FI74009C - FREQUENCY REQUIREMENT FOR THERAPEUTIC USE OF THERAPEUTIC MEASURE 2-carboxylate. - Google Patents

Description

1 74009

Process for the Preparation of Therapeutically Useful 3- [2- (1-Tetrahydrothiophenium) Ethyl] -7- (6-) (hydroxyethyl) -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate relates to a method for preparing a new carbapenem antibiotic. This antibiotic is 3- [2- (1-tetrahydrothiophenium) ethyl] -6- [α- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2.07] hept-2-ene-2-carboxylate, whose 10 formula is

OH H

J ..

* 1-f | p S-CH2CH2-Sn 1

Numerous β-lactam derivatives with a carbapenem core 20 6 have been described in the literature.

CM

0 4 These carbapenem derivatives have been reported to be useful as antibacterial agents and / or β-lactamase inhibitors.

The first carbapenem compounds were natural products such as thienamycin of the formula

OH

30 I H

] - '| pSCH2CH2NH2

O N COOH

35 obtained using the strain Streptomyces Cattley (U.S. Patent 3,950,357). Thienamycin is an exceptionally potent broad-spectrum antibiotic that is significantly 2,7009 active against a variety of Pseudomonas species that have been known to be resistant to β-lactam antibiotics.

Other natural products with a carbapenem core include olivic acid derivatives such as the antibiotic MM 13902 of the formula CH3 H0 _SCH = CHNHCOCH3

10 3 I I

_ N '

--COOH

disclosed in U.S. Patent 4,113,856, an antibiotic MM 17880 having the formula 15 L3 HOjSO- ^ N-j - ^ \ _ SCH2CH2NHCOCH3

--- N --- J-COOH

20 0 disclosed in U.S. Patent 4,162,304, an antibiotic MM 4550A having the formula 9H3 25? HO SO I-1 {- s-ch = chnhcoch3

__N _ [_ COOH

O

disclosed in U.S. Patent 4,172,129 and the antibiotic 690A, 3 is of the formula CH.

1 ° ^ .SCH = CHNHCCHO HO SO '> -f - 3 35 ||

N 'COOH

O

3,700,900 disclosed in U.S. Patent 4,264,735. In addition to natural products, U.S. Patent 4,264,734 discloses the compound desacetyl 890A ^ q of the formula «* 3 5 HC ^ SO ^^ N - ^ \ pScH2cH2NH2

* - N - COOH

O

10 prepared by enzymatic deacylation of the corresponding N-acetyl compound. Various naturally occurring derivatives of olivic acids have also been synthesized, e.g. compounds of formula X3

15 / \ NHCOCH

R 2 is a free, salted or esterified carboxyl group, n is 0 or 1 and R 2 is H, an acyl group or a group of the formula R 3 O 3 S , wherein R 3 is a salt-forming ion or a methyl or ethyl group described in European Patent Application 8885.

U.S. Patent 4,235,922 (see also European Patent Application 2058) discloses a carbapenem derivative having the formula

SCH0CH_NH

30 II

J-N-- COOH

O

while GB Patent Application 1,598,062 discloses 74009 compounds

SCH CH-NHCOCH

I I 6 6

^ _ N-J COOH

0 5 isolation from Streptomyces fermentation broth.

Carbapenems in which the 6-position is unsubstituted have also been synthesized. Thus, U.S. Patent 4,210,661 describes compounds of the formula 10S'R2

-N --- COOH

O

Wherein R 2 is phenyl or substituted phenyl, U.S. Patent 4,267,177 describes compounds of the formula 10 wherein R 1 is an optionally substituted pyridyl group, U.S. Patent 4,255,441 describes compounds of formula 25 = CR_R -f Tj-— 2 04

^ - N - * - COOH

Wherein R 2 and R 2 are hydrogen or alkyl and R 1 is NH-CO n R 8, wherein R 8 is alkyl, phenyl or substituted phenyl and n is 1 or 2, and U.S. Patent 4,282,236 describes compounds of formula 35 74009

__- p ^ V \ sp-CH = CR1 R2 -N - COOH

Wherein R 1 is H or alkyl and R 2 is CN or CO 2 R 3, wherein R 3 is H, alkyl, aryl or aralkyl.

Carbapenems of the general formula

R1NH - i ^ /> V'S'T'SR

ίο I I

J> - N - ^ COOH

O

18 wherein R is H or acyl and R is H or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, aralkyl, aralkenyl, aralkinyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl

O

in Patent 4,218,463. The publication does not disclose any R substituents of type 20

-A-SC

wherein A is alkylene.

The absolute configuration of the natural product thienamycin is 5R, 6S, 8R. This isomer, as well as the remaining seven thienamycin isomers, can be obtained by the overall synthesis described in U.S. Patent 4,234,596. Complete synthetic methods for preparing thienamycin are also described, for example, in U.S. Patents 4,287,123, 4,269,772, 4,282,148, 4,273,709, 4,290,947 and European Patent Application No. 30973. In the synthetic methods disclosed, the key intermediate is

?B

QJ * ~~ N -CO2pNB

6 74009 wherein pNB represents p-nitrobenzyl.

Due to the exceptional biological activity of thienamycin, a large number of derivatives have been prepared and described in the literature. These include (1) N-for-5 mimidoylthienamycin of the formula

OH

SCH2CH2N = C-NH2 li *

10 J-N -1- COOH

O

disclosed in European Patent Application 6639; (2) N-heterocyclic derivatives of thienamycin having the formula

15 0H

SCH_CH N (CH-) I 2 2 v i 2 Π

I \ N

o ^ ~ N C00H [20 R1 and (Z)

OH I P

25 I / "K

y ^ v ^ SCH.CH N (CH_)

—T II

Wherein the bifunctional ring may further have an unsaturated bond; and wherein n is one of the integers 1-6; p is 0, 1 or 2; R 1 is H, alkyl or aryl; and Z is imino, oxo, H, amino or alkyl, disclosed in U.S. Patent 4,189,493; 35 (3) Substituted N-methylene derivatives of thienamycin of formula 7 74009

OH

S CH 2 CH 2 N = ^ - X

s Τ 'n x

<f ~ N - COOH

1 2 wherein X and Y are H, R, OR, SR or NR R, wherein R is substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl , and R and R are H or R, disclosed in U.S. Patent 4,194,047; (4) compounds of the formula OR3 / \ ^ sch2ch2nr1r2

jj Y

20 O * N COOH

3 wherein R is aryl, alkyl, acyl or aralkyl and 1 2 R and R independently of one another are hydrogen or acyl (including acyl of the type 25 ft 11 11.

