GB2119799A - Aminosulfonylbenzoates - Google Patents
Aminosulfonylbenzoates Download PDFInfo
- Publication number
- GB2119799A GB2119799A GB08312120A GB8312120A GB2119799A GB 2119799 A GB2119799 A GB 2119799A GB 08312120 A GB08312120 A GB 08312120A GB 8312120 A GB8312120 A GB 8312120A GB 2119799 A GB2119799 A GB 2119799A
- Authority
- GB
- United Kingdom
- Prior art keywords
- compound
- formula
- compound according
- dichlorobenzoate
- aminosulfonyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/48—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom
- C07C311/49—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom to nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
- C07C311/52—Y being a hetero atom
- C07C311/64—X and Y being nitrogen atoms, e.g. N-sulfonylguanidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/20—Nitrogen atoms
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Virology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Compounds of the general formula <IMAGE> (wherein X and Y independently of each other are fluorine, chlorine, bromine or hydrogen, and R denotes alkyl, alkenyl, cycloalkyl, or benzyl) are antiviral agents.
Description
SPECIFICATION
Aminosulfonylbenzoate compounds, and a process for manufacturing the same DESCA1PTION The present invention relates to novel aminosulfonylbenzoate compounds and a process for manufacturing the same.
More specifically, the invention relates to novel aminosulfonylbenzoate compounds of the formula (I):
wherein X and Y independently of each other are fluorine, chlorine, bromine or hydrogen; R is alkyl, alkenyl, cycloalkyl, or benzyl, which compounds are of value on account of their antiviral action.
Upon strenuous study on the physiologically active substances, the present inventors have found that specific aminosulfonylbenzoate derivatives exhibit antiviral activities, and they have accomplished the invention based on such a finding.
The compounds according to the present invention may be generally produced in the following manner.
Halogenoaminosulfonylbenzoic acid chloride is obtained through heating halogenoaminosulfonylbenzoic acid in thionyl chloride (British patentNo. 915,259).
Halogenoaminosulfonylbenzoic acid chloride thus obtained is reacted with an alcohol of the formula (ill): wherein R has the same meaning as given in the formula (I), in the presence of a solvent such as dioxane, tetrahydrofuran, chloroform, dichloromethane, benzene or the like, or the alcohol of the formula (II), at room temperature, or under heating if necessary, so as to obtain the desired compound according to the present invention.
the alkyl in the group from which R is selected is a straight chain or branched chain alkyl group having 1 to 12 carbon atoms and is preferably methyl, ethyl, iso-propyl, n-propyl, n-butyl, sec-butyl, or n-octyl. The alkenyl in the group from which R is selected may preferably be allyl. The cycloalkyl group is preferably cyclohexyl.
The aminosulfonyl group may be preferably bonded to the 3 or 5 position of the phenyl ring, while
X and Y may be preferably bonded to the 2 and/or 4 position of this ring.
X and Y are preferably not both hydrogen atom at the same time.
The manufacture of the specific compounds according to the present invention will be described
by way of example in more detail, but it should be understood that they are merely illustrative of the invention and not interpreted to restrict its scope.
Synthesis Example 1:
1.08 g of benzyl alcohol was added to 2.89 g of 5-aminosulfonyl 2,4-dichlorobenzoic acid chloride dissolved in 10 ml of dioxane. After two hours of refluxing under heating, dioxane was recovered under
reduced pressure and the residue was recrystallized from methanol to obtain 3.19 g of benzyl 5-amino
sulfonyl-2,4-dichlorobenzoate as white crystals. When measured in accordance with the method
prescribed in the Japanese Pharmacopoeia, these crystals melt at 1 61 .5--1 63 OC. The elementary
analysis of this product is shown below.
C H Cl N S
Calculated: 46.68 3.08 19.68 3.89 8.90
Found: 46.40 3.01 19.39 3.92 8.75
Synthesis Example 2:
2.98 g of 3-aminosulfonyl-4-fluorobenzoic acid chloride were added to 1 5 ml of methanol. After
reaction at room temperature for four hours, the reaction mixture was concentrated under reduced
pressure, and the precipitated crystals were filtered out. The crystals were then recrystallized from
methanol to obtain 1.84 g of methyl 3-aminosulfonyl-4-fluorobenzoate as white crystals. When
measured in accordance with the method prescribed in the Japanese Pharmacopoeia, they melt at 1 22-1 240 C. The elementary analysis of this product is shown below.
C H F N S
Calculated: 41.20 3.46 8.15 6.01 13.75
Found: 41.40 3.41 8.10 5.92 13.65
The compounds shown in Table 1 were prepared in a similar manner to that of Synthesis
Examples 1 and 2.
