JPH0243752B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to ergoline derivatives, their production methods and uses, and more particularly to novel ergoline derivatives (including their salts) useful as prolactin secretion inhibitors, anti-Parkinson's disease agents or antidepressants, their production methods and pharmacological uses. . The present invention can provide compounds of the following formula: [In the formula, R ₁ represents n-propyl, R ₂ and R ₃ represent methyl or ethyl, and R ₄ represents hydrogen or methyl. ]. A wide range of ergolines, including compounds with prolactin secretion inhibitory and pamine activity (e.g. antiparkinsonian activity) and in which R ₄ is hydrogen, is described in the literature, for example in Swiss Patent No.
Disclosed in No. 605938. It is specified in the Swiss patent that position 6 of the ergoline nucleus is preferably substituted with methyl or α-branched alkyl (eg isopropyl). However, all of the confirmed example compounds relate to compounds having a methyl group at the 6-position. DE 26 56 344 discloses a wide class of ergolines having the above-mentioned activity, including compounds [ ] in which R ₁ is ethyl and R ₄ is methyl. However, the preferred substituent at the 6-position is methyl, and the confirmed example compounds only describe compounds having methyl as the 6-position substituent. The compound of the present invention [ ] having an n-propyl substituent at the 6-position of the ergon nucleus is not specifically disclosed or suggested in the literature. Compound [ ] also has very interesting pharmacological aspects and is a compound with particularly good tolerance and efficacy, as shown in the pharmacological tests described below. In the compound [] of the present invention, both R ₂ and R ₃ are preferably the same and are methyl or ethyl. Or the present invention has the formula: The compound represented by or its precursor and formula: It is possible to provide a method for producing the compound [ ], which includes a step of condensing the compound represented by or its precursor. [In the formula, R ₂ and R ₄ have the same meanings as above, R ₅ is hydrogen or n-propyl, R ₆ is hydrogen, methyl or ethyl, and one of X and Y is SO ₂ Z (where Z is chlorine or (bromine), the other represents hydrogen. ]. The above reaction is preferably performed with a compound [] in which X is hydrogen and the formula: Z- _SO2 - _NR2R6 [] [wherein _R2 , _R6 and Z have the _same meanings as above. ] It can be advanced by reacting. This reaction work-up can be carried out by conventional methods for preparing analogous compounds. Suitable solvents include, for example, suitable chlorinated aliphatic hydrocarbons such as methylene chloride or chloroform and suitable cyclic ethers (eg dioxane) or open chain ethyls. Appropriate reaction temperature is about -10~
It can be +80°C. Intermediates [ ] and/or [ ] refer to these respectively in their precursor form (e.g. protected compound)
In this case, the protecting group is removed later. The protecting group may be, for example, an amino protecting group attached to the nitrogen atom. When R ₅ and R ₆ are hydrogen, the resulting product is optionally n-propylated or methylated or ethylated to obtain the compound of the present invention [] in which R ₅ and/or R ₆ are other than hydrogen. Obtainable. In addition to alkylating the 1 and 6 positions of the erucorin nucleus, the amino group of sulfamoyl can also be easily alkylated. The desired transformations (eg n-propylation, methylation, ethylation) can be carried out in a conventional manner. The type and amount of the reagent used and the reaction conditions are selected so that the amino group is temporarily protected as necessary and the 1- or 6-position of the ergon nucleus is selectively substituted or the sulfamoyl group is substituted. can be selected. Substitution at position 1 or 6 of the ergoline nucleus can be used, for example, with the corresponding compound unsubstituted at position 1 or 6 of the formula: CH ₃ -Z or n-C ₃ H ₇ -Z [where Z is Leaving groups (e.g. atomic symbols 9-53
