DE3144689A1 - ANTIVIRUS - Google Patents

Description

MÜLLER - BOBiJ · BEUFEL · SCHÖN · HEHTEL

PATENT ADVOCATE BXXBOFBAN PATENT ATTOHHETS

DR. WOLFGANO MÜLLER-BOR 6 (PATENT ADVERTISER FROM 1927-1975) DR. PAUL DEUFEL. DIPL.-CHEM. DR. ALFRED SCHÖN. DIPL.-CHEM. WERNER HERTEL, DIPL.-PHYS.

M 3671

HOCHIDA SEIYAKU KABUSHIKI KAISHA, 1-7, Yotsuya, Shinjuku-ku, Tokyo, Japan

Antivirals

O MUNICH 86, SIEBERTSTR. 4 · POB 860720 ■ CABLE: MUGBOPAT · TEL. (089) «74003 ■ TELECOPIER XEROX 400 · TELEX! 5-24285

31U689

description

The invention relates and is particularly concerned with antiviral agents with antivirals containing aminosulfonylhalogen benzoic acid derivatives or their salts, these Funds are effective for the therapeutic treatment of various infectious diseases caused by viruses, e.g. infections of the upper respiratory tract, pneumonia, bronchitis etc.

The invention also relates to a method of treatment of viral diseases using these agents.

Vaccines, which are used to fight viral diseases, act slowly, with only a preventive one Use are limited. Furthermore, since the antigenicity of the respective viruses often changes, the effect is of vaccines insufficient.

2Q The invention has therefore set itself the task of producing pharmaceutical To find agents that show fast-acting therapeutic effects.

The invention is based on the finding that aminosulfonylhalobenzoic acid derivatives meet the above requirements.

The invention therefore relates to pharmaceutical agents with a Antiviral activity, the aminosulfonylhalobenzoic acid deri-2Q vate contained and effective for the therapeutic treatment of various infectious diseases caused by viruses, such as upper respiratory tract infections, pneumonia, bronchitis, etc.

The invention also relates to a method of treatment of viral diseases using these agents.

-A -

Further details can be found in the following description emerged.

The invention relates to antivirals which, as active ingredients, contain aminosulfonylhalogenbenzoic acid derivatives of the formula (I)

COOH

SO N ^ ^X (I)

10 _x

wherein X and Y are independently hydrogen, fluorine, chlorine, bromine, amino or nitro, R _{1 is} hydrogen or lower alkyl, R _{2 is} hydrogen, amino, lower alkyl, hydroxyalkyl, lower alkoxy, aryl, guanyl, guanidino, ureido, oxamoylamino or chlorine-substituted Pyridazinoamino symbolizes, or R ^ and R ₂ together with the nitrogen atom in the formula can form a saturated heterocyclic group with 4 or 5 carbon atoms, in which the carbon atoms can be replaced by an oxygen atom or an unsubstituted or lower alkyl-substituted nitrogen atom, or contain salts thereof .

The compounds which are the main ingredients of the invention Antivirals can be prepared as follows. Halobenzoic acid is heated in chlorosulfonic acid to produce chlorosulfonylhalobenzoic acid (GB-PS 8 961 137). The resulting chlorosulfonylhalobenzoic acid is treated with an amine of the formula

at room temperature in a solvent such as water, dioxane, THF, chloroform, dichloromethane, benzene, etc. or in a mixed solvent of water with one of these organic solvents in the presence of a deoxidizer ttels, for example an inorganic base, such as

3U4689

Sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate / sodium bicarbonate or the like, or an organic one Base such as triethylamine, pyridine and the like. Or by using

V ₂

as such as a deoxidizer / implemented.

The physicochemical properties of the aminosulfonylhalogenobenzoic acid derivatives produced in this way go from Table I.

Table I.

