DE2520545A1 - 3-SUBSTITUTED QUINOXALINE-2-CARBOXAMIDE-1,4-DIOXIDES - Google Patents

Description

1 BERLIN 33 8 MUNICH M

Augutte-Viktoria-Strafl · 66 r> οι lor ^ LJl ^ C SL PAPTMFR PaL · A Dr Ina Ruschke * ^ '· "* ^ ^ ^ * Πι \ Ε Ofc F / A l \ II ¹ IUIx

offirA ¹ ""' ⁰ ' PATENTANWÄLTE

Telephone: 030 / | »2S BERLIN - MÖNCHEN

TELEX: 1837ββ TELEX: 5227f7

P 841

Pfizer Inc., New ioric, New York, V.St.A.

3-Substituted hinoxaline-2-carboxaüiid-1,4-dioxide

The invention relates to ^ -substituted ohinoxaline-2-carboxamide-1,4-dioxide, as antibacterial agents for the defecation of numerous pathogenic microorganisms and as agents are suitable for promoting growth.

jji's began to make numerous analogous connections from the connections of the invention are suitable for such purposes. Typical Examples of such known analog compounds are described in US Pat. No. 3,644,360. Although these well-known analogous compounds have a suitable activity for the stated purposes, it has been found that these known compounds have toxic side effects if they are used, for example, in animal feed. Surprisingly it has been found that the compounds of the invention show a marked, unexpected reduction in these side effects and among other things with a higher degree of safety or in larger proportions for faster control of numerous pathogenic microorganisms and / or used as Mitxel to promote animal growth v / can ground.

It has been ijefariden that a number of 3-substituted Cninoxalin-2-carboxaiaid-1,4-dioxides are valuable antibacterial agents. These compounds have the formula

509847/1162

wherein X is a substituent in the 6- or T-position, which consists of hydrogen, halogen, lower alkoxy, trifluoromethyl, ijethyl, lower alkyl sulfide, lower alkyl sulfoxide or lower alkyl sulfone, Y is S, SO or SO ₂ , R-, lower alley 1 is that with hydroxy, lower alkoxy, amino, ιίοηο (lower alkyl) amino, di (lower alkyl) amino, lower alkoxy ^ carbonyl, carbamyl, mono (lower. alicyl) carbamyl ,. ! ^ (lower alkyl) carbamyl, halogen, mercapto, suIfο, lower alkyl sulfide, lower alicyl sulfoxide, lower alkyl sulfone, acetoxy, pyrrolidino, piperiüino, llorpholino, i'hiomorpholino, piperazino, N- (lower alkyl) piperazino, li-hydroxy ( lower alkyl) piperazino, substituted N- (lower Al ± canoyl) piperazino or N-carbo (lower alkoxy) piperazino, Rp, call it separately present, hydrogen or lower alkyl, R · ,, when present separately, hydrogen, Is phenyl, lower alkyl or substituted lower al. £ yl, v / orin the substituent alaino, mono (lower alkyl) amino, di (lower alkyl) amino, pyrrolidino, piperidino, morpholino, !! - (lower alkyl) piperazino, N-Hydroxy (lower alkyl) piperazino, N- (lower alkanoyl) piperazino, N-Carbo (lower alkoxy) piperazino, pyrrolo, piperazino, imidazolino, hydroxy, lower alkoxy, thio (lower alkyl), carboxy, Oarbo (lower alkoxy ), Carbainyl, mono (low eres alkyl) carbamyl, di (lower alkyl) carbamyl, lower alkanoyloxy or lower alkanoylamino, and Rp and R-, together with the nitrogen atom to which they are attached, are pyrrolo, pyrrolidino, piperidino, ^ torpholino, TMomorpholino , Piperazino-, !! - (lower AlKyI) -piperazino-, N-hydroxy (lower alkyl) piperazino-, N- (lower AlkanoyDpiperazino- or N-Garbo (lower alkoxy) piperazino group mean, and the compounds of the invention can also

509847/1162

In the form of pharmaceutically suitable acid addition salts, in which at least one of the groups R ₁ and R 1 is substituted lower alkyl, in which the substituent is a basic group.

The expressions lower alkyl, lower alkoxy, lower alkanoyl and lower alkanoyl are to be understood as meaning those alky, alkoxy, alkanoyl and alkanoyl groups that contain 1 to 4 atoms, namely those that are easily accessible from ieicnt Raw materials produced _; / can ground.

Compounds of the invention are effective antibacterial agents in vitro and in vivo. In addition, the compounds described here are v / irKsauie Hittei for promoting animal growth, " especially for poultry and poultry.

Preferred compounds of the invention include those of the abovementioned formula in which X is hydrogen, Y is S, SO or SOp, R- is lower alkyl substituted with hydroxy, and Rr and R are each hydrogen or lower alkyl. Among these preferred compounds there is a particularly preferred group, namely compounds in which iL is hydrogen and R1 is methyl. A particularly preferred group within the latter group includes compounds in which Y is SO ^ and R _{1 is} hydroxyethyl. To another specially preferred group within the latter group belong connexes in which Y is S and R 1 is hydroxyethyl.

A particularly preferred group of compounds also includes those in which R _{1 is} lower alkyl substituted with .ui (lower alkyl) auiino, Y is SO ₂ , X is hydrogen, a., Hydrogen or lower AlKyI and R ^ . -Hydrogen, more similar AlKyI or substituted lower alkyl, wherein the juDscituent III is (lower alkyl) amino, hydroxy or lower alkoxy. A very particularly preferred compound is üie compound in which R _{1 is} 3-piperidinopropyl, Y is SO _2, R ₂ 'is .asserstoff, R, is methyl and X is hydrogen.

50 9 847/1 162

The compounds of the invention in which Y is in can be prepared via either the amide route or the ester route. The amide route consists of (1) the blackening (or chlorination) of the corresponding 2-oil compound to form the corresponding bromine- (or non-chloro-) methyl derivative, (2) the conversion of the bromo- (chloro) methyl derivative into the corresponding one 'irixiiethjlauniioniuiniae thy! compound and (3) the replacement of the TrimethylaiuJioniuiiigruppe by -SR- ,. The erxialtene 3-OHoSa ₁ -SUlDstituierte 2-Oarboxaniid-1,4-dioxide compound can AAnn to the corresponding 3- or 3-0H ₂ -SOpR ₂₁ -] - compounds are oxidized. Instead of the steps (2) and (3) given above, it is also possible to replace the bromine (or chlorine) group of the bromine (or chlorine) methyl substituent directly with -SR-. to replace.

The ester route includes (1) the bromination (or chlorination) of the alkyl ester of 3-methyl-2-quinoxalinecarboxylic acid 1,4-dioxide, preferably of the ldetnyl ester, to the corresponding bromine (chlorine.) methyldexevate, (2) the replacement of the bromine group with the group -SR-, and (3) the amidation of the latter compound under BiI-

Formation of -GON as a substituent in 2-3 divisions. iVenn the

Desired substituent in 3-position -CH2S0R ₁ or -G is the allyl ester of 3-GH2SR ₁ -substituted 2-ühinoxalincarbonsäure-1,4-dioxide oxidized to form the desired substituent in 2-position and aann the sulfoxide or sulfoxide obtained fon amidated to the desired product.

The '3-methyl substituted starting materials for the amide route are in origin and can be prepared by the methods set forth in U.S. Patents 3,557,109 and 3,644,360 and numerous other patents and publications. Reference is made here to these patents and publications. The 3-methyl substituted From _ö angsmaterialien for the ester route are also known and can according to the data in the US Patent 3,753,967 and numerous other Patentscnriften and publications referred to herein are made.

509847/1162

The practice specified Amidweg for the preparation of the compounds The invention is explained in more detail below and in shown schematically in the accompanying Table A, and the oD'än specified Bsterweg - is in the following table B shown schematically.

The invention also proposes a process for the preparation of a compound of the formula

■ .vorin X eixx is a substituent in the 6- or 7-position, which is derived from. Halogen, lower alkoxy, trifluoromethyl, methyl, lower alkyl sulfide, lower alkyl sulfoxide or lower Alkylsulfone is composed, Y is S, SO or SOp, R-, lower Alkyl is that with hydroxy, lower alkoxy, amino, mono (lower alkyl) amino, di (lower alkyl) amino, lower alkoxycarbonyl, garbamyl, mono (lower alkyl) carbamyl, di- (lower alkyl) carbamyl, halogen, mercapto, SuIfο, lower Alkyl sulfide, lower alkyl sulfoxide, lower alkyl sulfone, acetoxy, pyrrolidino, piperidino, morpholino, thiomorpholino, Piperazino, N- (lower alkyl) piperazino, N-hydroxy (lower alicyl) piperazino, N- (lower alkanoyl) piperazino or N-Carbo (lower alkoxy) piperazino is substituted, Rp »if when it is separate, it is hydrogen or lower alkyl, R ,, when it is separate, hydrogen, phenyl, lower ■ Is alkyl or substituted lower alkyl where the substituent is amino, mono (lower alkyl) amino, di (lower alkyl) amino, pyrrolidino, piperidino, morpholino, N- (lower AlKyDpiperazino, N-hydroxy (lower alkyl) piperazino, N- (lower Alkanoyl) piperazino, N-Carbo (lower alkoxy) piperazino, Pyrrolo, piperazino, imidazolino, hydroxy, lower alkoxy,

509847/1162

Ihi (lower altcyl), üarboxy-Uarbo (lower aLcoxy), carbaiayl, mono (lower alkyl) carbamyl, di (lower alkyl) carbaiayl, lower alkanoyloxy or lower alkanoylaraino, and Rp ^ ¹⁰ '· ^ 5 together with the nitrogen atom, to which they are bound, a pyrroio-, pyrrolidino-, piperidino-, morpholino-, IMomorpholino-, piperazino-, !! - (lower alkyl) -piperazino, N-hydroxy (lower alkyl) piperazino-, N- (lower alkanoyl ) piperazino or N-Oarbo (lower alkoxy) piperazino groups, as well as the piiaruazeutiscn suitable acid addition salts of these compounds in which at least one of the groups R ₁ and R ^ is substituted lower alicyl in which the substituent is a basic G group , which is characterized in that a compound of the formula

¹ H ₀ -V

... I ¹

where Y is Gl, Br, N ⁺ (CH) _, 0l ~ "or N * (CH ~) U3r-, « exm Z -l /

11 Jl \

is where R _? and R ^ has the meaning given above, or V is Gl or Br- when Z is -O-lower alicyl, and X has the meaning given above,
with a compound of the formula

R ₁ -SH

vi / orin R _{1 has} the meaning given, in the presence of aqueous sodium or potassium hydroxide and, if necessary, in any order

(i) the compound so formed, wherein Z is -O-lower AlKyI is and X and R-, which ο denote the meaning given, with the connection the formula

H-converts, and / or

509847/1 162

(iij üie so ^ euildex compound iuit a suitable oxidation ^ iGOeI uüier reaction of a compound of the formula I ¹ , in which I -Hü- or SC ^ and X, R- ,, B. ,, and R ^, the ooen given meaning, and optionally forms the pharmaceutically suitable acid addition salts of these compounds, in which

ena is one of the groups R-, and [{ _y substituted lower in which the oubstituent is a basic group.

: ₂ N ⁺ (CH ₃ ) Br "

509847/1162

VI

.. 8 Sabellυ B - isterwe

CO ₂ CH ₃

H ₂ Br

VIII

O ₂ CH ₃

XIII

509847/1162

The starting materials, I, for the amide route are converted to the corresponding 3-bromo (or chloro) substituted compounds II by direct halogenation, with molecular bromine or chlorine being particular convenient agents. One procedure involves mixing 1 or 2 molar portions of I and halogenating agents in chloroform or another chlorinated solvent such as methylene chloride, carbon tetrachloride and chlorobenzene. In addition, solvents such as formic acid and acetic acid can also be used. The reaction is generally carried out at a temperature of from about 20 to 120 ^° C., preferably from about 1 to 4 hours.

20 to 120 ⁰ C, preferably from about 60 to 100 ⁰ C, within

The trimethylmonium derivatives, III, are prepared by treating the appropriate 3-bromo (or chloro) methyl compound, II, with trimethylamine. This reaction is carried out in a suitable diluent or solvent such as N, N-dimethylformamide, ethanol, benzene, xylene, chloroform, dioxane or Terahydrofuran, at temperatures of about 20 to about 100 ⁰ C, preferably from about 20 to 6O ⁰ C, carried out. Trimethylamine is bubbled into a mixture of the diluent and the appropriate reactant II with stirring until the mixture is saturated. The exothermic reaction mixture is stirred for about 1/2 hour to about 4 hours and the product is isolated by filtration or evaporation of the diluent.

The trimethylammonium group is replaced by -SR ₁ by reacting the product with the appropriate mercaptan (B ₁ SH) in the presence of aqueous sodium or potassium hydroxide. The mercaptan is mixed with a two phase system of aqueous sodium or potassium hydroxide and an organic solvent such as chloroform and then the trimethylammonium substituted compound, III, is added and then stirred for 1 to about 4 hours. The organic solvent phase then separates out and the 3-CH ₂ SH ₁ -substituted compound, IV, is isolated by removing the solvent. The latter

50984 7/1162

- ίο -

The compound can then be converted into the corresponding 3-CH ₂ SOR ₁ -substi; tuierte compound, V, or the 3-GH ₂ S0 ₂ R- _L -substituted compound, VI, by oxidation with potassium permanganate, an organic peroxide or an organic peracid, such as peracetic acid, perphthalic acid, perbenzoic acid or m-chloroperbenzoic acid. The latter peracid is particularly suitable because the by-product m-chlorobenzoic acid can be easily removed. The oxidation wiid in a solvent such as chloroform or methylene chloride, at about 0 to about 3O ⁰ C, up to 1 or 2 equivalents (depending on whether the SuIfinyl- or sulfonyl derivative is to be obtained) has been consumed. It is advantageous to use equimolar proportions of the reaction participants for the preparation of the sulfinyl derivative in order to avoid further oxidation or to limit it to a minimum. A 5 to 10 # excess of oxidizing agent is generally employed when the sulfonyl derivative is to be obtained.

An alternative method that can be used in the amide route involves the direct conversion of the 3-bromomethyl reactant, II, to the 3-GHgSH ₁ -Substituted Compound, IV. In this method, the starting material, II, is dissolved in an organic solvent such as For example chloroform, dissolved or slurried, then at least an equimolar amount of a mercaptan of the formula R ₁ SH and then an acid-binding agent, such as trimethylamine, are added at a rate which is able to regulate the exothermic reaction in a suitable manner. After the reaction, the desired product, VI, is isolated.

The starting materials, VII, for the ester route are converted into the corresponding 3-bromo (or chloro) substituted compounds VIII, converted by direct halogenation, for which molecular bromine or chlorine are used in a particularly convenient manner One way of doing this is to put bromine (or chlorine) in a suspension of VII in a water-miscible Solvent such as dimethylformamide while stirring the

509847/1162

Reaction mixtures until the end of the reaction enters and the product, YIII, is extracted with a solvent such as chloroform and the product is isolated from the chloroform.

To convert intermediate VIII into intermediate IX, bromine is replaced by SS ₁ , which can be done by several different procedures. One possibility is that triethylamine is added dropwise to an equimolar mixture of VIII and R ₁ SH in a solvent such as, for example, chloroform, and the desired product, IX, is isolated from the chloroform layer after being washed with water. The second possibility is similar to the first, but after this an excess of R- ^ SH reactant and an excess of diisopropylethylamine are used. With this possible procedure, dropwise addition is not necessary. The desired product is isolated in the same way as indicated for the first possible procedure. A third possible procedure is the same as the first except that a reaction medium such as methanol is used and an inorganic base such as sodium or potassium hydroxide is used in place of triethylamine. The required amount of inorganic base is entered at the beginning of the reaction.