-C-R wherein r may be, inter alia, alkyl substituted with a quaternary ammonium group, e.g., a group (C-CH2-V_ /) disclosed in U.S. Patent 4,266,870; (5) compounds of the formula

° r3 2 35 X / ^^.SCHjCH NRV

^ - N COOH

3,7009 wherein R is H, acyl or a monovalent optionally substituted hydrocarbon radical; R 1 is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl, and R is acyl (including acyl of the type 0 »» -CR, wherein R is alkyl substituted with a quaternary ammonium group, e.g.

15 4-C8'- \ = J

disclosed in GB Patent 1,604,276 (see also U.S. Patent 4,235,917); (6) compounds of the formula wherein J, R and R are independently selected from H and substituted or unsubstituted alkyl, alkenyl, alkynyl , cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, disclosed in U.S. Patent 4,235,920; (7) compounds of the formula 9 74009 OR3 ς I f © -sch2ch2n-c = nr1r2 a © I. [N - ^ cox 1 2 wherein R and R are each independently a radical of the type defined for R, a hydrogen atom , or a nitro, hydroxyl, C 1-6 alkoxy, amino, C 1-6 alkylamino, di (C 1-6 alkyl) amino or tri (C 1-8 alkylamino) radical, wherein in the latter case, an additional anion is present; or 12 R and R are joined together to form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted monocyclic or bicyclic heteroaryl or heterocyclyl residue having 4 to 10 ring atoms, one or more of which may be an additional heteroatom selected from oxygen, sulfur and nitrogen; R is a cyano group or a substituted or unsubstituted carbamoyl, carboxyl, (C 1-4 alkoxy) carbonyl, C 1-4 alkyl, C 2-10 alkenyl · C 2-10 alkynyl, C 3-10 cycloalkyl, C 4-10 alkynyl; 2-cycloalkylalkyl, C 3-8 cycloalkylalkenyl, C 3-10 cycloalkenyl, C 3-12 cycloalkenylalkenyl, C 4-22 cycloalkenylalkyl, C 8-10 aryl, C 7-16 aralkyl, C 8-16 aralkenyl,

C 1-6 aralkynyl or monocyclic or bicyclic heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl having <4-10 ring atoms, one or more of which is a heteroatom selected from oxygen, sulfur and nitrogen and wherein heteroaralkyl or the alkyl residue of the heterocyclylalkyl radical has 1 to 6 carbon atoms; as a substituent or substituents on the groups R, R, R, or in the ring formed by R and R joined together are: 74009 chlorine; bromine; iodine; fluorine; azido; C ^^ - alkyl; mercapto; sulpho; phosphono; cyanothio (-SCN); heart medicine; cyano; amino; hydrazine; amino or hydrazine having up to three C 1-6 alkyl substituents; hydroxy-5 si; C ^ _G alkoxy; C ^ _G-alkylthio; carboxyl, oxo; (C ^^ g alkoxy) carbonyl; C2_ ^ Q acyloxy; karbamo-yl; (C 1-4 alkyl) carbamoyl or di (C 1-4 alkyl) -2,4 carbamoyl; R is a hydrogen atom, an acyl radical or a radical of the type defined for R 4; R is 10 -alkyl; substituted carbonylmethyl; (C 1-8 alkoxy) - (C 1-8 alkyl), (C 3-8 cycloalkoxy) - (C 1-8 alkyl); C2-22 alkanoylalkyl; partially or fully halogenated C1-6 alkyl in which the halogen (s) are chlorine, bromine or fluorine; amino-15-alkyl; C2-C4-alkenyl; C2-C4-alkynyl; acyl; C 1-4 alkoxycarbonylalkyl; C 1-4 alkylamino-acetoxyalkyl; C2_ ^ 3 "alkanoylaminoalkyl; ar- (C 1-3 alkyl) having 6 to 10 carbon atoms in the aryl residue; monocyclic or bicyclic heteroaralkyl or hetero-20-cyclylalkyl having 4 to 10 ring atoms, 1 to 3 carbon atoms in the alkyl residue, and 1 to 4 heteroatoms selected from oxygen, sulfur and / or nitrogen; aralkyl or heteroaralkyl containing a ring substituent, wherein the substituent is chlorine, fluorine, bromine, iodine or C 1-6 alkyl; aryl or aryl having a ring substituent having 6 to 10 ring carbon atoms and wherein any ring substituent is hydroxy, C 1-6 alkyl, chlorine, fluorine or bromine; aralkoxyalkyl; C2-22-alkylthioalkyl; C ^^^ ykloalkyylitioalkyyli; (C 2-10 acylthio) - (C 1-6 alkyl); or phenylalkenyl having 2-6 carbon atoms in the alkenyl; R 1 is substituted or unsubstituted C 1-6 alkyl; C 2 -C 4 alkenyl or alkynyl; cycloalkyl, cycloalkenyl, cycloalkenylalkyl, and cycloalkylalkyl having 3 to 6 ring carbon atoms and up to 6 carbon atoms in each chain, with or without ring substituents; Cg_1Q-aryl; aralkyl / having 6 to 10 ring carbon atoms and 1 to 6 carbon atoms in the alkyl chain; monocyclic or bicyclic heteroaryl or heteroaralkyl having 4 to 10 ring atoms, one or more of which is oxygen, nitrogen or sulfur, and 1 to 6 carbon atoms in the alkyl chain; and the ring or chain is substituted with chlorine, bromine, iodine, fluorine, azido, cyano, amino, C 1-6 alkylamino, di (C 1-6 alkyl) amino or tri (C 1-6 alkyl) amino; .alkylamino) radical, in the latter case an additional anion, hydroxy, C 1-8 alkoxy, C 1-8 alkylthioalkyl, carboxyl, oxo, (C 1-8 alkoxy) carbonyl, C 1-6 acyloxy are present; carbamoyl; (C 1-4 alkyl) carbamoyl; di (C 1-4 alkyl) carbamoyl; cyanothio (-SCN) or nitro; is hydrogen, hydroxy, mercapto, R, -OR, -SR or 12 12 NR R wherein R, R and R are as defined above, 4 X is hydroxy, mercapto, amino, acyloxy, -OR, -SR4, -NHR4, -N-R4, -OM, -OQ or when the compound is R4 in zwitterionic form, -o ", in which case A- is absent; A, when the compound is not in the zwitterionic form, is a counterion; M is a pharmaceutically acceptable cation; and Q is a protecting group as defined above, disclosed in UK Patent 1,604,275; and (8 ) compounds of formula 12 74009 f eff