Synthesis
Example No. Compound Name Appearance m.p.(OC) 3 methyl 5-aminosulfonyl-2,4- white crystals 201 .5-2040C dichlorobenzoate
4 ethyl 5-aminosulfonyl-2,4- white crystals 124-126.50C dichlorobenzoate
5 n-propyl 5-aminosulfonyl- white crystals 124-126.50C 2,4-dichlorobenzoate
6 iso-propyl 5-aminosulfonyl- white crystals 149.5--151 OC 2,4-dichlorobenzoate
7 n-butyl 5-aminosulfonyl-2,4- white crystals 90-920C dichlorobenzoate
8 sec-butyl 5-aminosulfonyl- white crystals 137.5-1420C 2,4-dichlorobenzoate
9 n-octyl 5-aminosulfonyl-2,4- white crystals 81 -860C dichlorobenzoate
10 cyclohexyl 5-aminosulfonyl- white crystals 130-1330C 2,4-dichlorobenzoate
11 allyl 5-aminosulfonyl-2,4 white crystals 109122CC dichlorobenzoate
12 methyl 5-aminosulfonyl-4- white crystals 157-161 0C chloro-2-fluorobenzoate
13 ethyl 5-aminosulfonyl-2- white crystals 123-1290C chloro-4-fluorobenzoate
14 iso-propyl 3-aminosulfonyl- white crystals 187-1 900C 4-bromobenzoate 1 5 n-butyl 3-aminosulfonyl-4- white crystals 100-1 050C bromobenzoate
Each compound according to the present invention exhibited effective antiviral activity at an
application dosage of 30 or 100 mg/kg in a test for protective action in mice infected with influenza
virus A/WSN; especially compounds 7, 9, and 1 5 indicated ten times as strong efficacy as that of
Amantadine conventionally used as an antiviral agent.
The compounds according to present invention are highly safe in respect of LD50 values which are
more than 3,000 mg/kg in oral administration and more than 1 ,000 mg/kg in intraperitoneal injection.
More specifically, in the case that the compounds of the present invention are administered to a
human, the dosage for an adult is 30-5,000 mg/day for the compounds 2-5, 12 and 13; 10-5,000 mg/day for the compounds 7, 9 and 1 5; 50-5,000 mg/day for the compounds 1, 6, 8,10,
11 and 14. However, the dosage may be increased or decreased beyond the above range according to
symptoms, ages and other conditions.
The compounds according to the present invention can be formulated into pharmaceuticai
preparations in the conventional manner, singly or in combination with other active ingredients and, if
necessary, with pharmaceutically acceptable carriers, base materials, or excipients commonly used.
Such preparations can be, for example, capsules, tablets, powders or oral liquid preparations
(including dry syrups) for oral application; rectum suppositories for intrarectal application: for injection,
they can be, for example, freeze-dried preparations which can be dissolved in distilled water for injection
immediately before administration; other preparations such as nose drops or inhalants can also be
adopted.
The following are examples of pharmaceutical preparations, but such preparations are not limited
only to the illustrated ones.
Example 1: Tablets
I) Compound 7 50 g II) Lactose proper amounts
Ill) Crystalline cellulose 60 g
IV) Potato starch 54 g V) Magnesium stearate 2 9 200g
The ingredients (I) to (IV) were homogeneously mixed and 10% paste from part of the ingredient
(IV) which had been previously separated was added to the above mixture to prepare granules, and then the granules were dried. Next, the granules were mixed with the ingredient (V) to provide tablets each weighing 200 mg. If desired, the tablets may be coated with sugar in a usual manner.
Example 2: 1 0% Powders
Compound 9 100 g
Lactose 8909 Magnesium stearate 10 9 1000g
After each of the above ingredients was weighed, the ingredients were homogeneously mixed to prepare 10% powders.
Example 3: Capsules
I) Compound 15 50 g Il) Calcium hydrogen phosphate 50 g Ill) Aluminum silicate proper amount
IV) Crystalline cellulose 60 g
V) Magnesium stearate 2 9
200 g
The above ingredients (I) to (V) were put together and mixed well through a sieve; capsules each weighing 200 mg were prepared from the mixture in a usual manner.
Claims (24)
1. A compound of the formula (I):
wherein X and Y independently of each other are tluorine, chlorine, bromine or hydrogen; R is alkyl, alkenyl, cycloalkyl, or benzyl.
2. A compound according to claim 1, wherein X and Y are not both hydrogen at the same time, and R is a straight chain or branched chain alkyl having 1 to 1 2 carbon atoms, allyl, cycloalkyl, or cyclohexyl.
3. A compound according to claim 1, wherein the aminosulfonyl group is bonded to the 3 or 5 position of the benzene ring, and X and Y are bonded to the 2 and/or 4 positions of the benzene ring.
4. A compound according to claim 2, wherein the aminosulfonyl group is bonded to the 3 or 5 position of the benzene ring, and X and Y are bonded to the 2 and/or 4 positions of the benzene ring.
5. A compound according to claim 1, wherein the compound of the formula (I) is n-butyl 5 aminosulfonyl-2,4-dichlorobenzoate.
6. A compound according to claim 1, wherein the compound of the formula (I) is n-octyl 5 a minosulfonyl-2,4-dichlorobenzoate.
7. A compound according to claim 1, wherein the compound of the formula (I) is n-butyl 3 aminosulfonyl-4-bromobenzoate.
8. A compound according to claim 1, wherein the compound of the formula (I) is benzyl 5aminosulfonyl-2,4-dichlorobenzoate.