The conversion of the intermediate product IX into the final product X is carried out via an amidation with a reactant of the formula

/ 2

made and in the usual way by entering the reaction participants in a suitable solvent such as water, methanol or acetonitrile. An excess of that Amine reactants should of course be employed. The implementation generally proceeds with sufficient speed when the reaction mixture is allowed to stand at room temperature.

The conversion of intermediate IX into the intermediates XI and XII are carried out using the same procedure as described above for converting IV to V or VI on the

5 0 9 8 A 7/1 1 6 2

Amidweg is described. The intermediates XI and XII can then converted to end products XIII and XIV by amidation as indicated immediately above.

Acid addition salts of the compounds of the invention which have a Containing basic group are prepared by methods known to those skilled in the art. Following a simple method becomes the free Base in a suitable solvent, e.g. acetone, water, a lower alkenol such as ethanol or isopropanol, dissolved which contains the desired acid or to which this acid is subsequently added. The salts are filtered out, Precipitation with a non-solvent, evaporation of the solvent or, in the case of aqueous solutions, by lyophilization isolated. In this way the sulfate, nitrate, phosphate, acetate, propionate, butyrate, citrate, gluconate, benzoate, Pamoate, amsonate, lartrate, 3- * hydroxy-2-naphthoate, suI-fosalicylate and other salts can be produced.

The products of the invention are extremely effective against a wide variety of pathogenic microorganisms and are therefore used as industrial antimicrobial agents, e.g. for water treatment, slime control, paint preservation and im Wood protection and also for local application purposes as a disinfectant suitable.

In the case of in vitro use, e.g. for topical application, it is often convenient to combine the selected product with a pharmaceutical suitable carrier, such as vegetable oil or mineral oil or an emollient cream to mix. Likewise the compounds of the invention can be in liquid carriers or solvents such as water, alcohol, glycols or Mixtures thereof or other pharmaceutically acceptable inert agents, i.e. agents that do not have an adverse effect on the active ingredient, be dissolved or dispersed. For such purposes it is generally suitable to use concentrations of the active ingredients from about 0.01 to about 10 wt .- ^, based on the entire composition.

0 9 8 4 7/1162

The compounds described here show in contrast to the The usual gram-negative activity of quinoxaline di-N-oxides has a broad spectrum of activity, i.e. activity against both gram-negative and gram-positive bacteria, such as a.B. Staphylocoecusaureus, Streptoayees pyogenes, Esoherichia / and Fasturella multocida.

These new compounds can be used in in vivo for such Oral or parenteral purposes, e.g. by subcutaneous or intramuscular injections, with a dosage of about 1 mg / kg up to about 100 mg / kg body weight can be administered. iHir the carriers suitable for parenteral injection can either be aqueous, such as e.g. Water, isotonic saline solution, isotonic dextrose solution, Einger's solution, or non-aqueous, such as fatty oils of vegetable origin (cottonseed oil, peanut oil, corn oil, sesame oil), or dimethyl sulfoxide and other non-aqueous vehicles which do not interfere with the therapeutic efficacy of the preparation and in the one used Volume or the amount used are non-toxic (glycerine, propylene glycol, sorbitol). Also can Advantageously, preparations are made which are suitable for an extensive preparation of solutions prior to administration. Such preparations can contain liquid diluents, e.g. propylene glycol, diethyl carbonate, glycerine, Sorbitol, etc., polishing agents, hyaluronidase, local anesthetics and inorganic salts to achieve the desired pharmacological properties. The connections can too with numerous pharmaceutically suitable inert carriers which include solid diluents, aqueous vehicles, non-toxic organic solvents, and although in the form of capsules, tablets, troches, pills, dry mixtures, suspensions, solutions, elixirs and parenteral Solutions or suspensions. In general, the compounds will be used in numerous dosage forms at concentrations in the Range from about 0.5 to about 90 wt .- ^, based on the total Preparation, applied. Other methods include mixing with animal feed, making putter feed

509847/1162

concentrates and feed additives and diluted solutions or Suspensions, such as a 0, liquid solution, for drinking purposes. The addition of a small amount τοη one or more of the 3-substituted quinoxaline-2-carboxamide-1,4-dioxides described here to the diet of healthy animals, both ruminants and non-ruminants, so that these animals ingesting the product over a longer period of time, at a dosage of about 1 mg / kg to about 100 mg / kg body weight per day, especially in the main part of your academic period, leads to an acceleration of their growth rate and improves the utilization of forage (the number the pounds of food required to gain a pound in weight). To these two classes of animals include poultry (chickens, chickens, turkeys), hinds, sheep, dogs, cats, pigs, hats, mice, horses, goats, mules, Rabbits, mink and so on. The beneficial effects on the speed of growth and the utilization of forage lie above those normally obtained from a completely nutritionally balanced diet that includes all foods Contains vitamins, minerals and other factors known to be necessary for maximum growth of such animals are. In this way, the animals reach market size faster with less feed.

The feed preparations described here are, as has been found, particularly valuable and extraordinarily effective at Pigs. In some cases, the level of responsiveness may vary with the sex of the animals. The products can of course can be administered in a component part of the feed or can be mixed evenly into a compound feed. on the other hand the products, as indicated above, can be administered in an equivalent amount via the water ration of the animals will. A multitude of feed ingredients can be used in one nutritionally balanced feed should be included. Any animal feed which is conventional in nutritional terms can be prepared Balance of energies, proteins, minerals and vitamins with one or more of the above

5 Q 3 34 7/116 2

Contains ühinoxalin-di-N-oxide. Some of the numerous ingredients are generally grains such as ground grain and grain by-products, animal protein substances such as e.g. Meat and fish by-products, mixtures containing vitamins, e.g. vitamin A and D mixtures, fiiboflavin additives and other vitamins B complexes, and bone meal, lime, and other inorganic compounds that provide minerals.

The relative proportions of the compounds of the invention in feed and feed concentrates may vary somewhat depending on the compound, feed, with which they are used and the! animal that is supposed to make the connections. These substances are advantageously used in such relative proportions combined with edible carriers that premixes or concentrates are obtained which are easily incorporated into normal nutritionally balanced feed can be mixed in or given as an addition to normal feedings.

A wide variety of carriers, such as soybean meal, corn gluten meal, cottonseed meal, Sunflower seed meal, flax seed meal, corn meal, lime, and corncob meal, can be used to keep the even To facilitate distribution of the active substances in the finished feed with which the concentrate is mixed. The concentrate can if desired on the surface with numerous proteinaceous Edible wax materials such as zein, gelatin, microcrystalline rfachs and the like can be coated to obtain a To form a protective layer that seals off the active ingredients. The proportions of the drug preparation in such concentrates can be vary greatly because the amount of active ingredients in the finished feed can be obtained by mixing in the appropriate amount of concentrate in the feed can be adjusted so that the desired content of the additive is achieved. In the production of highly effective concentrates, i.e. premixes that need to be mixed in are suitable by the feed manufacturers for the production of finished feed or concentrates with less effectiveness, the Drug content in the range of about 0.1 to 50 g per 4-54 g

5 0 9 8 A 7/1 1 NC 2

Concentrate. The highly effective concentrates can be mixed with protein-containing carriers by the feed manufacturer such as soybean meal to produce concentrated additives that are suitable for direct feeding of the animals are. The amount of drug in these additives can range from about 0.1 to 10 grams per 454 grams of additive. A A particularly suitable concentrate is made by mixing 2 g of drug with 454 g of lime or 454 g of lime-soybean meal (1: 1) will. Other feed additives, such as vitamins, minerals, etc., can be added to the concentrates in appropriate cases will.

The concentrates described can also be added to the animal feed to achieve a nutritionally balanced finished product Manufacture feed containing from about 5 to about 125 grams of the compounds described herein per ton of finished feed. In that case For ruminants, the finished feed should contain protein, fat, fiber, carbohydrates, vitamins and minerals, respectively in an amount sufficient to meet nutritional requirements sufficient for the animal for which the feed is intended. Most of these substances are naturally occurring Contain feed materials, such as in alfalfa, hay or flour, ground corn, whole oats, soybean meal, corn silage, ground corn on the cob, wheat bran and dry molasses. Bone meal, lime, iodized salt and trace minerals will be Often added to supplement the required minerals, and urea is often used as an additional source of nitrogen admitted.

