JPS61183221A - Pharmaceutical composition containing 3-aminopropoxyindoles - 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 [Technical Field] This invention relates to 3-aminopropoginine indoles.

[Description of the invention]

In particular, this invention relates to the MilliP form or the pharmaceutically acceptable m(
=1 for the salted form.

R1j is preferably tJ benzoyl. The corresponding compound of formula (1) has the common name popinto
indolol) and 1. It is publicly known.

Compounds of formula (D and salts thereof) are potent β-adrenoceptor blockers. They are known per se, for example from Belgian patent 734126 and West German patent 2635209.

β-Adrenergic receptor blockers are suitable for the prevention and treatment of cardiovascular disorders such as hypertension, arrhythmia and angina pectoris.1. It is well known that

When administering such a drug once, for example, the duration of action of the drug is limited, so it is usually administered several times a day. Zunai Tsuchi, Pu [l Plano [l-
Le (propranolol)! JUsually, when used for hypertension, IEl IJ is approximately 80mg divided into two doses.
-about 480 mg and when used for angina pectoris, about 10 mg to about 160 mg divided into 3 or 4 times a day is administered orally for 11 days, and when used for other indications such as arrhythmia and migraine. Repeat [-1 throw) 5 on "1F" several times [Motan Drug Encyclopedia and Therapeutic Index (Modern
Drng Encyclopedia and The
rapeuticindex) J. Lewis, York Medical Books, 1981.824 pages].

Oral dosage of pindolol (pindc+]ol)
, when used for hypertension, it's 5 as 11 doses.
~15 mg or divided into 2 or 3 times per day or 20-30 mg once per day, and when used for other indications generally 1-11 doses in divided or delayed form 1 or 2 or 3 times a day (Sandoz-Index 19)
84-1986, +49 pages].

Similarly, for example, according to Belgian patent 734126:
The compound of formula (■) (where ■ is hydrogen) may be administered in 10 doses ranging from about 0.5 mg to about 50 mg, and an example of a tablet containing 5 mg of the compound =3- It is disclosed in the specification.

Surprisingly, the free form or pharmaceutically acceptable salt form of the compound of formula (I), even if not in sustained release form, is 1].
It has been found that it is suitable for administration at longer intervals, for example once or twice every other day or every other day.

The duration of the hypertensive action of formula (1) was greatly extended (j, as is clear from the following clinical studies, for example).

I have untreated essential hypertension and my diastolic blood pressure (DBP) is >
95 or -) < 125 mmm1- (and if mean arterial pressure (MAP) is 30 to 39 years old > 117 mmr-
Eight male patients with a systolic blood pressure (SBP) of > + 27 mmHg for r g aged 40-65 years were selected for the study. Average age is 54 years (range 35-03)
age), and the average weight was 87 kg (range 67.1 to ~1
14 kg). This study was part of a long-term study of Bovintrol [7-L], which included 101 doses of Bovintrol Img.
It was intended to be a double-blind comparison over a 6-week period of 3 doses versus 8 mg once weekly = 4 doses. Blood pressure (SBP and DBP) and heart rate (I
(R) was measured. The test formulation was replaced with Bovintrol Img
The dose was administered in the morning for 3 weeks, either daily as a capsule containing 8 mg of bovintrol, or as a capsule containing 8 mg of bovintrol at the beginning of the week, followed by a placebo capsule thereafter.

Mean values±SEM were calculated by conventional methods. Statistically significant differences from the values obtained with placebo treatment were calculated by analysis of variance using the Studen +-1 test.

Differences were considered significant if p<0.05.

Comparing the sitting position B) and HR measured at different dose ranges, it is clear from Figure 1 that during weekly treatment with 8 mg bovintrol, BP levels were lower when administered at 1 mg daily. The results are well maintained compared to the previous results. If Bobintrol was administered as a dose of 8'nig at the beginning of each week, B at the end of the 3 treatment weeks
P is +46±5/97±4, +41±6/90±5 and 143±7/96, ::L 5 mg 11g
Met. When 1 mg of Popindol [7-ru] is administered daily, the corresponding I3P is 139 xi: 5 /
97-! 4.142±6/95:L5 and 143±71/92±4 mg+-Ig. FIR
No significant difference was observed regarding (see Figure 1).

Figure 1 (Sitting position 1 during the treatment period by administering J1 Bobintrol at 1 mg a day or 8 mg Ij once a week)
[The values of Tl pressure (13P) and heart rate (t(R) are shown (tablet intake at time point 1, indicated by the arrow). The curve shows the value of 13P
Mean ± SE of (SIIP, D B P ) and TiR
M (n=8).

