JPS58914A - Medical composition with antiviral effect - Google Patents

Abstract

PURPOSE:The titled high-safety composition that contains an aminosulfonylhalogenobenzoic acid derivative as an active ingredient, thus being suitably used as a remedy for viral infections such as pneumonia or tracheitis, because of its quick-acting properties. CONSTITUTION:The objective composition contains an aminosulfonylhalogenobenzoic acid derivative of formulaI(X, Y are H, F, Cl, amino; R1 is H, lower alkyl; R2 is H, amino, lower alkyl; where 3-aminosulfonyl-4-halogenobenzoic acids are excluded) or its salt as a major active ingredient. The compound of formulaIshows a wide range of antiviral activity, for example, against influenza A0 or influenza A1 virus and high safety as well. The compound of formulaIis obtained by heating a halogenobenzoic acid in chlorosulfonic acid and making the resultant chlorosulfonylhalogenobenzoic acid react with an amine of formula II at room temperature in the presence of an acid acceptor such as triethylamine.

Description

[Detailed description of the invention] The present invention is a pharmaceutical composition having antiviral action.

For more details, see formula (■): [In the formula, X and Y are independently hydrogen atoms.

弗Ikmako represents a chlorine atom, a bromine atom, an amino group or a nitro group, RI represents a hydrogen atom or a lower alkyl group, R7 represents a hydrogen atom, an amino group, a lower alkyl group,
It represents a hydroxyalkyl group, a lower alkoxyl group, an aryl group, a guanyl group, a guanidino group, a ureido group, an oxythymoylamino group, a chloro-substituted pyridazinoamino group, or R3 and R, together with the nitrogen atom in the formula, have 4 carbon atoms. or 5 saturated heteroproduct groups (however, 1 carbon atom
11-11-1H substituted with one oxygen atom or a nitrogen atom unsubstituted or substituted with a lower alkyl group
← It's okay to be beaten. ) is formed. however.

Exclude 3-aminosulfonyl-4-herogenobenzoic acid.

The present invention relates to a pharmaceutical composition having an antiviral effect containing an aminosulfonylhalogenobenzoic acid derivative represented by the following formula and a salt thereof.

Vaccines currently used against viral diseases are slow-acting and are limited to prophylactic use. Moreover, the antigenicity of the target virus may change, so the effectiveness of the vaccine is not always sufficient. In view of this situation, the present inventors9 have been conducting extensive research in order to provide a drug that is fast-acting and has a therapeutic effect.

As a result, they found that aminosulfonylherogenoan 111M derivatives met this purpose and completed the present invention. The compound which is the main component of the pharmaceutical composition according to the present invention can be produced as follows. For example, chlorosulfonylhalogenobenzoic acid IN is obtained by heating halogenobenzoic acid in chlorosulfone M (Brit, 8961
．． 157).

Chlorosulfonyl 7-an 117R obtained in this way
.

Fragrant acid and amines represented by HN, XR2 are mixed at room temperature in a solvent such as water, diochitin, THF, chloroform, dichloromethane, benzene, or a mixed solvent of water and these organic solvents in caustic soda or caustic potash.

Inorganic bases such as soda carbonate, potassium carbonate, and sodium bicarbonate, or organic bases such as triethylamine and pyridine.

The physical and chemical properties of the aminosulfonyl/logenobenzoic acid derivative thus produced are shown in Table 11.

Table 1 Chemical Properties The efficacy, safety, usage and dosage of the aminosulfonital halogenobenzoic acid derivatives thus produced are explained below.

Experimental example t Antiviral effect Marks in cultured cells
The method described by Antimicrob.

Agents chemistry, vol. 4, p. 54~
B 8-51.1974).

monolayer cultured dog kidney cells (MDCK) monkey kidney cells (ve
ro) and Human Fetal Lung Fill:, (12%riν
Eagle's medium containing serum albumin and a diluted solution of the test compound were poured, and the virus solution diluted with Eagle's medium was added to make 12 ml, under 5% carbon dioxide gas.

The cells were cultured at 57°C for 2 to 3 days. l0TCID,. Table 2 shows the results of determining the minimum effective concentration of the test compound that completely inhibits cell degeneration caused by the virus.

The viruses used are as follows.

Influenza person/A Influenza A, B Influenza person, C Influenza BD Rose influenza type 3 E Eco-P Koksatsky i3. G-rai)
H Resviration - ■ Hydrocele stomatitis J Table 2 tn vitro antiviral active compounds 1~
No. 27 showed a wide range of antiviral effects, although each compound had specificity for the virus it acted on.