Physico-chemical properties "decomp." means "decomposition"

Verbin dung

Melting point, ⁰ C properties

3-Aminesulfcaiyl-4-fluorobenzoic acid S-Andjiosulfcnyl- ^ chlorobenzic acid S-Aininosulfcnyl- ^ brcitibenzoic acid S-Aninosulfonyl- ^ iodobenzoic acid

4K3ilor-3-nethylarninosulfonyl-

benzoic acid

4-CMor-3-et ± ylaminosulfonylbenzic acid

4H ^ chloro-3-d ± methylaminosulfc (nyl-

benzoic acid

237-238

260-263

268-270

273-276

236.5-239

190.5-192.5

248.5-249.5 white crystalline powder; insoluble in benzene, hexane; soluble in hot water, Methanol

White crystalline powder; insoluble in benzene, hexane; soluble in hot water, Methanol

White crystalline powder; insoluble in benzene, hexane; soluble in hot water, Methanol

White crystalline powder; insoluble in benzene, hexane? soluble in hot water, Methanol

White crystalline powder; insoluble in benzene, hexane; soluble in hot water, Methanol

White crystalline powder; insoluble in benzene, hexane; soluble in hot water, Methanol

White crystalline powder; insoluble in benzene, hexane; soluble in hot water, Methanol

Table I.

(Continuation)

Connect
manure

Melting point, ⁰ C

properties

8 4-chloro-3-itiethoxyaininosulfonylbenzoic acid

9 4HZhlor-3-hyä ^ xyethylaminesulfonyl ~ benzoic acid

10 4-Chloro-3-N-methylhydroxyethylaineinosulfonylbenzoic acid

11 4-chloro-3-hydrazinosulfonylbenzic acid

12 4-chloro-3-isopropylaitiinosulfony! Benzoic acid

13 3-Anilinosulfonyl-4-chlorobenzic acid

14 4-Chloro-3- / 2- (G-chloropyridazin-S-yl) -hydrazino-1-yl / sulfonylbenzenic acid

15 4-Ch.lor-3-nior £ diolinosulfony lbenz oes acid

16 4-Chloro-3- (pyrrolidinyl-1-sulfony 1) benzoic acid

17 4-Chloro-3- (4-methylpiperazixi-1 -y 1) sulfonyl benzoic acid

18 2-Aminecr-5-arainosulfonyl-4-chlorobenzoic acid

19 5-Aniijrosulfonyl-4-Chloro-3-nitrobenzoic acid

20 5-Aminosulfonyl-4-chloro-2-fluorobenzoic acid '

. 205-206 White
Hexane; 177-178 White
Hexane; 155.5-156.5 White
Hexane; 286.5-288
(Decomp.) White
Hexane; 189-191 White
Hexane; 208-210 White
Hexane; 186-188 White
Hexane; 187-189.5 White
Hexane; 237-239 White
Hexane; 120 - 121 White
Hexane; > 300 White
Hexane; 234-236 White
Hexane; 242-245 White
Hexane;

crystalline powder; insoluble in benzene, soluble in hot water, methanol

crystalline powder; insoluble in benzene, soluble in hot water, methanol

crystalline powder; insoluble in benzene, soluble in hot water, methanol

crystalline powder; insoluble in benzene, soluble in hot water, methanol

crystalline powder; insoluble in benzene, soluble in hot water, methanol

crystalline powder; insoluble in benzene, soluble in hot water, methanol

crystalline powder; insoluble in benzene, soluble in hot water, methanol

crystalline powder; insoluble in benzene, soluble in hot water, methanol

crystalline powder; insoluble in benzene, soluble in hot water, methanol

crystalline powder, insoluble in benzene, soluble in hot water, methanol

crystalline powder, insoluble in benzene, soluble in hot water, methanol

crystalline powder; insoluble in benzene, soluble in hot water, methanol

crystalline powder; insoluble in benzene, soluble in hot water, methanol

-P - CD OO CD

Table I (continued)

Link

Melting point, ⁰ C

properties

21 22 23 24 25 26 27 28 29

benzoic acid

5-Amnosulfanyl-2-broin-4-chlorobenzoic acid

5-AmiiiOSulfonyl-2,4-dichlorobenzoic acid

3-Aniincsulfcaiyl-4 _/ 5-dichlorobenzoic acid

2,4-Didü.or-5-guanidinosulfonylbenzoic acid

2,4 ~ Dic ^ co ^ 5-guanidinoaminosulfcsiylbenzoic acid

2,4-Dichlca: -5-beicarbazidesulfonylbenzoic acid

2,4-dichlca: -5- (2-oxamoylhydradine crr

sulfonyl} benzoic acid

S-ÄmiBOsulfonyl-S-chlorobenzoic acid 3-aminosulfonyl-5-bribribenzoic acid 2-aminosulfonyl-5-chlorobenzoic acid