The observed side effects were minimal and well tolerated.The frequency of side effects was no different from that of placebo therapy.

Based on the comparison results between once daily and once weekly dosing,
It can be seen that the drug is well tolerated even when taken twice, and blood pressure control can be maintained without causing an excessive decrease in heart rate or blood pressure during peak efficacy.

This unexpected soak tolerance allowed one week's worth of doses to be taken in only one dose or twice every half cycle. Additionally, there is no longer any risk of accidentally overdosing for short-term irritation.

Compounds of the Zunaichi formula (1) allow administration at intervals longer than 1[', for example every other day or once a week or (32 times).

This discovery is very surprising. In fact, beta-adrenergic receptor blockers such as propranolol or timolol remain effective for only a few hours of light exposure, so they must be administered at least once or twice every 11 days! However, sustained-release forms can extend the duration of efficacy to a limited extent, usually less than 24 hours. This is because the efficacy lasts at most for the time it takes for the drug to pass through the gastrointestinal tract.Furthermore, such sustained-release preparations are expensive and difficult to manufacture, and it is difficult to achieve a constant plasma concentration.

More recently, β-adrenergic receptor blockers, such as -7-adrenergic receptor blockers, such as nadolol, have been developed, which have an action of the drug itself that extends beyond about 24 hours. Until now, it has been possible to administer antihypertensive drugs with longer-lasting effects by administering them at less frequent intervals, i.e., once or twice a week. It seems that it has never been considered.

The above findings clearly have far-reaching implications. For example, if a young patient with mild hypertension is to undergo long-term treatment, even once-a-day treatment can dramatically improve compliance. Additionally, the influence of inter-patient differences, eg related to diet or gastrointestinal function, on the pharmacokinetic properties of the formulation is also reduced, since there is no need for sustained release formulations.

This invention therefore provides a pharmaceutical composition suitable for administration at longer intervals in cardiovascular pharmacotherapy, containing the free form or pharmaceutically acceptable salt form of the compound of formula (1). Hereinafter referred to as [-composition 1 of the present invention] is provided.

The compositions of this invention have made possible new solutions for the prevention and treatment of diseases normally treated with β-adrenoceptor blockers, especially cardiovascular diseases such as hypertension.

For the aforementioned applications, the exact dosage will, of course, vary depending on the compound used, the method of administration and the treatment desired; however, in general, from about 0.05 to about 0.5 mg/kg (animal body weight) per week. Bulk results are obtained when administered in divided doses 1 to 4 times per week, or in sustained release form if an even longer duration of action is desired. For large mammals, the total weekly dose is approximately A dosage form suitable for oral or parenteral administration is 1 mg to about 32 mg of the compound mixed with a solid or liquid pharmaceutical carrier or diluent. An example of a weekly dose. IJ is preferably about 4 mg to about 16 mg.
A weekly dose of ~10 mg, particularly about 4 mg to 8 mg. For twice-weekly dosing Jj, the ifI dosage is not reduced by half, ie, for canine mammals, the total [-twice-weekly] dose is about 2 mg to about 16 mg. Twice a week Yosato no 1
Example 1. te('', about 2 mg to about 5 mg, especially about 2 mg to
It is about 4 mg.

In formula (r), compounds in which R is hendiyl are preferred.

The compositions of this invention comprise a compound of formula (1) in free form or in a pharmaceutically acceptable salt form, preferably in acid salt form, such as the acidic malonate salt form, in a pharmaceutical carrier or diluent. It can be administered in combination with. Such salt forms exhibit the same order of activity as the free form and are easily prepared by conventional methods.

Compositions of the invention may take the form of capsules, transdermal plasters or tablets, for example. [transdermal]-1 and (J transdermal administration is preferred.

Alternatively, the present invention provides 1 [1
longer intervals, such as every other day or once or twice a week,
There is provided a method for the prevention and treatment of diseases normally treated with beta-adrenergic receptor blockers, comprising administering the compositions of this invention, preferably at weekly intervals.

The present invention also provides a compound comprising from about 1 mg to about 32 mg, administered at intervals of more than 10 mg in the prevention and treatment of diseases commonly treated with beta-adrenoceptor blockers, particularly cardiovascular disorders such as hypertension. Suitable for use in medium dosage forms.

Furthermore-! The findings in Section 1 show that the compound of formula (+) is perfectly suitable for combination with long-acting diuretics. However, the selection of the particular diuretic used ( Obviously, preference should be given to those which are relatively long-acting. Known diuretics, such as hydroch
loroLhiazide), chlorthalidone (chl
oral 1done), metolazone (meLol
azor+e), amiloride (ami 1oridc)
), indapamide F', etc., have a sustained action of 6 hours or more.