9. A compound according to claim 1, wherein the compound of the formula (I) is methyl 3aminosulfonyl-4-fluorobenzoate.
10. A compound according to claim 1, wherein the compound of the formula (I) is methyl 5 aminosulfonyl-2,4-dichlorobenzoate.
11. A compound according to claim 1, wherein the compound of the formula (I) is ethyl 5aminosulfonyi-2,4-dichlorobenzoate.
12. A compound according to claim 1, wherein the compound of the formula (I) is n-propyl 5 aminosulfonyl-2,4-dichlorobenzoate.
13. A compound according to claim 1, wherein the compound of the formula (I) is iso-propyl 5aminosulfonyl-2,4-dichlorobenzoate.
14. A compound according to claim 1, wherein the compound of the formula (I) is sec-butyl 5aminosulfonyl-2,4-dichlorobenzoate.
15. A compound according to claim 1, wherein the compound of the formula (I) is cyclohexyl 5 aminosulfonyl-2,4-dichlorobenzoate.
16. A compound according to claim 1, wherein the compound of the formula (I) is allyl 5a minosulfonyl-2,4-di chlorobenzoate.
17. A compound according to claim 1, wherein the compound of the formula (I) is methyl 5aminosulfonyl-4-chloro-2-fluorobenzoate.
18. A compound according to claim 1, wherein the compound of the formula (I) is ethyl 5a mi nosulfonyl-2-ch loro-4-fluorobenzoate.
19. A compound according to claim 1, wherein the compound of the formula (I) is iso-propyl 5aminosulfonyl-4-bromobenzoate.
20. A process for manufacturing a compound of the formula (I):
wherein X and Y independently of each other are fluorine, chlorine, bromine or hydrogen, R is alkyl, alkenyl, cycloalkyl, or benzyl, which process comprises reacting a halogenoaminosulfonylbenzoic acid of the formula:
wherein X and Y have the same meanings as given above, with thionyl chloride to obtain
halogenoaminosulfonylbenzoic acid chloride, and reacting thus obtained halogenoaminosulfonylbenzoic acid chloride with an alcohol of the formula:
ROH wherein R has the same meaning as given above.
21. A process according to claim 20, wherein X and Y are not both hydrogen at the same time and
R is straight chain or branched chain alkyl having 1 to 1 2 carbon atoms, allyl, cycloalkyl or cyclohexyl
22. A process according to claim 20, wherein the aminosulfonyl group is bonded to the 3 or 5 position of the benzene ring and X and Y are bonded to the 2 and/or 4 position of the benzene ring.
23. A process according to claim 21, wherein the aminosulfonyl group is bonded to the 3 or 5 position of the benzene ring and X and Y are bonded to the 2 and/or 4 position of the benzene ring.
24. A compound as claimed in claim 1 and substantially as described in any one of the specific examples hereinbefore set forth.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57075781A JPS58192863A (en) | 1982-05-06 | 1982-05-06 | Novel aminosulfonylbenzoic acid ester derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB8312120D0 GB8312120D0 (en) | 1983-06-08 |
| GB2119799A true GB2119799A (en) | 1983-11-23 |
Family
ID=13586096
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08312120A Withdrawn GB2119799A (en) | 1982-05-06 | 1983-05-04 | Aminosulfonylbenzoates |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPS58192863A (en) |
| DE (1) | DE3316632A1 (en) |
| FR (1) | FR2526426A1 (en) |
| GB (1) | GB2119799A (en) |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2946815A (en) * | 1959-03-11 | 1960-07-26 | Glenn H Hamor | 2-sulfamoylbenzoic acid esters |
| US3112337A (en) * | 1960-05-09 | 1963-11-26 | Parke Davis & Co | 4-halo-3-sulfamoylbenzoic acid esters |
| FR1311859A (en) * | 1961-09-18 | 1962-12-14 | Soc Ind Fab Antibiotiques Sifa | New sulfonamide derivatives, and method of preparation |
| GB1353357A (en) * | 1970-09-14 | 1974-05-15 | Pfizer | Substituted 5-sulphamylbenzoic acids |
| EP0068408A1 (en) * | 1980-11-10 | 1983-01-05 | Mochida Pharmaceutical Co., Ltd. | Antiviral compositions and a method for treating virus diseases |
| NL8220204A (en) * | 1981-06-22 | 1983-05-02 | Mochida Pharm Co Ltd | NEW AMINOSULPHONYLBENZOIC ACID DERIVATIVES AND PROCESS FOR PREPARING THEREOF. |
-
1982
- 1982-05-06 JP JP57075781A patent/JPS58192863A/en active Pending
-
1983
- 1983-05-04 GB GB08312120A patent/GB2119799A/en not_active Withdrawn
- 1983-05-06 DE DE19833316632 patent/DE3316632A1/en not_active Ceased
- 1983-05-06 FR FR8307646A patent/FR2526426A1/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JPS58192863A (en) | 1983-11-10 |
| FR2526426A1 (en) | 1983-11-10 |
| DE3316632A1 (en) | 1983-11-10 |
| GB8312120D0 (en) | 1983-06-08 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |