JPS5896019A - Remedy for drepanocytic anemia - Google Patents

Abstract

PURPOSE:A remedy for drepanocytic anemia that contains dilazep hydrochloride, hexobendine hydrochloride and maleic cinepazide as active ingredients. CONSTITUTION:The objective remedy contains a compound of formulaI, formula II (A is phenyl mono- - trisubstituted with lower alkoxy; n is 1-4; R1, R2 are H, lower alkyl, or R1 and R2 incorporate to form 2-3C alkylene) as an active ingredient. Examples of the active ingredient are tetrahydro-1H-1,4-diazepin-1,4(5H)dipropanol bis( 3,4,5-trimethoxybenzoate ); 3,3'-[ethylenebis(methylamino)]-di-1-propanol 3,4,5-trimethoxybenzoate; N-(3,4,5-trimethoxycinnamoyl)- N'-(pyrrolidino-carbonylmethyl)pyrazine and their salts. The dose is 0.1-1,000mg a day and it is given 1-4 times a day.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel therapeutic agent for sickle cell anemia. a phenyl group substituted with lower alkoxy groups, n represents an integer of 1 to 4, and R
1 and Rx Id are the same or different and represent a hydrogen atom or a lower alkyl group, or R1 and R2 combine to form an alkylene group having 2 or 3 carbon atoms) 3 - A compound represented by 7 <This article relates to a therapeutic agent for sickle cell anemia containing Baso salt as an active ingredient.

Sickle cell anemia occurs when the patient's red blood cells contain 1'! ″I
Among the α and β chains that make up the 5()tb molecule, the glutamic acid residue at the 6th position from the amino terminus of the β chain is replaced by a valine residue. It is a hereditary disease that is caused by the presence of the disease, and the majority of homozygotes die by the time they reach adulthood, and pederozygotes also exhibit symptoms of embolism, including hematuria, making it a tragic disease. .

The mechanism of onset of this disease has been almost completely elucidated from a molecular perspective, and its outline is as follows. That is, the production of H, bS by the mutant gene - HbS under hypoxic am
Polymer formation of molecules → gelation due to decrease in solubility →
Formation of sickle-shaped red blood cells→selective destruction of sickle-shaped red blood cells by the tiles, leading to severe hemolytic anemia and embolization of various organs such as bones, heart, lungs, brain, and liver, resulting in a wide variety of systemic symptoms.

Until now, there was no effective way to treat this disease, and the treatment had been limited to symptomatic treatment centered on blood supplementation, but relatively recently, as the polymer formation mechanism of HbS molecules has been clarified, attempts have been made to suppress it with drugs. In other words, attempts were made to suppress the formation of polymers by chemically modifying HbS molecules with urea, isocyanic acid, etc., but in reality, due to side effects, it was impossible to put them into practical use. The situation is far from 4-.There has been a strong desire to develop effective treatments for these conditions, which are said to number in the tens of millions of patients and carriers worldwide. .

Under such circumstances, the inventor has conducted extensive research and found that the compound ζh represented by the general formula (1> or (II)) or its salt has excellent effects for the above purpose. The invention was completed.

That is, the present invention provides a therapeutic agent for sickle cell anemia containing a compound of formula (1) ita uol) or a salt thereof as an active ingredient.

Representative examples of the compound represented by formula (1) or (11), which is the active ingredient of the present invention, include the following.

A) Tetrahydro-IH-1,4-diazepine-1
,4(5H) dibrobanol bis(3,4,5-)rimethoxybenzoate) 2-hydrochloride monohydrate (hereinafter referred to as "dirazep hydrochloride") B) 3 ,3'-(ethylene bis- (Methylamine)]] Di-1-Globanol 3,4.5) Rimethoxybenzoate dihydrochloride (hereinafter referred to as "hegisobendine hydrochloride") C) N-(3,4,5-trimethoxycinnamoyl)-
N'-(pyrrolidinocarbonylmethylbiperazine, maleic acid (hereinafter referred to as "cinepatid maleate") and kone are all known compounds, such as those described in No. 7-f3) and No. 47-1293 (C). The stiff compound, which can be easily produced by the above method, is known to have coronary vasodilatory effects, cerebral circulation improving effects, etc., but there is no evidence that it is useful for the treatment of sickle cell anemia. Not reported.

