viving phage particles were determined by the Gracia agar slope method. Antiphage activity was expressed as @ercentage inactivation using the formula

1 - - Co Cc �9 100,

where Co and C c are the numbers of surviving phage corpuscles in the experiment and the con- trol.

The compounds were dissolved in DMF, then diluted with sterile distilled water.

LITERATURE CITED

i. V.A. Sedavkina, I. V. Lizak, and L. K. Kulikova, Khim.-farm. Zh., No. I0, 34-38 (1978). 2. V.A. Bystrenina, A. D. Shebaldova, I. V. Lizak, et al., Khim.-farm. Zh., No. i, 65-67

(1982). 3. V.A. Sedavkina and I. V. Lizak, USSR Inventor's Certificate No. 513,972; Otkrytiya,

No. 18, 72 (1976).

SYNTHESIS AND CHEMOTHEREPEUTIC ACTIVITY OF NOVEL p-SULFA-

MOYLBENZYL [PHENETHYL] AMIDES OF BENZOFURAN-2-CARBOXYLIC

ACID IN STAPHYLOCOCCAL INFECTIONS

M. A. Kaldrikyan, V. A. Geboyan, UDC 615.281:547.551.525.211.1].012.1 Yu. Z. Ter-Zakharyan, and R. V. Paronikyan

In continuation of research on the synthesis of arylsulfonic acid derivatives [i], we here describe the preparation of some novel ~enzenesulfonamides (Ia-g) containing benzo- furoyl-2-aminoalkyl residues. The rationale for the synthesis of (Ia-g) was the existence of literature reports [2-4] that modification of the structures of well-known hypoglycemic and antibacterial drugs (glycylamide, butamide, and streptocide) leads to the creation of hfghly active analogs containing aliphatic and heterocyclic residues.

The sulfonamides (Ia-g) were synthesized as follows:

2 ~a,b

~ a,b I a - g

I~ g : R = NH2; Ib, d; R = piperidgl ; Ie, e : R = mo~holy l ;

If :R ~ N (CH~)2; Ia- e,III~ IVa:n = 1; M-g, IIIb, IVb:n = 2.

The literature route to compounds of this type involves numerous stages and is laborious (acetylation of phenylalkylamines, sulfochlorination, amidation, deacetylation, and acylation with various aromatic and heterocyclic residues) [5].

The method which we have developed for the preparation of (la-g) is more convenient and shorter, since it omits the acetylation and deacetylation steps. The phenylalkylamines were reacted with benzofuran-2-carbonyl chloride (II). Sulfochlorination of the resulting amides (llla, b) was effected in a large excess of freshly distilled chlorosulfuric acid at --5~ The sulfonyl chlorides (IVb) were crystalline compounds which on keeping in water or air were converted into the sulfonic acids. Treatment with aqueous ammonia or reaction with secondary amines gave the amides (la-g). In the mass spectrum of (la), in addition to the molecular ion at 330, ions were observed with m/e 169 and 160, showing that the sulfamoyl group is present in the benzene rather than the benzofuran ring. The IR spectrum contained S02 stretching

A. M. Mndzhoyan Institute of Fine Organic Chemistry, Academy of Sciences of the Armenian SSR, Erevan. Translated from Khimiko-farmatsevticheskii Zhurnal~ Vol, 18, No. i, pp. 58-61, January, 1984. Original article submitted April ii, 1983.

40 0091-150X/84/1801- 0040508.50 �9 1984 Plenum Publishing Corporation

TABLE 1 . amides

Compound

Ia Ib I c Id Ie I f Ig

Benzofuran-2-Carboxylic Acid p-Sulfamoylbenzyl(phenethyl)-

Yield,

70,0 50,6 40,5 40,8 64,0 35,0 60,0

rap, ~ ;~f

179--180 0,70 165--1661 0,70 146--1471 0,50 227--2281 0,75 177--1781 0,62 195--1961 0,75 243--2451 0,69

Found

N S

8,28 10,01 6,92 8,20 6,84 8,27 6,83 8,00 6,84 8,04 6,21 8,79 8,35 9,64

Empirical formula

C~6HI~N~O4S C=~H22N204S C~oH~oN2OsS C22H24N204S C21H22N20~S C19H=oN204S C19H2oN~04S

Calculated r

N S

8,48 9,73 7,03 8,04 7,00 8,00 6,79 7,76 6,76 7,73 7,52 8,60 8,13 9,30

absorption at 1160 and 1380 cm -~. CO absorption occurred at 1640 cm -~, and the NH-- bond at 3390 cm - 1 .

The purities and identities of the compounds (Ia-g) were conformed by chromatography.

EXPERIMENTAL CHEMISTRY

Mass spectra were obtained on an MX-1303 instrument, with direct introduction of the sample into the ionization region, ionizing electron energy 30 eV, temperature 30-40~ below the melting point. IR spectra were obtained on a UR-20 instrument as suspensions in vaseline oil. Chromatography was carried out on Silufol UV-254 plates in the system dry ether-- absolute ethanol (5:0.8), spots visualized using a UI-I ultrachemoscope.

Benzofuran-2-carboxylic Acid Phenylaklylamides (IIIa and b). To a 0.2 mole of the phenyl- alkylamine in i00 ml of dry benzene was added dropwise with stirring 0.I mole of the acid chloride (II) in i00 ml of dry benzene. The mixture was heated on the water bath for 4-5 h, filtered, and 20-30 ml of benzene distilled from the filtrate. The crystals which separated were filtered off to give 60.5% of (IIIa), mp 90-91~ Found, %: C 75.62; H 5.53; N 5.56. C~6H~3NO~. Calculated, %: C 76.10; H 5.17; N 5.56. Yield of (IIIb), 55.7%, mp. II0-111~ Found, %: C 76.50; H 6.01; N 5.10o C17HIs, NO2. Calculated, %: C 77.13; H 5.63; N 5.31.

p-Chlorosulfonylphenylalkylamides (IVa and b). To 300 g of chlorosulfuric acid, cooled to --i to --5~ was added with stirring in small portions 0.12 mole of the phenylalkylamide (IIIa or b) at such a rate that the temperature of the reaction mixture did not rise above 0~ Stirring was continued for 2 h at the same temperature, and the contents of the flask were then poured on to finely crushed ice. The crystals which separated were quickly filtered off, washed with ice-water until the filtrate was neutral, and dried in a vacuum desiccator. Yield of (IVa) 98.1%, mp 79-80~ Found, % CI 10.45; S 9.42. C16HI2CIN04S. Calculated, %: C1 10.13; S 9.16. Yield of (IVb) 90.1%, mp 54-55~ Found, %: C1 10.07, S 9.21. CITHI4CI- NO4S. Calculated, %: C1 9.75, S 8.81.

Benzofuran-2-carboxylic Acid p-Sulfamoylphenylalkylamides (Ia, g). A stream of ammonia was passed into a mixture of 0.046 mole of the chloride (IVa or b) and 300 ml of saturated aqueous ammonia with cooling for i0 min. The mixture was then heated on the water bath for 2 h. After distillation of 200 ml of water, the mixture was cooled, and the crystals which had separated were filtered off, washed with water, and air-dried (Table i).

N-Substituted Sulfamoylphenylalkylamides of Benzofuran-2-carboxylic Acid (Ib-f). To a mixture of 0.4 mole of the secondary amine and 30 ml of 10% sodium hydroxide was added 0.025 mole of the chloride (IVa or b). The mixture was stirred at ambient temperature for 2 h, and the crystals which separated were filtered off, washed with water, and recrystal- lized from ethanol (Table i).

EXPERIMENTAL BIOLOGY

The chemotherapeutic activity of the new sulfonamides (Ia-f) was examined in a model of generalized staphylococcal infection in white mice [6]. Tolerance of the compounds was studied in healthy mice following a single internal dose. In the experiments, 300 mongrel white mice weighing 17-18 g were used. Infection was carried out by intraperitoneal admini- stration of a culture of Staphylococcus aureus. The sensitive staphylococcal strains Smith, 12, 4-0 and the sulfanilamide- and benzylpenicillin-resistant strains 35 and 91 were employed.

41

TABLE 2. Chemotherapeutic Activity of (la-f) in a Dose of 1500

mg/kg, in Staphylococcal Infection in White Mice

Compound

] a I b l c l d l e I f

Norsulfazole

Control l a l b i c I,d I f

Norsulfazole

St~ain of Infect ive dose

No. of [TotaI extension of l ifespan of

[ ~ ,~ abs.

Smith

4 = 0

400 mi l l ion microbial cells

400 mil l ion microbial cel ls

10 10

lO 10 10

10-

10 10 5

10 5

10

0

10 8 3 3 2 6

0/100 0 20/100 20 10/100 10 20/50 40 10/50 20 0/100 0

80/I00 80 80/100 80

0/100 0

100/100 100 80/100 80 30/50 60 30/100 30 20/50 4O 60/100 6O

Control

I a I b I f Id I.e

Norsulfazole

Control ] a i b l e I f

Norsulfazole

Control

l a i b I e I f

Norsulfazoie

Control

12

35

91

800 mi l l ion microbial cel ls

400 mi l l ion microbial cel ls

400 mil l ion microbial cel ls

10

10 5 5 5 5

10

10

5 5 5 5 5

0/100

90/100 41/50 30/5O 4O/5O 40/50 73/100

10]100

31150 10/50 20/50 21/50 10/50

0/50

20/50 3/50

IO/50 10/50 10/50

0/50

0

90 82 60 80 80 73

10

62 20 40 42 20

0

40 6

20 20 20

Note. The numerator denotes the number of mouse-days in the

group, and the denominator the maximum possiblenumber of mouse- days over a period of observation of i0 days.

