JPS5824584A - Ergoline derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to ergoline derivatives, processes for their preparation, and pharmaceutical compositions containing them. , R1 represents a hydrogen atom or a methyl group; sR2 represents hydrogen;
The gen atom represents a methyl group, the hydrogen atom or the methoxy group, RJ represents a fluorinated hydrogen group having 1 to 4 carbon atoms, and R5 represents the formula 1. Seal, W
, V, W, wt*tiw Cao
Otori pI
v Seal 1 Nawate ■
(2) (%- in the formula represents a hydrogen or chlorine atom or a methoxy group, and 'E47, I'l. and R.

each independently represents an alkyl group having 1 to 5 vertical atoms before a hydrogen atom, provided that R represents a residue of the general formula and R2, R7 and R8 are all hydrogen atoms. , 'R4 does not represent a methyl group, or is not O or n /d O, or the substituent at C8 is not present in the β-configuration, and Shilo represents a hydrogen atom or 1 to 3 atoms. represents an alkyl group having carbon atoms, and R11 and R112 each independently represent a hydrogen atom,
Represents a lower alkyl group or phenyl group, or
11 and 'R12 are the residues of the nitrogen atom to which they are attached to form a complex An acceptable salt is provided.

In the above general formula, the term "halogen" is
(is interpreted as containing chlorine and bromine atoms, although the term "halogen" also includes fluorine atoms. In the definition of R4, hydrogen containing 1 to 4 carbon atoms The radicals are meant to include alkyl, cycloalkyl, and unsaturated (ethylenic and acetylenic) radicals. Representative radicals include methyl, ethyl, n-propyl, impropyl, butyl, tertiary-butyl, isobutyl, methylcyclo, Includes propyl, allyl and propargyl.

Kfk and R12 together with the nitrogen atom to which they are bonded are 3j! In case of tube formation, this
l is preferably pyrrolidine, biR lysino, morpholino,
selected from the group consisting of pyrazole, imidazole and virol.

The ergoline derivative according to the present invention is a relatively stable and easily available mixed acid of suitable 8-carboxyergoline It can be produced by a high-yield mixed anhydride process using anhydrides.

Mixed ethoxyformic anhydrides can be prepared by reaction with ethyl chloroformate in the presence of triethylamine in an ergoline derivative medium such as tetrahydrofuran, dimethylformamide or dioxane at .theta..degree. C. for 5 to 6 hours. The mixed acid anhydride thus obtained was prepared at room temperature for 2 to
K can be converted into ergoline derivatives of general formula I by reacting for 24 hours with the amine lll5-H in which R5 has the meaning given above.

The crude product is then purified by crystallization, ring formation, or by column chromatography on neutral aluminum oxide.
Can be purified. Ergoline-8-carboxylic acid ■
are known compounds or can be prepared by established methods.

Ergoline derivatives and their pharmaceutically acceptable salts according to the invention are useful antidepressants, and they also exhibit moderate to good antiprolactin activity and moderate to good antihypertensive activity. show.

Accordingly, it is also possible according to the invention to mix the general formula with a pharmaceutically acceptable diluent or carrier. A pharmaceutical composition containing an ergoline derivative having the following or a pharmaceutically acceptable salt thereof is provided.

The antidepressant activity of the ergoline derivatives according to the invention can be predicted by the antagonism of blepharospasm IIi and hypothermia induced by reserpine.

Since the compound disclosed in R. Rugi Patent No. 841,049 has a similar structural formula to ours, our tests showed that it had no effect on blepharospasm and hypothermia induced by lupine. (EDg when administered orally)
The Q value is 7. and 15wtr/1cf). The compound #il, 6-cymethyl-8-1 (
2-thiazolyl-cal/(moyl)-ergoline
, the inventors used that compound in addition to the bicyclic antidepressant ikenpramine as a standard drug for the compounds of the present invention.

The products according to the invention now have a surprisingly high activity compared to the above-mentioned prior art compounds in inhibiting the symptoms induced by reserpine, as shown in the table below.
Oral (p, 00) ID811 value is α2 we/]
cf to 59/noodles, and the acute toxicity was found to be extremely low.9.