halogen or organic sulfonic acid groups such as tosyloxy). ] This can be achieved by reacting the compounds shown below. This reaction can be conveniently carried out at about 10 DEG to 100 DEG C., preferably in an inert organic solvent, suitably in the presence of a base. The reaction at position 6 can also be carried out under reducing conditions, for example under mild reaction conditions by catalytic hydrogenation. Substitution of the sulfamoyl group on the nitrogen atom can be effected by conventional alkylation methods for amines. If R ₁ (or R ₅ ) or R ₄ of the intermediate is hydrogen, it is of course possible to substitute that position before reacting the intermediate. This reaction can preferably proceed by reacting the intermediate [] with a halide in acetone, dimethylformamide or a chlorinated hydrocarbon in the presence of a base. If mono-substitution is required on the nitrogen atom of the sulfamoylamino group (and if substitution is desired at position 1 or 6 of the ergoline nucleus), the halide is preferably added to the ergoline intermediate. Use at most equivalent amounts. If it is necessary to disubstitute the nitrogen atom of the sulfamoylamino group, it is preferred to use an excess amount of halide. The object compound of the present invention [ ] can be isolated and purified by conventional methods. The free base compound [ ] of the present invention can be converted into an acid addition salt compound by a conventional method, and the reverse conversion is also possible. Suitable acids for salt formation include, for example, hydrochloric acid, sulfuric acid, maleic acid, fumaric acid and tartaric acid. Note that the intermediate [] in which X is _-SO2Z can be obtained by introducing a _-SO2Z group into the corresponding compound [] in which X is hydrogen. For example, if Z is chloro, the nitrogen atoms at positions 1 and 6 (only when R ₄ or R ₁ (or R ₅ ) is hydrogen) of the ergoline nucleus of the intermediate [] may be temporarily protected if necessary. and an intermediate in which X is hydrogen []
_-SO2Z group can be introduced by reacting with, for example, sulfuryl chloride. Certain compounds of the intermediate [ ] where X is hydrogen, for example X is hydrogen and R ₄ is hydrogen or methyl,
Compounds [] in which R ₅ is hydrogen and X is hydrogen,
The compound [ ] in which R ₄ is methyl and R ₅ is n-propyl is a new compound. All intermediates [ ] in which X is hydrogen can be prepared from 8α-amino-6-methyl-ergoline by conventional methods. That is, the 8α-amino group may be protected with, for example, benzyloxycarbonyl, and the 6-methyl group of this protected compound is substituted with R ₁ group, and 1
By methylating the position, an intermediate [] in which X is hydrogen can be obtained. Intermediates are known or can be obtained by conventional methods, unless otherwise specified for their preparation. Next, a method for producing a preferred compound of the present invention will be specifically explained with reference to Examples. Example 1 8α-(N,N-diethylsulfamoylamino)-6-n-propylergoline (alias: N,
Production of N-diethyl-N'-(6-propylergolin-8α-yl)sulfamide): -8α-amino-6-n-propylergoline 2.2
A solution of 50 ml of chloroform and 5 ml of triethylamine is brought to reflux, and a solution of 2 ml (approximately 26 mmol) of diethylsulfamic acid chloride in 5 ml of chloroform is added dropwise. The mixture is refluxed for 12 hours and then cooled to room temperature. 10 ml of 2N sodium hydroxide are added and the mixture is stirred at room temperature for 1 hour. Extraction was performed three times with methylene chloride/isopropanol (9:1), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated to yield the title compound. The hydrochloride form of the compound is recrystallized from ethanol/methylene chloride (1:1). Melting point 160-162℃. [α] ²⁰ _D = -56° (in ethanol/water (1:1),
c=0.4). A method for producing the above ergoline intermediate is shown. a 8α-benzyloxycarbonylamino-6
-Production of methylergoline: -8α-amino-6-methylergoline 18g (74.7
To a suspension of 1000 ml of chloroform, 150 ml of isopropanol and 37 ml (74 mmol) of 2N sodium hydroxide are added 10.5 ml (75 mmol) of carbobenzyloxychloride at room temperature. After separating the organic layer, it is dried, filtered and concentrated. The crude product obtained is filtered over silica gel with methylene chloride/methanol (99:1) to give the title compound as a foam. b 8α-benzyloxycarbonylamino-6
- Production of cyanoergoline: - 29.5 g (79
mmol) and cyanobromide 25g (236 mmol)
A 600 ml solution of chloroform was stirred at room temperature for 65 hours.