However, two particular long-acting diuretics have been found to be particularly suitable in combination with compounds of formula (1), namely chlorthalidone and indapamide.

Accordingly, in another aspect, the present invention provides a pharmaceutical composition containing a compound of formula (1) in free form or a pharmaceutically acceptable mono-I+-acid addition salt form and either chlorzalidone or indapamito ( hereinafter referred to as "the combination of this invention").

Chlorzaridone and indapamide are ideally suited for combination with compounds of formula (1) and for use against hypertension. The onset of action is slow, so throw! While rapid diuresis within 2 hours immediately after administration can be avoided, the duration of action is relatively long for a diuretic, but it is not long enough to cause nocturnal diuresis.

The two active ingredients are preferably 1. < is a fixed formulation. In this case too, the compatibility of the active ingredients is surprisingly good.

Indeed, the development of fixed combinations is by no means a negligible problem, especially in the field of antihypertension, given its nature - the large and heterogeneous patient population involved. Since patients metabolize the active ingredients at different rates, the proportions of the ingredients are constantly changing. Consequently, the strength of therapeutic activity is also constantly changing17, thus making it pharmacodynamically compatible with respect to factors such as first-pass effects in the liver, etc.12
= It is important to select ingredients with a profile.

Bobintrol is preferred as a β-blocker.

Chlorthalidone is preferred as a diuretic. Administration of compositions with amphotropic ingredients can be carried out, for example, on a once daily basis or at longer intervals, such as every other day or once or twice a week.
It may be carried out on a once daily basis.

The compounds of formula (1) may be in free form or in salt form, such as hydrochloride, fumarate, acid malonate, etc., preferably acid malonate in the combination.

Few side effects are observed when this combination is used to treat antihypertension. No orthostatic hypotension was observed, and the symptoms that usually accompany antihypertensive treatment, such as dizziness, headache, tinnitus, and general fatigue, were minimal.

Antihypertensive treatment is surprisingly durable.

Although it is well known that β-receptor blockers reduce blood pressure in subjects undergoing antihypertensive treatment, it was unexpected that the combination of the present invention would have such a beneficial effect.

It also encompasses a pharmaceutical composition containing the combination of the present invention (J, the combination of the present invention in a form suitable for ingestion or parenteral administration, such as a tablet, sugar-coated tablet, etc.). To prepare such compositions, the combination is treated with conventional aorganic or inorganic pharmacologically inert auxiliaries, such as lactose, starch, polyvinylpyrrolidone, stearic acid, etc. , sorbic acid, talc, medylcellulose, alcohols, chrycerin, etc. The composition may contain suitable sweeteners or coloring agents, flavoring agents, and the like.

When used in combination with chlorthalidone or indapamide, as discussed above, the exact dosage will, of course, vary depending on the compound used, the method of administration, and the treatment desired. Generally, however, to obtain desirable results, a daily dose of about 1 mg to about 50 mg for diuretics, preferably about 2.5 mg to about 50 mg for chlorthalidone in particular.
, preferred 1. < is about 10πg to about 50uy, especially about 12.
5 uy to about 25 m9, also preferred in the case of indapamide,
<iJ in combination with a dose corresponding to about 1 g to about 5 shoulders 9, especially about 1 m7 to 2 g7 to a daily dose of about 0.1 mg to about 2 mg, preferably from about 0.5 mg to about 1 vrg. Administer β-receptor blockers at corresponding doses.

Throwing 1j is preferably done in the morning.

Zunaicchi, the two active ingredients are usually diuretics and Zuroβ.
- the receptor blocker has a heavy electric ratio of about 1.500=about 21, preferably about ]:]00 to about 1:1, more specifically about [
In the case of fluzaridone, preferably about 1 +500 to about 1
+1.25, especially about 1 +500 to about 15, especially about 12
50 to about 1:6.25, especially about 120, in the case of indapamide especially about 1:50 to about 21, preferably about 1.
It is present in a proportion of 20 to about 21, especially about 12.

〔Example〕

The present invention will be clarified by the following examples.

A) Administration of the active ingredient as part of cardiovascular drug therapy (once or twice a week).

=15 Example 1 Composition suitable for administration at weekly intervals for cardiovascular drug therapy.

Zaa no j (body blue □ cuff: Subeki Vjisu W minute------
------Scream g,----Bobbin)-Roll (acidic malonate) (=8mg base) 10.18
4 Lactose 191.066 Cornstarch +40.0 Silica [Acrosil] 200, Trademark,
Deguzza 175 Stearic Acid '70 350.0 Example 2 Composition suitable for weekly administration for cardiovascular drug therapy.

