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Publication numberUS3666754 A
Publication typeGrant
Publication dateMay 30, 1972
Filing dateJul 9, 1970
Priority dateNov 6, 1965
Publication numberUS 3666754 A, US 3666754A, US-A-3666754, US3666754 A, US3666754A
InventorsJun-Ichi Matsumoto, Shinsaku Minami, Masanao Shimizu, Yoshiyuki Takase
Original AssigneeDainippon Pharmaceutical Co
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
2-(5-nitrofuryl) nitrone derivatives
US 3666754 A
Abstract
Nitrone derivatives having antimicrobial activity comprising compounds having the formula:
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Description  (OCR text may contain errors)

United States Patent Minarni et al.

[54] Z-(S-NITROFURYL) NITRONE DERIVATIVES [72] Inventors: Shinsaku Minami, Yamato-Kouriyama; Jun-Ichi Matsumoto, Osaka; Masanao Shimizu, Kobe; Yoshiyuki Takase, Amagasaki, all of Japan [73] Assignee: Dainippon Pharmaceutical Co., Ltd.,

Osaka, Japan [22] Filed: July 9, 1970 [21] Appl. No.: 53,635

Related US. Application Data [60] Continuation-in-part of Ser. No. 746,749, July 23, 1968, which is a division of Ser. No. 592,265, Nov. 7, 1966, abandoned.

[30] Foreign Application Priority Data Nov. 6, 1965 Japan ..40/68l96 July 27, 1967 Japan... ..42/48362 Dec. 23, 1969 Japan... ..44/103620 Dec. 23, 1969 Japan... ..44/l0362l Aug. 1, 1969 Japan ..44/61208 July 30, 1969 Japan ..44/6022() [52] US. Cl ..260/240, 260/347.2, 260/347.4, 424/285 [51] Int. Cl. ..C07d 5/30 [58] Field of Search ..260/240, 347.2, 347.4

[5 6] References Cited UNITED STATES PATENTS 3,528,971 9/1970 Bambury et al ..260/347.7

[451 May 30, 1970 [57] ABSTRACT Nitrone derivatives having antimicrobial activity comprising compounds having the formula:

wherein R, represents a member selected from the group consisting of hydrogen, halogen, furyl and phenyl substituents; R represents a member selected from the group consisting of hydrogen, an alkyl having from about one to about four carbon atoms and phenyl; R represents a member of the group consisting of phenyl and A(X),., A(Y),,, and A(Z),, in which A represents an alkyl radical having from about one to about six carbon atoms; X represents a member selected from the group consisting of hydrogen, hydroxyl. furyl, alkyl-sulfonyloxy having an alkyl group of from about one to about four carbon atoms and alkanoyl having an alkyl group of from about one to about three carbon atoms; Y represents a member selected from the group consisting of an arylsulfonyloxy radical, an alkyl-sulfonyloxy radical having from about one to about four carbon atoms, an aroyloxy radical, an alkoxycarbonyloxy radical having an alkyl group of from about one to about four carbon atoms and a carboxyalkanoyloxy radical having from about three to about six carbon atoms and Z represents a member selected from the group consisting of hydrogen and hydroxy, n is an integer of from about 1 to about 3, and m is an integer of from about 0 to about i.

32 Claims, No Drawings 1 2-(5-NITROFURYL) NITRONE DERIVATIVES This application is a continuation-in-part of copending application Ser. No. 746,749, filed July 23, 1968.

The instant invention is directed to novel nitrone derivatives having excellent microbial activity. In addition, the instant invention is also directed to medicinal compositions containing novel nitrone derivatives.

Heretofore derivatives of N-substituted (5-nitro-2-furfurylidene) amine compounds have been known to possess antimicrobial activity. Such compounds, however, have been found to suffer either from untoward toxicity and/or a lack of potency which characteristics have limited their use.

Therefore, it is an object of the instant invention to provide novel compounds which have excellent antibacterial, antifungal and antiprotozoal activities.

A further object of the instant invention is to provide novel nitrone derivatives which have the foregoing characteristics.

A still further object of the instant invention is to provide novel nitrone derivatives which are useful as medicines both for human and veterinary use and further in the fields of food, agriculture, and the like.

These and other objects of the instant invention will become more evident from the following more detailed description thereof.

In particular, the instant invention relates to nitrone derivatives which may be represented by the general formula:

wherein R represents a member selected from the group consisting of hydrogen, halogen, fury] and phenyl substituents; R represents a member selected from the group consisting of hydrogen, an alkyl having from about one to about four carbon atoms and phenyl; R represents a member of the group consisting of phenyl and A (X),,, A (Y),,, and A (Z),,, in which A represents an alkyl radical having from about one to about six carbon atoms; X represents a member selected from the group consisting of hydrogen, hydroxyl, furyl, alkylsulfonyloxy having an alkyl group of from about one to four carbon atoms and alkanoyl having an alkyl group of from about one to about three carbon atoms; Y represents a member selected from the group consisting of an arylsulfonyloxy radical, an alkylsulfonyloxy radical having from about one to about four carbon atoms, an aroyloxy radical, an alkoxycarbonyloxy radical having an alkyl group of from about one to about four carbon atoms and a carboxyalkanoyloxy radical having from about three to about six carbon atoms and 2 represents a member selected from the group consisting of hydrogen and hydroxy, n is an integer of from about 1 to about 3, and m is an integer of from about 0 to about 1.