Concentration on a rotary evaporator and drying under high vacuum affords the title compound. c Production of 8α-benzyloxycarbonylaminoergoline: - Add 8α-benzyloxycarbonylamino-6 obtained in step b above to a suspension of 40 g of zinc and 100 ml of acetic acid.
- 18 g (46.5 mmol) of cyanoergoline and acetic acid
Add 100ml of the mixture. Add 40 ml of water to this and heat the mixture at 100°C for 10 hours. This is filtered through a filter aid such as Hyflo and concentrated on a rotary evaporator. The residue is partitioned between aqueous potassium bicarbonate solution and methylene chloride/isopropanol (9:1). Dry the organic layer with sodium sulfate,
Filter and concentrate to obtain the title compound as crude product. d8α-benzyloxycarbonylamino-6
- Production of n-propyl ergoline: - 17.5 g (about 46 mmol) of 8α-benzyloxycarbonylaminoergoline obtained in step c above,
Potassium carbonate 13.5g, n-propyl iodide 6ml
(62 mmol) and 300 ml of dimethylformamide
The suspension is stirred at room temperature for 18 hours. The mixture is filtered and concentrated on a rotary evaporator. The residue is treated with methylene chloride and shaken with water. Dry the organic layer over sodium sulfate, filter, and concentrate to obtain the title compound as a crude product. e Production of 8α-amino-6-n-propylergoline: - 12 g of 8α-henzyloxycarbonylamino-6-n-propylergoline obtained above
(approximately 30 mmol), palladium/carbon (10% by weight)
A mixture of 1.5 g and 500 ml of ethanol is hydrogenated at normal pressure until hydrogen absorption stops. Filter the mixture;
Concentrate. The product is crystallized from methanol to give the title compound. By a method similar to that described in Example 1,
Suitable intermediates [ ] where X is hydrogen and Y is ClSO ₂
Example 2 below by reacting the compound [ ] which is -
Compounds of the present invention [] shown in ~8 were obtained. Example 2 Production of 1-methyl-8α-(N,N-dimethylsulfamoylamino)-6-n-propylergoline: - Decomposed as hydrochloride from melting point 220°C, [α] ²⁰ _D =
−60° (in ethanol/water (1:1), c=
0.445). Example 3 Production of 8α-(N,N-dimethylsulfamoylamino)-6-n-propylergoline: - Decomposed as hydrochloride from melting point 220°C, [α] ²⁰ _D =
−63° (c=0.43 in ethanol/water (1:1)). Example 4 Production of 8α-(N,N-diethylsulfamoylamino)-1-methyl-6-n-propylergoline: - Decomposed as hydrochloride from melting point 180°C, [α] ²⁰ _D ;
−31.5° (in pyridine, c=0.96). The compound of the present invention [] has not been described in the literature. Compound [] represents pharmacological activity. Approximately 0.001-0.1 mg/Kg of active compound, especially in female rats 5 days after fertilization.
The compound [ ] exhibits prolactin secretion inhibitory activity, as shown by inhibition of implantation of unfertilized eggs in the uterus after subcutaneous administration (Experienta Vol. 34, 1330
(1978). ). The compounds of the present invention [ ] are therefore indicated for use as prolactin secretion inhibitors, for example for the treatment of endocrinological conditions associated with prolactin secretion. In this case, the compound of the invention is formulated in a unit dosage form or sustained release form containing about 0.003 to 0.5 mg, and the indicated daily dose is about 0.1 to 1 mg, which is administered 2 to 4 times per day. It can be conveniently administered in divided doses. In addition, the compounds of the present invention [ ] have been induced in rats with unilateral 6-hydroxydopamine-induced degeneration by intraperitoneal administration of about 0.05-2 mg/Kg of the active compound, as shown by contralateral rotation.
Has dopamine activity (U.Ungerstedt.Act.
