AU470552B2 - Aminocephalosporin derivatives - Google Patents

Description

49,51 672 This invention relates to new synthetic compounds of value as antibacterial agents, as nutritional supplements in animal feeds, as agents for the treatment of mastitis in cattle and as therapeutic agents In poultry and animals, including man, in the treatment of infectious diseases caused by Gram-positive and Gram-negative bacteria. More particularly, this invention relates to derivatives of certain a- aminocephalosporins, said derivatives being prepared by reaction of the a-aminocephalosporin with certain.aldehydes and ketones. Applicant's starting materials are a-aminocephalosporins having the general formula

0 II S R-CH- C -NH SNH2 0 N CH3 COOH I

wherein R is R1

n7j or

s TR 2

R3

in which R1 R2 and R3 are hydrogen, halo, hydroxy, (lower)- alkyl, nitro, amino (lower)alkanoyl, trifluoromethyl, (lower)- alkoxy or (lower)alkylmercapto. These starting material cephalosporins are described for example in U.K.Patents

470,552

49,516/72 ,174,335 and 1,240,687 and in U.S. Patent 3,352,858. It was an object of the present invention to provide ovel cephalosporin derivatives which would possess potent ntibacterial activity against a wide spectrum of Gram- ositive and Gram-negative bacteria. It was an additional bject of this invention to provide novel derivatives of he above-described a-aminocephalosporins which would be lubstantially superior in aqueous stability to the cephalosporins er se. The objects of the present invention have been achieved by roviding a process for the preparation of compounds of the general ormula R X S

CH3 0 COOH

Therein R is

S R2 R3 n which R1 R2 and R3 are hydrogen, halo, hydroxy, (lower)alkyl, itro, amino, (lower)alkanoyl, trifluoromethyl, (lower)alkoxy or

lower)alkylmercapto; and X is 0

C N H- N N- N NH- II C C RI/ R 4Z R R

470,55 2

49,516J72 5 in which either R is hydrogen and R is C2 -C 6 alkyl or

wherein Ak represents an aromatic radical of the formula 6 R

or P R 9

8 R

in which R R7 R R and R10 are hydrogen, nitro, di(lower)alkylamino, (lower)alkanoylamino, (lower)alkanoyloxy, (lower)alkyl, (lower)alkoxy, sulfamyl, halo, trifluoromethyl, (lower)alkylthio, (lower)alkylsulfonyl, carbo(lower)alkoxy, benzyl, phenethyl, cyclopentyl, cyclohexyl or cycloheptyl;. or R and R5 when taken together with the carbon atom to which .they are attached represent cycloalkylidene having 4 to 7 carbon atoms inclusive; and nontoxic phtrmaceutically acceptable salts thereof; which process comprises reacting a cephalosporin of the formula

0

NH2 N H3 0 I I COOH

wherein R is as defined above or a salt thereof, with a carbonyl compound selected from those .having the formula

0 I R44 R

A 470.552

49,51 6 2

wherein R and R are as defined above.

The term "(lower)alkyl" as used herein means both

straight and branched chain aliphatic hydrocarbon radicals

having from 1 to 6 carbon atoms. Similarly, where the term

"(lower)" is used as part of the description of another group,

e.g. (lower)alkoxy, it refers to the alkyl portion of such

group which is therefore as described above in connection

with (lower)alkyl.

The nontoxic pharmaceutically acceptable salts of the

compounds of formula II include, for example, nontoxic

pharmaceutically acceptable salts of the acidic carboxylic

acid group such as the sodium, potassium, calcium, aluminum

and ammonium salts and nontoxic substituted ammonium salts

with amines such as tri(lower)alkylamines, procaine,

dibenzylamine, N-benzyl-beta-phenethylamine, 1-ephenamine,

N,N'-dibenzylethylenediamine, dehydroabietylamine, N,N'-bis-

dehydroabietylethylenediamine, N-(lower)alkylpiperidines,

such as N-ethylpiperidine, and other amines which have been

used to form salts of benzylpenicillin; and nontoxic

pharmaceutically acceptable acid addition salts salts

of the basic nitrogen) such as the mineral acid addition

salts such as the hydrochloride, hydrobromide, hydroiodide,

sulfate, sulfamate, sulfonate, phosphate, etc. and the

organic acid addition salts such as the maleate, acetate,

citrate, tartrate, oxalate, succinate, benzoate, fumarate,

malate, mandelate, ascorbate, B-naphthalene sulfonate,

p-toluenesulfonate and the like. Also included are the easily hydrolyzed esters or amides of such acids which may

be converted to the free acid form by chemical or enzymatic

hydrolysis.