7 a5 0.6 >!
5006 2.5 4.0
>3004 0.2 0.6
>50014 to 1
．． 7 >8005 54
4.5 >600 tests are carried out in an air conditioned Jiufeng at a constant temperature of 19° ± 1°C. Randomized groups of male mice were each treated with vehicle (Methocel 0.5
1! % body weight per 100 t of body weight with an appropriate screening amount of the test compound suspended (maximum 2511/Ifi9 or less) or by feeding with vehicle alone. One hour later, the animals receive reserpine (t54/b, body weight 100 tons, 111 mg) by intraperitoneal injection, and one control group receives the same volume of vehicle alone (blank control). Pretreatment After 3 hours of reserpine or vehicle treatment II (02 hours), Hebin et al. [[J.

pharmaaol J Volume 120 $1125 page (19
Blepharospasm according to the scoring method proposed by [1957]!
Evaluate the following. Two hours after the above evaluation, a digital thermometer (IC1ab ]) U-5) K i! The animals' rectal temperatures are recorded with a suitable probe inserted.

EXAMPLES In order to further understand the present invention, examples will be given and explained below.

Example 4 6-methyl-8-1(6-chloro-3-pyridazinyl-
Carbamoyl) - Ercoline (Ni'hW Aya = PPH%
R4==CH! I%R5=W, R6=ct>6-methyl-8-1carboxyergoline 15.02F and triethylane 5 in anhydrous tetrahydrofuran 400-
- Warm the mixture at 50°C for 1 hour. To this cooled suspension was added ethyl chloride in tetrahydrofuran.
: Iforme) & 34m gradually, stirred and heated at 0℃ for 6 hours.
Continue stirring for an hour. After filtration, the clear bottle solution is treated with 3-amino-6-chloro-pyridazine 7,12 F and left overnight at room temperature. Concentrate the solution under vacuum,
Dissolve in chloroform and wash with calcium carbonate solution and then water.

The residue of the organic phase was chromatographed on a short column of aluminum using chloroform as the eluent.
The title compound 15 f (m, p.

252-254°C) is obtained.

Examples 2-3B Working analogously to Example 1, the following ergoline derivatives and amines yield the following compounds in Table 2: 31.34.4o
and 416-methyl-B, a-carboxy-ergoline 21-23 adenene 5-amino-6-medoxybili 2.36.41 dazine 5-thiono-5-methyl-inch 27.29.3° azole 3-a Nointhiazole 28,515-Methyl-5-amino-1,2,432-54-thiadiazole 3-7-linked nopyridazine 35.4° 5-amino-6-(1-pyrrolidyl)-pyridazine 3-agino 6-(1-pyrrolyl)38-pyridazine Example Product- 162,6-dimethyl-8β-(2-(5-methyl-1
,5,4-Thiadiazolyl)-carbamoyltwoergolineOHHHal171 Rgt'CHB
156-158 470HHH1-05H Tomi, i
gr-cH, 1194-196750Hca5 HC
Hg I, cHB to R9 258-260
70IHHI (CH black 1. Rygga=H285-2
87702HHHCH5 yen, assistance=Rs=H246~24
8 721 Hi(HC'H,N, R6<l 2
85-287 682HHHCH, W, R6w=C12
80~282 710HHHCH, shoe* Rg-CHH
29S~5690 HHHCHHj, Ry=R1=H
253-4 720HHHCH5W, R4=CI
gon 580 CHg HHn
-CHH7 seal+Ry=Rs”H16B~170 75
1 HHHCHI l, Re=CJ
300 482HHHCHs Seal, R9
1H, 275-277 710 HHHCHHV,
R16=CH1174-175 420HHHCHs
M 138-140 421H
HHCHI V, RH)-C'H, 138-14
0 452 HHHCHg V+R10-cH
g191-192 552HHI (CH, W
202~204 440HHHCH,■+RBl=
CH1151-182 681 HHHCHs
Vlw-1o<Flm 243~245 402
HHHCH3■, R16-CHH145~147 45
1 HHHCHs &, R6 Tomi E! 2
50-252 411 HHHCH5W, R6-,0
CH5258~240 711 HHHcH5■, R1
1 and 263-5 67120 Continuation of page 1 Priority claim 0 March 31, 1982 ■ United Kingdom (GB
)■8209544 0 Inventor Gabrieltra Trafandi Milano Cornatedalada Viaventesi Mocwinto Aprile, Italy 29 1- Author Rosanna Etchell Milano Cornatedalada Viaventesi Mocwinto Aprile 29 0 Inventor Aretz Sandro Lodge, Milan, Italy 7 0 Inventor: Patricia Salvatei, Milan, Italy 7

Claims (1)

