JPS63277677A - Ergoline derivative and acid addition salt thereof - Google Patents

Abstract

NEW MATERIAL:The 8beta-ergoline derivative of formula I and its acid addition salt. EXAMPLE:1-(2-Bromo-6-methyl-8beta-ergonylmethyl)-2-phenylimidazole. USE:A drug. A preventive and remedy for hypertension and various diseases accompanying hypertension. It has no influence to pulse rate and has extremely low side effects such as emesis. It is administered by oral administration at a dose of 0.005-10mg/kg body weight per day. PREPARATION:The compound of formula I can be produced by reacting a compound of formula II (X is eliminable group consisting of an acid residue such as halogen and sulfonyloxy) with 2-phenyl-imidazole or its metal salt in a solvent such as dimethyl-formamide in the presence of a base such as NaH at 50-140 deg.C for 5min-15hr.

Description

[Detailed description of the invention] A. Industrial application field Concerning acid addition salts.

The compounds of the present invention have excellent antihypertensive effects and are useful as pharmaceuticals for preventing or treating hypertensive diseases.

B. Prior Art and Questions Ergot alkaloids and related compounds have a wide variety of effects, and are also well known to have antihypertensive effects [e.g., Lancet, 211 (1977);
.

11ect,Czech,CheIIl,Commun
,,Dan, 1407 (+97?): Br, J, Phar
maco I, , 75.143p (1982);
Arzne im, -Forsch, 4th, +09
4 (+983); Arch, lnt, Pharmac
odyn, Ther, +272.71 (+984); see New Medicine and Clinical Research, 2, 63 (1986), etc. ] Dihydroergotoxin, a semi-synthetic alkaloid, is used as a certain remedy for cerebral and peripheral circulation disorders.

It is also used clinically as an antihypertensive drug [e.g.
See New Drugs and Clinical Practice, 35.63 (1986), etc. ].

Bubromocributi is acromegaly, pituitary gigantism.

It is used as a treatment for hyperprolactinemia and Parkinson's disease, but it is also being used for hypertension due to its antihypertensive effect [e.g. + Lancet, 211 (
197? ) etc. ]. ]゛On the other hand, ergot alkaloids and their related compounds have a variety of pharmacological actions;
It has poor selectivity in its pharmacological action, and nausea and vomiting, which are thought to be caused by its dopamine D2-receptor stimulating action, are observed quite frequently, which limits its clinical use.

For example, taking bromocriptine, nausea is 56.
1χ, vomiting was observed at an extremely high rate of 23.3X [Obstetrics and Gynecology, 48,117 (+981); 1
bid, 48.241 (+981), etc.]. For this reason, it is desired to create ergot alkaloid-related compounds that have strong and selective pharmacological effects and have few side effects such as nausea and vomiting.

Compounds closely related to the present compounds, ie.

6-methylergolin-8β-ylmethyl group or hetero 5
Only a few reports are known regarding compounds bonded to membered rings. JP-A-58-194884 describes 3°5-dimethyl-4-(6-methylergolin-8β-ylmethyl)pyrazole and related compounds, and mentions their antiprolactin and hypotensive effects. Particularly germane to the present application. That is, in the literature describing compounds in which a 6-methylergolin-8β-ylmethyl group is bonded to a nitrogen atom within a five-membered heterocyclic ring.

There are JP-A-59-206382 and JP-A-60-84286. The former.

For example, antihypertensive activity is disclosed in 1-(6-methylergolin-8β-ylmethyl)imidazolidine-2,4-dione and related compounds.

The former also describes the inhibitory effect on prolactin secretion. For example, 3-(2
PGF antagonism is disclosed for -pyridyl)-5-methyl-1-(6-methylergolin-8β-ylmethyl)pyrazole and related compounds. It also has anti-serotonin and hypotensive effects.

It describes prolactin level lowering effects and dopamine receptor agonist effects.

