JPH02243692A - Tricyclic compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R1 is (halogeno)lower alkyl, lower alkenyl, cycloalkyl or (substituted) phenyl; R2 is H, halogen, cyano or lower alkyloxy; R3 is halogen or group of formula II-IV (R5 and R10 are H, lower alkyl, etc.; R6, R7 and R11 are H, lower alkyl, etc.; R8 is H, halogen, lower alkyl, etc.; R9 is H, halogen, lower alkyl, etc.; n is 3-5); R4 is lower alkyl; X is S or O]. EXAMPLE:9-Cyclopropyl-6,7-difluoro-5-methyl-2,3,4,9-tetrahydrois-othia zolo[5,4-b]- quinoline-3,4-dione. USE:An antibacterial agent. PREPARATION:A 2-mercaptoquinolone derivative of formula V (R is lower alkyl) is made to react with an electrophilic amination agent in the presence of a base and the reaction product is separated from the system.

Description

[Detailed description of the invention]

FIELD OF APPLICATION ON 1rLyJ The present invention relates to novel tricyclic compounds, namely 5-al1-inchazoloquinolite/or inxazoloquinolite/derivatives and salts thereof, which exhibit excellent antibacterial activity. BACKGROUND OF THE INVENTION JP-A-02-187472 discloses various inthazoloquinolines and inxazoloquinolines/derivatives. However, these compounds do not have a substituent at the 5-position. OBJECTS OF THE INVENTION The present invention provides a J315-n-substituted inthazoloquinolite and inxazoloquinolite derivative having excellent antibacterial activity. Structure of the Invention The compound of the present invention has the following general formula (I) [wherein RI may have a lower alkyl group, a halogeno lower alkyl group, a lower alkenyl group, a cycloalkyl group, or a substituent], means a nyl group, R2 means a hydrogen atom, a halogen M atom, a cyano group or a lower alkyloxy group, R3 means a halogen atom or a group represented by the following formula, where R5 and Rho means a hydrogen atom, a lower alkyl group, or an acyl group (the acyl group may be substituted with a halogen atom), and R8, R7, and R11 are the same or different and represent a hydrogen atom, a lower alkyl group, or a halogeno-lower alkyl group. group, or R6 and R7 are combined,
A t11 junction or -(CI-1z)m- may be formed, where m is! or 2, R8 is a hydrogen atom, a halogen/atom, a lower alkyl group, a hydroxy lower alkyl group, a water II group. means an amino group, a mono- or di- or lower alkylamino group, an amino-lower alkyl group or a mono- or di-lower alkylamino lower alkyl group, R1+ means a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkyloxy group, n means an integer of 4 or 5, R4 means a lower alkyl group, and X means a sulfur atom or an alk atom. ] and its salts. In this specification, examples of the halogen atom include fluorine, chlorine, and bromine. Examples of lower alkyl include methyl, ethyl, propyl, butyl, isobutyl, t-butyl, bebutyl, neopentyl, and the like. Examples of the lower alkenyl group include vinyl, allyl, l-propenyl, impropenyl, and the like. Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclobearyl, and cyclohexyl. In addition, examples of the substituent in the phenyl group which may have a substituent include halogen, lower alkyl,
Examples include lower alkyloxy, halogeno-lower alkyl, hydroxy, nitro, and ami7. Examples of the acyl group optionally substituted with a halogen atom include formyl, acetyl, propionyl, butyryl, imbutyryl,
Examples include pivaloyl, trifluoroacetyl, chloroacetyl, and the like. Salts of the compound of the present invention include salts with inorganic acids such as hydrochloric acid and phosphoric acid; acetic acid, lactic acid, oxalic acid, succinic acid, etc. Salts with organic acids such as methanesulfo/acid, maleic acid, malonic acid, and gluconic acid; salts with acidic amino acids such as aspartic acid and glutamic acid. The compound represented by general formula (1) has the following formula (wherein,
R+, Rz, R3, R4 and X are the same as listed in 0j,
) These tautomers are also included in the compounds of the present invention. Compounds of the invention may also exist as hydrates. Therefore, such forms are naturally included in the compounds of the present invention. The compounds of the present invention include those having asymmetric carbon atoms, which may exist as optically active forms. Therefore, these optically active substances are included in the compounds of the present invention. Furthermore, some of the compounds of the present invention have multiple asymmetric carbon atoms and may exist as different stereoisomers. These stereoisomers are also included in the compounds of the present invention. The method for producing the compound of the present invention will be explained below. (1) The compound of the present invention in which X is a sulfur atom has the following general formula (II) (wherein, R means a lower alkyl group, R1゜Rz,