[Claims] 1) Formula I [where n is FiOll or 2], Aya represents a hydrogen atom type or a methyl group, R2 represents hydrogen, 9 represents a halogen atom or a methyl group, I 'll represents a hydrogen atom or a methoxy group, R4 represents a hydrocarbon group having 1 to 4 carbon atoms, and RlI is of the formula ■, 厘, ■, ■. Shoulder, W% is a circle line ■ ■ ■ ■ (However, in the formula, R6 represents hydrogen, a chlorine atom, or a methoxy group, and RlI and R each independently represent a hydrogen atom or 1 to 3 methoxy groups. Represents an alkyl group having a carbon atom, provided that when R5 represents a residue of general formula (3) and R2, R7 and R8 all represent hydrogen atoms, %R4 does not represent a methyl group or n is 0 or 't, the substituents of CI shall not be present in the β-configuration, RID represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and 'R1
1 and R13Fi each independently represent a hydrogen atom, a lower alkyl group, or a phenyl group, or R11 and R12 form an australian ring together with the nitrogen atom to which they are bonded. and a pharmaceutically acceptable salt thereof. 2) A compound according to claim 1, wherein the complex formed when Rzs and 'R12 are bonded together is selected from the group consisting of pyrrolidine, biyridine, morpholino, pyrazole, idazole and pyrrole. 3) The compound according to claim 11m1, which is 6-methyl-8β-(6-chloro'o-3-pyridazinyl-carbamoyl)-ergoline. 4) 6-Methyl-8β-(6-medoxy-5-pyridazinyl-carbamoyl)-ergoline! Compound described in Section 1. 5) 1,6-cymethyl-10-methoxy8-1 (
The compound according to claim II@paragraph 1 which is 6-chloro-3-pyridazinyl-carbamoyl)-ergoline. 6) 2.6” methyl-8β-(6-chloro-5
The insulator according to claim 1, which is ``''Y-pyridazinylcarbamoyl)-ergoline. 7) 6-allyl-8β-(6-chloro-3-bilitasierucarpamoyl)-ergolinte The compound according to claim 1. 8) 6-allyl-8β-(2-thiazolyl-carbamoyl)-ergoline! ! 1. The compound according to item 1. 9) The compound according to claim 1, which is 6-broby-8-1(2-thiazolyl-carbamoyl)-ergoline. 10) The compound according to claim 1, which is 6-isoprobyl-8-1(2-thiazolyl-carbamoyl)-ergoline. 11) The compound according to claim 1, which is 2.6-dimethyl-8β-(2-thiazolyl-"carbamoyl)-ergoline. 12) 6-Methyl-8β-(2-(5-methyl-1, 3
, 4-Thiadiazolyl)-carbamoyltudinirgoline. 13) 1,6-dimethyl-10-methoxy-8β-
(2-(5-methyl-1,3,4-thiadiazolyl)-
Claim 8 No. 1 which is carbamoyl two ergoline
Compounds described in Section. 14) The compound according to claim S, which is 1,6-dimethyl-8β-[2-(5-methyl-1,3,4-thiadiazolyl)-carbamoyltwoergoline. 15) 6-broby-8β-(2-(5-methyl-1,
! The compound according to claim 111, which is S,A-thiadiazolyl)-carbamoylzunylgoline. 16) 6-allyl-8β-(2-(5-methyl-1,3
, 4-thiadiazolyl)-ergoline]-ergoline. 17) 6-Itzorobyl-8β-[2-(5-methyl-
Compound 18) according to claim 1, which is 1,3,4-thiadiazolyl)-carnodimoyl]-ergoline 2,6-dimethyl-8β-[2-(5-methyl-1,3,4- 19) The compound according to claim 1 which is thiadiazolyl)-ergoline. 19) The compound according to claim 1 which is 6-methyl-8β-(2-thiazolyl-carbamoylmethyl)-ergoline. A compound according to item 1. 20) The compound according to claim 1 which is 6-methyl-8-1(2-(2-thiazolyl-carbamoyl)-ethyl)-erturin. 21) 6-Methyl-8β-(6-chloro The compound according to claim 1, which is a-5-pyridazinyl-carbamoylmethyl)-ergoline. 22) The compound according to claim 1, which is 6-methyl-8β-C2-C6-chloro-5-pyridazinyl-carbamoyl)-ethyl]-ergoline. 23) 6-methyl-8α-(2-(5-methyl-1,5
