CS203167B2 - Method of preparing 7-substituted amino-acetamidooxadethia-cephalosporins - Google Patents

Description

The invention relates to a process for the preparation of cephalosporins, in particular aminoacetamidooxadethiationphalosporins substituted at the 7-position, to esters thereof and to pharmaceutically acceptable salts thereof.

Said oxadethiacephalosporins, esters thereof, and pharmaceutically acceptable salts thereof are novel and potent drugs that exhibit excellent antibacterial activity.

Certain oxadethiationphalosporins are already known in the art. Japanese Patent Application Publication No. 133,593 / 1974 relates to oxadethiacephalosporins, but the compounds disclosed herein are different from the oxadethiacephalosporins of the present invention with respect to activity against resistant bacterial species.

The invention relates to a process for the preparation of compounds of the following formula (I)

f / J wherein R is O O

in which

R ³ represents a hydrogen atom or an alkyl group containing a total of from 1 to 5 carbon atoms; R represents a group of formula XR ⁵

II / —NCN

I \

R ⁴ R ⁶ where

X represents an oxygen or sulfur atom, and

R ⁴ , R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen or C 1 -C 5 -alkylalkyl;

X ¹¹ n?

-WCN-R '

LJ where

X represents oxygen or sulfur and ^R7 is hydrogen or a mesyl group, then R represents a group of formula -NCO-R ⁹

AND

R ⁸ where

R ⁸ represents a hydrogen atom or an alkyl group having a total of 1 to 5 carbon atoms, and

R ⁹ is phenyl (C 1-6) alkenyl, further R is phenyl substituted with one or two hydroxy or acetoxy group (s), oxothiopyranyl, or 8- (C 1-5) alkyl-3- (C 1-5) alkoxy A 5-oxo-5,8-dihydropyrido [2,3-c] pyridazinyl group,

Ar is a phenyl group optionally substituted by one or two groups selected from the group consisting of hydroxy, carbamoyloxy and acetoxy,

Y is a hydrogen atom or a methoxy group,

Het is 1- (C 1-5) alkyl-tetrazol-5-yl, 1,3,4-thiadiazol-5-yl or 2- (C 1-5) alkyl-1,3,4-thiadiazol-5-yl and

Z is hydroxy, C 1 -C 5 alkoxy, phenyl (C 1-6 alkoxy, diphenyl (C 1-5) alkoxy, sodium oxy or potassium oxy).

The process for the preparation of the above-mentioned 7-substituted aminoacetamidooxadethicephalosporins of the above general formula (I) consists in acylating a compound of the formula (IV)

CO 2 ^ NCHCONH- · Ar

O (IV) in which they have

Ar. Y, Z and Het as defined above, or derivatives of this compound at the α-amino or 7-glycylamino group by a carboxylic acid of the general formula V

RGOOH (V), wherein R is as defined above, or a functional derivative of the acid at the carboxyl group, said derivative selected from the group consisting of an acid halide, an acid anhydride, an active ester, an active amide, and ketene.

An example of the substituent R in the above compound of formula I is:

4-methyl-2,3-dioxopiperazinyl, 4-ethyl-2,3-dioxopiperazinyl, most preferred is 4-ethyl-2,3-dioxopiperazinyl.

In the case where R is a substituent

XR ⁶

II / —NCN I \

R @ ⁴ R @ 5 as examples of suitable substituents include:

—NHCONH2,

NHCSNHCH3,

-Ν'NH, ~ N N-SO £H.

O

X \ - / * ³ of which the more preferred are the groups:

O O χ Λ

-NΝΗ, -Ν N-SO..CH.

\ __ /

In the case where R is an -NCO-R ⁹

AND

R ⁸ is the most preferred N-methyl-N-cinnamoylamino group.

Preferably R is phenyl substituted with one to two hydroxy or acetyloxy groups.

Generally, " Ar " refers to an aryl group which may be used generally in this process, but according to the invention a phenyl group and a substituted phenyl group such as p-hydroxyphenyl, p-carbamoyloxyphenyl or p-acetoxyphenyl are used as aryl .

Pharmaceutical salts and esters of the compounds are also included.