It can be produced by reacting a 2-mercaptoquinolone derivative represented by (R3 and R4 are the same as above) with an electrophilic aminating agent in the presence of a base, and isolating the product by a conventional method. can. In this reaction, the starting compound (■) is mixed with an alcohol such as methanol, an inert solvent such as ether, 1,2-diethoxyethane/l tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, N-methyl birolide, etc., or a combination of these and water. In a mixed solvent, hydroxides such as sodium hydroxide and potassium hydroxide, sodium carbonate□
and carbonates such as potassium carbonate, bicarbonates such as sodium bicarbonate and potassium carbonate, potassium fufluoride, and sodium hydride. sodium ethoxide, potassium

[-Butoxide. It is carried out by stirring with an electrophilic aminolytic agent in the presence of a base such as butyllithium, triethylamine, 1,8-diazabicyclo[a4.0]-7-undecene (D BU ), preferably under a nitrogen stream. 0 reactions possible! !
f1F is usually -20 to 150°C, preferably -10 to 1
It is in the range of 00°C. Examples of electrophilic aminating agents include 0-furkylhumanxylamine, 0-arylhydroxylamine 7, Q
-Acylhydroxylamine, hydroxylamine-〇-sulfo/acid, 0-diphenylsulfinylhydroxylamine, and other known hydrogyramines 7 or chloramis 7 can be mentioned. The raw material compound (■) used in this reaction is, if possible,
The amine 7 group that does not participate in the reaction may be used in a protected form, and the protecting group may be removed by a conventional method after the reaction.As the M-preservation group, it may destroy the structure of the compound of the present invention formed by the reaction. Any protective group may be used as long as it can be removed without any damage, and protective groups commonly used as protective groups in the field of chemistry of peptides, amino sugars, nucleic acids, or β-lactam compounds can be used. Preferred #1 groups include acetyl and trifluoroacetyl. An easily hydrolyzable group such as Etquin carbonyl, or
An example is the zyl group. It can be prepared according to the following reaction formula. ■The compound of the present invention in which X is an oxygen atom can be expressed by the following general formula (
In) (wherein R'' means a lower alkyl group, k means 1 or 2, R1, R1, R, I, Ra and R are @
Same as above, by reacting the quinolone derivative represented by ) with hydroxyurea in the presence of a base and isolating the product by conventional methods! Li can be built. This reaction can be carried out under the same conditions as in reaction (1) above. If possible, the starting compound (rfl) used in this reaction is used in a form in which the amine 7 group that does not participate in the reaction is protected as described in (1) above, and after the reaction is completed, the protecting group is may be removed. The raw material compounds (■) and (Ill) are new n compounds ↓ (In the formula, 2 means a halogen atom, R' means a lower alkyl group, a lower alkylokynemethyl group, or a substituted benzyl group, R1, R2, R3, Ra
, R, R" and k are the same as above.) According to this reaction formula, Carbo/191 (1) is converted into acid chloride by a conventional method, and the resulting compound is condensed with Malo/Minister in the presence of a base. is deesterified to give a β-ketoester (2), which is then reacted with a substituted inthiocyanate and an optionally substituted alkyl halide in the presence of a base to obtain a minoketoester (3). cyclized in the presence of a base to form quinolone derivative 4
Let the body be (4). Starting compound (II) can be produced by treating compound (4) in which R' is a lower alkyloxydimethyl group or a substituted beadyl group with an acid. Alternatively, starting compound (Ill) can be produced by treating compound (4) with an oxidizing agent such as metachloroperbenzoic acid in a solvent. (2) The compound of the present invention in which R3 is a group other than a halogen atom has the following general formula (IV) (wherein, 2 means a halogen atom, and Rb R2゜R4
and It can be produced by isolation according to a method. This reaction is carried out in an inert solvent at 10-180°C, preferably at 2
This can be carried out by stirring the starting compounds (■) and (V) at 0 to 130°C for 10 minutes to 24 hours, preferably 30 minutes to 15 hours. As a solvent, for example, dimethylformamide. Ethanol, methanol, acetonitrile, water. Examples include chloroform and pyridine. These solvents may be used alone or in combination. This reaction is generally carried out in the presence of an acid acceptor using starting compound (V) in an equivalent or excess amount relative to starting compound (IV); It may also be used to serve as an acid receptor. Examples of acid acceptors include triethylamide/l dimethylaniline, N,N-diimpropylethylamide 7.1.