1-final summary)--1--- □-J Tobopindolol (acidic malonate) (-]Omg base) 12.7
3 Lactose 91.55 Cornstarch 128 Hydrogisib [J Pyl Methyl Cellulose [Pharmacor T・(
Pharmacoat) 603, trademark, manufactured by Nunetsu Co., Ltd.] 65 Iron oxide, red 0.0557
[Non-acid 021 Hydrogenated Castor Oil [Cutina 1-1, R, Trademark'] 1.9.5 Carbogysimethyl Starch Solium [Primojel, Trademark] 4.
2 Tablet diameter: 9mm 130.0
Examples 3 and 4 Compositions suitable for once or twice weekly administration in cardiovascular drug therapy.

Ingredients in tablets Example 3 Example 4 (once a week)
(twice a week) , ,,,, (m Lee-)
Hitobopindolol (acidic malonate X=IO or 5 mg base) 10.184
5.092 Lactose 166.29 147.30
6 cornstarch 22.0 19.
0 Hydrogine propyl methylcellulose (Pharmacoat 603, trademark, manufactured by Son-Etsu) +1.0 9.5 Iron oxide, red 0.0906 0.08 Malonic acid 0.02540.022 Hydrogenated castor oil [Kurtina] (Curtina) I-IR, Trademark] 3.3
2.85 Carpogynomedyl starch thorium (Primo, gel, trademark)? , 11
．． 6.15 total 220
190 tablet diameter: 9 mm
8mm Examples 5-8 Compositions suitable for administration in cardiovascular drug therapy.

Ingredients in hard gelatin capsules.

The components described in Examples 1 to 4 respectively, except that in place of bovintrol, a molar equivalent of 4-(3-butylamino-2-hydrogynopropixo)=2-methylindole [formula (1 ) (wherein R is hydrogen) is used in the acidic malonate form.

B) Administration of a combination of two active ingredients Examples 9 and 10 A composition for administration, eg, once a day, for hypertension.

Ingredients in tablets Example 9 Example 10
−−−−−−−”), −(mB face−lactose
0 mesh) 130.6] 118. I
I Hydroquine Propyl Medyl Cellulose 9,00 9.00
Cornstarch 18.0'0 18
．． 00 Bobintrol (acidic malonate) (-1mg base) 1.273 1
．． 273 Chlorthalidone (free form) 12.50
25.0 Iron oxide (red) 0.
076 0.076 malonic acid
0.02+ 0.021 Hydrogenated Castor Pork (Cutina HR, Trademark: I 2.70
2.70 Sodium carboxymedyl starch 5.82 5.82
Total 180.00 180.00
Tablet diameter: 8 mm Example 11 Composition for hypertension (e.g. once a day administration) Ingredients in tablet (mg) Lactose (2
00,)' っノゆ) 140.
61 Hydrogine Propyl methylcellulose 9.00 Cornstarch 18.00 Bobintrol (acidic malonate) (=]mg base) I',
273 Indapamide (free form) 25゜Iron oxide (red) 0.07
6 Malonic acid 0.02
1 Hydrogenated Castor Pork (Cutina) 2O- 1 (R1 Trademark) 2Nia 0 Carboquine Methyl Starch Sodium -j-1'j?
−.

Total 180.00 Tablet diameter 8 mm Examples I2, +3 and 14 Compositions for hypertension, e.g. Instead of Trol, a molar equivalent of 4-(3-
t-,-butylamino-2-hydroxypropixo)-
The acidic malonate form of 2-methylindole (i.e.
An amount corresponding to 0.76 mg of free base) is used.

[Brief explanation of the drawing]

Figure 1 shows bovintrol 1 mg daily or once a week.
Sitting blood pressure (B
P) and heart rate (IR) values are shown 4- (tablet taken at the time indicated by the arrow). The curve is BP (SBP, DBP
) and HR mean±S, EM is shown (n=8),
.

Claims (4)

[Claims] (1) Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R is hydrogen or benzoyl] Free form or pharmaceutically acceptable acid addition salt form of the compound is used for pharmaceutical purposes A pharmaceutical composition suitable for administration at intervals of more than one day in cardiovascular drug therapy, containing together with a carrier or diluent. (2) prophylaxis of diseases normally treated with β-adrenergic receptor blockers, or Treatment method. (3) A pharmaceutical composition comprising: a) a β-adrenergic receptor blocker represented by formula (I) according to claim 1; and b) a diuretic selected from chlorthalidone and indapamide. (4) A method for treating hypertension comprising administering a therapeutically effective amount of the composition according to claim 3 to a subject in need of treatment.