Experimental example & Preventing death from influenza A0 virus infection in mice After intranasal inoculation of influenza A0 virus to 10 mice per group, the test compound was administered intraperitoneally or orally twice a day for 14 days, and on the 15th day. The survival rate was observed. The results are shown in Tables 3 and 4.

Table 3 Intraperitoneal Administration Experiment Table 4 Oral Administration Experiment Compounds 1 to 27 all showed a protective effect against infection, and in particular, compounds 7.1g, 1., 19, and 20 showed extremely positive effects.

Acute toxicity given to Makusu Body weight zsg-after-dYl & male 19X 1xt.

The test compound was added to 10 m of S% gum arabic port solution.
After suspending it to a weight of 17 kg and administering it orally or intraperitoneally,
Observe the mortality rate for 7 days and calculate LD using the Quirkoxson and Litchfield calculation method. The values were calculated and shown in Table 5.

As is clear from the above experimental examples, compounds 1 to 27 all have a wide range of antiviral effects and are extremely safe. It is extremely useful in the treatment of inflammation, Ii inflammation, bronchitis, etc.

When administering the compounds of the present invention to the human body, the daily therapeutic dose for adults is 30-5000 mg for compounds 1-6.8-12, 14-18 and 25-27, and 30-5000 mg for compounds 7, 1.
i1? and 10~sooomg for 20, compound 21
-24 is so~soo.

mg, but it may be increased or decreased as appropriate depending on the medical condition, etc.

Compounds 1 to 27 can be prepared into a pharmaceutical preparation by a conventional method together with any conventional koji pharmaceutical carrier, base, or excipient.

Oral dosage forms include one tablet, powder, or oral preparation (including dry syrup).

For direct administration, it can be used as a rectal suppository, as an injection, it can be used, for example, as a freeze-dried injection, which is dissolved in distilled water for injection before use, or as a nasal drop or inhaler.

Examples of formulations are shown below, but the formulations are not limited to these.

Example t @ Scraping 1) Compound 7 50g Rin) Lactose (appropriate amount) Soda) Crystalline cellulose 60g ■) Matouge yam starch 54g V) Magnesium stearate 2 g0
0 g Of the above, Ill to (fVl) were mixed and a part of (IVI, which had been separated in advance, was added as a 10% glue to produce grains and dried. Then, (vl was added to this) and mix to make tablets each weighing 200 mg.The tablets may be sugar-coated by a conventional method if necessary.

Example 1 10% powder Compound 13 10011 Lactose 890g Magnesium stearate 10g000g Weigh each of the above ingredients and mix them evenly.

5% dispersion, III.

Mi 11i #4i Capsule ■) Compound 19 50g ■) Calcium hydrogen phosphate V cum sog■) Aluminum silicate appropriate amount■) Crystalline cellulose 60gV) Magnesium stearate
2 g2 (10Ji) Mix the above Iro~(Vl), pass through a sieve, mix well, and make into capsules of 200 mg per unit according to a conventional method.

Example 4. Injection Take 100g of sodium salt of Compound 20 and add it to 21
After dissolving in distilled water for injection, it is made into an injection of 100 mg/72 ml per ampoule using a conventional method.

Example 5 1% Drop Nose Rin Compound 20t) Tuumboku 10g Sodium Flaxide 5g Ri-a-lodecnol 5g 1 liter #Water Total 1 10 (lomJ) After weighing each of the above components and dissolving them in 95Qml of water.

Dilute to a total volume of 10,100O and use as -1% nasal drop.

Patent applicant Mochida Taiyaku Co., Ltd. (and 1 other person) Procedural amendment January 277, 1981 Commissioner of the Japan Patent Office - * Sodono 3, amended party 4, agent Address 1, Kanda Surugadai, Chiyoda-ku, Tokyo 6. Shufu no Tomo Bill Name (6271) Yumi Kaede (and 1 other person) 5. Date of amendment order 1' -- "Voluntary" 6. Subject of amendment 1 Contents of amendment (1) @ Application form jl 19 True form Bakedani 240 name 1-2
゜4-dichloro-5-oxyhydrazinosulfonylbenzoic acid J is corrected to "2,4-dichloro-5-(2-okinamoylhydrazinosulfonyl)benzoic acid".

(2) The name of Compound 25 in the table on page 749 is corrected to [5-aminosulfonyl-5-bromobenzoic acid] and trs-aminosulfonyl-5-chlorobenzoic acid.