Physiol.Scand.Suppl. Vol. 367, pp. 69-93 (1971
Based on the principle of ). Therefore, the compounds of the present invention are suitable for use as agents for Parkinson's disease. For this indication, the compound of the invention is formulated in unit dosage form or sustained release form containing about 0.15 to 5 mg, and the indicated daily dose is 0.5 to 10 mg, administered 2 to 4 times per day. It can be conveniently administered in divided doses. Furthermore, the compound of the present invention [ ] may be, for example, about
It exhibits antidepressant activity as shown in animal studies in which it is administered subcutaneously at doses of 0.01 to 0.1 mg/Kg to observe antagonism on reserpine-induced catalepsy and ptosis. Therefore, the compounds of the present invention are indicated for use as antidepressants. For this indication, the compounds of the present invention
formulated in unit dosage form or sustained release form containing 1 to 10 mg per day as directed.
This can be conveniently administered in 2 to 4 divided doses per day. The activity of the compound of the present invention as described above is shown in more detail as follows in comparison with known compounds. (Pharmacological test) The following compounds were used as test compounds. Compound A of the present invention: 8α-(N,N-diethylsulfamoylamino)-6-n-propylergoline hydrochloride (Example 1) Compound B: 8α-(N,N-diethylsulfamoylamino) -1-Methyl-6-n-propylergoline hydrochloride (Example 4) Known compound Compound a: 8α-(N,N-diethylsulfamoylamino)-6-methylergoline (implemented in Swiss Patent No. 615929) Example 12) Compound b: 8α-(N,N-diethylsulfamoylamino)-1,6-dimethylergoline methanesulfate (JP-A-52-78900
No. Example c) (Prolactin secretion inhibitory activity) (a) Adult proestrus rats (Ivanovas strain)
were allowed to cohabit with males whose reproductive potential was confirmed. The next morning (day 1), females showing positive semen were randomly divided into groups (10 animals/group). On the fifth day, 1 of the compound
Multiple doses were injected subcutaneously. On the 12th day, the rats were sacrificed and biopsied to determine whether the fetus or fertilized egg had implanted. If absent, it was determined that implantation was inhibited.
The dose that inhibits implantation in 50% of the animals (ED ₅₀ ) was calculated. (b) Female rats that secrete milk (Ivanovas series)
Groups of 5 to 6 animals were given compound or carrier at the fifth postnatal day.
The animals were orally administered daily on days 8 to 8, and the regression coefficient for the growth rate of the offspring was calculated based on the daily weight gain of the offspring as an index of milk production. The dose that reduces secretion to half the control amount (ID ₅₀ ) was calculated. The results are shown in the table below.

[Table] From the above results, the present invention compound A is effective in inhibiting implantation.
is significantly (approximately 4 times) more active than known compound a, and present compound B is significantly (approximately 2.5 times) more active than known compound b. Noticeably (approximately 13
It was found that the activity was high. (Anti-parkinsonian activity) (a) Male OFA rats (140-160 g) were placed in a David Kopp stereotaxic frame under anesthesia with pentobarbital (Nembutal). A sagittal incision was made in the skin and the underlying tissue was removed to expose the bregma (suture intersection). +4.2mm from bregma
A 2 mm wide hole was made anteriorly and 1 mm on the right side, and a cannula with an outer diameter of 0.3 mm was inserted to a depth of 7.5 mm under the dura. 4μ of 6-hydroxydopamine hydrochloride solution (2mg/ml in saline containing 0.2mg/ml ascorbic acid (an antioxidant)) was injected into the center of the substantia nigra over 2 minutes using a Hamilton syringe. The cannula was removed and the wound was clipped. One week later, the animals were administered subcutaneously 0.25 mg/Kg of apomorphine and the total number of rotations was measured. Animals that showed a contralateral rotational response to the injured side were selected. Apomorphine 0.25
The number of rotations for each animal was corrected based on the average value (560 rotations/animal) obtained for 40 rats injected intraperitoneally with mg/Kg. Total number of rotations, duration, and maximum value/min were recorded for groups of animals (minimum of 3 animals). The results are shown in the table below.

[Table] From the above results, it was found that the compound B of the present invention exhibited significantly (approximately 200 times) higher activity than the known compound b. (b) Male OFA (180-250 g) was placed in a perspex cylinder (diameter 23 cm) with a wire mesh bottom.