245-248 White
Hexane; 220-234 White
Hexane; 232-233.5 White
Hexane; 266-268 White
Hexane; 252-254 White
Hexane; 198-199
(Decomp.) White
Hexane; 220 (decomp.) White
Hexane; 217-219
(Decomp.) White
Hexane; 242-243 White
Hexane; 241-244 White
Hexane; 162 - 163.5 White
Hexane;

crystalline powder; insoluble in benzene, soluble in hot water, methanol

crystalline powder; insoluble in benzene, soluble in hot water, methanol

crystalline powder; insoluble in benzene, soluble in hot water, methanol

crystalline powder; insoluble in benzene, soluble in hot water, methanol

crystalline powder; insoluble in benzene, soluble in hot water, methanol

crystalline powder; insoluble in benzene, soluble in hot water, methanol

crystalline powder; insoluble in benzene, soluble in hot water, methanol

crystalline powder; insoluble in benzene, soluble in hot water, methanol

crystalline powder; insoluble in benzene, soluble in hot water, methanol

crystalline powder; insoluble in benzene, soluble in hot water, methanol

crystalline powder; insoluble in benzene, soluble in hot water, methanol

/ IO - · ···· --- 31U689

mm ST.-m

The aminosulfonylhalobenzoic acid derivatives prepared in this way can be converted into pharmaceutically acceptable salts. The salts can be obtained from the sodium salt, Potassium salt, lithium salt, ammonium salt, calcium salt, barium salt etc. consist.

The following are the effect, the safety, the application method and the dosage of the aminosulfonylhalobenzoic acid derivatives thus obtained. 10

Experimental Example 1. Antiviral Activity in Cultured Cells

The antiviral activity of the compounds according to the invention is described by the method of Marks (Antimicrob, Agents Chemother., Volume 6, pages 34-38, 1974).

A single-layer culture of MDCK, Vero and HEL cells is mixed with 0.1 ml of a serially 10-fold dilution of the virus in an Eagle medium (Eagle's minimum essential medium) containing 0.1 or 0.2% bovine serum albumin has been supplemented, inoculated with 0.1 ml of the solution of the compound 1 hour after the treatment. After an incubation for 2 or 3 days at 37 ⁰ C in a 5% _CO2 atmosphere, the cell pathological effect by the 100 TCID ₁ - observed has been induced the virus under a microscope. The minimum inhibitory concentration of the compound is defined as the lowest concentration of the compound that shows complete inhibition of the cell pathological effect induced by the virus. The results are shown in Table II.

Table II

In vitro antiviral activity

\ Virrit ». Minimum inhibiting concentration ^ g / ml) Influenza A2
(Kumamoto) Parainfluenza
Type 3 Rhino Coxsackie
Type B ₅ ECHO Ver \
binding \ Influenza Ao (WSN) 30th 300 300 > 300 > 300 1. 30th 30th 300 300 > 300 > 300 2 30th 100 300 300 > 300 > 300 3 100 100 300 300 > 300 > 300 4th 100

CD OO CO

3HA689

Experimental example 2

According to the method described in Example 1, the minimum inhibitory concentration of the 5 compounds according to the invention which completely inhibits the cell pathological effect _{induced by the TCID 50 of} the virus is investigated. The results are shown in Table III.

The viruses used were as follows:

Influenza Α _Λ Α

Influenza A. B

Influenza A ₂ · C

Influenza B D

Parainfluenza type 3 E

ECHO F

Coxsackie type B ₅ G 25

Rhino H.

Respiratory Virus I

Vesicular stomatitis J.