/ N, _ / '' '' S

J-i —i-co <P

5 O

with group

R

ψ V

O 10 attached to the amino nitrogen group of thienamycin represents a mono- or polycyclic N-containing heterocyclic group and R is H, substituted or unsubstituted: alkyl, aryl, alkenyl, heterocyclylalkenyl, aralkenyl, heterocyclylalkyl, aralkyl , C00R, CONRj / -OR, or CN, disclosed in European Patent Application 21082. Among the compounds described in U.S. Patent 4,235,920 are compound T Θ Θ

## X \ ^ _ ^^ VpSCH2CHaM (CH3) 3J A

25 V N — ‘COOH

O

wherein A is a pharmaceutically acceptable anion. The aforementioned quaternary amine derivative is also described in Recent Advances in the 30 Chemistry of / 3-Lactam Antibiotics, Royal Soviety of

Chemistry, London, 1981, pp. 240-254, where its average antibacterial activity has been reported to be approximately 1/2 to 1/3 of the thienamycin activity.

13 74009

Carbapenem derivatives having a 2-substituent of the 5-S-A-SC 2 type have not been described in the literature, although there are several recent patents which, in their broadest scope, may generally contain such compounds. Thus, for example, European Patent Application 40408 describes compounds of the formula R 1 i e CH-jCH cd 15 3 y-f if 51

-N - COOH

O

Wherein H, methyl or hydroxyl and Rg1 is a monovalent organic group, including, but not limited to, substituted alkyl or a group of the formula -CH2R7, wherein R1 is an optionally substituted 5- or 6-membered heterocyclic group; (2) European patent application 38869 describes compounds of the formula R7 SR8 30 R6-i— | |

N 2 COOH

14 74009 6 7 8 wherein R, R and R are independently selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms, cycloalkyl, cycloalkylalkyl and alkylcycloalkyl having a cycloalkyl-5 ring has 3 to 6 carbon atoms and 1 to 6 carbon atoms in alkyl groups; aryl such as phenyl; aralkyl, aralkenyl, and aralkynyl, wherein the aryl group is phenyl and the aliphatic moiety has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; wherein for the above radicals the substituent or substituents are selected from the group consisting of: -X ° halogen (chlorine, bromine, fluorine) -OH hydroxy 15 -OR 1 alkoxy, aryloxy 0 "12 -OCNR R carbamoyloxy 0 -CNR 1 R 1 carbamoyl amino .NR1 - ^ 0 amidinino

NNR R

R1 2 ^ -NOp nitro • 11 -N (R tri-substituted eunino (R group independently selected) R1 '2 -C = NOR oxyimino -SR1 alkyl- and arylthio -SO2NR1R2 sulfonieunido 0 -NHCNR1R2 ureido 35 0 1 "2 R CNR -amido * 15 74009 -C 0 H carboxy-CO 2 R carboxylate 0" 1 -CR acyl 5 0 "1 -OCR acyloxy -SH mercapto 0" 1 -SR alkyl and arylsulfinyl 0 H i 10 -SR alkyl and arylsulfonyl

II

0 -CN cyano -N7 azido o 7 8 wherein, for R, R and R, in the 1 2 15 substituents listed above, the groups R and R are independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl having 1 -10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl moieties; aryl such as phenyl; aralkyl, aralkenyl and aralkinyl, wherein the aryl moiety is phenyl and the aliphatic moiety has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl, and in the above-mentioned heterocyclic groups the heteroatom or atoms are selected from the group consisting of 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl groups attached to said heterocyclic moieties have 1-6 carbon atoms (see also European Patent Applications 1627, 1628, 50, 10317, 17992, 37080, 37081 and 37082); (4) European patent application 24832 describes compounds of the formula 16 740 0 9 R1 CH3-CH-1 - SR12

‘I

5 r ~ n - ^ co2h wherein R · ^ H is H or a group selected from OH, 23 OSO ^ H or a salt thereof or a C1-4 alkyl ester, OR, SR, OCO2, OCO2R2 or OCONHR2, wherein R2 is a C 1-6 alkyl group or an optionally substituted benzyl group 3 and R is a C 1-6 alkyl group or an optionally substituted benzyl or phenyl group and R is C 1-8 alkyl, C 2-8 alkenyl, C 1-6 alkyl. C 1-6 alkynyl, wherein the carbon adjacent to the sulfur atom does not have a triple bond, aralkyl, C 1-8 alkanoyl, aralkanoyl, aryloxyalkanoyl or arylcarbonyl, any such R group being optionally substituted, as antibacterial agents.