Said salts of the compounds of the invention may be organic and inorganic salts, for example, sodium salt, potassium salt, magnesium salt, calcium salt, triethylamine salt, dicyclohexylamine salt, morpholine salt and N-methylmorpholine salt, and the like.

The group of esters of compounds of the invention include tert-butyl, acyloxymethyl, phthalidyl, diphenylmethyl, trityl, benzyl, p-nitrotoenzylester, p-methoxybenzyl, 2,2,2-trichloroethyl ^r; rethylester 2-halogenethylester and phenacyl esters. other readily cleavable aliphatic esters, aromatic esters such as phenyl esters or indanyl esters, and the like.

In carrying out the process of the present invention for the preparation of the above compound of formula (I)

RCONUCHCONHAr

O (I)

CQZ in which Ar, R, Y, Het and Z are as previously defined in which they are acylated with an acylating agent of formula V

RCOOH (V) a compound of formula IV

in which R, Ar, Y, Z and Het are as previously defined, the aforementioned α-amino group may be activated to form isocyanate, isocyanate, 1-haloalkylideneamino, 1-alkoxyalkylideneamino, silylamino, enamino and the like prior to the reaction. . The compound of formula (V) may be in the form of, for example, free acid, acid halide, acid anhydride, active ester, active amide, ketene, and the like, containing the desired acyl residue. The above acylation may be carried out in the presence of a basic compound (e.g. triethylamine, pyridine or sodium bicarbonate), in the presence of a molecular sieve, a carbodiimide (such as dicyclohexylcarbodiimide), an epoxide (such as propylene oxide or butylene oxide) and an enzyme where necessarily. The acid chloride method, the acid anhydride method, the carbodiimide method and the active ester method may be used.

The oxadethiationphalosporins of the present invention can be used as highly effective active antibacterial agents against gram-negative species and species resistant to other cephalosporins and penicillins.

The antibacterial activity of several selected typical compounds of formula I that are dissolved in aqueous sodium bicarbonate is shown in Table I, which follows.

Table I

Bacteria tested Minimum inhibitory concentration [^ g / ml]

Compound

A B C

Staphylocockus aureus C — 14 1.6 3.1 1.6 Escherichia coli NIHJ JC —- 2 0.2 0.01 0.1 Escherichia coli 0.4 12.5 25 Klebsiella pneumoniae 0.01 0.01 0.05 Klebsiella sp. 363 0.1 12.5 100 ALIGN! Proteus mirahilis PR — 4 0.4 0.4 1.6 Proteus vulgaris CN — 329 0.2 0.2 0.8 Enterobacter cloacae 233 0.8 0,1 ' 0.8 Serratia marcescens 13 880 0.8 0.05 0.8 Pseudotnonas aeruginosa 25 619 3.1 0.8 0.8 Pseudomons aeruginosa Denken 12.5 6.3 6.3 Pseudomonas aeruginosa 24 25 3.1 6.3

Note: Test compounds (sodium salts)

A = 7'-methoxy-7 ', (3- [Da-phenyl-N- (4-ethyl-2,3-dioxo-1-piperazinylcarbonyl) glycylamino] -3- (1-methyl-1H-tetrazole-5) -ylthiomethyl) -1-oxadethia-3-cephem-4-carboxylic acid,

B = 7- [N- (p-hydroxyphenyl) -N- (4-ethyl-2,3-dioxo-1-piperazinylcarbonyl) glycylamino] -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) - 1-Oxadethia-3-cephem-4-carboxylic acid,

C - 7- [D-α- (p-hydroxyphenyl) -N- (4-ethyl-2,3-dioxo-1-piperazinylcarbonyl) glycylamino] -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) 13-Cef-4-carboxylic acid (control compound).

The results show that the compounds of the formula I exhibit a stronger antibacterial action, in particular against gram-negative bacterial species, than the corresponding thio compounds. The other compounds of the present invention exhibit similar antimicrobial activity to that of the test compounds.

The compounds of formula (I) of the present invention, including certain esters and pharmaceutically acceptable salts thereof, are effective in preventing or treating various human and animal diseases caused by bacteria. The compounds of formula I may be administered as such or in the form of mixtures. In addition, it will be appreciated that the compounds of the present invention may be administered in combination with pharmaceutically acceptable carriers, diluents, excipients and other suitable drugs where necessary.