- yr-

3UA689

Table III

In vitro antiviral activity

Minimal A. B. inhibiting] D. E. • concentration (μ G H ig / ml) J binding / \ 30th 300 C. 300 300 F. 100 300 I. 300 5 30th 300 300 300 300 300 300 300 300 300 6th 30th 300 300 300 300 300 300 300 100 300 7th 30th 300 300 100 300 300 300 300 300 300 8th - 30th 300 300 300 100 300 300 300 300 300 9 30th 300 100 300 300 300 300 300 100 300 10 10 300 300 loo 300 100 300 300 300 100 11 30th 100 100 300 300 300 300 300 300 300 12th 30th 300 300 300 300 300 100 300 300 300 13th 30th 300 300 300 300 300 300 300 300 300 14th 30th 300 300 300 300 100 300 300 300 3ΰΟ 15th 30th 300 300 300 300 100 100 300 300 300 16 10 100 300 100 300 300 100 300 300 300 17th 30th 100 300 300 300 300 300 300 300 300 18th 30th 300 300 300 300 300 300 300 300 300 19th 30th 300 300 300 300 100 30th 300 300 100 20th 30th 300 300 300 300 300 300 300 300 300 21st 30th 300 300 300 300 300 30th 300 300 300 22nd 10 300 30th 100 100 3 100 100 300 100 23 10 100 300 100 30th 100 300 30th 30th 30th 24 100 300 10 300 300 100 300 100 300 300 25th 300 300 300

Table III (continued)

A. Minimal inhibitory C. D. E. concentration G H ^ g / ml) J bond ^ 100 B. 100 300 300 F. 300 300 I. 300 26th 100 300 300 300 100 100 300 300 100 300 27 100 300 300 300 300 - 300 300 100 300 300 28 30th 300 300 100 300 300 300 300 300 300 29 30th 300 300 300 300 300 300 300 100 300 30th 30th 300 30th 100 300 100 300 100 300 300 31 300 300 300

All compounds 1 to 31 show broad spectrum antiviral activity, yet each compound is specific about the viruses to which it is more responsive.

Experimental example 3. Protective effect against the death of mice, who have been infected with influenza A "virus.

After the influenza A "virus on groups of 10 female ICR mice (16 to 18 g) have been inoculated with A'ther transnasally under light anesthesia, the inventive Compound administered orally or intraperitoneally in multiple doses twice a day starting 1 hour after Infection for a period of 14 days. The result the treatment results from an increase in the percentage of animals surviving on the 15th day.

The results are shown in Tables IV and V.

31U689

Table IV Result of intraperitoneal administration

Connect
manure dosage
mg / kg Survival
rate,% Connect
manure dosage
mg / kg. Survival
rate,% comparison 0 3 30th • 20th • ι 30th 40 4th 100 40 ■ 2 100 50 300 50 10 30th 300 • 50 30th 40 1000 60 100 60

Table V Result of intraperitoneal administration

Connect
manure dosage
mg / kg Survival
rate,% Connect
manure dosage
mg / kg. Survival
rate, % comparison 0 19th 100 50 5 100 40 20th 100 50 6th 100 40 21st 100 40 7th 100 40 22nd 30th 50 8th 100 50 23 100. 70 9 100 40 24 10 40 10 100. 60 25th 30th 50 11 10 30th 26th 10 40 12th 30th 50 27 30th 60 13th 100 40 28 Ίοο 70 14th 100 40 29 100 40 15th 100 40 30th 100 40 16 100 50 31 100 40 17th 100 40 100 ■ 40 18th 10 40 100 40 30th 50 100 40 100 40 100 40

Table VI

'Λ'

Result of oral administration

31U689

Connect
manure dosage
rag / kg Survival
rate,% Connect
manure Dosage'
mg / kg Survival
rate,% 0 19th 300 50 5 300 50 20th 300 50 6th 300 50 21st 300 40 7 - 300 50 ' 22 " 100 50 8th 300 40 . 23 300 70 9 300 50 24 30th 40 10 300 40 25th 100 60 11 100 4 0 26th 30th 40 12th 300 GO 27 100 60 13th 300 4 0 28 300 80 14th 300 4 0 29 300 50 15th 300 40 30th 300 40 IG 300 50 31. 300 40 ' 17th 300 40 300 50 18th 100 50 300 50 300 70 300 50 300 50 300 40

All compounds 1 to 31 show a protective effect against -25 over death as a result of infection, in particular developing

compounds 11, 17, 22, 23 and 24 show extreme activity.