The results of tests conducted on the anti-sickling effect of Kowara's compounds are shown below.

Inhibition of silver formation of red blood cells in vitro 1. Method: Red blood cells from patients with peterozygous sickle cell anemia (containing approximately 50% Hb S')''f After washing three times with physiological saline, the suspension (
hematocrit 20%) 8-(A) and sodium metasulfite physiological saline solution (
The effect of dilazep hydrochloride on the red blood cell sickling phenomenon that occurs in a mixture with 2,09/dt)@) was observed on a slide glass. That is, mix 1 drop each of A and B, mix with a fixed amount of dirazep hydrochloride physiological saline solution of different concentrations, cover the glass with a cover glass, seal the edges with paraffin, and leave at room temperature for 30 minutes or 90 minutes. Microscopic examination was performed at 300 minutes, and the rate of inhibition of red blood cell sickling was calculated. The results are shown in Table 1, and dirazep hydrochloride showed a strong effect of inhibiting red blood cell silver formation.

It is predicted that it will have a strong effect on

Table 1 Effect of dirazep hydrochloride on inhibiting red blood cell silver formation■ Clinical case Patient ○, G (26 years old, Ghanaian international student) In 1978, after studying abroad in Japan, he was hospitalized with a complaint of unexplained hematuria and underwent angiography. Afterwards, he suffered a serious leak (embolism attack), and as a result of careful examination, electrophoresis and other tests revealed that he had sickle cell anemia. Thereafter, the patient was resistant to various treatments, but the patient was finally discharged from the hospital after 3 months with alkali therapy.

In 1980, a severe case of hematuria reappeared after a traffic accident, and upon careful examination, it was thought that it was caused by a phenomenon in which red blood cells become armored. Therefore, this time, we will introduce the above-mentioned inv.
By orally administering dirazep hydrochloride at 0.31/day for one week, we succeeded in curing refractory hematuria in an extremely short period of time. During this time, no side effects were observed. Therefore, dirazep hydrochloride and its related substances have excellent therapeutic effects not only on hematuria in carriers of silver cell anemia, but also on all clinical symptoms that cannot be considered to be caused by the red blood cell armor phenomenon. It has an excellent therapeutic effect on colobular anemia, and its acute toxicity is low as shown in the following table, and there are few side effects, so it can be administered over a wide range of areas.

Acute toxicity LLDso value (y/Q)) (M oral administration) The therapeutic agent of the present invention can be administered in various dosage forms, such as oral preparations such as tablets, granules, and capsules, 12- suppositories, and injections. The dosage varies depending on the degree of anemia, but is usually 0.1 per day.
It is preferable to administer the drug in 1 to 4 doses of ~1000 μf.

Production example 1 Dirazep hydrochloride sugar-coated tablets 50 ■ Corn tenbun 27 ■ Crystalline cellulose 10 ■ Carboxymethyl cellulose 10 q Hydroxyglobil cellulose 2 q Magnesium stearate 1 ■ Subtotal 100 ■ Coating (sugar coating) t5 oq Total (per tablet) 250 + 11 v Multiple tablets were manufactured according to a conventional method using up to magnesium phosphate.

The product was then coated with sugar.

Production example 21! Sugar-coated tablets were produced in the same manner as in Production Example 1, except that hexobendine hydrochloride was used instead of dirazep hydrochloride.

Production Example 3 Sugar-coated tablets Sugar-coated tablets were produced in the same manner as in Production Example 1 except that Dirazep hydrochloride was replaced with Cinebatid. Production Example 4 Dirazep Hydrochloride tablets 25.0η Excipients (milk m) 20.0■ Temperature
50.0■ Cellulose 5.0■ Binder Appropriately Lubricant Appropriately The above compositions were mixed and compressed to produce tablets.

Production Example 5 Tablets were obtained in the same manner as Production Example 4, except that hexobendine hydrochloride was used instead of dirazep hydrochloride.

Production Example 6 Tablets were obtained in the same manner as Production Example 4, except that cinepatide maleate was used instead of dirazep hydrochloride.

