US2881166A

US2881166A - Sulfapyridine-1-oxides

Info

Publication number: US2881166A
Application number: US653516A
Authority: US
Inventors: John V Scudi; Scott J Childress; David B Reisner
Original assignee: Wallace and Tiernan Inc
Current assignee: US Filter Wallace and Tiernan Inc
Priority date: 1957-04-18
Filing date: 1957-04-18
Publication date: 1959-04-07
Anticipated expiration: 1976-04-07

Description

United States Patent This invention relates "to sulfapyridined-oxides and more particularly to new fderivatives of 'sulfapyridi'ne,

which are more 'soluble'in water endless toxic thanma'ny previously known sultap'yridine compounds. These new derivatives of smrapyndine, according .t'o the present invention, may be termed N-okides or l-oxides and have the following general formula:

In the termite shave, up to wo of the subst'ituent's R R, R and R may be lower alkyl groups, i.e. there may be no such l'ower alkyl grasps or oiie or two such groups, "the remainder of these substitiieht's in each instance being hydrogen. The present ihveiition'furthen includes compounds which are the w-a'cetyiacea derivatives of the compounds above referred to and which have the general formula:

a sasonacoea.

Itis also contemplated that the invention shall include the alkali metal salts fof any of the compounds represented by the formulae above referred to, he} in which the hy drogen atom, which is attac ed to the N pr sulfonamide nitrogen, is replaced by an alkalime'tal, as sodium, A

Many sulfonami'de compounds have been prepared and tested as anti-bacterial agents, which is the general field of utility of the compounds of the present invention. Only a few of the known sulfonainide compounds have been found acceptable in clinical use due to the fact that many such compounds are objectionable due to either 01" both of the following": (a) low, anti-bacterial activity or(b) such strong and undesirable side effects as to make the use of such compounds impracticable. Furthermore, most of these-called 'sulfa drugs" are characterized by relatively low solubility in water in the range of pH 57. I

This low water solubility may be attributable to the fact that sulfapyridine-type compounds are weak acids. Most of the commonly used sulfa'compounds have pK values in the range of about 6.5 to 10.5 (pK is a physical-chemical constantused for comparing acids and indicates the pH at which the acid tested is one-half neutralized) Thus, for example, sulfathiazole has a pK of 7.1, while sulfanilarnide hasa pK, of 'l0.4. Most of the sulfa drugs 5'. Only a few suira'dmgs' such as sulfisoxazole and sulsuch a drug in urihecanlea'd to dangerous calculus formulation in the rental tubules which can even terminate in death.

In conductingresearh work with sulfa drugs in attempting to' overcome some of "the undesirable characteristics of previously known drugs as aforesaid, it was discovered that the 11 -oxides :of "sulfapyridi'ne,according to the present'invention,' have xgenerally lower pK values, or .in other words, substantially "greater acidity. H While sul- :fapyridin'e itself "has a-pK' of 8.43, sulfapyridineal-oxide according 'to th'e'presentinvention has a-pK}, of 525; in other words, it is'rnore than'a thousand times as acidic as the *mostnearly corresponding, previously known sulfapyridirie. Practically, this means thatat physiological pH levels in. the bloodstream, the sulfapyridine-l-oxide will exist largely as the sodium salt, which "is much more soluble than is the free acid. Such salts are, therefore, to be .consideredwithin the purview of the present invention, whether they are formed by physiological action in the host or are formed by chemical action prior to administering the drug in question. In the present instance, however, it is noted thatthe free acid of the sulfapyridinel-oxide has'itself a high intrinsic solubilityyfor example, when :sulfapyridine is dissolved in water having a pH of 4 and a temperature of 37 C. (i.e. normal body temperature), it is soluble to the extent ,.of 50 mg. percent (i.e. 50 mg. of the drug are soluble in cc. of water); whereas sulfapy'ridine-l-oiride is 'soluble under the same termpertur'e and pH conditions to the extentof about 200 percent. There'is given below in tabular form a comparison between the solubility of sulfapyridine l-oxide', sulfisoxazole and aCetyISuIfapyIidine-I-oxide, the table illustrating the solubility of these three drugs at ,difie'rent pH values. The reason for including acetylsul'fapyridine-ljoxide is that this compound is believed to be a metabolic product i'esulting from the administration of sulfapyridinel-oxide. e