, 4-(thiadiazolyl)carbamoyltwoergoline [the compound according to claim 1]. 24) The compound according to claim N, which is 6-methyl-8α-(2-thiazolyl-carbamoyl)ergoline. 25) The compound according to claim 1, which is 6-methyl-8α-(6-chloro-3-pyridazinyl-carbamoyl)-ergoline. 26) The compound according to claim 1, which is 1-methyl-6-broby-8-1(2-thiazolyl-carbamoyl)-ergoline. 27) 6-Methyl-8β-(2-(5-methyl-1,3
, 4-thiadiazolyl)-carbamoylmethyltsunylgoline. 28) 6-Methyl-8β-(2-(2-(5-methyl-
The compound according to claim wE1, which is 1,3,4-thiadiazolyl)-carbamoyltoethyl)-ergoline. 29) The compound according to claim 1, which is 6-methyl-8-1(3-methyl-5-inchazolyl-carbamoyl)-ergoline. 30) Claim OIl which is 6-methyl-8β-(3-isothiazolyl-carbazoyl)-ergoline! Enclosure 1
Items described in Section 1. 31) The compound according to claim 1, which is 6-methyl-8β-(5-methyl-5-inchazolyl-carbamoylmethyl)-ergoline. 32) Compound 6 of Claim 1 which is 6-methyl-8β-(2-(3-methyl-5-inchazolyl-carbamoyl')-ethyl)-ergoline 33) 6-Methyl-8N-[ The compound according to claim 1, which is 2-(3-isothiazolylcarbamoyl)-ethyltwoergoline. 34) 6-Methyl-8β-[5-(!S-methyl-1.
2. The compound according to claim 1, which is 4-thiadiazolyl)-carbamoyl]-ergoline. 35) 6-methyl-8β-(5-(!S-methyl-1.
The compound according to claim 1gi which is 2.4-thiadiazolyl)-carbamoylmethyltsundylgoline. 36) 6-methyl-8-1(2-(5-(3-methyl-
The compound according to claim 1, which is ergoline (1,2,4-thiadiazolyl)-carbamoyltoethyl). 57) Claim 1 which is 6-methyl-8-1(3-♂ridazinyl-carbamoylmethyl)-ergoline
Compounds described in Section. 3B) The compound according to claim 1, which is 6-methyl-8fi-C6-medoxy5-pyridazinyl-carbamoylmethyl)-ergoline. 39) 6-methyl-Bfi-<6-7, electric trimethyl-5
The compound according to claim 1, which is -V sumedinyl-carno-4-soylmethyl)-ergoline. 40) 6-Methyl-8β-[6-(pyrrolyl)-3-birimedinyl-carbamoylmethylsuergoline, the compound O described in Claim H, Item 1. 41) 6-Methyl-Bfi-C5-pyridazinyl-carbamoyl)-ercoline, 6-methyl-8-(2-(
3-pyridazinyl-carbamoyl)ethyl-to-ergoline, 6-methyl-84-(2-(4-methoxy-3-pyridazinylcarbamoyl)ethyl-to-ergoline. 6-methyl-5p-<b-a-set-methyl-5 -pyridazinylcarbamoyl)-ergoline, 6-methyl-8β-
C2-C6-methyl-3-pyridazinylcarbamoyl)-ethylcholine, 4-/? Sil-l-(
2-(4-(1-pyrrolyl)-3-pyrimedinylcarbamoyl]ethyl)-ercoline, and 6-methyl-8
-1[6-(1-pyrrolyl)-3-pyridazinylcarbamoyltwo-ergoline, and the compound according to the main claim @IXJ. 42) A compound of formula ■ (where n, R1, R2, Rs and R4 are defined in Claim IB Item 1) in an aprotic solvent with ethyl chloroformate. The resulting compound is 2RH-H (in the formula,
Claim 11 consisting of condensation with Anne of Rg is defined in claim 1
18. A method for producing an ergoline derivative according to item 1. 43) The above aprotic solvent is tetrah)1) I8
43. The method of claim 42, wherein the method is selected from the group consisting of I-furan, dimethylformamide and dioxane. 44) Claims 42 and 43, wherein the reaction of the compound of formula KO as described in claim 41 with ethyl chloroformate is carried out in the presence of an organic base at a temperature of 0 for 5 to 6 hours. Method described. 45) The method according to claim 44, wherein the organic base is triethylamine. 46) A method according to claim 42, wherein the condensation is carried out at room temperature for 2 to 24 hours. 47) A pharmaceutical product for oral or parenteral administration containing a therapeutically effective amount of a compound according to claims 1 to 40 in admixture with a pharmaceutically acceptable carrier. Composition.