8-Diazabicyclo[a40]-7-U/decene (D
IIU), organic bases such as pyridine, hydroxides such as sodium hydroxide and potassium hydroxide, carbonates such as sodium carbonate and potassium carbonate, and bicarbonates such as sodium bicarbonate and potassium bicarbonate. The starting material compound (v) used in this reaction is, if possible,
As described in +1) above, the amine 7 group that does not participate in the reaction may be used in a protected form, and after the reaction is completed, the protecting group may be removed by a conventional method. Starting compound (IV) can be produced by the reaction (1) or (2) above. The compound of the present invention produced in this way can be prepared using conventional methods! Jirin is purified. Depending on the isolation and purification conditions, the compound of the present invention can be obtained in the form of a salt or a free form, but these can be mutually converted depending on the purpose to produce the compound of the present invention in the desired form. Stereoisomers of the compounds of the invention can be separated from each other by conventional methods, such as fractional crystallization, chromatographic separation, and the like. Note that the compound of the present invention having a corresponding specific steric configuration can also be produced by the above method using a starting compound having a specific steric configuration. The optically active form of the compound of the present invention can be separated by a series of known methods. Effects of the Invention Both the compounds thus obtained and their salts are new compounds, and as they exhibit extremely excellent antibacterial activity, they are valuable as antibacterial agents. Compounds (Summer)
or its salts, as well as human and veterinary medicines,
It can also be used as a fish disease medicine, pesticide, food preservative, etc. Next, data regarding the antibacterial activity of the compounds of the present invention are listed below. (Left below) Antibacterial effect in vitro “1” Ill small inhibitory concentration (MIC: μg/■1) is Cb
emothermpy, 29(1), 76(19♂heavy)
It was measured according to the method described in θ, and the results are shown in the table above. ll 2 A: Staphylococcus Y9 reus 209P JC-1 (S, 1Lureus
209P JC-1). B: X'tx9shiT-]ri NIHJ JC-
2 (E, coll NI+IJ JC-2). C: x 7-: l replacement P-51208 (E,
coll P-51208) D: Citrobaku 70 Indy P-880
1 (C, freund!IP-8801)E:
6-Ft Eggplant・Xh Zero/-112 (P, aer
ug+nosa 12). '3'A means the compound of Example 3 (the same applies hereinafter). The compounds of the invention exhibit excellent antibacterial activity and broad antibacterial spectrum in in vHro tests. Furthermore, the compounds of the present invention exhibit excellent inv+vo protective effects against local or systemic infections caused by various bacteria, and also exhibit good safety in general toxicity tests on animals. When the compound of the present invention is used as a human antibacterial agent, the dosage varies depending on the age of the patient, symptoms, route of administration, etc., but the dose is 5 g to 5 g per day, administered once or in several doses. It is recommended that you do so. The route of administration may be either oral or parenteral. The compound of the present invention may be administered as a g powder, but it is administered in a prepared form together with a carrier for the bulk formulation. Specific examples include tablets, liquids, capsules, granules, 11 granules, @