TABLE I Solubility campuses in 37 c.

t 1 4.1 15.1 5.6 6.4 pH. sulmpyfldme'l'md" l 213 420 1, 310 6,900 Solubility, mg. per '42" so 65 so ii p summamle 2s 50 340 Solubility,

mguper- 1 g Acet nuuapy is? 5 15 8 :4 goliihllity,

m tpercent.

with a pK of 5 .25 will form alkali [salts 1whi;c11flhavea neutral or nearly neutral reactiong' Hence these'highly soluble forms of the drug can be injected without causing an alkali necrosis of the tissues at the site of the injection; or in the case of an intravenous injection, the yenous thrombosis characteristic of those sulfa drugs which form the more alkaline salts. a I v Not only is sulfapyridine known in the prior art, but also a substantial number of the lower alkyl substituted s'ulfapyridines are known. In general, the compounds of the present invention are prepared bysuitably oxidizing the sulfapyridines of the prior art or the substituted sulfapy'ridine compounds, respectively, for example by oxidiaing the acetylderivatives thereof respectively with hydrogen peroxide in formic acid solutionor with p'eracetic acid. In general, this oxidation occurs at the pyridine ring nitrogen or at the sulfonamide nitrogen, giving rise to two products. The latter oxidation gives substituted hydroxamic acid-type compounds such as the N*-acetyl-N -hydroxysulfapyridine having the formula:

Since these hydroxy compounds do not exhibit the higher acidity, which is characteristic of the sulfapyridine-loxides of the present invention, it is possible to separate the two oxidation products, for example by dissolution of the,acetylsulfapyridine-l-oxide in sodium bicarbonate solution. The acetyl group may then be removed by basic hydrolysis so as to yield the sulfapyridine-l-oxide. Further particulars as to the preparation of this compound and the corresponding alkyl substituted compounds will be set forth hereinafter in examples which follow.

The structure of the sulfapyridine-l-oxide has been confirmed by acid hydrolysis, yielding sulfanilic acid and Z-aminopyridinc-l-oxide. The structureof the by-product (N -acetyl-N -hydroxysulfapyridine) has been similarly determined by acid hydrolysis, in this case yielding acetic acid, sulfanilic acid, and 2-hydroxylaminopyridine. The novel compounds, according to the present invention, may be prepared as particularly set out in the following examples:

I EXAMPLE 1 A solution of 17.7 g. of N -acetylsulfapyridine in 115 g. of 90% formic acid was treated with 17.7 g. of 30% hydrogen peroxide and kept at room temperature for four days. After removing the solvent in vacuo on a waterbath, the residue was dissolved in acetic acid and allowed to crystallize. The orange product was a mixture N-acetyl-N -hydroxysulfapyridine acetylsulfapyridine-l-oxide and amounted to 12 g. It was not necessary to separate the products before bydrolysis. Ten grams of the mixture were heated under reflux in 100 ml. of 2 N sodium hydroxide for one hour. The 4 g. of orange solid obtained on acidification were crystallized to give white crystals, M.P. 188.5 l89.5 C. This material was sulfapyridine-l-oxide. It gave a brickred color with ferric chloride. The Tollens test was negative.

EXAMPLE 2 Another method of preparation involved the separation of the mixture prepared by the method of Example 1 prior to hydrolysis of the N -acetyl group. This separation was readily accomplished by treatment with sodiumbicarbonate solution, the l-oxide dissolving. The insoluble N -acetyl-N -hydroxysulfapyridine melted at 178 C. (with decomposition) after crystallization from 90% alcohol. Acidification of thebicarbonate solution resulted in N acetyI-suIfa yI'idine-I-oxide, which was crystallized from water and alcohol to give the pure product, M.P.'220"-221 C. with decomposition. Hydrolysis of the N-oxide with 2 N sodium hydroxide gave sulfapyridine-l-oxide in a yield of 50%.

EXAMPLES Thirty grams of N -acetyl-6'-methylsulfapyridine was suspended in 90 g. of acetic acid and 30g. of 40% peracetic acid and kept at room temperature for 24 hours with occasional shaking. The compound slowly dissolved as the reaction took place. The solvent was distilled ofi under reduced pressure on a water-bathand the residue treated with 400 ml. of water and, suificient sodium bicarbonate to give an alkaline solution. After standing and N overnight, the insoluble material had crystallized and N acetyl N hydroxy 6' methylsulfapyridine (M.P. 168 C. with decomposition). This hydroxy compound was discarded as it does not have the desired antibacterial action for which the compounds of the present invention are particularly desired.