Exemplary of the substituents which R may represent in the above formula are the following. It is to be noted, however, that the following list is not intended to limit the scope of the instant invention but, rather as noted, is merely set forth for exemplary purposes:

methyl ethyl p py isopropyl butyl isobutyl pentyl hexyl heptyl 2-hydroxypropyl l-methyl-2-hydroxyethyl 1,3-dihydroxy-2-propyl 2-hydroxyethyl I l-dihydroxymethyl-Z-hydroxyethyl Z-furfuryl phenyl Z-methansulfonyloxy ethyl 2-acetyloxyethyl 2-benzoyloxyethyl 2-tosyloxyethyl 1, 3-bis-methaneaulfonyloxy-Z-propyl 2-ethoxycarbonyloxyethyl 2-( 2-carboxybenzoyloxy )ethyl 2-( beta-carboxypropionyloxy )ethyl and the like.

In connection with the above, the following compounds are representative of those encompassed by the above noted general formula and are set forth merely for exemplary purposes.

a-[ l-bromo-2-( 5-nitro-2-furyl )vinyl ]-N-methyl nitrone a-l l-bromo-2-( 5-nitro-2furyl )vinyl ]-N-( 2-hydroxpropyl nitrone hydroxyethyl )nitrone a-[ 1-bromo-2-(5-nitro-2-furyl)vinyl ]-N-( l ,3-dihydroxy-2- propyl )nitrone a-[ 1-bromo-2-( 5-nitro-2-furyl)vinyl]-N-( 2-hydroxyethyl) nitrone a-[ l-bromo-2-( 5-nitro-2-furyl )vinyl]-N-( 2-furfuryl) nitrone a-[ l-bromo-2-( 5-nitro-2-furyl)vinyl l-N-phenyl nitrone a-[ l-bromo-2-( 5-nitro-2-furyl )vinyl ]-N-( Z-methane-sulfonyloxyethyl )nitrone a-[ l-bromo-2-( 5-nitro-2-furyl )vinyl ]-N-( a-acetyloxyethyl )nitrone a-[ l-(2-furyl)-2-( 5-nitro-2-furyl)vinyl]-N-methyl nitrone nitrone nitrone a-[ 2-( 5-nitro-2-furyl)- l -phenylvinyl]-N-( l-methyl-2- hydroxyethyl) nitrone a-[ 2-( 5-nitro-2-furyl)- l -phenylvinyl ]-N-( 2-hydroxypropyl) nitrone a-[2-(5-nitro-2-furyl)- l-phenylvinyl1-N-methyl nitrone a-[ 2-( 5-nitro-2-furyl)- 1 -phenylvinyl ]-N-( 2-hydroxyethyl) nitrone a-[ 2-( 5-nitro-2-furyl l -phenylvinyl ]-N-( 2-furfuryl) nitrone a-[ 2-( 5-nitro-2-furyl )vinyl l-a-phenyl-N-methyl nitrone propyl )nitrone a-[ 2-( S-nitro-2-furyl)vinyl ]-N-( 2-benzoyloxyethyl nitrone a-[ (5-nitr0-2-furyl )-N-( 2-benzoyloxyethyl )nitrone a-(5-nitro-2-furyl)-N-(Z-methanesulfonyloxyethyl) nitrone a-( 5-nitro-2-furyl )-N-( 2-tosyloxyethyl )nitrone a-( 5-nitro-2-furyl )-N-( l ,3-bismethanesulfonyloxy-2- propyl )nitrone a-[ 2-( 5-nitro-2-furyl )vinyl ]-N-( 2-ethoxycarbonyloxyethyl) nitrone 'a-( 5-nitro-2-furyl )-N-[ 2-( Z-carboxybenzoyloxy )ethylln itrone a-( 5-nitr0-2-fury] )-N-[2-(a-carboxypropionyloxy )ethyl] nitrone a-methyl-a-[ 2-( 5-nitro-2-furyl )vinyl ]-N-( 2-benzoyloxyethyl )nitrone More particularly, the compounds of the instant invention may be further characterized by the following three formulas:

H II T N0r\0/ (CH CH) (]1 N R;

R1 (III) wherein R, represents a halogen, furyl or phenyl substituent; R represents a phenyl group or a grouping of the formula A (X), in which A represents an alkyl radical having from about one to about six carbon atoms, X represents a member selected from the class consisting of hydrogen, hydroxyl, fury], alkylsulfonyloxy having an alkyl group of from about one to about four carbon atoms and alkanoyl having an alkyl group of from about one to about three carbon atoms and n represents an integer of from about 1 to about 3; R represents a radical such as A (Z), in which A represents an alkyl radical having from about one to about six carbon atoms, Z represents a member selected from the group consisting of hydrogen, hydroxyl, and n is as defined above; R represents a member selected from the group consisting of hydrogen and an alkyl having from about one to about four carbon atoms; and R represents a substituent of the class A (Y), wherein A represents an alkyl radical having from about one to about six carbon atoms and Y represents a member selected from the group consisting of an arylsulfonyloxy radical, an alkylsulfonyloxy radical having from about one to about four carbon atoms, and aroyloxy radical, and alkoxycarbonyloxy radical having an alkyl group of from about one to about four carbon atoms and a carboxyalkanoyloxy radical having from about three to about six carbon atoms; and m represents an integer of from about 0 to about 1.

