WO1998041199A1

WO1998041199A1 - Decongestant for nose or eye

Info

Publication number: WO1998041199A1
Application number: PCT/JP1998/000994
Authority: WO
Inventors: Hiromichi Tsuru; Yojiro Ukai
Original assignee: Nippon Shinyaku Co., Ltd.
Priority date: 1997-03-14
Filing date: 1998-03-10
Publication date: 1998-09-24
Also published as: JP4096363B2

Abstract

A drug composition containing as the active ingredient any of 3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulfonanilide, an optical isomer thereof, and a pharmacologically acceptable salt of either. The compounds have a microvasoconstrictive effect on the nose or eyes and are effective in the remedy of nose or eye congestion without influencing blood pressure.

Description

Specification

Nasal or ocular hyperemia treatment

Technical field

The present invention relates to a ³ ′-(2-amino-1- 1-hydroxyxethyl) -14,1-fluoromethanesulfonylanilide (hereinafter referred to as a compound) having a microvasoconstriction of the nose or eyes and having a small effect on blood pressure. (Referred to as (1)) as an active ingredient.

Background technology

Nasal congestion is characteristic of diseases such as colds, allergic rhinitis, sinusitis or hay fever. Nasal congestion is caused by dilation of blood vessels in the nasal mucosa, resulting in swelling of the tissue covering the nasal cavity. The microvessels of the nasal mucosa are known to be rich in hy-adrenergic receptors. Eye hyperemia is also characteristic of allergic conjunctivitis. Eye hyperemia is caused by dilation of the conjunctival blood vessels.

A; L-adrenergic receptor agonists such as oxymetazoline, naphazoline, and amidefrin reduce congestion in nasal tissues by contracting microvessels in the nasal mucosa. These drugs also relieve eye redness.

The α-α-adrenergic receptor agonists used for the treatment of nasal microvascular hyperemia are problematic in that they have strong central nervous system side effects such as insomnia and agitation, or strong cardiovascular side effects such as increased blood pressure, palpitations and arrhythmias. Had become.

Disclosure of the invention

An object of the present invention is to provide a remedy for nasal or ocular hyperemia, which has a nasal or ocular microvasoconstriction effect and has few or no side effects such as increased blood pressure.

The present inventors have found that compound (1), its optical isomer, and any pharmaceutically acceptable salt thereof achieve the above object, and have completed the present invention.

Pharmaceutically acceptable salts of compound (1) include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p — Salts of organic acids such as toluenesulfonic acid, benzenesulfonic acid and methanesulfonic acid.

The compound according to the present invention has an excellent nasal microvasoconstriction effect. In addition, the present invention The compound according to the above has little effect on blood pressure and the like. This is a feature of the present invention. The compound according to the present invention also has a conjunctival microvascular contraction effect, has little effect on blood pressure and the like, and is also useful as a therapeutic agent for ocular hyperemia.

When the compound of the present invention is administered as a medicament, the compound of the present invention may be used as it is or in a pharmaceutically acceptable non-toxic and inert carrier, for example, 0.01 to 99.5%, preferably It is administered to animals including humans as a pharmaceutical composition containing 0.5 to 90%.

As the carrier of the pharmaceutical composition according to the present invention, one or more solid, semi-solid or liquid diluents, fillers and other prescription auxiliaries are used. Desirably, the pharmaceutical compositions are administered in dosage unit form. The pharmaceutical composition of the present invention can be administered orally, intravenously, transdermally, intranasally or by eye drops. Needless to say, it is administered in a dosage form suitable for these administration methods. For congestion of the nose, administration by a nebulizer or nasal drops or oral administration is particularly preferred. For ocular hyperemia, ophthalmic administration or oral administration is particularly preferred.

It is desirable that the dose of the compound of the present invention as a therapeutic agent for nasal or ocular hyperemia is determined in consideration of the patient's condition such as age and weight, the administration route, the nature and extent of the disease, and the like. Usually, the amount of the active ingredient of the compound of the present invention for an adult is generally in the range of 0.01 to 1000 mg / day, preferably in the range of 0.1 to 10 mg / day.

In some cases, lower doses may be sufficient, and conversely, higher doses may be required. It can also be administered in divided doses two to three times a day.

For oral administration, solid or liquid dosage units, such as powders, powders, tablets, dragees, capsules, granules, suspensions, solutions, emulsions, syrups, drops, sublingual tablets, etc. It can be performed with other dosage forms.

Intranasal administration can be carried out by nasal or spraying a solution, suspension, emulsion and the like. Suitable liquid media include pharmaceutically usable alcohols such as water and propylene glycol or pharmaceutically usable vegetable oils such as sesame oil or peanut oil. Intranasal administration can also be carried out in ointments, gels or other forms. Dosage forms for nasal administration may be sterile and require Depending on the type, auxiliary agents such as preservatives, stabilizers, emulsifiers, tonicity agents or buffering agents may be contained.

Administration by eye drops can be carried out with a solution, suspension, emulsion or the like. Suitable liquid media include pharmaceutically usable alcohols such as water or propylene dalicol. The dosage form for ophthalmic administration is generally sterile and may contain adjuvants such as preserving, stabilizing, emulsifying, isotonic or buffering agents as necessary. Good.

The pharmaceutical composition of the present invention may contain or combine other drugs, for example, other nasal or ocular hyperemia inhibitors.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail with reference to Test Examples and Formulation Examples of the compound of the present invention.

In the test examples and preparation examples, the salt of the optical isomer of compound (1) (R) — (I) 1-3, 1 (2-amino-1-hydroxylexetil) 14,4-fluoromethanesulfonanilide hydrochloride The salt is indicated as compound (1A).