The aforementioned European patent application 38 869 discloses the synthesis of carbapenem derivatives via intermediates having the general formula R7 r6_ | _ (^ γ ° 4 'N. CO 2 R 2' 30 O 2 6.7 2 'wherein R and R are as defined above. and R is a readily removable carboxyl protecting group Compounds of the formula 17 74009 'τ ^ τ 5 Jr-N - ^ 2' o CO 2 R * wherein X is a leaving group are also provided as intermediates.

Although, as mentioned above, carbapenem derivatives having a 2-substituent of the type -SAN- and derivatives having a 2-substituent of the type -SASR1 having a hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, phenyl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl, the applicants are not aware of any literature describing carbapenems directly having a 2-substituent, , so a group of type 25 -S-A-S 2.

Despite the enormous number of carbapenem derivatives reported in the literature, there is still a need for new carbapenems, as the 30 known derivatives can be improved in terms of activity spectrum, efficacy, stability and / or toxic side effects.

In the novel carbapenem derivative prepared according to the present invention, the 2-position substituent 35 is of the type 0 -S-A-S t ^. .

18 74009

The 3- (N- (1-tetrahydrothiophenium) ethyl-thio] -6-o ("ZJ" (R) -hydroxytethyl-7-7-oxo-1-azabicyclo [b] t-7hept-2-ene of formula I carboxylate is prepared according to the invention in such a way that a compound of formula 5

OH H

Where R is a conventional readily removable carboxyl protecting group, is reacted with tetrahydrothiophene in an inert organic solvent in the presence of a silver ion to give a compound of formula

OH H

/ -s, I χθ p lP s-ch2ch2-s ^ _ 20, - N -J,

Cr CO2R

wherein R is as defined above and P is the counter anion, after which the protecting group R is removed.

The invention also relates to the overall synthesis of a compound of formula I starting from compounds of formula

OH

λ- N -! - COOR

where R is as defined above. In this synthesis, 35 a) a compound of formula III is reacted with difiphenyl chlorophosphate in an inert organic solvent in the presence of a base to give a compound of formula 0H H n 5 ° 4'-j-γ X-0P «OC6H5> 2

1-N-L CO ~ R IV

o x 10 wherein R is as defined above; b) reacting a compound of formula IV with 2-mercaptoethanol in an inert organic solvent in the presence of a base to give a compound of formula 15?

Ts-ch2ch2-oh ιΓ Λ — N-— CO ~ R v Q 'Δ 20 where R is as defined above; c) reacting a compound of formula V with methanesulfonyl chloride in an inert organic solvent in the presence of a base to give a compound of formula OH h ____ S-CH 2 CH 2 -SO 2 CH 3

30 ^ -N-1CO2R VI

O

wherein R is as defined above; d) reacting a compound of formula VI with 35 iodide ion sources in an inert organic solvent to give a compound of formula

0H H

/? .

III »

r -N ^ COOR

5 Cr wherein R is as defined above, after which the compound of formula II is treated as described above.

Compounds of formula III are described, for example, in EP patent application 38,869 (compound .7) and can be prepared by the methods described therein.

In detail, in the above process, starting material III is reacted in an inert organic solvent such as methylene chloride, acetonitrile or dimethylformamide with approximately an equimolar amount of diphenyl chlorophosphate in the presence of a base such as diisopropylethylamine, triethylamine, naphthylamine, 4-dimethylamine, 4-dimethylamine intermediate IV is obtained. The acylation to obtain the leaving diphenylphosphoryloxy group at the 2-position of Compound III is preferably performed at a temperature of about -20 ° to + 40 ° C, most preferably at about 0 ° C. If desired, intermediate IV can be isolated, but it is convenient to use it in the next step without isolation or purification.

Next, intermediate IV is converted to intermediate V by a standard substitution reaction. Thus, Intermediate IV can be reacted with an approximately equimolar amount of 2-mercaptoethanol of the formula HS-CH 2 CH 2 OH in an inert organic solvent such as dioxane, dimethylformamide, dimethyl sulfoxide or acetonitrile or 4-natriethylcarbonyamine, a base such as diisopropylethylamine, in the presence of methylaminopyridine. The temperature used in the substitution-35 reaction is not critical, but the preferred temperature range is from 2i 7400 9 to about -40 ° C to + 25 ° C. Most conveniently, the reaction is carried out under cooling, e.g. at about 0 ° C.

Intermediate V is then acylated with methanesulfonyl chloride in an inert organic solvent and in the presence of a base to give Intermediate VI.

leaving methanesulfonyloxy group. The acylation is performed in an inert organic solvent such as tetrahydrofuran, methylene chloride, acetonitrile or dimethylformamide and in the presence of a suitable base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine and the like. The reaction may be carried out over a wide range of temperatures, e.g. from -40 ° C to + 40 ° C, but is most preferably carried out under cooling, e.g. from about -30 ° C to -40 ° C.

Next, Intermediate VI is subjected to a substitution reaction to obtain a leaving iodine group in Intermediate II. This particular group has been found to greatly facilitate the preparation of carbapenem end products of formula I.

Substitution of the leaving methanesulfonyloxy group is accomplished by reacting Intermediate VI with an iodide ion donating compound in an inert organic solvent such as acetone, dimethylformamide or dimethylsulfoxide. In this case, any compound which ionizes in the solvent used to produce iodide ions can be used, e.g. an alkali metal iodide such as Nai and KI. The temperature of the substitution reaction is not critical, although room temperatures or higher are most preferred to complete the reaction within a reasonable time. The iodide ion source 30 is used to such an extent that the amount of iodide ions is made approximately equivalent to or greater than that of intermediate VI.