(3) The name of Compound 11 in the 8th Table of Contents is corrected from [4-chloro-3-morpholinosulfonyl benzoin] to [4-chloro-5 to mol sulfonyl benzoin].

(4) t11] Name of compound *21 in J19a table [2,
4-dipacx-s-guanidinosulfonyl 5ita
Jwo is corrected to "2,4-cyclo-5-guanidinosulfonylbenzoic acid".

Procedural amendment 21111 (1) Name H with antiviral action
Pharmaceutical composition 3. Relationship with person to be amended f = Patent applicant (1 other person) 5. Contents of amendment to date of amendment order (1) In the procedural amendment submitted on January 29, 1980.

4th line from the bottom of page 2 to the last line, "(4) Same! Name of compound 21 in the table on page 9 r2.4
-diku*o-5-guanidinosulfonyl benzoic acid J'
Corrected with tr2,4-dichloro-5-guaniso/X sulfonylbenzoin IRJ. 71st order and 9 corrections.

(4) Name of compound 21 in Table 9 r2.a
-ditalolo-5-guanidino-2nosulfonylbenzoic acid" is corrected to "214-dichloro0-5-daanisinosulfonylbenzoic acid". ” Procedural amendment ■ Indication of the case 1982 Patent Application No. 916374〢“2
, Name of the invention: Pharmaceutical composition having antiviral action 3, Supplement 11: Relationship with the case Patent applicant 4, Agent 5, Supplementary IF Order 1-1 ``Spontaneous'' 6. Amendment Claims and Detailed Description of the Invention column in the Telephone Specification
Contents of amendment (1) Amendments will be made as shown in Appendix 11Y of Claims.

<2) "D" and "Jvr" on page 5, line 15 of the specification are amended to read ".

+31 pil 4th true line 6 “Completed. This invention”
"Completed.

"This invention" and correct it.

(4) 6th line 1i13 f) rTHFl'r? )
? h) Correct as “Roaran”.

(5) The 12th true mansion! Insert the following data into the thresholds for "Control" and "Test Compound 1" in Table 1.

[Test Compound Dose Survival Rate llv/4f Amantaji/100 40J(6) No. 41 on page 13! ! Insert the next Boolean Y after "test compound 27".

[Test compound dose survival rate wv%g% amantadine 30-40'' (separate)
Paper) Claims λ [In the formula, X and Y are each independently a water bulk atom, a fluorine atom, a chlorine atom, a bromine atom, an amino group or =) l”
ftkl! In my bag, the hydrogen atom is replaced by a lower alkyl group V.
- represents water, anno group, lower alkyl group, hydroxyalkyl group, lower alkoxy group, aryl group,
Represents a guanyl group, a guanidino group, an fp-reido group, an oquinamoylanno group, a chloro-substituted biridacynoyl group, or - and - together with the nitrogen atom in the formula represent a saturated heterocyclic ring having 4 or 5 vertical atoms. It forms a group (however, a carbon atom may be substituted with one oxygen atom or a nitrogen atom which is unsubstituted or substituted with a lower alkyl group). However, 3-aminosulfonyl-4-halogenobenzoic acid is excluded. ] A pharmaceutical composition having an antiviral action containing as a main component an aminosulfonylhalogenobenzoic acid derivative or a salt thereof.

(2) The aminosulfonylhalogenobenzoic acid derivative represented by the general formula (1) is S-aminosulfonyl-4-
Chlorobenzoic acid derivatives [wherein, X is a chlorine atom, Y is a hydrogen atom, R is a hydrogen atom or a lower alkyl group, - is a hydrogen atom, an amino group, a lower alkyl group, or a hydroxyalkyl group.

R4 and - represent an aryl group, a chloro-substituted pyridacynoa group, or R4 and - together with the nitrogen atom in the formula represent a saturated heterocyclic group having 4 or 5 carbon atoms (provided that 1 carbon atom
The two oxygen atoms may be unsubstituted or substituted with a lower alkyl group and substituted with a nitrogen atom. ) It forms a V. The pharmaceutical composition according to claim 1, wherein S-a (excluding nosulfonyl-4-halogenobenzoic acid).

+a+ Claim II wherein the aminosulfonylhalogenobenzoic acid derivative represented by general formula (1) is 2-amino-5-aminosulfonyl-4-chlorobenzoic acid
i. The pharmaceutical composition according to item 1.

(41 The aminosulfonylhalogenobenzoic acid derivative represented by the general formula (1) is 1,3-aminosulfonyl-4-
Claim 1 which is ri**-5 to nitrobenzoic acid
@Medicine composition described in Section.

(2) The mono-anosulfonyl-benzoic acid trout conductor represented by the general formula (1) is
Dihalogenobenzoic acid (wherein X and Y are fluorine, chlorine or bromine atoms.

- and islands represent hydrogen atoms. ) The pharmaceutical composition according to claim 1.

The aminosulfonylhalogenobenzoic acid derivative represented by the general formula (I) is 3-7minosulfonodi5t-a,
The pharmaceutical composition according to claim 1, which is 5-silalobenzoic acid.

(7) The aminosulfonylhalogenobenzoic acid derivative represented by the general formula (1) is 5-annosulfonyl-2,4
- Diku-a-benzoic acid derivative (wherein, X and Y are chlorine atoms, - is hydrogen atom, island is guanyl group, guanidino group,
Represents a ureido group or an oxymoylamino group. ) The pharmaceutical composition according to claim 1.

(...Aminosulfonyl halide represented by the general formula
**The composition according to claim 1, which is -halogenobenzoic acid (in the formula, X is a chlorine atom, χ is a bromine atom, and Y, -, and - are all hydrogen atoms).

(@The pharmaceutical composition according to claim 1, wherein the aminosulfonylhalogenobenzoic acid derivative represented by general formula (1) is 2-aminosulfonyl-5-chlorobenzoic acid.)

Claims (1)

[Claims] (1) General formula (1) [In the formula, X and Y are independently hydrogen atoms. Represents a fluorine atom, chlorine atom, bromine atom, amino group or nitro group, R3 represents a hydrogen atom or a lower alkyl group, R2 represents a hydrogen atom, an amino group, a lower alkyl group, a hydroxyrealkyl group, a lower alkoxy group, an aryl group. basis,
Guanyl group, guanidino group. Ureido group, octamoylamino group. chloro-substituted pyridazinoamino group, or R3 and R1 together with the nitrogen atom in the formula represent a saturated heterocyclic group having 4 or 5 carbon atoms (provided that the carbon atom is one oxygen atom or unsubstituted or substituted with a lower alkyl group). may be substituted with a nitrogen atom). However, 3-aminosulfonyl-4-herogenobenzoin is excluded. ] A pharmaceutical composition having antiviral activity, which contains as a main component an aminosulfonylherogenobenzoic acid derivative and a salt thereof. (2) The aminosulfonylherogenobenzoic acid derivative represented by the general formula (1) is 3-aminosulfonyl-4-.
Chlorobenzoic acid derivative [wherein, or R3 and R, together with the nitrogen atom in the formula, represent a saturated heterocyclic group having 4 or 5 carbon atoms (with the exception that a nitrogen atom in which the carbon atom is one oxygen atom or unsubstituted or substituted with a lower alkyl group) may be substituted with atoms). However, 3-aminosulfonyl-4-herogenobenzoic acid is excluded. ] The medical sm composition according to claim 1. (4) Claim 1X in which the aminosulfonylhalogenobenzoic acid derivative represented by general formula (1) is 2-amino-5-1 minosulfonyl-4-chlorobenzoic acid.
jl#i! , II. (4) The aminosulfonylhalogenobenzoic acid derivative represented by general formula (1) is 5-aminosulfonyl-4-chloro-5-nitrobenzoic acid, patent-2,4-dihalogenobenzoic acid (in the formula, and Y represents a fluorine atom, a chlorine atom, or a bromine atom, and R1 and R8 both represent a hydrogen atom. Pharmaceutical composition. (6) The aminosulfonylhalogenobenzoic acid derivative represented by the general formula (1) is 3-aminosulfonyl-4,5
-Dichlorobenzoic acid! H1lli
i Kishitoshi's medical S composition. (7,) The aminosulfonylhalogenobenzoic acid derivative represented by the general formula (1) is 5-aminosulfonyl-2,
Claim 111 which is a 4-dichlorobenzoic acid derivative (wherein X and Y are a chlorine atom, R1 is a hydrogen atom, and R1 represents a guanylate group, a guanidino group, a clade group, or an oquinamoylamino group) Medical products. (&), the aminosulfonylhalogenobenzoic acid derivative represented by the general formula (1) is 5-aminosulfonyl-5-
The pharmaceutical composition according to claim 1, which is a halogenobenzoic acid (wherein X represents a salt g atom or a bromine atom, and Y, R, and R1 all represent a hydrogen atom). (Phantom) The pharmaceutical composition according to claim 1, wherein the aminosulfonylhalogenobenzoic acid derivative represented by the general formula (1) is 2-aminosulfonyl-5-chlorobenzoic acid.