The compounds represented by formula (l),noted above, may be prepared by reacting a carbonyl derivative having the formula:

wherein R. is as previously defined with an N-substituted hydroxyl amine compound having the formula:

wherein R is as defined above.

A dehydrocondensation reaction follows and a 5-nitro-2-furylvinyl nitrone derivative having the formula (I) is obtained in good yields.

The reaction may be carried on at room temperature or in the alternative by heating the reaction mixture to an elevated temperature in the range of from about to about 100 C. One may employ any one of numerous solvents, however, preferred for use in connection with the preparation of compound (l) are water, methanol, ethanol, dioxane, tetrahydrofuran dimethylsulfoxide, and dimethyl forrnamide. It is noted that a catalytic amount of acetic acid may be added to the reaction system so as to create a weakly acidic condition. Such an acidic condition results in the acceleration of the condensation reaction, however, the use of the catalytic material is not required so as to produce the desired compounds. It is also noted that one may react a free hydroxyl amine or the salt thereof in the same manner so as to obtain similar results. The salt, however, should be employed in combination with enough base so as to free the hydroxyl amine from said salt. Preferably, one employs inorganic bases such as sodium hydroxide, potassium carbonate and sodium bicarbonate or organic bases such as sodium acetate, pyridine, triethylene and the like or mixtures thereof.

The subject compounds may be further reacted when R represents an alkyl group substituted by one to three hydroxyl groups with alkylsulfonic acid having from about one to four carbon atoms in alkyl group or an alkanoic acid having from about one to about three carbon atoms in the alkyl group or a with an N-substituted hydroxyl amine represented by the formula:

(VII) wherein R is defined as above. According to this process, a dehydrocondensation reaction is readily performed by mixing the compounds of formulas (VI) and (VII) in a suitable solvent therefor so as to obtain the desired 5-nitro-2-furylvinyl nitrone. The solvent system, reaction conditions, catalysts, and choice of free hydroxyl amine or salt are as noted in the preparation of the compounds having formula (I). That is to say, that one may react the individual compounds, either at room temperature or at an elevated temperature of from about 20 to about C in a solvent which may be any one of a wide variety suitable for such a reaction. Preferred, however, are water, methanol, ethanol, dioxane tetrahydrofuran, dimethylsulfoxide, dimethylformarnide and the like or mixtures thereof. Furthermore, the catalysts may be acetic acid which though it accelerates the reaction is not necessary to the completion thereof.

The compounds represented by formula (III) above may be prepared by reacting a compound having the formula:

wherein R is as previously defined and A is an alkyl radical having from about one to about six carbon atoms substituted with from about one to about three hydroxyl groups and m is as defined above, with an arylsulfonic acid, an alkyl sulfonic acid having from about one to about four carbon atoms in an alkyl group, an arylcarboxylic acid, an aliphatic dicarboxylic acid having from about three to six carbon atoms or a functional derivative of any one of the above acids, or an alkoxy carbonyl halide having from about one to about four carbon atoms in an alkyl group. ln this process, the subject nitrofuryl nitrones of formula Ill) can be obtained in high yield by reaction of the above compounds with an acid or a reactant derivative thereof either in the presence or absence of a solvent. It is also noted that one may optionally employ an accelerator (catalyst) depending upon the particular compounds involved. It is to be noted, however, that such an accelerator is not necessarily required to complete the reaction. This reaction may be successfully performed at room temperature but the cooling or heating of the reaction mixture may be effected according to the specific conditions of the particular reaction. Preferable acids or reactive derivatives for use in the esterification of the compounds of formula (Vlll) are organic acids such as benzoic acid, benzene sulfonic acid, acid halides such as benzoyl chloride, benzene sulfonyl chloride, methanesulfonyl chloride, chloroethyl formate, acid anhydrides such as benzoic anhydride, phthalic anhydride, and the like or mixtures thereof. In the event that one uses an acid halide in the above reaction, a tertiary organic base such as pyridine, dimethyl aniline. triethylamine and the like may be employed (VIII).

as an accelerator therefor. If an acid halide is employed, one may optionally employ as an accelerator pyridine, p-toluene sulfonic acid, boro and trifluoride, and the like. Furthermore, in the event that the esterification is effected with an acid it is preferred to employ trifluoro acetic anhydride as an accelerator. Such an accelerator may be employed either in an equivalent or an excessive amount relative to the amount of the compounds represented by formula (V111). It is to be noted, however, as discussed above, that such an accelerator need not be used.