Production example 7 Fine granules dirazep hydrochloride 50? lv lactose
447■ Corn b starch 119η15- Hydrogenated castor oil 80 ■ Carboxymethyl cellulose Sodium F. Lium 40 ■ Carboxymethyl cellulose calcium 119 ml 1 Hydroxypropyl cellulose 45 ■ Polyethylene glycol 6000 3 mg Pholioxyl stearate 40 2 ■ Talc
8q white sugar
30■ total
Fine granules were prepared according to a conventional method using 1000 ml of dirazep hydrochloride to hydroxypropylcellulose. Next, the remaining material was coated all around to form a product.

Production Example 8 Fine Granules-16- Fine granules were obtained in the same manner as Production f/117 except that dilazep hydrochloride was replaced with all hexobendine hydrochloride.

Production Example 9 Fine Granules A fine granule was obtained in the same manner as Production Example 7 except that cinepatide maleate was used instead of dirazep hydrochloride.

Production Example 10 Injection Dirazep Hydrochloride 0.51n? Sodium chloride 8.9 ■ Total amount 'f- with distilled water for injection
Let it be 1,0-.

After the above composition was completely dissolved, it was sterile filtered and filled into ampoules to produce an injection.

Production Example 11 An injection was obtained in the same manner as in Production Example 10, except that hexobendine hydrochloride was substituted for dilazep hydrochloride for injection. Production Example 12 An injection was obtained in the same manner as in Production Example 10, except that dilazep hydrochloride was replaced with maleic acid and patid. Injection f was obtained.

Production Example 13 Raw Naka 1 (1) Oil-based dirazep hydrochloride 50TNi Witepsol E-85100TIq Witepsol E-35778■ Polyoxyethylene sorbitan monooleate 10■
sorbitan monolaure) 1
0 Tng hydrogenated castor oil 2 ■ Anhydrous silicic acid 10 Tng total (per piece) 960 Tng From Lytep Sol E-85, dissolve hydrogenated castor oil by heating, add dirazep hydrochloride and anhydrous silicon [1],
After thorough stirring and dispersion, the mixture was poured into a container and cooled and molded.

(2) Water-soluble dirazep hydrochloride 50M9PEG4000
1257.9■PEG400
80m7BHT (2,6-di-tert-butyl-P-cresol) 2■Sodium thiosulfate 0.1■Total (per 11 solids)
1300■PEG4000 and 40
The mixture was completely heated and dissolved, and dirazep hydrochloride, BHT and sodium thiosulfate were added thereto, thoroughly stirred and dispersed, and then poured into a container and cooled and molded.

19- (3) Phthalate Capsule Hydrochloric Acid Shiranap 5Q++y#JII Seed Oil 663 ■ Castor Oil
15q Porioxyethylene sorbitan monooleate 2■
ηt (per piece) 750
(2) After thoroughly stirring and dispersing the upper and lower parts, the mixture was deposited on a phthalate capsule.

Production example 14 Suppository resistant dirazep? ! Each yuzu suppository was obtained by using the method of pouch manufacturing example 13 except that hexobendine was used.

Production example 15 Suppositories Dirazep hydrochloride is mixed with dipatid maleate for 120- Various suppositories were obtained in the same manner as in Production Example 13 except that the ingredients were changed.

that's all Applicant Kowa Co., Ltd. 130-

Claims (1)

[Scope of Claims] (In the formula, A represents a phenyl group substituted with 0 to 3 lower alkoxy groups, n represents a frequency of 1 to 4, and R
1 and R2 are the same or different and represent a bulky atom or a lower alkyl group, or R1 and R2 combine to form an alkylene group having 2 or 3 carbon atoms, or a compound thereof m containing salt as an active ingredient
A therapeutic agent for type cell anemia. 2. The active ingredient is tetrahydro-IH-1,4-diazepine-1,4(5H) dibrobanol bis(3,4,5-
)rimethoxypenzoate) or its salt %W
f. The therapeutic agent according to claim 1. 3. The active ingredient is a, a'-[ethylenebis-(methylamine)]di-1-furobanol 3,45-trimethoxybenzoate or a salt thereof %W! Therapeutic agent according to item 1, scope of fg profile. 4. The therapeutic agent according to claim 1, wherein the active ingredient is N-(3,4,5-)rimethoxycinnamoyl)-N'-(pyrrolidinocarbonylmethyl)piperazine or a salt thereof.