As is known to those skilled in the art, the types of nutrition are extremely variable, depending on the purpose, the type of feeding, the bass and so on. Specific diets for a variety of purposes are given by Morrison in the Appendix of "Feeds and Feeding", Morrison Publishing Company, Clinton, Iowa, 1959 ". In the case of nichtwiederkäuenden animals, such as dogs, a suitable feed may be about 50 to 80 grains #, 5 to 10 it animal protein, 5 to 50 yes vegetable protein, contain from 2 to minerals, together with additional vitamin sources.

509847/1162

Biological overcomes the activity of typical compounds explain the invention, as well as Ausfiihrungsbeiapiele that Preparation of typical compounds of the invention are given below. With these biological values and in the execution examples are standard abbreviations for certain Branches have been used. These abbreviations include Me for methyl, Bt for ethyl, Pr for n-propyl, Bu for n-butyl, 0 for Phenyl and Ac for acetyl.

The in vitro antibacterial activity of quinoxaline-1,4-dioxide of the invention is carried out according to the usual two-fold serial dilution technique shown with Hira-Herz-Infuaionabrühe (Difoo). Tue Broth is inoculated with bacteria and provided with the cinoxalin-1,4-dioxide to be tested and then under anaerobic conditions overnight Conditions incubated. The next sag can be the test result can be read visually. The minimum inhibitory concentration (MIG) of the test compound is the lowest concentration that prevents turbidity, i.e. that of the microorganism from growing prevented.

To determine the in vivo activity of the oxaline-1,4-dioxides of the invention, the solid compound is administered to mice which have been infected by intra-parenteral injection of a lethal inoculation of pathogenic bacteria. The test compound is administered by the oral (PO) or subcutaneous (SC) route using a multiple dose sequence. The inoculated bacteria material varies from about the lfachen up to about ten-fold the amount required to kill under the test conditions 100 1 "of the mice. At the end of the test, the activity of the compound is determined from the treated animals based on the number of surviving animals.

The values for di In vitro and in vivo activity of typical compounds of the invention are tabulated below listed for compounds of the form

509847/1162

-IR,

CTT NHMe (c ⁾ -SCH ₂ CH ₂ OH σ
CD NHCH ₂ CH ₂ OH (
² ( c)
c) -SCH ₂ CH ₂ OH OO
■ Ρ- NHPr -SCH ₀ CH ₀ OH -J NHCH ₂ CH ₂ CH ₂ OH -SCH ₂ CH ₂ OH cn NHCH ₀ CH, -SCH ₂ CH ₂ OH to NHBu -SCH ₂ CH ₂ OH NHCH '
0 -SO ₂ CH ₂ CH ₂ OH NH (CH ₀ ) ^ N (Et) ₀
d 0 d. -SO ₂ CH ₂ CH ₂ OH 2 2 3 -SO ₂ CH ₂ CH ₂ OH ^(a) S0 = subcutaneous an \ v) (

H H H H H H H H H Cl

COR

IN YITRO

MIC (mcg / ml)

Strep. E.
pyogenes coli

0.781
12.5

6.25
25th

3.125
50

1.562
200
100
50

0.781
50

25th
50

6.25
50

0.781
> 200
50
100

IN VIVO

Survivor SC (PO)

mg / kg.

Strep.
pyοgenes

10/10 (6/10)

3/10 (5/10)

5/10 (3/10)

1/10 (3/10)

2/10 (2/10)

2/10 (1/10)

8/10

1/10

2/10

9/10

25 mg / kg

E. coli

10/10 0/10 2/10 2/10

0/10 10/10 5/10 0/10 2/10

(PO) = refer to values in brackets

focus on oral administration

(c)

Tested as a hydrochloride salt

IN VIVO

IN VITRO

(a) surviving SC (PO)

MIC (sneeze / ml

50

25 mg / kg

R. -YR _{1 z} Strep.
pyogenes E.
coli Strep.
pyogenes E.
coli CJI NHEt -SO ₂ CH ₂ CH ₂ OH H 1.562 6.25 6/10 (8/10) 9/10 ΓΟ
CD NHCH ₂ CH ₂ OH -SO ₂ CH ₂ CH ₂ OH H 25th 100 3/10 (1/10) 1/10 cn NHPr -SO ₂ CH ₂ CH ₂ OH H 3.125 3.125 Vio (7/10) 2/10 on NHCH ₉ CHpCHpOH
£. <_, C-, -SO ₂ CH ₂ CH ₂ OH H 12.5 100 Vio (5/10) 0/10 -SO ₂ CH ₂ CH ₂ OH H 6.25 12.5 Vio (8/10) 0/10 in brackets refer to ^ ⁰ ^ as the hydrochloride salt
tested for oral administration -SO ₂ CH ₂ CH ₂ OH H 0.781 12.5 Vio (0/10) 0/10 2 NHCh ₂ CHOHCH ₂ OH -SO ₂ CH ₂ CH ₂ OH H 6.25 200 Vio (7/10) 0/10 JJ NHBu -SO ₂ CH ₂ CH ₂ OH H 1.562 25th 0/10 (Vio) Vio -3 NHCH ₂ CHOHCh ₃ -SO ₂ CH ₂ CH ₂ OH H 12.5 100 0/10 (1/10) 2/10 II NHCH ₂ 0 -SO ₂ CH ₂ CH ₂ OH H 0.781 200 2/10 (2/10) 2/10 ^ NHCHEKH ₂ OH -SO ₂ CH ₂ CH ₂ OH H 3.125 200 0/10 (8/10) 1/10 »° NH (CH ₂ ) ^ -SO ₂ CH ₂ CH ₂ OH H 3.125 > 200 1/10 (1/10) 2/10 NHMe -SCH ₂ CH ₂ CH ₂ OH H 1.562 12.5 0/10 (1/10) 2/10 NHMe -SO ₂ CH ₂ CH ₂ CH ₂ OH H 3.125 12.5 9/10 (3/10) 7/10 NHCH ₃ -SCH ₂ CO ₂ Et H 12.5 12.5 0/10 (0/10) 3/10 NHCH ₃ -SO ₂ CH ₂ CH ₂ OAc H <O, 391 3.125 9/10 (7/10) 8/10 NHCH ₂ CH ₂ OH -S (CH ₂ ) ₃ OAc H 6.25 100 1/10 (3/10) 5/10 NHCH ₅ ^ -SO ₂ (CH ₂ ) ■ $ (. CH ₃ ) ₂ H 5.125 6.25 10/10 10/10 ^(a) sc = subcutaneous ^(b) (P0) = Values
themselves