The desired carbapenem derivatives of formula I are prepared by nucleophilic replacement of the leaving iodine group of intermediate II with tetrahydrofuran. The intermediate is reacted with at least an equivalent amount of 22 7 4 0 0 9 valences, preferably excess tetrahydrothiophene, in an inert organic solvent and in the presence of a silver ion. Suitable inert organic solvents include, for example, tetrahydrofuran, di-5-oxane, methylene chloride, diglyme, dimethoxyethane and the like. As the silver ion source, any silver compound which is ionized mainly in a solvent and produces silver ions and an inert anion can be used, e.g., AgClO 2. To facilitate the substitution reaction, it is generally recommended to use approximately equivalent amounts (relative to intermediate II) of silver ions. The reaction may be carried out over a wide range of temperatures, e.g. from about -25 to about + 25 ° C, but is preferably carried out at about 0 ° C. Intermediate 1 'is bound to a counter anion (derived from the silver salt used), which can be replaced at this stage by a different counter anion, e.g. a pharmaceutically acceptable anion, by conventional methods. Alternatively, the counterion can then be removed in the deprotection step.

The deprotection step to remove the additional 1 'carboxyl 2' protecting group R of the intermediate is performed by conventional methods such as solvolysis, chemical reduction or hydrogenation. When a protecting group such as p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl, which can be removed by catalytic hydrogenation, is used, intermediate 1 'can be treated in a suitable solvent such as dioxane-hydrogen-ethanol-water-tetrahydrofuran-dicalal-tetrahydrofuran-dicalal. or the like in a solvent having a hydrogen pressure of 1 to 4 atmospheres, in the presence of a hydrogenation catalyst such as palladium on charcoal, palladium hydroxide, platinum oxide or the like at a temperature of 0 to 50 ° C for about 0.24 to For 4 hours. When R is an o-nitrobenzyl-35-like group, photolysis can also be used to deprotect. Protecting groups such as 2,2,2-trichloroethyl can be removed using mild zinc reduction. Similarly, other common carboxyl protecting groups can be removed by methods known to those skilled in the art. Finally, as mentioned above, compounds of formula 1 '2' 5 in which R is a physiologically hydrolyzable ester such as acetoxyethyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl, etc. can be used as such as drugs without deprotection, since such esters are hydrolyzed in in vivo in physiological conditions.

As with other β-lactam antibiotics, the compounds of general formula I can be converted by known methods into pharmaceutically acceptable salts which, for the purposes of this invention, are substantially equivalent to compounds which are not salts. Thus, for example, a compound of formula I may be dissolved in a suitable neutral solvent and then an equivalent amount of a pharmaceutically acceptable acid may be added. The desired acid addition salt can be recovered by conventional methods, e.g., solvent precipitation, freeze-drying, etc.

The new carbapenem derivatives of the general formula I are effective antibiotics with active activity against various gram-positive and gram-negative bacteria and can be used, for example, as animal feed additives for growth promotion, as nutrient preservatives, as bactericides in industrial applications. , for example in water-based paints and paper mill effluents to promote the growth of harmful bacteria and as disinfectants to kill or prevent the growth of harmful bacteria in medical and dental equipment. However, they are particularly useful in the treatment of infectious diseases of humans and other living organisms caused by gram-positive or gram-negative bacteria.

24 7 4 009 These pharmaceutically active compounds can be used alone or formulated into pharmaceutical compositions which contain, in addition to the active carbapenem moiety, a pharmaceutically acceptable carrier or diluent. The compounds may be administered in a variety of ways; substantially preferred routes are: oral, topical or parenteral (intravenous or intramuscular injection). The pharmaceutical compositions may be in solid form such as capsules, tablets, powders, etc., or in liquid form such as solutions, suspensions, or emulsions. Formulations for injection as the preferred form of administration may be presented in unit dosage form in ampoules or in multi-dose containers, and may contain formulatory agents such as suspending, stabilizing and dispersing agents. Formulations may be in ready-to-use form or in powder form for constitution with a suitable vehicle, e.g. sterile water, at the time of administration.

The dose to be administered will depend to a large extent on the particular compound used, the particular form of the composition, the route of administration, the nature and condition of the recipient and the particular site and organism being treated. The choice of a particular primary dose and route of administration will then be at the discretion of the treating person. In general, however, the compounds can be administered parenterally or orally to mammalian patients in an amount of about 5 to 200 mg / kg / day. Administration is usually carried out in divided doses, e.g. three to four times a day.

To illustrate the potent broad-spectrum antibacterial activity of the carbapenems of this invention, both in vitro and in vivo, and the low toxicity of the compounds, the biological values for the primary carbapenem compound of this invention, i.

3- {2- (1-tetrahydrothiophenium) ethylthio] -6 ° C-β- (R) -hydroxy-3-ethyl-7- (oxo-1-azabicyclo). 2 .J) ”7hept-2-ene-2-carboxylate prepared in Example 1.

25 7 4 0 0 9

In vitro activity

After a sample batch of the carbapenem compound identified above, dissolved in water and diluted with broth, the following minimum inhibitory concentrations (MICs) in mcg / ml against said microorganisms, as determined by the tube dilution method overnight at 37 ° C, were found to give: after incubation. N-formimidoylthienamycin is used as a reference compound.

10 In vitro

Antibacterial activity of the carbapenem derivative of Example I MIC (mcg / ml) ^ Organism The new N-formimidoyl compound thienamycin S. pneumoniae A-9585 0.002 0.004 S. pyogenes A-9604 0.004 0.001 S. aureus A-9537 0.008 0.004 20 S. aureus + 50% Serum A-9537 0.03 0.016 S. aureus (Pen-res.) A-9606 0.016 0.008 S. aureus 25 (Meth-res.) A15097 2 0.5 S. faecalis A20688 0.5 0, 5 E. coli (10 “4 dii.) A15119 0.03 0.016 E. coli 30 (ΙΟ-3) A15119 0.06 0.3 E. coli (10 ~ 2) A15119 0.06 0.06 E. coli (ΙΟ "4) A20341-1 0.03 0.3 35 E. coli (ΙΟ-3) A20341-1 0.03 0.03 26 7400 9

In vitro antibacterial activity of the carbapenem derivative of Example 1 - continued MIC (mcg / ml)