The carrier is determined according to the chemical properties of the compound of formula (I) to be used in the present case and the objective to be attained, as well as the mode of administration. Examples of suitable carriers for external and internal administration include lactose, sucrose, starch, dextrin, sodium bicarbonate, licorice powder, talc, kaolin, bentonite, calcium carbonate, paraffin, and the like. As a gel or liquid carrier, for example, gelatin, water, ethanol, isopropanol, chloroform, glycerol and the like can be mentioned. Further, freon (trade name) may be used in conjunction with the present invention in the form of an aerosol in the form of an aerosol.

Practical examples of suitable pharmaceutical formulations of the compounds of Formula I include tablets, capsules, pills, granules, powders and the like, for oral administration, and in the form of solutions for injection, ointments, aerosols, suppositories and the like for parenteral administration.

The pharmaceutical compositions according to the invention may contain the compound of the formula I as active ingredient in an amount ranging from 0.01 to 99% by weight. The compounds of formula (I) are generally administered to humans and animals at daily dosages ranging from about 250 mg to 5 g, the amount of said compound varying according to the objective to be achieved, the condition of the patient, the susceptibility of infectious bacteria and the method; administration interval.

The following examples are provided for illustrative purposes only and are not intended to limit the invention in any way.

Example 1 (1j) A solution of 7- [DDap-hydroxyphenylglycylamino] -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -1-oxadethia-3-cephem-4- of carboxylic acid (75 mg) in tetrahydrofuran (2.0 ml) was vigorously stirred while cooling in an ice bath, and a solution of 4-ethyl-2,3-dioxo-1-piperazinylcarbonyl chloride (100 mg) in tetrahydrofuran (100 mg) was added. 0.5 ml and a 5% aqueous solution of sodium bicarbonate at 2.0 ml over 5 minutes, followed by stirring at 0 ° C for 30 minutes. water was added to the mixture, washed with ethyl acetate, and then neutralized with dilute hydrochloric acid. The aqueous layer was evaporated to dryness under reduced pressure. The residue thus obtained is subjected to extraction with methanol and the extract is evaporated to remove the solvent. The residue and the oily residue thus obtained were subjected to chromatography on a silica gel column, eluting with 5: 1 ethyl acetate: acetic acid (5.0 ml). Silica gel contains 10% water, the total amount of which is 6 grams. The resulting ethyl acetate / acetic acid eluate (30 ml) was subjected to thin layer chromatography on silica gel using a mixture of ethyl acetate / acetic acid / water (8: 1: 1) as developing agent. Stain _Rf value of 0.15 are collected to give pure hygroscopic and 7- [DA- (p-hydroxyphenyl) -N- (4-ethyl-2,3-dioxo-piperaziriylkarbonyl) glycylamino] -3 (1-Methyl-1H-tetrazol-5-ylthiomethyl) -1-oxadethia-3-cephem-4-carboxylic acid as a powder, total yield 11 mg.

Elemental analysis for C 25 H 26 N 8 O 9 S. 2H2O: Calculated: (° / o)

C = 46.17, H f = 4.66, N = 17.23, S = 4.92 Found: (%)

C = 46.30, H = 4.55, N = 17.36, S = 4.80

IR ν _max (KBr): 3350, 1790, 1715, 1675 cm ^-1 , NMR δ CDCl 3 - CD 3 OD (1: 1): 1.15 t (7Hz)

3H, 3.50-4.70 m 10H, 3.97 s 3Ή, 5.02 d (4Hz) 1H, 5.45 s 1H, 5.53 d (4Hz) IH, 6.93 d (9Hz) 2H 7.32 d (9Hz) 2H.