R. -YR ₁ X IN YITRO E.
coli IN YIYO Cb) HS NHCHgCH ₅ -SOg (CHg) ₅ N (CH ₅ ) 2 MIG (mcs / ml) 12.5 survivor SG (PO) 25 ms /] NHCH ₂ GHgSCHgGH ₅ . GHgSOgCHgGHgOH Strep.
pyogenes 100 50 mg / kg E.
coli NHGH ₀ CHGh ₀ OCH-,
d, d 0 GHgSOgCHgCHgOH H 1.562 25th Strep,
■ pyogenes 10/10 CH ₅
NHCHgGH ₅ GHgSOgCH ₂ GH ₂ GH ₂ OH H 1.562 6.25 10/10 (10/10) 5/10 NHGHgCH ₅ CH ₂ SCH ₂ GH ₂ CH ₂ OAc H 0.781 25th 1/10 (0/10) 1/10 NHCHgGHgGH ₅ CH ₂ SO ₂ CH ₂ CH ₂ GH ₂ OAc H < 0.39 200 8/10 (1/10) 1/10 (JI
ro NHCHgCHgOCH ₅ CH ₂ SO ₂ CH ₂ CH ₂ CHgOAc H 3.125 100 8/10 (2/10) 0/10 CD
cn NHCHgCHgOH -SOg (CHgMGH ₅ ) g H 50 50 1/10 (2/10) ' - 0/10 «Η
CD NHGHpCHpOCH, -SO ₂ (OH ₂ ), N (OH,) ρ H 12.5 50 5/10 (o / io) 1/10 co
CXJ ddy
NHg -SOp (CHp) .N (GH.) Ρ H 50 25th 2/10 (1/10) 0/10 ^ ⁰ 'As a hydrochloride salt
tested N (CHO ρ H 1.562 3.125 6/10 (0/10) 1/10 NHCHgGHgCH ₅ -S0 ₂ (0Hp) ₅ N (CH.) ₂ H 1.562 25th 10/10 (5/10) 5/10 NH (GHg) ₅ CH ₅ -S0 ₂ (CH ₂ ) ₅ N (CH ₅ ) ₂ H 3.125 25th 10/10 (2/10) 10/10 C?
■ fc. Λ N (CH ₅ ) g ^(c) -SO ₂ (CH ₂ ) ₅ N (GH ₂ CH ₅ ) ₂ H 25th 25th 10/10 (6/10) 2/10 IN/ NHg ^(c) -SOg (GHg) ₅ N (GHgGH ₅ ) g H 25th 6.25 10/10 (8/10) 5/10 NHCH-,
3 -S0 ₂ (CH ₂ ) ₅ N (CHgGH ₅ ) g H 6.25 25th 10/10 (8/10) 0/10 ^(a) SC = subcutaneous ^ ¹¹ PO) = values
themselves H 3.125 Refer to brackets
oral administration 6/10 (1/10) 8/10 H 12.5 9/10 (5/10) 4/10 in
on 8/10 (0/10)

-YE ₁ \ " , 1
Z?
Z?
y X IN VITRO IN VIVO (8/10)
(7/10)
(1/10) CPO) 252054E Z? H
H MIC (mcf Ca;
survivor SC (6/10) yf
-SOp (CHp) _x N
\ ( H Strep.
pyoKenes E.
coli 50 jhk / 1 As a hydrochloride salt
tested Έ -SOg (CHg) ₃ N ^/ H LfN
O CM
LfN H O Ω
IA LfN 25 mg / kg NHCH-, ^ ⁰ ^
NHCHgCH ^ QO CC * XX ^ Tn
2 2 3 \ _
-SOg (CHg) _x N H
H 3.125 6.25 Strep.
pyogenes E.
coli NHCH _x
3 -SO ₂ (CHg) ₃ N
-SO ₂ (CHg) ₅ N
-SO ₂ (CHg) ₃ N MMM 6.25 12.5 - 2/10 cn
ο NHp
to -SO ₂ (CHg) ₃ N H 3.125
12.5 6.25
50 - 8/10 OO
-J 32
Il NHCH ₀ CH- / ⁰ ^ = subcutaneous ) = Verte
aich LfN
CM LfN LA
H OJ OJ IA LA LfN
OJ OJ OJ - 5/10 NHCH ₀ CH _x
2 5
NHCH _x
3
N (CH _x ) g 12.5 12.5 - 8/10
6/10 NHg 10/10
10/10
0/10 6/10
0/10
2/10 10/10 2/10 Cc '
in brackets refer to ^v '
on oral administration

(c)

X IN YITRO IN YIYO 25 mg / kg H MIC (moPi / ml) E.
coli Strep. E.
p; yo genes co II Ca; Cb; ■
survivor SC (PO) Vio -YR ₁ 50 100 50 ΐϊΐκ / ks -SO ₂ (CH ₂ ) ₃ Er] Strep.
p; yo genes -ri "

ο NHCH-co :

«> ITHCH ₀ CH ₀ OCH-,« o 2 2

ITHCH ₀ CH-

-SO ₂ (CH ₂ ),

-SO ₀ (CH ₀ )

C. CL

-SO ₀ (CH ₀ ).

50

6.25

25th

10/10 (2/10)

1.562 50

2/10

6.25 10/10 (7/10) 10/10

6.25 6.25 10/10 (Vio) 10/10

10/10 (10/10) 2/10

3.125 12.5 10/10 (9/10) 6/10

3.125 '3.125 10/10 (10/10) 9/10

Ca)

SC = subcutaneous

Cb) (PO) = refer to values in brackets

focus on oral administration

(ο)

Tested as a hydrochloride salt

NHCH-

NH.

CH ₂ SO ₂ (CH ₂ ) ₄ N

in VITRO

MIC

-YH ₂ X Strep. Ξ.
coli CH ₂₃ O ₂ CCH ₂ ) ^ Q H 6.25 12.5 CH ₀ SO ₀ (Ch ₀ ) JPX
έ dd Hi y H 6.25 12.5

12.5 25

6.25 12.5

in VIVO survivors (a) (bj
-SC (PO) 50 ng / kR Salmonella choleraesuis

10/10 (7/10)

8/10 (1/10)

9/10 (0/10)

(7/10)

(a)

SC = subcutaneous ^ (PO) = refer to values in brackets

focus on oral administration

The following examples illustrate the preparation of typical compounds of the invention. The Roman numerals correspond the relevant information in Tables A and B * above

example 1

Salt formation (II

III)

, CONHCH ₃

(CH ₃ ) ₃ Br "

A mixture of bromomethyl-II, methylehinoxaline-2-carboxamide-1,4-dioxide (20.0 g, 0.064 mol) and Ν, Ν-dimethylformamide (DMP) (200 ml) was stirred at room temperature and trimethyl gas was added for a blown in for half an hour. The exothermic reaction mixture was stirred for an additional hour and the product was isolated by filtration to give 20.4 g (86 # yield); i ¹ . 195-196 ⁰ c.

Salage atitution (III Example 2

IV)

CONHCH,

H ₂ N ⁺ (CH ₃ ) ₃ Br "

CONHCH ₃

CH ₂ SCH ₂ CH ₂ OH

2-mercaptoethanol (0.84 g, 0.011 mole) became a two phase system Clay sodium hydroxide (520 mg, 0.013 mol) in 20 ml of water and 20 ml of chloroform was added with stirring. To this mixture the trimethylammonium salt (2.0 g, 0.005 mol) was added in small portions. After 20 minutes the layers were separated

5098 4 7/1162

and fresh chloroform was added to the aqueous reaction mixture. The operation was repeated after 30 minutes. Me chloroform layers were then combined and evaporated to dryness. The solid was triturated with 30 ml of hexane and then isolated, and it was obtained 0.83 g (50 # yield) of melting at 160-164 ⁰ C product. The solid substance was recrystallized from hot ether-chloroform, and 0.56 g (35 # yield) was obtained? F. 164-165 ⁰ C.

Example 3 Substitution (II

IV)

ONHCH-

T ^T ₂ SCH ₂ CH ₂ OH

The bromomethylamide (200g, 0.64 mol) was added to 2 liters of chloroform in a five-liter, three-necked, round bottom flask equipped with a mechanical stirrer, addition funnel and thermometer. To the resulting slurry, 2-mercaptoethanol (54 g, 0.70 mol) was added, followed by the dropwise addition of triethylamine (77.8 g, 0.77 mol) in 100 ml of chloroform over 30 minutes. The temperature of the reaction mixture with exothermic heat of reaction rose from 24 to 4O ⁰ C. After drilling of the reaction mixture for 2 hours at ambient temperature was according to analysis by Dünnsehiehtchromatographie no more starting material present. The mixture was cooled to 15 ⁰ C, and the solid substance was isolated by suction filtration and with two 200 ml portions of ether. The solid substance was recrystallized from 1 l of hot water and yielded 119 g (61% Auebeut) yellow needles; Ϊ. 170-171 ⁰ C.

509847/1 162

Example 4

Oxidation of sulfide to sulfoxide (IY- »Y)

CONHCH.

A solution of 9 »4 g (0.0465 mol) of m-chloroperbenzoic acid in 75 ml of chloroform was added dropwise to a solution of 14.4 g (0.0465 mol) of the ester sulfide in 1100 ml of chloroform. After 1 hour, the reaction mixture was added added dropwise to 1.1 l of diethyl ether and precipitated a yellow solid substance. xile solid substance was isolated by filtration and washed well with 50 ml of diethyl ether and 100 ml of hexane and dried.