Examples include antibacterial agents, antibacterial agents, injections, and soft blue agents. These preparations are subjected to gga according to conventional methods. As a carrier for II oral preparations, Denzo/. Substances that are commonly used in the pharmaceutical field and do not react with the compound of the present invention are used, such as manonite, tAJ & cellulose + CMCNa + water, and ethanol. 1tQ#
Examples of the carrier include carriers commonly used in the field of injections such as water, physiological saline, glucose solution, and infusion preparations. Furthermore, the above-mentioned liquid formulations and ointments can also be used in treatments commonly referred to in otorhinolaryngology and ophthalmology. EXAMPLES Next, the method for producing the compounds of the present invention will be explained in more detail with reference to Examples and Reference Examples. Reference example 1 1-7 cloprovir-a7-difluoro-2-mercapto-5-methyl-1,4-dihydro 0-4-oxoquinolin 7-3-carbo/llI ethyl ester: (1) Known compound 2.4.5. 200 g of 6-titrafluoroinphthalonitrile was reacted with 130 g of diethyl malonate in the presence of potassium heptafluoride, and 332 g of 2.5.6-dolifluoro0-4-Cjethoxycarbonylmethyl)isophthalonitrile was added to the oil partition. get as. ■ Hydrolyze 181g of the above compound with 00% sulfuric acid to produce 4-
25 g of carboxymethyl-2,5,6-)rifluoroia 7tal FII are obtained. m, 9.212-214℃
. (2) 28 g of the above compound is heated to 140° C. in dimethyl sulfoxide in the presence of triethylamine to obtain 13 g of 24.8-t+)yl-ta-2-fif-benzoic acid a. m, p, 114-115°C. [4] Treating 24 g of the above compound with thionyl chloride &4
．． Rotrifluoro-2-methylbenzoic acid chloride is obtained. b, 9.98 to 100°C (40 mm mm 1 liter). This was reacted with sodium malon 1119 ethyl in anhydrous toluene to give (3,4,8-)refluoro0-2-methylbenzoyl) malon/l! II Obtain diethyl. Water and a catalytic amount of p-)luenesulfonic acid were added to this, and the mixture was heated under reflux for 4 hours to produce (3,4,B-trifluoro-
15.2 g of ethyl 2-methylbenzoyl)acetate are obtained as an oil fraction. b, p, 112~ 6℃ (3118g)
. ■Dissolve 20 g of the above compound in 7200 ml of dioxa and add 5.0 g of powdered potassium hydroxide. Add Og and rR for 2 hours at room temperature.
F51 The stirred reaction solution was concentrated under reduced pressure, and n-hexane was added to the residue to remove the glass solid. This mixture was added to a mixture of 8 g of 7-chloroprobyl inthio-7-anate and 101 g of p-methoxybenzyl chloride, toluene/float was further added, and the mixture was stirred for 15 hours. To this reaction solution, 6 g of potassium carbonate IO and 7150 dioxin
ml and heated and stirred at 100° C. for 17 n. The reaction solution was concentrated under reduced pressure, acidified with powdered hydrochloric acid, and extracted with chloroform. Concentrate the extract to obtain 1-cyclopropyl-
Obtain 10.1 g of ethyl 6,7-difluoro-2-(p-methoxybenzylthio)-5-methyl-1°4-dihydro-4-oxoquinoline-3-carboxylate am,
p, 111~I lid 2°C. (6) Dissolve 0.5 g of the above compound in 501 trifluoroacetic acid, add 3.41 g of aninole and 111.4 1 of trifluoromethanesulfo, and leave at room temperature for 5 days.The reaction solution is concentrated under reduced pressure. After adding ether to the residue, the mixture is extracted with a 5% aqueous sodium hydroxide solution. The extract is acidified with 20% hydrochloric acid and extracted with chloroform. The extract is concentrated to obtain 4.5 g of the desired product as red-orange crystals. Reference example 2 1-cyclopropyl-Q 7.8-trifluoro-2-
Mercapto-5-methyl-1,4-dihydro-4-oxoquinoliff-3-carboxylic acid ethyl ester: (1) Known compound 2.3.4.5-tetrafluoro a-(
1132g of 1-methylbenzoin and 27.5g of thionyl chloride
12.