(1 ') 0.5 ml of propylene oxide and 0.25 ml of bis (trimethylsilyl) acetamide were added to the suspension of 7- [Dap-hydroxyphenylglycylamino] -3- (1- methyl-1H-tetrazol-5-ylthiomethyl) -1-oxadethia-3-cephem-4-carboxylic acid 130 mg in 2 ml of acetonitrile while cooling in an ice bath, then stirred for 10 minutes and after stirring, 46 mg of 4-ethyl-2,3-dioxo-1-piperazinylcarhonyl chloride was added. The mixture was stirred for 1 hour at 0 ° C and then for an additional 30 minutes at ambient temperature, followed by the addition of 5% aqueous sodium bicarbonate and ethyl acetate. The aqueous layer is washed with ethyl acetate, the pH is adjusted to 2 with dilute hydrochloric acid and the precipitate is filtered off. The filtrate was subjected to silica gel column chromatography (containing 10% water and 7 grams total) and eluted with acetone / acetic acid (1: 1) to give the total amount of the eluent. is about 70 milliliters. The eluate obtained is then subjected to thin layer chromatography on silica gel using a mixture of ethyl acetate, acetic acid and water (8: 1: 1) as developing agent. Thereafter, the stain value R _f 0.20 is separated to give 7- [D-α- (p-hydroxyphenyl) -N- (4-ethyl-2,3-dioxo-l-piperazinylcarbonyl) glycylamino] -3- ( 1-methyl-1H-tetrazol-5-ylthiomethyl) -1-oxadethia-3-cephem-4-carboxylic acid as a powder and a total amount of 95 mg.

Yield: 68 ° / o,

Melting point: 175-178 ° C (dec.). EXAMPLE 2 (1) To a suspension of 7α-methoxy-7 ₍ 3- [Di - (p-hydroxyphenyl) glycylamino) -3- (1-methyl-1H-tetrazole) trifluoroacetate]. 5-thiomethyl) -1-oxadethia-3-cephem-4-carboxylic acid (160 ml) in acetonitrile (2 ml), propylene oxide (0.5 ml) and O, N-bis (trimethylsilyl) acetamide (0.30 ml) The mixture was stirred for 20 minutes and then treated with 4-ethyl-2,3-dioxo-1-piperazinylcarbonyl chloride (70 mg) and a further dilute aqueous bicarbonate solution was added. sodium and ethyl acetate after stirring the mixture for 1 hour, at 0 ° C and at ambient temperature each time, then the diluted sodium bicarbonate layer is separated, washed with ethyl acetate, and then neutralized with dilute hydrochloric acid. manner precipitated substance was filtered off and the filtrate was subjected to the chromatography using a silica gel containing 10% water. The 4: 1 acetone: acetic acid fractions were collected and evaporated to give 7H-methoxy-7H- [D-of- (p-hydroxyphenyl) -N- (4-ethyl-2,3-dioxo) acid. -1-piperazinylcarbonyl) glycylamino} -3- (1-methyl-1H-tetrazol-5-ylthlomethyl) -1-oxadethia-3-cephem-4-carboxylic acid in the form of a powder and in an amount of 90 mg.

Yield: 52%.

Melting point: 182-186 ° C (dec.).

IR _max (KBr): 3275 (br), 1775, 1708, 1670 ^cm-first

Example 1 a d 3

The procedure was as in Example 1- (1), starting from 7-Da-phenylglycylamino-3- (1-methyl-1H-tetrazol-5-ylthiomethyl) trifluoroacetate. -1-oxadethia-3-cephem-4-carboxylic acid, yielding crystals of 7- [α-phenyl-N- (4-ethyl-2,3-dioxo-1-piperazinylcarbonyl) glycylamino] -3- (1- methyl-1H-tetrazol-5-ylthiomethyl) -1-oxadethia-3-cephem-4-carboxylic acid in an amount of 54 mg.

Yield: 66 ° / o,

Melting point: 169-171 ° C.

IR ν _max (KBr): 1780, 1705, 1670 cm ^-1 . Example 4

The procedure is followed by reacting 7- [D-a-phenylglycylamino] -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -1-oxadethia-3-cephem-4-carboxylic acid trifluoroacetate 80 mg with dimethylureidocarbonyl chloride 82 mg to give 7- [Da-phenyl-N- (1,3-dimethylureidocarbonyl) glycylamino] -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) - 1-oxadethia-3-ε-fem-4-carboxylic acid in the form of a colorless powder and in an amount of 26 milligrams.

Yield: 32.5%.