Example 5 Oxidation of sulfide to sulfon (IY

YI)

H ", 9CF-CH ^ O
2? .

To a slurry of 76 g (0.245 mol) of the amide sulfide in 8900 ml of chloroform was added in small portions 109 g (0.539 mol) of 85% m-chloroperbenzoic acid. The temperature of the exothermic reaction mixture increases from 26 to 52 ⁰ C, and the entire solid substance went into solution. The solution was stirred for one hour and then cooled to 18-20 ⁰ C. A yellow solid substance precipitated and was isolated by suction filtration, washed well with 1.5 l of diethyl ether and dried, giving 75 g (90% yield); F. 188-190 ⁰ C.

50984 7/1162

Bromination (YII

- 27 Example 6

VIII)

GO ₂ CH ₅

«CO ₂ CH ₅

CH ₂ Br

To a thick slurry of 300 g (1.28 mol) of the ester in 473 ml of DMF, 64 ml (1.23 mol) of bromine were added with stirring over the course of 2 hours. The reaction mixture was then stirred for 3 days at room temperature. 30 l of biswater were added to the reaction mixture, and the product was extracted into 1 l of chloroform. The chloroform layer was dried and concentrated to a thick oil, and the oil was poured into 3 liters of diethyl ether. The solid substance obtained was isolated by filtration and dried to give 282 g (70 # yield)? F. 122-124 ⁰ C.

Substitution VIII

Example 7 (a) IX) - Option 1

HSCH ₂ CH ₂ OH

A solution of triethylamine (32 g, 0.32 mol) in 300 ml of chloroform was added dropwise to a solution of bromomethyl ester (100 g, 0.32 mol) and 2-mercaptoethanol (25 g, 0.32 mol) in 1 liter of chloroform given. The reaction temperature rose to 48 ⁰ C, and after one hour no more starting material was available.

5098A7 / 1162

act as determined by thin layer chromatography. The reaction mixture was then washed twice with 300 ml of water, once with 300 ml of 5 # NaHCO, solution and then twice with 200 ml Water washed. The chloroform solution was then added over sodium sulfate dried and evaporated to an oil, 90 g (9O # ige Yield). This material was used for without further purification the aminolysis reaction (Examples 10 (a) and 10 (b) was used.

Substitution (YIII

Example 7 (b)

IX) - option 2

H ₂ SCH ₂ CH ₂ OH

To a solution of 21.7 g (0.06 mol) of the bromomethyl ester in 250 ml of chloroform, first 6.7 ml (0.09 mol) of 2-mereaptoethanol and secondly 11.6 g (0.09 mol) of diisopropylethylamine were added. After 1.5 hours, the reaction mixture was washed three times with 200 ml of 5% sodium bicarbonate solution and twice with 200 ml of water. The chloroform layer was then dried over anhydrous sodium sulfate and evaporated to a solid substance. After trituration with 300 ml of hexane 20 g (97 # yield) were obtained of a melting at 122-124 ⁰ C solid.

Example 8 (a)

Oxidation of sulfide to sulfon (IX XII) - option 1

T f ^ tl Λ T

O ₀ Me

CH ₂ SO ₂ CH ₂ CH ₂ OH

509847/1162

To a solution of 50 g (0.16 mol) of the ester sulfide in 1 1 Chloroform was added in small portions to 50 g (0.29 mol) of 85 # m-chloroperbenzoic acid. After the Addition and cooling of the chloroform solution to room temperature, the reaction mixture was diluted with diethyl ether up to 1 l, whereby a yellow oil parted. The solvent was decanted off and the oil was crystallized from 250 ml of hot methanol, yielding 25.5 g (47 # yield); Ϊ. 129-151 ° 0.

Example 8 (b) Oxidation of sulfide to sulfon (IX - * XII) - option 2

A solution of ester sulfide (26 g, 0.067 mol) in 2N sulfuric acid (170 ml) and acetone (150 ml) was ^{cooled to 0} ° C. with an ice bath. An aqueous solution of potassium permanganate (22 g in 500 ml of water) was added to the heating mixture over 4-5 minutes while maintaining the temperature at 5 ° C. 5 minutes after the addition was complete, the mixture was decolorized with 30 # hydrogen peroxide; the pH was kept below 4 by adding more 2 normal sulfuric acid. The reaction mixture was extracted with chloroform (2 × 200 ml) and the chloroform extract was discarded. The reaction mixture, to which 600 ml of chloroform had been added, was carefully made slightly basic with solid sodium bicarbonate. The chloroform layer was separated off and the aqueous phase was extracted with further chloroform (2 × 150 ml). The combined chloroform extracts were dried over water-free magnesium sulfate and evaporated in vacuo, leaving a yellow oil back.

509847/1162 & φ ORIGINAL

remained (16.0 g, 56% yield). This material was without further purification used.

Example 9 Oxidation of sulphide to sulphoxide (IX

XI)

, .CO ₂ Me

A solution of 9.4 g (0.0465 mol) of m-chloroperbenzoic acid in 75 ml of chloroform was added dropwise to a solution of 13.8 g (0.0465 mol) of the ester sulfide in 100 ml of chloroform. To The reaction mixture was added dropwise to 1.1 diethyl ether for 1 hour given. A yellow solid substance precipitated out. The solid substance was isolated by filtration and washed with 50 ml Diethyl ether and 100 ml of hexane washed well and dried.

Example 10 (a) Amidation of sulfide (IX - »X)

ο ο

^ S ^ ^N S] NJ ^ ^c- '^ C ^ Ci O TJt

-ί-Ο

\\ ^T / CH ₂ -S-CH ₂ CH ₂ OH

1.0 g (0.003 mol) of dea ester sulfide were dissolved in 20 ml of a 4.1 molar solution of ethylamine in methanol. The solution was warmed gently on the steam bath for 10 minutes and then allowed to stand at room temperature for 3 hours. The fluffy yellow solid substance precipitated from the reaction chemical was isolated by filtration and gave 0.64 g (oO ^ ige yield)? melting at 184-186 ⁰ C.

509847/1162

BAD ORlGiNAL

- 31 Example 10 (b)

Amidation of sulfide (IX - »X)

r>

/ 1 V-

To a solution of 1.0 g (0.003 mol) of the ester sulfide in 20 ml 3.0 g (0.051 mol) of propylamine were added to acetonitrile, and the resulting solution was stirred at the edge temperature for 20 hours. The reaction mixture was then poured into 300 ml of diethyl ether. A yellow solid substance was obtained by decanting off the ether and trituration with an acetone-ether mixture (4: 1) isolated. The resulting slurry was filtered to give 0.35 g (30 # ige Yield); M.p.-181 ° C.

Example 11 Amidation of sulfoxide (XI - ■ * XIII)

• »N.

A solution of 1.0 g (3.2 used oil) of the ester sulfoxide and 3.0 g (large excess) of 3-diethylamino-n-propylamine in 20 ml Acetonitrile was left to stand at room temperature for 24 hours. The solution was then evaporated to dryness and the obtained

509847/1162

& AD ORIGINAL

solid substance was recrystallized from acetone to give the desired product.

Example 12 Amidation of sulfone (XII - ■ »XIY)

3.0 g (0.040 mol) of 2-methoxyethylamine were added to a solution of 1.0 g (0.003 mol) of the ester sulfone in 20 ml of acetonitrile. The solution was stirred at room temperature for 20 hours and then poured into 200 ml of diethyl ether. The yellow precipitate obtained was isolated and washed well with diethyl ether and gave 0.95 g (86% yield)} F. ⁰

Example 13

Compounds of the following formulas were made according to the given Methods made:

Method _n

R (table A or B) melting point. C.