3744689

Experimental example 4. Acute toxicity in mice

The compounds according to the invention are in a saline solution dissolved and administered orally or intraperitoneally (10 ml / kg) to groups of 10 male ddY mice (24 to 26 g). The mortality rate is then observed after 7 days. The LDj. " is made according to the Wilcoxon-Litchfield method determined. The results are shown in Tables VII and VIII.

Table VII

LD ₀ value (mg / kg)

Connect
manure Oral
Meet
chung Intra-
peritoneal
Meet
chung Connect
manure Oral
Meet
chung In t ra—
peritoneal
Meet
chung 1 > 10,000 3 290 3 > 10,000 > 5,000 2 > 10,000 3 520 4th > 10,000 > 5,000

Table VIII

^LD 50

Value (mg / kg)

Connect
manure Oral
Meet
chung Intra-
peritoneal
Meet
chung Connect
manure Oral '
Administration
cliung Intra-
perifoneal
Meet
chung 5 > 3,000 > 1,000 1.9 > 3,000 > 1 000 ' 6th > 3,000 > 1,000 20th > 3,000 > 1,000 7th > 3,000 > 1,000 21st > 3,000 > 1,000 8th > 3,000 > 1,000 22nd > 3,000 > 1,000 9 > 3,000 > 1,000 . 23 > 3,000 > 1,000 10 > 3,000 > 1,000 24 > 3,000 > 1,000 11 > 3,000 746 25th > 3,000 987 12th > 3,000 > 1,000 26th > 3,000 > 1,000 13th > 3,000 96S 27 > 3,000 > 1,000 1.4 > 3,000 > 1,000 28 > 3,000 > 1,000 15th > 3,000 > 1,000 29 > 3,000 >] 000 16 > 3,000 > 1,000 30th > 3,000 > 3,000 17th > 3,000 i> 1,000 31 > 3,000 > 1,000 18th > 3,000:> 1,000 _- -— - ~

■ · - ■ - :. -: - "^; -.:. 31U689 -yr-

As can be seen from the above experimental examples, all compounds 1 to 31 have antiviral activity within a wide range and are extremely secure. Hence, they are of great clinical value for treatment of various infectious diseases that are on Viral infections decrease, for example upper respiratory tract infections, pneumonia, bronchitis, etc.

If the compounds according to the invention are administered to humans a dosage in the case of an adult comes from 30 to 5,000 mg per day in the case of the compounds 1 to 10, 12 to 16, 18 to 22 and 29 to 31 possible, from 10 to 5000 mg per day in the case of the compounds 11, 17, and 24 and 50 to 5000 mg per day in the case of the compounds 25 to 28. However, the dosage may be beyond the ranges given above according to the symptoms and other states can be extended.

The compounds 1 to 31 can be used as pharmaceutical preparations according to conventional methods with pharmaceutical carriers, base materials such as extenders, such as they are usually used for this purpose, stretched. Such preparations can, for example from capsules, tablets / powders or oral liquid preparations (including dry syrups) for one oral administration or rectam suppository for one intrarectal administration. Freeze-dried preparations, for example, are used for injection purposes to be dissolved in distilled water for injection just prior to administration. Further you can use other preparations, such as nasal drops or inhalants.

The following examples explain pharmaceutical preparations, however, without restricting the invention.

31441

Example 1:

Tablets

10

Components

I) Prebinding 11 II) Lactose

1II) Kr Lutal] ine CeI I ■ can IV) Potato sticks; e V) Magnesium stearate

amounts

50 g

suitable amount 60 g 54 g 2 g

200 g

The components (I) to (IV) are mixed homogeneously and a 10% paste from the part of the component (IV), the has previously been separated, added to the mixture described above for the production of granules, whereupon the granules are dried. Then the granules are used with the constituent (V) for obtaining tablets 200 mg each mixed. If necessary, the tablets can coated with sugar in the traditional woise.

Example 2:

10% powder

Components

Connection 17

Lactose;

Mignesj umstea : at

M tight

100 g

890 g

10 g

1000 g

After each of the preceding B components has been weighed is to be the best; ndteile horn igen: ^ ur manufacture of 5% powders meshed.

