an alkanoyl residue ).

The process according to the invention is preferably carried out in a solvent for 30 minutes. Suitable solvents are, for example, methylene chloride and dioxane. When anhydride is used as the acylating agent, an excess of anhydride can also be used as a solvent.

It is generally preferred to operate at a reaction temperature of between -10 ° C and about room temperature. However, the N-formylation with a mixed anhydride of acetic acid and formic acid preferably takes place at a slightly elevated temperature, for example at about 40-60 ° C.

The process is preferably carried out in the presence of a tertiary amine such as triethylamine or preferably in the presence of pyridine or its homologues.

The compounds obtained by the process of the invention may be in free form as a base or in the form of their acid addition salts. Acid addition salts can be prepared from the free bases in a known manner and vice versa.

The starting materials are known or can be prepared by the methods described in A. Hofmann, Helv.Chim.Acta 30 (45-51 (1947)).

The compounds of the formula I in their free form or in the form of their physiologically tolerable acid addition salts (compounds of the invention) have interesting pharmacodynamic properties. They can be used as drugs.

Due to their dopaminergic properties, the compounds of the invention can be used in the treatment of Parkinson's disease.

In addition, the compounds of the invention have an inhibitory effect on prolactin secretion. Compounds that inhibit prolactin secretion can be used, for example, in the prophylaxis and treatment of physiological lactation and galactorrhoea.

The novel compounds of the formula I in which -COQCH3, -COOC2H5, -SO2N (CH3) 2 or -SO2-N (C2H5) 2 have a particularly pronounced inhibitory effect on prolactin secretion.

Medicaments containing a compound of the formula I in its free form or in the form of physiologically acceptable acid addition salts and which are, for example, in the form of a solution or tablets, can be prepared by known methods using customary excipients and carriers.

Pharmacological properties and comparative tests

The compounds of formula I and their salts have not been previously described in the literature. Experiments on experimental animals have shown interesting pharmacodynamic properties of 5,62537, in particular their stimulating effect on key dopaminergic receptors.

The effect of the compounds of formula I on key dopaminergic receptors was studied by the method of U. Unger-5 stedt published in the journal Acta Physiol, Scand., Suppl. 367, 69-93 (1971). 6-hydroxydopamine was unilaterally injected into the blackhead, which after one week caused unilateral degeneration of the nigrostrial pathways. This damage, in turn, caused hypersensitivity of the striatal dopaminergic receptors, which, after administration of the stimulant, manifested itself as behavior in which the animal rotated in the opposite direction of the lesion. When the compounds of formula I were administered to experimental animals intraperitoneally at about 0.5-40 mg / kg, the compounds were shown to clearly stimulate key dopaminergic receptors. The results are shown in Table I below.

Table I

20 Compound Dose (intra-dopaminergic peritoneal receptor) emulation 6-methyl-8 ° <-ethoxycarbonylamino-ergoline I 0.5 +++ 6-methyl-8- (N, N-dimethyl-25-sulfamoylamino) ) -ergoline II ++ 6-methyl-8 ° (-methoxycarbonylamino-ergoline I 1 +++ +++: strong effect ++: significant effect 30

The dopaminergic receptor stimulating effect of the compounds of formula I causes stereo-type behavioral symptoms in rats such as sniffing, licking and roof and wall biting. 35 rats weighing 180-220 g were placed in an observation cylinder 30 cm in diameter. The experimental animal was allowed to acclimate to the environment for 30 min.

6 62537, the animals were then administered the test substance intraperitoneally. The rat's behavior was monitored for a total of 7 h as follows: 2 min observation was performed at 30 min intervals for the first two hours 5 and then at 60 min intervals for the next 7 hours. The degree of ether stereotype was determined according to the method described in Costall, Naylor & Olley, Euro. J. Pharmac. 83-94 (1972). The dose administered intraperitoneally was 1-40 mg / kg.

The compounds of formula I clearly stimulate central dopaminergic receptors, which in this experiment are manifested by intense sniffing, licking and biting of the roof and walls.