As noted, a solvent may optionally be employed in connection with this reaction. It is not necessary, however, to do so when either or both of the acid or their reaction derivatives, or the accelerators are liquid in their normal state. It is to be noted that is preferred to employ a solvent which solvent may be chosen according to the specific properties and type of starting reactants. In this instance, it is noted that exemplary of such solvents are benzene, ether, dioxane, pyridine, and the like or mixtures thereof. It is to be noted that the compounds of formula (111) may also be prepared according to the process employed in connection with the compounds of formula (1) with the exception that the carbonyl derivative employed would have the formula:

The novel compounds of the present invention have been found to be particularly effective in the treatment of diseases of microbial origin. That is to say, that nitrone derivatives of the instant invention are particularly effective in the treatment of bacterial, fungal, and protozoal disease. The subject compounds have been found to be extremely potent and a relatively small dose thereof is sufficient for treatment. Furthermore, the toxicity of these nitrofuran derivatives is less than that of reviously known derivatives of the same type. The subject compounds may be utilized in the treatment of both humans and animals either topically, orally, or by injection either when compounded as a powder, ointment, liquid, or parenteral solution with a suitable carrier therefor, and conventionally employed pharmaceutical adjuvants. It is also noted that the subject compounds may be employed in a manner similar to that of other nitrofuran derivatives in the fields of foods, agricultures, and the like wherein the removal or prevention of the growth of microbial organisms is required.

The instant invention will now be illustrated by the following more detailed examples thereof. it is to be noted, however, that the instant invention is not deemed as being limited thereto.

EXAMPLE 1 Preparation of a-[l-bromo-2-(5-nitro-2-furyl)vinyl]-N- phenyl nitrone. To a solution of 2.46 grams of a-bromo-B-(S- nitro-2-furyl)acrolein and 500 ml of ethanol, 1.42 grams of phenyl hydroxylamine and 0.2 ml of glacial acetic acid were added. The reaction was effected by stirring the mixture for a period of about 2 hours at room temperature. The resulting precipitates were collected by filtration and recrystallized from acetyl nitrile to give 1.7 grams of the subject compound as reddish orange needles which have a melting point of 159 1 61 C.

EXAMPLE 2 Preparation of a-[1-bromo-2-(5-nitro-2-fiiryl)vinyl]-N-(2- methanesulfonyloxyethyl) nitrone.

The procedure of Example 1 was repeated with the exception that N( Z-methanesulfonyloxyethyl) hydroxy] amine was employed in lieu of phenyl hydroxy amine. As a result, greenish yellow plates of the subject compound were formed which have a melting point of 152l 53 C.

EXAMPLE 3 Preparation of a-[l-bromo-2-(5-nitro-2furyl)vinyl]-N-(2- acetyloxyethyl) nitrone.

The procedure of Example 1 was repeated with the exception that in lieu of phenyl hydroxyl amine, N-(Z-acetyloxyethyl) hydroxy] amine was employed. As a result, light yellow needles of the subject compound having a melting point of 131-133 C was formed.

Preparation of a-[ l-bromo-2-( 5-nitro-2-furyl)viny1]-N- methyl nitrone.

4.92 grams of a-bromo-B-(5nitro-2-furyl) acrolein was dissolved in ml of ethanol at 65 C with stirring. 2.16 g of N- methylhydroxylamine hydrochloride and 2.1 g of anhydrous sodium acetate were added and the reaction mixture was kept at room temperature. The mixture was allowed to stand for 6 hours with stirring. The precipitates were collected by filtration and the filtrate was concentrated to a half volume under reduced pressure. The resulting residue, on cooling, gave additional crystals which were combined with the preceding precipitates. The crystals were recrystallized from ethanol to give 4.4 g of the intended compound as yellow, fine needles melting at 180 181 C with decomposition.

EXAMPLE 5 Preparation of a-[2-(5-nitro-2-fury1)-l-pheny1vinyl1-N- methyl nitrone.

The procedure of Example 4 was repeated with the exception that a-phenyl-B-(5-nitro-2-furyl)acrolein was employed in lieu of a-bromo-/3-(5-nitro2-furyl)acrolein. As a result, the subject compound was formed as yellow plates having a melting point at 166 C with decomposition.

EXAMPLE 6 Preparation of a-[1-(2-furyl)-2-(5-nitro-2-furyl)-vinyl]-N- methyl nitrone.

The procedure of Example 4 was repeated with the excep tion that a-( 2-furyl)-B-(5-nitro-2-furyl)acrolein was employed in lieu of a-bromo-B-( 5-nitro-2-furyl)acrolein. As a result, the subject compound was formed as reddish-orange needles having a melting point of 179 180 C with decomposition.

EXAMPLE 7 Preparation of cisand trans-a-[2-( 5-nitro-2-furyl)-l-phen ylvinyl ]-N-( 2-hydroxyethyl) nitrones.

To a solution of 3.14 g of cis-a-phenyl-B-( 5-nitro-2-furyl) acrolein in 80 ml of ethanol there was added a solution of 1.20 g of N-(Z-hydroxyethyl) hydroxylamine in a 10 percent hydrochloric acid and 3.87 g of sodium acetate with stirring. The mixture was then heated at 50 55 C. After approximately 1 hour the reaction mixture was concentrated under reduced pressure, and the residue was extracted with chloroform, washed with water and dried, followed by removal of the chloroform by distillation. The remaining crystals were recrystallized from a mixture of ethanol and hexane to give 3.13 g of the intended compound of the cis-type as yellow plates melting at 1 14 1 16 C.

The mother liquor was concentrated to dryness and the residue was recrystallized from chlorofonn to give 0.15 g of the intended compound of the trans-type as yellow needles melting at 162 164 C.

EXANIPLE 8 Preparation of a-[ l-bromo-2-(5-nitro-2-furyl)vinyl]-N-( 2- hydroxyethyl) nitrone.