47 0552

49,516 72

Preferred embodiments of the present invention include the reaction products of the a-aminocephalosporins of formula I wherein R is unsubstituted phenyl, p-hydroxyphenyl or 3-chloro-4-hydroxyphenyl with aldehydes selected from benzaldehyde, p-tolualdehyde, o-methoxybenzaldehyde, 3,4- dimethoxybenzaldehyde, p-anisaldehyde, p-nitrobenzaldehyde, naphthaldehyde, valeraldehyde and isovaleraldehyde and ketones selected from cyclohexanone and cyclopentanone. Particularly preferred embodiments include the alkali metal salts (especially the sodium and potassium) of the above-mentioned carbonyl-amine reaction products. The a-carbon atom of the cephalosporin starting material bearing the free amino group is an asymmetric carbon atom and therefore, the compounds of the present invention can exist in two optically active isomeric forms (the D- and L-diastereo- isomers), as well as in a mixture of the two optically active forms. The most preferred compounds are those of the D- configuration. In preparing the compounds of formula II, the proportions of the cephalosporin and carbonyl compound are not critical. Thus, some reaction will occur regardless of the proportions of reactants. It is preferred, however, in order to obtain maximum yields, to use a molar excess of the carbonyl compound. The pH of the reaction mixture should be from about 5 to about 9 and preferably on the alkaline side. The temperature during the reaction is not critical. The reaction will proceed satisfactorily at room temperature and may be hastened by heating. After the cephalosporin has reacted with the carbonyl compound, the resultant compound may be recovered by the 6 470.552

49,516172

methods conventionally used with similar compounds, e.g.

precipitation, lyophilization, flash evaporation, etc.

The cephalosporin derivatives of the present invention have been found to be substantially more stable in aqueous

solution than the cephalosporins from which they are derived.

The compounds prepared by this invention have also been

found to possess potent antibacterial activity against a wide variety of both Gram-positive and Gram-negative bacteria.

The carbonyl-amine adducts of the present invention have been found to have either the Schiff base structure

0 R -CH-C H N CH N C COOH R4 R5

or the cyclic structure

0 II R I CH I C

H-N N S C 0 N CH3

R COOH

wherein R, R 4 and R 5 are all as defined above. The particular structure of any given compound is believed to depend on the

structure of the starting materials and/or the reaction

7 470,55 2

49,516 P2

conditions, e.g. solvents, etc. used in preparing the

carbonyl adduct. Compounds of both the Schiff base and cyclic structure are included within the scope of the

present invention.

The following examples will serve to illustrate the present invention without limiting it thereto.

470,55 2

49,516/72 Example 1

0

I

N C H-C o0 N CH COOK

The dimethylformnamlde solvate of cephalexin [cephalexin

(DMF) 2 (1.8 was slurried in 40 ml. n-butanol and

dissolved by adding 1.6 ml.triethylamlne. After addition

of 0.386 ml. benzaldehyde and 0.2 ml. water, the system

was allowed to react at 50-60°C for 30-45 minutes. Potassium

ethyl hexanoate wax (0.58 was added and went into

solution. A small amount of crystalline material precipitated

and the system was allowed to gradually cool. Some additional

solids precipitated but appeared to be amorphous. The

original crystals slowly dissolved and the system was

subjected to an ice-w&ter bath for 45 minutes after which the

product was recovered by filtration, washed with 20 ml. of

methylene chloride and dried under vacuum. The dried product,

the Schiff base benzaldehyde adduct of potassium cephalexin,

weighed 0.675 g. and appeared as white crystalline granules;

m.p. 157-C. The IR and NMR spectra were consistent

for the Schiff base structure shown above.

Elemental Analysis Calculated for Monohydrate: C, 56.00;

H, 4.66; N, 8.51.

Found: C, 55.36; H, 4.69, N, 8.52.

Moisture (Karl Fischer) 5.61%

9 470.552

49,51 6 /2 This compound was found to inhibit D. pneumoniae at a

concentration of 0.8 mcg./ ml., Str. pyogenes at 0.8 mcg./ml.,

Sal. enteritidis at 4 mcg./ml. and E. coli Juhl at 8 mcg./ml.