EXAMPLE 4 '-ethylsulfapyridine-]-oxide.A solution of g. of N-acetyl-6-ethylsulfapyridine in 140 g. of 98' formic acid and 280 g. of acetic acid was treated with 140 g. of 40% peracetic acid and kept three days in a water bath at room temperature. The solvent was concentrated to about 50 ml. in vacuo. Water was added and crystallization induced. The crystals were found to be N- acetyl-6'-ethylsulfapyridine-l-oxide and were recrystallized from alcohol to give 48 g. of cream-colored product, M.P. 233234 C. (dec.). The original filtrate was neutralized with sodium bicarbonate and the precipitate obtained was crystallized from alcohol several times, giving 14 g. of white product, M.P. C. (dec.). This was N -acetyl-N -hydroxy-6'-ethylsulfapyridine.

Hydrolysis for two hours of 47 g. of N -acetyl-6'- ethylsulfapyridine-l-oxide in 470 ml. of refluxing 2 N sodium hydroxide followed by acidification aiforded 6'- ethylsulfapyridine-l-oxide. Upon recrystallization from alcohol, there was obtained 31 g. of the desired compound, M.P. 153 -l55 C.

EXAMPLE 5 3'-methyIsulfapyridine-I-oxide.--Twenty-four grams of N -acetyl-3'-methylsulfapyridine was heated in 72 g. of acetic acid and 24 g. of 40% peracetic acid at 65 C. for 24 hours. The solvent was removed in vacuo and the residue treated with sodium bicarbonate solution. After standing overnight, the mixture was filtered, the filtrate was acidified and concentrated to yield 2.4 g. of N -aeetyl- 3'-methylsulfapyridine-l-oxide. Recrystallized from 50% alcohol, this melted at 235-237' C. (dec.). Upon hydrolysis of the acetyl group as in the other examples, there was obtained 0.6 g. of recrystallized 3'-methylsulfapyridine-l-oxide, M.P. 198' C. (dec.).

Although the bicarbonate-insoluble material from this oxidation showed a positive Tollens test, it consisted largely of unreacted starting material and N -acetyl-N hydroxy-3'-methylsulfapyridine was not isolated.

EXAMPLI B 4', '-dimethylsulfapyridine-1-0xide.A mixture of 30 g. of N -acetyl-4', '-dimethylsulfapyridine, 90 g. of acetic acid and 30 g. of 40% peracetic acid was kept overnight at room temperature. Some crystals had formed in the mixture and these proved to be N-acetyl-N -hydroxy-4', 6-dim'ethylsulfapyridine, 5 g., M.P. 181' C. (dec.) (from alcohol).

The solvent was removed in vacuo and the residue taken up in sodium bicarbonate solution and filtered. Acidification afiorded 6 g. of N-acetyl4',6'-dimethylsulfapyridine-l-oxide. After recrystallization from dilute alcohol the compound melted at 234'-236' C. (dec.).

Hydrolysis to 4',6-dimethylsulfapyridine-l-oxide, M.P. 221.5 -222.5 C., was accomplished as described above.

There is listed below in Table 11 certain data as to the N -acetylsulfapyridine-l-oxides which are to be included in the present invention as above generally set forth, this table showing certain characteristics as determined for different substituted and non-substituted compounds according to the present invention. The first column in the table below, designated R, indicates the substituent or substituents in the pyridine ring, it being understood that the nitrogen of the pyridine ring is of the 1-position in the general formula first given above and the numbering is counterclockwise in the usual manner. It is further to be understood that all substituentsas R R, R and R of the general formula above, which are not substituted by alkyl group, are represented by hydrogen in the compounds listed in Table H.