Melting point: 143-148 ° C, [a] _to ²² · ^5: -95.9 + 6.3 ° (c = 0.217: 1% aqueous sodium bicarbonate solution)

IR .nu.max (KBr): 3400, 1787, 1682, 1637, 1512 cm @ ^-1 .

Example 1 ad 5

In this example, propylene oxide (1.2 ml) and bis (trimethylsilyl) acetamide (0.5 ml) were added to the suspension of 7- [D-a-p-hydroxyphenylglycylamino] -3- (1- methyl-1H-tetrazol-5-ylthiomethyl) -1-oxadethia-3-cephem-4-carboxylic acid 300 mg in 5 ml of acetonitrile while cooling in an ice bath, then stirring for 10 minutes at ^0C C. to this mixture was added 4-methyl-2,3-dioxo-piperazinylkarbonylchlorid in 150 mg and the mixture was stirred for 1 hour at the same temperature for additional one hour at room temperature. This mixture was then treated in the same manner as in Example 12- (Γ) to give 7- [D-ia- (p-hydroxyphenyl) -N- (4-methyl-2,3-dioxo-1) acid. -piperazinylcarbonyl) glycylamino] -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -1-oxadethia-3-cephem-4-carboxylic acid in an amount of 180 mg (yield: 56%).

IR »max (KBr): 3280, 1780, 1700, 1680 cm ^first

The diphenylmethyl ester of the above compound has the following physical constants: IR v _max (CDCl 3): 3290, 1793, 1715, 1692 cm ^-1 , NMR δ CDCl 3: CD 3 OD (5: 1): 2.97 with 3H,

3.50-4.60 m 8H, 3.75 s 3H, 4.90 d (4Hz)

1H, 5.45d (6Hz) 1H, 5.50d — d (4Hz, 9Hz)

1H, 6.69 d (7Hz) 2H, 6.75 s 1H, 9.77 d (6Hz) 1H.

Examples 6 - 14

In embodiments of the examples, a compound of formula IV is reacted with a compound of formula V under the conditions set forth in Table 1 to give a compound of formula I. The physical constants are given in Table 2 below.

O (I)

Table 1

Compound (IV) Compound (V) Reaction Conditions Yield

Y Z Quantity of Solvents- R. Temperature Time (h) Catalysis- mg (%) (mg) body (ml) (mg) (ml) (° C) tor (mg)

Example No. Compound (IV) Compound (V) Reaction Conditions Yield

Ar Y Z Solvent Quantity- Solvent Quantity. Temperature Time (h) Catalyst- mg (%) (mg) body (ml) (mg) (ml) (° C) tor (mg) cm cn 00

it

What the

CD> N> CD

4->

'> »>

CD

O ra

O in

o in co o

CM

WHAT

CD s

O

Oj ó

o o

(

CD eo ffi

O

Oj

I o

o u

Ttl

P '- · »r o o«. **? dpw. W cd pq ra

O

Q CM

O

O β

O

CD

CD

El 0, 2 β> ra

S + j 3 03 4-i

SS fe>. r-c .2 g 43 £ ii <0 co η t3 'R o

i <3 & Λ g, O-i "

O

Cfl 0j ra

M a

* ra β

N

O

Oj

203187

CM

CM

ΙΌ

Ο

CM (β

X ř

θ'-p

Γ ”Χ

T-H NOS H3 H NO 3

Q

Ο

Ρύ

S ε

or (0 ο 2_ γ-Μ

Οη'Κ φ σ Η 'Λ

JL

- <C

CM +1 «

3-SI 2 hU 'Cf X 42 CM CO CM CM Cr Xf 42. 5 5 X co xf ⁷¹ E co £ CD CD co w Tf CO ° X X