After 30 minutes of acclimation, compounds were administered and observed at 30 minute intervals for 2 hours and then at 60 minute intervals for a total of 7 hours. Six animals were used for each dose. Eur.J.
Constant behavior was measured by the face value method (described below) as described in Pharmacol. (1972) 18 , p. 83. 1...Moderate intermittent biting behavior 2...Repetitive biting behavior, occasional licking behavior 3...Significant licking behavior, occasional moderate biting behavior 4...Strong/repetitive biting behavior The results are shown in the table below.

【table】

[Table] From the above results, it can be seen that the compound A of the present invention exhibits a significantly (approximately 3 times) higher total activity than the known compound d at low doses and has a longer duration, and that the compound B of the present invention exhibits a significantly higher total activity (about 3 times) than the known compound b at a high dose. It was found that it showed higher total activity. (Anti-depressant activity) (a) To groups of 10 male MNRI mice (18-25 g),
Reserpine 5 mg/Kg (ip) was injected, and 17 hours later the test compound was administered subcutaneously. (Reserpine-induced akinesia and blepharoptosis last for 24 hours.)
Akinesia and ptosis were assessed 0.5, 1, 2, 3 and 5 hours after administration of test compound. The number of mice exhibiting antagonism to akinesia, ie the ability to move away from the twin-covered horizontal bar in a coordinated manner, was recorded. From comparison with control animals (reserpine only), the % akinesia antagonist was calculated for each dose and time. Ptosis was similarly calculated using a standard scoring system. The results are shown in the table below.

[Table] Ptosis

Claims (1)

[Claims] 1 Formula: [In the formula, R ₁ represents n-propyl, R ₂ and R ₃ represent methyl or ethyl, and R ₄ represents hydrogen or methyl. ] In producing the compound represented by the formula or its acid addition salt, the formula: A compound represented by or its precursor and the formula: A compound represented by or a precursor thereof [wherein R ₂ and R ₄ have the same meanings as above. R ₅ is hydrogen or n-propyl, R ₆ is hydrogen, methyl or ethyl, one of X and Y represents SO ₂ Z (where Z is chlorine or bromine) and the other represents hydrogen. ] A method for producing the above-mentioned compound [], which comprises the step of condensing. 2 formula: [In the formula, R ₁ represents n-propyl, R ₂ and R ₃ represent methyl or ethyl, and R ₄ represents hydrogen or methyl. ] A compound or an acid addition salt thereof. 3. The compound according to item 2 above, wherein R ₁ is n-propyl and R ₄ is methyl. 4. The compound according to item 2 above, which is 8α-(N,N-diethylsulfamoylamino)-6-n-propylergoline. 5. The compound according to item 2 above, which is 1-methyl-8α-(N,N-dimethylsulfamoylamino)-6-n-propylergoline. 6. The compound according to item 2 above, which is 8α-(N,N-dimethylsulfamoylamino)-6-n-propylergoline. 7. The compound according to item 2 above, which is 8α-(N,N-diethylsulfamoylamino)-1-methyl-6-n-propylergoline. 8. The compound according to any one of items 2 to 7 above, which is a free base type. 9. The compound according to any one of items 2 to 7 above, which is an acid addition salt type. 10 Free base type or pharmacologically acceptable acid addition salt type Formula: [In the formula, R ₁ represents n-propyl, R ₂ and R ₃ represent methyl or ethyl, and R ₄ represents hydrogen or methyl. ] A prolactin secretion inhibitor containing a compound represented by the following as an active ingredient. 11 Free base type or pharmacologically acceptable acid addition salt type. formula: [In the formula, R ₁ represents n-propyl, R ₂ and R ₃ represent methyl or ethyl, and R ₄ represents hydrogen or methyl. ] An anti-Parkinson's disease agent containing a compound represented by the following as an active ingredient. 12 Free base type or pharmacologically acceptable acid addition salt type. formula: [In the formula, R ₁ represents n-propyl, R ₂ and R ₃ represent methyl or ethyl, and R ₄ represents hydrogen or methyl. ] An antidepressant containing a compound shown as an active ingredient.