35

-: - -: - " ^: - ^: -: - 314A689

Example 3: capsules

Ingredients Amounts I) Compound 23 50 g

5 II) Calcium hydrogen phosphate 50 g

III) Aluminum silicate suitable amount

IV) Crystalline cellulose 60 g

V) Magnesium stearate 2 g

The above components (I) to (V) are brought together and mixed thoroughly. There are capsules with 2 00 mg each from the mixture in the conventional manner manufactured.

15 Example 4: Injectable Solutions

100 g of the sodium salt of compound 2 are dissolved in 2 liters of distilled water for injection. Injectable solutions containing 100 mg .10 of the active ingredient in 2 ml of a solution per ampoule are prepared from this solution.

Example 5: 1% nasal drops

Components quantities

25 Compound (2) sodium salt 10 g

Sodium chloride 5 g

Chlorobutanol 5 g

Distilled water to adjust 1000 ml

Each of the ingredients described above is weighed out, followed by placing the ingredients together in 950 ml of water to be resolved. The solution is made up to 100C ml for the preparation of 1% nasal drops. 35

Claims (9)

Claims wherein X and Y are independently hydrogen, fluorine, chlorine, bromine, amino or nitro, R _{1 is} hydrogen or lower alkyl, R _{2 is} hydrogen, amino, lower alkyl, hydroxyalkyl, lower alkoxy, aryl, guanyl, guanidino, ureido, oxamoylamino or chlorine-substituted Represents pyridazinoamino, or R ₁ and R ₂ together with the nitrogen atom in the formula can form a saturated heterocyclic group having 4 or 5 carbon atoms, in which the carbon atoms can be replaced by an oxygen atom or an unsubstituted or lower alkyl-substituted nitrogen atom, or salts thereof contains. 2. Composition according to claim 1, characterized in that the aminosulfonylhalogenbenzoic acid derivative of the general formula (I) consists of an S-aminosulfonyl ^ chlorobenzoic acid derivative (in the formula X is chlorine, Y is hydrogen, R _{1 is} hydrogen or lower alkyl, R ₂ for 30 hydrogen, amino, lower alkyl, hydroxyalkyl, aryl • or chlorine-substituted pyridazinoamino, or R ₁ and R ₂ can form a saturated heterocyclic group with 4 or 5 carbon atoms with the nitrogen atom in the formula, in which the carbon atoms with an acid 35 atom or a substituted or lower alkyl substituted Nitrogen atom can be replaced). Mochida Seiyaku K.K. ° ι Our files: - 2 - 3. Composition according to claim 1 _# characterized in that the aminosulfonylhalogenobenzoic acid derivative of the general formula (I) from 2-amino-5-aminosulfonyl-4-chloro benzoic acid. 5. 4. Composition according to claim 1 _f, characterized in that the aminosulfonylhalogenbenzoic acid derivative of the general formula (I) consists of 3-aminosulfonyl-4-chloro-5-nitrobenzoic acid. 5. Agent according to claim 1, characterized in that the aminosulfonylhalobenzoic acid derivative of the general formula (I) consists of aminosulfony1-2,4-dihalobenzoic acid (in formula (I) X and Y denote fluorine, chlorine or bromine and both substituents R ₁ and R- hydrogen). 6. Composition according to claim 1, characterized in that the aminosulfonylhalobenzoic acid derivative of the general Formula (I) from a 3-aminosulfonylhalogenobenzoic acid derivative consists. 7. Means according to claim 1, characterized in that the aminosulfonylhalobenzoic acid derivative of the general .25 mean formula (I) consists of a 5-aminosulfonyl-2,4-dichlorobenzoic _{acid derivative (in the formula X and Y mean chlorine, R 1} hydrogen, R-guanyl? Guanidino, ureido, oxamoylamino). 8. Composition according to claim 1, characterized in that the aminosulfonylhalogenbenzoic acid derivative of the general formula (I) consists of an S-aminosulfonyl-S-halogenobenzoic acid derivative (in the formula X stands for chlorine or bromine and Y, R ₁ and R- for hydrogen) . 9. Composition according to claim 1, characterized in that the aminosulfonylhalobenzoic acid derivative of the general formula (I) from 2-aminosulfonyl-5-chlorosnzoic acid consists.