30.8 g of 3.45-tetrafluoro-6-methylbenzoic acid a-lide are obtained. b, p, 77-80℃ (19mm
mm1l. ■ 30.8 g of the above compound was reacted with ethoxymagnesium C17m diethyl in anhydrous Toluev,
Diethyl 4.5-tetrafluoro-6-methylbe7zoylmalonate 4:1.9 is obtained. This has water number 001 and p
-) Add 0.40 g of lue/sulfo/acid hydrate and heat under reflux for 2 hours. After cooling, the reaction solution was neutralized with saturated mW water,
Extract with OO, t, lv system. The extract was dried and concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain 2.3,4.5-tetrafluoro-8-methylbe/
23.5 g of ethyl zoylacetate are obtained. b, p,
122-128°C (5mmmm1l, ①The above compound was subjected to reaction treatment in the same manner as Reference Example 15) to obtain l-cyclopropyl-
m, ρ, 1
30-137°C. (a) The above compound is subjected to reaction treatment in the same manner as in Reference Example 1 (6) to obtain the desired product. m, 9.135-137°C. Example ! 9-Cyclopropyl-8,7-difluoro-5-methyl-2,':&4,9-tetrahydrothiazolo[he4
-b] Quinoline-3,4-dione: Dissolve 4.5 g of sodium bicarbonate in 250 μl of water, and add 3.7 g of human axylamide 7-Q-sulfonic acid. Add to this solution 1-cyclopropyl-7-difluoro-2-mercapto-5-methyl-1,4-dihydro 0-4-oxycarbo/phosphorus-3-carbo/1111 ethyl, and 5 g of a tetrahydrofurano solution ( (101) is added dropwise under a stream of elementary air. After stirring at room temperature for 1.5 hours, the reaction solution is made acidic with hydrochloric acid. The precipitated crystals are collected by filtration to obtain 3.08 g of the desired product.
8 Obtained as warm-colored crystals. m, f), 207~
270'C. Example 2 9-cyclopropyl-8,7,8-) IJ Fluoro-5-methyl-43,/1. (1-tetrahydrothiazolo[5,4-b]quinoline-he4-dione: l-
7Clopavir-a7.8-)lifluoro-2-mercapto-5-methyl-1,4-dihydro 4-oxoquinolif-3-carbo/fil ethyl is reacted in the same manner as in Example 1 to obtain the desired product. . m, p, 248-25+”C. Example 3 9-cyclopropyl-8-fluoro-5-methyl-7-
(l-piperazinyl) - 4.9-tetrahydrothiazolo[a4-b]quinoline-λ4-dione: 9-cyclopropyl-8,7-difluoro-5-methyl-2,149-tetrahydrothiazolo[ a4-b A mixture of 7370 mg of zuquinoline-he4-dio, 510 g of anhydrous piperazine and 1 pyridine/+5 is heated at 90°C for 6 hours and stirred.The reaction solution is concentrated to dryness under reduced pressure.
Ether is added to the residue and the crystals are collected by filtration. This crystal is 28
After stirring in 151% ammonia/monium water at room temperature for 1vIIX1, filter the mixture and wash with water. Furthermore, these crystals are mixed with ethanol 301
4Rj boiled for 10 minutes in addition to! ! Take it, object 3
Obtain 57 mg. m, p, 282-284℃ (decomposition) Using the corresponding raw material compounds, the following Example 4 was prepared in the same manner as Examples 1 to 3 and V4.
~9 compounds are obtained. Example 4 9-cyclopropyl-6-fluoro-5-methyl-7-
(3-methyl-1-piperazinyl)-43,4,0-tetrahydrothiazolo[5,4-blquinoline-3,
4-dione: m, 9.245-249°C. Example 5 9-cyclopropyl-6-fluoro-5-methyl-7-
(trans-3,5-:)methyl-1-piperazinyl)
-2,3,4,9-tetrahydrothiazolo[he4-
b] Quinoline-3,4-dione: m, p, 295~
300℃ (decomposition). Example 6 9-cyclopropyl-6-fluoro-5-methyl-7-
(4-Methyl-1-piperazinyl)-a & 4,9-tetrahydroisothiazolo[5,4-bl quinoliy-3,4
-Dione: m, 9.255-259°C. Example 7 7-(3-amino-1-pyrrolidinyl)-〇-cyc11
Zo1vir-6-fluoro-5-methyl-43,4,9-
Tetrahydrothiazolo[5,4-bl quinoli/- to 4-dio:/: m, p, 259-264°C. Example 8 7-(3-7mi/methyl-1-pyrrolidinyl)-9-7
4.9 to riropropyl-6-fluoro-5-methylose
-tetrahydrothiazolo[5,4-b]quinoly-
3,4-dione: m, 9.241-247°C. Example 9 9-7 cloprobyl-6-fluoro-7- (4-hydroxy-1-pyrrolidinyl)-5-methyl-2B4o-
Tetrahydrothiazolo[5,4b]quinori/-a4
-Dione: m, P, 281-28°C. Example 10 7-(3-amino-1-pyrrolidinyl)-9cyclopropyl-a8-difluoro-5-methyl-2,3,49-
Tetrahydroisothiazolo[5,4b]ki/su7-a4
-dione: 9-cyclopropyl-a7.8-)lifluoro-5-methyl-Q, 14.9-tetrahydrothiazolo[5,
4-bl quinoline-to-4-dio/326 g. 4301g of 3-aminopyrrolidine and 712g of pyridine
The mixture of step 1 is heated and stirred at 90° C. for 2 hours, the effluent is concentrated under reduced pressure, inpropyl ether is added to the residue, and the precipitated crystals are filtered and washed with water. The crystals were heated under reflux in ethanol for 10 minutes, collected by filtration, and dried to obtain the desired product 372.