However, there is no known compound in which a 2-bromo-6-methyl-8β-ergolinyl group is bonded to the nitrogen atom in the five-membered ring of 2-phenylimidazole.

The compound (T) of the present invention has excellent pharmacological properties that cannot be predicted from conventional techniques.

Means and action for solving the C1 problem The present inventors have synthesized and patented an ergoline derivative having excellent pharmacological action (Patent Nos. 60-299203 and 61-
177138), as a result of further intensive research, the present invention was completed by synthesizing the present compound (I), which is an 8β-ergoline derivative having extremely excellent pharmacological effects.

The compound (1) of the present invention has the general formula (wherein x represents a leaving group which is an acid residue such as a halogen atom such as chloro, bromine, and iodo atom, or a sulfonyloxy group represented by O20,R). .R is a lower alkyl group such as methyl, ethyl, propyl, or phenyl or chlorophenyl.

Indicates allyl groups such as methoxyphenyl and methylphenyl. ) [The compound in which X is a bromine atom is Ger, Offen, 2,335,750 (19
74) [Chem, Abstr., 80:146400
d (1974)], and US, 4,054.660 (
1977) [Chew, Abstr., 88:5107
0x (1977)], compounds where X is 05O2R and R is 4-methylphenyl group are Eur, Pat, Appl
, 8, 801 (1980) [Chem, Abstr.
, 93:132675d (1980)], and Eur.
, Pat, App1. , 30, 351 (1981) [C
hei+, Abstr., 95:187505v(+9
81)]. 2-phenylimidazole in a reaction-inert solvent such as dimethylformamide, dimethylsulfoxide, hexamethylphosphortriamide, acetone, methyl ethyl ketone, etc. in the presence of a base such as sodium hydride, potassium carbonate, sodium carbonate, or The compound (1) of the present invention can be easily produced by reacting the sodium salt or potassium salt of 2-phenylimidazole at a temperature of 50 to +40'' for 5 minutes to 15 hours. Any desired acid addition salt can be formed.Acid addition salts include chemically non-toxic salts such as fumaric acid, maleic acid,
Tartaric acid.

Salts such as hydrochloric acid, sulfuric acid and methanesulfonic acid are suitable.

Compound (I) of the present invention showed extremely excellent antihypertensive effects. The compound (1) of the present invention may be used alone or together with other compositions, such as nine tablets or troches.

Large portions, granules, powders, capsules, and ampoules.

It can be used in the form of suppositories. Other compositions include starch, dextrin, etc.

Sucrose, lactose, silicic acid, carboxymethyl cellulose, cellulose, gelatin, polyvinylpyrrolidone, glycerin, agar, calcium carbonate, sodium bicarbonate, paraffin, heptyl alcohol.

Stearate, kaolin, bentonite.

Examples include talc, calcium stearate, magnesium stearate, polyethylene glycol, water, ethanol, isopropyl alcohol, and propylene glycol.

The daily dosage of the compound (I) of the present invention, for example, for oral administration is 0.005 to 111 kg per 9 bodies.
IOB is appropriate. Naturally, the dosage may be increased or decreased as appropriate depending on the condition at the time of administration.

D, Example (1) 1-(2-Bromo-6-methyl-8β-ergolinylmethyl)-2-phenylimidazole 6 (H Add oily sodium hydride (0.8 g) to dimethylformamide (30 ml) Then, 2-phenylimidazole (3.0 g) was gradually added. After the foaming stopped, 2-bromo-6-methyl-8β-ergolinyl tosylate was added and heated on a water bath for 1 hour. After cooling, water was added. Dilute with water and leave to stand. Filter the precipitated crystals and wash with water. Silica gel column chromatography (ethyl acetate: ethanol = 1
6: Purified by I). Recrystallized from ethanol-hexane to give colorless prismatic crystals, mp260-267" (dec
omp, ), 0.95 g was obtained.