Example 2 0 II H C H I/ \NI

II CH3 H C

^COOK

CH3 A mixture of 0.388 g. potassium cephalexin, 0.13 ml.

p-tolualdehyde and 15.0 ml. methylene chloride was slurried

in a closed 50 ml..erlenmeyer flask. After stirring for

about 6 hours, complete dissolution had not taken place.

The system was kept at room temperature for another 15 hours

after which the product was recovered by filtration and

dried under vacuum. The dried product weighed 380 mg.;

m.p. 1650 C The IR and NMR are consistent for the

Schiff base form of the p-tolualdehyde adduct of potassium

cephalexin.

Analysis Calculated for Monohydrate: C, 57.0; H, 5.54;

N, 8.30. Found: C, 52.14; H, 4.53; N, 8.83.

Moisture (Karl Fischer) 12.01%

This compound was found to inhibit D. pneumoniae at a concentration of 0.3 mcg./ml., Str. pyogenes at 0.3 mcg./ml., S. aureus

BX1633-2 at 4 mcg./ml., Sal enteritidis at 4 mcg./ml, and

470.552

49,51 6 n K. pneumoniae at 8 mcg./ml.

Example 3 0 II I/H C S N

H -C CH3 CH3 O COOK

A mixture of 0.406 g. potassium cephalexin monohydrate, 0.15 ml. o-methoxybenzaldehyde and 15 ml. methylene chloride was slurried for about 4 hours. Dissolution did not occur after this time but the system became more viscous. The product was recovered by filtration, washed with methylene chloride and dried under vacuum. The dried product, the Schiff base o-methoxybenzaldehyde adduct of potassium cephalexin appeared very pale yellow and crystalline and weighed 300 mg.; m.p. >130*C The infrared spectrum was consistent for the Schiff base structure shown above. Analysis Calculated for Monohydrate: G, 55.28; H, 4.8; N, 8.05. Found: C, 53.42; H. 4.72; N, 8.48. Moisture (Karl Fischer) 8.63%. This compound was found to inhibit D. pneumoniae at a concentration of 0.16 mcg./ml., Str. pyogenes at 0.16 mcg./ml., S. aureus Smith at 0.6 mcg./ml., S. aureus BX1633-2 at 2 mcg./ ml., and Sal. enteritidis at 2 mcg./ml.

47 0.55 2

49,516 f72 Example 4

0

\Z jj/Cl II CH

H -C 3 JCOOK

CH 3

OCH 3

To a mixture of 0.406 g. potassium cephalexin monohydrate.

and 15 ml. methylene chloride was added with agitation 0.170 g.

3,4-dimethoxybenzaldehyde. Stirring was continued for an additional 3 hours during which the reaction mixture thickened.

After being allowed to stand at 25°C for 16 hours, the system

was filtered with suction and dried for 68 hours at 250 C in a vacuum oven. The product, the Schiff base 3,4-dimethoxy-

benzaldehyde adduct of potassium cephalexin, weighed 0.440 g.

and darkened upon heating at 130°C. The infrared spectrum

is consistent for the Schiff base structure shown above.

Analysis Calculated for Monohydrate: C, 54.60; H, 4.76;

N, 7.64;

Found: C, 51,32; H, 4.64; N, 8.35.

Moisture (Karl Fischer) 4.76%

470.55 2

49, 516 72

Example

0 II H C H

C N N II N CH CH 0 3 JCOOK

OCH 3

The dimethylformamide solvate of cephalexin [cephalexin

(DMF)2 (1.8 was slurried in 40 ml. n-butanol and dissolved by addition of 1.6 ml. triethylamine and 0.4 ml. water. To this solution was.added 0.495 g. p-anisaldehyde and the system was reacted for one hour. Potassium ethyl

hexanoate wax (0.58 was added and crystallization occurred. The crystals were allowed to form over a span of two hours and were collected by suction filtration. The product was

dried for 15 hours under vacuum and the dried product weighed 250 mg. and appeared as off-white crystals. The