Test example 1

Effects on nasal mucosa microvessels

Five to six adult male and female hybrid dogs (body weight: 7 to 18 kg) were anesthetized with pentobarbital sodium (35 mg / kg, iv), cardiac arrested by intravenous injection of aqueous potassium chloride solution, and the nasal septum and concha were observed. Was extracted. These were immediately immersed in an ice-cooled Krebs-bicarbonate solution previously passed with 95% O ₂ + 5% CO ₂ . Using a scalpel, mucosal tissues including microvessels were separated from the nasal septum and the concha, and 5X15 mm strip specimens were prepared. Specimens are suspended in a tissue bath containing Krebs solution, aerated with 95% O ₂ + 5% C02, maintained at 37 ° C, loaded with 0.5 g and flushed with Krebs solution every 15-20 minutes. Equilibrated for about 1 hour with replacement.

The concentration-response curves of the test drug (compound (1A) and control drug (norlepinephrine)) show that the neuronal uptake inhibitor desmethylimipramine (3X10 ^ M) and the extraneural tissue uptake inhibitor Test drug in the presence of hydrocortisone (8.7X10-.M) and propranolol ( ^3X10_7M ), a 3 _ adrenergic receptor antagonist Was obtained by accumulating and contracting the specimen. It was calculated pD ₂ value than its concentration first reaction curve _(P D ₂ value = - log (ED ₅₀ value (M))). Table 1 shows the results.

Test drug No. of patients pD ₂ (M) compound (1 A) 5 6.23

Nonolepinephrine 6 6.32 It is clear that the compound according to the present invention has a strong nasal mucosa microvasoconstriction action similar to that of norepinephrine.

Test example 2

Effects on blood pressure

The test was performed using 3-6 male male egrets (body weight: 1.4-3.1 kg) per group under anesthesia by subcutaneous administration of urethane 1-1.2 g / kg under fasting conditions. After making a midline incision in the abdomen immediately above the stomach, the required amount of the test drug (compound (1A), amidefrin) suspended in a 0.5% methylcellulose aqueous solution was administered into the duodenum at a volume of 0.5 ml / kg. Changes in blood pressure were measured over time after administration. Blood pressure was measured using a blood pressure measuring force-Yure inserted into the femoral artery. Table 2 shows the results.

Table 2

Test drug Number of patients Dose Blood pressure change rate (%)

(mg / kg) Time after administration (minutes)

10 20 30 60 90 120 180 Control 6 2.1 -0.8 -3.6 -7.2 -9.9 -12.3 -17.2 Compound (1 A) 6 0.1 2.7 1.9 3.3 0.5-5.0 -9.8 -14.9

6 0.3 2.8 4.0 4.7 7.9 ** 6.5 ** 3.3 * -10.0 Amidefrin 4 1 2.4 -0.1 2.2 7.2 * 14.3 ** 10.3 * 3.7 **

3 3 5.8 3.7 4.1 20.7 ** 34.4 **

*; P <0.05, **; P <0.01 (Dunnett's method)

Amidefrin has a strong vasopressor effect at doses considered necessary for onset However, it is clear that the compound according to the present invention has almost no effect on blood pressure in an effective amount.

Test example 3

Acute toxicity test

Mice (ddy male, 6 to 8 weeks old) were used as 4 rats per group, and rats (SD male, 6 to 7 weeks old) were used as 6 rats per group.

From the day before the administration (16 to 18 hours), the fasted animals were orally administered the required amounts of the test drugs (compound (1A) and amidefrin) in a volume of 10 ml / kg using an oral sonde. After administration of the drug, the animals were returned to a state where they could freely take food and water, and observed for general symptoms and deaths for 2 weeks. The test drug was orally administered by suspending it in a physiological saline solution containing 0.5% methylcellulose. Table 3 shows the results.

Table 3

Test drug Mouse rat

Dose Deaths Dose Deaths

(mg / kg) (mg / kg)

Compound (1A) 1000 0/4 500 0/6

3000 0/4 1000 0/6

Amidefrin 1000 0/4 5 0/6

3000 3/4 10 3/6

20 4/6

30 6/6 No deaths were observed and no abnormal findings were observed in the group administered with the compound (1A). It is clear that the compound according to the present invention has higher safety than amidedefrin. Formulation Example 1

Tablets (oral tablets)

Prescription 1 tablet in 120mg

Compound (1A) 1 mg

Lactose 60 mg. Corn starch 30 mg

Microcrystalline cellulose 20 mg

Hydroxypropinoresenololose 7 mg

Magnesium stearate 2 mg

The mixed powder in this ratio is tableted and made into an internal tablet.

Formulation Example 2

Liquid (for nose and eye drops)

In 9 kg of sterile purified water, 10 g of compound (1A), 5 g of sodium edetinate dihydrate, 5 g of sodium chloride, 68 g of sodium chloride, 1.25 g of benzalconium chloride, 4.38 g of citric acid, and 1 g of phosphoric acid Dissolve 64.8 g of sodium hydrogen dihydrate and 10 g of hydroxypropyl monomethyl cellulose. Add sterilized purified water to the resulting solution to make 10 L, mix carefully, and prepare a liquid formulation containing 0.1% of compound (1A).

Industrial applicability

As described above, the compound according to the present invention is useful as a therapeutic agent for nasal or ocular hyperemia.

Claims

The scope of the claims

1.3,-(2-Amino-1-hydroxicetyl) 1,4-Fluoromethanesulfonanilide or an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, a therapeutic agent for nasal congestion.

2.3 '-(2-amino-1-hydroxyl) 1-4'-Fluoromethanesulfonanilide or an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, a therapeutic agent for ocular hyperemia.