NMR (CDC1a) δ: 0.99 (IH, brq,
J12.0Hz), 1.56-2.97[10H,
m, 2.40 (3H, s)], 3.15 (l) I,
dd, J=14.3, 3.8Hz), 3.96(
2H, d, J = 6.882), 6.58-6.83 (
I) I, m), 6.90-7.20 (48, n+)
, 7.25-7.63(5)1, m), 8
．． 21 (1)1.

brs).

Anal, Calcd forC25H26B r N
4: C, 64,94: H+ 5.67; N!
12.12- Found: C* 64-77
; H, 5,56; N, 11.84° (2) Antihypertensive effect Using spontaneously hypertensive rats weighing 300 to 350 g (21 to 25 weeks old)! Tail artery systolic pressure was measured non-invasively with a blood pressure monitor under no anesthesia using the tail cuff method. Heart rate was measured simultaneously using a heart rate monitor connected to pulse wave output. For blood pressure measurement, rats were placed in a heating box at 40°C in advance.
After being inserted for 0 minutes, it was held in a rat holder.

The specimen was suspended in 0.5x gum arabic powder.

It was administered orally in a volume of 0.5 ml/100 g. Note that hydralazine hydrochloride was administered as an aqueous solution. The results are in Table 1
and 2.

81) S ratio (3) Emetic effect Mongrel adult dogs weighing 10 to 15 kg were used. After giving enough food, 30 minutes later, the test drug was administered into the brachial vein.
Time, vomiting and general behavior were observed. The test drug is O, l
After dissolving in NIC+, it was further diluted with physiological saline and administered. The results are shown in Table 3.

Table 3 Emetic effect E. Effect Compound (I) of the present invention has extremely excellent pharmacological properties.

In other words, while it exhibits a strong antihypertensive effect, side effects such as vomiting are extremely weak.

For example, as is clear from Table 1, Compound (1) of the present invention exhibited an extremely strong antihypertensive effect in spontaneously hypertensive rats, and this effect was long-lasting. The maximum hypotension when administered orally at 3 mg/4 was 76I) for the compound of the present invention (1).
The Ig was extremely large. on the other hand.

Bromocriptine methanesulfonate, cyanerboline [Arzneim, Forsh, 33.1094 (1
983)] and hydralazine hydrochloride had a maximum blood pressure reduction of 38.40.471 WmHg, respectively. For dihydroergotoxin methanesulfonate I
Even when OB/kg was administered, it was extremely low at 20gllHg.

Hydralazine hydrochloride, which is clinically used as an antihypertensive agent, is known to cause tachycardia as a side effect along with lowering blood pressure. As is clear from Table 2.

Strongly increases heart rate. On the other hand, two compounds of the present invention (1
) had no effect on heart rate.

The results of the emetic effect in dogs are shown in Table 3. Dihydroergotoxin methanesulfonate exhibited a strong emetic effect when administered intravenously at 10 μg/kg. Bromocriptine methanesulfonate showed an emetic effect at 10 to 30 μg/J (and cyanerboline showed an emetic effect at 100 μg/kg. On the other hand, the two compounds of the present invention (T) did not show an emetic effect even at 300 μg/kg.

Although the compound (1) of the present invention has an extremely strong antihypertensive effect as shown in 2 or more, it does not affect heart rate and has an extremely weak emetic effect.In other words, it has an extremely wide safety margin. It has excellent pharmacological properties. The compound (1) of the present invention is.

It is extremely useful as a drug for the prevention or treatment of hypertension and various diseases associated with hypertension.

Patent applicant: Marco Pharmaceutical Co., Ltd. 7″′

Claims (3)

[Claims] (1) 8β-ergoline derivative and its acid addition salt represented by the formula ▲Mathematical formula, chemical formula, table, etc.▼ (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X represents a leaving group that is an acid residue such as a halogen atom or a sulfonyloxy group.) A method for producing the compound according to claim 1, which comprises reacting 2-phenylimidazole or a metal salt thereof. (3) A therapeutic agent for hypertensive disease, which contains the compound described in claim 1 as an essential ingredient.