IR and NMR spectra were consistent for the Schiff base form of the p-anisaldehyde adduct of potassium cephalexin. Analysis Calculated for Monohydrate: C, 54.8; H, 5.33; N, 7.99; Found: C, 53.98; H, 4.93; N, 7.75. Moisture (Karl Fischer) 4.35% D. pneumoniae at a concentration This compound was found to inhibit

Str. pyogenes at 0.16 mcg./ml., S. aureus Smith of 0.16 mcg./ml.,

S. aureus Bx 1633-2 at 4 mcg./ml., E. coli Juhl at 0.6 mcg./ml.,

K. pneumoniae at 8 mcg./ml., Pr. mirabilis at at 8 mcg./ml.,

8 mcg./ml. and Sal. enteritidis at 4 mcg./ml. 13 470,.552

49, 516 72 Example 6

0

II I CH3 C 3 H COOK

The dimethylfornamide solvate of cephalexin [cephalexin

(DMF)2 (1.8 was slurried in 40 ml. n-butanol and dissolved by addition of 1.6 ml. triethylamine. To this

solution was added 0.568 ml. of 1-naphthaldehyde and 0.4 ml.

water and the system was allowed to stand for 15 minutes.

Upon addition of 0.58 g. KEH wax, a glassy waxlike precipitate

starting forming and the system was allowed to stand for

63 hours at 25°C. The product, the Schiff base 1-naphthaldehyde

adduct of potassium cephalexin, was recovered by suction

filtration, washed with 60 ml. of fresh butanol and dried

in a vacuum oven for 16 hours at 250 C. The dried product

weighed 1.15 g. The infrared and nuclear magnetic resonance

spectra were consistent with the Schiff base structure shown

above. Analysis Calculated for Monohydrate: C, 60.00; H, 4.66;

N, 7.77.

Found: C, 58.56; H, 4.44; N, 7.56.

Moisture (Karl Fischer) 3.52%

470.55 2

49,516 I This compound was found to inhibit D. pneumoniae at a concentration of 0.16 mcg./ml., Str. pyogenes at 0.16 mcg./mI., S. aureus Smith at 0.6 mcg./ml., S. aureus Bx 1633-2 at 2 mcg./ml., Sal. enteritidis at 4 mcg./ml., K. pneumoniae at 4 mcg./ml. and Pr. mirabilis at 4 micg./ml.

470,55 2

49,516 72 Example 7

0 II

0 NCH3 H-N CN C COOK

Potassium cephalexin monohydrate (0.812 and cyclohexanone (0.2 ml.) were reacted in 5 ml. methanol for 4

hours. Isopropanol (100 ml.) was then added in an attempt to shock-out the reaction product. When this failed, the system was flash evaporated and dried under vacuum to yield

0.81 g. of glassy product; m.p. 1650 C. The IR and N.M.R. spectra were consistent for the cyclic form of the

cyclohexanone adduct of potassium cephalexin.

Analysis Calc'd on basis of monohydrate: C, 54.70; H, 5.59; N, 8.69. Found: C, 53.14; H, 5.28; N, 8.75. Moisture (Karl Fischer) 5.98%. This compound was found to inhibit D. pneumoniae at a

concentration of 0.8 mcg./ml., Str. pyogenes at 0.8 mcg./ml., Sal.enteritidis at 4 mcg./ml., S. aureus Smith at 1.6 mcg./ml. and Pr. mirabilis at 8 mcg./ml.

Example 8

0 H II

0 C COOH COOH

470,55 2

49,51-6 I The dimethylformamide solvate of cephalexin

[cephalexin (DMF) 2 (1.8 was dissolved in 40 ml. water by adding 0.5 ml. triethylamine. Cyclohexanone

(0.45 ml.) was added and the solution was stirred for 2 hours. A total of 39 ml. 0.1N HC1 was added to bring

the solution to pH 3.0 whereupon a white, amorphous

precipitate formed. The product, the cyclic cyclohexanone

adduct of cephalexin, was recovered by filtration and dried under

vacuum to yield 100 mg.; m.p. >1650 C. The absence 1 of a 1500 -1550 cm peak and the presence of strong 2950 and

2870 cm 1 peaks on the IR spectrum are consistent for the cyclic structure shown above.