The compounds of formula I were also compared to N- (D-6-methyl-8-isoergolin-1-yl) -N ', N'-diethylurea known from the F1-pa-15 patent publication, which has a similar effect to the compounds of the present invention. . In this case, it was found that the compounds described in Examples 1 to 8 of the present specification are considerably superior in terms of dopaminergic activity than the compounds known from FI Patent Publication No. 53,127. In Ungerstedt's experiment, by causing unilateral deterioration of nigrostrial pathways in rats, the number of rotations in the opposite direction of injury was obtained as follows: 25

Compound_Number of spins

Example 1 2346 "2 3583" 3 2824 30 "4 1902" 5 1504 "6 1356" 7 as Example 4 "8 a) 3688 35" 8 b) 1297 "8 c) 1887" 8 d) 1709 "8 e) 1195 EN-53 127 Example 741 7 62537 Due to this dopaminergic activity, the compounds of the formula I can be used therapeutically for the treatment of Parkinson's disease and are administered daily in 0.5-100 mg, in particular 1-50 mg, in a single dose or in several unit doses.

The compounds of formula I also have an inhibitory effect on prolactin isolation, which was observed in female rats in the following experiment: the rats were caged with mature male rats. The next day-10, vaginal scraping was performed and the experiment was continued in fertilized rats; fertilization had occurred if spermatozoa were found when scraping the vagina.

Twelve days after fertilization, the animals were sacrificed, the uterine horns were examined, and implants and resorptions were determined macroscopically on the one hand and by Salewaki reaction on the other (Arch. Exp. Path. Pharm. 247, 367, 1964). The substance has an inhibitory effect on prolactin secretion if it prevents fertilization. When administered subcutaneously and at a dose of 0.01-3 mg / kg, the compounds of formula I have a clear inhibitory effect on pro-20 lactin secretion.

For example, 6-methyl-3e (-ethoxycarbonylaminoergoline-1 and 6-methyl-8o <- (Ν, Ν-dimethylsulfanoylamino) -ergoline-L, i.e. a dose that inhibits fertilization in 50% of animals , is 0.14 mg / kg and 0.012 mg / kg, respectively.

Due to this property, the compounds of the formula I can be used therapeutically, for example in the prophylaxis and treatment of physiological lactation and galactorrhoea. The compounds are administered daily from 0.05 to 10 mg in single or multiple unit doses.

The compounds of formula I can be administered both as the free base or as a salt having an activity of the same order of magnitude as the corresponding free base.

The following examples illustrate the invention. In them, the compounds of the formula I are called 8® (-ergoline-I-compounds 35 or (5R, 8S, 10R) -8-aminoergoline-I. The temperatures are in degrees Celsius).

3,62537

Example 1 6-Methyl-8c (-N, N-dimethylsulfamylamino)

ergoline I

2.41 g (10 mmol) of 6-methyl-8-amino-5-noergoline I were dissolved in a mixture of 200 ml of methylene chloride and 25 ml of absolute pyridine and added dropwise with stirring at room temperature a solution of 3.58 g. g (25 mmol) of dimethylsulfamyl chloride. After stirring for 12 hours, the reaction solution was poured into excess 10 2N sodium carbonate solution. The precipitate was filtered and air dried. The impure orange base was then chromatographed on 50 times silica gel and the title compound eluted with 2% methanol in methylene chloride. Sp. 223-226 ° from ethanol, yellowish needles, / of = -51.6 ° (c = 0.5 in pyridine).

The procedure was as in Example 1 and acylation of the corresponding compounds of formula II with the acid chloride gave the following compounds of formula I: 20 Ex, No. X __Sp._ 2 H CO 2 Cl 2 H 2 DEG C. from 120 ° (base), / * / *> = -29 ° (c = 0.35, dimethylformamide) m.p. 279-280 ° 4 H COC (CH 2) 3 base m.p. 199-200 ° 5 H CO 2 CH 2 Cl 3 117-119 °

Example 6

30 6-Methyl-8o-formylaminoergoline I

2.41 g (10 mmol) of 6-methyl-80- (amino-ergoline I) were dissolved in 5 ml of formic acid and 5 ml of acetic anhydride were added dropwise with stirring at 50-60 [deg.] C. After stirring for 1 hour, the evolution of gas was ceased.