TABLE II of the substituents R R3 R? and R are lower'alkyl groups'andithe":remainderrofisaid 'substitueutsaare each 1 I hydrogen, andietheralkalimetalisaltszthereof, and (b) N B 55- F acetylatedderivativesof'the compoundsofgroup-(1 ormula.v 4 5 5 abovehavmg'the:formula: 100;- lfound v cunnoims 1525s" 1555 R O1 H15O|N S 13.08 12289' OHHHOANQS. 13. 08 13. 00 CuHltOANsS 13.08 13.04 10 R RI C1|H15O|N5S 13. 08 13. 14 C15H17O NsS 12. 53 12. 60 051111011555 12. 53 12.40 R N NHSO|C NH-COCH 5 The following Table III lists data as to the suliapyridinel-oxides and substituted sulfapyridine-loxides with the 15 designations the same as given above in Table II. and the alkali metal salts thereof.

TABLE III Carbon, Hydrogen Nitrogen, percent percent percent R M.P., '0. Formula Calcd. Found Oslcd Found Calcd. Found 188.5189.5 CnHnOlNlS 40.80 49.09 4.15 4.20 15.34 15.70 0151115015158 51.50 51.80 4.59 4.01 15:05 14.86 0121311055158 51. 50 51.75 4. 09 4.51 v 15.05 14.02 CHHIJOBNSS 51. 00 51.75 4. 59 4.75 15.05 15.02 0151111011115 51.50 51.70 4. 09 4. 74 15.05 14.03 cnmioims 55.22 53.55 5.15 5.20 14.33 14.37 CnHJSOXNIS 53.22 52. 70 5.15 5.02 14.53 14.34

There is also given below, in Table IV, as a matter of 2. The compound, 6' methylsulfapyridine-l-oxide, disclosure a list of the properties of the N -hydroxy comhaving the formula: pounds, which are formed simultaneously with the desired compounds, but which are separated therefrom prior to the production of the desired compounds in pure form, the" designations in this table also being similar to those in -Tables II and III, and the term dec. meaning OH N NnsoiONn, that the compound in question melts, but only with ac- 40 L companying decomposition. 0

TABLE IV 3 The compound, 6' ethylsulfapyridine l-oxide,

having the formula:

Nltro en, M.P., "C. perc nt R (cm-r.) Formula Calcd. Found 1 0,11 NHSOa-O-NIh 17501550..-. oumsoiNts 15.05 15.04 f 175 (11550.-.. OnHNOtNsS 13.05 15.20 0 190 (dec.).... CuHrsOANsS 13.08 13.11 1555-;- 8"?8538 5-22 5 6 7 I 5 5 100 (dec.)... Ci5Hi10iN1s 12. 53 12.45 4. The compound, 4',6'-d1methylsulfapyr1d1ne-1-ox1de,

having the formula:

55 Whilethere is herein disclosed but a few of the possible equivalents which are intended to be embraced within the scope of this invention, others will suggest themselves to those skilled in the art from the foregoing particular disclosure. We do not wish to be limited, therefore, except NHSOPOAHQ by the scope of the appended claims, which are to be i I construed validly as broadly as the state of the prior 0 art permits.

What is claimed is: 5 Th e compound,4 methylsulfapyridine l-oxide Ural A sulfapyrrdme-l-oxide compound having the formhaving the formula:

R: (3111 R B R N NHSOONH: NHSO NH,

which is selected from the group (a) in which up to two (References on following page) References Cited inthe file;of-this patent UNI'IED STA'IVESPA'TENTS 8 A OTHER REFERENCES 7 Linsker at al.: Journal of The American Chemical So- 2.443,1 2 L 'renz une 22,1948 cieWvoL68,page192(1946) FOREIGN PATENTS 5 Ochiai: Journal of Organic Chemistry, vol. 18, pp.

458,539 Canada Aug. 2, 1949 535, 546 1953 870,428

France Mar. 11, 1942 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 2,881,166 April '7, 1959 John Va vScudi et al,

It is hereby certified that error appears in the-printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2, line 3, for "rental" read renal column 4, line 9, for "98 read 987 line 74 for "by alkyl read. by an alkyl e,

' Signed and sealed this 18th day of August 1959.

(SEAL) Attest:

KARL AXLTNE ROBERT C. WATSON Commissioner of Patents Attesting Officer

Claims

1. SULFAPYRIDINE-1-OXIDE COMPOUND HAVING THE FORMULA:

2. THE COMPOUND 6'' - METHYLSULFAPYRIDINE-1-OXIDE, HAVING THE FORMULA: FIG-03