Example 9

0

H c I/ 1

H-N-C SH-N-N CH3 CH3 (CH 2 3 0

CH3 COOK

Potassium cephalexin (0.388 was slurried in 15 ml.

methylene chloride and 0.1 ml. n-valeraldehyde. After stirring

in a closed container for about 4 hours, dissolution was

completed and the system was allowed to stand at ambient

temperature for 12 hours. After filtering, the filtrate was

flash evaporated to dryness. Complete drying was accomplished

under vacuum to yield 390 mg. of dried product; m.p. 1100 C.

The IR and NMR spectra were consistent for the

cyclic form of the valeraldehyde adduct of potassium cephalexin.

1' 410.552

49,51 6 172 Analysis Calc'd for monohydrate: C, 50.80; H, 5.49; N, 8.87. Found: C, 51.62; H, 5.26; N, 8.22. Moisture (Karl Fischer) 5.40%. This compound was found to inhibit D. pneumoniae at a con- centration of 1.3 mcg./ml., Str. pyogenes at 1.3 mcg./ml., S. aureus Bx 1633-2 at 8 mcg./ml. and Sal. enteritidis at 8 mcg./ml.

Example 0 II H C

H-N -C CH CH2 I COOK CH3 C CH3

H

To a slurry of potassium cephalexin monohydrate (0.406 g.) and 15 ml. methylene chloride was added 0.10 ml. isovaleraldehyde. The reaction flask was covered with foil and stirring continued for 4 hours. After being allowed to stand overnight at 250 C., a mostly clear solution had formed which was filtered and then dried by flash evaporation. Drying was completed in a vacuum oven at 250 C. for 63 hours. The dried product, the cyclic isovaleraldehyde adduct of potassium cephalexin, was found to weigh 0.415 m.p. 1000 C. (dec.) The IR and NMR spectra were consistent for the cyclic structure shown above. Analysis: Calc'd: C, 51.60; H, 5.37; N, 8.63. Found: C, 53.75; H, 5.60; N, 8.88. Moisture (Karl Fischer) 6.00%

470,552

49,516 /72 This compound was found to inhibit D. pneumoniae at a concentration of 0.3 mcg./ml., Str. pyogenes at 0.3 mcg./ml., S. aureus Smith at 1.3 mcg./ml., S. aureus Bx 1633-2 at 4 mcg./ml., K. pneumoniae at 8 mcg./ml. and Pr. mirabilis at 8 mcg./ml.

Example 11 0 II

H CH 03 COONa

Sodium cephalexin monohydrate (1.16 was dissolved in 6 ml. methanol and 0.3 ml. cyclopentanone was added. After being allowed to stand for 15 to 20 hours at ambient tem- perature, the solution was filtered and the filtrate flash- evaporated to dryness. Complete drying was accomplished under vacuum to yield 1.15 g. of a yellowish powder which appears to be about 50% crystalline chunks m.p. 1600 C. The IR and NMR spectra were

consistent for the cyclic form of the cyclopentanone adduct of sodium cephalexin. Analysis Calc'd on basis of monohydrate: C, 53.8; H, 5.33; N, 8.96. Found: C, 51.36; H, 5.27; N, 9.12. Moisture (Karl Fischer) 1.95%

470,55 2

49,51-6 72 This compound was found to inhibit D. penurnoniae at a concentration of 0.3 mcg./ml., Str. pyogenes at 0.3 mcg./ml., S. aureus Smith at 1.3 mcg./ml., S. aureus Bx 1633-2 at 4 mcg./ml., Sal. enteritidis at 4 mcg./.nl., E. coli Juhi at 8 mcg./ml., K. penumoniae at 8 mcg./ml. and Pr. mirabilis at 8 mcg./ml.

Example 12

0 HO CH C

C1 H-N NS

N CH3 COONa

The procedure of Example 9 is repeated except that the potassium cephalexin and n-valeraldehyde used therein are replaced by sodium 3-chloro-4-hydroxycephalexin and cyclopentanone, respectively. There is produced the cyclic cyclopentanone adduct of the sodium salt of 3;-chloro-4-hydroxycephalexin; m.p. 90-1000 C. (decomp.); purity :85-90%; specific rotation 25 ral D- +1420

(c,l in water)

The flR and N14R spectra were consistent with the cyclic structure shown above.