After cooling to 0 °, the reaction mixture was carefully neutralized with 4-potassium carbonate solution and extracted with methanolic chloroform. After drying and evaporation to dryness of the organic phase, the title compound crystallized from ethanol and recrystallized from methylene chloride-ethanol to give the title compound in pure form. The melting point was indeterminate (decomposes from 250 °), / <> (/ ^ - + 23 ° (c = 0.3, pyridine).

Example 7 6-Methyl-8α-pivaloylaminoergoline I The procedure was as in Example 1 (4), but pivalic anhydride was used as the acylating agent instead of pivalic acid chloride to give the title compound, m.p. 199-200 °.

Example 8 Using the method 15 described in Examples 1-7 and the corresponding starting materials, the following compounds of formula I are obtained: H., nhr4 20 1 Γ 11 J »

HN! L

25 X

R X Sp. la} 20 (cDMF: in R4 _ D)

C H

^ -SO 25 H 201-202® ^ -57 ° (0.3)

1 XC2H 218-220® ^ -27® (0.4) J

~ SO2 "^ ^ H 262-266®1" 59® (0.5) 35 "s ° 2- ^ ^ H 199-201 ° 1 -55 ° (0.5) 1042537 R4 X m.p. / 20

D

_ (c in DMF) δ -SO 2 -CF 3 h 206-208 ° 1 -45 ° (0.45) -SO 2 -CH 3 H 219-220 ° 1 -69 ° (0.5) (decomposes) 10 / -CH 3 2 -SO 2 -N Br 253-256 ° + 7 ° (0.5) (decomposes) 3 L as base 2 hydrochloride 3 in pyridine instead of DMF

Claims (4)

11,62537 Claim: A process for the preparation of therapeutically useful 8o <-ergoline-I compounds having dopaminergic and prolactin inhibitory activity and having the formula H NHR4 10 I HN-1 X 15 wherein X is a hydrogen, chlorine or bromine atom, and R 1 is a formyl group, an alkanoyl group having 2 to 5 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, a mono-, di- or a trihaloalkoxycarbonyl group, the alkoxy moiety of which cannot be substituted relative to oxygen, or a group SO 2 R 5 'in which R 1 is an alkyl group having 1 to 4 carbon atoms, a mono-, di- or trihaloalkyl group having 1 to 4 carbon atoms, a phenyl group , a pyridyl group, a phenyl group monosubstituted by halogen or alkoxy having 1 to 4 carbon atoms, or a group NRgR4 in which R8 and R1 represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and for the preparation of their acid addition salts, characterized in that a compound of formula 30 ηλ, 'NH2 NCH- I Ύ 3 11 HN --- CX 62537 wherein X is as defined above, is acylated with a reactive, functional derivative of an acid R 1 OH wherein R 1 is as defined above, andthe compound of formula I thus obtained is isolated in the form of a base 5 or an acid addition salt. 13 62537 Förfarande för framställning av therapeutiskt användbara 8 “=> (- ergoline-I-föreningar med dopaminergisk 5 och prolaktinsretionshämmande verkan och med formuleln H _NHR. Λ / 4 η" ^ ΓηΙ 10 3 1 HN-1 15 color X är väte- , chloro-bromine, and R-formyl groups, alkanoyl groups having 2-5 cholaters, alkoxycarbonyl groups having 2-5 cholaters, en 3-5 cholaters having a mono-, di-trihaloalkoxycarbonyl group, an alkoxy group which may be substituted by a substituent 20 with a single ring, or a group SC1 R1, a color R1 with an alkyl group having 1 to 4 colatomers, and a mono-, di or tri-haloalkyl group with 1 to 4 colatomers, en phenyl group, en pyridyl group, en phenyl group monosubstituted with halogen or alkoxy with 1-4 cholatomers, or group NRgR 2, color 25 Rg and R ^ betecnar en väteatom eller en alkylgrupp med 1-4 kolatomer, samt deras syraadditionssalter, känne-t e c k n a t därav, att en förening med formuleln \ ym2 35 HN- \ X