CM CM

S ^N

Ό ffi ιη o π cd - B io xí o,

Xro ^ f “tx '-' N d X what in

CM cf

X ”co CZ) in ..» £ «6 χ ca v>

^ CO CO

N '23 X in O rf ^ Xd CO 2 °, r' 'SK Ncd

XV χ '(' CZ CZ))),), m in n m co X xf * in

Xf> - · CO * Q CO CM rf> no

LH Sf <α β

3

> φ ο

r-H

GB5 • 0 * 3 in ^1-1

O M ___ 'i.Cs * N> .X xS ^

TH CM ^ 3 M t> - About what θ '. ⁵ ”, o

CO b >

CM at

X co

WHAT

.. ® ° * £ Cn 'CO

Sx

CO ta «« ¹⁰ | what ie what *

í-l c <T cmru WHAT 00 s ® í £ what rH «U O 00 00 o σ> in o what b * CM rH tH ^ OOrH +> WHAT cf P-I '2 o * what * With CO rf C Xf CO '§ rH t> CQ □ 5M cm CL 3 φ rH For CO rf O CO. . C0 in About CM 1 CMOS FM oo o cn l «0 05 { t> xh co l what what 1 rH cn rH Q CO rf i-4 WHAT O CD lf) WHAT CM rd '1 rH | F rH | 1 CM 1 1 o 1 in what CM tH tH r-i

X

P3

O ca o

'43

Pn

Λ

I ο

X

I a

Cu

Pz

X n

T? ®

Kh

2L ^

Ό v

O o ^T ~ ico * U5 «X“ f EN) S CM CO

3 ^ 3 I x

CM 1Ό §'x sé

U5 CO!>. 05 CM xf CO τ-1

U5CO * CO rf

05 CO CO. M X X 3 N

CM ^e S

CO xf b * O *

I ^H «x

CO rf

X 7? s-1 X oi in _ 1-1 O * —j

O),_.

WHAT

-O '. X X X rf O- rf

20316 7

Examples 15 - 18

The following compounds were prepared in the same manner as in the preceding examples.

Example #

D-RCONUCHCONH

AND

Ar

(0

Table 3 Ar

Melting point (° C)

IR: Pn, _ax KBr (cnr ⁴ )

Ph 185-190 3410, 1779, 1665, 1603, 1522

Ph 178—185 3400, 1789, 1740, 90, 1394, 1358, 1169 p-HO-Ph 204—211 3390, 1772, 1739, 1683, 1614, 1355, 1168

CHíNHCN—

Ph-3400, 1789, 1670, 1515, 1500

CHs

Claims (1)

A process for the preparation of 7-substituted aminoacetamidooxadethiationphalosporins of formula (I) X ŘS NCN RCONUCHCONlJ · Ar o (I) wherein R is O O where R ³ represents a hydrogen atom or an alkyl group having a total of 1 to 5 carbon atoms, or R represents a group wherein X represents an oxygen or sulfur atom and R ⁴ , R ^{5 and} R ⁶ are independently selected from the group consisting of hydrogen or an alkyl group having a total of 1 to 5 carbon atoms, or R represents a group X II? -NCN-R? LJ where X represents an oxygen or sulfur atom, and R ⁷ is a hydrogen atom or a mesyl group, 1S furthermore R represents an NCO-R ⁹ 2031B7 where R ⁸ represents a hydrogen atom or an alkyl group having a total of 1 to 5 carbon atoms, and R ⁹ is phenyl (C 1-5) alkenyl, phenyl substituted with one or two hydroxy or acetoxy groups or groups, oxo-thiopyranyl, or 8- (C 1-5) alkyl-3- (C 1-5) alkoxy-5-oxo-5,8-dlhydropyrido2 3-c] pyridazinyl, Ar is a phenyl group, optionally substituted with one or two groups selected from the group consisting of hydroxy, carbamoyloxy and acetoxy, Y is a hydrogen atom or a methoxy group, Het is 1- (C 1-5) alkyl-tetrazol-5-yl, 1,3,4-thiadiazol-5-yl or 2- (C 1-5) alkyl-1,3,4-thiadiazol-5-yl, and Z is a hydroxy group, an alkoxy group having from 1 to 5 carbon atoms, a phenyl (C 1-6 alkoxy, diphenyl (C 1-6) alkoxy, sodium oxy or potassium oxy group), characterized in that the compound of formula (IV) is acylated in which Ar, Y, Z and Het are as hereinbefore defined, or derivatives thereof with n-α-amino or 7-glycylamino with carboxylic acid of the general formula V RCOOH (Vj in which R is as defined above) or a functional derivative of the acid at the carboxyl group, said derivative selected from the group consisting of an acid halide, an acid anhydride, an active ester, an active amide, and ketene.