The procedure of Example 7 was repeated with the exception that a-bromo-B-(5-nitro-2-furyl) acrolein was employed in lieu of cis-a-phenyl-B-(5-nitro-2-furyl) acrolein. As a result, the subject compound was obtained which had a melting point of 1 60 1 62 C.

EXAMPLE 9 EXAMPLE Preparation of a-[1-bromo-2-(5-nitro-2-furyl)vinyl]-N-(2- hydroxypropyl) nitrone.

The procedure of Example 8 was repeated with the exception that N-(Z-hydroxypropyl)hydroxylamine was employed in lieu of N-(Z-hydroxyethyl) hydroxylamine. As a result, greenish-yellow needles of the subject compound were prepared having a melting point of 124 126 C.

EXAMPLE 1 1 Preparation of a-[l-bromo-2-(5-nitro-2-furyl)vinyl]-N-( methyl-Z-hydroxyethyl) nitrone.

The procedure of Example 8 was repeated with the exception that N-( 1-methyl-2-hydroxyethyl) hydroxylamine was employed in lieu of N-(Z-hydroxyethyl) hydroxylamine. As a result, yellow needles of the subject compound having a melting point of l 9 1 193 C was formed.

EXAMPLE 1 2 Preparation of a-[ l-bromo-2-( 5-nitro-2-furyl)-vinyl]-N-(2- furfuryl) nitrone.

The procedure of Example 8 was repeated with the exception that N-( 2-furfuryl)hydroxylamine was employed in lieu of N-(2-hydroxyethyl)hydroxylamine. As a result, greenish-yellow needles of the subject compound having a melting point of 8 159 C was produced.

EXAMPLE 1 3 Production of a-[2-(5-nitro-2-furyl)-1-phenylvinyl]-N-(lmethyI-Z-hydroxyethyl)nitrone.

The procedure of Example 1 l was repeated with the exception that a-phenyl-B-( 5-nitro-2-furyl) acrolein was employed in lieu of a a-bromo-[3-(5-nitro-2-furyl) acrolein. As a result, yellow needles of the subject compound having a melting point of 152 154 C were produced.

EXAMPLE 1 4 Preparation of a-[2-(5-nitro-2-furyl)-1-phenylvinyl]-N-(2- hydroxypropyl) nitrone.

The procedure of Example 13 was repeated with the exception that N-(Z-hydroxypropyl) hydroxylamine was employed in lieu of N-( l-methyl-Z-hydroxyethyl) hydroxylamine. As a result, yellow needles of the subject compound having a melting point of 156 157 C was formed.

EXAMPLE 15 Preparation of a-[l-bromo-2-(5-nitro-2-furyl)vinyl]-N- l ,3-di-hydroxy-2-propyl) nitrone.

The procedure of Example 12 was repeated with the exception that N-(1,3-di-hydroxypropyl) hydroxylamine was employed in lieu of N-(Z-furfuryl) hydroxylamine. As a result, greenish-yellow needles of the subject compound having a melting point of 186 187 C was produced.

EXAMPLE 1 6 Preparation of cisand trans-a-[Z-(S-nitro-Z-furyh-l-phenylvinyl]-N-( 2-furfuryl) nitrones.

The procedure of Example 12 was repeated with the exception that cisand trans-a-phenyl-B-(5-nitro2-furyl) acroleins were employed in lieu of a-bromo-B-(5-nitro-2-furyl) acroleins. As a result, the cisform of the subject compound as orange plates having a melting point of 138 140 C was produced. The transtype as yellowish-orange needles having a melting point at 168 169 C was produced.

EXAMPLE 1 7 Preparation of cisand trans-a-f 1-( 2-furyl)-2-( 5-nitro-2-furyl)vinyl]-N-(2-furfuryl) nitrones.

The procedure of Example 16 was repeated with the exception that cisand trans-a-( 2-furyl)-B-( S-nitro-Z-furyl) acroleins were employed in lieu of cisand trans-a-phenyl-B- (5-nitro-2-furyl) acroleins. As a result, needles melting at 157 158 C (cis-type) and 140 141 C (trans-type) were produced.

EXAMPLE 1 8 Preparation of a-[1-bromo-2-(3-nitro-2-furyl)vinyl1-N-2- methanesulfonyl-oxyethyl) nitrone.

To a solution of 1.0 g of a-[ l-bromo-2-(5-nitro-2-furyl) vinyl}-N-( 2-hydroxyethyl) nitrone in 8 ml of anhydrous pyridine there was added under cooling 0.5 g of methanesulfonyl chloride. The reaction mixture was allowed to stand with stirring at room temperature for 1 hour. Water was then added to the reaction mixture and the precipitating yellow crude crystals were collected by filtration, washed with water and recrystallized from ethanol to give 1.02 g of the intended compound as greenish-yellow plates melting at 152 153 C.

EXAMPLE 19 Preparation of a4 l-bro'rno-2-( 5-nitro-2-furyl )vinyl -N- (2acetyloxyethyl) nitron.