Organism New N-formimidoyl compound thienamycin E. coli A20341-1 0.06 0.13 <10 "2) K. pneumoniae A-9664 0.06 0.13 K. pneumoniae Α2Ό468 0.13 0.06 10 P mirabilis A-9900 0,13 0,06 P. vulgaris A21559 0,03 0,03 P. morganii A15153 0,06 0,13 P. rettgeri A22424 0,25 0,25 S. marcescens A20019 0,06 0, 03 15 E. cloacae A-9659 0.13 0.06 E. cloacae A-9656 0.13 0.06 P. aeruginosa A-9843A 1 1 P. aeruginosa A21213 0.25 0.25 H »Influenzae A-9833 8 16 20 H. influenzae A20178 8 32 H. influenzae A21518 8 32 H. Influenzae A21522 8 32 B. fragilis · A22862 0.06 0.016 B. fragilis A22053 0.06 0.06 25 B. fragilis A22696 0.25 0, 13 B. fragilis A22863 0.06 1

In vivo activity

Therapeutic efficacy of the compound of Example 1 and N-formimidoyl-thienamycin-30 in vivo after intramuscular administration to mice infected for the experiment with various organisms shown in the following table. Mentioned values are PD5Q values (dose mg / kg required to protect 50% of 35 infected mice).

27 74009 3 δ · Η S 's * m $ -5 * »n zi ^ H -h f *** rH« I ^ ° N ^ \ a> m * <r m o o N N ™ «> OO 5¾¾.

9 iS g Je q; «I ΪΙ i ^ 5 '$ j? ^ d -d • S J S33 · 0 - * gs ω + j $ u ^ s

-¾ -¾ S a i S

| , ..54 -h '"q -h cy, m S n ad w q0 -¾¾ h uj mm r- n vo ® n $ _ rö" * 53' EH Or-tinnr ^ moonmoOH ^ Sh mmm SH Λί Q) 1¾ gaji

Im ll-c | ä ISs | 5 λ -d s, ® 'νΰνονονηιηΓ ^ ιηνο ^ τττττ o o m hS mi'S'SSSSS ^ 0000®® 3¾¾¾

If ill x *********** ^ 535: 1 | a “rf || 2i | S a * U2 2 M (N rf -rj -P, CM -H CO (oo IB! d«) 3i <a s2 * 'rc'oo'ps, °' inrn, H® x ^ UJ θΓ-ΐνοιηοιηνο · «το ^ · ςοσ> Ό H vo» o. en 1 »n H hn co 'tm,.

minmftmriinmomoo m JL '^ lijL *** ^' -! · —j (-S | | (N N 1 2 e «n rt 15 5 w Ctfiwmys

• H -H 01 · Η Ή 0) o O O rt S

C <D '»H -H Jh- ^ I o c c C U R

3 9 5 1,4 ^ cn · Η · Η ^ <um • g 3 E y ja ie o · m «cr tr tr mj §j 0) * H3flnJtr4JtrO333 J * · • 3 3¾ a 3ρπ * ^ * Η3ς> θΐοα ) α) (ΐ) φ · Ϊ> §, η1ϋαυε> Κιε.ε (Τ) πΐΒ1 l + j WWXWftfcftJlO ^ HP, * 28 74009

Toxicity The toxicity of the compound of Example 1 to mice after intracranial administration was determined and is shown in the following table.

5 Toxicity to mice after intracranial administration__ * LD Maximum dose (mg / kg) u50 in clinical toxicity

Compound (mg / kg) without signs 10 Compound of Example 1> 40 ~ 5 N-formimidoylthienamycin 32 ^ 5 _ * Mean 25 mice / compound_ 15 Blood values in mice after intramuscular administration Blood values and half-life of the compound of Example 1 after administration intramuscularly in mice at 20 mg / kg is shown in the tau-20 lock below.

Blood value (^ ug / ml)

Compound 10 20 30 45 60 90 * teaspoon / 2 ** ADC

Minutes I gave after (min) (^ ug t / ml)

Compound of Example 1 14.7 13.5 8.7 3.2 0.9 <0.6 9 7.4 N-formimidoylthienamycin 12.6 9.9 7.3 2.6 0.7 < 0.3 9 6 3q The compounds were dissolved in 0.1 mol. phosphate buffer pH 7.

The values are the values of one experiment; 4 mice were used per compound.

* tl / 2 means half-life in minutes ** AUC means area under the curve 35 29 74009

Amount recovered from urine The amount of compound of Example 1 recovered from urine after intramuscular administration to mice (20 mg / kg) is shown in the following table.

5 Amount recovered from urine

Intramuscular dose to mice 20 mg / kg ___

Amount recovered from dose,% 0-3 3-6 6-24 0-24 10 Compound one hour after administration ___

Compound of Example 1 15.6 2.1 <0.2 17.7 + 2.9 N-formimidoylthienamycin__12.1 0.1 <0.1__12.2 + 3.6 The compounds were dissolved in 0.1 mol. phosphate buffer pH 7.

The values are the values of one experiment; 4 mice per compound.

The following examples illustrate, but do not limit, the scope of this invention.

74009 30

Example 1 3- [2- (1-Tetrahydrothiaphenium) ethylthio] -6 ·, - [(R) -hydroxyethyl,] - 7-oxo-1-azabicyclo [3.2.0], Preparation of 2-ene-2-carboxylate__ 5

? H H Λ © / I

} -S CH2CH2 "

10-p-Nitrobenzyl-3- (2-hydroxyethylthio) -6α - ((R) -hydroxyethyl * -7-oxo-1-azabicyclo [2.0.0] hept -2-ene-2-carboxylate

OH

l 20 1)