470,55 2

49,516 1 Example 13

0 II CH C I I

OCH 3 COONa

The procedure of Example 12 was repeated except that the cyclopentanone was replaced by p-anisaldehyde. There was obtained in quantitative yield the p-anisaldehyde adduct of the sodium salt of 3-chloro-4-hydroxy-cephalexin; m.p. 170-175°C. (decomp.); purity: 90-95%; specific rotation

[a]2d5 +138°. (c,l in water) The IR and NMR spectra were consistent for the cyclic structure shown above.

Example 14

O HO -CH C NH

I O H N 0 3 II COONa

0 470,55 2

49,51 6 J the The procedure of Example 12 was repeated except that

cyclopentanone was replaced by cyclohexanone and the sodium 3-

chloro-4-hydroxycephalexin by sodium p-hydroxycephalexin. There

was obtained in quantitative yield the cyclohexanone adduct of

the sodium salt of p-hydroxycephalexin; m.p. 235-240oC. (decomp.);

5 purity 90-95%; specific rotation [Ca +158. The IR and NMR (c,l in water)

spectra were consistent with the Schiff base structure shown

above.

Example

HO CH-- C H-N N O

0 SCOOH

NO2

The procedure of Example 12 was repeated except that

the cyclopenatnone was replaced by p-nitrobenzaldehyde and the

sodium 3-chloro-4-hydroxycephalexin by sodium p-hydroxycephalexin.

There was obtained in quantitative yield the p-nitrobenzaldehyde

adduct of the sodium salt of p-hydroxycephalexin; m.p. 0 164-166 C. (decomp.); purity: 85-90%; specific rotation 25 5 iac] (c,l in water)

The IR and NMR spectra were consistent with the cyclic

structure shown above. 2 47 0 552

Claims (1)

1. 49,516 I as follows: The claims defining the invention are

   1. A process for the preparation of compounds of the general formula

   S R X-

   N CH3 COOH

   II wherein R is

   or R2

   R3

   in which R 1 R2 and R3 are hydrogen, halo, hydroxy, (lower)- alkyl, nitro, amino,(lower)alkanoyl, trifluoromethyl, (lower)alkoxy or (lower)alkylmercapto; and X is

   0 0

   H-N N- or C C

   C N NH- R R5 C R R

   in which either R is hydrogen and R5 is C2 C6 alkyl

   or A. wherein A represents an aromatic radical of the formula

   470,55 2

   R6 49,51 6 1

   lO 8 or R9 R 7

   R8

   in which R6 R, R8 R and R10 are hydrogen, nitro, di(lower)alkylamino, (lower)alkanoylamino, (lower)- alkanoyloxy, (lower)alkyl, (lower)alkoxy, sulfamyl, halo, trifluoromethyl, (lower)alkylthio, (lower)alkylsulfonyl, carbo(lower)alkoxy, benzyl, phenethyl, cyclopentyl, cyclohexyl, or cyclcheptyl or R4 and R5 when taken together with the carbon atom to which they are attached represent cycloalkylidene having 4 to 7 carbon atoms inclusive; and nontoxic pharmaceutically acceptable salts thereof; which process comprises reacting a cephalosporin of the formula

   0 II S R-CH C -NH

   NH2 0 C 3

   COOH I

   wherein R is as defined above, or a salt thereof, with a carbonyl compound selected from those having the formula

   R4 R

   wherein R and R are as defined above.

   -24- 470,55 2

   49,51 6 f72 2. The process of Claim 1 wherein substituent R in the cephalosporin starting material is unnubstituted phenyl, p-hydroxyphenyl or 3-chloro-14-hydroxyphenyl.

   3. The process of Claim 2 wherein the carbonyl compound is selected from benzaldehyde, p-tolualdehyde, o-methoxy- benzaldehyde, 3,i4-dimethoxybenzaldehyde, p-anisaldehyde, l-naphthaldehyde, cyclohexanone, n-valeraldehyde, iso- valeraldehyde, cyclopentanone or p-nitrobenzaldehyde.