To a solution of 1.0 g of a-[l-bromo-2-(5-nitro-2-furyl) vinyl]-N-( Z-hydroxyethyl) nitrone in8 ml of anhydrous pyridine there was added with cooling 1 ml of acetic anhydride. The reaction was effected with stirring at room temperature for a period of about 2 hours. Water was added to the reaction mixture and the stirring was conducted for 30 minutes to decompose any excess acetic anhydride. The precipitating crystals were then collected by filtration and washed with water. The resulting crude crystals were recrystallized from ethanol to give 15 g of the intended compound as yellowish orange needles melting at 131 133 C.

EXAMPLE 20 Preparation of a-{2-(5-nitro-2-furyl) vinyl]-a-phenyl-N- methyl nitrone.

To a solution of 2.43 g of 5-nitro2-furfurylidene acetophenone in 20 ml of dioxane warmed at 50 C there was added 0.61 g of methylhydroxylamine and 0.1 ml of glacial acetic acid. The mixmre was kept at 50 C with stirring and then allowed to stand over-night at room temperature. The starting ketone which precipitated on standing was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was subjected to silicagel chromatography to afford crude crystals therefrom. The resulting crude crystals were recrystallized repeatedly from methanol to give 0.61 g of the intended compound as fine, orange needles melting at 194 196 C.

EXAMPLE 21 Preparation of a-[2-( 5-nitro-2furyl) vinyl]-a-phenyl-N-( 1- hydroxy-Z-propyl) nitrone.

To a solution of 2.43 g of S-nitro-Z-furfurylidene acetophenone in 50 ml of ethanol warmed at 50 60 C., there was added 1.65 g of l-hydroxy-2-propylhydroxylamine. The reaction was carried out at room temperature with stirring for 2 days. The reaction mixture was cooled and the precipitating crystals (starting ketone) were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica-gel chromatography to yield the crude product. The resulting crude crystals were recrystallized from a mixture of n-hexane and acetone to give 0.59 g of the intended compound as orange needles needles melting at 178 180 C.

EXAMPLE 22 Preparation of a-[2-(5-nitro-2-furyl) benzoyloxyethyl) nitrone.

To a solution of 0.2 g of a-[2-(5-nitro-2-furyl vinyl]-N-(2- hydroxyethyl) nitrone in 2 ml of anhydrous pyridine there was added 0.15 ml of benzoyl chloride with ice-cooling and stirring. After the reaction had progressed for about 3 hours under the same conditions, the reaction mixture was poured into ice water, and the precipitating crude crystals were collected by filtration and recrystallized from dilute ethanol to give 0.3 g of the intended compound as faintly orange needles melting at 126 128 C.

EXAMPLE 23 Preparation of a-( 5-nitro-2-furyl)-N-( Z-benzoyloxethyl) nitrone.

The procedure of Example 22 was repeated with the exception that a-(S-nitro-Z-furyl)-N-(2-hydroxyethyl) nitrone was employed in lieu of a-[2-(5-nitro-2-furyl)viny1]-N-( 2-hydroxyethyl) nitrone. The greenish-yellow needles of the subject compound were found to have a melting point of 141 143 C.

EXAMPLE 24 Preparation of a-methyl-a-[2-(5-nitro-2-furyl)vinyl]-N-(2- benzoyloxyethyl) nitrone.

The procedure of Example 23 was repeated with the exception that a-methyl-a[2-(5-nitro-2-furyl) vinyl]-N-(2-hydroxyethyl) nitrone was employed in lieu of a-( 5-nitro2-furyl)-N- (2-hydroxy-ethyl) nitrone. As a result, orange prisms of the subject compound having a melting point of 143 144 C were produced.

EXAMPLE 25 Preparation of a-(5-nitro-2-fi1ryl)-N-(2-ethoxycarbonyl-oxyethyl) nitrone.

To a solution of 0.8 g of a-(5-nitro-2-furyl)-N-(2-hydroxyethyl) nitrone in 8 ml of anhydrous pyridine there was added under ice-cooling and stirring 0.46 ml of chloroethyl forrnate, and the reaction was effected at room temperature for 9 hours. The reaction mixture was then poured into ice water and extracted with chloroform. The extracts were washed with water, dried with magnesium sulfate and concentrated under reduced pressure. To this residue ethanol was added and the separated crude crystals were collected by filtration and recrystallized from ethanol to give 1.13 g of the intended product as yellowish orange plates melting at 88 89 C.

EXAMPLE 26 Preparation of a-(5-nitro-2-fury1)-N-[2-(B-carboxypropionyloxy) ethyl] nitrone.

To a solution of 0.5 g of a-( 5-nitro-2-furyl)-N-(2-hydroxyethyl) nitrone in 3 ml of anhydrous pyridine there was added 300 mg of succinic anhydride, and the reaction was carried out at room temperature for 3 hours and at 95 C for an additional 2 hours under stirring. The reaction mixture was concentrated under reduced pressure, and the precipitating crystals were collected by filtration and recrystallized from ethanol to give 0.8 g of the intended product as yellowish scales melting at 137 139 C.

EXAMPLE 27 Preparation of a-( 5-nitro-2-furyl )-N-[2-( 2-carboxybenzoyloxy)ethyl] nitrone.

The procedure of Example 26 was repeated with the exception that phthalic anhydride was employed in lieu of succinic anhydride. As a result, yellow needles of the subject compound having a melting point of 101 102 C was produced.