The test compounds were administered internally, simultaneously with infection. All the com- pounds were tested in a dose of 1500 mg/kg. In each test, a group of animals was treated with norsulfazole (the control drug). The activity of the compounds was expressed as the total lifespan of the mice as a percentage of the maximum possible in the group over a period of observation of ten days. A dose for which this index was 80% or more was regarded as highly active, for which it was 40-80% as active, and for which it was 40% or less as slightly ac- tive, when the differences were significantly different from the controls as assessed by the

2 X criterion.

In acute experiments using healthy mice, sulfonamides (Ia-f) were well tolerated when administered internally in doses of 1500, 2000, and 4000 mg/kg. Higher doses were not tested.

Compounds (Ia-f) displayed weak therapeutic activity, or were inactive in staphylococcal infections induced by the Smith strain. In experiments involving infections induced by the

42

other strains (12 and 4-0), they were in general more active than norsulfazole, increasing the lifespan of the animals by 90-100%. In infections with the resistant staphylococcal strain 35, (Ia, b, e, and f) were more active than norsulfazole, but in infections with the other resistant strain (91), their activity was reduced (Table 2).

This study has therefore shown that sulfonamides (Ia-f) have considerable chemothera- peutic activity in staphylococcal infection, and that it is desirable to continue to seek novel sulfonamides containing residues of the heterocyclic system benzofuran.

LITERATURE CITED

i. M.A. Kaldrikyan, V. A. Geboyan, A. A. Aroyan, et al., Arm. Khim. Zh., 33, 242-246 (1980) .

2. V. Ambrogi , K. B lock , S. D a t u r i , e t a l . , Arzneim. F o r s c h . , 21 , 200-208 (1971) . 3. H. Weber, W. Aumul l e r , K. Muth, e t a l . , Arzneim. F o r s c h . , 19 , 1326-1346 (1969) . 4. V.A. Zasosov, Collected Proceedings of the All-Union Scientific-Research Institute of

Pharmaceutical Chemistry [in Russian], No. 2, 104-128 (1971). 5. E. Miller, J. M. Sprague, L. W. Kissinger, et al., J. Am. Chem. Soc., 62, 2099-2102

(1940). 6. G.N. Pershin (ed.), Methods of Experimental Chemotherapy [in Russian], 2nd edn., Moscow

(1971), p. 109.

SYNTHESIS AND ~NTISILICOTIC ACTIVITY OF COPOLY~RS OF N-VINYL-

PYRROLIDONE WITH ETHYLENE GLYCOL VINYL GLYCIDYL ETHER

L. V. Morozova, T. T. Minakova, G. M. Tizenberg, I. G. Kuznetsov, M. G. Voronkov, and B. A. Trofimov

UDC 615.235.012.1

The prophylaxis of pneumoconiosis is one of the most important tasks of industrial health and occupational pathology.

The use of antisilicotic polymers such as polyvinylpyridine N-oxide and polymeric N- oxides is of interest in this respect [i, 2]. Polyvinylpyrrolidone, which is used in medi- cine as a blood plasma replacement [3], has also been tested as a prophylactic and treatment for silicosis, but it showed no activity [4].

In a search for novel macromolecular compounds with antisilicotic acitivity, we have studied the copolymerizationof N-vinylpyrrolidone (I) with ethylene glycol vinyl glycidyl ether (vinylox) (II) [5] in the presence of azobisisobutyronitrile (Ill) as initiator.

Under free-radical conditions, copolymerization proceeds selectively at the double bond to give soluble products of linear structures with lateral pyrrolidone and epoxide rings [6]:

~ CH~--CH---- --~--CH~--CH--

N OCHoCH2OCH2CH--CHo ,

/ " \ co " ~o / I I I [mt I.

Ihe s t r u c t u r e s of the copo lymers were e s t a b l i s h e d from t h e i r IR and PMR s p e c t r a . The IR s p e c t r a had no ~ a b s o r p t i o n , b u t t hey c o n t a i n e d a l l the r e m a i n i n g bands o f ( I ) (1500, 1690, and 3015 cm-*) f o r the l a c t a m r i n g and the CO group [3 ] . The s p e c t r a a l s o c o n t a i n e d bands t y p i c a l o f t he e p o x i d e r i n g (765, 915, and 3060 cm -~) and the C--O-C bond ( l l 0 0 cm - z ) of ( I I ) .

The PMR spectra contained signals for the CH2 of the polymer chain at 1.8 ppm, CH at 3.52 ppm, NCH2 and lactam ring CH2 at 3.21 and 2.00 ppm, and CH2--~ at 2.3 ppm. Further

Irkutsk Institute of Organic Chemistry, Siberian Section of the Academy of Sciences of the USSR. Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 18, No. i, pp. 61-64, January, 1984. Original article submitted May ii, 1983.

0091-150X/84/1801- 0043508.50 �9 1984 Plenum Publishing Corporation 43