   -25- 47Q55 2

   49,51 6 72 Compounds of the formula

   S

   N C

   COOH II wherein R is R1

   or

   R2 R3

   1 in which R R 2 and R 3 are hydrogen, halo, hydroxy, (lower)-

   alkyl, nitro, amino, (lower)alkanoyl, trifluoromethyl, (lower)-

   alkoxy or (lower)alkylmercapto; and X is 0

   O H-N N- II C-- C or I 4' 5 N NH- R R II C

   R R

   in which either R4 is hydrogen and R5 is C2 C6 alkyl or wherein A represents an aromatic radical of the formula

   -26- 470:55 2

   49.516 I72

   RI or 9-oRio R7/

   Ln which R6 R, R8 R9 and R10 are hydrogen, nitro, li(lower)alkylamino, (lower)alkanoylamino, (lower)alkanoyloxy, :lower)alkyl, (lower)alkoxy, sulfamyl, halo, trifluoromethyl, lower)alkylthio, (lower)alkylsulfonyl, carbo(lower)alkoxy, )enzyl, phenethyl, cyclopentyl, cyclohexyl, or cycloheptyl )r R4 and R 5 when taken together with the carbon atom -o which they are attached represent cycloalkylidene having to 7 carbon atoms inclusive; and nontoxic pharmaceutically .cceptable salts thereof.

   Compounds of the formula

   0 11 R CH C I II S H-N N

   R C R N C H3 0 R R COOH

   wherein R, R and R are as defined in Claim 4, or nontoxic pharmaceutically acceptable salts thereof.

   -27- 470:55 2

   49,51 6 172 6. Compounds of the formula

   0

   R-CH- C- NH

   C H C( COOH

   wherein R, R4and R5are as defined in Claim 4, or nontoxic pharmaceutically acceptable salts thereof.

   7. The compounds of any of Claims 4-6 wherein R 4 is unsubstituted phenyl, p-hydroxyphelyl or 3-chloro- hydroxyphenyl, or nontoxic pharmaceutically acceptable salts thereof.

   8. The compound of the formula

   0

   C H C H N

   H- C 0 CH 3I

   COOR

   -28- -8-470.55 2

   49,51672 and nontoxic pharmaceutically acceptable salts thereof.

   9. The compound of the formula

   I -C

   ~1 coo H

   CH3

   and nontoxic pharmaceutically acceptable salts thereof.

   The compound of the formula

   0

   II

   N H- C C CH3 0. COOH

   -29- 470552 -29~

   49,51 6 and nontoxic pharmaceutically acceptable salts thereof.

   11. The compound of the formula

   H- COOH

   and nontoxic pharmaceutically acceptable salts thereof.

   12. The compound of the formula

   0

   N CH N II CH 0 3 COOH

   OCH3

   and nontoxic pharmaceutically acceptable salts thereof.

   49,516 In 13. The compound of the formula

   0

   and nontoxic pharmaceutically acceptable salts thereof.

   14. The compound of the formula 0~ II

   N C H H-c a a b 3h 0 COOH

   or nontoxic pharmaceutically acceptable salts thereof.

   -31- 470,55 2

   49,51 6 72n The compound of the formula

   0 H C

   C HN

   H-N-C I N ,O CH3 (cH2 3 o C, COOH

   or nontoxic pharmaceutically acceptable salts thereof.

   16. The compound of the formula

   0II H C

   0 I C H-N- I/N CN

   CH2 I S

   CH

   I COOH CH3 C CH3

   H

   or nontoxic pharmaceutically acceptable salts thereof.

   -32- 470552

   49,5$1 692 17. The compound of the formula

   COOH

   or nontoxic pharmaceutically acceptable salts thereof.

   18. The compound of the formula

   0 11 -C

   Cl li-N CH3

   COOH

   or nontoxic pharmaceutically acceptable salts thereof.

   -337 470552

   49,516/72 19. The compound of the formula

   oI 0

   HO CH C

   I I N S C1 H-N

   OCH 3 COOH

   or nontoxic pharmaceutically acceptable salts thereof.

   The compound of the formula

   0 S HO CH- C -NH

   0 3 N

   COO H 6 pharmaceutically nontoxic acceptable salts thereof. cooor

   or nontoxic pharmaceutically acceptable salts thereof.

   -34- 470,55 2

   49,516 In 21. The compound of the formula

   HO CH-- I. H-N I

   CH C0 H3 0 COOH

   or nontoxic pharmaceutically acceptable salts thereof.

   22. The sodium or potassium salts of the compounds

   of any of Claims 8-21.

   23. The compounds of any of Claims 8-22 having the

   D-configuration.

   DATED: 22nd November, 1972

   PHILLIPS ORMONDE FITZPATRICK Attorneys for: BRISTOL-MYERS COMPANY

   A ;<t

   470,55 2