EXAMPLE 28 EXAMPLE 29 Preparation of a-(5-nitro-2-furyl)-N-(1,3-bis-methane-sulfonyloxy-2-propy1) nitrone.

To a solution of 0.46 g of a-(5-nitro-2-fury1)-N-(1,3- dihydroxy-2-propyl) nitrone in 2 ml of anhydrous pyridine there was added under ice-cooling and stirring 570 mg of methanesulfonyl chloride, and the reaction was effected at room temperature for 1 hour. The reaction mixture was poured into water, and the precipitating crude crystals were collected and recrystallized from ethanol to give 0.7 g of the intended compound as greenish-yellow needles melting at 161 C.

EXAMPLE 30 Preparation of a-(5-nitro-2-furyl)-N-( Z-methanesulfonyloxyethyl) nitrone.

The procedure of Example 25 was repeated with the exception that methanesulfonyl chloride was employed in lieu of ptoluenesulfonyl chloride. As a result, greenish-yellow plates of the subject compound having a melting point of 151 152 C were produced.

What is claimed is:

l. A Nitrone derivative represented by the formula wherein m is an integer of 0 to l; R, represents a member selected from the group consisting of hydrogen, halogen, furyl and phenyl; R represents a member selected from the group consisting of hydrogen, alkyl having from 1 to 4 carbon atoms and phenyl; R represents a member of the group consisting of phenyl and A (X),,, only when R, represents a member selected from the group consisting of halogen, fury] and phenyl, R represents hydrogen and m is 1; A (Y),,, only when R, represents hydrogen and R represents a member selected from the group consisting of hydrogen and alkyl having from one to four carbon atoms; and A (2),, only when R, represents hydrogen, R represents phenyl and m is an integer of 1; in which A represents alkyl having from one to six carbon atoms; X represents a member selected from the group consisting of hydrogen, hydroxyl, furyl, alkylsulfonyloxy having an alkyl group of one to four carbon atoms and alkanoyl having an alkyl group of from one to three carbon atoms; Y represents a member selected from the group consisting of benzenesulfonyloxy, toluenesulfonyloxy, alkylsulfonyloxy having from one to four carbon atoms, benzoyloxy, salicyloyloxy, carboxy benzoyloxy and alkoxycarbonyloxy having an alkyl group of from one to four carbon atoms and carboxyalkanoyloxy having from three to six carbon atoms, Z represents a member selected from the group consisting of hydrogen and hydroxy, and n is an integer of from 1 to 3.

2. The compound of claim 1 wherein R represents a member selected from the group consisting of halogen, furyl and phenyl, R represents hydrogen and m is l.

3. The compound of claim 1 wherein R, represents hydrogen and R represents a member selected from the group consisting of hydrogen and an alkyl having from about one to about four carbon atoms.

4. The compound of claim 1 wherein R, represents hydrogen, R represents phenyl and m is l.

5. The nitrone derivative of claim 1 wherein said derivative is a-[ 1-bromo-2-(S-nitro-2-furyl)vinyl]-N-methyl nitrone.

6. The nitrone derivative of claim 1 wherein said derivative is a-{ lbrm0-2(Smitro-Z-furyl)vinyl]-N-( Z-hydroxypropyi) nitrone.

7. The nitrone derivative of claim 1 wherein said derivative is a-[ 1-bromo-2-( -nitro-2-fiiryl)vinyl ]-N-( l-methyl-2- hydroxyethyhnitrone.

8. The nitrone derivative of claim 1 wherein said derivative is a-[ l-brom0-2-(5-nitro-2-furyl)vinyl}-N-( 1,3-dihydroxy-2- propyl)nitrone.

9. The nitrone derivative of claim 1 wherein said derivative is a-[ l-bromo-2-( 5-nitro-2-furyl)vinyl]-N-( Z-hydroxyethyl)nitrone.

10. The nitrone derivative of claim 1 wherein said derivative is a-[ l bromo-2-(5-nitro-2-furyl)vinyl]-N-( 2-furfuryl) nitrone.

l l. The nitrone derivative of claim 1 wherein said derivative is a-[ l -bromo2-( S-nitro-Z-furyl)vinyl]-N-phenyl nitrone.

12. The nitrone derivative of claim 1 wherein said derivative is a-[ l -bromo-2-( 5-nitro-2-furyl )vinyl ]-N-( Z-methane-sulfonyloxyethyhnitrone.

13. The nitrone derivative of claim 1 wherein said derivative is a-[ 1-br0mo-2-( 5-nitro-2-furyl )vinyl ]-N-( 2-acetyloxyethyl)nitrone.

14. The nitrone derivative of claim 1 wherein said derivative is a-[ 2-( S-nitro-Z-furyl l -phenylvinyl]-N-( l-methyl-Z- hydroxyethyhnitrone.

15. The nitrone derivative of claim 1 wherein said derivative is a-[ 2-( 5-nitro-2-furyl 1 -phenylvinyl ]-N-( 2-hydroxypropyl)nitrone.

16. The nitrone derivative of claim 1 wherein said derivative is a-[ 2-( 5-nitro-2-furyl)- l-phenylvinyl1-N-methyl nitrone.

17. The nitrone derivative of claim 1 wherein said derivative is o:-[ 2-( S-nitro-Z-furyl l -phenylvinyl ]-N-( 2-hydroxyethyl)nitrone.