J — N —V

O 'CO2pNB

25 OH

1 5

<''. Z-S SCH ^ CH ^ OH

ΓΤ 1 -N ———

CT C02pNB

30 2 pNB = .CH2- ^ 02 35 3i 74009

A solution of 1.69 g (4.85 mmol) of p-nitrobenzyl-6 - (- (1R- (R) -hydroxyethyl) -3,7-dioxo-1-aza-bicyclo (3.2.0 ) hept-2-ene-2-carboxylate (1) in 20 ml of acetonitrile, cooled under nitrogen to 0 ° C. A solution of 726 mg (7.18 mmol) of diisopropylethylamine was added. 1.51 g (5.60 mmol) of diphenyl chlorophosphonate in 12 ml of acetonitrile were added dropwise over 3 minutes, and the resulting solution was stirred at 0 ° for 20 minutes to give p-nitrobenzene. silyl 3- (diphenylphosphoryloxy) -6e4- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate. a solution of 726 mg (7.18 mmol) of diisopropylethylamine in 2 ml of acetonitrile, followed by a solution of 439 mg (5.63 mmol) of 2-mercaptoethanol in 2 ml of acetonitrile. At 0 ° C for 3 hours and then diluted with 200 mL of ethyl acetate and Pest with 200 mL of water, 100 mL of 20% aqueous H 2 O 2, and brine. Evaporation of the dried solution (MgSO 4) to dryness gave a semi-solid which was triturated with methylene chloride and filtered to give 1.2 g (61% yield) of the title product 2 as a white amorphous solid.

NMR (DMSO-d 6) δ: 1.20 (3H, d, J = 6.0 Hz), 2.9-3.2 (9H, m), 5.22 (1H, d, J = 8, 5 Hz) and 8.23 (2H, d, J = 8.5 Hz); IR (KBr) f max: 3500, 1770 and 1700 cm-1.

Analysis calculated for c 18 H 20 N 2 O 7 S: C, 52.93; H, 4.94; N, 6.86; S, 7.85; Found: C, 52.83; H, 4.90; N, 6.42; S, 8.31.

32 74009 B. p-Nitrobenzyl-3- (2-methanesulfonyloxy-ethylthio) -6- [4- (1-) - (hydroxy) ethyl] -7-oxo-1-azabicyclo (3,2,0) hept-2- ene-2-carboxylate

5 ° H

J ', _ | x \ t_sch2ch2oh n cLX *

cf CO2pNB

10 - OH

J 1 f "" *. r ^ ^^^^ SCH OSO ^ CH ^ CH

π T

J-N - k *.

0 CO pNB

15 3

To a solution of 4.2 g (10.3 mmol) of the compound in 2,200 ml of tetrahydrofuran was added 1.3 g (11.3 mmol) of methanesulfonyl chloride at -40 ° C, followed by dropwise addition of 1.26 g. (12.4 mmol) of triethylamine in 5 ml of tetrahydrofuran. The reaction mixture was stirred for 5 hours at -40 ° C, then stirred for 2 hours at -30 ° C under a nitrogen atmosphere and then the mixture was poured into a mixture of ethyl acetate-25 (700 ml) and 5% aqueous phosphoric acid (100 ml). mL). The organic layer was washed with brine, dried over MgSO 4, filtered and condensed into a syrup. This material was purified on a silica gel chromatography column eluting with methylene chloride-diethyl acetate (3: 1) to give 3.55 g (75% yield) of the title compound as a white amorphous solid.

NMR (CDCl 3) δ Si 1.25 (3H, d, J = 6.0 Hz), 3.05 (3H, s), 3.06-3.40 (5H, m), 4.05-4.40 (4H, m), 5.25 (1H, d, 35 J = 14.0 Hz), 5.50 (1H, d, J = 14.0 Hz), 7.70 (2H, d, 33 7 4 0 0 9 J = 8.5 Hz), and 8.23 (2H, d, J = 8.5 Hz); IR (KBr) f max: 3400, 1770, 1600 cm Analysis calculated for C 19 H 22 N 2 O 9 S 2; C, 46.90; H, 4.56; N, 5.76; Found: C, 46.52; H, 4.32; N, 5.91.

C. p-Nitrobenzyl-3- (2-iodoethylthio) -6- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3,2,0) -hept-2-ene-2 carboxylate_ 10

OH

J '~. ^ _ | / \ ^ sch2ch2oso2ch3 15 'FT \ ->

/ 7-N CO 2 pNB

o 2 3

20 OH

J H ^

# -N- ^ * C0, pNB

O 2 25 i

A solution of 350 mg (0.72 mmol) of intermediate 3 and 216 mg (1.4 mmol) of sodium iodide in 20 ml of acetone was heated at reflux for 4 hours. Evaporation of 3β-acetone gave a white amorphous solid which was suspended in a mixture of ether (10 ml) and water (10 ml). Filtration of the white solid and drying in vacuo afforded 300 mg (80% yield) of the title compound 4 as a white amorphous powder.

34 74009 NMR (DMSO-d 6) δ: 1.18 (3H, d, J = 6.0 Hz), 3.20-3.60 (7H, m), 3.80-4.25 (2H, m ), 5.10 (1H, d, J = 5.5 Hz), 5.25 (1H, d, J = 12.0 Hz), 5.45 (1H, d, J = 12.0 Hz), 7.70 (2H, d, J = 8.5 Hz), and 8.27 (2H, d, J = 8.5 Hz); 5 IR (KBr) t max ·. 3500, 1768 and 1700 cm ”1.

Analysis calculated for C 18 H 19 N 2 O 6 J 1 C, 41.71; H, 3.70; N, 5.41; J, 24.48; Found: C, 42.10; H, 3.75; N, 5.97; J, 23.20.