Obtain intestinal g. m, p, 249-252°C Compounds of the following Examples 11-10 are obtained in the same manner as in Example 10 using the corresponding starting compounds. Implementation v411 7-(trans-3-amino-4-methyl-1-pyrrolidinyl)-9-cyclopropyl-a8-difluoro-5
-Methyl-2,3,4,0-tetrahydroisothiazo0
[翫4-b] Ki, Nori 7-3.4-Geo y: m,
9.231-235°C. Example 12 9-cyclopropyl-a8-difluoro-5-methyl-
7-(1-piperazinyl χ-43./1.0-tetrahydrothiazolo[5,4-b]quinoline-&4-dio7: m, p, 300°C or higher. Example 13 9-7 to lyloprovir-8 -difluoro-5=methyl-
7-(cis-a5-dimethyl-1-piperazinyl)-2
, &4,9-tetrahydrointhiazo O[he4-b]quinoline-3,4-dione: m, p, 272-275
°C (decomposition). Example ! 4 9-Cyclopropyl-a8-difluoro-5-methyl-
7-(4-methyl-1-piperazinyl)-2,3,40
-Tetrahydrointhiazorj[5,,4-b]quinoli/-14-dione: m, 9.252-25°C. Example 15 9-cyclopropyl-to8-difluoro-7-(3-hydroxy-1-pyrrolidinyl)-5-methyl~2.3.
4.9-tetrahydrointhiazoO[to4-b]quinoli7-3.4-dio/: m, p, 205-270°C. Example 16 9-cyclopropyl-a8-difluoro-5=methyl-
7-(2-N,N-dimethylami/methylmorpholino)
-21 to 4,9-tetrahydrothiazolo[5,4-
b] Ki/su7-3,4-dione: m, p, 193~
196℃. Patent applicant Dainippon Pharmaceutical Co., Ltd.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 is a lower alkyl group, a halogen lower alkyl group, a lower alkenyl group, a cycloalkyl group, or even if R_2 means a hydrogen atom, halogen atom, cyano group or lower alkyloxy group, R_3 means a halogen atom or a group represented by the following formula ▲ Numerical formula, chemical formula, table, etc. ▼、▲Mathematical formula, chemical formula,
There are tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ , where R_5 and R_1_0 are hydrogen atoms, lower alkyl groups, or acyl groups (the acyl groups may be substituted with halogen atoms) R_6, R_7 and R_1_1 or differently mean a hydrogen atom, a lower alkyl group or a halogen lower alkyl group, or R_6 and R_7 are combined to form a direct bond or -(CH_2)m- where m means 1 or 2, and R_8 is a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy-lower alkyl group, a hydroxyl group, an amino group, a mono- or di-lower alkylamino group, an amino-lower alkyl group, or a mono- or di-lower alkylamino group. or di-lower alkylamino lower alkyl group, R_9 means a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkyloxy group, and n is 3, 4 or 5.
, R_4 means a lower alkyl group, and X means a sulfur atom or an oxygen atom. ] and its salts.