18. The nitrone derivative of claim 1 wherein said derivative is a-[2-( 5-nitro-2-furyl l -phenylvinyl]-N-( 2-furfuryl) nitrone.

19. The nitrone derivative of claim 1 wherein said derivative is a-[ 2-( 5-nitro-2-furyl )vinyl ]a-phenyl-N-methyl nitrone.

20. The nitrone derivative of claim 1 wherein said derivative is a-[ 2-( S-nitro-Z-furyl )vinyl]-a-phenyl-N-( 1-hydroxy-2- propyl )nitrone.

21. The nitrone derivative of claim 1 wherein said derivative is a-[2-(5-nitro2-fi1ryl)vinyl]-N-( Z-benzoyloxyethyi) nitrone.

22. The nitrone derivative of claim 1 wherein said derivative is a-( 5-nitro-2-furyl )-N-( 2-benzoyloxyethyl)nitrone.

23. The nitrone derivative of claim 1 wherein said derivative is a-( S-nitro-Z-furyl )-N-( Z-methanesulfonyloxyethyl) nitrone.

24. The nitrone derivative of claim 1 wherein said derivative is oz-( 5-nitro-2-furyl)-N-( 2-tosyloxyethyl )nitrone.

25. The nitrone derivative of claim 1 wherein said derivative is a-( 5-nitro-2-furyl )-N-( l ,B-bismethanesulfonyloxy-Z- propyl)nitrone.

26. The nitrone derivative of claim 1 wherein said derivative is a-[ 2-( 5-nitro-2-fiiryl)vinyl]-N( 2-ethoxycarbonyl-oxyethyl)nitrone.

27. The nitrone derivative of claim 1 wherein said derivative is a-( 5-nitro-2-furyl )-N-[2-( 2-carboxybenzoyloxy) ethyl )nitrone.

28. The nitrone derivative of claim 1 wherein said derivative is a-( 5-nitro-2-furyl )-N-{ Z-(B-carboxypropionyloxy) 9. The nitrone derivative of claim I wherein said derivative is a-methyla-[2-( 5-nitro-2-furyl)vinyl ]-N-( Z-benzoyl-oxyethyl )nitrone.

30. The nitrone derivative of claim 1 wherein said derivative is a-[ l-( 2-furyl )-2-( 5-nitro-2-furyl )vinyl]-N-methyl nitrone.

31. The nitrone derivative of claim 1 wherein said derivative is a-[ l-( 2-furyl)-2-( 5-nitro-2-furyl )vinyl]-N-( 2-hydroxyethyl )nitrone.

32. The nitrone derivative of claim 1 wherein said derivative is a-[ l-( 2-furyl)-2-( 5-nitro-2-furyl)vinyl ]-N-( 2-furfuryl)nitrone.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTIGN Patent No. 3 a 666 754 Dated y 1970 Inventor(s) MINAMI ET AL It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Delete issuance date of "May 30, 1970" and insert "May 30, 1972."

Signed and sealed this 9th day of January 1973.

(SEAL) Attest:

EDWARD M.FLETCHER,JR.

Attesting Officer ROBERT GOTTSCHALK Commissioner of Patents FORM PO-105O (10-69) USCOMM'DC 6O376-P69 U 5. GOVERNMENT PRINTING OFFICE: 1969 O366-334

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US3528971 *Jul 5, 1968Sep 15, 1970Richardson Merrell IncCycloalkyl nitrofuryl nitrones
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US5256311 *Mar 26, 1991Oct 26, 1993Betz Laboratories, Inc.Hydroxyalkylhydroxylamine oxygen scavenger in aqueous mediums
US5942507 *Jul 17, 1997Aug 24, 1999Centaur Pharmaceuticals, Inc.Furan nitrone compounds
US5998469 *Jan 14, 1999Dec 7, 1999Centaur Pharmaceuticals, Inc.Nervous system diosrders; autoimmune diseases; antiinflammatory agents
US6015831 *Jan 14, 1999Jan 18, 2000Centaur Pharmaceuticals, Inc.Thiophene nitrone compounds
US6040444 *May 24, 1999Mar 21, 2000Centaur Pharmaceuticals, Inc.Process for preparing furan nitrone compounds
US6046232 *Oct 15, 1998Apr 4, 2000Centaur Pharmaceuticals, Inc.α-aryl-N-alkylnitrones and pharmaceutical compositions containing the same
US6051571 *May 24, 1999Apr 18, 2000Centaur Pharmaceuticals, Inc.Methods for treating medical dysfunctions and diseases using furan nitrone compounds
US6376540Jul 14, 1997Apr 23, 2002Centaur Pharmaceuticals, Inc.Furan nitrone compounds
US6441032Aug 9, 2000Aug 27, 2002Centaur Pharmaceuticals, Inc.Treating systemic lupis and multiple sclerosis
US6835754Jan 8, 2002Dec 28, 2004Renovis, Inc.Administering alpha-(4-hydroxy-3,5-di-tert-butylphenyl)-N-tert-octylnitrone for example
Classifications
U.S. Classification549/472, 549/473, 549/482, 549/481
International ClassificationC07D307/73
Cooperative ClassificationC07D307/73
European ClassificationC07D307/73