D. 3 - [(5- (1-Tetrahydrothiophenium) ethyl] -6- [10 (R) -hydroxyethyl] -7-oxo-1-azabicyclo [2.0.1] hept-2-ene-2-carboxylate__

15 OH H

(f N 2 CO 2 pNB

_4! 20

PH t - V

1 © / \ es

£ l-X

25 O 2 CO 2 pNB 7 5 0H ^ 1 3 θ / ^ |

30 I I J 2 2 vJ

Jr — N - / Γ) o cocP '

To a solution of p-nitrobenzyl-3- (2-iodo-ethylthio) -6efe- (1- (R) -hydroxyethyl) -7-oxo-1-azabicyclo (η 2 -2,3-hept-2 -ene-2-carboxylate (104 mg; 0.2 mmol-74009 35 l) in 5 ml of tetrahydrofuran, tetrahydrothiophene (0.3 ml; 0.35 mmol) was added followed by a solution of silver perchlorate (60 mg; 0.3 mmol) in 0.5 ml of tetrahydrofuran The mixture was stirred at room temperature for 60 minutes, the solvent was evaporated off in vacuo to give compound 5 as a yellow resin, which resin was digested with 100 ml of Celite to give an amorphous solid.

IR (KBr) fmax: 3400, 1772, 1700 and 1100 cm -1.

To a suspended solution of compound 5 in 20 mL of ether and 20 mL of tetrahydrofuran was added a solution of potassium hydrogen carbonate (40 mg; 0.4 mmol) and dibasic potassium phosphate (35 mg; 0.2 mol) in 20 mL of water. . 120 mg of 10% palladium / charcoal was then added and the mixture was hydrogenated at 40 psi on a Parr shaker for 60 minutes. The mixture was then filtered and the catalyst was washed with water (2 x 5 mL). The combined filtrate and washings were extracted with ether (2 x 50 mL) and then lyophilized to give a yellow powder. This crude material was purified on a C-gBONDAPAK reverse phase column (7 g) (Waters Associates), eluting with water at a pressure below 8 psi. Each fraction (15 ml) was filtered using high pressure liquid chromatography, and fractions whose UV absorption λ max nm 'was praised Da were lyophilized to give 12 mg (yield 18% of compound 4) of the title product as a white solid.

NMR (D 2 O) δ: 1.23 (3H, d, J = 6.0 Hz), 2.25-2.45 (4H, m), δ 3.0-3.70 (UH, m), δ Δ 95-4.30 (2 H, m); IR (KBr) f max: 3400, 1760 and 1590 cm-1.

UV λmax (CH 2 CH 2 OH) 289 nm (C = 8200).

Claims (7)

A process for the preparation of a therapeutically useful 3- [2- (1-tetrahydrothiophenium) ethyl] thic57-6-o (R) -hydroxyethyl-7-5-oxo-1-azabicyclo]. 2t for the preparation of hhept-2-ene carboxylate of the formula OH H I. - <~) -r i S-CH-CH 2 -S I '· jn_r. s OL ° 2 characterized in that A) a compound of formula pH 9 Jr "--S-CH-CH 2 -III II n co 2 r o 20 in which R is a conventional easily removable carboxyl protecting group is reacted with tetrahydrothiophene. in an inert organic solvent in the presence of a silver ion to give a compound of formula 25 OH H / - —I © «1-1 | TS'CH2CH? -Ssn x 1— N - \% CO 2 R 30 wherein R is as defined above and X® is a counter anion followed by removal of the protecting group R, or B) a) a compound of formula 37 74009 ^ Ί I r50 1. m) - N --L-coor Wherein R is a conventional easily removable carboxyl protecting group, is reacted with diphenyl chlorophosphate in an inert organic solvent in the presence of a base to give a compound of formula 4- - - | - K'N-oJ (OC6H5) 2 15 J- N -Lcor IV O wherein R is as defined above; b) reacting a compound of formula IV with 2-mercaptoethanol in an inert organic solvent in the presence of a base to give a compound of formula 0H H JL <η-r ^ --- S-CHoCHo-OH 25. I 2 2 V - N - CO 2 R O wherein R is as defined above; c) reacting a compound of formula V with methanesulfonyl chloride in an inert organic solvent in the presence of a base to give a compound of formula 38 7 4 0 0 9 OH H -C T-p ^ p ^ S-CH2CH2-0SO2CH3 I_ N _ [_ VI 5. CO R O 2 wherein R is as defined above; d) reacting a compound of formula VI with a source of iodide ion in an inert organic solvent to give a compound of formula OH H • C "Ί --- S-CH, CH, -IF! ~ N - ^ ~~ -COOR wherein R is as defined above, after which the compound of formula II is treated as described in A) 39 74009 For the preparation of therapeutically active compounds 3- [2- (1-tetrahydrothiophenium) ethylthio] - 6-O- [1- (R) -Hydroxy-5-ethyl] -7-oxo-1-azabicyclo [3.2.2] hex-2-ene-2-carboxylate with form OH H yL ® / I 10. YS-CH2CH2-S \ 1 0 7-N - ^ C02® kännetecknat därav, fig 15 A) en förening med formuleln OH 8 «" IS-CH2CH2-1 k 20 8- ^ α028 color R är en sedvanlig, lätt a carboxylic acid group, which consists of tetrahydrothiophene and inert organic solvents and a mixture of silver in the form of a mixture of 25 with the form OH H 1 ® / - 0 + "Ί-T> - S-CH.CH-S li 22 30 1- -N_I S C02R T. O z · * - Θ color R betecknar samma som ovan oc X X en motjon, var-efter skyddsgruppen R avlägsnas, eller 35 B) a) en förening med formeln <“74009 OH HJ — N -LLjCOOR 5 o / color R är en sedvanlig, lätt avlägsnad carboxylskyddande grupp, omsätts med diphenylklorfosfat i ett inert organiskt lostingmedel i nervvaro av en bas fermallande av en 10 förening med formuleln OH H 1. o * "Ί-f] | -OP ( OC6H5 »2 15. IV O N-C02R color R betecknar samma som ovan; b) for the preparation of Formula IV with 2-mercapto-20 ethanol and inert organic solvents and for the treatment of the formulation with the formula OH H! r 25 ✓ '•' -j-j ^ \ ^ S-CH2CH2-OH - N-L CO-R 0 * 30 color R betecknar samma som ovan; (c) Formulation of methanesulfonyl chloride and inert organic solvents in the form of nerves in the formulation of formulation