NHMe NHCH ₂ CH ₂ OH

NHPr NHCH ₂ CH ₂ CH ₂ OH

NHEt NHBu

II - * IY 173-175 IX - » X 186-187 IX - * X 180-181 IX - * X 169-171 IX -> X 184-186 IX - * X 155-157 3 β Π / 1 1 R 9 BATH ORIGINAL

Example 14-

Compounds of the following formulas were made according to the given Methods made:

CfV?

-T ¹ '^'} ^ Cl ₀ CV ^ 0Il

_H NHMe X_ method
(Table A or B) VI Melting point * C NH (CH ^) ₅ N (Et) ₂ H IV - * XIV 188-190 NHCHpCH ₉ H (Me) ρ H XII - » XIV 182-185 H XII - » XIV 188-190 NHBt ,, Cl XII - * XIV Iö5 NHCH ₂ CHgOH H XII -> XIV 174-176 NHPr H XII -> XIV 198-199 NHCHpCHpCHpOH H XII - » XIV 207-208 NH ₂ H XII - # XIV 192-193 NHCHgCHgOMe H XII - > XIV 223-225 NHCHgCHOHCHgOH
NHBu H XII - » XIV
XIV 164-165 OH
ι H
H XII ->
XII - * ■ 179-181
156-157 NHCHgCHCH ₃ XIV NHCHg0 H XII - » XIV 197-199 Bt H XII - * 187-189 NH-CHCHgOH XIV NH (CHg) ₄ 0 H XII - ^ XIV 159-161 NHCHgCHgSEt H XII - * XIV 150-152 CHgOMe H XII - * 115-117 NHCH ₂ CHCH ₃ XIV H XII - ^ 149-150

509847/1162

BATH ORIGINAL

example

The following connection was made using the method given:

Method (table TO melting point _r Q

NHMe. IX -> X 191

Example 16

Compounds of the following formulas were prepared according to the method given:

\ - tt rT, r ,,? _r ~, ^ ~

R. Method (Table B) Melting point, ⁰ C

NHMe XII -> XIV 196-197

NHEt XII - »XIV 166-168

XII - ^ XIV 178-180

Example 17

Compounds of the following formulas were prepared according to the methods given:

H method (Table A or B) Melting point, ⁰ C

NHMe II - 176-177 NHPr IX - 189-190 NHBu IX - 188-190 > IV > X * X

5 0 9 8 4 7/1162 B ^

Example 18

The following connection was made according to the method given manufactured"

Method (! Table A) Melting point, C.

NHMe III - * IV 147-148

Example 19

The following connection was made using the method given:

H method (! Table B) Melting point, ⁰ C

NHMe IV - * VI 178-179

Example 20

Compounds of the following formulas were prepared according to the specified Method made:

BATH ORIGINAL

509847/1162

R. - 36 -
Method ( Table B) Melting point, NHCH ₂ CH ₂ OH IX -4 ► X 153-155 NHBt IX -J ¹ X 190-192 example 21

Compounds of the following formulas were prepared according to the specified Method made:

NHPr NHBu NHCH ₂ CH ₂ OMe

Method (Table B) XII - * XIV

XII - * XIV XII - * XIV

Melting point «C 159-161 146-148 117-119

Example 22

The following connections were made according to the specified methods! . ·>

NHMe.HCl

NHCH ₂ CH ₅ NHCH ₂ CH ₂ OH NHCH ₂ CH ₂ OCH ₅ NH _n

NHCH ₂ CH CH

XIV XIV

Method (Table A or B) Melting point, C.

218-220 145-147 169-171 122-124 178-182 170-173 130-133 129-131

IV -> VI

XII - * XIV XII ->
XII - *

XII - »XIV

XII -f XIV

XII -> XIV

XII -> XIV

50984 7/1162

- 37 Example 23

manufactured:

N (CJj NH ₂ -HCl

.HGl

bindings were after the given meth O
] / Ij * (CH ₂ CH ₃ ) ₂ method B) Melting point, ⁰ C XII - 90-97 XII - 90-120 XII - 158-163 example 2OR 3H ₂ SO ₂ CH ₂ , (Tabel - XIV - XIV - XIV . 24

The following connections were made according to the method given:

I Xm ₂ SO ₂ CH ₂ CH ₂ CH ₂ CH ₂ N (CH ₃ )

R. method (Tabel B) melting point. "C 158-161 / NHCH ₅ -HCl XII - - XIV 110-112 H ₂ SO ₂ CH ₂ CH ₂ CH ₂ Nf NHCH ₂ CH ₅ -HCl XII - - XIV example 25th the specified method The following Connections were made after manufactured: OR O Ψ C
0

509847/1162

NHCH

NHCH ₂ GH ₅ .HCl

- 38 method (table B)

XII -> XIV

XII - * XIV

"XII - * XIV

XII - »XIV

Melting point, C.

173-175

179-180

163-167

70-110

example

The following connections were made according to the method given:

NHCH ₂ CH ₅
NHCH ₅

N (CH ₅ ) ₂

H ₇ SO ₇ CH ₂ CH ₂ CH ₂

Method (Table B) XII -f XIV XII - »XIV XII - ^ XIV XII -> XIV

Melting point, 178-181 144-146 140-143 178-181

example

The following compounds were made according to the method indicated manufactured:

H ₂ SO ₂ CH ₂ CH ₂ CH ₂

NHCH ₂ CH ₂ OH
NHCH,

Method (Table B) XII- * XIV

XII -> XIV

NHCH ₂ CH ₂ OCH ₅

NHCH ₂ CH ₅

N (CH ₅ ) ₂

NHCH ₂ CH ₂ N (CH ₅ ) 2.HC1

XII XII XII XII XII

XIV
XIV
XIV
XIV
XIV

Melting point, 140-142

162-165 174-176 128-130 139-142 169-171 100-110

5 09847/1162

Example 28

The following connections were made according to the method given manufactured:

O CH ₂ SO ₂ CH ₂ CH ₂ CH ₂ Ch ₂ N (Table B) Melting point, ° C method ■ »XIV 135-138 NHCH, XII - ■ * XIV 137-139 XII - - ^ XIV 172-176 NH ₂ XII - * XIV 145-149 NHCH CH XII - 29 example

The compounds listed below were selected according to the appropriate methods described and explained above.

O O

C -

CH-SR ₁

X 4-
O
1 H ₅ 7-OCH ₅ CH ₂ CONH ₂
(CH ₂ ) ₂ CONH (CH ₅ )
CH ₂ CON (CH ₅ ) ₂ CH ₂ NH ₂
CH ₂ NH (CH ₅ )
CH ₂ N (C ₂ H ₅ ) ₂ 7-SCH ₅ CH ₂ Cl CH ₂ -NCH ₂ CH ₂ CH ₂ Clh ₂ 7-SOCH ₅ (CH ₂ ) ₂ P CH ₂ - ^ CH ₂ CH ₂ CH ₂ OH ₂ Oh ₂ 7-SO ₂ CH ₅ CH ₂ SH (CHn) p— «CHoCHpOCHoüxlo H CH ₂ SO ₅ H CHp-ή CHpCHpN ν CH ^ t / GHpCHp H CH ₂ SCH ₅ CH ₂ -iNCH ₂ CH ₂ N (CH ₂ OH) CfHgCH ₂

509BA7 / 1 162

E ₁

40 - H,

7-Cl 7-Br

H H 7-Cl

CH ₂ SOCH ₅ COC ₄ H ₉ ) CH ₂ CiHg

-lNCHgCHgCHgCHgtfHg

CH ₂ -INCHgCHgOCHgOHg

CHg- ¹ NCHgCHgCH ₂ CiHg (CH ₂ ) ₅ -INCH ₂ CH ₂ N (COOC ₅ H ₇ ) CH ₂ CfH ₂ CH ₂ -NCH = CHCH = CIh (CH ₀ )

6-CH ₅ (CH ₂ ) g-lNCHgCHgSCHgdHg CHg-INCHgCHgNHCHgCHg CH ₂ - * NCHgCH ₂ N (CH ₅ ) CHgClH, CH ₂ -IiCH = IiCH = CH CH ₂ CH (CH ₅ ) CHgOH CH ₂ OC ₅ H ₇ CHgCOOH

(CHg) ₂ -INCHgCH ₂ N (CHgOH) CH ₂ CH ₂ CHgCOOCH, CH ₂ -iNCH ₂ CHgN (COCH ₅ ) CHgCiHg

CHgCONHg

7-SCH ₅ (CHg) ₄ -INCH ₂ CH ₂ N (COOC ₂ H ₅ ) CHgC! ^ CH ₂ CONH (CH ₅ )

CH ₂ OH

GH ₂ OC ₂ H ₅

(CH ₂ ) ₂ NH ₂

CH ₂ OH GHpSC pHj-OH ₂ CON (C ₂ H ₅ ) J CH ₉ OCCH,

CH ₉ (NH) CC ₉ Hp-

The corresponding compounds of the formula

/ CH.

and the formula

H ₂ -SO-R ₁

509847/1162

- 41 were made in the same way.

The compounds of the formula

were made in the same way:

A XL-)

CH ₂ OH -> NCH = CHCH = ClH H CH ₂ SO ₅ H nJ / HTT / * ITT ΛΤΪ / * BTT
*** m wXX ^^ W XX W ΧΙ J ₁ v / XX 6-Cl CH ₂ Cl
GHpSGH-z -! NCH ₂ CH ₂ CHgCH ₂ CiH ₂ 7-Br (CHg) ₂ OH ^ NCH ₂ CH ₂ OCH ₂ CiH ₂ H CHgCONHg -UCH ₂ CH ₂ SCH ₂ CfH ₂ 6-CP ₅ (CHg) 5CON (CH ₅ ) g -UCH ₂ CH ₂ CHCH ₂ CJh ₂ 7-SO ₂ CH ₅ CH ₂ OH -4fCH ₂ CH ₂ N (CH ₅ ) CHgCHg H CH ₂ OCgH ₅ -UCHgCH ₂ N (CHgOH) CH ₂ CH ₂ H CH ₂ 0t-C, H ₉ -INCH ₂ CH ₂ N (COCH ₅ ) CH ₂ CK ₂ H -NCH ₂ GH ₂ N (COOC ₂ H ₅ ) CHgCfHg 7-P

The analogous sulfoxide and sulfone compounds of the above compounds were prepared using the procedures outlined above manufactured.

Example 30

The acid addition salts of the compounds of the invention having a basic group were obtained by dissolving the appropriate 3-substituted quinoxaline-a-carboxamide-l ^ -dioxide (0.01 mol) in ethanol and then adding a stoichiometric amount of the chosen acid. The solution obtained was at Haum-

509847/1162

temperature stirred for 30 minutes, and the acid salt could through. Evaporation of the solvent or isolation by precipitation with a non-solvent such as ether. In this way the acid addition salts of sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, .butyric acid, citric acid, uluconic acid, benzoic acid, pamoic acid, amsonic acid, Tartaric acid, 3-hydroxy-2-naphthoic acid and sulfosalylic acid manufactured.

Claims

509847/1 162

Claims (11)

Patent address (ly compound of formula I wherein X is a substituent in 6- or 7-position, which consists of hydrogen, halogen, lower alkoxy, trifluoromethyl, methyl, lower alkyl sulfide, lower alkyl sulfoxide or lower alkyl sulfone, Y is S, SO or SO ₂ , R-. lower alkyl that is hydroxy, lower alkoxy, amino, mono (lower alkyl) amino, di (lower alkyl) amino, lower alkoxycarbonyl, carbamyl, mono (lower alkyl) carbamyl, di (lower alkyl) carbamyl, halogen, mercapto, SuIfο, lower alkyl sulfide, lower alkyl sulfoxide, lower alkyl sulfone, acetoxy, pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino, N- (lower alkyl) piperazino, N-hydroxy (lower alkyl) piperazino, !! - (lower alkanoyl) piperazino or N -Carbo (lower alkoxy) piperazino is substituted, Ä2 » ^{when ea is} separate, is hydrogen or lower alkyl, R ^, when it is separate, is hydrogen, phenyl, lower alkyl or substituted lower alkyl, in which the substituent is amino, mono ( lower alkyl) amino, di- (lower alkyl) amino, pyrrolidino, piperidino, morpholino, 5 0 9 8 4 7/1162 N- (lower alkyl) piperazino, di ~ hydroxy (lower alkyl) piperazino, N- (lower alkanoyl) piperazino, N-Carbo (lower alkoxy) piperazino, pyrrolo, piperazino, imidazolino, hydroxy, lower alkoxy, thi (lower alkyl) , Carboxy, garbo (lower alkoxy), garbamyl, mono (lower alkyl) carbamyl, di (lower alkyl) carbamyl, lower alkanoyloxy or lower alkanoylamino and S ₂ ^ ³¹⁰ % together with the nitrogen atom to which they are attached is a pyrrolo -, pyrrolidino, piperidino, morpholino, thiomorpholine, piperazino, !! - (lower alkydpiperazino-, N-hydroxy (lower alkyl) piperazino-, !! - (lower alkanoyl) piperazino- or N-carbo (lower alkoxy) piperazino group, and the pharmaceutically suitable acid addition salts of these compounds in which at least one of the groups R ₁ and IU is substituted lower alkyl in which the substituent is a basic group. 2. A compound according to claim 1, characterized in that X is hydrogen, Ϊ is S, SO or SO ₂ , R _{2 is} lower alkyl which is substituted by hydroxy, and R ₂ and R _{5 are} each hydrogen or lower alkyl. 3. A compound according to claim 2, characterized in that R _{2 is} hydrogen and R ^ is methyl. 4. A compound according to claim 3, characterized in that Y is SO ₂ and R _{1 is} hydroxyethyl. 5. A compound according to claim 3, characterized in that Y is S and R _{1 is} hydroxyethyl. 6. A compound according to claim 1, characterized in that X is hydrogen, Y is S, SO or SO ₂ , R _{1 is} lower alkyl substituted with di (lower alkyl) amino, R _{2 is} hydrogen or lower alkyl and R ₅ Is hydrogen, lower alkyl, or substituted lower alkyl substituted with! »! (Lower alkyl) amino, hydroxy or lower alkoxy. 509847/1 162 7. ■ A compound according to claim 6, characterized in that Y is SO ₂ , E _{1 is} 3-dimethylaminopropyl, R _{2 is} hydrogen and E _{5 is} methyl. 8. A compound according to claim 6, characterized in that Y is SO ₂ , E _{1 is} 3-dimethylaminopropyl, R _{2 is} hydrogen and R _{5 is} ethyl. A compound according to claim 1, characterized in that Y is SO ₂ , E _{1 is} 3-pyrrolidinopropyl, E _{2 is} hydrogen, E _{5 is} methyl and X is hydrogen. 10. A compound according to claim 1, characterized in that Y is SO ₂ , R _{1 is} 3-piperidinopropyl, R _{2 is} hydrogen, R 1 is methyl and X is hydrogen. 11. Process for the preparation of a compound of the formula I as defined in claim 1, characterized in that that one is a compound of the formula '0 ^y - I is ⁺ (CH-Z) 3r, 2 is -F ² , wherein V is Cl, Br N ¹ CCH ₅ ) ₅ C1 or NHCH ₅ ^ Br, 2 - _5th in which R ₂ and E _{5 have} the meaning given above, or V is Cl ~~ or Br- when Z is -0-lower alkyl, and X has the meaning given above,
with a compound of the formula R ₁ -SH wherein R _{1 has} the meaning given above, reacts in the presence of aqueous sodium or potassium hydroxide and, if necessary, in any order
(i) the compound so formed wherein Z is -O-lower alkyl 509847/1162 ist.and X and R-, the meanings given above, with a Compound of formula implements »and / or (ii) the compound thus formed is reacted with a suitable oxidizing agent to form a compound of the formula I ¹ , in which X is —SO— or —SO ₂ and X, R ₁ , R ₂ and R, have the meanings given above, and optionally forms the pharmaceutically acceptable acid addition salts of these compounds in which at least one of the groups R 1 and R 1 is substituted lower alkyl in which the substituent is a basic group. Cl / La 509847/1162